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Given the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC0-24) and the minimum concentration at 24 h (Cmin 24) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC0-24/MIC as determined by BMD of ≤600 relative to those with AUC0-24/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively, P = 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37; P = 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC0-24/MIC as determined by BMD of ≤600 present an increased risk of failure., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA IE) is associated with high morbidity and mortality. Vancomycin continues to be the primary treatment for this disease. The emergence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), defined as a modified population analysis profile (PAP) of ≥ 0.9, may affect patient outcomes. The objective of this study was to evaluate the relationship of vancomycin subpopulation susceptibility and the clinical outcomes of MRSA IE. We conducted a retrospective cohort study of patients treated with vancomycin for MRSA IE from 2002 to 2013 at the Detroit Medical Center. A modified PAP was used to measure the vancomycin PAP MIC and the PAP-to-area under the curve (AUC) ratio. Treatment failure was defined as bacteremia for ≥ 7 days or death attributed to MRSA. Classification and regression tree (CART) analysis was used to select a failure breakpoint between the PAP-AUC ratios and the PAP MIC. A total of 202 patients were included in the study. Twenty-seven percent of the patients had left-sided IE, 19% of the strains were hVISA, and 70% of the strains were staphylococcal cassette chromosome mec element (SCCmec) type IV. Overall treatment failure was observed in 64%; 59% had persistent bacteremia, and the 30-day attributable mortality rate was 21%. The CART breakpoint between failure and success in terms of the PAP-AUC ratio was 0.9035. On logistic regression analysis, intensive care unit (ICU) admission (adjusted odds ratio [aOR], 2.8; 95% confidence interval [CI], 1.5 to 5.2) and a PAP MIC of ≥ 4 mg/liter (aOR, 3.2; 95% CI, 1.3 to 8.4) were associated with failure (P = 0.001 and 0.015, respectively). A PAP MIC of ≥ 4 mg/liter and ICU admission were significant for treatment failure for patients with MRSA IE. The PAP-AUC ratio of ≥ 0.9035 predicted failure consistent with the hVISA definition. The role of population MIC analysis in predicting outcome with MRSA infections warrants further investigation., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Recent reports have described decreased effectiveness with vancomycin treatment for methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) when the vancomycin minimum inhibitory concentration (MIC) is >1 µg/mL., Methods: This matched, retrospective cohort study compared the clinical effectiveness of daptomycin with that of vancomycin for the treatment of MRSAB with vancomycin MICs >1 µg/mL. The primary outcome was clinical failure, defined as a composite of 30-day mortality or bacteremia persisting for ≥7 days., Results: One hundred seventy patients were matched 1:1 with respect to the antimicrobial administered. In the daptomycin group, all patients received <72 hours of vancomycin (median, 1.7 days [interquartile range, 1.1-2.3 days]) prior to switching to daptomycin. The rate of clinical failure at 30 days was significantly lower in the daptomycin arm compared to the vancomycin arm (20.0% vs 48.2%; P < 0.001). Both 30-day mortality and persistent bacteremia were significantly lower in the daptomycin group compared to the vancomycin group (3.5% vs 12.9% [P = .047] and 18.8% vs 42.4% [P = .001], respectively). Logistic regression confirmed the association between vancomycin treatment and increased risk of clinical failure (adjusted odds ratio, 4.5; 95% confidence interval, 2.1-9.8)., Conclusions: This is the first matched study comparing early daptomycin versus vancomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL. Treatment with daptomycin resulted in significantly improved outcomes, including decreased 30-day mortality and persistent bacteremia. These results support the practice of switching early from vancomycin to daptomycin for the treatment of MRSAB when the vancomycin MIC is >1 µg/mL.

