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URINARY TRACT INFECTION AND PROSTATITIS
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Enterococci are well-known causes of nosocomial UTI—the most common infection caused by these organisms (Chap. 33). Enterococcal UTIs are usually associated with indwelling catheters, instrumentation, or anatomic abnormalities of the genitourinary tract, and it is often challenging to differentiate between true infection and colonization (particularly in patients with chronic indwelling catheters). The presence of leukocytes in the urine in conjunction with systemic manifestations (e.g., fever) or local signs and symptoms of infection with no other explanation and a positive urine culture (≥105 colony-forming units [CFU]/mL) suggests the diagnosis. Moreover, enterococcal UTIs often occur in critically ill patients whose comorbidities may obscure the diagnosis. In many cases, removal of the indwelling catheter may suffice to eradicate the organism without specific antimicrobial therapy. In rare circumstances, UTIs caused by enterococci may run a complicated course, with the development of pyelonephritis and perinephric abscesses that may be a portal of entry for bloodstream infections (see below). Enterococci are also known causes of chronic prostatitis, particularly in patients whose urinary tract has been manipulated surgically or endoscopically. These infections can be difficult to treat because the agents most potent against enterococci (i.e., aminopenicillins and glycopeptides) penetrate prostatic tissue poorly. Chronic prostatic infection can be a source of recurrent enterococcal bacteremia.
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BACTEREMIA AND ENDOCARDITIS
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Bacteremia without endocarditis is one of the most common presentations of enterococcal disease. Intravascular catheters and other devices are commonly associated with these bacteremic episodes (Chap. 17). Other well-known sources of enterococcal bacteremia include the gastrointestinal and hepatobiliary tracts; pelvic and intraabdominal foci; and, less frequently, wound infections, UTIs, and bone infections. In the United States, enterococci are ranked second (after coagulase-negative staphylococci) as etiologic agents of central line–associated bacteremia. Patients with enterococcal bacteremia usually have comorbidities and have been in the hospital for prolonged periods; they commonly have received several courses of antibiotics. Several studies indicate that the isolation of E. faecium from the blood may lead to worse outcomes and higher mortality rates than when other enterococcal species are isolated; this finding may be related to the higher prevalence of vancomycin and ampicillin resistance in E. faecium than in other enterococcal species, with the consequent reduction of therapeutic options. In many cases (usually when the gastrointestinal tract is the source), enterococcal bacteremia may be polymicrobial, with gram-negative organisms isolated at the same time. In addition, several cases have now been documented in which enterococcal bacteremia was associated with Strongyloides stercoralis hyperinfection syndrome in immunocompromised patients.
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Enterococci are important causes of community- and health care–associated endocarditis, ranking second after staphylococci in the latter infections. The presumed initial source of bacteremia leading to endocarditis is the gastrointestinal or genitourinary tract—e.g., in patients who have malignant and inflammatory conditions of the gut or have undergone procedures in which these tracts are manipulated. The affected patients tend to be male and elderly and to have other debilitating diseases and heart conditions. Both prosthetic and native valves can be involved; mitral and aortic valves are affected most often. Community-associated endocarditis (usually caused by E. faecalis) also occurs in patients with no apparent risk factors or cardiac abnormalities. Endocarditis in women of childbearing age has been well described. The typical presentation of enterococcal endocarditis is a subacute course of fever, weight loss, malaise, and cardiac murmur; typical stigmata of endocarditis (e.g., petechiae, Osler’s nodes, Roth’s spots) are found in only a minority of patients. Atypical manifestations include arthralgias and manifestations of metastatic disease (splenic abscesses, hiccups, pain in the left flank, pleural effusion, and spondylodiscitis). Embolic complications are variable and can affect the brain. Heart failure is a common complication of enterococcal endocarditis, and valve replacement may be critical in curing this infection, particularly when multidrug-resistant organisms or major complications are involved. The duration of therapy is usually 4–6 weeks, with more prolonged courses suggested for multidrug-resistant isolates in the absence of valvular replacement.
