Effect of interleukin 6 on the hepatic metabolism of itraconazole and its metabolite hydroxyitraconazole using primary human hepatocytes.

A potential cytokine-drug interaction between interleukin 6 (IL-6) and itraconazole (ITZ) was studied using human hepatocytes in primary culture. Cultures from 5 adult males (mean age 42 +/- 15 years) who had not received any medicines known to interact with CYP3A4 were studied. Cultures were exposed to ITZ 500 ng/ml, and the effects of 120 microg/ml cimetidine, 50 ng/ml human IL-6, or IL-6 plus IL-6 receptor antagonist were analyzed for 2, 4, 8, and 12 h. Intracellular ITZ and hydroxyitraconazole concentrations were measured using HPLC and normalized to total cellular protein. Mean intracellular concentrations between groups were compared using one-way Anova (f test; p < 0.10) and corresponding Bonferroni versus control test for multiple comparisons (p < 0.02). Mean intracellular ITZ concentrations between the groups were similar at all time points. Human hepatocytes in primary culture can metabolize ITZ. However, IL-6 did not inhibit hydroxyitraconazole formation, but it may inhibit its subsequent metabolism.

Rapid and sensitive high-performance liquid chromatographic method for the determination of ritonavir in human plasma.

Ritonavir is an HIV-1 protease inhibitor that is often used to improve the systemic availability of concurrently administered protease inhibitors by impairing their metabolism through cytochrome P450 (CYP) 3A4. Pharmacodynamic relationships between plasma ritonavir concentrations and efficacy and toxicity have also been described. To date, published high-performance liquid chromatographic (HPLC) methods for the determination of ritonavir in human plasma are often complex, requiring the use of a buffered mobile phase that contains amine-modifiers (i.e. diethylamine, triethylamine). In the method herein, ritonavir was precipitated with acetonitrile plus barium hydroxide and zinc sulphate. Chromatographic separation was accomplished using a C-18 base-deactivated (250 x 4.6 mm I.D., 5 atm particle size) analytic column with a mobile phase composed of acetonitrile:water (52:48, v/v). Quantification was performed at 239 nm. Calibration curves were linear from 0.5-25 microg/ml (R2 > 0.999); percent errors, as a measure of accuracy, were < 12.7%. Intra- and inter-assay relative standard deviations (RSD) were below 12.8%. This method provides a rapid and simple means for the accurate and precise analysis of ritonavir in human plasma. Furthermore, the assay requires neither the use of a buffered mobile phase adjusted to a specific pH, nor the addition of amine modifiers. This method has been successfully used to determine plasma ritonavir concentrations in drug interaction studies.

Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with a history of penicillin allergy.

The purpose of this retrospective study was to assess cross-hypersensitivity between imipenem/cilastatin and penicillin in patients with reported penicillin allergies. Medical records of febrile neutropenic, penicillin-allergic bone marrow transplant recipients who received imipenem/cilastatin treatment were retrospectively reviewed. The findings of this study indicate the incidence of cross-reactivity between imipenem/cilastatin and penicillin among patients with a history of penicillin allergy may be lower than previously reported.

Investigation of an outbreak of gram-negative bacteremia among hematology-oncology outpatients.

OBJECTIVE: To identify risk factors associated with an outbreak of gram-negative bacteremia (GNB). SETTING: A university hospital. PATIENTS: Hematology-oncology outpatients. DESIGN: Retrospective case-control study. RESULTS: Thirty-eight patients developed GNB; 13 patients experienced more than one episode, and eight blood cultures grew more than one gram-negative organism. The most frequently isolated organisms were Stenotrophomonas maltophilia, Klebsiella pneumoniae, Acinetobacter baumannii, and Acinetobacter johnsonii. When the GNB patients (cases) were compared with randomly selected hematology-oncology patients (controls), central venous catheter (CVC) self-care (71% vs 39%; P=.02), and duration of recent hospital stay (median, 15 vs 4 days; P=.01) were identified as risk factors. In a logistic regression model, duration of recent hospital stay was the only risk factor significantly associated with GNB (odds ratio, 1.05; 95% confidence interval, 1.01-1.08; P<.02). CONCLUSIONS: Hematology-oncology patients providing their own CVC care who have recently been hospitalized for more than 2 weeks may be at increased risk of GNB. CVCs should be protected from possible environmental contamination in hematologyoncology patients. Patients providing their own CVC care should undergo continued rigorous education regarding proper CVC care.