Objective: We evaluated the clinical and molecular epidemiology of bloodstream infections (BSIs) due to methicillin-resistant Staphylococcus aureus (MRSA) in older versus younger patients treated with vancomycin, determining the independent effect of increased age on outcomes., Design: Observational retrospective cohort study., Setting: Detroit Medical Center, level I trauma center., Patients: Adult older (65 years and older) and younger (younger than 65 years) patients with documented BSIs due to MRSA treated with vancomycin (2005-2010)., Methods: Collected demographics, comorbidities, microbiology, treatment, outcomes. Multivariable model used to generate propensity score for each patient on the basis of the probability of being 65 years of age or older., Results: Three hundred twenty patients were eligible (69 patients 65 years and older; 251 patients younger than 65 years). Catheter-related infections and endocarditis were the most common sites of infection for older (20.3%) and younger (19.1%) adults, respectively. Median first total 24-hour vancomycin dose (1,000 vs 2,000 mg; [Formula: see text]) and initial trough (13.1 vs 15.0 mg/L; [Formula: see text]) was significantly lower in older versus younger patients. Vancomycin treatment failure rates were similar among older and younger patients (49.3% vs 53.4%; [Formula: see text]). In multivariable analysis of outcomes, after controlling for predictors of older age, there was no difference in clinical outcomes between older and younger adults., Conclusions: After accounting for confounders associated with increased age, failure rate of patients with BSIs due to MRSA treated with vancomycin was similar between older and younger patients. Older adults were less likely to have optimal vancomycin dosing and initial trough levels than younger patients. Efforts should be made to optimize dosing of medications such as vancomycin in older adults.

Study Objective: To compare clinical outcomes and costs in patients treated with the new vancomycin guidelines recommending goal serum trough concentrations of 15-20 mg/L versus patients treated with vancomycin doses targeting trough concentrations 5-20 mg/L prior to the new guidelines., Design: Retrospective quasi-experimental study., Setting: Urban level I trauma center., Patients: A total of 200 patients treated with vancomycin for at least 72 hours for confirmed, complicated methicillin-resistant Staphylococcus aureus (MRSA) bacteremia during one of two study phases relative to the implementation of the vancomycin dosing guidelines targeting serum trough concentrations of 15-20 mg/L: 2005-2007 (preperiod phase) and 2008-2010 (postperiod phase). One hundred patients in each phase were matched in a 1:1 ratio according to diagnosis, any concomitant nephrotoxic agents (e.g., aminoglycosides, colistin, acyclovir), and age ± 5 years., Measurements and Main Results: Patients in the preperiod had significantly lower success rates with vancomycin than those in the postperiod (45% vs 60%, p=0.034). Median length of stay (LOS) was not significantly higher in patients in the preperiod versus postperiod (15 days vs 13.5 days; p=0.28), and patients in the preperiod received a longer median duration of vancomycin versus those in the postperiod (13 days vs 8.5 days; p<0.001). No statistically significant difference was noted in total hospital costs for patients treated with vancomycin during the preperiod versus the postperiod ($32,754 vs $27,709, p=0.147). However, total drug and monitoring costs of vancomycin were significantly higher for patients in the postperiod. Initial vancomycin trough levels were significantly lower in patients in the preperiod versus postperiod (12.3 mg/L vs 15.8 mg/L, p=0.02). Patients in the preperiod had lower rates of nephrotoxicity than those in the postperiod, although this difference was not statistically significant (15% vs 18%; p=0.85). Median (interquartile range) LOS was significantly longer in patients who developed nephrotoxicity compared with patients who did not develop nephrotoxicity (17 days [11.5-36.5 days] vs 14 days [9-24 days], p=0.017). Costs associated with measurement of serum creatinine concentrations and vancomycin trough levels as well as labor were significantly higher in patients who developed nephrotoxicity., Conclusion: Higher vancomycin trough concentrations improved outcomes in patients with complicated MRSA bacteremia. In addition, more aggressive dosing was shown to significantly decrease overall duration of vancomycin therapy, which may affect total hospital LOS and cost. Patients who experienced nephrotoxicity had a significantly longer hospital LOS. Additional studies evaluating optimal therapy for MRSA bacteremia in a larger cohort of matched patients are warranted., (© 2012 Pharmacotherapy Publications, Inc.)

