Margaret Simpson

Itraconazole maintenance treatment for histoplasmosis in aids : A prospective, multicenter trial

PURPOSE To study the efficacy and safety of maintenance treatment with itraconazole for disseminated histoplasmosis in patients with AIDS. PATIENTS AND METHODS This was a prospective, multicenter, open-label study conducted at university-based hospitals participating in the AIDS Clinical Trial Group (ACTG). Forty-six AIDS patients with mild to moderate disseminated histoplasmosis who had successfully completed 12 weeks of induction treatment with itraconazole were treated with itraconazole, 200 mg once daily (42 patients) or 400 mg once daily (4 patients). Patients were followed at monthly intervals with clinical and laboratory assessment for relapse or toxicity. Primary outcome measures were relapse of histoplasmosis and survival. Secondary outcome measures included drug-limiting toxicity and changes in serum and urine Histoplasma polysaccharide antigen (HPA) levels. RESULTS Two patients relapsed during a median follow-up period of 87 weeks. The 1-year relapse-free rate was estimated to be 95.3% (95% CI, 85.3%-99.7%). One relapse may have been related to poor adherence to treatment and the second to concurrent administration of rifampin. From the start of maintenance treatment, the estimated 1-year survival rate was 73.0% (95% CI, 67.5%-77.9%). Five patients discontinued treatment because of suspected drug toxicity, three of whom had possible or probable hepatotoxicity. Median serum and urine HPA levels declined significantly during treatment. The only patient in whom antigen levels rose >2 U developed clinical relapse 1 week later; antigen levels were unavailable in the other relapsing patient. CONCLUSIONS Itraconazole, 200 mg daily, is effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. It is generally well tolerated, but clinicians should be alert for drug interactions and possible hepatotoxicity.

Activation-induced CD4+ T cell death in HIV-positive individuals correlates with Fas susceptibility, CD4+ T cell count, and HIV plasma viral copy number

The relevance of activation-induced cell death (AICD) of CD4+ T cells to AIDS pathogenesis is unknown. The present study investigates the relationship of AICD to a defined molecular mechanism regulating peripheral T cell homeostasis, Fas-mediated apoptosis, and clinical correlates of the pathogenesis of AIDS. Increased pokeweed mitogen (PWM)-induced AICD (22.8 versus 4.4%, p = 0.006) and Fas-mediated apoptosis (27.7 versus 12.0%, p = 0.002) of CD4+ T cells were observed in HIV+ versus HIV- individuals. Similarly, increased PWM-mediated AICD (16.2 versus 2.2%, p < 0.001) and Fas-mediated apoptosis (25.8 versus 7.6%, p = 0.005) were noted in CD8+ T cells from HIV+ versus HIV- individuals. PWM-induced AICD of CD4+ T cells was blocked (83% median specific inhibition) by Fas-blocking antibodies, whereas PWM-induced AICD of CD8+ T cells was Fas independent. Comparison between PWM- and anti-CD3-mediated AICD of CD4+ T cells indicated that PWM- and not CD3-induced AICD is Fas dependent. HIV+ individuals with an HIV RNA copy number of <30,000 copies/ml had lower PWM-induced AICD of CD4+ T cells than did those with an HIV RNA copy number of >30,000 copies/ml (5.7 versus 22.1%, p = 0.034), and PWM-induced AICD inversely correlated with CD4+ T cell count (R = -0.567, p = 0.043). Initiation of HAART decreased PWM-induced CD4+ T cell AICD from 24.4 to 9.4% posttreatment (p = 0.035). These results demonstrate that PWM-induced AICD of CD4+ T cells from HIV+ individuals is mediated by Fas/FasL, parallels the in vivo susceptibility of the CD4+ T cell to Fas-mediated apoptosis, and correlates with clinical markers of AIDS pathogenesis and response to HAART.