Current management of funguria.

Recent findings on the epidemiology and treatment of funguria are reviewed. Funguria, or candiduria, is a common nosocomial condition and may develop as early as the first two weeks of hospitalization. Risk factors include antibacterial therapy, an indwelling urinary catheter, urologic procedures, female sex, diabetes, and immunosuppressive therapy. Candida albicans is the species most commonly isolated from the urine of infected patients. Spontaneous resolution of funguria is relatively infrequent. Furthermore, although nonpharmacologic measures, such as removing unnecessary antibacterials and changing or removing indwelling urinary catheters, may be beneficial, they are often inadequate without additional, pharmacologic therapy. The most serious complication of untreated asymptomatic funguria is candidemia. Bladder irrigations with amphotericin B have been the standard of therapy for many years; recently, the optimal concentration and method of irrigation (continuous versus intermittent) have been debated. Studies indicate that intravesical amphotericin B and oral fluconazole therapy are each effective in clearing funguria. Intravesical amphotericin B appears to act more rapidly; however, the effect of systemic fluconazole therapy often persists longer than that of amphotericin B irrigation, and oral therapy is more convenient and less expensive. Oral fluconazole appears to have a more delayed but more lasting effect on funguria than amphotericin B bladder irrigation. Studies are needed to determine whether intravesical amphotericin B still has a role in the treatment of funguria and to refine strategies involving fluconazole.

Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers.

The systemic availability of itraconazole capsules may be reduced secondary to elevated gastric pH and possibly by presystemic intestinal metabolism via CYP3A4. Grapefruit juice is acidic and an inhibitor of intestinal CYP3A4. To determine the effect of grapefruit juice on the systemic availability of itraconazole capsules, serum itraconazole and hydroxy-itraconazole concentrations were determined in eleven healthy volunteers studied in a randomized, two-way crossover design. Concurrent grapefruit juice resulted in a 43% decrease in the mean itraconazole AUC0-48 (2507 ng x hr/mL versus 1434 ng x hr/mL, p = 0.046) and a 47% decrease in the mean hydroxy-itraconazole AUC0-72 (7264 ng x hr/mL versus 3880 ng x hr/mL, p = 0.025). Grapefruit juice also significantly increased the mean itraconazole Tmax (5.5 versus 4 hours). We conclude that concomitant grapefruit juice does not enhance the systemic availability of itraconazole capsules, but rather appears to impair itraconazole absorption. Therefore, concomitant grapefruit juice will not likely be useful in improving the oral availability of itraconazole capsules.

Antifungal prophylaxis to prevent invasive mycoses among bone marrow transplantation recipients.

We reviewed the effect of systemic, intranasal, and lipid formulations of amphotericin B, fluconazole, itraconazole for antifungal prophylaxis. Specifically we reviewed the effect of antifungal prophylaxis on the development of fungal colonization, frequency of superficial and invasive mycosis, and overall mortality and that due to invasive mycoses in bone marrow transplantation recipients. A MEDLINE search was conducted to identify literature describing the risk factors, epidemiology, and chemoprophylaxis of invasive mycosis in these patients. Preliminary data published as abstracts at national infectious diseases and hematology conferences within the last 5 years were included. Antifungal prophylaxis reduces fungal colonization and superficial infection. The ability of antifungal prophylaxis to prevent systemic infection or reduce the need for empiric amphotericin B depends on specific variables. Ultimately, antifungal prophylaxis has no affect on overall mortality, and very little impact on mortality attributed to fungi.

Therapeutic drug monitoring of vancomycin in a morbidly obese patient.