Study Objective: To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15-20 mg/L., Design: Prospective multicenter study., Setting: Five tertiary care teaching hospitals., Patients: A total of 200 adults who required vancomycin dosages targeted to attain recommended trough vancomycin serum concentrations of 15-20 mg/L., Intervention: The new nomogram, which based dosing on weight and renal function, was used to calculate patients' initial vancomycin dosages. Serum trough concentrations were measured before the fourth or fifth dose, and dosages were adjusted as needed., Measurements and Main Results: Median patient age was 56 years (interquartile range [IQR] 49-65 yrs), median weight was 71.2 kg (IQR 63-85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52-82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0-20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15-20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was -0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14-21 mg/L and 160 (80%) achieved troughs of 13-22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3-19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater., Conclusion: Fifty-eight percent of patients achieved the target trough of 15-20 mg/L (median 17.5 mg/L). The performance of the nomogram improved to 80% when the trough range was adjusted to 13-22 mg/L. Caution should be applied when using this nomogram. The nomogram should not replace clinical judgment, and dosage adjustments should be based on pharmacokinetic-pharmacodynamic targets and clinical response.

Background: High rates of vancomycin failure in methicillin-resistant Staphylococcus aureus (MRSA) infections have been increasingly reported over time. The primary objective of our study was to determine the impact of vancomycin exposure and outcomes in patients with MRSA bacteremia initially treated with vancomycin., Methods: This was a single-center retrospective analysis of 320 patients with documented MRSA bacteremia initially treated with vancomycin from January 2005 through April 2010. Two methods of susceptibility, Etest and broth microdilution, were performed for all isolates to determine the correlation of susceptibility testing to patient outcomes., Results: Among a cohort of 320 patients, more than half (52.5%) experienced vancomycin failure. Independent predictors of vancomycin failure in logistic regression included infective endocarditis (adjusted odds ratio [AOR], 4.55; 95% confidence interval [CI], 2.26-9.15), nosocomial-acquired infection (AOR, 2.19; 95% CI, 1.21-3.97), initial vancomycin trough <15 mg/L (AOR, 2.00; 95% CI, 1.25-3.22), and vancomycin minimum inhibitory concentration (MIC) >1 mg/L by Etest (AOR, 1.52; 95% CI, 1.09-2.49). With use of Classification and Regression Tree (CART) analysis, patients with vancomycin area under the curve at 24 h (AUC(24h)) to MIC ratios <421 were found to have significantly higher rates of failure, compared with patients with AUC(24h) to MIC ratios >421 (61.2% vs 48.6%; P = .038)., Conclusions: In light of the high failure rates associated with this antimicrobial, optimizing the pharmacokinetic/pharmacodynamic properties of vancomycin by targeting higher trough values of 15-20 mg/L and AUC(24h)/MIC ratios ≥400 in selected patients should be considered.

Vancomycin (VAN) and daptomycin (DAP) are approved as a monotherapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. A regimen of daptomycin plus ceftaroline (DAP+CPT) has shown promise in published case series of MRSA salvage therapy, but no comparative data exist to compare up-front DAP+CPT head-to-head therapy versus standard monotherapy as an initial treatment. In a pilot study, we evaluated 40 adult patients who were randomized to receive 6 to 8 mg/kg of body weight per day of DAP and 600 mg intravenous (i.v.) CPT every 8 h (q8h) (n = 17) or standard monotherapy (n = 23) with vancomycin (VAN; dosed to achieve serum trough concentrations of 15 to 20 mg/liter; n = 21) or 6 to 8 mg/kg/day DAP (n = 2). Serum drawn on the first day of bacteremia was sent to a reference laboratory post hoc for measurement of interleukin-10 (IL-10) concentrations and correlation to in-hospital mortality. Sources of bacteremia, median Pitt bacteremia scores, Charlson comorbidity indices, and median IL-10 serum concentrations were similar in both groups. Although the study was initially designed to examine bacteremia duration, we observed an unanticipated in-hospital mortality difference of 0% (0/17) for combination therapy and 26% (6/23) for monotherapy (P = 0.029), causing us to halt the study. Among patients with an IL-10 concentration of >5 pg/ml, 0% (0/14) died in the DAP+CPT group versus 26% (5/19) in the monotherapy group (P = 0.057). Here, we share the full results of this preliminary (but aborted) assessment of early DAP+CPT therapy versus standard monotherapy in MRSA bacteremia, hoping to encourage a more definitive clinical trial of its potential benefits against this leading cause of infection-associated mortality. (The clinical study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT02660346.).

