Pharmacokinetic/Pharmacodynamic Target Attainment of Ceftazidime in Adult Patients on General Wards with Different Degrees of Renal Function: A Prospective Observational Bicenter Cohort Study.

No prospective evidence exists on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime in adult patients on general wards. We aimed to investigate whether the PK/PD target of ceftazidime (50% T > MIC) is attained in adult patients on general wards with adequate and impaired renal function receiving regular and guideline-recommended reduced doses of ceftazidime. In this observational, prospective, bicenter cohort study, adult patients admitted to a general ward receiving ceftazidime as part of standard care were included. Three blood samples per patient within 72 h after start of treatment were collected. Data were analyzed with nonlinear mixed effects modeling. The primary endpoint was target attainment of 50% T > MIC during the first 24 h of treatment (50% T0-24 > MIC). Forty patients were included from whom 121 blood samples were obtained. All 25/25 patients with adequate renal function, 9/10 patients with moderately impaired renal function (eGFR 30-50 mL/min/1.73 m2) and 5/5 patients with severe impaired renal function (eGFR < 30 mL/min/1.73 m2) attained 50% T0-24 > MIC when applying the clinical breakpoint MIC for Pseudomonas aeruginosa of 8 mg/L. The one patient not attaining the PK/PD target did not differ in any of the collected patients' characteristics, except that this patient was the oldest in the study population. However, age was not statistically significantly associated with clearance or volume of distribution in the population pharmacokinetic model and, therefore, not likely the cause for this patient not attaining the PK/PD target. Our results suggest ≥90% probability of the PK/PD target attainment of ceftazidime in patients on general wards with adequate and impaired renal function receiving regular and guideline-recommended reduced doses of ceftazidime for treatment of infections with Pseudomonas aeruginosa and all bacteria with lower MIC-values.

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review.

Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of short-term empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Assay for the Determination of Total and Unbound Ciprofloxacin Concentrations in Human Plasma.

BACKGROUND: Although unbound ciprofloxacin is responsible for antibacterial effects, assays measuring the unbound drug plasma concentrations are scarce. This study aimed to develop and validate a rapid, reproducible, and sensitive liquid chromatography-tandem mass spectrometry assay for the determination of total and unbound ciprofloxacin plasma concentrations. METHODS: The determination of total ciprofloxacin concentrations required a 10 µL sample, while for unbound ciprofloxacin concentrations, it was 100 µL. Unbound ciprofloxacin was separated from protein-bound ciprofloxacin through ultrafiltration. A deuterated internal standard was used, and the sample preparation involved protein precipitation. The method was fully validated over a concentration range of 0.02-5.0 mg/L, according to the US Food and Drug Administration guidelines. In addition, its clinical application was demonstrated. RESULTS: The total run time was 1.5 minutes. For total ciprofloxacin plasma concentrations, the mean accuracy ranged from 94.5% to 105.0% across the validated range, the intraday imprecision was ≤7.6%, and the interday imprecision was ≤9.8%. For unbound ciprofloxacin plasma concentrations, the mean accuracy ranged from 92.8% to 102.1% across the validated range, the intraday imprecision was ≤7.0%, and the interday imprecision was ≤9.6%. Ciprofloxacin in plasma and ultrafiltrate remained stable for at least 96 hours at room temperature, at least 4 years at -80°C, and at least 3 freeze/thaw cycles (-80°C), with a minimum interval of 24 hours. CONCLUSIONS: The presented method is precise and accurate. It has been implemented in clinical care and research projects at a university hospital, permitting rapid determination of total and unbound ciprofloxacin.

Does dose reduction of renally cleared antibiotics in patients with impaired renal function lead to adequate drug exposure? A systematic review.

