InternalMed_Harrison

InternalMed_Harrison. The optimal duration of treatment for pneumococcal pneumonia is uncertain, but its continuation for at least 5 days once the patient becomes afebrile appears to be a prudent approach. Cases with a second focus of infection (e.g., empyema or septic arthritis) require longer therapy.


InternalMed_Harrison

InternalMed_Harrison. Amoxicillin (80–90 mg/kg per day) is recommended for children with acute otitis media except in situations where observation and symptom-based treatment without antibiotics are advocated. These situations include nonsevere illness and an uncertain diagnosis in children 6 months to 2 years of age and nonsevere illness (even if the diagnosis seems certain) in children >2 years of age. Although the optimal duration of therapy has not been conclusively established, a 10-day course is recommended for younger children and for children with severe disease at any age. For children >6 years old who have mild or moderate disease, a course of 5–7 days is considered adequate. Patients whose illness fails to respond should be reassessed at 48–72 h. If acute otitis media is confirmed and antibiotic treatment has not been started, administration of amoxicillin should be commenced. If antibiotic therapy fails, a change is indicated. Failure to respond to second-line antibiotics as well indicates that


InternalMed_Harrison

InternalMed_Harrison. has not been started, administration of amoxicillin should be commenced. If antibiotic therapy fails, a change is indicated. Failure to respond to second-line antibiotics as well indicates that myringotomy or tympanocentesis may need to be undertaken in order to obtain samples for culture.


InternalMed_Harrison

InternalMed_Harrison. The above recommendations can also be followed for the treatment of sinusitis. Detailed information on the further management of these conditions in children has been published by the American Academy of Pediatrics and the American Academy of Family Physicians. Measures to prevent pneumococcal disease include vaccination against S. pneumoniae and influenza viruses, reduction of comorbidities that increase the risk of pneumococcal disease, and prevention of antibiotic overuse, which fuels pneumococcal resistance.


InternalMed_Harrison

InternalMed_Harrison. Capsular Polysaccharide Vaccines The 23-valent pneumococcal polysaccharide vaccine (PPSV23), containing 25 μg of each capsular polysaccharide, has been licensed for use since 1983. Recommendations for its use vary by country. The U.S. Advisory Committee on Immunization Practices recommends PPSV23 for all persons ≥65 years of age and for those 2–64 years of age who have underlying medical conditions that put them at increased risk for pneumococcal disease or, if infected, disease of increased severity (Table 171-1; see also www.cdc .gov/vaccines/schedules/). The committee recently updated their recommendations to include the combined use of PPSV23 and a conjugate vaccine in at-risk individuals (see “Polysaccharide–Protein Conjugate Vaccines,” below). Revaccination 5 years after the first dose is recommended for persons >2 years of age who have underlying medical conditions but not routinely for those whose only indication is an age of ≥65 years. PPSV23 does not induce an anamnestic


InternalMed_Harrison

InternalMed_Harrison. dose is recommended for persons >2 years of age who have underlying medical conditions but not routinely for those whose only indication is an age of ≥65 years. PPSV23 does not induce an anamnestic response, and antibody concentrations wane over time; thus revaccination is particularly important for individuals with conditions resulting in loss of antibody. Concerns about repeated revaccination have focused on safety (i.e., local reactions) and the induction of immune hyporesponsiveness.


InternalMed_Harrison

InternalMed_Harrison. Neither the clinical relevance nor the biologic basis of hyporesponsive-953 ness is clear, but, given the possibility of its occurrence, more than one revaccination has not been recommended.


InternalMed_Harrison

InternalMed_Harrison. The effectiveness of PPSV23 against IPD, pneumococcal pneumonia, all-cause pneumonia, and death is controversial, with wide variation in observations. The many published meta-analyses of PPSV efficacy have often reached opposing conclusions with regard to a given clinical entity. Generally, observational studies cite greater effectiveness than do controlled clinical trials. The consensus is that PPSV is effective against IPD but is less effective or ineffective against nonbacteremic pneumococcal pneumonia. However, published trials, observational studies, and meta-analyses contradict this view. Efficacy is often lower in the elderly and in immunodeficient patients whose condition is associated with reduced antibody responses to vaccines than in younger, healthier populations. When PPSV is effective, the duration of protection following a single dose of vaccine is estimated to be ~5 years.


InternalMed_Harrison

InternalMed_Harrison. What is not disputed is that improved pneumococcal vaccines are needed for adults. Even in the setting of routine pneumococcal conjugate vaccination of infants (which indirectly protects adults from vaccine-serotype strains), disease caused by serotypes not represented in the conjugate vaccine continues to be a significant burden among adults.


InternalMed_Harrison

InternalMed_Harrison. Polysaccharide–Protein Conjugate Vaccines Infants and young children respond poorly to PPSV, which contains T cell–independent antigens. Consequently, another class of pneumococcal vaccines, the PCVs, were developed specifically for infants and young children. The first product, a 7-valent PCV, was licensed in 2000 in the United States. Three PCV products—containing 7, 10, and 13 serotypes, respectively—are currently (2014) commercially available. The serotypes included in these PCV formulations are important causes of IPD and antibiotic resistance among young children. Randomized controlled trials have demonstrated a high degree of efficacy of PCVs against vaccine-serotype IPD as well as efficacy against pneumonia, otitis media, nasopharyngeal colonization, and all-cause mortality. PCVs are recommended by the World Health Organization for inclusion in routine childhood immu nization schedules worldwide, especially in countries with high infant mortality rates.


InternalMed_Harrison

InternalMed_Harrison. The United States was the first country to introduce PCV and therefore has the longest experience with its community-wide effects. The introduction of PCV in the United States has resulted in a >90% reduction in vaccine-serotype IPD among the whole population (Fig. 171-7). This decline has been noted not only in those age groups immunized but also in adults and is attributable to the near elimination of vaccineserotype nasopharyngeal colonization in immunized infants, which reduces spread to adults. This protection of unimmunized community members through vaccination of a subset of the community is termed the indirect effect. Increases in colonization with—and concomitantly in disease due to—non-vaccine-serotype strains (i.e., replacement colonization and disease) have been seen; however, the absolute rate increases in IPD caused by non-vaccine serotypes are generally small, especially relative to decreases in vaccine-serotype IPD (see “Epidemiology,” above). Since vaccine-serotype


InternalMed_Harrison

InternalMed_Harrison. the absolute rate increases in IPD caused by non-vaccine serotypes are generally small, especially relative to decreases in vaccine-serotype IPD (see “Epidemiology,” above). Since vaccine-serotype strains are more commonly resistant to antibiotics than are non-vaccine serotypes, use of PCV has also resulted in dramatic declines in the proportion and absolute rates of drug-resistant pneumococcal disease. The recommendations of the Advisory Committee on Immunization Practices for the use of conjugate vaccines can be found at www.cdc.gov/MMWR/pdf/ wk/mm5909.pdf. Recently, PCV has been shown to prevent pneumococcal infection in HIV-infected adults. In the United States, PCV13 followed by a dose of PPSV23 is now recommended for all immunocompromised children and adults.


InternalMed_Harrison

InternalMed_Harrison. Other Prevention Strategies Pneumococcal disease can also be averted through the prevention of illnesses that predispose individuals to pneumococcal infections. Relevant measures include influenza vaccination and improved management and control of diabetes, HIV infection, heart disease, and lung disease. Finally, the reduction of antibiotic misuse is a strategy for the prevention of pneumococcal disease in that


InternalMed_Harrison

InternalMed_Harrison. FIGURE 171-7 Changes in invasive pneumococcal disease (IPD) incidence, by serotype group, among children <5 years old (top) and adults >65 years old (bottom), 1998–2009. 7-Valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States for routine administration to infants and young children during the second half of 2000, while PCV13 was introduced in 2010, the year following this surveillance period. PCV7 serotypes include serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F as well as cross-reactive serotype 6A. PCV13 serotypes include the PCV7 serotypes as well as serotypes 1, 3, 5, 6A, 7F, and 19A. (Reprinted with permission from Dr. M. Moore, Centers for Disease Control and Prevention.) antimicrobial resistance directly and indirectly perpetuates organism transmission and disease in the community.


InternalMed_Harrison

InternalMed_Harrison. American Academy of Pediatrics RED BOOK. The report of the Committee on Infectious Diseases: aapredbook.aappublications.org; Pneumococcal Regional Serotype Distribution for Pneumococcal AMC TPP: www.gavialliance.org/library/documents/amc/tpp-codebook/ Cases per 100,000 population Cases per 100,000 population Staphylococcal Infections Franklin D. Lowy Staphylococcus aureus, the most virulent of the many staphylococcal species, has demonstrated its versatility by remaining a major cause of morbidity and mortality worldwide despite the availability of numer-ous effective antistaphylococcal antibiotics. S. aureus is a pluripotent 172 pathogen, causing disease through both toxinand non-toxin-mediated mechanisms. This organism is responsible for numerous nosocomial and community-based infections that range from relatively minor skin and soft tissue infections to life-threatening systemic infections.


InternalMed_Harrison

InternalMed_Harrison. The “other” staphylococci, collectively designated coagulase-negative staphylococci (CoNS), are considerably less virulent than S. aureus but remain important pathogens in infections that are primarily associated with prosthetic devices. Staphylococci, gram-positive cocci in the family Micrococcaceae, form grapelike clusters on Gram’s stain (Fig. 172-1). These organisms (~1 μm in diameter) are catalase-positive (unlike streptococcal species), non-motile, aerobic, and facultatively anaerobic. They are capable of prolonged survival on environmental surfaces under varying conditions. Some species have a relatively broad host range, including mammals and birds, whereas for others the host range is quite narrow—i.e., limited to one or two closely related animals.


InternalMed_Harrison

InternalMed_Harrison. More than 30 staphylococcal species are pathogenic. Identification of the more clinically important species has generally relied on a series of biochemical tests. Automated diagnostic systems, kits for biochemical characterization, and DNA-based assays are available for species identification. With few exceptions, S. aureus is distinguished from other staphylococcal species by its production of coagulase, a surface enzyme that converts fibrinogen to fibrin. Latex kits that detect both protein A and clumping factor also distinguish S. aureus from most other staphylococcal species. S. aureus ferments mannitol, is positive for protein A, and produces DNAse. On blood agar plates, S. aureus tends to form golden β-hemolytic colonies; in contrast, CoNS produce small white nonhemolytic colonies. Increasingly, sequence-based methods (e.g., 16S rRNA) are being used to identify different staphylococcal species.


