Emergence of Fluoroquinolone Resistance in Mycobacterium tuberculosis during Continuously Dosed Moxifloxacin Monotherapy in a Mouse Model (original) (raw)
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Antimicrobial Agents and Chemotherapy, 2010
The prevalence of extensively drug-resistant tuberculosis (XDR-TB), defined as TB that is resistant to isoniazid, rifampin, fluoroquinolones, and aminoglycosides, is rising worldwide. The extent of Mycobacterium tuberculosis resistance to fluoroquinolones depends on the mutation in the DNA gyrase, the only target of fluoroquinolones. The MIC of moxifloxacin, the most active fluoroquinolone against M. tuberculosis, may be lower than its peak serum level for some ofloxacin-resistant strains of Mycobacterium tuberculosis. Therefore, if the MIC of moxifloxacin is lower than its peak serum level, it may be effective against XDR-TB. Our objective was to determine the efficacy of moxifloxacin in treating ofloxacin-resistant TB. We selected isogenic fluoroquinolone-resistant mutants of M. tuberculosis H37Rv in vivo. We infected Swiss mice with either wild-type H37Rv or one of three mutant strains with different MICs that are commonly seen in clinical practice. The MICs of the mutant strains ranged from below to above the peak moxifloxacin level seen in humans (3 g/ml). Each mouse was treated with one of four moxifloxacin doses for 1 month. Moxifloxacin was effective against mutant strain GyrB D500N, with the lowest MIC (0.5 g/ml), when the standard dose was doubled. Moxifloxacin reduced mortality in mice infected with mutant strain GyrA A90V with an intermediate MIC (2 g/ml). However, it had no impact on the mutant strain GyrA D94G with the highest MIC (4 g/ml). Our study underscores current WHO recommendations to use moxifloxacin when there is resistance to early-generation fluoroquinolones such as ofloxacin, restricting this recommendation to strains with moxifloxacin MICs of less than or equal to 2 g/ml.
Antimicrobial Agents and Chemotherapy, 1995
To examine the mechanism of resistance to fluoroquinolones in Mycobacterium tuberculosis, we selected spontaneous fluoroquinolone-resistant mutants from a susceptible strain, H37Rv, and studied the susceptibilities of these mutants and two fluoroquinolone-resistant clinical isolates (A-382, A-564) to various fluoroquinolones and to isoniazid and rifampin. Furthermore, since mutations within the quinolone resistance-determining region of the structural gene encoding the A subunit of DNA gyrase are the most common mechanism of acquired resistance, we amplified this region by PCR and compared the nucleotide sequences of the fluoroquinolone-resistant strains with that of the susceptible strain. Fluoroquinolone-resistant mutants of H37Rv appeared at frequencies of 2 x 10(-6) to 1 x 10(-8). For three mutants selected on ciprofloxacin, ofloxacin, and sparfloxacin, respectively, and the two clinical isolates, MICs of ciprofloxacin and ofloxacin were as high as 16 micrograms/ml, and those of...
