The in vitro activity of omadacycline, a new tetracycline derivative, was evaluated against isolates of Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum using a broth microtiter dilution assay. Omadacycline had MIC90 values of 2 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively. The in vitro activity of omadacycline against rapidly growing mycobacteria indicates that it may have the potential to improve therapy for infections caused by these organisms.

The use of gatifloxacin (GAT) in combination with ethionamide (ETA) with or without pyrazinamide (PZA) for a 12-week treatment period followed by an 8-week observation period was evaluated in a model of tuberculosis in mice. Mice treated with GAT at 300 mg/kg of body weight in combination with ETA (25 mg/kg) for 5 days per week had sterile lungs, whereas mice treated with GAT (100 mg/kg) and ETA (25 mg/kg) had about 10 CFU/lung; however, there was regrowth of the organisms in both groups at the end of the observation period. When PZA (450 mg/kg 5 days per week) was added to the high-dose GAT-ETA regimen, no viable mycobacteria were present after the 8-week observation period. GAT in combination with ETA and PZA has great promise for the treatment of tuberculosis.The activities of gatifloxacin (GAT) alone and in combination with ethionamide (ETA) and pyrazinamide (PZA) were recently studied in a murine tuberculosis model (1); GAT at 100 mg/kg of body weight daily was used alone and in combination with ETA at 75 mg/kg daily and performed well. The addition of PZA at 150 mg/kg daily did not enhance the activity of the GAT-ETA regimen.One of the newer 8-methoxyquinolones (GAT or moxifloxacin) with potent in vitro and in vivo (murine model) antituberculosis activities in combination with ETA might provide an effective regimen for the treatment of patients with multipledrug-resistant tuberculosis (MDRTB). It would be useful to develop a short-course regimen against MDRTB whose efficacy is comparable to that of isoniazid (INH)-rifampin (RIF)-PZA. GAT, a DNA gyrase inhibitor, has a mechanism of action different from those of established antimycobacterial agents. ETA is active against most INH-resistant tuberculosis isolates. It is reasonable to evaluate regimens for the treatment of MDRTB caused by a pansusceptible strain if there is minimal potential for cross-resistance among the agents studied.The aims of this study were to evaluate these agents in combination regimens by using a long-term treatment model (5) to evaluate their clinical potential for the treatment of MDRTB. MATERIALS AND METHODS Drugs.GAT was provided by Bristol-Myers Squibb Co., Princeton, N.J. INH, RIF, PZA, and ETA were purchased from Sigma Chemical Co., St. Louis, Mo. GAT was dissolved in 20% ethanol (80% distilled water), INH was dissolved in distilled water, while RIF, ETA, and PZA were dissolved in 20% dimethyl sulfoxide. INH-RIF and ETA-PZA were prepared, aliquoted, frozen at Ϫ20°C, and then thawed before use. The drug(s) was administered in a 0.2-ml volume by gavage. The mice were treated with ETA, ETA-PZA, or INH-RIF in the morning and with GAT in the afternoon. GAT was administered separately because the high-dose preparation was a fine suspension rather than a solution.Isolate. Mycobacterium tuberculosis ATCC 35801 (strain Erdman) was obtained from the American Type Culture Collection, Manassas, Va. The MICs of the antimicrobial agents other than PZA were determined in 7H10 broth (pH 6.6; 7H10 agar formulation with agar and malachite green...

Use of this model to screen potential chemotherapeutic agents will save time and resources.

Gatifloxacin in combination with rifampicin is a promising combination for potential evaluation in human clinical trials. Gatifloxacin plus rifampicin regimens had activities similar to or better than isoniazid plus rifampicin. A quinolone plus rifampicin combination may provide the foundation for shorter course regimens than the current isoniazid plus rifampicin-based regimen.

The in vitro activities of TP-271, a novel fluorocycline antimicrobial, against 22 isolates of Mycobacterium abscessus, 22 isolates of Mycobacterium fortuitum, and 19 isolates of Nocardia spp. were studied by a microtiter broth dilution method. The MIC 90 s for M. abscessus, M. fortuitum, and Nocardia spp. were 0.5 g/ml, 0.03 g/ml, and 8 g/ml, respectively. TP-271 was significantly more active than the respective control drug in virtually all tests. Mycobacterium abscessus and Mycobacterium fortuitum are rapidly growing mycobacteria that are associated primarily with opportunistic infections in immunocompromised subjects (2). Patients with bronchiectasis, especially those with cystic fibrosis, are at increased risk of M. abscessus infection. Other manifestations of M. abscessus infection include localized skin infections, postoperative wound infections, and infection of implanted medical devices. M. fortuitum is a relatively rare pathogen, even in immunocompromised individuals, but has been associated with skin infections and hospital-acquired postoperative infections (2). The most common clinical form of Nocardia infection is pulmonary nocardiosis, with and without dissemination, followed by skin and soft tissue infection (5).Infections due to these microorganisms are occurring with increasing frequency and are often difficult to treat, especially the mycobacterial infections. Successful treatment is often hindered by the need for combination therapy, resistance to multiple drugs, necessity of long treatment duration, and lack of sufficiently active oral drugs (2, 3, 6).While Nocardia remains susceptible to trimethoprim-sulfamethoxazole in the majority of cases, effective alternative oral therapy is lacking. Mortality from pulmonary nocardiosis remains high, in the range of 15 to 40% (5, 11).TP-271 is a novel, fully synthetic fluorocycline antimicrobial related to tetracycline ( Fig. 1) (1, 10). It has been shown to have potent broad-spectrum in vitro and in vivo activity against multiple community-acquired organisms, including Staphylococcus spp., Streptococcus spp., Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, and Acinetobacter baumannii, as well as biothreat organisms (Bacillus anthracis, Francisella tularensis, Burkholderia pseudomallei, and Burkholderia mallei) (4). The activity of TP-271 was shown to be unaffected by the Gram-positive tetracycline-specific pump tet(K) and ribosomal protection mechanism tet(M) and minimally affected by the most common Gram-negative efflux mechanisms, tet(A) and tet(B) (7). Promising oral activity was demonstrated by TP-271 in neutropenic mouse models of pneumonia caused by methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae and in immunocompetent models of pneumonia caused by S. pneumoniae in mice and H. influenzae in rats (4).As a first step in its assessment as a novel therapy to treat infections caused by M. abscessus, M. fortuitum, and Nocardia spp., we evaluated the in vitro activity of TP-271 in comparison to those of se...