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Enterococcal meningitis is an uncommon disease (accounting for only ~4% of meningitis cases) that is usually associated with neurosurgical interventions and conditions such as shunts, central nervous system (CNS) trauma, and cerebrospinal fluid (CSF) leakage. In some instances—usually in patients with a debilitating condition, such as cardiovascular or congenital heart disease, chronic renal failure, malignancy, receipt of immunosuppressive therapy, or HIV/AIDS—presumed hematogenous seeding of the meninges is seen in infections such as endocarditis or bacteremia. Fever and changes in mental status are common, whereas overt meningeal signs are less so. CSF findings are consistent with bacterial infection—i.e., pleocytosis with a predominance of polymorphonuclear leukocytes (average, ~500/μL), an elevated serum protein level (usually >100 mg/dL), and a decreased glucose concentration (average, 28 mg/dL). Gram’s staining yields a positive result in about half of cases, with a high rate of organism recovery from CSF cultures; the most common species isolated are E. faecalis and E. faecium. Complications include hydrocephalus, brain abscesses, and stroke. As mentioned before for bacteremia, an association with Strongyloides hyperinfection has also been documented.
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INTRAABDOMINAL, PELVIC, AND SOFT TISSUE INFECTIONS
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As mentioned earlier, enterococci are part of the commensal flora of the gastrointestinal tract and can produce spontaneous peritonitis in cirrhotic individuals and in patients undergoing chronic ambulatory peritoneal dialysis (Chap. 29). These organisms are commonly found (usually along with other bacteria, including enteric gram-negative species and anaerobes) in clinical samples from intraabdominal and pelvic collections. The presence of enterococci in intraabdominal infections is sometimes considered to be of little clinical relevance. Several studies have shown that the role of enterococci in intraabdominal infections originating in the community and involving previously healthy patients is minor, because surgery and broad-spectrum antimicrobial drugs that do not target enterococci are often sufficient to treat these infections successfully. In the last few decades, however, these organisms have become prominent as a cause of intraabdominal infections in hospitalized patients because of the emergence and spread of vancomycin resistance among enterococci and the increase in rates of nosocomial infections due to multidrug-resistant E. faecium isolates. In fact, several studies have now documented treatment failures due to enterococci, with consequently increased rates of postoperative complications and death among patients with intraabdominal infections. Thus, anti-enterococcal therapy is recommended for nosocomial peritonitis in immunocompromised and severely ill patients who have had a prolonged hospital stay, have undergone multiple procedures, have persistent abdominal sepsis and collections, or have risk factors for the development of endocarditis (e.g., prosthetic or damaged heart valves). Conversely, specific treatment for enterococci in the first episode of intraabdominal infections originating in the community and affecting previously healthy patients with no important cardiac risk factors for endocarditis does not appear to be beneficial.
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Enterococci are commonly isolated from soft tissue infections (Chap. 26), particularly those involving surgical wounds (Chap. 17). In fact, these organisms rank third as agents of nosocomial surgical-site infections, with E. faecalis the most frequently isolated species. The clinical relevance of enterococci in some of these infections—as in intraabdominal infections—is a matter of debate; differentiating between colonization and true infection is sometimes challenging, although in some cases enterococci have been recovered from lung, liver, and skin abscesses. Diabetic foot and decubitus ulcers are often colonized with enterococci and may be the portal of entry for bone infections.
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Enterococci are well-known causes of neonatal infections, including sepsis (mostly late-onset), bacteremia, meningitis, pneumonia, and UTI. Outbreaks of enterococcal sepsis in neonatal units have been well documented. Risk factors for enterococcal disease in newborns include prematurity, low birth weight, indwelling devices, and abdominal surgery. Enterococci have also been described as etiologic agents of bone and joint infections, including vertebral osteomyelitis, usually in patients with underlying conditions such as diabetes or endocarditis. Similarly, enterococci have been isolated from bone infections in patients who have undergone arthroplasty or reconstruction of fractures with the placement of hardware. Because enterococci can produce a biofilm that is likely to alter the efficacy of otherwise active anti-enterococcal agents, treatment of infections that involve foreign material is challenging, and removal of the hardware may be necessary to eradicate the infection. Rare cases of enterococcal pneumonia, lung abscess, and spontaneous empyema have been described.
