Assessing the Emergence of Resistance: The Absence of Biological Cost In Vivo May Compromise Fosfomycin Treatments for P. aeruginosa Infections

Abstract

Background: Fosfomycin is a cell wall inhibitor used efficiently to treat uncomplicated urinary tract and gastrointestinal infections. A very convenient feature of fosfomycin, among others, is that although the expected frequency of resistant mutants is high, the biological cost associated with mutation impedes an effective growth rate, and bacteria cannot offset the obstacles posed by host defenses or compete with sensitive bacteria. Due to the current scarcity of new antibiotics, fosfomycin has been proposed as an alternative treatment for other infections caused by a wide variety of bacteria, particularly Pseudomonas aeruginosa. However, whether fosfomycin resistance in P. aeruginosa provides a fitness cost still remains unknown. Principal Findings: We herein present experimental evidence to show that fosfomycin resistance cannot only emerge easily during treatment, but that it is also cost-free for P. aeruginosa. We also tested if, as has been reported for other species such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, fosfomycin resistant strains are somewhat compromised in their virulence. As concerns colonization, persistence, lung damage, and lethality, we found no differences between the fosfomycin resistant mutant and its sensitive parental strain. The probability of acquisition in vitro of resistance to the combination of fosfomycin with other antibiotics ( tobramycin and imipenem) has also been studied. While the combination of fosfomycin with tobramycin makes improbable the emergence of resistance to both antibiotics when administered together, the combination of fosfomycin plus imipenem does not avoid the appearance of mutants resistant to both antibiotics. Conclusions: We have reached the conclusion that the use of fosfomycin for P. aeruginosa infections, even in combined therapy, might not be as promising as expected. This study should encourage the scientific community to assess the in vivo cost of resistance for specific antibiotic-bacterial species combinations, and therefore avoid reaching universal conclusions from single model organisms.