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Background
Food and Drug Administration–approved daptomycin dosing uses actual body weight, despite limited dosing information for obese patients. Studies report alterations in daptomycin pharmacokinetics and creatine phosphokinase elevations associated with higher weight-based doses required for obese patients. Limited information regarding clinic...
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Although rare, rhabdomyolysis is a serious complication of cardiothoracic surgery. Daptomycin is a polypeptide antimicrobial agent used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections of the soft tissues. Daptomycin is associated with elevations in serum creatine kinase (CK).
A 50-year-old man with acute Stanford A-type aorti...
Citations
... The objective is to provide clinicians with the basis for recommendations based on a review of the scientific literature for an appropriate dose of antibiotic. Concerning daptomycin, three publications are at the origin of these recommendations (30)(31)(32). ...
Daptomycin is a concentration-dependent lipopeptide antibiotic for which exposure/effect relationships have been shown. Machine learning (ML) algorithms, developed to predict the individual exposure to drugs, have shown very good performances in comparison to maximum a posteriori Bayesian estimation (MAP-BE). The aim of this work was to predict the area under the blood concentration curve (AUC) of daptomycin from two samples and a few covariates using XGBoost ML algorithm trained on Monte Carlo simulations. Five thousand one hundred fifty patients were simulated from two literature population pharmacokinetics models. Data from the first model were split into a training set (75%) and a testing set (25%). Four ML algorithms were built to learn AUC based on daptomycin blood concentration samples at pre-dose and 1 h post-dose. The XGBoost model (best ML algorithm) with the lowest root mean square error (RMSE) in a 10-fold cross-validation experiment was evaluated in both the test set and the simulations from the second population pharmacokinetic model (validation). The ML model based on the two concentrations, the differences between these concentrations, and five other covariates (sex, weight, daptomycin dose, creatinine clearance, and body temperature) yielded very good AUC estimation in the test (relative bias/RMSE = 0.43/7.69%) and validation sets (relative bias/RMSE = 4.61/6.63%). The XGBoost ML model developed allowed accurate estimation of daptomycin AUC using C0, C1h, and a few covariates and could be used for exposure estimation and dose adjustment. This ML approach can facilitate the conduct of future therapeutic drug monitoring (TDM) studies.
... 1 Although antibiotic treatment plays a pivotal role in decreasing the mortality risk associated with infections, questions have often been raised regarding optimal antibiotic dosing to ensure positive outcomes and minimize side effects. 2 This can be achieved using different dosing strategies and understanding the pharmacokinetics and pharmacodynamics of each medication in different patient populations. 1 The obese population has been found to have increased kidney size and glomerular filtration rate (GFR), which has the potential to alter renal clearance and volume of distribution (Vd) of medications, including antibiotics. 3 Commonly influenced pharmacodynamic parameters related to antibiotics include the area under the concentration-time curve to the minimum inhibitory concentration ratio (AUC:MIC), the peak concentration (Cmax):MIC ratio, and the percentage of time that the antimicrobial concentration remains above the MIC (T>MIC). ...
... 13 In addition, in patients with class I, II, or III obesity, when daptomycin (4 -6 mg/kg) was administered using adjBW versus TBW, no difference was observed in the clinical failure rate. 2 When assessing the safety of a daptomycin dose of 8 mg/ kg (range, 7-11 mg/kg) using ABW in 61 patients, three patients had constitutional and/or musculoskeletal symptoms accompanying CPK levels >10 times the upper limit of normal (grade 3). All cases occurred after 24 days of treatment and improved after the daptomycin treatment was discontinued. ...
Purpose: To provide a comprehensive review of daptomycin weight-based dosing methods for obese patients. Methods: PubMed, Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched through December 31, 2022. Studies relevant to daptomycin weight-based dosing methods in obese adult patients were included. Results: Sixteen studies were included, of which five were case reports and 11 were cohort studies. Obese patients were included in all case reports, of which one was pregnant. The infections improved after receiving a daptomycin dose based on actual body weight (ABW) in all cases. Seven studies demonstrated that ABW, ideal body weight (IBW), and adjusted body weight (AjBW)-based daptomycin dosing differed in terms of treatment success, microbiological clearance, and creatinine phosphokinase (CPK) elevation. However, AjBW was not statistically equivalent to ABW in all evaluated outcomes, except for treatment success. Three studies showed a higher area under the concentration-time curve (AUC) by 60% in obese patients, whereas two studies indicated a higher maximum plasma concentration (Cmax) of ~2 folds. One study demonstrated that obese patients had higher levels of total clearance and volume of distribution, whereas other pharmacokinetic parameters were comparable between obese and non-obese patients. Conclusion: While most of the available evidence reported daptomycin dosing based on actual or total body weight, a few other studies have reported the use of ideal or adjusted body weight. A significant elevation in CPK was observed when daptomycin was administered based on AdjBW, but not with ABW and IBW. Further research is required to determine the optimal daptomycin weight-based dosing method in obese patients.
