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7,101 | uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 226 u Antimicrobial Stewardship 1691 Society for Healthcare Epidemiology of America (SHEA) guide line, the Centers for Disease Control and Prevention (CDC) Core Elements of Hospital Antibiotic Stewardship Programs, the CDC Core Elements of Outpatient Antibiotic Stewardship, and the WHO Practical Toolkit for Antimicrobial Stewardship Programmes in Healthcare Facilities in Low and Middle Income Countries. INPATIENT ANTIMICROBIAL STEWARDSHIP STRATEGIES Core elements of inpatient antimicrobial stewardship include hospi tal leadership commitment; accountability through appointment of a leader or coleaders; pharmacy expertise; implementation of actions or interventions to improve antibiotic use (Table 226.1); tracking Table 226.1 Summary of Inpatient Antimicrobial Stewardship Interventions ACTION DESCRIPTION PRIORITY ACTIONS Preauthorization Clinician must contact the stewardship program to obtain approval for use of the antimicrobial before prescribing (see also text and Table 226.2). Prospective audit and feedback Antimicrobials are reviewed by the stewardship program after 48 72 hr and recommendations for optimization are provided at that point (see also text and Table 226.2). Facility specific treatment guidelines These local guidelines should establish clear recommendations for commonly encountered infections based on published data or national guidelines, local susceptibility data, formulary options, and patient mix. These guidelines should address diagnostic testing, empiric treatment, and definitive treatment and should be developed in collaboration with clinician stakeholders. ADDITIONAL ACTIONS Antibiotic time outs A time out occurs after a set duration of antimicrobial therapy (e.g., 48 72 hr) and involves a clinician led reassessment of the need for and choice of antibiotics. This differs from prospective audit and feedback in that the review is led by the frontline clinician, not the stewardship program. Time outs may augment prospective audit and feedback led by the ASP but should not be considered an equivalent substitute. Assessing penicillin allergy Although penicillin allergies are reported in 1015 of hospitalized patients, less than 1 are true serious allergies. Patients with penicillin allergy labels receive broader spectrum antibiotics than would otherwise be recommended, and penicillin allergy labels may be associated with worse clinical outcomes. Clinicians or stewardship personnel may be able to delabel patients through performing a history andor administering a challenge dose of penicillin or amoxicillin. Documentation of antibiotic indications in orders or prescriptions Requiring documentation of an indication for antibiotics can improve antibiotic prescribing practices. In addition, this facilitates other interventions, such as audit with feedback, where knowledge of the intended indication is needed. Intravenous to oral antibiotic therapy Transitioning from intravenous to oral therapy when an oral antibiotic is available can reduce the duration of hospitalization, need for long term intravenous access, and improve patient satisfaction. Pharmacist based interventions Pharmacists are uniquely positioned to optimize antibiotic use through making recommendations for optimal antibiotic dosing and administration (e.g., extended infusions of lactam antibiotics, therapeutic drug monitoring for vancomycin and aminoglycosides, identifying duplicative therapy such as overlapping anaerobic coverage, and detectionprevention of antibiotic related drug drug interactions). Time sensitive automatic stop orders Including a stop date in antibiotic orders, after which the antimicrobial order is |
7,102 | removed from the patients active medication orders, can promote timely discontinuation of antibiotics. This may be particularly valuable for antibiotics where durations are short and well defined (e.g., surgical prophylaxis). Selective reporting of susceptibility testing results Microbiology labs can partner with stewardship programs to report select antibiotics that are consistent with hospital guidelines or use cascade reporting in which susceptibilities to broader spectrum agents are reported only if resistance to narrower spectrum drugs is demonstrated. Comments in microbiology reports Comments in microbiology reports may guide prescribers to making appropriate antibiotic decisions, for example, by indicating bacterial growth may reflect contamination or guiding providers to using specific preferred antibiotics. Rapid diagnostic tests for bacterial diagnostics Molecular diagnostic tests (for example, tests using PCR, microarrays, or mass spectroscopy) may allow more rapid identification of organisms or resistance determinants than traditional culture based techniques. When implemented together with real time stewardship program guidance, assays performed on positive blood cultures may reduce time to optimal antibiotic therapy and improve patient outcomes. Nursing based interventions Key opportunities to engage bedside nurses in stewardship activities include optimizing the appropriate collection of microbiology cultures, encouraging intravenous to oral transitions, and prompting antibiotic timeouts. PCR, Polymerase chain reaction. Adapted from Centers for Disease Control and Prevention. Core Elements of Hospital Antibiotic Stewardship Programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2019. Available at https:www.cdc.govantibiotic usecore elementshospital.html Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1692 Part XV u Infectious Diseases antibiotic use, resistance, and C. difficile rates; reporting antibiotic use and resistance metrics to prescribers and hospital leaders; and education. Prospective Audit and Feedback Versus Preauthorization Two broad approaches to antimicrobial stewardship are supported by the IDSASHEA guideline and the CDC Core Elements: preauthoriza tion and prospective audit and feedback. Preauthorization is a strategy in which the clinician must contact the ASP and secure approval for use of the antimicrobial before prescribing the drug. In contrast, pro spective audit and feedback is performed by the ASP 48 72 hours after the start of antimicrobial therapy, and recommendations for antimi crobial de escalation, discontinuation, transition from intravenous to oral therapy, change in dose, or changes in duration are made. Each of these approaches has pros and cons (Table 226.2), and ASPs gener ally adapt these broad strategies to the local context and availability of resources, often using a hybrid approach. Handshake stewardship is a specific type of audit and feedback where recommendations from the ASP are delivered face to face to prescribers; this approach has the advantage of developing collaborative relationships but is resource intensive and therefore may not be feasible in all settings. Regardless of which strategy is used, it is critical that ASPs view the interaction with the prescriber as an opportunity to collaboratively optimize anti microbial therapy and that the guidance provided is evidence based and, whenever |
7,103 | available, aligned with local clinical practice guidelines. Development and Implementation of Local Guidelines Creation of evidence based local guidelines containing recommen dations for empiric and definitive therapy for common infectious diseases diagnoses and syndromes is a key activity of ASPs. In pedi atrics, key target conditions include community acquired pneumonia, urinary tract infections, intraabdominal infections, skin and soft tissue infections, and neonatal and pediatric sepsis. Coproduction of these guidelines with relevant stakeholders, including prescribing clinicians, offers a unique opportunity to broadly improve antimicrobial prescrib ing through standardization of evidence based practices. Because the approach is agreed upon a priori, adhering to these recommendations may also be more appealing to prescribers relative to more top down approaches, where the ASP is either unilaterally authorizing antimicro bial use or providing directive feedback. Education While educational interventions alone are insufficient to improve anti microbial use, education is critical to the success of ASPs and should be integrated along with other strategies. Education can take place in many forms, including at the point of an individual prescriber steward interaction during preauthorization or prospective audit and feedback; as part of the implementation of a new local treatment guideline or other specific improvement intervention; or as a stand alone or recur ring lecture focused on a topic of relevance, preferably one deemed important to the learners. OUTPATIENT ANTIMICROBIAL STEWARDSHIP STRATEGIES The majority of antibiotic use in children occurs in the outpatient set ting. Effective outpatient antimicrobial stewardship is therefore critical and requires approaches distinct from the individual level preautho rization and prospective audit with feedback that form the founda tion of inpatient antimicrobial stewardship. Relative to hospital based stewardship, fewer studies have been conducted in outpatient settings to inform best practices. However, the CDC provides four elements to guide outpatient stewardship efforts, which include commit ment to optimizing antibiotic prescribing, including appointment of an accountable leader; actions for policy and practice; tracking and reporting antibiotic use; and education and expertise. Commitment In addition to commitment on the part of practice or system lead ership, a written and publicly displayed commitment poster stat ing that the individual clinician will only prescribe antibiotics when they are indicated is a powerful tool to reduce unnecessary antibiotic prescribing in the ambulatory setting. This strategy is particularly appealing, as it requires minimal resources to implement and may not only influence provider behavior but also stimulate a discussion between provider and patient around the importance of judicious antibiotic use. In addition, clear communication across clinic provid ers and staff to ensure this message is consistent and practices are aligned is paramount. Actions to Improve Antibiotic Prescribing As with hospital based stewardship programs, development and implementation of local guidelines to inform antibiotic prescribing for relevant conditions is a key strategy for ambulatory stewardship pro grams. Target conditions in this setting include acute respiratory tract infections, such as pharyngitis, sinusitis, otitis media, and community acquired pneumonia, given that these conditions account for the vast majority of ambulatory antibiotic use and are associated with sig |
7,104 | nificant variation in antibiotic prescribing practices across clinics. A number of strategies have been used to optimize adherence to such guidelines, including audit with feedback at the practice or provider level, clinician education, and computerized decision support. An additional evidence based practice that may improve antibiotic use in the outpatient setting for specific conditions is use of delayed prescrip tions, namely, prescriptions provided to patients with mild infections likely to improve without antibiotics at the time of the clinic visit, with instructions to fill the prescription only if symptoms worsen or fail to improve. Delayed prescribing is endorsed by the American Academy of Pediatrics for acute otitis media and acute sinusitis. This type of Table 226.2 Comparing Preauthorization and Prospective Audit and Feedback PREAUTHORIZATION PROSPECTIVE AUDIT AND FEEDBACK Allows stewardship oversight from the point of antimicrobial initiation. Stewardship oversight focuses on antimicrobial duration, de escalation, or discontinuation. Requires dedicated and expert personnel for real time phone calls or electronic communication through at least the majority of the day. Resource intensive, particularly if done hospital wide, but can be scaled to available resource (e.g., focused on a single unit). Opportunity to counsel provider on optimal diagnostic testing before starting antimicrobials. Culture and susceptibility testing may be available at the time the intervention is made, such that recommendations for definitive therapy can be made. Requires a coordinated process including providers, pharmacy, and the stewardship program to ensure approved antimicrobials are dispensed promptly and that antimicrobial requests that are declined are not dispensed. Prescribers may or may not follow the recommendations made by the stewardship program. May be seen as a threat to autonomy andor having the potential to delay therapy. Generally well received by providers, with high adherence to recommendations reported. Only the antimicrobials that are restricted are affected and only at the point of initiation. More flexibility for the stewardship team regarding the timing of interventions, as well as the potential to act on all antimicrobials prescribed to an individual patient during a single discussion. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 227 u Staphylococcus 1693 contingency plan may contribute to patient and parent acceptance of an initial recommendation against antibiotics. Education Education is also a fundamental element of outpatient stewardship. In contrast to education in the inpatient setting, which focuses on clini cians, education in the ambulatory setting additionally requires a focus on the patient and family, as well as teaching providers to promote optimal communication. For example, a commonly cited challenge to judicious antibiotic prescribing in the pediatric outpatient setting is a perception on the part of providers that antibiotic prescriptions are strongly desired by parents, even in situations where bacterial infec tions are unlikely. However, several studies have refuted this notion and instead suggest that communication of both positive treat ment recommendations (e.g., specific measures to take to improve symptoms) |
7,105 | and negative treatment recommendations (e.g., rec ommendations against using antibiotics when they are not indi cated, antibiotic adverse events) is a driver of parent satisfaction and desired by parents. TRACKING AND REPORTING ANTIMICROBIAL USE MEASURES Quantifying antimicrobial use and reporting it to key stakeholders, including clinicians and hospital leadership, are key elements for both inpatient and outpatient stewardship efforts. Antimicrobial Use Measures Most antimicrobial stewardship measures are process measures. The preferred metric for inpatient antimicrobial use is antimicrobial days of therapy (DOTs) per 1,000 patient days. Each antimicrobial prescribed on each hospital day counts as one DOT, independent of the number of doses the patient receives in the day. For example, if a patient with an intraabdominal infection receives ceftriaxone and metronida zole on the same day, each drug contributes 1 DOT and the total DOT is 2. If instead, this patient received meropenem alone, just 1 DOT would be recorded. DOT1,000 patient days is a metric particularly useful to track antimicrobial use over time or in response to a specific steward ship intervention and can be measured for an individual drug, a specific unit, or throughout the hospital. Limitations of the measure are that it does not measure the appropriateness of therapy or spectrum of activity, and as demonstrated in the previous example, multidrug regimens will contribute a greater number of DOTs even if the spectrum of the com bination of drugs is narrower than the single drug. Finally, DOT1,000 patient days does not account for differences in patient complexity, ill ness severity, or comorbid conditions, a limitation that should be consid ered when making comparisons across units or hospitals. Antibiotic use measures in the outpatient setting can include indi vidual or facility level tracking of antibiotic prescriptions in all visits, or in visits with a certain diagnosis or collection of diagnoses. Metrics could include the proportion of visits in which antibiotics were pre scribed, the appropriateness of the antibiotic choice (e.g., broad versus narrow spectrum, compliance with local guidelines), andor the cor rect duration of antibiotics for a given condition. Individual level measures are preferred, as they facilitate audit and feedback based on individual performance, as well as peer comparisons, strategies that have been used successfully to improve adherence to evidence based guidelines for antibiotic use in the outpatient setting. Outcome Measures The impact of reductions in antimicrobial use through implementa tion of ASPs or specific interventions should ideally be linked to clini cal outcomes. In practice, however, specific outcomes can be difficult to identify, particularly in children where adverse outcomes attributable to antibiotics are uncommon (e.g., C. difficile infection) or resource inten sive to measure (e.g., drug adverse events, patient reported outcomes). Improvement in antibiotic resistance rates over time is an appealing hospital level measure, but improvement occurs slowly and is influ enced by multiple factors other than inpatient antibiotic use, including infection prevention and control practices and outpatient prescribing patterns. Other outcome measures that may be considered include revisits, readmissions, or hospital length of stay, though |
7,106 | few studies have evaluated these outcomes, which may be confounded by multifactorial influences. Importantly, because antibiotic exposure has been clearly linked to development of antibiotic resistance, C. difficile infection, and other adverse drug events, decreases in antibiotic use process measures without a worsening of clinical outcomes are relevant and should be considered sufficient for defining success, even if the reduction in anti biotic use does not result in improved clinical outcomes. SUMMARY Antimicrobial stewardship is an important element of patient safety and quality that is the responsibility of all clinicians prescribing antimicro bials. Formal ASPs can guide these local efforts, and abundant evidence demonstrates the positive impact of these programs on improving anti biotic use in both the inpatient and ambulatory settings. Key needs in the field of pediatric antimicrobial stewardship include development of risk adjusted antibiotic use measures for benchmarking across cen ters; development of measures to quantify antibiotic associated harm; incorporating perspectives from nursing and patientsfamilies; and adapting stewardship strategies and organizational structures success ful in acute care hospitals to other settings. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 227 Staphylococcus Carol M. Kao, Patrick J. Reich, and Stephanie A. Fritz Section 4 GramPositive Bacterial Infections Staphylococci are hardy, aerobic, gram positive bacteria that grow in pairs and clusters and are ubiquitous as normal flora of humans and present on fomites and in dust. They are resistant to heat and dry ing and may be recovered from nonbiologic environments weeks to months after contamination. Strains are classified as Staphylococcus aureus if they are coagulase positive or as one of the many species of coagulase negative staphylococci (e.g., S. epidermidis, S. lugdunensis, S. saprophyticus, S. haemolyticus). S. aureus has many virulence fac tors that mediate various serious diseases, whereas coagulase negative staphylococci tend to be less pathogenic unless an indwelling foreign body (e.g., intravascular catheter) is present. S. aureus strains resistant to lactam antibiotics, typically referred to as methicillin resistant Staphylococcus aureus (MRSA), are a significant problem in both community and hospital settings. 227.1 Staphylococcus aureus Carol M. Kao, Patrick J. Reich, and Stephanie A. Fritz S. aureus is the most common cause of skin and soft tissue infections (SSTIs). Bacteremia (primary or secondary) is common and can be associated with, or can result in, musculoskeletal infection (osteo myelitis, pyomyositis, septic arthritis), pneumonia, endocarditis, and rarely meningitis. Toxin mediated diseases, including food poisoning, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1694 Part XV u Infectious Diseases staphylococcal scarlet fever, scalded skin syndrome, and toxic shock syndrome (TSS), are caused by certain S. aureus strains. ETIOLOGY S. aureus strains produce a wide spectrum of virulence factors. These factors contribute to pathogenesis in human disease by protecting the organism from host defenses, causing local tissue damage, and affect ing noninfected sites through toxin elaboration. Most strains of S. aureus possess factors that protect |
7,107 | the organism from host defenses. The microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) are a family of cell wallanchored proteins with a broad spectrum of virulence properties, including host tissue and cell adhesion and invasion, biofilm formation, and evasion of the host immune response. Many staphylococci produce a loose extra cellular polysaccharide that promotes formation of biofilms, which may interfere with opsonophagocytosis. Production of clumping factor and coagulase differentiates S. aureus from coagulase negative staphylo cocci. Clumping factor interacts with fibrinogen to create large clumps of organisms, interfering with effective phagocytosis. Coagulase causes plasma to clot by interacting with fibrinogen and may have an impor tant role in abscess formation. Protein A is located on the outermost coat of the cell wall and can absorb serum immunoglobulins, preventing opsonization and thus inhibiting phagocytosis. The chemotaxis inhib iting protein of S. aureus (ChIPS) and extracellular adherence pro tein (Eap) interfere with the native host immune response by inhibiting leukocyte chemotaxis. The staphylococcal enzyme catalase inactivates hydrogen peroxide, promoting intracellular survival. Many strains of S. aureus produce substances that cause local tissue destruction. A number of immunologically distinct hemolysins that act on cell membranes and cause tissue necrosis have been identified ( toxin, hemolysin, hemolysin). The leukocidins (LukAB, LukDE, Panton Valentine leucocidin) are pore forming cytotoxins resulting in increased cell membrane permeability and eventual cell death. Strains of S. aureus that produce Panton Valentine leukocidin are associated with more severe and invasive skin disease, necrotizing pneumonia, and osteo myelitis. Many strains of S. aureus release one or more exotoxins. Exfo liatins A and B are serologically distinct proteins that produce localized (bullous impetigo) or generalized (scalded skin syndrome, staphylococcal scarlet fever) dermatologic manifestations (see Chapter 706). S. aureus can produce 20 distinct enterotoxins (types A V). Inges tion of preformed enterotoxin, particularly types A or B, can result in food poisoning, resulting in vomiting and diarrhea and, in some cases, profound hypotension. Toxic shock syndrome toxin 1 (TSST 1) is associated with toxic shock syndrome (TSS), related to menstruation and focal staphylo coccal infection (see Chapter 227.2). TSST 1 is a superantigen that induces production of interleukin (IL) 1 and tumor necrosis factor (TNF), resulting in hypotension, fever, and multisystem involvement. Focal infections associated with enterotoxins A or B also may be asso ciated with nonmenstrual TSS. S. aureus also possesses intrinsic factors that can contribute to patho genesis, including proteins that promote adhesion to fibrinogen, fibro nectin, collagen, and other human proteins. Expression of proteins that mediate antibiotic resistance is also of critical importance. Although historically sensitive to penicillin, S. aureus isolates now almost uni versally produce penicillinase or lactamase, which inactivates many lactams at the molecular level and represents the major resistance mechanism against many penicillin and some cephalosporin antibi otics. Thus treatment of S. aureus with lactam antibiotics requires either a penicillinase resistant lactam ring (e.g., antistaphylococcal penicillins such as oxacillin or nafcillin) or combination with a lactamase inhibitor (e.g., ampicillin sulbactam). Production of altered penicillin binding proteins |
7,108 | (PBPs) in the bacterial cell wall mediates resistance to penicillinase resistant antibiotics; an altered PBP 2A, encoded by the gene mecA, is responsible for the methicillin, cephalo sporin, and carbapenem resistance of MRSA isolates. EPIDEMIOLOGY S. aureus is a significant cause of morbidity and mortality, particularly in pediatric healthcare associated infections including infections of the bloodstream, surgical sites, and respiratory tract. Genetically distinct strains of MRSA are termed community associated MRSA (CA MRSA); USA300 is the predominant pulsotype circulating in the United States. These strains led to an epidemic of SSTIs, and occasionally necrotiz ing invasive infections, in healthy individuals without the traditional healthcare associated risk factors for MRSA. Ambulatory visits for purulent SSTIs rose from 5 million to 11 million annually between 2000 and 2013 but have since plateaued and even declined in some populations. Additionally, the incidence of invasive nosocomial MRSA infections (e.g., bacteremia) has also declined; however, the incidence of SSTIs and bloodstream infections caused by MSSA has increased. Approximately 2040 of healthy individuals carry at least one strain of S. aureus in the anterior nares at any given time, with inter mittent carriage occurring in up to 70 of individuals. In children, the oropharynx, umbilicus, inguinal folds, and rectum are also important reservoirs of S. aureus carriage. Many neonates are colonized within the first 2 months of life, usually by a maternal strain. The prevalence of colonization with MRSA in the general pediatric population ranges from 2 to 10, with higher prevalence in some locales and in children with significant healthcare exposure and chronic medical conditions. S. aureus is acquired and transmitted through close person to person contact and contact with contaminated objects or environmen tal surfaces. S. aureus colonization poses a risk for subsequent S. aureus infection. In community settings, populations traditionally at high risk for S. aureus infection have included athletes, military personnel, young children, veterinarians, injection drug users, and inmates in correctional facilities. However, given the high colonization prevalence in the community, S. aureus infections commonly occur in individu als with no identifiable risk factors. In the outpatient setting, SSTI is the most common entity caused by S. aureus, accounting for 8 million annual ambulatory visits. Households are an important reservoir for S. aureus transmission because of close personal contact among colonized family members. Increased disease frequency occurs among household contacts of S. aureuscolonized or infected individuals. Additionally, S. aureus can persist on environmental surfaces over time. Contamination of envi ronmental surfaces such as hand towels, television remote controls, and bed linens can further perpetuate transmission among household members and is a risk factor for recurrent infection. Thus preventive strategies are aimed at decreasing the burden of S. aureus carriage in affected individuals and household members, as well as targeted house hold environmental surfaces. PATHOGENESIS Except in the case of food poisoning resulting from ingestion of pre formed enterotoxins, disease associated with S. aureus typically begins with colonization. Subsequent disease manifestations in susceptible indi viduals results either directly from tissue invasion or from |
7,109 | injury caused by various toxins and enzymes produced by the organism (Fig. 227.1). The most significant risk factor for the development of infection is disruption of intact skin, including breaches from wounds, skin diseases such as eczema, epidermolysis bullosa, insect bites, burns, ventriculoperitoneal shunts, and central venous catheter placement. Additional risk factors include immunodeficiency and malnutrition, although infection can also occur in otherwise healthy children. Viral infections of the respiratory tract, especially influenza virus infection, may predispose to secondary bacterial infection with staphylococci. Congenital defects in chemotaxis (hyper IgE syndromes, Chdiak Higashi, and Wiskott Aldrich syndromes) and defective phagocytosis and killing (neutropenia, chronic granulomatous disease) increase the risk for staphylococcal infections. Patients with HIV infection have neutrophils that are defective in their ability to kill S. aureus in vitro. Young infants with invasive infection or individuals with recurrent pyogenic infection should be evaluated for immune defects, especially those involving neutrophil dysfunction. Poor mucus clearance in chil dren with cystic fibrosis frequently leads to chronic pulmonary staphy lococcal colonization and persistent inflammation in these patients. Infants may acquire type specific humoral immunity to staphylo cocci transplacentally. Older children and adults develop antibodies to staphylococci as a result of colonization or minor infections. Antibody Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 227 u Staphylococcus 1695 to the various S. aureus toxins appears to protect against those specific toxin mediated diseases, but humoral immunity does not necessarily protect against focal or disseminated S. aureus infection with the same organisms. CLINICAL MANIFESTATIONS S. aureus has the potential to invade any tissue. Disease severity is influ enced by local suppuration, systemic dissemination with metastatic infection, or systemic effects of toxin production. Newborn S. aureus is an important cause of neonatal infections (see Chapter 148). Skin S. aureus is an important cause of pyogenic skin infections, includ ing impetigo contagiosa, ecthyma, bullous impetigo, folliculitis, furun cles (boils), carbuncles (multiple coalesced boils), and paronychia. Toxigenic infection with skin manifestations include staphylococcal scalded skin syndrome and staphylococcal scarlet fever. S. aureus is a frequent cause of superinfection of underlying dermatologic condi tions, such as eczema, hidradenitis suppurativa, or insect bites. Skin abscesses caused by CA MRSA commonly affect the lower extremities and buttocks. Up to 70 of individuals with SSTI will experience a recurrent infection. S. aureus is also an important cause of traumatic and surgical wound infections and can cause deep soft tissue involve ment, including cellulitis and, rarely, necrotizing fasciitis. Respiratory Tract Infections of the upper respiratory tract (otitis media, sinusitis) caused by S. aureus are rare, in particular considering the frequency with which the anterior nares are colonized. S. aureus sinusitis is relatively common in children with cystic fibrosis or defects in leukocyte func tion and may be the only focus of infection in some children with TSS. Suppurative parotitis is a rare infection, but S. aureus |
7,110 | is a common cause. A membranous tracheitis that complicates viral croup may result from infection with S. aureus, although other organisms may also be responsible. Pneumonia caused by S. aureus is uncommon but can present with rapidly progressive respiratory failure. Children may present with recent flulike illness (see Chapter 449). Hematogenous pneumonia may be secondary to septic emboli from right sided endocarditis or septic thrombophlebitis, with or without intravascular devices. Inha lation pneumonia is caused by alteration of mucociliary clearance, leukocyte dysfunction, or bacterial adherence initiated by a viral infec tion. Common symptoms and signs include high fever, abdominal pain, tachypnea, dyspnea, and localized or diffuse bronchopneumonia or lobar disease. In particular, USA300 strains of S. aureus often cause a necrotizing pneumonitis that may be associated with early devel opment of empyema, pneumatoceles, pyopneumothorax, and bron chopleural fistulas (Fig. 227.2). Chronic pulmonary infection with S. aureus contributes to progressive pulmonary dysfunction in children with cystic fibrosis (see Chapter 454). Bacteremia and Sepsis S. aureus bacteremia and sepsis may be primary or secondary because of a localized infection such as an infected central venous catheter or thrombus, bone, or skin and soft tissue. Risk factors for S. aureus bacte remia include presence of a central venous catheter, immunodeficiency, malnutrition, recent MRSA STTI, and recent surgery. The onset may be acute and marked by nausea, vomiting, myalgia, fever, and chills. Prolonged S. aureus bacteremia is associated with an increased risk of developing complications such as septic emboli, thrombi, and metastatic foci of infection. Methicillin resistance, musculoskeletal infection, endovascular infection, and delayed intervention for source control are risk factors for prolonged bacteremia. In general, removal of an infected central venous catheter is recommended because of the difficulty clearing S. aureus bacteremia in these patients. A positive blood culture for MRSA or methicillin sensitive S. aureus (MSSA) should always be considered pathogenic, and antistaphylococcus treatment should be initiated with vancomycin or daptomycin with a lactam until antimicrobial susceptibility is available. In the absence of an obvious source (isolated bacteremia), endocarditis must be considered. MSSA bacteremia should be treated with a lactam such as cefazolin or oxacillin, given poorer outcomes in children treated with vancomycin. Although vancomycin has been traditionally used as first line treatment of MRSA bacteremia in children, daptomycin and ceftaroline, a lactam and fifth generation cephalosporin, can also be considered. The dura tion of antibiotic therapy depends on the age and presence of associated infections. In general, 7 14 days of intravenous therapy is appropriate for uncomplicated bacteremia; however, additional studies are needed to determine the optimal duration in children. Repeat blood cultures should be obtained until negative for 2 days to document clearance of bacteremia. Prolonged positive blood cultures while on therapy suggest endocarditis, an infected thrombus, abscess formation, foreign body (central lines, bone prosthesis, or internal fixation of fractures), or other factors leading to poor source control. Whole body MRI or PET MRI scanning may detect unrecognized metastatic foci. Infectious disease consultation has been shown to improve cure rates and |
7,111 | outcomes in children with S. aureus bacteremia, including decreased mortality and decreased recurrence of bacteremia. Staphylococcus aureus Cell wall Capsule 4. Secreted toxins and virulence factors Superantigens Enterotoxins Toxic shock syndrome toxin1 Exfoliative toxins Exfoliative toxins A and B Poreforming toxins Hemolysin A ( toxin) Hemolysin Leukocidin AB (LukAB) Leukocidin ED (LukED) PantonValentine leukocidin Phenolsoluble modulins Manipulation of host coagulation Coagulase von Willebrand factorbinding protein (vWbp) 1. Surface immune evasion Antibody interference Protein A (Spa) Staphylokinase Staphylococcal binder of Ig (Sbi) Biofilm adhesion PolyNacetylglucosamine (PNAG) 2. Membrane bound proteins MSCRAMMs Clumping factor Fibrinogenbinding protein Fibronectinbinding proteins Bone sialoprotein binding protein Nutrient acquisition proteins Iron uptake via heme (Isd system) Manganese transport (MntABC) 3. Polysaccharide microcapsule (not expressed by all clinical isolates) Fig. 227.1 Schematic of virulence factors and relevant surface adhesins of Staphylococcus aureus. YY, Immunoglobulin binding site; MSCRAMMs, microbial surface components that recognize adhesive matrix molecules. (From Thomsen I, Creech CB. Staphylococcus aureus. In Long SS, Prober CG, Fischer M, Kimberlin DW, eds. Principles and Practice of Pediatric Infectious Diseases, 6th ed. Philadelphia: Elsevier; 2023, Fig. 115.1, p. 711.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1696 Part XV u Infectious Diseases Muscle Localized staphylococcal abscesses in muscle, sometimes without sep ticemia, have been called pyomyositis. This disorder is reported most frequently from tropical areas and is termed tropical pyomyositis, but also occurs in the United States in otherwise healthy children. Mul tiple abscesses occur in 3040 of cases, most commonly affecting the pelvic and lower extremity muscles. History may include prior trauma at the site of the abscess. More commonly, pyomyositis results from seeding secondary to bacteremia, often near the site of osteomyelitis. Surgical drainage and appropriate antibiotic therapy are essential. Bones and Joints S. aureus is the most common cause of osteomyelitis and suppurative arthritis in children, most commonly the result of hematogenous seed ing and, less often, from a contiguous focus of infection or through inoc ulation from trauma or a surgical procedure (see Chapters 725 and 726). Central Nervous System Meningitis caused by S. aureus is uncommon; it is associated with pen etrating cranial trauma and neurosurgical procedures (craniotomy, cerebrospinal fluid CSF shunt placement) and, less frequently, with endocarditis, parameningeal foci (epidural or brain abscess), prema turity, complicated sinusitis, diabetes mellitus, or malignancy. The CSF profile of S. aureus meningitis is indistinguishable from that in other forms of bacterial meningitis (see Chapter 643.1). Heart S. aureus is a common cause of acute endocarditis on native valves and results in high rates of morbidity and mortality. Left sided endocarditis is most common. The clinical presentation can be indolent with symp toms such as malaise, weight loss, or myalgias, and the typical signs of endocarditis are often not present in children (see Chapter 486). Kidney S. aureus is a common cause of renal and perinephric abscess, usually of hematogenous origin. |
7,112 | Pyelonephritis and cystitis caused by S. aureus are unusual (see Chapter 575). Toxic Shock Syndrome S. aureus, more commonly MSSA than MRSA, is the principal cause of TSS, which should be suspected in anyone with fever, shock, andor a diffuse erythroderma (see Chapter 227.2). Intestinal Tract Staphylococcal enterocolitis may rarely follow overgrowth of normal bowel flora by S. aureus, which can result from broad spectrum oral antibiotic therapy. Diarrhea is associated with blood and mucus. Peri tonitis associated with S. aureus in patients receiving long term ambu latory peritoneal dialysis usually involves the catheter tunnel. Food poisoning may be caused by ingestion of preformed entero toxins produced by staphylococci in contaminated foods (see Chapter 387). The source of contamination is often colonized or infected food workers. Approximately 2 7 hours after ingestion of the toxin, sud den, severe vomiting begins. Watery diarrhea may develop, but fever is absent or low grade. Symptoms rarely persist 12 24 hours. Rarely, shock and death may occur. DIAGNOSIS The diagnosis of S. aureus infection depends on isolation of the organ ism in culture from the site of infection, such as cellulitis aspirates, abscess cavities, blood, bone, or joint aspirates, or other sites of infec tion. In patients with musculoskeletal infection, 50 of children will have blood cultures that yield S. aureus. Thus surgical debridement or an aspirate or biopsy obtained by interventional radiology can maxi mize recovery of the organism, which is important for targeted antibi otic selection. Tissue samples or fluid aspirates in a syringe provide the best culture material. Because of the high prevalence of MRSA and the severity of S. aureus infections, it is important to obtain cultures before starting antibiotic treatment. The organism can be grown readily in liq uid and on solid media. After isolation, identification is made on the basis of Gram stain and coagulase, clumping factor, and catalase activ ity. Molecular techniques and mass spectrometry are used to supple ment traditional identification and antibiotic susceptibility methods. These technologies may allow for rapid species identification from positive blood cultures and simultaneously identify genetic patterns associated with methicillin resistance, such as presence of the mecA gene produced by MRSA. Diagnosis of S. aureus food poisoning is usu ally made on the basis of epidemiologic and clinical findings. Differential Diagnosis Many of the clinical entities caused by S. aureus can also be caused by other bacterial pathogens, and consideration of the differential diagno sis is particularly important when making empirical antibiotic choices before definitive identification of the offending pathogen. Skin lesions caused by S. aureus may be indistinguishable from those caused by group A streptococci, although S. aureus usually expands slowly and is more likely to be suppurative, whereas group A streptococci are prone to spread more rapidly and can be very aggressive. Fluctuant skin and soft tissue lesions also can be caused by other organisms, including Mycobacterium tuberculosis, atypical mycobacteria, Nocardia, Bartonella henselae (cat scratch disease), Francisella tularensis, and various fungi. S. aureus pneumonia is often suspected in very |
