Center for Research in Anti-Infectives and Biotechnology, Creighton University School of Medicine, Omaha, NE 68178, USA
The introduction of oral antimicrobial agents with broad-spectrum activity extending to methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and other multiply antibiotic-resistant pathogens made the fluoroquinolones an attractive choice for empirical therapy for an extensive range of conditions. As a consequence there has been heavy and indiscriminate use of these agents in some centres16 resulting in fluoroquinolone resistance emerging more rapidly than anticipated in certain pathogens, especially those that were only marginally susceptible.3,4,79 With the recent releases of more potent agents such as trovafloxacin, grepafloxacin, sparfloxacin and levofloxacin, and others under development, there is now a concern that resistance to the newer agents may also develop. Two factors will be critical in determining the rate at which resistance to these agents developsthe manner in which fluoroquinolones (old and new) are used, and whether or not there are differences between the agents in their propensity to promote the development and spread of resistance.
Prescribing behaviours and infection control
The fluoroquinolones represented a new class of antimicrobial when they were introduced and there was, initially, a poorer understanding of their limitations compared with other more familiar classes of antibiotics. A high level of optimism arising from early publications, marketing launches and post-marketing activities probably contributed to fluoroquinolone overuse. Today, there is considerable experience with these agents and a better understanding of their optimal uses, benefits and limitations. For example, it is now understood that the factors responsible for the development of resistance to other antibiotic classes apply also to the fluoroquinolones. This now intuitively obvious fact is contrary to early speculations that the emergence of resistance to fluoroquinolones would be less common than occurred with other drug classes.4 Therefore, as with other drug classes, attempts to minimize resistance must aim to restrict fluoroquinolone use to situations in which these agents are necessary, and to contain resistance that emerges by proven infection control procedures.6 With this understanding firmly established, fluoroquinolones should now be used with greater wisdom than in the past. These considerations apply to all antibiotic classes, but there are also fluoroquinolone-specific considerations, in that some agents may retard the development of resistance more than others. Such agents can, therefore, be regarded as ecologically less harmful than others. This concept is discussed below. That is, if fluoroquinolone use can be restricted to appropriate indications, and ecologically preferable agents are used, it should be possible to reduce the selection pressure, and extend the effectiveness of the fluoroquinolone class of agents.
Ecologically preferred properties of fluoroquinolones
There are three main properties relevant to the ecological impact of a fluoroquinolone (in terms of its promoting or minimizing resistance): pharmacokinetics, potency and dissociated resistance.
Pharmacokinetics
There are now on the market fluoroquinolones that are well distributed and have adequate in vivo potency against many pathogens both within and outside the urinary tract. Therefore, it is not necessary to use agents that may achieve only marginal potency against some common pathogens at sites outside the urinary tract, e.g. norfloxacin, lomefloxacin and enoxacin. These agents are theoretically suboptimal because they are more likely to promote resistance in tissue infections and among the normal flora, especially the staphylococcal skin flora. Although there are no published human studies to validate this doctrine, it is supported by animal data showing that underdosing may cause resistance,10 and by in vitro studies demonstrating that subinhibitory concentrations of fluoroquinolones are more likely to select less susceptible mutants than higher concentrations.11
Potency
There is general agreement that resistance is more likely to emerge in a single mutational step when an organism that is only marginally susceptible is exposed to a fluoroquinolone.3,4 This is because single-step mutations usually cause only modest decreases in susceptibility, i.e. eight-fold or less.79 Agents that are highly potent are likely to prevent resistance emerging by killing both the parental organism and its less susceptible single-step mutant.
The importance of potency is demonstrated in Table I. Increased MICs of trovafloxacin, ciprofloxacin and ofloxacin resulted when first-step mutants were selected from a clinical isolate of Streptococcus pneumoniae after exposure to trovafloxacin and ciprofloxacin. The MIC increases were typically eight-fold or less. However, because trovafloxacin was up to 32-fold more potent than ciprofloxacin and ofloxacin against the mutants, the mutants remained susceptible only to trovafloxacin. Extrapolating these results to the clinical situation, trovafloxacin was the only agent in this study that was likely to prevent resistance emerging by being able to kill both the parent and its mutants.
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Dissociated fluoroquinolone resistance is the phenomenon whereby a resistance mechanism significantly reduces the activity of one agent more than another. A dramatic example of this was a multi-step mutational study in which fluoroquinolone MICs of the third-step mutant of S. aureus obtained after exposure to ofloxacin exhibited a 256-fold increase in the MIC of grepafloxacin but only eight-fold increases in the MICs of ciprofloxacin and ofloxacin.12 That is, grepafloxacin was 32-fold more affected than ciprofloxacin and ofloxacin by this mutational step. At present there is only partial understanding of the mechanisms responsible for this type of phenomenon. However, it is clear that fluoroquinolones are not all equally affected by resistance mechanisms.
