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 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.

Mechanism‐Based Disease Progression Model Describing Host‐Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia

“…The model was able to describe bacterial dynamics based on these mechanisms. The estimated bacterial growth rate constant ( : 0.327 h −1 ; representing net replication) was comparable to previous studies modeling A. baumannii . As neutrophils were the only measured immune cells, transit compartments were used to represent neutrophil signaling.…”

“…The estimated bacterial growth rate constant (k g : 0.327 h 21 ; representing net replication) was comparable to previous studies modeling A. baumannii. 29,30 As neutrophils were the only measured immune cells, transit compartments were used to represent neutrophil signaling. Transit compartments serve as placeholders for these natural antibacterial processes to be quantified in future studies.…”

Severe Infusion-Related Adverse Events and Renal Failure in Patients Receiving High-Dose Intravenous Polymyxin B

“…Schemes of high-dose PMB to overcome the emergence of resistance to this antibiotic during exposure have been evaluated in in vitro infection models, with promising results (14)(15)(16)(17). Moreover, few observational studies have suggested that increased doses might be associated with improved clinical outcomes (8)(9)(10)18).…”

“…In addition, resistance to both polymyxins has increasingly been reported, and in vitro studies have shown that the emergence of resistance is relatively common even by isolates exposed to polymyxin concentrations similar to those expected in vivo after the administration of an adequate dose of polymyxins (11)(12)(13). To counteract this occurrence, in vitro exposures to very high concentrations of PMB through the use of distinct strategies, such as administration of a loading dose or the use of high doses in combination schemes, have been evaluated, with promising results (14)(15)(16)(17). However, the toxicity of such regimens, in particular, the toxicity related to the infusion of high doses, is largely unknown.…”

Infections Due to Acinetobacter baumannii in the ICU: Treatment Options

“…1 Strategies involving higher doses, longer dosing intervals, loading doses, extended infusions, and pharmacokinetic/pharmacodynamic (PK/PD) principles have been proposed to optimize efficacy and prevent the development of resistance. [178][179][180] However, colistin has relatively poor PK/PD properties, and it may be difficult to achieve high enough serum concentrations quickly. 155 CMS (a prodrug) has to be converted to the active form (colistin) in the plasma, and concentrations may be suboptimal for 2 to 3 days until a steady state is achieved; thus, a loading dose is recommended.…”