Synergy of ciprofloxacin with fosfomycin in vitro against Pseudomonas isolates from patients with cystic fibrosis.

Pseudomonas aeruginosa remains the most common respiratory pathogen causing morbidity and mortality in cystic fibrosis (CF) patients. The in-vitro activity of ciprofloxacin and fosfomycin (calcium and tromethamine salts) in combination against P. aeruginosa isolates from CF patients, all of whom had received previous courses of ciprofloxacin, was evaluated by agar plate dilution chequerboard technique. The concentrations of drugs used were those that would be achieved in patients by oral and intravenous (fosfomycin only) routes. Synergy, taking into account fosfomycin concentrations achievable intravenously, was found against 60% of P. aeruginosa isolates. With concentrations achieved after an oral dose, 17% of isolates were synergistically inhibited. Time-kill experiments confirmed these findings. Ciprofloxacin MICs against resistant P. aeruginosa were reduced to achievable sputum and serum levels in the presence of fosfomycin. However, in progressive resistance studies fosfomycin failed to delay the development of resistance to ciprofloxacin. The combinations of ofloxacin/fosfomycin and ciprofloxacin/fosmidomycin were also tested, but showed minimal synergy. No antagonism was observed with any combination. Fosfomycin, ciprofloxacin and azlocillin in triple combination did not show synergy. The antimicrobial combinations tested against P. cepacia isolates from CF patients were indifferent. The combination of ciprofloxacin and fosfomycin may be clinically useful in selected P. aeruginosa pulmonary exacerbations in cystic fibrosis patients, particularly as an oral out-of-hospital treatment alternative or in cases where MICs for ciprofloxacin are elevated.