Prolonged vs Intermittent Infusions of ß-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis.

Importance: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged ß-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of ß-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of ß-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of ß-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged ß-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration: PROSPERO Identifier: CRD42023399434.

COVID-19 Drug Treatments Are Prone to Sequestration in Extracorporeal Membrane Oxygenation Circuits: An Ex Vivo Extracorporeal Membrane Oxygenation Study.

Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO.

Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

In silico Evaluation of a Vancomycin Dosing Guideline Among Adults with Serious Infections.

BACKGROUND: This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections. METHODS: In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets. RESULTS: Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001). CONCLUSIONS: A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.

In silico evaluation of a beta-lactam dosing guideline among adults with serious infections.

STUDY OBJECTIVE: The aim of this study was to compare the achievement of therapeutic pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for beta-lactam antibiotics using product information dosing or guideline-based dosing for the treatment of serious infections. DESIGN: In silico study. DATA SOURCE: ID-ODSTM (Individually Designed Optimum Dosing Strategies). PATIENTS AND INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: In silico product information and guideline-based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK-PD targets. A multiple linear regression model was constructed to identify the effect of guideline-based dosing covariates on achieving pre-defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline-based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline-based and product information-based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline-based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA. CONCLUSIONS: Our study demonstrated that achievement of PK-PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline-based dosing; especially at 48 h.

Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).

Pharmacokinetics and pharmacodynamics of beta-lactam antibiotics in critically ill patients.

Optimal antibiotic therapy for critically ill patients can be complicated bythe altered physiology associated with critical illness. Antibiotic pharmacokineticsand exposures can be altered driven by the underlying critical illnessand medical interventions that critically ill patients receive in the intensivecare unit. Furthermore, pathogens that are usually isolated in the intensivecare unit are commonly less susceptible and "resistant" to common antibiotics.Indeed, antibiotic dosing that does not consider these unique differenceswill likely fail leading to poor clinical outcomes and the emergenceof antibiotic resistance in the intensive care unit. The aims of this narrativereview were to describe the pharmacokinetics of beta-lactam antibiotics incritically ill patients, to highlight pharmacokinetic/pharmacodynamic targetsfor both non-critically ill and critically ill patients, and to discuss importantstrategies that can be undertaken to optimize beta-lactam antibiotic dosingfor critically ill patients in the intensive care unit.

La terapia antibiótica óptima en los pacientes en estado crítico puedecomplicarse por la alteración de la fisiología asociada a esta etapa de laenfermedad. La farmacocinética y la exposición a los antibióticos puedenverse alteradas por la enfermedad crítica subyacente y las intervencionesmédicas que reciben estos pacientes en la unidad de cuidados intensivos.Además, las cepas que suelen encontrarse en la unidad de cuidados intensivossuelen ser menos susceptibles y "resistentes" a los antibióticos máshabituales. De hecho, una dosificación de antibióticos que no tenga encuenta estas diferencias únicas, probablemente fracasará y dará lugar aresultados clínicos deficientes y a la aparición de resistencia a los antibióticosen la unidad de cuidados intensivos. Los objetivos de esta revisión sondescribir la farmacocinética de los antibióticos betalactámicos en pacientescríticos, destacar los objetivos farmacocinéticos/farmacodinámicos paralos pacientes y exponer algunas estrategias importantes que pueden optimizarla dosificación de los antibióticos betalactámicos en pacientes críticosen la unidad de cuidados intensivos.

Machines that help machines to help patients: optimising antimicrobial dosing in patients receiving extracorporeal membrane oxygenation and renal replacement therapy using dosing software.

