Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model

Dandekar, Prachi K.; Tessier, Pamela R.; Williams, Peter; Nightingale, C H; Nicolau, David P.

doi:10.1093/jac/dkg337

Cited by 117 publications

(74 citation statements)

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“…They concluded that more studies with strains that grew better were needed because low growth (⌬G 26Ϫ2 Ͻ 0.4 log 10 CFU/g) led to overestimation of the drug's efficacy against E. faecium (AUC/MIC for stasis was 0.94 to 1.67) compared to that with S. aureus (388 to 537) or S. pneumoniae (75 to 237) (13). Other authors have obtained similarly biased results (9).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the usual lack of a full doseresponse curve hinders the determination of pharmacokinetic/ pharmacodynamic (PK/PD) indices necessary to translate the results to humans (5,7). Moreover, the bacterial growth in all enterococcal models is either not quantified (e.g., peritonitis model) (8), poor (ϳ1 log 10 CFU/g), or even negative (e.g., thigh infection) (9,10), and the variability is high (e.g., rabbit endocarditis models) (11), particularly with vancomycin (VAN)-resistant enterococcus (VRE) strains (12). Negligible growth and high-level dispersion may lead to inaccurate estimations of antibiotic PD, as has been the case with daptomycin (13).…”

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confidence: 99%

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An Optimized Mouse Thigh Infection Model for Enterococci and Its Impact on Antimicrobial Pharmacodynamics

Rodríguez

Agudelo

González

et al. 2015

Antimicrob Agents Chemother

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Negligible in vivo growth of enterococci and high-level dispersion of data have led to inaccurate estimations of antibiotic pharmacodynamics (PD). Here we improved an in vivo model apt for PD studies by optimizing the in vitro culture conditions for enterococci. The PD of vancomycin (VAN), ampicillin-sulbactam (SAM), and piperacillin-tazobactam (TZP) against enterococci were determined in vivo, comparing the following different conditions of inoculum preparation: aerobiosis, aerobiosis plus mucin, and anaerobiosis plus mucin. Drug exposure was expressed as the ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC) (VAN) or the time in a 24-h period that the drug concentration for the free, unbound fraction exceeded the MIC under steady-state pharmacokinetic conditions (fT >MIC ) (SAM and TZP) and linked to the change in log 10 CFU/thigh. Only anaerobiosis plus mucin enhanced the in vivo growth, yielding significant PD parameters with all antibiotics. In conclusion, robust in vivo growth of enterococci was crucial for better determining the PD of tested antibacterial agents, and this was achieved by optimizing the procedure for preparing the inoculum. Enterococci are commensal organisms in the gastrointestinal tracts of many species, from insects to humans (1), but are also the third leading cause of hospital infections (2, 3). They display intrinsic and acquired resistance to almost all antibiotics in clinical use, and no single agent is able to kill more than 3 log 10 CFU/g in vivo (4). Animal models of infection are invaluable tools for anti-infective pharmacology, and numerous in vivo enterococcal models have been used to test old and new drugs, but their validation for assessing the efficacy of antimicrobial agents is frequently not reported (5). The enterococcal endocarditis rabbit model is perhaps used the most, but it is also more expensive, cumbersome, and centered on a tissue with complex pharmacokinetics (i.e., cardiac valves), limiting its relevance for other systemic infections (6). Additionally, the usual lack of a full doseresponse curve hinders the determination of pharmacokinetic/ pharmacodynamic (PK/PD) indices necessary to translate the results to humans (5, 7). Moreover, the bacterial growth in all enterococcal models is either not quantified (e.g., peritonitis model) (8), poor (ϳ1 log 10 CFU/g), or even negative (e.g., thigh infection) (9, 10), and the variability is high (e.g., rabbit endocarditis models) (11), particularly with vancomycin (VAN)-resistant enterococcus (VRE) strains (12). Negligible growth and high-level dispersion may lead to inaccurate estimations of antibiotic PD, as has been the case with daptomycin (13).We optimized the in vitro culture conditions for enterococci by using anaerobic incubation and mucin supplementation, aiming to enhance the in vivo growth of vancomycin-susceptible enterococcus (VSE) and VRE strains and to determine its impact on the PD of three antibiotics: VAN, ampicillin-sulbactam (SAM), an...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

An Optimized Mouse Thigh Infection Model for Enterococci and Its Impact on Antimicrobial Pharmacodynamics

Rodríguez

Agudelo

González

et al. 2015

Antimicrob Agents Chemother

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“…Animal model data suggest that the AUC/minimum inhibitory concentration (MIC) ratio is the pharmacodynamic parameter that best describes daptomycin's activity (15)(16)(17)(18). However, the AUC/ MIC ratio associated with maximal effect varies.…”

Section: Monte Carlo Simulation (Mcs)mentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Intravenous Daptomycin during Continuous Ambulatory Peritoneal Dialysis

