Nonsteroidal antiinflammatory drugs for adjunctive tuberculosis treatment.

Tuberculosis continues to cause 1.4 million deaths annually despite effective treatment being available since the 1970s. The standard 4-drug tuberculosis treatment regimen involving isoniazid, rifampicin, pyrazinamide, and ethambutol achieves 90%cure rates in programmatic settings [1]. Mycobacterium tuberculosis bacilli are difficult to eradicate since they exist in a spectrum of replication states, from metabolically active, “rapid” replicators to nearly “dormant” nonreplicating persisters. Thus, treatment is required for a duration of at least 6 months in 2 phases: a 2-month intensive phase involving all 4 drugs and a 4-month continuation phase involving rifampicin and isoniazid. Major challenges for tuberculosis control programs include poor compliance, resulting in the emergence of multidrug-resistant M. tuberculosis strains, which require the use of more toxic second-line drugs for at least 24 months [1]; problems also arise from failures in drug supply and from drug intolerance. Shortening of the tuberculosis treatment period for both drugsusceptible and drug-resistant tuberculosis would greatly improve tuberculosis management and infection control. Immunotherapy has been considered as a possible approach toward shortening the duration of chemotherapy, with a wide range of cytokines or their inhibitors and chemical or biological immunomodulatory compounds being explored [2]. However, the factors that determine the replication rate ofM. tuberculosis and synergize or antagonize the effectiveness of mycobactericidal drugs remain poorly understood. Efforts at developing new drugs that act on replicating populations of M. tuberculosis, which thrive under the influence of nitric oxide and hypoxia, identified rhodanines [3]. Postchemotherapy relapse was shown to require cyclosporine-sensitive and genetically influenced host immunity, which develops early after infection [4]. Such a relapse can be alleviated by the immunomodulatory agent muramyl dipeptide [5] or by passive antibody, combined with interferon γ (IFN-γ) and anti-interleukin 2 treatment [6]. Recently, an antiinflammatory drug, oxyphenbutazone, was found to be cidal against both replicating and dormant forms ofM. tuberculosis [7]. Adjunct treatment for tuberculosis in experimentalmousemodels, using generic, nonsteroidal antiinflammatory and analgesic drugs (NSAIDs), showed that diclofenac (2-[2,6-dichloranilino] phenylacetic acid) inhibited colony-forming units in spleen and liver [8]. Further synergistic activity was observed in combination with streptomycin. Aspirin and ibuprofen (iso-butyl-propanoic-phenolic acid) were reported to enhance the mycobactericidal effect of pyrazinamide [9]. Inhibition of the synthesis of PGE2, which is elevated in the lungs at a late phase of tuberculosis, has been shown to reduce infection [10]. This finding is plausible, considering that PGE2 inhibits phagocytosis, bacterial killing, production of nitrite, and T-helper 1 cytokines. These immunomodulatory functions are exerted via 4 EP receptors [11]. In this issue of the Journal, Vilaplana et al report that ibuprofen, in clinical use for several decades, can alleviate the lung pathology in a special mouse model, in which the lesions are similar to those caused by tuberculosis in humans. There are several ramifications of this finding relating to the cellular targeting mechanisms and for clinical translation into improving tuberculosis treatment in humans. NSAIDs are the most commonly used analgesic and antiinflammatory drugs worldwide. The therapeutic effects of NSAIDs are primarily due to their ability to inhibit COX-1 and COX-2 cyclooxygenases, which convert arachidonic acid Received and accepted 13 February 2013; electronically published 5 April 2013. Correspondence: Juraj Ivanyi, MD, PhD, Clinical and Diagnostic Sciences Department, Hodgkin Bldg, 2nd Fl, Guy’s Campus of Kings College London, London SE1 1UL United Kingdom ( [email protected]). The Journal of Infectious Diseases 2013;208:185–8 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit153