Correspondence

The Rapid Development of Fluoroquinolone Resistance in M. tuberculosis

N Engl J Med 2003; 349:1977-1978November 13, 2003

Article

To the Editor:

The development of resistance in Mycobacterium tuberculosis after empirical monotherapy could limit the role of fluoroquinolones in the treatment of tuberculosis. A 36-year-old man with AIDS (CD4+ lymphocyte count, 40 per cubic millimeter) presented with weight loss, flank pain, fevers, and dysuria. Examination revealed prostatic nodules, and computed tomography revealed abscesses. He received six days of levofloxacin therapy for prostatitis; ethambutol and clarithromycin were added for possible M. avium complex infection. There was no clinical improvement. He then received ciprofloxacin alone for seven days and afterward underwent transurethral prostatic resection; acid-fast smears were positive. A urine culture obtained four days before the initiation of levofloxacin therapy grew M. tuberculosis (isolate 1). A culture of a prostatic abscess subsequently also grew M. tuberculosis (isolate 2).

Testing of the M. tuberculosis with the Bactec method1 revealed that both isolates were susceptible to isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. The susceptibility of the M. tuberculosis to ciprofloxacin (2 μg per milliliter), ofloxacin (2 μg per milliliter), levofloxacin (1 μg per milliliter and 2 μg per milliliter), gatifloxacin (1 μg per milliliter), and moxifloxacin (1 μg per milliliter) was determined with the use of a modified proportion method.1 Although isolate 1 was susceptible to all the fluoroquinolones we tested, isolate 2 was resistant to all of them. The minimal inhibitory concentration of ciprofloxacin was less than 0.25 μg per milliliter for isolate 1 but 4.0 μg per milliliter for isolate 2. Restriction-fragment–length polymorphism (RFLP) analysis, performed according to standardized methods,2 revealed an identical 10-band pattern in both isolates of M. tuberculosis. Amplification by polymerase chain reaction and sequencing of the A and B subunits of DNA gyrase (gyrA and gyrB) from the M. tuberculosis demonstrated a single nucleotide change in the quinolone-resistance–determining region of gyrA of isolate 2, resulting in the substitution of cysteine for glycine at position 88. The sequenced regions were otherwise identical among isolate 1, isolate 2, and the laboratory M. tuberculosis strain H37Rv.

The fluoroquinolone-resistant M. tuberculosis emerged after just 13 days of therapy. Resistance in isolate 2 most likely resulted from the killing of fluoroquinolone-susceptible organisms by levofloxacin and ciprofloxacin and the subsequent expansion of a previously existing resistant population. The RFLP pattern of the two isolates was identical, a finding consistent with the development of fluoroquinolone resistance in vivo rather than through reinfection with a resistant strain.

Six days of ethambutol therapy did not prevent fluoroquinolone resistance, nor did it result in ethambutol resistance. It is possible that fluoroquinolone resistance developed during the seven-day course of ciprofloxacin therapy without ethambutol. The patient's advanced immunosuppression may have influenced the development of resistance, as has been reported with fluoroquinolones and rifamycins.3,4 A single missense mutation known to be associated with fluoroquinolone resistance was in the quinolone-resistance–determining region of gyrA in isolate 2 and was the likely mechanism of resistance.3,5

The standard duration of fluoroquinolone treatment is 10 to 14 days for most bacterial infections. The generation of high-level fluoroquinolone-resistant M. tuberculosis over such a period could severely limit the use of this class of antituberculosis drugs, which otherwise have the potential to be first-line agents.

Editor's note: Dr. Bishai reports having received research grants from Aventis, Abbott, Bayer, Merck, and Pfizer and having served as a member of speakers' bureaus for Aventis, Abbott, Merck, Pfizer, and Roche.

Amy Sarah Ginsburg, M.D., M.P.H.
Samuel C. Woolwine, Ph.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21231

Nancy Hooper, B.A.
Maryland Department of Health and Mental Hygiene, Baltimore, MD 21201

William H. Benjamin, Jr., Ph.D.
University of Alabama at Birmingham, Birmingham, AL 35294

William R. Bishai, M.D., Ph.D.
Susan E. Dorman, M.D.
Timothy R. Sterling, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21231
timothysterling@vanderbilt.edu

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Citing Articles (14)

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   Li-li Zhao, Qiang Xia, Nan Lin, Zhi-guang Liu, Xiu-qin Zhao, Kang-lin Wan. (2011) Multiplex allele-specific PCR combined with PCR-RFLP analysis for rapid detection of gyrA gene fluoroquinolone resistance mutations in Mycobacterium tuberculosis. Journal of Microbiological Methods
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   CUI HUA LIU, NAN YANG, QI WANG, YONG LIANG HU, LING LI, GUANG YU ZHANG, BAOLI ZHU. (2011) Risk factors associated with fluoroquinolone-resistant tuberculosis in a Beijing tuberculosis referral hospital. Respirology 16:6, 918-925
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   Sujata Sharma, Mark A Yoder. (2011) New Weapons in the War on Tuberculosis. American Journal of Therapeutics 18:4, e101-e112
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   Yi Hu, Barun Mathema, Weibing Wang, Barry Kreiswirth, Weili Jiang, Biao Xu. (2011) Population-based investigation of fluoroquinolones resistant tuberculosis in rural eastern China. Tuberculosis 91:3, 238-243
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   Francesca Sánchez, José L. López Colomés, Elsa Villarino, Jacques Grosset. (2011) New drugs for tuberculosis treatment. Enfermedades Infecciosas y Microbiología Clínica 29, 47-56
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   Tun-Chieh Chen, Po-Liang Lu, Chun-Yu Lin, Wei-Ru Lin, Yen-Hsu Chen. (2011) Fluoroquinolones are associated with delayed treatment and resistance in tuberculosis: a systematic review and meta-analysis. International Journal of Infectious Diseases 15:3, e211-e216
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   Cheuk-Ming Tam, Wing-Wai Yew, Kwok-Yung Yuen. (2009) Treatment of multidrug-resistant and extensively drug-resistant tuberculosis: current status and future prospects. Expert Review of Clinical Pharmacology 2:4, 405-421
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    Alberto Matteelli, Giovanni Battista Migliori, Daniela Cirillo, Rosella Centis, Enrico Girard, Mario Raviglione. (2007) Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis : epidemiology and control. Expert Review of Anti-infective Therapy 5:5, 857-871
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    I. Escribano, J.C. Rodr&iacute;guez, B. Llorca, E. Garc&iacute;a-Pachon, M. Ruiz, G. Royo. (2007) Importance of the Efflux Pump Systems in the Resistance of <i>Mycobacterium tuberculosis</i> to Fluoroquinolones and Linezolid. Chemotherapy 53:6, 397-401
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