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InternalMed_Harrison. Microbiologic evidence: positive blood culture but not meeting major criterion, as noted previously,d or serologic evidence of active infection with an organism consistent with infective endocarditis aDefinite endocarditis is defined by documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria. See text for further details. bTransesophageal echocardiography is required for optimal assessment of possible prosthetic valve endocarditis or complicated endocarditis. cValvular disease with stenosis or regurgitation, presence of a prosthetic valve, congenital heart disease including corrected or partially corrected conditions (except isolated atrial septal defect, repaired ventricular septal defect, or closed patent ductus arteriosus), prior endocarditis, or hypertrophic cardiomyopathy. dExcluding single positive cultures for coagulase-negative staphylococci and diphtheroids, which are common culture contaminants, or for organisms that do


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InternalMed_Harrison. or hypertrophic cardiomyopathy. dExcluding single positive cultures for coagulase-negative staphylococci and diphtheroids, which are common culture contaminants, or for organisms that do not cause endocarditis frequently, such as gram-negative bacilli.


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InternalMed_Harrison. Source: Adapted from JS Li et al: Clin Infect Dis 30:633, 2000. With permission from Oxford University Press. bacteremia characteristic of endocarditis. Among patients with untreated endocarditis who ultimately have a positive blood culture, 95% of all blood cultures are positive. The diagnostic criteria attach significance to the species of organism isolated from blood cultures. To fulfill a major criterion, the isolation of an organism that causes both endocarditis and bacteremia in the absence of endocarditis (e.g., S. aureus, enterococci) must take place repeatedly (i.e., persistent bacteremia) and in the absence of a primary focus of infection. Organisms that rarely cause endocarditis but commonly contaminate blood cultures (e.g., diphtheroids, CoNS) must be isolated repeatedly if their isolation is to serve as a major criterion.


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InternalMed_Harrison. Blood Cultures Isolation of the causative microorganism from blood cultures is critical for diagnosis and for planning treatment. In patients with suspected NVE, PVE, or CIED endocarditis who have not received antibiotics during the prior 2 weeks, three 2-bottle blood 820 culture sets, separated from one another by at least 2 h, should be obtained from different venipuncture sites over 24 h. If the cultures remain negative after 48–72 h, two or three additional blood culture sets should be obtained, and the laboratory should be consulted for advice regarding optimal culture techniques. Pending culture results, empirical antimicrobial therapy should be withheld initially from hemodynamically stable patients with suspected subacute endocarditis, especially those who have received antibiotics within the preceding 2 weeks. Thus, if necessary, additional blood culture sets can be obtained without the confounding effect of empirical treatment. Patients with acute endocarditis or with


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InternalMed_Harrison. within the preceding 2 weeks. Thus, if necessary, additional blood culture sets can be obtained without the confounding effect of empirical treatment. Patients with acute endocarditis or with deteriorating hemodynamics who may require urgent surgery should receive empirical treatment immediately after three sets of blood cultures are obtained over several hours.


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InternalMed_Harrison. Non-Blood-Culture Tests Serologic tests can be used to implicate organisms that are difficult to recover by blood culture: Brucella, Bartonella, Legionella, Chlamydia psittaci, and C. burnetii. Pathogens can also be identified in vegetations by culture, microscopic examination with special stains (i.e., the periodic acid–Schiff stain for T. whipplei), or direct fluorescence antibody techniques and by the use of polymerase chain reaction to recover unique microbial DNA or DNA encoding the 16S or 28S ribosomal unit (16S rRNA or 28S rRNA); sequencing of these DNAs allows identification of bacteria and fungi, respectively.


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InternalMed_Harrison. Echocardiography Echocardiography anatomically confirms and measures vegetations, detects intracardiac complications, and assesses cardiac function (Fig. 155-3). Transthoracic echocardiography (TTE) is noninvasive and exceptionally specific; however, it cannot image vegetations <2 mm in diameter, and in 20% of patients it is technically inadequate because of emphysema or body habitus. TTE detects vegetations in 65–80% of patients with definite clinical endocarditis but is not optimal for evaluating prosthetic valves or detecting intracardiac complications. TEE is safe and detects vegetations in >90% of patients with definite endocarditis; nevertheless, initial studies may yield false-negative results in 6–18% of endocarditis patients. When endocarditis is likely, a negative TEE result does not exclude the diagnosis but rather warrants repetition of the study once or twice in 7–10 days. TEE is the optimal method for the diagnosis of PVE, the detection of myocardial abscess, valve


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InternalMed_Harrison. does not exclude the diagnosis but rather warrants repetition of the study once or twice in 7–10 days. TEE is the optimal method for the diagnosis of PVE, the detection of myocardial abscess, valve perforation, or intracardiac fistulae and for the detection of vegetations in patients with CIED. In patients with CIED and negative blood cultures, a mass adherent to the lead is likely to be a bland thrombosis rather than an infected vegetation.


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InternalMed_Harrison. Because S. aureus bacteremia is associated with a high prevalence of endocarditis, routine echocardiographic evaluation (TTE or preferably TEE) is recommended in these patients. Patients with nosocomial S. aureus bacteremia are at increased risk of endocarditis if one or more of the following are present: positive blood cultures for 2–4 days, hemodialysis dependency, a permanent intracardiac device, spine infection, nonvertebral osteomyelitis, or an endocarditis-predisposing valve abnormality. Ideally, these patients should be evaluated with TEE. In patients with none of these findings, the risk of endocarditis is low and evaluation with TTE may suffice.


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InternalMed_Harrison. Experts favor echocardiographic evaluation of all patients with a clinical diagnosis of endocarditis; however, the test should not be used to screen patients with a low probability of endocarditis (e.g., patients with unexplained fever). An American Heart Association approach to the use of echocardiography for evaluation of patients with suspected endocarditis is illustrated in (Fig. 155-4). Other Studies Many studies that are not diagnostic—i.e., complete blood count, creatinine determination, liver function tests, chest radiography, and electrocardiography—are important in the management of patients with endocarditis. The erythrocyte sedimentation rate, C-reactive protein level, and circulating immune complex titer are commonly increased in endocarditis (Table 155-2). Cardiac catheterization is useful primarily to assess coronary artery patency in older individuals who are to undergo surgery for endocarditis.


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InternalMed_Harrison. FIGURE 155-3 Imaging of a mitral valve infected with Staphylococcus aureus by low-esophageal, four-chamber-view, transesophageal echocardiography (TEE). A. Two-dimensional echocardiogram showing a large vegetation with an adjacent echo-lucent abscess cavity. B. Color-flow Doppler image showing severe mitral regurgitation through both the abscess-fistula and the central valve orifice. A, abscess; A-F, abscess-fistula; L, valve leaflets; LA, left atrium; LV, left ventricle; MR, mitral central valve regurgitation; RV, right ventricle; veg, vegetation. (With permission of Andrew Burger, MD.)


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InternalMed_Harrison. To cure endocarditis, all bacteria in the vegetation must be killed. However, it is difficult to eradicate these bacteria because local host defenses are deficient and because the bacteria are largely nongrowing and metabolically inactive and thus are less easily killed by antibiotics. Accordingly, therapy must be bactericidal and prolonged. Antibiotics are generally given parenterally to achieve serum concentrations that, through passive diffusion, result in effective concentrations in the depths of the vegetation. To select effective therapy requires knowledge of the susceptibility of the causative microorganisms. The decision to initiate treatment empirically must balance the need to establish a microbiologic diagnosis against the potential progression of disease or the need for urgent surgery (see “Blood Cultures,” earlier). Simultaneous infection at other sites (such as the meninges), allergies, end-organ dysfunction, interactions with concomitantly administered medications, and


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InternalMed_Harrison. surgery (see “Blood Cultures,” earlier). Simultaneous infection at other sites (such as the meninges), allergies, end-organ dysfunction, interactions with concomitantly administered medications, and risks of adverse events must be considered in the selection of therapy.


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InternalMed_Harrison. Although given for several weeks longer, the regimens recommended for the treatment of PVE (except that caused by staphylococci) are similar to those used to treat NVE (Table 155-4). Recommended doses and durations of therapy should be followed Initial TTE Initial TEE High suspicion persists Repeat TEE Alternative diagnosis established Follow-up TEE or TTE to reassess vegetations, complications, or Rx response as clinically indicated Low suspicion persists Increased suspicion during clinical course Rx Rx Rx Rx High-risk echo features* No high-risk echo features TEE for detection of complications No TEE unless clinical status deteriorates TEE Look for other source Look for other source + + + +– – – – –+ Look for other source of symptoms


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InternalMed_Harrison. FIGURE 155-4 The diagnostic use of transesophageal and transtracheal echocardiography (TEE and TTE, respectively). †High initial patient risk for infective endocarditis (IE), as listed in Table 155-8, or evidence of intracardiac complications (new regurgitant murmur, new electrocardiographic conduction changes, or congestive heart failure). *High-risk echocardiographic features include large vegetations, valve insufficiency, paravalvular infection, or ventricular dysfunction. Rx indicates initiation of antibiotic therapy. (Reproduced with permission from Diagnosis and Management of Infective Endocarditis and Its Complications. Circulation 98:2936, 1998. © 1998 American Heart Association.) unless alterations are required by end-organ dysfunction or adverse events.


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InternalMed_Harrison. Organism-Specific Therapies • streptococci Optimal therapy for streptococcal endocarditis is based on the minimal inhibitory concentration (MIC) of penicillin for the causative isolate (Table 155-4). The 2-week penicillin/gentamicin or ceftriaxone/gentamicin regimens should not be used to treat PVE or complicated NVE. Caution should be exercised in considering aminoglycoside-containing regimens for the treatment of patients at increased risk for aminoglycoside toxicity. The regimens recommended for relatively penicillin-resistant streptococci are advocated for treatment of group B, C, or G streptococcal endocarditis. Nutritionally variant organisms (Granulicatella or Abiotrophia species) and Gemella species are treated with the regimens for moderately penicillin-resistant streptococci, as is PVE caused by these organisms or by streptococci with a penicillin MIC of >0.1 μg/mL (Table 155-4).


