Treatment failure in a case of extensively drug-resistant tuberculosis associated with selection of a GyrB mutant causing fluoroquinolone resistance

Abstract

Multidrug-resistant tuberculosis (MDR-TB), defined by resistance to both isoniazid and rifampin, is an increasing problem that accounts for 400,000 new cases worldwide each year [1]. The prognosis of individuals infected with MDR-TB remains poor, with 10–30% of cases resulting in failure and death [2]. Fluoroquinolones are some of the few potent antibiotics still active against most MDR strains of M. tuberculosis, and their use has been identified as a favorable prognostic factor in cases of MDR-TB [3]. Recently, the emergence of extensively drug-resistant strains (XDR) has been reported and these strains have been associated with a worse prognosis than MDR-TB strains [2]. XDR-TB is an infection with a MDR strain that is resistant to any fluoroquinolone and at least one of the three injectable drugs (capreomycin, kanamycin or amikacin) [4]. We describe here a clinical case of XDR-TB that illustrates the critical role fluoroquinolones play in the management of drugresistant tuberculosis. The case involved a 51-year-old man with no comorbid conditions who had been treated in Algeria for pulmonary tuberculosis since June 2001. The initial antibiotic susceptibility profile of the causative strain was unknown. His original treatment, which included isoniazid, rifampin, ethambutol and pyrazinamide for 3 months followed by isoniazid and ethambutol, had been taken irregularly. When hospitalized in Limoges, France, in June 2002, he suffered fever, anorexia, weight loss (15 kg), cough and hemoptysis. A computed tomography scan showed bilateral cavitations of the upper lobes (Fig. 1). Sputum-smear examination detected abundant acid-fast bacilli. Treatment with rifampin, isoniazid and pyrazinamide was initiated. Culture grew M. tuberculosis. Susceptibility testing of first-line drugs revealed resistance to rifampin, isoniazid, pyrazinamide and streptomycin. Treatment was consequently switched to amikacin (750 mg/day), ofloxacin (800 mg/day), ethionamide (500 mg/day) and ethambutol (1 g/day). Molecular studies performed at the National Reference Center revealed mutations in the katG gene (S315T), rpoB gene (H526D) and pncA gene (T100P), but no mutation in the gyrA gene [5, 6]. Further drug susceptibility tests showed resistance to isoniazid, rifampin, pyrazinamide, streptomycin, ethambutol, kanamycin, ethionamide, thiacetazone and cycloserine. The strain remained susceptible to amikacin, capreomycin, fluoroquinolones and para aminosalicylic acid. As a result, treatment was switched to amikacin (750 mg/day), ofloxacin (800 mg/day) and PAS (10 g/day) for 4 months. Under this treatment the patient’s general condition improved. In January 2003, treatment was continued with the combination of moxifloxacin (400 mg/day) and PAS and maintained for 12 more months. However, in May 2003 the patient returned to Algeria, where he again took his medication irregularly. In March 2004, he was readmitted Eur J Clin Microbiol Infect Dis (2007) 26:423–425 DOI 10.1007/s10096-007-0298-0