A unique response to staphylococcal enterotoxin B by intrahepatic lymphocytes and its relevance to the induction of tolerance in the liver

Unusual before AIDS epidemic, non tuberculosis mycobacterial infections were observed in HIV-infected patients with CD4 cells count less than 75/mm3. Primary prophylaxis with rifabutin, clarithromycin or azythromycin may be used. Secondary prophylaxis are necessary with association of two or three drugs among clarithromycin, azythromycin, ethambutol and rifabutin. In immunocompromised patients, without HIV infection, risk of disseminated infection seems lower, but no study evaluate it.     

Nontuberculous mycobacterial infections

The acquired immunodeficiency syndrome (AIDS) pandemic has led to greater understanding and respect for the pathogenic potential of non-tuberculous mycobacteria. Mycobacterium avium complex (MAC) has emerged as the most common systemic bacterial infection in AIDS, causing debilitating disseminated disease in late-stage HIV-infected patients. With the release of the macrolide antibiotics, clarithromycin and azithromycin, effective and well-tolerated therapeutic regimens for MAC have been developed which prolong survival and increase quality of life. The macrolides and rifabutin are also effective as preventive therapy for MAC in patients with AIDS. Mycobacterium kansasii, which causes pulmonary disease similar to tuberculosis as well as disseminated disease in AIDS, is treatable with isoniazid, rifampin and ethambutol. Clinical syndromes and therapeutic options for other non-tuberculous mycobacteria in AIDS are also reviewed.     

Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium

Disseminated Mycobacterium avium complex (MAC) infection continues to be a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). The optimal therapy for disseminated MAC infection is unclear. We compared azithromycin plus ethambutol with clarithromycin plus ethambutol in the treatment of disseminated MAC infection in HIV type 1-infected patients, examining the frequency of bacteremia clearance, time to clearance, and study drug tolerance after 16 weeks of therapy. Fifty-nine patients for whom blood cultures were positive for MAC were enrolled in the study from 10 university-affiliated Veterans Affairs Medical Centers. Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in 37.5% of azithromycin-treated patients and in 85.7% of clarithromycin-treated patients (P = .007). The estimated median time to clearance of bacteremia was also significantly different between the two treatment arms: 4.38 weeks for clarithromycin recipients vs. > 16 weeks for azithromycin recipients (P = .0018). Only one isolate developed macrolide resistance during therapy. Abatement of symptoms, other laboratory-evident abnormalities, and adverse effects were similar in the two groups. At the doses used in this study, clarithromycin/ethambutol produced a more rapid resolution of bacteremia than did azithromycin/ethambutol, and clarithromycin/ethambutol was more effective at sterilization of blood cultures after 16 weeks of therapy.     

Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.     

Clinical features and outcome in disseminated mycobacterial diseases in AIDS patients in Taiwan

OBJECTIVE: To describe and compare the clinical features and outcome of disseminated tuberculosis (TB) and Mycobacterium avium complex (MAC) disease in AIDS patients. DESIGN: Prospective cohort study. SETTING: A 1800-bed university teaching hospital, the largest centre for HIV/AIDS patients in Taiwan. METHODS: From July 1994 through June 1997, a standardized protocol was used to record the demographic and clinical features in all hospitalized HIV-infected patients, and to perform routine studies and invasive procedures for diagnosis of disseminated mycobacterial diseases. To compare the survival, control patients were selected from the HIV-infected patients hospitalized in the same hospital during the same study period, and had similar age, sex, CD4+ cell counts and antiretroviral therapy regimens. RESULTS: A total of 22 cases of disseminated TB and 15 cases of disseminated MAC were identified. Disseminated TB and MAC occurred in patients with similarly low CD4+ cell counts (median, 23 versus 5 x 10(6)/l; P = 0.08). The clinical features favouring disseminated TB included night sweats, peripheral lymphadenopathy, acid-fast bacilli in sputum smears, chest radiographic findings of hilar enlargement, and lack of prior AIDS-defining illnesses. Hepatosplenomegaly, elevated serum alkaline phosphatase (more than twice the upper limit of normal), elevated serum gamma-glutamyl transpeptidase (more than three times the upper limit of normal), and leukopenia favoured disseminated MAC. The patients with disseminated TB survived much longer than patients with disseminated MAC (mean survival, 96 versus 22 weeks, P = 0.008) but had a similar outcome to control patients (P = 0.60). CONCLUSION: Disseminated TB and MAC are distinguishable by clinical features in AIDS patients with similar immunocompromised states. Those features may facilitate diagnosis and selection of specific therapeutic regimens. Disseminated TB was not associated with a shortened survival period in AIDS patients when they completed anti-TB treatment. In contrast, disseminated DMAC was associated with shortened survival despite treatment with potent regimens. These results may emphasize the importance of prophylaxis for MAC in this population.     