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InternalMed_Harrison. enterococci Enterococci are resistant to oxacillin, nafcillin, and the cephalosporins and are only inhibited—not killed—by penicillin, ampicillin, teicoplanin (not available in the United States), and vancomycin. To kill enterococci requires the synergistic interaction of a cell wall–active antibiotic that is effective at achievable serum concentrations (penicillin, ampicillin, vancomycin, or teicoplanin) and an aminoglycoside (gentamicin or streptomycin) to which the isolate does not exhibit high-level resistance. An isolate’s resistance to cell wall–active agents or its ability to replicate in the presence of gentamicin at ≥500 μg/mL or streptomycin at 1000–2000 μg/mL—a phenomenon called high-level aminoglycoside resistance—indicates that the ineffective antimicrobial agent cannot participate in the interaction to produce killing. High-level resistance to gentamicin predicts that tobramycin, netilmicin, amikacin, and kanamycin also will be ineffective. In fact, even when enterococci


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InternalMed_Harrison. in the interaction to produce killing. High-level resistance to gentamicin predicts that tobramycin, netilmicin, amikacin, and kanamycin also will be ineffective. In fact, even when enterococci are not highly resistant to gentamicin, it is difficult to predict the ability of these other aminoglycosides to participate in synergistic killing; consequently, they should not, in general, be used to treat enterococcal endocarditis. High concentrations of ampicillin plus ceftriaxone or cefotaxime, by expanded binding of penicillin-binding proteins, also kill E. faecalis in vitro and in animal models of endocarditis.


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InternalMed_Harrison. Enterococci must be tested for high-level resistance to streptomycin and gentamicin, β-lactamase production, and susceptibility to penicillin and ampicillin (MIC, <8 μg/mL) and to vancomycin (MIC, ≤4 μg/mL) and teicoplanin (MIC ≤2 μg/ml). If the isolate produces β-lactamase, ampicillin/sulbactam or vancomycin can be used as the cell wall–active component; if the penicillin/ampicillin MIC is ≥8 μg/mL, vancomycin can be considered; and if the vancomycin MIC is ≥8 μg/mL, penicillin or ampicillin can be considered. In the absence of high-level resistance, gentamicin or streptomycin should be used as the aminoglycoside (Table 155-4). Although the dose of gentamicin used to achieve bactericidal synergy in treating enterococcal endocarditis is smaller than that used in standard therapy, nephrotoxicity (or vestibular toxicity with streptomycin) is not uncommon during treatment lasting 4–6 weeks. Regimens in which the aminoglycoside component is given for only 2–3 weeks have been curative and


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InternalMed_Harrison. (or vestibular toxicity with streptomycin) is not uncommon during treatment lasting 4–6 weeks. Regimens in which the aminoglycoside component is given for only 2–3 weeks have been curative and associated with less nephrotoxicity than those using longer courses of gentamicin. Thus regimens wherein gentamicin is administered for only 2–3 weeks are preferred by some.


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InternalMed_Harrison. If there is high-level resistance to both gentamicin and streptomycin, a synergistic bactericidal effect cannot be achieved by the addition of an aminoglycoside; thus no aminoglycoside should be given. Instead, an 8to 12-week course of a single cell wall–active agent can be considered; for E. faecalis endocarditis, high doses of ampicillin combined with ceftriaxone or cefotaxime are suggested (Table 155-4). Nonrandomized comparative studies suggest that ampicillin-ceftriaxone may be as effective as (and less nephrotoxic than) penicillin or ampicillin plus an aminoglycoside in the treatment of E. faecalis endocarditis. Given the reduced risk G (4–5 mU IV q4h) plus gentamicind (1 mg/kg IV q8h), both for 4–6 weeks (2 g IV q4h) plus gentamicind (1 mg/kg IV q8h), both for 4–6 weeks (15 mg/kg IV q12h) plus gentamicind (1 mg/kg IV q8h), both for 4–6 weeks (2 g IV q4h) plus ceftriaxone (2 g IV q12h), both for 6 weeks


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InternalMed_Harrison. Can use streptomycin (7.5 mg/kg q12h) in lieu of gentamicin if there is not high-level resistance to streptomycin. Use vancomycin plus gentamicin for penicillin-allergic patients (or desensitize to penicillin) and for isolates resistant to penicillin/ ampicillin. Use for E. faecalis isolates with high-level resistance to gentamicin and streptomycin or for patients at high risk for aminoglycoside nephrotoxicity (see text). • Nafcillin, oxacillin, or flucloxacillin (2 g IV q4h for 4–6 weeks) • Nafcillin, oxacillin, or flucloxacillin (2 g IV q4h for 6–8 weeks) Rifampini (300 mg PO q8h for 6–8 weeks) Can use penicillin (4 mU q4h) if isolate is penicillin-susceptible (does not produce β-lactamase). Can use cefazolin regimen for patients with nonimmediate penicillin allergy. Use vancomycin for patients with immediate (urticarial) or severe penicillin allergy; see text regarding addition of gentamicin, fusidic acid, or rifampin.


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InternalMed_Harrison. Use vancomycin for patients with immediate (urticarial) or severe penicillin allergy; see text regarding addition of gentamicin, fusidic acid, or rifampin. No role for routine use of rifampin (see text). Consider alternative treatment (see text) for MRSA with vancomycin MIC >1.0 or persistent bacteremia during vancomycin therapy. Use gentamicin during initial 2 weeks; determine susceptibility to gentamicin before initiating rifampin (see text); if patient is highly allergic to penicillin, use regimen for MRSA; if β-lactam allergy is of the minor nonimmediate type, cefazolin can be substituted for oxacillin/nafcillin. Use gentamicin during initial 2 weeks; determine gentamicin susceptibility before initiating rifampin (see text). (2 g/d IV as a single dose for 4 weeks) Can use another third-generation cephalosporin at comparable dosage.


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InternalMed_Harrison. • Ceftriaxone (2 g IV q24h) or ampicillin (2 g IV q4h) or If patient is highly allergic to β-lactams, use doxycycline. doxycycline (100 mg q12h PO) for 6 weeks aDoses are for adults with normal renal function. Doses of gentamicin, streptomycin, and vancomycin must be adjusted for reduced renal function. Ideal body weight is used to calculate doses of gentamicin and streptomycin per kilogram (men = 50 kg + 2.3 kg per inch over 5 feet; women = 45.5 kg + 2.3 kg per inch over 5 feet). bMIC, ≤0.1 μg/mL. cVancomycin dose is based on actual body weight. Adjust for trough level of 10–15 μg/mL for streptococcal and enterococcal infections and 15–20 μg/mL for staphylococcal infections. dAminoglycosides should not be administered as single daily doses for enterococcal endocarditis and should be introduced as part of the initial treatment. Target peak and trough serum concentrations of divided-dose gentamicin 1 h after a 20to 30-min infusion or IM injection are ~3.5 μg/mL and ≤1 μg/mL,


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InternalMed_Harrison. be introduced as part of the initial treatment. Target peak and trough serum concentrations of divided-dose gentamicin 1 h after a 20to 30-min infusion or IM injection are ~3.5 μg/mL and ≤1 μg/mL, respectively; target peak and trough serum concentrations of streptomycin (timing as with gentamicin) are 20–35 μg/mL and <10 μg/mL, respectively. eNetilmicin (4 mg/kg qd, as a single dose) can be used in lieu of gentamicin. fMIC, >0.1 μg/mL and <0.5 μg/mL. gMIC, ≥0.5 μg/mL and <8 μg/mL. hAntimicrobial susceptibility must be evaluated; see text. iRifampin increases warfarin and dicumarol requirements for anticoagulation.


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InternalMed_Harrison. Abbreviations: MIC, minimal inhibitory concentration; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus. of nephrotoxicity with ampicillin-ceftriaxone therapy, this regimen may also be preferred in patients who are at increased risk for aminoglycoside nephrotoxicity. If the enterococcal isolate is resistant to all of the commonly used agents, suppression of bacteremia followed by surgical treatment should be considered. The role of newer agents potentially active against multidrug-resistant enterococci (quinupristin/dalfopristin [E. faecium only], linezolid, and daptomycin) in the treatment of endocarditis has not been established.


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InternalMed_Harrison. stapHylococci The regimens used to treat staphylococcal endocarditis (Table 155-4) are based not on coagulase production but rather on the presence or absence of a prosthetic valve or foreign device, the native valve(s) involved, and the susceptibility of the isolate to penicillin, methicillin, and vancomycin. All staphylococci are considered penicillin-resistant until shown not to produce penicillinase. Similarly, methicillin resistance has become so prevalent among staphylococci that empirical therapy should be initiated with a regimen that covers methicillin-resistant organisms and should later be revised if the isolate proves to be susceptible to methicillin. The addition of 3–5 days of gentamicin to a β-lactam antibiotic or vancomycin to enhance therapy for native mitral or aortic valve endocarditis has not improved survival rates and may be associated with nephrotoxicity. Neither this addition nor the addition of fusidic acid or rifampin is recommended.


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InternalMed_Harrison. For treatment of endocarditis caused by methicillin-resistant S. aureus (MRSA), vancomycin, dosed to achieve trough concentrations of 15–20 μg/mL, is recommended, with the caveat that this regimen may be associated with nephrotoxicity. Although resistance to vancomycin among staphylococci is rare, reduced vancomycin susceptibility among MRSA strains is increasingly encountered. Isolates with a vancomycin MIC of 4–16 μg/mL have intermediate susceptibility and are referred to as vancomycin-intermediate S. aureus (VISA). Isolates with an MIC of 2 μg/mL may harbor subpopulations with higher MICs. These heteroresistant VISA (hVISA) isolates are not detectable by routine susceptibility testing. Because of the pharmacokinetics/pharmacodynamics of vancomycin, killing of MRSA with a vancomycin MIC of >1.0 μg/mL is unpredictable, even with aggressive vancomycin dosing. Although not approved by the


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InternalMed_Harrison. U.S. Food and Drug Administration for this indication, daptomycin (6 mg/kg [or, as some experts prefer, 8–10 mg/kg] IV once daily) has been recommended as an alternative to vancomycin, particularly for left-sided endocarditis caused by VISA, hVISA, or isolates with a vancomycin MIC of >1.0 μg/mL. These isolates should be tested to document daptomycin susceptibility. Daptomycin activity against MRSA—even against some isolates with reduced daptomycin susceptibility—is enhanced by the addition of nafcillin or ceftaroline. Case reports suggest that either the latter combinations or ceftaroline alone (600 mg IV q8h) may be effective in recalcitrant MRSA endocarditis. Nevertheless, a discussion of treatment of endocarditis in which MRSA bacteremia persists despite therapy is beyond the scope of this chapter and requires consultation with an infectious disease specialist. The efficacy of linezolid for left-sided MRSA endocarditis has not been established. Although not widely adopted by other


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InternalMed_Harrison. this chapter and requires consultation with an infectious disease specialist. The efficacy of linezolid for left-sided MRSA endocarditis has not been established. Although not widely adopted by other groups, the recommendation of the British Society for Antimicrobial Chemotherapy is that a second drug be added to vancomycin (rifampin) or to daptomycin (rifampin, gentamicin, or linezolid) for the treatment of NVE due to MRSA.


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InternalMed_Harrison. Methicillin-susceptible S. aureus endocarditis that is uncomplicated and limited to the tricuspid or pulmonic valve can often be treated with a 2-week course that combines oxacillin or nafcillin (but not vancomycin) with gentamicin. However, patients with prolonged fever (≥5 days) during therapy or multiple septic pulmonary emboli should receive standard-duration therapy. Vancomycin plus gentamicin for 2 weeks as treatment for right-sided endocarditis caused by MRSA yields suboptimal results; thus this entity is treated for 4 weeks with vancomycin or daptomycin (6 mg/kg as a single daily dose).


