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Letter

Factors Influencing Fluoroquinolone Resistance

Daniel F. Sahm,* Clyde Thornsberry,* Mark E. Jones,* and James A. Karlowsky*
*Focus Technologies, Herndon, Virginia, USA

Suggested citation for this article: Sahm DF, Thornsberry C, Jones ME, Karlowsky JA. Factors influencing fluoroquinolone resistance. Emerg Infect Dis [serial online]. 2003 Dec. [date cited]. Available from: URL: http://www.cdc.gov/ncidod/EID/vol9no12/03-0168.htm

To the Editor: Recently, Scheld summarized factors that he considered to have an influence on the efficacy of fluoroquinolones (1). In the review, ciprofloxacin was presented as the most active fluoroquinolone against Pseudomonas aeruginosa with MICs typically two- to eightfold lower than those for levofloxacin, moxifloxacin, or gatifloxacin. However, because the National Committee for Clinical Laboratory Standards (NCCLS) MIC interpretative breakpoints are fluoroquinolone-specific, percent susceptibility is considered to be a better measure by which to compare fluoroquinolone activities. Our company has conducted annual investigations called TRUST (Tracking Resistance in the United States Today) since 1996. These surveillance studies have consistently shown similar susceptibility rates for levofloxacin (67.7% in 2002) and ciprofloxacin (67.4% in 2002) against P. aeruginosa (2,3). Both agents show higher in vitro activity against P. aeruginosa than gatifloxacin and moxifloxacin (2–4). A critique of antipseudomonal fluoroquinolone activity should also consider peak achievable fluoroquinolone levels at a site of infection, the area under the serum concentration curve in 24 hours (AUC_24h), and the AUC_24h/MIC ratio (5). At equivalent dosages for nosocomial pneumonia, levofloxacin (750 mg intravenously, once daily) has a threefold higher peak serum level (C_max) and threefold higher AUC_24h than ciprofloxacin (400 mg intravenously, every 8 hours) (package inserts for Levaquin and Cipro). While certain P. aeruginosa isolates have lower ciprofloxacin than levofloxacin MICs, the two fluoroquinolones have equivalent activity against P. aeruginosa because of their equivalent AUC_24h /MIC ratios (6). We agree strongly with Scheld’s suggestion that the fluoroquinolone used clinically should be the fluoroquinolone tested by the laboratory and reported; surrogate testing of fluoroquinolones may lead to major errors in reporting, particularly for Enterobacteriaceae (2,3,7).

The review also stated that levofloxacin-resistant strains of P. aeruginosa emerge at a significantly higher rate than with ciprofloxacin. However, a recent study of P. aeruginosa isolated from cystic fibrosis patients reported that fewer resistant mutants were isolated after exposure to levofloxacin (11 mutants) than to ciprofloxacin (28 mutants) (8).

With regards to S. pneumoniae, the review stated that in vitro studies have demonstrated that ciprofloxacin (1–4 mg/L) and levofloxacin (1–2 mg/L) are not as active as moxifloxacin (0.06–0.25 mg/L) and gatifloxacin (0.5–1 mg/L) against pneumococci. As with P. aeruginosa, fluoroquinolone comparisons against S. pneumoniae should not be limited to MICs alone because pharmacokinetic and pharmacodynamic characteristics differ for each fluoroquinolone. Pneumococcal time-kill studies with levofloxacin, gatifloxacin, and moxifloxacin in a pharmacodynamic model have demonstrated that these three agents possess equal bactericidal activity and are equally effective in preventing resistance development because the lower in vitro MICs for gatifloxacin and moxifloxacin were offset by the higher serum and tissue levels of levofloxacin (9). In the same study, ciprofloxacin did not exhibit rapid killing and selected for resistance faster than the other three agents (9). TRUST and other U.S. surveillance studies, using the NCCLS-recommended broth-dilution method, have shown that S. pneumoniae remain highly susceptible to levofloxacin with resistance rates in the United States of <1%; the MIC₉₀ for levofloxacin in these studies has remained at 1 mg/L from 1997 through 2002 (10–15). Further, levofloxacin, gatifloxacin, and moxifloxacin are equally effective in rates of clinical cure and microbiologic eradication of pneumococcal respiratory infections (16, and FDA website; available from: URL: http://www.fda.gov/cder/foi/nda/99/21061_Tequin.htm and http://www.fda.gov/cder/foi/nda/2001/21277_Avelox.htm)

