Persistence, Not Resistance, Is the Cause of Loss of Isoniazid Effect

Wallis, Robert S.; Palaci, Moisés; Eisenach, Kathleen D.

doi:10.1086/518044

Cited by 17 publications

(10 citation statements)

References 5 publications

(10 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Results from in vitro experiments performed with isoniazid, and also previously with moxifloxacin and ciprofloxacin (Gumbo et al, 2005(Gumbo et al, , 2004, suggest that the cessation of the bactericidal activities of those drugs after a few days of therapy may be due to the emergence of a resistant subpopulation of M. tuberculosis. Other scientists have argued that those results, obtained in in vitro studies using a single drug, cannot explain the loss of activity of anti-TB drugs observed in patients treated with multiple drugs for which the bacterial sensitivity was controlled by laboratory tests (Wallis et al, 2007). Those authors support the classical ''special populations'' hypothesis to explain clinical data.…”

Section: Discussionmentioning

confidence: 98%

“…This has been the subject of an interesting debate in the specialized literature after the publication of a recent work by Gumbo et al on isoniazid (Gumbo et al, 2007b;Mitchison et al, 2007;Wallis et al, 2007). Results from in vitro experiments performed with isoniazid, and also previously with moxifloxacin and ciprofloxacin (Gumbo et al, 2005(Gumbo et al, , 2004, suggest that the cessation of the bactericidal activities of those drugs after a few days of therapy may be due to the emergence of a resistant subpopulation of M. tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mathematical modeling of pulmonary tuberculosis therapy: Insights from a prototype model with rifampin

Goutelle

Bourguignon

Jelliffe

et al. 2011

Journal of Theoretical Biology

View full text Add to dashboard Cite

There is a critical need for improved and shorter tuberculosis (TB) treatment. Current in vitro models of TB, while valuable, are poor predictors of the antibacterial effect of drugs in vivo. Mathematical models may be useful to overcome the limitations of traditional approaches in TB research. The objective of this study was to set up a prototype mathematical model of TB treatment by rifampin, based on pharmacokinetic, pharmacodynamic and disease submodels. The full mathematical model can simulate the time-course of tuberculous disease from the first day of infection to the last day of therapy. Therapeutic simulations were performed with the full model to study the antibacterial effect of various dosage regimens of rifampin in lungs. The model reproduced some qualitative and quantitative properties of the bactericidal activity of rifampin observed in clinical data. The kill curves simulated with the model showed a typical biphasic decline in the number of extracellular bacteria consistent with observations in TB patients. Simulations performed with more simple pharmacokinetic/pharmacodynamic models indicated a possible role of a protected intracellular bacterial compartment in such a biphasic decline. This modeling effort strongly suggests that current dosage regimens of RIF may be further optimized. In addition, it suggests a new hypothesis for bacterial persistence during TB treatment.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Mathematical modeling of pulmonary tuberculosis therapy: Insights from a prototype model with rifampin

Goutelle

Bourguignon

Jelliffe

et al. 2011

Journal of Theoretical Biology

View full text Add to dashboard Cite

show abstract

“…It has long been speculated that M. tuberculosis in a latent or dormant state may play a role in the drug tolerance observed during infection[2, 3, 5, 7, 21]. Antibacterials in use today are generally more effective against actively replicating bacteria[7, 15, 22–26].…”

Section: Introductionmentioning

confidence: 99%

The DosR regulon of M. tuberculosis and antibacterial tolerance

et al. 2009

View full text Add to dashboard Cite

SummaryAdaptation of Mycobacterium tuberculosis to an anaerobic dormant state that is tolerant to several antibacterials is mediated largely by a set of highly expressed genes controlled by DosR. A DosR mutant was constructed to investigate whether the DosR regulon is involved in antibacterial tolerance. We demonstrate that induction of the regulon is not required for drug tolerance either in vivo during a mouse infection or in vitro during anaerobic dormancy. Thus, drug tolerance observed in these models is due to other mechanisms such as the bacilli simply being in a non-replicating or low metabolic state. Our data also demonstrate that the DosR regulon is not essential for virulence during chronic murine infection. However, decreased lung pathology was observed in the DosR mutant. We also show that the DosR regulon genes are more highly conserved in environmental mycobacteria, than in pathogenic mycobacteria lacking a latent phase or environmental reservoir. It is possible that the DosR regulon could contribute to drug tolerance in human infections; however, it is not the only mechanism and not the primary mechanism for tolerance during a mouse infection. These data suggest that the regulon evolved not for pathogenesis or drug tolerance but for adaptation to anaerobic conditions in the environment and has been adapted by M. tuberculosis for survival during latent infection.

show abstract

“…Mycobacterium tuberculosis surviving in a persistent state during latent infection usually displays a reduced antibiotic susceptibility compared to that of the bacterium during active growth (12,(27)(28)(29). Conversely, exposure to antibiotics may also induce a transformation of M. tuberculosis from an active growth to a persistent state (11).…”

mentioning

confidence: 99%