Daptomycin Minimum Inhibitory Concentration Research Articles

Association between daptomycin susceptibility and teicoplanin resistance in Staphylococcus epidermidis

Staphylococcus epidermidis infections are a common occurrence in hospitals, particularly in catheter-related bloodstream and surgical site infections and infective endocarditis. Higher daptomycin minimum inhibitory concentration (MIC) values may be associated with daptomycin treatment failure among patients with S. epidermidis infections. We therefore conducted a retrospective cohort study to determine the predictive value of daptomycin susceptibility. A retrospective study was undertaken in 1,337 patients with S. epidermidis infections. Data were collected from 1 January 2013 to 31 December 2016 at Ehime University Hospital, and included the following clinicopathological factors for evaluation: age, sex, resistance to vancomycin or teicoplanin, and history of antimicrobial therapy. Multiple analysis was performed using logistic regression to identify factors that independently and significantly affected the daptomycin resistance. Daptomycin-resistant S. epidermidis was identified in 38 (2.8%) patients. According to the multiple analysis, only higher MIC values (≥16 mg/L) for teicoplanin (P < 0.0001) were independently associated with an increased risk of developing daptomycin resistance. In conclusion, higher teicoplanin MIC values may predict resistance to daptomycin treatment in S. epidermidis infections.

Optimizing the Dosing Regimens of Daptomycin Based on the Susceptible Dose-Dependent Breakpoint against Vancomycin-Resistant Enterococci Infection.

Daptomycin, a lipopeptide antibiotic, is one of the therapeutic options used for the treatment of vancomycin-resistant enterococci (VRE). Recently, the Clinical and Laboratory Standards Institute (CLSI) M100 30th edition has removed the susceptibility (S) breakpoint for Enterococcus faecium and replaced it with a susceptible dose-dependent (SDD) breakpoint of ≤4 μg/mL, with a suggested dosage of 8–12 mg/kg/day. Herein, we aimed to determine the minimum inhibitory concentration (MIC) values of daptomycin against clinical VRE isolates and to study the appropriate daptomycin dosing regimens among critically ill patients based on the new susceptibility CLSI breakpoint. The MIC determination of daptomycin was performed using E-test strips among clinical VRE strains isolated from patients at the Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the ratio of the free area under the curve to MIC (fAUC0–24/MIC) > 27.4 and fAUC0–24/MIC > 20 for survival and microbiological response, respectively, at the first day and steady state. Further, we determined that the simulated daptomycin dosing regimen met the minimum concentration (Cmin) requirements for safety of being below 24.3 mg/L. All of the 48 VRE isolates were E. faecium strains, and the percentiles at the 50th and 90th MIC of daptomycin were 1 and 1.5 μg/mL, respectively. At MIC ≤ 2 μg/mL, a daptomycin dosage of 12 mg/kg/day achieved the PTA target of survival and microbiological response at the first 24 h time point and steady state. For a MIC of 4 μg/mL, none of the dosage regimens achieved the PTA target. For CFR, a dosage of 8–12 mg/kg/day could achieve the 90% CFR target at the first day and steady state. All dosing regimens had a low probability of Cmin being greater than 24.3 mg/L. In conclusion, the MIC of VRE against daptomycin is quite low, and loading and maintenance doses with 8 mg/kg/day were determined to be optimal and safe.

Daptomycin resistance in methicillin-resistant Staphylococcus aureus is conferred by IS256 insertion in the promoter of mprF along with mutations in mprF and walK