InternalMed_Harrison

InternalMed_Harrison. Determining whether multiple staphylococcal isolates from different patients are the same or different is often relevant when there is concern that a nosocomial outbreak is due to a common point source (e.g., a contaminated medical instrument). Molecular typing methods, such as pulsed-field gel electrophoresis and sequence-based techniques (e.g., staphylococcal protein A [SpA] typing), have increasingly been used for this purpose. More recently, whole-genome sequencing has enhanced the ability to discriminate among clinical isolates. S.AUREUS INFECTIONS


InternalMed_Harrison

InternalMed_Harrison. S.AUREUS INFECTIONS S. aureus is both a commensal and an opportunistic pathogen. Approximately 30% of healthy persons are colonized with S. aureus, with a smaller percentage (~10%) persistently colonized. The rate of colonization is elevated among insulin-dependent diabetics, HIV-infected patients, patients undergoing hemodialysis, injection drug users, and individuals with skin damage. The anterior nares and oropharynx are frequent sites of human colonization, although the skin (especially when damaged), vagina, axilla, and perineum may also be colonized. These colonization sites serve as a reservoir for future infections.


InternalMed_Harrison

InternalMed_Harrison. Transmission of S. aureus most frequently results from direct personal contact. Colonization of different body sites allows transfer from one person to another during contact. Spread of staphylococci in aerosols of respiratory or nasal secretions from heavily colonized individuals has also been reported. Most individuals who develop S. aureus infections become infected with a strain that is already a part of their own commensal flora. Breaches of the skin or mucosal membrane allow S. aureus to initiate infection. FIGURE 172-1 Gram’s stain of S. aureus in a sputum sample. (From ASM MicrobeLibrary.org.© Pfizer, Inc.)


InternalMed_Harrison

InternalMed_Harrison. FIGURE 172-1 Gram’s stain of S. aureus in a sputum sample. (From ASM MicrobeLibrary.org.© Pfizer, Inc.) Some diseases increase the risk of S. aureus infection; diabetes, for example, combines an increased rate of S. aureus colonization and the use of injectable insulin with the possibility of impaired leukocyte function. Individuals with congenital or acquired qualitative or quantitative defects of polymorphonuclear leukocytes (PMNs) are at increased risk of S. aureus infections; this group includes neutropenic patients (e.g., those receiving chemotherapeutic agents), those with chronic granulomatous disease, and those with Job’s or Chédiak-Higashi syndrome. Other groups at risk include individuals with end-stage renal disease, HIV infection, skin abnormalities, or prosthetic devices.


InternalMed_Harrison

InternalMed_Harrison. S. aureus is a leading cause of health care–associated infections (Chap. 168). It is the most common cause of surgical wound infections and is second only to CoNS as a cause of primary bacteremia. These isolates are generally resistant to multiple antibiotics; thus available therapeutic options are limited. In the community, S. aureus remains an important cause of skin and soft tissue infections, respiratory infections, and (among injection drug users) infective endocarditis. The increasing use of home infusion therapy is another cause of community-acquired staphylococcal infections. In the past two decades, there has been a dramatic change in the epidemiology of infections due to methicillin-resistant


InternalMed_Harrison

InternalMed_Harrison. S. aureus (MRSA). In addition to its major role as a nosocomial pathogen, MRSA has become an established community-based pathogen. Numerous outbreaks of community-associated MRSA (CA-MRSA) infections have been reported in both rural and urban settings in widely separated regions throughout the world. The outbreaks have occurred among such diverse groups as children, prisoners, athletes, Native Americans, and drug users. Risk factors common to these outbreaks include poor hygienic conditions, close contact, contaminated material, and damaged skin. These infections have been caused by a limited number of MRSA strains. In the United States, strain USA300 (defined by pulsed-field gel electrophoresis) has been the predominant clone. In other geographic regions of the world, different strains of CA-MRSA have been responsible for these community-based outbreaks. Although the majority of infections caused by these strains have involved the skin and soft tissue, 5–10% have been invasive and


InternalMed_Harrison

InternalMed_Harrison. of CA-MRSA have been responsible for these community-based outbreaks. Although the majority of infections caused by these strains have involved the skin and soft tissue, 5–10% have been invasive and potentially life-threatening. CA-MRSA strains have also been responsible for an increasing number of nosocomial infections. Of concern has been the apparent capacity of CA-MRSA to cause disease in immunocompetent individuals.


InternalMed_Harrison

InternalMed_Harrison. PATHOGENESIS General Concepts S. aureus is a pyogenic pathogen known for its capacity to induce abscess formation at sites of both local and metastatic infections. This classic pathologic response to S. aureus defines the framework within which the infection will progress. The bacteria elicit an inflammatory response characterized by an initial intense infiltration of PMNs and a subsequent infiltration of macrophages and fibroblasts. Either the host cellular response (including the deposition of fibrin and collagen) contains the infection, or infection spreads to the adjoining tissue or the bloodstream.


InternalMed_Harrison

InternalMed_Harrison. In toxin-mediated staphylococcal disease, infection is not invariably present. For example, once toxin has been elaborated into food, staphylococcal food poisoning can develop in the absence of viable bacteria. In staphylococcal toxic shock syndrome (TSS), conditions allowing toxin elaboration at colonization sites (e.g., the presence of a superabsorbent tampon) suffice for initiation of clinical illness.


InternalMed_Harrison

InternalMed_Harrison. The S. aureus Genome The complete genomes of numerous strains of S. aureus have now been fully sequenced. Among the interesting revelations are (1) the high degree of nucleotide sequence similarity of the core genomes of different strains; (2) acquisition of a relatively large amount of genetic information by horizontal transfer from other bacterial species; and (3) the presence of unique “pathogenicity” or “genomic” islands—mobile genetic elements that contain clusters of enterotoxin and exotoxin genes and/or antimicrobial 955 resistance determinants. Among the genes in these islands are those carrying mecA, the gene responsible for methicillin resistance. Methicillin resistance–containing islands have been designated staphylococcal cassette chromosome mec (SCCmec) types and range in size from ~20 to 60 kb. To date, 11 SCCmec types have been identified. Among the more common types, types 1–3 are traditionally associated with nosocomial MRSA isolates, whereas types 4–6 have been


InternalMed_Harrison

InternalMed_Harrison. size from ~20 to 60 kb. To date, 11 SCCmec types have been identified. Among the more common types, types 1–3 are traditionally associated with nosocomial MRSA isolates, whereas types 4–6 have been associated with the epidemic CA-MRSA strains.


InternalMed_Harrison

InternalMed_Harrison. A limited number of MRSA clones have been responsible for most communityand hospital-associated infections worldwide. A comparison of these strains with those from earlier outbreaks (e.g., the phage 80/81 strains from the 1950s) has revealed preservation of the nucleotide sequence over time. This observation suggests that these strains possess determinants that facilitate survival and spread.


InternalMed_Harrison

InternalMed_Harrison. Regulation of Virulence Gene Expression In both toxin-mediated and non-toxin-mediated diseases due to S. aureus, the expression of virulence determinants associated with infection depends on a series of regulatory genes (e.g., accessory gene regulator [agr] and staphylococcal accessory regulator [sar]) that coordinately control the expression of many virulence genes. The regulatory gene agr is part of a quorum-sensing signal transduction pathway that senses and responds to bacterial density. Staphylococcal surface proteins are synthesized during the bacterial exponential growth phase in vitro. In contrast, many secreted proteins, such as α toxin, the enterotoxins, and assorted enzymes, are released during the postexponential growth phase in response to transcription of the effector molecule of agr, RNAIII.


InternalMed_Harrison

InternalMed_Harrison. It has been hypothesized that these regulatory genes serve a similar function in vivo. Successful invasion requires the sequential expression of these different bacterial elements. Bacterial adhesins are needed to initiate colonization of host tissue surfaces. The subsequent release of various enzymes enables the colony to obtain nutritional support and permits bacteria to spread to adjacent tissues. Studies with strains in which these regulatory genes are inactivated show reduced virulence in several animal models of S. aureus infection.


InternalMed_Harrison

InternalMed_Harrison. Pathogenesis of Invasive S. aureus Infection Staphylococci are opportunists. For these organisms to invade the host and cause infection, some or all of the following steps are necessary: contamination and colonization of host tissue surfaces, breach of cutaneous or mucosal barriers, establishment of a localized infection, invasion, evasion of the host response, and metastatic spread. Colonizing strains or strains transferred from other individuals are introduced into damaged skin, a wound, or the bloodstream. Recurrences of S. aureus infections are common, apparently because of the capacity of these pathogens to survive, to persist in a quiescent state in various tissues, and then to cause recrudescent infections when suitable conditions arise.


InternalMed_Harrison

InternalMed_Harrison. s.aureus colonization of body surfaces The anterior nares is one of the primary sites of staphylococcal colonization in humans. Colonization appears to involve the attachment of S. aureus to keratinized epithelial cells of the anterior nares. Other factors that may contribute to colonization include the influence of other resident nasal flora and their bacterial density, host factors, and nasal mucosal damage (e.g., that resulting from inhalational drug use). Other colonized body sites, such as damaged skin, the groin, and the oropharynx, may be particularly important reservoirs for CA-MRSA strains. inoculation and colonization of tissue surfaces Staphylococci may be introduced into tissue as a result of minor abrasions, administration of medications such as insulin, or establishment of IV access with catheters. After their introduction into a tissue site, bacteria replicate and colonize the host tissue surface. A family of structurally related


InternalMed_Harrison

InternalMed_Harrison. S. aureus surface proteins referred to as MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) plays an important role in mediating adherence to these sites. By adhering to exposed matrix molecules (e.g., fibrinogen, fibronectin), MSCRAMMs such as clumping factor and collagen-binding protein enable the bacteria to colonize different tissue surfaces; these proteins contribute to 956 the pathogenesis of invasive infections such as endocarditis and septic arthritis by facilitating the adherence of S. aureus to surfaces with exposed fibrinogen or collagen. Although CoNS are classically known for their ability to elaborate biofilms and to colonize prosthetic devices, S. aureus also possesses the genes responsible for biofilm formation, such as the intercellular adhesion (ica) locus. Binding to these devices occurs in a stepwise fashion, involving staphylococcal adherence to serum constituents that have coated the device surface and subsequent biofilm elaboration.


InternalMed_Harrison

InternalMed_Harrison. (ica) locus. Binding to these devices occurs in a stepwise fashion, involving staphylococcal adherence to serum constituents that have coated the device surface and subsequent biofilm elaboration. S. aureus is thus a frequent cause of biomedical-device infections.


InternalMed_Harrison

InternalMed_Harrison. invasion After colonization, staphylococci replicate at the initial site of infection, elaborating enzymes that include serine proteases, hyaluronidases, thermonucleases, and lipases. These enzymes facilitate bacterial survival and local spread across tissue surfaces, although their precise role in infections is not well defined. The lipases may facilitate survival in lipid-rich areas such as the hair follicles, where S. aureus infections are often initiated. The S. aureus toxin Panton-Valentine leukocidin is cytolytic to PMNs, macrophages, and monocytes. Strains elaborating this toxin have been epidemiologically linked with cutaneous and more serious infections caused by strains of CA-MRSA. MSCRAMMs also appear to play an important role in the ability of S. aureus to spread and cause disease at other tissue sites.


