Factors associated with development of nephrotoxicity in patients treated with vancomycin versus daptomycin for severe Gram-positive infections: A practice-based study / Factores asociados con el desarrollo de nefrotoxicidad en pacientes tratados con vancomicina frente a daptomicina en infecciones graves por grampositivos: Un estudio basado en la práctica clínica

Objectives. To evaluate nephrotoxicity development in patients treated with vancomycin (VAN) and daptomycin (DAP) for proven severe Gram-positive infections in daily practice. Patients and methods. A practice-based, observational, retrospective study (eight Spanish hospitals) was performed including patients ≥18 years with a baseline glomerular filtration rate (GFR)>30 mL/min and/or serum creatinine level<2 mg/dL treated with DAP or VAN for >48h. Nephrotoxicity was considered as a decrease in baseline GRF to <50 mL/min or decrease of >10 mL/min from a baseline GRF<50 mL/min. Multivariate analyses were performed to determine factors associated with 1) treatment selection, 2) nephrotoxicity development, and 3) nephrotoxicity development within each antibiotic group. Results. A total of 133 patients (62 treated with DAP, 71 with VAN) were included. Twenty-one (15.8%) developed nephrotoxicity: 4/62 (6.3%) patients with DAP and 17/71 (23.3%) with VAN (p=0.006). No differences in concomitant administration of aminoglycosides or other potential nephrotoxic drugs were found between groups. Factors associated with DAP treatment were diabetes mellitus with organ lesion (OR=7.81, 95%CI:1.39-4.35) and basal creatinine ≥0.9 mg/dL (OR=2.53, 95%CI:1.15-4.35). Factors associated with VAN treatment were stroke (OR=7.22, 95%CI:1.50-34.67), acute myocardial infarction (OR=6.59, 95%CI:1.51-28.69) and primary bacteremia (OR=5.18, 95%CI:1.03-25.99). Factors associated with nephrotoxicity (R2=0.142; p=0.001) were creatinine clearance<80 mL/min (OR=9.22, 95%CI:1.98-30.93) and VAN treatment (OR=6.07, 95%CI:1.86-19.93). Factors associated with nephrotoxicity within patients treated with VAN (R2=0.232; p=0.018) were congestive heart failure (OR=4.35, 95%CI:1.23-15.37), endocarditis (OR=7.63, 95%CI:1.02-57.31) and basal creatinine clearance<80 mL/min (OR=7.73, 95%CI:1.20-49.71). Conclusions. Nephrotoxicity with VAN was significantly higher than with DAP despite poorer basal renal status in the DAP group

Objectivos: Evaluar el desarrollo de nefrotoxicidad en la práctica clínica diaria en pacientes con infecciones graves probadas por grampositivos, tratados con vancomicina (VAN) y daptomicina (DAP). Pacientes y métodos: Se diseñó un estudio observacional retrospectivo, basado en la práctica clínica diaria (ocho hospitales españoles), en el que se incluyeron pacientes ≥ 18 años con una tasa basal de filtrado glomerular (GFR) > 30 mL/min y/o una creatinina sérica < 2 mg/dl para los pacientes tratados con DAP o vancomicina durante > 48 horas. La nefrotoxicidad fue considerada como una disminución del GRF basal a < 50 mL/min o una disminución de > 10 mL/min desde un GRF basal de < 50 ml/min. Se diseñaron análisis multivariantes para determinar los factores asociados con: 1) la selección del tratamiento, 2) el desarrollo de nefrotoxicidad y 3) el desarrollo de nefrotoxicidad con cada antibiótico. Resultados: Se incluyeron 133 pacientes (62 tratados con DAP, 71 con vancomicina). Veintiuno (15,8%) desarrollaron nefrotoxicidad: 4/62 (6,3%) pacientes con DAP y 17/71 (23,3%) con VAN (p=0,006). No se encontraron diferencias entre los grupos en la administración concomitante de aminoglucósidos u otros fármacos potencialmente nefrotóxicos. Los factores asociados con el tratamiento con DAP fueron diabetes mellitus con lesión orgánica (OR=7,81; IC95%:1,39-4,35) y una creatinina basal ≥0,9 mg/dL (OR=2,53; IC95%:1,15-4,35). Los factores asociados con tratamiento con VAN fueron ictus (OR=7,22; IC95%:1,50-34,67), infarto agudo de miocardio (OR=6,59; IC95%:1,51-28,69) y bacteriemia primaria (OR=5,18, IC95%:1,03-25,99). Los factores asociados con nefrotoxicidad (R2=0,142; p=0,001) fueron aclaramiento de creatinina <80 mL/min (OR=9,22; IC95%:1,98-30,93) y tratamiento con VAN (OR=6,07; IC95%:1,86-19,93). Los factores asociados con nefrotoxicidad en los pacientes tratados con VAN (R2=0,232; p=0,018) fueron insuficiencia cardíaca congestiva (OR=4.35; IC95%:1,23-15,37), endocarditis (OR=7,63; IC95%:1,02-57,31) y una creatinina basal <80 mL/min (OR=7,73; IC95%:1,20-49,71). Conclusiones: La nefrotoxicidad con VAN fue significativamente más alta que la de DAP a pesar del pobre status basal renal del grupo de DAP

