Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models.

OBJECTIVES: As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens. METHODS: The efficacy of single versus multi-dose regimens of azithromycin was compared in mouse pneumonia, acute peritonitis, and neutropenic thigh infection models and in a gerbil model of Haemophilus influenzae acute otitis media. Azithromycin was administered as a single oral dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days. The pharmacokinetics of azithromycin was profiled following single and multi-dose regimens with the single dose data fit to an Emax model to characterize the PK-PD of azithromycin. RESULTS: In the mouse efficacy models, administration of single-dose azithromycin produced superior rates of survival and bacterial clearance compared with the same total dose divided over 2 or 3 days. In the gerbil model, a single dose sterilized the middle ear and more rapidly cleared H. influenzae. The pharmacokinetic evaluation confirmed similar total exposure (AUC) in serum and pulmonary tissue for the three regimens. Correlation of PK-PD parameters and antimicrobial efficacy confirmed a concentration-dependent and dosing-independent relationship for azithromycin. CONCLUSIONS: These data are consistent with data reported from clinical studies and indicate that a single-dose regimen would be at least as effective as the same dose administered over several days.

Rationale and design of a secondary prevention trial of antibiotic use in patients after myocardial infarction: the WIZARD (weekly intervention with zithromax [azithromycin] for atherosclerosis and its related disorders) trial.

Mounting evidence supports the contention that atherosclerosis is an inflammatory disease. Recently a possible role for infectious microorganisms has gathered attention. Chlamydia pneumoniae is one possible pathogen. If C. pneumoniae is a target organism, antibiotics with antichlamydial activity may be able to ameliorate plaque instability. The WIZARD trial is a secondary prevention study that is assessing the impact of a 3-month course of azithromycin compared with placebo on the progression of clinical coronary heart disease. The study will enroll 3300 patients who have had a prior myocardial infarction and who have a C. pneumoniae IgG titer of >/=1:16. The primary end point is a composite of time to either recurrent myocardial infarction, death, a revascularization procedure, or hospitalization for angina. This study is the first of a series of adequately powered clinical trials that will attempt to bridge insights from preclinical investigations to interventions applicable to patient care.

Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients.

This multicenter, randomized, dose-ranging study was performed to determine the safety and efficacy of two different doses of azithromycin for treating disseminated Mycobacterium avium complex (MAC) in patients with AIDS. Eighty-eight AIDS patients with symptoms and blood cultures consistent with disseminated MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62 patients completed the entire 6 weeks of study. Of note, this study was done prior to the time when combination antiretroviral or anti-MAC regimens were the standard of care. Over the 6-week study period, symptomatic improvement was noted in both dose groups. Microbiological responses were comparable, with mean decreases of 1. 5 and 2.0 log CFU/ml in the high- and low-dose groups, respectively. Sterilization of blood cultures occurred in 54% of samples; patients with lower baseline colony counts were more likely to achieve culture negativity. Resistance developed in one patient. Gastrointestinal symptoms were the most common side effects and were more frequent in patients receiving 1,200 mg. Azithromycin is a useful alternative treatment for disseminated MAC infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.

Efficacy of azithromycin in prevention of Pneumocystis carinii pneumonia: a randomised trial. California Collaborative Treatment Group.

BACKGROUND: Azithromycin in combination with sulphonamides is active against Pneumocystis carinii pneumonia (PCP) in animals. We assessed the clinical efficacy of azithromycin for PCP prophylaxis in human beings. METHODS: We identified HIV-1-infected patients with PCP during a prospective randomised trial comparing azithromycin, rifabutin, and the two drugs in combination for prevention of disseminated Mycobacterim avium infection. Patients had CD4-cell counts less than 100/microL at entry and received PCP prophylaxis according to the standard practice of their clinician. Analysis was by intention to treat. FINDINGS: Patients receiving azithromycin, either alone (n=233) or in combination with rifabutin (n=224), had a 45% lower risk of developing PCP than those receiving rifabutin alone (n=236; p=0.008). Compared with rifabutin alone, hazard ratio for azithromycin was 0.54 (95% CI 0.32-0.94), for azithromycin plus rifabutin was 0.55 (0.32-0.94), and for regimens containing azithromycin was 0.55 (0.35-0.86). The most common side-effects involved the gastrointestinal tract with dose-limiting toxicities, and were mainly seen in patients receiving combination therapy. INTERPRETATION: Azithromycin as prophylaxis for M. avium complex disease provides additional protection against P. carinii over and above that of standard PCP prophylaxis. Use of azithromycin is beneficial only as primary prophylaxis.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial.