InternalMed_Harrison

InternalMed_Harrison. S. aureus to spread and cause disease at other tissue sites. Constitutional findings may result from either localized or systemic infections. The staphylococcal cell wall—consisting of alternating N-acetyl muramic acid and N-acetyl glucosamine units in combination with an additional cell wall component, lipoteichoic acid—can initiate an inflammatory response that includes the sepsis syndrome. Staphylococcal α toxin, which causes pore formation in various eukaryotic cells, can also initiate an inflammatory response with findings suggestive of sepsis.


InternalMed_Harrison

InternalMed_Harrison. evasion of Host defense mecHanisms Staphylococci have a multitude of immune evasion strategies that are critical to their success as invasive pathogens. They possess an antiphagocytic polysaccharide microcapsule. Most human S. aureus infections are due to capsular types 5 and 8. The zwitterionic (both negatively and positively charged) S. aureus capsule plays a critical role in the induction of abscess formation. Protein A, an MSCRAMM unique to S. aureus, acts as an Fc receptor, binding the Fc portion of IgG subclasses 1, 2, and 4 and preventing opsonophagocytosis by PMNs. Both chemotaxis inhibitory protein of staphylococci (CHIPS, a secreted protein) and extracellular adherence protein (EAP, a surface protein) interfere with PMN migration to sites of infection.


InternalMed_Harrison

InternalMed_Harrison. An additional potential mechanism of S. aureus evasion is its capacity for intracellular survival. Both professional and nonprofessional phagocytes internalize staphylococci. Internalization by these cells may provide a sanctuary that protects bacteria against the host’s defenses. The intracellular environment favors the phenotypic expression of S. aureus small-colony variants. Small-colony variants are found in patients receiving antimicrobial therapy (e.g., with aminoglycosides) and in those with cystic fibrosis or osteomyelitis. These variants, whether intraor extracellular, may facilitate prolonged staphylococcal survival in different tissue sites and enhance the likelihood of recurrences. Finally, S. aureus can survive within PMNs and may use these cells to spread and to seed other tissue sites.


InternalMed_Harrison

InternalMed_Harrison. patHogenesis of community-acQuired mrsa infections A number of virulence determinants have been identified as contributing to the pathogenesis of CA-MRSA infections. There is a strong epidemiologic association linking the presence of the gene for the Panton-Valentine leukocidin with skin and soft tissue infections as well as with necrotizing postinfluenza pneumonia. Other determinants that play a role in the pathogenesis of these infections include the arginine catabolic mobile element (ACME), a cluster of unique genes that may facilitate evasion of host defense mechanisms; phenol-soluble modulins, a family of cytolytic peptides; and α toxin.


InternalMed_Harrison

InternalMed_Harrison. Host Response to S. aureus Infection The primary host response to S. aureus infection is the recruitment of PMNs. These cells are attracted to infection sites by bacterial components such as formylated peptides or peptidoglycan as well as by the cytokines tumor necrosis factor (TNF) and interleukins (ILs) 1 and 6, which are released by activated macrophages and endothelial cells. Although most individuals have antibodies to staphylococci, it is not clear that antibody levels are qualitatively or quantitatively sufficient to protect against infection. Although anticapsular and anti-MSCRAMM antibodies facilitate opsonization in vitro and have been protective against infection in several animal models, they have not yet successfully prevented staphylococcal infections in clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Pathogenesis of Toxin-Mediated Disease S. aureus produces three types of toxin: cytotoxins, pyrogenic toxin superantigens, and exfoliative toxins. Both epidemiologic data and studies in animals suggest that antitoxin antibodies are protective against illness in TSS, staphylococcal food poisoning, and staphylococcal scalded-skin syndrome (SSSS). Illness develops after toxin synthesis and absorption and the subsequent toxin-initiated host response.


InternalMed_Harrison

InternalMed_Harrison. enterotoxin and toxic sHocK syndrome toxin 1 (tsst-1) The pyrogenic toxin superantigens are a family of small-molecular-size, structurally similar proteins that are responsible for two diseases: TSS and food poisoning. TSS results from the ability of enterotoxins and TSST-1 to function as T cell mitogens. In the normal process of antigen presentation, the antigen is first processed within the cell, and peptides are then presented in the major histocompatibility complex (MHC) class II groove, initiating a measured T cell response. In contrast, enterotoxins bind directly to the invariant region of MHC—outside the MHC class II groove. The enterotoxins can then bind T cell receptors via the vβ chain; this binding results in a dramatic overexpansion of T cell clones (up to 20% of the total T cell population). The consequence of this T cell expansion is a “cytokine storm,” with the release of inflammatory mediators that include interferon γ, IL-1, IL-6, TNF-α, and TNF-β. The resulting


InternalMed_Harrison

InternalMed_Harrison. T cell population). The consequence of this T cell expansion is a “cytokine storm,” with the release of inflammatory mediators that include interferon γ, IL-1, IL-6, TNF-α, and TNF-β. The resulting multisystem disease produces a constellation of findings that mimic those in endotoxin shock; however, the pathogenic mechanisms differ. The release of endotoxin from the gastrointestinal tract may synergistically enhance the toxin’s effects.


InternalMed_Harrison

InternalMed_Harrison. A different region of the enterotoxin molecule is responsible for the symptoms of food poisoning. The enterotoxins are heat stable and can survive conditions that kill the bacteria. Illness results from the ingestion of preformed toxin. As a result, the incubation period is short (1–6 h). The toxin stimulates the vagus nerve and the vomiting center of the brain. It also appears to stimulate intestinal peristaltic activity. exfoliative toxins and ssss The exfoliative toxins are responsible for SSSS. The toxins that produce disease in humans are of two serotypes: ETA and ETB. These toxins are serine proteases, which cleave desmosomal cadherins in the superficial layer of the skin, triggering exfoliation. The result is a split in the epidermis at the granular level, which is responsible for the superficial desquamation of the skin that typifies this illness.


InternalMed_Harrison

InternalMed_Harrison. Staphylococcal infections are readily diagnosed by Gram’s stain (Fig. 172-1) and microscopic examination of abscess contents or of infected tissue. Routine culture of infected material usually yields positive results, and blood cultures are sometimes positive even when infections are localized to extravascular sites. S. aureus is rarely a blood culture contaminant. Polymerase chain reaction (PCR)–based assays have been applied to the rapid diagnosis of S. aureus infection and are increasingly used in clinical microbiology laboratories. A number of point-of-care tests are now available to screen patients for colonization with MRSA. Determining whether patients with documented S. aureus bacteremia also have infective endocarditis or a metastatic focus of infection remains a diagnostic challenge. Uniformly positive blood cultures suggest an endovascular infection such as endocarditis (see “Bacteremia, Sepsis, and Infective Endocarditis,” below).


InternalMed_Harrison

InternalMed_Harrison. Skin and Soft Tissue Infections S. aureus causes a variety of cutaneous infections, many of which can also be caused by group A streptococci Folliculitis Abscess, furuncle, carbuncle Cellulitis Impetigo Mastitis Surgical wound infections Ventilator-associated or nosocomial pneumonia Septic pulmonary emboli Postviral pneumonia (e.g., influenza) Empyema Sepsis, septic shock Metastatic foci of infection (kidney, joints, bone, lung) Infective endocarditis Device-Related Infections (e.g., intravascular catheters, prosthetic joints) Toxin-Mediated Illnesses


InternalMed_Harrison

InternalMed_Harrison. Staphylococcal scalded-skin syndrome Invasive Infections Associated with Community-Acquired Methicillin-Resistant S. aureus or (less commonly) other streptococcal species. Common factors predisposing to S. aureus cutaneous infection include chronic skin conditions (e.g., eczema), skin damage (e.g., insect bites, minor trauma), injections (e.g., in diabetes, injection drug use), and poor personal hygiene. These infections are characterized by the formation of pus-containing blisters, which often begin in hair follicles and spread to adjoining tissues. Folliculitis is a superficial infection that involves the hair follicle, with a central area of purulence (pus) surrounded by induration and erythema. Furuncles (boils) are more extensive, painful lesions that tend to occur in hairy, moist regions of the body and extend from the hair follicle to become a true abscess with an area of central purulence. Carbuncles are most often located in the lower neck and are even more severe and


InternalMed_Harrison

InternalMed_Harrison. regions of the body and extend from the hair follicle to become a true abscess with an area of central purulence. Carbuncles are most often located in the lower neck and are even more severe and painful, resulting from the coalescence of other lesions that extend to a deeper layer of the subcutaneous tissue. In general, furuncles and carbuncles are readily apparent, with pus often expressible or discharging from the abscess. Other cutaneous


InternalMed_Harrison

InternalMed_Harrison. S. aureus infections include impetigo and cellulitis. S. aureus is one of the most common causes of surgical wound infection. Mastitis develops in 1–3% of nursing mothers. This infection of the breast, which generally presents within 2–3 weeks after delivery, is characterized by findings that range from cellulitis to abscess formation. Systemic signs, such as fever and chills, are often present in more severe cases.


InternalMed_Harrison

InternalMed_Harrison. Musculoskeletal Infections S. aureus is among the most common 957 causes of bone infections—both those resulting from hematogenous dissemination and those arising from contiguous spread from a soft tissue site. Hematogenous osteomyelitis in children most often involves the long bones. Infections present as fever and bone pain or with a child’s reluctance to bear weight. The white blood cell count and erythrocyte sedimentation rate are often elevated. Blood cultures are positive in ~50% of cases. When necessary, bone biopsies for culture and histopathologic examination are usually diagnostic. Routine x-rays may be normal for up to 14 days after the onset of symptoms. 99mTc-phosphonate scanning often detects early evidence of infection. MRI is more sensitive than other techniques in establishing a radiologic diagnosis.


InternalMed_Harrison

InternalMed_Harrison. In adults, hematogenous osteomyelitis involving the long bones is less common. However, vertebral osteomyelitis is among the more common clinical presentations. Vertebral bone infections are most often seen in patients with endocarditis, those undergoing hemodialysis, diabetics, and injection drug users. These infections may present as intense back pain and fever but may also be clinically occult, presenting as chronic back pain and low-grade fever. S. aureus is the most common cause of epidural abscess, a complication that can result in neurologic compromise. Patients complain of difficulty voiding or walking and of radicular pain in addition to the symptoms associated with their osteomyelitis. Surgical intervention in this setting often constitutes a medical emergency. MRI most reliably establishes the diagnosis (Fig. 172-2).


