High-dose Daptomycin Research Articles

Combination of High-Dose Daptomycin and Ceftriaxone for Cardiac Implantable Electronic Device Infections: A 10-Year Experience

PurposeCardiac implantable electronic device (CIED) infections are increasingly common. Gram-positive bacteria such as coagulase negative staphylococci and Staphylococcus aureus are the most commonly involved pathogens. The aim of this study was to describe the characteristics and outcome of patients with CIED infections who underwent device removal and were empirically treated with high dose (8–12 mg/kg daily) daptomycin (DAP) in combination with ceftriaxone (CRO). MethodsRetrospective, single center study including patients admitted at IRCCS San Raffaele Hospital (Milan, Italy), from June 2011 to June 2021, who underwent device removal for CIED infection and were empirically treated with DAP/CRO. FindingsOverall, 147 patients were included in this study. Median duration of therapy was 16 days (IQR 14–26). Empirical treatment with DAP/CRO was confirmed as definitive treatment in 140 patients (95.2%). In 7 (4.8%) patients DAP/CRO were discontinued according to the definite microbiological isolates: Corynebacterium spp. (4), Pseudomonas aeruginosa (2), Enterobacter cloacae (1). Ten patients (6.8%) underwent treatment simplification to narrow-spectrum antibiotics. One patient (0.6%) interrupted DAP-CRO due to pancytopenia.6-month follow-up was available for 123/147 patients (83.7%): 9 patients recurred with a CIED infection (7.3%), and 9 died (7.3%). ImplicationsIn our 10-year experience, high-dose DAP in combination with CRO represented a good option for empirical therapy of CIED infections. DAP-CRO combination was safe and effective, showing no significant drug-related adverse events and low rates of 6-month recurrence and mortality.

Development of VRE meningitis due to haematogenous spread while on high-dose daptomycin therapy.

Vancomycin-resistant Enterococcus faecium (VRE) meningitis accounts for only 0.3%-4.0% of bacterial meningitis cases and typically occurs following neurosurgical intervention. We describe a rare case of a patient without neurological devices in situ or a recent neurological procedure who developed VRE meningitis via haematogenous spread. Optimal treatment for VRE meningitis is unknown. A 67-year-old male with end-stage liver failure underwent liver transplantation complicated by VRE bacteraemia and subsequently developed VRE meningitis while on high-dose daptomycin therapy (12 mg/kg/day). Due to clinical and microbiological failure with daptomycin, he was switched to linezolid and symptoms resolved rapidly. He completed 2 weeks of linezolid, fully recovered, and continued to do well without complications at the 5 month follow-up. This case highlights the severity of VRE infections in solid organ transplant recipients and raises concerns about daptomycin penetration into the CNS. Linezolid could be considered the preferred treatment for VRE CNS infections rather than high-dose daptomycin.

A Pharmacovigilance Analysis of Daptomycin Use Based on CLSI Susceptible Dose-Dependent Category.

Daptomycin doses 8-12mg/kg are recommended for susceptible dose-dependent Enterococcus species. However, data remain limited on safety outcomes of such dosing, compared to standard 4-6mg/kg dosing. In this retrospective cohort study, patients were stratified into daptomycin standard-dose (≤ 6.5mg/kg) versus high-dose (≥ 7.5mg/kg) groups. The primary outcome was daptomycin safety based on a composite of creatine kinase elevation, daptomycin-related peripheral blood eosinophilia, eosinophilic pneumonitis, alanine aminotransferase elevation, and alkaline phosphatase elevation. A secondary aim was to identify risk factors for daptomycin adverse effects. Inclusion criteria were age ≥ 18years old, daptomycin receipt for ≥ 48h, and Enterococcus cultures with a daptomycin minimal inhibitory concentration 2-4mg/L. A total of 119 patients were included for analysis. Median daptomycin doses were 6.0mg/kg (IQR 5.4, 6.1) and 8.1mg/kg (IQR 7.9, 9.6) in the standard- and high-dose cohorts, respectively. Median durations were 13.5days (standard-dose) and 16days (high-dose) (p = 0.02). The composite safety endpoint occurred in 32.0% of the standard-dose group and 32.5% of the high-dose group (p = 0.96). Daptomycin was dose-reduced or held in 8.1% of patients experiencing an adverse effect. Concurrent antihistamine usage was associated with the composite outcome; however, there was no association with daptomycin dose or concurrent statin use. High-dose daptomycin was not associated with increased laboratory abnormalities or adverse drug reactions compared to standard-dose daptomycin.