The review implied that, in general, higher AUC_24h/MIC ratios were associated with better patient outcomes. For S. pneumoniae, several pharmacodynamic studies have demonstrated that a target AUC_24h/MIC ratio of 30 to 35 for fluoroquinolones is the best correlate for successful bacteriologic eradication, clinical cure, and prevention of emergence of resistance during therapy (5,9,17–19). Levofloxacin, gatifloxacin, and moxifloxacin all achieve this AUC_24h/MIC ratio (9). Zhanel et al. demonstrated that AUC_24h/MIC ratios above the target value of 30 to 35 did not improve bacteriologic eradication or reduce the emergence of resistance (9). Moreover, no clinical data support the claim that higher AUC_24h/MIC ratios correlate with better patient outcomes.

The review discusses the question of whether C-8-methoxyquinolones (moxifloxacin and gatifloxacin) have a lower propensity to select resistant mutants of S. pneumoniae compared with levofloxacin. Mutation prevention concentration is a theoretical laboratory concept based on agar dilution methodology, and no published data have shown any clinical correlation between this theory and clinical outcomes. NCCLS does not recommend agar dilution for susceptibility analysis of S. pneumoniae. Moreover, the extremely low levels of resistance in S. pneumoniae (<1%) after many years of fluoroquinolone use do not support the theory of mutation prevention concentration. The review did not reference an analysis of 16 penicillin-resistant S. pneumoniae strains by Kolhepp et al. (20). In that broth-dilution study, in vitro resistance developed in a greater proportion of strains exposed to gatifloxacin (11/16) and moxifloxacin (8/16) than to levofloxacin (2/16). Similarly, in a study by Klepser et al. that used an in vitro pharmacodynamic model, levofloxacin was less likely than moxifloxacin to select for resistant isolates of S. pneumoniae; moreover, after 24 hours of exposure, levofloxacin MICs remained unchanged while moxifloxacin MICs increased two- to eightfold (21).

Levofloxacin, gatifloxacin, and moxifloxacin all have susceptibility rates >99% for S. pneumoniae (22,23). Although resistance is rare, considerable cross-resistance among fluoroquinolones is observed once two or more key mutations (e.g., Ser⁷⁹ in ParC, Ser⁸¹ in GyrA) are detected (24,25). Using topoisomerase IV-selecting fluoroquinolones (ciprofloxacin and levofloxacin) in the same patient population as DNA gyrase-selecting fluoroquinolones (gatifloxacin and moxifloxacin) could potentially accelerate the development of double mutants (ParC and GyrA) and clinically important class resistance because selective pressure would be applied to both enzyme targets (26).

The review stated that, since 1999, at least 20 case reports of pulmonary infection that did not respond to levofloxacin therapy have been published. This number is remarkably small considering that >250 million patients have been treated with levofloxacin worldwide. A number of the treatment failures cited had documentation of prior ciprofloxacin use and ciprofloxacin failure, and many isolates were not tested for levofloxacin susceptibility before treatment (27). We agree with the recommendation in the cited Davidson et al. reference: a patient’s failure to respond to one fluoroquinolone is sufficient reason not to use other fluoroquinolones (27). Isolated clinical failures will occur with the use of any antimicrobial agent when treating pneumococcal pneumonia.

The notion that fluoroquinolone therapy can be “targeted” for an indication requires challenge as fluoroquinolone therapy will always result in systemic drug levels. Evidence does not indicate that the use of two fluoroquinolones, such as ciprofloxacin and moxifloxacin, minimizes fluoroquinolone resistance. Targeted fluoroquinolone therapy may in fact have adverse implications for the patient and for overall institutional resistance patterns. For example, the use of ciprofloxacin for urinary tract infections exposes resident streptococci in the respiratory tract to an agent that has demonstrated weaker activity against pneumococci, thus potentially selecting for pneumococcal resistance (9). Moreover, 20%-35% of ciprofloxacin is excreted through the intestinal tract (Cipro package insert), compared to 4% of levofloxacin (Levaquin package insert). Studies have shown that ciprofloxacin displays weaker in vitro activity (lower percentage of isolates susceptible) than levofloxacin for several gram-negative enteric bacteria (2,3). Stepwise adaptive changes towards fluoroquinolone resistance in enteric bacteria may be selected by fluoroquinolones with weaker in vitro activity and higher levels of exposure in the intestinal tract. Therefore, ciprofloxacin would have a greater potential than levofloxacin for the selection of resistant strains of intestinal gram-negative pathogens. A recent report stated that ciprofloxacin-resistant Escherichia coli were isolated from the feces of 48% of patients treated with ciprofloxacin for prostatitis; before ciprofloxacin therapy, only ciprofloxacin-susceptible E. coli were isolated from the feces of these patients (28). Further, given that 25% of moxifloxacin is excreted through the intestinal tract (Avelox package insert), the use of moxifloxacin for respiratory infections exposes bacteria in the intestinal tract to a fluoroquinolone with greater activity against Bacteroides fragilis and other intestinal anaerobes than levofloxacin (29,30). Moxifloxacin has a greater potential than other fluoroquinolones to alter the normal intestinal flora and select for vancomycin-resistant enterococci (31) and intestinal gram-negative strains with increased fluoroquinolone resistance.