InternalMed_Harrison

InternalMed_Harrison. Bone infections that result from contiguous spread tend to develop from soft tissue infections, such as those associated with diabetic or vascular ulcers, surgery, or trauma. Exposure of bone, a draining fistulous tract, failure to heal, or continued drainage suggests involvement of underlying bone. Bone involvement is established by bone culture and histopathologic examination (revealing evidence of PMN infiltration). Contamination of culture material from adjacent tissue can make the diagnosis of osteomyelitis difficult in the absence of pathologic confirmation. In addition, it is sometimes hard to distinguish radiologically between osteomyelitis and overlying soft tissue infection with underlying osteitis.


InternalMed_Harrison

InternalMed_Harrison. In both children and adults, S. aureus is the most common cause of septic arthritis in native joints. This infection is rapidly progressive and may be associated with extensive joint destruction if left untreated. It presents as intense pain on motion of the affected joint, swelling, and fever. Aspiration of the joint reveals turbid fluid, with >50,000 PMNs/μL and gram-positive cocci in clusters on Gram’s stain (Fig. 172-1). In FIGURE 172-2 S. aureus vertebral osteomyelitis and epidural abscess involving the thoracic disk between T9 and T10. Sagittal postcontrast MRI of the spine illustrates destruction of the T9–T10 intervertebral space with enhancement (arrow). There is impingement on the thoracic cord and an epidural collection extending from T9 through T11 (short arrows).


InternalMed_Harrison

InternalMed_Harrison. 958 adults, septic arthritis may result from trauma, surgery, or hematogenous dissemination. The most commonly involved joints include the knees, shoulders, hips, and phalanges. Infection frequently develops in joints previously damaged by osteoarthritis or rheumatoid arthritis. Iatrogenic infections resulting from aspiration or injection of agents into the joint also occur. In these settings, the patient experiences increased pain and swelling in the involved joint in association with fever. Pyomyositis is an unusual infection of skeletal muscles that is seen primarily in tropical climates but also occurs in immunocompromised and HIV-infected patients. It is believed to arise from occult bacteremia. Pyomyositis presents as fever, swelling, and pain overlying the involved muscle. Aspiration of fluid from the involved tissue yields pus. Although a history of trauma may be associated with the infection, its pathogenesis is poorly understood.


InternalMed_Harrison

InternalMed_Harrison. S. aureus occur in selected clinical settings. S. aureus is a cause of serious respiratory tract infections in newborns and infants; these infections present with shortness of breath, fever, and respiratory failure. Chest x-ray may reveal pneumatoceles (shaggy, thin-walled cavities). Pneumothorax and empyema are recognized complications.


InternalMed_Harrison

InternalMed_Harrison. In adults, nosocomial S. aureus pulmonary infections are common among intubated patients in intensive care units. Nasally colonized patients are at increased risk of these infections. The clinical presentation is no different from that encountered in pulmonary infections of other bacterial etiologies. Patients produce increased volumes of purulent sputum and develop respiratory distress, fever, and new pulmonary infiltrates. Distinguishing bacterial pneumonia from respiratory failure or other causes of new pulmonary infiltrates in critically ill patients is often difficult and relies on a constellation of clinical, radiologic, and laboratory findings.


InternalMed_Harrison

InternalMed_Harrison. Community-acquired respiratory tract infections due to S. aureus usually follow viral infections—most commonly influenza. Patients may present with fever, bloody sputum production, and midlung-field pneumatoceles or multiple, patchy pulmonary infiltrates. Diagnosis is made by sputum Gram’s stain and culture. Blood cultures, although useful, are usually negative. Bacteremia, Sepsis, and Infective Endocarditis S. aureus bacteremia may be complicated by sepsis, endocarditis, vasculitis, or metastatic seeding (establishment of suppurative collections at other tissue sites). The frequency of metastatic seeding during bacteremia has been estimated to be as high as 31%. Among the more commonly seeded tissue sites are bones, joints, kidneys, and lungs.


InternalMed_Harrison

InternalMed_Harrison. Recognition of these complications by clinical and laboratory diagnostic methods alone is often difficult. Comorbid conditions that are frequently seen in association with S. aureus bacteremia and that increase the risk of complications include diabetes, HIV infection, and renal insufficiency. Other host factors associated with an increased risk of complications include presentation with community-acquired S. aureus bacteremia (except in injection drug users), lack of an identifiable primary focus of infection, and the presence of prosthetic devices or material. Clinically, S. aureus sepsis presents in a manner similar to that documented for sepsis due to other bacteria. The well-described progression of hemodynamic changes—beginning with respiratory alkalosis and clinical findings of hypotension and fever—is commonly seen. The microbiologic diagnosis is established by positive blood cultures.


InternalMed_Harrison

InternalMed_Harrison. The overall incidence of S. aureus endocarditis has increased over the past 20 years. S. aureus is now the leading cause of endocarditis worldwide, accounting for 25–35% of cases. This increase is due, at least in part, to the increased use of intravascular devices. Studies of patients with S. aureus bacteremia and intravascular catheters that used transesophageal echocardiography found an infective endocarditis incidence of ~25%. Other factors associated with an increased risk of endocarditis are injection drug use, hemodialysis, the presence of intravascular prosthetic devices at the time of bacteremia, and immunosuppression. Patients with implantable cardiac devices (e.g., permanent pacemakers) are at increased risk of endocarditis or device-related infections. Despite the availability of effective antibiotics, mortality rates from these infections continue to range from 20% to 40%, depending on both the host and the nature of the infection. Complications of


InternalMed_Harrison

InternalMed_Harrison. S. aureus endocarditis include cardiac valvular insufficiency, peripheral emboli, metastatic seeding, and central nervous system (CNS) involvement (e.g., mycotic aneurysms, embolic strokes).


InternalMed_Harrison

InternalMed_Harrison. S. aureus endocarditis is encountered in four clinical settings: (1) right-sided endocarditis in association with injection drug use, (2) left-sided native-valve endocarditis, (3) prosthetic-valve endocarditis, and (4) nosocomial endocarditis. In each of these settings, the diagnosis is suspected by recognition of clinical stigmata suggestive of endocarditis. These findings include cardiac manifestations, such as new or changing cardiac valvular murmurs; cutaneous evidence, such as vasculitic lesions, Osler’s nodes, or Janeway lesions; evidence of rightor left-sided embolic disease; and a history suggesting a risk for S. aureus bacteremia. In the absence of antecedent antibiotic therapy, blood cultures are almost uniformly positive. Transthoracic echocardiography, while less sensitive than transesophageal echocardiography, is less invasive and may establish the presence of valvular vegetations. The Duke criteria (see Table 155-3) are now commonly used to help establish the likelihood


InternalMed_Harrison

InternalMed_Harrison. transesophageal echocardiography, is less invasive and may establish the presence of valvular vegetations. The Duke criteria (see Table 155-3) are now commonly used to help establish the likelihood of this diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Acute right-sided tricuspid valvular S. aureus endocarditis is most often seen in injection drug users. The classic presentation includes a high fever, a toxic clinical appearance, pleuritic chest pain, and the production of purulent (sometimes bloody) sputum. Chest x-rays or CT scans reveal evidence of septic pulmonary emboli (small, peripheral, circular lesions that may cavitate with time) (Fig. 172-3). A high percentage of affected patients have no history of antecedent valvular damage. At the outset of their illness, patients may present with fever alone, without cardiac or other localizing findings. As a result, a high index of clinical suspicion is essential for diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Individuals with antecedent cardiac valvular damage more commonly present with left-sided native-valve endocarditis involving the damaged valve. These patients tend to be older than those with right-sided endocarditis, their prognosis is worse, and their incidence of complications (including peripheral emboli, cardiac decompensation, and metastatic seeding) is higher. S. aureus is one of the more common causes of prosthetic-valve endocarditis. This infection is especially fulminant in the early postoperative period and is associated with a high mortality rate. In most instances, medical therapy alone is not sufficient and urgent valve replacement is necessary. Patients are prone to develop valvular insufficiency or myocardial abscesses originating from the region of valve implantation. FIGURE 172-3 CT scan illustrating septic pulmonary emboli in a patient with methicillin-resistant Staphylococcus aureus bacteremia.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 172-3 CT scan illustrating septic pulmonary emboli in a patient with methicillin-resistant Staphylococcus aureus bacteremia. The increased frequency of nosocomial endocarditis (15–30% of cases, depending on the series) reflects in part the increased use of intravascular devices. This form of endocarditis is most commonly caused by S. aureus. Because patients often are critically ill, are receiving antibiotics for various other indications, and have comorbid conditions, the diagnosis is often missed. Urinary Tract Infections Urinary tract infections (UTIs) are infrequently caused by S. aureus. The presence of S. aureus in the urine generally suggests hematogenous dissemination. Ascending S. aureus infections occasionally result from instrumentation of the genitourinary tract.


InternalMed_Harrison

InternalMed_Harrison. Prosthetic Device–Related Infections S. aureus accounts for a large proportion of prosthetic device–related infections. These infections often involve intravascular catheters, prosthetic valves, orthopedic devices, peritoneal catheters, pacemakers, left-ventricular-assist devices, and vascular grafts. In contrast with the more indolent presentation of CoNS infections, S. aureus device-related infections are often more acute, with both localized and systemic manifestations. The latter infections also tend to progress more rapidly. It is relatively common for a pyogenic collection to be present at the device site. Aspiration of these collections and performance of blood cultures are important components in establishing a diagnosis. S. aureus infections tend to occur more commonly soon after implantation unless the device is used for access (e.g., intravascular or hemodialysis catheters). In the latter instance, infections can occur at any time. As in most prosthetic-device infections,


InternalMed_Harrison

InternalMed_Harrison. implantation unless the device is used for access (e.g., intravascular or hemodialysis catheters). In the latter instance, infections can occur at any time. As in most prosthetic-device infections, successful therapy usually involves removal of the device. Left in place, the device is a potential nidus for either persistent or recurrent infections.


InternalMed_Harrison

InternalMed_Harrison. Infections Associated with Community-Acquired MRSA Although the skin and soft tissues are the most common sites of infection associated with CA-MRSA, 5–10% of these infections are invasive and can even be life-threatening. The latter unique infections, including necrotizing fasciitis, necrotizing pneumonia, and sepsis with Waterhouse-Friderichsen syndrome or purpura fulminans, were rarely associated with S. aureus prior to the emergence of CA-MRSA. These life-threatening infections reflect the increased virulence of CA-MRSA strains.