7,113 | ill appearing children or after failure to improve with standard treatment that does not cover Staphylococcus, or on the basis of chest radiographs that reveal pneuma toceles, pyopneumothorax, or lung abscess (see Fig. 227.2). Other eti ologies of cavitary pneumonias include group A streptococci, Klebsiella pneumoniae, and M. tuberculosis. In bone and joint infections, culture is the only reliable way to differentiate S. aureus from other etiologies, including group A streptococci and, in young children, Kingella kingae. TREATMENT Antibiotic therapy alone is rarely effective in individuals without source control of the focus of infection. Loculated collections of purulent material should be relieved by incision and drainage. Foreign bodies (e.g., orthopedic instrumentation, ventricular shunts, central venous catheters) should be removed, if possible. Therapy always should be initiated with an antibiotic consistent with the local staphylococcal sus ceptibility patterns, severity, and anatomic site of infection. For most patients with serious S. aureus infection, initial intravenous (IV) treat ment is usually recommended, and transition to oral therapy can be considered based on clinical response and source of infection. Treatment of S. aureus osteomyelitis (Chapter 725), meningitis (Chapter 643.1), and endocarditis (Chapter 486) is discussed in the respective chapters on these diagnoses. Initial treatment for serious infections thought to be caused by methicillin susceptible S. aureus (MSSA) should include a semisyn thetic penicillin (e.g., nafcillin, oxacillin) or a first generation cephalo sporin (e.g., cefazolin). Penicillin and ampicillin are not appropriate, because 90 of all staphylococci isolated, regardless of source, are resistant to these agents. Addition of a lactamase inhibitor (clavulanic acid, sulbactam, tazobactam) to a penicillin based drug also confers antistaphylococcal activity but has no effect on MRSA. The spectrum of these lactam lactamase inhibitor agents (which includes gram negative bacteria and anaerobes) can be an advantage when broad empirical coverage is needed, but narrower coverage should be selected once S. aureus is identified. Antistaphylococcal penicillins and most cephalosporins do not provide activity against MRSA. Vancomycin is typically selected for initial treatment for penicillin allergic individuals and those with suspected serious infections caused by MRSA. Although serum level monitoring has traditionally been used for patients receiving vancomycin, this method is no longer rec ommended for severe MRSA infections. Instead, calculating the ratio of area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) as the primary predictor of vancomycin activity is currently recommended. Monitoring for nephrotoxicity is also impor tant while on vancomycin therapy. Vancomycin intermediate S. aureus strains (VISAs), defined as having an MIC of vancomycin greater than 2 gmL, and, rarely, vancomycin resistant strains of S. aureus (VRSA, MIC of vancomycin 16 gmL) have also been reported, mostly in patients being treated with vancomycin. For critically ill patients with Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 227 u Staphylococcus 1697 suspected S. aureus infection, empirical therapy with both vancomy cin |
7,114 | and a lactam (cefazolin or nafcillin) should be considered until culture results are available. Initial treatment with IV clindamycin fol lowed by a transition to oral clindamycin can be considered in bone, joint, and soft tissue infection; however, not all strains of MSSA or MRSA are susceptible to clindamycin. Inducible clindamycin resis tance in isolates initially reported as susceptible must be ruled out by D test or molecular methods. Clindamycin is bacteriostatic and should not be used to treat endocarditis, persistent bacteremia, or CNS infections caused by S. aureus. Given that the mechanism of action of clindamycin involves inhibition or protein synthesis, many experts use clindamycin as an adjunctive agent to treat S. aureus toxinmediated illnesses (e.g., TSS) to inhibit toxin production. Although the broad spectrum carbapenems (meropenem, ertapenem, and imipenem) have activity against MSSA, they have no activity against MRSA. As a result, carbapenems are rarely used for empirical therapy of possible staphylococcal infection and are too broad in most cases for use in identified MSSA infections. Linezolid, daptomycin, and ceftaroline are useful for serious S. aureus infections, providing excellent coverage of MRSA and MSSA (Table 227.1). A number of novel antistaphylococ cal antibiotics have emerged for use in resistant or refractory MSSA and MRSA infection in adults that may be required for pediatric therapy in select patients under the guidance of a pediatric infectious disease spe cialist. These include the lipoglycopeptides, including telavancin, orita vancin, and dalbavancin, which are structurally related to vancomycin but have very long half lives and broad activity against gram positive organisms. Rifampin or gentamicin in addition to a lactam or van comycin are recommended for prosthetic valve endocarditis, although patients need to be monitored closely for adverse side effects; their use as combined therapy for other infections is not recommended. In many infections, after an initial period of parenteral therapy, patients may be transitioned to oral antimicrobials to complete the course of treatment after determination of antimicrobial susceptibili ties. Oral antimicrobials can be used as initial treatment in less severe infections (e.g., skin abscess). Cephalexin (25 100 mgkg24 hr divided 3 4 times daily PO) and cefadroxil (30 mgkg24 hr divided 2 times daily PO for noninvasive infections, 50 60 mgkg24 hr divided 2 times daily PO for osteoarticular infections) are absorbed well orally (PO) and are effective against MSSA. (Variable cefadroxil dosing regimens have been described, ranging from 30150 mgkgday divided 24 times daily PO.) Amoxicillin clavulanate (40 80 mg amoxicillinkg24 hr divided 3 times daily PO) is also effective when a broader spectrum of coverage is required. Clindamycin (30 40 mgkg24 hr divided 3 4 times daily PO) is highly absorbed from the intestinal tract and is fre quently used for empirical coverage when both MRSA and MSSA are possible and for susceptible MRSA infections or for MSSA in penicillin cephalosporin allergic patients. Compliance with oral clindamycin may be limited in small children because of poor palatability of liquid for mulations. Trimethoprim sulfamethoxazole (TMP SMX) may be an effective oral antibiotic |
7,115 | for many strains of both MSSA and MRSA for SSTI. Oral linezolid is an option for severe MRSA infections that have improved but require ongoing therapy when more common options are not tolerated or are ineffective because of resistance patterns. The duration of linezolid therapy is typically limited to 2 3 weeks given tox icities such as myelosuppression and peripheral and optic neuropathy with prolonged courses. Despite in vitro susceptibility of S. aureus to ciprofloxacin and other quinolone antibiotics, these agents should not routinely be used in serious staphylococcal infections, because their use is associated with rapid development of resistance. The duration of antibiotic therapy depends on the anatomic site and severity of infection and response, as determined by the clinical response and, in some cases, radiologic and laboratory findings. PROGNOSIS Untreated S. aureus septicemia is associated with a high fatality rate, which has been reduced significantly by appropriate antibiotic treat ment. S. aureus pneumonia can be fatal at any age but is more likely to be associated with high morbidity and mortality in young infants or in patients whose therapy has been delayed. Prognosis also may be influ enced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. PREVENTION S. aureus is transmitted primarily by direct contact. Strict attention to hand hygiene is the most effective measure for preventing the spread of staphylococci between individuals (see Chapter 216). Hospital surveil lance programs to identify nosocomial acquisition of S. aureus coloni zation andor infection are common, particularly in neonatal intensive care units. Clusters of nosocomial cases may be defined by molecular typing, and if associated with a singular molecular strain, investiga tion to identify any potential point sources (e.g., a colonized healthcare worker or contaminated environmental reservoir) should occur. As S. aureus colonization often predisposes to infection, a number of protocols are aimed at decolonization, which is the application of topical antimicrobials to the skin andor nares to eradicate S. aureus colonization. In healthcare settings, decolonization is often performed among vulnerable populations to prevent nosocomial infections. In community settings, decolonization is often recommended for patients with recurrent S. aureus skin infections. Decolonization regimens often involve combinations of decontaminating baths (hypochlorite, 1 tsp common bleach solution per gallon of water, or chlorhexidine 4 soap), nasal mupirocin twice daily for at least 5 days, and enhanced hygiene measures, including frequent laundering of household linens and targeted decontamination of frequently touched household sur faces. Although success is not universal, recurrent infections may be reduced, particularly when eradication is done in both the patient and household contacts, especially those with history of SSTI. Most cases of mild, recurrent disease will resolve in time without these measures. Because of the potential severity of infections with S. aureus and concerns about emerging resistance, much work has focused on A B C D E Fig. 227.2 Progressive methicillin resistant Staphylococcus aureus (MRSA) pneumonia with pneumatoceles in a previously healthy 9 mo old male. Chest radiographic findings spanning 4 days |
7,116 | showed a perihilar right lower lobe infiltrate (A) progressing to a worsening infiltrate and large hydro pneumothorax with mediastinal shift (B and C) despite appropriate therapy. Axial CT of the chest without contrast (lung windows) showed partial loculation of hydropneumothorax, multilobar consolidation, pneumatoceles, and atelectasis (D and E). Video assisted thoracoscopic surgery (VATS) was performed, and a chest tube was placed for 3 days. MRSA was isolated from pleural fluid. After 2 weeks of clindamycin therapy, the chest radio graph had only minor abnormalities. (Courtesy Dr. Sarah S. Long.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1698 Part XV u Infectious Diseases developing a staphylococcal vaccine for use in high risk patients, but to date, clinical trials have been disappointing. Because S. aureus is fre quently a co infection in severe influenza infections, an indirect pre ventive impact against staphylococcal pneumonia and tracheitis may be achieved through annual influenza vaccination. To prevent S. aureus food poisoning, cooked foods should be eaten immediately or refrigerated within 2 hours of preparation to prevent multiplication of S. aureus that may have contaminated the food (see Chapter 387). Treatment is supportive. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 227.2 Toxic Shock Syndrome Carol M. Kao, Patrick J. Reich, and Stephanie A. Fritz Toxic shock syndrome (TSS) is an acute and potentially severe ill ness characterized by fever, hypotension, diffuse erythroderma with subsequent desquamation on the hands and feet, and multisystem involvement. ETIOLOGY TSS is caused by TSST 1producing and some enterotoxin producing strains of S. aureus, which may colonize the skin or mucous mem branes or cause focal sites of staphylococcal infection. EPIDEMIOLOGY TSS continues to occur in the United States in men, women, and chil dren, with the highest rates in menstruating women 15 25 years of age. Nonmenstrual TSS is associated with S. aureusinfected nasal pack ing and wounds, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary bacteremia. The majority of strains of S. aureus associated with TSS are methicillin susceptible. Most strains of USA300, the predominant clone of community associated MRSA in the United States, do not possess the genes expressing the most com mon TSS superantigens; however, MRSA associated TSS can occur. PATHOGENESIS The primary toxin associated with TSS is TSST 1, although a significant proportion of nonmenstrual TSS is caused by one or more staphylococ cal enterotoxins. These toxins act as superantigens, which trigger cyto kine release, causing massive loss of fluid from the intravascular space and end organ cellular injury. Epidemiologic and in vitro studies suggest that these toxins are selectively produced in a clinical environment con sisting of a neutral pH, a high Pco2, and an aerobic Po2, which are the conditions found in abscesses and the vagina with tampon use during menstruation. The risk factors for symptomatic disease include a non immune host who is colonized with a |
7,117 | toxin producing organism that is exposed to focal growth conditions (menstruation plus tampon use or abscess) that in turn induce toxin production. Some hosts may have a varied cytokine response to TSST 1 exposure, helping to explain a spec trum of severity of TSS that may include staphylococcal scarlet fever. The overall mortality rate of treated patients is 35 when treated early. Approximately 90 of adults have antibody to TSST 1 without a history of clinical TSS, suggesting that most individuals are colonized at some point with a toxin producing organism at a site (e.g., ante rior nares) where low grade or inactive toxin exposure results in an immune response without disease. Table 227.1 Parenteral Antimicrobial Agent(s) for Treatment of Serious Staphylococcus aureus Infections SUSCEPTIBILITY ANTIMICROBIALS COMMENTS I. INITIAL EMPIRICAL THERAPY (ORGANISM OF UNKNOWN SUSCEPTIBILITY) Drugs of choice Vancomycin nafcillinoxacillin or cefazolin For life threatening infections (e.g., septicemia, endocarditis, CNS infection); linezolid, daptomycin, or ceftaroline could be substituted depending on the clinical scenario and site of infection Vancomycin For nonlife threatening infection without signs of severe sepsis (e.g., skin infection, cellulitis, osteomyelitis, pyarthrosis) when prevalence of MRSA infection in the community is 20 of all S. aureus infections Cefazolin or nafcillinoxacillin For nonlife threatening infection when low likelihood of MRSA is suspected Clindamycin For nonlife threatening infection without signs of severe sepsis when rates of MRSA infection in the community is substantial (20 of all S. aureus infections) and prevalence of clindamycin resistance is low II. METHICILLIN SUSCEPTIBLE, PENICILLIN RESISTANT S. AUREUS Drugs of choice Cefazolin or oxacillinnafcillin May change to oral therapy after infection is controlled in low risk situations Alternatives (depending on susceptibility results) Clindamycin Only for patients with a serious penicillin allergy and clindamycin susceptible strain Vancomycin Only for penicillin and cephalosporin allergic patients Ampicillin sulbactam When broader coverage, including gram negative organisms andor anaerobes is required III. METHICILLIN RESISTANT S. AUREUS (MRSA) Drugs of choice Vancomycin (some combine with a lactam) (some may begin with ceftaroline) Linezolid, daptomycin, or ceftaroline could be substituted or added depending on the clinical scenario, site of infection, or persistent bacteremia Alternatives: susceptibility testing results available before alternative drugs are used Clindamycin (if susceptible) Trimethoprim sulfamethoxazole Doxycycline Linezolid, daptomycin, and ceftaroline are agents with activity and efficacy against multidrug resistant, gram positive organisms, including S. aureus. Because experience with these agents in children is limited, consultation with an infectious diseases specialist should be considered before use. Daptomycin is ineffective for treatment of pneumonia, as it is inacti vated by pulmonary surfactant. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 227 u Staphylococcus 1699 CLINICAL MANIFESTATIONS The diagnosis of TSS is based on clinical manifestations (Table 227.2). Milder cases and those with incomplete clinical characteristics may be common, particularly if the nidus of infection is addressed quickly (e.g., removal of a tampon or nasal packing). |
7,118 | The onset of classic TSS is abrupt, with high fever, vomiting, and diarrhea, and is accompanied by sore throat, headache, and myalgias. A diffuse erythematous rash (sunburn like or scarlatiniform) appears within 24 hours and may be associated with hyperemia of pharyngeal, conjunctival, and vaginal mucous membranes. A strawberry tongue is common. Symptoms may include alterations in the level of consciousness, oliguria, and hypoten sion, which in severe cases may progress to shock and disseminated intravascular coagulation. Complications, including acute respira tory distress syndrome (ARDS), myocardial dysfunction, and renal failure, are commensurate with the degree of shock. Recovery occurs within 7 10 days and is associated with desquamation, particularly of the palms and soles; hair and nail loss have also been observed after 1 2 months. Immunity to the toxins is slow to develop, so recurrences can occur, especially if there is inadequate antibiotic treatment and or recurrent tampon use. Many cases of apparent scarlet fever without shock may be caused by TSST 1producing S. aureus strains. DIAGNOSIS There is no specific laboratory test, and diagnosis depends on meeting certain clinical and laboratory criteria in the absence of an alternative diagnosis (see Fig. 227.2). Appropriate tests reveal involvement of multiple organ systems, including the hepatic, renal, muscular, gastrointestinal, cardiopulmonary, and central nervous systems. Bacterial cultures of the associated focus (vagina, abscess) before administration of antibiotics usu ally yield S. aureus, although this is not a required element of the definition. Differential Diagnosis Group A streptococci can cause a similar TSS like illness, termed streptococcal TSS (see Chapter 229), which is often associated with severe streptococcal sepsis or a focal streptococcal infection such as cellulitis, necrotizing fasciitis, or pneumonia. Kawasaki disease closely resembles TSS clinically but is usually not as severe or rapidly progressive. Both conditions are associated with fever unresponsive to antibiotics, hyperemia of mucous membranes, and an erythematous rash with subsequent desquamation. However, many of the clinical features of TSS are rare in Kawasaki disease, includ ing diffuse myalgia, vomiting, abdominal pain, diarrhea, azotemia, hypotension, ARDS, and shock (see Chapter 208). Kawasaki disease typically occurs in children 5 years old. Measles, scarlet fever, Rocky Mountain spotted fever, leptospirosis, toxic epidermal necrolysis, and bacterial sepsis must also be considered in the differential diagnosis. TREATMENT Identification and drainageremoval of any focal source of infection (e.g., abscess, tampon, nasal packing), when present, is essential. Rec ommended antibiotic therapy for TSS should include the combina tion of a lactamaseresistant antistaphylococcal antibiotic (nafcillin, oxacillin, or cefazolin) plus clindamycin to reduce toxin production. Although TSS is most often caused by MSSA, clinicians should con sider use of vancomycin in addition to the lactam in areas where MRSA rates are very high, when hospital acquired MRSA is suspected, and when the clinical picture overlaps with staphylococcal sepsis. TSS often requires intensive supportive care, including aggressive fluid replacement to prevent or treat hypotension, renal failure, and cardiovascular collapse. Inotropic agents may be needed to treat shock; intravenous immunoglobulin may be helpful in severe cases. PREVENTION The risk |
7,119 | for acquiring menstrual TSS is low (1 2 cases100,000 men struating women). Changing tampons at least every 8 hours is recom mended. If a fever, rash, or dizziness develops during menstruation, any tampon should be removed immediately and medical attention sought. Avoidance of tampon use with subsequent menstrual cycles may also reduce the risk for recurrent menstrual TSS. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 227.3 Coagulase Negative Staphylococci Carol M. Kao, Patrick J. Reich, and Stephanie A. Fritz At present, there are approximately 50 identified species of coagulase negative staphylococci (CoNS) affecting or colonizing humans. Staphylococcus epidermidis and, less often, Staphylococcus hominis, S. haemolyticus, and others are widely distributed on the skin and are sig nificant causes of nosocomial infection, particularly in the bloodstream of neonatal and immunocompromised hosts, in surgical patients, and in those with indwelling catheters and other medical devices. Staphylococ cus saprophyticus is a common cause of urinary tract infection (UTI). Staphylococcus lugdunensis and Staphylococcus schleiferi can cause severe infection similar to S. aureus and have been increasingly recognized as important pathogens since improved species identification with matrix assisted laser desorptionionization time of flight (MALDI TOF) mass spectrometry in clinical microbiology laboratories. EPIDEMIOLOGY In the United States, CoNS may be the most common cause of hospital acquired infection, particularly in neonatal intensive care units (NICUs). In many instances, growth of CoNS from clinical specimens represents contamination from skin rather than a cause of true disease, posing significant challenges for clinicians and infection prevention specialists. CoNS are normal inhabitants of the human skin, throat, Table 227.2 Toxic Shock Syndrome (Other Than Streptococcal) (TSS) 2011 Case Definition CLINICAL CRITERIA 1. Fever: temperature 102.0F (38.9C) 2. Rash: diffuse macular erythroderma 3. Desquamation: 12 weeks after onset of rash 4. Hypotension: systolic blood pressure 90 mm Hg for adults or less than fifth percentile by age for children age less than 16 years 5. Multisystem involvement (three or more of the following organ systems): Gastrointestinal: vomiting or diarrhea at onset of illness Muscular: severe myalgia or creatine phosphokinase level at least twice the upper limit of normal Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia Renal: blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or urinary sediment with pyuria (5 leukocytes per highpower field) in the absence of urinary tract infection Hepatic: total bilirubin, alanine aminotransferase enzyme, or aspartate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory Hematologic: platelets less than 100,000mm3 Central nervous system: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent LABORATORY CRITERIA FOR DIAGNOSIS Negative results on the following tests, if obtained: Blood or cerebrospinal fluid cultures (blood culture may be positive for Staphylococcus aureus) Negative serologies for Rocky Mountain spotted fever, leptospirosis, or measles CASE CLASSIFICATION Probable A case that meets the laboratory criteria and in which four of the five clinical criteria described above are present Confirmed A case that meets the laboratory criteria and in which |
7,120 | all five of the clinical criteria described above are present, including desquamation, unless the patient dies before desquamation occurs From Centers for Disease Control and Prevention: https:ndc.services.cdc.govc asedefinitionstoxicshocksyndrome2011 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1700 Part XV u Infectious Diseases mouth, vagina, and urethra. S. epidermidis is the most common and persistent species, representing 6590 of staphylococci present on the skin and mucous membranes. Colonization, sometimes with strains acquired during hospitalization, precedes infection. Alternatively, direct inoculation during surgery may initiate infection of CSF shunts, prosthetic valves, or indwelling vascular lines. PATHOGENESIS CoNS produce an exopolysaccharide protective biofilm, particularly on indwelling medical devices, that surrounds the organism and may enhance adhesion to foreign surfaces, resist phagocytosis, and impair penetration of antibiotics. However, the low virulence of CoNS usu ally requires the presence of another factor for development of clinical disease. Of these, the most significant is the presence of an indwelling catheter or other medical device, including central venous catheters (CVCs), hemodialysis shunts and grafts, CSF shunts (meningitis), peri toneal dialysis catheters (peritonitis), pacemaker wires and electrodes (local infection), prosthetic cardiac valves (endocarditis), and pros thetic joints (septic arthritis). Other risk factors for the development of infection include immature or compromised immunity and significant exposure to antibiotics. CLINICAL MANIFESTATIONS Bacteremia CoNS, specifically S. epidermidis, are the most common cause of nosocomial bacteremia, usually in association with central vascular catheters. In neonates, CoNS bacteremia, with or without a CVC, can manifest as localized disease in the CNS, lungs, skin, heart, bones, and joints, or even as sepsis or necrotizing enterocolitis. Persistent posi tive blood cultures despite adequate antimicrobial therapy is common, particularly when catheters are not removed. In older children with intact immune systems, CoNS bacteremia is indolent and is not usually associated with overwhelming septic shock. Endocarditis Infection of native heart valves or the right atrial wall may occur sec ondary to an infected thrombosis at the end of a central line. S. epi dermidis and other CoNS may rarely produce native valve subacute endocarditis in previously healthy hosts without a CVC. CoNS is a common cause of prosthetic valve endocarditis, presumably a result of inoculation at surgery. Infection of the valve sewing ring, with abscess formation and dissection, produces valve dysfunction or obstruction, dehiscence, or arrhythmias (see Chapter 486). S. lugdunensis has been increasingly associated with severe endocardial infection in adults but remains an uncommon cause in children. Central Venous Catheter Infection CVCs become infected through the exit site and subcutaneous tunnel, which provide a direct path to the bloodstream. S. epidermidis is the most frequent pathogen, in part because of its high rate of cutaneous coloniza tion. Line sepsis is usually manifested as fever and leukocytosis; tenderness and erythema may be present at the exit site or along the subcutaneous tunnel. Catheter thrombosis may complicate line sepsis. Disease severity with CoNS |
7,121 | is often less severe than other etiologies of line infection. Cerebrospinal Fluid Shunts CoNS, introduced at surgery, is the most common pathogen associated with CSF shunt meningitis. Most infections (7080) occur within 2 months of the operation and manifest as signs of meningeal irritation, fever, increased intracranial pressure (headache, vomiting), or peritonitis from the intraabdominal position of the distal end of the shunt tubing. Urinary Tract Infection S. saprophyticus is a common cause of primary UTIs in sexually active females. Manifestations are similar to those characteristics of UTI caused by Escherichia coli (see Chapter 575). CoNS also cause asymp tomatic UTI in hospitalized patients with urinary catheters and after urinary tract surgery or transplantation. DIAGNOSIS Because S. epidermidis is a common skin inhabitant and may contami nate poorly collected blood cultures, differentiating bacteremia from con tamination is often difficult. True bacteremia should be suspected if blood cultures grow rapidly (within 15 hours of incubation in a continuously monitored blood culture system), more than one blood culture is posi tive with the same CoNS strain, cultures from both the blood and another sterile site are positive, and clinical and laboratory signs and symptoms compatible with CoNS sepsis are present and subsequently resolve with appropriate therapy. Growth of CoNS from a blood culture in a neonate or patient with an intravascular catheter should be considered evidence of true bacteremia until careful review of the foregoing criteria and evalua tion of the patient. Before initiating presumptive antimicrobial therapy in such patients, it is always prudent to draw two separate blood cultures to facilitate subsequent interpretation if CoNS is grown. Molecular and mass spectrometry assays similar to those used for identification of S. aureus allow for rapid identification of CoNS in positive blood cultures. TREATMENT Because most CoNS strains are resistant to methicillin (with the excep tion of S. lugdunensis and S. saprophyticus, which are generally methicil lin susceptible), vancomycin is the initial drug of choice. Resistance to vancomycin has rarely been reported with S. haemolyticus. For patients with indwelling medical devices, the addition of rifampin to vancomy cin may increase antimicrobial efficacy because of good penetration of this antibiotic into biofilms. Other antibiotics with good in vitro activity against CoNS may be considered in certain circumstances. These include linezolid, ceftaroline, and daptomycin. Removal of an infected catheter is ideal. However, this is not always possible because of the therapeutic requirements of the underlying disease (e.g., nutrition for short bowel syndrome, chemotherapy for malignancy). A trial of IV vancomycin (potentially with the addition of rifampin) with the retained catheter can be attempted to preserve the use of the central line, as long as sys temic manifestations of infection are not severe. Antibiotic therapy given through an infected CVC and the use of antibiotic locks in conjunction with systemic therapy may increase the likelihood of curing CoNS line sepsis without line removal. Prosthetic heart valves and CSF shunts usu ally need to be removed to adequately treat the infection. Peritonitis caused by S. epidermidis in |
7,122 | patients on continuous ambu latory peritoneal dialysis is an infection that may be treated with IV or intraperitoneal antibiotics without removing the dialysis catheter. If the organism is resistant to methicillin, vancomycin adjusted for renal function is appropriate therapy. Unlike most CoNS, S. saprophyticus is usually methicillin susceptible, and UTIs can typically be treated with a first generation cephalosporin (cephalexin), amoxicillinclavulanic acid, or TMP SMX. PROGNOSIS Most episodes of CoNS bacteremia respond successfully to antibiot ics and removal of any foreign material that is present. Poor prognosis is associated with malignancy, neutropenia, and infected prosthetic or native heart valves. CoNS infections increase the morbidity, duration of hospitalization, and mortality among patients with underlying com plicated illnesses. PREVENTION Iatrogenic morbidity and resource use caused by contaminated blood cultures can be reduced by following recommended strategies to pre vent CVC associated bloodstream infections during catheter inser tion and maintenance. These strategies include basic techniques such as central line care bundles, which incorporate good hand hygiene, decontamination of hubs and ports before access, minimizing fre quency of access, and frequent replacement of external connections and infusion materials. Antibiotic impregnated catheters can be con sidered when other preventive measures have failed. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Streptococcus pneumoniae (pneumococcus) is an important pathogen that results in more than 1 million children deaths each year. Child hood invasive pneumococcal disease is prevalent and typically severe, causes numerous clinical syndromes, and is a major cause of life threatening pneumonia, bacteremia, endocarditis, and meningitis; it may also cause sinusitis, otitis media, and bone and joint infections. Antimicrobial resistance in pneumococcus is a major public health problem, with 1530 of isolates worldwide classified as multidrug resistant (MDR; resistant to at least three classes of antibiotics). Pneu mococcal polysaccharide protein conjugate vaccines (PCVs) devel oped for infants have been highly successful in the control of disease caused by virulent vaccine specific serotypes. Epidemiologic surveil lance reveals a dynamic pneumococcal ecology with emergence of highly virulent MDR serotypes. Ongoing vaccine development and distribution efforts remain the best approach to control this threat to childhood health. ETIOLOGY S. pneumoniae is a gram positive, lancet shaped, polysaccharide encapsulated diplococcus, occurring occasionally as individual cocci or in chains; 90 serotypes have been identified by type specific cap sular polysaccharides. Antisera to some pneumococcal polysaccha rides cross react with other pneumococcal types, defining serogroups (e.g., 6A and 6B). Encapsulated strains cause most serious disease in humans. Capsular polysaccharides impede phagocytosis. Virulence is related in part to capsule size, but pneumococcal types with capsules of the same size can vary widely in virulence. On solid media, S. pneumoniae forms unpigmented, umbilicated colonies surrounded by a zone of incomplete () hemolysis. S. pneu moniae is bile soluble (i.e., 10 deoxycholate) and optochin sensitive. S. pneumoniae is closely related to the |
7,123 | viridans groups of Streptococ cus mitis, which typically overlap phenotypically with pneumococci. The conventional laboratory definition of pneumococci continues to rely on bile and optochin sensitivity, although considerable confu sion occurs in distinguishing pneumococci and other hemolytic streptococci. Pneumococcal capsules can be microscopically visual ized and typed by exposing organisms to type specific antisera that combine with their unique capsular polysaccharide, rendering the capsule refractile (Quellung reaction). Specific antibodies to capsular polysaccharides confer protection on the host, promoting opsoniza tion and phagocytosis. Additionally, CD4 T cells have a direct role in antibody independent immunity to pneumococcal nasopharyngeal colonization. Conjugated PCVs promote T cell immunity and protect against pneumococcal colonization, in contrast to the pneumococcal polysaccharide vaccine (PPSV23) that is used in adults and certain high risk pediatric populations and that does not affect nasopharyn geal colonization. EPIDEMIOLOGY Most healthy individuals carry (colonized) various S. pneumoniae serotypes in their upper respiratory tract; 90 of children between 6 months and 5 years of age harbor S. pneumoniae in the nasopharynx at some time. A single serotype usually is carried by a given individ ual for an extended period (45 days to 6 months). Carriage does not consistently induce local or systemic immunity sufficient to prevent later reacquisition of the same serotype. Rates of pneumococcal car riage peak during the first and second year of life and decline gradu ally thereafter. Carriage rates are highest in institutional settings and during the winter and are lowest in summer. Nasopharyngeal carriage of pneumococci is common among young children attending out of home care, with rates of 2159 in point prevalence studies. Before the introduction of heptavalent pneumococcal conjugate vac cine (PCV7) in 2000, serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F caused most invasive childhood pneumococcal infections in the United States. The introduction of PCVs resulted in a marked decrease in invasive pneumococcal infections (IPIs) in children. By 2005, however, IPIs began to increase slightly because of an increase in non PCV7 sero types, particularly serotype 19A. Serotype replacement can result from expansion of existing nonvaccine serotypes and from vaccine type pneumococci acquiring the polysaccharide capsule of a nonvac cine serotype (serotype switching). Since the introduction of PCV13 in 2010 in the United States, there has been a decline in IPIs caused by new vaccine serotypes, including 19A. Nonetheless, 19A remains an important cause of meningitis. Indirect protection of unvaccinated persons has occurred since PCV introduction, and this herd protec tion is likely a result of decreases in nasopharyngeal carriage of virulent pneumococcal vaccine serotypes. S. pneumoniae is the most frequent cause of bacteremia, bacterial pneumonia, and bacterial meningitis and among the most common causes of otitis media and sinusitis in children. The decreased ability in children 2 years old to produce antibody against the T cellinde pendent polysaccharide antigens and the high prevalence of coloniza tion may explain an increased susceptibility to pneumococcal infection and the decreased effectiveness of polysaccharide vaccines. Children at increased risk of pneumococcal infections include those with sickle cell |
7,124 | disease, asplenia, deficiencies in humoral (B cell) immunity, deficien cies in complement mediated immunity, toll like receptor deficien cies, HIV infection, certain malignancies (e.g., leukemia, lymphoma), chronic heart, lung, or renal disease (particularly nephrotic syndrome), cerebrospinal fluid (CSF) leak, and cochlear implants. Table 228.1 lists other high risk groups. Some American Indian, Alaska Native, and African American children may also be at increased risk. Children 5 years old in out of home daycare are at increased risk (approximately twofold higher) of experiencing IPIs than other children. Males are more frequently affected than females. Because immunocompetent vaccinated children have had fewer episodes of IPI, the proportion of infected children with immunologic risk factors has increased (esti mated at 20). Pneumococcal disease usually occurs sporadically but can be spread from person to person by respiratory droplet transmission. S. pneu moniae is an important cause of secondary bacterial pneumonia in patients with influenza. During influenza epidemics and pandemics, most deaths result from bacterial pneumonia, and pneumococcus is the predominant bacterial pathogen isolated in this setting. Pneumo coccal co pathogenicity may be important in disease caused by other respiratory viruses as well. PATHOGENESIS Invasion of the host is affected by a number of factors. Nonspecific defense mechanisms, including the presence of other bacteria in the nasopharynx, may limit multiplication of pneumococci. Aspiration of secretions containing pneumococci is hindered by the epiglottic reflex and by respiratory epithelial cell cilia, which move infected mucus toward the pharynx. Similarly, normal ciliary flow of fluid from the middle ear through the eustachian tube and sinuses to the nasophar ynx usually prevents infection with nasopharyngeal flora, including pneumococci. Interference with these normal clearance mechanisms by allergy, viral infection, or irritants (e.g., smoke) may allow coloniza tion and subsequent infection with these organisms in otherwise nor mally sterile sites. Virulent pneumococci are intrinsically resistant to phagocytosis by alveolar macrophages. Pneumococcal disease frequently is facilitated by viral respiratory tract infection, which may produce mucosal injury, diminish epithelial cell ciliary activity, and depress the function of Chapter 228 Streptococcus pneumoniae (Pneumococcus) Kacy A. Ramirez and Timothy R. Peters Chapter 228 u Streptococcus pneumoniae (Pneumococcus) 1701 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1702 Part XV u Infectious Diseases alveolar macrophages and neutrophils. Phagocytosis may be impeded by respiratory secretions and alveolar exudate. In the lungs and other tissues, the spread of infection is facilitated by the antiphagocytic prop erties of the pneumococcal capsule. Surface fluids of the respiratory tract contain only small amounts of immunoglobulin G (IgG) and are deficient in complement. During inflammation, there is limited influx of IgG, complement, and neutrophils. Phagocytosis of bacteria by neutrophils may occur, but normal human serum may not opsonize pneumococci and facilitate phagocytosis by alveolar macrophages. In tissues, pneumococci multiply and spread through the lymphatics or bloodstream or, less often, by direct extension from a local site |
