Gatifloxacin Pharmacokinetics/Pharmacodynamics-based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis. 2018

Devyani Deshpande, and Jotam G Pasipanodya, and Shashikant Srivastava, and Paula Bendet, and Thearith Koeuth, and Sujata M Bhavnani, and Paul G Ambrose, and Wynand Smythe, and Helen McIlleron, and Guy Thwaites, and Mourad Gumusboga, and Armand Van Deun, and Tawanda Gumbo
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.

Gatifloxacin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The optimal dose is unknown. We performed a 28-day gatifloxacin hollow-fiber system model of tuberculosis (HFS-TB) study in order to identify the target exposures associated with optimal kill rates and resistance suppression. Monte Carlo experiments (MCE) were used to identify the dose that would achieve the target exposure in 10000 adult patients with meningeal or pulmonary MDR-TB. The optimal doses identified were validated using probit analyses of clinical data from 2 prospective clinical trials of patients with pulmonary and meningeal tuberculosis. Classification and regression-tree (CART) analyses were used to identify the gatifloxacin minimum inhibitory concentration (MIC) below which patients failed or relapsed on combination therapy. The target exposure associated with optimal microbial kill rates and resistance suppression in the HFS-TB was a 0-24 hour area under the concentration-time curve-to-MIC of 184. MCE identified an optimal gatifloxacin dose of 800 mg/day for pulmonary and 1200 mg/day for meningeal MDR-TB, and a clinical susceptibility breakpoint of MIC ≤ 0.5 mg/L. In clinical trials, CART identified that 79% patients failed therapy if MIC was >2 mg/L, but 98% were cured if MIC was ≤0.5 mg/L. Probit analysis of clinical data demonstrated a >90% probability of a cure in patients if treated with 800 mg/day for pulmonary tuberculosis and 1200 mg/day for meningeal tuberculosis. Doses ≤400 mg/day were suboptimal. Gatifloxacin doses of 800 mg/day and 1200 mg/day are recommended for pulmonary and meningeal MDR-TB treatment, respectively. Gatifloxacin has a susceptible dose-dependent zone at MICs 0.5-2 mg/L.

UI MeSH Term Description Entries
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009010 Monte Carlo Method In statistics, a technique for numerically approximating the solution of a mathematical problem by studying the distribution of some random variable, often generated by a computer. The name alludes to the randomness characteristic of the games of chance played at the gambling casinos in Monte Carlo. (From Random House Unabridged Dictionary, 2d ed, 1993) Method, Monte Carlo
D009169 Mycobacterium tuberculosis A species of gram-positive, aerobic bacteria that produces TUBERCULOSIS in humans, other primates, CATTLE; DOGS; and some other animals which have contact with humans. Growth tends to be in serpentine, cordlike masses in which the bacilli show a parallel orientation. Mycobacterium tuberculosis H37Rv
D011446 Prospective Studies Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. Prospective Study,Studies, Prospective,Study, Prospective
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077734 Gatifloxacin A fluoroquinolone antibacterial agent and DNA TOPOISOMERASE II inhibitor that is used as an ophthalmic solution for the treatment of BACTERIAL CONJUNCTIVITIS. 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid,AM 1155,AM-1155,BMS-206584,CG 5501,Gatifloxacine,Tequin,Zymar,BMS 206584,BMS206584
D000995 Antitubercular Agents Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. Anti-Tuberculosis Agent,Anti-Tuberculosis Agents,Anti-Tuberculosis Drug,Anti-Tuberculosis Drugs,Antitubercular Agent,Antitubercular Drug,Tuberculostatic Agent,Tuberculostatic Agents,Antitubercular Drugs,Agent, Anti-Tuberculosis,Agent, Antitubercular,Agent, Tuberculostatic,Anti Tuberculosis Agent,Anti Tuberculosis Agents,Anti Tuberculosis Drug,Anti Tuberculosis Drugs,Drug, Anti-Tuberculosis,Drug, Antitubercular
D014390 Tuberculosis, Meningeal A form of bacterial meningitis caused by MYCOBACTERIUM TUBERCULOSIS or rarely MYCOBACTERIUM BOVIS. The organism seeds the meninges and forms microtuberculomas which subsequently rupture. The clinical course tends to be subacute, with progressions occurring over a period of several days or longer. Headache and meningeal irritation may be followed by SEIZURES, cranial neuropathies, focal neurologic deficits, somnolence, and eventually COMA. The illness may occur in immunocompetent individuals or as an OPPORTUNISTIC INFECTION in the ACQUIRED IMMUNODEFICIENCY SYNDROME and other immunodeficiency syndromes. (From Adams et al., Principles of Neurology, 6th ed, pp717-9) Meningitis, Tuberculous,TB Meningitis,Tubercular Meningitis,Tuberculosis Meningitis,Tuberculous Hypertrophic Pachymeningitis,Hypertrophic Pachymeningitides, Tuberculous,Hypertrophic Pachymeningitis, Tuberculous,Meningeal Tuberculoses,Meningeal Tuberculosis,Meningitides, Tubercular,Meningitides, Tuberculosis,Meningitides, Tuberculous,Meningitis, Tubercular,Meningitis, Tuberculosis,Pachymeningitides, Tuberculous Hypertrophic,Pachymeningitis, Tuberculous Hypertrophic,TB Meningitides,Tubercular Meningitides,Tuberculoses, Meningeal,Tuberculosis Meningitides,Tuberculous Hypertrophic Pachymeningitides,Tuberculous Meningitides,Tuberculous Meningitis
D014397 Tuberculosis, Pulmonary MYCOBACTERIUM infections of the lung. Pulmonary Consumption,Pulmonary Phthisis,Pulmonary Tuberculoses,Pulmonary Tuberculosis,Tuberculoses, Pulmonary,Consumption, Pulmonary,Consumptions, Pulmonary,Phthises, Pulmonary,Phthisis, Pulmonary,Pulmonary Consumptions,Pulmonary Phthises

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