Scott A. McConnell

Results of autologous stem cell transplant in multiple myeloma patients with renal failure

Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine > 176·8 μmol/l) at the time of autologous stem cell transplantation (auto‐SCT), including 38 patients on dialysis. The median age was 53 years (range: 29–69) and 26% had received more than 12 months of prior chemotherapy. CD34+ cells were mobilized with granulocyte colony‐stimulating factor (G‐CSF) alone (n = 51) or chemotherapy plus G‐CSF (n = 27), yielding medians of 10 and 16 × 106 CD34+ cells/kg respectively (P = 0·003). Sixty patients (27 on dialysis) received melphalan 200 mg/m2 (MEL‐200). Because of excessive toxicity, the subsequent 21 patients (11 on dialysis) received MEL 140 mg/m2 (MEL‐140). Thirty‐one patients (38%) completed tandem auto‐SCT, including 11 on dialysis. Treatment‐related mortality (TRM) was 6% and 13% after the first and second auto‐SCT. Median times to absolute neutrophil count (ANC) > 0·5 × 109/l and to platelets > 50 × 109/l were 11 and 41 d respectively. Non‐haematological toxicities included mucositis, pneumonitis, dysrhythmias and encephalopathy. At a median follow up of 31 months, 30 patients have died. Complete remission (CR) was achieved in 21 patients (26%) after first SCT and 31 patients (38%) after tandem SCT. Two patients discontinued dialysis after SCT. Median durations of complete remission (CR) and overall survival (OS) have not been reached; probabilities of event‐free survival (EFS) and OS at 3 years were 48% and 55% respectively. Dialysis dependence and MEL dose did not affect EFS or OS. Sensitive disease prior to SCT, normal albumin level and younger age were independent prognostic factors for better OS. In conclusion, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. MEL‐140 had an acceptable toxicity and appeared equally effective as MEL‐200. In the setting of renal failure, the role of auto‐SCT early in the disease course and benefits of tandem SCT require further evaluation.

Do Antimicrobial-Impregnated Central Venous Catheters Prevent Catheter-Related Bloodstream Infection?

Controversy surrounds the role of central venous catheters (CVCs) impregnated with antimicrobial agents in the prevention of catheter-related bloodstream infection (CRBSI). We reviewed the current literature to evaluate the efficacy of antimicrobial-impregnated CVCs for preventing CRBSI. Eleven randomized studies published in article form were identified that included a control group that received nonimpregnated CVCs. We evaluated study methodologies, inclusion of key patient characteristics, use of clinically relevant end points, and molecular-relatedness studies. Review of these 11 trials revealed several methodological flaws, including inconsistent definitions of CRBSI, failure to account for confounding variables, suboptimal statistical and epidemiological methods, and rare use of clinically relevant end points. This review also failed to demonstrate any significant clinical benefit associated with the use of antimicrobial-impregnated CVCs for the purpose of reducing CRBSI or improving patient outcomes. More rigorous studies are required to support or refute the hypothesis that antimicrobial-impregnated CVCs reduce the rate of or prevent CRBSI.

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.

Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers

Study Objective. To evaluate the effect of repeated ingestion of grapefruit juice on the systemic availability of itraconazole (ITZ) and hydroxy‐itraconazole (OHITZ) serum concentrations in subjects administered hydroxypropyl‐β‐cyclodextrin‐ITZ (HP‐β‐CD ITZ) oral solution.

Characterizing and predicting amphotericin B-associated nephrotoxicity in bone marrow or peripheral blood stem cell transplant recipients.

Study Objective. To characterize amphotericin B‐associated nephrotoxicity and to determine the variables associated with it that can be used to identify, a priori, at‐risk patients.

Review and comparison of advanced-generation macrolides clarithromycin and dirithromycin.

We reviewed English‐language clinical studies, abstracts, and review articles identified from MEDLINE searches from January 1966–August 1998, and bibliographies of identified articles to compare advanced‐generation macrolides dirithromycin and clarithromycin and their use for respiratory tract infections. Both agents have superior adverse effect profiles compared with erythromycin, the original macrolide. Both have broad antibacterial coverage, but clarithromycin usually has a lower MIC90 to susceptible organisms than dirithromycin; for most isolates this difference is not clinically significant. Clarithromycin has better in vitro coverage of Haemophilus influenzae, but this activity varies with formation of its bioactive metabolite, 14‐hydroxyclarithromycin. Neither agent is ideal for H. influenzae eradication. The agents differ markedly in terms of pharmacokinetics, pharmacodynamics, metabolism, and cost, and thus with respect to drug interaction profiles and dosages. Dirithromycins drug interaction profile is markedly better than clarithromycins. Clarithromycin is dosed twice/day; dirithromycins pharmacokinetics allow once/day dosing. Dirithromycin is less expensive with regard to both cost/day and cost/treatment regimen. Clarithromycin has been studied and approved for administration to children. In adults with respiratory tract infections who are receiving drugs that would interact with clarithromycin, and in those with renal dysfunction with or without coexisting hepatic dysfunction, dirithromycin appears to be superior in terms of safety and equivalent to clarithromycin in terms of efficacy.

Steady-State Pharmacokinetics of Oral Voriconazole and Its Primary Metabolite, N-Oxide Voriconazole, Pre- and Post-Autologous Peripheral Stem Cell Transplantation

ABSTRACT Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT.

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 µg/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.