Review
Fluoroquinolones, tuberculosis, and resistance

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Summary

Although the fluoroquinolones are presently used to treat tuberculosis primarily in cases involving resistance or intolerance to first-line antituberculosis therapy, these drugs are potential first-line agents and are under study for this indication. However, there is concern about the development of fluoroquinolone resistance in Mycobacterium tuberculosis, particularly when administered as monotherapy or as the only active agent in a failing multidrug regimen. Treatment failures as well as relapses have been documented under such conditions. With increasing numbers of fluoroquinolone prescriptions and the expanded use of these broad-spectrum agents for many infections, the selective pressure of fluoroquinolone use results in the ready emergence of fluoroquinolone resistance in a diversity of organisms, including M tuberculosis. Among M tuberculosis, resistance is emerging and may herald a significant future threat to the long-term clinical utility of fluoroquinolones. Discussion and education regarding appropriate use are necessary to preserve the effectiveness of this antibiotic class against the hazard of growing resistance.

Section snippets

In vitro activity

Fluoroquinolones have in vitro activity against M tuberculosis.15, 16 The newer fluoroquinolones, sparfloxacin, gatifloxacin, and moxifloxacin, have lower minimum inhibitory concentrations (MICs) than levofloxacin, ciprofloxacin, and ofloxacin (table 1).1724 Against rifampicin-tolerant persistent organisms–bacilli that survive and persist despite chemotherapy–in an in-vitro model examining sterilising activity, gatifloxacin and moxifloxacin had the greatest bactericidal activities of the

Fluoroquinolones in the treatment of tuberculosis

There is a need for more clinical trials evaluating fluoroquinolones as part of first-line therapy against M tuberculosis.16,77,81,82 In a clinical trial from India, patients with drug-susceptible and drug-resistant pulmonary tuberculosis were treated for 4–5 months with an ofloxacin-containing regimens under direct observation.62 Patients were randomly assigned to one of four treatment arms: (1) isoniazid, rifampicin, pyrazinamide, and ofloxacin daily for 3 months; (2) isoniazid, rifampicin,

Mechanism of fluoroquinolone resistance

As the only presently licensed antibiotics that directly inhibit DNA synthesis, fluoroquinolones target bacterial topoisomerases II and IV. Unlike most other bacterial species, M tuberculosis lacks topoisomerase IV and includes only topoisomerase II or DNA gyrase, a tetramer consisting of two A and two B subunits, encoded by the genes gyrA (2517 bp) and gyrB (2060 bp), respectively.89 The primary target of fluoroquinolones in Staphylococcus aureus is topoisomerase IV, whereas in Escherichia coli

Conclusions

Fluoroquinolones are rapidly emerging as important drugs for the treatment of tuberculosis. With most of their current use in multidrug-resistant tuberculosis, fluoroquinolones are also under investigation for first-line treatment of pulmonary tuberculosis. There is concern about the rapid development of resistance particularly when fluoroquinolones are administered as the only active agent in a failing multidrug regimen, and treatment failures as well as relapses have been documented under

Search strategy and selection criteria

Data for this review were identified by searches of PubMed and references from relevant articles. Search terms were “tuberculosis”, “Mycobacterium tuberculosis”, “quinolones”, “fluoroquinolones”, “activity”, “safety”, “use”, “treatment”, “resistance”, “mechanism”, “gyrase”, “quinolone resistance-determining region”, “human immunodeficiency virus”, and “acquired immunodeficiency syndrome”. English language papers were reviewed.

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