Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 9, Number 12—December 2003
Letter

Factors Influencing Fluoroquinolone Resistance

Cite This Article

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 (24). 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 (AUC24h), and the AUC24h/MIC ratio (5). At equivalent dosages for nosocomial pneumonia, levofloxacin (750 mg intravenously, once daily) has a threefold higher peak serum level (Cmax) and threefold higher AUC24h 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 AUC24h /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 (1015). 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_medr_PI and http://www.fda.gov/cder/foi/nda/2001/21277_Avelox_medr_PI)

The review implied that, in general, higher AUC24h/MIC ratios were associated with better patient outcomes. For S. pneumoniae, several pharmacodynamic studies have demonstrated that a target AUC24h/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 (5,11,2123). Levofloxacin, gatifloxacin, and moxifloxacin all achieve this AUC24h/MIC ratio (9). Zhanel et al. demonstrated that AUC24h/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 AUC24h/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 isnert), 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 for 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 pathogens in the intestinal tract to a fluoroquinolone with higher anaerobic 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 strains of intestinal gram-negative strains with increased resistance towards fluoroquinolones.

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.

Top

Acknowledgment

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

Top

Daniel F. Sahm*, Clyde Thornsberry*, Mark E. Jones*, and James A. Karlowsky*Comments to Author 

Author affiliations: *Focus Technologies, Herndon, Virginia, USA

Top

References

  1. Scheld  WM. Maintaining fluoroquinolone class efficacy: review of influencing factors. Emerg Infect Dis. 2003;9:19.PubMed
  2. Karlowsky  JA, Kelly  LJ, Thornsberry  C, Jones  ME, Evangelista  AT, Critchley  IA, Susceptibility to fluoroquinolones among commonly isolated Gram-negative bacilli in 2000: TRUST and TSN data for the United States. Int J Antimicrob Agents. 2002;19:2131. DOIPubMed
  3. Blosser-Middleton  RS, Sahm  D, Evangelista  AT, Thornsberry  C, Jones  ME, Critchley  IA, 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;44:11027. DOIPubMed
  5. Craig  WA. Does dose matter? Clin Infect Dis. 2001;33(Suppl 3):S2337. DOIPubMed
  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;43:3459. DOIPubMed
  7. Sahm  DF, Thornsberry  C, Jones  ME, Blosser  R, Critchley  IA, Evangelista  AT, 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;19:37782. DOIPubMed
  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;47:43540. DOIPubMed
  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;43:261223.PubMed
  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;31:4550. DOIPubMed
  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):S1623. DOIPubMed
  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;45:17219. DOIPubMed
  14. Thornsberry  C, Sahm  DF, Kelly  LJ, Critchley  IA, Jones  ME, Evangelista  AT, 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):S416. DOIPubMed
  15. Sahm  DF, Thornsberry  C, Jones  ME, Blosser  RS, Critchley  IA, Evangelista  AT, 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, A critical review of the fluoroquinolones: focus on respiratory infections. Drugs. 2002;62:1359. DOIPubMed
  17. Lacey  MK, Lu  W, Xu  X, Tessier  PR, Nicolau  DP, Quintiliani  R, Pharmacodynamic comparisons of levofloxacin, ciprofloxacin, and ampicillin against Streptococcus pneumoniae in an in vitro model of infection. Antimicrob Agents Chemother. 1999;43:6727.PubMed
  18. Nightingale  CH, Grant  EM, Quintiliani  R. Pharmacodynamics and pharmacokinetics of levofloxacin. Chemotherapy. 2000;46(Suppl 1):614. DOIPubMed
  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;45:27937. DOIPubMed
  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;45:6738. DOIPubMed
  22. Low  D, de Azavedo  J, Weiss  K, Mazzulli  T, Kuhn  M, Church  D, Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob Agents Chemother. 2002;46:1295301. DOIPubMed
  23. Brueggemann  AB, Coffman  SL, Rhomberg  P, Huynh  H, Almer  L, Nilius  A, Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994–1995. Antimicrob Agents Chemother. 2002;46:6808. DOIPubMed
  24. Evangelista  AT, Loeloff  M, Pfelger  S, Davies  T, Bush  K, Mauriz  Y, 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;46:11924. DOIPubMed
  27. Davidson  R, Covalcanti  R, Brunton  JL, Bast  DI, de Azavedo  JC, Kibsey  P, Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med. 2002;346:74750. DOIPubMed
  28. Horcajada  JP, Vila  J, Moreno-Martínez  A, Ruiz  J, Martínez  J, Sánchez  M, Molecular epidemiology and evolution of resistance to quinolones in Escherichia coli after prolonged administration of ciprofloxacin in patients with prostatitis. J Antimicrob Chemother. 2002;49:559. DOIPubMed
  29. Hoellman  DB, Kelly  LM, Jacobs  MR, Appelbaum  PC. Comparative antianaerobic activity of BMS 284756. Antimicrob Agents Chemother. 2001;45:58992. DOIPubMed
  30. Ednie  LM. Jacobs, Appelbaum PC. Activities of gatifloxacin compared to those of seven other agents against anaerobic organisms. Antimicrob Agents Chemother. 1998;42:245962.PubMed
  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.

Top

Cite This Article

DOI: 10.3201/eid0912.030168

Related Links

Top

Table of Contents – Volume 9, Number 12—December 2003

Comments

Please use the form below to submit correspondence to the authors or contact them at the following address:

James A. Karlowsky, Focus Technologies, 13665 Dulles Technology Drive, Suite 200, Herndon, VA 20171-4603, USA; fax: (703) 480-2654

Send To

10000 character(s) remaining.

Top

Page created: March 16, 2011
Page updated: March 16, 2011
Page reviewed: March 16, 2011
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external