Effectiveness of tuberculosis chemotherapy correlates with resistance to Mycobacterium tuberculosis infection in animal models

Zahoor Ahmad, Mostafa M. Fraig, Michael L. Pinn, Sandeep Tyagi, Eric L. Nuermberger, Jacques H. Grosset, Petros C. Karakousis

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: It is widely believed that persistent Mycobacterium tuberculosis inhabits necrotic lung granulomas in humans and that the microenvironmental conditions encountered therein render the bacilli phenotypically tolerant to antibiotics, accounting for the long duration required for successful treatment of tuberculosis (TB). To validate this belief, we directly compared the activity of rifampicin/isoniazid/pyrazinamide (RHZ) against chronic TB infection in guinea pigs, which exhibit caseous granulomas histologically resembling human caseous foci, and in mice, which lack necrotic granulomas. Methods: Guinea pigs and mice were aerosol-infected with M. tuberculosis CDC1551 and twice weekly treatment with RHZ was started 4 weeks later. Culture-positive relapse was assessed in subgroups of guinea pigs after 3 months and 4 months of treatment. Results: All guinea pig lungs exhibited histological evidence of granulomas with central caseation, while mouse lungs exhibited cellular lesions at the initiation of antibiotic treatment. Guinea pig lungs became culturenegative after 2 months of RHZ given twice weekly at human-equivalent doses. Relapse rates in guinea pigs were 0% (0/10) both after 3 months and 4 months of treatment. In contrast, all mouse lungs remained culture-positive after 4 months of equivalent RHZ exposures. Conclusions: Caseous necrosis does not reduce the sterilizing activity of the standard antituberculosis regimen of RHZ. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.

Original languageEnglish (US)
Article numberdkr188
Pages (from-to)1560-1566
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume66
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • Antibiotics
  • Caseous necrosis
  • Chemotherapy
  • Chronic tuberculosis
  • Granuloma
  • Guinea pig
  • Hypoxia
  • Mouse
  • Persistence

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

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