Correspondence
Resistance to Levofloxacin and Failure of Treatment of Pneumococcal Pneumonia
N Engl J Med 2002; 347:65-67July 4, 2002
- Article
To the Editor:
Davidson et al. (March 7 issue)1 describe four patients with pneumococcal pneumonia in whom therapy with oral levofloxacin failed. We report on a patient with pneumococcal pneumonia and bacteremia in whom meningitis and sepsis developed after an initial clinical response to levofloxacin therapy.
A 79-year-old man was admitted to Saint Elizabeth's Medical Center in Boston in January 1999 with fever, dyspnea, and left-lower-lobe pneumonia. Treatment with intravenous levofloxacin was started, and the fever resolved. Blood cultures grew Streptococcus pneumoniae, which was sensitive to ceftriaxone, with intermediate resistance to penicillin. Treatment was switched to oral levofloxacin on the third hospital day. On the sixth hospital day, the patient's condition deteriorated, with recurrent fever, obtundation, renal failure, hypotension, and worsening pneumonia, requiring intubation. Therapy with intravenous ceftriaxone (2 g every 12 hours) was begun. Repeated blood cultures grew S. pneumoniae with high-level resistance to levofloxacin by E test (minimal inhibitory concentration [MIC], >32 μg per milliliter). Cerebrospinal fluid obtained after the initiation of treatment with ceftriaxone was purulent, with a white-cell count of 5170 per cubic millimeter, 81 percent polymorphonuclear leukocytes, and negative cultures for bacterial pathogens. The patient died on the 17th hospital day.
Our experience supports the recommendation of Davidson et al. that microbiology laboratories routinely test S. pneumoniae for susceptibility to fluoroquinolones. Given the deaths of our patient and Patient 3 in the report by Davidson et al., we suggest that if a fluoroquinolone is used to treat bacteremic pneumococcal pneumonia, a beta-lactam antibiotic, such as ceftriaxone, also be administered until the results of tests for susceptibility to fluoroquinolones are available.
1 ReferencesJohn J. Ross, M.D.
Michael G. Worthington, M.D.
Sherwood L. Gorbach, M.D.
Saint Elizabeth's Medical Center, Boston, MA 02135
jrossmd@cchcs.org 1
Davidson R ,Cavalcanti R ,Brunton JL , et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747-750
Full Text | Web of Science | Medline
To the Editor:
Davidson et al. emphasize that routine susceptibility testing should be more widely implemented, but routine testing is unlikely to detect resistant strains, particularly if they represent a minority of the pathogen population. Furthermore, the use of susceptibility breakpoints can cause the accumulation of strains with intermediate resistance to go unrecognized. This is important in the development of resistance to fluoroquinolones because bacterial species contain two intracellular targets (DNA gyrase and DNA topoisomerase IV). The first mutation increases the probability of a second mutation by several orders of magnitude. Thus, we lack an early-warning system for the development of levofloxacin-resistant pneumococci.
As the use of levofloxacin increases, it is likely, for pharmacodynamic reasons, to result in the selection of strains with first-step mutations, thus decreasing the avidity of the newer fluoroquinolones for DNA gyrase and topoisomerase IV. The resultant double-mutation strains will be difficult to treat with any of the available fluoroquinolones.1 The increase in mutant pneumococcal strains with the widespread use of levofloxacin will ultimately reduce the usefulness of the new compounds, thus further decreasing the efficacy of this class of antibiotics.
1 ReferencesGlenn S. Tillotson, M.Sc.
Xilin Zhao, Ph.D.
Karl Drlica, Ph.D.
