Enterococcus

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Chapter 179 Enterococcus

David B. Haslam

Enterococcus has long been recognized as a pathogen in select populations and over the past 2 decades has become a common and particularly troublesome cause of hospital-acquired infection. Enterococci were formerly classified with Streptococcus bovis and Streptococcus equinus as the Lancefield group D streptococci and are now placed in a separate genus. These organisms are notorious for their frequent resistance to antibiotics.

Etiology

Enterococci are gram-positive, catalase-negative facultative anaerobes that grow in pairs or short chains. Most are nonhemolytic (also called γ-hemolytic) on sheep blood agar, although some isolates have α- or β-hemolytic activity. Enterococci are distinguished from most Lancefield groupable streptococci by their ability to grow in bile and hydrolyze esculin. Enterococci are able to grow in 6.5% NaCl and hydrolyze L-pyrrolidonyl-β-naphthylamide (PYR), features used by clinical laboratories to distinguish them from group D streptococcus. Identification at the species level is enabled by differing patterns of carbohydrate fermentation.

Epidemiology

Enterococci are normal inhabitants of the gastrointestinal tract of humans and animals and are also often found in oral secretions and dental plaque, the upper respiratory tract, the skin, and the vagina. Enterococcus faecalis is commonly acquired in the 1st week of life and is nearly ubiquitous by adulthood. Enterococcus faecium colonization is less common, although approximately 25% of adults harbor this organism.

E. faecalis accounts for approximately 80% of enterococcal infections, and E. faecium is responsible for almost all of the remaining enterococcal infections. Only rarely are other species such as Enterococcus gallinarium and Enterococcus cassiliflavus associated with infection. Typically, the patient’s indigenous flora is presumed to be the source of enterococcal infection. Direct spread from person to person or from contaminated medical devices may occur, particularly within newborn nurseries and intensive care units. Nosocomial spread is an important source of hospital outbreaks.

Pathogenesis

Enterococci are not aggressively invasive organisms, usually causing disease only in children with damaged mucosal surfaces or impaired immune response. Their dramatic emergence as a cause of nosocomial infection is predominantly due to their resistance to antibiotics commonly used in the hospital setting. Aside from antibiotic resistance genes, few classic virulence factors have been described among enterococci. Adhesion-promoting factors, such as the surface protein Eps, likely account for the propensity of these organisms to cause endocarditis and urinary tract infections (UTIs). The ability to form biofilms likely facilitates the colonization of urinary and vascular catheters. Many isolates also produce a cytolysin that has a broad range of host cells and is released at high bacterial density in a process called quorum sensing. The cytolysin contributes to virulence in experimental models of endocarditis, peritonitis, and endophthalmitis. Other proposed virulence factors include aggregation substance, gelatinase, and extracellular superoxide.

Antimicrobial Resistance

Enterococci are highly resistant to cephalosporins and semisynthetic penicillins such as nafcillin, oxacillin, and methicillin. They are moderately resistant to extended-spectrum penicillins such as ticarcillin and carbenicillin. Ampicillin, imipenem, and penicillin are the most active β-lactams against these organisms. Some strains of E. faecalis and E. faecium demonstrate resistance to ampicillin and penicillin due to mutations in penicillin binding protein 5. In addition, occasional strains of E. faecalis produce a plasmid-encoded β-lactamase similar to that found in Staphylococcus. These isolates are completely resistant to penicillins, necessitating the combination of a penicillin plus a β-lactamase inhibitor or the use of imipenem or vancomycin. Any active drug may be insufficient if used alone for serious infections wherein high bactericidal activity is desired (Tables 179-1 and 179-2).