In conclusion, we believe that the data we have briefly presented here supplements the previous discussion by Scheld (1) and will help facilitate an improved understanding of the factors influencing the maintenance of fluoroquinolone efficacy.

Focus Technologies is the central testing laboratory for the TRUST antimicrobial susceptibility testing surveillance program, sponsored by Ortho-McNeil Pharmaceutical.

References

1. Scheld WM. Maintaining fluoroquinolone class efficacy: review of influencing factors. Emerg Infect Dis 2003;9:1–9.
2. Karlowsky JA, Kelly LJ, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, et al. Susceptibility to fluoroquinolones among commonly isolated Gram-negative bacilli in 2000: TRUST and TSN data for the United States. Int J Antimicrob Agents 2002;19:21–31.
3. Blosser-Middleton RS, Sahm D, Evangelista AT, Thornsberry C, Jones ME, Critchley IA, Karlowsky JA. Antimicrobial susceptibilities of common pathogens causing nosocomial pneumonia: 2001–2002 TRUST surveillance. Annual Meeting Infectious Disease Society of America, 2002, abstract 71.
4. Milatovic D, Schmitz F-J, Brisse S, Verhoef, Fluit AC. In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8,796 clinical bacterial isolates. Antimicrob Agents Chemother 2000;44:1102–7.
5. Craig WA. Does dose matter? Clin Infect Dis 2001;33(Suppl 3):S233–7.
6. MacGowan AP, Wootton M, Holt HA. The antibacterial efficacy of levofloxacin and ciprofloxacin against Pseudomonas aeruginosa assessed by combining antibiotic exposure and bacterial susceptibility. J Antimicrob Chemother 1999;43:345–9.
7. Sahm DF, Thornsberry C, Jones ME, Blosser R, Critchley IA, Evangelista AT, Karlowsky JA. Antimicrobial susceptibility of Enterobacteriaceae and Pseudomonas aeruginosa from inpatient infections in the U.S.: 1999–2002 TRUST surveillance. Critical Care Congress, 2003, Abstract 22015.
8. Gillespie T, Masterton RG. Investigation into the selection frequency of resistant mutants and the bacterial kill rate by levofloxacin and ciprofloxacin in non-mucoid Pseudomonas aeruginosa isolates from cystic fibrosis patients. Int J Antimicrob Agents 2002;19:377–82.
9. Zhanel GG, Walters M, Laing N, Hoban DJ. In vitro pharmacodynamic modeling simulating free serum concentrations of fluoroquinolones against multidrug-resistant Streptococcus pneumoniae. J Antimicrob Chemother 2001;47:435–40.
10. Thornsberry C, Ogilvie PT, Holley HP Jr, Sahm DF. Survey of susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective U.S. study. Antimicrob Agents Chemother 1999;43:2612–23.
11. Biedenbach DJ, Barrett MS, Croco MA, Jones RN. Bay 12-8039, a novel fluoroquinolone, activity against important respiratory tract pathogens. Diagn Microbiol Infect Dis 1998;31:45–50.
12. Jones RN, Pfaller MA. In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance data from the Sentry antimicrobial surveillance program. Clin Infect Dis 2000;31(Suppl 2):S16–23.
13. Doern GV, Heilmann KP, Huynh HK, Rhomberg PR, Coffman SL, Brueggemann AB. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994–1995. Antimicrob Agents Chemother 2001;45:1721–9.
14. Thornsberry C, Sahm DF, Kelly LJ, Critchley IA, Jones ME, Evangelista AT, et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST surveillance program, 1999-2000. Clin Infect Dis 2002;34(Suppl 1):S4–16.
15. Sahm DF, Thornsberry C, Jones ME, Blosser RS, Critchley IA, Evangelista AT, et al. Correlation of antimicrobial resistance among Streptococcus pneumoniae in the U.S.: 2001–2002 TRUST surveillance. Interscience Conference on Antimicrobial Agents and Chemotherapy, 2002, Abstract C2-1640.
