Thomas C. Hardin

Pharmacokinetics of itraconazole following oral administration to normal volunteers.

The pharmacokinetics of itraconazole, an orally effective, broad-spectrum, systemic antifungal agent, were evaluated in five healthy male volunteers. Each subject was studied on days 1 and 15 at the following dosages: 100 mg once daily (regimen A), 200 mg once daily (regimen B), and 200 mg twice daily (regimen C). On each study day, itraconazole was administered with a standardized meal. Plasma samples were collected for 72 h postdose, and 24-h urine specimens were obtained. On day 1 of regimen C, plasma samples were collected following the second dose. Samples were assayed for itraconazole by a sensitive, reverse-phase, high-performance liquid chromatography method. Wide intersubject variations in itraconazole concentration in plasma versus time profiles were observed on all study days. Absorption appeared to be slow, with day 1 mean peak itraconazole concentrations in plasma of 110 ng/ml at 2.8 h (regimen A), 272 ng/ml at 3.0 h (regimen B), and 553 ng/ml at 3.4 h (regimen C). Mean peak itraconazole concentrations in plasma on day 15 were 412 ng/ml at 3.0 h (regimen A), 1,070 ng/ml at 4.4 h (regimen B), and 1,980 ng/ml at 6.0 h (regimen C). The steady state was achieved by day 13. Respective elimination half-lives on days 1 and 15 were 15 and 34 h (regimen A), 20.7, and 36.5 h (regimen B), and 25 and 41.7 h (regimen C), respectively. The areas under the plasma concentration versus time curves (0 to infinity) on day 1 were 1,320 (regimen A), 4,160 (regimen B), and 12,600 ng.h/ml (regimen C). With the exception of one patient on day 15 of regimen C, itraconazole was not detected in the urine. All data support dose-dependent pharmacokinetic behavior for itraconazole.

Association of Antibiotic Utilization Measures and Control of Multiple-Drug Resistance in Klebsiella pneumoniae

OBJECTIVE To study the association of antibiotic-utilization measures and control of multidrug-resistant (MDR) Klebsiella pneumoniae after emergence in two hospitals in our medical center. DESIGN AND SETTING Rates of MDR K. pneumoniae at two hospitals were compared before and after acute interventions, including emphasis on Contact Precautions and education in antibiotic utilization. Antipseudomonal beta-lactam antibiotic use was measured before and after the interventions at both hospitals. Pulsed-field gel electrophoresis of whole cell DNA was used as a marker of strain identity. RESULTS Clonal strain dissemination was the major mechanism of emergence at hospital A; emergence was polyclonal at hospital B. Antibiotic-utilization interventions at both institutions included physician education regarding the association of ceftazidime use and MDR K. pneumoniae. At hospital A, ceftazidime use decreased from 4,301 g in the preintervention period, to 1,248 g in the postintervention period. Piperacillin-tazobactam use increased from 12,455 g to 17,464 g. Ceftazidime resistance in K. pneumoniae decreased from 110 (22%) of 503 isolates to 61 (15%) of 407 isolates (P<.05); piperacillin-tazobactam resistance decreased from 181 (36%) of 503 to 77 (19%) of 407 isolates (P<.05). At hospital B, ceftazidime use decreased from 6,533 g in the preintervention period to 4,792 g in the postintervention period. Piperacillin-tazobactam use increased from 58,691 g to 67,027 g. Ceftazidime resistance in K. pneumoniae decreased from 42 (10%) of 415 isolates to 19 (5%) of 383 isolates (P<.05). Piperacillin-tazobactam resistance decreased from 91 (22%) of 415 isolates to 54 (14%) of 383 isolates (P<.05). Follow-up data showed continued decrease in piperacillin-tazobactam resistance despite increased use at both hospitals. CONCLUSIONS Antibiotic-use measures may be particularly important for control of MDR K. pneumoniae, whether emergence is clonal or polyclonal.

High-dose itraconazole in the treatment of severe mycoses.

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (less than 2.5 micrograms/ml) in both patients. All other patients had mean trough levels in serum above 5 micrograms/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Hyperlipidemia Associated with Protease Inhibitor Therapy

