An innovative population pharmacokinetic/pharmacodynamic strategy for attaining aggressive joint PK/PD target of continuous infusion ceftazidime/avibactam against KPC- and OXA-48- producing Enterobacterales and preventing resistance development in critically ill patients.

OBJECTIVES: Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients. METHODS: A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam. RESULTS: The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable. CONCLUSIONS: This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice.

Piperacillin-tazobactam vs. carbapenems for treating hospitalized patients with ESBL-producing Enterobacterales bloodstream infections: a systematic review and meta-analysis.

OBJECTIVES: To meta-analyze the clinical efficacy of piperacillin-tazobactam vs. carbapenems for treating hospitalized patients affected by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales bloodstream infections (BSIs). METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database up to 17 January 2024, to retrieve randomized controlled trials (RCTs) or observational studies comparing piperacillin-tazobactam vs. carbapenems for the management of hospitalized patients with ESBL-BSIs. Data were independently extracted by the two authors, and the quality of included studies was independently assessed according to ROB 2.0 or ROBINS-I tools. Mortality rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) retrieved from studies providing adjustment for confounders using a random-effects model with the inverse variance method. RESULTS: After screening 3,418 articles, 10 studies were meta-analyzed (one RCT and nine retrospective observational studies; N=1,962). Mortality rate did not significantly differ between treatment with piperacillin-tazobactam vs. carbapenems (N=6; OR 1.41; 95%CI 0.96-2.07; I²=23.6%). The findings were consistent also in subgroup analyses assessing patients receiving empirical therapy (N=5; OR 1.36; 95%CI 0.99-1.85), or patients having in ≥50% of cases urinary/biliary tract as the primary BSI source (N=2; OR 1.26; 95%CI 0.84-1.89). Conversely, the mortality rate was significantly higher with piperacillin-tazobactam only among patients having in <50% of cases urinary/biliary tract as the primary source of BSI (N=3; OR 2.02; 95%CI 1.00-4.07). CONCLUSIONS: This meta-analysis showed that, after performing appropriate adjustments for confounders, mortality and clinical outcome in patients having ESBL-producing Enterobacterales BSIs did not significantly differ among those receiving piperacillin-tazobactam compared to those receiving carbapenems.

Population Pharmacokinetics and Pharmacodynamics of Dalbavancin and C-Reactive Protein in Patients with Staphylococcal Osteoarticular Infections.

BACKGROUND AND OBJECTIVE: Dalbavancin is increasingly used for the long-term treatment of chronic osteoarticular infections. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis for assessing the relationship between dalbavancin exposure and C-reactive protein (C-RP) over time was conducted. METHODS: Non-linear mixed-effect modeling was fitted to dalbavancin and C-RP concentrations. Monte Carlo simulations assessed the weekly percentage of C-RP reduction associated with different dosing regimens, starting from baseline to < 1 mg/dL. RESULTS: A total of 45 patients were retrospectively included in the analysis. The PK of dalbavancin was described by a two-compartment model, and the PD of C-RP was described by an indirect turnover maximum inhibition model. The total dalbavancin concentration model estimate producing 50% of maximum C-RP production inhibition (IC50) was 0.70 mg/L. Monte Carlo simulations showed that in patients with staphylococcal osteoarticular infections targeting total dalbavancin concentrations at > 14.5 mg/L at any time point may achieve C-RP production inhibition over time in > 95% of patients. Based on this, the findings showed that a cumulative dose of 3000 mg administered in the first 3 weeks may lead to a > 90% C-RP decrease versus baseline in approximately 5-6 weeks. In patients needing treatment prolongation, an additional 1500 mg dose after this period may maintain C-RP concentrations < 1 mg/dL for other 3 weeks. CONCLUSIONS: A decrease in C-RP is related to dalbavancin exposure in osteoarticular infections. Targeting dalbavancin plasma concentrations above the efficacy threshold may be associated with effective treatment.

