World Health Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or untapped potential?
BACKGROUND
Treatment of multidrug-resistant or extensively drug-resistant tuberculosis (DR-tuberculosis) is challenging because commonly used second-line drugs are poorly efficacious and highly toxic. Although World Health Organization group 5 drugs are not recommended for routine use because of unclear activity, some may have untapped potential as more efficacious or better tolerated alternatives.


METHODS
We conducted an exhaustive review of in vitro, animal, and clinical studies of group 5 drugs to identify critical research questions that may inform their use in current treatment of DR-tuberculosis and clinical trials of new DR-tuberculosis regimens.


RESULTS
Clofazimine may contribute to new short-course DR-tuberculosis regimens. Beta-lactams merit further evaluation-specifically optimization of dose and schedule. Linezolid appears to be effective but is frequently discontinued due to toxicity. Thiacetazone is too toxic to warrant further evaluation. Mycobacterium tuberculosis has intrinsic inducible resistance to clarithromycin.


CONCLUSIONS
Clofazimine and beta-lactams may have unrealized potential in the treatment of DR-tuberculosis and warrant further study. Serious toxicities or intrinsic resistance limit the utility of other group 5 drugs. For several group 5 compounds, better understanding of structure-toxicity relationships may lead to better-tolerated analogs.
Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. kdooley1@jhmi.edu
Kelly E
KE
Dooley
Ekwaro A
EA
Obuku
Nadza
N
Durakovic
Vera
V
Belitsky
Carole
C
Mitnick
Eric L
EL
Nuermberger
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014944:World Health Organization
D000995:Antitubercular Agents