Vancomycin-Resistant Enterococcus

US Pharm. 2014;39(8):HS1-HS8.

ABSTRACT: Vancomycin-resistant Enterococcus (VRE) is a major cause of hospital-acquired infections in the United States. Pharmacists across practice settings can play an important role in preventing the emergence of VRE and treating patients with established VRE infections. An understanding of the transmission, risk factors, microbiology, and surveillance of this resistant organism is essential. Many types of infections are caused by VRE, and various nonpharmacologic and pharmacologic measures are employed to treat these infections. It is important for pharmacists to know not only which medications are active against VRE, but also the limitations of these agents and the circumstances under which each should be used. Armed with this information, pharmacists can help optimize patient care, as well as prevent VRE-related morbidity and mortality.

As antimicrobial resistance continues to rise globally, multidrug-resistant (MDR) organisms have posed a significant challenge for clinicians, owing to the dearth of effective therapeutic options to combat them. Enterococcus species are a leading cause of hospital-acquired infections and the second most common nosocomial bloodstream pathogen in the United States. Infections caused by vancomycin-resistant Enterococcus (VRE) have rapidly emerged as a predominant concern, particularly among vulnerable patient populations. When it was first described in the U.S. in 1989, VRE represented <1% of enterococcal isolates but has since risen to a “serious threat” level in recent years, accounting for nearly 30% of 66,000 healthcare-associated enterococcal infections and 1,300 deaths annually.^1,2 The effective management and prevention of VRE requires appropriate antimicrobial selection and aggressive infection-control measures, and pharmacists across healthcare settings play a significant role in optimal patient care.³

VRE Colonization

Transmission: Enterococci are part of the normal gastrointestinal (GI) flora. Once Enterococcus species colonize the GI tract, the development of antibiotic resistance increases, as does the risk of transmission between patients and providers. Once VRE is introduced into a healthcare facility, its persistence and transmission are difficult to control; many VRE isolates are capable of prolonged (>1 week) survival in most hospital environments.⁴

Surveillance: Surveillance cultures to detect colonization are obtained by rectal swabs or stool cultures, and although some facilities may require screening of all patients, selective screening is frequently performed on patients who are at higher risk for developing an infection. VRE colony counts are similar in the stools of colonized and infected patients, so diagnosis of infection requires additional clinical assessment and culture techniques, as discussed below.⁵

Risk Factors: Whether or not colonization leads to infection depends largely on the health of the patient. Immunocompromised patients with hematologic malignancies or recent recipients of solid-organ transplants are often at highest risk for VRE colonization and infection.^5,6 Additional risk factors include prolonged stay in a hospital or healthcare facility, presence of invasive devices such as bladder catheters, and exposure to certain antibiotics, such as vancomycin, third-generation cephalosporins, and antianaerobic agents.^7,8

Microbiology

Resistant Enterococcus: Enterococci impart resistance to antibiotics in a variety of ways. Although some species are inherently resistant to vancomycin, they are far less common than species that acquire resistance through transfer of genetic material. Plasmid-mediated gene complexes confer high-level resistance to vancomycin and are often used as targets for molecular detection of VRE.^9,10 The two major resistant phenotypes are VanA and VanB, which are also the most globally prevalent phenotypes. VanA is responsible for a high level of resistance to vancomycin, whereas VanB confers a lower level of resistance. Most VRE isolates reported in the U.S. are Enterococcus faecium containing vanA.^11,12

E faecium isolates, which account for the majority of vancomycin-resistant isolates causing infection (77%), are typically resistant to beta-lactams (ampicillin) and aminoglycosides, two of the traditionally useful antienterococcal agents.^1,10 In contrast, Enterococcus faecalis isolates, which are less common than E faecium isolates, are usually susceptible to beta-lactams. Culture techniques that isolate VRE are important for diagnosing infection, assessing antimicrobial susceptibility, and identifying clonality, particularly in the event of an outbreak.^4,13

Vancomycin Breakpoints: According to the Clinical and Laboratory Standards Institute (CLSI), resistance is defined as having a minimum inhibitory concentration (MIC) ³32 mcg/mL. For intermediate resistance (8-16 mcg/mL), vancomycin is not recommended.¹³

Treatment Principles

Overall, 20,000 VRE infections varying in site and severity occur in hospitalized patients each year. The most common infections caused by VRE are urinary tract infections (UTIs), bacteremia, and wound infections.¹ Other VRE infections, such as endocarditis and meningitis, are serious and may require more aggressive combination therapy.^5,8 For noninvasive infections, nonpharmacologic interventions (e.g., catheter or foreign-body removal or drainage of an enclosed infection) are often necessary in conjunction with antimicrobial therapy. Although the optimal approach for treating VRE is uncertain in many clinical situations, appropriate antimicrobial selection is guided by severity and site of infection, as well as in vitro susceptibility and pharmacokinetic or pharmacodynamic properties of agents. Several choices for current, and possibly future, treatment of VRE infection are described below.¹⁴