Daptomycin Exposure as a Risk Factor for Daptomycin-Induced Eosinophilic Pneumonia and Muscular Toxicity.

High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin. All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model. From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L. We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.

Treatment decisions in VRE bacteraemia: a survey of infectious diseases pharmacists.

VRE infections increased in 2020. High-dose daptomycin (≥10 mg/kg) has shown mortality benefit over other regimens, though daptomycin resistance is increasing. Limited data exist on the practice patterns of ID pharmacists for VRE bloodstream infections (VRE BSIs). To describe practice patterns for VRE BSI in ID pharmacists. A 22-question REDCap survey was distributed to ID pharmacist members of the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (ID PRN) via e-mail listserv. The survey was distributed on 7 April 2022 and remained open for 4 weeks. Sixty-eight pharmacists responded. All pharmacists completed additional training or certification in infectious diseases past their PharmD, and most (70.5%) had been practising for 10 years or less. Pharmacists at academic medical centres (80.0%) were more likely (P = 0.001) to have implemented the updated CLSI breakpoints than pharmacists at other types of institutions (55.2%). Daptomycin was the preferred drug for VRE BSI (92.6%), with 10 mg/kg (72.1%) being the preferred dose. Adjusted body weight was the most common weight (61.2%) used for obese patients. Fourteen days (76.1%) was the most common treatment duration for VRE BSI. Pharmacists defined persistent VRE BSI as 5 days (68.7%) after first blood culture. ID pharmacists overwhelmingly selected high-dose daptomycin for VRE BSI. There were variations in practice and response rate when selecting combination therapy, managing persistent bacteraemia, and treating patients with high daptomycin MICs or previous exposure to daptomycin.

Comparison of the efficacy and safety of standard- and high-dose daptomycin: A systematic review and meta-analysis.

Standard doses of daptomycin at 4 and 6mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4-6mg/kg) and high-dose (HD, >6mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30-0.76 and OR 0.50, 95% CI 0.30-0.82) and HD2 group (OR 0.38, 95% CI 0.21-0.69 and OR 0.30, 95% CI 0.15-0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses.

The Combination of Daptomycin with Fosfomycin is More Effective than Daptomycin Alone in Reducing Mortality of Vancomycin-Resistant Enterococcal Bloodstream Infections: A Retrospective, Comparative Cohort Study.