7,125 | of infec tion (e.g., sinuses). In bacteremia the severity of disease is related to the number of organisms in the bloodstream and to the integrity of specific host defenses. A poor prognosis correlates with very large numbers of pneumococci and high concentrations of capsular polysaccharide in the blood and CSF. Invasive pneumococcal disease is 30 to 100 fold more prevalent in children with sickle cell disease and other hemoglobinopathies and in children with congenital or surgical asplenia than in the general popu lation. This risk is greatest in infants 2 years old, the age when anti body production to most serotypes is poor. The increased frequency of pneumococcal disease in asplenic persons is related to both deficient opsonization of pneumococci and absence of clearance by the spleen of circulating bacteria. Children with sickle cell disease also have defi cits in the antibody independent properdin (alternative) pathway of complement activation in addition to functional asplenia. Both com plement pathways contribute to antibody independent and antibody dependent opsonophagocytosis of pneumococci. With advancing age (e.g., 5 years), children with sickle cell disease produce anticapsular antibody, augmenting antibody dependent opsonophagocytosis and greatly reducing, but not eliminating, the risk of severe pneumococcal disease. Deficiency of many of the complement components (e.g., C2 and C3) is associated with recurrent pyogenic infection, including S. pneumoniae infection. The efficacy of phagocytosis also is diminished in patients with B and T cell immunodeficiency syndromes (e.g., agammaglobulinemia, severe combined immunodeficiency) or loss of immunoglobulin (e.g., nephrotic syndrome) and is largely caused by a deficiency of opsonic anticapsular antibody. These observations suggest that opsonization of pneumococci depends on the alternative complement pathway in antibody deficient persons and that recovery from pneumococcal disease depends on the development of anticapsu lar antibodies that act as opsonins, enhancing phagocytosis and killing of pneumococci. Children with HIV infection also have high rates of IPI similar to or greater than rates in children with sickle cell disease, although rates of invasive pneumococcal disease decreased after the introduction of highly active antiretroviral therapy (HAART). CLINICAL MANIFESTATIONS The signs and symptoms of pneumococcal infection are related to the anatomic site of disease. Common clinical syndromes include oti tis media (see Chapter 680), sinusitis (see Chapter 429), pneumonia (Fig. 228.1) (see Chapter 449), and sepsis (see Chapter 85). Before rou tine use of PCVs, pneumococci caused 80 of bacteremia episodes in infants 3 36 months old with fever without an identifiable source (i.e., occult bacteremia). Bacteremia may be followed by meningitis (see Chapter 643), osteomyelitis (see Chapter 725), suppurative (sep tic) arthritis (see Chapter 726), endocarditis (see Chapter 486), and, rarely, brain abscess (see Chapter 644). Primary peritonitis (see Chap ter 419.1) may occur in children with peritoneal effusions caused by nephrotic syndrome and other ascites producing conditions. Local complications of infection may occur, causing empyema, pericardi tis, mastoiditis, epidural abscess, periorbital cellulitis, or meningitis. Hemolytic uremic syndrome (see Chapter 533.4) and disseminated intravascular coagulation also occur as rare complications of pneumo coccal infections. Epidemic conjunctivitis caused by nonencapsulated |
7,126 | or encapsulated pneumococci occurs as well. DIAGNOSIS The diagnosis of pneumococcal infection is established by recovery of S. pneumoniae from the site of infection or the bloodsterile body fluid. Although pneumococci may be found in the nose or throat of patients with otitis media, pneumonia, septicemia, or meningitis, cultures of these locations are generally not helpful for diagnosis, because they are not indicative of causation. Blood cultures should be obtained in chil dren with pneumonia, meningitis, endocarditis, arthritis, osteomyeli tis, peritonitis, pericarditis, or gangrenous skin lesions. Because of the implementation of universal vaccination with PCVs, there has been a substantial decrease in the incidence of occult bacteremia, but blood A B Fig. 228.1 Bacterial round pneumonia caused by Streptococcus pneumoniae in 2 yr old child with a 2 day history of cough, high fever, leukocytosis, and back pain. Table 228.1 Children at Increased Risk of Invasive Pneumococcal Infection RISK GROUP CONDITION Immunocompetent children Chronic heart disease Chronic lung disease Chronic kidney disease (excluding dialysis and nephrotic syndrome) Chronic liver disease Diabetes mellitus Cerebrospinal fluid leaks Cochlear implant Children with immunocompromising conditions HIV infection Maintenance dialysis or nephrotic syndrome Congenital or acquired asplenia or splenic dysfunction Congenital or acquired immunodeficiencies Sickle cell disease and other hemoglobinopathies Congenital immunodeficiency Diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasm, leukemia, lymphoma, and Hodgkin disease, or solid organ transplantation Particularly cyanotic congenital heart disease and cardiac failure. Including moderate persistent or severe persistent asthma. Includes humoral or T lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3 and C4 deficiency; and phagocytic disorders (excluding chronic granulomatous disease). Adapted from Kobayashi M, Farrar JI, Gierke R, et al. Use of 15 valent pneumococcal conjugate vaccine among U.S. children: updated recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(4):1174 1181; and Centers for Disease Control and Prevention. ACIP updates: Recommendations for use of 20 valent pneumococcal conjugate vaccine in childrenUnited States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(39):1072. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 228 u Streptococcus pneumoniae (Pneumococcus) 1703 cultures should still be considered in febrile patients with clinical toxic ity or significant leukocytosis. Leukocytosis often is pronounced, with total white blood cell (WBC) counts frequently 15,000L. In severe cases of pneumococcal disease, WBC count may be low. Pneumococci can be identified in body fluids as gram positive, lancet shaped diplococci. Early in the course of pneumococcal men ingitis, many bacteria may be seen in relatively acellular CSF. With methods of continuously monitored blood culture systems, the average time to isolation of pneumococcal organisms is 14 15 hours. Multi plex real time polymerase chain reaction (PCR) assays are specific and more sensitive than culture of CSF and blood, particularly in patients who have recently received antimicrobial therapy. Antigen detection of C polysaccharide in urine may |
7,127 | be useful in adults with pneumococ cal pneumonia but lacks specificity in children who may have positive results with asymptomatic colonization. Antigen immunochromato graphic or PCR assays on pleural fluid are not routinely used but could be considered. TREATMENT Antimicrobial resistance among S. pneumoniae continues to be a serious healthcare concern, especially for the widely used lactams, macrolides, and fluoroquinolones. Serotypes 6A, 6B, 9V, 14, 19A, 19F, and 23F are the most common serotypes associated with resistance to penicillin. Consequently, the introduction of the 7 and 13 valent pneumococcal conjugate vaccines (PCV7 and PCV13) has altered antimicrobial resistance patterns. By 2014, only 5 of pneumococ cal strains were penicillin nonsusceptible. However, pneumococcal serotypes 11A, 35F, and 35B have contributed to steady erosion of pneumococcal antibiotic susceptibility to penicillin, third generation cephalosporins, fluoroquinolones, and carbapenems. Resistance in pneumococci to penicillin and cephalosporins is defined by the minimum inhibitory concentration (MIC) and clinical syn drome. Pneumococci are considered susceptible, intermediate, or resis tant to various antibacterial agents based on specific MIC breakpoints. For patients with pneumococcal meningitis, penicillin susceptible strains have MICs 0.06 gmL, and penicillin resistant strains have MICs 0.12 gmL. For patients with nonmeningeal pneumococcal infections, breakpoints are higher; in particular, penicillin susceptible strains have MICs 2 gmL, and penicillin resistant strains have MICs 8 gmL. For patients with meningitis, ceftriaxone susceptible strains have MICs 0.5 gmL, and resistant strains have MICs 2.0 gmL. For patients with nonmeningeal pneumococcal disease, breakpoints are higher, and ceftriaxone susceptible strains have MICs 1 gmL, and resistant strains have MICs 4 gmL. In cases when pneumococ cus is resistant to erythromycin but sensitive to clindamycin, a D test should be performed to determine whether clindamycin resistance can be induced; if the D test is positive, clindamycin should not be used to complete treatment of the patient. More than 30 of pneumococcal isolates are resistant to trimethoprim sulfamethoxazole (TMP SMX); levofloxacin resistance is low but has also been reported. All isolates from children with severe infections should be tested for antibiotic sus ceptibility, given widespread pneumococcal MDR strains. Resistance to vancomycin has not been seen at this time, but vancomycin tolerant pneumococci that are killed at a slower rate have been reported, and these tolerant pneumococci may be associated with a worse clini cal outcome. Linezolid is an oxazolidinone antibacterial with activity against MDR gram positive organisms, including pneumococcus, and has been used in the treatment of MDR pneumococcal pneumonia, meningitis, and severe otitis media. Despite early favorable studies, use of this drug is limited by myelosuppression and high cost, and linezolid resistance in pneumococcus is reported. Children 1 month old with suspected pneumococcal meningitis should be treated with combination therapy using vancomycin (60 mgkg24 hr divided every 68 hr IV) and high dose ceftriaxone (100 mgkg24 hr divided every 12 hr IV). Proven pneumococcal meningitis can be treated with penicillin alone or ceftriaxone alone if the isolate is penicillin susceptible. If the organism is nonsusceptible (i.e., intermedi ate or full resistance) to penicillin but |
7,128 | susceptible to ceftriaxone, pneu mococcal meningitis can be treated with ceftriaxone alone. However, if the organism is nonsusceptible to penicillin and to ceftriaxone, pneu mococcal meningitis should be treated with combination vancomycin plus ceftriaxone, not with vancomycin alone, and consideration should be given to the addition of rifampin. Some experts recommend use of corticosteroids in pneumococcal meningitis early in the course of disease, but data demonstrating clear benefit in children are lacking. The 2011 Infectious Diseases Society of America guidelines rec ommend amoxicillin as first line therapy for previously healthy, appropriately immunized infants and preschool children with mild to moderate, uncomplicated community acquired pneumonia. Ampi cillin or penicillin G may be administered to the fully immunized infant or school age child admitted to a hospital with uncomplicated community acquired pneumonia when local epidemiologic data doc ument lack of substantial high level penicillin resistance for invasive S. pneumoniae. Empirical therapy with parenteral ceftriaxone should be prescribed for hospitalized infants and children who are not fully immunized, in regions where local epidemiology of invasive pneu mococcal strains documents widespread penicillin resistance, or for infants and children with life threatening infection, including those with empyema. Non lactam agents, such as vancomycin, have not been shown to be more effective than ceftriaxone in the treatment of pneumococcal pneumonia, given the degree of drug resistance cur rently seen in the United States. Higher doses of amoxicillin (80 90 mgkg24 hr) have been successful in the treatment of otitis media caused by relatively penicillin resistant pneumococcal strains. If the patient has failed initial antibiotic therapy, alternative agents should be active against penicillin nonsusceptible pneumococcus as well as lactamase producing Haemophilus influenzae and Moraxella catarrhalis. These include high dose oral amoxicillin clavulanate (in the 14:1 formula tion to reduce the risk of diarrhea), oral cefdinir, cefpodoxime, or cefuroxime or a 3 day course of daily intramuscular (IM) ceftriaxone if patients fail oral therapy. Empirical treatment of pneumococcal disease should be based on knowledge of susceptibility patterns in specific communities. For individuals with a nontype I allergic reaction to penicil lin, cephalosporins (standard dosing) can be used. For type I aller gic reactions (immediate, anaphylactic) to lactam antibiotics, clindamycin and levofloxacin are preferred alternatives depending on the site of infection (e.g., clindamycin may be effective for pneu mococcal infections other than meningitis). TMP SMX may also be considered for susceptible strains but should be avoided in the absence of susceptibility results. Erythromycin and related macro lides (e.g., azithromycin, clarithromycin) should be avoided given high rates of resistance. PROGNOSIS Prognosis depends on the integrity of host defenses, virulence and numbers of the infecting organism, age of the host, site and extent of the infection, and adequacy of treatment. The mortality rate for pneu mococcal meningitis is approximately 10 in most studies. Pneumo coccal meningitis results in sensorineural hearing loss in 2030 of patients and can cause other serious neurologic sequelae, including paralysis, epilepsy, blindness, and intellectual deficits. Invasive pneumococcal disease is associated with various primary immunodeficiency states, leading some |
7,129 | to suggest screening for immune defects in all or some patients with invasive diseases. In the absence of other risk factors (see Table 228.1), screening for immune defects (complement, B cell, toll like receptor, asplenia) may be indi cated for patients with recurrent invasive disease, infection by a sero type covered by vaccination in a fully vaccinated child, children 2 years of age, or in some centers all patients with invasive disease. PREVENTION The highly successful PCVs have resulted in a marked decrease in IPIs in children. PCVs provoke protective antibody responses in 90 of infants given these vaccines at 2, 4, and 6 months of age, and greatly enhanced responses (e.g., immunologic memory) are apparent after vaccine doses given at 12 15 months of age (Table 228.2). In a large Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1704 Part XV u Infectious Diseases clinical trial, PCV7 was shown to reduce invasive disease caused by vaccine serotypes by up to 97 and to reduce invasive disease caused by all serotypes, including serotypes not in the vaccine, by 89. Children who received PCV7 had 7 fewer episodes of acute otitis media and underwent 20 fewer tympanostomy tube placements than unvaccinated children. After PCV13, a 98 reduction in IPIs caused by vaccine serotypes has been seen, particularly in children 5 years old. The number of pneumococcal isolates and percentage of isolates with high level penicillin resistance from cultures taken from children with otitis media or mastoiditis for clinical indica tions decreased, largely related to decreases in serotype 19A. Rates of hospitalization for pneumococcal pneumonia among U.S. children decreased after PCV13 introduction. The number of cases of pneu mococcal meningitis in children remain unchanged, but the propor tion of PCV13 serotypes has decreased significantly. In addition, pneumococcal conjugate vaccines significantly reduce nasopharyn geal carriage of vaccine serotypes. PCVs have significantly decreased rates of invasive pneumococcal disease in children with sickle cell disease, and studies suggest substantial protection for HIV infected children and splenectomized adults. Adverse events after the admin istration of PCV have included local swelling and redness and slightly increased rates of fever when used in conjunction with other child hood vaccines. Currently, the predominant non PCV13 serotypes are 22F, 12F, 33F, 24F, 15C, 15B, 23B, 10A, 11A, 35B, 35F, and 38. Serotypes 12F and 24F have high invasive disease potential, with the latter responsible for a rebound in incidence of pneumococcal meningitis since 2015. Sero types 11A, 35F, and 35B in nasopharyngeal and middle ear samples are increasingly resistant to antibiotics. PCV15 or PCV20, which have replaced PCV13, do not contain serotypes 24 or 35, but PCV20 includes 11A and 12F. Immunologic responsiveness and efficacy after administration of pneumococcal polysaccharide vaccines (PPSV23) is unpredictable in children 2 years old. PPSV23 contains purified polysaccharide of 23 pneumococcal serotypes responsible for 95 of invasive disease. The |
7,130 | clinical efficacy of PPSV23 is controversial, and studies have yielded conflicting results. Immunization with PCV15 or PCV20 is recommended for all infants on a schedule for primary immunization, in previously unvac cinated infants, and for transition for those partially vaccinated (Table 228.3). High risk children 2 years old, such as those with asplenia, sickle cell disease, some types of immune deficiency (e.g., antibody deficiencies), HIV infection, cochlear implant, CSF leak, diabetes mellitus, and chronic lung (including moderate persistent or severe persistent asthma), heart, liver, or kidney disease (including nephrotic syndrome) or immunocompromising conditions, such as asplenia, sickle cell disease, some types of immune deficiency (e.g., antibody deficiencies), HIV infection, etc., may also benefit from PPSV23 administered after 2 years of age after priming with the scheduled doses of PCV15 or 20. Thus it is recommended that children 2 years of age and older with these conditions receive supplemental vacci nation with PPSV23. A second dose of PPSV23 is recommended 5 years after the first dose of PPSV23 for persons 2 years old who have immunocompromising conditions including sickle cell disease and functional or anatomic asplenia. Additional doses of PPSV23 are not required, however, if the patient has ever received PCV20. Additional Table 228.2 Comparison of Pneumococcal Vaccines Licensed in United States CARRIER PROTEIN PNEUMOCOCCAL CAPSULAR POLYSACCHARIDES MANUFACTURER Diphtheria CRM197 protein 4, 6B, 9V, 14, 18C, 19F, 23F Wyeth Lederle (PCV7, Prevnar) Diphtheria CRM197 protein 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F Wyeth Lederle (PCV13, Prevnar 13) Diphtheria CRM197 protein 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 32F Merck Sharp and Dohme (PCV15, Prevnar 15) Diphtheria CRM197 protein 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, 32F Merck Sharp and Dohme (PCV20, Prevnar 20) None 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F Sanofi Pasteur MSD (PPSV23, Pneumovax II) PCV7 serotypes in bold. Table 228.3 Recommended Routine Vaccination Schedule for 15 or 20 Valent Pneumococcal Conjugate Vaccine (PCV15 or 20) Among Infants and Children Who Have Not Received Previous Doses of Conjugate Vaccines, by Age at First DoseUnited States, 2010 AGE AT FIRST DOSE (MO) PRIMARY PCV15 OR PCV20 SERIES PCV15 OR PCV20 BOOSTER DOSE 2 6 3 doses 1 dose at age 12 15 mo 7 11 2 doses 1 dose at age 12 15 mo 12 23 2 doses 24 59 (healthy children) 1 dose 24 71 (children with certain chronic diseases or immunocompromising conditions) 2 doses The minimum interval between doses is 8 wk except for children vaccinated at age 12 mo, for whom the minimum interval between doses is 4 wk. The minimum age for administration of the first dose is 6 wk. Given at least 8 wk after the previous dose. See Table 228.1. If two doses of PCV15 are used, then 1 dose of PPSV23 vaccine |
7,131 | is given 8 weeks later. Adapted from Kobayashi M, Farrar JI, Gierke R, et al. Use of 15 valent pneumococcal conjugate vaccine among U.S. children: updated recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(4):1174 1181; and Centers for Disease Control and Prevention. ACIP updates: Recommendations for use of 20 valent pneumococcal conjugate vaccine in childrenUnited States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(39):1072. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 228 u Streptococcus pneumoniae (Pneumococcus) 1705 recommendations have been made for at risk children 6 18 years old (Table 228.4). Immunization with pneumococcal vaccines also may prevent pneu mococcal disease caused by nonvaccine serotypes that are serotypi cally related to a vaccine strain. However, because current vaccines do not eliminate all pneumococcal invasive infections, penicillin prophylaxis is recommended for children at high risk of invasive pneumococcal disease, including children with asplenia or sickle cell disease. Oral penicillin V potassium (125 mg twice daily for children 3 years old; 250 mg twice daily for children 3 years old) decreases the incidence of pneumococcal sepsis in children with sickle cell dis ease. Once monthly IM benzathine penicillin G (600,000 units every 3 4 weeks for children weighing 60 lb; 1,200,000 units every 3 4 weeks for children weighing 60 lb) may also provide prophylaxis. Erythromycin may be used in children with penicillin allergy, but its efficacy is unproven. Prophylaxis in sickle cell disease has been safely discontinued after the fifth birthday in children who have received all recommended pneumococcal vaccine doses and who had not experienced invasive pneumococcal disease. Prophylaxis is often administered for at least 2 years after splenectomy or up to 5 years of age. Efficacy in children 5 years old and adolescents is unproven. If oral antibiotic prophylaxis is used, strict compliance must be encouraged. Given the rapid emergence of penicillin resistant pneumococci, especially in children receiving long term, low dose therapy, prophy laxis cannot be relied on to prevent disease. High risk children with fever should be promptly evaluated and treated regardless of vaccina tion or penicillin prophylaxis history. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. TABLE 228.4 CDC Advisory Committee on Immunization Practices Recommendations for Use of PCV in Children, June 2023 AGE AND RISK GROUP RECOMMENDATIONS Children age 24 mo Use of either PCV15 or PCV20 is recommended for all children age 223 mo according to previously recommended PCV dosing and schedules. If only PCV13 is available when the child is scheduled to receive a PCV, PCV13 may be given as previously recommended. If a child started the PCV series with PCV13, the child may complete the series with PCV15 or PCV20 without giving additional doses; the PCV series does not need to be restarted. For children who have received all recommended dosing and schedules with PCV13 or PCV15, |
7,132 | a supplemental dose of PCV20 is not indicated. Healthy children age 2459 mo with an incomplete PCV vaccination status A single dose of either PCV15 or PCV20 is recommended. A supplemental dose of PCV15 or PCV20 is not indicated for healthy children who have received 4 doses of PCV13 or who completed another age appropriate PCV13 schedule. Children age 2471 mo with any risk condition Use either PCV15 or PCV20 according to previously recommended PCV dosing and schedules. If only PCV13 is available when the child is scheduled to receive a PCV, PCV13 may be given as previously recommended. Children age 218 yr with any risk condition who completed a recommended PCV series before age 6 yr Completed series includes 1 dose of PCV20: No additional doses of any pneumococcal vaccine are indicated. This recommendation may be updated as additional data become available. Completed series using PCV13 or PCV15 (no PCV20): Either a single dose of PCV20 or PPSV23 using previously recommended dosing and schedules is recommended to complete the recommended vaccine series. Children age 618 yr with any risk condition with no previous PCV13, PCV15, or PCV20 vaccination For children age 618 yr with any risk condition who have not received any dose of PCV (PCV13, PCV15, or PCV20) a single dose of either PCV15 or PCV20 is recommended. If the child has previously received PCV7 andor PPSV23, a single dose of either PCV15 or PCV20 is recommended 8 wk after the most recent dose of pneumococcal vaccination. PCV15 should be followed by a dose of PPSV23 if not previously given. PCV20 does not need to be followed by a dose of PPSV23. Children who have received HSCT Children who received HSCT are recommended to receive three doses of PCV20, 4 wk apart starting 36 mo after HSCT. A fourth PCV20 dose is recommended 6 mo after the third PCV20 dose, or 12 mo after HSCT, whichever is later. HSCT recipients who have started their pneumococcal vaccine series with PCV13 or PCV15 may complete their 4 dose pneumococcal vaccine series with PCV20 without giving extra doses. If PCV20 is not available, three doses of PCV15, 4 wk apart starting 36 mo after HSCT, followed by a dose of PPSV23 12 mo after HSCT may be given. For patients with chronic graft versus host disease who are receiving PCV15, a fourth dose of PCV15 can be given in place of PPSV23 since these children are less likely to respond to PPSV23. A patients clinical team is best positioned to determine the appropriate timing of vaccination. Routine use of PCV is not recommended for healthy children age 5 yr. Risk conditions include: cerebrospinal fluid leak; chronic heart disease; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persistent asthma); cochlear implant; diabetes mellitus; immunocompromising conditions (on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases |
7,133 | and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; and sickle cell disease or other with these conditions who received PCV13 or PCV15 are also recommended to receive 23 valent pneumococcal polysaccharide vaccine. PCV, pneumococcal conjugate vaccine; PCV13, 13 valent PCV; PCV15, 15 valent PCV; PCV20, 20 valent PCV; PPSV23, 23 valent pneumococcal polysaccharide vaccine; HSCT, hematopoietic stem cell transplant. From Centers for Disease Control and Prevention. ACIP updates: Recommendations for use of 20 valent pneumococcal conjugate vaccine in childrenUnited States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(39):1072. (Table 1). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1706 Part XV u Infectious Diseases Group A Streptococcus (GAS), also known as Streptococcus pyogenes, is a common cause of infections of the upper respiratory tract (pharyn gitis) and the skin (impetigo, pyoderma) in children. Less frequently, GAS causes perianal cellulitis, vaginitis, septicemia, pneumonia, empy ema, endocarditis, pericarditis, osteomyelitis, suppurative arthritis, myositis, cellulitis, omphalitis, and other infections. This organism also causes distinct clinical entities (scarlet fever and erysipelas), as well as streptococcal toxic shock syndrome and monomicrobial necrotizing fasciitis. GAS is also the cause of at least two potentially serious non suppurative complications: rheumatic fever (see Chapters 229.1 and 487) and acute glomerulonephritis (see Chapter 559.4). ETIOLOGY Group A streptococci are gram positive, coccoid shaped bacteria that tend to grow in chains. Streptococci are broadly classified by their hemolytic activity on mammalian (typically sheep) red blood cells. The zone of complete hemolysis that surrounds colonies grown on blood agar distinguishes hemolytic (complete hemolysis) from hemolytic (green or partial hemolysis) and (nonhemolytic) spe cies. The hemolytic streptococci can be divided into groups by a group specific polysaccharide (Lancefield C carbohydrate) located in the bacterial cell wall. More than 20 serologic groups are identified, designated by the letters A through V, although only A through D are medically important. Serologic grouping by the Lancefield method is precise, but group A organisms can be identified more readily by any of a number of latex agglutination, coagglutination, molecular assays or enzyme immunoassays. Group A strains can also be distinguished from other groups by differences in sensitivity to bacitracin, as other groups are generally resistant to this antibiotic. GAS can be subdivided into at least 220 serotypes on the basis of the M protein antigen, which is located on the cell surface and in fimbriae that project from the outer surface of the cell. Currently, a molecular approach to M typing GAS isolates using the polymerase chain reac tion (PCR) is based on sequencing the terminal portion of the emm gene of GAS that encodes the M protein. This emm typing system cor relates with known serotypes and emm types. The emm types can be grouped into emm clusters that share structural and binding proper ties. It is |
7,134 | important to note that immunity is largely based on type specific opsonic anti M antibody. Memm typing is valuable for epidemiologic studies; specific GAS diseases tend to be associated with certain M types. Types 1, 12, 28, 4, 3, and 2 (in that order) are the most common causes of uncomplicated streptococcal pharyngitis in the United States. M types usually asso ciated with pharyngitis rarely cause skin infections, and the M types associated with skin infections rarely cause pharyngitis. A few pharyn geal GAS strains (e.g., M type 12) are associated with glomerulone phritis, but many more skin GAS strains (e.g., M types 49, 55, 57, and 60) are considered nephritogenic. Several pharyngeal serotypes (e.g., M types 1, 3, 5, 6, 18, and 29), but no proven skin strains, are associated with acute rheumatic fever in North America. EPIDEMIOLOGY Humans are the natural reservoir for GAS. These bacteria are highly communicable and can cause disease in normal individuals of all ages who do not have type specific immunity against the particular serotype involved. Disease in neonates is uncommon in developed countries, probably because of maternally acquired antibody. The incidence of pharyngitis is highest in children 5 15 years of age, especially in young school age children. Acute streptococcal phar yngitis is uncommon in children younger than 3 years, and testing is generally not recommended. These infections are most common in the northern regions of the United States, especially during win ter and early spring. Children with untreated acute pharyngitis spread GAS by salivary droplets and nasal discharge. Transmission is favored by close proximity; therefore schools, military barracks, and homes are important environments for spread. GAS has the potential to be an important upper respiratory tract pathogen and to produce outbreaks of disease in the daycare setting. Foods contaminated by GAS occasionally cause explosive outbreaks of pharyngotonsillitis. The incubation period for pharyngitis is usually 2 5 days. Children are usually no longer infectious within 24 hours of starting appro priate antibiotic therapy. Chronic pharyngeal carriers of GAS rarely transmit this organism to others. Streptococcal pyoderma (impetigo, pyoderma) occurs most fre quently during the summer in temperate climates, or year round in warmer climates, when the skin is exposed and abrasions and insect bites are more likely to occur (see Chapter 727). Colonization of healthy skin by GAS usually precedes the development of impetigo. Because GAS cannot penetrate intact skin, impetigo and other skin infections usually occur at the site of open lesions (insect bites, trau matic wounds, burns). Although impetigo serotypes may colonize the throat, spread is usually from skin to skin, not via the respiratory tract. Fingernails and the perianal region can harbor GAS and play a role in disseminating impetigo. Multiple cases of impetigo in the same family are common. Both impetigo and pharyngitis are more likely to occur among children living in crowded homes and in poor hygienic circumstances. The incidence of severe invasive GAS infections, including bac teremia, pneumonia and empyema, osteomyelitis, septic arthritis, retropharyngeal abscess, lymphadenitis, |
7,135 | streptococcal toxic shock syndrome, scarlet fever, and necrotizing fasciitis, has increased in recent decades. The incidence appears to be highest in very young and elderly persons. Before the routine use of varicella vaccine, varicella was the most commonly identified risk factor for invasive GAS infection in children. Other risk factors include diabetes mel litus, HIV infection, intravenous drug use, and chronic pulmonary or chronic cardiac disease. The portal of entry is unknown in almost 50 of cases of severe invasive GAS infection; in most cases, it is believed to be skin or, less often, mucous membranes. Severe invasive disease rarely follows clinically apparent GAS pharyngitis. Invasive GAS disease was reported in many childrens hospitals in multiple countries during the COVID 19 pandemic. It is unclear why this has happened, but masking, social distancing, and school closures may have reduced exposure to common viral pathogens or colonization with GAS, resulting in more severe infection when mask and social distancing have stopped and schools have reopened. Co infection with respiratory viruses (respiratory syncytial virus RSV, other) may predispose to more severe infection. PATHOGENESIS The virulence of GAS depends primarily on the M protein, and strains rich in M protein resist phagocytosis in fresh human blood, whereas M negative strains do not. M protein stimulates the production of pro tective opsonophagocytic antibodies that are type specific, protecting against infection with a homologous M type but much less so against other M types. Therefore multiple GAS infections attributable to vari ous M types are common during childhood and adolescence. By adult life, individuals are probably immune to many of the common M types in the environment. GAS produces a large variety of extracellular enzymes and toxins, including erythrogenic toxins, known as streptococcal pyrogenic exo toxins. Streptococcal pyrogenic exotoxins A, C, and SSA, alone or in combination, are responsible for the rash of scarlet fever and are elab orated by streptococci that contain a particular bacteriophage. These exotoxins stimulate the formation of specific antitoxin antibodies that provide immunity against the scarlatiniform rash but not against other streptococcal infections. Pathogenic variants in genes that are promot ers of several virulence genes, including pyrogenic exotoxins, as well as several newly discovered exotoxins, appear to be involved in the Chapter 229 Group A Streptococcus Stanford T. Shulman and Ami B. Patel Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 229 u Group A Streptococcus 1707 pathogenesis of invasive GAS disease, including streptococcal toxic shock syndrome. The importance of other streptococcal toxins and enzymes in human disease is not yet established. Many of these extracellular substances are antigenic and stimulate antibody production after an infection. However, these antibodies do not confer immunity. The measurement of select toxins and antibodies is useful for establishing evidence of a recent streptococcal infection to aid in the diagnosis of postinfectious illnesses. Tests for antibodies against streptolysin |
7,136 | O (antistreptolysin O) and DNase B (antiDNase B) are the most frequently used antibody determinations. CLINICAL MANIFESTATIONS The most common infections caused by GAS involve the respiratory tract and the skin and soft tissues. Respiratory Tract Infections GAS is an important cause of acute pharyngitis (see Chapter 430) and pneumonia, often with empyema (see Chapter 449). Scarlet Fever Scarlet fever is GAS pharyngitis associated with a characteristic rash, which is caused by an infection with pyrogenic exotoxin (erythrogenic toxin)producing GAS in individuals who do not have antitoxin anti bodies. It is now encountered less often and is less virulent than in the past, but the incidence is cyclic, depending on the prevalence of toxin producing strains and the immune status of the population. The modes of transmission, age distribution, and other epidemiologic features are otherwise similar to those for GAS pharyngitis. The scarlet fever rash appears within 24 48 hours after the onset of symptoms, although it may appear with the first signs of illness (Fig. 229.1A). It often begins around the neck and spreads over the trunk and extremities. The rash is a diffuse, finely papular, erythem atous eruption producing bright red discoloration of the skin, which blanches on pressure. It is often accentuated in the creases of the elbows, axillae, and groin (Pastia lines). The skin has a goose pimple appearance and feels rough. The cheeks are often erythematous with perioral pallor. After 3 4 days, the rash begins to fade and is fol lowed by desquamation, initially on the face, progressing caudally, and often resembling a mild sunburn. Occasionally, sheetlike des quamation may occur around the free margins of the fingernails, the palms, and the soles. Examination of the pharynx of a patient with scarlet fever reveals essentially the same findings as with GAS pharyngitis. In addition, the tongue is usually coated and the papil lae are swollen (see Fig. 229.1B). After desquamation, the reddened papillae are prominent, giving the tongue a strawberry appearance (see Fig. 229.1C). Typical scarlet fever is not difficult to diagnose; the milder form with equivocal pharyngeal findings can be confused with viral exanthems, Kawasaki disease, and drug eruptions. Staphylococcal infections are occasionally associated with a scarlatiniform rash. A history of recent exposure to a GAS infection is helpful. Identification of GAS in the pharynx confirms the diagnosis. Impetigo Impetigo (or pyoderma) has traditionally been classified into two clinical forms: bullous and nonbullous (see Chapter 706.1). Nonbul lous impetigo is the more common form and is a superficial infection of the skin that appears first as a discrete papulovesicular lesion sur rounded by a localized area of redness. The vesicles rapidly become purulent and covered with a thick, confluent, amber colored crust that gives the appearance of having been stuck onto the skin. The lesions may occur anywhere but are most common on the face and extremi ties. If untreated, nonbullous impetigo is a mild but chronic illness, often spreading to other parts of the body, but occasionally self limited. Regional lymphadenitis is |
7,137 | common. Nonbullous impetigo is gener ally not accompanied by fever or other systemic signs or symptoms. Impetiginized excoriations around the nares are seen with active GAS infections of the nasopharynx, particularly in young children. How ever, impetigo is rarely associated with overt streptococcal infection of the upper respiratory tract. Bullous impetigo is less common and occurs most often in neo nates and young infants. It is characterized by flaccid, transpar ent bullae usually 3 cm in diameter on previously untraumatized skin. The usual distribution involves the face, buttocks, trunk, and perineum. Although Staphylococcus aureus has traditionally been accepted as the sole pathogen responsible for bullous impetigo, there has been confusion about the organisms responsible for nonbullous impetigo. In most episodes of nonbullous impetigo, either GAS or S. aureus (or both) is isolated. Earlier investigations suggested that GAS was the causative agent in most cases of nonbullous impetigo and that S. aureus was only a secondary invader. However, S. aureus has emerged as the causative agent in most cases of nonbullous impetigo. Culture of the lesions is the only way to distinguish nonbullous impetigo caused by S. aureus from that caused by GAS. Erysipelas Erysipelas is a relatively rare acute GAS infection involving the deeper layers of the skin and the underlying connective tissue. The skin in the affected area is edematous, highly erythematous, and very tender. The erythema associated with erysipelas is very bright, which differentiates it from the dusky appearance of necrotizing fasciitis. Superficial blebs may be present. The most characteristic finding is a sharply defined, slightly elevated border. At times, reddish streaks of lymphangitis project out from the margins of the lesion. The onset is abrupt, and signs and symptoms of a systemic infection, such as high fever and sepsis, are often present. Cultures obtained by needle aspirate of the advancing margin of the inflamed area often reveal the causative agent. Perianal Dermatitis Perianal dermatitis, also called perianal cellulitis or perianal strep tococcal disease, is a distinct clinical entity characterized by well demarcated, perianal erythema associated with anal pruritus, painful defecation, and occasionally blood streaked stools. Most children are 2 7 years old (range: 18 days 12 years). Physical examination reveals flat, pink to beefy red perianal erythema with sharp margins extending A B C Fig. 229.1 Scarlet fever. A, Punctate, erythematous rash (second day). B, White strawberry tongue (first day). C, Red strawberry tongue (third day). (Courtesy Dr. Franklin H. Top, Professor and Head of the Department of Hygiene and Preventive Medicine, State University of Iowa, College of Medicine, Iowa City, IA; and Parke, Davis Companys Therapeutic Notes. From Gershon AA, Hotez PJ, Katz SL. Krugmans Infectious Diseases of Children, 11th ed. Philadelphia: Mosby; 2004, Plate 53.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1708 Part XV u Infectious Diseases as far as 2 cm from the anus. Erythema may |