Cardone

Lodise²,

Patel³

et al. 2011

Clinical Journal of the American Society of Nephrology

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Summary Background and objectives This study sought to (1) characterize the pharmacokinetic (PK) profile of intravenous (IV) daptomycin among patients receiving continuous ambulatory peritoneal dialysis (CAPD); (2) identify optimal IV CAPD dosing schemes; and (3) determine extent of daptomycin penetration into the peritoneal space after IV administration. Design, setting, participants, & measurements A PK study was conducted among eight CAPD patients. Population PK modeling and Monte Carlo simulation (MCS) were used to identify CAPD dosing schemes providing efficacy and toxicity plasma profiles comparable with those obtained from MCS using the daptomycin population PK model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. The primary efficacy exposure target was the area under the curve (AUC). For toxicity, the goal was to identify CAPD dosing schemes that minimized plasma trough concentrations in excess of 24.3 mg/L. Finally, peritoneal cavity penetration was determined. Results Administration of IV daptomycin 4 or 6 mg/kg, depending on indication, every 48 h was identified as the optimal CAPD dosing scheme. This regimen provided cumulative (AUC0–48) and daily partitioned (AUC0–24h and AUC24–48h) plasma AUC values similar to the SAB-IE or “typical patient” simulations. In addition, the proportion of patients likely to experience an elevated trough concentration in excess of 24.3 mg/L was similar between every 48 h CAPD dosing and the referent group. Penetration into the peritoneal cavity was 6% of plasma. Conclusions Daptomycin 4 or 6 mg/kg, on the basis of indication, IV every 48 h was found to be the optimal IV CAPD dosing scheme.

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“…Animal model data suggest that daptomycin is a concentration-dependent antibiotic, and the AUC/ MIC ratio is the pharmacodynamic (PD) parameter that best describes its activity (3,5,9,11). However, the AUC/MIC ratio associated with maximal effect has varied (3,5,9,11). Given the lack of a definitive AUC/MIC threshold, especially for patients with bloodstream infections, the distribution of AUC values (the PD target most closely linked to effect) for any candidate HD dosing scheme should at least be comparable to what is typically observed in non-HD patients.…”

mentioning

confidence: 99%

“…For efficacy, the primary exposure target was the area under the curve (AUC). Animal model data suggest that daptomycin is a concentration-dependent antibiotic, and the AUC/ MIC ratio is the pharmacodynamic (PD) parameter that best describes its activity (3,5,9,11). However, the AUC/MIC ratio associated with maximal effect has varied (3,5,9,11).…”

mentioning

confidence: 99%

Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

Patel

Cardone

Grabe

et al. 2011

Antimicrob Agents Chemother

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This study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of >24. Daptomycin is a lipopeptide approved for the treatment of Staphylococcus aureus bacteremia and complicated skin and skin structure infections, both of which are common in patients receiving hemodialysis (HD) (1,4,(14)(15)(16)(17)(18). While the pharmacokinetic (PK) properties of daptomycin are well described for the general population, there are scant data for patients on HD (12, 13). An understanding of how PK changes during HD is essential to determining optimal dosing schemes for these patients. Furthermore, such dosage adjustments necessitate cognizance of interactions between antibiotic exposure, efficacy, and toxicity. Given the dearth of treatment options available against methicillin-resistant S. aureus (MRSA), it is imperative that daptomycin regimens be optimized for those on HD.The two objectives of this study were (i) to characterize the PK profile of daptomycin in patients receiving traditional thrice-weekly hemodialysis and (ii) to identify the optimal dosing scheme for daptomycin among patients on HD. With respect to the latter, the intent was to identify HD dosing schemes with efficacy and toxicity profiles comparable to those obtained from Monte Carlo simulations (MCS) employing the daptomycin population PK model derived from patients enrolled in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) clinical study for doses of 4 mg/kg of body weight given intravenously (i.v.) every 24 h (q24h) and 6 mg/kg given i.v. q24h (2, 7).Separate dosing schemes were developed for both FDAapproved daptomycin dosing regimens (4 mg/kg i.v. q24h and 6 mg/kg i.v. q24h) and for the two interdialytic periods (48 and 72 h). For efficacy, the primary exposure target was the area under the curve (AUC). Animal model data suggest that daptomycin is a concentration-dependent antibiotic, and the AUC/ MIC ratio is the pharmacodynamic (PD) parameter that best describes its activity (3,5,9,11). However, the AUC/MIC ratio associated with maximal effect has varied (3,5,9,11). Given the lack of a definitive AUC/MIC threshold, especially for patients with bloodstream infections, the ...

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Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model

Abstract: These data reveal the potent in vivo bactericidal activity of daptomycin against MRSA and Enterococcus species using clinically achievable drug exposures (dose 4-6 mg/kg per day) currently under investigation in man.

Cited by 117 publications

References 13 publications

An Optimized Mouse Thigh Infection Model for Enterococci and Its Impact on Antimicrobial Pharmacodynamics

An Optimized Mouse Thigh Infection Model for Enterococci and Its Impact on Antimicrobial Pharmacodynamics

Pharmacokinetics and Pharmacodynamics of Intravenous Daptomycin during Continuous Ambulatory Peritoneal Dialysis

Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

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