Isoniazid

CDC recommends 4-month regimen for drug-susceptible TB

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The CDC published a recommendation and interim guidance in MMWR for a 4-month regimen to treat patients aged 12 years or older with drug-susceptible pulmonary tuberculosis.

The regimen containing rifapentine, moxifloxacin, isoniazid and pyrazinamide was shown in a recent clinical trial to be noninferior to the standard 6-month regimen in curing drug-susceptible TB.

Source: Adobe Stock.
The CDC recommended a 4-month regimen as treatment for drug-susceptible pulmonary tuberculosis. Source: Adobe Stock.

“Clinical practice guidelines for treatment of drug-susceptible tuberculosis (TB) in the U.S. were published in 2016,” Wendy Carr, PhD, and colleagues in the CDC’s Division of Tuberculosis Elimination, wrote. “This interim guidance updates 2016 guidelines by recommending and providing implementation considerations for a novel 4-month daily treatment regimen.”

The recommendation follows results of an open-label phase 3 randomized, controlled trial that compared 4-month rifapentine-based regimens with a 6-month regimen of rifampin, isoniazid, pyrazinamide, and ethambutol.

The trial assessed outcomes among participants with newly diagnosed pulmonary TB at 34 sites in 13 countries — Brazil, China (Hong Kong), Haiti, India, Kenya, Malawi, Peru, South Africa, Thailand, Uganda, the United States, Vietnam, and Zimbabwe.

Overall, the researchers assessed 2,234 study participants 726 in the standard 6-month treatment control group, 756 in a group in which rifampin was replaced with rifapentine and ethambutol with moxifloxacin, and 752 in a group in which rifampin was replaced with rifapentine.

The study showed that rifapentine with moxifloxacin was noninferior to the control regimen (15.5% vs. 14.6% with an unfavorable outcome; 95% CI, 2.6 to 4.5) in the microbiologically eligible population and in the assessable population (11.6% vs. 9.6%; 95% CI, 1.1 to 5.1). Additionally, the study showed that rifapentine without moxifloxacin was not noninferior to the control in either the population (17.7% vs. 14.6 and 14.2% vs. 9.6%, respectively).

Based on these findings, the CDC recommended a 4-month regimen consisting of 8 weeks of daily treatment with rifapentine, isoniazid, pyrazinamide and moxifloxacin, followed by a continuation phase of 9 weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin in patients with drug-susceptible tuberculosis.

Carr and colleagues noted that the CDC does not recommend the regimen for people with body weight less than 40 kg; patients aged younger than 12 years; women who are pregnant or breastfeeding; patients with most types of suspected or documented extrapulmonary TB infection; people with known drug-drug interactions with any of the regimen medications; or patients infected with a baseline Mycobacterium tuberculosis isolate known or suspected to be resistant to isoniazid, pyrazinamide, rifampin or fluoroquinolones.

“Clinicians should carefully review a patient’s clinical history, concurrent medications, social determinants of health, and risk factors for adverse drug reactions when making the decision to use this regimen,” Carr and colleagues wrote.

Rifampicin and moxifloxacin for tuberculous meningitis.

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Ravina Ruslami and colleagues presented a study assessing pharmacokinetics, safety, and survival benefit of different treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting.1

Their findings that a treatment regimen containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease are important to note.

We agree with the authors that, on the basis of the small number of patients per group, clinical results should be interpreted carefully. To compensate for small group sizes, one could consider a different strategy with drug exposure as a continuous variable. Additionally, isoniazid concentrations should also be measured since isoniazid contributes to rapid culture conversion and penetrates well in cerebrospinal fluid. Receiver operating characteristic analysis could show the extent to which cumulative drug exposures of rifampicin, moxifloxacin, and isoniazid relate to outcome. Resultant potentially crucial values for positive treatment outcome could be detected and related to the antagonistic effect on cell kill as observed after co-administration of rifampicin and moxifloxacin in in vitro and in vivo studies.2, 3

Another consideration is the potential benefit of a higher oral dosage to reach similar drug exposure as achieved with intravenous dosing. The proposed alternative strategy to analyse the data would also compensate for the difference in drug exposure due to intravenous administration compared with oral dosing, especially in the presence of predisposing factors for poor drug absorption like HIV co-infection.

We therefore would like to encourage the authors to do further analyses of their data to generate additional hypotheses.

References

1 Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet infect Dis 2013; 13: 27-35. Summary | Full Text | PDF(279KB) |CrossRef | PubMed

2 Drusano GL, Sgambati N, Eichas A, Brown DL, Kulawy R, Louie A. The combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of Mycobacterium tuberculosis as determined in a hollow-fiber infection model. mBio 2010; 1: e00139. e00110 PubMed

3 Balasubramanian V, Solapure S, Gaonkar S, et al. Effect of coadministration of moxifloxacin and rifampin onMycobacterium tuberculosis in a murine aerosol infection model. Antimicrob Agents Chemother 2012; 56: 3054-3057. PubMed

Source:Lancet