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InternalMed_Harrison. Staphylococcal PVE is treated for 6–8 weeks with a multidrug regimen. Rifampin is an essential component because it kills staphylococci that are adherent to foreign material in a biofilm. Two other agents (selected on the basis of susceptibility testing) are combined with rifampin to prevent in vivo emergence of resistance. Because many staphylococci (particularly MRSA and Staphylococcus epidermidis) are resistant to gentamicin, the isolate’s susceptibility to gentamicin or an alternative agent should be established before rifampin treatment is begun. If the isolate is resistant to gentamicin, then another aminoglycoside, a fluoroquinolone (chosen on the basis of susceptibility), or another active agent should be substituted for gentamicin.


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InternalMed_Harrison. otHer organisms In the absence of meningitis, endocarditis caused by Streptococcus pneumoniae isolates with a penicillin MIC of ≤1 μg/mL can be treated with IV penicillin (4 million units every 4 h), ceftriaxone (2 g/d as a single dose), or cefotaxime (at a comparable dosage). Infection caused by pneumococcal strains with a penicillin MIC of ≥2 μg/mL should be treated with vancomycin. If meningitis is suspected or present, treatment with vancomycin plus ceftriaxone—at the doses advised for meningitis—should be initiated until susceptibility results are known. Definitive therapy should then be selected on the basis of meningitis breakpoints (penicillin MIC, 0.06 μg/mL; or ceftriaxone MIC, 0.5 μg/mL). P. aeruginosa endocarditis is treated with an antipseudomonal penicillin (ticarcillin or piperacillin) and high doses of tobramycin (8 mg/kg per day in three divided doses). Endocarditis caused by Enterobacteriaceae is treated with a potent β-lactam antibiotic plus an aminoglycoside.


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InternalMed_Harrison. or piperacillin) and high doses of tobramycin (8 mg/kg per day in three divided doses). Endocarditis caused by Enterobacteriaceae is treated with a potent β-lactam antibiotic plus an aminoglycoside. Corynebacterial 824 endocarditis is treated with a penicillin plus an aminoglycoside (if the organism is susceptible to the aminoglycoside) or with vancomycin, which is highly bactericidal for most strains. Therapy for Candida endocarditis consists of amphotericin B plus flucytosine and early surgery; long-term (if not indefinite) suppression with an oral azole is advised. Echinocandin treatment of Candida endocarditis has been effective in sporadic cases; nevertheless, the role of echinocandins in this setting has not been established.


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InternalMed_Harrison. Empirical Therapy In designing therapy (largely with antimicrobials and doses from Table 155-4 to target putative microorganisms) to be administered before culture results are known or when cultures are negative, clinical clues (e.g., acute vs. subacute presentation, site of infection, patient’s predispositions) as well as epidemiologic clues to etiology must be considered. Thus empirical therapy for acute endocarditis in an injection drug user should cover MRSA and gram-negative bacilli. Treatment with vancomycin plus gentamicin, initiated immediately after blood samples are obtained for culture, covers these organisms as well as many other potential causes. Similarly, treatment of health care–associated endocarditis must cover MRSA. In the treatment of culture-negative episodes, marantic endocarditis must be excluded and fastidious organisms sought by serologic testing. In the absence of prior antibiotic therapy, it is unlikely that S. aureus, CoNS, or enterococcal infection will


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InternalMed_Harrison. endocarditis must be excluded and fastidious organisms sought by serologic testing. In the absence of prior antibiotic therapy, it is unlikely that S. aureus, CoNS, or enterococcal infection will present with negative blood cultures; thus, in this situation, recommended empirical therapy targets not these organisms but rather nutritionally variant organisms, the HACEK group, and Bartonella species. Pending the availability of diagnostic data, blood culture–negative subacute NVE is treated with gentamicin plus ampicillin-sulbactam (12 g every 24 h) or ceftriaxone; doxycycline (100 mg twice daily) is added for enhanced Bartonella coverage. For culture-negative PVE, vancomycin, gentamicin, cefepime, and rifampin should be used if the prosthetic valve has been in place for ≤1 year. Empirical therapy for infected prosthetic valves in place for >1 year is similar to that for culture-negative NVE. If cultures may be negative because of confounding by prior antibiotic administration, broader


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InternalMed_Harrison. therapy for infected prosthetic valves in place for >1 year is similar to that for culture-negative NVE. If cultures may be negative because of confounding by prior antibiotic administration, broader empirical therapy may be indicated, with particular attention to pathogens that are likely to be inhibited by the specific prior therapy.


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InternalMed_Harrison. CIED Endocarditis Antimicrobial therapy for CIED endocarditis is adjunctive to complete device removal. The antimicrobial selected is based on the causative organism and should be used as recommended for NVE (Table 155-4). Bacteremic CIED infection may be complicated by coincident NVE or remote-site infection (e.g., osteomyelitis). A 4to 6-week course of endocarditis-targeted therapy is recommended for patients with CIED endocarditis and for those with bacteremia that continues during ongoing antimicrobial therapy after device removal. Although S. aureus bacteremia (and persistent CoNS bacteremia) in patients who have a CIED in place is likely—in the absence of another source—to reflect endocarditis and should be managed accordingly, not all bloodstream infections in these patients indicate endocarditis. If evidence suggesting endocarditis is lacking, bloodstream infection due to gram-negative bacilli, streptococci, enterococci, and Candida species may not indicate device infection.


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InternalMed_Harrison. endocarditis. If evidence suggesting endocarditis is lacking, bloodstream infection due to gram-negative bacilli, streptococci, enterococci, and Candida species may not indicate device infection. However, in the absence of another source, relapse after antimicrobial therapy increases the likelihood of CIED endocarditis and warrants treatment as such.


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InternalMed_Harrison. Outpatient Antimicrobial Therapy Fully compliant, clinically stable patients who are no longer bacteremic, are not febrile, and have no clinical or echocardiographic findings that suggest an impending complication may complete therapy as outpatients. Careful follow-up and a stable home setting are necessary, as are predictable IV access and use of antimicrobial agents that are stable in solution. Recommended regimens should not be compromised to accommodate outpatient therapy. Monitoring Antimicrobial Therapy Measurement of the serum bactericidal titer—the highest dilution of the patient’s serum during therapy that kills 99.9% of the standard inoculum of the infecting organism—is not recommended for assessment of standard regimens but may be useful for assessment of the treatment of endocarditis caused by unusual organisms. Serum concentrations of aminoglycosides and vancomycin should be monitored and doses adjusted to avoid or address toxicity.


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InternalMed_Harrison. Antibiotic toxicities, including allergic reactions, occur in 25–40% of patients and commonly arise after several weeks of therapy. Blood tests to detect renal, hepatic, and hematologic toxicity should be performed periodically.


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InternalMed_Harrison. Blood cultures should be repeated daily until sterile in patients with endocarditis due to S. aureus or difficult-to-treat organisms, rechecked if there is recrudescent fever, and performed again 4–6 weeks after therapy to document cure. Blood cultures become sterile within 2 days after the start of appropriate therapy when infection is caused by viridans streptococci, enterococci, or HACEK organisms. In S. aureus endocarditis, β-lactam therapy results in sterile cultures in 3–5 days, whereas in MRSA endocarditis, positive cultures may persist for 7–9 days with vancomycin or daptomycin treatment. MRSA bacteremia persisting despite an adequate dosage of vancomycin may indicate infection due to a strain with reduced vancomycin susceptibility and therefore may point to a need for alternative therapy. When fever persists for 7 days despite appropriate antibiotic therapy, patients should be evaluated for paravalvular abscess, extracardiac abscesses (spleen, kidney), or complications


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InternalMed_Harrison. therapy. When fever persists for 7 days despite appropriate antibiotic therapy, patients should be evaluated for paravalvular abscess, extracardiac abscesses (spleen, kidney), or complications (embolic events). Recrudescent fever raises the possibility of these complications but also of drug reactions or complications of hospitalization. Vegetations become smaller with effective therapy; however, 3 months after cure, 50% are unchanged and 25% are slightly larger.


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InternalMed_Harrison. Intracardiac and central nervous system complications are important causes of morbidity and death due to infective endocarditis. In some cases, effective treatment for these complications requires surgery. The indications for cardiac surgical treatment of endocarditis (Table 155-5) have been derived from observational studies and expert opinion. The strength of individual indications varies; thus the risks and benefits as well as the timing of surgery must be individualized (Table 155-6). From 25% to 40% of patients with left-sided endocarditis undergo cardiac surgery during active infection, with slightly higher surgery rates for PVE than NVE. Intracardiac complications (which are most reliably detected by TEE) and CHF are the most commonly cited indications for surgery. The benefit of surgery has been assessed primarily in studies comparing populations of medically and surgically treated patients matched for the necessity of


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InternalMed_Harrison. Moderate to severe congestive heart failure due to valve dysfunction Partially dehisced unstable prosthetic valve Persistent bacteremia despite optimal antimicrobial therapy Lack of effective microbicidal therapy (e.g., fungal or Brucella endocarditis) S. aureus prosthetic valve endocarditis with an intracardiac complication Relapse of prosthetic valve endocarditis after optimal antimicrobial therapy Surgery to Be Strongly Considered for Improved Outcomea Perivalvular extension of infection Poorly responsive S. aureus endocarditis involving the aortic or mitral valve Large (>10 mm in diameter) hypermobile vegetations with increased risk of embolism, particularly with prior embolic event or with significant valve dysfunction Poorly responsive or relapsed endocarditis due to highly antibiotic-resistant enterococci or gram-negative bacilli aSurgery must be carefully considered; findings are often combined with other indications to prompt surgery.


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InternalMed_Harrison. aSupported by a single-institution randomized trial showing benefit from early surgery. Implementation requires clinical judgment. Source: Adapted from L Olaison, G Pettersson: Infect Dis Clin North Am 16:453, 2002. surgery (indications assessed in studies as propensity), with adjustments for predictors of death (comorbidities) and timing of the surgical intervention. Although study results vary, surgery for currently advised indications appears to convey a significant survival benefit (27–55%) that becomes apparent only with follow-up for ≥6 months. During the initial weeks after surgery, mortality risk may appear increased (disease + surgery–related mortality).


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InternalMed_Harrison. Indications • congestive Heart failure Moderate to severe refractory CHF caused by new or worsening valve dysfunction is the major indication for cardiac surgery. At 6 months of follow-up, patients with left-sided endocarditis and moderate to severe heart failure due to valve dysfunction who are treated medically have a 50% mortality rate, while among matched patients who undergo surgery the mortality rate is 15%. The survival benefit with surgery, which is most predictable among patients with the most weighty indications (propensity), is seen in both NVE and PVE. Surgery can relieve functional stenosis due to large vegetations or restore competence to damaged regurgitant valves by repair or replacement.


