Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results.

BACKGROUND: Prostate-specific antigen (PSA) is used as an outcome measure for relapsed disease in prostate cancer. Nonetheless, there are considerable concerns about its indiscriminate use as a surrogate endpoint for cell growth or survival. We hypothesized that treatment with a luteinizing hormone releasing hormone (LHRH) analog would decrease PSA levels even in the absence of malignant disease. METHODS: We determined testosterone and PSA levels in 30 healthy volunteers after a single intramuscular injection of a LHRH depot formulation. Testosterone and PSA levels were quantified by radioimmunoassay and electrochemi-luminescence immunoassay, respectively. RESULTS: After an initial flare-up during the first 3 days testosterone decreased reaching castration levels in 18 of the 30 young men (60%). After the nadir on day 28, testosterone levels increased to normal again. Changes in PSA paralleled those of testosterone. Castration reduced PSA levels by 29% (95% CI 19%-39%) compared to baseline (p<0.0001). CONCLUSIONS: LHRH superagonists decrease PSA levels by testosterone deprivation. Conferring these findings to tumor patients, decreases in PSA after treatment with LHRH analogs might not only reflect disease regression but also a direct testosterone mediated effect on PSA. Thus, PSA levels should be cautiously interpreted when patients receive hormonal therapy.

Prospective observational study comparing three different treatment regimes in patients with Clostridium difficile infection.

In a hospital-based, prospective cohort study, the effects of the three standard treatment regimens for mild Clostridium difficile infection (CDI), oral (p.o.) metronidazole at 500 mg three times/day, intravenous (i.v.) metronidazole at 500 mg three times/day, and oral (p.o.) vancomycin at 250 mg four times/day, were compared with respect to the risk of occurrence of complications, sequelae, and all-cause death within 30 days after the date of starting treatment. Differences in the incidence of these outcomes were tested by χ² or Fisher's exact tests. A Poisson regression model was performed to control for possible confounding effects of sex, age, and severity of comorbidity categorized according to the Charlson comorbidity index. The highest mortality was observed in the metronidazole i.v. group, with a mortality rate 38.1% (16/42) compared to mortality rates of 7.4% (9/121) in the metronidazole p.o. group and 9.5% (4/42) in the vancomycin p.o. group (P < 0.001). After adjustment for possible effects of sex, age (> 65 years), and severity of comorbidity, the relative risk of a 30-day fatal outcome for patients receiving metronidazole i.v. was 4.3 (95% confidence interval [CI] = 1.92 to 10; P < 0.0001) compared to patients treated with metronidazole p.o. and 4.0 (95% CI = 1.31 to 5.0; P < 0.015) compared to patients treated with vancomycin p.o. There were no significant differences in the risk of complications between the three treatment groups. This study generates the hypothesis that treatment with i.v. metronidazole is inferior to the oral alternatives metronidazole and vancomycin.

Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration.

OBJECTIVES: Daptomycin is bactericidal against Gram-positive bacteria, with peak-dependent effect but trough-dependent toxicity. This study was performed to develop dosing recommendations in continuous venovenous haemodiafiltration (CVVHDF). PATIENTS AND METHODS: Nine critically ill patients in intensive care units of the Medical University Hospital of Vienna, requiring CVVHDF due to acute renal failure and antimicrobial treatment, were included. Blood and effluent samples were collected over 72 h to determine daptomycin concentrations by HPLC. Pharmacokinetic parameters were based on 10 sampling timepoints during the first 24 h, and peak and trough samples thereafter. An open two-compartment model was fitted to each subject's plasma concentration-time data. Simulations of serum concentration-time profiles after different doses and intervals were performed using ADAPT 5. RESULTS: Peak plasma concentrations with 6 mg/kg daptomycin were 62.2 ± 16.2, 66.1 ± 17.3 and 78.5 ± 22.1 mg/L on days 1, 2 and 3, respectively. The total clearance was 6.1 ± 4.9 mL/min, and the elimination half-life was 17.8 ± 9.7 h. Daptomycin was filtrated and could therefore be measured in the effluent. Protein binding was lower than that seen in healthy volunteers. The unbound fraction was 16 ± 4.5%. All subjects maintained trough serum concentrations above 4 mg/L, at which relevant pathogens are considered daptomycin-susceptible. Accumulation resulted when daptomycin was given every 24 h. Simulation of 8 mg/kg daptomycin given every 48 h resulted in adequate levels without accumulation. CONCLUSIONS: We recommend 8 mg/kg daptomycin every 48 h in patients on CVVHDF and therapeutic drug monitoring, if possible.

Pandemic influenza A H1N1 vaccine in recipients of solid organ transplants: immunogenicity and tolerability outcomes after vero cell derived, non-adjuvanted, whole-virion vaccination.

During the 2009/10 pandemic of influenza A (H1N1), the American Society of Transplantation and other health organizations recommended that immunocompromised patients should be vaccinated as the key preventive measure. Since there are no data available for the immunogenicity of the unadjuvanted pandemic influenza vaccine in immunocompromised patients - as opposed to the adjuvanted preparation - the objective of this study was to evaluate the immunogenicity of an adjuvant-free H1N1 vaccine in recipients of solid organ transplants. Patients were recruited at the Vienna General Hospital, Austria. The vaccination schedule consisted of 2 doses of a whole-virion, vero cell derived, inactivated, non-adjuvanted influenza A/California/07/2009 (H1N1) vaccine given with an interval of 3 weeks. A hemagglutination inhibition (HI) assay on blood samples obtained prior to the first and after each vaccination was used for serologic analysis. The primary immunologic endpoint was the seroconversion rate, defined as the proportion of subjects with an individual 4-fold increase in HI titer of at least 1:40. In addition, virus-specific IgG antibodies to the pandemic H1N1 strain were measured using a commercially available ELISA. Twenty-five organ transplant patients (16 males, 9 females) aged 25-79 years were vaccinated and provided blood samples for serologic analysis. The time elapsed since transplantation was 10 months to 25 years (mean: 9 years; 95% CI 6-13 years). The vaccine was well tolerated and no local adverse events were noticed. After two vaccinations 37% of the patients demonstrated seroconversion in the HI assay as defined above and 70% had virus-specific IgG antibodies. Among the HI vaccine responders were 6 of 14 heart transplant recipients and 1 of 4 liver transplant recipients. The number and type of immunosuppressive agents did not significantly differ in their effect on the immune response. Our results show that the novel vero cell derived and adjuvant-free pandemic A/California/07/2009 (H1N1) influenza vaccine induced limited but measurable immune responses in adult recipients of solid organ transplants.