7,138 | involve the vulva and vagina. Lesions may be very tender and, particularly when chronic, may fissure and bleed. Systemic symptoms and fever are unusual. Cul ture or a rapid streptococcal test of a perianal swab will yield GAS or detect antigen. Vaginitis GAS is a common cause of vaginitis in prepubertal girls (see Chapter 586). Patients usually have a serous discharge with marked erythema and irritation of the vulvar area, accompanied by discomfort in walk ing and in urination. Severe Invasive Disease Invasive GAS infection is defined by isolation of GAS from a normally sterile body site and includes three overlapping clinical syndromes. GAS toxic shock syndrome (TSS) is differentiated from other types of invasive GAS infections by the presence of shock and multiorgan system dysfunction early in the course of the infection (Table 229.1). The second syndrome is GAS necrotizing fasciitis, characterized by extensive local necrosis of subcutaneous soft tissues and skin. The third syndrome is the group of focal and systemic infections that do not meet the criteria for TSS or necrotizing fasciitis and includes bacte remia with sepsis with no identified focus, meningitis, pneumonia and empyema, peritonitis, puerperal sepsis, osteomyelitis, suppurative arthritis, myositis, and surgical wound and other infections. GAS TSS, necrotizing fasciitis, and focal and systemic infections can be present in any combination. The pathogenic mechanisms responsible for severe, invasive GAS infections, including streptococcal TSS and necrotizing fasciitis, have yet to be defined completely, but an association with streptococcal pyrogenic exotoxins is strongly suspected. At least two of the three original streptococcal pyrogenic exotoxins (A and C) and potentially other as yet unidentified toxins produced by GAS act as superantigens, which stimulate intense activation and proliferation of T lymphocytes and macrophages, resulting in the production of large quantities of proinflammatory cytokines. These cytokines are capable of inducing shock and tissue injury and appear to mediate many of the clinical manifestations of severe, invasive GAS infections. DIAGNOSIS OF GAS PHARYNGITIS When deciding whether to perform a diagnostic test on a patient presenting with acute pharyngitis, the clinical and epidemiologic findings should be considered. A history of close contact with a well documented case of GAS pharyngitis is helpful, as is an awareness of a high prevalence of GAS infections in the community. The signs and symptoms of streptococcal and nonstreptococcal pharyngitis over lap too broadly to allow the requisite diagnostic precision on clinical grounds alone. The clinical diagnosis of GAS pharyngitis cannot be made with reasonable accuracy even by the most experienced physi cians, and laboratory confirmation is required, except for patients with overt viral signs and symptoms (e.g., rhinorrhea, cough, mouth ulcers, hoarseness), who generally do not need a GAS diagnostic test per formed, as GAS is highly unlikely. Culture of a throat swab on a sheep blood agar plate is effective for documenting the presence of GAS and for confirming the clinical diag nosis of acute GAS pharyngitis. When performed correctly, a single throat swab has a sensitivity of 9095 for detecting the presence of |
7,139 | GAS in the pharynx. The significant disadvantage of culturing a throat swab on a blood agar plate is the delay (overnight or longer) in obtaining the culture result. Streptococcal rapid antigen detection tests are available for the identification of GAS directly from throat swabs. Their advantage over culture is the speed in providing results, often 10 15 minutes. Rapid identification and treatment of patients with streptococcal pharyngitis can reduce the risk for spread of GAS, allowing the patient to return to school or work sooner, and can reduce the acute morbidity of this illness. Almost all currently available rapid antigen detection tests have excellent specificity of 95 compared with blood agar plate cultures. False positive test results are quite unusual, and therefore therapeutic decisions can be made with confidence on the basis of a positive test result. Unfortunately, the sensitivity of most of these tests is 7090 when compared with blood agar plate culture. Therefore a negative rapid test does not completely exclude the presence of GAS, and a confirmatory throat culture should be performed in children and adolescents, but not necessarily in adults, who are at exceptionally low risk for developing acute rheumatic fever. Definitive studies are not available to determine whether some rapid antigen detection tests are significantly more sensitive than others or whether any of these tests is sensitive enough to be used routinely in children and ado lescents without throat culture confirmation of negative test results. Some experts believe that physicians who use a rapid antigen detec tion test without culture backup should compare the results with that specific test to those of throat cultures to confirm adequate sensitivity in their practice. In point of care settings and laboratories testing for GAS phar yngitis, culture methods are being replaced by rapid antigen and molecular assays. These molecular assays include PCR methods and nucleic acid amplification tests using isothermal loop amplification. Some of these methods have been reported to have a sensitivity of up to 100 and specificity of 96 compared to culture or PCR. This very high sensitivity may lead to higher numbers of positive results, which in turn may contribute to identification of more patients with asymptomatic GAS colonization and unnecessary antibiotic therapy. Therefore it is important that the appropriate clinical context to per form these highly sensitive tests be considered. However, the benefit of faster results, sometimes 10 minutes, which ensures more expe dited initiation of appropriate antibiotic therapy for patients with GAS pharyngitis, may be of value. GAS infection can also be diagnosed retrospectively on the basis of an elevated or increasing streptococcal antibody titer. The antistrep tolysin O assay is the streptococcal antibody test most often used. The test is not specific for group A infection because streptolysin O also is produced by groups C and G streptococci. The antistreptolysin O response can be feeble after streptococcal skin infection. In contrast, the antiDNase B responses are generally present after either skin or throat infections. A significant antibody increase is usually defined as |
7,140 | an increase in titer of two or more dilution increments ( fourfold rise) between the acute phase and convalescent phase specimens, regard less of the actual height of the antibody titer. Physicians frequently misinterpret streptococcal antibody titers because of a failure to appre ciate that the normal levels of these antibodies are substantially higher among school age children than adults. Both the traditional anti streptolysin O and the antiDNase B tests are neutralization assays. Newer tests use latex agglutination or nephelometric assays. Unfortu nately, these newer tests often have not been well standardized against the traditional neutralization assays. Physicians should be aware of these potential problems when interpreting the results of streptococcal serologic testing. Table 229.1 Definition of Streptococcal Toxic Shock Syndrome CLINICAL CRITERIA Hypotension plus two or more of the following: Renal impairment Coagulopathy Hepatic involvement Adult respiratory distress syndrome Generalized erythematous macular rash Soft tissue necrosis DEFINITE CASE Clinical criteria plus group A Streptococcus from a normally sterile site PROBABLE CASE Clinical criteria plus group A Streptococcus from a nonsterile site Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 229 u Group A Streptococcus 1709 Differential Diagnosis Viruses are the most common cause of acute pharyngitis in children. Respiratory viruses such as influenza virus, parainfluenza virus, rhino virus, coronavirus, adenovirus, and RSV are frequent causes of acute pharyngitis. Other viral causes of acute pharyngitis include enterovi ruses and herpes simplex virus. Epstein Barr virus is a frequent cause of acute pharyngitis that is often accompanied by other clinical find ings of infectious mononucleosis (e.g., splenomegaly, generalized lymphadenopathy). Systemic infections with other viral agents, includ ing cytomegalovirus, rubella virus, measles virus, and HIV, may be associated with acute pharyngitis. GAS is by far the most common cause of bacterial pharyngitis, accounting for 1530 of cases of acute pharyngitis in children and a lower proportion in adults. Groups C and G hemolytic streptococ cus also cause acute pharyngitis, typically in teens and young adults (see Chapter 231). Arcanobacterium haemolyticum and Fusobacte rium necrophorum are additional, less common causes. Neisseria gon orrhoeae can occasionally cause acute pharyngitis in sexually active adolescents and adults. Other bacteria, such as Francisella tularensis and Yersinia enterocolitica, as well as mixed infections with anaer obic bacteria (Vincent angina), are very rare causes of acute phar yngitis. Chlamydia pneumoniae and Mycoplasma pneumoniae have been implicated as causes of acute pharyngitis, particularly in adults. Corynebacterium diphtheriae is a serious cause of pharyngitis but is very rare in areas with universal immunization (see Chapter 233). Although other bacteria (e.g., S. aureus, Haemophilus influenzae, Streptococcus pneumoniae) are frequently cultured from the throats of children with acute pharyngitis, their etiologic role in pharyngitis has not been established, because they are often isolated from healthy children. GAS pharyngitis is the only common cause of acute pharyngitis for which antibiotic therapy is definitely indicated. Therefore when |
7,141 | con fronted with a patient with acute pharyngitis, the clinical decision that usually needs to be made is whether or not the pharyngitis is attribut able to GAS. TREATMENT OF GAS PHARYNGITIS Timely antibiotic therapy for patients with GAS pharyngitis can prevent acute rheumatic fever (RF), shorten the clinical course of the illness, reduce transmission of the infection to others, and prevent suppurative complications. For the patient with classic scarlet fever, antibiotic ther apy should be started immediately, but for the majority of patients, who present with much less distinctive findings, treatment should be withheld until there is laboratory confirmation by throat culture, molecular assay, or rapid antigen detection test. Rapid antigen detection tests, because of their high degree of specificity, allow initiation of antibiotic therapy immediately for the patient with a positive test result. GAS is exquisitely sensitive to penicillin and cephalosporins, and resistant strains have never been encountered. Penicillin or amoxicil lin is therefore the drug of choice (except in patients who are allergic to penicillins) for pharyngeal infections and for suppurative complica tions. Oral penicillin V (250 mgdose 2 or 3 times daily bid tid for children weighing 60 lb and 500 mgdose bid tid for children 60 lb) is recommended but must be taken for a full 10 days, even though symptomatic improvement may occur within 2 3 days. Penicillin V (phenoxymethylpenicillin) is preferred over penicillin G, because it may be given without regard to mealtime. The major concern with all forms of oral therapy is the risk that the drug will be discontin ued before the 10 day course has been completed. Therefore when oral treatment is prescribed, the necessity of completing a full course of therapy must be emphasized. If the parents seem unlikely to com ply with oral therapy because of family disorganization, difficulties in comprehension, or other reasons, parenteral therapy with a single intramuscular (IM) injection of benzathine penicillin G (600,000 IU for children weighing 60 lb and 1.2 million IU for children 60 lb) is the most efficacious and often the most practical method of treatment. Disadvantages include soreness around the site of injection, which may last for several days, and potential for injection into nerves or blood vessels if not administered correctly. The local reaction is diminished when the refrigerated drug is warmed to room temperature and when benzathine penicillin G is combined in a single injection with procaine penicillin G, although it is necessary to ensure that an adequate dose of benzathine penicillin G is administered. In several comparative clinical trials, once daily amoxicillin (50 mg kg, maximum: 1,000 mg) for 10 days has been demonstrated to be as effective in treating GAS pharyngitis as amoxicillin administered orally multiple times per day. This somewhat broader spectrum agent has the advantage of once daily dosing, which may enhance adherence. In addition, amoxicillin is relatively inexpensive and is considerably more palatable than penicillin V suspension. A 10 day course of a narrow spectrum oral cephalosporin is rec ommended for most penicillin |
7,142 | allergic individuals. It has been sug gested that a 10 day course with an oral cephalosporin is superior to 10 days of oral penicillin in eradicating GAS from the pharynx. Analysis of these data suggests that the difference in eradication is mainly the result of a higher rate of eradication of GAS carriage included unin tentionally in these clinical trials. Some penicillin allergic persons (up to 10) are also allergic to cephalosporins, and these agents should be avoided in patients with immediate (anaphylactic type) hypersensi tivity to penicillin. Most oral broad spectrum cephalosporins are con siderably more expensive than penicillin or amoxicillin and are more likely to select for antibiotic resistant flora. Oral clindamycin is an appropriate agent for treating penicillin allergic patients, and resistance to clindamycin among GAS isolates in the United States is currently 6. An oral macrolide (erythromycin or clarithromycin) or azalide (azithromycin) is also an appropriate agent for patients allergic to penicillins. Ten days of therapy is indi cated except for azithromycin, which is given at 12 mgkg on day 1 and then 6 mgkg on days 2 5. Erythromycin is associated with substan tially higher rates of gastrointestinal side effects than the other agents. In recent years, macrolide resistance rates among pharyngeal isolates of GAS in most areas of the United States have been approximately 510. Sulfonamides and the tetracyclines are not recommended for treatment of GAS pharyngitis. However, studies showed that trimethoprim sulfamethoxazole (TMP SMX) is highly active in vitro against GAS and was comparable to IM penicillin for GAS impetigo in clinical trials. Most oral antibiotics must be administered for the conventional 10 days to achieve maximal pharyngeal eradication rates of GAS and pre vention of RF, but certain newer agents are reported to achieve com parable bacteriologic and clinical cure rates when given for 5 days. However, definitive results from comprehensive studies are not avail able to allow full evaluation of these proposed shorter courses of oral antibiotic therapy, which therefore cannot be recommended at this time. In addition, these antibiotics have a much broader spectrum than penicillin and are generally more expensive, even when administered for short courses. The majority of patients with GAS pharyngitis respond clinically to antimicrobial therapy, and GAS is eradicated from the pharynx. Posttreatment throat cultures are indicated only in the relatively few patients who remain symptomatic, whose symptoms recur, or who have had RF or rheumatic heart disease and are therefore at unusually high risk for recurrence. Treatment of GAS Skin Infections Antibiotic therapy for a patient with nonbullous impetigo can prevent local extension of the lesions, spread to distant infectious foci, and transmission of the infection to others. However, the ability of antibi otic therapy to prevent poststreptococcal glomerulonephritis has not been definitively demonstrated. Patients with a few superficial, isolated lesions and no systemic signs can be treated with topical antibiotics. Mupirocin is a safe and effective agent that has become the topical treatment of choice. If there are widespread lesions or systemic signs, oral |
7,143 | therapy with coverage for both GAS and S. aureus is needed. With the rapid emergence of methicillin resistant S. aureus in many commu nities, one should consider using clindamycin alone or a combination Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1710 Part XV u Infectious Diseases of TMP SMX and amoxicillin as first line therapy. Oral cefuroxime is an effective treatment of perianal streptococcal disease. Treatment of Invasive GAS Infection Theoretical considerations and experimental data suggest that intrave nous clindamycin is a more effective agent for the treatment of severe, invasive GAS infections than IV penicillin. However, because approxi mately 46 of GAS isolates in the United States are resistant to clindamycin, clindamycin initially should be used in combination with penicillin for these infections until susceptibility to clindamycin has been established. If necrotizing fasciitis is suspected, immediate surgi cal exploration may be required to identify a deep soft tissue infection that should be debrided immediately. Patients with streptococcal TSS require rapid and aggressive fluid replacement, management of respira tory or cardiac failure, if present, and anticipatory management of mul tiorgan system failure. Limited data suggest that intravenous immune globulin (IVIG) is effective as adjunctive therapy in the management of streptococcal TSS. COMPLICATIONS Suppurative complications from the spread of GAS to adjacent struc tures were extremely common in the preantibiotic era. Cervical lymph adenitis, peritonsillar abscess, retropharyngeal abscess, otitis media, mastoiditis, and sinusitis still occur in children in whom the primary illness has gone unnoticed or in whom treatment of the pharyngitis has been inadequate. GAS pneumonia can also occur. Acute rheumatic fever (see Chapter 229.1) and acute poststrepto coccal glomerulonephritis (see Chapter 559.4) are both nonsuppura tive sequelae of infections with GAS that occur after an asymptomatic latent period. These complications occur after the initial GAS infection resolves and involves sites distal to the initial GAS infection site. These sequelae are thought to be the result of the immune response and not of direct GAS infection. Acute RF and acute glomerulonephritis differ in their clinical manifestations, epidemiology, and potential morbidity. In addition, acute glomerulonephritis follows a GAS infection of either the upper respiratory tract or the skin, but acute RF is only proven to follow an infection of the upper respiratory tract. Some investigators have suggested that in some highly endemic areas, particularly in New Zealand and Australia, GAS skin infection may trigger acute RF, but this remains controversial. PROGNOSIS The prognosis for appropriately treated GAS pharyngitis is excellent, and complete recovery is the rule. When therapy is instituted within 9 days of the onset of symptoms and continued for the full course, acute RF is almost always prevented. There is no comparable evi dence that acute poststreptococcal glomerulonephritis can be pre vented once pharyngitis or pyoderma with a nephritogenic strain of GAS has occurred. In rare instances, particularly in neonates or in |
7,144 | children whose response to infection is compromised, fulminant pneumonia, septicemia, and death may occur despite usually ade quate therapy. PREVENTION The only specific indication for long term use of an antibiotic to pre vent GAS infections is for patients with a history of acute RF andor rheumatic heart disease. Mass prophylaxis is generally not feasible except possibly to reduce the number of infections during epidemics of impetigo and to control epidemics of pharyngitis in military popula tions and in schools. Because the ability of antimicrobial agents to pre vent GAS infections is limited, a group A streptococcal vaccine would offer the possibility of a more effective approach. Several candidate vaccines are in development, including a 30 valent M proteinbased recombinant vaccine, another recombinant vaccine that includes several conserved nonM protein epitopes that induce protective antibody, and an M protein vaccine that includes an epitope in a highly conserved region of M protein to provide broad immunity. All these vaccines are in relatively early stages of development. Poststreptococcal Reactive Arthritis Poststreptococcal reactive arthritis (PSRA) describes a syndrome characterized by the onset of acute arthritis after an episode of GAS pharyngitis in a patient whose illness does not fulfill the Jones Cri teria for diagnosis of acute RF. It is still unclear whether this entity represents a distinct syndrome or is a variant of acute RF. Although PSRA usually involves the large joints, similar to the arthritis of acute RF, it may also involve small peripheral joints and the axial skeleton and is typically nonmigratory, a characteristic distinct from the arthritis of acute RF. The latent period between the antecedent episode of GAS pharyngitis and PSRA may be considerably shorter (usually 10 days) than that typically seen with acute RF (usually 14 21 days). In contrast to the arthritis of acute RF, PSRA does not respond dramatically to therapy with aspirin or other nonsteroi dal antiinflammatory drugs (NSAIDs). In addition, fewer patients with PSRA than with acute RF have a temperature 38C (100.4F). Even though no more than half of PSRA patients with throat cul ture have GAS isolated, all have serologic evidence of a recent GAS infection. Because a very small proportion of patients with PSRA have been reported to develop valvular heart disease subsequently, these patients should be carefully observed for several months for clinical evidence of carditis. Some recommend that these patients receive secondary antistreptococcal prophylaxis for up to 1 year. If clinical evidence of carditis is not observed at that point, the pro phylaxis can be discontinued. If valvular disease is detected, the patient should be classified as having had acute RF and should continue to receive secondary prophylaxis appropriate for RF patients. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus pyogenes Pediatric autoimmune neuropsychiatric disorders associated with S. pyogenes (PANDAS) is a term proposed for a group of neuro psychiatric disorders (originally obsessive compulsive disorder OCD, tic disorder, and Tourette syndrome, or only OCD or feed ing abnormality) for which a possible relationship with GAS infec tions has |
7,145 | been hypothesized (see Chapter 37). This relationship has not been proved. It has been proposed that this subset of patients with OCDs may produce autoimmune antibodies in response to a GAS infection that cross react with brain tissue, similar to the autoimmune response believed to be responsible for the manifes tations of Sydenham chorea. It has also been suggested that sec ondary prophylaxis that prevents recurrences of rheumatic fever, including Sydenham chorea, might also be effective in preventing exacerbations of OCDs in these patients, but clinical trials have not confirmed this. It has also been proposed that these patients may benefit from immunoregulatory therapy such as plasma exchange or IVIG, but these unproven modalities should only be used in a clinical research trial. That PANDAS may represent an extension of the spectrum of acute RF is intriguing, but it should be consid ered only as a yet unproven hypothesis. Until carefully designed and well controlled studies have established a causal relationship between neurobehavioral abnormalities and GAS infections, rou tine diagnostic laboratory testing for GAS and antistreptococcal antibodies, long term antistreptococcal prophylaxis, or immuno regulatory therapy (e.g., IVIG, plasma exchange) to treat exacerba tions of this disorder clearly are not recommended (see Chapter 37). It has also been suggested that a broad spectrum of infectious agents may have the ability to trigger exacerbations in children with these neurobehavioral disorders, which have been termed pediatric acute onset neuropsychiatric syndrome (PANS), but this remains highly controversial. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 229 u Group A Streptococcus 1711 229.1 Rheumatic Fever Stanford T. Shulman and Ami B. Patel See also Chapter 487. Overwhelming evidence supports the link between antecedent GAS pharyngitis and acute rheumatic fever (RF) and rheumatic heart disease. As many as two thirds of patients with an acute epi sode of RF have a history of an upper respiratory tract infection several weeks before; the peak age and seasonal incidence of acute RF closely parallel that of GAS pharyngitis. Patients with acute RF almost always have serologic evidence of a recent GAS infection. Their antibody titers are usually considerably higher than those seen in patients with uncomplicated GAS infections. Outbreaks of GAS pharyngitis in closed communities, such as boarding schools or mili tary bases, may be followed by community outbreaks of acute RF. Antimicrobial therapy that eliminates GAS from the pharynx also prevents initial episodes of acute RF, and long term, continuous anti biotic prophylaxis that prevents GAS pharyngitis also prevents recur rences of acute RF. Not all serotypes of GAS can cause RF. When some GAS strains (e.g., M type 4) caused acute pharyngitis in a very susceptible rheu matic population, there were no recurrences of RF. In contrast, episodes of pharyngitis caused by other serotypes in the same popu lation led to frequent |
7,146 | recurrences of acute RF, suggesting that the lat ter organisms were rheumatogenic. The concept of rheumatogenicity is further supported by the observation that although serotypes of GAS frequently associated with skin infection can be isolated also from the upper respiratory tract, they rarely cause recurrences of RF in individuals with a previous history of RF or first episodes of RF. In addition, certain serotypes of GAS (M types 1, 3, 5, 6, 18, and 29) are more frequently isolated from patients with acute RF than are other serotypes. EPIDEMIOLOGY The annual incidence of acute RF in some developing countries exceeds 50 per 100,000 children, and very high rates are also seen in ethnic minority populations within Australia and New Zealand. Worldwide, rheumatic heart disease remains the most common form of acquired heart disease in all age groups, accounting for up to 50 of all car diovascular disease and 50 of all cardiac admissions in many devel oping countries. Striking differences in the incidence of acute RF and rheumatic heart disease among different ethnic groups are often evi dent within the same country; these differences are partially related to differences in socioeconomic status, and there is a genetic basis for increased susceptibility. In the United States at the beginning of the 20th century, acute RF was a leading cause of death among children and adolescents, with annual incidence rates of 100 200 per 100,000 population. In addi tion, rheumatic heart disease was a leading cause of heart disease among adults 40 years old. At that time, as many as 25 of pediat ric hospital beds in the United States were occupied by patients with acute RF or its complications. By the 1940s, the annual incidence of acute RF had decreased to 50 per 100,000 population, and over the next 4 decades, the decline in incidence accelerated rapidly. By the early 1980s, the annual incidence in some areas of the United States was as low as 0.5 per 100,000 population, and rates of acute RF since the 1980s have declined substantially. This sharp decline in the inci dence of acute RF has been observed in other industrialized countries as well. The explanation for this dramatic decline in the incidence of acute RF and rheumatic heart disease in the United States and other industri alized countries is not clear but is likely related in large part to a decline in circulating rheumatogenic strains causing acute pharyngitis. Histori cally, acute RF was associated with poverty and overcrowding, particu larly in urban areas. Much of the decline in the incidence of acute RF in industrialized countries during the preantibiotic era was probably the result of improved living conditions. Of the various manifestations of poverty, crowding, which facilitates the spread of GAS infections, is most closely associated with the incidence of acute RF. The decline in incidence of acute RF in industrialized countries over the past 4 decades is also attributable to the greater availability of medical care and to the widespread use of antibiotics. Antibiotic |
7,147 | therapy of GAS pharyngitis is important in preventing initial attacks and, particularly, recurrences of the disease. In addition, the decline in the United States is attributed to a shift in the prevalent strains of GAS causing pharyngi tis from mostly rheumatogenic to nonrheumatogenic. Certain rheumatogenic serotypes (types 1, 3, 5, 6, and 18) that were isolated less often during the 1970s and early 1980s dramatically reap peared during rheumatic fever outbreaks, and their appearance in selected communities was probably a major factor. GAS that are asso ciated with rheumatogenicity often form highly mucoid colonies on throat culture plates. In addition to the specific characteristics of the infecting strain of GAS, the risk of developing acute RF also depends on various host factors. The incidence of both initial attacks and recurrences of acute RF peaks in children 5 15 years old, the age of greatest risk for GAS pharyngitis. Patients who have had an attack of acute RF tend to have recurrences, and the clinical features of the recurrences tend to mimic those of the initial attack. In addition, there appears to be a genetic predisposition to acute RF. Studies in twins show a higher concordance rate of acute RF in monozygotic than in dizygotic twin pairs. Prelimi nary studies from Oceania in a population with high rates of rheumatic heart disease have identified an allele of interest that increases ones risk of rheumatic heart disease. PATHOGENESIS The cytotoxicity theory suggests that a GAS toxin is involved in the pathogenesis of acute RF and rheumatic heart disease. GAS produces a number of enzymes that are cytotoxic for mammalian cardiac cells, such as streptolysin O, which has a direct cytotoxic effect on mam malian cells in tissue culture. A major problem with the cytotoxicity hypothesis is its inability to explain the substantial latent period (usu ally 10 21 days) between GAS pharyngitis and onset of acute RF. An immune mediated pathogenesis for acute RF and rheumatic heart disease has been suggested by its clinical similarity to other ill nesses with an immunopathogenesis and by the latent period between the GAS infection and acute RF. The immunologic cross reactivity of several GAS cellular and extracellular epitopes with cardiac antigenic epitopes also lends support to the hypothesis of molecular mimicry. Common epitopes are shared between certain GAS components (e.g., M protein, cell membrane, group A cell wall carbohydrate, capsular hyaluronate) and specific mammalian tissues (e.g., heart valve, sarco lemma, brain, joint). CLINICAL MANIFESTATIONS AND DIAGNOSIS The current Jones Criteria, as revised in 2015 by the American Heart Association (AHA), are intended for diagnosis of the initial attack of acute RF and recurrent attacks (Table 229.2). There are five major and four minor criteria and a requirement for evidence of recent GAS infection. The 2015 revision includes separate criteria for low risk populations (defined as those with incidence 2 per 100,000 school age children per year or all age rheumatic heart disease prevalence of 1 per 1,000 population) and moderatehigh risk populations (defined as those |
7,148 | with higher incidence or prevalence rates). Virtually all of the United States, Canada, and Western Europe are low risk, whereas moderatehigh risk populations include Maoris in New Zea land, aborigines in Australia, Pacific Islanders, and most developing countries. Diagnosis of a first attack or recurrent attack of acute RF can be established when a patient fulfills two major or one major and two minor criteria and has evidence of preceding GAS infection. Diagnosis of recurrent acute RF can also be made only in the moder atehigh risk population by the presence of three minor criteria with evidence of preceding GAS infection. In the 2015 Jones Criteria, a major change from previous versions expands the definition of the major criterion carditis to include subclinical evidence (e.g., in the absence of a murmur, echocardiographic evidence of mitral regurgi tation MR meeting specific criteria to distinguish physiologic from Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1712 Part XV u Infectious Diseases pathologic MR) (see Table 487.1). Areas in which the Jones Criteria differ in low risk from moderatehigh risk populations relate to the major criterion of arthritis and the minor criteria of arthralgia, defi nition of fever, and elevated inflammatory markers (see Table 229.2 and text that follows). These changes are designed to make it easier to fulfill the Jones Criteria in patients from moderatehigh risk popula tions. Even with strict application of the criteria, overdiagnosis and underdiagnosis of acute RF may occur. The diagnosis of acute RF can be made without strict adherence to the Jones Criteria in three cir cumstances: (1) when chorea occurs as the only major manifestation of acute RF, (2) when indolent carditis is the only manifestation in patients who first come to medical attention only months after the apparent onset of acute RF, and (3) in a limited number of patients with recurrence of acute RF in particularly high risk populations. The Five Major Criteria Migratory Polyarthritis Arthritis occurs in approximately 75 of patients with acute RF and typically involves larger joints, particularly the knees, ankles, wrists, and elbows. Involvement of the spine, small joints of the hands and feet, or hips is uncommon. Rheumatic joints are classically hot, red, swollen, and exquisitely tender, with even the friction of bedclothes being uncomfortable. The pain can precede and can appear to be dis proportionate to the objective findings. The joint involvement is char acteristically migratory in nature; that is, a severely inflamed joint can become normal within 1 3 days without treatment, even as one or more other large joints become involved. Severe arthritis can per sist for several weeks in untreated patients. Monoarticular arthritis is unusual unless antiinflammatory therapy is initiated prematurely, aborting the progression of the migratory polyarthritis. If a child with fever and arthritis is suspected to have acute RF, it is frequently useful to withhold antiinflammatory medications |
7,149 | like salicylates or NSAIDs and observe for migratory progression. A dramatic response to even low doses of salicylates is another characteristic feature of the arthri tis, and the absence of such a response should suggest an alternative diagnosis. Rheumatic arthritis is almost never deforming. Synovial fluid in acute RF usually has 10,000 100,000 white blood cellsL with a pre dominance of neutrophils, protein level of approximately 4 gdL, nor mal glucose level, and formation of a good mucin clot. Frequently, arthritis is the earliest manifestation of acute RF and may correlate temporally with peak antistreptococcal antibody titers. There is often an inverse relationship between the severity of arthritis and the sever ity of cardiac involvement. In moderatehigh risk populations only, monoarthritis in the absence of prior inflammatory therapies, or even polyarthralgia without frank objective signs of arthritis, can fulfill this major criterion. Before polyarthralgia should be considered a major criterion in the moderatehigh risk population, other potential causes should be excluded. Carditis A major change in the 2015 revision of the Jones Criteria is the accep tance of subclinical carditis (defined as without a murmur of valvulitis but with echocardiographic evidence of valvulitis) or clinical carditis (with a valvulitis murmur) as fulfilling the major criterion of carditis in all populations. The echocardiographic features of subclinical carditis must meet those included in Table 487.1 in Chapter 487 to distinguish pathologic from physiologic degrees of valve regurgitation. Silent or latent rheumatic heart disease describes echocardiographic evidence of rheumatic heart disease in individuals with no known history of acute RF and no clinical symptoms. In endemic regions, active surveillance via screening echocardiography has emerged as a potential strategy to detect asymptomatic subclinical rheumatic heart disease. Carditis and resultant chronic rheumatic heart disease are the most serious manifestations of acute RF and account for essentially all the associated morbidity and mortality. Rheumatic carditis is character ized by pancarditis, with active inflammation of the myocardium, pericardium, and endocardium (see Chapter 487). Cardiac involve ment during acute RF varies in severity from fulminant, potentially fatal exudative pancarditis to mild, transient cardiac involvement. Endocarditis (valvulitis) is a universal finding in rheumatic cardi tis, whereas the presence of pericarditis or myocarditis is variable. Myocarditis andor pericarditis without clinical evidence of endo carditis almost never is rheumatic carditis; alternative etiologies (especially viral) need to be sought. Most rheumatic heart disease is isolated mitral valvular disease or combined aortic and mitral valvu lar disease. Isolated aortic or right sided valvular involvement is quite uncommon. Serious and long term illness is related entirely to the severity of valvular heart disease as a consequence of a single attack or recurrent attacks of acute RF. Valvular insufficiency is characteristic of both acute and convalescent stages of acute RF, whereas mitral and or aortic valvular stenosis usually appears years or even decades after the acute illness. However, in developing countries, where acute RF often occurs at a younger age, mitral stenosis and aortic stenosis may develop sooner after acute RF than in developed countries |
7,150 | and can occur in young children. Acute rheumatic carditis usually presents as tachycardia and car diac murmurs, with or without evidence of myocardial or pericardial Table 229.2 Guidelines for the Diagnosis of an Initial or Recurrent Attack of Rheumatic Fever (Jones Criteria, Updated 2015)15 MAJOR MANIFESTATIONS MINOR MANIFESTATIONS SUPPORTING EVIDENCE OF ANTECEDENT GROUP A STREPTOCOCCAL INFECTION Carditis Polyarthritis Erythema marginatum Subcutaneous nodules Chorea Clinical features: Arthralgia Fever Positive throat culture or rapid streptococcal antigen test Elevated or increasing streptococcal antibody titer Laboratory features: Elevated acute phase reactants: Erythrocyte sedimentation rate C reactive protein Prolonged P R interval 1Initial attack: Two major manifestations or one major and two minor manifestations plus evidence of recent GAS infection. Recurrent attack: Two major, or one major and two minor, or three minor manifestations (the latter only in the moderatehigh risk population), plus evidence of recent GAS infection (see text). 2Low risk population is defined as acute rheumatic fever (ARF) incidence 2 per 100,000 school age children per year or all age rheumatic heart disease (RHD) prevalence of 1 per 1,000 population. Moderatehigh risk population is defined as ARF incidence 2 per 100,000 school age children per year or all age RHD prevalence of 1 per 1,000 population. 3Carditis is now defined as clinical andor subclinical (echocardiographic valvulitis). See Table 229.3. 4Arthritis (major) refers only to polyarthritis in low risk populations but also to monoarthritis or polyarthralgia in moderatehigh risk populations. 5Minor criteria for moderatehigh risk populations only include monoarthralgia (polyarthralgia for low risk populations), fever of 38C (38.5C in low risk populations), and ESR 30 mmhr (60 mmhr in low risk populations). From Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131(20):18061818. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 229 u Group A Streptococcus 1713 involvement. Moderate to severe rheumatic carditis can result in cardio megaly and heart failure with hepatomegaly and peripheral and pulmo nary edema. Echocardiographic findings include pericardial effusion, decreased ventricular contractility, and aortic andor mitral regurgita tion. Mitral regurgitation is characterized typically by a high pitched apical holosystolic murmur radiating to the axilla. In patients with sig nificant MR, this may be associated with an apical mid diastolic mur mur of relative mitral stenosis. Aortic insufficiency is characterized by a high pitched decrescendo diastolic murmur at the left sternal border. Carditis occurs in approximately 5060 of all cases of acute RF. Recurrent attacks of acute RF in patients who had carditis with their initial attack are associated with high rates of carditis with increasing severity of cardiac disease. The major consequence of acute rheumatic carditis is chronic, progressive valvular disease, particularly valvular stenosis, which can require surgical intervention. Chorea Sydenham chorea occurs in approximately 1015 |