InternalMed_Harrison

InternalMed_Harrison. Toxin-Mediated Diseases • food poisoning S. aureus is among the most common causes of foodborne outbreaks of infection in the United States. Staphylococcal food poisoning results from the inoculation of toxin-producing S. aureus into food by colonized food handlers. Toxin is then elaborated in such growth-promoting food as custards, potato salad, or processed meats. Even if the bacteria are killed by warming, the heat-stable toxin is not destroyed. The onset of illness is rapid, occurring within 1–6 h of ingestion. The illness is characterized by nausea and vomiting, although diarrhea, hypotension, and dehydration may also occur. The differential diagnosis includes diarrhea of other etiologies, especially that caused by similar toxins (e.g., the toxins elaborated by Bacillus cereus). The rapidity of onset, the absence of fever, and the epidemic nature of the presentation (without second-degree spread) arouse suspicion of staphylococcal food poisoning. Symptoms generally resolve within


InternalMed_Harrison

InternalMed_Harrison. of onset, the absence of fever, and the epidemic nature of the presentation (without second-degree spread) arouse suspicion of staphylococcal food poisoning. Symptoms generally resolve within 8–10 h. The diagnosis can be established by the demonstration of bacteria or the documentation of enterotoxin in the implicated food. Treatment is entirely supportive.


InternalMed_Harrison

InternalMed_Harrison. toxic sHocK syndrome TSS gained attention in the early 1980s, when a nationwide outbreak occurred in the United States among young, otherwise healthy, menstruating women. Epidemiologic investigation demonstrated that these cases were associated with the use of a highly absorbent tampon that had recently been introduced to the market. Subsequent studies established the role of TSST-1 in these illnesses. Withdrawal of the tampon from the market resulted in a rapid decline in the incidence of this disease. However, menstrual and nonmenstrual cases continue to be reported. Nonmenstrual cases are frequently seen in patients with surgical or postpartum wound infections. The clinical presentation is similar in menstrual and nonmenstrual TSS. Evidence of clinical S. aureus infection is not a prerequisite. CASE DEfInITIon of S. AUREUS ToxIC SHoCk SynDRoME 1. Fever: temperature of ≥38.9°C ( ≥102°F) 2.


InternalMed_Harrison

InternalMed_Harrison. CASE DEfInITIon of S. AUREUS ToxIC SHoCk SynDRoME 1. Fever: temperature of ≥38.9°C ( ≥102°F) 2. Hypotension: systolic blood pressure of ≤90 mmHg or orthostatic hypo-tension (orthostatic drop in diastolic blood pressure by ≥15 mmHg, orthostatic syncope, or orthostatic dizziness) 3. Diffuse macular rash, with desquamation 1–2 weeks after onset (including the palms and soles) 4. a. Hepatic: bilirubin or aminotransferase levels ≥2 times normal b. Hematologic: platelet count ≤100,000/μL c. Renal: blood urea nitrogen or serum creatinine level ≥2 times the normal upper limit d. Mucous membranes: vaginal, oropharyngeal, or conjunctival hyperemia e. Gastrointestinal: vomiting or diarrhea at onset of illness f. Muscular: severe myalgias or serum creatine phosphokinase level ≥2 times the normal upper limit g.


InternalMed_Harrison

InternalMed_Harrison. Gastrointestinal: vomiting or diarrhea at onset of illness f. Muscular: severe myalgias or serum creatine phosphokinase level ≥2 times the normal upper limit g. Central nervous system: disorientation or alteration in consciousness without focal neurologic signs and in the absence of fever and hypo-tension 5. Negative serologic or other tests for measles, leptospirosis, and Rocky Mountain spotted fever as well as negative blood or cerebrospinal fluid cultures for organisms other than S. aureus Source: M Wharton et al: Case definitions for public health surveillance. MMWR 39:1, 1990; with permission.


InternalMed_Harrison

InternalMed_Harrison. TSS results from the elaboration of an enterotoxin or the structurally related enterotoxin-like TSST-1. More than 90% of menstrual cases are caused by TSST-1, whereas a high percentage of nonmenstrual cases are caused by enterotoxins. TSS begins with relatively nonspecific flu-like symptoms. In menstrual cases, the onset usually comes 2 or 3 days after the start of menstruation. Patients present with fever, hypotension, and erythroderma of variable intensity. Mucosal involvement is common (e.g., conjunctival hyperemia). The illness can rapidly progress to symptoms that include vomiting, diarrhea, confusion, myalgias, and abdominal pain. These symptoms reflect the multisystemic nature of the disease, with involvement of the liver, kidneys, gastrointestinal tract, and/or CNS. Desquamation of the skin occurs during convalescence, usually 1–2 weeks after the onset of illness. Laboratory findings may include azotemia, leukocytosis, hypoalbuminemia, thrombocytopenia, and liver function


InternalMed_Harrison

InternalMed_Harrison. of the skin occurs during convalescence, usually 1–2 weeks after the onset of illness. Laboratory findings may include azotemia, leukocytosis, hypoalbuminemia, thrombocytopenia, and liver function abnormalities.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis of TSS still depends on a constellation of findings rather than one specific finding and on a lack of evidence of other possible infections (Table 172-2). Other diagnoses to be considered are drug toxicities, viral exanthems, Rocky Mountain spotted fever, sepsis, and Kawasaki disease. Illness occurs only in persons who lack antibody to TSST-1. Recurrences are possible if antibody fails to develop after the illness.


InternalMed_Harrison

InternalMed_Harrison. stapHylococcal scalded-sKin syndrome SSSS primarily affects newborns and children. The illness may vary from a localized blister to exfoliation of much of the skin surface. The skin is usually fragile and often tender, with thin-walled, fluid-filled bullae. Gentle pressure results in rupture of the lesions, leaving denuded underlying skin (Nikolsky’s sign; Fig. 172-4). The mucous membranes are usually spared. In more generalized infection, there are often constitutional symptoms, including fever, lethargy, and irritability with poor feeding. Significant amounts of fluid can be lost in more extensive cases. Illness usually follows localized infection at one of a number of possible sites. SSSS is much less common among adults but can follow infections caused by exfoliative toxin–producing strains.


InternalMed_Harrison

InternalMed_Harrison. Primary prevention of S. aureus infections in the hospital setting involves hand washing and careful attention to appropriate isolation procedures. Through careful screening for MRSA carriage and strict isolation practices, several Scandinavian countries have been remarkably FIGURE 172-4 Evidence of staphylococcal scalded-skin syn-drome in a 6-year-old boy. Nikolsky’s sign, with separation of the superficial layer of the outer epidermal layer, is visible. (Reprinted with permission from LA Schenfeld et al: N Engl J Med 342:1178, 2000. © 2000 Massachusetts Medical Society. All rights reserved.) successful at preventing the introduction and dissemination of MRSA in hospitals.


InternalMed_Harrison

InternalMed_Harrison. Decolonization strategies, using both universal and targeted approaches with topical agents (e.g., mupirocin) to eliminate nasal colonization and/or chlorhexidine to eliminate cutaneous colonization with S. aureus, have been successful in some clinical settings (e.g., intensive care units) where the risk of infection is high. An analysis of clinical trials suggests that there may also be a reduction in the incidence of postsurgical infections among persons who are nasally colonized with S. aureus.


InternalMed_Harrison

InternalMed_Harrison. “Bundling” (the application of selected medical interventions in a sequence of prescribed steps) has reduced rates of nosocomial infections related to such procedures as the insertion of intravenous catheters, in which staphylococci are among the most common pathogens (see Table 168-4). A number of immunization strategies to prevent S. aureus infections—both active (e.g., capsular polysaccharide–protein conjugate vaccine) and passive (e.g., clumping factor antibody)—have been investigated. However, none has been successful for either prophylaxis or therapy in clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Although considerably less virulent than S. aureus, CoNS are among the most common causes of prosthetic-device infections. Approximately half of the identified CoNS species have been associated with human infections. Of these species, Staphylococcus epidermidis is the most common human pathogen. This component of the normal human flora is found on the skin (where it is the most abundant bacterial species) as well as in the oropharynx and vagina. Staphylococcus saprophyticus, a novobiocin-resistant species, is a common pathogen in UTIs. S. epidermidis is the CoNS species most often associated with pros-thetic-device infections. Infection is a two-step process, with initial adhesion to the device followed by colonization. S. epidermidis is uniquely adapted to colonize these devices by its capacity to elaborate the extracellular polysaccharide (glycocalyx or slime) that facilitates formation of a protective biofilm on the device surface.


InternalMed_Harrison

InternalMed_Harrison. Implanted prosthetic material is rapidly coated with host serum or tissue constituents such as fibrinogen or fibronectin. These molecules serve as potential bridging ligands, facilitating initial bacterial attachment to the device surface. A number of staphylococcal surface-associated proteins, such as autolysin (AtlE), fibrinogen-binding protein, and accumulation-associated protein (AAP), may play a role in attachment to either modified or unmodified prosthetic surfaces. The polysaccharide intercellular adhesin facilitates subsequent staphylococcal colonization and accumulation on the device surface. In S. epidermidis, intercellular adhesin (ica) genes are more commonly found in strains associated with device infections than in strains associated with colonization of mucosal surfaces. Biofilm appears to act as a barrier protecting bacteria from host defense mechanisms as well as from antibiotics, while providing a suitable environment for bacterial survival. Poly-γ-DL-glutamic acid


InternalMed_Harrison

InternalMed_Harrison. appears to act as a barrier protecting bacteria from host defense mechanisms as well as from antibiotics, while providing a suitable environment for bacterial survival. Poly-γ-DL-glutamic acid is secreted by S. epidermidis and provides protection against neutrophil phagocytosis.


InternalMed_Harrison

InternalMed_Harrison. Two additional staphylococcal species, Staphylococcus lugdunensis and Staphylococcus schleiferi, produce more serious infections (nativevalve endocarditis and osteomyelitis) than do other CoNS. The basis for this enhanced virulence is not known, although both species appear to share more virulence determinants with S. aureus (e.g., clumping factor and lipase) than do other CoNS. The capacity of S. saprophyticus to cause UTIs in young women appears to be related to its enhanced capacity to adhere to uroepithelial cells. A 160-kDa hemagglutinin/adhesin may contribute to this affinity.


InternalMed_Harrison

InternalMed_Harrison. Although the detection of CoNS at sites of infection or in the bloodstream is not difficult by standard microbiologic culture methods, interpretation of these results is frequently problematic. Because these organisms are present in large numbers on the skin, they often contaminate cultures. It has been estimated that only 10–25% of blood cultures positive for CoNS reflect true bacteremia. Similar problems arise with cultures obtained from other sites. Among the clinical findings suggestive of true bacteremia are fever, evidence of local infection (e.g., erythema or purulent drainage at the IV catheter site), leukocytosis, and systemic signs of sepsis. Laboratory findings suggestive of true bacteremia include multiple isolations of the same strain (i.e., the same species with the same antibiogram or a closely related DNA fingerprint) from separate cultures, growth of the strain within 48 h, and bacterial growth in both aerobic and anaerobic bottles.


