Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

Comparison of daptomycin and glycopeptide efficacy and safety for the treatment of Gram-positive infections: a systematic review and meta-analysis.

BACKGROUND: The indications of daptomycin have been extended to off-label indications including prosthesis-related infection, and bone and joint infection (BJI). However, efficacy and safety have not been thoroughly demonstrated compared with the standard of care. This systematic review and meta-analysis aimed to compare the treatment effect of daptomycin and glycopeptides for complicated infections. MATERIALS AND METHODS: MEDLINE, Embase and Web of Science were searched for randomized controlled trials (RCTs) comparing daptomycin and standard of care for Gram-positive infections, published until 30 June 2021. The primary outcome was defined as all-cause mortality. Secondary outcomes were clinical and microbiological success. The main safety outcome was any severe adverse event (SAE) (grade  ≥3). RESULTS: Overall, eight RCTs were included in the meta-analysis, totalling 1095 patients. Six (75%) were in complicated skin and soft-structure infections, one (12.5%) in bacteraemia and one (12.5%) in a BJI setting. Six RCTs used vancomycin as a comparator and two used either vancomycin or teicoplanin. All-cause mortality and clinical cure were not different between groups. The microbiological cure rate was superior in patients who received daptomycin [risk ratio (RR) = 1.17 (95% CI: 1.01-1.35)]. The risk of SAEs [RR = 0.57 (95% CI: 0.36-0.90)] was lower in the daptomycin arm. CONCLUSIONS: While daptomycin is associated with a significantly lower risk of SAEs and a better microbiological eradication, substantial uncertainty remains about the best treatment strategy in the absence of good-quality evidence, especially in bacteraemia and endocarditis where further RCTs should be conducted.

Daptomycin Plus Oxacillin for Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia.

BACKGROUND: The preferred antibiotic salvage regimen for persistent methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) is unclear. Ertapenem with cefazolin or an antistaphylococcal penicillin has been primarily described, but identifying alternative carbapenem-sparing options may support antibiotic stewardship efforts and decrease the risk of antibiotic-associated Clostridioides difficile infection. OBJECTIVE: We sought to evaluate the effectiveness and safety of daptomycin plus oxacillin (D/O) for persistent MSSAB. METHODS: This was a single-center, retrospective cohort of patients with persistent MSSAB who received D/O between January 1, 2014, and January 1, 2023. Adult patients were included if they had blood cultures positive for MSSA ≥72 hours and received D/O combination for ≥48 hours. Patients were excluded if they were pregnant, incarcerated, or received another antibiotic considered to have excellent activity against MSSA. The primary outcome was time to MSSA bacteremia clearance post-daptomycin initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day all-cause mortality, MSSA bacteremia-related mortality, 90-day readmission for MSSAB, and incidence of antibiotic-associated adverse effects. Time to MSSAB clearance post-D/O initiation was plotted using Kaplan-Meier estimation. RESULTS: Seven unique patient encounters were identified including 4 with endocarditis. Despite a median MSSA bacteremia duration of 7.8 days, median clearance was 2 days post-daptomycin initiation. All achieved microbiological cure, and no adverse effects were reported. Ninety-day all-cause mortality, MSSAB-related mortality, and 90-day readmission for MSSAB occurred in 28.6%, 14.3%, and 14.3% of patients, respectively. CONCLUSIONS AND RELEVANCE: D/O was an effective, well-tolerated salvage regimen in this cohort and may represent a carbapenem-sparing option for persistent MSSAB.

Daptomycin-induced eosinophilic pneumonia.

ABSTRACT: Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare complication of daptomycin use. Manifestations most commonly include fever, hypoxia, dyspnea, cough, eosinophilia, and lung changes on radiographs and CT. Patients typically have had recent daptomycin exposure and develop fever, dyspnea, infiltrates on chest radiograph, more than 25% eosinophils on bronchoalveolar lavage, and improvement of symptoms after withdrawal of daptomycin. Treatment includes discontinuation of daptomycin, corticosteroids, and supportive measures such as supplemental oxygen. Clinicians should have a high index of suspicion for DIEP in patients who develop new onset of pulmonary and systemic signs and symptoms after initiation of daptomycin.

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

AIMS: Standard doses of daptomycin at 4 and 6 mg/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. METHODS: A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4-6 mg/kg) and high-dose (HD, >6 mg/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 (≥8 mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. RESULTS: 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. CONCLUSION: 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.

[Efficacy and safety of daptomycin in the treatment of gram-positive infective endocarditis: a meta-analysis].