High-dose daptomycin-based combinations are recommended for vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI). Preclinical data have shown a synergistic effect of daptomycin/fosfomycin combinations against VRE. However, clinical studies comparing daptomycin monotherapy with daptomycin/fosfomycin combinations are unavailable. An observational study of VRE-BSI was performed between 2010-2021 on patients receiving daptomycin monotherapy (≥ 8mg/kg) or daptomycin combined with intravenous fosfomycin. Patients treated with concomitant β-lactam combinations were excluded. The primary outcome was in-hospital mortality. Outcomes were analyzed using multivariable logistic regression and augmented inverse probability weighting (AIPW) analyses. Among 224 patients, 176 received daptomycin monotherapy, and 48 received fosfomycin combinations. The median daptomycin and fosfomycin doses were 9.8mg/kg and 12g/day, respectively. In-hospital mortality was 77.3% and 47.9% in the daptomycin monotherapy and fosfomycin combination groups (P < 0.001), respectively. Multivariable logistic regression analysis predicted lower mortality with fosfomycin combination treatment (adjusted odds ratio, 0.35; 95% confidence interval (CI), 0.17-0.73; P = 0.005). AIPW demonstrated a 17.8% reduced mortality with fosfomycin combinations (95% CI, - 30.6- - 4.9%; P = 0.007). The survival benefit was significant, especially among patients with a lower Pitt bacteremia score or fosfomycin minimum inhibitory concentration (MIC) ≤ 64mg/l. Fosfomycin combination resulted in higher hypernatremia (10.4% vs. 2.8%, P = 0.04) and hypokalemia (33.3% vs. 15.3%, P = 0.009) compared to daptomycin monotherapy. The combination of high-dose daptomycin with fosfomycin improved the survival rate of patients with VRE-BSI compared to daptomycin alone. The benefit of the combination was most pronounced for VRE with fosfomycin MIC ≤ 64mg/l and for patients with a low Pitt bacteremia score.

Evaluation of Limited Sampling Strategies for Bayesian Estimation of Daptomycin Area Under the Concentration-Time Curve: A Short Communication.

Increasing evidence supports daptomycin therapeutic drug monitoring. The author's reference center used to perform therapeutic drug monitoring in patients who receive high-dose daptomycin for bone and joint infections, with a three-sample strategy to estimate the daptomycin daily area under the concentration-time curve (AUC). The objective of this study was to evaluate simpler strategies based on only 2 or 1 sample(s). The authors used the BestDose software to estimate the daptomycin AUC after Bayesian posterior estimation of individual pharmacokinetic (PK) parameters at steady state. The reference AUC (AUC full ) was based on 3 samples obtained predose (T0) and approximately 1 hour (T1) and 6 hours (T6) after the start of a 30-minute infusion of IV daptomycin. It was compared with the AUC based on all possible 2-sample and 1-sample strategies. Bias, imprecision, regression, and Bland-Altman plots were used to assess the performance of the alternative strategies. Data from 77 patients were analyzed. The mean AUC full value was 936 ± 373 mg·h/L. The best 2-sample strategy was T0 + T6, with a mean prediction bias of 0.13 mg·h/L and absolute imprecision of 3%. The T0 + T1 strategy also performed well with a mean bias of -10 mg·h/L and imprecision of 3%. The best 1-sample strategy was the T6 sample only with a bias of 2.19 mg·h/L and imprecision of 6%. Bayesian estimation of daptomycin AUC based on a two-sample strategy was associated with negligible bias and imprecision compared with the author's usual three-sample strategy. The trough and peak strategy may shorten and simplify patient visits and reduce assay labor and costs.

An Update on Treatment Options for Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia: A Systematic Review.

Since the last century, methicillin-resistant Staphylococcus aureus (MRSA) bacteremia has become a major global and public health concern not only in terms of morbidity and mortality but also the duration of hospital stay, healthcare cost, and antimicrobial choices. Especially alarming is the growing antimicrobial resistance due to their misuse and overuse, which has led the world to be exhausted of its effective antibiotic resources. In this review article, we sought to figure out the most efficacious antimicrobial agents to treat MRSA-related bloodstream infections. We compared the data from reviewing reports from 2017 to 2022 and summarized their comparative efficacy and cost-effectiveness. Although we focused on vancomycin and daptomycin, which are the current Infectious Disease Society Of America (IDSA)-recommended antibiotics for MRSA bacteremia treatment, a deep dive into the newer agents revealed better efficacy and treatment outcome in the combination of ceftaroline (β-lactam) with daptomycin compared to traditional standard monotherapy (vancomycin/daptomycin monotherapy). Also, the IDSA recommended high-dose daptomycin (8-10 mg/kg) therapy for MRSA bacteremia treatment to be more effective in cases with vancomycin-reduced susceptibility. Moreover, we did not find any trial or study describing the use of ceftaroline as a monotherapy to compare its efficacy in MRSA bacteremia with the current standard therapy. The upshot is that we need more large-scale clinical trials exploring in-depth effectiveness and adverse effects to decide on newer agents like β-lactams to use as routine therapy for MRSA bacteremia.