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InternalMed_Harrison. perivalvular infection This complication, which is most common with aortic valve infection, occurs in 10–15% of native valve and 45–60% of prosthetic valve infections. It is suggested by persistent unexplained fever during appropriate therapy, new electrocardiographic conduction disturbances, or pericarditis. TEE with color Doppler is the test of choice to detect perivalvular abscesses (sensitivity, ≥85%). For optimal outcome, surgery is required, especially when fever persists, fistulae develop, prostheses are dehisced and unstable, or infection relapses after appropriate treatment. Cardiac rhythm must be monitored since high-grade heart block may require insertion of a pacemaker.


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InternalMed_Harrison. uncontrolled infection Continued positive blood cultures or otherwise-unexplained persistent fevers (in patients with either blood culture–positive or –negative endocarditis) despite optimal antibiotic therapy may reflect uncontrolled infection and may warrant surgery. Surgical treatment is also advised for endocarditis caused by organisms against which effective antimicrobial therapy is lacking (e.g., yeasts, fungi, P. aeruginosa, other highly resistant gram-negative bacilli, Brucella species).


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InternalMed_Harrison. s. aureus endocarditis The mortality rate for S. aureus PVE exceeds 50% with medical treatment but is reduced to 25% with surgical treatment. In patients with intracardiac complications associated with S. aureus PVE, surgical treatment reduces the mortality rate twentyfold. Surgical treatment should be considered for patients with S. aureus native aortic or mitral valve infection who have TTE-demonstrable vegetations and remain septic during the initial week of therapy. Isolated tricuspid valve endocarditis, even with persistent fever, rarely requires surgery.


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InternalMed_Harrison. prevention of systemic emboli Death and persisting morbidity may result from cerebral or coronary artery emboli. Predicting a high risk of systemic embolization by echocardiographic determination of vegetation size and anatomy does not by itself identify those patients in whom surgery to prevent emboli will result in increased chances of survival. Net benefits from surgery to prevent emboli are most likely when other surgical benefits can be achieved simultaneously—e.g., repair of a moderately dysfunctional valve or debridement of a paravalvular abscess. Only 3.5% of patients undergo surgery solely to prevent systemic emboli. Valve repair, with the consequent avoidance of prosthesis insertion, improves the benefitto-risk ratio of surgery performed to address vegetations.


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InternalMed_Harrison. cied endocarditis Removal of all hardware is recommended for patients with established CIED infection (pocket or intracardiac lead) or erosion of the device through the skin. Percutaneous lead extraction is preferred. With lead vegetations of >3 cm and the resulting risk of a pulmonary embolus or with retained hardware after attempted percutaneous extraction, surgical removal should be considered. Removal of the infected CIED during the initial hospitalization is associated with increased 30-day and 1-year survival rates over those attained with antibiotic therapy and device retention. If necessary, the CIED can be reimplanted percutaneously or surgically (epicardial leads) at a new site after at least 10–14 days of effective antimicrobial therapy. CIEDs should be removed and replaced subsequently when patients undergo valve surgery for endocarditis.


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InternalMed_Harrison. Timing of Cardiac Surgery With the more life-threatening indications for surgery (valve dysfunction and severe CHF, paravalvular abscess, major prosthesis dehiscence), early surgery—i.e., during the initial week of therapy—is associated with a greater chance of survival than later surgery. With less compelling indications, surgery may reasonably be delayed to allow further treatment as well as improvement in overall health (Table 155-6). After 14 days of recommended antibiotic therapy, excised valves are culture-negative in 99% and 50% of patients with streptococcal and S. aureus endocarditis, 826 respectively. Recrudescent endocarditis on a new implanted prosthetic valve follows surgery for active NVE and PVE in 2% and 6–15% of patients, respectively. These frequencies do not justify the risk of an adverse outcome due to a delay in surgery, particularly in patients with severe heart failure, valve dysfunction, and uncontrolled staphylococcal infections. Delay is justified when


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InternalMed_Harrison. the risk of an adverse outcome due to a delay in surgery, particularly in patients with severe heart failure, valve dysfunction, and uncontrolled staphylococcal infections. Delay is justified when infection is controlled and CHF is resolved with medical therapy. Neurologic complications of endocarditis may be exacerbated as a consequence of cardiac surgery. The risk of neurologic deterioration is related to the type of neurologic complication and the interval between the complication and surgery. Whenever feasible, cardiac surgery should be delayed for 2–3 weeks after a nonhemorrhagic embolic infarction and for 4 weeks after a cerebral hemorrhage. A ruptured mycotic aneurysm should be treated before cardiac surgery.


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InternalMed_Harrison. Antibiotic Therapy after Cardiac Surgery Organisms have been detected on Gram’s stain—or their DNA has been detected by polymerase chain reaction—in excised valves from 45% of patients who have successfully completed the recommended therapy for endocarditis. In only 7% of these patients are the organisms, most of which are unusual and antibiotic resistant, cultured from the valve. Detection of organisms or their DNA does not necessarily indicate antibiotic failure; in fact, relapse of endocarditis after surgery is uncommon. Thus, when valve cultures are negative in uncomplicated NVE caused by susceptible organisms, the duration of preoperative plus postoperative treatment should equal the total duration of recommended therapy, with ~2 weeks of treatment administered after surgery. For endocarditis complicated by paravalvular abscess, partially treated PVE, or cases with culture-positive valves, a full course of therapy should be given postoperatively.


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InternalMed_Harrison. Extracardiac Complications Splenic abscess develops in 3–5% of patients with endocarditis. Effective therapy requires either image-guided percutaneous drainage or splenectomy. Mycotic aneurysms occur in 2–15% of endocarditis patients; one-half of these cases involve the cerebral arteries and present as headaches, focal neurologic symptoms, or hemorrhage. Cerebral aneurysms should be monitored by angiography. Some will resolve with effective antimicrobial therapy, but those that persist, enlarge, or leak should be treated surgically if possible. Extracerebral aneurysms present as local pain, a mass, local ischemia, or bleeding; these aneurysms are treated surgically.


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InternalMed_Harrison. Factors that can adversely affect outcome include older age, severe comorbid conditions and diabetes, delayed diagnosis, involvement of prosthetic valves or the aortic valve, an invasive (S. aureus) or antibiotic-resistant (P. aeruginosa, yeast) pathogen, intracardiac and major neurologic complications, and an association with health care. Death and poor outcome often are related not to failure of antibiotic therapy but rather to the interactions of comorbidities and endocarditis-related end-organ complications. In developed countries, overall survival rates are 80–85%; however, rates vary considerably among subpopulations of endocarditis patients. Survival rates for patients with NVE caused by viridans streptococci, HACEK organisms, or enterococci (susceptible to synergistic therapy) are 85–90%. For S. aureus NVE in patients who do not inject drugs, survival rates are 55–70%, whereas 85–90% of injection drug users survive this infection. PVE beginning within 2 months of valve


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InternalMed_Harrison. are 85–90%. For S. aureus NVE in patients who do not inject drugs, survival rates are 55–70%, whereas 85–90% of injection drug users survive this infection. PVE beginning within 2 months of valve replacement results in mortality rates of 40–50%, whereas rates are only 10–20% in later-onset cases.


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InternalMed_Harrison. To prevent endocarditis (long a goal in clinical practice), past expert committees have supported systemic antibiotic administration prior to many bacteremia-inducing procedures. A reappraisal of the evidence for antibiotic prophylaxis for endocarditis by the American Heart Association and the European Society of Cardiology culminated in guidelines advising its more restrictive use. At best, the AnTIBIoTIC REgIMEnS foR PRoPHyLAxIS of EnDoCARDITIS In ADuLTS wITH HIgH-RISk CARDIAC LESIonSa,b A. Standard oral regimen Amoxicillin: 2 g PO 1 h before procedure B. Inability to take oral medication Ampicillin: 2 g IV or IM within 1 h before procedure C. Penicillin allergy 1. Clarithromycin or azithromycin: 500 mg PO 1 h before procedure 2. Cephalexinc: 2 g PO 1 h before procedure 3. Clindamycin: 600 mg PO 1 h before procedure D. Penicillin allergy, inability to take oral medication 1. Cefazolinc or ceftriaxonec: 1 g IV or IM 30 min before procedure 2.


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InternalMed_Harrison. Clindamycin: 600 mg PO 1 h before procedure D. Penicillin allergy, inability to take oral medication 1. Cefazolinc or ceftriaxonec: 1 g IV or IM 30 min before procedure 2. Clindamycin: 600 mg IV or IM 1 h before procedure aDosing for children: for amoxicillin, ampicillin, cephalexin, or cefadroxil, use 50 mg/kg PO; cefazolin, 25 mg/kg IV; clindamycin, 20 mg/kg PO or 25 mg/kg IV; clarithromycin, 15 mg/ kg PO; and vancomycin, 20 mg/kg IV. bFor high-risk lesions, see Table 155-8. Prophylaxis is not advised for other lesions. cDo not use cephalosporins in patients with immediate hypersensitivity (urticaria, angioedema, anaphylaxis) to penicillin. Source: Table created using the guidelines published by the American Heart Association and the European Society of Cardiology (W Wilson et al: Circulation 116:1736, 2007; and G Habib et al: Eur Heart J 30:2369, 2009).


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InternalMed_Harrison. benefit of antibiotic prophylaxis is minimal. Most endocarditis cases do not follow a procedure. Although dental treatments have been widely considered to predispose to endocarditis, such infection occurs no more frequently in patients who are undergoing dental treatment than in matched controls who are not. Furthermore, the frequency and magnitude of bacteremia associated with dental procedures and a routine day’s activities (e.g., tooth brushing and flossing) are similar; because dental procedures are infrequent events, exposure of cardiac structures to bacteremic oral-cavity organisms is notably greater from routine daily activities than from dental care. The relation of gastrointestinal and genitourinary procedures to subsequent endocarditis is even more tenuous than that of dental procedures. In addition, cost-effectiveness and cost-benefit estimates suggest that antibiotic prophylaxis represents a poor use of resources.