Objective: To assess the efficacy and safety of daptomycin in the treatment of gram-positive infective endocarditis (IE) systematically. Methods: China Biology Medicine Database (CBM), China National Knowledge Internet (CNKI), Wanfang Data, VIP Database, PubMed, Embase, the Cochrane Library, and Web of Science were searched from the time of establishing databases to April 2022 to obtain relevant controlled and uncontrolled studies of daptomycin for gram-positive infective endocarditis, using key search terms ("daptomycin","gram-positive bacterial infections","endocarditis"). We performed literature screening according to inclusion/exclusion criteria, data extraction, and quality assessment, and performed random-effects meta-analyses for pooled results data using R software. Results: A total of 11 studies (including 13 articles) were included. The findings in the three controlled studies showed that in the treatment of staphylococcus aureus endocarditis, there was no statistically significant differences in in-hospital death risk (RR=0.66, 95%CI: 0.24-1.84, P=0.427) and 6-month death risk (RR=1.27, 95%CI: 0.75-2.14, P=0.374) for daptomycin versus anti-staphylococcal penicillin or vancomycin; in the treatment of enterococcal endocarditis, there was no statistically significant difference in death risk (both P>0.05) for daptomycin versus ampicillin combined with ceftriaxone (RR=0.39, 95%CI: 0.06-2.49) and ampicillin or vancomycin plus or minus gentamicin (RR=0.42, 95%CI: 0.05-3.36); and for daptomycin versus ampicillin or vancomycin combined with an aminoglycoside antibiotic, the differences in in-hospital death risk (RR=0.80, 95%CI: 0.11-5.83) and 6-month death risk (RR=0.47, 95%CI: 0.07-3.21) were not statistically significant(both P>0.05). In a cost-effectiveness study, daptomycin as first-line treatment could save the medical cost of 4 037 pounds per patient compared with vancomycin over a longer period of patient treatment. The results of the meta-analysis of uncontrolled studies showed that the mean clinical success rate of daptomycin for left-side endocarditis was 77% (95%CI: 70% to 83%; I2=28%), for MSSA-infective right-side endocarditis was 87% (95%CI: 73%-95%), and for MRSA-infective right-side endocarditis was 78% (95%CI: 38%-95%; I2=49%); while the mortality rate [mean mortality rate for left-side endocarditis was 13% (95%CI: 11%-17%; I2=0); the mortality rate for right-side endocarditis was reported in only 2 studies, 3% and 27%, respectively] or the rate of daptomycin-related adverse events (4%) was within the acceptable ranges for clinical practice. Conclusions: The death risk in the treatment of infective endocarditis with dattomycin is comparable to that of other antibiotics, and the clinical success rate is higher. Some efficacy may be achieved with daptomycin while other treatments are not effective in treating IE.

Association Between Statin Use and Daptomycin-related Musculoskeletal Adverse Events: A Mixed Approach Combining a Meta-analysis and a Disproportionality Analysis.

BACKGROUND: There is a growing concern about the association between the combined use of daptomycin (DAP) and statins and the occurrence of musculoskeletal adverse events (MAEs), but this remains controversial. This study aimed to clarify the association between statin use and DAP-related MAEs. METHODS: We used a mixed approach that combines 2 methodologies. First, we conducted a meta-analysis to examine the effects of statin use on DAP-related MAEs. Second, we conducted a disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to further confirm the results of the meta-analysis and to examine the effect of each type of statin on DAP-related MAEs in a large population. RESULTS: In the meta-analysis, statin use significantly increased the incidence of DAP-related rhabdomyolysis (odds ratio [OR]: 3.83; 95% confidence interval [CI]: 1.43-10.26) but not DAP-related myopathy (OR: 1.72; 95% CI: .95-3.12). In the disproportionality analysis using the FAERS, the use of statin significantly increased the reporting OR (ROR) for DAP-related myopathy (ROR: 5.69; 95% CI: 4.31-7.51) and rhabdomyolysis (ROR: 5.77; 95% CI: 4.33-7.68). Atorvastatin, rosuvastatin, and simvastatin all increased the incidence of DAP-related myopathy and rhabdomyolysis. CONCLUSION: The mixed approach combining a meta-analysis and disproportionality analysis showed that statin use was associated with the occurrence of DAP-related rhabdomyolysis. The appropriate use of statins and DAP should be performed with careful consideration of its safety.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Factors affecting creatine phosphokinase elevation during daptomycin therapy using a combination of machine learning and conventional methods.

AIMS: Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. METHODS: A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and >200 IU/L, and (2) >1000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. RESULTS: Of the 2970 patients who received DAP, 706 were included. Elevation of CPK values >200 IU/L and >1000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In decision tree analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. CONCLUSION: Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: A systematic review and meta-analysis.