... The factors conferring an increased risk for daptomycin-induced myopathy or rhabdomyolysis may be dose-related [20]. Daptomycin is recommended to be dosed based on total body weight, and patients with baseline renal impairment and obesity may have increased daptomycin exposure [20][21][22][23]. ...
Background:
Myopathy is one of the most common adverse reactions of daptomycin and statins. We aimed to evaluate the muscular toxicity of the combination therapy of daptomycin and statins in a large pharmacovigilance database.
Methods:
This was a retrospective disproportionality analysis based on real-world data. All cases reported between the first quarter of 2004 and the fourth quarter of 2022 where daptomycin and statins were reported were gathered from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionality analyses were conducted by estimating the proportional reporting ratios (PRRs), reporting odds ratio (ROR), and information component (IC).
Results:
A total of 971,861 eligible cases were collected from the FAERS database. Data analysis showed that rosuvastatin (ROR: 124.39, 95% CI: 87.35-178.47), atorvastatin (ROR: 68.53, 95% CI: 51.93-90.43), and simvastatin (ROR: 94.83, 95% CI: 71.12-126.46) combined with daptomycin increased the reporting frequency of myopathy. Moreover, myopathy was reported more frequently with the 3-drug combination (ROR: 598.01, 95% CI: 231.81-1542.71). For rhabdomyolysis, the frequency of reports also increased when daptomycin was combined with rosuvastatin (ROR: 156.34, 95% CI: 96.21-254.05), simvastatin (ROR: 72.65, 95% CI: 47.36-111.44), and atorvastatin (ROR: 66.31, 95% CI: 44.06-99.81).
Conclusions:
The combination of daptomycin and statins increased the association of myopathy and rhabdomyolysis, especially with rosuvastatin, simvastatin, and atorvastatin.
... Also, factors associated with the causes of eosinophilia (obesity and daptomycin dosing) have been inferred from case reports, but not clearly demonstrated [6,7]. With increased dosing of daptomycin to 8 mg/kg recommended for S. aureus infections, there has been no guidance on whether this should be on actual body weight (as recommended by the Food and Drug Administration [FDA]) or adjusted body weight, making it complicated for dosing in morbidly obese patients [8,9]. ...
... Dosing of daptomycin in patients with weight >100 kg has not been clearly established and can vary by site of infection, indication, and clinical pharmacist. In comparing adjusted with actual body weight dosing of daptomycin, there was no difference in clinical outcomes or CPK elevations in a retrospective review [9]. Our site changed from actual to adjusted body weight in our period of review, which impacted our ability to determine the effect of elevated BMI on eosinophilia. ...
Background
Daptomycin pulmonary eosinophilia (DPE) has been well described in case reports and reporting from the Food and Drug Administration. We report 3 eosinophilic syndromes associated with daptomycin use.
Methods
This is a retrospective review of all patients who received daptomycin (inpatient or outpatient) from 2010 to 2020 at the Veterans Affairs Portland Healthcare System. Patients who developed DPE while receiving daptomycin were evaluated to determine risk factors. Data collected included daptomycin dose and duration, body mass index, creatinine clearance, and peripheral eosinophilia.
Results
Of 330 patients who received daptomycin, 81.5% developed a peripheral eosinophilia, with 109 (33%) developing peripheral eosinophilia ≥5%. Fifty-one (16%) met criteria for DPE. Primary DPE occurred in 38 of the 51 patients with a median 26 days of treatment, and 49% had peripheral eosinophilia ≥5%. Re-exposure DPE occurred in the other 13 patients and occurred a median of 3 days after initiation of daptomycin. The presence of an elevated peripheral eosinophilia of ≥5% during daptomycin usage was significantly associated with primary (odds ratio [OR], 2.23; 95% CI, 1.2–4.09; P = .008) and re-exposure DPE (OR, 12; 95% CI, 1.6–103; P = .003). All patients recovered after withdrawal of daptomycin without complications.
Conclusions
There are 3 daptomycin eosinophilic syndromes: peripheral eosinophilia, primary DPE occurring about 4 weeks into therapy, and re-exposure DPE. Elevated peripheral eosinophilia ≥5% was a risk factor for both primary and re-exposure DPE, but still identified about half the cases. Peripheral eosinophilia should be carefully monitored during daptomycin treatment, and clinicians should be aware that prior eosinophilia may predict an acute pulmonary reaction upon daptomycin re-exposure.
... Alobaid et al. (2016) stated that daptomycin and bacteriakilling lipopeptide are examples of antimicrobials affected by such changes. Fox et al. (2019) stated that daptomycin is another drug given to obese individuals and very effective against gram-positive bacteria. These authors also stated that the bactericidal prowess of daptomycin is chiefly in that the proportion of area under the concentration-time curve of daptomycin and mean inhibitory concentration (MIC) is sufficient. ...