Activity of rifabutin, clarithromycin, ethambutol, sparfloxacin and amikacin, alone and in combination, against Mycobacterium avium complex in human macrophages

Disseminated infection with Microbacterium avium complex (MAC) in patients with AIDS is currently treated with a combination of antimycobacterial agents in order to prevent the selection of resistant mutant strains. Although clinical and microbiological responses can generally be achieved within a few weeks, relapses are common and require modification of the combination regimen or identification of effective alternate therapies. In this study we investigated the activities of rifabutin 0.5 mg/L, sparfloxacin 1 mg/L, clarithromycin 4 mg/L, amikacin 16 mg/L and ethambutol 2 mg/L, alone and in combination, against nine strains of M. avium isolated from the blood of patients with AIDS in order to identify regimens with the greatest therapeutic potential. Macrophages derived from human monocytes were infected with M. avium and inoculated with a single drug or a combination of drugs; cfu counts were performed at 0, 4 and 7 days after infection. At day 4 and at day 7, the combination of rifabutin, clarithromycin, amikacin and sparfloxacin displayed the highest degree of activity. However, the activity did not differ significantly from that of the combination of rifabutin, clarithromycin and ethambutol. The results of this study confirm the activity of combinations including rifabutin and clarithromycin (+/- ethambutol) in human monocyte-derived macrophages and suggest potentially useful associations in incorporating sparfloxacin and amikacin.     

New trends in the drug therapy of localized and disseminated Mycobacterium avium complex infection

Recent advances in the drug therapy of localized and disseminated infection with Mycobacterium avium complex (MAC) are reviewed. MAC infection is the most commonly reported bacterial infection in patients with AIDS, and the frequency of this infection in patients negative for the human immunodeficiency virus (HIV) is increasing. The main portals of entry for MAC are the gastrointestinal and respiratory tracts. Localized MAC infection is more common in HIV-negative than HIV-infected patients. The symptoms of disseminated MAC disease are those typical of advanced HIV disease. The most reliable diagnosis is provided by blood cultures; radiometric culturing techniques are favored. The overall treatment of MAC infection has improved greatly with the introduction of new agents during the past 15 years; survival time has been extended. Clarithromycin and azithromycin have proven effective against both localized and disseminated MAC infection. Clarithromycin is the cornerstone of therapy for disseminated infection. Ciprofloxacin has been successfully used to treat disseminated infection as part of a four-drug regimen including rifampin, ethambutol, and clofazimine. Rifabutin has substantial efficacy when combined with other agents. Liposomal aminoglycosides, such as amikacin, and interferon gamma have shown some initial promise. Rifabutin is currently recommended for the prevention of MAC disease in HIV-infected patients. Clarithromycin and azithromycin have also shown efficacy for prophylaxis, and fluoroquinolones may play a preventive role as well. New drug therapies are improving the outlook for persons infected with MAC.     

Prevalence of gallstones in the neonatal period]

The prevalence of infection with Mycobacterium avium complex (MAC) has increased since the outbreak of the HIV pandemic. This complex comprises two organisms: M. avium (mostly) and M. intracellulare (rarely). The source of MAC infection is not known. The principal risk factors for disseminated MAC infection in a patient with HIV infection are a low CD4 count and a previous opportunistic infection. The symptoms of disseminated MAC infection resemble those of HIV wasting; a positive culture of normally sterile tissue confirms a MAC infection. There is reserve with regard to routine prophylaxis in HIV-infected persons because of the possible development of resistance, interaction with other drugs used in AIDS, toxicity and possible absorption disorders which might cause prophylaxis to fail. For the treatment of disseminated MAC infection, a combination of at least two medicaments (macrolides and ethambutol) is recommended.     

