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The genomic DNA patterns (genotypes) of 55 episodes of late positive sputum isolates, collected after >or=4 consecutive months of negative sputum cultures, in prospective macrolide treatment trials of Mycobacterium avium complex (MAC) lung disease were assessed by pulsed-field gel electrophoresis (PFGE). Having >or=2 cultures positive for MAC after completion of therapy was documented 23 times; of 20 episodes studied by PFGE, 17 (85%) represented new genotypes (i.e., new infections), and 87% occurred in patients with nodular bronchiectasis. With >or=2 positive cultures after therapy was stopped prematurely, 6 (86%) of 7 episodes were relapses. Single positive cultures after completion of therapy occurred 16 times; only 1 (6%) was predictive of a subsequent relapse. No late isolates were macrolide resistant. Thus, relapses of MAC lung disease with these macrolide regimens are unusual, and most infections after completing therapy resulted from new strains in patients with nodular bronchiectasis.

Ninety-two patients were assessable in 3 consecutive, open, noncomparative, prospective, controlled, single-center trials of the use of multidrug regimens that contain azithromycin for treating pulmonary Mycobacterium avium complex (MAC) disease. Azithromycin was provided at a dose of 300-600 mg per day with oral companion drugs administered daily (regimen A, 29 patients); 600 mg 3 times weekly (t.i.w.), with oral companion drugs administered daily (regimen B, 20 patients); and 600 mg (t.i.w.), with oral companion drugs administered t.i.w. (regimen C, 43 patients). All regimens included rifabutin (or rifampin) and ethambutol as companion drugs as well as initial streptomycin. Treatment success was defined as 12 months of negative cultures while on therapy. Treatment failure was defined as sputum culture positivity after at least 6 months of therapy. Of the patients in each regimen who reached study end points, 17 of 29 (59%) were in regimen A, 11 of 20 (55%) were in regimen B, and 28 of 43 (65%) were in regimen C met the treatment success criterion. There were no statistically significant differences in outcome between the 3 regimens. These studies demonstrate the effectiveness of daily and t.i.w. regimens containing azithromycin for treatment of MAC lung disease.

To evaluate the immunologic factors that contribute to protection against Mycobacterium avium complex (MAC), cytokine production by peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus-negative persons with pulmonary MAC (MAC patients) and healthy control subjects with a delayed hypersensitivity skin test response to M. avium sensitin (MAS-positive control subjects) was measured. In MAC patients, mycobacterium-stimulated PBMC produced higher concentrations of interleukin (IL)-10 but lower concentrations of interferon (IFN)-gamma, IL-12, and tumor necrosis factor (TNF)-alpha, compared with PBMC from MAS-positive control subjects. Immunolabeling for intracellular IL-10 revealed that this cytokine was produced by both monocytes and T cells. Alveolar macrophages produced TNF-alpha and IL-10 in response to MAC, which suggests that these cytokines are produced in the lungs of patients with pulmonary disease caused by this pathogen. Our findings suggest that IFN-gamma, TNF-alpha, and IL-12 contribute to protection against MAC, whereas IL-10 is immunosuppressive.

Two consecutive, open, prospective trials of intermittent azithromycin (600 mg), usually given Monday, Wednesday, and Friday (TIW) for Mycobacterium avium complex (MAC) lung disease were initiated in human immunodeficiency virus-negative patients. Regimen A consisted of TIW azithromycin and daily ethambutol (15 mg/kg/day), daily rifabutin (300 mg/day), and initial twice weekly (BIW) streptomycin. Regimen B consisted of TIW azithromycin, TIW ethambutol (25 mg/kg/dose), TIW rifabutin (600 mg/dose), and initial BIW streptomycin. Of 19 patients enrolled in regimen A who completed at least 6 months of therapy, 14 (74%) had sputum samples become culture-negative. Of 39 patients enrolled in regimen B who completed at least 6 months of therapy, 24 (62%) had sputum conversion. These sputum conversion rates are comparable to previous rates at 6 months in patients receiving daily clarithromycin- or azithromycin-containing regimens. No resistance to azithromycin emerged with either regimen. This is the first study to demonstrate the efficacy of intermittent administration of medication for MAC lung disease.