We conducted a randomized, double-blind, placebo-controlled multicenter trial of azithromycin (1,200 mg once weekly) for the prevention of Mycobacterium avium complex (MAC) infection in patients with AIDS and a CD4 cell count of < 100/mm3. In an intent-to-treat analysis through the end of therapy plus 30 days, nine (10.6%) of 85 azithromycin recipients and 22 (24.7%) of 89 placebo recipients developed MAC infection (hazard ratio, 0.34; P = .004). There was no difference in the ranges of minimal inhibitory concentrations of either clarithromycin or azithromycin for the five breakthrough (first) MAC isolates from the azithromycin group and the 18 breakthrough MAC isolates from the placebo group. Of the 76 patients who died during the study, four (10.5%) of 38 azithromycin recipients and 12 (31.6%) of 38 placebo recipients had a MAC infection followed by death (P = .025). For deaths due to all causes, there was no difference in time to death or number of deaths between the two groups. Episodes of non-MAC bacterial infection per 100 patient years occurred in 43 azithromycin recipients and 88 placebo recipients (relative risk, 0.49; 95% confidence interval, 0.33-0.73). The most common toxic effect noted during the study was gastrointestinal, reported by 78.9% of azithromycin recipients and 27.5% of placebo recipients. Azithromycin given once weekly is safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections in patients with AIDS and CD4 cell counts of < 100/mm3.

Human immunodeficiency virus replication in AIDS patients with Mycobacterium avium complex bacteremia: a case control study. California Collaborative Treatment Group.

The development of opportunistic infections and the administration of vaccines have been associated with transient increases of human immunodeficiency virus (HIV) RNA plasma levels in HIV-infected patients. To determine the relationship between Mycobacterium avium complex (MAC) bacteremia and HIV RNA levels, HIV RNA levels in patients who developed MAC bacteremia (cases) were compared with levels in patients who remained free of MAC disease (controls). Cases and controls were matched for CD4 cell count, prophylaxis against MAC disease, antiretroviral therapy, and duration of follow-up. Mean baseline HIV RNA levels were 4.8 log10 copies/mL in cases and 4.6 log10 copies/mL in controls (P = 0.22). HIV RNA levels increased by a median of 0.4 log in cases but not controls at the time of MAC bacteremia (P = 0.01). In AIDS patients, the onset of MAC bacteremia is associated with a modest but significant increase in serum HIV RNA levels. Increased HIV replication may contribute to the higher mortality associated with MAC bacteremia.

Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya.

Azithromycin prevents malaria in animal models and early clinical trials. We determined the prophylactic efficacy of three antibiotic regimens given for 10 weeks (azithromycin, 250 mg daily; azithromycin, 1,000 mg weekly; and doxycycline, 100 mg daily) relative to that of placebo for 232 adult volunteers residing in an area of intense malaria transmission. Any confirmed parasitemia during the study was considered a prophylactic failure. Two hundred thirteen volunteers (92%) completed the study. The prophylactic efficacies were as follows: daily azithromycin, 82.7% (95% confidence interval [CI], 68.5%-91.1%); weekly azithromycin, 64.2% (95% CI, 47.1%-77.1%); and daily doxycycline, 92.6% (95% CI, 79.9%-97.5%). All regimens were well tolerated. We concluded that both 100 mg of doxycycline and 250 mg of azithromycin, given daily, were effective as prophylaxis for malaria in this setting. If studies with nonimmune volunteers confirm these results for semi-immune volunteers, a daily azithromycin regimen may have special utility for individuals with contraindications to treatment with doxycycline or other antimalarial agents.

Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group.

BACKGROUND: Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS: We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS: In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS: For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.