Gatifloxacin in combination with rifampicin in a murine tuberculosis model

Cynamon, Michael H.; Sklaney, Mary; Shoen, Carolyn

doi:10.1093/jac/dkm200

Cited by 17 publications

(8 citation statements)

References 10 publications

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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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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

View full text Add to dashboard Cite

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“…Gatifloxacin distributes widely throughout the body (1), achieving MICs for Mycobacterium tuberculosis observed in vitro of 0.031 to 0.5 g/ml (2,3,4), and demonstrates strong bactericidal activity in the mouse model (2,5). Furthermore, gatifloxacin displays excellent early bactericidal activity (EBA), only slightly lower than that of isoniazid (6); replacing ethambutol with gatifloxacin in the standard first-line regimen resulted in accelerated killing of M. tuberculosis in the sputum of patients with pulmonary tuberculosis (7).…”

mentioning

confidence: 99%

Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations

Smythe

Merle

Rustomjee

et al. 2013

Antimicrob Agents Chemother

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A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of >125 for the area under the concentration time curve to infinity (AUC 0 -ؕ ) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC 0 -ؕ of 41.2 g · h/ml decreased on average by 14.3% (90% confidence interval [CI], ؊90.5% to ؉61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of >125 only when the MIC was <0.125 g/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.) F luoroquinolones represent a promising class of drug for the treatment of tuberculosis. Gatifloxacin distributes widely throughout the body (1), achieving MICs for Mycobacterium tuberculosis observed in vitro of 0.031 to 0.5 g/ml (2, 3, 4), and demonstrates strong bactericidal activity in the mouse model (2, 5). Furthermore, gatifloxacin displays excellent early bactericidal activity (EBA), only slightly lower than that of isoniazid (6); replacing ethambutol with gatifloxacin in the standard first-line regimen resulted in accelerated killing of M. tuberculosis in the sputum of patients with pulmonary tuberculosis (7). A single-dose crossover study in healthy volunteers showed a reduction in the elimination rate of gatifloxacin resulting in a 14% increase in the area under the concentration time curve to infinity (AUC 0 -ϱ ) when it was given together with rifampin, isoniazid, and pyrazinamide (8). Reports of dysglycemia related to the use of gatifloxacin in elderly patients with renal insufficiency (9, 10, 11, 12) have raised concerns that pharmacokinetic interactions may lead to an increased risk of toxicity related to higher gatifloxacin exposure. On the other hand, in vitro and in vivo studies suggest a target ratio of Ն125 for the free drug area under the concentration versus time curve to MIC (fAUC/MIC) for maximal bactericidal effect and prevention of resistance to fluoroquinolones (13...

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“…Mice received 250 mg/L of isoniazid (isonicotinic acid hydrazine; INH, Sigma) and 100 mg/L of rifampin (rifampicin; RIF, Sigma) in the drinking water for 12 weeks. The protocol was modified [] and based on consumption of 6 mL of water per mouse per day []. The targeted doses were 25–50 mg/kg/day for INH and 10–20 mg/kg/day for RIF, which are below the carcinogenic [] or toxic [] levels.…”

Section: Methodsmentioning

confidence: 99%

CBA/J mice generate protective immunity to soluble Ag85 but fail to respond efficiently to Ag85 during natural Mycobacterium tuberculosis infection

et al. 2012

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Summary In CBA/J mice, susceptibility to Mycobacterium tuberculosis (M.tb) is associated with low interferon-gamma (IFN-γ) responses to antigens (Antigen 85 (Ag85) and Early Secreted Antigenic Target-6 (ESAT-6)) that have been defined as immunodominant. Here, we asked whether the failure of CBA/J mice to recognize Ag85 is a consequence of M.tb infection or whether CBA/J mice have a general defect in generating specific T cell responses to this protein antigen. We compared CBA/J mice during primary M.tb infection, Ag85 vaccination followed by M.tb challenge, or M.tb memory immune mice for their capacity to generate Ag85-specific IFN-γ responses and to control M.tb infection. CBA/J mice did not respond efficiently to Ag85 in the context of natural infection or re-infection. In contrast, CBA/J mice could generate Ag85-specific IFN-γ responses and protective immunity when this antigen was delivered as a soluble protein. Our data indicate that although M.tb infection of CBA/J mice does not drive an Ag85 response, they can fully and protectively respond to Ag85 if it is delivered as a vaccine. The data from this experimental model suggest that the Ag85-containing vaccines in clinical trials should protect M.tb susceptible humans.

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Gatifloxacin in combination with rifampicin in a murine tuberculosis model

Cited by 17 publications

References 10 publications

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

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

Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations

CBA/J mice generate protective immunity to soluble Ag85 but fail to respond efficiently to Ag85 during natural Mycobacterium tuberculosis infection

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