InternalMed_Harrison

InternalMed_Harrison. CoNS cause a diverse array of prosthetic device–related infections, including those that involve prosthetic cardiac valves and joints, vascular grafts, intravascular devices, and CNS shunts. In all of these settings, the clinical presentation is similar. The signs of localized infection are often subtle, the rate of disease progression is slow, and the systemic findings are often limited. Signs of infection, such as purulent drainage, pain at the site, or loosening of prosthetic implants, are sometimes evident. Fever is frequently but not always present, and there may be mild leukocytosis. Acute-phase reactant levels, the erythrocyte sedimentation rate, and the C-reactive protein concentration may be elevated.


InternalMed_Harrison

InternalMed_Harrison. Infections that are not associated with prosthetic devices are infrequent, although native-valve endocarditis due to CoNS has accounted for ~5% of cases in some reviews. S. lugdunensis appears to be a more aggressive pathogen in this setting, causing greater mortality and rapid valvular destruction with abscess formation.


InternalMed_Harrison

InternalMed_Harrison. Surgical incision and drainage of all suppurative collections constitute the most important therapeutic intervention for staphylococcal infections. The emergence of MRSA in the community has increased the importance of culturing all collections in order to identify pathogens and to determine antimicrobial susceptibility. Successful therapy for prosthetic-device infections generally requires device removal. In situations in which removal is not possible or the infection is due to CoNS, an initial attempt at medical therapy without device removal may be warranted. Because of the well-recognized risk of complications associated with S. aureus bacteremia (e.g., endocarditis, metastatic foci of infection), therapy is generally prolonged (4–6 weeks) unless the patient is identified as being among those individuals who are at low risk for complications. Debate continues regarding the duration of therapy for bacteremic


InternalMed_Harrison

InternalMed_Harrison. Debate continues regarding the duration of therapy for bacteremic S. aureus infections. Patients with “complicated” bacteremia are at increased risk of endocarditis and metastatic infections. Among the findings associated with an increased risk of complicated bacteremia are persistently positive blood cultures 96 h after institution of therapy, acquisition of the infection in the community, failure to remove a removable focus of infection (i.e., an intravascular catheter), and infection with cutaneous or embolic manifestations. For immunocompetent patients in whom short-course therapy is planned, transesophageal echocardiography to rule out endocarditis is warranted because neither clinical nor laboratory findings can reliably detect cardiac involvement. In addition, an aggressive radiologic investigation to identify potential metastatic collections is indicated. All symptomatic body sites must be carefully evaluated.


InternalMed_Harrison

InternalMed_Harrison. The choice of antimicrobial agents to treat both coagulasepositive and coagulase-negative staphylococcal infections has become increasingly problematic because of the prevalence of multidrug-resistant strains. Staphylococcal resistance to most antibiotic families, including β-lactams, aminoglycosides, fluoroquinolones, and (to a lesser extent) glycopeptides, has increased. This trend is more apparent with CoNS: >80% of nosocomial isolates are resistant to methicillin, and these methicillin-resistant strains are usually resistant to most other antibiotics as well. Because the selection of antimicrobial agents for S. aureus infections is similar to that for CoNS infections, treatment options for these pathogens are discussed together and are summarized in Table 172-3.


InternalMed_Harrison

InternalMed_Harrison. As a result of the widespread dissemination of plasmids containing the enzyme penicillinase, few strains of staphylococci (≤5%) remain susceptible to penicillin. However, penicillin remains the drug of choice against susceptible strains if the laboratory can reliably test for penicillin susceptibility. Penicillin-resistant isolates are treated with semisynthetic penicillinase-resistant penicillins (SPRPs), such as oxacillin or nafcillin. Methicillin, the first of the SPRPs, is now used infrequently. Cephalosporins are alternative therapeutic agents for these infections. Secondand third-generation cephalosporins do not offer a therapeutic advantage over first-generation cephalosporins for the treatment of staphylococcal infections. The carbapenems have excellent activity against methicillin-sensitive S. aureus but not against MRSA.


InternalMed_Harrison

InternalMed_Harrison. The isolation of MRSA was reported within 1 year of the introduction of methicillin. Since then, the prevalence of MRSA has steadily increased. In many hospitals, 40–50% of S. aureus isolates are now resistant to methicillin. Resistance to methicillin indicates resistance to all SPRPs as well as to all cephalosporins (except ceftaroline). Production of a novel penicillin-binding protein (PBP2a) is responsible for methicillin resistance. This protein is synthesized by the mecA gene, which (as stated above) is part of a large mobile genetic element—a pathogenicity or genomic island—called SCCmec. It is hypothesized that this genetic material was acquired via horizontal transfer from a related staphylococcal species, such as Staphylococcus sciuri. Phenotypic expression of methicillin resistance may be constitutive (i.e., expressed in all organisms in a population) or heterogeneous (i.e., displayed by only a proportion of the total organism population). Detection of methicillin resistance


InternalMed_Harrison

InternalMed_Harrison. may be constitutive (i.e., expressed in all organisms in a population) or heterogeneous (i.e., displayed by only a proportion of the total organism population). Detection of methicillin resistance in the clinical microbiology laboratory can be difficult if the strain expresses heterogeneous resistance. Therefore, susceptibility studies are routinely performed at reduced temperatures (≤35°C for 24 h), with increased concentrations of salt in the medium to enhance the expression of resistance. In addition to PCR-based techniques, a number of rapid methods for the detection of methicillin resistance have been developed.


InternalMed_Harrison

InternalMed_Harrison. In light of decreasing susceptibility of MRSA isolates to vancomycin, both vancomycin and daptomycin are now recommended as the drugs of choice for the treatment of MRSA infections. Vancomycin is less effective than SPRPs for the treatment of infections due to methicillin-susceptible strains. Alternatives to SPRPs should be used only after careful consideration in patients with a history of serious β-lactam allergies.


InternalMed_Harrison

InternalMed_Harrison. Three types of staphylococcal resistance to vancomycin have 961 emerged. (1) Minimal inhibitory concentration (MIC) “creep” refers to the incremental increase in vancomycin MICs that has been detected in various geographic areas. Studies suggest that infections due to S. aureus strains with vancomycin MICs of >1 μg/mL may not respond as well to vancomycin therapy as those due to strains with MICs of <1 μg/mL. Some authorities (e.g., The Medical Letter) have recommended choosing an alternative agent in this setting. (2) In 1997, an S. aureus strain with reduced susceptibility to vancomycin (vancomycin-intermediate S. aureus [VISA]) was reported from Japan. Subsequently, additional VISA clinical isolates were reported. These strains were all resistant to methicillin and many other antimicrobial agents. The VISA strains appear to evolve (under vancomycin selective pressure) from strains that are susceptible to vancomycin but are heterogeneous, with a small proportion of the bacterial


InternalMed_Harrison

InternalMed_Harrison. agents. The VISA strains appear to evolve (under vancomycin selective pressure) from strains that are susceptible to vancomycin but are heterogeneous, with a small proportion of the bacterial population expressing the resistance phenotype. The mechanism of VISA resistance is in part due to an abnormally thick cell wall. Vancomycin is trapped by the abnormal peptidoglycan cross-linking and is unable to gain access to its target site.


InternalMed_Harrison

InternalMed_Harrison. (3) In 2002, the first clinical isolate of fully vancomycin-resistant S. aureus was reported. Resistance in this and several additional clinical isolates was due to the presence of vanA, the gene responsible for expression of vancomycin resistance in enterococci. This observation suggested that resistance was acquired as a result of horizontal conjugal transfer from a vancomycin-resistant strain of Enterococcus faecalis. Several patients had both MRSA and vancomycin-resistant enterococci cultured from infection sites. The vanA gene is respon sible for the synthesis of the dipeptide D-Ala-D-Lac in place of D-AlaD-Ala. Vancomycin cannot bind to the altered peptide.


InternalMed_Harrison

InternalMed_Harrison. Daptomycin, a parenteral bactericidal agent with antistaphylococcal activity, is approved for the treatment of bacteremia (including right-sided endocarditis) and complicated skin infections. It is not effective in respiratory infections. This drug has a novel mechanism of action: it disrupts the cytoplasmic membrane. Staphylococcal resistance to daptomycin, sometimes developing during therapy, has been reported. Linezolid—the first oxazolidinone—is bacteriostatic against staphylococci and offers the advantage of comparable bioavailability after oral or parenteral administration. Cross-resistance with other inhibitors of protein synthesis has not been detected. However, resistance to linezolid has been reported. Serious adverse reactions to linezolid include thrombocytopenia, occasional cases of neutropenia, and rare instances of peripheral and optic neuropathy.


InternalMed_Harrison

InternalMed_Harrison. Tedizolid, a second oxazolidinone released in 2014, is available as both oral and parenteral preparations. It has enhanced in vitro activity against antibiotic-resistant gram-positive bacteria, including staphylococci. Tedizolid is administered once a day. Ceftaroline is a fifth-generation cephalosporin with bactericidal activity against MRSA (including strains with reduced susceptibility to vancomycin and daptomycin). It is approved for use in nosocomial pneumonias and for skin and soft tissue infections. The parenteral streptogramin antibiotic quinupristin/dalfopristin displays bactericidal activity against all staphylococci, including VISA strains. This drug has been used successfully to treat serious MRSA infections. In cases of resistance to erythromycin or clindamycin, quinupristin/dalfopristin is bacteriostatic against staphylococci. There are limited data on the efficacy of either quinupristin/dalfopristin or linezolid for the treatment of infective endocarditis.