Effect of incremental tazobactam concentrations on the bactericidal activity of piperacillin against ESBL-producing enterobacterales clinical isolates causing bacteraemia.

We evaluated the activity of piperacillin in relation to INCREASING TAZOBACTAM CONCENTRATION against ESBL-producing Enterobacterales collected from patients with bacteraemia. Increasing tazobactam concentration (4, 12 or 24 mg/L) exerted a reduction of piperacillin MICs under the clinical breakpoint in a concentration-dependent manner (0%, 60% and 90% of clinical isolates). Also, activity of piperacillin/tazobactam based at higher achievable serum concentrations (123/14 mg/L) is needed to reduce the bacterial growth in 92% of ESBL-producers. CHANGES IN THE PIPERACILLIN MIC IN RELATION TO INCREASING TAZOBACTAM SUGGEST THAT REALTIME TDM COULD BE USED FOR DRIVEN ANTIMICROBIAL THERAPY WITH PIPERACILLIN/TAZOBACTAM IN BSI DUE TO ESBL STRAINS.

A Sensitive Liquid Chromatography-Tandem Mass Spectrometry Method for Measuring Fosfomycin Concentrations in Human Prostatic Tissue.

The aim of this study was to develop and validate a fast and sensitive bioanalytical method for the accurate quantification of fosfomycin concentrations in human prostatic tissue. The sample preparation method only required milligrams of tissue sample. Each sample was mixed with two times its weight of water and homogenized. A methanol solution that was three times the volume of the internal standard (fosfomycin-13C3) was added, followed by vortex mixing and centrifugation. After its extraction from the homogenized prostatic tissue, fosfomycin was quantified by means of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) triple quadrupole system operating in negative electrospray ionization and multiple reaction monitoring detection mode. The analytical procedure was successfully validated in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and stability, according to EMA guidelines. The validation results, relative to three QC levels, were 9.9% for both the within-day and inter-day accuracy (BIAS%); 9.8% for within-day precision; and 9.9 for between-day precision. A marked matrix effect was observed in the measurements but was corrected by normalization with the internal standard. The average total recovery was high (approximatively 97% at the three control levels). The dynamic range of the method was 0.1-20 µg/g (R2 of 0.999). Negligible carry-over was observed after the injection of highly concentrated samples. F in the sample homogenate extracts was stable at 10 °C and 4 °C for at least 24 h. In the tissue sample freeze-thaw experiments, a significant decrease in F concentrations was observed after only two cycles from -80 °C to room temperature. The novel method was successfully applied to measure fosfomycin in prostatic tissue samples collected from 105 patients undergoing prostatectomy.

Impact of attaining aggressive vs. conservative PK/PD target on the clinical efficacy of beta-lactams for the treatment of Gram-negative infections in the critically ill patients: a systematic review and meta-analysis.

BACKGROUND: To perform a systematic review with meta-analysis with the dual intent of assessing the impact of attaining aggressive vs. conservative beta-lactams PK/PD target on the clinical efficacy for treating Gram-negative infections in critical patients, and of identifying predictive factors of failure in attaining aggressive PK/PD targets. METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 23rd December 2023, to retrieve studies comparing the impact of attaining aggressive vs. conservative PK/PD targets on clinical efficacy of beta-lactams. Independent predictive factors of failure in attaining aggressive PK/PD targets were also assessed. Aggressive PK/PD target was considered a100%fT>4xMIC, and clinical cure rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) extrapolated from studies providing adjustment for confounders using a random-effects model with inverse variance method. RESULTS: A total of 20,364 articles were screened, and 21 observational studies were included in the meta-analysis (N = 4833; 2193 aggressive vs. 2640 conservative PK/PD target). Attaining aggressive PK/PD target was significantly associated with higher clinical cure rate (OR 1.69; 95% CI 1.15-2.49) and lower risk of beta-lactam resistance development (OR 0.06; 95% CI 0.01-0.29). Male gender, body mass index > 30 kg/m2, augmented renal clearance and MIC above the clinical breakpoint emerged as significant independent predictors of failure in attaining aggressive PK/PD targets, whereas prolonged/continuous infusion administration of beta-lactams resulted as protective factor. The risk of bias was moderate in 19 studies and severe in the other 2. CONCLUSIONS: Attaining aggressive beta-lactams PK/PD targets provided significant clinical benefits in critical patients. Our analysis could be useful to stratify patients at high-risk of failure in attaining aggressive PK/PD targets.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

