Sterilising action of pyrazinamide in models of dormant and rifampicin-tolerant Mycobacterium tuberculosis.
METHODS
Pyrazinamide (PZA) is an effective sterilising drug in tuberculosis, but its mode of action is controversial.


OBJECTIVE
To test the bactericidal activity of 1.56-100 microg/ml PZA in Hu/Coates models of dormant and rifampicin (RMP) tolerant Mycobacterium tuberculosis.


METHODS
In model 1, bactericidal activity was tested in pH 5.5 medium against 4-day, 30-day or 100-day static, hypoxic cultures. In models 2 and 3, 100 microg/ml RMP was added to a 100-day culture and PZA was added either during incubation with RMP in model 3, or after resuspension in RMP-free medium in model 2.


RESULTS
Model 1: cfu counts on the 100-day and 30-day cultures fell by a maximum of about 1.6 log cfu/ml with increasing culture age, PZA concentration and incubation period, while counts on the 4-day culture showed little change. Model 2: cfu counts at the end of 7 days of recovery showed little bactericidal activity. Model 3: viable bacilli were almost completely eliminated. Bactericidal activity in these models increased with decreasing metabolic bactericidal activity, as measured by the uptake of [3H] uridine into bacterial RNA.


CONCLUSIONS
PZA differs from other anti-tuberculosis drugs in showing greater bactericidal activity the slower the bacillary metabolic activity, hence its great value as a sterilising drug, likely to remain as an effective companion drug with newer sterilising drugs.
Department of Cellular and Molecular Medicine, St George's, University of London, London, United Kingdom.
Y
Y
Hu
A R
AR
Coates
D A
DA
Mitchison
D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D011718:Pyrazinamide / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D018440:beta-Lactam Resistance
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D011718:Pyrazinamide; D012293:Rifampin