Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone

Hughes, Walter T.; Kennedy, Wren; Dugdale, Marion; Land, Mack A.; Stein, Daniel S.; Weems, J. John; Palte, Stephen B.; Lancaster, Danny J.; Gidan-Kovnar, Susanne; Morrison, Robert E.

doi:10.1016/0140-6736(90)92533-n

Cited by 48 publications

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“…As expected on the basis of the half-lives of 23-25 hours for dapsone and 80-105 hours for pyrimethamine [28,29], serum concentrations of dapsone decreased considerably throughout the weekly dosing interval, whereas pyrimethamine levels remained relatively stable in most of the sera examined [20]. Maintenance of high serum levels may be less important for prophylaxis than for cure, as shown by the experience with weekly doses of dapsone [18] and that with intermittent doses of trimethoprim-sulfamethoxazole [6,24,30]: both regimens prevented PCP, although the dosing interval exceeded the half-life of the individual compounds severalfold. Investigators in one of the latter studies reported undetectable trough levels in the majority of patients despite prophylactic efficacy [30].…”

Section: Discussionmentioning

confidence: 75%

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confidence: 99%

“…Dapsone and pyrimethamine have been active against both organisms in vitro and in murine models [15][16][17]; therefore, this combination was chosen for evaluation as combined prophylaxis for PCP and toxoplasmic encephalitis. Low cost and the potential for once-weekly administration [18] are additional attractive features of the dapsone/ pyrimethamine combination. As aerosolized pentamidine was the standard prophylaCtic agent against PCP at the time the trial was designed, we planned a prospective, randomized comparison of dapsone/pyrimethamine and aerosolized pentamidine administered as primary and secondary prophylaxis for PCP and as primary prophylaxis for toxoplasmic encephalitis.…”

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Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Opravil

Hirschel

Lazzarin

et al. 1995

Clinical Infectious Diseases

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To evaluate combined prophylaxis for Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis, 533 patients with symptomatic human immunodeficiency virus infection and/ or CD4 lymphocyte counts of <200/AL were randomized to receive dapsone/pyrimethamine (200/75 mg once weekly) or aerosolized pentamidine (300 mg every 4 weeks). The median CD4 lymphocyte count was 110/AL; 47.5% were seropositive for toxoplasma antibodies. The median duration of follow-up was 483 days. In the intent-to-treat analysis, 12 cases of PCP and 14 of toxoplasmic encephalitis occurred in the dapsone/pyrimethamine group and 13 and 20 cases, respectively, in the aerosolized pentamidine group (adjusted relative risk for toxoplasmosis, 0.56; P = .10). However, only two of the 14 cases of toxoplasmic encephalitis in the dapsone/ pyrimethamine group developed during actual treatment. The mortality among the two groups was similar. Dapsone/pyrimethamine was not tolerated by 30% of participants. A subanalysis of 240 matched, tolerant patients yielded a relative risk for toxoplasmosis of 0.21 (P = .014), a result favoring the use of dapsone/pyrimethamine. Dapsone/pyrimethamine was as effective as aerosolized pentamidine as prophylaxis for PCP and significantly reduced the incidence of toxoplasmic encephalitis among those participants who tolerated it.Prophylaxis for opportunistic infections has had a strong impact on the management of immunosuppressed human immunodeficiency virus (HIV)-infected patients in recent years, and epidemiological data indicate that Pneumocystis carinii pneumonia (PCP) has become less frequent as a consequence of prevention [1]. Aerosolized pentamidine became available in Switzerland in 1987 and was subsequently proven effective for both primary and secondary prophylaxis for PCP in controlled trials [2,3]. Among systemic prophylactic agents, trimethoprim-sulfamethoxazole became widely used [4] and was later shown to be more effective but also more toxic than aerosolized pentamidine [5,6] nations, such as dapsone and trimethoprim [7] or pyrimethamine and sulfadiazine [8], have been used for treatment of PCP before, but sparse data exist concerning their prophylactic efficacy [9]. Only recently, the prophylactic efficacy of the combination of dapsone and pyrimethamine against PCP and toxoplasmosis was demonstrated [ 10].Since in >95% of all AIDS patients with toxoplasmic encephalitis there is serological evidence of previous infection with Toxoplasma gondii [10][11][12][13], reactivation of a latent infection is the principal pathogenetic step in the development of toxoplasmic encephalitis during immunodeficiency. Considering the increasing frequency of toxoplasmic encephalitis among AIDS-defining opportunistic infections [ 1] and the 50% seroprevalence of toxoplasma antibodies in Switzerland [14], primary prophylaxis for toxoplasmic encephalitis seems desirable and clinically important, at least for seropositive patients.The sequential inhibition of dihydrofolate reductase by pyrimethamine and of dihydropteroate sy...

