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1.  Reduced Susceptibility to Host-Defense Cationic Peptides and Daptomycin Coemerge in Methicillin-Resistant Staphylococcus aureus From Daptomycin-Naive Bacteremic Patients 
The Journal of Infectious Diseases  2012;206(8):1160-1167.
Background. We hypothesized that, for methicillin-resistant Staphylococcus aureus (MRSA), in vitro daptomycin susceptibility could be influenced by exposures to endogenous host defense peptides (HDPs) prior to clinical exposure to daptomycin.
Methods. Two endovascular HDPs were used: thrombin-induced platelet microbicidal protein (tPMP) and human neutrophil defensin-1 (hNP-1) from neutrophils. Forty-seven unique MRSA isolates obtained from bacteremic patients in multicenter prospective clinical trials were studied. Clinical characteristics, microbiologic parameters, prior vancomycin therapy, and susceptibilities to tPMP, hNP-1, and daptomycin were compared using univariate and multivariate analyses.
Results. All strains were daptomycin susceptible. Daptomycin minimum inhibitory concentrations (MICs) were inversely related to in vitro tPMP (but not hNP-1) killing. Strains with a daptomycin MIC of 1 mg/L exhibited significantly less killing by tPMP, compared with strains with an MIC of ≤ 0.5 mg/L. Prior vancomycin therapy did not influence this relationship. Regression tree modeling confirmed that reduced tPMP-induced killing in vitro was the strongest predictor of higher daptomycin MICs within the daptomycin-susceptible range.
Conclusions. Among daptomycin-susceptible MRSA isolates from patients who had never received daptomycin, higher daptomycin MICs tracked with increased resistance to killing by platelet-derived but not neutrophil-derived HDPs. These findings support the notion that endogenous exposure of MRSA to specific HDPs may play a role in selecting strains with an intrinsically higher daptomycin MIC phenotype.
doi:10.1093/infdis/jis482
PMCID: PMC3448966  PMID: 22904338
2.  Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment 
Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant β-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.
doi:10.1128/AAC.02192-12
PMCID: PMC3591880  PMID: 23254428
3.  Ampicillin Enhances Daptomycin- and Cationic Host Defense Peptide-Mediated Killing of Ampicillin- and Vancomycin-Resistant Enterococcus faecium 
We studied an ampicillin- and vancomycin-resistant Enterococcus faecium (VRE) isolate from a patient with endocarditis and bacteremia refractory to treatment with daptomycin (6 mg/kg of body weight) plus linezolid. Blood cultures cleared within 24 h of changing therapy to daptomycin (12 mg/kg) plus ampicillin. We examined the effects of ampicillin on daptomycin-induced growth inhibition and killing, surface charge, and susceptibility to several prototypical host defense cationic antimicrobial peptides. MICs and time-kill curves with daptomycin were assessed in the presence and absence of ampicillin. The impact of ampicillin on surface charge was assessed by flow cytometry and a poly-l-lysine binding assay. The effects of ampicillin preexposures upon VRE killing by five distinct cationic peptides of different structure, charge, origin, and mechanism of action were analyzed using the epidermal cathelicidin LL-37, thrombin-induced platelet microbicidal proteins (tPMPs), and a synthetic congener modeled after tPMP microbicidal domains (RP-1), human neutrophil peptide-1 (hNP-1), and polymyxin B (bacteria derived). Fluoroscein-Bodipy-labeled daptomycin was used to evaluate daptomycin binding to VRE membranes in the presence or absence of ampicillin. In media containing ampicillin (25 to 100 mg/liter), daptomycin MICs decreased from 1.0 to 0.38 mg/liter. Based on time-kill analysis and an in vitro pharmacodynamic model, ampicillin enhanced daptomycin activity against the study VRE from a bacteriostatic to a bactericidal profile. VRE grown in ampicillin (25 to 150 mg/liter) demonstrated an incremental reduction in its relative net positive surface charge. When grown in the presence (versus absence) of ampicillin (25 and 100 mg/liter), the VRE strain (i) was more susceptible to killing by LL-37, tPMPs, hNP-1, and RP-1 but not to polymyxin B and (ii) exhibited greater binding to Bodipy-labeled daptomycin. We conclude that ampicillin induces reductions in net positive bacterial surface charge of VRE, correlating with enhanced bactericidal effects of cationic calcium-daptomycin and a diverse range of other cationic peptides in vitro. While the mechanism(s) of such β-lactam-mediated shifts in surface charge remains to be defined, these finding suggest a potential for β-lactam-mediated enhancement of activity of both daptomycin and innate host defense peptides against antibiotic-resistant bacteria.