AIMS: The present systematic review and meta-analysis evaluated the incidence of elevated creatine phosphokinase (CPK) levels between daptomycin alone and concomitant daptomycin and statin use. METHODS: We searched the PubMed, Web of Sciences, Cochrane Library and ClinicalTrials.gov databases. We analysed the incidence of elevated CPK between daptomycin alone and concomitant daptomycin and statins among studies defining CPK elevation as levels ≥ the upper limit of normal (ULN) or ≥5× ULN. We also analysed the incidence of rhabdomyolysis between the groups. We then calculated the odds ratios (ORs) and 95% confidence intervals (CIs) based on the included studies. RESULTS: Comparing CPK elevation defined as CPK levels ≥ULN, a significantly higher incidence of CPK elevation was observed with concomitant daptomycin and statin use than with daptomycin alone (OR = 2.55, 95% CI 1.78-3.64, P < .00001, I2  = 0%). Likewise, when CPK elevation was defined as CPK levels ≥5× ULN, a significantly higher incidence of CPK elevation was detected with concomitant daptomycin and statin use than with daptomycin alone (OR = 1.89, 95% CI 1.06-3.35, P = .03, I2  = 48%). The incidence of rhabdomyolysis was significantly higher following concomitant daptomycin and statin use than with daptomycin alone (OR = 11.60, 95% CI 1.81-74.37, P = .01, I2  = 0%). CONCLUSION: The combined use of daptomycin and statins were significant risk factors for the incidence of CPK elevation defined as levels ≥ULN or ≥5× ULN and rhabdomyolysis.

Target Therapeutic Ranges of Anti-MRSA Drugs, Linezolid, Tedizolid and Daptomycin, and the Necessity of TDM.

The target therapeutic ranges of vancomycin, teicoplanin, and arbekacin have been determined, and therapeutic drug monitoring (TDM) is performed in clinical practice. However, TDM is not obligatory for daptomycin, linezolid, or tedizolid. In this study, we examined whether TDM will be necessary for these 3 drugs in the future. There was no significant difference in therapeutic effects on acute bacterial skin and skin structure infection between linezolid and tedizolid by meta-analysis. Concerning the therapeutic effects on pneumonia, the rate of effectiveness after treatment with tedizolid was significantly lower than with linezolid. With respect to safety, the incidences of gastrointestinal adverse events and blood/lymphatic system disorders related to tedizolid were significantly lower than those related to linezolid. Linezolid exhibits potent therapeutic effects on pneumonia, but the appearance of adverse reactions is indicated as a problem. There was a dose-dependent decrease in the platelet count, and the target trough concentration (Ctrough) was estimated to be 4-6 or 2-7 µg/mL in accordance with the patient's condition. The efficacy of linezolid may be obtained while minimizing the appearance of adverse reactions by performing TDM. The target therapeutic range of tedizolid cannot be achieved in immunocompromised or severe patients. Therefore, we concluded that TDM was unnecessary, considering step-down therapy with oral drugs, use in non-severe patients, and high-level safety. Concerning daptomycin, high-dose administration is necessary to achieve an area under the curve (AUC) of ≥666 as an index of efficacy. To secure its safety, Ctrough (<20 µg/mL) monitoring is important. Therefore, TDM is necessary.

Efficacy and safety of daptomycin in Japanese pediatric participants with complicated skin and soft tissue infections or bacteremia caused by gram-positive cocci.

INTRODUCTION: Complicated skin and soft tissue infections (cSSTIs) and bacteremia caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), are common causes of infection for children worldwide. Here, the safety and efficacy of daptomycin in Japanese pediatric participants are reported. METHODS: This open-label, single-arm phase 2 study (NCT03643952) enrolled Japanese pediatric participants (age 1-17 years) with cSSTI or bacteremia caused by gram-positive cocci. Participants received age-adjusted doses of intravenous daptomycin for 5 to up to 14 days (cSSTI) or 5 to up to 42 days (bacteremia). The primary objective was safety and tolerability; efficacy among participants with infections caused by MRSA was a secondary objective. RESULTS: A total of 18 participants (cSSTI, n = 14; bacteremia, n = 4) were enrolled across 12 study sites in Japan. The most common pathogen was S. aureus (15/18 [83.3%]), including methicillin-susceptible and -resistant isolates. Adverse events (AE) were reported in 42.9% (6/14) of participants with cSSTI and 100% (4/4) of participants with bacteremia. No deaths, serious AEs, discontinuations of study medication due to an AE, or events of clinical interest occurred in the study. In participants with infections caused by MRSA, 87.5% [7/8] achieved favorable clinical response at test of cure (TOC) visit (cSSTI, 85.7% [6/7]; bacteremia, 100% [1/1]). In this population, favorable microbiological response at TOC was achieved by 71.4% (5/7) of participants with cSSTI and 100% (1/1) of participants with bacteremia. CONCLUSIONS: Daptomycin was well tolerated, exhibited a favorable safety profile, and was effective for the treatment of cSSTI or bacteremia in Japanese children.