OBJECTIVE: To report a case of extreme hyperlipidemia associated with protease inhibitor–based antiretroviral therapy and review the relevant literature concerning lipid abnormalities with HIV infection and antiretroviral therapy. CASE SUMMARY: A 35-year-old HIV-infected man developed a serum cholesterol of 1472 mg/dL and fasting serum triglycerides of 8660 mg/dL after initiation of antiretroviral therapy consisting of ritonavir, saquinavir, nevirapine, and didanosine. All other medications had been stable during this time period and the abnormality resolved after discontinuation of antiretroviral therapy and initiation of lipid-lowering therapy. The elevated cholesterol and triglyceride concentrations did not recur when therapy was reinstituted with nelfinavir, saquinavir, nevirapine, and didanosine. The hyperlipidemia then was attributed to ritonavir. DISCUSSION: Lipid abnormalities are common in patients with HIV infection and usually consist of hypocholesterolemia and moderate hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia have been reported with ritonavir and, less commonly, with other currently available protease inhibitors. Some cases of ritonavir-associated hyperlipidemia have been extreme. Although an association between hyperlipidemia and clinical consequences such as pancreatitis and atherosclerotic disease has not been well described with protease inhibitor therapy, pancreatitis is common in HIV-infected patients. It is possible that in some cases, protease inhibitor–induced hypertriglyceridemia may contribute to the development of pancreatitis. CONCLUSIONS: Optimal management of lipid abnormalities in HIV-infected patients is controversial. The potential benefit of reducing the incidence of pancreatitis and atherosclerotic events must be weighed against the risk of intolerance, toxicity, and drug interactions.

A Prospective Double-Blind Trial of Intracorporeal Papaverine Versus Prostaglandin E1 in the Treatment of Impotence

A randomized prospective, double-blind clinical trial was performed comparing intracorporeal injections of papaverine (30 mg. per ml.) with prostaglandin E1 (10 mcg. per ml.) as pharmacological treatment of impotence. A total of 15 men completed the study, receiving papaverine and prostaglandin E1 in a crossover design. Over-all, 9 of 15 evaluable patients had a full erection with either 1 or both drugs: 3 secondary to papaverine only, 2 to prostaglandin E1 only, and 4 to both drugs. No major complications were observed. We conclude that intracorporeal prostaglandin E1 may be used successfully to stimulate pharmacological erections and that it might be useful in patients not responding to intracorporeal papaverine.

Treatment of Aspergillosis with Itraconazole

OBJECTIVE: To review the role of itraconazole as oral therapy for the major infections caused by Aspergillus spp.: allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis. DATA SOURCES: A MEDLINE search of articles published in the English language between 1986 and 1993 was used to identify relevant citations, including review articles. In addition, a search of the published abstracts of the past two Interscience Conferences on Antimicrobial Agents and Chemotherapy (ICAAC) was performed. STUDY SELECTION: Clinical trials that evaluated itraconazole therapy in either allergic bronchopulmonary aspergillosis, aspergilloma, or invasive aspergillosis were critically reviewed. Trials were evaluated based upon entry criteria for the diagnosis of each type of aspergillosis, risk factors for the development of aspergillosis (neutropenia, transplant recipient, hematologic malignancy), prior antifungal chemotherapy, and dose and duration of itraconazole therapy. DATA SYNTHESIS: Overall, the clinical trials of itraconazole therapy for aspergillosis are limited and of variable quality. In the treatment of allergic bronchopulmonary aspergillosis, itraconazole has been reported to prompt a reduction in corticosteroid dosage in selected patients. There have been no controlled trials of itraconazole as treatment for aspergilloma, but data from several open-label trials suggest that this agent may be of clinical benefit in aspergilloma, primarily as an alternative to surgery. The use of itraconazole for invasive aspergillosis has been evaluated in several trials, most often in patients who were intolerant to amphotericin B treatment. Response to oral itraconazole has generally been promising. CONCLUSIONS: Although itraconazole offers promise for oral therapy against infections caused by Aspergillus spp., it should not presently be regarded as primary therapy for any of these diseases. Amphotericin B, in doses ranging from 1 to 1.5 mg/kg to a total dose of 1.5–4.0 g, should remain the treatment of choice in both aspergilloma and invasive aspergillosis. Itraconazole use should be restricted to patients who experience severe toxicity with amphotericin B therapy. Corticosteroids continue to be first-line therapy for allergic bronchopulmonary aspergillosis, with the use of itraconazole reserved for those patients who would benefit from a reduction in corticosteroid dose.