Does a New Antibiotic Scheme Improve the Outcome of Staphylococcus aureus-Caused Acute Prosthetic Joint Infections (PJI) Treated with Debridement, Antibiotics and Implant Retention (DAIR)?

One of the most commonly used treatments for acute prosthetic joint infection (PJI) is DAIR (debridement, antibiotics and implant retention), which comprises the debridement and the retention of the implant, followed by antibiotic treatment. The efficacy of DAIR remains unclear, as the literature has demonstrated variable success rates, ranging from 26% to 92%. The Staphylococcus aureus is one of the most closely related causative microorganisms, especially with acute and late-acute PJI; it has been identified as one of the most significant predictors of DAIR failure. The current guidelines consider the use of vancomycin as the therapy of choice, but it requires the close control of possible side effects. The aim of this study is to determine if a new combination of antibiotics (a highly bactericidal initial combination followed by an antibiofilm scheme) decreases the failure of DAIR-treated acute prosthetic joint infection (PJI) caused by Staphylococcus aureus. A retrospective analysis of cases of orthopedic infections during a nine-year period (2011–2019) was performed. A total of 45 acute PJI cases caused by S. aureus were diagnosed. The results of two antibiotic schemes were compared: a novel scheme comprising 5 days of daptomycin (10 mg/kg/24 h) + cloxacillin (2 g/6 h) followed by levofloxacin (500 mg/24 h) + rifampicin (600 mg/24 h), versus a traditional, less bactericidal scheme of vancomycin (1000 mg/12 h) plus rifampicin (600 mg/24 h) or levofloxacin (500 mg/24 h) plus rifampicin (600 mg/24 h). Twenty-two out of the twenty-four patients treated with the new scheme (91.6%) were free of infection after 24.8 months of mean follow-up, whereas fourteen out of twenty-one patients (66.6%) were free of infection after 46.6 months of follow-up. This difference was statistically significant (p = 0.036). Demographic comparisons demonstrated homogeneous features, except the Charlson score, which was higher in the novel scheme group (p = 0.047). The combination of high-dose daptomycin and cloxacillin, followed by levofloxacin plus rifampicin, together with surgical treatment, shows better results when compared with other antibiotic schemes for treating acute PJI caused by S. aureus in which DAIR was performed.

Influence of daptomycin doses on the outcomes of VRE bloodstream infection treated with high-dose daptomycin.

The CLSI recommended high-dose daptomycin (8-12 mg/kg) for treating Enterococcus faecium bloodstream infections (BSI). The current study was designed to determine the safety and efficacy of increasing the daptomycin dose for VRE BSI patients receiving ≥8 mg/kg. We conducted a multicentre prospective observational study of patients who received a ≥8 mg/kg dose of daptomycin for treatment of VRE BSI. The primary outcome was 28 day mortality. A total of 661 patients were included. The 28 day mortality rate was 45.1%. The survivors received higher doses of daptomycin than non-survivors (10.1 versus 9.8 mg/kg; P < 0.001). An increase in the daptomycin dose independently predicted lower mortality [adjusted OR (aOR) = 0.85; 95% CI = 0.73-0.99; P = 0.03]. Eighty-six survivors (23.7%) and 43 non-survivors (14.4%) received a ≥11 mg/kg dose of daptomycin (P = 0.003). The 8 to <11 and ≥11 mg/kg doses of daptomycin differed in the 28 day mortality in the higher MIC group (≥2 mg/L) (49.4% versus 33.3%; P = 0.004), but not in the lower MIC group (≤1 mg/L) (29.3% versus 29.4%; P = 0.99). A dose of ≥11 mg/kg was associated with a higher (3.9%) rate of highly elevated creatine kinase (>2000 U/L) compared with 1.1% with 8 to <11 mg/kg (P = 0.04). The efficacy of daptomycin is dose dependent. A high daptomycin dose, especially at ≥11 mg/kg, improved survival in patients with VRE BSI, but was associated with highly elevated creatine kinase. We recommend a ≥11 mg/kg dose of daptomycin be considered for treatment of VRE BSI, particularly for isolates with higher MICs.