7,151 | of patients with acute RF and usually presents as an isolated, frequently subtle, movement disorder. Emotional lability, incoordination, poor school performance, uncontrollable movements, and facial grimacing are characteristic, all exacerbated by stress and disappearing with sleep. Chorea occasionally is unilateral (hemichorea). The latent period from acute GAS infection to chorea is usually substantially longer than for arthritis or carditis and can be months. The onset can be insidious, with symptoms being present for several months before recognition. Clinical maneuvers to elicit features of chorea include (1) demonstration of milkmaids grip (irregular contractions and relaxations of the muscles of the fingers while squeezing the exam iners fingers), (2) spooning and pronation of the hands when the patients arms are extended, (3) wormian darting movements of the tongue on protrusion, and (4) examination of handwriting to evalu ate fine motor movements. Diagnosis is based on clinical findings with supportive evidence of GAS antibodies. However, in the usual patient with a long latent period from the inciting streptococcal infection to onset of chorea, antibody levels have often declined to normal. Although the acute illness is distressing, chorea rarely, if ever, leads to permanent neurologic sequelae. Erythema Marginatum Erythema marginatum is a rare (approximately 1 of patients with acute RF) but characteristic rash of acute RF. It consists of erythema tous, serpiginous, macular lesions with pale centers that are not pru ritic (Fig. 229.2). It occurs primarily on the trunk and extremities, but not on the face, and it can be accentuated by warming the skin. Subcutaneous Nodules Subcutaneous nodules are a rare (1 of patients with acute RF) find ing and consist of firm nodules approximately 0.5 1 cm in diameter along the extensor surfaces of tendons near bony prominences. There is a correlation between the presence of these nodules and significant rheumatic heart disease. Minor Criteria These are more nonspecific than major criteria, and the 2015 revised Jones Criteria have included some changes from the previous criteria. The first of the two clinical minor criteria involve joint manifesta tions (only if arthritis is not used as a major criterion) and is defined as polyarthralgia in low risk populations and monoarthralgia in mod eratehigh risk populations. The second clinical minor manifestation is fever, defined as at least 38.5C in low risk populations and at least 38.0C in moderatehigh risk populations. The two laboratory minor criteria are (1) elevated acute phase reactants, defined as erythrocyte sedimentation rate (ESR) at least 60 mmhr andor C reactive protein (CRP) at least 3.0 mgdL (30 mgL) in low risk populations and ESR at least 30 mmhr andor CRP at least 3.0 mgdL (30 mgL) in moderate high risk populations and (2) prolonged P R interval on ECG (unless carditis is a major criterion). However, a prolonged P R interval alone does not constitute evidence of carditis or predict long term cardiac sequelae. Recent Group A Streptococcus Infection An absolute requirement for the diagnosis of acute RF is supporting evidence of a recent GAS infection. Acute RF typically |
7,152 | develops 10 21 days after an acute episode of GAS pharyngitis at a time when clinical findings of pharyngitis are no longer present and when only 1020 of patients still harbor GAS in the throat. One third of patients with acute RF have no history of an antecedent clinically symptomatic phar yngitis. Therefore evidence of an antecedent GAS infection is usually based on elevated or rising serum antistreptococcal antibody titers. If only a single antibody is measured (usually antistreptolysin O), only 8085 of patients with acute RF have an elevated titer; however, 95100 have an elevation if three different antibodies (antistrepto lysin O, antiDNase B, antihyaluronidase) are measured. Therefore when acute RF is suspected clinically, multiple antibody tests should be performed. Except for chorea, the clinical findings of acute RF gen erally coincide with peak antistreptococcal antibody responses. Most patients with chorea have elevation of antibodies to at least one GAS antigen. However, in patients with a long latent period from the incit ing GAS infection, antibody levels may have declined to within the normal range. The diagnosis of acute RF should not be made in those patients with elevated or increasing streptococcal antibody titers who do not fulfill the Jones Criteria. Differential Diagnosis The differential diagnosis of RF includes many infectious and noninfectious illnesses (Table 229.3). When children present with arthritis, a collagen vascular disease must be considered. Juvenile idiopathic arthritis (JIA) must be distinguished from acute RF. Children with JIA tend to be younger and usually have less joint pain relative to their other clinical findings than those with acute RF. Spiking fevers, nonmigratory arthritis, lymphadenopathy, and sple nomegaly are more suggestive of JIA than acute RF. The response to salicylate therapy is also much less dramatic with JIA than with acute RF. Systemic lupus erythematosus (SLE) can usually be dis tinguished from acute RF by antinuclear antibodies in SLE. Other causes of arthritis such as pyogenic arthritis, malignancies, serum sickness, Lyme disease, sickle cell disease, and reactive arthritis related to gastrointestinal infections (e.g., Shigella, Salmonella, Yer sinia) should also be considered. Poststreptococcal reactive arthritis is discussed earlier (see Chapter 229). When carditis is the sole major manifestation of suspected acute RF, viral myocarditis, viral pericarditis, Kawasaki disease, and infec tive endocarditis should also be considered. Patients with infective Fig. 229.2 Polycyclic red borders of erythema marginatum in a febrile child with acute rheumatic fever. (From Schachner LA, Hansen RC, eds. Pediatric Dermatology, 3rd ed. Philadelphia: Mosby; 2003:808.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1714 Part XV u Infectious Diseases Table 229.3 Differential Diagnosis of Acute Rheumatic Fever ARTHRITIS CARDITIS CHOREA Juvenile idiopathic arthritis Viral myocarditis Huntington chorea Reactive arthritis (e.g., Shigella, Salmonella, Yersinia) Viral pericarditis Wilson disease Serum sickness Infective endocarditis Systemic lupus erythematosus Sickle cell disease Kawasaki disease Tic disorder Malignancy Congenital heart disease Hyperactivity Systemic lupus erythematosus |
7,153 | Mitral valve prolapse Encephalitis (infectious or autoimmune) Lyme disease (Borrelia burgdorferi) Innocent murmurs Pyogenic arthritis MIS C Poststreptococcal reactive arthritis Lyme disease MIS C, Multisystem inflammatory syndrome in children (COVID 19). endocarditis may present with both joint and cardiac manifestations. These patients can usually be distinguished from patients with acute RF by blood cultures and the presence of extracardiac findings (e.g., hema turia, splenomegaly, splinter hemorrhages). When chorea is the sole major manifestation of suspected acute RF, Huntington chorea, Wilson disease, SLE, and various encephalitides should also be considered. TREATMENT All patients with acute RF should be placed on bed rest and monitored closely for evidence of carditis. They can be allowed to ambulate when the signs of acute inflammation have improved. However, patients with carditis require longer periods of bed rest. Antibiotic Therapy Once the diagnosis of acute RF has been established and regardless of the throat culture results, the patient should receive 10 days of orally administered penicillin or amoxicillin or a single IM injection of ben zathine penicillin to ensure eradication of GAS from the upper respi ratory tract. If penicillin allergic, 10 days of erythromycin, 5 days of azithromycin, or 10 days of clindamycin is indicated. After this initial course of antibiotic therapy, long term antibiotic prophylaxis for sec ondary prevention should be instituted (see later). Antiinflammatory Therapy Antiinflammatory agents (e.g., salicylates, corticosteroids) should be withheld if arthralgia or atypical arthritis is the only clinical manifes tation of presumed acute RF. Premature treatment with one of these agents may interfere with the development of the characteristic migra tory polyarthritis and thus obscure the diagnosis of acute RF. Acet aminophen can be used to control pain and fever while the patient is being observed for more definite signs of acute RF or for evidence of another disease. Patients with typical migratory polyarthritis and those with cardi tis without cardiomegaly or congestive heart failure should be treated with oral salicylates. The usual dose of aspirin is 50 70 mgkgday in four divided doses orally (PO) for 3 5 days, followed by 50 mgkgday in four divided doses PO for 2 3 weeks and half that dose for another 2 4 weeks. Determination of the serum salicylate level is not necessary unless the arthritis does not respond or signs of salicylate toxicity (tin nitus, hyperventilation) develop. There is no evidence that NSAIDs are more effective than salicylates. Patients with carditis and more than minimal cardiomegaly andor congestive heart failure should receive corticosteroids. The usual dose of prednisone is 2 mgkgday in four divided doses for 2 3 weeks, fol lowed by half the dose for 2 3 weeks, and then tapering of the dose by 5 mg24 hr every 2 3 days. When prednisone is being tapered, aspirin should be started at 50 mgkgday in four divided doses for 6 weeks to prevent rebound of inflammation. Supportive therapies for patients with moderate to severe carditis include digoxin, fluid and salt restric tion, diuretics, and oxygen. The cardiac toxicity of |
7,154 | digoxin is enhanced with myocarditis. Termination of the antiinflammatory therapy may be followed by the reappearance of clinical manifestations or of elevation in ESR and CRP (rebound). It may be prudent to increase salicylates or cor ticosteroids until near normalization of inflammatory markers is achieved. Sydenham Chorea Because chorea often occurs as an isolated manifestation after the reso lution of the acute phase of the disease, antiinflammatory agents are usually not indicated. Sedatives may be helpful early in the course of chorea; phenobarbital (16 32 mg every 6 8 hours PO) is the drug of choice. If phenobarbital is ineffective, haloperidol (0.01 0.03 mgkg24 hr divided twice daily PO) or chlorpromazine (0.5 mgkg every 4 6 hours PO) should be initiated. Some patients may benefit from a few week course of corticosteroids. COMPLICATIONS The arthritis and chorea of acute RF resolve completely without sequelae. Therefore the long term sequelae of RF are essentially limited to the heart (see Chapter 487). The AHA has published updated recommendations regarding the use of prophylactic antibiotics to prevent infective endocarditis (see Chapter 486). The AHA recommendations no longer suggest routine endocarditis prophylaxis for patients with rheumatic heart disease who are undergoing dental or other procedures. However, the maintenance of optimal oral healthcare remains an important component of an over all healthcare program. For the relatively few patients with rheumatic heart disease in whom infective endocarditis prophylaxis remains rec ommended, such as those with a prosthetic valve or prosthetic mate rial used in valve repair, the current AHA recommendations should be followed (see Chapter 486). These recommendations advise using an agent other than a penicillin to prevent infective endocarditis in those receiving penicillin prophylaxis for RF because oral hemolytic strep tococci are likely to have developed resistance to penicillin. PROGNOSIS The prognosis for patients with acute RF depends on the clinical mani festations present at the initial episode, the severity of the initial episode, and the prevention of recurrences. Approximately 5070 of patients with carditis during the initial episode of acute RF recover with no residual heart disease; the more severe the initial cardiac involvement, the greater the risk for residual heart disease. Patients without carditis during the initial episode are less likely to have carditis with recurrent attacks, but there is a stepwise increase in cardiac involvement as the number of episodes increases. In contrast, patients with carditis during the initial episode are very likely to have carditis with recurrences, and the risk for permanent heart damage increases with each recurrence. Patients who have had acute RF are susceptible to recurrent attacks after reinfection of the upper respiratory tract with GAS, with approxi mately 50 risk with each GAS pharyngitis. Therefore these patients require long term continuous chemoprophylaxis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 229 u Group A Streptococcus 1715 Before antibiotic prophylaxis was available, |
7,155 | 75 of patients who had an initial episode of acute RF had one or more recurrences in their lifetime. These recurrences were a major source of morbidity and mor tality. The risk of recurrence is highest in the first 5 years after the initial episode and decreases with time. Approximately 20 of patients who present with isolated chorea who are not given secondary prophylaxis develop rheumatic heart disease within 20 years. Therefore patients with chorea, even in the absence of other manifestations of RF, require long term antibiotic prophylaxis (Table 229.4). PREVENTION Prevention of both initial and recurrent episodes of acute RF depends on controlling GAS infections of the upper respiratory tract. Preven tion of initial attacks (primary prevention) depends on identification and eradication of GAS causing acute pharyngitis. A New Zealand study in a population with very high rates of acute RF showed that a school based GAS pharyngitis screening and management program using oral amoxicillin substantially decreased pharyngeal GAS preva lence and rates of acute RF. Individuals who have already suffered an attack of acute RF are particularly susceptible to recurrences of RF with any subsequent GAS upper respiratory tract infection, whether or not they are symptomatic. Therefore these patients should receive continuous antibiotic prophylaxis to prevent recurrences (secondary prevention). Primary Prevention Appropriate antibiotic therapy instituted before the ninth day of symp toms of acute GAS pharyngitis is highly effective in preventing the first attacks of acute RF. However, approximately 30 of patients with acute RF do not recall a preceding episode of pharyngitis and did not seek therapy. Secondary Prevention Secondary prevention is directed at preventing acute GAS pharyngitis in patients at substantial risk of recurrent acute RF. Secondary preven tion requires continuous antibiotic prophylaxis, which should begin as soon as the diagnosis of acute RF has been made and immediately after a full course of antibiotic therapy has been completed. Because patients who have had carditis with their initial episode of acute RF are at higher risk for having carditis with recurrences and for sustaining additional cardiac damage, they should receive long term antibiotic prophylaxis well into adulthood and perhaps for life (see Table 229.4 and Table 229.5). Patients who did not have carditis with their initial episode of acute RF have a relatively low risk for carditis with recurrences. Antibiotic prophylaxis should continue in these patients until the patient reaches 21 years of age or until 5 years have elapsed since the last RF attack, whichever is longer. The decision to discontinue prophylactic antibiot ics should be made only after careful consideration of potential risks and benefits and of epidemiologic factors such as the risk for exposure to GAS infections. The regimen of choice for secondary prevention is a single IM injec tion of benzathine penicillin G (600,000 IU for children weighing 60 lb and 1.2 million IU for those 60 lb) every 4 weeks (see Table 229.4). In certain high risk patients and in certain areas of the world where the incidence of RF |
7,156 | is particularly high, use of benzathine penicillin G every 3 weeks may be necessary because serum concentrations of penicillin may decrease to marginally effective levels after 3 weeks. In the United States, administration of benzathine penicillin G every 3 weeks is recommended only for those who have recurrent acute RF despite adherence to a 4 week regimen. In compliant patients, continu ous oral antimicrobial prophylaxis can be used. Penicillin V (250 mg twice daily) and sulfadiazine or sulfisoxazole (500 mg for those weigh ing 60 lb or 1,000 mg for those 60 lb, once daily) are equally effective when used in such patients. For the exceptional patient who is aller gic to both penicillin and sulfonamides, a macrolide (erythromycin or clarithromycin) or azalide (azithromycin) may be used. Table 229.5 notes the duration of secondary prophylaxis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 229.4 Chemoprophylaxis for Recurrences of Acute Rheumatic Fever (Secondary Prophylaxis) DRUG DOSE ROUTE Penicillin G benzathine 600,000 IU for children weighing 60 lb and 1.2 million IU for children 60 lb, every 4 wk Intramuscular or Penicillin V 250 mg, twice daily Oral or Sulfadiazine or sulfisoxazole 500 mg once daily for patients weighing 60 lb Oral 1000 mg once daily for patients weighing 60 lb FOR PEOPLE WHO ARE ALLERGIC TO PENICILLIN AND SULFONAMIDE DRUGS Macrolide or azalide Variable Oral In high risk situations, administration every 3 wk is recommended. Adapted from Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young. Circulation. 2009;119:1541 1551. Table 229.5 Duration of Prophylaxis for People Who Have Had Acute Rheumatic Fever: AHA Recommendations CATEGORY DURATION Rheumatic fever without carditis 5 yr or until 21 yr of age, whichever is longer Rheumatic fever with carditis but without residual heart disease (no valvular disease) 10 yr or until 21 yr of age, whichever is longer Rheumatic fever with carditis and residual heart disease (persistent valvular disease) 10 yr or until 40 yr of age, whichever is longer; sometimes lifelong prophylaxis Clinical or echocardiographic evidence. Adapted from Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association (AHA) Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young. Circulation. 2009;119:15411551. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1716 Part XV u Infectious Diseases Group B Streptococcus (GBS), or Streptococcus agalactiae, is a major cause of neonatal bacterial sepsis worldwide. Although advances in prevention strategies have led to a decline in the incidence of neona tal disease, GBS remains a dangerous pathogen for neonates, pregnant women, and nonpregnant |
7,157 | adults. ETIOLOGY Group B streptococci are facultative, anaerobic, gram positive cocci that form chains or diplococci in broth and small, gray white or orange tinged colonies on solid medium. GBS is definitively identified by demonstration of the Lancefield group B carbohydrate antigen, such as with latex agglutination techniques widely used in clinical labora tories. Presumptive identification can be established on the basis of a narrow zone of hemolysis on blood agar, resistance to bacitracin and trimethoprim sulfamethoxazole (TMP SMX), lack of hydrolysis of bile esculin, and elaboration of CAMP factor (named for the discoverers, Christie, Atkins, and Munch Petersen), an extracellular protein that, in the presence of the toxin of Staphylococcus aureus, produces a zone of enhanced hemolysis on sheep blood agar. Individual GBS strains are serologically classified according to the presence of one of the structur ally distinct capsular polysaccharides, which are important virulence factors and stimulators of antibody associated immunity. Ten GBS capsular types have been identified: types Ia, Ib, II, III, IV, V, VI, VII, VIII, and IX. EPIDEMIOLOGY GBS emerged as a prominent neonatal pathogen in the late 1960s. For the next 2 decades, the incidence of neonatal GBS disease remained fairly constant, affecting 1.0 5.4 per 1,000 liveborn infants in the United States. Two patterns of disease were seen: early onset disease, which presents at 7 days of age, and late onset disease, which presents at 7 days of age. Since the early 1990s, widespread implementation of maternal intrapartum antibiotic prophylaxis has led to a striking decrease in the incidence of early onset neonatal GBS disease in the United States, from 1.7 to 0.19 per 1,000 live births in recent years. This strategy has not had a significant effect on the incidence of late onset disease, which has remained stable at approximately 0.3 0.4 per 1,000 live births (Fig. 230.1). The incidence of neonatal GBS disease is higher in premature and low birthweight infants, although most cases occur in full term infants. Rates of both early and late onset disease are higher in Black infants. Colonization by GBS in healthy adults is common. Vaginal or rectal colonization occurs in up to approximately 30 of pregnant women and is the usual source for GBS transmission to newborn infants. In the absence of maternal antibiotic prophylaxis, approximately 50 of infants born to colonized women acquire GBS colonization, and 12 of infants born to colonized mothers develop early onset disease. Heavy maternal colonization increases the risk for infant colonization and development of early onset disease. Additional risk factors for early onset disease include prolonged rupture of membranes, intra partum fever, prematurity, maternal bacteriuria during pregnancy, and previous delivery of an infant who developed GBS disease. Risk factors for late onset disease are less well defined. Whereas late onset disease may follow vertical transmission, horizontal acquisition from nursery or other community sources (such as family, healthcare providers, or environmental exposure) has also been described. GBS is also an important cause of invasive disease in adults. GBS may cause urinary |
7,158 | tract infections, bacteremia, endometritis, chorioamnio nitis, and wound infection in pregnant and parturient women. In non pregnant adults, especially those with underlying medical conditions such as diabetes mellitus, cirrhosis, or malignancy, GBS may cause seri ous infections such as bacteremia, skin and soft tissue infections, bone and joint infections, endocarditis, pneumonia, and meningitis. In the era of maternal chemoprophylaxis, most invasive GBS infections occur in nonpregnant adults. Unlike neonatal disease, the incidence of inva sive GBS disease in adults has increased substantially, roughly tripling between 1990 and 2016. The serotypes most frequently associated with neonatal GBS disease are types Ia, III, and V. Strains of serotype III are the most common subtype isolated from colonized pregnant women and are also the most frequent cause of invasive disease among newborns and adults. Global epidemiologic studies have revealed regional variation in sub type prevalence, some of which may reflect local dietary and healthcare practices. PATHOGENESIS A major risk factor for the development of early onset neonatal GBS infection is maternal vaginal or rectal colonization by GBS. Infants acquire GBS by ascending infection or during passage through the birth canal. Fetal aspiration of infected amniotic fluid may occur. The incidence of early onset GBS infection increases with the duration of rupture of membranes. Infection may also occur through transcellular passage across intact membranes. In cases of late onset infection, GBS may be vertically transmitted or acquired later from maternal or non maternal sources. Several bacterial factors are implicated in the pathogenesis of inva sive GBS disease, primarily the type specific capsular polysaccharide. Strains that are associated with invasive disease in humans elaborate more capsular polysaccharide than do colonizing isolates. All GBS cap sular polysaccharides are high molecular weight polymers composed of repeating oligosaccharide subunits that include a short side chain terminating in N acetylneuraminic acid (sialic acid). Studies of type III GBS show that the sialic acid component of the capsular polysac charide prevents activation of the alternative complement pathway in the absence of type specific antibody. Sialylated capsular polysaccha ride on the GBS surface also interacts with sialic acidbinding lectins or siglecs on human leukocytes to dampen inflammatory gene acti vation. Thus the capsular polysaccharide appears to exert a virulence effect by protecting the organism from opsonophagocytosis in the non immune host and by downregulating leukocyte activation. In addition, type specific virulence attributes are suggested by the fact that type III strains are implicated in most cases of late onset neonatal GBS disease and meningitis. Type III strains are taken up by brain endothelial cells Chapter 230 Group B Streptococcus Thomas A. Hooven 2.0 First AAP and ACOG statement 0.5 1.0 R at e pe r 1, 00 0 liv e bi rt hs 1.5 0.0 19 90 19 95 20 00 20 05 20 10 20 15 20 20 Consensus guidelines Earlyonset disease Lateonset disease Universal screening Fig. 230.1 Incidence of early and late onset invasive group B strep tococcal (GBS) diseaseactive bacterial core surveillance areas, 1990 2019, and activities for |
7,159 | prevention of GBS disease. AAP, American Academy of Pediatrics; ACOG, American College of Obstetricians and Gynecologists. (Adapted from Jordan HT, Farley MM, Craig A, et al. Re visiting the need for vaccine prevention of late onset neonatal group B streptococcal disease: a multistate, population based analysis. Pediatr Infect Dis J. 2008;27:10571064.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 230 u Group B Streptococcus 1717 more efficiently in vitro than are strains of other serotypes, although studies using acapsular mutant strains demonstrate that the capsule by itself does not facilitate cellular invasion. A single clade of type III GBS is highly associated with late onset disease and meningitis. This clonal group, ST 17, produces a surface anchored protein called hypervirulent GBS adhesin (HvgA) that is not present in other GBS isolates. HvgA contributes to GBS adherence to intestinal and endo thelial cells and mediates invasion into the central nervous system (CNS) in an experimental infection model in mice. Other putative GBS virulence factors include GBS surface proteins, which may play a role in adhesion to host cells; C5a peptidase, which is postulated to inhibit the recruitment of polymorphonuclear cells to sites of infec tion; hemolysincytolysin, which has been associated with cell injury in vitro; and hyaluronidase, which has been postulated to act as a spreading factor in host tissues. In a classic study of pregnant women colonized with type III GBS, those who gave birth to healthy infants had higher levels of capsular polysaccharide specific antibody than those who gave birth to infants who developed invasive disease. In addition, there is a high correlation between antibody titer to GBS type III in the mother and titer in the paired infants. These observations indicate that transplacental trans fer of maternal antibody is critically involved in neonatal immunity to GBS. Optimal immunity to GBS also requires an intact complement system. The classical complement pathway is an important compo nent of GBS immunity in the absence of specific antibody; in addition, antibody mediated opsonophagocytosis may proceed by the alternative complement pathway. These and other results indicate that anticapsular antibody can overcome the prevention of C3 deposition on the bacterial surface by the sialic acid component of the type III capsule. The precise steps between GBS colonization and invasive disease remain unclear. In vitro studies showing GBS entry into alveolar epi thelial cells and pulmonary vasculature endothelial cells suggest that GBS may gain access to the bloodstream by invasion from the alveolar space, perhaps after intrapartum aspiration of infected amniotic fluid. hemolysincytolysin may facilitate GBS entry into the bloodstream after inoculation into the lungs. Other studies have demonstrated intestinal GBS colonization preceding invasive disease among new borns, suggesting translocation across the intestinal wall as a patho genic mechanism. GBS induces the release of proinflammatory cytokines. The group B antigen and the peptidoglycan component of the GBS cell |
7,160 | wall are potent inducers of tumor necrosis factor release in vitro, whereas purified type III capsular polysaccharide is not. Even though the cap sule plays a central role in virulence through avoidance of immune clearance, the capsule does not directly contribute to cytokine release and the resultant inflammatory response. The complete genome sequences of hundreds of GBS strains have been reported, facilitating a genomic approach to better understand ing GBS. Analysis of these sequences shows that GBS is closely related to Streptococcus pyogenes and Streptococcus pneumoniae. Many known and putative GBS virulence genes are clustered in the genome in patho genicity islands that also contain mobile genetic elements, suggesting that interspecies acquisition of genetic material plays an important role in genetic diversity. CLINICAL MANIFESTATIONS Two syndromes of neonatal GBS disease are distinguishable on the basis of age at presentation, epidemiologic characteristics, and clini cal features (Table 230.1). Early onset neonatal GBS disease presents within the first 6 days of life and is often associated with maternal obstetric complications, including chorioamnionitis, prolonged rup ture of membranes, and premature labor. Infants may appear ill at the time of delivery, and most infants become ill within 24 hours of birth. In utero infection may result in septic abortion or immediate distress after birth. More than 80 of early onset GBS disease pres ents as sepsis; pneumonia and meningitis are other common mani festations. Asymptomatic bacteremia is uncommon but can occur. In symptomatic patients, nonspecific signs such as hypothermia or fever, irritability, lethargy, apnea, and bradycardia may be present. Respi ratory signs are prominent regardless of the presence of pneumonia and include cyanosis, apnea, tachypnea, grunting, flaring, and retrac tions. A fulminant course with hemodynamic abnormalities, including tachycardia, acidosis, and shock, may ensue. Persistent fetal circulation may develop. Clinically and radiographically, pneumonia associated with early onset GBS disease is difficult to distinguish from respira tory distress syndrome. Patients with meningitis often present with nonspecific findings as described for sepsis or pneumonia, with more specific signs of CNS involvement initially absent. Late onset neonatal GBS disease presents at 7 days of life. Most cases occur within the first 3 months of life, but later presentations are also possible. Like early onset disease, late onset illness usually mani fests as bacteremia (4565), often accompanied by meningitis (25 35). Focal infections involving bone and joints, skin and soft tissue, the urinary tract, or lungs may also be seen. Cellulitis and adenitis are often localized to the submandibular or parotid regions. In contrast to early onset disease, maternal obstetric complications are not risk fac tors for the development of late onset GBS disease. Infants with late onset disease are often less severely ill on presentation than infants with early onset disease, and the disease is often less fulminant. Invasive GBS disease in children beyond early infancy is uncom mon. Bacteremia without a focus is the most common syndrome associated with childhood GBS disease beyond early infancy. Focal infections may include meningitis, pneumonia, endocarditis, and bone and joint infections. |
7,161 | DIAGNOSIS A major challenge is distinguishing between respiratory distress syn drome and invasive neonatal GBS infection in preterm infants because the two illnesses share clinical and radiographic features. Severe apnea, early onset of shock, abnormalities in the peripheral leukocyte count, and greater lung compliance may be more likely in infants with GBS disease. Other neonatal pathogens, including Escherichia coli and Liste ria monocytogenes, may cause illness that is clinically indistinguishable from that caused by GBS. Table 230.1 Characteristics of Early and Late Onset Group B Streptococcus Disease EARLY ONSET DISEASE LATE ONSET DISEASE Age at onset 0 6 days 7 90 days Increased risk after obstetric complications Yes No Common clinical manifestations Sepsis, pneumonia, meningitis Bacteremia, meningitis, osteomyelitis, other focal infections Common serotypes Ia, III, V Ia, III Case fatality rate 4.5 3.3 Adapted from Seale AC, Bianchi Jassir F, Russell NJ, et al. Estimates of the burden of Group B streptococcal disease worldwide for pregnant women, stillbirths, and children. Clin Infect Dis. 2017;65(Suppl 2):S200S219. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1718 Part XV u Infectious Diseases The diagnosis of invasive GBS disease is established by isolation and identification of the organism from a normally sterile site, such as blood, urine, or cerebrospinal fluid (CSF). Isolation of GBS from gas tric or tracheal aspirates or from skin or mucous membranes indicates colonization and is not diagnostic of invasive disease. CSF should be examined in all neonates suspected of having sepsis because specific CNS signs are often absent in the presence of meningitis, especially in early onset disease. Antigen detection methods that use group B polysaccharidespecific antiserum, such as latex particle agglutina tion, are available for testing of urine, blood, and CSF, but these tests are less sensitive than culture. Moreover, antigen is often detected in urine samples collected by bag from otherwise healthy neonates who are colonized with GBS on the perineum or in the rectum. Commer cially available methods for polymerase chain reaction (PCR) ampli fication of GBS specific DNA sequences from blood or CSF samples are increasingly available, allowing earlier presumptive diagnosis than traditional culture. When possible, PCR based diagnosis should be verified with a sterilely obtained culture; however, in certain cases the PCR result may be more accurate than the culture. A common example is a PCR performed on CSF sampled from an infant who has already received empiric antibiotic therapy, in which case the culture may remain negative despite the persistence of PCR detectable GBS DNA. Test results must therefore be interpreted in the context of a patients specific clinical history. LABORATORY FINDINGS Frequently present are abnormalities in the peripheral white blood cell count, including an increased or decreased absolute neutrophil count, elevated band count, increased ratio of bands to total neutrophils, or leukopenia. An elevated C reactive protein level has been investigated as a potential early marker, |
7,162 | but this test is nonspecific and cannot be used in isolation to diagnose GBS disease. Findings on chest radiograph are often indistinguishable from those of respiratory distress syndrome and may include reticulogranular patterns, patchy infiltrates, general ized opacification, pleural effusions, or increased interstitial markings. GBS meningitis is diagnosed based on a positive microbiologic test (culture or PCR), usually in combination with elevated CSF protein levels, leukocytic infiltration, and hypoglycorrhachia (decreased CSF glucose concentration). TREATMENT Penicillin G is the treatment of choice for confirmed GBS infection. Empirical therapy of neonatal sepsis that could be caused by GBS gen erally includes ampicillin and an aminoglycoside, both for the need for broad coverage pending organism identification and for synergistic bactericidal activity. Once GBS has been definitively identified and a good clinical response has occurred, therapy may be completed with penicillin alone. Especially in patients with meningitis, high doses of penicillin (450,000 500,000 unitskgday) or ampicillin (300 mgkg day) are recommended because of the relatively high mean inhibitory concentration (MIC) of penicillin for GBS and the potential for a high initial CSF inoculum. The duration of therapy varies according to the site of infection and should be guided by clinical circumstances (Table 230.2). Extremely ill near term patients with respiratory failure have been successfully treated with extracorporeal membrane oxygenation. Although some experts recommend that, in culture proven menin gitis, additional CSF be sampled at 24 48 hours to determine whether sterility has been achieved, there is no strong evidence to support this practice. A repeat lumbar puncture, preferably paired with intracra nial imaging such as MRI or CT, may be considered in patients with persistent neurologic symptoms after initiation of appropriately dosed antibiotics. The purpose in such a case is to rule out the presence of an abscess or other focal nidus of infection that may be escaping effective antibiotic exposure. For recurrent neonatal GBS disease, standard intravenous anti biotic therapy recommendations for the infant should be followed. GBS recurrence can be caused by contaminated breast milk. Therefore breastfed infants with more than one episode of GBS infection should receive formula or pasteurized breast milk until expressed breast milk can be cultured for the presence of GBS. If breast milk contamination is confirmed, the mother should be counseled to consider a 5 to 7 day course of amoxicillin or rifampin to eradicate GBS carriage, followed by retesting of the milk. PROGNOSIS Studies from the 1970s and 1980s showed that up to 30 of infants surviving GBS meningitis had major long term neurologic sequelae, including developmental delay, spastic quadriplegia, microcephaly, sei zure disorder, cortical blindness, or deafness. A study of infants who survived GBS meningitis diagnosed from 1998 through 2006 found that 19 had severe neurologic impairment and 25 had mild to moderate impairment at long term follow up. Periventricular leuko malacia and severe developmental delay may result from GBS disease and accompanying shock in premature infants, even in the absence of meningitis. The outcome of focal GBS infections outside the CNS is generally favorable. |
7,163 | In 2015, a global survey on the impact of GBS disease found the case fatality rates associated with early and late onset neonatal GBS disease in developed countries were 4.5 and 3.3, respectively. Case fatality rates were higher in developing countries. Mortality is higher in premature infants; one study reported a case fatality rate of 30 in infants at gestational age 33 weeks and 2 in those 37 weeks. The case fatality rate in children age 3 months to 14 years was 9 and was 11.5 in nonpregnant adults. PREVENTION Persistent morbidity and mortality from perinatal GBS disease despite advances in neonatal care have spurred intense investigation into modes of prevention. Two basic approaches to GBS prevention have been investigated: elimination of colonization from the mother or infant (chemoprophylaxis) and induction of protective immunity (immunoprophylaxis). Chemoprophylaxis Administration of antibiotics to pregnant women before the onset of labor does not reliably eradicate maternal GBS colonization and is not an effective means of preventing neonatal GBS disease. Interruption of neonatal colonization is achievable through administration of anti biotics to the mother during labor. Infants born to GBS colonized women with premature labor or prolonged rupture of membranes who were given intrapartum chemoprophylaxis had a substantially lower rate of GBS colonization (9 vs 51) and early onset disease (0 vs 6) than did the infants born to women who were not treated. Maternal postpartum febrile illness was also decreased in the treatment group. In the mid 1990s, guidelines for chemoprophylaxis were issued that specified administration of intrapartum antibiotics to women identi fied as high risk by either culture based or risk factorbased criteria. These guidelines were revised in 2002 after epidemiologic data indi cated the superior protective effect of the culture based approach in the prevention of neonatal GBS disease, and further revised guidelines Table 230.2 Recommended Duration of Therapy for Manifestations of Group B Streptococcus Disease TREATMENT DURATION Bacteremia without a focus 10 days Uncomplicated meningitis 14 days Ventriculitis At least 4 wk Septic arthritis or osteomyelitis 3 4 wk Data from the American Academy of Pediatrics. Group B streptococcal infections. In Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2021 2024 Report of the Committee on Infectious Diseases, 32nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 2021:707713. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 230 u Group B Streptococcus 1719 were issued in 2010 and 2020. According to current recommendations, vaginorectal GBS screening cultures or PCR testing (where avail able) should be performed for all pregnant women at 36 07 to 37 67 weeks of gestation, except for those with GBS bacteriuria during the current pregnancy or a previous infant with invasive GBS disease. Any woman with a positive prenatal screening culture, GBS bacteriuria during pregnancy, or a previous infant with inva sive GBS disease should receive intrapartum |