Comparative pharmacokinetics of zidovudine in healthy volunteers and in patients with AIDS with and without hepatic disease

To understand whether disease caused by the human immunodeficiency virus (HIV) affects zidovudine disposition, we compared the drugs pharmacokinetics in six healthy volunteers; six persons with the acquired immunodeficiency syndrome (AIDS) and no evidence of gastrointestinal (nausea, vomiting, diarrhea), renal (elevated blood urea nitrogen, serum creatinine), or hepatic (elevated liver function tests) disease; and three patients with AIDS and hepatic disease. After a single oral dose of zidovudine, serial blood samples were analyzed for drug concentration by radioimmunoassay. A one‐compartment oral absorption model was fit to the concentration‐time data. The absorption rate constant (4.05 vs 2.11 hr−1) and time to maximum concentration (0.61 vs 1.03 hr) were significantly different in healthy volunteers versus patients with AIDS without hepatic disease. Differences in half‐life, oral clearance, and area under the curve were not statistically significant. In the three patients with AIDS plus hepatic disease, clearance was reduced an average of 63%, and area under the curve was increased by a factor of 2.3. These comparative pharmacokinetic data do not support profound differences between zidovudines disposition in healthy volunteers and individuals with AIDS; however, the differences and trends that were observed may represent an effect of HIV disease. Although the presence of hepatic disease clearly indicates a need to modify individual dosages, these pharmacokinetic data may have more generalized implications for zidovudine dosing as the relationships between drug concentration and therapeutic or toxic effects are clarified.

Norfloxacin in the treatment of uncomplicated gonococcal infections

Norfloxacin, an oral fluoroquinolone antibacterial, is active in vitro against a variety of gram-positive and gram-negative pathogens, including both penicillinase-producing and non-penicillinase-producing strains of Neisseria gonorrhoeae. An earlier study demonstrated that a two-dose regimen of norfloxacin was as effective as standard therapy with spectinomycin for treating gonococcal urethritis, including infections caused by penicillinase-producing organisms. In this randomized study of treatment for uncomplicated gonococcal infection in men and women, three oral treatment regimens were compared: patients received either two doses of norfloxacin (600 mg twice daily), a single dose of norfloxacin (800 mg), or a single-dose ampicillin (3.5 g)/probenecid (1.0 g) regimen (as recommended by the Centers for Disease Control). All three treatment regimens achieved similar cure rates. Although the number of patients treated was too small to yield statistically significant conclusions, it appears that norfloxacin may be slightly better treatment for rectal and pharyngeal gonococcal infections than ampicillin and probenecid. Additionally, norfloxacin was well tolerated in this study. Thus, based on a review of these data, norfloxacin appears to be an alternative, single-dose, oral treatment regimen for uncomplicated gonococcal infection.

Treatment of gonorrhea: comparison of cefotaxime and penicillin.

Ninety-seven patients with 118 sites infected with Neisseria gonorrhoeae were treated with a single dose of either procaine penicillin G (4.8 x 10(6) U) or cefotoxime (1.0 g) intramuscularly. Only the penicillin group took 1 g of probenecid orally. The numbers of infected sites in each treatment group were as follows: penicillin-urethra, 37; rectum, 9; cervix, 8; and pharynx, 4; cefotaxime-urethra, 42; rectum, 9; cervix, 5; and pharynx, 4. The cure rates in each treatment group were 100%. No adverse reactions were noted in either group. beta-Lactamase-positive N. gonorrhoeae strains were not found. Ninety-five percent of clinical isolates were inhibited by less than or equal to 0.007 micrograms of cefotaxime and less than or equal to 0.25 micrograms of penicillin per ml. In this study cefotaxime was as effective as procaine penicillin in the treatment of uncomplicated gonorrhea.

Comparative in vitro activity of cefmenoxime, cefotaxime, cefuroxime, cefoxitin, and penicillin against Neisseria gonorrhoeae.

