Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients

Lai, Chih Cheng; Sheng, Wang-Huei; Wang, Jann-Tay; Cheng, Aristine; Chuang, Yu‐Chung; Chen, Yee‐Chun; Chang, Shan-Chwen

doi:10.1186/1471-2334-13-66

Cited by 34 publications

(35 citation statements)

References 31 publications

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“…However, Sakoulas et al found that a dosage of 40 mg/kg in rats is comparable to a dosage of 6 mg/kg in humans (19). Hence, the dosage of 60 mg/kg in rats used in the present study appears comparable to the increasingly higher doses of daptomycin applied in humans currently (20).…”

Section: Discussionmentioning

confidence: 67%

Daptomycin plus Fosfomycin, a Synergistic Combination in Experimental Implant-Associated Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus in Rats

Lingscheid

Poeppl

Bernitzky

et al. 2015

Antimicrob Agents Chemother

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The aim of this study was to evaluate the combination of daptomycin and fosfomycin in experimental chronic implant-associated osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA). Infection was induced in the tibiae of rats by the insertion of a bacterial inoculum (1 to 5 ؋ 10 8 CFU/ml) of a clinical MRSA isolate and a titanium wire. Four weeks after infection, each animal was assigned to a treatment group: daptomycin monotherapy at 60 mg/kg of body weight once daily (n ‫؍‬ 10), fosfomycin monotherapy at 40 mg/kg once daily (n ‫؍‬ 10), or daptomycin and fosfomycin combined at 60 mg/kg and 40 mg/kg, respectively, once daily (n ‫؍‬ 9). Ten animals were left untreated. After a 3-week treatment period, the animals were euthanized, and the infected tibiae and implants were processed for quantitative bacterial cultures. The bacterial cultures from bones were positive for MRSA in all animals in the untreated group, the daptomycin group, and the fosfomycin group, with median bacterial counts of 2.34 ؋ 10 6 CFU/g bone, 1.57 ؋ 10 6 CFU/g bone, and 3.48 ؋ 10 2 CFU/g bone, respectively. In the daptomycin-fosfomycin group, 6 out of 9 animals were positive for MRSA, with a median count of 7.92 CFU/g bone. Bacterial cultures derived from the titanium wires were negative in the fosfomycin-and daptomycin-fosfomycin-treated groups. Based on bacterial counts in bones, treatment with daptomycin-fosfomycin was statistically significantly superior to all that of the other groups (P < 0.003). Fosfomycin was superior to daptomycin and no treatment (P < 0.0001). No development of resistance was observed in any treatment arm. The combination of daptomycin and fosfomycin demonstrated synergism against MRSA in experimental implantassociated osteomyelitis.

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Section: Discussionmentioning

confidence: 67%

Daptomycin plus Fosfomycin, a Synergistic Combination in Experimental Implant-Associated Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus in Rats

Lingscheid

Poeppl

Bernitzky

et al. 2015

Antimicrob Agents Chemother

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“…The existence of a relationship between the daily dose and the occurrence of DIMT has been assessed in some studies that compared HD with SD daptomycin [5,9,13,74,75]. In the study by Lai et al, the incidence of CPK elevation was significantly higher in patients treated with daptomycin >8 mg/kg compared with ≤8 mg/kg (16.7% vs. 0%; P = 0.02) [9].…”

Section: Safety Of High-dose Daptomycin Therapymentioning

confidence: 97%

“…In the study by Lai et al, 67 patients, the majority of whom were treated in intensive care units for miscellaneous infections with daptomycin at a median daily dose of 7.61 mg/kg (range 6.03-11.5 mg/kg) for a median duration of 14 days, had an outcome unrelated to the daily dosage of daptomycin (i.e. ≥8 mg/kg or <8 mg/kg) [9]. Similar results were found in a single-centre retrospective study in which time to microbiological cure was assessed in 46 patients, including 28 (61%) neutropenic patients with bacteraemia due to Enterococcus spp.…”

Section: Clinical Data Justifying the Use Of High Dosesmentioning

confidence: 97%

“…Type of infection Daptomycin daily dose (mg/kg/day) Relationship between daily dosing and outcome [3] cSSSI 10 No [4] Gram-positive infections ≥8 [18/94 patients (19%) >10] No [5] Staphylococcus aureus infections Mean, 8 (range, 7-9) Yes [clinical success, 16/22 (73%) in the SD group vs. 29/31 (94%) in the HD group; P = 0.05] [6] Any Gram-positive infections ≥8 No [7] Complicated Gram-positive infections Median, 8.9 (IQR 8.0-10.0) No [8] Cardiac implantable electric device infections Median, 8.3 (range, 6.4-10.7) No [9] Severe Gram-positive infections Median, 7.61 (range, 6.03-11.53)…”

