High-dose Daptomycin Research Articles

High-Dose Daptomycin Is Well Tolerated via 2-Minute IV Push Administration.

The purpose of this study was to evaluate the safety of administering high-dose daptomycin (HDD; > 6 mg/kg actual body weight) as a 2-minute intravenous (IV) push (IVP) compared to traditional 30-minute IV piggyback (IVPB) infusion. Retrospective cohort study comparing patients receiving HDD as an IVP or IVPB infusion. The primary outcome was the proportion of patients with a documented infusion-related reaction (IRR) to daptomycin. Three hundred patients were included in the final analysis, 200 patients received IVP, and 100 patients received IVPB representing a total of 1697 administrations. Median (IQR) daptomycin dose was IVP 700 mg (550-900) and IVPB 700 mg (600-900), with mg/kg doses of 8.2 (7.9-10) and 8.3 (8-10), respectively. After adjudication, IRR occurred in 1% of subjects in each treatment group. This study provides data in more than 1100 administrations of HDD administered via IVP. Infusion-related reactions were documented in 1% of patients regardless of infusion method, suggesting comparable safety to traditional infusion methods. This practice may be useful during fluid shortage and in the outpatient setting.

Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4–6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 μg/mL. For an MIC of 1 μg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable.

Observational retrospective single-centre study in Japan to assess the clinical significance of serum daptomycin levels in creatinine phosphokinase elevation.

Daptomycin-induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (Ctrough ; breakpoint of 24.3μg/mL). However, even with high-dose treatment (ie, > 8mg/kg), the safety of daptomycin treatment is widely demonstrated with low or no significant incidence of CPK elevation or other adverse effects, despite the possibility of Ctrough above 24.3μg/mL. Therefore, we questioned the clinical significance of Ctrough levels of 24.3μg/mL. In this study, we retrospectively evaluated the significance of Ctrough in the clinical setting, in addition to completing a retrospective safety assessment of daptomycin utilizing electronic health records. Patients who had received daptomycin treatment for >4days from July 2011 to June 2015 were enrolled. Serum daptomycin levels, including Ctrough and peak (Cpeak ), were measured by high-performance liquid chromatography equipped with a photodiode array. To evaluate the safety, patients' characteristics and relevant laboratory test values were reviewed retrospectively using an electronic medical record system. A total of 52 therapeutic cases for 46 patients were identified; of these, Ctrough and Cpeak levels were measured in 27 and 28 cases, respectively, and 6 patients received multiple courses of daptomycin treatment. The median age of the 52 patients was 68years (range: 19-88years), and 14 patients initially had an estimated creatinine clearance of less than 30mL/min. Seven cases indicated a Ctrough of above 24.3μg/mL; however, none of these presented CPK elevation, which meets with the study definition for abnormality. Furthermore, of the two patients with abnormal CPK elevations, only one patient had a measured Ctrough (of 10.9μg/mL). Their CPK abnormalities were temporal and did not result in treatment discontinuation. The other four patients discontinued daptomycin treatment due to suspicions of adverse effects. Of the discontinued patients, two had measured Ctrough levels; these were 8.6 and 8.1μg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited Ctrough levels lower than 24.3μg/mL. In this study, two patients receiving high-dose daptomycin (ie, 9.4 and 10.0mg/kg) had observed Ctrough levels similar to patients who received doses of daptomycin <9mg/kg. The safety of daptomycin treatment was suggested in this study. Ctrough level of 24.3μg/mL was not suggested as a significant clinical index for the incidence of CPK elevation, adverse effects or treatment discontinuation. Thus, acceptable tolerability towards higher Ctrough levels than 24.3μg/mL was also suggested, though further studies are required. On the other hand, low levels of daptomycin in blood were unexpectedly observed in two cases, despite the high-dose treatments. Accordingly, the monitoring of serum daptomycin levels may also be useful to assess cases in which subtherapeutic levels were achieved.