The authors describe the therapeutic drug monitoring of vancomycin in a man who is morbidly obese. Because serum vancomycin concentration (SVC) monitoring continues to be deemphasized, nomogram use will likely increase. However, vancomycin dosing nomograms have not been studied in patients who are morbidly obese. Furthermore, in nomograms that incorporate body weight, it is unclear whether ideal or total body weight (IBW and TBW, respectively) should be used to dose the morbidly obese. Therefore, the authors retrospectively evaluated four nomograms (Moellering, Matzke, Lake-Peterson, and Rodvold) and an individualized method in the simulated vancomycin dosing of their patient. Total body weight was more accurate than IBW in selecting a vancomycin dose when using the individualized method and in all nomograms except the Matzke nomogram. The Rodvold nomogram and the individualized method yielded the most appropriate doses. All nomograms suggested dosing intervals that were unacceptably short; the individualized method suggested an appropriately longer interval. Thus, if nomograms or the individualized method are used to empirically dose vancomycin, TBW--not IBW--should be used. Because these nomograms yielded inappropriately short dosing intervals in the patient, it is likely that patients who are morbidly obese represent a unique population in which at least one set of SVCs are necessary to select an appropriate dosing regimen.

Rapid and sensitive high performance liquid chromatographic method for the determination of itraconazole and its hydroxy-metabolite in human serum.

Published high performance liquid chromatographic (HPLC) methods for the determination of itraconazole (ITZ) in biological matrices are labor intensive, extraction-based procedures which operate at a pH approaching the limit of column tolerance, and unless modified, cannot measure its hydroxy-metabolite (OH-ITZ). A protein precipitation-based method requiring no solvent extraction and utilizing a base-deactivated C18 analytical column to minimize peak tailing is described herein. Calibration curves for OH-ITZ and ITZ were linear from 25-1500 ng ml-1 (r2 > or = 0.999). Intra-assay relative standard deviations (R.S.D.) were below 12%. Inter-assay R.S.D. were below 14%. This method provides a rapid means for the accurate and precise determination of both OH-ITZ and ITZ concentrations in human serum.

The association between cryptococcal variety and immunocompetent and immunocompromised hosts.

The varieties of Cryptococcus neoformans serotypes are neoformans and gattii. Data suggest an association between cryptococcal variety and host immune status. In addition, the two varieties differ in their epidemiology and pathogenicity. Furthermore, symptoms, outcome, and response of cryptococcosis to antifungal therapy may vary. The two varieties also differ in immune-modulating effects. Sparse clinical data suggest var. gattii is more virulent and may be more recalcitrant to antifungal therapy. Also, its infections produce more sequelae. A better understanding of how cryptococcal variety influences the clinical course and response to the treatment of cryptococcosis is needed. Clinicians should be aware of the association, especially in patients with refractory disease. It may be useful to type the isolate to the variety level and administer prolonged antifungal therapy.

Relative bioavailability of itraconazole from an extemporaneously prepared suspension and from the marketed capsules.

The bioavailability of itraconazole from an extemporaneously prepared suspension was compared with its bioavailability from the commercially available capsules. Ten healthy volunteers were fed breakfast and were then randomly assigned to receive either 400 mg of itraconazole 40-mg/mL oral suspension or four 100-mg itraconazole capsules with 240 mL of water. They were not allowed to rest in a supine position for six hours, eat for four hours, or take any beverages for two hours post-dose. Blood samples were taken immediately after the subjects had eaten and at intervals up to 72 hours post-dose. Serum was separated and stored at -70 degrees C. Serum itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography. After 14 days, each subject was given the dosage form that he or she did not previously receive, and testing was repeated. Maximum concentration (Cmax) and time to reach maximum concentration (tmax) were determined, and the area under the serum concentration-versus-time curve from 0 to 72 hours (AUC0-72) was estimated. The suspension:capsule ratios of least-squares means for Cmax, tmax, and AUC0-72 for itraconazole were 0.15 (90% confidence interval [CI], 0.11-0.21), 0.95 (90% CI, 0.75-1.20), and 0.12 (9% CI, 0.06-0.23), respectively. The results for hydroxyitraconazole were similar: 0.19 (0.13-0.28), 0.95 (0.81-1.12), and 0.13 (0.07-0.23), respectively. The bioavailability of itraconazole from the extemporaneously prepared suspension is much lower than that from capsules.