Influence of daptomycin dose and fosfomycin susceptibility on outcome of vancomycin-resistant Enterococcus faecium bloodstream infections treated with daptomycin and fosfomycin combination.

Synergistic combinations of daptomycin and β-lactam antibiotics are currently recommended for treatment of VRE bloodstream infection (BSI). The efficacy of these combinations is jeopardized by VRE inherently resistant to β-lactam antibiotics. The combination of daptomycin and fosfomycin is recommended as an alternative therapy for VRE BSI; however, clinical data to support use of this combination are lacking. We conducted a prospective observational multicentre study of patients treated with a combination of daptomycin and fosfomycin for VRE BSI during 2016-20. The primary outcome was 28 day mortality. Multivariable logistic regression was performed for outcome analysis. The study included 106 patients from 1112 VRE BSI episodes. The overall 28 day mortality was 40.6%. The median (IQR) daptomycin dose was 10.18 mg/kg (9.43-10.70). The fosfomycin dose was 16 g/day (8-22.5). Ninety-six isolates were available for MIC testing. The fosfomycin MIC was 32 mg/L in 6 (6.3%), 64 mg/L in 68 (70.8%) and ≥128 mg/L in 22 (22.9%) isolates. Independent of Charlson comorbidity index and Pitt bacteraemia score, fosfomycin MIC ≥128 mg/L [adjusted OR (aOR) = 3.05; 95% CI = 1.01-9.19; P = 0.047] and daptomycin dose (aOR = 0.64; 95% CI = 0.43-0.97; P = 0.04) predicted mortality. Higher daptomycin dose and susceptibility to fosfomycin were independently associated with lower mortality in patients with VRE BSI. Our results suggest that higher doses of daptomycin are indicated for VRE BSI, whether or not it is used in combination with fosfomycin. The combination was less effective for patients with fosfomycin-resistant isolates.

166. Evaluation of Daptomycin Prescribing Practices Based on Microbiologic Susceptibility Determination of “Susceptible-Dose Dependent” (SDD)

BackgroundRecent changes in CLSI microbiologic interpretations of daptomycin and enterococci include the “susceptible-dose dependent” (SDD) category. The effectiveness of SDD for directing clinicians to employ higher dosing of daptomycin is unknown. The study objective was to determine if implementation of SDD paired with a comment recommending higher doses of daptomycin (8-12mg/kg) and ID consultation in 2019 was associated with changes in rates of daptomycin use and prescribed doses for enterococcal bloodstream infections (BSI). MethodsSingle-center, retrospective cohort study of adult inpatients with enterococcal BSI and daptomycin susceptibility results reported from Aug 2016-Jul 2020. Chart review was performed to collect demographics, source of infection, and clinical management strategy. Rate of daptomycin use for definitive therapy (antimicrobial on day 4 after final susceptibilities) and median prescribed dose were compared for BSI caused by S and SDD isolates. Annual (Aug 1-Jul 31) trends in infections and daptomycin use were tabulated. Results189 blood cultures were reviewed, yielding 56 unique episodes of enterococcal BSI. Patients had a mean age of 59 years and majority had an immunocompromising disease or medication. Of the cases in which it was a clinically appropriate option, clinicians selected daptomycin for definitive treatment in 81% of S and 71% of SDD cases (p = 0.46, Chi-square). Median daptomycin dose prescribed was 10mg/kg for both interpretations; dose range was 6-12mg/kg for S and 9.5-12mg/kg for SDD isolates. No temporal trend in prescribed dose noted over the 4-year study period. Repeat blood cultures performed in 50/56 (89%). Within 90 days, rates of relapse were low but mortality was 26/56 (46%). Table 1. Infection and Treatment Characteristics Chart 1. Frequency of prescribed daptomycin dose (mg/kg) for susceptible (A) and SDD (B) enterococci BSI isolates. ConclusionNo difference detected in rate of daptomycin use nor median prescribed dose based on microbiologic interpretation. While the majority of doses were adequate (10mg/kg) based on current guidance for enterococcal BSI, the use of a directive comment to guide dosing and ID consultation may have recused outliers. Additional data is needed to characterize the impact of specific microbiologic interpretations on clinician prescribing and determine the most effective messaging strategies. Disclosures David J. Weber, MD, MPH, PDI (Consultant)