InternalMed_Harrison

InternalMed_Harrison. Telavancin is a parenteral lipoglycopeptide derivative of vancomycin that is approved for the treatment of complicated skin and soft tissue infections and for nosocomial pneumonia. The drug has two targets: the cell wall and the cell membrane. It remains active against VISA strains. Because of its nephrotoxicity, it should be avoided in patients with renal disease. Dalbavancin is a long-acting, parenterally administered lipoglycopeptide that has been used to treat skin and soft tissue infections. Because of its long half-life, it can be administered on a weekly basis. There are limited data on its use in the treatment of invasive staphylococcal infections. Sensitivity/Resistance of Isolate Drug of Choice Alternative(s) Comments


InternalMed_Harrison

InternalMed_Harrison. Sensitivity/Resistance of Isolate Drug of Choice Alternative(s) Comments Sensitive to methicillin Dicloxacillin (500 mg qid), cephalexin Minocycline or doxycycline (100 mg It is important to know the antibiotic susceptibility of (500 mg qid) q12hb), TMP-SMX (1 or 2 ds tablets isolates in the specific geographic region. All drain-bid), clindamycin (300–450 mg/kg tid), age should be cultured. linezolid (600 mg PO q12h), tedizolid (200 mg PO q24h)


InternalMed_Harrison

InternalMed_Harrison. Resistant to methicillin Clindamycin (300–450 mg/kg tid), Same options as under “Drug of It is important to know the antibiotic susceptibility of TMP-SMX (1 or 2 ds tablets bid), mino-Choice” isolates in the specific geographic region. All draincycline or doxycycline (100 mg q12hb), age should be cultured. linezolid (600 mg bid) or tedizolid (200 mg once daily) aRecommended dosages are for adults with normal renal and hepatic function. bThe dosage must be adjusted for patients with reduced creatinine clearance. cFor the treatment of prosthetic-valve endocarditis, the addition of gentamicin (1 mg/kg q8h) and rifampin (300 mg PO q8h) is recommended, with adjustment of the gentamicin dosage if the creatinine clearance rate is reduced. dDaptomycin cannot be used for the treatment of pneumonia. eVancomycin-resistant S. aureus isolates from clinical infections have been reported.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: ds, double-strength; TMP-SMX, trimethoprim-sulfamethoxazole; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus. Source: Modified with permission from FD Lowy: N Engl J Med 339:520, 1998 (© 1998 Massachusetts Medical Society. All rights reserved.); C Liu et al: Clin Infect Dis 52:285, 2011; DL Stevens et al: Clin Infect Dis 59:148, 2014; and Med Lett Drugs Ther 56:39, 2014.


InternalMed_Harrison

InternalMed_Harrison. Although the quinolones are active against staphylococci in vitro, Tigecycline, a broad-spectrum minocycline analogue, has bactethe frequency of staphylococcal resistance to these agents has riostatic activity against MRSA and is approved for use in skin and increased progressively, especially among methicillin-resistant isolates. soft tissue infections as well as intraabdominal infections caused by Of particular concern in MRSA is the possible emergence of quinolone S. aureus. Other antibiotics, such as minocycline and trimethoprimresistance during therapy. Therefore, quinolones are not recom-sulfamethoxazole, have been used successfully to treat MRSA infecmended for the treatment of MRSA infections. Resistance to the quino-tions in cases of vancomycin toxicity or intolerance. lones is most commonly chromosomal and results from mutations of Combinations of antistaphylococcal agents have been used to the topoisomerase IV or DNA gyrase genes, although multidrug efflux enhance


InternalMed_Harrison

InternalMed_Harrison. is most commonly chromosomal and results from mutations of Combinations of antistaphylococcal agents have been used to the topoisomerase IV or DNA gyrase genes, although multidrug efflux enhance bactericidal activity in the treatment of serious infecpumps may also contribute. Although the newer quinolones exhibit tions such as endocarditis or osteomyelitis. In selected instances increased in vitro activity against staphylococci, it is uncertain whether (e.g., right-sided endocarditis), drug combinations are also used to this increase translates into enhanced in vivo activity. shorten the duration of therapy. Among the antimicrobial agents used in combinations are rifampin, aminoglycosides (e.g., gentamicin), and fusidic acid (not readily available in the United States). To date, clinical studies have not documented a therapeutic benefit; recent reports have raised concern about the potential nephrotoxicity of gentamicin and about adverse drug reactions from the addition of rifampin.


InternalMed_Harrison

InternalMed_Harrison. studies have not documented a therapeutic benefit; recent reports have raised concern about the potential nephrotoxicity of gentamicin and about adverse drug reactions from the addition of rifampin. As a result, the use of gentamicin in combination with β-lactams or other antimicrobial agents is no longer routinely recommended for the treatment of endocarditis. Rifampin continues to be used for the treatment of prosthetic device–related infections and for osteomyelitis.


InternalMed_Harrison

InternalMed_Harrison. The combination of daptomycin with a β-lactam antibiotic has been successfully used to treat patients with persistent MRSA bacteremia, even those infected with isolates that exhibit reduced susceptibility to daptomycin. The combination appears to enhance the bactericidal activity of daptomycin, perhaps by reducing the bacterial cell surface charge and thus allowing more daptomycin binding. When necessary, the use of oral antistaphylococcal agents for uncomplicated skin and soft tissue infections is usually successful. For other infections, parenteral therapy is indicated. S. aureus endocarditis is usually an acute, life-threatening infection. Thus, prompt collection of blood for cultures must be followed immediately by empirical antimicrobial therapy. For life-threatening


InternalMed_Harrison

InternalMed_Harrison. S. aureus native-valve endocarditis, therapy with a β-lactam is recommended. If a MRSA strain is isolated, vancomycin (15–20 mg/kg every 8–12 h, given in equal doses up to a total of 2 g) or daptomycin (6 mg/kg every 24 h) is recommended. The vancomycin dose should be adjusted on the basis of trough vancomycin levels. Patients are generally treated for 4–6 weeks, with duration depending on whether there are complications. For prosthetic-valve endocarditis, surgery in addition to antibiotic therapy is often necessary. The combination of a β-lactam agent—or, if the isolate is β-lactam-resistant, vancomycin (30 mg/kg every 24 h, given in doses up to a total of 2 g) or daptomycin (6 mg/kg every 24 h)—with an aminoglycoside (gentamicin, 1 mg/kg IV every 8 h) and rifampin (300 mg orally or IV every 8 h) for ≥6 weeks is recommended.


InternalMed_Harrison

InternalMed_Harrison. For hematogenous osteomyelitis or septic arthritis in children, a 4-week course of therapy is usually adequate. In adults, treatment is often more prolonged. For chronic forms of osteomyelitis, surgical debridement is necessary in combination with antimicrobial therapy. For joint infections, a critical component of therapy is the repeated aspiration or arthroscopy of the affected joint to prevent damage from leukocytes. The combination of rifampin with ciprofloxacin has been used successfully to treat prosthetic joint infections, especially when the device cannot be removed. The efficacy of this combination may reflect enhanced activity against staphylococci in biofilms as well as the attainment of effective intracellular concentrations.


InternalMed_Harrison

InternalMed_Harrison. The choice of empirical therapy for staphylococcal infections depends in part on susceptibility data for the local geographic area. Increasingly, vancomycin and daptomycin are the drugs of choice for both communityand hospital-acquired infections. The increase in CA-MRSA skin and soft tissue infections has drawn attention to the need for initiation of appropriate empirical therapy. Oral agents that have been effective against these isolates include clindamycin, trimethoprim-sulfamethoxazole, doxycycline, linezolid, and tedizolid.


InternalMed_Harrison

InternalMed_Harrison. Supportive therapy with reversal of hypotension is the mainstay of therapy for TSS. Both fluids and pressors may be necessary. Tampons or other packing material should be promptly removed. The role of antibiotics is less clear. Some investigators recommend a combination of clindamycin and a semisynthetic penicillin or vancomycin (if the isolate is resistant to methicillin). Clindamycin is advocated because, as a protein synthesis inhibitor, it reduces toxin synthesis in vitro. Linezolid also appears to be effective. A semisynthetic penicillin or glycopeptide is suggested to eliminate any potential focus of infection as well as to eradicate persistent carriage that might increase the likelihood of recurrent illness. Anecdotal reports document the successful use of IV immuno-963 globulin to treat TSS. The role of glucocorticoids in the treatment of this disease is uncertain.


InternalMed_Harrison

InternalMed_Harrison. Anecdotal reports document the successful use of IV immuno-963 globulin to treat TSS. The role of glucocorticoids in the treatment of this disease is uncertain. Therapy for staphylococcal food poisoning is entirely supportive. For SSSS, antistaphylococcal therapy targets the primary site of infection. Michael R. Wessels


InternalMed_Harrison

InternalMed_Harrison. Many varieties of streptococci are found as part of the normal flora colonizing the human respiratory, gastrointestinal, and genitourinary tracts. Several species are important causes of human disease. Group A Streptococcus (GAS, Streptococcus pyogenes) is responsible for streptococcal pharyngitis, one of the most common bacterial infections of school-age children, and for the postinfectious syndromes of acute rheumatic fever (ARF) and poststreptococcal glomerulonephritis (PSGN). Group B Streptococcus (GBS, Streptococcus agalactiae) is the leading cause of bacterial sepsis and meningitis in newborns and a major cause of endometritis and fever in parturient women. Viridans streptococci are the most common cause of bacterial endocarditis. Enterococci, which are morphologically similar to streptococci, are now considered a separate genus on the basis of DNA homology studies. Thus, the species previously designated as Streptococcus faecalis and Streptococcus faecium have been renamed


InternalMed_Harrison

InternalMed_Harrison. streptococci, are now considered a separate genus on the basis of DNA homology studies. Thus, the species previously designated as Streptococcus faecalis and Streptococcus faecium have been renamed Enterococcus faecalis and Enterococcus faecium, respectively. The enterococci are discussed in Chap. 174.


InternalMed_Harrison

InternalMed_Harrison. Streptococci are gram-positive, spherical to ovoid bacteria that characteristically form chains when grown in liquid media. Most streptococci that cause human infections are facultative anaerobes, although some are strict anaerobes. Streptococci are relatively fastidious organisms, requiring enriched media for growth in the laboratory. Clinicians and clinical microbiologists identify streptococci by several classification systems, including hemolytic pattern, Lancefield group, species name, and common or trivial name. Many streptococci associated with human infection produce a zone of complete (β) hemolysis around the bacterial colony when cultured on blood agar. The β-hemolytic streptococci can be classified by the Lancefield system, a serologic grouping based on the reaction of specific antisera with bacterial cell-wall carbohydrate antigens. With rare exceptions, organisms belonging to Lancefield groups A, B, C, and G are all β-hemolytic, and each is associated with characteristic


InternalMed_Harrison

InternalMed_Harrison. antisera with bacterial cell-wall carbohydrate antigens. With rare exceptions, organisms belonging to Lancefield groups A, B, C, and G are all β-hemolytic, and each is associated with characteristic patterns of human infection. Other streptococci produce a zone of partial (α) hemolysis, often imparting a greenish appearance to the agar. These α-hemolytic streptococci are further identified by biochemical testing and include Streptococcus pneumoniae (Chap. 171), an important cause of pneumonia, meningitis, and other infections, and the several species referred to collectively as the viridans streptococci, which are part of the normal oral flora and are important agents of subacute bacterial endocarditis. Finally, some streptococci are nonhemolytic, a pattern sometimes called γ hemolysis. Among the organisms classified serologically as group D streptococci, the enterococci are classified as a distinct genus (Chap. 174). The classification of the major streptococcal groups causing human


InternalMed_Harrison

InternalMed_Harrison. the organisms classified serologically as group D streptococci, the enterococci are classified as a distinct genus (Chap. 174). The classification of the major streptococcal groups causing human infections is outlined in Table 173-1.


