Real-Time Optimization of Pharmacodynamic Target Attainment at Infection Site during Treatment of Post-Neurosurgical Ventriculitis Caused by Carbapenem-Resistant Gram Negatives with Ceftazidime–Avibactam-Based Regimens: A Report of Two Cases

We present two cases of post-neurosurgical ventriculitis caused by carbapenem-resistant Gram-negative pathogens successfully treated with high-dose ceftazidime/avibactam. The existence of a real-time clinical pharmacological advice program, by enabling the optimization of the PK/PD targets over time at the infection site, turned out to be very helpful.

Target Attainment in the Production of English Vowels by Polish Students: The Influence of Language Instruction in the Time of Covid-19, Imitation, and Musicality

This pilot experimental study pursues a number of goals. Firstly, it aims to assess the phonetic attainment of selected English vowels among twelve Polish students of English philology after one term of intensive online pronunciation training in pandemic conditions. Secondly, it looks at potential differences between production outcomes in two experimental contexts, that is, reading and imitation. Finally, it seeks to determine if there is any correlation between musicality and target attainment with a view to identifying a broader scope for potential future research questions. For this purpose, recorded samples of read and imitated English words containing vowels in a uniform context /h_d/ were assessed by six raters using a 5-point Likert scale. The results, including those of an online musicality test, were analysed and subjected to statistical testing. The majority of total scores exceed the assumed acceptability benchmark of 50%. The study yielded a number of unexpected results. Firstly, female participants performed significantly better than male ones in the reading experiment, but not in imitation. Secondly, a stronger correlation was found between the reading results and musicality than between imitation results and musicality.

Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients

Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.

Population pharmacokinetics of intra-peritoneal gentamicin and the impact of varying dwell times on pharmacodynamic target attainment in patients with acute peritonitis undergoing peritoneal dialysis

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data was obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio >10) and toxicity (plasma AUC < 120 mg*h/L) was determined for 0.3 to 1.2 mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 hours and for the duration of 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L, and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility break point of 4 mg/L only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. Probability of achieving exposure below the threshold of 120 mg*h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2 mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical break point of 4 mg/L is likely to produce early toxic levels of exposure that is expected to be detrimental to the renal system.

The Pharmacokinetics of Beta-Lactam Antibiotics Using Scavenged Samples in Pediatric Intensive Care Patients: The EXPAT Kids Study Protocol

Background: Emerging evidence supports the importance of optimized antibiotic exposure in pediatric intensive care unit (PICU) patients. Traditional antibiotic dosing is not designed for PICU patients, as the extreme pharmacokinetic (PK) behavior of drugs threatens the achievement of optimal antibiotic treatment outcomes. Scavenged sampling is a sampling strategy which may have positive implications for routine TDM and PK research, as well as monitoring other biomarkers. EXPAT Kids study was designed to analyze whether current empiric dosing regimens of frequently used beta-lactam antibiotics achieve defined therapeutic target concentrations in PICU patients.Methods: A mono-centre, exploratory pharmacokinetic and pharmacodynamic study was designed to assess target attainment of beta-lactam antibiotics. One hundred forty patients will be included within 24 months after start of inclusion. At various time points serum concentration of the study antibiotic (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, and meropenem) are determined. In parallel with these sampling moments, residual material is collected to validate the use of blood of scavenged heparinized astrup syringes for the quantification of antibiotic exposure. The primary outcome is the time that the free (unbound) concentration of the study antibiotic remains above one to four the minimal inhibitory concentration during a dosing interval (100%ƒT &gt; MIC and 100%ƒT&gt;4xMIC). Other included outcomes are disease severity, safety, length of stay, and inflammatory biomarkers.Discussion: Potentially, scavenged sampling may enrich the EXPAT Kids dataset, and reduce additional blood sampling and workload for clinical personnel. The findings from the EXPAT Kids study will lead to new insights in the PK parameters of beta-lactams and consecutive effects on target attainment and clinical outcomes. Is there a need for more precision in dosing? Netherlands Trial Register Number: Trial NL9326.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.