Public Health Research Institute, New York, NY 10066
gtillotson@fusionmdnetwork.com 1
Li X ,Zhao X ,Drlica K . Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin. Antimicrob Agents Chemother 2002;46:522-524
CrossRef | Web of Science | Medline
To the Editor:
Davidson et al. report that the S. pneumoniae isolated from Patient 1 had a mutation in both parC (S79F) and gyrA (S81F) and was resistant to levofloxacin (MIC, 8 μg per milliliter). The authors state that this organism had intermediate resistance to gatifloxacin (MIC, 2 μg per milliliter) and was susceptible to moxifloxacin (MIC, 1 μg per milliliter). It is surprising that an S. pneumoniae isolate with both parC S79F and gyrA S81F mutations was found not to have either intermediate or full resistance to all the new fluoroquinolones (i.e., levofloxacin, gatifloxacin, and moxifloxacin). The available evidence to date indicates that any fluoroquinolone-resistant S. pneumoniae strain with both parC S79F and gyrA S81F must be considered to have intermediate or full resistance to levofloxacin, gatifloxacin, and moxifloxacin and that no fluoroquinolone will effectively eradicate these strains.1-4 The implication that a fluoroquinolone-resistant S. pneumoniae strain with both parC S79F and gyrA S81F is susceptible to moxifloxacin but is resistant to levofloxacin and has intermediate resistance to gatifloxacin may give clinicians the impression that moxifloxacin may be used in this setting.
4 ReferencesGeorge G. Zhanel, Ph.D.
Daryl J. Hoban, Ph.D.
University of Manitoba, Winnipeg, MB R3A 1R9, Canada
ggzhanel@pcs.mb. ca Charles K. Chan, M.D.
University of Toronto, Toronto, ON M5G 2C4, Canada1
Weigel LM ,Anderson GJ ,Facklam RR ,Tenover FC . Genetic analyses of mutations contributing to fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001;45:3517-3523
CrossRef | Web of Science | Medline2
Brueggemann AB ,Coffman SL ,Rhomberg P , et al. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995. Antimicrob Agents Chemother 2002;46:680-688
CrossRef | Web of Science | Medline3
Zhanel GG ,Ennis K ,Vercaigne L , et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs 2002;62:13-59
CrossRef | Web of Science | Medline4
Zhanel GG ,Roberts D ,Waltky A , et al. Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. J Antimicrob Chemother 2002;49:807-812
CrossRef | Web of Science | Medline
To the Editor:
Canadians were already liberal consumers of fluoroquinolones when levofloxacin became available in 1998. The level of consumption of drugs in the fluoroquinolone category of the Anatomical Therapeutical Chemical classification was 1.38 defined daily doses per 1000 inhabitants per day in 1997; by 2001, this rate had risen to 2.28 defined daily doses per 1000 per day — a 65 percent increase (Rhodes D, IMS Health: personal communication). In contrast, the rate in Denmark has been quite stable, averaging 0.19 defined daily dose per 1000 inhabitants per day during the same period (Sorenson T: personal communication).
In hospitals, the use of fluoroquinolones has increased even more dramatically. On the medical service of a 300-bed, university-affiliated community hospital in my area, the rate of use of fluoroquinolones rose from 8.6 defined daily doses per 100 bed-days in the first quarter of 2001 to 24.4 defined daily doses per 100 in the fourth quarter. Fluoroquinolones are now the most commonly used class of antimicrobial agents. This phenomenon is probably widespread in Canadian hospitals, since there has been very aggressive marketing focused on the recommendations in the updated Canadian Guidelines for treating community-acquired pneumonia.1 A “respiratory” fluoroquinolone is recommended as the “first choice” for all patients admitted to a hospital.
I urge more caution with recommendations for empirical treatment for community-acquired respiratory tract infections. The majority of antibiotics are prescribed for these indications, many inappropriately. Widespread promotion of fluoroquinolones for the treatment of community-acquired pneumonia will undoubtedly result in large increases in overall consumption and therefore in rates of resistance. This remarkable class of antimicrobial agents may be squandered within 20 short years of use.