575. Evaluation of Risk Factors and Clinical Outcomes of Patients with Vancomycin-Resistant Enterococcus Infections

BackgroundVancomycin-resistant Enterococci (VRE) occurs with enhanced frequency in hospitalized patients and are usually associated with poor clinical outcomes. The purpose of this study was to evaluate the risk factors and clinical outcomes of patients with VRE infections.MethodsThis study was an IRB-approved multi-center retrospective chart review conducted at a three-hospital health system between August 2016-November 2018. Inclusion criteria were patients ≥18 years and admitted for ≥24 hours with cultures positive for VRE. Patients pregnant or colonized with VRE were excluded. The primary endpoint was to analyze the association of potential risk factors with all-cause in-hospital mortality (ACM) and 30-day readmission. The subgroup analysis focused on the association of risk factors with VRE bacteremia. The secondary endpoint was to evaluate the impact of different treatment groups of high dose daptomycin (HDD) (≥10 mg/kg/day) vs. low dose daptomycin (LDD) (< 10 mg/kg/day) vs. linezolid (LZD) on ACM and 30-day readmission. Subgroup analysis focused on the difference of length of stay (LOS), length of therapy (LOT), duration of bacteremia (DOB) and clinical success (CS) between the treatment groups.ResultsThere were 81 patients included for analysis; overall mortality was observed at 16%. Utilizing multivariate logistic regression analyses, patients presenting from long-term care facilities (LTCF) were found to have increased risk for mortality (OR 4.125, 95% CI 1.149–14.814). No specific risk factors were associated with 30-day readmission. Patients with previous exposure to fluoroquinolones (FQ) and cephalosporins (CPS), nosocomial exposure and history of heart failure (HF) showed association with VRE bacteremia. ACM was similar between HDD vs. LDD vs. LZD (16.7% vs. 15.4% vs. 0%, P = 0.52). No differences were seen between LOS, LOT, CS, and DOB between the groups.ConclusionAdmission from LTCFs was a risk factor associated with in-hospital mortality in VRE patients. Individuals with history of FQ, CPS and nosocomial exposure as well as history of HF showed increased risk of acquiring VRE bacteremia. There was no difference in ACM, LOS, LOT, and DOB between HDD, LDD and LZD.Disclosures All authors: No reported disclosures.

759. High-Dose Daptomycin Is Well Tolerated via 2-Minute Infusion

BackgroundIntravenous (IV) base solution shortages pose issues in the administration of IV antimicrobials and necessitate alternative administration strategies. Safety data supports 2-minute infusions of IV daptomycin up to the labeled dose of 6 mg/kg. The purpose of this study was to evaluate the safety of administering high-dose daptomycin (HDD) (>6 mg/kg) as a 2 minute IV infusion compared with traditional 30-minute infusion.MethodsIRB-approved, retrospective cohort in a five-hospital health system admitted 9/1/17–9/1/18. Inclusion criteria: Patients receiving HDD as either a rapid 2 minute IV push (IVP) or a traditional 30-minute infusion (IVI) while inpatient. Exclusion criteria: <2 doses of HDD, pregnant, age <18, concomitant medication associated with infusion reactions (e.g., amphotericin B or monoclonal antibody). Primary outcome: proportion of patients with infusion-related reactions (IRR) after daptomycin administration. Infusion-related reactions were assessed using the Naranjo algorithm and adjudicated by 2 reviewers blinded to administration strategy. Bivariate statistical tests were used to compare patient characteristics and outcomes between groups. Data were reported using descriptive statistics and measures of central tendency.Results300 patients included: IVP n = 200, IVI n = 100, representing a total of 1697 administrations. Median age IVP 61 (49, 71), IVI 63 (52, 74). Median BMI IVP 28 (23, 35), IVI 27 (23, 32). Median daptomycin dose IVP 700 (550, 900), IVI 700 (600, 900) with mg/kg doses of 8.2 (7.9, 10) and 8.3 (8, 10), respectively. Administration site was similar in both groups with the most common central venous catheters. Potential IRR occurred in 4% of the IVP arm and 1% of IVI arm, P = 0.28. After adjudication, IRR occurred in 1% of both treatment groups. Descriptions of IRR are in Table 1 and only 1 patient in the IVI arm required discontinuation. CPK elevations: 3% of entire cohort.ConclusionAdministering HDD as an IVP was not associated with increased risk of IRR compared with IVI. This administration may be advantageous during fluid shortages and in outpatient administration. Disclosures All authors: No reported disclosures.