Mechanisms underlying the emergence of daptomycin resistance in Staphylococcus aureus remain unclear. In this study, Staphylococcus aureus strain 3d0, isolated from a patient with bloodstream infection and belonging to the predominant Chinese hospital-associated methicillin-resistant S. aureus (MRSA) clone ST239, was serially passaged on gradient broth containing daptomycin for 34 days. The whole genomes of 3d0 and its serial passage strains were sequenced and compared. Five single nucleotide polymorphisms, four IS256 insertions, and one 39-bp insert occurred in the progress of daptomycin resistance acquisition. IS256 insertion in the mprF promoter region resulted in mprF overexpression. Two novel point mutations in mprF and walK, leading to amino acid substitutions in MprF (G299V and L473I) and WalK (L7Q and Y225N), were shown by allelic replacement experiments to increase the minimum inhibitory concentration (MIC) of daptomycin by 2-4 times. Allelic replacement of both mprF and walK in strain 3d0 increased the daptomycin MIC by 4-8-fold, indicating that mprF and walK mutations synergistically contribute to daptomycin non-susceptibility. Notably, these mutants acquired resistance without losing fitness and exhibited decreased expression of cell wall degradation-related genes. In conclusion, this study revealed novel mutations of MRSA daptomycin resistance acquisition in vitro as well as several novel mutations in walK and mprF, and includes the first in-depth analysis of the mprF promoter. This study sheds light on how MRSA may acquire daptomycin resistance during daptomycin treatment.

2441. Outcomes of Patients With Vancomycin-Resistant Enterococcus Blood Stream Infections (BSI) Treated With Daptomycin

BackgroundReports of poor outcomes in patients (patients) infected with VRE strains with daptomycin (DAP) minimum inhibitory concentrations (MIC) near the susceptible breakpoint (<=4 μg/ml) are noted in the literature. We assessed the relationship of clinical outcomes for patients treated with DAP to the initial MIC.MethodsRetrospective study of consecutive adult patients with VRE BSI treated with DAP for at least 48 hours (November 2011–January 2015) in a tertiary hospital in Cleveland, OH. Patients were grouped based on the initial DAP MIC (MIC ≤ 2 μg/mL and MIC = 4 μg/mL) determined by a commercial broth microdilution method (Sensititre). Demographic and clinical data were extracted via EMR. Outcomes for all-cause mortality at 30 days (30-D mortality) and 90 days (90-D mortality), 30-day mortality attributed directly to VRE BSI (30-D mortality VRE) and microbiological failure (MF) were measured. MF was defined as duration of bacteremia ≥4 days after at least 48 hours of DAP use and achievement of source control when possible. We also assessed the impact of concomitant β-lactam use on MF.ResultsA total of 192 patients were identified. Baseline characteristics are shown in Table 1. Outcomes for MF, 30-D mortality VRE, 30-D mortality and 90-D mortality are shown in Table 2. Impact of concomitant β-lactam use on MF is shown in Figure 1.ConclusionIn this retrospective study, MF and mortality were not significantly higher for BSI caused by VRE with DAP MICs of 4 μg/ml, regardless of concomitant β-lactam use. Disclosures S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant.

Vancomycin, linezolid and daptomycin susceptibility pattern among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) from Sub- Himalyan Center

INTRODUCTION:The efficacy of vancomycin, drug of choice for methicillin-resistant Staphylococcus aureus (MRSA), has become questionable due to the emergence of MRSA isolates with reduced susceptibility. The present study was conducted to determine the vancomycin, linezolid, and daptomycin susceptibility pattern in clinical isolates of MRSA and to observe minimum inhibitory concentration (MIC) creep over 2 years if any.MATERIALS AND METHODS:MIC of vancomycin, linezolid, and daptomycin were determined by E-test in 198 MRSA isolates and their MIC 50, MIC 90, and geometric mean MIC were calculated.RESULTS:While all isolates were sensitive to vancomycin, linezolid, and daptomycin, MIC 90 of vancomycin increased from 1.5 μg/ml in 2015 to 2 μg/ml in 2016. The percentage of isolates with vancomycin MIC >2 μg/ml doubled in 2016 (12.9%) as compared to 2015 (6.1%). MIC 90 for linezolid remained steady as 3 μg/ml, but geometric mean MIC increased from 2.20 μg/ml in 2015 to 2.29 μg/ml in 2016, and more than 40% isolates showed MIC 3 μg/ml. MIC 90 and geometric mean MIC of daptomycin decreased from 0.75 μg/ml to 0.5 μg/ml and 0.50 μg/ml to 0.36 μg/ml in 2015 and 2016, respectively.CONCLUSION:MIC creep was observed with vancomycin. Although linezolid MIC was within the susceptible zone, more than 40% strains showing MIC 3 μg/ml may herald the future development of either resistant or heteroresistant. Daptomycin showed good sensitivity against MRSA isolates. Therefore, it could be considered as an alternative agent for the treatment of infections caused by MRSA. However, it should be reserved where this class has a clear therapeutic advantage over other anti-MRSA drugs.