High-Dose Daptomycin and Clinical Applications.

OBJECTIVE: To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d). DATA SOURCES: 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. STUDY SELECTION AND DATA EXTRACTION: Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included. DATA SYNTHESIS: 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). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: 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. CONCLUSIONS: The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

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

WHAT IS KNOWN: 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). OBJECTIVE: To determine the incidence and characteristics of significant adverse effects in patients receiving high-dose daptomycin with severe renal dysfunction. METHODS: A single-centre, retrospective study was conducted to assess safety outcomes of high-dose daptomycin in patients with an estimated creatinine clearance less than 30 mL/min. Adult patients aged 18 to 89 years 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 7.5 mg/kg based on actual body weight. The primary outcome was overall incidence of creatine phosphokinase (CK) elevation, myopathy and rhabdomyolysis. RESULTS AND DISCUSSION: 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. WHAT IS NEW AND CONCLUSION: In a cohort of patients with severe renal dysfunction treated with daptomycin 7.5 mg/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.

Antibiotic Exposure and Risk for Hospital-Associated Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is a health care-associated infection associated with significant morbidity and cost, with highly varied risk across populations. More effective, risk-based prevention strategies are needed. Here, we investigate risk factors for hospital-associated CDI in a large integrated health system. In a retrospective cohort of all adult admissions to 21 Intermountain Healthcare hospitals from 2006 to 2012, we identified all symptomatic (i) hospital-onset and (ii) health care-facility-associated, community-onset CDI. We then evaluated the risk associated with antibiotic exposure, including that of specific agents, using multivariable logistic regression. A total of 2,356 cases of CDI among 506,068 admissions were identified (incidence, 46.6 per 10,000). Prior antibiotic use was the dominant risk factor, where for every antibiotic day of therapy prior to the index admission, the odds of subsequent CDI increased by 12.8% (95% confidence interval [CI], 12.2 to 13.4%; P < 0.0001). This was a much stronger association than was inpatient antibiotic exposure (odds ratio [OR], 1.007 [95% CI, 1.005 to 1.009]; P < 0.0001). The highest-risk antibiotics included second-generation and later cephalosporins (especially oral), carbapenems, fluoroquinolones, and clindamycin, while doxycycline and daptomycin were associated with a lower CDI risk. We concluded that cumulative antibiotic exposure prior to admission is the greatest contributor to the risk of subsequent CDI. Most classes of antibiotics carry some risk, which varies by drug and route. This information may be useful for antimicrobial stewardship efforts.

Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin.

OBJECTIVE: To review the current literature describing pharmacology, pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and safety of linezolid and daptomycin for the treatment of central nervous system (CNS) infections caused by vancomycin-resistant Enterococcus (VRE) faecium. DATA SOURCES: A literature search of PubMed/MEDLINE databases was conducted (from 1950 to April 2020) utilizing the following key terms: vancomycin-resistant Enterococcus, VRE, meningitis, ventriculitis, CNS infection, daptomycin, and linezolid. STUDY SELECTION AND DATA EXTRACTION: All relevant studies and case reports describing the treatment of VRE faecium from the CNS with linezolid or daptomycin were included. DATA SYNTHESIS: A total of 17 reports describing 22 cases were identified. There were 15 of 19 cases involving linezolid that reported clinical cure, of which 53.3% were monotherapy. Only 5 of 9 cases involving intravenous (IV) daptomycin resulted in cure; all 4 cases reporting daptomycin administration via the intrathecal or intraventricular route achieved clearance from the cerebrospinal fluid (CSF). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The preferred treatment option for VRE faecium infections involving the CNS remains unclear. Supporting evidence through observational case reports have described varying outcomes with linezolid and daptomycin. This review compares reported outcomes between the 2 agents and provides a thorough discussion on drug- and patient-specific variables to consider. CONCLUSIONS: Linezolid monotherapy appears to be safe and effective for the treatment of susceptible-VRE faecium CNS infections, with consideration of therapeutic drug monitoring in special populations and with prolonged treatment duration. Daptomycin is an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. The role of IV daptomycin remains inconclusive.

