Performance and Robustness of the Monte Carlo Importance Sampling Algorithm Using Parallelized S-ADAPT for Basic and Complex Mechanistic Models

Bulitta, Jürgen B.; Landersdorfer, Cornelia B.

doi:10.1208/s12248-011-9258-9

Cited by 85 publications

(54 citation statements)

References 43 publications

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“…For each A. baumannii strain, PK/PD model parameters were simultaneously estimated in S-ADAPT (version 1.57) (39) using a Monte Carlo parametric expectation maximization algorithm (i.e., importance sampling pmethod ϭ 4 in S-ADAPT). SADAPT-TRAN was used to facilitate modeling analysis (40,41). To assess the significance and overall contribution of each model component, alternate simplified models that lacked the respective model feature or parameter were fit to the experimental data.…”

Section: Methodsmentioning

confidence: 99%

Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Cheah

Tsuji

et al. 2016

Antimicrob Agents Chemother

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dInfections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused >4 log 10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log 10 CFU/ ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.

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Section: Methodsmentioning

confidence: 99%

Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Cheah

Tsuji

et al. 2016

Antimicrob Agents Chemother

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“…All PD model parameters were simultaneously estimated using all viable-count data from the respective strain via the importance sampling algorithm (pmethod ϭ 4) in parallelized S-ADAPT (version 1.57). The analysis was facilitated by the SADAPT-TRAN tool (35,36). The between-curve variability of the PD parameters was fixed to a coefficient of variation of 10% during the end of the estimation (28).…”

Section: Methodsmentioning

confidence: 99%

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Yadav

Landersdorfer

Nation

et al. 2015

Antimicrob Agents Chemother

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cAcinetobacter baumannii is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize ␤-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii. We studied combinations of 10 ␤-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of A. baumannii using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (<2.3 log 10 ) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other ␤-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/ liter combined with an aminoglycoside yielded synergistic killing (>5 log 10 ) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MIC, 32 mg/ liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log 10 killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.A ntimicrobial resistance in Gram-negative bacteria is one of the three greatest threats to human health (1-3). Acinetobacter baumannii is one of the three most challenging Gram-negative pathogens, especially in intensive care units. In approximately 14,000 critically ill patients, A. baumannii infections were highly associated (P Ͻ 0.001) with increased mortality (4). A. baumannii often causes bloodstream, respiratory tract (including ventilatorassociated pneumonia), and wound infections (including burns and combat wounds); these are associated with high morbidity (1, 2, 5) and up to 87% mortality (6). Multidrug-resistant A. baumannii strains have caused major outbreaks in the United States and worldwide (7,8).In the past, ␤-lactams and aminoglycosides were successfully used to treat susceptible A. baumannii (9), but unfortunately, strains have emerged that are resistant to virtually all antibiotics in monotherapy (10, 11). While carbapenems were hitherto considered the treatment of choice against severe A. baumannii infe...

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“…Estimation was performed using parallelized S-ADAPT software (version 1.57) facilitated by SADAPT-TRAN using the importance sampling Monte Carlo parametric expectation maximization method (p method ¼ 4). 29 An additive residual error model on a log 10 scale was used for bacterial counts ≥100 cfu/mL. To account for high sampling error at low concentrations, an error model containing both proportional and Poisson distributions was used for the bacteria.…”

Section: Model Estimationmentioning

confidence: 99%

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

Rao

Bulitta

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. Methods:The pharmacodynamics of polymyxin B together with doripenem were evaluated in time -kill experiments over 48 h against 10 8 cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 10 9 cfu/mL of ATCC 19606.Results: In static time -kill studies, polymyxin B concentrations .4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a .7.5 log 10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (.8 log 10 ) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance.Conclusions: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.

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Performance and Robustness of the Monte Carlo Importance Sampling Algorithm Using Parallelized S-ADAPT for Basic and Complex Mechanistic Models

Cited by 85 publications

References 43 publications

Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

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