201. Safety and Effectiveness of Daily vs. Every Other Day Dosing of Daptomycin in Patients with Renal Insufficiency

BackgroundDaptomycin administered at 48-hour (q48h) intervals is recommended in patients with renal impairment. Our institution utilizes daily dosing (q24h) of daptomycin in patients with renal impairment to theoretically optimize the area under the curve (AUC) in each 24-hour interval. However, the safety and effectiveness of this approach are unknown.MethodsThis retrospective descriptive analysis evaluated outcomes of comparable daptomycin dosing schemes administered q24h vs. q48h in patients with renal impairment (estimated creatinine clearance < 30 mL/minute). Inpatient adults ≥18 years old were included if they had at least one creatinine phosphokinase (CPK) obtained during admission and received either a q24h or q48h renally-adjusted daptomycin dose from May 2014 through December 2018. High-dose daptomycin therapy was defined as >3 mg/kg q24h or >6 mg/kg q48h. The primary outcome was difference in CPK elevations in the q24h vs. q48h dosing groups. Secondary outcomes included clinical and microbiological response, mortality, and hospital length of stay.ResultsThirty-seven patients met inclusion criteria [23 (62%) q24h vs. 14 (38%) q48h]. Median treatment duration was 5 (7 vs. 4) days. Twenty-two (59%) patients had enterococcal infections [17 (73%) q24h vs. 5 (35%) q48h]. Twenty-two (59%) patients received high-dose daptomycin therapy [18 (82%) vs. 4 (18%)]. Nine patients [7 (19%) vs. 2 (5%)] received a statin during daptomycin therapy. One (3%) patient developed a CPK elevation (statin and q24h group). No daptomycin dose was discontinued due to CPK elevation, or rhabdomyolysis. Median hospital length of stay was 10 days in both dosing groups. Clinical response [9 (64%) vs. 16 (69%)] and microbiological response [9 (64%) vs. 15 (65%)] were similar between the two dosing groups. However, 30-day mortality [5 (35%) vs. 4 (17%)] and 90-day mortality [6 (42%) vs. 5 (21%)] were higher in the q48h dosing group. The difference in effectiveness outcomes was greatest in the subset of patients with enterococcal infections (Table 1).ConclusionA daily daptomycin dosing strategy in patients with renal insufficiency was well tolerated and may be associated with improved effectiveness outcomes, particularly for enterococcal infections. Additional investigations of this approach are warranted. Disclosures All authors: No reported disclosures.

Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: An updated systematic review and meta-analysis

ObjectivesA systematic review and meta-analysis were conducted to re-assess the efficacy and safety of daptomycin compared with linezolid treatment for vancomycin-resistant enterococcal (VRE) bacteraemia and to explore whether high-dose daptomycin is beneficial. MethodsPubMed, EMBASE, the Cochrane Library, and meeting abstracts were searched from inception to February 2019. Studies evaluating daptomycin and linezolid treatment for VRE bacteraemia were included. ResultsTwenty-two observational studies were identified. A non-significant higher mortality (OR 1.27; 95% CI 0.99–1.63) and significantly lower risk of thrombocytopenia (OR 0.78; 95% CI 0.61–0.99) were found with daptomycin compared with linezolid treatment. Clinical response (OR 0.88; 95% CI 0.59–1.33), microbiological cure (OR 0.82; 95% CI 0.53–1.28), recurrence of bacteraemia (OR 0.96; 95% CI 0.70–1.32), and risk of creatine kinase elevation (OR 0.82; 95% CI 0.46–1.47) were similar for the two agents. In the subgroup analysis of studies focusing on high-dose daptomycin treatment, similar mortality was observed (OR 0.92; 95% CI 0.46–1.84). Moreover, patients receiving daptomycin tended to show a higher clinical response (OR 1.61; 95% CI 0.37–7.09) and microbiological cure (OR 2.09; 95% CI 0.43–10.1) and a lower risk of bacteraemia relapse (OR 0.47; 95% CI 0.15–1.45), although the difference was not significant. ConclusionsCompared with linezolid treatment, daptomycin treatment showed comparable clinical and microbiological outcomes but a lower incidence of thrombocytopenia. Because of the dose-dependent effect that was observed, high-dose daptomycin should be considered for patients with VRE bacteraemia.