7,164 | antibiotics. Women whose culture status is unknown (culture not done, incomplete, or results unknown) and present in labor with a substantial risk of preterm birth, prolonged rupture of membranes (18 hr), or intra partum fever (38C 100.4F) should also receive intrapartum che moprophylaxis (Table 230.3). Routine intrapartum prophylaxis is not recommended for women with GBS colonization undergoing planned cesarean delivery who have not begun labor or had rup ture of membranes. Penicillin remains the preferred agent for maternal chemoprophy laxis because of its narrow spectrum and the universal penicillin susceptibility of GBS isolates associated with human infection (Fig. 230.2). Ampicillin is an acceptable alternative. If amnionitis is sus pected, broad spectrum antibiotic therapy that includes an agent active against GBS should replace GBS prophylaxis. Occasional GBS isolates have demonstrated increased MICs to penicillin and other lactam antibiotics in association with mutations in penicillin binding proteins. However, the clinical significance of these higher MIC val ues is unclear. Table 230.3 Summary and References for GBS PreventionTreatment Guidelines AT RISK POPULATION KEY PREVENTION TREATMENT PRACTICES PRACTICE GUIDELINE GOVERNING BODY Women with history of a previous neonate with invasive GBS disease Administer IAP during labor ACOG Women with GBS bacteriuria during current pregnancy Administer IAP during labor ACOG Women with uncomplicated pregnancy Perform prospective GBS colonization screening at 36 07 to 37 67 weeks of gestation ACOG Administer IAP to colonized women during labor Women who present in term labor with unknown GBS status may qualify for IAP depending on additional clinical details Mothers with PROM, preterm labor, preterm intraamniotic infection, and unknown GBS colonization status Administer IAP ACOG Term or late preterm (34 wk) newborns with risk factors for GBS infection For persistent clinical symptoms consistent with sepsis, obtain a blood culture and start empiric antibiotics with anti GBS activity AAP Redbook AAP Pediatrics In the absence of clinical symptoms, three possible approaches are available: 1. Categorical risk based management 2. Use of an online Bayesian sepsis risk calculator to guide management 3. Serial observation of the infant Preterm newborns 34 wk with risk factors for GBS For persistent clinical symptoms consistent with sepsis, obtain a blood culture and start empiric antibiotics with anti GBS activity AAP Redbook AAP Pediatrics If delivery followed spontaneous preterm labor, PROM, or concern for intraamniotic infection, obtain a blood culture and administer empiric antibiotics If delivery followed induction of labor and there was concern for intraamniotic infection or if IAP was indicated but not provided, obtain a blood culture and administer empiric antibiotics Infants with signs of late onset GBS disease For empiric therapy of late onset GBS disease in those who are not critically ill and in whom meningitis is not suspected, initial empiric therapy with ampicillin plus either gentamicin or cefotaxime is appropriate. If meningitis is suspected, ampicillin plus cefotaxime is recommended AAP Redbook Infants born by cesarean section for maternal indications with no preceding labor or ROM: postnatal management should be guided by the newborns clinical status and subsequent risk of GBS exposure. |
7,165 | AAP, American Academy of Pediatrics; ACOG, American College of Obstetrics and Gynecology; IAP, Intrapartum antibiotic prophylaxis; PROM, Preterm rupture of membranes Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1720 Part XV u Infectious Diseases For women who report a penicillin allergy but who have not under gone formal sensitivity testing, the American College of Obstetrics and Gynecology recommends allergy skin testing, which can be per formed safely during pregnancy. Because of frequent resistance of GBS to clindamycin (up to 46), first generation cephalosporins (such as cefazolin) should be used for intrapartum chemoprophy laxis for penicillin intolerant women with a low risk of anaphylaxis. For penicillin allergic women at high risk for anaphylaxis, clindamy cin should be used only if isolates are demonstrated to be susceptible. Vancomycin should be used if isolates are resistant to, or demonstrate inducible resistance to, clindamycin or if clindamycin susceptibility is unknown. In 2019, the American Academy of Pediatrics (AAP) published updated guidelines with recommendations for prevention of early onset GBS disease in newborns with risk factors (see Table 230.3). These replaced earlier prevention guidelines released by the AAP and Centers for Disease Control and Prevention. A key point of these revised recommendations is that newborns with risk factors for GBS disease (such as inadequately treated maternal colonization or preterm delivery) who have persistent signs of infection after birth (beyond those attributable to transitional physiology) should undergo a laboratory evaluation that includes a blood culture and should receive empiric antibiotic therapy until infection has been ruled out. For asymptomatic or minimally symptomatic infants born after 35 07 weeks of gestation, the extent of newborn evaluation and the decision to institute empiric antibiotics may be guided by one of three systems for risk assessment: a categorical decision chart based on the presence or absence of specific risk factors, repeated clinical evaluations, or a validated online sepsis calculator tool, developed from large datasets, which can estimate a newborns risk of early onset disease based on historical factors and clinical presenta tion. For infants born before 35 07 weeks of gestation, the AAP recommends a blood culture and empiric antibiotics in all cases where spontaneous preterm labor, preterm rupture of the mem branes, or any concern of intraamniotic infection preceded birth. Empiric treatment is also recommended in any case of a vaginal delivery before 35 07 weeks in which maternal chemoprophylaxis was indicated but not administered (see Table 230.3). Increasingly, there is recognition that decisions about whether to start empiric antibiotics for well appearing infants with sepsis risk factors must also take into consideration the local resources available for systematic, serial examination. In medical environments where well trained staff are available for careful, repeated observations of the newborn for 36 48 hours after birth, the threshold for initiating empiric antibiotics may be higher than sites where serial examinations are not possible. Of |
7,166 | note, in the era of maternal chemoprophylaxis, most cases of early onset disease are seen in infants born to women with negative prenatal screening cultures. Data from a large epidemio logic study indicate that the administration of maternal intrapartum antibiotics does not change the clinical spectrum or delay the onset of clinical signs in infants who developed GBS disease despite maternal prophylaxis. A significant concern with maternal intrapartum chemopro phylaxis has been that large scale antibiotic use among parturient women might lead to increased rates of antimicrobial resistance or infection in infants with organisms other than GBS, but this has not been borne out. In a population based study of early onset neonatal infection from 2005 to 2014, the incidence of early onset sepsis both overall and caused by E. coli remained stable. At present, the sub stantial decline in early onset neonatal GBS disease favors continued broad scale intrapartum chemoprophylaxis, but continued surveil lance is required. A limitation of the maternal chemoprophylaxis strategy is that intra partum antibiotic use is unlikely to have an impact on late onset neo natal disease, miscarriages, or stillbirths attributed to GBS or adult GBS disease. In addition, with wider implementation of maternal chemo prophylaxis, an increasing percentage of early onset neonatal disease has been detected in patients born to women with negative cultures, that is, false negative screens. Maternal Immunization Human studies demonstrate that transplacental transfer of naturally acquired maternal antibody to the GBS capsular polysaccharide protects newborns from invasive GBS infection and that efficient transplacental passage of vaccine induced GBS antibodies occurs. Conjugate vaccines composed of the GBS capsular polysaccharides coupled to carrier proteins have been produced for human use. In early clinical trials, conjugate GBS vaccines were well tolerated and induced levels of functional antibodies well above the range believed to be protective in 90 of recipients. A trivalent vaccine containing three subtypes of GBS capsule polysaccharide coupled to CRM197 was safely administered to pregnant women in a phase 2 clinical trial, eliciting functionally active type specific antibodies that were efficiently transported to the fetus remaining detectable in the newborn. A more recent hexavalent vaccine candidate led to protective antibodies against six GBS capsular subtypes in experi mental animal pregnancy models and generated robust antibody elaboration in nonpregnant adults in a phase 12 trial. Vaccines containing GBS surface proteins have been considered as a means to provide serotype independent GBS protection, and availability of whole genome sequencing has enabled identification of vaccine protein candidates. A successful GBS maternal vaccine administered before or during pregnancy should lead to transplacental passage of vaccine induced antibody that protects the fetus and newborn against infection by several GBS serotypes. Such a vaccine would eliminate the need for cumbersome cultures during pregnancy, circumvent the various risks associated with large scale antibiotic prophylaxis, likely have an impact on both early and late onset disease, and provide a prevention strategy in middle and low income countries, where maternal chemoprophy laxis may not be feasible. Intrapartum chemoprophylaxis will likely |
7,167 | remain an important aspect of prevention, particularly for women in whom opportunities for GBS immunization are missed and for infants born so early that levels of transplacentally acquired antibodies may not be high enough to be protective. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 80 20 40 P er ce nt r es is ta nt 60 0 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18 20 19 Year Erythromycin Clindamycin Cefotaxime Penicillin Vancomycin Fig. 230.2 GBS antibiotic resistance rates measured through Centers for Disease Control and Prevention active bacterial core surveillance, 2006 2019. Resistant includes those isolates intermediate or fully re sistant to antibiotics tested. Before 2011, only constitutive resistance to clindamycin was tested. In 2011 and beyond, both constitutive and inducible resistance to clindamycin were tested. (Courtesy Centers for Disease Control and Prevention.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 231 u NonGroup A or B Streptococci 1721 The genus Streptococcus is exceptionally diverse and includes the major human pathogens Streptococcus pyogenes (group A Streptococcus Strep tococcus agalactiae (group B Streptococcus), and Streptococcus pneu moniae (Table 231.1). Other important pathogens include large colony species bearing groups C and G Lancefield antigens and numerous small colony variants that may or may not express Lancefield carbo hydrate antigen included among the viridans streptococci (see Table 231.1). This chapter focuses on Streptococcus dysgalactiae subspecies equisimilis (SDSE), commonly known as group C and G streptococci, while Chapter 228 discusses S. pneumoniae and Chapter 232 discusses enterococci. All members of the genus Streptococcus are gram positive, catalase negative organisms. Lancefield carbohydrate antigen, hemolytic activ ity, and colony morphology have classically been used to further distinguish and classify streptococci. These features provide a useful framework for the clinician and are still the most commonly used classification schema. However, grouping based on these phenotypic features does not precisely correlate with genetic relatedness, and it is becoming clear that disease propensity is better correlated with sequence homology than Lancefield grouping or hemolytic activity. In this chapter, groups C and G streptococci refer exclusively to the large colony forming organisms, often called S. pyogeneslike, as their microbiologic and clinical features tend to mimic those of group A Streptococcus. Despite their different Lancefield antigens, the large colony forming C and G streptococci are grouped together as SDSE. The remaining large colony group C streptococci, predominantly animal pathogens, are grouped as S. dysgalactiae subspecies dysgalac tiae. Nonhuman group G isolates are often considered part of a single species designated Streptococcus canis and are genetically distinct from the SDSE group G organisms. The groups C and G streptococci share a number of virulence factors with S. pyogenes, including the production of streptolysin O, M protein, streptococcal pyrogenic exotoxin B, and hyaluronidase. The M protein |
7,168 | is similar to that of S. pyogenes and may account for the postinfectious glomerulonephritis that is occasionally seen after infection with these organisms. A toxic shocklike syndrome associated with groups C and G streptococcal infection has been related to M protein type and pro duction of a pyrogenic exotoxin by SDSE. SDSE are common habitants of the pharynx, being detected in up to 5 of asymptomatic children. Other potential sites of colonization include the skin and gastrointestinal tract. Colonization of the vagina is reported and may be the source of occasional SDSE isolated from the umbilicus of healthy neonates. Clinical manifestations of disease caused by SDSE overlap those of S. pyogenes. In children, these organisms are implicated most commonly in pharyngitis. The true role of these organisms as a cause of pharyngi tis is difficult to determine because asymptomatic colonization is com mon. Nevertheless, several epidemics of SDSE pharyngitis have been reported, including foodborne outbreaks. A large study from Sweden recently demonstrated similar rates of detection of S. pyogenes (15) and SDSE (14) in children with pharyngitis. S. pyogenes was most prevalent in young children, whereas SDSE predominated in older children and adolescents. The clinical presentation of SDSE is indis tinguishable from S. pyogenesassociated pharyngitis. Isolated case reports have described SDSE pneumonia in children, which is com monly complicated by abscess formation, empyema, and bacteremia. Additional respiratory infections include rare reports of epiglottitis and sinusitis. SDSE are a significant cause of skin and soft tissue infections. As with S. pyogenes, lymphangitis can complicate superficial infections caused by SDSE. Necrotizing fasciitis caused by SDSE is being described with increasing frequency. Musculoskeletal infections, particularly pyogenic arthritis, occasionally are caused by SDSE. Pediatric cases are uncom mon but may be increasing in incidence. Chapter 231 NonGroup A or B Streptococci David B. Haslam Table 231.1 Relationship of Large Colony Streptococci Identified by Hemolysis and Lancefield Grouping to Sites of Colonization and Disease GROUP A STREPTOCOCCUS (S. pyogenes) GROUP B STREPTOCOCCUS (S. agalactiae) OTHER HEMOLYTIC STREPTOCOCCI VIRIDANS STREPTOCOCCI Hemolysis Lancefield group A B C H, K V Especially C and G Species or strains M types (180) Serotypes (Ia, Ib, II, III, IV, V, VI, VII, and VIII) S. dysgalactiae subspecies equisimilis S. dysgalactiae subspecies dysgalactiae S. canis Streptococcus bovis Streptococcus mitis Streptococcus mutans Streptococcus sanguis Many others Normal flora Pharynx, skin, anus Gastrointestinal and genitourinary tract Pharynx, skin, gastrointestinal and genitourinary tracts Pharynx, nose, skin, genitourinary tract Common human diseases Pharyngitis, tonsillitis, erysipelas, impetigo, septicemia, wound infections, necrotizing fasciitis, cellulitis, meningitis, pneumonia, scarlet fever, toxic shocklike syndrome, rheumatic fever, acute glomerulonephritis Puerperal sepsis, chorioamnionitis, endocarditis, neonatal sepsis, meningitis, osteomyelitis, pneumonia Wound infections, cellulitis, necrotizing fasciitis, pneumonia, endocarditis, brain abscess, sepsis, nosocomial infections, opportunistic infections Endocarditis, human bite infections , Partial hemolysis; , complete hemolysis; , no hemolysis (nonhemolytic). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1722 |
7,169 | Part XV u Infectious Diseases Reactive arthritis has been described after SDSE infection; however, unlike S. pyogenes, the association between SDSE infection and acute rheumatic fever has not clearly been defined, and antibiotic prophy laxis is not recommended after reactive arthritis with this organism. Endocarditis, bacteremia, brain abscess, and toxic shock syndrome caused by SDSE have all been described but are uncommon in chil dren. These infections generally occur in children with immune defi cits or in adolescents after delayed recognition of sinusitis. These organisms can cause neonatal septicemia similar to early onset group B streptococcal disease. Risk factors include prematurity and prolonged rupture of membranes. Respiratory distress, hypoten sion, apnea, bradycardia, and disseminated intravascular coagulation may be seen, and associated maternal infection is common. Neonatal toxic shock syndrome associated with SDSE has also been described. Treatment of SDSE infections is similar to that of S. pyogenes. These organisms retain susceptibility to penicillin and other lactams. Other agents with reliable activity include linezolid, daptomycin, and vanco mycin, though occasional isolates demonstrate tolerance to vancomy cin. Clindamycin and macrolides have poor bactericidal activity against these organisms, and resistance rates are significant. Resistance to qui nolones is reported, and up to 70 of SDSE are resistant to tetracycline. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Enterococcus has long been recognized as a pathogen in select popula tions and has become a common and particularly troublesome cause of hospital acquired infection in recent years. Enterococci were formerly classified with Streptococcus bovis and Streptococcus equinus as Lance field group D streptococci but are now placed in a separate genus and are notorious for their propensity to cause infection in compromised hosts and frequent resistance to antibiotics. ETIOLOGY Enterococci are gram positive, catalase negative facultative anaerobes that grow in pairs or short chains. Most are nonhemolytic (also called hemolytic) on sheep blood agar, although some isolates have or hemolytic activity. Enterococci are distinguished from most Lancefield groupable streptococci by their ability to grow in bile and hydrolyze esculin. They are able to grow in 6.5 NaCl and hydrolyze L pyrrolidonyl naphthylamide, features used by clinical laboratories to distinguish enterococci from group D streptococcus. Identification at the species level is enabled by differing patterns of carbohydrate fermentation. EPIDEMIOLOGY Enterococci are normal inhabitants of the gastrointestinal tract of humans and organisms throughout the animal kingdom, suggest ing they are highly evolved to occupy this niche. Oral secretions and dental plaque, the upper respiratory tract, skin, and vagina may also be colonized by these organisms. Enterococcus faecalis is the predomi nant enterococcal species, with colonization commonly occurring in the first week of life. By the time of adulthood, E. faecalis coloniza tion is nearly ubiquitous. Enterococcus faecium colonization is less con sistent, although approximately 25 of adults harbor this organism. Disruption of the normal intestinal microbiota by antibiotic exposure or hematopoietic stem cell transplantation markedly enriches for fecal enterococcal abundance and dramatically increases the risk of subse quent bloodstream infection (BSI). E. faecalis accounts for approximately 80 of |
7,170 | enterococcal infec tions, with almost all of the remaining infections caused by E. faecium. Chapter 232 Enterococcus David B. Haslam Only rarely are other species, such as Enterococcus gallinarum and Enterococcus casseliflavus, associated with invasive infection, but these organisms are notable for their intrinsic low level vancomy cin resistance. Whole genome sequencing suggests that the patients indigenous flora is the source of enterococcal infection in most cases. However, direct spread from person to person or from contaminated medical devices may occur, particularly within newborn nurseries and intensive care units, where nosocomial spread has resulted in hospital outbreaks. PATHOGENESIS Enterococci are not aggressively invasive organisms, usually causing disease only in children with damaged mucosal surfaces or an impaired immune system. Their dramatic emergence as a cause of nosocomial infection is predominantly a result of their resistance to antibiotics commonly used in the hospital setting. Hospital associated enterococci generally lack CRISPR (clustered regularly interspaced short palin dromic repeats) elements that defend against phage mediated hori zontal gene transfer, an important source of antimicrobial resistance genes. Secreted and cell surface molecules are implicated in pathogen esis. Adhesion promoting factors such as the surface protein Eps likely account for the propensity of these organisms to cause endocarditis and urinary tract infections (UTIs). The ability to form biofilms likely facilitates the colonization of urinary and vascular catheters. Other proposed virulence factors include cytolysin, aggregation substance, gelatinase, and extracellular superoxide. Antimicrobial Resistance Enterococci are highly resistant to cephalosporins and semisynthetic penicillins such as nafcillin, oxacillin, and methicillin. They are moder ately resistant to extended spectrum penicillins such as ticarcillin and carbenicillin. Ampicillin and penicillin are the most active lactams against these organisms. Some strains of E. faecalis and E. faecium dem onstrate decreased resistance to lactam antibiotics because of muta tions in one of the penicillin binding proteins. In addition, occasional strains of E. faecalis produce a plasmid encoded lactamase similar to that found in Staphylococcus aureus. These isolates are completely resistant to penicillins, necessitating the combination of a penicillin plus a lactamase inhibitor or the use of imipenem or vancomycin. Any active drug may be insufficient if used alone for serious infections wherein high bactericidal activity is desired (Tables 232.1 and 232.2). All enterococci have intrinsic low level resistance to aminogly cosides because these antibiotics are poorly transported across the Enterococcus cell wall. Concomitant use of a cell wallactive agent, such as a lactam or glycopeptide antibiotic, improves the permeability of the cell wall for the aminoglycosides, resulting in synergistic killing. However, some isolates demonstrate high level resistance, defined as mean inhibitory concentration (MIC) 2,000 gmL and a result of modification or inactivation of aminoglycoside agents. Strains demon strating high level resistance and even some isolates with moderate level resistance are not affected synergistically by aminoglycosides and cell wallactive antibiotics. Table 232.1 Intrinsic Resistance Mechanisms Among Enterococci ANTIMICROBIAL MECHANISM Ampicillin, penicillin Altered binding protein Aminoglycoside (low level) Decreased permeability, altered ribosomal binding Clindamycin Altered ribosomal binding Erythromycin Altered ribosomal binding Tetracyclines Efflux pump Trimethoprim sulfamethoxazole |
7,171 | Utilize exogenous folate Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 232 u Enterococcus 1723 Resistance to almost all other antibiotic classes, including tetracy clines, macrolides, and glycopeptides, has been described among the enterococci, necessitating individual susceptibility testing for these antibiotics when their use is considered. Despite apparent susceptibility in vitro, trimethoprim sulfamethoxazole has poor activity in vivo and should not be used as the primary agent against enterococcal infections. Vancomycin has traditionally been effective against Enterococcus iso lates, but resistance to vancomycin, defined as MIC 32 gmL, and other glycopeptides, including teicoplanin, is increasingly common. The emer gence of vancomycin resistant Enterococcus (VRE) has become a major challenge in the care of hospitalized patients. In particular, mortality in patients with VRE BSIs is considerable, and treatment is complicated by frequent resistance of VRE to most other antibiotic classes. High level vancomycin resistance (MIC 64 gmL) can be transferred by way of conjugation and usually results from plasmid mediated transfer of the vanA gene. High level resistance is most common among E. faecium but is increasingly seen among E. faecalis isolates. Moderate level resis tance (MIC 8 256 gmL) results from a chromosomal homolog of vanA known as vanB. Isolates that harbor the vanB gene are only moderately resistant to vancomycin and initially demonstrate susceptibility to tei coplanin, although resistance can emerge during therapy. Resistance to newer agents, including linezolid and daptomycin, is rare thus far. Line zolid resistance is a result of mutations in the 26S ribosomal subunit, whereas daptomycin resistance is associated with pathogenic variants in genes required for membrane synthesis and repair. CLINICAL MANIFESTATIONS Enterococcus infections traditionally occurred predominantly in new born infants; infection in older children is increasingly common. Most enterococcal infections occur in patients with breakdown of normal physical barriers such as the gastrointestinal tract, skin, or urinary tract. Other risk factors for enterococcal infection include prolonged hospitalization, indwelling vascular catheters, prior use of antibiotics, and compromised immunity. Neonatal Infections Enterococcus accounts for up to 15 of all neonatal bacteremia and septicemia. Like group B streptococcus infections, enterococcal infec tions are seen in two distinct settings in neonatal patients. Early onset infection (7 days of age) may mimic early onset group B streptococcus septicemia but tends to be milder. Early onset enterococcal sepsis most often occurs in full term infants who are otherwise healthy. Late onset infection (7 days of age) is associated with risk factors such as extreme prematurity, presence of an intravascular catheter, or necrotizing entero colitis or follows an intraabdominal surgical procedure. Symptoms in late onset disease are more severe than those in early onset disease and include apnea, bradycardia, and deteriorating respiratory function. Focal infections such as scalp abscess and catheter infection are commonly associated. Mortality rates range from 6 in early onset septicemia to 15 in late onset infections associated with necrotizing enterocolitis. |
7,172 | Enterococci are an occasional cause of meningitis. In neonates in particular, meningitis usually occurs as a complication of septicemia. Alternatively, the organism may gain access to the central nervous sys tem by way of contiguous spread, such as through a neural tube defect or in association with an intraventricular shunt. Enterococcal meningi tis can be associated with minimal abnormality of cerebrospinal fluid. Infections in Older Children Enterococcus rarely causes UTIs in healthy children but accounts for approximately 15 of cases of nosocomially acquired UTIs in both children and adults. Presence of an indwelling urinary catheter is the major risk factor for nosocomial UTIs. Enterococcus is frequently isolated in intraabdominal infections after intestinal perforation or surgery. The significance of enterococci in polymicrobial infections has been questioned, although reported mortality rates are higher when intraabdominal infections include enterococci. Enterococcus is increasingly common as a cause of nosocomial bacteremia; these organisms accounted for approximately 10 of nosocomial BSIs in children, ranking second only to coagulase negative staphylococci. Predisposing factors for enterococcal bacteremia and endocarditis include an indwelling central venous catheter, gastrointestinal surgery, immunodeficiency, and cardiovascular abnormalities. Risk factors for vancomycin resistant enterococcal bacteremia include prolonged mechanical ventilation, immunosuppression, and recent vancomycin exposure. TREATMENT Treatment of invasive enterococcal infections must recognize that these organisms are resistant to antimicrobial agents frequently used as empirical therapy. In particular, cephalosporins should not be relied upon in situations where Enterococcus is known or suspected to be involved. In general, in the immunocompetent host, minor local ized infections caused by susceptible Enterococcus can be treated with ampicillin alone. Antibiotics containing lactamase inhibitors (clavu lanate or sulbactam) provide advantage only for the very few organ isms whose resistance is caused by the production of lactamase. In uncomplicated UTIs, nitrofurantoin is efficacious when the organism is known to be sensitive to this antibiotic. Invasive infections such as sepsis and meningitis have traditionally been treated with a combination of penicillin or ampicillin and an ami noglycoside when the isolate is susceptible. Recent experience suggests that adjunctive aminoglycosides may increase the risk of nephrotoxicity without improving outcomes in uncomplicated BSIs. Vancomycin can be substituted for the penicillins in allergic patients but should be used with an aminoglycoside because vancomycin alone is not bactericidal. Endo carditis from strains possessing high level aminoglycoside resistance may relapse even after prolonged therapy. Continuous infusion penicil lin or the combination of ampicillin plus ceftriaxone has been proposed for treatment of these infections in adults, yet ultimately valve replace ment may be necessary. In patients with catheter associated enterococ cal bacteremia, the catheter should be removed promptly in most cases, although salvage of infected lines has occurred with the combined use of ampicillin or vancomycin with an aminoglycoside. Treatment of Vancomycin Resistant Enterococci The treatment of serious infections caused by multiresistant, vancomycin resistant strains is particularly challenging. The two most commonly used antibiotics are linezolid and daptomycin. Linezolid, an oxazolidinone antibiotic that inhibits protein synthesis, is bac teriostatic against most E. faecium and E. faecalis isolates, including vancomycin resistant |
7,173 | isolates. Response rates to linezolid are generally over 90, including cases of bacteremia and sepsis, and this antibiotic is currently the only drug approved by the FDA for treatment of VRE infections. Anecdotal reports reveal the success of linezolid in treating meningitis caused by VRE. Unfortunately, as seen with other antibiot ics, linezolid resistance is documented, and nosocomial spread of resis tant organisms can occur. Linezolid frequently causes reversible bone marrow suppression after prolonged use and is associated with rare occurrences of lactic acidosis and irreversible peripheral neuropathy. Table 232.2 Acquired Resistance Mechanisms Among Enterococci ANTIMICROBIAL MECHANISM Ampicillin, penicillin (high level) Mutation of PBP5 Aminoglycoside (high level) Enzyme modification Quinolones DNA gyrase mutation Chloramphenicol Efflux pump Glycopeptide Altered cell wall binding Quinupristindalfopristin Ribosomal modification, efflux pump Linezolid Point mutation Daptomycin Unknown Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1724 Part XV u Infectious Diseases Serotonin syndrome may be seen in patients taking concomitant selec tive serotonin uptake inhibitor antidepressants. Newer oxazolidinones include tedizolid, which has better in vitro activity against enterococci and appears to have favorable pharmacokinetic and toxicity profiles when compared to linezolid. Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against a broad range of gram positive organisms. The antibiotic inserts into the bacterial cell wall, causing membrane depolarization and cell death. It has been approved for the treatment of adults with serious skin and soft tissue infections, right sided endocarditis, and bacteremia caused by susceptible organisms. Most strains of VRE (both E. faecium and E. faecalis) are susceptible to daptomycin in vitro, and daptomycin has become the first line agent for VRE treatment in many centers. How ever, treatment failures occur when administered at the standard dose of 6 mgkgday, necessitating higher treatment doses in patients with severe invasive infections. Furthermore, daptomycin dosages may need to be higher in children when compared with adults because of more rapid renal clearance. The addition of a lactam antibiotic, such as ampicillin or ceftaroline, may enhance activity of daptomycin and pro vide benefit over daptomycin alone for severe VRE infections, includ ing endocarditis. Daptomycin has unreliable activity in the lung and therefore should not be used as a sole agent to treat pneumonia. Resis tance of both S. aureus and Enterococcus to daptomycin has rarely been described, sometimes arising during therapy. Several studies and meta analyses have suggested that clinical outcomes of invasive VRE infection are similar when linezolid and daptomycin are used. However, infection related mortality remains significant, especially among adults, and alternative or combination therapies continue to be explored. Ceftaroline, a fifth generation cephalosporin with activity against methicillin resistant S. aureus, has activity against many E. faeca lis strains but is inadequate when used alone for the treatment of E. faecium. Newer tetracyclines have been developed with activity against VRE, including tigecycline, omadacycline, and eravacycline. Tigecycline is approved for use |
7,174 | in complicated intraabdominal and skin and soft tis sue infections but fails to achieve high serum concentrations and may be associated with treatment failure for VRE BSIs. Gastrointestinal side effects are common with tigecycline and may be intolerable. Experi ence with omadacycline and eravacycline in treatment of pediatric patients with VRE infection is lacking. Lipoglycopeptides are a newer class of antibiotics that possess a core structure similar to vancomycin with the addition of a lipid substituent. Lipoglycopeptides include telavancin, dalbavancin, and oritavancin. Only oritavancin has reliable activity against VRE, but resistance may develop, and thus far clinical experience in children is limited. PREVENTION Strategies for preventing enterococcal infections include timely removal of urinary and intravenous catheters and debridement of necrotic tissue. Infection control strategies, including surveillance cul tures, patient and staff cohorting, and strict gown and glove isolation, are effective at decreasing colonization rates with VRE. Unfortunately, these organisms may persist on inanimate objects such as stethoscopes, complicating efforts to limit their nosocomial spread. In order to pre vent the emergence and spread of vancomycin resistant organisms, the Centers for Disease Control and Prevention has developed a series of guidelines for prudent vancomycin use. Antibiotics with broad activity against anaerobic organisms are also thought to contribute to coloni zation with VRE, suggesting that prudent use of such antibiotics may also help limit spread of VRE. Decolonization strategies have been attempted but are generally ineffective in eradicating skin or gastro intestinal carriage of VRE. In particular, antimicrobial therapy is not indicated for this purpose. The role of probiotic agents in eliminating VRE colonization is currently unclear but may be a useful adjunct to prudent antimicrobial usage and other infection control interventions in limiting nosocomial spread of VRE. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 233 Diphtheria (Corynebacterium diphtheriae) Amruta Padhye and Stephanie A. Fritz Diphtheria is an acute toxic infection caused by toxin producing strains of Corynebacterium diphtheriae and, less often, by toxin producing strains of Corynebacterium ulcerans. Nontoxin producing C. diphtheriae can also cause disease, although less severe. C. ulcerans is more often isolated from animal sources and can cause human disease similar to C. diphtheriae. Although respiratory and cutaneous presentations of diphtheria are the most common, mortality is substantially higher with respiratory diphtheria. Classic respiratory diphtheria caused by toxigenic Cory nebacterium species is the main focus of World Health Organization (WHO) case surveillance. In the United States, the case definition was modified in 2019, and currently toxigenic cases of diphtheria, includ ing respiratory and nonrespiratory (e.g., skin, wound, conjunctiva, ear, genital mucosa) forms, are reportable to the Centers for Disease Con trol and Prevention (CDC). ETIOLOGY Corynebacteria are aerobic, nonencapsulated, nonspore forming, mostly nonmotile, pleomorphic, gram positive bacilli. C. diphtheriae is by far the most frequently isolated agent of diphtheria. Toxigenic C. ulcerans can cause mastitis in cattle and respiratory infections in animals and can spread to humans through close contact with secre tions. It can cause cutaneous and respiratory illnesses that are clini cally indistinguishable from diphtheria |
7,175 | in humans. Person to person transmission of C. ulcerans is possible, though not well established. A selective medium (e.g., cystine tellurite blood agar or Tinsdale agar) that inhibits growth of competing organisms is required for isolation and, when reduced by C. diphtheriae, renders colonies gray black. Differentiation of C. diphtheriae from C. ulcerans is based on urease activity; C. ulcerans is urease positive. Four C. diphtheriae biotypes (mitis, intermedius, belfanti, gravis) are capable of causing diphtheria and are differentiated by colony morphology, hemolysis, and fermen tation reactions. The ability of either C. diphtheriae or C. ulcerans to produce diphtheritic toxin results from acquisition of a lysogenic cory nebacteriophage, which encodes the diphtheritic toxin gene and con fers diphtheria producing potential in these strains. Demonstration of diphtheritic toxin production by the modified Elek test, an agar immu noprecipitin technique, alone or in conjunction with polymerase chain reaction (PCR) testing for carriage of the toxin gene, is necessary to confirm disease. Toxigenic and nontoxigenic strains are indistinguish able by colony type, microscopic features, or biochemical test results. EPIDEMIOLOGY Unlike other diphtheroids (coryneform bacteria), which are ubiquitous in nature, C. diphtheriae is an exclusive inhabitant of human mucous membranes and skin. Spread is primarily by respiratory droplets, direct contact with respiratory secretions of symptomatic individu als, or exudate from infected skin lesions. Asymptomatic respiratory tract carriage is important in transmission. In areas where diphtheria is endemic, 35 of healthy individuals can carry toxigenic organisms, but carriage is exceedingly rare in nonendemic areas. Skin infection and skin carriage are silent reservoirs of C. diphtheriae, and organisms can remain viable in dust or on fomites for up to 6 months. In the 1920s, 125,000 diphtheria cases and 10,000 diphtheriarelated deaths were reported annually in the United States, with the highest fatality Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 233 u Diphtheria (Corynebacterium diphtheriae) 1725 rates among very young and elderly persons. The incidence then began to decrease and, with widespread use of diphtheria toxoid in the United States after World War II, declined steadily through the late 1970s. From 1996 to 2018, only 14 cases of respiratory diphtheria, including 1 fatal case, were reported in the United States, an average of 1 case annually. During this same period, five cases of culture confirmed respiratory diphtheria like ill ness caused by toxigenic C. ulcerans were also identified. Despite the worldwide decrease in disease incidence, diphtheria remains endemic in many developing countries with poor immuniza tion rates against diphtheria. Since the introduction of toxoid immu nization, the disease has shifted from affecting children 15 years old to adults who lack natural exposure to toxigenic C. diphtheriae in the vaccine era and have low rates of booster immunization. The largest outbreak of diphtheria in the developed world since the 1960s occurred from 1990 to 1996 in the newly independent countries |