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TREATMENT Enterococcal Infections GENERAL PRINCIPLES
Enterococci are intrinsically resistant and/or tolerant to several antimicrobial agents (with tolerance defined as lack of killing by drug concentrations 32 times higher than the minimal inhibitory concentration [MIC]). Monotherapy for endocarditis with a β-lactam antibiotic (to which many enterococci are tolerant) has produced disappointing results, with low cure rates at the end of therapy. However, the addition of an aminoglycoside to a cell wall–active agent (a β-lactam or a glycopeptide) increases cure rates and eradicates the organisms; moreover, this combination is synergistic and bactericidal in vitro. Therefore, for many decades, combination therapy with a cell wall–active agent and an aminoglycoside has been the standard of care for endovascular infections caused by enterococci. This synergistic effect can be explained, at least in part, by the increased penetration of the aminoglycoside into the bacterial cell, presumably as a result of cell wall alterations produced by the β-lactam (or glycopeptide). Nonetheless, attaining synergistic bactericidal activity in the treatment of severe enterococcal infections has become increasingly difficult because of the development of resistance to virtually all antibiotics available for this purpose.
The treatment of E. faecalis differs substantially from that of E. faecium (Tables 45-1 and 45-2), mainly because of differences in resistance profiles (see below). For example, resistance to ampicillin and vancomycin is rare in E. faecalis, whereas these antibiotics are only infrequently useful against current isolates of E. faecium. Moreover, as a consequence of the challenges and therapeutic limitations posed by the emergence of drug resistance in enterococci, valve replacement may need to be considered in the treatment of endocarditis caused by multidrug-resistant enterococci. Less severe infections are often related to indwelling intravascular catheters; removal of the catheter increases the likelihood of enterococcal eradication by a subsequent short course of appropriate antimicrobial therapy.
CHOICE OF ANTIMICROBIAL AGENTS Among the β-lactams, the most active are the aminopenicillins (ampicillin, amoxicillin) and ureidopenicillins (i.e., piperacillin); next most active are penicillin G and imipenem. For E. faecium, a combination of high-dose ampicillin (up to 30 g/d) plus an aminoglycoside has been suggested—even for ampicillin-resistant strains if the MIC is ≤64 μg/mL—because a plasma ampicillin concentration of >100 μg/mL can be achieved at high doses. The only two aminoglycosides recommended for synergistic therapy in severe enterococcal infections are gentamicin and streptomycin. The use of amikacin is discouraged, tobramycin should never be used against E. faecium, and aminoglycoside monotherapy is not effective. Vancomycin is an alternative to β-lactam drugs for the treatment of E. faecalis infections but is less useful against E. faecium because resistance is common.
As mentioned above, use of the aminoglycoside–ampicillin combination for E. faecalis infections has become increasingly problematic because of toxicity in critically ill patients and increased rates of high-level resistance to aminoglycosides. A recent observational, nonrandomized, comparative study encompassing a multicenter cohort was conducted in 17 Spanish hospitals and 1 Italian hospital; this study found that the combination of ampicillin and ceftriaxone is as effective as ampicillin plus gentamicin in the treatment of E. faecalis endocarditis, with less risk of toxicity. Therefore, this regimen should be considered in patients at risk for aminoglycoside toxicity and could be considered for all patients.
Linezolid and quinupristin/dalfopristin (Q/D) are two agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of some VRE infections (Table 45–2). Linezolid is not bactericidal, and its use in severe endovascular infections has produced mixed results; therefore, it is recommended only as an alternative to other agents. In addition, linezolid may cause significant toxicities (thrombocytopenia, peripheral neuropathy, and optic neuritis) when used in regimens given for >2 weeks. Nonetheless, linezolid may play a role in the treatment of enterococcal meningitis and other CNS infections, although clinical data are limited. Q/D is not active against most E. faecalis isolates, and its in vivo efficacy against E. faecium may often be compromised by resistance (see below). Adverse reactions to Q/D are common, including pain and inflammation at the infusion site and severe arthralgias and myalgias leading to discontinuation of treatment. Thus, Q/D should be used with caution and probably combined with other agents (Table 45–2).
