The Early Bactericidal Activity of Isoniazid Related to Its Dose Size in Pulmonary Tuberculosis

Donald, Peter R.; Sirgel, F A; Botha, F J; Seifart, H. I.; Parkin, D. P.; Vandenplas, Michel L.; Wal, B. W. Van de; Maritz, J. S.; Mitchison, D.A.

doi:10.1164/ajrccm.156.3.9609132

Cited by 111 publications

(86 citation statements)

References 14 publications

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“…In accordance with this finding, increasing the daily INH dose up to 600 mg gave little increase in bactericidal effects, even in FA subjects, when the MIC was at the lower end of the MIC range. Those results are in accordance with clinical studies that found no increase in the EBA when the INH dose was increased beyond 150 to 300 mg per day (6,15,38). While those studies did not report the MICs of isolated strains of M. tuberculosis, we may hypothesize that those MICs were relatively low.…”

Section: Discussionsupporting

confidence: 89%

“…However, the need for INH dose optimization and adjustment for acetylator status is controversial. Clinical studies that assessed the EBA values with various doses of INH found that the EBA seems to plateau at 300 mg daily, as no significant increase in the EBA was observed with larger INH doses (6,15,38). However, it was shown that the EBA of INH in fast acetylators was significantly lower than that in slow acetylators (15).…”

Section: Discussionmentioning

confidence: 99%

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Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Lalande

Bourguignon

Bihari

et al. 2015

Antimicrob Agents Chemother

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Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Lalande

Bourguignon

Bihari

et al. 2015

Antimicrob Agents Chemother

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“…In an assessment of early bactericidal activity of isoniazid, Donald et al observed that the CFU counts of baseline sputum specimens were associated with the patient's radiographic extent of disease (P Ͻ 0.001) and cavity size (P Ͻ 0.001) (6). We observed a correlation between severity of disease in chest X-ray and both the presence of cavities and CFU counts, thus confirming this finding.…”

supporting

confidence: 87%

Cavitary Disease and Quantitative Sputum Bacillary Load in Cases of Pulmonary Tuberculosis

et al. 2007

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“…bactericidal activity or EBA) (1)(2)(3)(4)(5). There is, however, no known relationship between EBA and the outcome of treatment.…”

mentioning

confidence: 99%

Predicting the Outcome of Therapy for Pulmonary Tuberculosis

Wallis

Perkins

Phillips

et al. 2000

Am J Respir Crit Care Med

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Patients vary considerably in their response to treatment of pulmonary tuberculosis. Although several studies have indicated that adverse outcomes are more likely in those patients with delayed sputum sterilization, few tools are available to identify those patients prospectively. In this study, multivariate models were developed to predict the response to therapy in a prospectively recruited cohort of 42 HIV-uninfected subjects with drug-sensitive tuberculosis. The cohort included 2 subjects whose initial response was followed by drug-sensitive relapse. The total duration of culture positivity was best predicted by a model that included sputum M. tuberculosis antigen 85 concentration on Day 14 of therapy, days-to-positive in BACTEC on Day 30, and the baseline radiographic extent of disease (R = 0.63). A model in which quantitative AFB microscopy replaced BACTEC also performed adequately (R = 0.58). Both models predicted delayed clearance of bacilli in both relapses (> 85th percentile of all subjects) using information collected during the first month of therapy. Stratification of patients according to anticipated response to therapy may allow TB treatment to be individualized, potentially offering superior outcomes and greater efficiency in resource utilization, and aiding in the conduct of clinical trials.There is substantial variability in the response to therapy for pulmonary tuberculosis, even in those patients with fully drug sensitive isolates. In some patients, bacilli are killed rapidly and cleared quickly from sputum. In others, viable organisms persist for many weeks or months, despite multidrug treatment. In yet others, bacilli are cleared, only to reappear after therapy is stopped. These observations form the basis for the definitions of treatment failure and relapse, respectively. The causes of this phenomenon are not well understood, but they may involve mycobacterial and host biologic factors as well as host behavioral factors.The search for tools to monitor tuberculosis therapy and predict outcome is made particularly complex by the observation that mycobacterial killing is not a single uniform process. Most actively replicating bacilli are killed rapidly during the first 1 to 2 wk of therapy. This phase of treatment can be measured by quantitative sputum culture (early HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript bactericidal activity or EBA) (1-5). There is, however, no known relationship between EBA and the outcome of treatment. Prolonged treatment is required to eradicate persisting organisms with reduced or otherwise altered metabolic activity. Nonreplicating bacilli show reduced susceptibility to the bactericidal activities of antimycobacterial drugs (6, 7). This later, sterilizing phase of therapy appears to be distinct from the first, based in part on the differential activities of antimycobacterial drugs during the two phases.Two studies indicate that, in contrast to EBA, the time to sterilization is an important determinant of outco...

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The Early Bactericidal Activity of Isoniazid Related to Its Dose Size in Pulmonary Tuberculosis

Cited by 111 publications

References 14 publications

Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Population Modeling and Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Isoniazid in Lungs

Cavitary Disease and Quantitative Sputum Bacillary Load in Cases of Pulmonary Tuberculosis

Predicting the Outcome of Therapy for Pulmonary Tuberculosis

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