Optimising use of fosfomycin against multidrug-resistant Pseudomonas aeruginosa

Rising resistance to most antibiotics coupled with a marked decline in antibiotic discovery has led to a recent increase in the use of fosfomycin for treatment of systemic infections due to multidrug-resistant (MDR) bacteria, including MDR Pseudomonas aeruginosa. Fosfomycin retains significant activity against a range of MDR Gram-positive and Gram-negative bacteria, including P. aeruginosa, and has an excellent safety profile. However, fosfomycin was identified and developed prior to the introduction of modern drug development and approval procedures. Consequently, substantial gaps in our knowledge of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of fosfomycin currently exist. These properties are required to optimize the use of fosfomycin and improve patient care and outcomes by maximizing bacterial killing and minimizing the emergence of resistance. The in vitro PD properties of fosfomycin, namely the minimum inhibitory concentrations (MICs), bacterial killing (including the effect of inoculum), population analysis profiles (PAPs) and the post-antibiotic effect (PAE) were systematically investigated against clinical isolates of P. aeruginosa, including MDR isolates. MICs ranged from 1 – >512 mg/L, with 61% of isolates considered fosfomycin-susceptible (MIC ≤64 mg/L). Baseline PAPs indicated heteroresistance in all isolates tested. Time-kill studies showed moderate, time- dependent killing at the low inoculum, with regrowth of fosfomycin-resistant colonies. Bacterial killing was virtually eliminated at the high inoculum. The data suggest fosfomycin monotherapy may be problematic for the treatment of infections caused by P. aeruginosa. Resistance is known to develop rapidly when fosfomycin is used as monotherapy, particularly against P. aeruginosa, and combination regimens with a second ntibiotic have been suggested to overcome this potential problem. Bacterial killing and resistance emergence with fosfomycin monotherapy and in combination with tobramycin, polymyxin B or ciprofloxacin were systematically investigated using static-time kill methodology (inocula cfu/mL). The combination of fosfomycin with polymyxin B or tobramycin at clinically relevant concentrations substantially improved bacterial killing of fosfomycin-susceptible P. aeruginosa, while fosfomycin plus ciprofloxacin substantially improved bacterial killing of fosfomycin-resistant isolates. No combination was able to suppress the emergence of fosfomycin resistance. In brief, this thesis established a range of PD properties for fosfomycin against P. aeruginosa. It shows for the first time, as far as we are aware, in P. aeruginosa the presence of fosfomycin heteroresistance and that the antimicrobial activity of fosfomycin is time-dependent. The first systematic investigation into fosfomycin combination therapy, as far as we are aware, is undertaken, including the first examination of the emergence of fosfomycin resistance with combination therapy over time. The studies reported here will increase our understanding of fosfomycin PD, both in mono- and combination-therapy, and will assist in the design of optimal fosfomycin dosing regimens that will maximize bacterial killing and minimize the emergence of fosfomycin resistance.