Two agents, linezolid (LZD) and quinupristin-dalfopristin (QPD), have been approved by the FDA for the treatment of infections caused by VRE; however, several alternatives are considered in clinical practice. For treatment of severe VRE infections, options include penicillin or amoxicillin +/– aminoglycoside, QPD, or newer agents such as LZD, daptomycin, and tigecycline. Some older agents, such as ampicillin, chloramphenicol, doxycycline, and rifampin, also may be useful against VRE infections, and more recent studies suggest synergistic effects when these agents are used in combination with newer agents.^5,15

Beta-Lactams: Beta-lactams such as penicillin, aminopenicillins, and their combinations (ampicillin-sulbactam) have demonstrated activity against certain strains of VRE, particularly when used at higher doses. This strategy, however, may be limited by elevated MICs to beta-lactams.¹⁶ In addition, 95% of E faecium isolates and <5% of E faecalis isolates are thought to have acquired resistance to penicillin or ampicillin via mutation of penicillin-binding proteins.¹⁶ Therefore, since a limited number of vancomycin-resistant E faecalis strains are susceptible to penicillin and ampicillin and the vast majority of E faecium strains exhibit high-level resistance (MIC >128 mcg/mL), these agents are not useful for the majority of VRE infections.^16,17 It is important to consider site of infection when deciding whether to use a penicillin. Several drugs achieve higher concentrations in the urine than in the blood, so penicillins may be a viable option in the treatment of UTIs, despite elevated MICs.¹⁸

QPD: QPD, a bacteriostatic, injectable mixture of streptogramin antibiotics, was the first FDA-approved agent for infections caused by vancomycin-resistant E faecium only. Most E faecalis isolates and many other non–E faecium species are intrinsically resistant to QPD, so the agent’s recommended use is in nonsevere MDR cases and as alternative therapy in nonsevere beta-lactam–susceptible and aminoglycoside-susceptible (E faecalis, Enterococcus gallinarum, Enterococcus casseliflavus) cases.⁵ Literature suggests QPD as an alternative for severe infections only when used in combination with both doxycycline and rifampin. QPD presents several limitations, including the need for central venous administration, development of resistance, and an unfavorable adverse event (AE) profile (i.e., myalgia, arthralgia), that have significantly limited the agent’s widespread use in clinical practice.⁵

LZD: A synthetic oxazolidinone, LZD also has bacteriostatic activity against VRE. It is available in both oral and IV forms, which is particularly useful for transitioning patients to outpatient treatment. LZD is indicated in children and adults with hospital-acquired pneumonia, ventilator-associated pneumonia (VAP), complicated and uncomplicated skin and skin-structure infections (SSSIs), and gram-positive bacteremia in patients without renal failure.⁵

In a retrospective review of 113 patients with MDR VRE (112 E faecium, 1 E faecalis) bacteremia who were treated with QPD (n = 20) or LZD (n = 71), overall mortality was 37.2%, with six deaths (five QPD patients and one LZD patient) directly related to VRE, showing a significant advantage for LZD. However, this advantage disappeared when underlying factors were taken into account.¹⁹ Anemia, thrombocytopenia, leukopenia, and peripheral and optic neuropathy (including blindness) have been reported with LZD.⁵ Serotonin syndrome may occur as a result of a drug-drug interaction with other serotonergic agents. It has been suggested that LZD be used for treatment of VRE endocarditis when AEs, resistance patterns, and allergies prevent the use of appropriate alternative antibiotics. Because of its excellent central nervous system penetration, LZD is often considered a first-line therapy for enterococcal meningitis.²⁰

Daptomycin: Daptomycin is a bactericidal cyclic lipopeptide that is indicated for the treatment of vancomycin-susceptible E faecalis–complicated SSSIs.^5,21 Although it is not approved for the treatment of E faecium infections and VRE, daptomycin is commonly used in clinical practice to treat enterococcal infections, and retrospective studies have shown success rates of 87% to 90% in bacteremia caused by VRE.^19,20 Surveillance and susceptibility analyses reveal daptomycin to be active against E faecium and E faecalis, with MICs ranging from 1 mg/L to 4 mg/L.^22-25 The CLSI committee has designated daptomycin MICs £4 mg/L as susceptible; however, resistance breakpoints have not been defined.^26,27 Although daptomycin has been clinically proven as an option for VRE treatment, reports of resistance have emerged with its use.²⁸ Additionally, there have been conflicting reports concerning whether the FDA-approved dose of daptomycin is sufficient to treat VRE, with some clinical sites suggesting the use of high-dose daptomycin; thus, further research regarding daptomycin for VRE treatment is warranted.²⁹

