TreatmentUpdate40: February 1993
Sean Hosein

CLARITHROMYCIN

Researchers in New York have been performing experiments on mice infected with MAC and testing various doses of clarithromycin and several other drugs. They have found that a combination of clarithromycin with clofazimine or rifabutin showed increased anti-MAC activity compared with clarithromycin alone. The researchers also suggest that these combinations be tested in experiments on HIV-infected subjects. Other results from their experiments found that clarithromycin together with one of amikacin, ethambutol, temafloxacin or rifampin did not provide superior anti-MAC activity to that seen with clarithromycin alone. Other researchers plan to use high doses of rifabutin (450 to 900 mg/day) as part of an anti-MAC combination therapy. Doctors in Paris have recently reported on their experience in treating nearly 200 patients with MAC. They recommend use of clarithromycin in doses of 30 mg/kg/day. Although some patients may develop symptoms of toxicity such as nausea, elevated liver enzymes and reduction in the ability to hear sounds, the French doctors recommend that therapy be continued until the infection has been brought under control. When the French doctors tried to add drugs such as ciprofloxacin, ofloxacin or sparfloxacin in patients already taking clarithromycin, the combinations proved to be too toxic. The doctors found that a combination of clarithromycin with ethambutol in doses of 20 to 25 mg/ kg/day to be more useful. One of the problems in treating patients with widespread MAC infection is thaL drugs given orally may not always be absorbed.

Others are still experimenting with standard anti-MAC/ tuberculosis drugs. Doctors at UCLA tested various combinations of two drugs at a time. The drugs used were etharnbutol, rifampin and clofazimine in subjects with MAC whose average CD4+ count was 30 cells. Drugs were given in the following doses: clofazimine 200 mg/ day, ethambutol 15 mg/kg/day, rifampin 10 mglkg/day. No combination of two of the 3 drugs produced statistically significant benefits. A problem associated with rifampin is that it can reduce blood levels of methadone and may also cause nausea and loss of appetite. SULPHA DRUGS

In laboratory experiments with cells and MAC, sulpha drugs clearly have anti-MAC effects. There is little information on the potential for drugs such as Bactrim/Septra to treat or prevent MAC infection. Doctors at the UCLA School of Medicine have recently reported their results in treating a MAC-infected patient with Bactrim/Septra. The patient (who did not have HIV infection) had night sweats, fevers, sustained weight loss as well as abscesses in his chest. He was given Bactrim/Septra (320 mg trimethoprim and 1600 mg sulpha) twice per day. Leucovorin in a dose of 5 mg/day was also prescribed to reduce the bone marrow toxicity of the antibiotics. The patient's symptoms decreased and he stopped taking the drugs after 4 months of treatment. Two months later he died from a bacterial infection. The doctors suggest that sulpha drugs alone are unlikely to have significant anti-MAC action. They suggest that data from the American study ACTG 021 be examined to see if subjects who received Bactrim/Septra were protected from MAC infection. Researchers at military bio-medical centres in the USA have confirmed that Bactrim/Septra has anti-MAC activity in laboratory experiments and also suggest that the drug be considered as a treatment for MAC infection

SPAR (SPARFLOXACIN)

This drug "related" to ciprofloxacin is a Japanese antibiotic being tested by Warner-Lambert/Parke-Davis in North America and Rhone-Poulenc in the EC. In laboratory experiments the drug has anti-MAC effects. Sparfloxacin remains in the blood for a relatively long period of time so in some trials the drug is given only twice daily. We have preliminary results from a trial in the USA. Doctors enrolled 45 subjects with AIDS and randomly assigned 23 to receive sparfloxacin 200 mg/day and the remaining 22 to 300 mg/day, both for 4 weeks. At the end of that time they were given the antibiotic ethambutol in a dose of 15mg/kg of body weight/day for 8 weeks. Unfortunately, the researchers found that subjects did not have significant recovery from MAC infection and 11 died. Some subjects did have reduced blood levels of MAC while in the study. Another trial is planned where the dose of sparfloxacin is to be increased to 400 mg/day, which is the dose being tested in France.

LIPOSOMAL GENTAMICIN (TLC G-65)

As MAC infects the cells of the immune system, antiMAC drugs need to penetrate these cells and the parasites within. Packaged into tiny spheres of fat called liposomes, the antibiotic gentamicin (now described as liposomal gentamicin) can penetrate into MAC-infected cells in the spleen, liver and lungs. In experiments on people with HIV infection, liposomal gentamicin has been given intravenously in a dose of 1.7 mg/kg of body weight twice weekly for 4 weeks. No drug resistance developed and blood levels of MAC fell by 90% by the 4th week of the study. Subjects had reductions in symptoms such as night sweats and fevers. However, diarrhea, fatigue and unintentional weight loss continued. As the drug appears to have increased anti-MAC effect when tested with clarithromycin, the Liposome company may test liposomal gentamicin together with clarithromycin.

REFERENCES:

1. Klemans SP, DeStefano MS, and Cynamon MH. Activity of clarithromycin against Mycobacterium aviwn complex infection in beige mice. Antimicrobial Agents and Chemotherapy 1992;36(1 1):2413-2417.

2. Dautzenberg B, Hazebroucq J, Chauvin JP, and the French Clarithromycin trial group (abstract 893). In:Program and abstracts of the 32nd Interscienee Conference on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Microbiology, 1992:259.

3. Kemper C, Havlir D, Haghighat D, et al. Effect of ethambutol, rifampin, and clofazimine in combinations of two on Mycobacterium avium bacteremia (abstract 894). In: Program and abstracts of the 32nd Interscienee Conferenee on Antimicrobial Agents and Chemotherapy(Anaheim). Washington, DC:American Society for Microbiology, 1992:259.

4. Gordon S, Horsburgh R, Havlik J, et al. Impaired absorption of oral regimen in treaLment of disseminated Mycobacterium avium complex infection (abstract 896). In: Program and abstracts of the 32nd Interscience Conferenee on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Microbiology, 1992:260.

5. Young LS, Wu M, Bender J, and the Sparfloxacin study group. Pilot study of sparfloxacin for Mycobacterium avium complex bacteremia complicating AIDS. (abstract 897). In: Program and abstracts of the 32nd Interscience Conferenee on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Micmbiology, 1992:260.

6. Nightingale S, Saletan S, Swenson C, et al. Phase I/II study of TLC G-65 (liposomal encapsulated gentamicin) for treatment of Mycobacterium aviwn complex disease (abstract 898). In: Program and abstracts of t'ne 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Microbiology, 1992:260

7.Chang WJ and Goetz MV. Response to treatment of infection due to Mycobacteriwn aviwn complex wilh trimethoprim-sulpha methoxazole. Clinical Infectious Diseases 1992; 14: 1267- 1268.

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