Musculoskeletal toxicities in patients receiving concomitant statin and daptomycin therapy.

PURPOSE: This article evaluates the musculoskeletal safety of concomitant therapy with daptomycin and Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins). SUMMARY: Often indicated for severe gram-positive infections, daptomycin is commonly administered with statins but there is limited guidance on the appropriate management of concomitant therapy with daptomycin and statins. A narrative review was conducted to review contemporary clinical evidence of the safety of concomitant therapy with daptomycin and statins. A total of 5 studies were identified comparing daptomycin monotherapy versus daptomycin and statin concomitant therapy for the primary outcome of creatine phosphokinase (CPK) elevations in a variety of patient populations with systemic, skin/soft tissue, and bone/joint infections. Of these studies, 4 also compared myalgia or myopathy as a secondary outcome. Case studies, the case-control study and 1 prospective registry comparing statin alone versus daptomycin and statin concomitant therapy were excluded. These studies showed that concomitant therapy with daptomycin and statin was not significantly associated with CPK elevation or higher event rate of myalgia or myopathy, compared to daptomycin monotherapy. CONCLUSION: Published cohort studies do not demonstrate a statistically significant difference in the rate of CPK elevations or musculoskeletal toxicities between patients receiving daptomycin monotherapy and daptomycin plus a statin. Patients receiving statins who start daptomycin therapy should continue statin but with weekly monitoring of CPK levels. Continuation of statins is especially important in high-risk patients receiving statins for secondary prevention for atherosclerotic cardiovascular diseases. If myalgia develops, it is reasonable to evaluate the degree of CPK elevation and reassess the need for statin use during daptomycin treatment.

Improvement of the antibacterial activity of daptomycin-loaded polymeric microparticles by Eudragit RL 100: an assessment by isothermal microcalorimetry.

The aim of the present study was to develop novel daptomycin-loaded acrylic microparticles with improved release profiles and antibacterial activity against two clinically relevant methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains (MSSA and MRSA, respectively). Daptomycin was encapsulated into poly(methyl methacrylate) (PMMA) and PMMA-Eudragit RL 100 (EUD) microparticles by a double emulsion-solvent evaporation method. For comparison purposes similar formulations were prepared with vancomycin. Particle morphology, size distribution, encapsulation efficiency, surface charge, physicochemical properties, in vitro release and biocompatibility were assessed. Particles exhibited a micrometer size and a spherical morphology. The addition of EUD to the formulation caused a shift in the surface charge of the particles from negative zeta potential values (100% PMMA formulations) to strongly positive. It also improved daptomycin encapsulation efficiency and release, whereas vancomycin encapsulation and release were strongly hindered. Plain and antibiotic-loaded particles presented comparable biocompatibility profiles. The antibacterial activity of the particles was assessed by isothermal microcalorimetry against both MSSA and MRSA. Daptomycin-loaded PMMA-EUD particles presented the highest antibacterial activity against both strains. The addition of 30% EUD to the daptomycin-loaded PMMA particles caused a 40- and 20-fold decrease in the minimum inhibitory (MIC) and bactericidal concentration (MBC) values, respectively, when compared to the 100% PMMA formulations. On the other hand, vancomycin-loaded microparticles presented the highest antibacterial activity in PMMA particles. Unlike conventional methods, isothermal microcalorimetry proved to be a real-time, sensitive and accurate method for assessment of antibacterial activity of antibiotic-loaded polymeric microparticles. Finally, the addition of EUD to formulations proved to be a powerful strategy to improve daptomycin encapsulation efficiency and release, and consequently improving the microparticles activity against two relevant S. aureus strains.

