trimethoprim--sulfamethoxazole-drug-combination and Glanders

Burkholderia mallei, the causative agent of glanders, is a CDC Tier 1 Select Agent for which there is no preventive vaccine and antibiotic therapy is difficult. In this study, we show that a combination of vaccination using killed cellular vaccine and therapy using moxifloxacin, azithromycin, or sulfamethoxazole-trimethoprim can protect BALB/c mice from lethal infection even when given 5 days after infectious challenge. Vaccination only, or antibiotic therapy only, was not efficacious. Although antibiotics evaluated experimentally can protect when given before or 1 day after challenge, this time course is not realistic in the cases of natural infection or biological attack, when the patient seeks treatment after symptoms develop or after a biological attack has been confirmed and the agent has been identified. Antibiotics can be efficacious after a prolonged interval between exposure and treatment, but only if the animals were previously vaccinated.

Topics: Aerosols; Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Vaccines; Burkholderia mallei; Combined Modality Therapy; Female; Fluoroquinolones; Glanders; Mice; Mice, Inbred BALB C; Moxifloxacin; Spleen; Trimethoprim, Sulfamethoxazole Drug Combination; Vaccination

Burkholderia pseudomallei is the causative agent of the disease melioidosis, which is prevalent in tropical countries and is intractable to a number of antibiotics. In this study, the antibiotic co-trimoxazole (trimethoprim/sulfamethoxazole) was assessed for the post-exposure prophylaxis of experimental infection in mice with B. pseudomallei and its close phylogenetic relative Burkholderia mallei, the causative agent of glanders. Co-trimoxazole was effective against an inhalational infection with B. pseudomallei or B. mallei. However, oral co-trimoxazole delivered twice daily did not eradicate infection when administered from 6h post exposure for 14 days or 21 days, since infected and antibiotic-treated mice succumbed to infection following relapse or immunosuppression. These data highlight the utility of co-trimoxazole for prophylaxis both of B. pseudomallei and B. mallei and the need for new approaches for the treatment of persistent bacterial infection.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Burkholderia mallei; Burkholderia pseudomallei; Chemoprevention; Disease Models, Animal; Female; Glanders; Inhalation Exposure; Melioidosis; Mice; Mice, Inbred BALB C; Post-Exposure Prophylaxis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The US Public Health Emergency Medical Countermeasures Enterprise convened subject matter experts at the 2010 HHS Burkholderia Workshop to develop consensus recommendations for postexposure prophylaxis against and treatment for Burkholderia pseudomallei and B. mallei infections, which cause melioidosis and glanders, respectively. Drugs recommended by consensus of the participants are ceftazidime or meropenem for initial intensive therapy, and trimethoprim/sulfamethoxazole or amoxicillin/clavulanic acid for eradication therapy. For postexposure prophylaxis, recommended drugs are trimethoprim/sulfamethoxazole or co-amoxiclav. To improve the timely diagnosis of melioidosis and glanders, further development and wide distribution of rapid diagnostic assays were also recommended. Standardized animal models and B. pseudomallei strains are needed for further development of therapeutic options. Training for laboratory technicians and physicians would facilitate better diagnosis and treatment options.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anti-Bacterial Agents; Burkholderia mallei; Burkholderia pseudomallei; Ceftazidime; Disease Models, Animal; Disease Susceptibility; Glanders; Humans; Melioidosis; Meropenem; Post-Exposure Prophylaxis; Risk Factors; Thienamycins; Trimethoprim, Sulfamethoxazole Drug Combination

Among the known species of Burkholderia only two are obligate pathogens, i.e., B. mallei and B. pseudomallei, causative agents of glanders and melioidosis respectively. The other species are saprophytes as natural inhabitants of water reservoirs and soil, still capable of causing opportunistic infections in humans and animals under definite conditions. All the species of Burkholderia are characterized by high resistance to antibacterials, including antibiotics. By the MICs, the most efficient chemotherapeutics against pathogenic burkholderias are tetracyclines, fluoroquinolones, penems and combined sulfanilamides. In the treatment of experimental glanders and melioidosis the set of the effective drugs had the inverse variation dependence on the infection severity and the desease process rate. Co-trimoxasole showed the best results, then followed doxicycline, ciprofioxacin and ceftazidime in the diminishing succession. The modification of the method for determination of antibiotic susceptibility with addition of native blood to the medium and the subculture under the atmosphere of 5% CO2 was shown useful in estimation of the prospects of the use of chemotherapeutics for the treatment of Burkholderia infections.

Topics: Animals; Anti-Bacterial Agents; Burkholderia mallei; Burkholderia pseudomallei; Ceftazidime; Ciprofloxacin; Cricetinae; Doxycycline; Drug Resistance, Bacterial; Glanders; Humans; Melioidosis; Microbial Sensitivity Tests; Rats; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The time course of the clinical, biochemical and serological indices was studied during the treatment of malleus in monkeys. The internal organs of the animals infected with Pseudomonas mallei were investigated pathomorphologically. The efficacy of the biseptol/oxalinic acid combination in the therapy of malleus was estimated.

Topics: Animals; Anti-Infective Agents, Urinary; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Glanders; Liver; Lung; Male; Papio; Trimethoprim, Sulfamethoxazole Drug Combination