Synergistic Activities of Azithromycin and Amphotericin B against Naegleria fowleri In Vitro and in a Mouse Model of Primary Amebic Meningoencephalitis

Abstract

Naegleria fowleri is responsible for producing a rapidly fatal central nervous system infection known as primary amebic meningoencephalitis (PAM). To date, amphotericin B, an antifungal agent, is the only agent with established clinical efficacy in the treatment of PAM. However, amphotericin B is not always successful in treating PAM and is associated with severe adverse effects. We previously found azithromycin to be more effective than amphotericin B in a mouse model of PAM. We therefore investigated the combination of amphotericin B and azithromycin in vitro and in a mouse model of PAM. For the in vitro studies, 50% inhibitory concentrations were calculated for each drug alone and for the drugs in fixed combination ratios of 1:1, 3:1, and 1:3. We found amphotericin B and azithromycin to be synergistic at all three of the fixed combination ratios. In our mouse model of PAM, a combination of amphotericin B (2.5 mg/kg of body weight) and azithromycin (25 mg/kg) protected 100% of the mice, whereas amphotericin B alone (2.5 mg/kg) protected only 27% of mice and azithromycin alone (25 mg/kg) protected 40% of mice. This study indicates that amphotericin B and azithromycin are synergistic against the Lee strain of N. fowleri, suggesting that the combined use of these agents may be beneficial in treating PAM.Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. Victims are usually healthy young persons with a recent history of swimming or other water exposure. The ameba enters the nasal cavity during inhalation or aspiration of contaminated water and then migrates along the olfactory nerves, crosses the cribriform plate, and enters the central nervous system. Once in the brain, N. fowleri causes extensive inflammation, hemorrhage, and necrosis, leading to death in 3 to 7 days (15).The mortality of persons with PAM is Ͼ95% (3) owing to the rapid progression of the disease, the often delayed diagnosis, and the lack of effective therapeutic agents. A wide range of antiparasitic, antimicrobial, and other pharmacologic agents have been evaluated against N. fowleri, but most of these agents have shown limited activity against the protozoon (5, 7-9, 11, 26, 28, 29). Amphotericin B is the only agent with established clinical efficacy for PAM, and at least eight persons have been treated successfully with amphotericin B alone or in combination with other drugs (1,2,12,17,20,22,30,31). However, not all patients treated with amphotericin B either alone or in combination have survived PAM (6, 23-25). Moreover, amphotericin B is one of the most toxic antibiotics used today, and it may cause serious renal toxicity and electrolyte disturbances as well as hematopoietic effects and damage to other organs.We previously investigated the activities of novel agents against N. fowleri in vitro and in a mouse model of PAM in order to identify agents with potential clinical usefulness against this infection. In these studies, we found that azithromycin was highly active again...

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

“…A wide range of antiparasitic, antimicrobial, and other pharmacologic agents have been evaluated against N. fowleri, but these agents have shown limited activity against the pathogen (15,27,31). The current drug of choice in treating PAM is the antifungal antibiotic amphotericin B.…”

“…Amphotericin B may also cause anemia, and many patients experience chills, fever, nausea, vomiting, and headache (23,25). Moreover, only 10 persons with PAM have been treated successfully with amphotericin B, alone or in combination with other drugs (1,2,6,17,20,21,24,(28)(29)(30)(31)(33)(34)(35). Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM.…”

Amebiasis del sistema nervioso central: reporte de seis casos en el Perú

“…Diversas drogas han mostrado actividad contra amebas de vida libre en estudios in vitro, sin embargo la poca accesibilidad de los fármacos a las lesiones intracerebrales y la rápida evolución del proceso infeccioso presentan un reto a terapias en evaluación. Se han reportado al menos diez casos de B. mandrillaris tratados con una combinación de miltefosina, albendazol y fluconazol que lograron sobrevivir, tres de ellos en Perú, sin embargo, a pesar del uso de albendazol y fluconazol en el caso 6, su evolución fue tórpida y falleció a los tres días de tratamiento (5,(26)(27)(28) .…”

Cardiac Involvement with Parasitic Infections

“…Successful therapy has been rare, and when reported, amphotericin B is usually part of the therapy (51,294,330). In a mouse model of PAM, azithromycin and amphotericin B have demonstrated synergistic success and may hold promise as combination therapy (305).…”