Isoniazid (INH) is one of the primary chemotherapeutic and prophylactic drugs used against Mycobacterium tuberculosis, the causative agent of tuberculosis, which remains the leading single cause of death due to an infectious agent throughout the world. Recent studies indicate that the median rate of primary resistance to INH is 7.3% (range, 1.5 to 32%) and that the rates of acquired resistance range from 5.3 to 70% globally (9, 45). The overall rate of resistance to INH is 8.4% in the United States and has remained relatively stable in the last decade (23). Global reports of clusters of tuberculosis cases caused by drug-resistant strains together with the emergence and dissemination of multidrug-resistant tuberculosis have underscored the need for research into the mechanisms of drug resistance and the design of more effective antituberculous agents. Despite the use of INH for several decades, the molecular basis for its bactericidal action and the mechanisms by which INH resistance evolves in M. tuberculosis are only beginning to be understood.INH has a simple chemical structure consisting of a hydrazide group attached to a pyridine ring, but its mode of action is very complex (8). It is proposed that INH enters M. tuberculosis as a prodrug by passive diffusion and is activated by catalase-peroxidase, encoded by katG, to generate free radicals, which then attack multiple targets in the cells (6). Recent studies have shown that an NADH-dependent enoyl acyl carrier protein (ACP) reductase, encoded by inhA, and a ␤-ketoacyl ACP synthase, encoded by kasA, are two potential intracellular enzymatic targets for activated INH; and both of these enzymes are involved in the biosynthesis of mycolic acids (4,19,20). Resistance-associated amino acid substitutions have been identified in the katG, inhA, and kasA genes of INHresistant clinical isolates of M. tuberculosis (7,20,24,26,29). In addition, mutations in the oxyR-ahpC intergenic region have been identified in INH-resistant isolates (36). Additional genetic and biochemical studies have shown that certain promoter mutations of alkylhydroperoxide reductase, encoded by ahpC, in INH-resistant isolates result in overexpression of ahpC as a compensatory mechanism for the loss of catalase activity due to katG mutations (15, 32). Recently, missense mutations were identified in ndh, a gene encoding NADH dehydrogenase, which is an essential respiratory chain enzyme that regulates the NADH/NAD ϩ ratio in cells (18,22). The molecular mechanism by which mutations in ndh confer INH resistance in M. tuberculosis is poorly understood. In addition, low-level INH resistance in mycobacteria has been shown to be

In central and northern Wisconsin methicillin-resistant Staphylococcus aureus (MRSA) was first detected in 1989. Over the next 10-year period, 581 MRSA isolates were collected, 17.2% of which came from patients who were treated at five Native American clinics. These isolates were typed by SmaI-macrorestricted pulsed-field gel electrophoresis (PFGE). The PFGE patterns clustered the isolates into six major clonal groups (MCGs), i.e., MCGs 1 to 6, and 19 minor clonal groups (mCGs). The 25 clonal groups were represented by 109 unique PFGE types. Sixty-five percent of the MCG-2 isolates were recovered from patients who were treated at Native American clinics. Ninety-four percent of the MCG-2 isolates harbored the staphylococcal cassette chromosome mec (SCCmec) IVa. These isolates also had PFGE profiles that were clonally related to the midwestern community-associated MRSA (CA-MRSA) strain, MW2. The representative isolates from MCG-2 had the multilocus sequence type allelic profile 1-1-1-1-1-1-1 and contained pvl genes. They were also susceptible to various antibiotics, a finding consistent with the CA-MRSA phenotype. SCCmec IV was also present in other mCGs. Unlike MCG-2, isolates from the remaining five MCGs harbored SCCmec II and were resistant to multiple antibiotics, suggesting their nosocomial origin. The 19 mCGs were represented by diverse SCCmec types and three putative new variants referred to as SCCmec Ib, IIa, and IIb.

Interleukin (IL)-8 is involved in the pathogenesis of human tuberculosis (TB). However, the contribution of polymorphisms of the IL-8 gene and its receptor genes CXCR-1 and CXCR-2 to human TB susceptibility remains untested. In a case-control study, white subjects with TB disease were more likely to be homozygous for the IL-8 -251A allele, compared with control subjects (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.52-7.64). African Americans with TB also showed an increased odds of being homozygous for this allele (OR, 3.46; 95% CI, 1.48-8.08). To exclude population artifacts in the case-control study, a separate analysis that used a transmission-disequilibrium test with 76 informative families confirmed that the IL-8 -251A allele was preferentially transmitted to TB-infected children (P=.02). CXCR-1 and CXCR-2 did not demonstrate significant associations with TB susceptibility. These data suggest that IL-8 is important in the genetic control of human TB susceptibility.

Screening for latent tuberculosis infection (LTBI) with