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Polymyxin B in Combination with Doripenem Against Heteroresistant Acinetobacter Baumannii: Pharmacodynamics of New Dosing Strategies

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Polymyxin B in Combination with Doripenem Against Heteroresistant Acinetobacter Baumannii: Pharmacodynamics of New Dosing Strategies J Antimicrob Chemother 2016; 71: 3148–3156 doi:10.1093/jac/dkw293 Advance Access publication 3 August 2016 Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii: pharmacodynamics of new dosing strategies Gauri G. Rao1,2, Neang S. Ly1,2,Ju¨rgen B. Bulitta1,3, Rachel L. Soon1,2, Marie D. San Roman1,2, Patricia N. Holden1,2, Cornelia B. Landersdorfer4, Roger L. Nation4, Jian Li4, Alan Forrest1,5 and Brian T. Tsuji1,2* 1Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; 2The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; 3Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA; 4Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia; 5Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, NC, USA *Corresponding author. Tel: +1-716-881-7543; Fax: +1-716-849-6890; E-mail: [email protected] Received 13 October 2015; returned 3 January 2016; revised 14 June 2016; accepted 19 June 2016 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 experi- ments 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 inocu- lum 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 math- ematical 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. Introduction A. baumannii is an extremely difficult pathogen to treat as it has an ability to adapt through multiple mechanisms of re- The emergence of antimicrobial resistance is a major threat to sistance in the face of antibiotic therapy. Clinicians have already human health and is jeopardizing our ability to treat infections.1 been confronted with the reality of infections caused by Gram-negative resistance is at the top of the infectious diseases A. baumannii strains that are resistant to all clinically available research agenda,2 as new therapeutic options are urgently agents except polymyxins (polymyxin B and colistin) and tigecyc- needed. The CDC has highlighted Acinetobacter baumannii,a line.5,6 Together with the first report of plasmid-mediated poly- Gram-negative ‘superbug’, as a serious threat to human health.3 myxin resistance in E. coli that could be transferred to other Gram-negative pathogens account for 70% of the infections Gram-negative strains,7 the reports send a very strong warning. among intensive care unit patients and there has been an alarm- Colistin is administered as an inactive prodrug, colistin methane- ing increase in the incidence of nosocomial infections caused by sulfonate (CMS), and requires conversion in vivo into the active A. baumannii.4 form of colistin, a process that occurs slowly and incompletely # The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] 3148 Polymyxin B combinations versus A. baumannii JAC in humans.8 Polymyxin B does not suffer from these limitations as Mueller–Hinton agar plates using a Whitley automatic spiral plater (WASP; it is administered as the active antibiotic. The pharmacokinetic Don Whitley Scientific, Shipley West Yorkshire, UK). Colonies were counted (PK) and pharmacodynamic (PD) knowledge necessary to opti- by a ProtoCOL automated colony counter (Synbiosis, Cambridge, UK) after mize dosing for polymyxin B is limited,9,10 and suboptimal dosing an incubation period of 24 h at 378C. The lower limit of counting was at currently recommended doses may have contributed to 20 cfu/mL. Time–kill experiments were conducted at polymyxin B concentra- increasedresistanceinGram-negativepathogens.10,11 Dose tions of 0.5, 1, 2, 4, 8, 16, 32 and 64 mg/L, and a doripenem concentration of 25 mg/L, alone and in combination. escalation of daily doses of polymyxin B is impractical as nephro- toxicity is a major dose-limiting adverse effect that occurs in up to 60% of patients even with currently recommended dosage regi- mens as administered.12 – 14 Polymyxin B combination therapy HFIM has been shown to be more effective against MDR A. baumannii 15,16 The HFIM was used