Therapeutics for Vancomycin-Resistant Enterococcal Bloodstream Infections. Clinical microbiology reviews Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern with a limited treatment pipeline. Significant challenges exist in the management of VRE BSI, including drug dosing, the emergence of resistance, and the optimal treatment for persistent bacteremia and infective endocarditis. Therapeutic drug monitoring (TDM) for antimicrobial therapy is evolving for VRE-active agents; however, there are significant gaps in the literature for predicting antimicrobial efficacy for VRE BSIs. To date, TDM has the greatest evidence for predicting drug toxicity for the three main VRE-active antimicrobial agents daptomycin, linezolid, and teicoplanin. This article presents an overview of the treatment options for VRE BSIs, the role of antimicrobial dose optimization through TDM in supporting clinical infection management, and challenges and perspectives for the future. 10.1128/cmr.00059-22

Vancomycin-resistant enterococcal urinary tract infections. Heintz Brett H,Halilovic Jenana,Christensen Cinda L Pharmacotherapy Enterococci are a common cause of urinary tract infections (UTIs) among hospitalized patients. The rising prevalence of vancomycin-resistant enterococci (VRE) is of particular concern within many institutions because of its association with increased mortality and health care costs, as well as limited treatment options. Clinicians need to differentiate between VRE-associated urinary colonization, asymptomatic bacteriuria, and UTIs in order to determine the need for treatment, optimal therapeutic options, and length of therapy. Unnecessary use of antibiotics in patients simply colonized and not infected with VRE in the urine has become a large problem in both hospitals and long-term care facilities. A PubMed-MEDLINE search was conducted to identify all English-language literature published between January 1975 and March 2010 in order to summarize diagnostic criteria and treatment options for VRE UTIs. Several antimicrobials are discussed, with the specific focus on those with the potential to treat VRE UTIs and susceptibility patterns of VRE from urinary sources: ampicillin, amoxicillin, daptomycin, doxycycline, fosfomycin, imipenem-cilastatin, linezolid, nitrofurantoin, penicillin, piperacillin, quinupristin-dalfopristin, tetracycline, and tigecycline. Recommendations for empiric treatment of enterococcal UTIs and definitive treatment of VRE UTIs, including an evidence-based treatment algorithm, are proposed. Ampicillin generally is considered the drug of choice for ampicillin-susceptible enterococcal UTIs, including VRE. Nitrofurantoin, fosfomycin, and doxycycline have intrinsic activity against enterococci, including VRE, and are possible oral options for VRE cystitis. Linezolid and daptomycin should be reserved for confirmed or suspected upper and/or bacteremic VRE UTIs among ampicillin-resistant strains. Use of other antimicrobials, such as quinupristin-dalfopristin and tigecycline, should be evaluated on a case-by-case basis due to concerns of toxicity, resistance, and insufficient supportive data. Additional clinical data are needed to determine the optimal management and duration of therapy for VRE UTIs. 10.1592/phco.30.11.1136

Treatment options for vancomycin-resistant enterococcal infections. Linden Peter K Drugs Serious infection with vancomycin-resistant enterococci (VRE) usually occurs in patients with significantly compromised host defences and serious co-morbidities, 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 (MIC(90)) = 2 microg/ml] but is not active against Enterococcus faecalis (MIC(90 )= 16 microg/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 (MIC(90) = 2 to 4 microg/ml) and E. faecalis (MIC(90) = 2 to 4 microg/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 (600 mg 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 > or = 8 microg/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 (quinupristin/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. 10.2165/00003495-200262030-00002