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InternalMed_Harrison. Nevertheless, studies in animal models suggest that antibiotic prophylaxis may be effective. Thus it is possible that rare cases of endocarditis are prevented. Weighing the potential benefits, potential adverse events, and costs associated with antibiotic prophylaxis, the American Heart Association and the European Society of Cardiology now recommend prophylactic antibiotics (Table 155-7) only for those patients at highest risk for severe morbidity or death from endocarditis (Table 155-8). Maintaining good dental hygiene is essential. Prophylaxis is recommended only when there is manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa (including surgery on the respiratory tract). Prophylaxis is not advised for patients undergoing gastrointestinal or genitourinary tract procedures. High-risk patients should be treated before or


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InternalMed_Harrison. Prosthetic heart valves Prior endocarditis Unrepaired cyanotic congenital heart disease, including palliative shunts or Completely repaired congenital heart defects during the 6 months after repair Incompletely repaired congenital heart disease with residual defects adjacent to prosthetic material Valvulopathy developing after cardiac transplantationa aNot a target population for prophylaxis according to recommendations of the European Society for Cardiology. Source: Table created using the guidelines published by the American Heart Association and the European Society of Cardiology (W Wilson et al: Circulation 116:1736, 2007; and G Habib et al: Eur Heart J 30:2369, 2009). when they undergo procedures on an infected genitourinary tract or on infected skin and soft tissue.


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InternalMed_Harrison. when they undergo procedures on an infected genitourinary tract or on infected skin and soft tissue. In patients with aortic or mitral valve regurgitation or a prosthetic valve, treatment of acute Q fever with doxycycline plus hydroxychloroquine (for doses, see Table 155-4) for 12 months is highly effective in preventing C. burnetii endocarditis. The National Institute for Health and Clinical Excellence in the United Kingdom has advised discontinuation of all antibiotic prophylaxis for endocarditis. Limited surveillance studies have not detected increased viridans streptococcal endocarditis subsequent to the promulgation of guidelines that are more restrictive or advise no prophylaxis. Infections of the Skin, Muscles, Dennis L. Stevens


InternalMed_Harrison

InternalMed_Harrison. Skin and soft tissue infections occur in all races, all ethnic groups, and all geographic locations, although some have unique geographic niches. In modern times, the frequency and severity of some skin and soft tissue infections have increased for several reasons. First, microbes are rapidly disseminated throughout the world via efficient air travel, acquiring genes for virulence factors and antibiotic resistance. Second, natural disasters, such as earthquakes, tsunamis, tornadoes, and hurricanes, appear to be increasing in frequency, and the injuries sustained during these events commonly cause major skin and soft-tissue damage that predisposes to infection. Third, trauma and casualties resulting from combat and terrorist activities can markedly damage or destroy tissues and provide both endogenous and exogenous pathogens with ready access to deeper structures. Unfortunately, because the marvels of modern medicine may not be available during human-instigated and natural disasters,


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InternalMed_Harrison. endogenous and exogenous pathogens with ready access to deeper structures. Unfortunately, because the marvels of modern medicine may not be available during human-instigated and natural disasters, primary treatment may be delayed and the likelihood of severe infection and death increased.


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InternalMed_Harrison. ANATOMIC RELATIONSHIPS: CLUES TO THE DIAGNOSIS OF SOFT TISSUE INFECTIONS Skin and soft tissue infections have been common human afflictions for centuries. However, between 2000 and 2004, hospital admissions for skin and soft tissue infections rose by 27%, a remarkable increase that was attributable largely to the emergence of the USA300 clone of methicillin-resistant Staphylococcus aureus (MRSA). This chapter provides an anatomic approach to understanding the types of soft tissue infections and the diverse microbes responsible.


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InternalMed_Harrison. Protection against infection of the epidermis depends on the mechanical barrier afforded by the stratum corneum, since the epidermis itself is devoid of blood vessels (Fig. 156-1). Disruption of this layer by burns or bites, abrasions, foreign bodies, primary dermatologic disorders (e.g., herpes simplex, varicella, ecthyma gangrenosum), surgery, or vascular or pressure ulcer allows penetration of bacteria to the deeper structures. Similarly, the hair follicle can serve as a portal either for components of the normal flora (e.g., Staphylococcus) or for extrinsic bacteria (e.g., Pseudomonas in hot-tub folliculitis). Intracellular infection of the squamous epithelium with vesicle formation may arise from cutaneous inoculation, as in infection with herpes simplex virus (HSV) type 1; from the dermal capillary plexus, as in varicella and infections due to other viruses associated with viremia; or from cutaneous nerve roots, as in herpes zoster. Bacteria infecting the epidermis, such as


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InternalMed_Harrison. the dermal capillary plexus, as in varicella and infections due to other viruses associated with viremia; or from cutaneous nerve roots, as in herpes zoster. Bacteria infecting the epidermis, such as Streptococcus pyogenes, may be translocated laterally to deeper structures via lymphatics, an event that results in the rapid superficial spread of erysipelas. Later, engorgement or obstruction of


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InternalMed_Harrison. FIGURE 156-1 Structural components of the skin and soft tissue, superficial infections, and infections of the deeper structures. The rich capillary network beneath the dermal papillae plays a key role in the localization of infection and in the development of the acute inflammatory reaction. lymphatics causes flaccid edema of the epidermis, another characteristic of erysipelas.


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InternalMed_Harrison. The rich plexus of capillaries beneath the dermal papillae provides nutrition to the stratum germinativum, and physiologic responses of this plexus produce important clinical signs and symptoms. For example, infective vasculitis of the plexus results in petechiae, Osler’s nodes, Janeway lesions, and palpable purpura, which, if present, are important clues to the existence of endocarditis (Chap. 155). In addition, metastatic infection within this plexus can result in cutaneous manifestations of disseminated fungal infection (Chap. 240), gonococcal infection (Chap. 181), Salmonella infection (Chap. 190), Pseudomonas infection (i.e., ecthyma gangrenosum; Chap. 189), meningococcemia (Chap. 180), and staphylococcal infection (Chap. 172). The plexus also provides bacteria with access to the circulation, thereby facilitating local spread or bacteremia. The postcapillary venules of this plexus are a prominent site of polymorphonuclear leukocyte sequestration, diapedesis, and chemotaxis to the


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InternalMed_Harrison. thereby facilitating local spread or bacteremia. The postcapillary venules of this plexus are a prominent site of polymorphonuclear leukocyte sequestration, diapedesis, and chemotaxis to the site of cutaneous infection.


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InternalMed_Harrison. Amplification of these physiologic mechanisms by excessive levels of cytokines or bacterial toxins causes leukostasis, venous occlusion, and pitting edema. Edema with purple bullae, ecchymosis, and cutaneous anesthesia suggests loss of vascular integrity and necessitates exploration of the deeper structures for evidence of necrotizing fasciitis or myonecrosis. An early diagnosis requires a high level of suspicion in instances of unexplained fever and of pain and tenderness in the soft tissue, even in the absence of acute cutaneous inflammation. Table 156-1 indicates the chapters in which the infections described below are discussed in greater detail. Many of these infections are illustrated in the chapters cited or in Chap. 25e (Atlas of Rashes Associated with Fever).


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InternalMed_Harrison. (Table 156-1) Vesicle formation due to infection is caused by viral proliferation within the epidermis. In varicella and variola, viremia precedes the onset of a diffuse centripetal rash that progresses from macules to vesicles, then to pustules, and finally to scabs over the course of 1–2 weeks. Vesicles of varicella have a “dewdrop” appearance and develop in crops randomly about the trunk, extremities, and face over 3–4 days. Herpes zoster occurs in a single dermatome; the appearance of vesicles is preceded by pain for several days. Zoster may occur in persons of any age but is most common among immunosuppressed individuals and elderly patients, whereas most cases of varicella occur in young children. Vesicles due to HSV are found on or around the


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InternalMed_Harrison. CHAPTER 156 Infections of the Skin, Muscles, and Soft Tissues lips (HSV-1) or genitals (HSV-2) but also may appear on the head and neck of young wrestlers (herpes gladiatorum) or on the digits of health care workers (herpetic whitlow). Recurrent herpes labialis (HSV-1) and herpes genitalis commonly follow primary infection. Coxsackievirus A16 characteristically causes vesicles on the hands, feet, and mouth of children. Orf is caused by a DNA virus related to smallpox virus and infects the fingers of individuals who work around goats and sheep. Molluscum contagiosum virus induces flaccid vesicles on the skin of healthy and immunocompromised individuals. Although variola (smallpox) in nature was eradicated as of 1977, post-millennial terrorist events have renewed interest in this devastating infection (Chap. 261e). Viremia beginning after an incubation period of 12 days is followed by a diffuse maculopapular rash, with rapid evolution to vesicles, pustules, and then scabs. Secondary


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InternalMed_Harrison. infection (Chap. 261e). Viremia beginning after an incubation period of 12 days is followed by a diffuse maculopapular rash, with rapid evolution to vesicles, pustules, and then scabs. Secondary cases can occur among close contacts.


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InternalMed_Harrison. Rickettsialpox begins after mite-bite inoculation of Rickettsia akari into the skin. A papule with a central vesicle evolves to form a 1to 2.5-cm painless crusted black eschar with an erythematous halo and proximal adenopathy. While more common in the northeastern United States and the Ukraine in 1940–1950, rickettsialpox has recently been described in Ohio, Arizona, and Utah. Blistering dactylitis is a painful, vesicular, localized S. aureus or group A streptococcal infection of the pulps of the distal digits of the hands.


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InternalMed_Harrison. (Table 156-1) Staphylococcal scalded-skin syndrome (SSSS) in neonates is caused by a toxin (exfoliatin) from phage group II S. aureus. SSSS must be distinguished from toxic epidermal necrolysis (TEN), which occurs primarily in adults, is drug-induced, and is associated with a higher mortality rate. Punch biopsy with frozen section is useful in making this distinction since the cleavage plane is the stratum corneum in SSSS and the stratum germinativum in TEN (Fig. 156-1). Intravenous γ-globulin is a promising treatment for TEN. Necrotizing fasciitis and gas gangrene also induce bulla formation (see “Necrotizing Fasciitis,” below). Halophilic vibrio infection can be as aggressive and fulminant as necrotizing fasciitis; a helpful clue in its diagnosis is a history of exposure to waters of the Gulf of Mexico or the Atlantic seaboard or (in a patient with cirrhosis) the ingestion of raw seafood. The etiologic organism (Vibrio vulnificus) is highly susceptible to tetracycline.


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InternalMed_Harrison. (Table 156-1) Impetigo contagiosa is caused by S. pyogenes, and bullous impetigo is due to S. aureus. Both skin lesions may have an early bullous stage but then appear as thick crusts with a golden-brown color. Epidemics of impetigo caused by MRSA have been reported. Streptococcal lesions are most common among children 2–5 years of age, and epidemics may occur in settings of poor hygiene, particularly among children in lower socioeconomic settings in tropical climates. It is important to recognize impetigo contagiosa because of its relationship to poststreptococcal glomerulonephritis. Rheumatic fever is not a complication of skin infection caused by S. pyogenes. Superficial dermatophyte infection (ringworm) can occur on any skin surface, and skin scrapings with KOH staining are diagnostic. Primary infections with dimorphic fungi such as Blastomyces dermatitidis and Sporothrix schenckii can initially present as crusted skin lesions resembling ringworm. Disseminated infection with


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InternalMed_Harrison. Primary infections with dimorphic fungi such as Blastomyces dermatitidis and Sporothrix schenckii can initially present as crusted skin lesions resembling ringworm. Disseminated infection with Coccidioides immitis can also involve the skin, and biopsy and culture should be performed on crusted lesions in patients from endemic areas. Crusted nodular lesions caused by Mycobacterium chelonei have been described in HIVseropositive patients. Treatment with clarithromycin looks promising.