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

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confidence: 99%

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Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Opravil

Hirschel

Lazzarin

et al. 1995

Clinical Infectious Diseases

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“…Dapsone is a synthetic antifolate that has activity against Mycobacterium leprae (15) and, when it is used alone or in combination with pyrimethamine, prevents Pneumocystis cannii pneumonia (6,21); dapsone has been reported to have in vitro activity against MAC (16). We now report on the use of clarithromycin alone or in combination with dapsone to treat and prevent disseminated MAC infection in beige mice.…”

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Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice

Bermudez

Inderlied

Kolonoski

et al. 1994

Antimicrob Agents Chemother

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Bacteremic infection caused by organisms of the Mycobacterium avium complex (MAC) is common in patients with AIDS. We evaluated both clarithromycin and dapsone alone and in combination for the treatment and prevention of disseminated MAC disease in beige mice. In the therapeutic model, C57BL/6 beige mice were infected intravenously with strain 101 of MAC (serovar 1). After 1 week postinfection, mice were given clarithromycin (200 mg/kg of body weight per day) and dapsone (15 mg/kg of body weight per day) alone or in combination by gavage. Treatment with clarithromycin resulted in a significant reduction in bacteremia and the numbers of CFU of MAC in the liver and spleen. Treatment with dapsone had no effect on the mycobacterial counts in blood, liver, or spleen, and the combination of dapsone with clarithromycin was no better than clarithromycin as a single agent. Clarithromycin and dapsone were used to prevent systemic disease in beige mice infected orally with MAC 101. Clarithromycin prophylaxis was associated with a significant reduction in the numbers of bacteria in the liver, spleen, and appendix compared with those in controls. Prophylaxis with dapsone resulted in a mild reduction in the numbers of MAC in the spleen but not in the other tissues. Clarithromycin both treats and prevents MAC disease in beige mice. Dapsone has no therapeutic effect, but it does have a slight prophylactic eflect, and in combination with clarithromycin it does not abrogate the effect of clarithromycin.Organisms of the Mycobacterium avium complex (MAC) are the most common cause of bacterial infection in patients with AIDS. Autopsy studies in AIDS patients have shown a large number of acid-fast bacilli in the liver, spleen, bone marrow, and intestines (17,20,28). Current observations suggest that most of the cases of MAC infection in AIDS patients are acquired by the gastrointestinal tract, and colonization of the gut appears to precede the onset of bacteremia (5,8).MAC is resistant to many of the standard antituberculosis antimicrobial agents, but some strains may be susceptible in vitro and in vivo to agents such as ethambutol, amikacin, rifabutin, macrolides, and azalides (clarithromycin, roxithromycin, and azithromycin), clofazimine, and certain fluoroquinolones (9, 10, 12-14, 22, 23). Clarithromycin, a new macrolide that is structurally related to erythromycin, is active in vitro (19,(25)(26)(27), inhibiting 90% of MAC strains (MICs, 1 to 8 ,ug/ml). Clarithromycin concentrates within macrophages and tissues (2), and it has also been shown to be active in experimental animals (12, 24) and AIDS patients with MAC infection, as shown in clinical trials (7, 9-11). The development of MAC resistance to clarithromycin has been observed in patients taking the antibiotic (18). For instance, in a recent compassionate-use study, resistance following clarithromycin therapy developed in 33% of patients (9).Dapsone is a synthetic antifolate that has activity against Mycobacterium leprae (15) vitro activity against MAC (16). We now report o...

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“…Alternative prophylactic regimens for the sulfa-allergic patient include aerosolized pentamidine (for patients Ͼ 5 years of age) 78 and dapsone. 79 Tuberculosis (TB) is of concern in recipients of LTx. Development of TB after pediatric LTx is extremely uncommon, with only 11 cases reported to date, [80][81][82] although the incidence of TB after LTx in adults in Europe and the United States has ranged from 0.9% to 2.3%.…”

Section: Opportunistic Infectionsmentioning

confidence: 99%

Immunizations and infectious diseases in pediatric liver transplantation

Halasa

Green

2008

Liver Transpl

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Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone

Cited by 48 publications

References 0 publications

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice

Immunizations and infectious diseases in pediatric liver transplantation

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