1 ReferencesJim Hutchinson, M.D.
Memorial University of Newfoundland, St. John's, NF A1B 3V6, Canada
hcc.hutj@hccsj. nf. ca Author/Editor Response
The authors reply:
To the Editor: Both Tillotson et al. and Zhanel et al. provide compelling arguments for the ability to detect the presence of amino acid substitutions in the fluoroquinolone-resistance–determining region of parC or gyrA, or both, in pneumococci, which current in vitro susceptibility testing does not reliably do.1 Tillotson et al. raise the additional concern that the current category of pathogens that are susceptible to levofloxacin, with susceptibility defined as a MIC of no more than 2 μg per milliliter,2 includes isolates with amino acid substitutions in the fluoroquinolone-resistance–determining region of parC, thereby eliminating the possibility of an early-warning system for the emergence of resistance and resulting in an increase in strains with low-level resistance that favor secondary selection for more resistant strains in treated patients.3 We previously characterized pneumococcal isolates for which the MIC of ciprofloxacin was more than 2 μg per milliliter and found first-step mutations in isolates that were susceptible to levofloxacin and also in isolates that were susceptible to gatifloxacin and moxifloxacin, with susceptibility defined as a MIC of no more than 1 μg per milliliter.4
Zhanel et al. question the wisdom of our reporting a pneumococcal isolate as susceptible to moxifloxacin when it had amino acid substitutions in both parC and gyrA. Their concern is warranted, especially in the case of an infection with a high biomass, such as pneumococcal pneumonia (i.e., more than 1010 infecting organisms), when spontaneous mutations occur at a frequency of 1 in 106 to 1 in 109. We have previously described three such isolates that were susceptible to moxifloxacin yet had amino acid substitutions in parC and gyrA.4
For 99 percent of susceptible pneumococci, the MIC of levofloxacin is no more than 1 μg per milliliter.5 These isolates are proportionately much less likely to have type II topoisomerase substitutions than isolates with a MIC of 2 μg per milliliter. Therefore, one possible solution would be to lower the susceptibility breakpoint for levofloxacin to a MIC of 1 μg per milliliter. Such a change would not be as effective for moxifloxacin or gatifloxacin in identifying isolates with first-step mutations in the susceptible category, emphasizing the need for alternative testing methods. Being able to identify first-step mutations not only is important for detecting the emergence of low-level resistance but also may be important for making decisions about the management of infection.
5 ReferencesDonald E. Low, M.D.
Joyce de Azavedo, Ph.D.
Darrin Bast, Ph.D.
Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada1
Richardson DC ,Bast D ,McGeer A ,Low DE . Evaluation of susceptibility testing to detect fluoroquinolone resistance mechanisms in Streptococcus pneumoniae. Antimicrob Agents Chemother 2001;45:1911-1914
CrossRef | Web of Science | Medline2
Performance standards for antimicrobial susceptibility testing: twelfth informational supplement. Wayne, Pa.: National Committee for Clinical Laboratory Standards, 2002. (NCCLS document M100-S12.)
3
Baquero F . Low-level antibacterial resistance: a gateway to clinical resistance. Drug Resist Updat 2001;4:93-105
CrossRef | Web of Science | Medline4
Bast DJ ,Low DE ,Duncan CL , et al. Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob Agents Chemother 2000;44:3049-3054
CrossRef | Web of Science | Medline5
Low DE ,de Azavedo J ,Weiss K , et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob Agents Chemother 2002;46:1295-1301
CrossRef | Web of Science | Medline
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Wael E Shams, Martin E Evans. (2005) Guide to Selection of Fluoroquinolones in Patients with Lower Respiratory Tract Infections. Drugs 65:7, 949-991
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M. W. R. Pletz, L. McGee, O. Burkhardt, H. Lode, K. P. Klugman. (2005) Ciprofloxacin treatment failure in a patient with resistant Streptococcus pneumoniae infection following prior ciprofloxacin therapy. European Journal of Clinical Microbiology & Infectious Diseases 24:1, 58-60
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