InternalMed_Harrison

InternalMed_Harrison. Lancefield’s group A consists of a single species, S. pyogenes. As its species name implies, this organism is associated with a variety of suppurative infections. In addition, GAS can trigger the postinfectious syndromes of ARF (which is uniquely associated with S. pyogenes infection; Chap. 381) and PSGN (Chap. 338). TABLE 173-1 CLASSIfICATIon of STREPToCoCCI A S. pyogenes β Pharyngitis, impetigo, cellulitis, scarlet fever B S. agalactiae β Neonatal sepsis and meningitis, puerperal infection, urinary tract infection, diabetic ulcer infection, endocarditis C, G S. dysgalactiae subsp. equisimilis β Cellulitis, bacteremia, endocarditis D Enterococcia: E. faecalis, E. faecium Usually nonhemolytic Urinary tract infection, nosocomial bacteremia, endocarditis Nonenterococci: S. gallolyticus Usually nonhemolytic Bacteremia, endocarditis (formerly S. bovis) Variable or nongroupable Viridans streptococci: S. sanguis, α Endocarditis, dental abscess, brain abscess S. mitis


InternalMed_Harrison

InternalMed_Harrison. Variable or nongroupable Viridans streptococci: S. sanguis, α Endocarditis, dental abscess, brain abscess S. mitis Intermedius or milleri group: S. interme-Variable Brain abscess, visceral abscess dius, S. anginosus, S. constellatus Anaerobic streptococcib: Usually nonhemolytic Sinusitis, pneumonia, empyema, brain abscess, liver abscess aSee Chap. 174. bSee Chap. 201.


InternalMed_Harrison

InternalMed_Harrison. Worldwide, GAS infections and their postinfectious sequelae the emm gene, which encodes M protein. DNA sequence analysis of (primarily ARF and rheumatic heart disease) account for an the amplified gene segment can be compared with an extensive data-estimated 500,000 deaths per year. Although data are incom-base (developed at the Centers for Disease Control and Prevention plete, the incidence of all forms of GAS infection and that of rheumatic [CDC]) for assignment of emm type. This method eliminates the need heart disease are thought to be tenfold higher in resource-limited for typing sera, which are available in only a few reference laboratories. countries than in developed countries (Fig. 173-1). The presence of M protein on a GAS isolate correlates with its capacity to resist phagocytic killing in fresh human blood. This phenomenon PATHOGENESIS appears to be due, at least in part, to the binding of plasma fibrinogen GAS elaborates a number of cell-surface components and


InternalMed_Harrison

InternalMed_Harrison. phagocytic killing in fresh human blood. This phenomenon PATHOGENESIS appears to be due, at least in part, to the binding of plasma fibrinogen GAS elaborates a number of cell-surface components and extracel-to M protein molecules on the streptococcal surface, which interferes lular products important in both the pathogenesis of infection and with complement activation and deposition of opsonic complement the human immune response. The cell wall contains a carbohydrate fragments on the bacterial cell. This resistance to phagocytosis may antigen that may be released by acid treatment. The reaction of such be overcome by M protein–specific antibodies; thus individuals with acid extracts with group A–specific antiserum is the basis for defini-antibodies to a given M type acquired as a result of prior infection are tive identification of a streptococcal strain as S. pyogenes. The major protected against subsequent infection with organisms of the same M surface protein of GAS is M protein,


InternalMed_Harrison

InternalMed_Harrison. of prior infection are tive identification of a streptococcal strain as S. pyogenes. The major protected against subsequent infection with organisms of the same M surface protein of GAS is M protein, which occurs in more than 100 type but not against that with different M types.


InternalMed_Harrison

InternalMed_Harrison. antigenically distinct types and is the basis for the serotyping of strains GAS also elaborates, to varying degrees, a polysaccharide capsule with specific antisera. The M protein molecules are fibrillar structures composed of hyaluronic acid. The production of large amounts of anchored in the cell wall of the organism that extend as hairlike pro-capsule by certain strains imparts a characteristic mucoid appearance jections away from the cell surface. The amino acid sequence of the to the colonies. The capsular polysaccharide plays an important role in distal or amino-terminal portion of the M protein molecule is quite protecting GAS from ingestion and killing by phagocytes. In contrast variable, accounting for the antigenic variation of the different M to M protein, the hyaluronic acid capsule is a weak immunogen, and types, while more proximal regions of the protein are relatively con-antibodies to hyaluronate have not been shown to be important in pro- served. A newer technique for


InternalMed_Harrison

InternalMed_Harrison. is a weak immunogen, and types, while more proximal regions of the protein are relatively con-antibodies to hyaluronate have not been shown to be important in pro- served. A newer technique for assignment of M type to GAS isolates tective immunity. The presumed explanation is the apparent structural uses the polymerase chain reaction to amplify the variable region of identity between streptococcal hyaluronic acid and the hyaluronic


InternalMed_Harrison

InternalMed_Harrison. Presence of rheumatic heart disease (cases per 1000) 0.3 1.01.3 3.5 0.8 1.8 2.2 5.7 FIGURE 173-1 Prevalence of rheumatic heart disease in children 5–14 years old. The circles within Australia and New Zealand represent indigenous populations (and also Pacific Islanders in New Zealand). (From JR Carapetis et al: Lancet Infect Dis 5:685, 2005, with permission.) acid of mammalian connective tissues. The capsular polysaccharide may also play a role in GAS colonization of the pharynx by binding to CD44, a hyaluronic acid–binding protein expressed on human pharyngeal epithelial cells.


InternalMed_Harrison

InternalMed_Harrison. GAS produces a large number of extracellular products that may be important in local and systemic toxicity and in the spread of infection through tissues. These products include streptolysins S and O, toxins that damage cell membranes and account for the hemolysis produced by the organisms; streptokinase; DNAses; SpyCEP, a serine protease that cleaves and inactivates the chemoattractant cytokine interleukin 8, thereby inhibiting neutrophil recruitment to the site of infection; and several pyrogenic exotoxins. Previously known as erythrogenic toxins, the pyrogenic exotoxins cause the rash of scarlet fever. Since the mid1980s, pyrogenic exotoxin–producing strains of GAS have been linked to unusually severe invasive infections, including necrotizing fasciitis and the streptococcal toxic shock syndrome (TSS). Several extracellular products stimulate specific antibody responses useful for serodiagnosis of recent streptococcal infection. Tests for these antibodies are used primarily for


InternalMed_Harrison

InternalMed_Harrison. syndrome (TSS). Several extracellular products stimulate specific antibody responses useful for serodiagnosis of recent streptococcal infection. Tests for these antibodies are used primarily for detection of preceding streptococcal infection in cases of suspected ARF or PSGN.


InternalMed_Harrison

InternalMed_Harrison. CLINICAL MANIFESTATIONS Pharyngitis Although seen in patients of all ages, GAS pharyngitis is one of the most common bacterial infections of childhood, accounting for 20–40% of all cases of exudative pharyngitis in children; it is rare among those under the age of 3. Younger children may manifest streptococcal infection with a syndrome of fever, malaise, and lymphadenopathy without exudative pharyngitis. Infection is acquired through contact with another individual carrying the organism. Respiratory droplets are the usual mechanism of spread, although other routes, including food-borne outbreaks, have been well described. The incubation period is 1–4 days. Symptoms include sore throat, fever and chills, malaise, and sometimes abdominal complaints and vomiting, particularly in children. Both symptoms and signs are quite variable, ranging from mild throat discomfort with minimal physical findings to high fever and severe sore throat associated with intense erythema and swelling of the


InternalMed_Harrison

InternalMed_Harrison. symptoms and signs are quite variable, ranging from mild throat discomfort with minimal physical findings to high fever and severe sore throat associated with intense erythema and swelling of the pharyngeal mucosa and the presence of purulent exudate over the posterior pharyngeal wall and tonsillar pillars. Enlarged, tender anterior cervical lymph nodes commonly accompany exudative pharyngitis.


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis of streptococcal pharyngitis includes the many other bacterial and viral etiologies (Table 173-2). Streptococcal infection is an unlikely cause when symptoms and signs suggestive of viral infection are prominent (conjunctivitis, coryza, cough, hoarseness, or discrete ulcerative lesions of the buccal or pharyngeal mucosa). Because of the range of clinical presentations of streptococcal pharyngitis and the large number of other agents that can produce the same clinical picture, diagnosis of streptococcal pharyngitis on clinical grounds alone is not reliable. The throat culture remains the diagnostic gold standard. Culture of a throat specimen that is properly collected (i.e., by vigorous rubbing of a sterile swab over both tonsillar pillars) and properly processed is the most sensitive and specific means of definitive diagnosis. A rapid diagnostic kit for latex agglutination or enzyme immunoassay of swab specimens is a useful adjunct to throat culture. While


InternalMed_Harrison

InternalMed_Harrison. is the most sensitive and specific means of definitive diagnosis. A rapid diagnostic kit for latex agglutination or enzyme immunoassay of swab specimens is a useful adjunct to throat culture. While precise figures on sensitivity and specificity vary, rapid diagnostic kits generally are >95% specific. Thus a positive result can be relied upon for definitive diagnosis and eliminates the need for throat culture. However, because rapid diagnostic tests are less sensitive than throat culture (relative sensitivity in comparative studies, 55–90%), a negative result should be confirmed by throat culture.


InternalMed_Harrison

InternalMed_Harrison. In the usual course of uncomplicated streptococcal pharyngitis, symptoms resolve after 3–5 days. The course is shortened little by treatment, which is given primarily to prevent suppurative complications and ARF. Prevention of ARF depends on eradication of the organism from the pharynx, not simply on resolution of symptoms, Common cold Common cold Pharyngoconjunctival fever Influenza Cold, croup Herpangina, hand-foot-and-mouth Group A streptococci Pharyngitis, scarlet fever Group C or G streptococci Pharyngitis Mixed anaerobes Vincent’s angina Arcanobacterium haemolyticum Pharyngitis, scarlatiniform rash Neisseria gonorrhoeae Pharyngitis Treponema pallidum Secondary syphilis Francisella tularensis Pharyngeal tularemia Corynebacterium diphtheriae Diphtheria Yersinia enterocolitica Pharyngitis, enterocolitis Yersinia pestis Plague Chlamydiae


InternalMed_Harrison

InternalMed_Harrison. Chlamydia pneumoniae Bronchitis, pneumonia Chlamydia psittaci Psittacosis Mycoplasmas Mycoplasma pneumoniae Bronchitis, pneumonia and requires 10 days of penicillin treatment (Table 173-3). A first-generation cephalosporin, such as cephalexin or cefadroxil, may be substituted for penicillin in cases of penicillin allergy if the nature of the allergy is not an immediate hypersensitivity reaction (anaphylaxis or urticaria) or another potentially life-threatening manifestation (e.g., severe rash and fever).