Determination of the Postexposure Prophylactic Benefit of Oral Azithromycin and Clarithromycin Against Inhalation Anthrax in Cynomolgus Macaques.

BACKGROUND: Sufficient and diverse medical countermeasures against severe pathogenic infections, such as inhalation anthrax, are a critical need. Azithromycin and clarithromycin are antimicrobials commonly used for both upper and lower respiratory infections. They inhibit protein synthesis by blocking the formation of the 50S ribosomal subunit. To expand the armamentarium, these 2 antibiotics were evaluated in a postexposure prophylactic model of inhalation anthrax in cynomolgus macaques. METHODS: This prophylaxis study had 4 test arms: azithromycin, clarithromycin, a levofloxacin control, and a placebo. Beginning 24 hours after exposure to a target challenge dose of 200 lethal dose 50 (LD50) of Bacillus anthracis Ames spores, animals were treated orally until 30 days postchallenge and then observed until 75 days postchallenge. RESULTS: The test group that received clarithromycin had a survival rate of 67%. The test group that received azithromycin had a survival rate of 50%, but the peak azithromycin plasma levels achieved were <30 ng/mL-much lower than the expected 410 ng/mL. The levofloxacin positive control had a survival rate of 50%; all of the negative controls succumbed to infection. CONCLUSIONS: The efficacy of clarithromycin prophylaxis was statistically significant compared with placebo, while azithromycin prophylaxis was indistinguishable from placebo. Given the low plasma concentrations of azithromycin achieved in the study, it is not surprising that half the animals succumbed to anthrax during the dosing period; the animals that survived beyond the time during which placebo control animals succumbed survived to the end of the observation period.

Evaluation of Amoxicillin and Amoxicillin-Clavulanate (Augmentin) for Antimicrobial Postexposure Prophylaxis Following Bacillus anthracis Inhalational Exposure in Cynomolgus Macaques.

Amoxicillin is a broad-spectrum antibiotic used to treat a variety of gram-positive and gram-negative infections, such as infections of the ear, nose, and throat, genitourinary tract, skin, and lower respiratory tract; gonorrhea; and Helicobacter pylori. The prophylactic benefit of both amoxicillin and Augmentin (amoxicillin-clavulanate for use against ß-lactamase-expressing bacteria) was evaluated for inhalation anthrax in cynomolgus macaques in 2 studies. A pilot study on amoxicillin-clavulanate that used a portion of the study animals demonstrated empirically that dosing twice a day was efficacious. In a subsequent study on both amoxicillin and amoxicillin-clavulanate that used the remaining study animals, the animals were treated orally every 12 hours on days 1-28 postchallenge and followed for an additional 60 days (total of 88 days from day of aerosol challenge to when the animals were culled). The animals from each treatment arm of the 2 studies were completely protected. All untreated animals succumbed to the infection. The degree of protection observed in this study suggests that both amoxicillin and amoxicillin-clavulanate, administered prophylactically over a period of 28 days after a lethal exposure to Bacillus anthracis spores, is sufficient for full protection.

Pre- and Postlicensure Animal Efficacy Studies Comparing Anthrax Antitoxins.

BACKGROUND: The deliberate use of Bacillus anthracis spores is believed by the US government to be a high bioweapons threat. The first line of defense following potential exposure to B. anthracis spores would be postexposure prophylaxis with antimicrobials that have activity against B. anthracis. Additional therapies to address the effects of toxins may be needed in systemically ill individuals. Over the last 2 decades, the United States government (USG) collaborated with the private sector to develop, test, and stockpile 3 antitoxins: anthrax immunoglobulin intravenous (AIGIV), raxibacumab, and obiltoxaximab. All 3 products target protective antigen, a protein factor common to the 2 exotoxins released by B. anthracis, and hamper or block the toxins' effects and prevent or reduce pathogenesis. These antitoxins were approved for licensure by the United States Food and Drug Administration based on animal efficacy studies compared to placebo. METHODS: We describe USG-sponsored pre- and postlicensure studies that compared efficacy of 3 antitoxins in a New Zealand White rabbit model of inhalation anthrax; survival following a lethal aerosolized dose of B. anthracis spores was the key measure of effectiveness. To model therapeutic intervention, intravenous treatments were started following onset of antigenemia. RESULTS: In pre- and postlicensure studies, all 3 antitoxins were superior to placebo; in the postlicensure study, raxibacumab and obiltoxaximab were superior to AIGIV, but neither was superior to the other. CONCLUSIONS: These data illustrate the relative therapeutic benefit of the 3 antitoxins and provide a rationale to prioritize their deployment.