High-Dose Daptomycin and Clinical Applications.

To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d). A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms daptomycin, high dose, and dosing. Review article references and society guidelines were reviewed. Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included. Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant Staphylococcus aureus (when vancomycin minimum inhibitory concentration is >1 mg/L) and Enterococcus. High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg). This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards. The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

Daptomycin-induced eosinophilic pneumonia: Are there any risk factors?

ObjectivesDaptomycin is a widely used antibiotic. Rhabdomyolysis related to daptomycin is one of the adverse effects of treatment, justifying the need for regular monitoring of muscle enzymes throughout treatment. Daptomycin may also lead to eosinophilic pneumonia. However, risk factors for this adverse reaction have not been identified and do not permit targeting of at-risk populations who could benefit from appropriate monitoring. Patients and methodsLiterature was reviewed for cases of daptomycin-induced eosinophilic pneumonia (DIEP), which that were compared to cases of patients without this adverse effect. ResultsFifty patients with DIEP and 54 controls were identified. Age, sex, and treatment dose are not associated with the occurrence of DIEP. A high dose of daptomycin is not associated with an early onset of DIEP. About one third of patients with eosinophilic lung disease have diabetes or renal impairment. ConclusionsFurther studies may help to identify additional factors.

Safety outcomes with high‐dose daptomycin in patients with acute kidney injury and/or end‐stage renal disease

Daptomycin is associated with a number of adverse effects including eosinophilic pneumonia, hypersensitivity reaction, myopathy, rhabdomyolysis, headache and transaminitis. The adverse effects of high-dose daptomycin have not been fully evaluated in patients with end-stage renal disease (ESRD). To determine the incidence and characteristics of significant adverse effects in patients receiving high-dose daptomycin with severe renal dysfunction. A single-centre, retrospective study was conducted to assess safety outcomes of high-dose daptomycin in patients with an estimated creatinine clearance less than 30mL/min. Adult patients aged 18 to 89years admitted between 1 July 2015 and 1 July 2019 were eligible for inclusion. Patients must have received definitive daptomycin therapy with doses greater than or equal to 7.5mg/kg based on actual body weight. The primary outcome was overall incidence of creatine phosphokinase (CK) elevation, myopathy and rhabdomyolysis. A total of 74 patients who received daptomycin therapy were screened with 50 included in the study. The population was well distributed in terms of gender (48% male, n=24) with a median age of 61 (IQR, 48-67) years. The primary indication for daptomycin use was Gram-positive bacteremia. The median daptomycin dose was 750 (IQR, 600-875) mg, or 8.46 (IQR, 7.92-9.96) mg/kg based on actual body weight, with a median patient weight of 81 (IQR, 65-113) kg. The median duration of therapy was 27 (IQR, 14-42) days. One patient experienced significant CK elevation while on daptomycin therapy with rhabdomyolysis; however, daptomycin was continued as there was an alternative explanation for an elevated CK. One patient experienced daptomycin discontinuation due to CK elevation without meeting the definition for significant CK elevation. In a cohort of patients with severe renal dysfunction treated with daptomycin 7.5mg/kg or greater, significant CK elevation on daptomycin therapy was infrequently observed. Future research should confirm these findings, with special consideration for higher mg/kg dosages and/or obese populations.