7,176 | of the former Soviet Union, involving 150,000 cases in 14 countries. Of these, 60 of cases occurred in individuals 14 years old. Case fatality rates ranged from 3 to 23 by country. Factors contributing to the epidemic included a large population of underimmunized adults, decreased childhood immunization rates, population migration, crowding, and failure to respond aggressively during early phases of the epidemic. Cases of diphtheria among travelers from these endemic areas were transported to many countries in Europe. WHO surveillance reports indicate that most cases of diphtheria worldwide occur in the Southeast Asia and Africa regions, reporting more than 10,000 cases worldwide in 2020. India contributes a sub stantial proportion to the global burden of diphtheria, with an average of over 4,000 cases annually reported to the WHO in the past decade. Although diphtheria was reduced from a major cause of childhood death to a medical rarity in the Western Hemisphere in the early 20th century, recurring reminders of the fragility of this success, particu larly in conflict areas, emphasize the need to continue vigorous pro motion of those same control principles across the global community. The largest diphtheria outbreak in the refugee setting occurred when the Rohingya people were displaced from Myanmar to Bangladesh in 2017, eventually lasting over 2 years and with 7064 cases and 45 deaths reported as of November 2019. Along with outbreaks in Venezuela, Haiti, Yemen, and more recently Nigeria, these are stark reminders of the threat of re emergence that vaccine preventable diseases pose. Improving surveillance, vaccination coverage, and public awareness of the disease are key for control of disease during outbreaks. When diphtheria was common, cutaneous diphtheria accounted for more than 50 of reported C. diphtheriae isolates in the United States. This indolent local infection, compared with mucosal infection, is associated with more prolonged bacterial shedding, greater contami nation of the environment, and increased transmission to the pharynx and skin of close contacts. Outbreaks are associated with homelessness, crowding, poverty, alcoholism, poor hygiene, contaminated fomites, underlying dermatosis, and introduction of new strains from exog enous sources. It is no longer a tropical or subtropical disease; 1,100 C. diphtheriae infections were documented in a Seattle neighborhood (the site of the last major U.S. outbreak) from 1971 to 1982; 86 were cuta neous, and 40 involved toxigenic strains. The incidence of C. diphthe riae isolates from cutaneous infections has risen dramatically over the past decade. Cutaneous diphtheria is an important source of toxigenic C. diphtheriae in the United States, and its importation from endemic areas is frequently the source of subsequent sporadic cases of respira tory tract diphtheria. Between 2015 and 2018, the CDC confirmed four cases of cutaneous diphtheria from toxin producing C. diphtheriae in U.S. residents returning from travel to endemic areas. Cutaneous diph theria caused by C. ulcerans from travel to tropical countries or animal contact has also been increasingly reported. In Europe, increasing reports of respiratory and systemic infections have been attributed to C. ulcerans; animal contact is the predominant risk |
7,177 | factor. In the United Kingdom, from 2008 to 2017, of the 33 toxi genic cases of diphtheria, just over half of the cases were caused by C. diphtheriae, and the remainder were caused by C. ulcerans. Most of the C. diphtheriae cases were cutaneous, while the C. ulcerans cases were equally respiratory and cutaneous. Travel to an endemic area was the major risk factor for C. diphtheriae acquisition, while contact with a companion animal was the major factor associated with acquisition of C. ulcerans. Incomplete vaccination status was strongly associated with the risk of hospitalization and death. PATHOGENESIS Both toxigenic and nontoxigenic strains of C. diphtheriae cause skin and mucosal infection and can rarely cause invasive disease, includ ing endocarditis and bacteremia. The organism usually remains in the superficial layers of skin lesions or respiratory tract mucosa, inducing a local inflammatory reaction. The major virulence of the organism lies in its ability to produce a potent polypeptide exotoxin, the diph theritic toxin, which inhibits protein synthesis and causes local tissue necrosis and the resultant local inflammatory response. Within the first few days of respiratory tract infection (usually in the pharynx), a dense necrotic coagulum of organisms, epithelial cells, fibrin, leukocytes, and erythrocytes forms, initially white and advancing to become a gray brown, leather like, adherent pseudomembrane (diphtheria is Greek for leather). Removal is difficult and reveals a bleeding, edematous sub mucosa. Paralysis of the palate and hypopharynx is an early local effect of diphtheritic toxin. Toxin absorption can lead to systemic manifes tations: kidney tubule necrosis, thrombocytopenia, cardiomyopathy, and demyelination of nerves. Because the latter two complications can occur 2 10 weeks after mucocutaneous infection, the pathophysiology in some cases is suspected to be immunologically mediated. Among infected adults in the Seattle outbreak, 3 with cutaneous infections and 21 with symptomatic nasopharyngeal infection demonstrated toxic myocarditis, neuropathy, or obstructive respiratory tract compli cations. All had received at least 20,000 units of equine antitoxin at the time of hospitalization. CLINICAL MANIFESTATIONS The manifestations of C. diphtheriae infection are influenced by the anatomic site of infection, the immune status of the host, and the pro duction and systemic distribution of toxin. Although 98 of infections occur in the respiratory tract, other sites include cutaneous, conjuncti val, ear, and vaginal mucosa. New estimates of epidemiologic and clinical aspects of diphthe ria from a comprehensive update by Truelove et al., with systematic reviews including recent literature, are summarized in Figure 233.1. Respiratory Tract Diphtheria The pharynx or tonsils is the most common location of infection in the respiratory tract (7594), followed by the larynx (25). Although the incubation period has traditionally been regarded to be 2 5 days (range 1 10 days), emerging data suggest that the median time from infec tion to onset of prodromal symptoms is only 1.4 days. An estimated 80 of untreated symptomatic cases progress to membranous diph theria in an average of 2 3 days after symptom onset. In tonsillar and pharyngeal diphtheria, sore throat is the universal early |
7,178 | symptom. Only half of patients have fever, and fewer have dysphagia, hoarseness, malaise, or headache. Mild pharyngeal injection is followed by unilat eral or bilateral tonsillar membrane formation, which can extend to involve the uvula (which may cause toxin mediated paralysis), soft pal ate, posterior oropharynx, hypopharynx, or glottic areas (Fig. 233.2). Underlying soft tissue edema and enlarged lymph nodes can cause a bull neck appearance. The degree of local extension correlates directly with profound prostration, bull neck appearance, and fatality caused by airway compromise or toxin mediated complications (Fig. 233.3). In infants, infection of the anterior nares is more common and causes serosanguineous, purulent, erosive rhinitis with membrane formation. Shallow ulceration of the external nares and upper lip is characteristic. The characteristic adherent pseudomembrane, extension beyond the faucial area, dysphagia, and relative lack of fever help differentiate diphtheria from exudative pharyngitis caused by Streptococcus pyo genes or Epstein Barr virus. Vincent angina, infective phlebitis with thrombosis of the jugular veins (Lemierre syndrome), and mucositis in patients undergoing cancer chemotherapy are usually differentiated by the clinical setting. Infection of the larynx, trachea, and bronchi Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1726 Part XV u Infectious Diseases Unvaccinated individual Vaccinated individual Infection with toxigenic Clostridium diphtheriae 30 Asymptomatic carriage 10 Prodromal symptoms develop 90 Asymptomatic carriage 70 Prodromal symptoms develop 80 Membranous diphtheria develops 20 Recovery without developing fulminant disease 550 Death from complications 5095 Recovery Fig. 233.1 Clinical manifestations of Clostridium diphtheriae infection among unvaccinated and vaccinated individuals. Among unvaccinated individuals infected with toxigenic C. diphtheriae, prodromal symptoms develop in 70, of whom 80 develop membranous diphtheria. Of those with membranous diphtheria, case fatality can be as high as 550. Among vaccinated individuals infected with toxigenic C. diphtheriae, the toxoid vaccine provides protection from symptoms; 10 develop prodromal symptoms, whereas 90 become asymptomatic carriers. These symptomatic vaccinated individuals have a lower risk of severe disease and death and are more likely to recover. (Adapted from Truelove SA, Keegan LT, Moss WJ, et al. Clinical and epidemiological aspects of diphtheria: a systematic review and pooled analysis. Clin Infect Dis. 2020;711:8997.) Fig. 233.2 Tonsillar diphtheria. (Courtesy Franklin H. Top, MD, Profes sor and Head of the Department of Hygiene and Preventive Medicine, State University of Iowa, College of Medicine, Iowa City, IA; and Parke, Davis Companys Therapeutic Notes.) Fig. 233.3 Diphtheria. Bull neck appearance of diphtheritic cervical lymphadenopathy. (From the Centers for Disease Control and Preven tion CDC. Public health image library PHIL, image 5325. Available at: https:phil.cdc.govDetails.aspx?pid5325.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 233 u Diphtheria (Corynebacterium diphtheriae) 1727 can be primary or a secondary extension from the pharyngeal infec tion, presenting with hoarseness, |
7,179 | stridor, dyspnea, and croupy cough. Differentiation from bacterial epiglottitis, severe viral laryngotracheo bronchitis, and staphylococcal or streptococcal tracheitis hinges par tially on the relative paucity of other signs and symptoms in patients with diphtheria and primarily on visualization of the adherent pseudo membrane at laryngoscopy and intubation. Patients with laryngeal diphtheria are at significant risk for suffocation because of local soft tissue edema and airway obstruction by the diphthe ria membrane. This progression of airway obstruction in laryngeal infec tion within 1 2 weeks after symptom onset is responsible for 6065 of overall deaths. Establishment of an artificial airway and resection of the pseudomembrane can be lifesaving, but further obstructive complica tions are common, and systemic toxic complications are inevitable. Cutaneous Diphtheria Classic cutaneous diphtheria is an indolent, nonprogressive infection characterized by a superficial, ecthyma like, nonhealing ulcer with a gray brown membrane. Diphtheria skin infections cannot always be differentiated from streptococcal or staphylococcal impetigo, and these conditions frequently coexist. In most cases, a primary process, such as dermatosis, laceration, burn, bite, or impetigo, becomes secondarily infected with C. diphtheriae. Extremities are more often affected than the trunk or head. Pain, tenderness, erythema, and exudate are typical. Local hyperesthesia or hypesthesia is unusual. Respiratory tract coloni zation or symptomatic infection with toxic complications occurs in the minority of patients with cutaneous diphtheria. Infection at Other Sites C. diphtheriae occasionally causes mucocutaneous infections at other sites, such as the ear (otitis externa), the eye (purulent and ulcerative conjunctivitis), and the genital tract (purulent and ulcerative vulvovag initis). The clinical setting, ulceration, membrane formation, and sub mucosal bleeding help differentiate diphtheria from other bacterial and viral causes. Rare cases of septicemia are described and are universally fatal. Sporadic cases of endocarditis occur, and clusters among intrave nous drug users have been reported in several countries; the skin was the probable portal of entry, and almost all strains were nontoxigenic. Sporadic cases of pyogenic arthritis, mainly from nontoxigenic strains, have been reported in adults and children. Diphtheroids isolated from sterile body sites should not be routinely dismissed as contaminants without careful consideration of the clinical setting. DIAGNOSIS Specimens for culture should be obtained from the nose and throat and any other mucocutaneous lesion. A portion of membrane should be removed and submitted for culture along with underlying exudate. The laboratory must be notified to use selective medium. C. diphtheriae survives drying. If obtained in a remote area, a dry swab specimen can be placed in a silica gel pack and sent to the laboratory. Evaluation of a direct smear using Gram stain or specific fluorescent antibody is unre liable. Culture isolates of coryneform organisms should be identified to the species level, and toxigenicity and antimicrobial susceptibility tests should be performed for C. diphtheriae isolates. It is recommended that all isolates be sent to a reference laboratory. In the United States, the CDCs Pertussis and Diphtheria Laboratory provides support to local and state health departments needing assistance with isolation, identi fication, and subtyping of |
7,180 | C. diphtheriae and C. ulcerans. COMPLICATIONS Respiratory tract obstruction by pseudomembranes may require bron choscopy or intubation and mechanical ventilation. Two other tissues usually remote from sites of C. diphtheriae infection can be signifi cantly affected by diphtheritic toxin: the heart and the nervous system. Toxic Cardiomyopathy Toxic cardiomyopathy occurs in 1025 of patients with respiratory diphtheria, resulting in death in 3560 of cases with this complication and responsible for 2025 of deaths overall. Subtle signs of myocarditis can be detected in most patients, especially the elderly, but the risk for sig nificant complications correlates directly with the extent and severity of exudative local oropharyngeal disease, along with a delay in administra tion of antitoxin. The first evidence of cardiac toxicity characteristically occurs 7 14 days after the onset of respiratory symptoms but can appear acutely as early as the first week of illness, a poor prognostic sign, or as late as the sixth week. Tachycardia disproportionate to fever is common and may be evidence of cardiac toxicity or autonomic nervous system dysfunction. A prolonged P R interval and changes in the ST T wave on an electrocardiographic tracing are relatively frequent findings; dilated and hypertrophic cardiomyopathy detected by echocardiogram has been described. Single or progressive cardiac dysrhythmias can occur, includ ing first , second , and third degree heart block. Temporary transvenous pacing may improve outcomes. Atrioventricular dissociation and ven tricular tachycardia are also described, the latter having a high associ ated mortality. Heart failure may appear insidiously or acutely. Elevation of the serum aspartate transaminase concentration closely parallels the severity of myonecrosis. Severe dysrhythmia portends death. Histologic postmortem findings are variable: little or diffuse myonecrosis with acute inflammatory response. Recovery from toxic myocardiopathy is usually complete, although survivors of more severe dysrhythmias can have per manent conduction defects. Toxic Neuropathy Neurologic complications occur in 2025 of untreated cases, result ing in death in 50 of cases who develop them and responsible for 15 of deaths overall. They parallel the severity of primary infection and are multiphasic in onset. Acutely or 2 3 weeks after onset of oropharyn geal inflammation, hyperesthesia and local paralysis of the soft palate typically occur. Weakness of the posterior pharyngeal, laryngeal, and facial nerves may follow, causing a nasal quality in the voice, difficulty in swallowing, and risk for aspiration. Cranial neuropathies charac teristically occur in the fifth week, leading to oculomotor and ciliary paralysis, which can cause strabismus, blurred vision, or difficulty with accommodation. Symmetric demyelinating polyneuropathy has onset 10 days to 3 months after oropharyngeal infection and causes princi pally motor deficits with diminished deep tendon reflexes. Nerve con duction velocity studies and cerebrospinal fluid findings in diphtheritic polyneuropathy are indistinguishable from those of Guillain Barr syndrome. Paralysis of the diaphragm may ensue. Complete neurologic recovery is likely, but rarely vasomotor center dysfunction 2 3 weeks after onset of illness can cause hypotension or cardiac failure. Recovery from myocarditis and neuritis is often slow but usually complete. Corticosteroids do not diminish these |
7,181 | complications and are not recommended. TREATMENT Specific diphtheria antitoxin is the mainstay of therapy and should be administered as soon as possible, without delay on the basis of clini cal diagnosis. Because it neutralizes only free toxin, antitoxin efficacy diminishes with elapsed time after the onset of mucocutaneous symp toms. Equine diphtheria antitoxin is available in the United States only from the CDC. Physicians treating a case of suspected diphtheria should contact the CDC Emergency Operations Center at 1 770 488 7100 after consulting with their state health department. Antitoxin is avail able from CDC under expanded access investigational new drug appli cation protocol. Antitoxin is administered as a single empirical dose of 20,000 100,000 units based on the degree of severity, site, and duration of illness. Skin testing for hypersensitivity must be performed before administration of antitoxin. Patients with positive sensitivity testing or with a history of hypersensitivity reaction to horse equine protein should be desensitized. Antitoxin is probably of no value for local manifestations of cutaneous diphtheria, but its use is prudent because toxic sequelae can occur. Commercially available intravenous immunoglobulin prepa rations contain low titers of antibodies to diphtheria toxin; their use for therapy of diphtheria is not proven or approved. Antitoxin is not recom mended for asymptomatic carriers. The role of antimicrobial therapy is to halt toxin production, treat localized infection, and prevent transmission of the organism Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1728 Part XV u Infectious Diseases to contacts. Although C. diphtheriae is usually susceptible to vari ous agents in vitro, including penicillins, erythromycin, clindamy cin, rifampin, and tetracycline, only erythromycin or penicillin are recommended for treatment. Erythromycin is marginally superior to penicillin for eradication of nasopharyngeal carriage. Resistance to erythromycin is common in populations where the drug has been used broadly, and resistance to penicillin has also been reported. Appropri ate therapy is erythromycin (40 50 mgkgday divided every 6 hours by mouth PO or intravenously IV; maximum 2 gday), aqueous crystalline penicillin G (150,000 250,000 unitskgday divided every 6 hr IV or intramuscularly IM, up to 23 million unitsday), or pro caine penicillin (300,000 units every 12 hr IM for those 10 kg in weight; 600,000 units every 12 hr IM for those 10 kg in weight) for 14 days. Once oral medications are tolerated, oral erythromycin (see dosing above) or penicillin V (50 mgkgday, divided every 6 hr, maxi mum 2 g per day) may be used for the remaining duration of therapy. Antibiotic therapy is not a substitute for antitoxin therapy. Some patients with cutaneous diphtheria have been treated for 7 10 days. Elimina tion of the organism should be documented by negative results of at least two successive cultures of specimens from the nose and throat (or skin) obtained at least 24 hours apart, collected 24 hours after comple tion of |
7,182 | antimicrobial therapy. Treatment with erythromycin should be repeated if either culture yields C. diphtheriae. Individuals untreated with antibiotics, including those with either symptomatic or asymptomatic infection, remain colonized with C. diphtheriae for an average of 18.5 days, with 5 remaining colonized longer than 48 days. With antibiotic treatment, they clear C. diphthe riae colonization within an average of 5.2 days, reducing the duration of infectiousness by 2 weeks. SUPPORTIVE CARE Droplet precautions are instituted for patients with pharyngeal diphtheria; for patients with cutaneous diphtheria, contact precautions are observed until the results of specimen cultures taken after cessation of therapy are negative. Cutaneous wounds are cleaned thoroughly with soap and water. Bed rest is essential during the acute phase of disease, usually for 2 weeks until the risk for symptomatic cardiac damage has passed, with return to physical activity guided by the degree of toxicity and cardiac involvement. PROGNOSIS The prognosis for patients with diphtheria depends on the virulence of the organism (subspecies gravis has the highest fatality rate), patient age, immunization status, site of infection, and speed of administration of the antitoxin. Mechanical obstruction from laryngeal diphtheria or bull neck diphtheria and the complications of myocarditis account for most diphtheria related deaths. The case fatality ratio for untreated, never vaccinated cases is 29, improving to 10 with antitoxin treat ment. The risk of fatality increases with every day of delayed antitoxin treatment. Children age 5 years are more likely to die from symptom atic infection than adults 20 years of age, whereas children 5 19 years of age are less likely to die from infection than adults age 20 years. At recovery, administration of diphtheria toxoid is indicated to complete the primary series or booster doses of immunization, because not all patients develop antibodies to diphtheria toxin after infection. PREVENTION Protection against serious disease caused by imported or indigenously acquired C. diphtheriae depends on immunization. In the absence of a precisely determined minimum protective level for diphtheria anti toxin, the presumed minimum is 0.01 0.10 IUmL. In outbreaks, 90 of individuals with clinical disease have had antibody values 0.01 IUmL, and 92 of asymptomatic carriers have had values 0.1 IU mL. In serosurveys in the United States and Western Europe, where almost universal immunization during childhood has been achieved, 25 to 60 of adults lack protective antitoxin levels, with typically very low levels in elderly persons. A serosurvey in the United States (19881994) indicated that 60 of the overall population had protec tive immunity against diphtheria; however, this level of protection declined from 80 in persons age 12 19 years to about 30 in per sons age 60 69 years. All suspected diphtheria cases should be reported to local and state health departments. Investigation is aimed at preventing secondary cases in exposed individuals and at determining the source and carriers to halt spread. The serial interval, or time between symptom onset of the infectorinfectee pair, is a median of 5.9 days, with 5 of intervals 0.8 days and 5 longer |
7,183 | than 21 days. Asymptomatic Case Contacts All household contacts and people who have had intimate respiratory or habitual physical contact with a patient are closely monitored for ill ness for 7 days. Cultures of the nose, throat, and any cutaneous lesions are performed. Antimicrobial prophylaxis is presumed effective and is administered regardless of immunization status, using a single injec tion of benzathine penicillin G (600,000 units IM for patients weighing 30kg, or 1,200,000 units IM for patients weighing 30 kg or adults,) or erythromycin (40 50 mgkgday divided every 6 hr PO for 710 days; max 1 gday). Diphtheria toxoid vaccine, in age appropriate form, is given to immunized individuals who have not received a booster dose within 5 years. Children who have not received their fourth dose should be vaccinated. Those who have received fewer than three doses of diph theria toxoid or who have uncertain immunization status should be immunized with an age appropriate preparation on a primary schedule. Asymptomatic Carriers When an asymptomatic carrier is identified, antimicrobial prophylaxis is given for 10 14 days, and an age appropriate preparation of diphtheria toxoid vaccination is administered immediately if a booster has not been given within 1 year. Droplet precautions (respiratory tract colonization) or contact precautions (cutaneous colonization only) are observed until at least two subsequent cultures obtained at least 24 hours apart, col lected 24 hours after cessation of therapy, have negative results. Repeat cultures are performed about 2 weeks after completion of therapy for cases and carriers; if results are positive, an additional 10 day course of oral erythromycin should be given and follow up cul tures performed. Susceptibility testing of isolates should be performed, as erythromycin resistance is reported. Neither penicillin nor erythro mycin eradicates carriage in 100 of individuals. In one report, a single course of therapy failed in 21 of carriers. Transmission of diphtheria in modern hospitals is rare. Only those who have an unusual contact with respiratory or oral secretions should be managed as contacts. Investigation of the casual contacts of patients and carriers or persons in the community without known exposure has yielded extremely low carriage rates and is not routinely recommended. Vaccine Universal immunization with diphtheria toxoid throughout life, designed to provide constant protective antitoxin antibody levels and to reduce severity of C. diphtheriae disease, is the only effective control measure. Although immunization does not preclude subsequent respi ratory or cutaneous carriage of toxigenic C. diphtheriae, it decreases local tissue spread, prevents toxic complications, diminishes trans mission of the organism, and provides herd immunity when at least 8085 of a population is immunized. Full vaccination is highly effective in preventing symptomatic dis ease (87 with three or more doses, increasing to 99 with five doses), severe disease (defined as local and systemic symptoms plus a major complication; 81), and death (93). Even though vaccines do not prevent colonization, they reduce transmission by 60, likely through reduced symptomatic shedding. Asymptomatic carriers are still able to transmit infection, albeit at only 24 the |
7,184 | rate of symptomatic cases. In an outbreak setting, both vaccination and antibiotic treatment to clear colonization are necessary to interrupt transmission. Although full vaccination coverage can interrupt transmission in only 27 of outbreak settings, this figure increases to 70 when rapid antibiotic treatment is initiated in 90 of symptomatic cases. The COVID 19 pandemic resulted in disruptions in immunization services in 2020, leading to 3.5 million children missing their first dose of diphtheria, tetanus, and pertussis vaccine (DTP) as compared with 2019. Global annual vaccination coverage for first dose DTP vaccine decreased from 90 in 2019 to 87 in 2020; third dose DTP vaccine Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 234 u Listeria monocytogenes 1729 decreased from 86 in 2019 to 83 in 2020. The impact this will have on the resurgence of vaccine preventable infections is yet to be determined. Diphtheria toxoid is prepared by formaldehyde treatment of toxin, standardized for potency and adsorbed to aluminum salts, enhancing immunogenicity. Two preparations of diphtheria toxoids are formu lated according to the limit of flocculation (Lf) content, a measure of the quantity of toxoid. The pediatric (6 months to 6 years) prepara tions (i.e., DTaP diphtheria and tetanus toxoids with acellular pertus sis vaccine and DT diphtheria and tetanus toxoids vaccine) contain 6.7 25.0 Lf units of diphtheria toxoid per 0.5 mL dose; tetanus toxoid with vaccines for 7 years (Td tetanus and diphtheria toxoid vac cine and Tdap diphtheria and tetanus toxoids with acellular pertussis vaccine) contain no more than 2 2.5 Lf units of toxoid per 0.5 mL dose. The higher potency (D) formulation of toxoid is used for primary series and booster doses for children through 6 years of age, given its superior immunogenicity and minimal reactogenicity. For individuals 7 years old, Td or Tdap is recommended for the primary series and booster doses because the lower concentration of diphtheria toxoid is adequately immunogenic and increasing the content of diphtheria tox oid heightens reactogenicity with increasing age. For children 6 weeks to 6 years of age, five 0.5 mL doses of diphtheria containing (D) vaccine (DTaP preferred) are given in the primary series, including doses at 2, 4, and 6 months of age, and a fourth dose, an integral part of the primary series, at 15 18 months. Dose 4 may be administered as early as age 12 months if at least 6 months have elapsed since dose 3. A booster dose is given at 4 6 years of age (unless the fourth primary dose was administered at 4 years). For persons 7 years to 18 years not previously immunized for diphtheria, three 0.5 mL doses of lower level diphtheria containing (d) vaccine are given in a primary series of two doses at least 4 weeks apart and a third dose 6 months after the second dose. The first |
7,185 | dose should be Tdap, and sub sequent doses can be Td or Tdap. A booster dose, consisting of Tdap, is recommended at 11 12 years of age. Tdap may be administered regardless of the interval since the last tetanus and diphtheria toxoid containing vaccine. Adolescents 13 18 years old who have not received Tdap at 11 12 years should receive a single dose of Tdap, then a Td or Tdap booster every 10 years. Pregnant women should receive a single dose of Tdap during every pregnancy, preferably during gestational weeks 27 36. Adults who have never received Tdap should receive a single dose of Tdap, regardless of when they last got Td. A Td or Tdap booster should be given every 10 years. Updated recommendations allow for use of either Td or Tdap vac cine in situations where previously only Td was recommended. This includes the decennial Td booster, tetanus prophylaxis for wound man agement, and for additional required doses in the catch up immuniza tion schedule if a person has received at least one Tdap dose. The only contraindication to tetanus and diphtheria toxoid is a his tory of neurologic or severe hypersensitivity reaction after a prior dose. For children 7 years old in whom pertussis immunization is contra indicated, DT is used. Those whose immunization is begun with DTaP or DT before 1 year of age should have a total of five 0.5 mL doses of diphtheria containing (D) vaccines by 6 years of age. For those whose immunization is begun at around 1 year old, the primary series is three 0.5 mL doses of diphtheria containing (D) vaccine, with a booster given at 4 6 years, unless the third dose was given after the fourth birthday. There is no association of DT or Td with seizures. Local adverse effects alone do not preclude continued use. The rare patient who experiences an Arthus type hypersensitivity reaction or a temperature 39.4C (103F) after a dose of Td usually has high serum tetanus anti toxin levels and should not be given Td more frequently than every 10 years, even if the patient sustains a significant tetanus prone injury. The DT or Td preparation can be given concurrently with other vac cines. Meningococcal and pneumococcal conjugate vaccines contain ing diphtheria toxoid or a variant of diphtheria toxin, CRM197 protein, are not substitutes for diphtheria toxoid immunization and do not affect reactogenicity. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 234 Listeria monocytogenes Ashley C. Howard and Thomas S. Murray Listeriosis in humans is caused principally by Listeria monocyto genes, 1 of 17 species of the genus Listeria that are widely distrib uted in the environment and throughout the food chain. Human infections can usually be traced to an animal reservoir. Infection usually occurs at the extremes of age. In the pediatric population, perinatal infections predominate and usually occur secondary to maternal infection or colonization. Outside the newborn period, disease is most often encountered in immunosuppressed (usually T cell deficiencies) children and |
7,186 | adults and in elderly persons. For most people the major risk for infection with Listeria is food borne transmission. In the United States, food borne outbreaks are caused by improperly processed dairy products and contaminated vegetables and principally affect the same individuals at risk for spo radic disease. ETIOLOGY Members of the genus Listeria are facultatively anaerobic, non spore forming, motile, gram positive bacilli that are catalase posi tive. The 17 Listeria species are divided into two genomically distinct groups on the basis of DNA DNA hybridization studies. One group contains the species L. grayi, and 10 others discovered since 2009 are considered nonpathogenic. The second group contains six spe cies: the nonhemolytic species L. innocua, L. welshimeri, and L. marthii and the hemolytic species L. monocytogenes, L. seeligeri, and L. ivanovii. L. ivanovii is pathogenic primarily in animals, and the vast majority of both human and animal disease is caused by L. monocytogenes. Subtyping of L. monocytogenes isolates for epidemiologic purposes is now performed predominately with whole genome sequencing. This demonstrates the clonal structure of populations of L. monocytogenes as well as the sharing of populations between human and animal sources. Subtyping is an important component of determining whether cases are connected or sporadic but usually requires collaboration with a specialized laboratory. Historically, selected biochemical tests, together with the demon stration of tumbling motility, an umbrella type formation below the surface in semisolid medium, hemolysis, and a typical cyclic adenos ine monophosphate test, are usually sufficient to establish a presump tive identification of L. monocytogenes. Once growth is present, L. monocytogenes can now be rapidly identified with matrix assisted laser desorptionionization time of flight (MALDI TOF) mass spectrometry. EPIDEMIOLOGY L. monocytogenes is widespread in nature, has been isolated through out the environment, and is associated with epizootic disease and asymptomatic carriage in 42 species of wild and domestic animals and 22 avian species. Epizootic disease in large animals (e.g., sheep, cattle) is associated with abortion and circling disease, a form of bas ilar meningitis. L. monocytogenes is isolated from sewage, silage, and soil, where it survives for 295 days. Human to human transmission rarely occurs except in maternal fetal transmission. The annual inci dence of listeriosis decreased by 36 between 1996 and 2004 and has remained level since then, estimated between two and five cases per year per million people. However, food borne outbreaks continue to occur. The rate of Listeria infections varies among states. Epidemic human listeriosis has been associated with food borne transmission in several large outbreaks, especially in association with aged soft cheeses; improperly pasteurized milk and milk products; contaminated raw and ready to eat beef, pork, and poultry and packaged meats and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1730 Part XV u Infectious Diseases salads; and vegetables, both fresh and frozen, harvested from farms where the ground |
7,187 | is contaminated with the feces of colonized animals. In 2017 2018, the largest Listeria outbreak ever recorded occurred in South Africa with 900 cases and 200 deaths related to a processed contaminated meat product, polony. U.S. food borne outbreaks from 2019 to 2020 included deli meats and cheeses, packaged hard boiled eggs, and enoki mushrooms. The ability of L. monocytogenes to grow at temperatures as low as 4C (39.2F) increases the risk for transmission from aged soft cheeses and stored contaminated food. Listeriosis is an uncommon but important recognized etiology of neo natal sepsis and meningitis. Small clusters of nosocomial person to person transmission have occurred in hospital nurseries and obstetric suites. Sporadic endemic listeriosis is less well characterized. Likely routes include food borne infection and zoonotic spread. Zoonotic transmission with cutaneous infections occurs in veterinarians and farmers who handle sick animals. Reported cases of listeriosis are clustered at the extremes of age. Some studies show higher rates in males and a seasonal predomi nance in the late summer and fall in the Northern Hemisphere. In the United States, there is an increased risk of infection in nonpreg nant non Hispanic Asians, non Hispanic Blacks, and Hispanics compared with non Hispanic Whites. Outside the newborn period and during pregnancy, disease is usually reported in patients with underlying immunosuppression, with a 100 300 times increased risk in HIV infected persons and in the elderly population (Table 234.1). In a prospective cohort study for listeriosis, 82.5 of par ticipants had at least one immunocompromising condition, and those with bacteremia and neurolisteriosis disease were found to have a fivefold increased risk of death if there was an underlying malignancy. The incubation period, which is defined only for common source food borne disease, is 21 30 days but in some cases may be longer. Asymptomatic carriage and fecal excretion are reported in 15 of healthy persons and 5 of abattoir workers, but duration of excretion, when studied, is short (1 month). PATHOLOGY One of the major concepts of Listeria pathology and pathogenesis is its ability to survive as an intracellular pathogen. Listeria incites a mononuclear response and elaboration of cytokines, producing multisystem disease, particularly pyogenic meningitis. Granuloma tous reactions and microabscess formation develop in many organs, including the liver, lungs, adrenals, kidneys, central nervous sys tem (CNS), and notably the placenta. Animal models demonstrate translocation, the transfer of intraluminal organisms across intact intestinal mucosa. Histologic examination of tissues, including the placenta, shows granulomatous inflammation and microabscess for mation. Intracellular organisms can often be demonstrated with spe cial stains. PATHOGENESIS Listeria organisms usually enter the host through the gastrointesti nal (GI) tract. Gastric acidity provides some protection, and drugs that raise gastric pH may promote infection. Studies of intracellular and intercellular spread of L. monocytogenes have revealed a com plex pathogenesis. Four pathogenic steps are described: internal ization, escape from the vacuole, nucleation of actin filaments, and cell to cell spread. Listeriolysin O, a hemolysin, mediates lysis of vacuoles and is responsible for the zone |
7,188 | of hemolysis around colonies on blood containing solid media. In cell to cell spread, locomotion proceeds via polymerization of actin filaments, which extrude the bacteria in pseudopods, which in turn are internalized by adjacent cells, necessitating escape from a double membrane vacuole. This mechanism protects intracellular bacteria from the humoral arm of immunity and is responsible for the well known requirement of T cellmediated activation of monocytes by lymphokines for clear ance of infection and establishment of immunity. The significant risk for listeriosis in patients with depressed T cell immunity speaks for the role of this arm of the immune system. The role of opsoniz ing antibody in protecting against infection is unclear. In addition, siderophores scavenge iron from the host, enhancing growth of the organism and likely explaining the relatively high risk of listeriosis in iron overload syndromes. CLINICAL MANIFESTATIONS The clinical presentation of listeriosis depends greatly on the age of the patient and the circumstances of the infection. Listeriosis in Pregnancy Pregnant women have increased susceptibility to Listeria infections (approximately 20 times higher than nonpregnant women), prob ably because of a relative impairment in cell mediated immunity. L. monocytogenes has been grown from placental and fetal cultures of pregnancies ending in spontaneous abortion. The usual presenta tion in the second and third trimesters is a flulike illness that may result in seeding of the uterine contents by bacteremia. Rarely is maternal listeriosis severe, but meningitis in pregnancy has been reported. Recognition and treatment at this stage are associated with normal pregnancy outcomes, but the fetus may not be infected even if listeriosis in the mother is not treated. In other instances, placental listeriosis develops with infection of the fetus that may be associated with stillbirth or premature delivery. Delivery of an infected premature fetus is associated with very high infant mortal ity. Disseminated disease is apparent at birth, often with a diffuse pustular rash. Infection in the mother usually resolves without spe cific therapy after delivery, but postpartum fever and infected lochia may occur. Neonatal Listeriosis Two clinical presentations are recognized for neonatal listeriosis: early onset neonatal disease (5 days, usually within 1 2 days of birth), which is a predominantly septicemic form, and late onset neona tal disease (5 days, mean 14 days of life), which is a predominantly meningitic form (Table 234.2). The principal characteristics of the two presentations resemble the clinical syndromes described for group B Streptococcus (see Chapter 230). Early onset disease occurs with milder transplacental or ascending infections from the female genital tract. There is a strong association with recovery of L. monocytogenes from the maternal genital tract, obstetric complications, prematurity, and neonatal sepsis with multi organ involvement, including rash, but without CNS localization (Fig. 234.1). The mortality rate is approximately 2030. The epidemiology of late onset disease is poorly understood. Onset is usually after 5 days but before 30 days of age. Affected infants fre quently are full term, and the mothers are culture negative and asymp tomatic. The presenting syndrome is |
