Fluoroquinolone Resistance in Neisseria gonorrhoeae: Fitness Cost or Benefit?

Abstract

The successful treatment of gonorrhea, presently the second most prevalent bacterial sexually transmitted infection worldwide, has historically taken full advantage of the introduction of successive new categories of antimicrobial agents to successfully eliminate the microorganism causing this disease, Neisseria gonorrhoeae. New antibiotics have replaced older ones for treatment because N. gonorrhoeae has progressively developed resistance to each class introduced; first to sulphonamides, then to penicillins, tetracyclines, and then quinolones and macrolides [1, 2]. While the last class of antimicrobial effective for the treatment of gonorrhea is the third-generation cephalosporins, more and more reports are emerging of in vitro decreased susceptibility and treatment failures to the oral cephalosporins, such as cefixime, coupled with recent reports of strains with highlevel resistance to ceftriaxone [3–5]. The strains with high-level resistance to cephalosporins also exhibited resistance or reduced susceptibility to several other antibiotics. Thus, there is a great concern that gonorrhea has become an untreatable superbug in certain instances, and the search for effective alternative treatment strategies and therapies, possibly a combination of antibiotics, is urgent [5, 6]. The emergence of resistance to some classes of antimicrobial has been so rapid and sustained that a basic understanding of the factors underscoring the ability of N. gonorrhoeae isolates to survive in potentially lethal antimicrobial environments, a measure of fitness, is lacking. The report by Kunz et al in this issue of the Journal of Infectious Diseases describes fluoroquinolone resistance in N. gonorrhoeae as it relates to microbial fitness. Fluoroquinolones were introduced for the treatment of gonorrhea infections in the late 1980s following the rise and worldwide dissemination of both plasmid-mediated and chromosomal resistance to penicillins and tetracyclines [1, 2]. However, the introduction of fluoroquinolones, such as ciprofloxacin, for treatment was quickly followed by reports of resistance, first in Asia and subsequently worldwide [7, 8]. Once resistance to fluoroquinolones reached 5% of the N. gonorrhoeae isolates tested in any region, the accepted cutoff where it is recommended that treatment be changed, the third-generation cephalosporins were then recommended as the primary antibiotics to treat gonorrhea infections [9, 10]. Interestingly, some countries reported almost 100% resistance of N. gonorrhoeae isolates to fluoroquinolones [11], and this high percentage of resistance has not diminished appreciably. In other countries, despite some diminution of total percentages of resistant isolates, fluoroquinolone resistance persists at levels higher than 5% despite the withdrawal of these antimicrobials for the treatment of gonorrhea [11, 12]. The withdrawal of antibiotics can result in some modest diminution of resistance levels, possibly because antibiotic resistant isolates may have less survival advantage, or be less fit, than susceptible isolates [13]. However, given the maintenance of high percentages of ciprofloxacin resistant N. gonorrhoeae, it seems that, in some circumstances, antibioticresistant N. gonorrhoeae isolates may have a fitness advantage and not a fitness deficit. Bacterial fitness has been broadly described as the ability of a particular strain to survive and reproduce [13]. Fitness, often measured by growth rate and generation time, is frequently adversely affected by the development of antibiotic resistance. Most models used for bacterial fitness analysis involve in vitro and in vivo competition assays [13], and a mathematical model with high predictive value that associates fitness costs with drug-resistant bacteria has been reported [14]. Overall, the challenge in measuring bacterial fitness in antimicrobial environments is to choose a set of assays in the context of different bacterial environmental niches, genetic Received 5 September 2011; accepted 16 December 2011; electronically published 5 April 2012. Correspondence: Jo-Anne R Dillon, PhD, Professor, Dept of Biology, and Research Scientist, Vaccine and Infectious Disease Organization, University of Saskatchewan, 120 Veterinary Rd, Saskatoon, Saskatchewan, Canada S7N-5E3 ( j.dillon@usask.ca). The Journal of Infectious Diseases 2012;205:1775–7 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/infdis/jis281