Table 179-1 INTRINSIC RESISTANCE MECHANISMS AMONG ENTEROCOCCUS

ANTIMICROBIAL	MECHANISM
Ampicillin, penicillin	Altered binding protein
Aminoglycoside (low level)	Decreased permeability, altered ribosomal binding
Clindamycin	Altered ribosomal binding
Erythromycin	Altered ribosomal binding
Tetracyclines	Efflux pump
Trimethoprim-sulfamethoxazole	Utilize exogenous folate

Table 179-2 ACQUIRED RESISTANCE MECHANISMS AMONG ENTEROCOCCUS

ANTIMICROBIAL	MECHANISM
Ampicillin, penicillin (high level)	Mutation of PBP-5
Aminoglycoside (high level)	Enzyme modification
Quinolones	DNA gyrase mutation
Chloramphenicol	Efflux pump
Glycopeptide	Altered cell wall binding
Quinupristin/dalfopristin	Ribosomal modification, efflux pump
Linezolid	Point mutation
Daptomycin	Unknown

All enterococci have intrinsic low-level resistance to aminoglycosides because these antibiotics are poorly transported across the Enterococcus cell wall. Concomitant use of a cell wall–active agent, such as a β-lactam or glycopeptide antibiotic, improves the permeability of the cell wall for the aminoglycosides, resulting in synergistic killing. However, some isolates demonstrate high-level resistance, defined as mean inhibitory concentration (MIC >2,000 µg/mL), due to modification or inactivation of aminoglycoside agents. Strains demonstrating high-level resistance and even some strains with moderate resistance are not affected synergistically by aminoglycosides and cell wall–active antibiotics.

Resistance to almost all other antibiotic classes, including tetracyclines, macrolides, and chloramphenicol, has been described among the enterococci, necessitating individual susceptibility testing for these antibiotics when their use is considered. Despite apparent susceptibility in vitro, trimethoprim-sulfamethoxazole has poor activity in vivo and should not be used as the primary agent against enterococcal infections.

Vancomycin has traditionally been effective against Enterococcus isolates, but resistance to vancomycin, defined as MIC >32 µg/mL, and other glycopeptides, including teicoplanin, is increasingly common. The emergence of vancomycin-resistant Enterococcus (VRE) has become a major challenge in the care of hospitalized patients. In particular, mortality in patients with VRE bloodstream infections is considerable, and treatment is complicated by frequent resistance of VRE to most other antibiotic classes. Both high- and moderate-level resistance are described in E. faecalis and E. faecium. High-level resistance (MIC ≥64 µg/mL) can be transferred by way of conjugation and is usually due to plasmid-mediated transfer of the vanA gene. High-level resistance is most common among E. faecium but is observed increasingly among E. faecalis isolates. Moderate-level resistance (MIC 8-256 µg/mL) results from a chromosomal homologue of vanA known as vanB. Isolates that harbor the vanB gene are only moderately resistant to vancomycin and initially demonstrate susceptibility to teicoplanin, although resistance can emerge during therapy.

Clinical Manifestations

Enterococcus infections traditionally occurred predominantly in newborn infants but infection in older children is increasingly common. Most Enterococcus infections occur in patients with breakdown of normal physical barriers such as the gastrointestinal tract, skin, or urinary tract. Other risk factors for Enterococcus infection include prolonged hospitalization, indwelling vascular catheters, prior use of antibiotics, and compromised immunity.

Neonatal Infections

Enterococcus accounts for up to 15% of all neonatal bacteremia and septicemia. Like group B streptococcus infections, Enterococcus infections are seen in 2 distinct settings in neonatal patients. Early-onset infection (<7 days of age) may mimic early-onset group B streptococcus septicemia but tends to be milder. Early-onset Enterococcus sepsis most often occurs in full-term infants who are otherwise healthy. Late-onset infection (≥7 days of age) is associated with risk factors such as extreme prematurity, presence of an intravascular catheter, and necrotizing enterocolitis, or follows an intra-abdominal surgical procedure. Symptoms in late-onset disease are more severe than those in early-onset disease and include apnea, bradycardia, and deteriorating respiratory function. Focal infections such as scalp abscess and catheter infection are commonly associated. Mortality rates range from 6% in early-onset septicemia to 15% in late-onset infections associated with necrotizing enterocolitis.

