Safety and Effectiveness of Daptomycin Across a Hospitalized Obese Population: Results of a Multicenter Investigation in the Southeastern United States

Bookstaver, P. Brandon; Bland, Christopher M.; Qureshi, Zaina P.; Faulkner-Fennell, Carmen; Sheldon, Margrit A.; Caulder, Celeste R.; Hartis, Charles; Investigators, Serge

doi:10.1002/phar.1298

Cited by 33 publications

(43 citation statements)

References 40 publications

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“…These findings are not unexpected considering obese patients have higher daptomycin AUC and C max exposure compared with normal‐weight patients and that its clearance does not proportionately increase. Clinical experience in the obese population also found a trend toward increasing rates of CPK elevations as BMI class increases (BMI class I [3.6%], BMI class II [10.3%], BMI class III [10.5%]; p=0.554), with therapy discontinuation due to adverse drug events having occurred in 8 (6.3%) patients and one developed rhabdomyolysis on day 9 of therapy …”

Section: Review Of Specific Antimicrobial Agentsmentioning

confidence: 91%

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

et al. 2017

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Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity-specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., β-lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing.

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Section: Review Of Specific Antimicrobial Agentsmentioning

confidence: 91%

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

et al. 2017

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“…A subsequent study revealed an approximate 60% increase in maximum concentration and area under the curve following a 4-mg/kg dose in morbidly obese healthy patients compared to normal-weight patients (15). A recent study showed an increased rate of CPK elevation in obese patients, but discontinuation rates remained low (16). Use of actual body weight in all patients is currently recommended for daptomycin.…”

Section: Discussionmentioning

confidence: 99%

Musculoskeletal Safety Outcomes of Patients Receiving Daptomycin with HMG-CoA Reductase Inhibitors

Bland

Bookstaver

Zhiqiang

et al. 2014

Antimicrob Agents Chemother

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dDaptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P ‫؍‬ 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P ‫؍‬ 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P ‫؍‬ 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population.

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“…Indeed, other animal or clinical studies also demonstrate the safety or protective effect of daptomycin against renal function . However, high body weight (eg, more than 70 kg) is recently reported as a risk of CPK elevation . Our study included only seven patients with body weights higher than 70 kg.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, a few cases presented with a defined abnor- 8,19,20 However, high body weight (eg, more than 70 kg) is recently reported as a risk of CPK elevation. 16,21 Our study included only seven patients with body weights higher than 70 kg. Therefore, in light of the risk of CPK elevation, our findings concerning the safety of daptomycin treatment may be limited to patients with normal body weight.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Safety and Effectiveness of Daptomycin Across a Hospitalized Obese Population: Results of a Multicenter Investigation in the Southeastern United States

Abstract: Although elevations in CPK increased in high-risk obese patients on daptomycin, discontinuation rates due to ADEs remained low. Further evaluation in a prospective trial is warranted.

Cited by 33 publications

References 40 publications

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

Musculoskeletal Safety Outcomes of Patients Receiving Daptomycin with HMG-CoA Reductase Inhibitors

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

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