Should High-dose Daptomycin be an Alternative Treatment Regimen for Enterococcal Endocarditis?

IntroductionPrevious series on the use of daptomycin in enterococcal infective endocarditis (EIE) have shown various outcomes, including higher mortality rates. We analyzed the effectiveness of high-dose daptomycin for the treatment of EIE.MethodsWe performed a prospective study from 2010 to 2018 in a referral center in patients with native (NVE) and prosthetic valve endocarditis (PVE) due to Enterococcus spp. The standard high-dose daptomycin at our institution is 10–12 mg/kg/day (CLCr > 30 ml/min). We compared the efficacy of a daptomycin-based regimen (DBR) versus daptomycin-sparing regimen (DSR) and daptomycin monotherapy versus combination therapy. Primary endpoints of the study were evaluation of risk factors associated with 30-day mortality and failure at end of therapy.ResultsWe collected 43 EIE cases; 29 were NVE (67.4%). Overall, 16 (37.2%) were treated with DBR, mainly with combination regimens (11, 68.7%), in the majority of cases in association with ß-lactam (7, 43.7%). The mean administered dose of daptomycin was 10.125 mg/kg/day (range 8–12 mg/kg/day). Overall, patients treated with DBR compared with patients treated with DSR had no higher mortality rates and/or failure at end of therapy (6.2% vs. 22. 2%; P 0.41 and MICs 0.25–2 mg/l, 6.2% vs. 3.7%; P 1.0). In the sub-group of patients with NVE and PVE treated with DBR and DSR, no difference was found regarding the primary endpoints on the single or combined use of daptomycin.ConclusionOur findings suggest that high-dose daptomycin might be used as an alternative treatment regimen in EIE.

Daptomycin-containing regimens for treatment of Gram-positive endocarditis

Infective endocarditis (IE) is a severe infection, and a leading cause of mortality and morbidity. Due to its favourable microbiological and pharmacological characteristics, daptomycin is routinely used in clinical practice for treating IE. A prospective study was conducted at a large tertiary-care hospital in Italy over an 8-year period (January 2010-January 2018) on all patients with native-valve endocarditis (NVE) or prosthetic-valve endocarditis (PVE) caused by Gram-positive bacteria. Patients with NVE and PVE treated with regimens that included daptomycin at different dosages (daptomycin-containing regimens, DCR) were compared with those treated with non-DCR. Primary endpoints of the study were 30-day mortality and clinical treatment failure. During the study period, 327 patients with Gram-positive NVE (n = 224, 68.8%) or PVE (n = 103, 31.2%) were analysed. Eighty-four (37.5%) NVE patients were treated with daptomycin, alone (59.9%) or with other antimicrobials. Most PVE patients (n = 61, 58%) were treated with a DCR, which always consisted of daptomycin plus other drugs. Among PVE patients, treatment with a DCR was associated with lower 30-day mortality than treatment with a non-DCR (6.5% vs. 38%, P < 0.001). Among NVE patients treated with DCRs, risk factors for 30-day mortality were streptococcal infections, persistent bacteraemia, and standard-dose (4-6 mg/kg) rather than high-dose daptomycin therapy. Overall, surgical treatment of IE and DCR were associated with clinical success and 30-day survival. Compared with non-DCRs, using single-drug or multiple-drug DCRs is associated with lower 30-day mortality in PVE, but with higher 30-day mortality in NVE at approved doses and in a subgroup of streptococcal IE.

Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold. Data were pooled from seven published trials assessing outcomes in daptomycin-treated enterococcal bacteraemia, including patients receiving daptomycin (≥72 h) and any β-lactam, intravenous aminoglycoside, linezolid, tigecycline and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding and daptomycin Etest MIC. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following pooling of data, 240 adults were included; 137 (57.1%) were alive at 30 days. A majority of patients were immunosuppressed (65.8%) and received a β-lactam (94.6%). Examining the threshold in low-acuity patients (n = 135) to control for co-morbidities, these patients were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% vs. 20.0%; P = 0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (P = 0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤ 2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteraemia.

A study on combination of daptomycin with selected antimicrobial agents: in vitro synergistic effect of MIC value of 1\u2009mg/L against MRSA strains

BackgroundDaptomycin is an important drug used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. A high dose of daptomycin is indicated for an MRSA infection with a minimum inhibitory concentration (MIC) of 1 mg/L for daptomycin. Combination therapies with daptomycin and other antimicrobial agents, including fosfomycin, display in vitro synergism potentially. This study was conducted to investigate the in vitro synergistic effect of daptomycin-based combination therapy against MRSA strains with high daptomycin MIC.MethodThe synergistic effects of daptomycin in combination with fosfomycin, gentamicin, linezolid, oxacillin, or rifampicin against MRSA with an MIC of 1 mg/L for daptomycin were measured using the microbroth checkerboard assay in vitro.ResultA total of 100 MRSA isolates was tested. The synergistic interactions of the drugs were evaluated using the fractional inhibitory concentration index. The MIC values revealed that all isolates (100%) were found to be susceptible to linezolid, 85% to fosfomycin, 8% to gentamicin, 69% to rifampicin, and no isolate was susceptible to oxacillin. The in vitro synergism rates of daptomycin in combination with fosfomycin, oxacillin, gentamicin, linezolid, and rifampicin were 37, 11, 5, 3, and 1%, respectively.ConclusionThe combination of daptomycin plus fosfomycin may be an effective therapeutic option for MRSA infection.

Daptomycin-Containing Regimens for Treatment of Gram-Positive Endocarditis

Background: Infective endocarditis (IE) is a severe infection and a leading cause of mortality and morbidity. In clinical practice, daptomycin is routinely used in IE for its favorable microbiological and pharmacological characteristics. Methods: A prospective study was conducted in a large tertiary-care hospital in Italy over an 8-year period (January 2010 - January 2018) on all patients with native- (NVE) or prosthetic-valve endocarditis (PVE) caused by gram-positive bacteria. Patients with NVE and PVE treated with regimens that included daptomycin at different dosages (daptomycin-containing regimens, DCR) were compared with those treated with non-DCR. The primary endpoints of the study were 30-day mortality and clinical treatment failure. Findings: During the study period, we analyzed 327 patients with gram-positive NVE (n=224, 68.8%) or PVE (n=103, 31.2%). Eighty-four (37.5%) NVE patients were treated with daptomycin, alone (59.9%) or with other antimicrobials. Most PVE patients (n=61, 58%) were treated with a DCR, which always consisted of daptomycin plus other drugs. Among PVE patients, treatment with a DCR was associated with lower 30-day mortality than treatment with a non-DCR (6.5% vs. 38%, p<0.001). Among NVE patients treated with DCRs, risk factors for 30-day mortality were streptococcal infections, persistent bacteremia, and standard-dose (4-6 mg/kg) rather than high-dose daptomycin therapy. Overall, surgical treatment of IE was associated with clinical success. Interpretation: Compared with non-DCRs, use of single- or multiple-drug DCRs is associated with lower 30-day mortality in PVE, but with higher 30-day mortality in NVE at approved doses and in the subgroup of streptococcal IE. Funding Statement: The authors state: No funding. Declaration of Interests: The authors state: None to declare. Ethics Approval Statement: The study was pre-approved by the local ethics committee and conducted in accordance with the principles of the Declaration of Helsinki.

