Population pharmacokinetics of posaconazole in allogeneic haematopoietic stem cell transplant patients.

BACKGROUND: Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation. OBJECTIVES: To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures. METHODS: We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. RESULTS: Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these. CONCLUSIONS: Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting.

Diagnosing sepsis in the ICU: Comparison of a gene expression signature to pre-existing biomarkers.

PURPOSE: We aimed to identify a gene signature that discriminates between sepsis and aseptic inflammation in patients administered antibiotics in the intensive care unit and compare it to commonly utilised sepsis biomarkers. METHODS: 91 patients commenced on antibiotics were retrospectively diagnosed as having: (i) blood culture positive sepsis; (ii) blood culture negative sepsis; or (iii) aseptic inflammation. Bloods were collected after <24 h of antibiotic commencement for both gene expression sequencing analysis and measurement of previously identified biomarkers. RESULTS: 53 differentially expressed genes were identified that accurately discriminated between blood culture positive sepsis and aseptic inflammation in a cohort of patients given antibiotics [aROC 0.97 (95% CI, 0.95-0.99)]. This gene signature was validated in a publicly available database. The gene signature outperformed previously identified sepsis biomarkers including C-reactive protein [aROC 0.72 (95% CI, 0.57-0.87)], NT-Pro B-type Natriuretic Peptide [aROC 0.84 (95% CI, 0.73-0.96)], and Septicyte™ LAB [aROC 0.8 (95% CI, 0.68-0.93)], but was comparable to Procalcitonin [aROC 0.96 (95% CI, 0.9-1)]. CONCLUSIONS: A gene expression signature was identified that accurately discriminates between sepsis and aseptic inflammation in patients given antibiotics in the intensive care unit.

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.

Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CLCR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

The effect of the ABCDE/ABCDEF bundle on delirium, functional outcomes, and quality of life in critically ill patients: A systematic review and meta-analysis.

BACKGROUND: The effect of the ABCDEF bundle (Assess, prevent, and manage pain; Both spontaneous awakening and spontaneous breathing trials; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; and Family engagement and empowerment) on patient outcomes such as delirium is potentially optimised when the bundle is implemented in its entirety. OBJECTIVE: To systematically synthesise the evidence on the effectiveness of the ABCDEF bundle delivered in its entirety on delirium, function, and quality of life in adult intensive care unit patients. DESIGN: Systematic review and meta-analysis. DATA SOURCE: Electronic databases including MEDLINE, CINAHL, PsycINFO, Web of Science, Cochrane Library, Joanna Briggs Institute's Evidence Based Practice, Australian New Zealand Clinical Trials Registry, and Embase were searched from 2000 until December 2021. REVIEW METHODS: Inclusion criteria included (1) adult intensive care unit patients (2) studies that described the ABCDE or ABCDEF bundle in its entirety (3) studies that evaluated delirium, functional outcomes, or quality of life. Studies were excluded if they investigated long-term intensive care unit rehabilitation patients. Two reviewers independently screened records and full text, extracted data, and undertook quality appraisals with discrepancies discussed until consensus was reached. Random effects meta-analyses were conducted for delirium but was not possible for other outcomes. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess the certainty of the synthesised findings of the body of evidence. The study protocol was registered on PROSPERO (CRD 42019126407). RESULTS: A total of 18 studies (29,576 patients) were included in the descriptive synthesis. Meta-analysis of six studies (2000 patients) identified decreased delirium incidence following implementation of the ABCDEF bundle when compared with standard practice, (risk ratio = 0.57; CI, 0.36-0.90 p = 0.02) although heterogeneity was high (I2 = 92%). When compared with standard practice, a meta-analysis of five studies (3418 patients) showed the ABCDEF bundle statistically significantly reduced the duration of intensive care unit delirium (mean difference (days) - 1.37, 95% CI -2.61 to -0.13 p = 0.03; I2 96%). Valid functional assessments were included in two studies, and quality of life assessment in one. CONCLUSIONS: Although the evidence on the effect of the ABCDEF bundle delivered in its entirety is limited, positive patient delirium outcomes have been shown in this meta-analysis. As this meta-analysis was based on only 4736 patients in eight studies, further evidence is required to support its use in the adult intensive care unit. REGISTRATION DETAILS: PROSPERO (CRD 42019126407).