7,189 | usually purulent meningitis with parenchymal brain involvement, which, if adequately treated, has a mortality rate of 20. Table 234.1 Types of Listeria monocytogenes Infections Listeriosis in pregnancy Neonatal listeriosis Early onset Late onset Food borne outbreaksfebrile gastroenteritis Listeriosis in normal children and adults (rare) Focal Listeria infections (e.g., meningitis, endocarditis, pneumonia, liver abscess, osteomyelitis, septic arthritis) Listeriosis in immunocompromised persons Lymphohematogenous malignancies Collagen vascular diseases Diabetes mellitus HIV infection Transplantation Renal failure with peritoneal dialysis Listeriosis in elderly persons Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 234 u Listeria monocytogenes 1731 Postneonatal Infections Listeriosis beyond the newborn period may rarely occur in otherwise healthy children but is most often encountered in association with underlying malignancies (especially lymphomas) or immunosuppres sion. When associated with food borne outbreaks, disease may cause GI symptoms or any of the Listeria syndromes. The clinical presenta tion is usually meningitis, less commonly sepsis, and rarely other CNS involvement, such as cerebritis, meningoencephalitis, brain abscess, spinal cord abscess, or a focus outside the CNS, such as suppurative arthritis, osteomyelitis, endocarditis, peritonitis (associated with peri toneal dialysis), or liver abscess. It is not known whether the frequent GI signs and symptoms result from enteric infection because the mode of acquisition is often unknown. DIAGNOSIS Listeriosis should be included in the differential diagnosis of infec tions in pregnancy, of neonatal sepsis and meningitis, and of sepsis or meningitis in older children who have underlying malignancies (lymphomas), are receiving immunosuppressive therapy, or have undergone transplantation. The diagnosis is established by culture of L. monocytogenes from blood or cerebrospinal fluid (CSF). Cultures from the maternal cervix, vagina, lochia, and placenta, if possible, should be obtained when intrauterine infections lead to premature delivery or early onset neonatal sepsis. Cultures from closed space infections may also be useful. It is helpful to alert the laboratory to suspected cases so that Listeria isolates are not discarded as contami nating diphtheroids. Histologic examination of the placenta is also useful. Molecular assays are now commercially available to detect L. monocytogenes from CNS samples and directly from positive blood culture bottles. Serodi agnostic tests are not useful. Differential Diagnosis Listeriosis is indistinguishable clinically from neonatal sepsis and meningitis caused by other organisms. The presence of increased peripheral blood monocytes suggests listeriosis. Monocytosis or lymphocytosis may be modest or striking. Beyond the neonatal period, L. monocytogenes CNS infection is associated with fever, headache, seizures, and signs of meningeal irritation. The brain stem may be characteristically affected. The white blood cell concentration may vary from normal to slightly elevated, and the CSF laboratory findings are variable and less striking than in the more common causes of bacterial meningitis. Polymorpho nuclear leukocytes or mononuclear cells may predominate, with shifts from polymorphonuclear to mononuclear cells in sequen tial lumbar puncture specimens. The CSF glucose concentration may be normal, but a low level mirrors |
7,190 | the severity of disease. The CSF protein concentration is moderately elevated. L. monocyto genes is isolated from the blood in 4075 of cases of meningitis caused by the organism. Deep focal infections from L. monocyto genes, such as endocarditis, osteomyelitis, and liver abscess, are also indistinguishable clinically from such infections from more common organisms. Cutaneous infections should be suspected in patients with a history of contact with animals, especially prod ucts of conception. TREATMENT The emergence of multiantibiotic resistance mandates routine sus ceptibility testing of all isolates. The recommended therapy is ampi cillin (100 200 mgkgday divided every 6 hours intravenously IV; 300 400 mgkgday divided every 6 hours IV if meningitis is pres ent), alone or in combination with an aminoglycoside (2.0 3.0 mg kgday IV divided every 8 24 hours depending on postnatal age). The aminoglycoside enhances the bactericidal activity and is gener ally recommended in cases of endocarditis and meningitis. The adult dose is ampicillin 4 6 gday divided every 6 hours plus an aminogly coside. The ampicillin dose is doubled if meningitis is present. Spe cial attention to dosing is required for neonates, who require longer dosing intervals because of the longer half lives of the antibiotics in their bodies. L. monocytogenes is not susceptible to the cephalo sporins, including third generation cephalosporins. If these agents are used for empirical therapy for neonatal sepsis or meningitis in a newborn, ampicillin must be added for possible L. monocytogenes infection. Vancomycin, vancomycin plus an aminoglycoside, and trimethoprim sulfamethoxazole are alternatives to ampicillin. The duration of therapy is usually 2 3 weeks, with 3 weeks recommended for immunocompromised persons and patients with meningitis. A longer course is needed for endocarditis, brain abscess, and osteomy elitis. Antibiotic treatment is unnecessary for gastroenteritis without invasive disease. PROGNOSIS Early gestational listeriosis may be associated with abortion or stillbirth, although maternal infection with sparing of the fetus has been reported. There is no convincing evidence that L. monocyto genes is associated with repeated spontaneous abortions in humans. The mortality rate is 50 for premature infants infected in utero, 30 for early onset neonatal sepsis, 15 for late onset neonatal meningitis, and 10 in older children with prompt institution of appropriate antimicrobial therapy. Mental retardation, hydrocepha lus, and other CNS sequelae are reported in survivors of Listeria meningitis. Table 234.2 Characteristic Features of Early and Late Onset Neonatal Listeriosis EARLY ONSET (5 DAYS) LATE ONSET (5 DAYS) Positive result of maternal Listeria culture Negative results of maternal Listeria culture Obstetric complications Uncomplicated pregnancy Premature delivery Term delivery Low birthweight Normal birthweight Neonatal sepsis Neonatal meningitis Mean age at onset 1.5 days Mean age at onset 14.2 days Mortality rate 30 Mortality rate 20 Nosocomial outbreaks Fig. 234.1 Listeria monocytogenes. The generalized maculopapu lar rash present at birth disappeared within a few hours of life. (From Benitez Segura I, Fiol Jaume M, Balliu PR, Tejedor M. Listeria mono cytogenes: generalized maculopapular rash may be the clue. Arch Dis Child Fetal Neonatal Ed. 2013;981:F64, Fig. 1.) |
7,191 | Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1732 Part XV u Infectious Diseases PREVENTION Listeriosis can be prevented by pasteurization and thorough cooking of foods. Irradiation of meat products may also be beneficial. Consump tion of unpasteurized or improperly processed dairy products should be avoided, especially aged soft cheeses, uncooked and precooked meat products that have been stored at 4C (39.2F) for extended periods, and unwashed vegetables (Table 234.3). This avoidance is particularly important during pregnancy and for immunocompromised persons. Infected domestic animals should be avoided when possible. Education regarding risk reduction is aimed particularly at pregnant women and people being treated for cancer. Careful handwashing is essential to prevent nosocomial spread within obstetric and neonatal units. Immunocompromised patients given prophylaxis with trimethoprim sulfamethoxazole are protected from Listeria infections. Cases, and especially outbreaks, should be reported immediately to public health authorities so that timely inves tigation can be initiated in order to interrupt transmission from the contaminated source. ACKNOWLEDGMENTS We would like to acknowledge Robert S. Baltimore, MD, for his contri bution to this chapter and Michelle R. Rychalsky, PharmD, for review ing antibiotic dosing regimens. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 234.3 Prevention of Food Borne Listeriosis Including pregnant women, persons with a weakened immune system, and older adults. FDA, Food and Drug Administration; USDA, U.S. Department of Agriculture. Adapted from Centers for Disease Control and Prevention: Listeria (listeriosis): prevention. http:www.cdc.govlisteriaprevention.html. GENERAL RECOMMENDATIONS TO PREVENT LISTERIA INFECTION FDA recommendations for washing and handling food: Rinse raw produce, such as fruits and vegetables, thoroughly under running tap water before eating, cutting, or cooking. Even if the produce will be peeled, it should still be washed first. Scrub firm produce, such as melons and cucumbers, with a clean produce brush. Dry the produce with a clean cloth or paper towel. Separate uncooked meats and poultry from vegetables, cooked foods, and ready to eat foods. Keep your kitchen and environment cleaner and safer: Wash hands, knives, countertops, and cutting boards after handling and preparing uncooked foods. Be aware that Listeria monocytogenes can grow in foods in the refrigerator. Use an appliance thermometer, such as a refrigerator thermometer, to check the temperature inside your refrigerator. The refrigerator should be 4.5C (40F) or lower and the freezer 17.8C (0F) or lower. Clean up all spills in your refrigerator promptly, especially juices from hot dog and lunch meat packages, raw meat, and raw poultry. Clean the inside walls and shelves of your refrigerator with hot water and liquid soap, then rinse. Cook meat and poultry thoroughly: Thoroughly cook raw food from animal sources, such as beef, pork, or poultry, to a safe internal temperature. For a list of recommended temperatures for meat and poultry, visit the safe minimum cooking temperatures chart at http:www.FoodSafety.gov. Store foods safely: Use precooked or ready to eat food as soon as |
7,192 | you can. Do not store the product in the refrigerator beyond the use by date; follow USDA refrigerator storage time guidelines: Hot dogs: store opened package no longer than 1 wk and unopened package no longer than 2 wk in the refrigerator. Luncheon and deli meat: store factory sealed, unopened package no longer than 2 wk. Store opened packages and meat sliced at a local deli no longer than 3 5 days in the refrigerator. Divide leftovers into shallow containers to promote rapid, even cooling. Cover with airtight lids or enclose in plastic wrap or aluminum foil. Use leftovers within 3 4 days. Choose safer foods: Do not drink raw (unpasteurized) milk, and do not eat foods that have unpasteurized milk in them. RECOMMENDATIONS FOR PERSONS AT HIGHER RISK In addition to the recommendations listed above, include: Meats Do not eat hot dogs, luncheon meats, cold cuts, other deli meats (e.g., bologna) or fermented or dry sausages unless they are heated to an internal temperature of 73.9C (165F) or until steaming hot just before serving. Avoid getting fluid from hot dog and lunch meat packages on other foods, utensils, and food preparation surfaces, and wash hands after handling hot dogs, luncheon meats, and deli meats. Pay attention to labels. Do not eat refrigerated pt or meat spreads from a deli or meat counter or from the refrigerated section of a store. Foods that do not need refrigeration, such as canned or shelf stable pt and meat spreads, are safe to eat. Refrigerate after opening. Cheeses Do not eat soft cheese such as feta, queso blanco, queso fresco, brie, Camembert, blue veined, or panela (queso panela) unless it is labeled as made with pasteurized milk. Make sure the label says Made With Pasteurized Milk. Seafood Do not eat refrigerated smoked seafood, unless it is contained in a cooked dish, such as a casserole, or unless it is a canned or shelf stable product. Refrigerated smoked seafood, such as salmon, trout, whitefish, cod, tuna, and mackerel, is most often labeled as nova style, lox, kippered, smoked, or jerky. These fish are typically found in the refrigerator section or sold at seafood and deli counters of grocery stores and delicatessens. Canned and shelf stable tuna, salmon, and other fish products are safe to eat. Follow this general FDA advice for melon safety: Consumers and food preparers should wash their hands with warm water and soap for at least 20 sec before and after handling any whole melon, such as cantaloupe, watermelon, or honeydew. Scrub the surface of melons, such as cantaloupes, with a clean produce brush under running water and dry them with a clean cloth or paper towel before cutting. Be sure that your scrub brush is sanitized after each use to avoid transferring bacteria between melons. Promptly consume cut melon or refrigerate promptly. Keep your cut melon refrigerated 4.5C (40F) (01.1C 3234F is best) for no more than 7 days. Discard cut melons left at room temperature for 4 hours. Downloaded |
7,193 | for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 235 u Actinomyces 1733 TAXONOMY AND MICROBIOLOGY Members of the phylum Actinobacteria are common soil and water gram positive bacteria with high guanine and cytosine DNA content and play important roles in the decomposition of organic materials. A proportion of Actinobacteria form filamentous and branching struc tures (similar to Nocardia spp.) that resemble fungal mycelia; these are included in the class Actinomycetia. The genus Actinomyces (which translates literally to ray fungus) belongs to the order Actinomyceta les (along with Mycobacteria and Nocardia) and family Actinomyceta ceae and constitutes several microaerophilic to facultatively anaerobic nonmotile species that are fastidious and slow growing. More than 50 species of Actinomyces have been identified using 16S rRNA sequencing, with more than half of these species associated with human infection. Actinomyces israelii is the predominant species causing human actinomycosis. Other species associated with infection include but are not limited to A. odontolyticus, A. meyeri, A. naeslundii, A. graevenitzii, A. neuii, and A. turicensis. PATHOGENESIS AND EPIDEMIOLOGY Actinomyces are commensal organisms of the human oropharynx and gastrointestinal and urogenital tracts, and infections by these organ isms (termed actinomycosis) typically emanate from these anatomic sites. The hallmark of actinomycosis is contiguous spread that fails to respect tissue or fascial planes. As such, these infections can extend to contiguous structures and form abscesses and chronically suppura tive granulomatous infections and sinus tracts. Cicatricial healing can then ensue, from which the organism can further spread by burrow ing along fascial planes, causing deeply communicating scarred sinus tracts. Sites of infection show dense cellular infiltrates and suppuration that form many interconnecting abscesses and sinus tracts. Bacteremia and infections of more distal sites (such as endocarditis, pericarditis, and central nervous system CNS infections) have also been docu mented. Notably, polymicrobial infections are typical, especially with copathogens such as Aggregatibacter (formerly Actinobacillus) acti nomycetemcomitans, as well as Fusobacterium, Clostridia, Eikenella, Enterococcus, Bacteroides, and Peptostreptococcus spp. Knowledge regarding the epidemiology of actinomycosis is limited to case reports and case series. Based on these reports, actinomycosis appears to affect people of all ages, with no racial or ethnic predilec tion, seasonality, or occupational associations. Actinomycosis occurs in immunocompetent and immunocompromised hosts. However, pediatric actinomycosis only represents approximately 3 of reported cases. Risk factors in children include trauma, dental caries, debilita tion, and poorly controlled diabetes. Although actinomycosis is not a common opportunistic infection, disease has been associated with corticosteroid use, leukemia, renal failure, congenital immunodefi ciencies, HIV infection, and solid organ or hematopoietic stem cell transplantation. Given the sites of colonization, the most common presentations of Actinomyces infections include cervicofacial, abdominalpelvic, and thoracic regions (in order of frequency). Importantly, certain medical interventions can result in mucosal barrier injuries and infection. For instance, use of intrauterine contraceptive devices can predispose to pelvic actinomycosis, and aspiration events, poor dentition, and recent dental |
7,194 | procedures can result in involvement of the thoracic region. However, more than one third of patients do not have an identifiable antecedent event that would explain the onset of actinomycosis. Importantly, actinomyces infections are not contagious. DIAGNOSIS Diagnosis of actinomycosis relies on identification of the organism in tissues of affected areas via culture, molecular methods, andor histo pathology. However, growth in cultures can take up to 2 3 weeks, and up to 50 of cultures may reveal no growth because of prior antibi otic exposure, failure to maintain anaerobic conditions during sample transport, or inadequate incubation. The presence of sulfur granules on macroscopic or microscopic evaluation (Fig. 235.1) of involved tissue is suggestive of actinomycosis. Despite their name, these granules are not composed of sulfur, instead deriving this designation because of their typical yellow color on mac roscopic appearance; they can also be white, gray, or brown. Similar granules can be formed by Nocardia brasiliensis, Streptomyces madu rae (which can cause mycetomas), and Staphylococcus aureus (which can cause botryomycosis). Microscopically, these granules appear on hematoxylin eosin or Gomori methenamine silver stains as masses of gram positive, branching, filamentous rods surrounded by the host immune cells (e.g., polymorphonuclear neutrophils) and a milieu of eosinophilic staining inert material, often referred to as the Splendore Hoeppli phenomenon. Notably, A. meyeri is nonbranching and A. odontolyticus does not form sulfur granules. Nocardia are indistinguishable from Actinomyces on Gram stain, but Nocardia take up the modified acid fast stain, whereas Actinomy ces spp. do not. Although suggestive of actinomycosis, sulfur gran ules are often absent, and thus additional testing such as cultures are necessary for the diagnosis. Affected tissues can be cultured on Chapter 235 Actinomyces Hamid Bassiri A B Fig. 235.1 Actinomycosis. A, Small cluster of Actinomyces on left, with sulfur granule and surrounding mixed inflammation demonstrating the Splendore Hoeppli phenomenon (200). B, Gomori methenamine silver stain of the same field, highlighting the filamentous forms (200). (From Johnson MM. Ear, nose, and throat infections. In: Kradin RL, ed. Diagnostic Pathology of Infectious Disease, 2nd ed. Philadelphia: Else vier; 2018: Fig. 7.6.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1734 Part XV u Infectious Diseases brain heart infusion agar incubated at 37C anaerobically and aero bically to reveal organisms within the lines of streak at 24 48 hours. A. israelii colonies appear as loose masses of delicate, branching fila ments with a characteristic spider like growth. Unfortunately, even under the right conditions, it is challenging to grow Actinomyces, and the yield of different culturing techniques varies by species. Addition ally, conventional biochemical testing for speciation is complex and may result in misclassifications. The evolution of diagnostic tools such as 16S rRNA sequence analysis and matrix assisted laser desorp tionionization time of flight (MALDI TOF) mass spectrometry has improved the accuracy of speciation of cultured organisms and high lighted |
7,195 | the potential for detection of Actinomyces directly from the involved tissue without culture. Importantly, actinomycosis is usually, if not always, polymicrobial in nature. In a large study of 650 cases, infection with Actinomyces was identified in pure culture in only 1 case. Cultures usually also identify other endogenous flora, including members of the HACEK group, which includes Haemophilus spp. (typically H. aphrophilus, H. parainfluenzae, or H. paraphrophilus), A. actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. A. actinomycetemcomitans is a fastidious, gram negative bacillus that is part of the oral flora and has been implicated in periodontal disease. Other bacteria frequently isolated concomitantly in human actinomy cosis include Fusobacterium, Bacteroides, Capnocytophaga, and aerobic and anaerobic streptococci. CT or MRI of involved areas is often employed in the initial patient evaluation. Imaging evidence of an invasive process spreading across tissue planes and ignoring anatomic boundaries is highly suggestive of actinomycosis. Furthermore, imaging can be helpful in establishing the extent of the infection, guiding subsequent diagnostic and therapeutic interventions, and monitoring for disease resolution. COMMON CLINICAL PRESENTATIONS Cervicofacial Actinomycosis Cervicofacial disease is the most common form of pediatric actinomy cosis and often manifests as a neck or submandibular mass that per sists for weeks to months. Less than half of patients will have associated pain, and less than one third of patients will have fever. A minority of patients will report dysphagia or have a draining sinus (Fig. 235.2). Less frequently, cervicofacial actinomycosis manifests clinically as an acute pyogenic infection with a tender, fluctuant mass with trismus, firm swelling, and fistulas with drainage containing sulfur granules. Bone is not involved early in the disease, but periostitis, mandibular osteomyelitis, or perimandibular abscess may subsequently develop. Infection may spread through sinus tracts to cranial bones, possibly leading to meningitis. The ability of Actinomyces to burrow through tissue planes, including the periosteum, is a key difference between actinomycosis and nocardiosis. Whereas predisposing factors for cer vicofacial actinomycosis are not well defined for children, adult cases are often preceded by a history of oral trauma, oral surgery, dental procedures, or caries, facilitating entry of organisms into cervicofacial tissues. Abdominal and Pelvic Actinomycosis Of all the forms of actinomycosis, delayed diagnosis is most typical for abdominal and pelvic infection. A disruption of the mucosa of the gastrointestinal (GI) tract (e.g., acute GI perforation, abdominal trauma, prior abdominal surgery) is often postulated as the inciting event for adult onset abdominopelvic actinomycosis. In pediatric patients, however, medical history sometimes fails to identify prior evidence of mucosal barrier injury. In a contemporary pediatric case series of abdominal and pelvic actinomycosis, prior abdominal sur gery (all appendectomies) was reported in only 21 of patients and dental caries in 11. In two thirds to three fourths of patients, the presenting signs are abdominal pain and a palpable mass on physi cal exam. Fever accompanies the abdominal pain in more than half of cases, with weight loss in almost one third. As with other forms of actinomycosis, abdominopelvic infection can spread across tissue |
7,196 | planes by contiguous extension involving any tissue or organ, includ ing muscle, solid abdominopelvic viscera, and walls of the intesti nal tract. Imaging studies may reveal a mass with invasion of tissue planes, leading to misdiagnosis of malignancies, inflammatory bowel disease with fistulae, or abdominal tuberculosis. Genitourinary acti nomycosis is often associated with use of intrauterine contraceptive devices (IUDs) in adults and can mimic gynecologic tumors, but these infections are quite rare in adolescents. Because of delays in diagnosis, more than one third of pediatric cases present with drain ing sinus fistulae. Thoracic Actinomycosis Thoracic actinomycosis may present with cough, chest pain, hemop tysis, and fever. In a retrospective review of reported pediatric cases of thoracic infection, almost half presented with a chest wall mass. Additional symptoms such as cough, fever, chest pain, and weight loss were reported in 40 of patients. Radiographic imaging may reveal hilar lymphadenopathy, endobronchial infection, tumor like lesions, diffuse pneumonia, pleural effusions, or abscesses with or without cavitation and parenchymal lung destruction. These abscesses can also form sinus tracts to the diaphragm or mediastinum, which are often pathognomonic for actinomycosis. Other complications include bony destruction of adjacent ribs, sternum, and vertebral bodies. Multiple lobe involvement of the lungs is occasionally found. Impor tantly, evidence of thoracic actinomycosis can be found incidentally on radiographs ordered for noninfectious concerns. The variation in presentation and indolent nature of thoracic actinomycosis often delay the diagnosis. Other Forms of Actinomycosis CNS actinomycosis is often the result of hematogenous spread to the brain parenchyma from a distant site but can also ensue from con tiguous spread from a cervicofacial lesion. The former often results in multiple brain abscesses. Laryngeal actinomycosis rarely has been reported in older teenagers. Oropharyngeal colonization with Acti nomyces may be involved in the development of obstructive tonsil lar hypertrophy. Severe forms of periodontitis, particularly localized juvenile periodontitis, are associated with Actinomyces, especially in adolescents. Actinomyces has a propensity for infecting heart valves, a process that results in subacute endocarditis, with fever present in less than half of cases. DIFFERENTIAL DIAGNOSIS Actinomycosis has been referred to as a great imitator with presenta tions that mimic appendicitis, pseudoappendicitis caused by Yersinia enterocolitica, amebiasis, malignancy, and inflammatory bowel disease. Actinomycosis must be differentiated from other chronic infections, Fig. 235.2 A 2 yr old male with HIV infection who has cervicofacial actinomycosis and a draining fistula. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 236 u Nocardia 1735 including tuberculosis, nocardiosis, polymicrobial bacterial infections, and fungal infections. TREATMENT Most cases of actinomycosis can be managed with antibiotics, although surgery can be adjunctive and may shorten the duration of antibiotic use. Routine susceptibility testing is not typically performed, as most Actinomyces spp. are susceptible to penicillin. Accordingly, penicillin G is the drug of choice for parenteral therapy, and penicillin V or amoxi cillin is the |
7,197 | preferred enteral antibiotic. Because actinomycosis is often found to be polymicrobial in nature, use of combination lactam lactamase inhibitors (e.g., ampicillin sulbactam or amoxicillin clavulanate) may be warranted, especially if there is an initial poor response. In particular, A. actinomycetemcomitans is a copathogen in at least 30 of cases of actinomycosis. Failure to recognize this organism and treat it adequately has resulted in clinical relapse and deterioration. Treating actinomycosis in a patient with a penicillin allergy can be challenging, as there is variation in susceptibility by Actinomyces spp. to other antibiotic classes; alternatives generally include cephalo sporins, carbapenems, macrolides, and tetracyclines. Despite being anaerobic, a large percentage of Actinomyces are not susceptible to metronidazole, and isolates are variably susceptible to clindamy cin. Fluoroquinolones and aminoglycosides have little to no activ ity against Actinomyces spp. Infectious disease specialists should be consulted to guide antibiotic usage in patients with penicillin allergy or deep seated infections such as brain abscesses, endocarditis, or osteomyelitis. Commercially available sensitivity testing methods are available and can be employed in patients with severe disease or poor response to initial therapy. No definitive comparative effectiveness data exist to guide the opti mal route and duration of therapy. For severe or extensive infections, most experts recommend initial parenteral administration of anti biotics for 4 6 weeks and then transitioning to enteral therapy upon documentation of clinical improvement. The exceptions include endocarditis and CNS disease, which generally require parenteral administration for the entire course of therapy. In cases of mild or limited disease, enteral antibiotics could be considered even at initia tion. Given concern for relapses, antibiotics are often continued for several months, with total durations ranging between 2 6 months for mildlimited disease and 6 12 months for severeextensive disease. Shorter courses of antibiotic therapy can result in relapses, especially in cases of thoracic actinomycosis without surgical debridement. Longer courses up to 18 months have also been used in invasive dis ease and in immunocompromised patients. At the same time, courses of antibiotic therapy 3 months have been used successfully in cases of local disease, especially after surgical resection. Close follow up and monitoring are indicated in patients treated with short courses of antibiotics. The total duration of treatment is often ultimately dic tated by the location of the infection and follow up clinical exams and imaging. Traditionally, an adjunctive surgical intervention was thought to be necessary for a successful outcome. However, in some case series a subset of patients have responded well to medical management alone. In the setting of significant abscesses andor sinus tracts, a surgical approach to establish source control and, if possible, completely resect involved issue can hasten clinical improvement. The morbidity of the surgical procedure needs to be weighed against the potential benefits for each patient. PROGNOSIS The prognosis is excellent with early diagnosis, prompt initiation of antibiotic therapy, adherence to a prolonged course of antibiotics, and adequate surgical debridement, if necessary. Despite a good overall prognosis, permanent scarring can still develop. Although actinomyco sis |
7,198 | can present in immunocompetent children, disseminated or recalci trant actinomycosis should raise suspicion for immunodeficiency. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 236 Nocardia Coralee Del Valle Mojica Various Nocardia species have been identified causing localized and disseminated disease in children and adults. These organisms are predominantly opportunistic pathogens infecting immunocom promised individuals, but cases in immunocompetent hosts are increasingly reported. Infection caused by these bacteria is termed nocardiosis, which consists of acute, subacute, or chronic suppurative manifestations. ETIOLOGY Nocardia spp. are a complex group of environmental, gram positive bacteria that belong to aerobic actinomycetes. They can grow on diverse media (e.g., blood agar, brain heart infusion agar, Lowenstein Jensen media, buffered charcoal yeast extract BCYE, Sabouraud dextrose agar) and have been referred to as bacteria that masquerade as fungi, sometimes misdirected to the mycology or mycobacteriology section of clinical laboratories for identification. Colonies can appear as early as 48 hours, but typically growth of Nocardia is slower than in other bacteria and may take 1 2 weeks. Growth appears as waxy, folded, or heaped colonies at the edges, and yield is best achieved in conditions that include a temperature of 37C (98.6F) with 10 carbon dioxide. However, many isolates of Nocardia are thermophilic and will grow at temperatures up to 50C (122F). Microscopically, Nocardia spp. are weakly gram positive, rod shaped, filamentous bacteria. For some isolates, there may be alternating areas of gram positive and gram negative staining, giving a beaded appearance often described with Nocardia. These organisms are also weakly acid fast, and the modi fied Kinyoun acid fast staining technique can be helpful to identify organisms from clinical specimens such as a tissue biopsy or bron choalveolar lavage (BAL). To date, more than 80 species of Nocardia have been described and 50 species have been identified to be human pathogens. The distribution of Nocardia spp. causing disease varies across studies, partly because of revisions in taxonomic classification over time. A retrospective study looking at isolates in the United States from 1995 to 2004 reported N. nova, N. brasiliensis, and N. farcinica as the most common species. In contrast, a more recent study from China reported N. otitidiscaviarum as the most common species, and a systematic review from Iran from 1992 to 2021 reported N. asteroi des and N. cyriacigeorgica as the two most common species. Species identification can be critical for optimal clinical outcomes because of variability in virulence strategies and antibiotic resistance profiles. Traditional approaches to speciation require biochemical processing that can be laborious and inefficient. Techniques such as 16S rDNA polymerase chain reaction (PCR) or matrix assisted laser desorp tionionization (MALDI) time of flight (TOF) mass spectrometry are now considered the gold standard. EPIDEMIOLOGY Once thought to be a rare human disease, nocardiosis is being recog nized more frequently and has been diagnosed in people of all ages. Pediatric patients with compromised cellular immunity are at par ticular risk, including children receiving immune suppression after solid organ or stem cell transplantation, chemotherapy for malig |
7,199 | nancy, prolonged corticosteroid therapy, children with poorly con trolled HIV infection, or those with a primary immunodeficiency, especially chronic granulomatous disease. Notably, nocardiosis has been described in patients without an identified immune defect, although in these clinical scenarios, other predisposing factors such as bronchiectasis are often present. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1736 Part XV u Infectious Diseases A B Fig. 236.1 A 9 yr old healthy child with infected knee laceration (A) 10 days after falling onto concrete in his school playground, compli cated by nodular lymphangitis (B). (From Williams PCM, Bartlett AW, Palasanthiran P, McMullan B. A not so innocuous playground fall: lym phocutaneous nocardiosis in an immunocompetent boy. Arch Dis Child. 2022;1073:257258, Figs. 1 and 2.) Due to the lack of a national reporting system for Nocardia infec tions and the molecular advances impacting the classification of this organism, measuring the incidence of the disease remains a challenge. Current knowledge of nocardiosis incidence in the United States is based on a historical survey of 171 infectious diseases physicians from 1974 and isolates received at the CDC reference laboratory, estimating 5001000 cases annually. Prevalence estimates in highrisk populations have been reported to be less than 1, with conflicting reports about the trends of infections in different geographic locations around the world. PATHOGENESIS Nocardia organisms are environmental saprophytes that are ubiquitous in soil and decaying vegetable matter and have been isolated from soil worldwide. Infection can be acquired via inhalation or direct cutane ous inoculation, including after arthropod and cat bites. From 70 to 80 of Nocardia infections originate in the pulmonary parenchyma, with 1025 being primary cutaneous disease. Nocardia can disseminate from the primary site of infection to any organ or any musculoskeletal location. Dissemination after primary lung infection is common, occurring in 1550 of patients; those with an underlying immunocompromised condition are more likely to have disseminated disease. The central nervous system (CNS) is the most concerning and most common secondary site of infection, compli cating as much as 25 of pulmonary disease. Although rare, isolated CNS disease has been described. Whereas most cases are the result of environmental exposure, Nocardia species diversity in the hospital environment has been reported as a reservoir for the development of nosocomial infections. CLINICAL AND RADIOGRAPHIC MANIFESTATIONS The clinical presentation can be nonspecific, with fever reported in approximately 60 of patients, cough in 30, and dyspnea in 25. Extrapulmonary signs and symptoms can correspond to the site of infection. In particular, neurologic deficit has been reported in up to 25 of all cases and in more than 50 of patients with CNS involve ment. Neurologic complaints can include headache, confusion or altered mental status, weakness, and speech impairment. Renal nocar diosis can cause dysuria, hematuria, or pyuria, and gastrointestinal (GI) involvement may be associated with nausea, vomiting, diarrhea, abdominal distention, or melena. |
7,200 | Skin infection can manifest with nodular lymphangitis (Fig. 236.1). Mycetoma is a chronic, progressive infection developing days to months after inoculation, usually on a dis tal location on the limbs. Musculoskeletal, endovascular, and ocular infections have also been reported. Given the nonspecific symptoms and signs of nocardiosis (with the exception of cutaneous lesions), radiographic imaging is often neces sary to define the location and extent of disease. Pulmonary infection can appear as a consolidation consistent with typical bacterial pneu monia or even as a necrotizing pneumonia with or without a pleural effusion. Single or multiple nodules and cavitary lesions have also been described. Cavitary lesions are more common in patients with an underlying immunocompromising condition. CNS disease can take the form of meningitis or focal lesions. Meningitis presents as neutro phil or lymphocyte predominant pleocytosis, elevated cerebrospinal fluid protein, and hypoglycorrhachia. For focal lesions, CT or MRI of the brain often reveals single or multiple ring enhancing lesions. Sim ilar to the brain, when other organs or soft tissues are involved, CT or MRI also typically reveals single or multiple ring enhancing lesions, suggestive of an abscess or abscesses. DIAGNOSIS Microbiologic evidence is necessary to confirm the diagnosis of nocar diosis. In one systematic review, blood cultures were the only positive microbiologic specimen in 38 of cases, thus serving as an important noninvasive diagnostic test for nocardiosis. In the remaining patients, an invasive procedure such as bronchoscopy, tissue biopsy, or abscess aspiration is necessary to procure specimens for diagnostic testing. Histopathologic staining of such material can reveal beaded, weakly gram positive or modified acid fast filamentous bacteria. Histopathol ogy can also show delicately branching bacteria with a proclivity to fragment. Molecular methodologies, specifically gene sequencing, have become the most accurate for definitively identifying Nocardia to the species level. Speciation of Nocardia is becoming increasingly reliant on 16S rDNA PCR or MALDI TOF technologies, with a specificity of 74 and a sensitivity of 88 in a multicenter study assessing the per formance of 16S sequencing in 68 patients with proven or probable nocardiosis. Given that Nocardia spp. can colonize the respiratory airway, a sputum or BAL culture that yields a Nocardia species is not itself confirmatory of nocardiosis. However, a positive microbiologic test for a Nocardia species from one of these specimens in conjunc tion with the clinical and radiographic findings is strongly supportive of nocardiosis. When a diagnosis of nocardiosis is made, strong consideration should be given to evaluation for disseminated disease, even in the absence of signs or symptoms, especially in the immunocompromised host. Although data are limited, most experts agree that, at a minimum, MRI of the brain should be performed in the immunocompromised host with nocardiosis. TREATMENT The choice, dose, and duration of antimicrobial treatment depend on the site and extent of infection, immune status of the patient, initial clinical response, and species and susceptibility testing of the Nocardia isolate. Several therapeutic options exist for the treatment of nocardiosis; however, there are no comparative effectiveness studies to |
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