We initiated a prospective trial of an azithromycin-containing regimen for the treatment of human immunodeficiency virus-negative patients with Mycobacterium avium complex (MAC) lung disease; the initial 4 months of therapy were with azithromycin (600 mg/d) alone. The primary study endpoint was microbiological response measured at 4 and 6 months of therapy. Of 29 patients enrolled in the study, 23 completed therapy. Fifty-two percent of these 23 patients were male, and 65% were smokers. All 23 patients were older than 45 years of age; 83% had bilateral disease, and 48% had fibrocavitary disease. Macrolide (clarithromycin)-susceptible MAC isolates were recovered from these 23 patients before treatment. Cultures of sputum from 38% of these patients became negative, and the positivity of cultures of sputum from 76% of these patients was significantly reduced. Sixty-eight percent of sputum cultures were strongly positive (> 200 colonies) before therapy, while only 27% were strongly positive after therapy. Although most patients continued to receive 600 mg of azithromycin/d, the high incidence of gastrointestinal side effects (76%) and altered hearing (41%) suggests the need for lower or less frequent dosing. Macrolide (clarithromycin) resistance did not develop in any MAC isolates during monotherapy. These results, which demonstrate that azithromycin is active against MAC pulmonary disease, provide a rationale to include this drug in the initial multidrug regimens recommended for the treatment of this disease.

Intermediate results of the first 50 patients treated with clarithromycin (CLARI) regimens for Mycobacterium avium-intracellulare (MAI) lung disease were evaluated. Patients were HIV negative, and pretreatment isolates were susceptible to CLARI. Patients received CLARI 500 mg twice daily, ethambutol, rifampin (RMP), or rifabutin (RBT) and initial streptomycin, and they were treated until culture-negative 1 yr. Eleven of 50 patients (22%) were dropped in the first 3 mo. Of the remaining 39 patients, 36 (92%) converted their sputa to negative, and 32 (82%) remain culture negative to date. This includes 11 of 16 (69%) with prior drug therapy and 21 of 23 (91%) with no prior therapy. One or more companion drugs were discontinued in 16 of 39 (41%) of patients because of adverse events. Isolates from six of 39 patients (15%) became CLARI-resistant. Of 23 patients who are alive and were culture-negative a mean of 12.0 mo while receiving therapy, all remain culture-negative without therapy a mean of 19.1 mo. Despite reduced CLARI serum levels in patients also receiving RMP, 10 of 13 patients (77%) receiving this regimen were successfully treated. Although not directly compared with previous regimens, the success of this regimen strongly suggests it is superior to previous non-CLARI-containing regimens.

We initiated a multidrug trial that included high-dose rifabutin for the treatment of pulmonary Mycobacterium avium complex (MAC) disease. Twenty-six patients received rifabutin (600 mg/d) in combination with ethambutol, streptomycin, and either clarithromycin (500 mg b.i.d.; 15 patients) or azithromycin (600 mg/d; 11 patients). Rifabutin-related adverse events occurred in 77% of patients. Fifty-eight percent of patients required a dosage adjustment or discontinuance of rifabutin therapy. The most common adverse event was a reduction in the mean total white blood cell (WBC) count, which decreased from 8,600 +/- 2,800/mm3 before treatment to 4,500 +/- 2,100/mm3 during treatment (P = .0001). Although all patients had some decrease in WBC count, only three patients (12%) required a dosage adjustment for this reason. Other common adverse events included gastrointestinal symptoms (nausea, vomiting, or diarrhea; 42%) and abnormal liver enzyme levels (12%). Eight of 11 patients (73%) with gastrointestinal symptoms, including one patient with abnormal liver enzyme levels, required a rifabutin-dosage adjustment. The most severe adverse events, always requiring an adjustment of therapy, were a diffuse polyarthralgia syndrome (19%) and anterior uveitis (8%). The latter toxicity has previously been reported to occur only in patients with AIDS and was seen only in patients who also were receiving clarithromycin. On the basis of the current findings, we recommend that rifabutin be used at a dose of 300 mg/d in multidrug regimens that include a macrolide for treatment of MAC lung disease.

Sputum conversion rates in Mycobacterium avium-intracellulare (MAI) complex lung disease have ranged from only 50 to 80% despite the use of three to five antituberculosis agents. We initiated a prospective, open, noncomparative trial of initial clarithromycin monotherapy at 500 mg twice a day for 4 months in HIV-negative patients with MAI lung disease. The primary study end point was microbiologic improvement. Of 30 patients enrolled, 20 completed therapy. This latter group was predominantly male (60%), smokers (70%), older than 45 yr of age (90%), infected with Mycobacterium intracellulare (70%) and with bilateral disease (85%). Of 19 patients with pretreatment minimum inhibitory concentrations (MIC) for clarithromycin < 16 micrograms/ml, 58% became sputum-negative, and 21% showed significant reductions in sputum positivity. Heavily positive sputum cultures (> 200 colonies) were reduced from 30 to 47 samples pretherapy (64%) to three of 54 (6%) post-therapy (p < 0.0001); 18 of 19 patients (95%) showed an improvement in sputum cultures, chest radiographs, or both. Only two patients (7%) discontinued the drug because of adverse events. Only three (16%) of 19 isolates developed clarithromycin resistance (MIC > 32 micrograms/ml). Clarithromycin-susceptible and -resistant MAI isolates from the same patient had identical DNA large-restriction fragment patterns. Clarithromycin is the first single agent to be shown efficacious in the treatment of MAI lung disease.