Fluoroquinolones for Treatment of Community‐Acquired Pneumonia and Tuberculosis: Putting the Risk of Resistance into Perspective

Community-acquired pneumonia (CAP) is a common and important disease that occurs in all age groups worldwide. Streptococcus pneumoniae is the most common cause of CAP and is the pathogen associated with the greatest morbidity and mortality [1]. High-level penicillin-resistant and drug-resistant S. pneumoniae infections are now a global problem; thus, the number of therapeutic options for the empirical treatment of CAP is limited. The fluoroquinolones for treatment of respiratory diseases, including gatifloxacin, moxifloxacin, and levofloxacin, have an excellent spectrum, providing coverage for the most important respiratory pathogens, including drug-resistant S. pneumoniae and atypical pathogens. The rate of fluoroquinolone-resistant pneumococcus infection is <3% in most countries [2–4]. As a result, the fluoroquinolones for treatment of respiratory diseases have been recommended and are increasingly being used as preferred or alternative therapy for the treatment of CAP [1, 5]. Given that an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and ∼1.6 million deaths worldwide in 2006 were attributable to tuberculosis (TB), TB remains a major public health concern. Fluoroquinolones have excellent in vitro activity against M. tuberculosis. They are one of the most important drug classes for the treatment of multidrug-resistant TB and of patients who experience severe adverse effects of first-line anti-TB therapy [6, 7]. Furthermore, fluoroquinolone-containing regimens are likely to be proved to be effective for shortening the treatment duration for drug-susceptible disease [6]. Depending on the prevalence of TB in a specific region, a percentage of patients with CAP who are empirically treated with a fluoroquinolone will actually have pulmonary TB with or without infection due to a copathogen. In a study of CAP in adult patients in Asian countries, Song et al. [8] found that the etiology was M. tuberculosis in 3.3% of cases. There's the rub. Monotherapy with a fluoroquinolone may temporarily improve the patient's symptoms and, therefore, delay diagnosis [9–12] and/or may select for fluoroquinolone-resistant M. tuberculosis strains. In this issue of Clinical Infectious Diseases, Long et al. [13] put the threat of the emergence of fluoroquinolone resistance into perspective. With access to 2 large provincial TB registries with linkages to corresponding prescription drug plans, the authors found that, although outpatient fluoroquinolone use (ostensibly for CAP) was not uncommon among patients with pulmonary TB, fluoroquinolone-resistant M. tuberculosis was identified infrequently; only 3 of 74 patients who had been treated with a fluoroquinolone prior to the diagnosis of pulmonary TB were infected with a fluoroquinolone-resistant strain. All 3 patients had received >1 fluoroquinolone prescription during the 3 months before the diagnosis of TB. Ginsburg et al. [14, 15] performed a retrospective cohort study that involved patients with newly diagnosed, culture-confirmed TB. Fifty-five patients were included in the study, 19 of whom had previous fluoroquinolone exposure and 36 of whom did not. Two of the 19 patients, both of whom had AIDS, had isolates of M. tuberculosis that demonstrated decreased fluoroquinolone susceptibility, compared with 0 of 36 patients who did not have previous fluoroquinolone exposure. Both patients had AIDS, and 1 of these patients, who has been described previously elsewhere [12], had received >1 course of fluoroquinolone therapy. Huang et al. [16] performed a study to determine the frequency of the emergence of fluoroquinolone-resistant strains in Taiwan and to assess whether such resistance might be attributable to use of fluoroquinolones for treatment of patients with multidrug-resistant TB or to the increased use of fluoroquinolones in the community. The authors found an increase in the rates of resistance to ciprofloxacin, ofloxacin, and levofloxacin only in the group of patients with mulitdrug-resistant TB, which suggests that fluoroquinolone resistance was likely the result of treatment of patients with multidrug-resistant TB rather than of use in the general community. In a study performed in Taiwan by Wang et al. [17], a total of 420 clinical isolates of M. tuberculosis from 420 patients (2004–2005) had rates of susceptibility to levofloxacin and moxifloxacin of 98.6%, and 97.6%, respectively, with an overall resistance rate of 3.3% to any fluoroquinolone tested. The authors found that 45 patients had previous fluoroquinolone exposure for >1 week and that 63 patients had previous fluoroquinolone exposure for ⩽1 week. However, neither the previous exposure to fluoroquinolones nor the duration of fluoroquinolone exposure was correlated with the fluoroquinolone resistance of M. tuberculosis isolates. First-line anti-TB drug resistance and prior anti-TB treatment were significantly associated with fluoroquinolone resistance of M. tuberculosis isolates. Although the rates are low, are they likely to increase in the future with the increasing use of the fluoroquinolones for the empirical treatment of CAP and other infections treated with fluoroquinolones in the community [18]? Not necessarily, if the right fluoroquinolones are used at the right dosage and for the right duration. Fluoroquinolones exert their effects by trapping a DNA-drug-enzyme complex and specifically inhibiting ATP-dependent enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. In M. tuberculosis, there is only 1 target, DNA gyrase, because topoisomerase IV is absent. DNA gyrase consists of 2 components encoded by the gyrA and gyrB genes. Most mutations conferring changes in drug susceptibility occur in a quinolone-resistant–determining region in gyrA and, more rarely, in gyrB. Reduced susceptibility can also occur as a result of changes in drug efflux [19]. However, these 2 mechanisms only account for ∼50% of the resistance described in clinical isolates [14]. Alterations in DNA gyrase that result in reduced susceptibility occur through selection of spontaneously preexisting mutants in the quinolone-resistant–determining region. The wild-type bacillary population in the lung of an infected patient is >1×108. Preexisting mutants with reduced susceptibility to the fluoroquinolones are present at a predictable frequency of 1×10-6–1×10-8. The usual approach for prevention of the emergence of these preexisting mutants is to use combination therapy. This is effective because of the rule of independence of mutation; each drug is active on preexisting mutants that are resistant to other drugs [20]. Another approach proposed by Drlica and Zhao [21] is to administer the drug at doses that produce blood concentrations that continuously exceed the resistance level of all spontaneous mutants and, thereby, prevent the selective amplification of any mutant population. The greater the activity of the agent, the less likely they will select for mutants that have reduced susceptibility [22]. The newer fluoroquinolones, including moxifloxacin, levofloxacin, and gatifloxacin, have better in vitro and bactericidal activity and more favorable pharmacokinetic properties, compared with the older fluoroquinolones, ciprofloxacin and ofloxacin [22–26]. The duration of exposure of the M. tuberculosis infecting organisms to the fluoroquinolone may also be a risk factor for the development of resistance. During the past decade, results from clinical trials have supported a reduction in the duration of therapy with the newer fluoroquinolones for CAP to 5 days [1]. Although most of the information regarding the time to emergence of resistance to therapy has been for older, less-active agents, the information available suggests that resistance is unlikely to emerge with a short duration of therapy with an active agent [14]. At the end of the day, the most important strategy to reduce the risk of a mistaken diagnosis of CAP in a patient with pulmonary TB is to always consider the “great mimicker” as a possible cause and, when suspected, to perform the relevant diagnostic tests before prescribing fluoroquinolones [27]. Potential conflicts of interest.D.E.L. has received research funding from Bayer, Ortho-McNeil, and Pfizer and has served as a consultant to Bayer, Ortho-McNeil, Oscient, and Sanofi-Aventis.

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