Evaluation of Daptomycin-Induced Cellular Membrane Injury in Skeletal Muscle.

Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against Gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.

Retrospective study on clinical efficacy and safety for daptomycin intermittent doses with or without loading dose in renal failure patients.

This retrospective study is to evaluate the efficacy and safety of daptomycin (DAP) intermittent doses and the effectiveness of DAP loading dose in renal failure patients received DAP intermittent doses. One hundred and ninety-seven patients received DAP for at least 3 days from 2014 to 2017. Clinical and microbiological outcomes and the safety were assessed. A total of 183 patients (93, 60 and 30 patients received DAP daily dose, every 48 h dose and thrice per week dose) were included. DAP intermittent doses, such as every 48 h dose (28.3%) and thrice per week dose (30.0%), showed significantly higher mortality rates than that of DAP daily dose (6.5%) (p = 0.0320). Especially for bacteremia patients, significantly higher mortality was admitted, compared with patients received DAP daily doses (p = 0.0160). Moreover, patients received DAP intermittent doses were admitted slower improvements of their inflammation after DAP therapy started, compared with patients received daily dose. Additionally, DAP loading dose for renal failure patients decreased their mortality and improved patients' inflammation early. Especially for patients received DAP thrice per week dose, they showed significantly lower mortality than patients received non-loading dose (p = 0.0306). Additionally, these clinical enhancements of DAP therapy with loading dose were admitted without any enhancements of its adverse effect risks, except alkaline phosphatase elevation, compared with non-loading dose. In conclusion, DAP intermittent doses showed poor clinical outcomes, compared with daily dose. Then, DAP loading dose would be better clinical option for patients received DAP intermittent doses.

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

WHAT IS KNOWN AND OBJECTIVE: Daptomycin-induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (Ctrough ; breakpoint of 24.3 µg/mL). However, even with high-dose treatment (ie, > 8 mg/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 24.3 µg/mL. Therefore, we questioned the clinical significance of Ctrough levels of 24.3 µg/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. METHODS: Patients who had received daptomycin treatment for > 4 days 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. RESULTS AND DISCUSSION: 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 68 years (range: 19-88 years), and 14 patients initially had an estimated creatinine clearance of less than 30 mL/min. Seven cases indicated a Ctrough of above 24.3 µg/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 10.9 µg/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 8.1 µg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited Ctrough levels lower than 24.3 µg/mL. In this study, two patients receiving high-dose daptomycin (ie, 9.4 and 10.0 mg/kg) had observed Ctrough levels similar to patients who received doses of daptomycin < 9 mg/kg. WHAT IS NEW AND CONCLUSIONS: The safety of daptomycin treatment was suggested in this study. Ctrough level of 24.3 µg/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 24.3 µg/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.

[Daptomycin-induced eosinophilic pneumonia associated with an early endoprosthesis infection]. / Daptomycin-induzierte eosinophile Pneumonitis im Rahmen eines Endoprothesenfrühinfektes.

Acute eosinophilic pneumonia (AEP) is a rare disease characteristically involving eosinophilic infiltration of lung parenchyma as well as fever, dyspnea, and coughing. A differentiation is made between primary and secondary AEP depending on the underlying etiology. Substances that most frequently cause secondary AEP are antibiotics, such as the lipopeptide daptomycin. This is a case report about a 69-year-old female patient who underwent antibiotic treatment with daptomycin for an infection of a knee prosthesis. During the treatment, signs of pneumonia developed and included the increased dependence on mechanical ventilation of the previously intubated patient, infiltrates on a chest X­ray, fever, and an increase in serum inflammation markers. Proof of bacteria as an underlying pathogen was not possible. A thoracic computed tomography (CT) scan showed opacities that are commonly seen in interstitial lung disease. Termination of daptomycin treatment due to renal failure led to an improvement of pulmonary symptoms. Re-exposure to daptomycin resulted in a recurrence of the symptoms. The diagnostic criteria for AEP according to Uppal et al. include 1) current exposure to daptomycin, 2) dyspnea with increased oxygen requirements or necessity for mechanical ventilation, 3) new infiltrates on chest X­ray or CT scan, 4) bronchoalveolar lavage with eosinophilia >25%, 5) improvement of clinical symptoms following daptomycin withdrawal, and 6) fever. With 5 out of the 6 criteria by Uppal et al. positive-an eosinophilia >25% being the only unmet criteria-an AEP induced by daptomycin was diagnosed. Withdrawal of daptomycin as well as high-dose cortisol bolus treatment led to a rapid recovery.