Optimisation of alternative antibiotic dosing regimens for maximal antibacterial activity and suppression of emergence of resistance

Abstract

Infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, e.g., Escherichia coli and Klebsiella pneumoniae can be severe and often deadly in critically-ill patients in intensive care units (ICUs). Achieving target antibiotic concentrations to increase bacterial killing and suppress the emergence of resistance is a highly desirable aim of therapy. However, achieving these endpoints can be challenging in these patients with conventional dosing regimens because of variable pathophysiology affecting antibiotic dosing requirements and because the concentrations that suppress emergence of resistance are not well defined. Beta-lactams are the most commonly used to empirical agents in ICU patients. These antibiotics exhibit time-dependent bacterial killing, therefore, prolonged infusion (i.e., extended/continuous infusion) of beta-lactams may effectively kill bacteria and suppress the emergence of resistance by maintaining antibiotic concentrations above minimum inhibitory concentration of pathogens better than with shorter infusions. Thus, optimisation of beta-lactam dosing regimens through an improved characterisation of the pharmacokinetics/ pharmacodynamics (PK/PD) of prolonged infusions may help define maximally effective dosing for critically-ill patients. Furthermore, evaluation of beta-lactams in combination with aminoglycosides for synergistic bactericidal activity and resistance suppression is highly likely to provide an additional therapeutic option for treating multidrug resistant infections.This thesis aims to use the dynamic in vitro hollow fibre infection model (HFIM) to compare the bacterial killing and the emergence of resistance of clinical Enterobacterales isolates by prolonged (extended and continuous) and intermittent infusion of the commonly used beta-lactam, piperacillin/tazobactam (PTZ). This thesis also aims to evaluate the effect of a beta-lactam and aminoglycoside combination regimen for describing the rate and extent of bacterial killing and the emergence of resistance of less-susceptible Enterobacterales. This thesis contains six chapters. The introductory chapter (Chapter 1) highlights the limitations with conventional antibiotic dosing regimens of beta-lactams used in critically-ill septic patients for achieving antibiotic concentrations associated with effective bacterial killing and suppression of the emergence of resistance. This chapter also highlights the importance of optimisation of alternative beta-lactam dosing regimens and evaluation of beta-lactam and aminoglycoside combination therapy against Enterobacterales to achieve target PK/PD. Chapter 2 is a systematic review where the antibiotic exposures required to suppress the emergence of resistance in a Gram-negative bacterial isolates are described. Among the 59 included studies, 57 pre-clinical (in vitro and in vivo) and 2 clinical studies investigated PK/PD of beta-lactams, aminoglycosides, fluoroquinolones, tetracyclines, polymyxin B, and fosfomycin monotherapy. The findings highlighted that the antibiotic PK/PD exposures required to suppress the emergence of resistance generally exceed that associated with clinical efficacy.Chapter 3 reports the findings of the bacterial killing and the emergence of resistance of intermittent versus prolonged (extended and continuous) infusion of PTZ against ceftriaxone-resistant E. coli 44 (Ec44, MIC 2 mg/L, no beta-lactamase-producing) and E. coli 50 (Ec50, MIC 8 mg/L, CMY-2-like, CTX-M-55, TEM-1B-producing) clinical isolates. Prolonged and intermittent infusion dosing regimens of PTZ were simulated considering a critically-ill patient with a creatinine clearance (CLCr) of 100 mL/min in the HFIM over 7 days. All simulated dosing regimens against Ec44 exhibited effective bacterial killing and suppressed emergence of resistance throughout the experiment. However, all simulated dosing regimens against Ec50 failed to suppress the emergence of resistance. This study showed no appreciable differences in bacterial killing or the resistance suppression between intermittent and prolonged infusions of PTZ for both E. coli isolates.Chapter 4 reports the findings of the bacterial killing and emergence of resistance of intermittent versus prolonged infusion of PTZ against ceftriaxone-resistant K. pneumoniae 68 (Kp68, MIC 8 mg/L, SHV-106, DHA-1-producing) and K. pneumoniae 69 (Kp69, MIC 1 mg/L, CTX-M-14-producing). Prolonged and intermittent infusion dosing regimens of PTZ were simulated in the HFIM as described in Chapter 3. All dosing regimens against Kp68 failed to suppress a resistant subpopulation. Continuous infusion of PTZ against Kp69 prevented bacterial regrowth and suppressed of emergence of resistance. The overall findings suggest that there is no difference in bacterial killing and suppression of emergence of resistant subpopulations of less-susceptible ESBL-producing K. pneumoniae. However, only continuous infusion suppressed of emergence of less-susceptible subpopulations from a highly-susceptible ESBL-producing K. pneumoniae.Chapter 5 reports the findings of PTZ-tobramycin combination regimens tested against ceftriaxone-resistant ESBL-producing Ec50 (MIC 8 mg/L) and Kp68 (MIC 8 mg/L) clinical isolates in HFIM. The pharmacokinetics in a critically-ill patient of tobramycin alone and in combination with intermittent and prolonged infusion of PTZ were simulated in the HFIM (CLCr of 100 mL/min) over 7 days. Tobramycin monotherapies were associated with bacterial regrowth and a failure to suppress the resistant subpopulation, whereas all simulated combinations of PTZ-tobramycin against both Ec50 and Kp68 achieved synergistic killing and prevented regrowth throughout the 7 days. This study suggests that for less-susceptible ESBL-producing E. coli and K. pneumoniae, PTZ-tobramycin combination can be a potential therapeutic option. In the final chapter (Chapter 6), the overall findings of this thesis are summarised, the implications and future directions are discussed.