Treatment and prophylaxis of disseminated Mycobacterium avium complex in HIV-infected individuals

OBJECTIVE: To review the pathophysiology, epidemiology, treatment, and prophylaxis of disseminated Mycobacterium avium complex (MAC) infection in HIV-infected individuals. DATA SOURCES: A MEDLINE (January 1966-July 1997) and AIDSLINE (January 1980-July 1997) search of basic science articles pertinent to the MAC infection in HIV-infected patients. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. DATA SYNTHESIS: The organism, epidemiology, and pathophysiology of disseminated MAC are discussed for background. A review of clinical trials for the treatment and prophylaxis of disseminated MAC are presented, along with unresolved issues concerning these topics. CONCLUSIONS: The incidence of disseminated MAC has increased dramatically with the AIDS epidemic. The infection can lead to increased morbidity and mortality in HIV-infected patients. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin. Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50/mm3.     

Developmental toxicity of 4-substituted amphetamines in mice

Until recently, therapy for most Nontuberculous Mycobacterial (NTM) disease, especially disease caused by Mycobacterium avium-complex (MAC), has been difficult and frustrating. The introduction of the newer macrolides (clarithromycin and azithromycin) has significantly added to the efficacy of regimens for both disseminated and pulmonary MAC disease. Clinical activity of these agents is lost when a MAC isolate develops in-vitro resistance that is facilitated by use of the macrolides as single agents. These valuable drugs should, therefore, never be used as single agents for the treatment of disseminated or pulmonary MAC disease. The newer macrolides also show promise for the treatment of other NTM infections such as those caused by M. abscessus, M. fortuitum, M. chelonae, M. xenopi, M. marinum, M. haemophilum, and M. genavense. Rifabutin, a derivative of rifamycin S, is an effective agent for prophylaxis against disseminated MAC and may have utility for treatment of pulmonary and disseminated MAC disease. Interactions between clarithromycin and rifamycin may alter efficacy of the macrolide and enhance toxicity of rifabutin. Although therapy of many NTM infections remains difficult with somewhat unpredictable results, the introduction of newer drugs, particularly the macrolides, has appreciably improved a previously dismal outlook for successful therapy.     

Inducing properties of rifabutin, and effects on the pharmacokinetics and metabolism of concomitant drugs

Rifabutin, a rifamycin derivative like rifampicin, has been registered for the treatment of pulmonary tuberculosis and for the prophylaxis and treatment of MAC in patients with AIDS. Rifabutin induces cytochrome P-450 3A4. The effect of rifabutin on the pharmacokinetics and metabolism of drugs administered concomitantly to humans (isoniazid, ethambutol, zidovudine, didanosine, delavirdine, fluconazole, itraconazole, methadone, clarithromycin, theophylline and cyclosporin) has been reviewed.     

Effect of anesthetic technique on cardiac morbidity following carotid artery surgery

Clarithromycin and rifabutin are among the most promising drugs for the therapy of infections caused by Mycobacterium avium or other atypical mycobacteria. Since synergism of combined drugs is important in order to achieve strong antimycobacterial activity, the combined inhibitory effects of antibacterial agents should also be investigated when agents are evaluated for possible use in antimycobacterial drug therapy. In the present study we examined the antimycobacterial activity of clarithromycin, rifabutin, and their combination against 51 clinical isolates of the M. avium complex from patients with acquired immune deficiency syndrome (AIDS) with disseminated mycobacteriosis. A concentration-dependent inhibition was seen for each drug. The antibacterial effect was significantly more pronounced for the combined drugs than for the agents tested separately. Synergism, against up to 88% of the strains tested, was seen for the tested drugs combined at different concentrations. All 51 M. avium strains were susceptible to the combination of 4 mg/l clarithromycin and 2 mg/l rifabutin.     

