Evidence map›Paper›PMID 22467670›Full record

SynthesisClinical infectious diseases : an official publication of the Infectious Diseases Society of America2012

Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy.

Jotam G Pasipanodya, Shashikant Srivastava, Tawanda Gumbo

Abstract readMeta-AnalysisRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 137 papers, 9 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
137citing papers in PubMed, 9 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

137 citing papers in PubMed, 9 syntheses or guidelines pooled it.

  1. Pooled it
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  6. A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2020
    Pooled it
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  9. A meta-analysis of self-administered vs directly observed therapy effect on microbiologic failure, relapse, and acquired drug resistance in tuberculosis patients.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2013
    Pooled it
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  12. Artificial intelligence-derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2018
    Trial
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  14. Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial.American journal of respiratory and critical care medicine · 2018
    Trial
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  20. HBV/HCV coinfection and anti-tuberculosis drug-induced liver injury: from risk assessment and exploration of mechanisms to preventive considerations.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2026
    Review

77 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

3 authors.

Jotam G PasipanodyaOffice of Global Health and Department of Medicine, University of Texas Southwestern Medical Center at Dallas, TX 75390-8507, USA.
Shashikant Srivastava
Tawanda Gumbo

Funding

PK-PD of combination antituberculosis therapy for suppression of drug-resistanceR01AI079497 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI GUMBO, TAWANDA · 2008 to 2011
$2.3M
NIAID NIH HHS R01 AI079497
6 · The paper itself

Abstract

backgroundUsing hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic.

methodsPreferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators.

resultsThirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI, .9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or small-study effects were observed for the outcomes evaluated.

conclusionsPharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.

Indexed as

Drug Resistance, BacterialAntitubercular AgentsHumansIsoniazidMycobacterium tuberculosisProspective StudiesRandomized Controlled Trials as TopicRecurrenceSputumTreatment FailureTuberculosis, Multidrug-ResistantAntitubercular AgentsIsoniazid

Identifiers

PMID22467670
PMCPMC3491771

What OpenQuestion holds

Textmetadata
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.