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InternalMed_Harrison. (Table 156-1) Hair follicles serve as portals for a number of bacteria, although S. aureus is the most common cause of localized folliculitis. Sebaceous glands empty into hair follicles and ducts and, if these portals are blocked, form sebaceous cysts that may resemble staphylococcal abscesses or may become secondarily infected. Infection of sweat glands (hidradenitis suppurativa) also can mimic infection of hair 829 follicles, particularly in the axillae. Chronic folliculitis is uncommon except in acne vulgaris, where constituents of the normal flora (e.g., Propionibacterium acnes) may play a role.


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InternalMed_Harrison. Diffuse folliculitis occurs in two settings. Hot-tub folliculitis is caused by Pseudomonas aeruginosa in waters that are insufficiently chlorinated and maintained at temperatures of 37–40°C. Infection is usually self-limited, although bacteremia and shock have been reported. Swimmer’s itch occurs when a skin surface is exposed to water infested with freshwater avian schistosomes. Warm water temperatures and alkaline pH are suitable for mollusks that serve as intermediate hosts between birds and humans. Free-swimming schistosomal cercariae readily penetrate human hair follicles or pores but quickly die and elicit a brisk allergic reaction, causing intense itching and erythema.


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InternalMed_Harrison. (Table 156-1) Raised lesions of the skin occur in many different forms. Mycobacterium marinum infections of the skin may present as cellulitis or as raised erythematous nodules. Similar lesions caused by Mycobacterium abscessus and M. chelonei have been described among patients undergoing cosmetic laser surgery and tattooing, respectively. Erythematous papules are early manifestations of cat-scratch disease (with lesions developing at the primary site of inoculation of Bartonella henselae) and bacillary angiomatosis (also caused by B. henselae). Raised serpiginous or linear eruptions are characteristic of cutaneous larva migrans, which is caused by burrowing larvae of dog or cat hookworms (Ancylostoma braziliense) and which humans acquire through contact with soil that has been contaminated with dog or cat feces. Similar burrowing raised lesions are present in dracunculiasis caused by migration of the adult female nematode Dracunculus medinensis. Nodules caused by Onchocerca volvulus


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InternalMed_Harrison. with dog or cat feces. Similar burrowing raised lesions are present in dracunculiasis caused by migration of the adult female nematode Dracunculus medinensis. Nodules caused by Onchocerca volvulus measure 1–10 cm in diameter and occur mostly in persons bitten by Simulium flies in Africa. The nodules contain the adult worm encased in fibrous tissue. Migration of microfilariae into the eyes may result in blindness. Verruga peruana is caused by Bartonella bacilliformis, which is transmitted to humans by the sandfly Phlebotomus. This condition can take the form of single gigantic lesions (several centimeters in diameter) or multiple small lesions (several millimeters in diameter). Numerous subcutaneous nodules may also be present in cysticercosis caused by larvae of Taenia solium. Multiple erythematous papules develop in schistosomiasis; each represents a cercarial invasion site. Skin nodules as well as thickened subcutaneous tissue are prominent features of lepromatous leprosy. Large


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InternalMed_Harrison. erythematous papules develop in schistosomiasis; each represents a cercarial invasion site. Skin nodules as well as thickened subcutaneous tissue are prominent features of lepromatous leprosy. Large nodules or gummas are features of tertiary syphilis, whereas flat papulosquamous lesions are characteristic of secondary syphilis. Human papillomavirus may cause singular warts (verruca vulgaris) or multiple warts in the anogenital area (condylomata acuminata). The latter are major problems in HIV-infected individuals.


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InternalMed_Harrison. (Table 156-1) Cutaneous anthrax begins as a pruritic papule, which develops within days into an ulcer with surrounding vesicles and edema and then into an enlarging ulcer with a black eschar. Cutaneous anthrax may cause chronic nonhealing ulcers with an overlying dirty-gray membrane, although lesions may also mimic psoriasis, eczema, or impetigo. Ulceroglandular tularemia may have associated ulcerated skin lesions with painful regional adenopathy. Although buboes are the major cutaneous manifestation of plague, ulcers with eschars, papules, or pustules are also present in 25% of cases.


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InternalMed_Harrison. Mycobacterium ulcerans typically causes chronic skin ulcers on the extremities of individuals living in the tropics. Mycobacterium leprae may be associated with cutaneous ulcerations in patients with lepromatous leprosy related to Lucio’s phenomenon, in which immune-mediated destruction of tissue bearing high concentrations of M. leprae bacilli occurs, usually several months after initiation of effective therapy. Mycobacterium tuberculosis also may cause ulcerations, papules, or erythematous macular lesions of the skin in both immunocompetent and immunocompromised patients.


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InternalMed_Harrison. Infections of the Skin, Muscles, and Soft Tissues 830 Decubitus ulcers are due to tissue hypoxemia secondary to pressure-induced vascular insufficiency and may become secondarily infected with components of the skin and gastrointestinal flora, including anaerobes. Ulcerative lesions on the anterior shins may be due to pyoderma gangrenosum, which must be distinguished from similar lesions of infectious etiology by histologic evaluation of biopsy sites. Ulcerated lesions on the genitals may be either painful (chancroid) or painless (primary syphilis).


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InternalMed_Harrison. (Table 156-1) Erysipelas is due to S. pyogenes and is characterized by an abrupt onset of fiery-red swelling of the face or extremities. The distinctive features of erysipelas are well-defined indurated margins, particularly along the nasolabial fold; rapid progression; and intense pain. Flaccid bullae may develop during the second or third day of illness, but extension to deeper soft tissues is rare. Treatment with penicillin is effective; swelling may progress despite appropriate treatment, although fever, pain, and the intense red color diminish. Desquamation of the involved skin occurs 5–10 days into the illness. Infants and elderly adults are most commonly afflicted, and the severity of systemic toxicity varies.


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InternalMed_Harrison. (Table 156-1) Cellulitis is an acute inflammatory condition of the skin that is characterized by localized pain, erythema, swelling, and heat. It may be caused by indigenous flora colonizing the skin and appendages (e.g., S. aureus and S. pyogenes) or by a wide variety of exogenous bacteria. Because the exogenous bacteria involved in cellulitis occupy unique niches in nature, a thorough history (including epidemiologic data) provides important clues to etiology. When there is drainage, an open wound, or an obvious portal of entry, Gram’s stain and culture provide a definitive diagnosis. In the absence of these findings, the bacterial etiology of cellulitis is difficult to establish, and in some cases staphylococcal and streptococcal cellulitis may have similar features. Even with needle aspiration of the leading edge or a punch biopsy of the cellulitis tissue itself, cultures are positive in only 20% of cases. This observation suggests that relatively low numbers of bacteria may cause


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InternalMed_Harrison. of the leading edge or a punch biopsy of the cellulitis tissue itself, cultures are positive in only 20% of cases. This observation suggests that relatively low numbers of bacteria may cause cellulitis and that the expanding area of erythema within the skin may be a direct effect of extracellular toxins or of the soluble mediators of inflammation elicited by the host.


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InternalMed_Harrison. Bacteria may gain access to the epidermis through cracks in the skin, abrasions, cuts, burns, insect bites, surgical incisions, and IV catheters. Cellulitis caused by S. aureus spreads from a central localized infection, such as an abscess, folliculitis, or an infected foreign body (e.g., a splinter, a prosthetic device, or an IV catheter). MRSA is rapidly replacing methicillin-sensitive S. aureus (MSSA) as a cause of cellulitis in both inpatient and outpatient settings. Cellulitis caused by MSSA or MRSA is usually associated with a focal infection, such as a furuncle, a carbuncle, a surgical wound, or an abscess; the U.S. Food and Drug Administration preferentially refers to these types of infection as purulent cellulitis. In contrast, cellulitis due to S. pyogenes is a more rapidly spreading, diffuse process that is frequently associated with lymphangitis and fever and should be referred to as nonpurulent cellulitis. Recurrent streptococcal cellulitis of the lower extremities may be


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InternalMed_Harrison. diffuse process that is frequently associated with lymphangitis and fever and should be referred to as nonpurulent cellulitis. Recurrent streptococcal cellulitis of the lower extremities may be caused by organisms of group A, C, or G in association with chronic venous stasis or with saphenous venectomy for coronary artery bypass surgery. Streptococci also cause recurrent cellulitis among patients with chronic lymphedema resulting from elephantiasis, lymph node dissection, or Milroy’s disease. Recurrent staphylococcal cutaneous infections are more common among individuals who have eosinophilia and elevated serum levels of IgE (Job’s syndrome) and among nasal carriers of staphylococci. Cellulitis caused by Streptococcus agalactiae (group B Streptococcus) occurs primarily in elderly patients and those with diabetes mellitus or peripheral vascular disease. Haemophilus influenzae typically causes periorbital cellulitis in children in association with sinusitis, otitis media, or


InternalMed_Harrison

InternalMed_Harrison. patients and those with diabetes mellitus or peripheral vascular disease. Haemophilus influenzae typically causes periorbital cellulitis in children in association with sinusitis, otitis media, or epiglottitis. It is unclear whether this form of cellulitis will (like meningitis) become less common as a result of the impressive efficacy of the H. influenzae type b vaccine.


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InternalMed_Harrison. Many other bacteria also cause cellulitis. It is fortunate that these organisms occur in such characteristic settings that a good history provides useful clues to the diagnosis. Cellulitis associated with cat bites and, to a lesser degree, with dog bites is commonly caused by Pasteurella multocida, although in the latter case Staphylococcus intermedius and Capnocytophaga canimorsus also must be considered. Sites of cellulitis and abscesses associated with dog bites and human bites also contain a variety of anaerobic organisms, including Fusobacterium, Bacteroides, aerobic and anaerobic streptococci, and Eikenella corrodens. Pasteurella is notoriously resistant to dicloxacillin and nafcillin but is sensitive to all other β-lactam antimicrobial agents as well as to quinolones, tetracycline, and erythromycin. Ampicillin/clavulanate, ampicillin/sulbactam, and cefoxitin are good choices for the treatment of animal or human bite infections. Aeromonas hydrophila causes aggressive cellulitis


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InternalMed_Harrison. and erythromycin. Ampicillin/clavulanate, ampicillin/sulbactam, and cefoxitin are good choices for the treatment of animal or human bite infections. Aeromonas hydrophila causes aggressive cellulitis in tissues surrounding lacerations sustained in freshwater (lakes, rivers, and streams). This organism remains sensitive to aminoglycosides, fluoroquinolones, chloramphenicol, trimethoprim-sulfamethoxazole, and third-generation cephalosporins; it is resistant to ampicillin, however.