Vancomycin and daptomycin minimum inhibitory concentrations as a predictor of outcome of methicillin-resistant Staphylococcus aureus bacteraemia.

The aim of this study was to determine the persistence of the adverse prognostic effect of elevated vancomycin minimum inhibitory concentration (MIC) in methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in a setting with low vancomycin use. A retrospective study focusing on episodes of bacteraemia due to MRSA diagnosed from January 2010 through December 2015 was designed. The main outcome measures were 30-day mortality and treatment failure. Multivariate logistic regression analysis was used to identify variables associated with patient mortality and treatment outcome. In total, 79 MRSA bacteraemia episodes were included. The vancomycin MIC was >1.0μg/mL in 53 episodes (67.1%). The presence of high vancomycin MIC was not associated with a higher mortality rate or treatment success. A daptomycin MIC≥0.5μg/mL was present in 16 (26.2%) of 61 episodes for which the daptomycin MIC was obtained and was associated with 30-day mortality in the multivariate analysis (odds ratio=4.72, 95% confidence interval 1.19-18.71). None of the antimicrobials used were associated with a lower risk of treatment failure or mortality. The pernicious effect of high vancomycin MIC disappears in the absence of a predominant use of this antibiotic. However, a high daptomycin MIC in MRSA bacteraemia is associated with higher mortality in patients with bacteraemia, irrespective of antimicrobial treatment choice.

Institution-wide and Within-Patient Evolution of Daptomycin Susceptibility in Vancomycin-Resistant Enterococcus faecium Bloodstream Infections.

We report daptomycin minimum inhibitory concentrations (MICs) for vancomycin-resistant Enterococcus faecium isolated from bloodstream infections over a 4-year period. The daptomycin MIC increased over time hospital-wide for initial isolates and increased over time within patients, culminating in 40% of patients having daptomycin-nonsusceptible isolates in the final year of the study. Infect Control Hosp Epidemiol 2018;39:226-228.

Treatment of Vancomycin-Resistant Enterococci: Focus on Daptomycin.

Vancomycin-resistant Enterococci (VRE) infections are problematic due to limited availability of anti-VRE agents and their potential for adverse effects and drug interactions. This review focuses on the role of daptomycin in treating VRE infections by summarizing key points of relevant clinical studies. Higher doses of daptomycin (≥6mg/kg), as compared to standard doses, were found to be safe in terms of creatinine phosphokinase elevation and associated with successful infection outcomes and microbiological clearance. High doses are especially important in treatment of infections involving elevated daptomycin minimum inhibitory concentration (MIC) values (3-4μg/mL). Daptomycin, especially in higher doses, has been shown to be an effective and safe VRE agent for a variety of serious infection types, such as catheter-associated bloodstream and intra-abdominal infections, and for different populations including oncology. Infections involving higher daptomycin MIC values were associated with previous daptomycin use and prosthetic devices.

In vitro stepwise selection of reduced susceptibility to lipoglycopeptides in enterococci

The propensity of oritavancin to select for stably elevated oritavancin minimum inhibitory concentrations (MICs) was studied by serial passaging of strains in broth containing oritavancin for 20days. Seven clinical strains of Enterococcus faecalis and E. faecium were studied; they included vancomycin-susceptible and both VanA and VanB vancomycin-resistant isolates. Stepwise oritavancin selection yielded stably elevated oritavancin MICs in six of the seven strains, with MIC increases ranging from 4–32-fold. By comparison, stepwise selection with comparator agents dalbavancin (4- to >128-fold MIC increases), telavancin (4–8-fold MIC increases) and daptomycin (4–32-fold MIC increases) also yielded selectants with elevated MICs of the respective agents. Oritavancin selectants retained parental MICs of vancomycin, daptomycin, linezolid and rifampicin. Some, but not all of the oritavancin selectants also showed MIC increases to the lipoglycopeptides telavancin, dalbavancin and teicoplanin, suggesting that within the lipoglycopeptide class, different mechanisms of action may be elucidated.