Intensive care unit (ICU) patients with end-organ failure will require specialised machines or extracorporeal therapies to support the failing organs that would otherwise lead to death. ICU patients with severe acute kidney injury may require renal replacement therapy (RRT) to remove fluid and wastes from the body, and patients with severe cardiorespiratory failure will require extracorporeal membrane oxygenation (ECMO) to maintain adequate oxygen delivery whilst the underlying pathology is evaluated and managed. The presence of ECMO and RRT machines can further augment the existing pharmacokinetic (PK) alterations during critical illness. Significant changes in the apparent volume of distribution (Vd) and drug clearance (CL) for many important drugs have been reported during ECMO and RRT. Conventional antimicrobial dosing regimens rarely consider the impact of these changes and consequently, are unlikely to achieve effective antimicrobial exposures in critically ill patients receiving ECMO and/or RRT. Therefore, an in-depth understanding on potential PK changes during ECMO and/or RRT is required to inform antimicrobial dosing strategies in patients receiving ECMO and/or RRT. In this narrative review, we aim to discuss the potential impact of ECMO and RRT on the PK of antimicrobials and antimicrobial dosing requirements whilst receiving these extracorporeal therapies. The potential benefits of therapeutic drug monitoring (TDM) and dosing software to facilitate antimicrobial therapy for critically ill patients receiving ECMO and/or RRT are also reviewed and highlighted.

Population pharmacokinetics of ciprofloxacin in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

INTRODUCTION: This study aimed to describe the pharmacokinetics (PK) of ciprofloxacin in critically ill patients receiving ECMO and recommend a dosing regimen that provides adequate drug exposure. METHODS: Serial blood samples were taken from ECMO patients receiving ciprofloxacin. Total ciprofloxacin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. Dosing simulations were performed to ascertain the probability of target attainment (PTA) represented by the area under the curve to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 125. RESULTS: Eight patients were enrolled, of which three received concurrent continuous venovenous haemodiafiltration (CVVHDF). Ciprofloxacin was best described in a two-compartment model with total body weight and creatinine clearance (CrCL) included as significant predictors of PK. Patients not requiring renal replacement therapy generated a mean clearance of 11.08 L/h while patients receiving CVVHDF had a mean clearance of 1.51 L/h. Central and peripheral volume of distribution was 77.31 L and 90.71 L, respectively. ECMO variables were not found to be significant predictors of ciprofloxacin PK. Dosing simulations reported that a 400 mg 8 -hly regimen achieved > 72% PTA in all simulated patients with CrCL of 30 mL/min, 50 mL/min and 100 mL/min and total body weights of 60 kg and 100 kg at a MIC of 0.5 mg/L. CONCLUSION: Our study reports that established dosing recommendations for critically ill patients not on ECMO provides sufficient drug exposure for maximal ciprofloxacin activity for ECMO patients. In line with non-ECMO critically ill adult PK studies, higher doses and therapeutic drug monitoring may be required for critically ill adult patients on ECMO.

Treatment of ventilator-associated pneumonia due to carbapenem-resistant Gram-negative bacteria with novel agents: a contemporary, multidisciplinary ESGCIP perspective.

INTRODUCTION: In the past 15 years, treatment of ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) has represented an intricate challenge for clinicians. AREAS COVERED: In this perspective article, we discuss the available clinical data about novel agents for the treatment of CR-GNB VAP, together with general pharmacokinetic/pharmacodynamic principles for the treatment of VAP, in the attempt to provide some suggestions for optimizing antimicrobial therapy of CR-GNB VAP in the daily clinical practice. EXPERT OPINION: Recently, novel ß-lactams and ß-lactam/ß-lactamase inhibitor combinations have become available that have shown potent in vitro activity against CR-GNB and have attracted much interest as novel, less toxic, and possibly more efficacious options for the treatment of CR-GNB VAP compared with previous standard of care. Besides randomized controlled trials, a good solution to enrich our knowledge on how to use these novel agents at best in the near future, while at the same time remaining adherent to current evidence-based guidelines, is to improve our collaboration to conduct larger multinational observational studies to collect sufficiently large populations treated in real life with those novel agents for which guidelines currently do not provide a recommendation (in favor or against) for certain causative organisms.

