Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy

Abstract

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 10⁸ CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 10⁸ to 10⁹ CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

Keywords: multidrug resistance; nebulized; pharmacodynamics; pharmacokinetics.

FIG 1

Observed concentration-time profiles of amikacin and fosfomycin during the first dosing interval.

FIG 2

The effect of amikacin-fosfomycin combination therapy on the density of the total bacterial population of a P. aeruginosa clinical isolate (PA SAT 290) in an HFIM simulating pharmacokinetic decay of peak concentrations of 300 mg/liter amikacin–1,200 mg/liter fosfomycin in comparison with growth with monotherapy with each antibiotic.

FIG 3

The effect of amikacin-fosfomycin combination therapy on the density of resistant bacterial populations of a P. aeruginosa clinical isolate (PA SAT 290) in an HFIM simulating pharmacokinetic decay of peak concentrations of 300 mg/liter amikacin–1,200 mg/liter fosfomycin in comparison with growth with monotherapy with each antibiotic.

FIG 4

The effect of amikacin-fosfomycin combination therapy on the density of the total bacterial population of a K. pneumoniae clinical isolate (K.p. 301) in an HFIM simulating pharmacokinetic decay of peak concentrations of 300 mg/liter amikacin–1,200 mg/liter fosfomycin in comparison with growth with monotherapy with each antibiotic.

FIG 5

The effect of amikacin-fosfomycin combination therapy on the density of resistant bacterial populations of a K. pneumoniae clinical isolate (K.p. 301) in an HFIM simulating pharmacokinetic decay of peak concentrations of 300 mg/liter amikacin–1,200 mg/liter fosfomycin in comparison with growth with monotherapy with each antibiotic.