The lipopeptide daptomycin is a bactericidal antibiotic with potent in vitro activity against all enterococci. Although daptomycin is not approved by the FDA for the treatment of VRE or E. faecium infections, it has been used alone (at high dosage) or in combination with other agents (ampicillin, ceftaroline, and tigecycline) with apparent success against multidrug-resistant enterococcal infections (Tables 45–1 and 45–2). The main adverse reactions to daptomycin are elevated creatine phosphokinase levels and eosinophilic pneumonitis (rare). Daptomycin is not useful against pulmonary infections because the pulmonary surfactant inhibits its antibacterial activity. Although the glycylcycline drug tigecycline is active in vitro against all enterococci (regardless of the isolates’ vancomycin susceptibility), its use as monotherapy for endovascular or severe enterococcal infections is not recommended because of low attainable blood levels. Telavancin, a lipoglycopeptide approved by the FDA for the treatment of skin and soft tissue infections as well as hospital-associated pneumonia, is active against vancomycin-susceptible enterococci but not VRE. Oritavancin, a compound of the same class that is active against VRE, has recently been approved by the FDA for the treatment of bacterial skin and soft tissue infections and may offer promise for the treatment of VRE in the future.
ANTIMICROBIAL RESISTANCE As mentioned above, resistance to β-lactam agents continues to be observed only infrequently in E. faecalis, although rare outbreaks caused by β-lactamase-producing isolates have occurred in the United States and Argentina. However, ampicillin resistance is common in E. faecium. The mechanism of this resistance is related to a penicillin-binding protein (PBP) designated PBP5, which is the target of β-lactam antibiotics. PBP5 exhibits lower affinity for ampicillin and can synthesize cell wall in the presence of this antibiotic, even when other PBPs are inhibited. Two common mechanisms of high-level ampicillin resistance (MIC, >64 μg/mL) in clinical strains are (1) mutations in the PBP5-encoding gene that further decrease the protein’s affinity for ampicillin and (2) hyperproduction of PBP5. These factors preclude the use of all β-lactam agents in the treatment of E. faecium infections.
Vancomycin is a glycopeptide antibiotic that inhibits cell wall peptidoglycan synthesis in susceptible enterococci and has been widely used against enterococcal infections in clinical practice when the utility of β-lactams is limited by resistance, allergy, or adverse reactions. This effect is mediated by binding of the antibiotic to peptidoglycan precursors (UDP-MurNAc-pentapeptides) upon their exit from the bacterial cell cytoplasm. The interaction of vancomycin with the peptidoglycan is specific and involves the last two d-alanine residues of the precursor. The first isolates of VRE were documented in 1986, and vancomycin resistance (particularly in E. faecium) has since increased considerably around the world. The mechanism involves the replacement of the last d-alanine residue of peptidoglycan precursors with d-lactate or d-serine, with consequent high- and low-level resistance, respectively. There is significant heterogeneity among isolates, but either substitution substantially decreases the affinity of vancomycin for the peptidoglycan; with the d-lactate substitution, the MIC is increased by up to 1000-fold. Vancomycin-resistant organisms also produce enzymes that destroy the d-alanine-d-alanine ending precursors, ensuring that additional binding sites for vancomycin are not available.
High-level resistance to aminoglycosides (of which gentamicin and streptomycin are the only two tested by clinical laboratories) abolishes the synergism observed between cell wall–active agents and the aminoglycoside. This important phenotype is routinely sought in isolates from serious infections (Tables 45–1 and 45–2). The laboratory reports high-level resistance as gentamicin and streptomycin MICs of >500 μg/mL and >2000 μg/mL, respectively (agar dilution method) or as “SYN-R” (resistance to synergism). Genes encoding aminoglycoside-modifying enzymes are usually the cause of high-level resistance to these compounds and are widely disseminated among enterococci, decreasing the options for the treatment of severe enterococcal infections. The aforementioned enterococcal resistance to newer antibiotics such as linezolid (usually due to mutations in the 23S rRNA genes and the presence of an rRNA methylase), Q/D, daptomycin (involving major changes in cell membrane homeostasis), and tigecycline further reduces therapeutic alternatives.
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