The underlying basis for dissociated resistance is beginning to be clarified by molecular studies. For example, it has been shown that certain mutations are phenotypically silent against some fluoroquinolones but can cause modest increases in the MICs of others, and multiple mutations appear to be necessary to cause the dramatic differentials between fluoroquinolones of the type mentioned above. Fournier and Hooper,13 showed that the occurrence of single specific mutations in the genes of DNA gyrase subunits A and B (gyrA and gyrB) of a strain of S. aureus did not alter the MICs of ciprofloxacin, norfloxacin or sparfloxacin, while a mutation in the topoisomerase IV gene (grlA) increased the MICs of ciprofloxacin and norfloxacin four- and 16-fold, respectively, without altering the MIC of sparfloxacin. Furthermore, when the previously silent gyrA and gyrB mutations were combined with the grlA mutation, the sparfloxacin MIC increased 128-fold, but the MICs of ciprofloxacin and norfloxacin increased only 16- and four-fold, respectively. Studies have also identifed molecular events that are associated with dissociated fluoroquinolone resistance in S. pneumoniae.14,15
More studies are required for a comprehensive and clinically useful understanding of the effects of the variety of mutations and combinations of mutations that occur in clinical isolates. It is currently known that mutations in the quinolone resistance-determining regions of the chromosome can affect different fluoroquinolones idiosyncratically, causing phenotypic unpredictability.13,16 However, until more complete data are available, it is too early to expect molecular analyses to predict reliably all possible resistance phenotypes.
The unpredictability and complexity of the clinical situation is reflected in the three clinical isolates of S. aureus shown in Table II. Strain 202 is more resistant to ciprofloxacin than to grepafloxacin. In contrast, strain 205 is more resistant to grepafloxacin than ciprofloxacin, while strain 204 has similar MICs of both drugs. All strains are highly resistant (ciprofloxacin MICs
8 mg/L), suggesting that multiple mutations are present and therefore that different combinations of mutations are responsible for the different phenotypes. The considerable variability of these isolates suggests that caution is necessary when applying the results of molecular studies of single strains with only a few specific mutations to the more diverse clinical situation.
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It can be argued that dissociated resistance is clinically irrelevant and only of academic interest if it occurs only at drug concentrations higher than those achieved in humans. The merit of this criticism is difficult to assess. Different fluoroquinolones can have very different intrinsic potencies against different organisms (e.g. S. aureus in comparison with S. pneumoniae or Escherichia coli), making dissociated resistance clinically relevant in the more susceptible genera, even if it is not in those that are less susceptible. Furthermore, an organism that is highly resistant to one fluoroquinolone may still be susceptible to another more potent agent (e.g. clinical isolates of S. aureus with a trovafloxacin MIC of 1 mg/L and a ciprofloxacin MIC of 128 mg/L). Ultimately, for some isolates, MICs of all fluoroquinolones may be elevated sufficiently to exceed clinically attainable concentrations, but for other less resistant isolates of the same species the dissociated resistance characteristics may be therapeutically and ecologically relevant. In addition, the consistent patterns of dissociated resistance reported in Table III are suggestive of general principles that may be applicable to many, possibly all, organism groups. Although this may not have direct therapeutic implications for the individual patient, there may be advantages in having a better understanding of the drug organism interactions of the various fluoroquinolones when considering their potential clinical roles. In this context, dissociated resistance analyses may be more helpful to identify agents that are ecologically desirable than the more traditional MIC studies of the past in which mostly susceptible wild-type isolates were tested, and which may be misleading about the long-term utility of the agents.
Conclusion
Given the concerns about the newer fluoroquinolones promoting the development and spread of resistance, there appear to be grounds for cautious optimism. Wisdom gained from previous use of the older fluoroquinolones should have convinced clinicians of the need to reserve these agents for situations in which they are drugs of choice. Furthermore it is possible to identify agents that are likely to be ecologically preferable because they have a lower propensity to promote resistance. These are agents that have favourable pharmacokinetic properties, enhanced potency and good dissociated resistance characteristics.
Notes
* Tel: +1-402-80-1881; Fax: +1-402-280-1225; E-mail: kstaac{at}creighton.edu
References
1 . Cheek, W. A. (1993). Physicians must rethink use of antibiotics to curb rise in drug-resistant microbes. ACP Observer 13, 159.
2 . Cherubin, C. E., Smith, S. M., Eng, R. H. K. & Pudi, K. (1992). An extension of quinolone resistance in Gram-negatives of the Proteae tribe and a theory of antibiotic use, Pascal's Wager'. Infectious Disease Newsletter 11, 579.
3 . Köhler, T. & Pechère, J. C. (1998). Bacterial resistance to quinolones. In The Quinolones, 2nd edn, (Andriole, V. T., Ed.), pp. 11742. Academic Press, San Diego, CA.