doi:10.1128/AAC.05551-11
PMCID: PMC3264218  PMID: 22123698
4.  Factors Influencing Time to Vancomycin-Induced Clearance of Nonendocarditis Methicillin-Resistant Staphylococcus aureus Bacteremia: Role of Platelet Microbicidal Protein Killing and agr Genotypes 
Background
Vancomycin susceptibility, the accessory gene global regulator (agr) genotype and function, staphylococcal cassette chromosome (SCC) mec type, and susceptibility to cationic thrombin-induced platelet microbicidal protein 1 (tPMP-1) have been individually predictive of duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. This investigation evaluated the interrelationship of these factors with time to clearance of MRSA bacteremia during vancomycin therapy in patients without endocarditis.
Methods
Vancomycin minimum inhibitory concentration and in vitro killing, agr function (δ-hemolysin activity), agr group, SCCmec type, and survival in tPMP-1 killing assays were determined for 29 MRSA bacteremia isolates.
Results
Increased resistance to tPMP-1 killing was observed with agr group III MRSA (P =.025) and MRSA with reduced or absent agr function (P =.023). The median time to clearance of MRSA bacteremia was earlier for agr group III (3 days) versus group I (10.5 days) or II (15 days) (P =.001). In multivariate analysis, agr group II, reduced tPMP-1 killing in vitro, and prior vancomycin exposure were significant independent predictors of longer MRSA bacteremia duration.
Conclusions
Specific genotypic, phenotypic, and clinical parameters appear to correlate with persistent MRSA bacteremia. The interrelationship of these and other factors probably contributes to vancomycin-mediated clearance of MRSA bacteremia.
doi:10.1086/649429
PMCID: PMC2819315  PMID: 20001853
5.  Vancomycin Ototoxicity: a Reevaluation in an Era of Increasing Doses ▿  
Nephrotoxicity and ototoxicity have historically been documented as relatively rare complications of vancomycin monotherapy. Recent reports have linked aggressive vancomycin dosing strategies to significant risks of nephrotoxicity. We evaluated the rate of high-frequency hearing loss detected by audiometry for patients on vancomycin therapy. For this purpose, we used retrospective case-control analysis of audiometry results for patients on vancomycin therapy for whom baseline and follow-up exams were available. Analysis of 89 patients for whom audiograms were performed after an average of 27 days of vancomycin therapy showed a 12% rate of high-frequency hearing loss, with a trend in univariate analysis toward a higher rate with advanced age. The mean of the highest vancomycin trough levels for both patients with worsening audiograms and those without worsening audiograms was 19 mg/liter. Regression tree modeling demonstrated that for patients <53 years old, the rate of high-frequency hearing loss detected by audiogram was 0%, while for patients >53 years old, the incidence was 19% (P = 0.008). We conclude that a significant rate of high-frequency hearing loss in older patients receiving vancomycin monotherapy was detected by audiometry. While these data urge caution against continued indiscriminate vancomycin dose escalation to treat infections caused by Staphylococcus aureus strains for which vancomycin MICs are 2 mg/liter, further prospective studies are needed to determine the clinical significance and reversibility of these effects.
doi:10.1128/AAC.01088-08
PMCID: PMC2630630  PMID: 19001107
6.  Genotypic and phenotypic relationships among methicillin-resistant Staphylococcus aureus from three multicentre bacteraemia studies 
Background
At a time when the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) was changing, we sought to characterize several genotypic markers and glycopeptide susceptibility features of clinical isolates from patients with bacteraemia.