The in vitro activity of a new beta-lactam antibiotic, cefmenoxime, was compared with those of cefotaxime, cofuroxime, cefoxitin, and penicillin against 72 beta-lactamase-negative and 26 beta-lactamase-positive Neisseria gonorrhoeae. Cefmenoxime was as active as cefotaxime and more active than the other three antimicrobial agents. It inhibited all isolates, regardless of beta-lactamase activity, at a concentration of less than or equal to 0.015 microgram/ml.

HIV-1 counseling and testing sites, Minnesota: analysis of trends in client characteristics.

We report here a summary of the data obtained from two HIV-1 antibody counseling and testing sites in Minneapolis-St. Paul for the first 48 months of operation (24,911 persons tested). The HIV-1 antibody seroprevalence rate for all persons tested was 5 percent. The highest seroprevalence rates were in male homosexual/bisexual intravenous drug users (23 percent) and homosexual/bisexual men (13 percent). There was a significant decrease in the HIV-1 antibody seroprevalence rate among clients during the 48-month period from 14 percent in the first six months to 3 percent in the last six months. This decrease coincided with an increase in the number of low-risk female clients and low-risk heterosexual male clients, and a decrease in the number of homosexual/bisexual males participating in the programs. These findings suggest the need for development and implementation of other strategies to identify and reach persons at highest risk for HIV-1 infection.

Comparative efficacy of cefmenoxime versus penicillin in the treatment of gonorrhea.

A total of 121 men with complicated infections caused by beta-lactamase-negative Neisseria gonorrhoeae were included in this study. They were randomly assigned to regimens of either cefmenoxime (1.0 g) or procaine penicillin G (4.8 X 10(6) U) intramuscularly. Only the penicillin group also took 1.0 g of probenecid orally. A total of 99 patients completed the study, providing data from 108 infected sites. In the cefmenoxime group, there were 49 urethral, 1 rectal, and 2 pharyngeal infections; in the penicillin group, there were 49 urethral, 4 rectal, and 3 pharyngeal infections. In the cefmenoxime group, all except one urethral infection were eradicated. This patient admitted having had sexual intercourse during the follow-up period and was considered to be reinfected. In the penicillin group, all except one pharyngeal infection were cured. No adverse reactions were noted in either group. In this study, cefmenoxime was as effective as penicillin in the treatment of gonococcal urethritis in men.

Comparison of piperacillin and penicillin in the treatment of uncomplicated gonorrhea.

A total of 120 men with uncomplicated infections caused by beta-lactamase-negative, highly penicillin-susceptible strains of Neisseria gonorrhoeae were included in this study. They were randomly assigned to regimens of either piperacillin (2.0 g) or procaine penicillin G (4.8 X 10(6) U) intramuscularly, both delivered concomitantly with an oral dose of 1.0 g probenecid. A total of 103 patients completed the study, providing data from 112 infected sites: for the penicillin regimen--urethra, 46; pharynx, 5; and rectum, 4; for the piperacillin regimen--urethra, 53; pharynx, 3; and rectum, 1. In the penicillin group, there were no failures at any of the infected sites. In the piperacillin group, all except one pharyngeal infection were cured. Also, in the piperacillin group, four men visit, whereas no cases of this type occurred in the penicillin group. No major side effects were noted in either group. Clinically, piperacillin was as effective as procaine penicillin G in the treatment of gonococcal urethritis in men. Pharyngeal infection may be refractory to piperacillin therapy.

Comparative in vitro activity of Sch 29,482, a new oral penem, against Neisseria gonorrhoeae.

The in vitro activity of Sch 29,482, a new oral beta-lactam antimicrobial agent, was compared with those of norfloxacin, rosoxacin, ampicillin, erythromycin, and tetracycline against 142 Neisseria gonorrhoeae strains. Sch 29,482 was as active as norfloxacin and rosoxacin. Its activity was greater than the other three antimicrobial agents. It inhibited 90% of the isolates, regardless of beta-lactamase activity, at a concentration of less than or equal to 0.06 micrograms/ml.