Implementation and validation of a Bayesian method for accurately forecasting duration of optimal pharmacodynamic target attainment with dalbavancin during long-term use for subacute and chronic staphylococcal infections.

Dalbavancin is increasingly being used for long-term treatment of subacute and chronic staphylococcal infections. In this study, a new Bayesian model was implemented and validated using MwPharm software for accurately forecasting the duration of pharmacodynamic target attainment above the efficacy thresholds of 4.02 mg/L or 8.04 mg/L against staphylococci. Forecasting accuracy improved substantially with the a posteriori approach compared with the a priori approach, particularly when two measured concentrations were used. This strategy may help clinicians to estimate the duration of optimal exposure with dalbavancin in the context of long-term treatment.

Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections.

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.

Fast and Sensitive Analysis of Fosfomycin in Human Plasma Microsamples Using Liquid Chromatography-Tandem Mass Spectrometry for Therapeutic Drug Monitoring.

BACKGROUND: Fosfomycin is an antibiotic recently repurposed as a potential combination treatment for difficult-to-treat Gram-negative bacterial infections. The pharmacokinetic features of fosfomycin have demonstrated that different pathophysiologic alterations may affect its exposure. Therapeutic drug monitoring may improve real-time management of fosfomycin therapy in different clinical scenarios. OBJECTIVES: To develop and validate a fast and sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in human plasma microsamples (3 µL). METHODS: Analysis was preceded by a user-friendly pre-analytical single-step process performed via a rapid chromatographic run of 2.5 minutes, followed by negative electrospray ionization and detection on a high-sensitivity triple quadrupole tandem mass spectrometer operated in the multiple reaction monitoring mode. European Medicines Agency guidelines were used to validate the specificity, sensitivity, linearity, precision, accuracy, matrix effects, extraction recovery, limits of quantification, and stability of the analytical method. RESULTS: The new assay produced accurate (BIAS%: 0.9-9.1) and precise (coefficient of variation [CV]%: 8.1-9.5) measurements of fosfomycin over a concentration range of 1-1000 mg/L. Overall, analyte recovery was consistent (mean values: 91.2%-97.2%) at all tested concentration levels. The analyte was also stable in human plasma and the final extract under various storage conditions. The clinical applicability of the assay was confirmed through quantitation of plasma samples obtained from patients. CONCLUSIONS: A sensitive liquid chromatography - tandem mass spectrometry method for measuring fosfomycin in plasma was developed and validated according to the European Medicines Agency criteria. Quantitation of fosfomycin in clinical plasma samples confirmed that the assay is suitable for therapeutic drug monitoring in clinical scenarios.

Impact of a newly established expert clinical pharmacological advice programme based on therapeutic drug monitoring results in tailoring antimicrobial therapy hospital-wide in a tertiary university hospital: Findings after the first year of implementation.

