Defining Daptomycin Resistance Prevention Exposures in Vancomycin-Resistant Enterococcus faecium and E. faecalis

Abstract

Daptomycin is used off-label for enterococcal infections; however, dosing targets for resistance prevention remain undefined. Doses of 4 to 6 mg/kg of body weight/day approved for staphylococci are likely inadequate against enterococci due to reduced susceptibility. We modeled daptomycin regimens in vitro to determine the minimum exposure to prevent daptomycin resistance ( Enterococcus spp. are among the leading causes of nosocomial infections (1). Vancomycin-resistant Enterococcus faecium has been recognized as an important multidrug-resistant pathogen for which new or improved therapies are urgently needed (2, 3). Daptomycin is a lipopeptide antibiotic with potent in vitro bactericidal activity against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE). Although daptomycin lacks an approved indication from the FDA, it is frequently utilized as an alternative agent for the management of VRE infections. However, the optimal pharmacokinetic/pharmacodynamic (PK/PD) targets for resistance prevention and therapeutic success with daptomycin have not been defined (4). In fact, the susceptibility breakpoint designating resistance in enterococci also remains questionable; however, for ease of presentation, we will use the term resistance to refer to nonsusceptible enterococci with daptomycin MICs of Ͼ4 mg/liter. Most experts agree that the daptomycin doses of 4 to 6 mg/kg of body weight/day used for staphylococcal infections are likely inadequate for VRE infections due to reduced susceptibility observed in enterococci (3-5). Daptomycin MIC 50 and MIC 90 are 2 and 4 mg/liter for E. faecium, and 0.5 and 1 mg/liter for Enterococcus faecalis versus 0.25 and 0.5 mg/liter for staphylococci (6). Reports of daptomycin resistance are now becoming more common, emphasizing the need for improved daptomycin dosing paradigms to help preserve the utility of this drug against these difficult to treat pathogens (7-10). Due to the substantial morbidity and mortality associated with enterococcal infections, it is critical to identify characteristics that correlate with treatment failure and therefore improve antimicrobial optimization and patient outcomes.In order to derive daptomycin exposure targets for resistance prevention, we evaluated simulated daptomycin regimens from 4 to 12 mg/kg/day in a 14-day PK/PD model of simulated endocardial vegetations (SEVs) against two daptomycin-susceptible clinical VRE strains (E. faecium S447 and E. faecalis S613). Resistant strains derived from these models were then subjected to a variety of phenotypic and genotypic analyses to evaluate characteristics associated with development of daptomycin resistance. MATERIALS AND METHODSBacterial strains. Two daptomycin-susceptible and vancomycin-resistant enterococcal strains, E. faecalis S613 and E. faecium S447 recovered from the bloodstream and urine, respectively, of patients before daptomycin therapy, were evaluated (11, 12). Both isolates developed daptomycin-resistant derivatives in vivo during daptomycin therapy (11, 12) and

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

“…In an in vitro model, Werth and colleagues recently demonstrated that the prevention of DAP resistance is accomplished with a DAP AUC 0 -24 /MIC ratio of 1,562 for E. faecalis and 781 for E. faecium (38). In our study, DAP alone was able to achieve fAUC 0 -24 /MIC ratios of 60.8 and 30.4 for E. faecalis and E. faecium, respectively.…”

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Daptomycin is one of the only agents to offer bactericidal activity against VRE, but dose optimization remains a challenge (38). The general consensus among experts is that high doses of daptomycin (greater than 8 mg/kg/day) are necessary to achieve clinical success in the setting of serious enterococcal infections, and emerging data indicate that doses of Ն10 mg/kg/day are necessary for resistance prevention (20,(38)(39)(40)(41)(42). Resistance to daptomycin in VRE is an emerging threat that requires immediate attention to derive new therapeutic strategies, such as dose optimization and combination therapy, in order to preserve the clinical utility of this drug.…”

In Vitro Activity of Daptomycin in Combination with β-Lactams, Gentamicin, Rifampin, and Tigecycline against Daptomycin-Nonsusceptible Enterococci

“…Daptomycin MICs for this isolate progressed from 16 g/ml to 256 g/ml over the course of several months, while the patient was on daptomycin therapy (15). Supporting in vitro data from a simulated endocardial vegetation pharmacokinetic/pharmacodynamic model dem-onstrated that exposure of enterococci to daptomycin concentrations equivalent to FDA-cleared doses (i.e., 4 to 6 mg/kg/day) results in the development of the DNS phenotype (16).…”

“…In order to mitigate the development of DNS, a minimum dose of 10 mg/kg/day, particularly in cases with high bacterial burden, such as cases of endocarditis, has been suggested for the enterococci (16). Alternatively, combination therapy, such as with a ␤-lactam plus daptomycin, has been suggested for successful treatment of DSD Enterococcus infections (13,16).…”