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InternalMed_Harrison. P. aeruginosa causes three types of soft tissue infection: ecthyma gangrenosum in neutropenic patients, hot-tub folliculitis, and cellulitis following penetrating injury. Most commonly, P. aeruginosa is introduced into the deep tissues when a person steps on a nail. Treatment includes surgical inspection and drainage, particularly if the injury also involves bone or joint capsule. Choices for empirical treatment while antimicrobial susceptibility data are awaited include an aminoglycoside, a third-generation cephalosporin (ceftazidime, cefoperazone, or cefotaxime), a semisynthetic penicillin (ticarcillin, mezlocillin, or piperacillin), or a fluoroquinolone (although drugs of the last class are not indicated for the treatment of children <13 years old).


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InternalMed_Harrison. Gram-negative bacillary cellulitis, including that due to P. aeruginosa, is most common among hospitalized, immunocompromised hosts. Cultures and sensitivity tests are critically important in this setting because of multidrug resistance (Chap. 189).


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InternalMed_Harrison. The gram-positive aerobic rod Erysipelothrix rhusiopathiae is most often associated with fish and domestic swine and causes cellulitis primarily in bone renderers and fishmongers. E. rhusiopathiae remains susceptible to most β-lactam antibiotics (including penicillin), erythromycin, clindamycin, tetracycline, and cephalosporins but is resistant to sulfonamides, chloramphenicol, and vancomycin. Its resistance to vancomycin, which is unusual among gram-positive bacteria, is of potential clinical significance since this agent is sometimes used in empirical therapy for skin infection. Fish food containing the water flea Daphnia is sometimes contaminated with M. marinum, which can cause cellulitis or granulomas on skin surfaces exposed to the water in aquariums or injured in swimming pools. Rifampin plus ethambutol has been an effective therapeutic combination in some cases, although no comprehensive studies have been undertaken. In addition, some strains of M. marinum are susceptible to


InternalMed_Harrison

InternalMed_Harrison. plus ethambutol has been an effective therapeutic combination in some cases, although no comprehensive studies have been undertaken. In addition, some strains of M. marinum are susceptible to tetracycline or to trimethoprim-sulfamethoxazole.


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InternalMed_Harrison. (Table 156-1) Necrotizing fasciitis, formerly called streptococcal gangrene, may be associated with group A Streptococcus or mixed aerobic– anaerobic bacteria or may occur as a component of gas gangrene caused by Clostridium perfringens. Strains of MRSA that produce the Panton-Valentine leukocidin (PVL) toxin have been reported to cause necrotizing fasciitis. Early diagnosis may be difficult when pain or unexplained fever is the only presenting manifestation. Swelling then develops and is followed by brawny edema and tenderness. With progression, dark-red induration of the epidermis appears, along with bullae filled with blue or purple fluid. Later the skin becomes friable and takes on a bluish, maroon, or black color. By this stage, thrombosis of blood vessels in the dermal papillae (Fig. 156-1) is extensive. Extension of infection to the level of the deep fascia causes this tissue to take on a brownish-gray appearance. Rapid spread occurs along fascial planes, through venous


InternalMed_Harrison

InternalMed_Harrison. (Fig. 156-1) is extensive. Extension of infection to the level of the deep fascia causes this tissue to take on a brownish-gray appearance. Rapid spread occurs along fascial planes, through venous channels and lymphatics. Patients in the later stages are toxic and frequently manifest shock and multiorgan failure.


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InternalMed_Harrison. Necrotizing fasciitis caused by mixed aerobic-anaerobic bacteria begins with a breach in the integrity of a mucous membrane barrier, such as the mucosa of the gastrointestinal or genitourinary tract. The portal can be a malignancy, a diverticulum, a hemorrhoid, an anal fissure, or a urethral tear. Other predisposing factors include peripheral vascular disease, diabetes mellitus, surgery, and penetrating injury to the abdomen. Leakage into the perineal area results in a syndrome called Fournier’s gangrene, characterized by massive swelling of the scrotum and penis with extension into the perineum or the abdominal wall and the legs.


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InternalMed_Harrison. Necrotizing fasciitis caused by S. pyogenes has increased in frequency and severity since 1985. There are two distinct clinical presentations: those with no portal of entry and those with a defined portal of entry. Infections in the first category often begin deep at the site of a non-penetrating minor trauma, such as a bruise or a muscle strain. Seeding of the site via transient bacteremia is likely, although most patients deny antecedent streptococcal infection. The affected patients present with only severe pain and fever. Late in the course, the classic signs of necrotizing fasciitis, such as purple (violaceous) bullae, skin sloughing, and progressive toxicity, develop. In infections of the second type, S. pyogenes may reach the deep fascia from a site of cutaneous infection or penetrating trauma. These patients have early signs of superficial skin infection with progression to necrotizing fasciitis. In either case, toxicity is severe, and renal impairment may precede the


InternalMed_Harrison

InternalMed_Harrison. penetrating trauma. These patients have early signs of superficial skin infection with progression to necrotizing fasciitis. In either case, toxicity is severe, and renal impairment may precede the development of shock. In 20–40% of cases, myositis occurs concomitantly, and, as in gas gangrene (see below), serum creatine phosphokinase levels may be markedly elevated. Necrotizing fasciitis due to mixed aerobic-anaerobic bacteria may be associated with gas in deep tissue, but gas usually is not present when the cause is S. pyogenes or MRSA. Prompt surgical exploration down to the deep fascia and muscle is essential. Necrotic tissue must be surgically removed, and Gram’s staining and culture of excised tissue are useful in establishing whether group A streptococci, mixed aerobic-anaerobic bacteria, MRSA, or Clostridium species are present (see “Treatment,” below).


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InternalMed_Harrison. (Table 156-1) Muscle involvement can occur with viral infection (e.g., influenza, dengue, or coxsackievirus B infection) or parasitic invasion (e.g., trichinellosis, cysticercosis, or toxoplasmosis). Although myalgia develops in most of these infections, severe muscle pain is the hallmark of pleurodynia (coxsackievirus B), trichinellosis, and bacterial infection. Acute rhabdomyolysis predictably occurs with clostridial and streptococcal myositis but may also be associated with influenza virus, echovirus, coxsackievirus, Epstein-Barr virus, and Legionella infections.


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InternalMed_Harrison. Pyomyositis is usually due to S. aureus, is common in tropical areas, and generally has no known portal of entry. Cases of pyomyositis caused by MRSA producing the PVL toxin have been described among children in the United States. Muscle infection begins at the exact site of blunt trauma or muscle strain. Infection remains localized, and shock does not develop unless organisms produce toxic shock syndrome toxin 1 or certain enterotoxins and the patient lacks antibodies to the toxin produced by the infecting organisms. In contrast, S. pyogenes may induce primary myositis (referred to as streptococcal necrotizing myositis) in association with severe systemic toxicity. Myonecrosis occurs concomitantly with necrotizing fasciitis in ~50% of cases. Both are part of the streptococcal toxic shock syndrome.


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InternalMed_Harrison. Gas gangrene usually follows severe penetrating injuries that result in interruption of the blood supply and introduction of soil into wounds. Such cases of traumatic gangrene are usually caused by the clostridial species C. perfringens, C. septicum, and C. histolyticum. Rarely, latent or recurrent gangrene can occur years after penetrating trauma; dormant spores that reside at the site of previous injury are most likely responsible. Spontaneous nontraumatic gangrene among patients with neutropenia, gastrointestinal malignancy, diverticulosis, or recent radiation therapy to the abdomen is caused by several clostridial species, of which C. septicum is the most commonly involved. The tolerance of this anaerobe to oxygen probably explains why it can initiate infection spontaneously in normal tissue anywhere in the body.


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InternalMed_Harrison. Gas gangrene of the uterus, especially that due to Clostridium sor-831 dellii, historically occurred as a consequence of illegal or self-induced abortion and nowadays also follows spontaneous abortion, vaginal delivery, and cesarean section. C. sordellii has also been implicated in medically induced abortion. Postpartum C. sordellii infections in young, previously healthy women present as a unique clinical picture: little or no fever, lack of a purulent discharge, refractory hypotension, extensive peripheral edema and effusions, hemoconcentration, and a markedly elevated white blood cell count. The infection is almost uniformly fatal, with death ensuing rapidly. C. sordellii and C. novyi have also been associated with cutaneous injection of black tar heroin; mortality rates are lower among the affected individuals, probably because their aggressive injection-site infections are readily apparent and diagnosis is therefore prompt.


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InternalMed_Harrison. Synergistic nonclostridial anaerobic myonecrosis, also known as necrotizing cutaneous myositis and synergistic necrotizing cellulitis, is a variant of necrotizing fasciitis caused by mixed aerobic and anaerobic bacteria with the exclusion of clostridial organisms (see “Necrotizing Fasciitis,” above).


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InternalMed_Harrison. This chapter emphasizes the physical appearance and location of lesions within the soft tissues as important diagnostic clues. Other crucial considerations in narrowing the differential diagnosis are the temporal progression of the lesions as well as the patient’s travel history, animal exposure or bite history, age, underlying disease status, and lifestyle. However, even the astute clinician may find it challenging to diagnose all infections of the soft tissues by history and inspection alone. Soft tissue radiography, CT (Fig. 156-2), and MRI may be useful in determining the depth of infection and should be performed when the patient has rapidly progressing lesions or evidence of a systemic inflammatory response syndrome. These tests are particularly valuable for defining a localized abscess or detecting gas in tissue. Unfortunately, they may reveal only soft tissue swelling and thus are not specific for fulminant infections such as necrotizing fasciitis or myonecrosis caused by


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InternalMed_Harrison. abscess or detecting gas in tissue. Unfortunately, they may reveal only soft tissue swelling and thus are not specific for fulminant infections such as necrotizing fasciitis or myonecrosis caused by group A Streptococcus (Fig. 156-2), where gas is not found in lesions.


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InternalMed_Harrison. Aspiration of the leading edge or punch biopsy with frozen section may be helpful if the results of imaging tests are positive, but false-negative results occur in ~80% of cases. There is some evidence that aspiration alone may be superior to injection and aspiration with normal saline. Frozen sections are especially useful in distinguishing SSSS from TEN and are quite valuable in cases of necrotizing fasciitis. Open surgical inspection, with debridement as indicated, is clearly the best way to determine the extent and severity of infection and to obtain material for Gram’s staining and culture. Such an aggressive approach is important and may be lifesaving if undertaken early in the course of fulminant infections where there is evidence of systemic toxicity. FIGURE 156-2 CT showing edema and inflammation of the left chest wall in a patient with necrotizing fasciitis and myonecrosis caused by group A Streptococcus. Infections of the Skin, Muscles, and Soft Tissues


InternalMed_Harrison

InternalMed_Harrison. Infections of the Skin, Muscles, and Soft Tissues TREATMEnT InfecTIons of The skIn, muscles, And sofT TIssues A full description of the treatment of all the clinical entities described herein is beyond the scope of this chapter. As a guide to the clinician in selecting appropriate treatment, the antimicrobial agents useful in the most common and the most fulminant cutaneous infections are listed in Table 156-2.