Ventilator-associated pneumonia by methicillin-susceptible Staphylococcus aureus: do minimum inhibitory concentrations to vancomycin and daptomycin matter?

The use of vancomycin minimum inhibitory concentration (MIC) as an outcome predictor in patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia has become an important topic for debate in the last few years. Given these previous results, we decided to investigate whether MICs to vancomycin or daptomycin had any effect on the evolution of patients with ventilator-associated pneumonia (VAP) due to MSSA. An observational, retrospective, multicenter study was conducted among patients with MSSA VAP. We analyzed the relationship between vancomycin and daptomycin MICs and early clinical response (72 h), 30-day mortality, intensive care unit (ICU) length of stay (LOS), and duration on mechanical ventilation. Univariate and multivariate analyses were performed. Sixty-six patients from 12 centers were included. Twenty-six patients (39%) had an infection due to MSSA strains with a vancomycin MIC ≥1.5 μg/mL. Daptomycin MIC was determined in 58 patients, of whom 17 (29%) had an MIC ≥1.0 μg/mL. Ten patients (15%) did not respond to first-line treatment. Only daptomycin MIC ≥1.0 μg/mL had a significant association [odds ratio (OR): 30.00; 95% confidence interval (CI): 2.91-60.41] with early treatment failure. The 30-day mortality was 12% (n = 8). Any variable was associated with mortality in the multivariate analysis. None of the variables studied were associated with ICU LOS or duration on mechanical ventilation. In patients with MSSA VAP, vancomycin MIC does not influence the response to antibiotic treatment or the 30-day mortality. Daptomycin MIC was directly related to early treatment failure.

Effect of Daptomycin Dose on the Outcome of Vancomycin-Resistant, Daptomycin-Susceptible Enterococcus faecium Bacteremia.

Treatment options for vancomycin-resistant enterococci (VRE) bloodstream infection (BSI) are limited. Daptomycin, although not currently approved for this indication, is frequently used for the treatment of VRE-BSI. Its optimal dose still needs to be determined. We conducted a prospective, observational, cohort study during 2010-2015. We included patients who received a daptomycin dose of ≥6 mg/kg for the treatment of VRE-BSI caused by daptomycin-susceptible VRE. The primary endpoint was 14-day mortality, and multivariable logistic regression was performed for outcome analysis. We included 112 patients treated with daptomycin for VRE-BSI and with evaluable clinical outcomes. The daptomycin minimum inhibitory concentration (MIC) was 4 mg/L in 78 (69.6%) and ≤2 mg/L in 34 (30.4%) isolates. The overall mortality was 40/112 (35.7%). The unadjusted mortality was 18/36 (50.0%) for a daptomycin dose of <7 mg/kg, 17/51 (33.3%) for a dose of 7-9 mg/kg, and 5/25 (20%) for a dose of ≥9 mg/kg (P = .05). The best outcomes were associated with a daptomycin dose of ≥9 mg/kg compared to doses of <7 mg/kg (adjusted odds ratio [aOR], 10.57; 95% confidence interval [CI], 2.25-49.62; P=.003) and 7-9 mg/kg (aOR, 5.01; 95% CI, 1.14-21.98; P=.03). There was no significant difference in mortality with respect to the daptomycin MIC. There was no association between daptomycin dose and elevated creatinine kinase. Higher daptomycin doses (≥9 mg/kg) were associated with lower mortality in patients with VRE-BSI. Our results suggest that higher daptomycin doses need to be considered for VRE-BSI treatment.