BACKGROUND: There is inconsistency between many guidelines in the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function. OBJECTIVES: This systematic review summarizes the available evidence on the adequacy of the recommended dose reduction in terms of achieving sufficient antibiotic drug exposure or pharmacokinetic/pharmacodynamic target attainment after treatment with these reduced doses. DATA SOURCES: We systematically searched Ovid Medline and Embase from inception (respectively 1946 and 1947) through July 2019. STUDY ELIGIBILITY CRITERIA: All studies reporting antibiotic drug exposure and/or pharmacokinetic/pharmacodynamic (PK/PD) target attainment after dose reduction of antibiotics in patients with impaired renal function. PARTICIPANTS: Adult patients with or without infections. INTERVENTIONS: Administration of reduced doses of antibiotics (orally, intravenously or intramuscularly). METHODS: The reduced dose was considered adequate when the most relevant parameters of drug exposure or PK/PD target attainment in patients with impaired renal function were within a range of 80% to 125% of that patients with adequate renal function receiving a regular dose (reference) or when PK/PD target attainment was attained in at least 90% of the patients with impaired renal function, regardless of the lack of a reference group. RESULTS: Twenty-seven of the 4202 identified studies were included. The quality of 15 of 27 studies was fair, and most studies were of ß-lactams (12/27). Best evidence was available for meropenem: four studies were included, of which two studies were of good quality. Drug exposure for meropenem is 158% to 286% higher in patients with impaired renal function receiving reduced doses compared to patients with adequate renal function receiving regular doses. For all other antibiotics, a maximum of one good-quality study could be identified. CONCLUSIONS: No good-quality evidence on the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function is present, with the exception of meropenem.

Pharmacokinetic/pharmacodynamic target attainment of ciprofloxacin in adult patients on general wards with adequate and impaired renal function.

Limited prospective data on pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ciprofloxacin in patients with adequate and impaired renal function (eGFR <30 mL/min/1.73m2) are available in the literature. We aimed to investigate whether the PK/PD target (AUC/MIC ≥125) is attained in patients with adequate and impaired renal function receiving regular and reduced ciprofloxacin doses. This prospective observational cohort study included adult patients on general wards treated with ciprofloxacin. Three blood samples per patient were obtained for ciprofloxacin concentration measurement. Individual AUCs were calculated using a population PK model developed by non-linear mixed-effects modelling. Forty patients were included, of whom eight had impaired renal function and were treated with a guideline-recommended reduced dose. Using the clinical breakpoint MIC of the most isolated bacteria (Escherichia coli, 0.25 mg/L), AUC0-24/MIC ≥125 was attained in 13/32 (41%) patients with adequate renal function receiving regular doses and in 1/8 (13%) patients with impaired renal function receiving reduced doses. Median drug exposure (AUC0-24) for patients with impaired renal function was 19.0 [interquartile range (IQR) 14.2-23.3] mg/L•h, which was statistically significantly lower than that for patients with adequate renal function [29.3 (IQR 25.0-36.0) mg/L•h] (P < 0.01). AUC0-24/MIC ≥125 is not attained in the majority of adult patients on general wards for clinically relevant bacteria with MICs at or just below the clinical breakpoint. The risk of not attaining the target appears to be highest in patients with impaired renal function receiving guideline-recommended reduced doses, as drug exposure is significantly lower in these patients.

Risk of subsequent gastrointestinal cancer among childhood cancer survivors: A systematic review.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk of developing subsequent malignant neoplasms, including gastrointestinal (GI) cancer. We performed a systematic review to summarize all available literature on the risk of, risk factors for, and outcome after subsequent GI cancer among CCS. METHODS: A systematic search of the literature databases Medline/PubMed (1945-2014) and Embase (1947-2014) was performed to identify studies that consisted of ⩾1000 CCS and assessed incidence of or mortality from subsequent GI cancer as an outcome. RESULTS: A total of 45 studies were included. Studies that reported risk measures for subsequent GI cancer compared to the general population showed a 3.2 to 9.7-fold elevated risk in cohort studies including all childhood cancer types. Abdominal radiotherapy was associated with an increased risk of subsequent GI cancer in all four studies that assessed this risk. Survivors who had received procarbazine and platinum agents were also suggested to be at increased risk. CONCLUSION: Abdominal radiotherapy is a risk factor for developing a subsequent GI cancer. Few studies examined detailed treatment-related risk factors and most studies had small number of GI cancer cases. Therefore, no conclusions could be drawn on the effect of time since childhood cancer on GI cancer risk and on outcome after a subsequent GI cancer. Additional research is necessary to further explore risk factors for and outcome after a subsequent GI cancer, and to systematically evaluate the harms and benefits of GI screening among high-risk survivors in order to give sound screening recommendations.