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Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis.

ABSTRACT: Over the last 10 years, interest in pediatric tuberculosis (TB) has increased dramatically, together with increased funding and research. We have a better understanding of the burden of childhood TB as well as a better idea of how to diagnose it. Our appreciation of pathophysiology is improved and with it investigators are beginning to consider pediatric TB as a heterogeneous entity, with different types and severity of disease being treated in different ways. There have been advances in how to treat both TB infection and TB disease caused by both drug-susceptible as well as drug-resistant organisms. Two completely novel drugs, bedaquiline and delamanid, have been developed, in addition to the use of older drugs that have been re-purposed. New regimens are being evaluated that have the potential to shorten treatment. Many of these drugs and regimens have first been investigated in adults with children an afterthought, but increasingly children are being considered at the outset and, in some instances studies are only conducted in children where pediatric-specific issues exist.

SUBMITTER: Seddon JA

PROVIDER: S-EPMC5471710 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis.

Seddon James A JA Schaaf H Simon HS

Pneumonia (Nathan Qld.) 20161124

Over the last 10 years, interest in pediatric tuberculosis (TB) has increased dramatically, together with increased funding and research. We have a better understanding of the burden of childhood TB as well as a better idea of how to diagnose it. Our appreciation of pathophysiology is improved and with it investigators are beginning to consider pediatric TB as a heterogeneous entity, with different types and severity of disease being treated in different ways. There have been advances in how to ...[more]

PMID: 28702299

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Project description:BackgroundPatients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.MethodsIn an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.ResultsA total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.ConclusionsThe combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

Project description:BACKGROUND:Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS:We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS:By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P=0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS:Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.).

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Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis.

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Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis.

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