Effectiveness of Standard Daptomycin Dose in Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia

Background: Daptomycin is considered an effective alternative to vancomycin in patients with methicillin-resistant Staphylococcus aureus bloodstream infection (MRSA BSI). Objective: We investigated the real-world effectiveness of recommended daptomycin doses compared with vancomycin. Methods: This nationwide retrospective cohort study included patients from 124 Veterans’ Affairs hospitals who had a MRSA BSI and were initially treated with vancomycin during 2007–2014. Patients were categorized into 3 groups by daptomycin dose calculated using adjusted body weight: low (&gt;6 mg/kg/day), standard (6–8 mg/kg/day), and high (≥8 mg/kg/day). International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes were used to identify other prior or concurrent infections and comorbidities. Multivariate cox regression was used to compare 30-day all-cause mortality as the primary outcome comparing patients on either low-dose, standard-dose, or high-dose daptomycin with vancomycin. Hazard ratio (HR) and 95% confidence intervals (CIs) were reported. Results: Of the 7,518 patients in the cohort, 683 (9.1%) were switched to daptomycin after initial treatment with vancomycin for their MRSA BSI episode. A low dose of daptyomycin was administered to 181 patients (26.5%), a standard dose was given to 377 patients (55.2%), and a high dose was administered to 125 patients (18.3%). Dose groups differed significantly in body mass index (BMI), presence of an osteomyelitis diagnosis, and diagnosis of diabetes. Thirty-day mortality was significantly lower in daptomycin patients than in those given vancomycin (11.3% vs 17.6%; P &lt; .0001). Treatment with daptomycin was associated with improved 30-day survival compared with vancomycin (HR, 0.66; 95% CI, 0.53–0.84), after adjusting for age, BMI, diagnosis of endovascular infection, skin and soft-tissue infection and osteomyelitis, hospitalization in the prior year, immunosuppression, diagnosis of diabetes, and vancomycin minimum inhibitory concentration (MIC). Treatment with a standard dose of daptomycin was associated with lower mortality compared with vancomycin (HR, 0.63; 95% CI, 0.46–0.86). High and low daptomycin dose groups had a trend toward improved 30-day survival compared with vancomycin (Fig. 1). In 2 separate sensitivity analyses excluding vancomycin patients, there was no difference in 30-day mortality between a standard dose and a high dose (HR, 1.01; 95% CI, 0.51–1.97). However, we detected a trend toward poor survival with a low dose compared with a standard dose (HR, 1.21; 95% CI, 0.73–2.02). Conclusions: A standard dose of daptomycin was significantly associated with lower 30-day mortality compared with continued vancomycin treatment. Accurate dosage of daptomycin and avoidance of low-dose daptomycin should be a part of good antibiotic stewardship practice.Funding: NoneDisclosures: None

Daptomycin in the treatment of enterococcal bloodstream infections and endocarditis: a EUCAST position paper