Fluoroquinolone Resistance in Mycobacterium tuberculosis
American Journal of Respiratory and Critical Care Medicine, 2009
Rationale: Fluoroquinolones are the most commonly prescribed antibiotic class in the United States. They have the potential to become first-line antituberculosis therapy, but the effect of fluoroquinolone use on fluoroquinolone resistance in Mycobacterium tuberculosis is not well characterized. Objectives: To determine the prevalence of and risk factors for fluoroquinolone-resistant tuberculosis in a large United States population. Methods: We identified all people with culture-confirmed tuberculosis enrolled in TennCare (Medicaid) and reported to the Tennessee Department of Health from January 2002 to December 2006. People with fluoroquinolone-resistant M. tuberculosis isolates (cases) were compared with those with susceptible isolates (control subjects). Fluoroquinolone resistance was determined by agar proportion using ofloxacin 2 mg/ml. Outpatient fluoroquinolone exposure in the 12 months before tuberculosis diagnosis was ascertained from TennCare pharmacy data. Measurements and Main Results: Of 640 study patients, 116 (18%) had fluoroquinolone exposure in the 12 months before diagnosis, and 16 (2.5%; 95% confidence interval [CI], 1.4-4.0%) M. tuberculosis isolates were fluoroquinolone resistant. Among the 54 patients with more than 10 days of fluoroquinolone exposure, 7 (13%) had fluoroquinolone resistance. In multivariable logistic regression analyses using propensity score to control for age, sex, race, HIV serostatus, and site of disease, more than 10 days of fluoroquinolone exposure before tuberculosis diagnosis was associated with fluoroquinolone resistance (odds ratio 7.0; 95% CI, 2.3-20.6; P 5 0.001). Fluoroquinolone exposure for more than 10 days that occurred more than 60 days before tuberculosis diagnosis was associated with the highest risk of resistance (20.8%; odds ratio 17.0; 95% CI, 5.1-56.8; P , 0.001 compared with no exposure). Conclusions: Overall, fluoroquinolone resistance was relatively low. However, receipt of fluoroquinolones for more than 10 days, particularly more than 60 days before tuberculosis diagnosis, was associated with a high risk of fluoroquinolone-resistant tuberculosis.
Fluoroquinolone Resistance in Mycobacterium tuberculosis and Mutations in gyrA and gyrB
Antimicrobial Agents and Chemotherapy, 2009
This study evaluated cross-resistance of Mycobacterium tuberculosis strains to ofloxacin, moxifloxacin, and gatifloxacin and investigated the presence of mutations in gyrA and gyrB. Fluoroquinolone susceptibilities were determined for 41 M. tuberculosis strains by the proportion method on 7H11, and MICs were determined by the resazurin microtiter assay. Forty strains shared the same resistance results for the three fluoroquinolones. However, one strain, with an Asn-533 3 Thr mutation in gyrB, was susceptible to ofloxacin but resistant to moxifloxacin and gatifloxacin.
Antimicrobial Agents and Chemotherapy, 2011
DC-159a is a new fluoroquinolone with more potent in vitro activity than available fluoroquinolones against both drug-susceptible and fluoroquinolone-resistant Mycobacterium tuberculosis . Here, we report that DC-159a displays pharmacokinetics similar to those of moxifloxacin yet is more active than moxifloxacin during both the initial and continuation phases of treatment in a murine model. These results warrant further preclinical evaluation of DC-159a in selected drug combinations against drug-susceptible and fluoroquinolone-resistant tuberculosis.
Fluoroquinolone Resistance in Patients with Newly Diagnosed Tuberculosis
Clinical Infectious Diseases, 2003
Fluoroquinolones are widely used for the treatment of bacterial infections and are also second-line therapy for tuberculosis. However, fluoroquinolone resistance in patients with newly diagnosed cases of tuberculosis is not routinely assessed. We performed in vitro susceptibility testing of Mycobacterium tuberculosis to fluoroquinolones for all culture-confirmed tuberculosis cases in adults that were diagnosed at Johns Hopkins Hospital (Baltimore) between January 1998 and March 2002. Fifty-five patients were included in the study; 19 received fluoroquinolone monotherapy before the initiation of antituberculosis therapy. Two of 55 M. tuberculosis isolates (4%; 95% CI, 1%-13%) had decreased susceptibility to fluoroquinolones, including 2 of 19 of those from patients who had received fluoroquinolones (11%; 95% CI, 1%-33%) and 0 of 36 isolates from those who had not (95% CI, 0%-10%). The 2 fluoroquinolone-resistant M. tuberculosis strains were both from patients with acquired immunodeficiency syndrome and a CD4 + lymphocyte count of !50 cells/mm 3. The incidence of M. tuberculosis fluoroquinolone resistance in this small sample of patients with newly diagnosed tuberculosis was high, particularly among patients with prior fluoroquinolone exposure. Fluoroquinolones are broad-spectrum antimicrobial agents that have been used with increasing frequency over the past decade. As of August 2002, fluoroquinolones accounted for 11% of all antibiotic sales in the United States (IMS Health, personal communication). The particular advantages of fluoroquinolones are their high bioavailability, convenient dosing intervals, and efficacy against a wide array of bacterial infections, including community-acquired pneumonia [1, 2]. Fluor