... The initial administration of daptomycin before being approved as stated by Fox et al. (2019) was dependent on the actual body weight (ABW) which was placed between 4 and 6 mg/kg as observed. They further stated that the whole exercise did not properly capture morbidly obese patients. ...
... As reported by these authors, trough concentration-based toxicity associated with an elevated AUC and optimum concentration was observed. However, the impact of administering daptomycin based on ABW may be slightly felt so long as drug dispersal is kept at the optimal level (Fox et al., 2019). ...
In the gut of almost all animals including humans is Enterococcus which are Gram-positive, hardy organism and are capable of causing serious infection especially among hospitalized patients. The emergence of obesity, atherosclerosis and the rest of non-communicable chronic diseases could be attributed to the presence of bacteria in the intestine of humans as seen in data gathered over the years. Obesity in the last ten years have significantly increased and these rates call for concern. There are several factors responsible for the emergence of obesity, among which are sedentary lifestyle, consumption of high-fat diet, hormonal, neural, epigenetic and genetic factors. Since VRE is one of the leading causes of nosocomial infections, its association with obesity in patients seeking treatment in the hospital could lead to increased treatment failure and worse outcome. This review, therefore, seeks to bring to light the relationship between VRE, antibiotics and obesity, it also seeks to elucidate the role played by mechanisms in promoting this association and it finally provides instances of cases of VRE in obese patients. Antimicrobials are of vital importance in the fight against bacterial infections and more specifically, VRE. However, the need for discreet and reasonable use of antibiotics including regimented dosage cannot be overemphasized. A dietary supplement is the most likely and effective tool in this microbial war in obesity against bacterial colonization. It is important to carry out further studies to lay bare the seeming association between VRE, obesity and antibiotics as this review has shown an indirect relationship.
Introduction:
Enterococcus faecium is a commensal microorganism that can cause infections such as bacteremia. Incidence of ampicillin-resistant and vancomycin-susceptible E. faecium (EfARSV) bacteremia is on the rise, and the mortality rate is high. Despite much data, the most appropriate treatment remains a question.
Areas covered:
This article mostly reviews the relevant aspects of EfARSV bacteremia: microbiology, gastrointestinal tract colonization and invasion, antibiotic resistance, epidemiology, risk factors, mortality, and treatment, including pharmacologic components of employed agents and related clinical evidence. A literature search was conducted on PubMed on 31 July 2022, which was updated on 15 November 2022.
Expert opinion:
EfARSV bacteremia presents high mortality. However, it is uncertain whether mortality is attributable to or a marker of severity/comorbidities. Considering its antibiotic resistance pattern, EfARSV is considered a difficult-to-treat microorganism. Glycopeptides have been used to treat EfARSV, with linezolid and daptomycin serving as potential alternative agents. Yet, the use of daptomycin is controversial due to a higher risk of treatment failures. Clinical evidence on this issue is scarce, unfortunately, and subject to many limitations. Despite increased incidence and mortality, EfARSV bacteremia presents multiple aspects to be addressed in well-conducted studies.
Background
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).
Objectives
To describe practice patterns for VRE BSI in ID pharmacists.
Methods
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.
Results
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.
Conclusions
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.
Drug dosing in obese patients continues to be challenging due to a lack of high‐quality evidence to guide dosing recommendations. We first published guidance for antibiotic dosing in obese adults in 2017, in which we critically reviewed articles identified from a broad search strategy to develop dosing recommendations for 35 antimicrobials. In this updated narrative review, we searched Pubmed, Web of Science, and the Cochrane Library using Medical Subject Headings including anti‐infectives, specific generic antimicrobial names, obese, pharmacokinetics, and others. We reviewed 393 articles, cross‐referenced select cited references, and when applicable, referenced drug databases, package inserts, and clinical trial data to update dosing recommendations for 41 antimicrobials. Most included articles were pharmacokinetic studies, other less frequently included articles were clinical studies (mostly small, retrospective), case reports, and very rarely, guidelines. Pharmacokinetic changes are frequently reported, can be variable, and sometimes conflicting in this population, and do not always translate to a documented difference in clinical outcomes, yet are used to inform dosing strategies. Extended infusions, high doses, and therapeutic drug monitoring remain important strategies to optimize dosing in this population. Additional studies are needed to clinically validate proposed dosing strategies, clarify optimal body size descriptors, dosing weight scalars, and estimation method of renal function in obese patients.
Rhabdomyolysis is a well-documented side effect of daptomycin and is associated with hyperuricemia. However, the occurrence of acute gouty arthritis secondary to rhabdomyolysis-induced hyperuricemia has not been reported. We report a case of a patient who presented with daptomycin-induced rhabdomyolysis prior to the usual 7-10-day administration period. This case was complicated with acute gouty arthritis after 7 days from the onset of rhabdomyolysis symptoms. Treatment consisted of fluid management with the addition of prednisone for gouty arthritis treatment given his poor kidney function. This report indicates the importance of early monitoring of creatine kinase levels in patients on daptomycin to prevent complications from rhabdomyolysis.