Tigecycline: Tigecycline, a derivative of minocycline, is a glycylcycline bacteriostatic antibiotic that possesses broad-spectrum in vitro activity against many gram-positive and gram-negative pathogens, anaerobes, and atypical species.^5,6 It is currently approved for complicated SSSIs (cSSSIs), intra-abdominal infections, and community-acquired pneumonia. Although it is not approved to treat VRE infections, tigecycline has shown activity against VRE based on in vitro and animal data and published case reports.^5,30,31 Data supporting the use of tigecycline for VRE treatment are limited, however, and concerns were raised during clinical trials when cSSSI patients receiving tigecycline had a higher mortality rate than controls.⁵ This, in addition to concerns about whether recommended dosages can achieve effective serum concentrations for the treatment of bacteremia, may warrant further investigation regarding tigecycline’s use.^6,30,32

Tetracycline: Older tetracyclines, such as doxycycline and minocycline, have been used to treat VRE. Doxycycline susceptibility rates among urinary VRE isolates have been reported to be approximately 60% and 31% for vancomycin-resistant E faecium and E faecalis, respectively.^18,33 Doxycycline’s improved intrinsic activity against VRE and less-frequent dosing make it a viable option for the treatment of VRE UTIs, particularly in the outpatient setting.¹⁸ However, since these agents possess only bacteriostatic activity, their use is questioned for serious infections, such as VRE bacteremia.^6,18

Telavancin: This agent, a derivative of vancomycin, is a bactericidal lipoglycopeptide that is approved for the treatment of SSSIs and pneumonia. In addition, similarly to vancomycin’s activity on the bacterial cell wall, telavancin disrupts the membrane potential and leads to increased cell permeability.⁵ In vitro data suggest good activity against isolates with a VanB phenotype and less potent activity against VanA strains (MIC₉₀ 4-16 mcg/mL). Telavancin +/– LZD is a suggested first-line therapy in severe MDR E faecium infections.⁵ Other studies suggest that effective killing may not be attained at recommended dosages, so additional clinical efficacy data are needed.

Chloramphenicol: A variety of single agents may be effective for the treatment of UTIs caused by VRE. Chloramphenicol, a broad-spectrum bacteriostatic antibiotic, has been reported to be successful in treating VRE infections. In a survey of urinary isolates of vancomycin-resistant E faecium, nearly all strains were susceptible to chloramphenicol, and in retrospective studies its clinical efficacy varied from 57% to 61%.^18,29,34 However, the drug’s utility is limited by the emergence of VRE strains resistant to chloramphenicol and by its toxicity profile.³⁵ Despite chloramphenicol’s toxicity profile, drug susceptibility may necessitate its consideration as a therapy option.

Fosfomycin: Fosfomycin is another bacteriostatic agent approved for the treatment of uncomplicated UTIs from Escherichia coli or E faecalis (although E faecium is also usually sensitive). Fosfomycin has shown good activity against VRE isolated in urine, as well.^13,15 Retrospective chart reviews suggest that oral fosfomycin is a potential cost-effective option for treating VRE-associated UTIs; however, further studies are warranted.³⁶

Teicoplanin: This semisynthetic glycopeptide antibiotic is not available in North America, but it is used in Europe and some South American countries to treat certain VRE infections.⁵ Teicoplanin is effective against most VRE strains that express the VanB phenotype and those expressing the VanC phenotype (E gallinarum and E casseliflavus), but it is rarely active against the VanA phenotype.^5,37 However, strains expressing the VanB phenotype have been reported to develop resistance to teicoplanin.³⁷

Antimicrobial Stewardship

A number of efforts can be undertaken via antimicrobial-stewardship teams to appropriately manage patients with VRE, including the collection of regional and institutional data required for predicting resistance trends.¹ A multifaceted approach in which antimicrobial stewardship plays a key role is necessary to limit the impact of antibiotic resistance on patients and public health, as well as the incidence of VRE in the general population.³⁸ Since epidemiologic studies have continuously identified antimicrobial exposure as a risk factor for VRE culture positivity, the initiation of proper antimicrobial-stewardship practices in institutions must focus on eliminating the inappropriate or excessive use of antibiotic prophylaxis and therapy.^39,40 Treatment of VRE infections should be individualized based on clinical and pharmacologic data and in vitro susceptibilities of the organisms.³⁵ In addition, it has been recommended that antimicrobial-stewardship teams consider restricting the use of vancomycin and certain cephalosporins, when appropriate, to reduce the selective pressure favoring vancomycin resistance.³⁹

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