MRSA bacteraemia (MRSAB), including infective endocarditis, carries a high mortality rate, with up to 50% of patients failing initial therapy with vancomycin and requiring salvage therapy. Persistent MRSAB can be difficult to successfully eliminate, especially when source control is not possible due to an irremovable focus or the bacteraemia still persists despite surgical intervention. Although vancomycin and daptomycin are the only two antibiotics approved by the US FDA for the treatment of patients with MRSAB as monotherapy, the employment of novel strategies is required to effectively treat patients with persistent MRSAB and these may frequently involve combination drug therapy. Treatment strategies that are reviewed in this manuscript include vancomycin combined with a β-lactam, daptomycin-based therapy, ceftaroline-based therapy, linezolid-based therapy, quinupristin/dalfopristin, telavancin, trimethoprim/sulfamethoxazole-based therapy and fosfomycin-based therapy. We recommend that combination antibiotic therapy be considered for use in MRSAB salvage treatment. [ABSTRACT FROM AUTHOR]

The longer methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) persists uncontrolled, the more pharmacotherapy is hindered. With rapid diagnostics, superior combination antimicrobial therapy, and the selective pressure consequences of prolonged in vivo persistence, MRSAB should clear within 3–4 days.Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB) is associated with poor outcomes and serious complications. The MRSA guidelines define treatment failure and persistent bacteremia as lasting ≥7 days; however, this definition requires reevaluation. Aggressively reducing the bacterial inoculum promptly is critical because factors already in place before clinical presentation are driving resistance to the few antibiotics that are available to treat MRSAB. Alternative approaches to treat MRSAB should be considered within 3–4 days of persistent MRSAB. With rapid molecular diagnostics emerging in clinical microbiology laboratories and biomarkers as a potential for early patient risk stratification, a future shorter threshold may become possible. [ABSTRACT FROM PUBLISHER]

Study Objective Daptomycin is a therapeutic option for patients with underlying renal insufficiency who are vulnerable to nephrotoxicity from vancomycin. We evaluated the efficacy and safety of daptomycin in patients with renal impairment. Design Multicenter, retrospective, observational, case series analysis. Setting Two academic medical centers. Patients One hundred and sixty adults with creatinine clearance (Clcr) of 50 ml/minute or less who received daptomycin for at least 72 hours for complicated Gram-positive infections from 2008-2011. Measurements and Main Methods Clinical and microbiologic outcomes were assessed at the end of daptomycin therapy. Safety evaluations were documented for all patients, and when available, creatine phosphokinase ( CPK) levels were recorded. Thirty-eight (23.8%) patients were on hemodialysis, and 122 (76.3%) had a decreased baseline renal clearance not requiring hemodialysis with a median interquartile range ( IQR) Clcr of 32.4 ml/minute (24.2-40.4 ml/min). The median ( IQR) daptomycin dose was 6.0 mg/kg (5.8-7.8 mg/kg) administered every 24 hours in 68 patients (42.5%) and every 48 hours in 92 patients (57.5%). Daptomycin success, including cure or improvement, (Cure: signs and symptoms resolved and no additional antibiotic therapy required, or infection cleared with negative cultures reported at the end of daptomycin therapy; Improvement: partial resolution of signs and symptoms and additional antibiotic therapy necessary at the end of daptomycin therapy) was achieved in 128 of 160 (80.0%) patients at the end of therapy. Methicillin-resistant Staphylococcus aureus ( MRSA) was the most common pathogen (45%) isolated. The most frequent reason for using daptomycin was due to vancomycin-associated nephrotoxicity (20%). Daptomycin therapy was discontinued in six patients (3.8%) because of elevated CPK (median time to onset, 11.5 days). Loss of daptomycin susceptibility occurred in two patients with complex endovascular infections who were on hemodialysis. Conclusions Daptomycin demonstrated clinical and microbiologic success rates comparable with prior studies. Discontinuation of therapy because of elevated CPK levels may have been avoided in some patients with adjustment to every 48-hour dosing for Clcr less than 30 ml/minute. The relatively early time to onset suggests the need for CPK monitoring more frequently than once/week in renally impaired patients receiving daptomycin. The treatment of bacteremia in patients with renal insufficiency warrants further study. [ABSTRACT FROM AUTHOR]