Survival analysis of two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex in AIDS

OBJECTIVES: Rifabutin prophylaxis has been shown to significantly decrease the incidence of Mycobacterium avium complex (MAC) bacteremia in two randomized controlled clinical trials, but a survival benefit has not been observed. An analysis of complete follow-up of these patients through August 1992 was performed to assess subsequent survival, because although follow-up in the previous trials was limited at the time of initial analysis, the analysis did suggest that a survival benefit might be emerging. METHODS: Data from 1146 AIDS patients with CD4+ counts < or = 200 x 10(6)/l enrolled at 73 US and Canadian sites in two clinical trials of MAC prophylaxis were analyzed using Cox proportional hazards analysis with rifabutin use modeled as a time-dependent covariate, taking into account the initial randomized double-blind phase of the trials and the subsequent open-label phase of follow-up of those patients. Survival from date of enrollment was analyzed. Other covariates adjusted for in the analysis were CD4+ lymphocytes count, Karnofsky performance score and hospitalization for opportunistic complications of AIDS. RESULTS: Patients who received open-label rifabutin may have had a better prognosis than those who did not, based on Karnofsky score and occurrence of opportunistic disease. Adjusting for these variables and for use of rifabutin as time-dependent covariates, the relative hazard (RH) of dying while receiving rifabutin prophylaxis was 0.74 for the entire cohort [95% confidence interval (CI), 0.60-0.91; P < 0.004]. For patients with an enrollment CD4+ count < or = 50 x 10(6)/l (n = 655), the RH was 0.75 (95% CI, 0.58-0.98), and for patients with an enrollment CD4+ count of > 50 x 10(6)/l (n = 491), the RH was 0.69 (95% CI, 0.49-0.99). CONCLUSIONS: An analysis of the combined double-blind and open-label follow-up of two clinical trials of rifabutin prophylaxis for MAC supports the suggestion of the double-blind study that rifabutin improves survival of AIDS patients.     

Population pharmacokinetics of rifabutin in human immunodeficiency virus-infected patients

Rifabutin pharmacokinetics were studied by the population approach (NONMEM) with 40 human immunodeficiency virus-infected patients receiving rifabutin at different doses for prophylaxis or therapy of mycobacterial infections. A two-compartment open model with first-order absorption was used as the structural pharmacokinetic model. Parameter estimates were the absorption rate constant (0. 201/h), clearance/bioavailability (CL/F; 60.9 liters/h), volume of the central compartment/bioavailability (231 liters), intercompartmental clearance (60.3 liters/h), and volume of the peripheral compartment/bioavailability (Vp/F; 1,050 liters). The distribution and elimination half-lives were 1.24 and 25.4 h, respectively. The covariates tested for influence on CL/F and Vp/F were sex, age, weight, height, body surface area, tobacco smoking, drug addiction, alanine aminotransferase levels, creatinine clearance, total protein, bilirubin, numbers of CD4(+) cells, presence of diarrhea, cachexia index, rifabutin use (prophylaxis versus therapy), rifabutin dose, study site, and the concomitant administration of clarithromycin, fluconazole, phenobarbital, ciprofloxacin, azithromycin, or benzodiazepines. The only statistically significant effects on rifabutin pharmacokinetic parameters were a 27% decrease in Vp/F due to the concomitant administration of azithromycin and a 39% increase in Vp/F due to tobacco smoking. Such effects may be considered clinically unimportant. Our results confirm the lack of a correlation of rifabutin pharmacokinetic parameters with parameters of disease progression and gastrointestinal function. Also, the lack of a correlation with covariates which were previously found to be significant, such as concomitant fluconazole and clarithromycin use, may suggest that the effect of such covariates may be less important in the real clinical setting, in which several concomitant factors may influence pharmacokinetic parameters, with an overall effect of no apparent correlation.     

Arthritis caused by use of rifabutine++ in Mycobacterium avium infection

A 60-year-old HIV-seronegative man with a Mycobacterium avium pulmonary infection was treated with rifabutin, ethambutol and clarithromycin. He developed a serious arthritis which disappeared after interruption of the medication and recurred after resumption. The arthritis was attributed to the use of rifabutin. This adverse effect is more frequent with higher doses and in combination with the use of macrolide antibiotics.     

Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers

A 14-day, randomized, open, phase I clinical trial was designed to examine possible pharmacokinetic interactions between rifabutin and two other antibiotics, azithromycin and clarithromycin, used in the treatment of Mycobacterium avium complex infections. Thirty healthy male and female volunteers were divided into five groups of six participants each: 18 received 300 mg/day of rifabutin, 12 in combination with therapeutic doses of either azithromycin or clarithromycin; the remaining 12 received azithromycin or clarithromycin alone. On day 10 the study was terminated because of adverse events, including severe neutropenia. Fourteen participants who received rifabutin developed neutropenia, including all 12 participants who received azithromycin or clarithromycin concomitantly. Analyses of serum revealed no apparent pharmacokinetic interaction between azithromycin and rifabutin. However, the mean concentrations of rifabutin and 25-O-desacetyl-rifabutin (an active metabolite) in participants who received clarithromycin and rifabutin concomitantly were more than 400% and 3,700%, respectively, of concentrations in those who received rifabutin alone. Physicians should be aware that recommended prophylactic doses of rifabutin may be associated with severe neutropenia within 2 weeks after initiation of therapy, and all patients receiving rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.     

Thirteen bovine microsatellite markers that are polymorphic in sheep

Macrolide resistance in disseminated Mycobacterium avium infection is of major concern in AIDS patients as these drugs represent the main component of combination therapy. Clarithromycin and azithromycin should not be used alone for the treatment and prophylaxis of the disease because of the risk of selecting resistant strains. We report the case of a clarithromycin resistant disseminated M. avium infection in an AIDS patient, acquired after long term monotherapy with clarithromycin for the treatment of cryptosporidiosis.     

Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis

The rise of multidrug-resistant Mycobacterium tuberculosis has complicated therapy for tuberculosis and led us to search for a potentially active combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were determined by use of the BACTEC radiometric method. All strains were resistant to at least two of the antituberculous drugs. Clarithromycin and 14-hydroxyclarithromycin MICs were in the range indicating resistance at > or = 8.0 micrograms/ml for all strains. Combination testing by the BACTEC method was performed with various concentrations of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-hydroxyclarithromycin at fixed concentrations of 2.0/0.5 micrograms/ml, respectively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs of isoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between standard antituberculous drugs and clarithromycin/14-hydroxyclarithromycin. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections.     

Spatial and temporal Mg2+ signaling in single human tracheal gland cells

Multidrug therapy is recommended for treatment of Mycobacterium avium complex (MAC) bacteremia in patients with AIDS. Azithromycin, clarithromycin, rifabutin, ciprofloxacin, ethambutol, clofazimine, and amikacin have all been suggested for use in treating MAC bacteremia, but the most active combinations of these drugs have not been identified, nor has the minimum number of drugs needed for effective therapy been determined. To address the former, the in vitro bactericidal activities of all two-, three-, and four-drug combinations of these seven agents was determined by using 10 blood-derived strains of MAC isolated from patients with AIDS. The activities of the 132 drug combinations were compared by statistical analysis of survival means (analysis of variance) and further evaluated by determining the percentage of strains considered susceptible to each combination. When susceptibility was defined as a decrease in CFU of > or = 2 log10, no two- or three-drug combination and only two four-drug combinations were active against all 10 MAC strains. When a less stringent definition was applied (> or = 1 log10 decrease in CFU), 1 two-drug combinations, 9 three-drug combinations, and 31 four-drug combinations showed activity against all 10 strains. Eighteen selected drug combinations were also tested for intracellular activity in MAC-infected J774 cells. Combinations which contained amikacin as a component were considerably less active against intracellular MAC organisms than against organisms in broth. The opposite result was obtained for the combination of clarithromycin plus clofazimine.     

Western blot monitoring of disseminated Nocardia nova infection treated with clarithromycin, imipenem, and surgical drainage

A case of disseminated infection due to Nocardia nova with subcutaneous popliteal and retrosternal abscesses and lung involvement in an immunocompromised patient is reported. The patient did not respond to sulfonamide therapy. Clinical recovery was obtained upon treatment with imipenem then clarithromycin. Western blot studies revealed an antibody response to a known Nocardia-specific 55-kDa antigen in four successive sera samples collected in the period from the time of admission to seven months later. The resolution of the disseminated nocardiosis and efficacy of the clarithromycin treatment were assessed on the basis of disappearance of the antibodies to the 55-kDa antigen, without invasive sampling.