Effectiveness of Daptomycin in Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Vancomycin

BackgroundClinicians often switch therapy in patients with persistent methicillin-resistant Staphylococcus aureus(MRSA) bacteremia despite prolonged vancomycin therapy. We evaluated the utilization of daptomycin in MRSA bacteremic patients who failed vancomycin therapy.MethodsThis single center, retrospective evaluation of adult patients who received daptomycin after receiving vancomycin for MRSA bacteremia from January 2011 to September 2016. Persistent bacteremia was defined as continued positive blood culture(s) despite receiving more than 72 hours of vancomycin. Patients with bacteremia from presumed pneumonia or MRSA bacteremia within 30 days of admission were excluded. Daptomycin dose was evaluated for appropriateness based upon patient weight and renal function. Duration of bacteremia was evaluated, including whether source control was achieved. Creatinine phosphokinase (CPK) levels drawn during daptomycin therapy were assessed to evaluate safety. Hospital length of stay and patient disposition were collected for each patient. Data were presented with descriptive statistics.Results700 patient received daptomycin during this study period; 66 were duplicates, 596 did not meet inclusion criteria and 38 patients were included. Minimum inhibitory concentrations (MICs) of isolates were 1mcg/mL (31.6%), 1.5mcg/mL (42.1%) and 2mcg/mL (26.3%). Daptomycin dose was 4mg/kg (10.5%), 6mg/kg (63%), 8mg/kg (16%) and 10mg/kg (10.5%). Twenty-eight (73.7%) of 38 patients cleared bacteremia with daptomycin. Ten patients were switched back to vancomycin for the following reasons: persistent bacteremia (6), increase in daptomycin MIC (3), and blood culture was negative on the date daptomycin was initiated (1). Duration of bacteremia while receiving vancomycin vs. daptomycin was 8.5 ± 6.6 days and 4.9 ± 5.4 days, respectively. Only one patient experienced elevated CPK > 5 times upper normal limit. Daptomycin was utilized appropriately in 97.4 % of the patients who failed vancomycin according to our current protocol.ConclusionDaptomycin was effective in a majority of the patients in clearing bacteremia but MICs increased in some patients. Prospective studies should be performed to confirm these findings.Disclosures All authors: No reported disclosures.

Vancomycin, teicoplanin, daptomycin, and linezolid MIC creep in methicillin-resistant Staphylococcus aureus is associated with clonality.

The purpose of this study is to evaluate the susceptibility trend of vancomycin, teicoplanin, daptomycin, and linezolid against methicillin-resistant Staphylococcus aureus (MRSA) blood isolates of different clones over an 11-year period.From 2000 to 2010, all bloodstream MRSA isolates from Chang Gung Memorial Hospital in Taiwan were prospectively collected. Three periods, namely 2000 to 2001, 2004 to 2005, and 2010, were included and 124 MRSA isolates were selected from each period. Minimum inhibitory concentrations (MICs) were determined by E-test. All the isolates were molecularly characterized.MRSA molecular epidemiology evolved from 1 predominant pulsotype (type A) to 5 major pulsotypes of 3 clonal complexes (CC). Vancomycin, teicoplanin, and daptomycin MICs creep were observed, particularly for pulsotype A-CC 239-staphylococcal cassette chromosome mec (SCCmec) III though its prevalence dramatically decreased since 2004 to 2005. Throughout the study period, the overall vancomycin modal MIC was stable at 1.5 mg/L, but teicoplanin and linezolid modal MIC increased to 2 and 2 mg/L, respectively. Isolates with teicoplanin and linezolid ≧ 2 ug/mL belonged to multiple clones. Pulsotype F-ST5-SCCmec II with a high rate of teicoplanin MIC ≧ 2 ug/mL continued clonal spread. Teicoplanin MIC had a high correlation with linezolid MIC.Molecular epidemiology MRSA bloodstream isolates in northern Taiwan evolved from 2000 throughout 2010, which was subsequently associated with the changing distribution of antibiotic MICs. While vancomycin MIC level remained unchanged, teicoplanin, daptomycin, and linezolid MIC levels increased. The impact of these changes on clinical treatment response deserves further investigations.

Vancomycin-resistant enterococci with reduced daptomycin susceptibility in Singapore: prevalence and associated factors.