OBJECTIVES: Therapeutic drug monitoring (TDM) may be helpful in tailoring antimicrobial treatment, and expert interpretation of the results may make it more clinically useful. METHODS: This study aimed to assess retrospectively the first-year impact (July 2021 to June 2022) of a newly established expert clinical pharmacological advice (ECPA) programme based on TDM results in tailoring therapy with 18 antimicrobials hospital-wide in a tertiary university hospital. All patients having ≥1 ECPA were grouped in five cohorts [haematology, intensive care unit (ICU), paediatrics, medical wards and surgical wards]. Four indicators of performance were identified: total ECPAs; total ECPAs recommending dosing adjustments/total ECPAs both at first and at subsequent assessments; and turnaround time (TAT) of ECPAs, defined as optimal (<12 h), quasi-optimal (12-24 h), acceptable (24-48 h) or suboptimal (>48 h). RESULTS: A total of 8484 ECPAs were provided for tailoring treatment in 2961 patients, mostly admitted in the ICU (34.1%) and medical wards (32.0%). The proportion of ECPAs recommending dosing adjustments was >40% at first assessment (40.9% haematology; 62.9% ICU; 53.9% paediatrics; 59.1% medical wards; and 59.7% surgical wards), and decreased consistently at subsequent TDM assessments (20.7% haematology; 40.6% ICU; 37.4% paediatrics; 32.9% medical wards; and 29.2% surgical wards). The overall median TAT of the ECPAs was optimal (8.11 h). CONCLUSION: The TDM-guided ECPA programme was successful in tailoring treatment with a wide panel of antimicrobials hospital-wide. Expert interpretation by medical clinical pharmacologists, short TATs, and strict interaction with infectious diseases consultants and clinicians were crucial in achieving this.

Fast and Sensitive Method for Simultaneous Quantification of Meropenem and Vaborbactam in Human Plasma Microsamples by Liquid Chromatography-Tandem Mass Spectrometry for Therapeutic Drug Monitoring.

Meropenem (MRP)-Vaborbactam (VBR) is a novel beta-lactam/beta-lactamase inhibitor used for the management of difficult-to-treat Gram-negative infections. Among critically ill patients, MRP-VBR shows remarkable inter-individual variability in pharmacokinetic behavior, thus justifying the implementation of therapeutic drug monitoring (TDM) for improving real-time management in different challenging scenarios. In this study, we developed and validated a fast and sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method for the simultaneous quantification of MRP and VBR in human plasma microsamples of 3 microliters. The analysis required only a single-step sample preparation and was performed by means of a fast chromatographic run of 4 min, followed by positive electrospray ionization and detection on a high-sensitivity triple quadrupole tandem mass spectrometer operated in multiple reaction monitoring modes. The straightforward analytical procedure was successfully validated, based on the EMA guidelines, in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, the limit of quantification, and stability. The novel method was successfully applied for simultaneously measuring MRP and VBR concentrations in more than 42 plasma samples collected from critically ill patients affected by carbapenem-resistant Gram-negative bacteria infections.

A descriptive case series of the relationship between maintenance of conservative PK/PD efficacy thresholds of dalbavancin over time and clinical outcome in long-term treatment of staphylococcal osteoarticular infections.

OBJECTIVE: To describe the relationship between maintenance of pharmacokinetic/pharmacodynamic (PK/PD) dalbavancin efficacy thresholds over time and clinical outcome in a case series of patients who underwent therapeutic drug monitoring (TDM) during long-term treatment of staphylococcal osteoarticular infections (OIs). METHODS: Patients who received two 1500-mg doses of dalbavancin 1 week apart for documented staphylococcal OIs, underwent TDM assessment, and had clinical outcome assessable at follow-up were included retrospectively. Dalbavancin concentrations ≥4.02 and/or ≥8.04 mg/L were identified as conservative PK/PD efficacy thresholds. The percentage of time of the overall treatment period with dalbavancin concentrations above these efficacy thresholds was calculated and correlated with clinical outcome. RESULTS: In total, 17 patients were included in this study. Long-term dalbavancin was used mainly for treating prosthetic joint infections (9/17, 52.9%). In 13/17 patients (76.5%), clinical outcome was assessable after at least 6 months of follow-up and was always successful (100.0%). In four of 17 patients (23.5%), clinical outcome is favourable after 3.7, 4.8, 5.1 and 5.3 months of follow-up, respectively. In most patients, both dalbavancin PK/PD efficacy thresholds were reached for most of the treatment period (%time ≥4.02 mg/L: 100% in 13 cases, 75-99.9% in two cases, 50-74.99% in two cases; %time ≥8.04 mg/L: 100% in eight cases, 75-99.9% in four cases, 50-74.99% in four cases, <50% in one case). CONCLUSIONS: These findings could support the idea that maintenance of conservative PK/PD efficacy thresholds of dalbavancin for the majority of the treatment period may represent a valuable approach in dealing efficaciously with long-term treatment of staphylococcal OIs.

