Kathryn DeRiemer

Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis.

Understanding the ecology of drug-resistant pathogens is essential for devising rational programs to preserve the effective lifespan of antimicrobial agents and to abrogate epidemics of drug-resistant organisms. Mathematical models predict that strain fitness is an important determinant of multidrug-resistant Mycobacterium tuberculosis transmission, but the effects of strain diversity have been largely overlooked. Here we compared the impact of resistance mutations on the transmission of isoniazid-resistant M. tuberculosis in San Francisco during a 9-y period. Strains with a KatG S315T or inhA promoter mutation were more likely to spread than strains with other mutations. The impact of these mutations on the transmission of isoniazid-resistant strains was comparable to the effect of other clinical determinants of transmission. Associations were apparent between specific drug resistance mutations and the main M. tuberculosis lineages. Our results show that in addition to host and environmental factors, strain genetic diversity can influence the transmission dynamics of drug-resistant bacteria.

Effect of Drug Resistance on the Generation of Secondary Cases of Tuberculosis

BACKGROUNDnThe results of animal studies suggest that isoniazid-resistant strains of Mycobacterium tuberculosis are less pathogenic than isoniazid-susceptible strains. Here, we assess the relative pathogenicity of drug-resistant and drug-susceptible strains, in a human population.nnnMETHODSnWe linked IS6110 genotype patterns of M. tuberculosis strains with drug-susceptibility test results and epidemiologic information for 85% of culture-positive incident cases of tuberculosis (TB) in San Francisco during 1991-1999. We assumed that drug-susceptible and drug-resistant strains were transmitted to secondary case patients if the drug-resistance and genotype patterns were identical. We calculated the number of secondary cases for each drug-resistance pattern and determined the relative secondary-case rate ratio (SR) of drug-resistant TB to drug-susceptible TB.nnnRESULTSnThere were 1800 patients with culture-positive TB, drug-susceptibility test results, and genotyping results. The overall SR of drug-resistant to drug-susceptible TB cases was 0.51 (95% confidence interval [CI], 0.37-0.69). The SR was 0.29 (95% CI, 0.15-0.57) for isoniazid-resistant strains, 0.10 (95% CI, 0.02-0.42) for strains resistant to both isoniazid and streptomycin, and 0.88 (95% CI, 0.53-1.47) for streptomycin-resistant strains. There were no secondary cases caused by multidrug-resistant (MDR) TB. The SR for rifampin-resistant cases was 2.33 (95% CI, 1.04-5.25). Seventy-eight percent (7/9) of the patients with rifampin-resistant secondary cases of TB were seropositive for human immunodeficiency virus.nnnCONCLUSIONnIn the context of an effective TB program in San Francisco, strains that were resistant to isoniazid either alone or in combination with other drugs were less likely to result in secondary cases than were drug-susceptible strains. In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drug-resistant TB cases.

Does DOTS work in populations with drug-resistant tuberculosis?

BACKGROUNDnDirectly observed therapy (DOTS) is the main strategy for prevention and control of tuberculosis worldwide. However, its effect on tuberculosis transmission in populations with moderate rates of drug-resistant disease is not known.nnnMETHODSnThis population-based prospective study in southern Mexico between March, 1995, and February, 2000, was based on passive case finding and detection of acid-fast bacilli in sputum samples to diagnose pulmonary tuberculosis. We also used cultures, drug-susceptibility testing, bacterial genotyping, and monitoring of treatment outcomes.nnnFINDINGSnWe enrolled 436 patients; the HIV seroprevalence rate was 2%. We used three indicators to monitor continuing tuberculosis transmission: the incidence rate of pulmonary tuberculosis, which decreased by 54.4% between 1995 and 2000, from 42.1 to 19.2 per 10(5) population (p=0.00048); the percentage of clustered pulmonary tuberculosis cases, which decreased by 62.6% from 22% to 8% (p=0.02); and the rate of primary drug resistance, which decreased by 84.0% from 9.4 to 1.5 per 10(5) population (p=0.004). Rates of multidrug-resistant (MDR) tuberculosis also decreased (p<0.0001). The case-fatality ratio was 12% for MDR tuberculosis (five of 41), 7% for strains resistant to at least one drug after exclusion of MDR (four of 55), and 3% for pansusceptible strains (nine of 272). There were 13 treatment failures (11%) in 1995 and one (2%) in 2000 (p=0.012).nnnINTERPRETATIONnEven in settings with moderate rates of MDR tuberculosis, DOTS can rapidly reduce the transmission and incidence of both drug-susceptible and drug-resistant tuberculosis. However, further interventions, such as drug-susceptibility testing and standardised or individualised treatment regimens, are needed to reduce mortality rates for MDR tuberculosis.