Section: Referencementioning

confidence: 99%

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Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data

Senneville

Caillon

Calvet

et al. 2016

International Journal of Antimicrobial Agents

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“…The lack of an impressive change in the mean probabilities of clinical success and decreased susceptibility was expected, as the daptomycin AUC and, thus, dose would need to more than double (e.g., the dose would need to increase from 6 to 12 mg/kg/day) to provide exposures adequate to cover a 1-dilution increase in the MIC. Increasing numbers of reports and amounts of data from clinical studies provide support for the use of higher doses of daptomycin (8 to 12 mg/kg/day) to improve outcomes among patients with serious and life-threatening infections (21)(22)(23)(24)(25)(26). The results of simulations conducted to evaluate the mean probabilities of favorable outcomes with daptomycin at 8 and 10 mg/kg/day should be interpreted with some caution since the exposures and model-predicted probabilities estimated were at or beyond those for the exposure range studied; thus, some degree of extrapolation was required.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations

Bhavnani

Ambrose

Hammel

et al. 2016

Antimicrob Agents Chemother

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bThe choice of an antimicrobial agent must balance optimization of efficacy endpoints with the minimization of safety events. The risk versus benefit of daptomycin for patients with Staphylococcus aureus bacteremia with or without infective endocarditis receiving daptomycin at 6, 8, and 10 mg/kg of body weight/day was assessed. The relationships between the area under the concentration-time curve over 24 h (AUC)/MIC ratio and both clinical response and time to decreased susceptibility were evaluated using data from patients with such infections who received daptomycin at 6 mg/kg/day. Using these relationships, plus the previously identified relationship between the minimum concentration and an elevation in the creatine phosphokinase (CPK) concentration (CPK elevation) (S. M. Bhavnani, C. M. Rubino, P. G. Ambrose, and G. L. Drusano, Clin Infect Dis 50:1568 -1574, 2010) and Monte Carlo simulation, the probability of each outcome by MIC for daptomycin at 6, 8, and 10 mg/kg/day was calculated. The function for exposure-response relationships for clinical response (P ‫؍‬ 0.06) and time to decreased susceptibility (P ‫؍‬ 0.01) resembled U and inverted U shapes, respectively. Multivariable analyses demonstrated AUC/MIC ratio, creatinine clearance, albumin concentration, and disease category to be predictors of clinical response. The results of simulations failed to demonstrate large improvements in the probabilities of clinical success among cohorts of simulated patients defined by the abovedescribed predictive factors or the probability of decreased susceptibility at 30 days when the daptomycin dose was increased from 6 to 10 mg/kg/day. The probability of CPK elevation increased from 0.073 to 0.156 over this dose range. These data can be used to inform risk-versus-benefit decisions for daptomycin dose selection in patients with S. aureus bacteremia with or without infective endocarditis. The risk of CPK elevation, which is reversible, should be weighed in the context of the mortality and severe morbidity associated with these types of serious staphylococcal infections.A s with all drugs, the choice of antimicrobial agent must balance efficacy with safety. Safety considerations may have an impact upon the choice of dosing regimen and the duration of therapy. This is the case with aminoglycoside antimicrobial agents, for which clinicians must explicitly balance the need for efficacy against the risk of nephrotoxicity (1). On the other hand, some drug toxicities are of less concern relative to the risk of clinical failure in patients with serious and life-threatening infections. Thus, there is more flexibility with the use of higher doses and longer treatment durations. For daptomycin-treated patients with Staphylococcus aureus infective endocarditis, the need for efficacy may supersede the concern regarding an elevation in the creatine phosphokinase (CPK) concentration (referred to here as CPK elevation), a sensitive biochemical signal of potential muscle toxicity which has been observed during daptomycin therapy but wh...

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Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients

Cited by 34 publications

References 31 publications

Daptomycin plus Fosfomycin, a Synergistic Combination in Experimental Implant-Associated Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus in Rats

Daptomycin plus Fosfomycin, a Synergistic Combination in Experimental Implant-Associated Osteomyelitis Due to Methicillin-Resistant Staphylococcus aureus in Rats

Towards a definition of daptomycin optimal dose: Lessons learned from experimental and clinical data

Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations

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