4 . Peterson, L. R. (1993). Quinolone resistance in clinical practice: occurrence and importance. In Quinolone Antimicrobial Agents, 2nd edn, (Hooper, D. C. & Wolfson, J. S., Eds), pp. 11937. American Society for Microbiology, Washington, DC.
5 . Frieden, T. R. & Mangi, R. J. (1990). Inappropriate use of oral ciprofloxacin. Journal of the American Medical Association 264, 143840.[Abstract]
6 . Thomson, K. S., Sanders, W. E. & Sanders, C. C. (1994). USA resistance patterns among UTI pathogens. Journal of Antimicrobial Chemotherapy 33, Suppl. A, 915.[ISI][Medline]
7 . Hooper, D. C. & Wolfson, J. S. (1993). Mechanisms of bacterial resistance to quinolones. In Quinolone Antimicrobial Agents, 2nd edn, (Hooper, D. C. & Wolfson, J. S., Eds), pp. 97118. American Society for Microbiology, Washington, DC.
8 . Oram, M. & Fisher, L. M. (1991). 4-Quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrobial Agents and Chemotherapy 35, 3879.[ISI][Medline]
9 . Sanders, C. C. (1990). Microbiology of fluoroquinolones. In Fluoroquinolones in the Treatment of Infectious Diseases, (Sanders, W. E. & Sanders, C. C., Eds), pp. 127. Physicians and Scientists Publishing Co., Glenview, IL.
10 . Michéa-Hamzehpour, M., Auckenthaler, R., Regamey, P. & Pechère, J. C. (1987). Resistance occurring after fluoroquinolone therapy of experimental Pseudomonas aeruginosa peritonitis. Antimicrobial Agents and Chemotherapy 31, 18038.[ISI][Medline]
11 . Fung-Tomc, J., Kolek, B. & Bonner, D. P. (1993). Ciprofloxacin-induced, low-level resistance to structurally unrelated antibiotics in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 37, 128996.[Abstract]
12 . Thomson, K. S. & Sanders, C. C. (1994). Dissociated resistance among fluoroquinolones. Antimicrobial Agents and Chemotherapy 38, 2095100.[Abstract]
13
.
Fournier, B. & Hooper, D. C. (1998). Mutations in topoisomerase IV and DNA gyrase of Staphylococcus aureus: novel pleiotropic effects on quinolone and coumarin activity. Antimicrobial Agents and Chemotherapy 42, 1218.
14
.
Piddock, L. J. V., Johnson, M., Ricci, V. & Hill, S. L. (1998). Activities of new fluoroquinolones against fluoroquinolone-resistant pathogens of the lower respiratory tract. Antimicrobial Agents and Chemotherapy 42, 295660.
15
.
Pan, X.-S. & Fisher, L. M. (1998). DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 42, 28106.
16
.
Fournier, B. & Hooper, D. C. (1998). Effects of mutations in GrlA of topoisomerase IV from Staphylococcus aureus on quinolone and coumarin activity. Antimicrobial Agents and Chemotherapy 42, 210912.
17 . Thomson, K. S. & Sanders, C. C. (1998). The effects of increasing levels of quinolone resistance on in-vitro activity of four quinolones. Journal of Antimicrobial Chemotherapy 42, 17987.[Abstract]
18 . Thomson, K. S., Moland, E. S. & Sanders, C. C. (1997). Mutational increases in fluoroquinolone resistance. In Economic and Clinical Implications of Quinolones in Hospital Pharmacy: a poster symposium presented during the Thirty-Second Annual ASHP Midyear Clinical Meeting, Atlanta, GA, 1997. Abstract, pp. 467. DesignWrite, Inc., Princeton, NJ.
19 . National Committee for Clinical Laboratory Standards. (1999). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow AerobicallyApproved Standard M7-A4. NCCLS, Villanova, PA.
20
.
Pong, A., Thomson, K. S., Moland, E. S., Chartrand, S. A. & Sanders, C. C. (1999). Activity of moxifloxacin against pathogens with decreased susceptibility to ciprofloxacin. Journal of Antimicrobial Chemotherapy 44, 6217.
21 . Thomson, K. S., Moland, E. S. & Sanders, C. C. (1999). Activity of trovafloxacin against antibiotic-resistant bacterial pathogens. Infectious Diseases in Clinical Practice 8, Suppl. 1, S7S16.[ISI]
22 . Thomson, K. S., Sanders, C. C. & Hayden, M. E. (1991). In vitro studies with five quinolones: evidence for changes in relative potency as quinolone resistance rises. Antimicrobial Agents and Chemotherapy 35, 232934.[ISI][Medline]
23 . Thomson, K. S., Moland, E. S. & Sanders, C. C. (1999). Activity of gatifloxacin against clinical isolates with various levels of resistance to ciprofloxacin. In Program and Abstracts of the Thirty-Ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1999. Abstract 354, p. 248. American Society for Microbiology, Washington, DC.