Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus.

Fluconazole inhibits cytochrome P-450-mediated enzymatic metabolism of several drugs. Since hepatic metabolism is partially responsible for 2',3'-dideoxyinosine (didanosine or ddI) elimination, fluconazole therapy may lead to increased ddI concentrations in serum and subsequent concentration-dependent adverse effects. The purpose of this study was to determine if ddI pharmacokinetics are influenced by a 7-day course of oral fluconazole. Twelve adults with human immunodeficiency virus (HIV) who had received a constant dosage of ddI for at least 2 weeks were investigated. On study day 1, multiple serum samples for determination of ddI concentrations were obtained over 12 h. Then subjects received a 7-day course of oral fluconazole (200 mg every 12 h for two doses and then 200 mg once daily for 6 days) while ddI therapy continued. Following the last dose of fluconazole, serum samples for determination of ddI concentrations were again obtained over 12 h. ddI concentrations in serum were analyzed by radioimmunoassay. In contrast to previously published data, there was marked between-subject variability in ddI areas under the concentration-time curve, even when the dose was normalized for weight. No significant differences were found between mean ddI areas under the concentration-time curve from 0 to 12 h on study day 1 (1,528 +/- 902 ngx.hr/ml) and following fluconazole treatment (1,486 +/- 649 ngx.hr/ml) . There were no significant differences in other pharmacokinetic parameters, such as ddI peak concentrations in serum (971 +/- 509 and 942 +/- 442 ng/ml) or half-lives (80 +/- 32 and 85 +/- 21 min.) before and after fluconazole treatment, respectively. We conclude that a 7-day course of oral fluconazole does not significantly alter ddI pharmacokinetics in adults that are infected with human immunodeficiency virus.

Management of genital herpes infection.

Genital herpes infections are a major source of morbidity. These infections are responsible for significant health problems, including direct physical discomfort associated with outbreaks, potential complications such as neonatal transmission, and the often devastating psychological effects of a chronic illness. In addition, herpes infections have been identified as a significant co-factor in the transmission of human immunodeficiency virus infection. Accurate and rapid diagnosis and treatment are important steps necessary to minimize these effects.

Painful gingivitis may be an early sign of infection with the human immunodeficiency virus.

Anecdotal reports have suggested that painful gingivitis may be associated with infection due to the human immunodeficiency virus (HIV). Twenty patients who presented to the emergency department with a chief complaint of gum pain were evaluated for HIV infection, CD4/CD8 T lymphocyte profiles, complete blood cell counts and differentials, and lymphocyte function (response to mitogenic stimulation). Seven of the 20 patients (35%) were seropositive for HIV. Three of the seven HIV-seropositive patients were unaware of their HIV infection until tested in this study (with use of an ELISA and western blotting). The HIV-seropositive patients were significantly older than the HIV-seronegative patients (31.4 +/- 3 years and 24 +/- 1 year, respectively). Two of the seven HIV-seropositive patients presented with severe CD4 lymphocyte depletion. The other five HIV-seropositive patients presented with CD4 lymphocyte counts of 473 +/- 155 (mean +/- SE). Regardless of HIV serological status, all patients demonstrated a severely depressed mitogenic response when compared with control subjects. There were no remarkable differences in complete blood cell counts and differentials within each serological group. Significant differences, however, were noted when CD4/CD8 lymphocyte counts and ratios were measured. Identification of clinical presentations, such as painful gingivitis, that reflect an early stage of HIV infection could aid in the timing of therapy and prevention of the spread of HIV infection.

Ambulatory care for patients with HIV/AIDS: creating a specialty clinic.

This paper describes the development of a primary care HIV/AIDS clinic at a large university teaching hospital. A multidisciplinary team of health professionals provides direct care and education to an HIV/AIDS population that has increased from 36 patients in 1986 to 500 in 1990. Collaborative planning and decision making by physicians, nurses, and hospital administrators has been key to the institution's ability to support the needs of such a rapidly expanding population. This paper presents a description of the planning and implementation process used to develop an HIV/AIDS specialty clinic at this institution.

Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection. The Acyclovir Study Group.

In this 3-year study of suppressive acyclovir for recurrent genital herpes, patients with more than six recurrences per year were randomized initially to 400 mg of acyclovir or placebo orally two times per day, with recurrences treated with 200 mg of acyclovir five times per day for 5 days. In the second year of the study, all patients received acyclovir as a daily suppressive or intermittent acute therapy; in the third year, all received daily acyclovir. Among 525 patients completing 3 study years, 289 received 3 years of suppressive therapy and 236 received 1 year of acute therapy followed by 2 years of suppressive therapy. Of those who completed the third year, 61% were recurrence free that year; 25% of the suppressive therapy-only group were recurrence free for all 3 years. The annual recurrence rate dropped from more than 12 recurrences per year at baseline to 1.0 (suppressive therapy) and 1.4 (acute and suppressive therapy) recurrences during the third year. No significant toxic effects were detected. Daily suppressive acyclovir therapy was effective and well tolerated.

A prospective study of infections in hemodialysis patients: patient hygiene and other risk factors for infection.

We performed a prospective randomized study on 71 patients on chronic outpatient hemodialysis to determine whether a sterile technique was better than a clean technique for preparation of the skin over the vascular access site prior to cannulation. In addition, we wanted to determine overall and site-specific infection rates, microbial etiologies of infection, and risk factors for infection. The overall infection rate was 4.7 infections per 100 dialysis months; the vascular access-site infection rate was 1.3 infections per 100 dialysis months; and the rate for bacteremia was 0.7 cases per 100 dialysis months. Staphylococcus aureus was the most common pathogen, but infections were equally divided between gram-positive cocci and gram-negative bacilli. Advanced age (P = 0.02), a low Karnofsky activity score (P = 0.05), poor hygiene (P = 0.0004) and number of hospitalizations (P = 0.0002) were risk factors for infections in general while only poor hygiene (P = 0.002) was a risk factor for vascular access-site infection. Sterile preparation of the skin over the vascular access site was no more effective at preventing infection than was clean technique (P = 0.80). Maintenance of good personal hygiene may be one of the most important measures for prevention of infections in hemodialysis patients.

Intravenous acyclovir therapy of first episodes of genital herpes: a multicenter double-blind, placebo-controlled trial.

PURPOSE: A collaborative multicenter double-blind, placebo-controlled trial of intravenous acyclovir treatment of first-episode genital herpes was performed in order to substantiate previous findings on the efficacy and safety of this drug, to evaluate the influence of parenteral therapy on recurrence frequency, and to obtain further data on the natural history of genital herpes. PATIENTS AND METHODS: Eighty-two patients with first episodes of genital herpes simplex virus (HSV) infection were randomly assigned in a double-blind fashion to treatment with intravenous acyclovir (5 mg/kg every eight hours) or placebo for five days. Before therapy, all lesions in the genital/perineal area and in extragenital sites were cultured. New lesions appearing in both areas after the onset of therapy were cultured separately. Lesions in all groups were cultured until completely healed. Sera were collected from all patients on entry to the study and on Day 21 to determine presence or absence of antibodies to HSV-1 and HSV-2. Time to healing, time to crusting, time to cessation of viral shedding, and appearance of new lesions during therapy were compared for each treatment group. RESULTS: Patients receiving acyclovir experienced a significant reduction in the median duration of pain (4.3 versus 4.8 days, p = 0.019), viral shedding (1.9 versus 8.4 days, p less than 0.001), and time to healing (8.4 versus 11.5 days, p = 0.02) compared with placebo recipients. These differences were largely attributable to the effect of therapy in the subset of patients with primary disease in whom acyclovir reduced the median duration of pain from 10.6 days to 4.2 days, the median duration of viral shedding from 17.1 days to 1.9 days, and the median time to healing from 14.2 days to 8.3 days. The rate of subsequent recurrence of genital herpes was not altered by acyclovir treatment: 24 of 32 acyclovir recipients (75 percent) experienced one or more recurrences during a mean follow-up of 14 months compared with 19 of 27 placebo recipients (70 percent). Among patients experiencing recurrences, the mean number of recurrences per month among acyclovir recipients was 0.25 compared with 0.19 for patients given placebo. CONCLUSION: This multicenter trial confirms the efficacy of intravenous acyclovir in the management of first-episode genital herpes, especially in patients with primary infection. However, therapy did not alter the frequency of recurrences.