Prevalence of vancomycin-resistant enterococci (VRE) and use of daptomycin are increasing in Asia. To determine the prevalence of daptomycin non-susceptible enterococci (DNSE) and understand factors associated with reduced daptomycin susceptibility in VRE, we conducted a case-control study in a 1600-bed adult tertiary hospital in Singapore. All VRE isolates from inpatients in 2012 were tested for daptomycin susceptibility. Patients with VRE isolates of daptomycin minimum inhibitory concentration (MIC) ⩾3 µg/ml were classified as daptomycin-reduced susceptible VRE (DRS-VRE) and those with daptomycin MIC 4 µg/ml (DNSE). About half (135, 55%) had reduced susceptibility to daptomycin (MIC 3-4 µg/ml). None in the DS-VRE group had prior exposure to daptomycin. After adjusting for age, gender, comorbidity, hospitalization duration, surgical history, indwelling device use, and duration of antibiotic exposure in the prior 3 months, >1 movement between wards [odds ratio (OR) 0·35, 95% confidence interval (CI) 0·16-0·74, P = 0·006] and minocycline resistance (OR 0·45, 95% CI 0·25-0·84, P = 0·011) were independently associated with DRS-VRE. Our study suggests that daptomycin exposure, >1 movement between wards, and resistance to minocycline, were associated with reduced daptomycin susceptibility in VRE.

Influence of Minimum Inhibitory Concentration in Clinical Outcomes of Enterococcus faecium Bacteremia Treated With Daptomycin: Is it Time to Change the Breakpoint?

Daptomycin has become a front-line antibiotic for multidrug-resistant Enterococcus faecium bloodstream infections (BSIs). We previously showed that E. faecium strains with daptomycin minimum inhibitory concentrations (MICs) in the higher end of susceptibility frequently harbor mutations associated with daptomycin resistance. We postulate that patients with E. faecium BSIs exhibiting daptomycin MICs of 3-4 µg/mL treated with daptomycin are more likely to have worse clinical outcomes than those exhibiting daptomycin MICs ≤2 µg/mL. We conducted a multicenter retrospective cohort study that included adult patients with E. faecium BSI for whom initial isolates, follow-up blood culture data, and daptomycin administration data were available. A central laboratory performed standardized daptomycin MIC testing for all isolates. The primary outcome was microbiologic failure, defined as clearance of bacteremia ≥4 days after the index blood culture. The secondary outcome was all-cause in-hospital mortality. A total of 62 patients were included. Thirty-one patients were infected with isolates that exhibited daptomycin MICs of 3-4 µg/mL. Overall, 34 patients had microbiologic failure and 25 died during hospitalization. In a multivariate logistic regression model, daptomycin MICs of 3-4 µg/mL (odds ratio [OR], 4.7 [1.37-16.12]; P = .014) and immunosuppression (OR, 5.32 [1.20-23.54]; P = .028) were significantly associated with microbiologic failure. Initial daptomycin dose of ≥8 mg/kg was not significantly associated with evaluated outcomes. Daptomycin MICs of 3-4 µg/mL in the initial E. faecium blood isolate predicted microbiological failure of daptomycin therapy, suggesting that modification in the daptomycin breakpoint for enterococci should be considered.

More accurate measurement of vancomycin minimum inhibitory concentration indicates poor outcomes in meticillin-resistant Staphylococcus aureus bacteraemia

Meticillin-resistant Staphylococcus aureus (MRSA) is an important pathogen associated with community-acquired and nosocomial infections. The aim of this study was to validate the vancomycin (VAN) minimum inhibitory concentration (MIC) and administration of VAN that may affect the prognosis of patients with MRSA bacteraemia. In total, 140 clinical MRSA strains from blood cultures were collected from January 2009 to December 2013 at a university hospital in Tokyo (Japan). Patient background, their clinical situation and the susceptibility of isolates to anti-MRSA agents in all cases were reviewed, and factors contributing to 30-day mortality were analysed. Susceptibility to anti-MRSA agents was measured by a microdilution susceptibility testing method. The VAN MIC was further evaluated at 0.25μg/mL intervals from 0.5μg/mL to 2.0μg/mL. Multiple logistic regression analysis revealed a 4-fold increase in mortality of patients with a VAN MIC ≥1.5μg/mL [odds ratio (OR)=3.952, 95% confidence interval (CI) 1.471–10.614; P=0.006]. A one-score increase in the Charlson co-morbidity index resulted in a 1.2-fold increase in the risk of death (OR=1.199, 95% CI 1.054–1.364; P=0.006). However, no significant difference was found in the ratio of the VAN 24-h area under the concentration–time curve to MIC between VAN MIC ≥1.5μg/mL and <1.5μg/mL. A significant increase in the MICs of teicoplanin and daptomycin was observed in strains with high VAN MICs. For patients with high VAN MICs, administration of these anti-MRSA antibiotics may have a poor outcome owing to cross-resistance.