Methods
One hundred and sixty-eight MRSA bloodstream isolates obtained from three multicentre clinical trials were microbiologically and genotypically characterized.
Results
All isolates were susceptible to vancomycin (MIC ≤ 2 mg/L); 38% belonged to accessory gene regulator (agr) group I, 52% belonged to group II and 10% belonged to group III. Typing of the staphylococcal cassette chromosome mec (SCCmec) showed that 67% were type II and 33% were type IV. The agr group II polymorphism was associated with SCCmec II (P < 0.001). Fifty-three percent of SCCmec II and 27% of SCCmec IV isolates had vancomycin MICs ≥1 mg/L (P = 0.001). One hundred percent of agr II strains were predicted to be members of clonal complex 5. SCCmec II was the genetic marker most predictive of vancomycin MICs of ≥1 mg/L. SCCmec IV isolates were more likely to have vancomycin MICs ≤0.5 mg/L.
Conclusions
Given that SCCmec IV is a marker for a community-based organism for which less prior vancomycin exposure is predicted, we conclude that prior antibiotic exposure in agr group II organisms may account for their increased vancomycin MICs.
doi:10.1093/jac/dkp047
PMCID: PMC2667134  PMID: 19261624
MRSA; SCCmec types; clonal types; Staphylococcus spp.
7.  Microbiological and Genotypic Analysis of Methicillin-Resistant Staphylococcus aureus Bacteremia▿  
In a recent landmark trial of bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) isolates, vancomycin MICs were ≥1 μg/ml for only 16% of the isolates, and accessory gene regulator (agr) function as measured by delta-hemolysin activity was absent or reduced in only 28.1% of the isolates. This clinical study did not capture a population of MRSA isolates predictive of vancomycin treatment failure.
doi:10.1128/AAC.00357-08
PMCID: PMC2533503  PMID: 18606839
8.  Vancomycin In Vitro Bactericidal Activity and Its Relationship to Efficacy in Clearance of Methicillin-Resistant Staphylococcus aureus Bacteremia▿  
We examined the relationship between the time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia while patients were receiving vancomycin therapy and the in vitro bactericidal activity of vancomycin. Vancomycin killing assays were performed with 34 MRSA bloodstream isolates (17 accessory gene regulator group II [agr-II] and 17 non-agr-II isolates) from 34 different patients with MRSA bacteremia for whom clinical and microbiological outcomes data were available. Vancomycin doses were prospectively adjusted to achieve peak plasma concentrations of 28 to 32 μg/ml and trough concentrations of 8 to 12 μg/ml. Bactericidal assays were performed over 24 h with ∼107 to 108 CFU/ml in broth containing 16 μg/ml vancomycin. The median time to clearance of bacteremia was 6.5 days for patients with MRSA isolates demonstrating ≥2.5 reductions in log10 CFU/ml at 24 h and >10.5 days for patients with MRSA isolates demonstrating <2.5 log10 CFU/ml by 24 h (P = 0.025). The median time to clearance was significantly longer with MRSA isolates with vancomycin MICs of 2.0 μg/ml compared to that with MRSA isolates with MICs of ≤1.0 μg/ml (P = 0.019). The bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of a longer duration of bacteremia (10 days and 6.5 days, respectively; P = 0.27) and had a decreased probability of eradication (44% and 78%, respectively; P = 0.086). We conclude that strain-specific microbiological features of MRSA, such as increased vancomycin MICs and decreased killing by vancomycin, appear to be predictive of prolonged MRSA bacteremia while patients are receiving vancomycin therapy. Prolonged bacteremia and decreased delta-hemolysin expression may also be related. Evaluation of these properties may be useful in the consideration of antimicrobial therapies that can be used as alternatives to vancomycin for the treatment of MRSA bacteremia.
doi:10.1128/AAC.00939-06
PMCID: PMC1913284  PMID: 17452488

Results 1-8 (8)