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Extreme Drug Tolerance of Mycobacterium tuberculosis in Caseum
- Source :
- Antimicrobial Agents and Chemotherapy
- Publication Year :
- 2018
- Publisher :
- American Society for Microbiology, 2018.
-
Abstract
- Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence, and drug tolerance are among the factors driving the long therapy duration. Assays to measure in situ drug susceptibility of Mycobacterium tuberculosis bacteria in pulmonary lesions are needed if we are to discover new fast-acting regimens and address the global TB threat. Here we take a first step toward this goal and describe an ex vivo assay developed to measure the cidal activity of anti-TB drugs against M. tuberculosis bacilli present in cavity caseum obtained from rabbits with active TB. We show that caseum M. tuberculosis bacilli are largely nonreplicating, maintain viability over the course of the assay, and exhibit extreme tolerance to many first- and second-line TB drugs. Among the drugs tested, only the rifamycins fully sterilized caseum. A similar trend of phenotypic drug resistance was observed in the hypoxia- and starvation-induced nonreplicating models, but with notable qualitative and quantitative differences: (i) caseum M. tuberculosis exhibits higher drug tolerance than nonreplicating M. tuberculosis in the Wayne and Loebel models, and (ii) pyrazinamide is cidal in caseum but has no detectable activity in these classic nonreplicating assays. Thus, ex vivo caseum constitutes a unique tool to evaluate drug potency against slowly replicating or nonreplicating bacilli in their native caseous environment. Intracaseum cidal concentrations can now be related to the concentrations achieved in the necrotic foci of granulomas and cavities to establish correlations between clinical outcome and lesion-centered pharmacokinetics-pharmacodynamics (PK-PD) parameters.
- Subjects :
- 0301 basic medicine
Bacilli
caseum
Tuberculosis
030106 microbiology
Antitubercular Agents
Drug resistance
Mycobacterium tuberculosis
03 medical and health sciences
in vitro potency model
Drug tolerance
medicine
Animals
Potency
pharmacokinetics-pharmacodynamics
Pharmacology (medical)
Pharmacology
biology
business.industry
Drug Tolerance
persistence
Pyrazinamide
biology.organism_classification
medicine.disease
Rifamycins
3. Good health
Infectious Diseases
Immunology
Rabbits
business
Ex vivo
medicine.drug
Subjects
Details
- ISSN :
- 10986596 and 00664804
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy
- Accession number :
- edsair.doi.dedup.....c4cca49ecd2ae2fcc38f509e2379df6f