to evaluate the effect of selected polymyxin B and dori- strains as compared with monotherapy with polymyxin B. penem monotherapy and combination regimens on bacterial burden and sup- Previous in vitro studies have shown that polymyxin combinations pression of resistance against A. baumannii ATCC 19606 over 240 h, as 17 with a carbapenem are highly bactericidal against A. baumannii previously described.22 Cellulosic hollow-fibre cartridges (C3008; Fiber Cell although the rapid bactericidal activity of this combination is fol- System, Inc., Fredrick, MD, USA) were utilized in all experiments. Twenty-three lowed by regrowth with the emergence of resistant subpopula- samples (0.5 mL) were serially collected over 240 h to determine bacterial tions.18 Therefore, this underscores the need to develop novel counts for each experiment. Samples were quantified for the total population strategies to combat A. baumannii focused on polymyxin combi- by depositing appropriately diluted bacterial samples on CAMHA plates, as pre- 23 nations to maximize bactericidal activity, minimize resistance and viously described. Aliquots of the diluted sample were plated on CAMHA decrease drug exposure. plates containing 0.5, 1, 2, 3, 4, 6, 8 or 10 mg/L polymyxin B for in-depth ana- lysis of the time-course of resistant subpopulations at pre-dose at 24, 48, 72, In an attempt to define optimal dosing strategies for poly- 20 myxin B combinations with doripenem, we first examined via sta- 96, 144, 192 and 240 h, as previously described. HFIM experiments consisted of clinically achievable monotherapy and tic time–kill studies the concentration–response relationship combination therapy regimens, which were informed by mechanism- across a wide range of polymyxin B and doripenem concentra- basedpopulationmodellingofthestatic time–kill experiments. The tions alone and in combination against A. baumannii. Next, we rationale for dosing polymyxin B as a continuous infusion was based employed mechanism-based mathematical models to guide on the flat PK profile seen in critically ill patients receiving polymyxin the design of new polymyxin B combination regimens. Finally, B. Patients in this study received polymyxin B doses ranging from 0.45 we simulated traditional and novel polymyxin B combination regi- to 3.38 mg/kg/day every 12 h. Based on this previous study, the unscaled mens in the hollow-fibre infection model (HFIM) and profiled the population estimate of the half-life was 11.9 h and fAUCs ranged from dynamics of subpopulations over 10 days. 6.2 to 53.5 mg.h/L with a median of 26.5 mg.h/L, average of 29.4 mg.h/L and standard deviation of 10.4 mg.h/L.24 The experimental design consisted of a no treatment control arm and eight monotherapy Materials and methods and combination regimens, as follows: Antibiotics, medium and bacterial isolates (a) Polymyxin B traditional monotherapy: free steady-state concentration (fC ) of 2 mg/L administered as a continuous infusion, based on the Analytical grade polymyxin B sulphate was purchased from Sigma-Aldrich ss PK in critically ill patients.24 (St Louis, MO, USA) and doripenem was provided by Shionogi Inc. (Florham (b) Polymyxin B traditional monotherapy: as above but with a fC of Park, NJ, USA). Fresh stock solutions of polymyxin B and doripenem were ss 5 mg/L administered as a continuous infusion. prepared immediately prior to each experiment and filter sterilized using a (c) Doripenem monotherapy: fC of 25 mg/L every 8 h based on PK in 0.22 mm Millex GP filter (Millipore, Bedford, MA, USA). Cation-adjusted max critically ill patients.25 Mueller–Hinton broth (CAMHB) (Difco, Detroit, MI, USA) supplemented (d) Combination of polymyxin B traditional (fC of 2 mg/L continuous with calcium (25 mg/L) and magnesium (12.5 mg/L) was used as the ss infusion) and doripenem (fC of 25 mg/L every 8 h). growth medium for all time–kill and HFIM experiments. max (e) Combination of polymyxin B ‘front-loaded’ (fC of 5 mg/L continuous MIC values were determined in quadruplicate according to CLSI guide- ss infusion for 24 h followed by fC of 2 mg/L thereafter) and doripenem lines.19 A.
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