Clinical Epidemiology and Global Health
Background: The phenomenon of Drug Resistant Tuberculosis (DRTB) has been evolving aggressively and is posing great threat to tuberculosis control programs worldwide. But what really is fueling drug resistance in high disease burden countries apart from other well known risk factors, with this intent in mind the present study was developed and carried out to. The aim was to capture the presence of Fluoroquinolone (FQ) mono-resistance among drug-sensitive TB cases. Methods: A total of 1280 sputum smear-positive patients were enrolled in the study and were subjected for Drug Susceptibility Testing (DST) using First-Line Drugs (FLD's; Rifampicin, Streptomycin, Isoniazid and Ethambutol) using liquid culture DST and Line Probe Assay. These samples were further subjected to second-line drugs DST (ofloxacin and kanamycin) and DNA sequencing to confirm FQ mono-resistance. Results: The occurrence of FQ mono-resistance among FLD sensitive cases was found to be 3.2% (35/1099). Xpert MTB/RIF assay and rpoB gene sequencing were showed 100% concordance with FLD DST. A total of 35 FQ mono-resistant isolates were further sequenced for gyrA, gyrB and rrs genes. The gene sequencing was found to be in agreement with the DST results for 34 (3.1%) isolates with gyrA and gyrB genes. Conclusion: Presence of FQ resistance among drug sensitive TB cases is a red flag sign. The findings of the present study suggest that, second-line DST should be routinely performed not only for drug-resistant cases but also for drug-sensitive cases so as to capture prevailing true drug resistance at an initial stage.
The role of fluoroquinolones in the treatment of Tuberculosis
The inability to use powerful antituberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug regimens are being investigated for pulmonary TB to counteract emergence of drug resistance. Intensified regimens with high-dose anti-TB drugs during the first weeks of treatment are being investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin, gatifloxacin and levofloxacin are seen as core agents in case of resistance or intolerance against first-line anti-TB drugs. However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing could be optimized. We prepared a comprehensive summary of clinical trials investigating the outcome of TB regimens based on moxifloxacin, gatifloxacin and levofloxacin in recent years. In the majority of clinical trials, treatment success was not in favour of these drugs compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into the armamentarium of drug-development tools is needed to clarify the role of moxifloxacin, gatifloxacin and levofloxacin for TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability advocates for concentration-guided dosing in patients at risk for too low a drug-exposure.
The Journal of Infectious Diseases, 2004
Background. Moxifloxacin is a quinolone antimicrobial that has potent activity against Mycobacterium tuberculosis. To optimize moxifloxacin dose and dose regimen, pharmacodynamic antibiotic-exposure targets associated with maximal microbial kill and complete suppression of drug resistance in M. tuberculosis must be identified. Methods. We used a novel in vitro pharmacodynamic infection model of tuberculosis in which we exposed M. tuberculosis to moxifloxacin with a pharmacokinetic half-life of decline similar to that encountered in humans. Data obtained from this model were mathematically modeled, and the drug-exposure breakpoint associated with the suppression of drug resistance was determined. Monte-Carlo simulations were performed to determine the probability that 10,000 clinical patients taking different doses of moxifloxacin would achieve or exceed the drugexposure breakpoint needed to suppress resistance to moxifloxacin in M. tuberculosis. Results. The ratio of the moxifloxacin-free (non-protein-bound) area under the concentration-time curve from 0 to 24 h to the minimum inhibitory concentration associated with complete suppression of the drug-resistant mutant population was 53. For patients taking moxifloxacin doses of 400, 600, or 800 mg/day, the calculated target-attainment rates to suppress drug resistance were 59%, 86%, and 93%, respectively. Conclusion. A moxifloxacin dose of 800 mg/day is likely to achieve excellent M. tuberculosis microbial kill and to suppress drug resistance. However, tolerability of this higher dose is still unknown.