Enterococci are an occasional cause of neonatal meningitis usually as a complication of septicemia. Alternatively, the organism may gain access to the central nervous system by way of contiguous spread, such as through a neural tube defect or in association with an intraventricular shunt. Enterococcal meningitis can be associated with minimal abnormality of cerebrospinal fluid laboratory tests.

Infections in Older Children

Enterococcus rarely causes UTIs in healthy children but accounts for approximately 15% of cases of nosocomially acquired UTIs, both in children and adults. Presence of an indwelling urinary catheter is the major risk factor for nosocomial UTIs. Enterococcus is frequently isolated in intra-abdominal infections following intestinal perforation or surgery. The significance of enterococci in polymicrobial infections has been questioned, although reported mortality rates are higher when intra-abdominal infections include enterococci. Enterococcus is increasingly common as a cause of nosocomial bacteremia; these organisms account for approximately 10% of nosocomial bloodstream infection in children, ranking second only to coagulase-negative staphylococci. Predisposing factors for enterococcal bacteremia and endocarditis include an indwelling central venous catheter, gastrointestinal surgery, immunodeficiency, and cardiovascular abnormalities.

Treatment

Treatment of invasive Enterococcus infections must recognize that these organisms are resistant to antimicrobial agents frequently used as empirical therapy. In particular, cephalosporins should not be relied on in situations where Enterococcus is known or suspected to be involved. In general, in the immunocompetent host, minor localized infections due to susceptible Enterococcus can be treated with ampicillin alone. Antibiotics containing β-lactamase inhibitors (clavulanate or sulbactam) provide advantage only for the few organisms whose resistance is due to production of β-lactamase. In uncomplicated UTIs, nitrofurantoin is efficacious when the organism is known to be sensitive to this antibiotic.

Invasive infections such as sepsis, meningitis, and endocarditis are usually treated with a combination of penicillin or ampicillin and an aminoglycoside when the isolate is susceptible. Vancomycin can be substituted for the penicillins in allergic patients but should be used with an aminoglycoside, because vancomycin alone is not bactericidal. Endocarditis from strains possessing high-level aminoglycoside resistance may relapse even after prolonged therapy. High-dose or continuous infusion penicillin has been proposed for treatment of these infections in adults, but ultimately valve replacement may be necessary. In patients with catheter-associated enterococcal bacteremia, the catheter should be removed promptly in most cases, although salvage of infected lines has occurred with the combined use of ampicillin or vancomycin with an aminoglycoside.

Vancomycin-Resistant Enterococci

The treatment of serious infections due to multiresistant, vancomycin-resistant strains is particularly challenging. Linezolid, an oxazolidinone antibiotic that inhibits protein synthesis, is bacteriostatic against most isolates of E. faecium and E. faecalis, including vancomycin-resistant isolates. Response rates to linezolid are generally over 90%, and this antibiotic has become the preferred agent in treatment of VRE infections in many institutions, including cases of bacteremia and sepsis. Anecdotal reports reveal the success of linezolid in treating meningitis due to vancomycin-resistant enterococci. Unfortunately, as seen with other antibiotics, linezolid resistance is documented and nosocomial spread of resistant organisms can occur. Linezolid frequently causes reversible bone marrow suppression after prolonged use and has been associated with rare occurrences of lactic acidosis and irreversible peripheral neuropathy. Serotonin syndrome may be seen in patients taking concomitant selective serotonin reuptake inhibitor (SSRI) antidepressants.

Quinupristin/dalfopristin is a combined streptogramin antibiotic that inhibits bacterial protein synthesis at 2 different stages. It has activity against most E. faecium strains, including those with high-level vancomycin resistance. Approximately 90% of E. faecium strains are susceptible to quinupristin/dalfopristin in vitro. Notably, it is inactive against E. faecalis and therefore should not be used as the sole agent against gram-positive organisms until culture results exclude the presence of E. faecalis. Studies in children suggest that this antibiotic is effective and generally well tolerated, though episodes of arthralgia and myalgia during therapy is reported. Emergence of resistance to quinupristin/dalfopristin is rare but has been demonstrated.