Medical care costs of patients with acquired immunodeficiency syndrome in Richmond, Va. A quantitative analysis.

This study examines inpatient charges for 52 adult patients with the acquired immunodeficiency syndrome (AIDS) who had 102 admissions to the Medical College of Virginia Hospitals, Richmond, from October 1983 through December 1986. Complete charge data were available for 81 hospitalizations; the mean charge per hospitalization was +13,830 (SD, +13,610), the average length of stay was 14.8 days (SD, 13.1 days), and the mean per diem charge was +1058 (SD, +802). For patients who received all their AIDS-related medical care at the Medical College of Virginia Hospitals, total lifetime hospital charges averaged +27,264, the mean number of hospital stays was 2.29, and the average length of stay was 12 days. The average length of hospital stay, total charges per hospitalization, and average charge per day of hospitalization decreased over the study period. These findings suggest that inpatient costs of treating individual patients with AIDS are less than initially estimated and are decreasing due to the ability to more effectively manage these patients.

Prospective study of microbial colonization of the nose and skin and infection of the vascular access site in hemodialysis patients.

We conducted a prospective study of nasal and skin floras in 71 patients receiving chronic hemodialysis. We wished to determine whether a sterile skin preparation technique was more effective than a clean technique in removing microorganisms from the skin of the vascular access site. We also examined the effect of administration of antibiotics and status of patient hygiene on microbial flora. The presence of Staphylococcus aureus in the nose had a low predictive value for the simultaneous presence of the microorganism on the skin. The status of skin colonization can be accurately assessed only by culture of the skin. Sterile technique was no more effective at removing microorganisms from skin than was clean technique. Antibiotics significantly affected nasal flora but not skin flora. S. aureus was significantly more likely to remain on the skin after application of an antiseptic in patients with poor hygiene than in patients with good hygiene (P = 0.002). Patients with poor hygiene also had a significantly higher concentration of S. aureus on the skin of the vascular access site after application of antiseptic than patients with good hygiene (P = 0.005). We found no evidence to support a change from clean to sterile technique for skin preparation, but improvement in personal hygiene may be an effective strategy for prevention of vascular access infections.

Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks.

One hundred ninety-four patients with cryptococcal meningitis were enrolled in a multicenter, prospective, randomized clinical trial to compare the efficacy and toxicity of four as compared with six weeks of combination amphotericin B and flucytosine therapy. Among 91 patients who met preestablished criteria for randomization, cure or improvement was noted in 75 percent of those treated for four weeks and in 85 percent of those treated for six weeks. The estimated relapse rate for the four-week regimen was higher--27 as compared with 16 percent--whereas the incidence of toxic effects for the two regimens was similar--44 as compared with 43 percent. Among 23 transplant recipients, 4 of 5 treated for four weeks relapsed, leading to the decision to treat the rest of the group for six weeks. Only 3 of the 18 treated for six weeks relapsed. In a third group of 80 patients, the protocol was not followed during the initial four weeks, and these patients were not randomized. Thirty-eight died or relapsed. Multifactorial analysis of pretreatment factors for all 194 patients identified three significant predictors (P less than 0.05) of a favorable response: headache as a symptom, normal mental status, and a cerebrospinal fluid white-cell count above 20 per cubic millimeter. These and other findings in this study are consistent with the view that the four-week regimen should be reserved for patients who have meningitis without neurologic complications, underlying disease, or immunosuppressive therapy; a pretreatment cerebrospinal fluid white-cell count above 20 per cubic millimeter and a serum cryptococcal antigen titer below 1:32; and at four weeks of therapy, a negative cerebrospinal fluid India ink preparation and serum and cerebrospinal fluid cryptococcal-antigen titers below 1:8. Patients who do not meet these criteria should receive at least six weeks of therapy.