16. Zhanel GG, Ennis K, Vercaigne L, Walkty A, Gin AS, Embil J, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs 2002;62:13–59.
17. Lacey MK, Lu W, Xu X, Tessier PR, Nicolau DP, Quintiliani R, Nightingale CH. Pharmacodynamic comparisons of levofloxacin, ciprofloxacin, and ampicillin against Streptococcus pneumoniae in an in vitro model of infection. Antimicrob Agents Chemother 1999;43:672–7.
18. Nightingale CH, Grant EM, Quintiliani R. Pharmacodynamics and pharmacokinetics of levofloxacin. Chemotherapy 2000;46(Suppl 1):6–14.
19. Ambrose PG, Grasela DM, Grasela TH, Passarell J, Mayer HB, Pierce PF. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections. Antimicrob Agents Chemother 2001;45:2793–7.
20. Kolhepp SJ, Grunkemeier G, Leggett JE, Dworkin RJ, Slaughter SE, Gilbert DN. Phenotypic resistance of penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae after single and multiple in vitro exposures to ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovofloxacin. Annual Meeting Infectious Diseases Society of America, 2000, Abstract 97.
21. Klepser M, Ernst E, Petzold CR, Rhomberg P, Doern GV. Comparative bactericidal activities of ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Streptococcus pneumoniae in a dynamic in vitro model. Antimicrob Agents Chemother 2001;45:673–8.
22. Low D, de Azavedo J, Weiss K, Mazzulli T, Kuhn M, Church D, et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob Agents Chemother 2002;46:1295–301.
23. Brueggemann AB, Coffman SL, Rhomberg P, Huynh H, Almer L, Nilius A, et al. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994–1995. Antimicrob Agents Chemother 2002;46:680–8.
24. Evangelista AT, Loeloff M, Pfelger S, Davies T, Bush K, Mauriz Y, et al. Cross-resistance among fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae. J Antimicrob Chemother 2001;47(Suppl 1):29, Abstract P50.
25. Davies TA, Pfleger S, Goldschmidt R, Bush K, Sahm DF, Evangelista AT. Characterization of U.S. clinical Streptococcus pneumoniae strains from 2000–2001 that are cross-resistant to ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin. Annual Meeting Infectious Disease Society of America 2002, Abstract 78.
26. Davies TA, Evangelista A, Pfleger S, Bush K, Sahm DF, Goldschmidt R. Prevalence of single mutations in topoisomerase type II genes among levofloxacin-susceptible clinical isolates of Streptococcus pneumoniae isolated in the United States in 1992–1996 and 1999–2000. Antimicrob Agents Chemother 2002;46:119–24.
27. Davidson R, Covalcanti R, Brunton JL, Bast DI, de Azavedo JC, Kibsey P, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747–50.
28. Horcajada JP, Vila J, Moreno-Martínez A, Ruiz J, Martínez J, Sánchez M, Soriano E, et al. Molecular epidemiology and evolution of resistance to quinolones in Escherichia coli after prolonged administration of ciprofloxacin in patients with prostatitis. J Antimicrob Chemother 2002;49:55–9.
29. Hoellman DB, Kelly LM, Jacobs MR, Appelbaum PC. Comparative antianaerobic activity of BMS 284756. Antimicrob Agents Chemother 2001;45:589–92.
30. Ednie LM, Jacobs, Appelbaum PC. Activities of gatifloxacin compared to those of seven other agents against anaerobic organisms. Antimicrob Agents Chemother 1998;42:2459–62.
31. Zhanel GG, Laing NM, DeCorby M, Nichol KA, Hoban DJ. Pharmacodynamic activity of fluoroquinolones in a mixed infection simulationg an artificial bowel: effect of eradicating Bacteroides fragilis. American Society for Microbiology, 2002, Abstract A-145.

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