Other antibiotics with reliable activity against VRE include daptomycin and tigecycline. Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against a broad range of gram-positive organisms. The antibiotic inserts into the bacterial cell wall, causing membrane depolarization and cell death. It has been approved for the treatment of adults with serious skin and soft tissue infections, right-sided endocarditis, and bacteremia due to susceptible organisms. Most strains of VRE (both E. faecium and E. faecalis) are susceptible to daptomycin in vitro, and efficacy of daptomycin in adult patients with VRE appears to be similar to that of linezolid. Experience with daptomycin in children is limited, particularly in the setting of Enterococcus infections. However, based on the experience with adult patients, daptomycin may be an alternative to linezolid when resistance or side effects limit utility of that antibiotic. Daptomycin dosages may need to be higher in children when compared to adults due to more rapid renal clearance. The antibiotic has unreliable activity in the lung and therefore should not be used as a sole agent to treat pneumonia. Resistance of both S. aureus and Enterococcus to daptomycin has been described rarely, sometimes arising during therapy.

Tigecycline is an expended-spectrum derivative of the tetracycline family. The agent inhibits protein synthesis by binding to the 30S ribosome and is bacteriostatic against susceptible organisms. Tigecycline has broad activity against gram-positive, gram-negative, and anaerobic organisms, including methicillin-resistant S. aureus and VRE, and is approved for the treatment of adults with skin and soft tissue infections and intra-abdominal infections due to susceptible organisms. Its efficacy in VRE infections has not yet been demonstrated in clinical trials; clinical isolates are almost uniformly susceptible in vitro, suggesting it may be a viable alternative in adult patients in whom other antibiotics cannot be used due to resistance or intolerable side effects. There is very little published experience with the use of tigecycline in children. Like other tetracycline antibiotics, tigecycline use may cause discoloration of the teeth and should generally be avoided in children less than 8 yr of age. Gastrointestinal side effects are common and may be intolerable.

Prevention

Strategies for preventing enterococcal infections include timely removal of urinary and intravenous catheters and debridement of necrotic tissue. Infection control strategies, including surveillance cultures, patient and staff cohorting, and strict gown and glove isolation are effective at decreasing colonization rates with vancomycin-resistant enterococci. Unfortunately, these organisms may persist on inanimate objects such as stethoscopes, complicating efforts to limit their nosocomial spread. To prevent the emergence and spread of vancomycin resistant organisms, the Centers for Disease Control and Prevention has developed a series of guidelines for prudent vancomycin use (www.cdc.gov/mmwr/preview/mmwrhtml/00039349.htm). Antibiotics with broad activity against anaerobic organisms are also thought to contribute to colonization with VRE, suggesting that that prudent use of such antibiotics may also help limit spread of VRE. Decolonization strategies have been attempted but are generally ineffective in eradicating skin or gastrointestinal carriage of VRE. In particular, antimicrobial therapy is not indicated for this purpose. The role of probiotic agents in eliminating VRE colonization is currently unclear but may be a useful adjunct to prudent antimicrobial usage and other infection control interventions in limiting nosocomial spread of VRE.

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Centers for Disease Control and Prevention. Recommendations for preventing the spread of vancomycin resistance. Hospital Infection Control Practices Advisory Committee (HICPAC). Infection Control Hosp Epidemiol. 1995;16:105-113. 498

Florescu I, Beuran M, Dimov R, et al. Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study. J Antimicrob Chemother. 2008;62(Suppl 1)):i17-i28.

Gupte G, Jyothi S, Beath SV, et al. Quinupristin-dalfopristin use in children is associated with arthralgias and myalgias. Pediatr Infect Dis J. 2006;25:281.

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Mave V, Garcia-Diaz J, Islam T, et al. Vancomycin-resistant enterococcal bacteraemia: is daptomycin as effective as linezolid? J Antimicrob Chemother. 2009;64:175-180.

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