Amphotericin B lipid complex.

OBJECTIVE: To evaluate the published data on the effectiveness and safety of amphotericin B lipid complex (ABLC) for the treatment of invasive mycosis and to evaluate data describing the pharmacologic properties and pharmacokinetic behavior of ABLC in both animals and humans. DATA SOURCE: A MEDLINE search was conducted to identify literature published from 1965 to January 1997 for amphotericin B deoxycholate (DCAB) and ABLC. In addition, preliminary data published as abstracts and presented at national conferences on infectious disease and hematology within the last 6 years were also included in this review. STUDY SELECTION: Both human and animal studies were reviewed. Animal and in vitro studies were selected to evaluate the pharmacologic and toxicologic properties of ABLC. For the evaluation of the efficacy, safety, and pharmacokinetic behavior of ABLC, large, well-controlled studies were reviewed. In addition, data from open-label and emergency use protocols were also included in the review. DATA EXTRACTION: The study and analytical methods, results, and conclusions of the selected studies were evaluated. Pharmacokinetic data for both ABLC and DCAB that were derived from human subjects were also evaluated. DATA SYNTHESIS: DCAB has been the cornerstone for the treatment of invasive mycosis, even though it has a narrow therapeutic index. Infusion-related toxicities (e.g., fever, chills, rigors) are likely due to DCAB stimulation of cytokine and prostaglandin synthesis. Conversely, nephrotoxicity, the primary non-infusion-related toxicity, likely results from the nonselective cytotoxic interaction between DCAB and cholesterol-containing mammalian cells. ABLC represents a new approach to improving the therapeutic index of DCAB. Mammalian cytotoxicity is attenuated by complexing amphotericin B to a mixture of phospholipids. This alters the affinity of amphotericin B and decreases its selective transfer from the complex to cholesterol-containing mammalian cells. Fungi also possess lipase, which improves the selective transfer from the complex to ergosterol-containing cell membranes. In humans, the lipid formulation increases the volume of distribution of amphotericin B. Thus, compared with DCAB, larger doses of ABLC can be administered for a longer duration with less nephrotoxicity. However, the prevalence of infusion-related toxicities associated with ABLC is similar to that of DCAB. Whether the alteration in distribution improves efficacy by improving tissue concentrations of amphotericin B has not been determined. The cost of this agent will limit its use. CONCLUSIONS: ABLC has been shown to be at least as effective as DCAB, and it has been well tolerated in the clinical studies to date. Despite large dosages and extended courses of administration, there is little nephrotoxicity associated with its use. However, the cost of this agent will limit its use to the treatment of refractory mycosis or to cases where DCAB is contraindicated due to significant renal insufficiency.

Intrapulmonary pharmacokinetics of azithromycin in healthy volunteers given five oral doses.

The intrapulmonary pharmacokinetics of oral azithromycin were studied in 25 healthy volunteers, each of whom received an initial dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340, and 508 h after the first dose was administered. Azithromycin concentrations in epithelial lining fluid (ELF), alveolar macrophages, peripheral blood monocytes, and serum were measured by high-performance liquid chromatography. Azithromycin was extensively concentrated in cells and ELF. Drug concentrations in AMs (peak mean +/- standard deviation, 464 +/- 65 micrograms/ml) exceeded 80 micrograms/ml up to 508 h (21 days) following the first dose, while concentrations in PBMs (peak, 124 +/- 28 micrograms/ml) exceeded 20 micrograms/ml up to 340 h (14 days). Azithromycin concentrations in ELF peaked at 124 h (3.12 +/- 0.93 micrograms/ml) and were detectable up to 172 h (7 days), when they were 20 times the concurrent serum concentrations. Although the clinical significance of antibiotic concentrations in these compartments is nuclear, the sustained lung tissue penetration and extensive phagocytic accumulation demonstrated in this study support the proven efficacy of azithromycin administered on a 5-day dosage schedule in the treatment of extracellular or intracellular pulmonary infections.

