Moxifloxacin and Gatifloxacin in an Acid Model of Persistent<i>Mycobacterium tuberculosis</i>

Kubendiran, G; Paramasivan, C. N.; Sulochana, S.; Mitchison, D.A.

doi:10.1179/joc.2006.18.6.617

Cited by 28 publications

(17 citation statements)

References 13 publications

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“…However, true antagonism between the standard drugs was never observed, and HRZ always showed equivalent or better activity than RZ. Similar to our results, other investigators using models of in vitro (23) and in vivo combination drug efficacy experiments have failed to find antagonism (9). Others have also described better or equivalent activity of HRZ versus RZ (20).…”

Section: Discussionsupporting

confidence: 82%

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Groote

Gilliland

Wells

et al. 2011

Antimicrob Agents Chemother

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Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.For the first time in many years, there is a portfolio of promising new compounds at every level of tuberculosis (TB) drug discovery and development (4; www.tballiance.org). However, careful selection of new drug candidates is imperative, and efficient screening models for new drugs, including pertinent animal models, need to be further developed and studied. Preclinical testing in animals of newly discovered agents alone, and in combination with new and old agents, prior to being tested in humans is a crucial but lengthy process. These drug regimens include agents that provide bactericidal activities against rapidly growing bacilli, but they especially aim to include those that possess potent sterilizing activities and hence prevent relapse (8). The most commonly used animal species in TB drug development is the mouse, mainly because of economical and practical reasons, but also because of the limited requirement of compound (26).Various mouse Mycobacterium tuberculosis infection models are utilized by both industry and academia, and they differ in the route of infection with M. tuberculosis, inoculum and strain of M. tuberculosis, strain of mice, timing of the start of treatment after infection, the length of treatment, etc. A model where therapy is started immediately after in...

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Section: Discussionsupporting

confidence: 82%

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Groote

Gilliland

Wells

et al. 2011

Antimicrob Agents Chemother

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“…In vitro studies and studies in mice showed improved activity of rifampin and isoniazid when gatifloxacin was added and even more when the regimen also included pyrazinamide (26,81,87). Ethambutol interfered with gatifloxacin in vitro as it did with moxifloxacin: it caused a remarkable increase in the MIC 90 of gatifloxacin (87).…”

Section: Ii) Gatifloxacin (A) Mechanism Of Actionmentioning

confidence: 99%

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Boogaard

Kibiki

Kisanga

et al. 2009

Antimicrob Agents Chemother

216

132

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2One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENTThere are several major problems associated with the currently available TB treatment. First, the duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease (168). Second, adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence (19,168). Third, the increasing incidence of multidrug-resistant (MDR; resistance to at least rifampin and isoniazid) and extensively drug-resistant (XDR; MDR resistance plus resistance to a fluoroquinolone and an aminoglycoside) TB is a serious concern. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure) (175). The prevalence of MDR TB in new TB cases ranged from 0% in some Western European countries to more than 22% in Azerbaijan (2002 to 2007 survey); 14 of 72 participating countries reported an MDR TB prevalence of more than 5% (177). Second-line drugs for drug-resistant TB are not available everywhere and are less effective, more toxic, and require longer use than first-line drugs (61). Fourth, coinfection of TB and HIV is a problem by itself. Combined treatment of TB and HIV involves a high pill count with associated adherence problems, overlapping toxicity profiles of the antiretroviral and anti-TB drugs, drug interactions between rifampin and the antiretroviral protease inhibitors, and the risk of immune reconstitution syndrome (104). Fifth, prophylactic therapy of latent TB (TB infection without symptoms) with isoniazid is also associated with problems of nonadherence (180). Attempts to shorten treatment with alternative drugs resulted in severe adverse events (64,150,155).The World Health Organization (WHO) has developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources (49). In addition, TB diagnosis in the DOTS strategy is based on sputum microscopy, rather than sputum culture (173). Only advanced pulmonary TB is detected by sputum...

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“…The MICs of gatifloxacin against M. tuberculosis range from 0.2 to 0.5 mg/l (Rodriguez et al 2002). In vitro studies and studies in mice showed improved activity of rifampin and isoniazid when gatifloxacin was added, and even more efficacy was noted when the regimen also included pyrazinamide (Kubendiran et al 2006). A multicenter trial is currently enrolling patients at five locations in Africa (Umubyeyi et al 2007).…”

Section: Moxifloxacin and Gatifloxacinmentioning

confidence: 99%

Development of New Anti-tuberculosis Drug Candidates

Shi

Sugawara

2010

Tohoku J. Exp. Med.

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Moxifloxacin and Gatifloxacin in an Acid Model of PersistentMycobacterium tuberculosis

Cited by 28 publications

References 13 publications

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Development of New Anti-tuberculosis Drug Candidates

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