Does Cytokine-Release Syndrome Induced by CAR T-Cell Treatment Have an Impact on the Pharmacokinetics of Meropenem and Piperacillin/Tazobactam in Patients with Hematological Malignancies? Findings from an Observational Case-Control Study.

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS.

Successful and Safe Real-Time TDM-Guided Treatment of Invasive Pulmonary and Cerebral Aspergillosis Using Low-Dose Isavuconazole in a Patient with Primary Biliary Cirrhosis: Grand Round/A Case Study.

BACKGROUND: The authors present a case of a 67-year-old woman with primary biliary cirrhosis (Child-Pugh class B) who was treated with isavuconazole for invasive pulmonary and cerebral aspergillosis. Isavuconazole treatment was initiated with the standard maintenance dose of 200 mg daily. Therapeutic drug monitoring (TDM) was performed to target trough concentrations within the desired range of 1.0-5.13 mg/L. METHODS: Real-time TDM and pharmacokinetic analyses were used to determine the dose adjustments. Liver transaminases (alanine aminotransferase and gamma-glutamyl transferase) were assessed to monitor hepatotoxicity. RESULTS: The trough plasma levels gradually increased over time up to 17.8 mg/L. TDM-guided clinical pharmacological advice was helpful to initially reduce the dose, then to temporarily suspend drug administration, and finally to calculate the correct dose that allowed for long-term treatment up to day 258. No major signs and/or symptoms of drug-related toxicity occurred, apart from a transient increase in gamma-glutamyl transferases that normalized after the drop in isavuconazole trough levels within the desired range. CONCLUSIONS: TDM-guided clinical pharmacological advice was essential for the successful and safe management of isavuconazole treatment in this patient with moderate liver dysfunction.

Fast and Sensitive Analysis of Cefiderocol in Human Plasma Microsamples by Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry for Therapeutic Drug Monitoring.

Cefiderocol (C) is a parenteral siderophore cephalosporin with relevant inter-individual pharmacokinetic variability among critically ill patients, which may potentially affect effective drug exposure. Therapeutic drug monitoring (TDM) may concur in improving the real-time management of C therapy in clinics. In this study, we developed and validated a fast and sensitive Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry (LC-ITD-MS/MS) method for measuring C in human plasma microsamples, as small as 3 microliters. Analysis was preceded by a user-friendly pre-analytical single-step and was performed by means of a very fast chromatographic run of 4 min, followed by positive electrospray ionization and detection on a high sensitivity triple quadrupole tandem mass spectrometer operated in multiple reaction monitoring mode. The straightforward analytical procedure was successfully validated, based on the European Medicines Agency (EMA) guidelines, in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, and stability. The novel method was successfully applied to TDM of C in more than 50 cases of critically carbapenem-resistant Gram-negative bacterial infections and enabled us to optimize antibiotic therapy.

Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients.