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InternalMed_Harrison. Furuncles, carbuncles, and abscesses caused by MRSA and MSSA are common, and their treatment depends upon the size of the lesion. Furuncles <2.5 cm in diameter are usually treated with moist heat. Those that are larger (4.5 cm of erythema and induration) require surgical drainage, and the occurrence of these larger lesions in association with fever, chills, or leukocytosis requires both drainage and antibiotic treatment. A study in children demonstrated that surgical drainage of abscesses (mean diameter, 3.8 cm) was as effective when used alone as when combined with trimethoprimsulfamethoxazole treatment. However, the rate of recurrence of new lesions was lower in the group undergoing both drainage and antibiotic treatment.


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InternalMed_Harrison. Early and aggressive surgical exploration is essential in cases of suspected necrotizing fasciitis, myositis, or gangrene in order to (1) visualize the deep structures, (2) remove necrotic tissue, (3) reduce compartment pressure, and (4) obtain suitable material for Gram’s staining and for aerobic and anaerobic cultures. Appropriate empirical antibiotic treatment for mixed aerobic–anaerobic infections could consist of ampicillin/sulbactam, cefoxitin, or the following combination: (1) clindamycin (600–900 mg IV every 8 h) or metronidazole (500 mg every 6 h) plus (2) ampicillin or ampicillin/sulbactam (1.5–3 g IV every 6 h) plus (3) gentamicin (1–1.5 mg/kg every 8 h). Group A streptococcal and clostridial infection of the fascia and/or muscle carries a mortality rate of 20–50% with penicillin treatment. In experimental models of streptococcal and clostridial necrotizing fasciitis/myositis, clindamycin has exhibited markedly superior efficacy, but no comparative clinical trials have been


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InternalMed_Harrison. treatment. In experimental models of streptococcal and clostridial necrotizing fasciitis/myositis, clindamycin has exhibited markedly superior efficacy, but no comparative clinical trials have been performed. A retrospective study of children with invasive group A streptococcal


InternalMed_Harrison

InternalMed_Harrison. See Also Diagnosis/Condition Primary Treatment Alternative Treatment Chap(s).


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InternalMed_Harrison. aPasteurella multocida, a species commonly associated with both dog and cat bites, is resistant to cephalexin, dicloxacillin, clindamycin, and erythromycin. Eikenella corrodens, a bacterium commonly associated with human bites, is resistant to clindamycin, penicillinase-resistant penicillins, and metronidazole but is sensitive to trimethoprim-sulfamethoxazole and fluoroquinolones. bThe frequency of erythromycin resistance in group A Streptococcus is currently ~5% in the United States but has reached 70–100% in some other countries. Most, but not all, erythromycin-resistant group A streptococci are susceptible to clindamycin. Approximately 90% of Staphylococcus aureus strains are sensitive to clindamycin, but resistance—both intrinsic and inducible—is increasing. cSevere hospital-acquired S. aureus infections or community-acquired S. aureus infections that are not responding to the β-lactam antibiotics recommended in this table may be caused by methicillin-resistant strains, requiring


InternalMed_Harrison

InternalMed_Harrison. S. aureus infections or community-acquired S. aureus infections that are not responding to the β-lactam antibiotics recommended in this table may be caused by methicillin-resistant strains, requiring a switch to vancomycin, daptomycin, or linezolid. dSome strains of methicillin-resistant S. aureus (MRSA) remain sensitive to tetracycline and trimethoprim-sulfamethoxazole. Daptomycin (4 mg/kg IV q24h) or tigecycline (100-mg loading dose followed by 50 mg IV q12h) is an alternative treatment for MRSA.


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InternalMed_Harrison. infection demonstrated higher survival rates with clindamycin treatment than with β-lactam antibiotic therapy. Hyperbaric oxygen treatment also may be useful in gas gangrene due to clostridial species. Antibiotic treatment should be continued until all signs of systemic toxicity have resolved, all devitalized tissue has been removed, and granulation tissue has developed (Chaps. 173, 179, and 201). In summary, infections of the skin and soft tissues are diverse in presentation and severity and offer a great challenge to the clinician. This chapter provides an approach to diagnosis and understanding of the pathophysiologic mechanisms involved in these infections. More in-depth information is found in chapters on Lawrence C. Madoff


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InternalMed_Harrison. Lawrence C. Madoff Although Staphylococcus aureus, Neisseria gonorrhoeae, and other bacteria are the most common causes of infectious arthritis, various mycobacteria, spirochetes, fungi, and viruses also infect joints (Table 157-1). Since acute bacterial infection can destroy articular cartilage rapidly, all inflamed joints must be evaluated without delay to exclude noninfectious processes and determine appropriate antimicrobial therapy and drainage procedures. For more detailed information on infectious arthritis caused by specific organisms, the reader is referred to the chapters on those organisms.


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InternalMed_Harrison. Acute bacterial infection typically involves a single joint or a few joints. Subacute or chronic monarthritis or oligoarthritis suggests mycobacterial or fungal infection; episodic inflammation is seen in syphilis, Lyme disease, and the reactive arthritis that follows enteric infections and chlamydial urethritis. Acute polyarticular inflammation occurs as an immunologic reaction during the course of endocarditis, rheumatic fever, disseminated neisserial infection, and acute hepatitis B. Bacteria and viruses occasionally infect multiple joints, the former most commonly in persons with rheumatoid arthritis. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. Aspiration of synovial fluid—an essential element in the evaluation of potentially infected joints—can be performed without difficulty in most cases by the insertion of a large-bore needle into the site of maximal fluctuance or tenderness or by the route of easiest access. Ultrasonography or fluoroscopy may be used to guide aspiration of difficult-to-localize effusions of the hip and, occasionally, the shoulder and other joints. Normal synovial fluid contains <180 cells (predominantly mononuclear cells) per microliter. Synovial cell counts averaging 100,000/μL (range, 25,000–250,000/μL), with >90% neutrophils, are characteristic of acute bacterial infections. Crystal-induced, rheumatoid, and other noninfectious inflammatory arthritides usually are associated with <30,000–50,000 cells/μL; cell counts of 10,000–30,000/μL, with 50–70% neutrophils and the remainder lymphocytes, are common in mycobacterial and fungal infections. Definitive diagnosis of an infectious process relies on


InternalMed_Harrison

InternalMed_Harrison. cell counts of 10,000–30,000/μL, with 50–70% neutrophils and the remainder lymphocytes, are common in mycobacterial and fungal infections. Definitive diagnosis of an infectious process relies on identification of the pathogen in stained smears of synovial fluid, isolation of the pathogen from cultures of synovial fluid and blood, or detection of microbial nucleic acids and proteins by nucleic acid amplification (NAA)–based assays and immunologic techniques.


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InternalMed_Harrison. Bacteria enter the joint from the bloodstream; from a contiguous site of infection in bone or soft tissue; or by direct inoculation during surgery, injection, animal or human bite, or trauma. In hematogenous infection, bacteria escape from synovial capillaries, which have no limiting basement membrane, and within hours provoke neutrophilic infiltration of the synovium. Neutrophils and bacteria enter the joint space; later, bacteria adhere to articular cartilage. Degradation of cartilage begins within 48 h as a result of increased intraarticular pressure, release of proteases and cytokines from chondrocytes and synovial macrophages, and invasion of the cartilage by bacteria and inflammatory cells. Histologic studies reveal bacteria lining the synovium and 834 cartilage as well as abscesses extending into the synovium, cartilage, and—in severe cases—subchondral bone. Synovial proliferation results in the formation of a pannus over the cartilage, and thrombosis of inflamed synovial


InternalMed_Harrison

InternalMed_Harrison. extending into the synovium, cartilage, and—in severe cases—subchondral bone. Synovial proliferation results in the formation of a pannus over the cartilage, and thrombosis of inflamed synovial vessels develops. Bacterial factors that appear important in the pathogenesis of infective arthritis include various surface-associated adhesins in S. aureus that permit adherence to cartilage and endotoxins that promote chondrocyte-mediated breakdown of cartilage.


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InternalMed_Harrison. The hematogenous route of infection is the most common route in all age groups, and nearly every bacterial pathogen is capable of causing septic arthritis. In infants, group B streptococci, gram-negative enteric bacilli, and S. aureus are the most common pathogens. Since the advent of the Haemophilus influenzae vaccine, the predominant causes among children <5 years of age have been S. aureus, Streptococcus pyogenes (group A Streptococcus), and (in some centers) Kingella kingae. Among young adults and adolescents, N. gonorrhoeae is the most commonly implicated organism. S. aureus accounts for most nongonococcal isolates in adults of all ages; gram-negative bacilli, pneumococci, and β-hemolytic streptococci—particularly groups A and B but also groups C, G, and F—are involved in up to one-third of cases in older adults, especially those with underlying comorbid illnesses.


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InternalMed_Harrison. Infections after surgical procedures or penetrating injuries are due most often to S. aureus and occasionally to other gram-positive bacteria or gram-negative bacilli. Infections with coagulase-negative staphylococci are unusual except after the implantation of prosthetic joints or arthroscopy. Anaerobic organisms, often in association with aerobic or facultative bacteria, are found after human bites and when decubitus ulcers or intraabdominal abscesses spread into adjacent joints. Polymicrobial infections complicate traumatic injuries with extensive contamination. Bites and scratches from cats and other animals may introduce Pasteurella multocida or Bartonella henselae into joints either directly or hematogenously, and bites from humans may introduce Eikenella corrodens or other components of the oral flora. Penetration of a sharp object through a shoe is associated with Pseudomonas aeruginosa arthritis in the foot.


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InternalMed_Harrison. NONGONOCOCCAL BACTERIAL ARTHRITIS Epidemiology Although hematogenous infections with virulent organisms such as S. aureus, H. influenzae, and pyogenic streptococci occur in healthy persons, there is an underlying host predisposition in many cases of septic arthritis. Patients with rheumatoid arthritis have the highest incidence of infective arthritis (most often secondary to S. aureus) because of chronically inflamed joints; glucocorticoid therapy; and frequent breakdown of rheumatoid nodules, vasculitic ulcers, and skin overlying deformed joints. Diabetes mellitus, glucocorticoid therapy, hemodialysis, and malignancy all carry an increased risk of infection with