Population Pharmacokinetics and Dosing Simulations of Ceftriaxone in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (An ASAP ECMO Study).

BACKGROUND: Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting. OBJECTIVE: The aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO. METHODS: Serial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics®. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT>MIC). RESULTS: In total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L). CONCLUSIONS: Dosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation.

Therapeutic Drug Monitoring of Antibiotics: Defining the Therapeutic Range.

PURPOSE: In the present narrative review, the authors aimed to discuss the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) of antibiotics and clinical response (including efficacy and toxicity). In addition, this review describes how this relationship can be applied to define the therapeutic range of a particular antibiotic (or antibiotic class) for therapeutic drug monitoring (TDM). METHODS: Relevant clinical studies that examined the relationship between PK/PD of antibiotics and clinical response (efficacy and response) were reviewed. The review (performed for studies published in English up to September 2021) assessed only commonly used antibiotics (or antibiotic classes), including aminoglycosides, beta-lactam antibiotics, daptomycin, fluoroquinolones, glycopeptides (teicoplanin and vancomycin), and linezolid. The best currently available evidence was used to define the therapeutic range for these antibiotics. RESULTS: The therapeutic range associated with maximal clinical efficacy and minimal toxicity is available for commonly used antibiotics, and these values can be implemented when TDM for antibiotics is performed. Additional data are needed to clarify the relationship between PK/PD indices and the development of antibiotic resistance. CONCLUSIONS: TDM should only be regarded as a means to achieve the main goal of providing safe and effective antibiotic therapy for all patients. The next critical step is to define exposures that can prevent the development of antibiotic resistance and include these exposures as therapeutic drug monitoring targets.

Population Pharmacokinetics of Vancomycin in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation (an ASAP ECMO Study).

Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on Pmetrics. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC0-24) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (Vc). The mean vancomycin renal clearance and Vc were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).

Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

OBJECTIVES: This study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. METHODS: Serial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (Cmin) of 8-20 mg/L. Six patients were enrolled, of which one was receiving renal replacement therapy. Cefepime was best described in a two-compartment model, with total body weight and creatinine clearance (CrCL) as significant predictors of PK parameters. The mean clearance and central volume of distribution were 2.42 L/h and 15.09 L, respectively. RESULTS: Based on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40-44% probability of efficacy (Cmin > 8 mg/L) and 1-6% toxicity (Cmin > 20 mg/L). Patients with CrCL 30 mL/min and 65 mL/min receiving 1 g 12-hourly dosing achieved an 84-92% and 46-53% probability of efficacy and 8-44% and 1-8% probability of toxicity, respectively. Simulations demonstrated a lower probability of efficacy and higher probability of toxicity with decreasing patient weight. CONCLUSION: This study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.

Pharmacokinetics of fluconazole and ganciclovir as combination antimicrobial chemotherapy on ECMO: a case report.

Extracorporeal membrane oxygenation (ECMO) can affect antimicrobial pharmacokinetics. This case report describes a 33-year-old male with newly diagnosed acquired immunodeficiency syndrome presenting in acute severe type 1 respiratory failure. On investigation, the patient had positive cultures for Candida albicans from respiratory specimens and high blood cytomegalovirus titres, and required venovenous ECMO therapy for refractory respiratory failure. Intravenous fluconazole (6 mg/kg, 24-h) and ganciclovir (5 mg/kg, 12-h) was commenced. Pre-oxygenator, post-oxygenator and arterial blood samples were collected after antibiotic administration, and were analysed for total fluconazole and ganciclovir concentrations. Although there was a 40% increase in the volume of distribution for fluconazole relative to healthy volunteers, the pharmacodynamic targets for prophylaxis were still met. The area under the curve exposure of ganciclovir (50.78 mg•h/L) achieved target thresholds. The ECMO circuit had no appreciable effect on achievement of therapeutic exposures of fluconazole and ganciclovir.

Population Pharmacokinetics of Piperacillin and Tazobactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation: an ASAP ECMO Study.

Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analyzed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (%fT>MIC) and toxic exposures of greater than 360 mg/liter. The tazobactam target of percentage of time free concentrations of >2 mg/liter was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models, with body mass index, creatinine clearance, and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5-g every 6 hours regimen administered over 4 hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/liter while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT, a frequency reduction to every 12 hours dosing lowers the probability of toxic concentrations, although this remains at 7 to 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.

Prolonged infusion of beta-lactam antibiotics for Gram-negative infections: rationale and evidence base.

PURPOSE OF REVIEW: The aim of this review is to discuss the rationale of and current evidence for prolonged beta-lactam infusion in the management of Gram-negative infections. RECENT FINDINGS: Pharmacokinetic/pharmacodynamic (PK/PD) data from various in-vitro and in-vivo experimental studies conclusively support prolonged infusion over intermittent infusion in terms of achieving effective beta-lactam exposure for maximal bacterial killing. Superior PK/PD target attainment has been demonstrated with prolonged beta-lactam infusion in patient populations that are more likely to have less susceptible Gram-negative infections. These populations include critically ill patients, cystic fibrosis patients and patients with malignant diseases. The clinical impact of prolonged beta-lactam infusion is likely to be the greatest in these patient groups: critically ill patients with a high level of illness severity who are not receiving renal replacement therapy; patients with nonfermenting Gram-negative bacilli infection and patients with respiratory infection. Critically ill patients with augmented renal clearance may not achieve effective beta-lactam exposure even with the use of prolonged infusion. Maximizing the effectiveness of prolonged beta-lactam infusion via therapeutic drug monitoring is becoming a more common strategy in the management of critically ill patients with Gram-negative infection. SUMMARY: Prolonged beta-lactam infusion may not benefit all patients but only for those who are critically ill and/or immunocompromised, who are also more likely to have less susceptible Gram-negative infections.

Increasing ventilator surge capacity in COVID 19 pandemic: design, manufacture and in vitro-in vivo testing in anaesthetized healthy pigs of a rapid prototyped mechanical ventilator.

OBJECTIVE: The advent of new technologies has made it possible to explore alternative ventilator manufacturing to meet the worldwide shortfall for mechanical ventilators especially in pandemics. We describe a method using rapid prototyping technologies to create an electro-mechanical ventilator in a cost effective, timely manner and provide results of testing using an in vitro-in vivo testing model. RESULTS: Rapid prototyping technologies (3D printing and 2D cutting) were used to create a modular ventilator. The artificial manual breathing unit (AMBU) bag connected to wall oxygen source using a flow meter was used as air reservoir. Controlled variables include respiratory rate, tidal volume and inspiratory: expiratory (I:E) ratio. In vitro testing and In vivo testing in the pig model demonstrated comparable mechanical efficiency of the test ventilator to that of standard ventilator but showed the material limits of 3D printed gears. Improved gear design resulted in better ventilator durability whilst reducing manufacturing time (< 2-h). The entire cost of manufacture of ventilator was estimated at 300 Australian dollars. A cost-effective novel rapid prototyped ventilator for use in patients with respiratory failure was developed in < 2-h and was effective in anesthetized, healthy pig model.

What Are the Current Approaches to Optimising Antimicrobial Dosing in the Intensive Care Unit?

Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens achieving target exposures associated with optimal patient outcomes. Therefore, the aim of this review is to explore the various methods for optimisation of antimicrobial dosing in ICU patients. Dosing nomograms developed from pharmacokinetic/statistical models and therapeutic drug monitoring are commonly used. However, recent advances in mathematical and statistical modelling have resulted in the development of novel dosing software that utilise Bayesian forecasting and/or artificial intelligence. These programs utilise therapeutic drug monitoring results to further personalise antimicrobial therapy based on each patient's clinical characteristics. Studies quantifying the clinical and cost benefits associated with dosing software are required before widespread use as a point-of-care system can be justified.