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix. Ganciclovir concentrations and CMV viral loads were obtained retrospectively from kidney transplant patients receiving routine clinical care. Ten thousand Monte Carlo simulations were performed with the licensed dosages adjusted for renal function to assess the probability of attaining a viral load target of ≤290 and ≤137 IU/mL. Fifty-seven patients provided 343 ganciclovir concentrations and 328 CMV viral loads for PK/PD modeling. A one-compartment pharmacokinetic model coupled with an indirect viral turnover growth model with stimulation of viral degradation pharmacodynamic model was devised. Simulations showed that 1- and 2-log10 reduction of CMV viral load mostly occurred between a median of 5 to 6 and 12 to 16 days, respectively. The licensed dosages achieved a probability of reaching the viral load target ≥90% at days 35 to 49 and 42 to 56 for the thresholds of ≤290 and ≤137 IU/mL, respectively. Simulations indicate that in patients with an estimated glomerular filtration rate of 10 to 24 mL/min/1.73m2, a dose increase to 450 mg every 36 h may reduce time to optimal viral load target to days 42 and 49 from a previous time of 49 and 56 days for the thresholds of ≤290 and ≤137 IU/mL, respectively. Currently licensed dosages of valganciclovir for preemptive therapy of CMV infection may achieve a viral load reduction within the first 2 weeks, but treatment should continue for ≥35 days to ensure viral load suppression.

Fast and Simple Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Dalbavancin in Long-Term Treatment of Subacute and/or Chronic Infections.

Dalbavancin (DBV) is a long-acting antistaphylococcal lypoglycopeptide that is being increasingly used for long-term treatment of a wide range of subacute and/or chronic infections, mainly osteo-articular infections (OAI). Population pharmacokinetic studies showed that two 1500 mg doses 1 week apart can ensure effective treatment for several weeks. In this scenario, therapeutic drug monitoring (TDM) can be a helpful tool for providing clinicians with real-time feedback on the duration of optimal treatment by measuring drug concentrations over time in each single patient. The aim of this study was to develop and validate a fast and simple analytical method based on the Liquid Chromatography-Isotope Dilution Tandem Mass Spectrometry (ITD LC-MS/MS) technique for measuring DBV concentrations in human plasma microsamples. It will allow an innovative, very convenient and minimally invasive way of sampling. Analysis was performed by simple single-step sample preparation and very short instrumental run time (4 min). Analytical performance met all criteria in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability under different conditions set by the European Medicines Agency (EMA) for drug quantification by means of bioanalytical methods. The method was successfully applied for measuring DBV concentrations (range = 2.0-77.0 mg/L) in a cohort of patients receiving long-term DBV treatment of subacute and/or chronic infections.

Measuring Creatinine Clearance Is the Most Accurate Way for Calculating the Proper Continuous Infusion Meropenem Dose for Empirical Treatment of Severe Gram-Negative Infections among Critically Ill Patients.

Assessment of glomerular filtration rate (GFR) is necessary for dose adjustments of beta-lactam that are excreted by the kidneys, such as meropenem. The aim of this study was to compare the daily dose of 24 h-continuous infusion (CI) meropenem when GFR was calculated by means of measured creatinine clearance (mCLCR) or estimated by the CKDEPI (eGFRCKDEPI), Cockcroft-Gault (eGFRCG), and MDRD (eGFRMDRD) equations. Adult critically ill patients who underwent therapeutic drug monitoring (TDM) for the assessment of 24 h-CI meropenem steady state concentration (Css) and for whom a 24 h-urine collection was performed were retrospectively enrolled. Meropenem clearance (CLM) was regressed against mCLCR, and meropenem daily dose was calculated based on the equation infusion rate = daily dose/CLM. eGFRCKDEPI, eGFRCG, and eGFRCKDEPI were regressed against mCLCR in order to estimate CLM. Forty-six patients who provided 133 meropenem Css were included. eGFRCKDEPI overestimated mCLCR up to 90 mL/min, then mCLCR was underestimated. eGFRCG and eGFRMDRD overestimated mCLCR across the entire range of GFR. In critically ill patients, dose adjustments of 24 h-CI meropenem should be based on mCLCR. Equations for estimation of GFR may lead to gross under/overestimates of meropenem dosages. TDM may be highly beneficial, especially for critically ill patients with augmented renal clearance.