The Use of Vasopressin in the Treatment of Upper Gastrointestinal Haemorrhage

SummaryVasopressin is a potent vasoconstrictor which greatly reduces mesenteric blood flow. In patients with portal hypertension this results in decreased portal venous flow and portal pressure. Because of this property, vasopressin has been used for years in the therapy of variceal haemorrhage. A few controlled trials show that vasopressin causes a decrease in bleeding but has no effect on survival. It has been shown that intravenous vasopressin is just as effective as intra-arterial, and is associated with fewer complications.The inability to influence the outcome of variceal haemorrhage significantly may be related to suboptimal dosing due to the occurrence of systemic complications at higher doses. The combination of vasopressin with either sodium nitroprusside or nitroglycerin (glyceryl trinitrate) has resulted in a further decline of portal pressure, along with amelioration of most of the adverse haemodynamic effects of vasopressin. Whether or not clinical efficacy is increased when vasopressin is combined with sodium nitroprusside or nitroglycerin remains to be proven.Analogues of vasopressin, such as terlipressin, held early promise as agents which would be as effective as vasopressin, without the cardiac adverse effects. Recent data have not supported this and at present there is little to suggest any advantage of terlipressin over vasopressin.Virtually no adequate studies have yet been performed to support the use of vasopressin in the treatment of non-variceal haemorrhages. There is reason to suspect that vasopressin can effectively control bleeding from haemorrhagic gastritis, but the subsequent results of inducing gastric ischaemia in an already damaged gastric mucosa are unknown.In summary, vasopressin appears to have little effect on the mortality of patients with variceal haemorrhage. It may, however, help control the haemorrhage in some patients by lowering the portal pressure. Cardiovascular complications limit the dose that can be used but it is hoped that by combining vasopressin with nitroglycerin, a more effective and safe therapy will be available for variceal haemorrhages.

Telavancin Hospital-Acquired Pneumonia Trials: Impact of Gram-Negative Infections and Inadequate Gram-Negative Coverage on Clinical Efficacy and All-Cause Mortality

BACKGROUND When hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is caused by gram-positive and gram-negative pathogens or both (mixed infections), the adequacy of gram-negative coverage (GNC) can confound the assessment of a gram-positive agent under study. This analysis examines the influence of gram-negative infections and the adequacy of GNC on clinical efficacy and all-cause mortality in the telavancin HABP/VABP phase 3 ATTAIN trials (Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia). METHODS This post hoc analysis evaluated 3 patient groups from ATTAIN: (1) gram-positive-only infections, (2) gram-positive-only and mixed infections-adequate GNC, and (3) gram-negative-only infections and mixed infections with inadequate GNC. For each, clinical efficacy at test of cure and all-cause mortality at day 28 were compared for telavancin and vancomycin. RESULTS/CONCLUSIONS In the ATTAIN safety population there were 16 more deaths in the telavancin arms than in the vancomycin arms. Of these, 13 were in patients with gram-negative-only infections (n = 9) or with mixed infections and inadequate GNC (n = 4) and all had estimated baseline creatinine clearances of <30ml/min. Based on this analysis, clinical response and all-cause mortality could be confounded because there were more patients with gram-negative pathogens at baseline and more patients received inadequate treatment of these gram-negative infections in the telavancin groups.

Comparison of ampicillin-sulbactam and ticarcillin-clavulanic acid in patients with chronic renal failure: Effects of differential pharmacokinetics on serum bactericidal activity

Study Objectives. To evaluate the pharmacodynamic antibacterial activity of ticarcillin‐clavulanic acid (T‐C) and ampicillin‐sulbactam (A‐S) combinations against reference bacterial strains in patients with end‐stage renal disease maintained on long‐term hemodialysis.

Amphotericin B Enzyme-Linked Immunoassay for Clinical Use: Comparison with Bioassay and HPLC

OBJECTIVE: To evaluate a new enzyme-linked immunosorbent assay (ELISA) for amphotericin B in serum samples. Results are compared with those obtained by HPLC and bioassay. DESIGN: Comparison of results obtained by ELISA, HPLC, and bioassay. METHODS: We developed a new ELISA using a polyclonal rabbit antibody to measure serum amphotericin B concentrations. Blinded samples of amphotericin B in concentrations of 0.15–78 μg/mL were prepared in human serum and assayed simultaneously by the ELISA, HPLC, and bioassay. The results of each assay were derived from standard curves and evaluated by using the Table Curve 2D computer program. These data were compared by using correlation analysis with evaluation of Pearsons correlation coefficient by Students t-est. RESULTS: ELISA and bioassay compared favorably at amphotericin B concentrations of 0.3–20 μg/mL with a correlation coefficient of r = 0.993, while ELISA and HPLC compared with a correlation coefficient of r = 0.944. The average coefficient of variation over the range 0.3–20.0 μg/mL was 28% ± 7% for HPLC, 26% ± 9% for ELISA, and 13% ± 4% for bioassay. Comparison of all three assays revealed the highest correlation with the ELISA assay (r = 0.998) for the range of concentrations (0.3–20 μg/mL) routinely achieved. Samples containing concentrations in excess of 20 μg/mL could be diluted. Desiccation for concentrations less than 0.3 μg/mL was not tested. CONCLUSIONS: The determination of serum amphotericin B concentrations by ELISA gave results similar to those obtained by a bioassay and HPLC technique. Although variability appears greater with ELISA, the ease of performing this assay expedites the evaluation of many samples. Finally, this assay may allow the determination of amphotericin B concentrations from lipid formulations without interference from coadministered antibacterials or azole antifungals.