Impact of Molecular Epidemiology and Reduced Susceptibility to Glycopeptides and Daptomycin on Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia.

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) bacteremia was associated with high mortality, but the risk factors associated with mortality remain controversial.MethodsA retrospective cohort study was designed. All patients with MRSA bacteremia admitted were screened and collected for their clinical presentations and laboratory characteristics. Minimum inhibitory concentration (MIC) and staphylococcal cassette chromosome mec (SCCmec) type of bacterial isolates were determined. Risk factors for mortality were analyzed.ResultsMost MRSA isolates from the 189 enrolled patients showed reduced susceptibility to antibiotics, including MIC of vancomycin ≥ 1.5 mg/L (79.9%), teicoplanin ≥ 2 mg/L (86.2%), daptomycin ≥ 0.38 mg/L (73.0%) and linezolid ≥ 1.5 mg/L (64.0%). MRSA with vancomycin MIC ≥ 1.5 mg/L and inappropriate initial therapy were the two most important risk factors for mortality (both P < 0.05; odds ratio = 7.88 and 6.78). Hospital-associated MRSA (HA-MRSA), carrying SCCmec type I, II, or III, was associated with reduced susceptibility to vancomycin, teicoplanin or daptomycin and also with higher attributable mortality (all P < 0.05). Creeping vancomycin MIC was linked to higher MIC of teicoplanin and daptomycin (both P < 0.001), but not linezolid (P = 0.759).ConclusionsGiving empirical broad-spectrum antibiotics for at least 5 days to treat catheter-related infections, pneumonia, soft tissue infection and other infections was the most important risk factor for acquiring subsequent HA-MRSA infection. Choice of effective anti-MRSA agents for treating MRSA bacteremia should be based on MIC of vancomycin, teicoplanin and daptomycin. Initiation of an effective anti-MRSA agent without elevated MIC in 2 days is crucial for reducing mortality.

Real-World Treatment of Enterococcal Infections with Daptomycin: Insights from a Large European Registry (EU-CORE).

IntroductionEvolution of antibacterial resistance in pathogenic enterococcal strains poses a growing therapeutic challenge. Daptomycin, a cyclic lipopeptide, exhibits broad antibiotic activity against Gram-positive bacteria.MethodsThe European Cubicin® Outcomes Registry and Experience, a multicenter, retrospective, non-interventional study, recorded clinical outcomes following daptomycin treatment.ResultsOverall, 472 patients (predominantly elderly Caucasian males) were treated for enterococcal infections. Of those, 72.7% received antibiotics prior to daptomycin treatment, whereas 77.1% received other antibiotics concomitantly. Failure of previous therapy, resistant or non-susceptible pathogen, and narrowing of antibiotic therapy were the main reasons for switching to daptomycin treatment. Nosocomial infections comprised 55.8% of the cohort. Bacteremia (29.9%), complicated skin and soft tissue infection (29.2%) and endocarditis (12.3%) were the most common primary infections. Clinical success was achieved in 77.1% of patients, with similar success rates across all primary infection categories. The overall clinical success rate was marginally higher (82.5% vs 74.6%, p = 0.09) with daptomycin use as first-line versus second-line therapy. Patients receiving higher doses of daptomycin exhibited the highest clinical success rates (85.7% for ≥8 mg/kg/day vs 75.8% for <8 mg/kg/day, p = 0.08). While 81 (17.2%) patients reported at least one adverse event (AE), only 11 (2.3%) and 3 (0.6%) had treatment-related AEs and serious AEs, respectively. Separate microbiologic findings from Leipzig University Hospital demonstrate small proportions of Enterococcus faecium isolates with daptomycin minimum inhibitory concentrations = 4 mg/L (4%) or ≥8 mg/L (0.8%), which are regarded as non-susceptible.ConclusionFor enterococcal infections, daptomycin appears to be an effective and well-tolerated treatment option, exhibiting highest clinical success rates at higher doses.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-015-0072-z) contains supplementary material, which is available to authorized users.