Treatment of vancomycin-resistant staphylococcal infections.

The reports of vancomycin resistance, though sparse, cannot be ignored. They document evidence of emerging vancomycin resistance. Because of the absence of suitable alternatives and a poor current understanding of the mechanisms involved, much work is needed to prevent such resistance from becoming widespread. Only by understanding the mechanism(s) of resistance involved can we develop strategies to combat resistant strains.

Blastomycosis in children.

Infections due to Blastomyces dermatitidis are not commonly encountered in children and adolescents. Knowledge of the diagnosis and treatment of this disease is largely based upon experience with adult patients. We recently reviewed our experience with blastomycosis to evaluate the difficulties in diagnosis and treatment of this disease in the pediatric population. Ten patients with blastomycosis were identified during our review, and five had pulmonary disease alone. Of these five patients, four required open-lung biopsy for diagnosis, even though three had previously undergone bronchoalveolar lavage. The response to treatment with the oral azole antifungal agents (ketoconazole, fluconazole, and itraconazole) was limited, and the agent with the greatest success remains amphotericin B. Until more data are available, amphotericin B should be used for complicated and life-threatening cases of blastomycosis. If oral azole agents are used for non-life-threatening cases, patients should be followed closely, and if clinical deterioration occurs or serum levels of medications are not adequate, then amphotericin B should be substituted for the oral azole agent.

Surveillance of treated and untreated funguria in a university hospital.

STUDY OBJECTIVE: To determine the influence of treatment on the microbiologic outcome of funguria. DESIGN: Retrospective case series. SETTING: A 300-bed tertiary care teaching hospital in a large metropolitan area. SUBJECTS: 141 hospitalized patients, 18 years of age or older, with at least one urine culture positive (> or = 10(2) cfu/ml) for fungi. INTERVENTIONS: Retrospective review of medical records to determine the microbiologic outcome of funguria. MAIN RESULTS: Funguria developed rapidly in individuals with known predisposing factors. Urinalysis did not routinely detect the presence of fungi or pyuria. Symptoms such as fever, dysuria, and frequency were generally absent. Funguria persisted whether it was due to Candida albicans or nonalbicans species. There were no statistical differences in the microbiologic outcomes of treated and untreated funguria. CONCLUSIONS: Funguria is a rapidly developing, often benign and persistent process. Minimizing predisposing risks, such as removing indwelling urinary catheters, is beneficial in its management. Pharmacologic treatment of funguria due to C. albicans or non-albicans species does not influence the microbiologic outcome.

Frequency, pathogenicity and microbiologic outcome of non-Candida albicans candiduria.

A retrospective review of urine cultures obtained from patients at the University of Illinois Hospital revealed that the frequency of isolation of non-albicans Candida species increased significantly from 1990 to 1991 (p = 0.0003), while the frequency of isolation of Candida albicans species decreased significantly (p = 0.0006). Patients with urine cultures positive for non-albicans Candida species of Torulopsis glabrata during 1991 were identified for review. Sixty-seven patients were eligible for evaluation. Non-albicans candiduria developed in an average of 12 days. Identical fungal species were isolated from the blood following a positive urine culture in only two patients. Twenty patients were treated; candiduria persisted in 9 (45%), while resolution occurred in 11 (55%). The remaining 47 patients were not treated. Non-albicans candiduria persisted in 30 (64%) of these patients and resolved in 15 (32%); in the remaining two patients (4%) the microbiologic outcome was undetermined. The difference in microbiologic outcomes between treated and untreated patients was not significant using the Chi-square test (p = 0.170). Non-albicans candiduria developed rapidly, frequently persisted whether treated or untreated, and rarely progressed to candidemia.