Impact of isoniazid resistance-conferring mutations on the clinical presentation of isoniazid monoresistant tuberculosis.

BACKGROUND: Specific isoniazid (INH) resistance conferring mutations have been shown to impact the likelihood of tuberculosis (TB) transmission. However, their role in the clinical presentation and outcomes of TB has not been evaluated. METHODS: We included all cases of culture-confirmed, INH monoresistant tuberculosis reported to the San Francisco Department of Public Health Tuberculosis Control Section from October 1992 through October 2005. For cases with stored culture isolates, we used polymerase chain reaction (PCR) testing and gene sequencing to identify INH resistance-conferring mutations, and compared genotypic and phenotypic characteristics. RESULTS: Among 101 consecutive cases of INH monoresistant TB in San Francisco 19 (19%) had isolates with a katG mutation other than S315T; 38 (38%) had isolates with the katG S315T mutation, 29 (29%) had isolates with a inhA-15;c-t promoter mutation, and 15 (15%) had isolates with other mutations. The katG S315T mutation was independently associated with high-level INH resistance (risk ratio [RR] 1.56, 95% confidence interval [CI] 1.07-2.27), and the inhA-15;c-t promoter mutation was inversely associated with high-level INH resistance (RR 0.43, 95% CI 0.21-0.89). However, specific INH resistance-conferring mutations were not associated with the clinical severity or outcomes of INH monoresistant TB cases. CONCLUSION: These data suggest that INH resistance-conferring mutations do not impact the clinical presentation of TB.

Evaluation of the Cepheid Xpert MTB/RIF assay for direct detection of Mycobacterium tuberculosis complex in respiratory specimens.

A total of 217 specimens submitted for routine smear and culture from three different sites within the western United States were used to evaluate the GeneXpert MTB/RIF assay (for research use only) (Cepheid, Sunnyvale, CA). Overall agreement compared to culture was 89% (98% for smear positives and 72% for smear negatives) for detection of Mycobacterium tuberculosis.

Comparison of restriction fragment length polymorphism with the polymorphic guanine-cytosine-rich sequence and spoligotyping for differentiation of Mycobacterium tuberculosis isolates with five or fewer copies of IS6110.

The use of IS6110 as a marker for molecular epidemiological studies is limited when a Mycobacterium tuberculosis isolate has five or fewer copies of IS6110. Restriction fragment length polymorphism analysis with a highly polymorphic GC-rich repetitive sequence located in the plasmid pTBN12 (PGRS RFLP) and spoligotyping (based on the polymorphism of the DR region) are two frequently used secondary typing methods. The aim of this study was to compare the performance of these two methods in a population-based study in San Francisco. We included all patients with culture-positive tuberculosis from 1999 to 2007 with IS6110 RFLP results presenting five or fewer bands. PGRS RFLP and spoligotyping were performed using standardized methods. We determined the concordance between the two methods regarding cluster status and the risk factors for an isolate to be in a cluster with each of the methods. Our data indicate that both methods had similar discriminatory power and that the risk factors associated with clustering by either method were the same. Although the cluster/unique status was concordant in 84% of the isolates, patients were clustered differently depending on the method. Therefore, the methods are not interchangeable, and the same method should be used for longitudinal studies.

Imipenem for treatment of tuberculosis in mice and humans.

Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first- or second-line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M. tuberculosis. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.

Randomized controlled trial of interventions to improve follow-up for latent tuberculosis infection after release from jail.

BACKGROUND: Adherence to treatment of persons with latent tuberculosis infection after release from jail has been poor. METHODS: A randomized controlled trial was conducted at the San Francisco City and County Jail, San Francisco, Calif. Subjects undergoing therapy for latent tuberculosis infection who spoke either English or Spanish were randomly allocated to receive education every 2 weeks while in jail; an incentive if they went to the San Francisco County Tuberculosis Clinic within 1 month of release; or usual care. The main outcome measures were completion of a visit to the tuberculosis clinic within 1 month of release and completion of therapy. RESULTS: Of 558 inmates enrolled, 325 were released before completion of therapy. Subjects in either intervention group were significantly more likely to complete a first visit than were control subjects (education group, 37%; incentive group, 37%; and controls, 24%) (adjusted odds ratio based on pooled results for the education and incentive groups, 1.85; 95% confidence interval, 1.04-3.28; P =.02). Those in the education group were twice as likely to complete therapy compared with controls (adjusted odds ratio, 2.2; 95% confidence interval, 1.04-4.72; P =.04). Of those who went to the tuberculosis clinic after release, subjects in the education group were more likely to complete therapy (education group, 65% [24/37]; incentive group, 33% [14/42]; and control group, 48% [12/25]; P =.02). CONCLUSIONS: Education or the promise of an incentive improved initial follow-up. Education was superior to an incentive for the completion of therapy. Fairly modest strategies provided in jail can improve adherence. Further links between jail health services and community care should be explored.