ScopeThis position paper describes the view adopted by EUCAST on the role of daptomycin in the treatment of serious infections caused by Enterococcus species. BackgroundHigh-dose daptomycin is considered effective in the treatment of enterococcal bloodstream infection (BSI) and endocarditis, although published clinical experience with the latter condition is limited. MethodsEUCAST reviewed the available published data on pharmacokinetics–pharmacodynamics (PK-PD), resistance selection, clinical efficacy and safety for the use of 10–12 mg/kg/day of daptomycin for these conditions, noting that the doses licensed by the European Medicines Agency are only 4–6 mg/kg/day, and only for infections caused by Staphylococcus aureus. Findings and recommendationsThe PK-PD evidence shows that, even with doses of 10–12 mg/kg/day, it is not possible to treat infections caused by isolates at the upper end of the wild-type distributions of Enterococcus faecalis (with MICs of 4 mg/L) and E. faecium (with MICs of 4 or 8 mg/L). For this reason, and because there are ongoing issues with the reliability of laboratory testing, EUCAST lists daptomycin breakpoints for Enterococcus species as “IE”—insufficient evidence. EUCAST advises increased vigilance in the use of high-dose of daptomycin to treat enterococcal BSI and endocarditis. Additional PK-PD studies and prospective efficacy and safety studies of serious Enterococcal infections treated with high-dose daptomycin may permit the setting of breakpoints in the future.

The Efficacy and Safety of High-dose Daptomycin in the Treatment of Complicated Skin and Soft Tissue Infections in Asians

ObjectiveTo compare the efficacy and safety of standard-dose (SD) daptomycin with those of high-dose (HD) daptomycin in complicated skin and soft tissue infections (cSSTIs) in an Asian population. Materials and MethodsPatients from three medical centers diagnosed with cSSTIs were screened in the clinical information system. Patients included in the analysis were divided into two groups: those who received daptomycin at doses ≥ 6 mg/kg (HD group) and those receiving 4 mg/kg (SD group). The demographics and clinical treatment information were analyzed. ResultsOverall, 155 patients were recruited, including 108 patients in the SD group and 47 patients in the HD group. The rate of healthcare-associated infections was higher in the HD group (61.70% vs. 37.04%), demonstrating a statistically significant difference (P = 0.005). Compared with the SD group, the HD group had statistically significant early clinical stabilization (72.34% vs 52.78%, P = 0.023). The results of the multivariate analysis indicated that HD daptomycin was an independent effector for early clinical stabilization (HR=0.394, P < 0.001). The rate of drug-related adverse events was equally distributed in the HD and SD groups (36.17% vs. 26.85%, P = 0.243). ConclusionCompared with SD daptomycin, HD daptomycin increased the rate of early clinical stabilization in Asian patients with cSSTIs, whereas the incidence of adverse events did not increase.

Efficacy and Safety of High Vs Standard Daptomycin Doses Examined in Chinese Patients With Severe Burn Injuries by Pharmacokinetic Evaluation.

Previous studies and the concentration-dependent antibacterial actions of daptomycin suggested that a high dose would be needed for difficult-to-treat infections in burn patients. Here, we evaluated the effects of administration of low and high doses of daptomycin in patients with severe burn injuries. The study retrospectively analyzed 10 patients with severe burn injuries, using pharmacokinetic (PK) and pharmacodynamic (PD) evaluations of daptomycin doses given to combat serious infections. Daptomycin was administered as a single dose or by multiple doses intravenously at a standard dose of 6 mg/kg/d or a high dose of 12 mg/kg/d for 7 to 14 days. The serum concentrations of daptomycin from patients were analyzed by liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS). Burn injury patients treated with high-dose daptomycin had a linear PK profile and a negative correlation between the AUC0–24 and Baux score (R2 = .953 and R2 = .801). The Cmax, AUC0–24, and t(h)½ increased significantly compared with patients given a standard dose. The efficacy of daptomycin against Staphylococcus aureus showed significantly higher rates of (AUC0–24)/MIC and Cmax/MIC after high-dose daptomycin compared with the standard dose, reflected in a significant correlation between a high dose and the Baux score (r = .976, P < .001). Positive S. aureus cultures from two of three high-dose and none of two daptomycin low-dose patients converted from positive to negative after therapy. No serious adverse events or discontinuation of the drug occurred during the treatment period. Daptomycin doses up to 12 mg/kg/d were well tolerated in Chinese patients with severe burn injuries, which were complicated by infections with S. aureus.