Daptomycin versus teicoplanin for bloodstream infection due to methicillin-resistant Staphylococcus aureus with a high teicoplanin minimal inhibitory concentration ≥1.5 mg/L: a propensity score-based analysis.

BackgroundRecent reports have described decreased effectiveness of teicoplanin in the treatment of bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) with teicoplanin minimal inhibitory concentration (MIC) ≥1.5 mg/L. Consensus guidelines recommend considering use of alternative agents for MRSA infections involving a higher teicoplanin MIC, despite of limited data to support this recommendation.Patients and methodsTo compare the clinical outcome among patients with bacteremia due to MRSA with teicoplanin MIC ≥1.5 mg/L, we included patients who received high-dose daptomycin (≥8 mg/kg/day) and those who received standard-dose (6 mg/kg/day) or high-dose (6 mg/kg/12 hours) maintenance teicoplanin. The primary endpoint was a favorable outcome, defined as the resolution of clinical signs and symptoms and a negative culture report at the end of therapy. Adjusted analyses were performed by multivariate analysis and propensity score-based matching.ResultsOf 142 patients eligible for inclusion, 28 (19.7%) were treated with high-dose daptomycin, 27 (19.0%) with high-dose teicoplanin, and 87 (61.3%) with standard-dose teicoplanin. In multivariate regression analysis, Pittsburgh bacteremia score ≥4 (OR, 5.3; 95%CI, 1.9–14.5) was independently associated with an unfavorable outcome. After propensity-score matching with age and Pittsburgh bacteremia score ≥4, patients on high-dose daptomycin were more likely to have favorable outcomes than those on standard-dose teicoplanin (74.1% vs 42.6%; P=0.02). However, there was no significant difference in terms of favorable outcomes (P=0.12) between patients receiving high-dose daptomycin and those receiving high-dose teicoplanin after the same propensity-score matching.ConclusionTreatment with high-dose daptomycin resulted in significantly better outcomes than with standard-dose teicoplanin in the treatment of MRSA bacteremia with teicoplanin MIC ≥1.5 mg/L. However, the clinical outcome of the patients receiving high-dose teicoplanin was similar to that of the patients receiving high-dose daptomycin.

Survival of Patients With Vancomycin-Resistant Enterococcus faecium Bacteremia Treated With Conventional or High Doses of Daptomycin or Linezolid Is Associated With the Rate of Bacterial Clearance.

Vancomycin-resistant enterococci are important pathogens for healthcare-associated infections. Although linezolid is bacteriostatic and daptomycin is rapidly bactericidal against vancomycin-resistant enterococci in vitro, it is not clear whether they differ in their effect on bacterial clearance in patients with vancomycin-resistant enterococci bloodstream infections. Prospective observational study. Two university hospitals and research laboratory. Patients with vancomycin-resistant enterococci bloodstream infection proven by blood cultures were prospectively enrolled from January 2010 to July 2015. Sequential blood samples were collected. Real-time quantitative polymerase chain reaction was used to monitor bacterial loads. One hundred eight patients with vancomycin-resistant enterococci bloodstream infection were enrolled. Quantitative polymerase chain reaction assays were performed on 465 blood isolates. We found this method to be closely correlated with colony-forming units and more sensitive than culture. Sixty-three patients (58.3%) received "conventional dose" daptomycin (6-9 mg/kg), 15 (13.9%) received high-dose daptomycin (≥ 9 mg/kg), and 30 (27.8%) were treated with linezolid (600 mg every 12 hr) as sole agents. The initial mean bacterial load was 1.03 log10 copies/mL and unrelated to survival. Survivors had a more rapid early bacterial clearance than nonsurvivors (Δ log10 copies/mL/d; -0.16 vs 0.31; p = 0.02). Multivariable logistic regression showed that a slower early bacterial clearance independently predicted increased mortality (odds ratio, 3.21; 95% CI, 1.03-10.02; p = 0.045). Conventional dose daptomycin was associated with a significantly slower rate of bacterial clearance than high-dose daptomycin (Δ log10 copies/mL/d; -0.04 vs -0.41; p < 0.001) and linezolid (-0.04 vs -0.56; p = 0.043). We found that survivors of vancomycin-resistant enterococci bloodstream infection had a significantly more rapid early bacterial clearance by quantitative polymerase chain reaction than nonsurvivors. High-dose daptomycin and linezolid were associated with more rapid bacterial clearance than conventional dose daptomycin. These results support recommendations that conventional dose daptomycin not be used for the treatment of patients with vancomycin-resistant enterococci bloodstream infection.

