Etoposide is a derivative of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumours and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumour cells from repairing DNA breaks. However, the clinical advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concentrations of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metabolism of etoposide with specific cytochrome P450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were associated with increased bioavailability, although they were characterised by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concentration between two oral administrations (C(24,trough)), drug exposure time above a threshold value and area under the plasma concentration-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic-pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concentrations do not exceed 3-5 mg/L and C(24,trough) is under the threshold limit of 0.3 mg/L. To maintain effective etoposide plasma concentrations during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metabolism and elimination. Dosage reduction is generally useful to avoid haematological toxicity in patients with renal dysfunction (creatinine clearance <50 mL/min). The need for dosage adjustment based on liver function in patients with liver dysfunction is not completely defined, but generally is not indicated in patients with minor liver dysfunction. Adaptive dosage adjustment based on individual pharmacokinetic parameters, estimated using limited sampling strategies and population pharmacokinetic models, is more appropriate. This approach has been used with success in different clinical trials to increase the etoposide dosage, without significantly increasing toxicity. Various pharmacodynamic models have been proposed to guide etoposide oral dosage. However, they lack precision and accuracy and need to be refined by considering other predictor variables in order to extend their application in current clinical practice.

Aims  To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.Methods  A prospective, open label, cross‐over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P‐Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.Results  Mean clearance was 1.14 l h−1 (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r2 = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l−1 h; CV 64%; range 0.4–9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l−1 h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l−1 h) than in patients with stable (2.1 mg l−1 h) or progressive disease (2.3 mg l−1 h) (P = 0.01).Conclusions  Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

Objective: Ceftobiprole is an advance generation cephalosporin which has broad-spectrum bacterial activity (both against Gram-positive and negative pathogens) and was approved for the treatment of communityacquired pneumonia (CAP) and non-ventilated hospital-acquired pneumonia (HAP) in most European countries. We aimed to evaluate the efficacy and safety of ceftobiprole in the treatment of pneumonia in a cohort of severely ill patients admitted to the emergency department (ED). Methods: 1-year observational retrospective mono-centric study. Were defined two primary endpoints: first, to evaluate the clinical cure at the test-of-cure (TOC); the second, to evaluate the early improvement, defined as a reduction of symptoms and inflammatory parameters 72 hours after the start of treatment. The secondary endpoint is to evaluate the reduction of antibiotic "burden" using ceftobiprole despite standard of care in severe hospital-acquired pneumonia. Results: During the study period, a total of 48 patients with severe pneumonia received ceftobiprole: twenty-two patients (45.8%) as empiric therapy, 9 (18.5%) as a de-escalation option from previous combination therapies, 13 patients (27.1%) as an escalation therapy from ceftriaxone or amoxicillin/clavulanate and four patients (8.3%) as a targeted therapy based on microbiological results. Ceftobiprole mean duration therapy was 10.2 days. Forty-six patients with severe pneumonia had an early clinical improvement 72 hours after the start of treatment (95.8%). In general, ceftobiprole was well tolerated; only one patient suspended the drug because of poor tolerability. The clinical cure at TOC was 85.4% and 30-days crude mortality was 10.4%. Conclusions: This study confirms that ceftobiprole is effective in severely ill patients with pneumonia at risk of poor outcomes.

No abstract

During COVID-19 pandemic, implementing and maintaining an antimicrobial stewardship protocol obtained both low rates of MDR microorganisms and low antimicrobial use in an 800-bed hospital network in northern Italy. Infectious diseases specialist consulting was crucial to maintain this protocol active.