Treatment options for vancomycin-resistant enterococcal infections

Abstract

Serious infection with vancomycin-resistant enterococci (VRE) usually occurs in patients with significantly compromised host defences and serious comorbidities, and this magnifies the importance of effective antimicrobial treatment. Assessments of antibacterial efficacy against VRE have been hampered by the lack of a comparator treatment arm(s), complex treatment requirements including surgery, and advanced illness-severity associated with a high crude mortality. Treatment options include available agents which don't have a specific VRE approval (chloramphenicol, doxycycline, high-dose ampicillin or ampicillin/sulbactam), and nitrofurantoin (for lower urinary tract infection). The role of antimicrobial combinations that have shown in vitro or animal-model in vivo efficacy has yet to be established. Two novel antimicrobial agents (quinupristin/dalfopristin and linezolid) have emerged as approved therapeutic options for vancomycin-resistant Enterococcus faecium on the basis of in vitro susceptibility and clinical efficacy from multicentre, pharmaceutical company-sponsored clinical trials. Quinupristin/dalfopristin is a streptogramin, which impairs bacterial protein synthesis at both early peptide chain elongation and late peptide chain extrusion steps. It has bacteriostatic activity against vancomycin-resistant E. faecium [minimum concentration to inhibit growth of 90% of isolates (MIC90) = 2μgg/ml] but is not active against Enterococcus faecalis (MIC90= 16 μg/ml). In a noncomparative, nonblind, emergency-use programme in patients who were infected with Gram-positive isolates resistant or refractory to conventional therapy or who were intolerant of conventional therapy, quinupristin/dalfopristin was administered at 7.5 mg/kg every 8 hours. The clinical response rate in the bacteriologically evaluable subset was 70.5%, and a 65.8% overall response (favourable clinical and bacteriological outcome) was observed. Resistance to quinupristin/dalfopristin on therapy was observed in 6/338 (1.8%) of VRE strains. Myalgia/arthralgia was the most frequent treatment-limiting adverse effect. In vitro studies which combine quinupristin/dalfopristin with ampicillin or doxycyline have shown enhanced killing effects against VRE; however, the clinical use of combined therapy remains unestablished. Linezolid, an oxazolidinone compound that acts by inhibiting the bacterial pre-translational initiation complex formation, has bacteriostatic activity against both vancomycin resistant E. faecium (MIC90 = 2 to 4 μg/ml) and E. faecalis (MIC90 = 2 to 4 μg/ml). This agent was studied in a similar emergency use protocol for multi-resistant Gram-positive infections. 55 of 133 evaluable patients were infected with VRE. Cure rates for the most common sites were complicated skin and soft tissue 87.5% (7/8), primary bacteraemia 90.9% (10/11), peritonitis 91.7% (11/12), other abdominal/pelvic infections 91.7% (11/12), and catheter-related bacteraemia 100% (9/9). There was an all-site response rate of 92.6% (50/54). In a separate blinded, randomised, multicentre trial for VRE infection at a variety of sites, intravenous low dose linezolid (200mg every 12 hours) was compared to high dose therapy (600mg every 12 hours) with optional conversion to oral administration. A positive dose response (although statistically nonsignificant) was seen with a 67% (39/58) and 52% (24/46) cure rate in the high- and low-dose groups, respectively. Adverse effects of linezolid therapy have been predominantly gastrointestinal (nausea, vomiting, diarrhoea), headache and taste alteration. Reports of thrombocytopenia appear to be limited to patients receiving somewhat longer courses of treatment (>14 to 21 days). Linezolid resistance (MIC ≥8 μg/ml) has been reported in a small number of E. faecium strains which appears to be secondary to a base-pair mutation in the genome encoding for the bacterial 23S ribosome binding site. At present a comparative study between the two approved agents for VRE (quinuprisin/dalfopristin and linezolid) has not been performed. Several investigational agents are currently in phase II or III trials for VRE infection. This category includes daptomycin (an acidic lipopeptide), oritavancin (LY-333328; a glycopeptide), and tigilcycline (GAR-936; a novel analogue of minocycline). Finally, strategies to suppress or eradicate the VRE intestinal reservoir have been reported for the combination of oral doxycyline plus bacitracin and oral ramoplanin (a novel glycolipodepsipeptide). If successful, a likely application of such an approach is the reduction of VRE infection during high risk periods in high risk patient groups such as the post-chemotherapy neutropenic nadir or early post-solid abdominal organ transplantation. The emergence of enterococci with high level resistance to vancomycin (VRE) in the US and some other parts of the world during the 1990s has severely constrained therapeutic options for the management of serious infection since enterococci already possess intrinsic and acquired resistance to most other antimicrobials.[1-3] Recent multicentre nosocomial surveillance studies in the US have demonstrated that 18 to 20% of enterococcal blood-stream isolates were resistant to vancomycin.[4,5] A significant divergence has been observed in the incidence of vancomycin-resistance between Enterococcus faecium and Enterococcus faecalis. Up to 51% of E. faecium strains isolated from the blood-stream exhibit vancomycin-resistance while only 3% of E. faecalis strains were vancomycin-resistant and the vast majority retain susceptibility to ampicillin.[5] Serious VRE infection has disproportionately affected patients in the intensive care unir (ICU), immunosuppressed hosts, particularly liver and other solid organ recipients and patients with post-chemotherapy neutropenia, and patients with intravascular and bladder catheter devices.[6-11] Other dominant risk factors include prolonged hospital or ICU length of stay, previous antibacterial exposure (vancomycin, later generation cephalosporins, anti-anaerobic agents), and exposure to healthcare workers caring for other patients with VRE colonisation. It is critical for the clinician to discriminate between colonisation with VRE versus true infection as this has a direct bearing on the intent-to-treat with VRE-directed antimicrobials. VRE isolates from superficial wounds, removed intravascular catheters without accompanying local or systemic signs of infection, nonpyuric urine, and intraperitoneal or biliary drains are common examples of VRE colonisation which do not merit therapy. Some less serious VRE infections may respond to conservative management (wound debridement, catheter-removal) without VRE-directed antimicrobial therapy[12] (table I). Isolation of VRE from two or more blood culture sets and other sterile body sites, with accompanying local or systemic signs of infection are significant findings. Such deep-seated infections do require specific antimicrobial therapy either alone or as an adjunct to non-antimicrobial management (percutaneous- or surgical drainage, catheter removal, etc). The current review focuses on antimicrobial options for VRE infection, and the level of evidence which supports their efficacy and safety in these patients with complex conditions.