Ototoxic effect of daptomycin applied to the guinea pig middle ear.

CONCLUSION: Daptomycin applied topically at a concentration of 50 mg/ml caused mild but statistically significant hearing impairment. Outer hair cells were not damaged by daptomycin. Great care must be taken when there is a chance that daptomycin can reach the middle ear. OBJECTIVE: Ototopic antibiotic eardrops are frequently used to treat external and middle ear infections. Daptomycin is a new anti-methicillin-resistant Staphylococccus aureus (MRSA) drug with unknown ototoxicity. The current study examined the ototoxic effect of daptomycin in topical applications to guinea pig ears. METHODS: Twenty-three male Hartley guinea pigs (weight, 250-640 g) were divided into three groups receiving daptomycin (50 mg/ml), gentamicin (50 mg/ml, positive control), or saline solution (negative control). After insertion of a pressure-equalizing tube, pretreatment auditory brainstem responses (ABRs) were obtained. Topical solutions of 0.1 ml were applied through the tube into the middle ear twice a day for 7 days. Post-treatment ABRs were obtained 7 days after the last treatment. Hair cell loss was investigated with whole-mount cochlear surface preparations. RESULTS: The saline-treated (negative control) group showed no deterioration of ABR threshold. The daptomycin-treated group showed mild deterioration and the gentamicin-treated group showed severe deterioration in ABR threshold. Hair cells were preserved in the daptomycin- and saline-treated groups but severely damaged in the gentamicin group.

Eficacia y seguridad de daptomicina en dosis elevadas (mayor o igual que 8mg/kg/día) / Efficacy and safety of high dose (≥ 8 mg/kg/day) daptomycin

Introducción Se disponen de pocos datos acerca de la seguridad y eficacia de daptomicina en dosis elevadas (> 8mg/kg/día).Material y métodos Estudio ambispectivo de todos los pacientes que recibieron daptomicina (..) (AU)

Introduction: There is a paucity of data regarding efficacy and safety of high dose (> 8 mg/kg/day)daptomycin. Material and methods: This ambispective study included all patients that received (..) (AU)

Intravitreal daptomycin: a safety and efficacy study.

PURPOSE: To determine the ocular toxicity of intravitreally injected daptomycin, a novel antibiotic for treatment of vancomycin-resistant organisms, and its efficacy in treating intraocular infection with coagulase-negative Staphylococcus epidermidis. METHODS: Four doses of intravitreal daptomycin were injected (75, 188, 375, and 750 µg) into 1 eye of Dutch belted rabbits (n = 3 per dose). Clinical examination, electroretinography, and histologic analysis were performed preinjection and 2 weeks after injection and compared with the fellow eye that received only intravitreal balanced salt solution. Experimental S epidermidis endophthalmitis was induced in Dutch belted rabbits (n = 24), and the ability of 200 µg of intravitreal daptomycin to result in culture-negative vitreous samples was measured at 24 hours and 48 hours. RESULTS: Seventy-five micrograms and 188 µg of daptomycin demonstrated acceptable safety profiles when injected intravitreally in Dutch belted rabbits. There was a dose-dependent increase in cataract formation, electroretinogram suppression, and photoreceptor damage with higher doses. Two hundred micrograms of intravitreal daptomycin resulted in near-complete vitreous sterilization 24 hours after treatment. Vitreous sterilization was complete by 48 hours. CONCLUSION: A dose of 200 µg of intravitreal daptomycin appears to be safe and efficacious in a rabbit model of bacterial endophthalmitis. Future investigations should focus on daptomycin as a therapeutic option for treating intraocular infection caused by vancomycin-resistant organisms.

Characterization of skeletal muscle effects associated with daptomycin in rats.

Daptomycin is a lipopeptide antibiotic with strong bactericidal effects against Gram-positive bacteria and minor side effects on skeletal muscles. The type and magnitude of the early effect of daptomycin on skeletal muscles of rats was quantified by histopathology, examination of contractile properties, Evans Blue Dye uptake, and effect on the patch repair process. A single dose of daptomycin of up to 200 mg/kg had no effect on muscle fibers. A dose of 150 mg/kg of daptomycin, twice per day for 3 days, produced a small number of myofibers (