Dataset Information

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

ABSTRACT:

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 10⁸ 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 10⁹ 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 log₁₀ reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (>8 log₁₀) 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.

SUBMITTER: Rao GG

PROVIDER: S-EPMC5079300 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Rao Gauri G GG Ly Neang S NS Bulitta Jürgen B JB Soon Rachel L RL San Roman Marie D MD Holden Patricia N PN Landersdorfer Cornelia B CB Nation Roger L RL Li Jian J Forrest Alan A Tsuji Brian T BT

The Journal of antimicrobial chemotherapy 20160803 11

<h4>Objectives</h4>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.<h4>Methods</h4>The pharmacodynamics of polymyxin B together with doripenem were evaluated in time-kill experiments over 48 h against 10<sup>8</sup> cfu/mL of two polymyxin-heter ...[more]

PMID: 27494922

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Project description:ObjectivesIncreased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB.MethodsA. baumannii (N16870; MICmeropenem = 16 mg/L, MICPMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 108 cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters.ResultsMonotherapies resulted in regrowth to ~1010 cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC50 (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 108 cfu/mL starting inoculum to a point of 100 cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be 'loaded' with 80.5% and 42.2% of the daily dose, respectively).ConclusionThis study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the 'traditional' indices of antibiotic action.

Project description:Polymyxins are currently used as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As resistance to polymyxins emerges in A. baumannii with monotherapy, combination therapy is often the only remaining treatment option. A novel approach is to employ the combination of polymyxin B with non-antibiotic drugs. In the present study, we employed metabolomics to investigate the synergistic mechanism of polymyxin B in combination with the antineoplastic drug mitotane against polymyxin-susceptible and -resistant A. baumannii. The metabolomes of four A. baumannii strains were analyzed following treatment with polymyxin B, mitotane and the combination. Polymyxin B monotherapy induced significant perturbation in glycerophospholipid (GPL) metabolism and histidine degradation pathways in polymyxin-susceptible strains, and minimal perturbation in polymyxin-resistant strains. Mitotane monotherapy induced minimal perturbation in the polymyxin-susceptible strains, but caused significant perturbation in GPL metabolism, pentose phosphate pathway and histidine degradation in the LPS-deficient polymyxin-resistant strain (FADDI-AB065). The polymyxin B - mitotane combination induced significant perturbation in all strains except the lipid A modified polymyxin-resistant FADDI-AB225 strain. For the polymyxin-susceptible strains, the combination therapy significantly perturbed GPL metabolism, pentose phosphate pathway, citric acid cycle, pyrimidine ribonucleotide biogenesis, guanine ribonucleotide biogenesis, and histidine degradation. Against FADDI-AB065, the combination significantly perturbed GPL metabolism, pentose phosphate pathway, citric acid cycle, and pyrimidine ribonucleotide biogenesis. Overall, these novel findings demonstrate that the disruption of the citric acid cycle and inhibition of nucleotide biogenesis are the key metabolic features associated with synergistic bacterial killing by the combination against polymyxin-susceptible and -resistant A. baumannii.

Project description:Polymyxins have resurged as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As reports of polymyxin resistance in A. baumannii with monotherapy have become increasingly common, combination therapy is usually the only remaining treatment option. A novel and effective strategy is to combine polymyxins with non-antibiotic drugs. This study aimed to investigate, using untargeted metabolomics, the mechanisms of antibacterial killing synergy of the combination of polymyxin B with a synthetic cannabidiol against A. baumannii ATCC 19606. The antibacterial synergy of the combination against a panel of Gram-negative pathogens (Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa) was also explored using checkerboard and static time-kill assays. The polymyxin B-cannabidiol combination showed synergistic antibacterial activity in checkerboard and static time-kill assays against both polymyxin-susceptible and polymyxin-resistant isolates. The metabolomics study at 1 h demonstrated that polymyxin B monotherapy and the combination (to the greatest extent) significantly perturbed the complex interrelated metabolic pathways involved in the bacterial cell envelope biogenesis (amino sugar and nucleotide sugar metabolism, peptidoglycan, and lipopolysaccharide (LPS) biosynthesis), nucleotides (purine and pyrimidine metabolism) and peptide metabolism; notably, these pathways are key regulators of bacterial DNA and RNA biosynthesis. Intriguingly, the combination caused a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids) compared to very minimal changes induced by monotherapies. At 4 h, polymyxin B-cannabidiol induced more pronounced effects on the abovementioned pathways compared to the minimal impact of monotherapies. This metabolomics study for the first time showed that in disorganization of the bacterial envelope formation, the DNA and RNA biosynthetic pathways were the most likely molecular mechanisms for the synergy of the combination. The study suggests the possibility of cannabidiol repositioning, in combination with polymyxins, for treatment of MDR polymyxin-resistant Gram-negative infections.

Dataset Information

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

Objectives

Methods

Results

Conclusions

Publications

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

Similar Datasets

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