Gender differentials of pulmonary tuberculosis transmission and reactivation in an endemic area

Background: In most low income countries there are twice as many cases of tuberculosis (TB) reported among men than among women, a difference commonly attributed to biological and epidemiological characteristics as well as socioeconomic and cultural barriers in access to health care. The World Health Organization has encouraged gender specific comparisons in TB rates to determine whether women with TB are less likely than men with TB to be diagnosed, reported, and treated. A study was undertaken to identify gender based differences in patients with pulmonary TB and to use this information to improve TB control efforts. Methods: Individuals with a cough for more than 2 weeks in southern Mexico were screened from March 1995 to April 2003. Clinical and mycobacteriological information (isolation, identification, drug susceptibility testing and IS6110 based genotyping, and spoligotyping) was collected from those with bacteriologically confirmed pulmonary TB. Patients were treated in accordance with official norms and followed to ascertain treatment outcome, retreatment, and vital status. Results: 623 patients with pulmonary TB were enrolled. The male:female incidence rate ratio for overall, reactivated, and recently transmitted disease was 1.58 (95% CI 1.34 to 1.86), 1.64 (95% CI 1.36 to 1.98), and 1.41 (95% CI 1.01 to 1.96), respectively. Men were more likely than women to default from treatment (adjusted OR 3.30, 95% CI 1.46 to 7.43), to be retreated (hazard ratio (HR) 3.15, 95% CI 1.38 to 7.22), and to die from TB (HR 2.23, 95% CI 1.25 to 3.99). Conclusions: Higher rates of transmitted and reactivated disease and poorer treatment outcomes among men are indicators of gender differentials in the diagnosis and treatment of pulmonary TB, and suggest specific strategies in endemic settings.

Does Resistance to Pyrazinamide Accurately Indicate the Presence of Mycobacterium bovis

ABSTRACT Mycobacterium bovis is best identified by screening those isolates of the Mycobacterium tuberculosis complex that have any pyrazinamide (PZA) resistance, using a confirmatory test such as spoligotyping, biochemical testing, or genomic deletion analysis. The sensitivity for detection of M. bovis is lowered to 82% when only PZA-monoresistant isolates are screened.

TOXICITY AND PHARMACOLOGY OF EXTRACTS FROM DORID NUDIBRANCHS

1. Aqueous extracts of digestive glands of specimens of the dorid nudibranchs Cadlina flavomaculata, Doriopsilla albopunctata, Anisodoris nobilis, Archidoris montereyenis, and A. odhneri were lethal when injected into shore crabs and when injected intraperitoneally into mice. 2. Aqueous extracts of the degestive glands of Doriopsilla albopunctata and of Anisodoris nobilis were shown by bioassay (guinea pig ileum)and by chemical determination to contain histamine. The amount present was far too small to account for the toxicity of the glands. 3. Extracts of the digestive glands of Anisodoris nobilis were fractionated by column chromatography on Biogel P-2 to yield an active fraction designated dorid toxin. This produces lethargy and bradycardia in mice. In anesthetized rats it produces sustained (60 min or more) bradycardia and hypotension. On isolated hearts, especially spontaneously beating guinea pig atria, it has negative inotropic and chronotropic effects. 4. Dorid toxin has a molecular weight under 8000. It is heat stable and is not destroyed by trypsin, chymotrypsin or Pronase. It is therefore unlikely that it is a polypeptide.

Choline esters in the marine gastropods Nucella emarginata and Acanthina spirata: A new choline ester, tentatively identified as N-methylmurexine

Abstract 1. Several tissues of two intertidal gastropod mollusks belonging to the superfamily Muricacea contained, in addition to acetylcholine, other choline esters that produced contraction of the frog rectus abdominis muscle. 2. One major active choline ester found in acetone extracts of the hypobranchial gland of Acanthina spirata had pharmacological properties and a nuclear magnetic resonance spectrum consistent with murexine [urocanylcholine, β -[4-imidazolyl]acrylcholine). 3. A principal active compound from the hypobranchial gland of Nucella ( = Thais ) emarginata differed pharmacologically from murexine and was tentatively identified by nuclear magnetic resonance spectroscopy as the previously unreported N -methyl derivative of murexine, β -[4-(1-or 3-methyl)-imidazolyl]acrylcholine.

The Molecular Epidemiology of Tuberculosis

The ability to track specific strains of Mycobacterium tuberculosis as they spread through a population is critical for our understanding of the transmission and pathogenesis of tuberculosis. However, until recently, the only phenotypic markers that distinguished different strains of M. tuberculosis were drug resistance patterns and mycobacterial phage typing (Gruft et al. 1984). Molecular genotyping techniques that allow us to differentiate isolates of M. tuberculosis for the purpose of tracking strains in the Community and designing prevention and control strategies to block further transmission of M. tuberculosis are now available.