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.

Psychological factors predict symptoms of severe recurrent genital herpes infection.

In a group of patients with severe recurrent genital herpes infection, we measured symptoms (pain and itching), psychological factors (depression, anxiety, somatisation, interpersonal sensitivity, and life change) and objective indices of disease (number of recurrences in the previous year, total number of recurrences, duration of recurrences, number of lesions per recurrence). Psychological factors were more predictive of pain and itching than were somatic indices, even after correcting for sex.

Psychological factors in recurrent genital herpes infection: stress, coping style, social support, emotional dysfunction, and symptom recurrence.

The relationship among stress, coping style, emotional dysfunction, social support, and severity of symptoms (frequency of recurrence, and pain, duration, and bother of recurrences) was investigated in 35 females and 32 males suffering from severe cases of genital herpes infection. Level of emotional dysfunction as measured by the SCL-90 approached two standard deviations above the mean as compared with non-patient normals, and frequency, pain, and bother of recurrences were associated with level of emotional dysfunction. Negative life stress (as measured by the Life Experiences Survey) was unrelated to psychopathology, and was associated only with duration among the symptom measures. Regression analyses indicated that higher frequencies of recurrence and greater discomfort associated with symptoms were associated with an external locus of control orientation and with a tendency to use emotion-focused wishful thinking and to avoid using cognitive strategies to cope with the stress associated with herpes. It was suggested that stress management procedures involving teaching of problem-focused coping strategies and provision of social support would be most effective for this population.

Detection of Chlamydia trachomatis in genital specimens by the Microtrak direct specimen test.

The conventional cell culture method for detection of Chlamydia trachomatis requires two to six days and is technically difficult to perform. The authors evaluated a new, relatively simple, non-culture method (MicroTrak, Syva Co., Palo Alto, CA) that requires less than one hour to complete. Two hundred fifty-one cervical and 209 male urethral specimens from three Richmond health clinics were read by direct immunofluorescence staining and compared with cell culture technics using iodine staining. Patient specimens were applied directly onto microscope slides (8 mm well) and stained with a fluorescein-labeled monoclonal antibody. Slides were examined for 10-15 minutes at X1,000 using an AO epifluorescent microscope and were considered positive if five or more typical elementary bodies were seen. The sensitivity, specificity, positive and negative predictive values for the direct smear were 89%, 97%, 85%, and 98% for males, and 93%, 96%, 85%, and 98% for females, respectively. The rapid direct specimen test appears to be a satisfactory method for detecting chlamydia in male and female genital specimens.

Correlation of rickettsial titers, circulating endotoxin, and clinical features in Rocky Mountain spotted fever.

Blood rickettsial titers, skin biopsy results, and circulating endotoxin measurements were correlated with the clinical course of disease in patients with Rocky Mountain spotted fever (RMSF). Nine of 11 patients with documented RMSF had Rickettsia rickettsii isolated from plasma samples. Of the eight patients in whom rickettsial titers were measured, seven had 10(0.7) to 10(1.2) median tissue culture infective doses (TCID50) per milliliter; all seven had mild to moderately severe disease. One patient with fulminant, fatal untreated RMSF had 10(3) TCID50/mL of postmortem plasma. Two patients from whom rickettsiae were not isolated had positive direct immunofluorescent stains of skin biopsy material for R rickettsii. Circulating endotoxin was present in two patients, one with documented rickettsemia and one with a positive skin biopsy alone. Only low levels of circulating rickettsiae are present in patients with moderately severe disease. Measurement of plasma endotoxin is not useful in the early diagnosis of RMSF.