Mycobacterium tuberculosis strains that are resistant to an increasing number of second-line drugs used to treat multidrug-resistant tuberculosis (MDR TB) are becoming a threat to public health worldwide. We surveyed the Network of Supranational Reference Laboratories for M. tuberculosis isolates that were resistant to second-line anti-TB drugs during 2000-2004. We defined extensively drug-resistant TB (XDR TB) as MDR TB with further resistance to >3 of the 6 classes of second-line drugs. Of 23 eligible laboratories, 14 (61%) contributed data on 17,690 isolates, which reflected drug susceptibility results from 48 countries. Of 3,520 (19.9%) MDR TB isolates, 347 (9.9%) met criteria for XDR TB. Further investigation of population-based trends and expanded efforts to prevent drug resistance and effectively treat patients with MDR TB are crucial for protection of public health and control of TB. These drugs are more costly, toxic, and less effective than first-line drugs used for routine treatment of TB (3-6). As with other diseases, resistance to TB drugs results primarily from nonadherence by patients, incorrect drug prescribing by providers, poor quality drugs, or erratic supply of drugs (7).To facilitate treatment of MDR TB in resource-limited countries, where most TB cases occur (1,2), the World Health Organization (WHO) and its partners developed the Green Light Committee, which helps ensure proper use of second-line drugs, to prevent further drug resistance (8). Nonetheless, the Green Light Committee encountered numerous anecdotal reports of MDR TB cases with resistance to most second-line drugs. Once a strain has developed resistance to second-line drugs, these new TB strains are even more difficult to treat with existing drugs. Untreated or inadequately treated patients are at increased risk of spreading their disease in the community, which could lead to outbreaks in vulnerable populations and widespread emergence of a lethal, costly epidemic of drugresistant TB, reminiscent of the MDR TB outbreaks in the early 1990s (9-13). Therefore, to determine whether these anecdotal reports were isolated events, early evidence of an emerging epidemic, or the occurrence of virtually

To evaluate the histopathological features observed in patients with cutaneous infections due to nontuberculous mycobacteria (NTM) and to compare the histopathological patterns observed in immunosuppressed patients and normal hosts. Twenty-eight biopsy specimens corresponding to 27 patients with cutaneous infections due to NTM were reviewed. Eighteen biopsies corresponded to normal hosts (14 Mycobacterium marinum, 2 Mycobacterium chelonae, 1 Mycobacterium terrae and 1 Mycobacterium gordonae) and 10 biopsy specimens were obtained from 9 immunosuppressed patients (3 Mycobacterium chelonae, one of which had two biopsies, 1 Mycobacterium abscessus, 2 Mycobacterium kansasii, 1 Mycobacterium marinum, 1 Mycobacterium avium complex and 1 Mycobacterium simiae). A panel of histopathological features was evaluated by two independent observers in each biopsy specimen. Epidermal changes (acanthosis, pseudoepitheliomatous hyperplasia, exocytosis) were mainly observed in M. marinum infections. In immunosuppressed patients the infiltrate tended to be deeper, involving the subcutaneous tissue (100%) with a more diffuse distribution and constant abscess formation. A marked granulomatous inflammatory reaction was observed in 83% of immunocompetent and in 60% of immunosuppressed patients. In immunosuppressed patients a relationship between the chronic evolution of the disease and granuloma formation was demonstrated. A diffuse infiltrate of histiocytes with occasionally foamy appearance was noted in three biopsy specimens from three patients with AIDS. Acute and chronic panniculitis was detected in 8 biopsy specimens. In one biopsy (M. chelonae) an acute suppurative folliculitis was observed. Different histopathological patterns can be noted in biopsy specimens from cutaneous nontuberculous mycobacterial infections. The evolution of the disease and the immunologic status of the host may explain this spectrum of morphological changes. Tuberculoid, palisading and sarcoid-like granulomas, a diffuse infiltrate of histiocytic foamy cells, acute and chronic panniculitis, non-specific chronic inflammation, cutaneous abscesses, suppurative granulomas and necrotizing folliculitis can be detected. Suppurative granulomas are the most characteristic feature in skin biopsy specimens from cutaneous NTM infections. Some histopathological patterns seem more prevalent in immunosuppressed patients.

Cutaneous manifestations of nontuberculous mycobacterial infections may be classified according to criteria such as cutaneous lesions and immune status.

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

In this multicenter study, the reliability of two nonradiometric, fully automated systems, the MB/BacT and BACTEC MGIT 960 systems, for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid, rifampin, ethambutol, and streptomycin was evaluated in comparison with the radiometric BACTEC 460TB system. The arbitration of discrepant results was done by the reanalysis of the strain, the determination of the MIC, and the molecular characterization of some resistance determinants. The overall level of agreement with BACTEC 460TB results was 96% with the MB/BacT test and 97.2% with the BACTEC MGIT 960 system. With both methods, the level of agreement with BACTEC 460TB results was 96.3% for isoniazid, 98.8% for rifampin, and 98.8% for ethambutol. The level of agreement for streptomycin was 90.2% with MB/BacT and 97.5% with BACTEC MGIT 960. Overall, there were 11 very major errors and 2 major errors with the MB/BacT method and 5 very major errors and 2 major errors with the BACTEC MGIT 960 system. In general, the MB/BacT and BACTEC MGIT 960 systems showed good performance for susceptibility testing with first-line antituberculosis drugs.Tuberculosis (TB) is one of the most prevalent infectious diseases in the world. According to a recent report of the World Health Organization, in 2003 there were 8.8 million new TB cases and around 1.7 million deaths attributable to the disease (25). In addition, multidrug-resistant TB is becoming increasingly common and is a major health concern in many regions of the world, particularly in developing nations (24). Rapid, accurate diagnosis and the determination of drug susceptibility are crucial to optimize treatment and prevent transmission. The most widely used method for Mycobacterium tuberculosis drug susceptibility testing is the proportion method, either on solid medium or on liquid broth. The BACTEC 460TB system (Becton Dickinson Biosciences, Sparks, MD) has been widely validated for approximately 20 years for the reliable and rapid testing of the susceptibilities of M. tuberculosis isolates (9, 16, 21). The radiometric BACTEC 460TB test requires fewer than 14 days of incubation before results are available, but it is semiautomated and entails the disposal of a radioactive substance (16).New liquid medium-based systems have recently been introduced for the nonradiometric susceptibility testing of M. tuberculosis (4, 10, 17-19). These include the ESP Culture System II (AccuMed International, Westlake, OH), the MB Redox system (Biotest, Dreieich, Germany), the BACTEC MGIT 960 mycobacterial growth indicator tube system (Becton Dickinson Microbiology Systems, Sparks, MD), and the MB/BacT system (bioMérieux, Marcy l'Etoile, France).In the present multicenter study, we evaluated the reliability of the MB/BacT and BACTEC MGIT 960 systems for testing M. tuberculosis susceptibility to streptomycin, isoniazid, rifampin, and ethambutol (a combination known as SIRE) and compared the results obtained with these methods to those obtained with the radiometric BACTEC ...