An investigation of vancomycin minimum inhibitory concentration creep among methicillin-resistant Staphylococcus aureus strains isolated from pediatric patients and healthy children in Northern Taiwan.

The phenomenon of vancomycin minimum inhibitory concentration (MIC) creep is an increasingly serious problem in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. In this study, we investigated the vancomycin and daptomycin MIC values of MRSA strains isolated from pediatric patients and MRSA colonized healthy children. Then, we assessed whether there was evidence of clonal dissemination for strains with an MIC to vancomycin of ≥ 1.5μg/mL. We collected clinical MRSA isolates from pediatric patients and from healthy children colonized with MRSA during 2008-2012 at a tertiary medical center in northern Taiwan and obtained vancomycin and daptomycin MIC values using the Etest method. Pulse-field gel electrophoresis (PFGE) and staphylococcal cassette chromosome (SCCmec) typing were used to assess clonal dissemination for strains with an MIC to vancomycin of ≥ 1.5μg/mL. A total 195 MRSA strains were included in this study; 87 were isolated patients with a clinical MRSA infection, and the other 108 strains from nasally colonized healthy children. Vancomycin MIC≥1.5μg/mL was seen in more clinical isolates (60/87, 69%) than colonized isolates (32/108, 29.6%), p<0.001. The PFGE typing of both strains revealed multiple pulsotypes. Vancomycin MIC creeps existed in both clinical MRSA isolates and colonized MRSA strains. Great diversity of PFGE typing was in both strains collected. There was no association between the clinical and colonized MRSA isolates with vancomycin MIC creep.

The Prevalence of Vancomycin-Intermediate Staphylococcus aureus and Heterogeneous VISA Among Methicillin-Resistant Strains Isolated from Pediatric Population in a Turkish University Hospital.

There are limited data regarding the prevalence of vancomycin-intermediate Staphylococcus aureus (VISA)/heterogeneous VISA (hVISA) among pediatric population. Our objective was to determine the distribution of vancomycin and daptomycin minimum inhibitory concentrations (MICs) and explore the phenomenon of vancomycin MIC creep and the VISA/hVISA prevalence among the methicillin-resistant Staphylococcus aureus (MRSA) strains belonging to pediatric population by population analysis profile-area under the curve (PAP-AUC) and Etest macromethod. Vancomycin and daptomycin susceptibilities of 94 pediatric isolates of MRSA were tested by broth microdilution (BMD) and Etest methods. To determine the prevalence of VISA/hVISA, Etest macromethod and PAP-AUC was performed on all isolates. All isolates were susceptible to vancomycin and daptomycin by both BMD and Etest methods. Twenty-eight (29.8%) isolates had vancomycin MICs of 2 μg/ml by BMD. No increase in vancomycin MICs was observed over time. There were no VISA among 94 MRSA tested but 20 (21.3%) hVISA isolates were identified by PAP-AUC. Results of Etest macromethod were compared to PAP-AUC. Etest macromethod was 60.0% sensitive and 90.5% specific. The hVISA isolates represented 53.6% of isolates with vancomycin MICs of 2 μg/ml. Also, 75% of hVISA isolates had vancomycin MICs of 2 μg/ml. To our knowledge, this is the first study investigating the prevalence of VISA/hVISA among MRSA isolated from pediatric patients by PAP-AUC method. Based on our findings, MRSA isolates, which have vancomycin MIC of 2 μg/ml can be investigated for the presence of hVISA. In this study, daptomycin showed potent activity against all isolates and may represent a therapeutic option for MRSA infections.