Study Objective To evaluate a clinical pathway using daptomycin in patients with bacteremia caused by methicillin-resistant Staphylococcus aureus ( MRSA) isolates exhibiting vancomycin minimum inhibitory concentrations (MICs) greater than 1 mg/L. Design Two-phase quasi-experimental study. Setting Level I trauma center in Detroit, Michigan. Patients The study population consisted of a total of 170 patients with MRSA bacteremia susceptible to vancomycin: 70 patients who had initial blood MRSA isolates exhibiting a vancomycin MIC > 1 mg/L and were treated with vancomycin were included in phase I (retrospective baseline period [2005-2007]) and 100 patients who were switched to daptomycin after initial vancomycin therapy according to the institutional MRSA bacteremia treatment pathway were included in phase II (the period after implementation of the treatment pathway [2008-2010]). Intervention The MRSA bacteremia treatment pathway was as follows: vancomycin therapy was initiated, optimizing target trough concentrations to 15-20 mg/L; for isolates demonstrating vancomycin MICs greater than 1 mg/L, therapy was switched to daptomycin, initiated at dosages of 6 mg/kg/day or higher. Measurements and Main Results Infection characteristics, patient outcomes, and costs were evaluated. Patient characteristics were similar between the phase I and phase II groups. Phase II patients were more likely to achieve clinical success than were phase I patients (75.0% vs 41.4%, p<0.001). Phase II patients demonstrated a shorter total hospital length of stay and shorter durations of inpatient therapy, fever, and bacteremia. Treatment during phase I was independently associated with failure. Nine patients during phase I experienced nephrotoxicity, and two patients during phase II experienced increases in creatine kinase level. Costs were similar between phases I and II ($18,385 vs $19,755, p>0.05), although the hospital readmission rate was higher in phase I (33% vs 21%, p=0.08). Conclusion Among the patients with bacteremia who had MRSA isolates that exhibited elevated vancomycin MICs, the switch to daptomycin improved clinical success without increasing treatment cost. [ABSTRACT FROM AUTHOR]

Background Daptomycin and ceftaroline (DAP-CPT) have been used for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB), but have rarely been compared with other therapies. This study provides an exploratory analysis of patients placed on DAP-CPT vs standard of care (SOC) for MRSAB. Methods This is a retrospective, matched cohort study MRSAB patients at 4 hospitals in the United States. Patients receiving DAP-CPT for ≥72 hours at any point in therapy were matched 2:1 when possible, 1:1 otherwise, to SOC, first by infection source, then age and renal function. SOC was empiric treatment with vancomycin or daptomycin and any subsequent combination antibiotic(s), except for DAP-CPT. Results Fifty-eight patients received DAP-CPT with 113 matched SOC. Ninety-six percent of SOC received vancomycin, and 56% (63/113) escalated therapy at least once in the treatment course. Twenty-four patients received DAP-CPT within 72 hours of index culture; 2 (8.3%) died within 30 days vs 14.2% (16/113) with SOC (P > .05). Subgroup analysis identified numerically lower mortality in DAP-CPT patients with a Charlson comorbidity index ≥3, endovascular source, and receipt of DAP-CPT within 72 hours of index culture. The median MRSAB duration was 9.3 vs 4.8 days for DAP-CPT and SOC, respectively. DAP-CPT was initiated on day 6 on average; after receipt of DAP-CPT, MRSAB duration was 3.3 days. Conclusions DAP-CPT treatment is often delayed in MRSAB. Combination therapy may be more beneficial if initiated earlier, particularly in patients at higher risk for mortality. Blinded, randomized, prospective studies are needed to eliminate selection bias inherent in retrospective analyses when examining DAP-CPT vs SOC. [ABSTRACT FROM AUTHOR]