Enterococcal Infections

Definition

Enterococci are endogenous human gut flora that are increasingly important health care–associated pathogens. Enterococci cause urinary tract infections, bacteremia, intra-abdominal infections, and, rarely, endocarditis and meningitis. Their emergence as major pathogens results from their inherent resistance to commonly used antimicrobial agents, persistence in the environment, association with indwelling devices, and transmission from patient to patient, mostly by way of the contaminated hands of health care personnel.

Epidemiology

Enterococci are part of the normal human gut flora, and infections in both hospitalized and non-hospitalized patients can arise from either an endogenous or exogenous source. The proportion of infections caused by enterococci in hospitalized patients has increased over the past several decades. Overall, urinary tract infections ( Chapter 263 ) are the most common clinical condition caused by enterococci. Enterococcal species also are the second most common isolates for any health care–associated infection ( Chapter 261 ) and the single most common cause of central line–associated blood stream infections in patients who are hospitalized on regular hospital floors, intensive care units (ICUs), and inpatient oncology units. Enterococci also cause about 15% of both catheter-associated urinary tract infections and surgical site infections in North America. In community settings, enterococci cause both complicated and uncomplicated urinary tract infections and are involved in approximately 5 to 15% of all cases of infective endocarditis ( Chapter 61 ). Outside of the United States, these organisms are less common but increasingly important causes of infections.

Enterococcus species, especially E. faecium, in hospitalized patients increasingly may be resistant to vancomycin, ampicillin, or gentamicin. By 2017, 82% of E. faecium isolates and 7% of E. faecalis isolates from health care–associated infections were resistant to vancomycin. Vancomycin-resistant enterococci are associated with about 55,000 infections in hospitalized patients and 5400 deaths in the United States, each year. Although the proportion of vancomycin resistance among enterococcal clinical isolates in hospitalized patients has been historically lower in Europe than in the United States, about 18% of all European E. faecium isolates were resistant to vancomycin in 2019, with the prevalence varying from 0 to 50% in individual countries.

Most vancomycin-resistant enterococcus infections are associated with health care ( Chapter 261 ), especially hospitalization in the prior year, and result from either an exogenous source (i.e., transmission from the environment, another patient, or the hands of health care personnel) or antimicrobial exposure. Nearly all infections are preceded by a period of colonization, primarily in the gastrointestinal tract, where patients may harbor the strain for years after colonization. Although many colonized patients do not develop infections, they are still able to contaminate the environment, shed and transmit bacteria to other hospitalized patients, and precipitate an outbreak.

Apart from preexisting gastrointestinal colonization, risk factors for enterococcal infections, particularly vancomycin-resistant infections, include severe underlying conditions such as renal failure ( Chapter 116 ), previous solid organ (especially liver; Chapter 140 ) or hematopoietic stem cell transplantation ( Chapter 163 ), solid tumor and hematologic malignancies, diabetes mellitus ( Chapter 210 ), and neutropenia ( Chapter 153 ). Other factors associated with infection include prior surgical or gastrointestinal procedures, presence of a vascular or urinary indwelling catheter, hospital factors such as location in an ICU or an inpatient oncology service, proximity to colonized patients, prolonged length of hospitalization, and recent exposure to antimicrobial agents.

Most classes of antimicrobials increase the risk of colonization with vancomycin-resistant enterococcus and subsequent clinical infections, but vancomycin, cephalosporins, and drugs that cure anaerobic organisms are especially implicated. Colonization with vancomycin-resistant enterococcus may coexist with Clostridioides difficile ( Chapter 271 ) infection in high-risk patients, such as inpatients with hematologic malignancies.

Pathobiology

Enterococci are commensal organisms that colonize the human gastrointestinal tract and female genital tract. They contaminate and also can be recovered from the environment. Although they are not as intrinsically virulent as other gram-positive pathogens, under certain conditions the commensal relationship is disrupted and serious infections occur. Several adhesion factors have been identified, including aggregation substance, which allow binding to epithelial surfaces and enhance the ability for colonization. The ability to adhere to heart valves and urinary tract epithelium enables enterococci to cause endocarditis and urinary tract infections. Enterococci are also known to secrete potential virulence factors, including cytolysin-hemolysin, which is a bacterial toxin that is produced in a higher proportion of infecting strains compared with stool-colonizing strains. Infecting strains also possess the ability to translocate across the intestinal epithelium, although the exact mechanisms of this process have yet to be determined. In addition, some encoded cell surface determinants may mediate adherence to host tissues that may be important in this organism’s role in endocarditis. The exact role of capsular polysaccharides in colonization or infection is unknown. Strains have been shown to survive within phagocytic cells, yet it is unclear whether this represents successful host defense or evasion by the enterococci.

The intrinsic resistance to multiple antimicrobials (including cephalosporins, clindamycin, trimethoprim-sulfamethoxazole, and low-level aminoglycosides) that enterococci possess, along with their ability to acquire resistance to a wide range of antibiotics (including high concentrations of penicillins, fluoroquinolones, tetracycline, nitrofurantoin, and glycopeptides) through mutation or acquisition of new genes, enhances their ability to survive and multiply in the many hospitalized patients treated with broad-spectrum antimicrobials.

In the 21st century, additional antimicrobial resistance has emerged primarily in E. faecium . Two major genotypes, VanA and VanB, are responsible for acquired vancomycin resistance. The genes encoding the VanA phenotype, which also result in high-level resistance to teicoplanin, are carried on a plasmid or a conjugative transposon that is transferable. VanA is mostly found in E. faecium and, less frequently, in E. faecalis . VanB is associated with variable resistance to vancomycin, but isolates are usually susceptible to teicoplanin.

VanA and VanB are rarely found in other enterococci, but VanC is intrinsically recovered from E. casseliflavus and E. gallinarum . Importantly, these genetic elements have been integrated into the genome of S. aureus ( Chapter 267 ) that is resistant to vancomycin. Resistance to ampicillin and high-level resistance to gentamicin have also been reported ( Chapter 258 ).

Clinical Manifestations

Enterococci cause urinary tract infections, intra-abdominal abscesses, wound infection, bacteremia (including central line–associated blood stream infections), endocarditis, and meningitis, but no specific clinical manifestations can help distinguish enterococcal infections from infections caused by other bacteria. Enterococci are not thought to cause lower respiratory tract infections and, if found in this setting, likely represent colonization and not infection. Enterococci act as opportunistic pathogens in severely ill and compromised patients, and fecal proliferation of enterococci has been implicated in graft-versus-host disease after hematopoietic stem cell transplantation ( Chapter 163 ).