Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models.
PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs.
PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment.
The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.
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Colony forming units
Multiple drug resistant
Mass median aerodynamic diameter
- Mtb :
Pyrazinoic acid esters
Extensively drug resistant
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ACKNOWLEDGMENTS AND DISCLOSURES
Funded by AIDS Clinical Trials Group (ACTG) UM1 AI068636, DAIDS, NIAID, co-principal investigators Dr. Miriam Braunstein and Dr. Anthony J. Hickey. We appreciate statistical support provided by Dr. Feng-Chang Lin of the NC-TraCS Biostats core.
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Young, E.F., Perkowski, E., Malik, S. et al. Inhaled Pyrazinoic Acid Esters for the Treatment of Tuberculosis. Pharm Res 33, 2495–2505 (2016). https://doi.org/10.1007/s11095-016-1974-5
- inhaled therapy
- pyrazinoic acid
- pyrazinoic acid esters
- TB drugs