Correction to: Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Correction to: Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Treatment strategies for persistent methicillin-resistant Staphylococcus aureus bacteraemia.

Treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a long-standing challenge to health care, often complicated by metastatic infections, treatment failure and mortality. When MRSA bacteraemia persists despite adequate initial treatment, current Infectious Diseases Society of America guidelines recommend evaluation and removal of possible sources of infection. In addition, a change in therapy may be considered. The objective of this review was to explore the therapeutic options for the treatment of persistent MRSA bacteraemia. A literature search of PubMed, MEDLINE and Google Scholar was performed using the following search terms: [methicillin-resistant Staphylococcus aureus OR MRSA] AND [bacteraemia OR bloodstream infection] AND [persistent OR persistence OR refractory OR treatment failure OR salvage] AND treatment. We evaluated relevant, adult, English-language, peer-reviewed studies published between 1985 and May 2018. In vitro and animal studies were considered as supportive of in vivo data. Randomized, controlled trials are lacking. However, case series and case reports support multiple treatment options including high-dose daptomycin in combination with an antistaphylococcal β-lactam, ceftaroline, trimethoprim-sulfamethoxazole (TMP-SMX) or fosfomycin; ceftaroline alone or in combination with vancomycin or TMP-SMX; linezolid alone or in combination with a carbapenem, or telavancin. Given the heterogeneity of the data, a preferred regimen has not emerged. Prescribers must take into consideration recent exposure, source control, and available synergy and clinical data. Further comparative trials are needed to establish a preferred regimen and the creation of a universal treatment algorithm.

Association of daptomycin dosing regimen and mortality in patients with VRE bacteraemia: a review.

VRE are associated with ∼1300 deaths per year in the USA. Recent literature suggests that daptomycin, a cyclic lipopeptide antibiotic with concentration-dependent bactericidal activity, is the preferred treatment option for VRE bacteraemia, yet the optimal dosing strategy for this indication has not been established. In vitro evidence suggests that higher-than-labelled doses of daptomycin are required to optimally treat VRE bacteraemia and to inhibit the development of resistance. However, concern of dose-dependent toxicities, notably increases in creatine phosphokinase and the development of rhabdomyolysis, are a barrier to initiating high-dose schemes in clinical practice. Thus, the effectiveness and safety of high-dose daptomycin regimens in clinical practice have remained unclear. While early studies failed to identify differences in mortality, newer, larger investigations suggest high-dose (≥9 mg/kg) daptomycin is associated with reduced mortality in patients with VRE bacteraemia compared with standard (6 mg/kg) dosing regimens. Additionally, the high-dose regimens appear to be safe and may be associated with improved microbiological outcomes. The purpose of this review is to examine the published evidence on the effectiveness and safety of high-dose daptomycin compared with standard dosing regimens for VRE bacteraemia.

Safety of high-dose daptomycin in patients with severe renal impairment.

BackgroundTreatment options are limited for infections due to multidrug-resistant Gram-positive pathogens. Daptomycin is a lipopeptide antibiotic with concentration-dependent killing characteristic and dose-dependent post-antibiotic effect. To achieve optimized pharma-codynamic effect, some experts advocated using a high dose of daptomycin (≥9 mg/kg) for severe infections. However, the safety of high-dose therapy in patients with renal impairment remains unknown. This study was aimed to evaluate the safety of daptomycin in patients with severe renal impairment.MethodsThis was a retrospective study performed by reviewing electronic medical records. Patients with severe renal impairment who were treated with daptomycin in a tertiary teaching hospital between January 1, 2013, and June 30, 2016, were included for evaluation. The incidence rates of creatine kinase (CK) elevation between high-dose (≥9 mg/kg) and standard-dose (<9 mg/kg) groups were compared.ResultsOverall, 164 patients met the inclusion criteria, and 114 (69.5%) of them were on renal replacement therapy. Vancomycin-resistant enterococci were the most common pathogens (61.3%) of the patients with documented pathogens. The treatment success rate was 51.6% in the 91 patients with bacteremia. The average dose of daptomycin was 8.0±2.3 mg/kg, and 37 (22.6%) patients received ≥9 mg/kg. CK levels were followed in 108 (65.9%) patients. Significantly higher incidence of CK elevation was found in the high-dose group compared with that in the standard-dose group (10.8% vs 1.6%, P<0.05). Moreover, patients with elevated CK received a higher dose of daptomycin than those without (9.3±1.2 vs 7.9±2.3 mg/kg, P<0.05). There was no significant difference in the rate of CK elevation between patients treated with different dosing frequency or with the concurrent use of statins, fibrate, or colchicine.ConclusionsIn patients with severe renal impairment, high-dose (≥9 mg/kg) daptomycin therapy may result in a significantly higher incidence of CK elevation. More frequent CK monitoring is warranted to avoid potential harm in this population.

High-Dose Daptomycin Is Effective as an Antibiotic Lock Therapy in a Rabbit Model of Staphylococcus epidermidis Catheter-Related Infection.

Long-term catheter-related bloodstream infections (CRBSIs) involving coagulase-negative staphylococci are associated with poor patient outcomes, increased hospitalization, and high treatment costs. The use of vancomycin lock therapy has been an important step forward in treatment of these biofilms, although failures occur in 20% of patients. In this study, we report that a high dose of daptomycin lock therapy may offer a therapeutic advantage for these CRBSIs in just 24 h of treatment.

Clinical characteristics and treatment outcomes of vancomycin-resistant Enterococcus faecium bacteremia.

Vancomycin-resistant Enterococcus faecium (VRE-fm) bacteremia causes significant mortality in hospitalized patients. We sought to investigate clinical characteristics, treatment outcomes, and microbiological eradication associated with VRE-fm bacteremia. A retrospective cohort study was conducted and included 210 adult patients admitted between January 1, 2011 and December 31, 2015. The mean Pitt bacteremia score was 4.7. ICU stay (48.6%) and mechanical ventilation (46.2%) were common. Diabetes mellitus was the most common concomitant disease (43.3%), followed by malignancies, including hematologic malignancies (14.3%) and solid cancers (28.1%). The 14-day and 28-day mortality rates were 37.1% and 50.5%, respectively. Linezolid or daptomycin treatment for at least 10 days and higher Pitt bacteremia scores were independently associated with 14-day and 28-day mortality. Longer treatment duration of linezolid or daptomycin predicted microbiological eradication independently. Daptomycin-treated patients tended to have higher 14-day and 28-day mortality, and lower microbial eradication rates (20.8% versus 8.7%; 40.6% versus 26.1%; 14.1% versus 26.1%; respectively) than linezolid-treated patients, and cumulative survival rates at 14 and 28 days tended to be lower in patients who received low-dose daptomycin (<10mg/kg/day) than that in those who received linezolid and high-dose daptomycin (≥10mg/kg/day); however, the differences were not statistically significant. Higher disease severity and inappropriate treatment were associated with increased mortality and longer treatment duration of linezolid or daptomycin was associated with microbial eradication for the patient with VRE-fm bacteremia.