This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nilsson, A. I. Articles by Andersson, D. I. Search for Related Content PubMed PubMed Citation Articles by Nilsson, A. I. Articles by Andersson, D. I.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2003, p. 2850-2858, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2850-2858.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Biological Costs and Mechanisms of Fosfomycin Resistance in Escherichia coli

Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82 Stockholm,¹ Microbiology and Tumour Biology Center, Karolinska Institute, S-171 77 Stockholm,² Department of Molecular Evolution, Uppsala University, S-752 36 Uppsala,³ Division of Clinical Bacteriology, Karolinska Institute, Huddinge University Hospital, S-141 86 Stockholm,⁴ Central Hospital Clinical Microbiology, S-351 85 Växjö, Sweden⁵

Received 10 December 2002/ Returned for modification 26 May 2003/ Accepted 19 June 2003

Fosfomycin is a cell wall inhibitor used mainly for the treatment of uncomplicated lower urinary tract infections. As shown here, resistance to fosfomycin develops rapidly in Escherichia coli under experimental conditions, but in spite of the relatively high mutation rate in vitro, resistance in clinical isolates is rare. To examine this apparent contradiction, we mathematically modeled the probability of resistance development in the bladder during treatment. The modeling showed that during a typical episode of urinary tract infection, the probability of resistance development was high (>10^-2). However, if resistance was associated with a reduction in growth rate, the probability of resistance development rapidly decreased. To examine if fosfomycin resistance causes a reduced growth rate, we isolated in vitro and in vivo a set of resistant strains. We determined their resistance mechanisms and examined the effect of the different resistance mutations on bacterial growth in the absence and presence of fosfomycin. The types of mutations found in vitro and in vivo were partly different. Resistance in the mutants isolated in vitro was caused by ptsI, cyaA, glpT, uhpA/T, and unknown mutations, whereas no cyaA or ptsI mutants could be found in vivo. All mutations caused a decreased growth rate both in laboratory medium and in urine, irrespective of the absence or presence of fosfomycin. According to the mathematical model, the reduced growth rate of the resistant strains will prevent them from establishing in the bladder, which could explain why fosfomycin resistance remains rare in clinical isolates.

This article has been cited by other articles:

• Sandegren, L., Lindqvist, A., Kahlmeter, G., Andersson, D. I. (2008). Nitrofurantoin resistance mechanism and fitness cost in Escherichia coli. J Antimicrob Chemother 62: 495-503 [Abstract] [Full Text]  
• Knottnerus, B. J., Nys, S., ter Riet, G., Donker, G., Geerlings, S. E., Stobberingh, E. (2008). Fosfomycin tromethamine as second agent for the treatment of acute, uncomplicated urinary tract infections in adult female patients in The Netherlands?. J Antimicrob Chemother 62: 356-359 [Abstract] [Full Text]  
• Yang, L., Haagensen, J. A. J., Jelsbak, L., Johansen, H. K., Sternberg, C., Hoiby, N., Molin, S. (2008). In Situ Growth Rates and Biofilm Development of Pseudomonas aeruginosa Populations in Chronic Lung Infections. J. Bacteriol. 190: 2767-2776 [Abstract] [Full Text]  
• Vickers, A. A., O'Neill, A. J., Chopra, I. (2007). Emergence and maintenance of resistance to fluoroquinolones and coumarins in Staphylococcus aureus: predictions from in vitro studies. J Antimicrob Chemother 60: 269-273 [Abstract] [Full Text]  
• Rozen, D. E., McGee, L., Levin, B. R., Klugman, K. P. (2007). Fitness Costs of Fluoroquinolone Resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 51: 412-416 [Abstract] [Full Text]  
• Ellington, M. J., Livermore, D. M., Pitt, T. L., Hall, L. M. C., Woodford, N. (2006). Mutators among CTX-M {beta}-lactamase-producing Escherichia coli and risk for the emergence of fosfomycin resistance. J Antimicrob Chemother 58: 848-852 [Abstract] [Full Text]  
• Nilsson, A. I., Zorzet, A., Kanth, A., Dahlstrom, S., Berg, O. G., Andersson, D. I. (2006). Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes. Proc. Natl. Acad. Sci. USA 103: 6976-6981 [Abstract] [Full Text]  
• O'Neill, A. J., Huovinen, T., Fishwick, C. W. G., Chopra, I. (2006). Molecular Genetic and Structural Modeling Studies of Staphylococcus aureus RNA Polymerase and the Fitness of Rifampin Resistance Genotypes in Relation to Clinical Prevalence. Antimicrob. Agents Chemother. 50: 298-309 [Abstract] [Full Text]  
• Schrag, S. J., McGee, L., Whitney, C. G., Beall, B., Craig, A. S., Choate, M. E., Jorgensen, J. H., Facklam, R. R., Klugman, K. P., the Active Bacterial Core Surveillance Team, (2004). Emergence of Streptococcus pneumoniae with Very-High-Level Resistance to Penicillin. Antimicrob. Agents Chemother. 48: 3016-3023 [Abstract] [Full Text]