Evaluation of Fosfomycin-Sulbactam Combination Therapy against Carbapenem-Resistant Acinetobacter baumannii Isolates in a Hollow-Fibre Infection Model.

Static concentration in vitro studies have demonstrated that fosfomycin- or sulbactam-based combinations may be efficacious against carbapenem-resistant Acinetobacter baumannii (CRAB). In the present study, we aimed to evaluate the bacterial killing and resistance suppression potential of fosfomycin-sulbactam combination therapies against CRAB isolates in a dynamic infection model. We simulated clinically relevant dosing regimens of fosfomycin (8 g every 8 h, 1 h infusion) and sulbactam (12 g continuous infusion or 4 g every 8 h, 4 h infusion) alone and in combination for 7 days in a hollow-fibre infection model (HFIM) against three clinical isolates of CRAB. The simulated pharmacokinetic profiles in the HFIM were based on fosfomycin and sulbactam data from critically ill patients. Fosfomycin monotherapy resulted in limited bacterial killing. Sulbactam monotherapies resulted in ~ 3 to 4 log10 kill within the first 8 to 32 h followed by regrowth of up to 8 to 10 log10 CFU/mL. A combination of fosfomycin and continuous infusion of sulbactam led to a ~2 to 4 log10 reduction in bacterial burden within the first 24 h, which was sustained throughout the duration of the experiments. A combination of fosfomycin and extended infusion of sulbactam produced a ~4 log10 reduction in colony count within 24 h. This study demonstrated that fosfomycin in combination with sulbactam is a promising option for the treatment of MDR A. baumannii. Further studies are needed to further assess the potential clinical utility of this combination.

Comparison of continuous versus intermittent enteral feeding in critically ill patients: a systematic review and meta-analysis.

BACKGROUND: The enteral route is commonly utilised to support the nutritional requirements of critically ill patients. However, there is paucity of data guiding clinicians regarding the appropriate method of delivering the prescribed dose. Continuous enteral feeding is commonly used; however, a bolus or intermittent method of administration may provide several advantages such as minimising interruptions. The purpose of this meta-analysis is to compare a continuous versus an intermittent or bolus enteral nutrition administration method. METHODS: A systematic review and meta-analysis were performed with studies identified from the PubMed, EMBASE, Cochrane Library and Web of Science databases. Studies were included if they compared a continuous with either an intermittent or bolus administration method of enteral nutrition in adult patients admitted to the intensive care unit. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. Review Manager was used for performing the random-effects meta-analysis on the outcomes of mortality, constipation, diarrhoea, increased gastric residuals, pneumonia, and bacterial colonisation. RESULTS: A total of 5546 articles were identified, and 133 were included for full text review. Fourteen were included in the final analysis. There was an increased risk of constipation with patients receiving continuous enteral nutrition (relative risk 2.24, 95% confidence interval 1.01-4.97, p = 0.05). No difference was identified in other outcome measures. No appreciable bias was identified. CONCLUSION: The current meta-analysis has not identified any clinically relevant difference in most outcome measures relevant to the care of critically ill patients. However, there is a paucity of high-quality randomised controlled clinical trials to guide this decision. Therefore, clinicians may consider either dosing regimen in the context of the patient's care requirements.

Pharmacodynamic evaluation of intermittent versus extended and continuous infusions of piperacillin/tazobactam in a hollow-fibre infection model against Escherichia coli clinical isolates.

OBJECTIVES: To compare the bacterial killing and emergence of resistance of intermittent versus prolonged (extended and continuous infusions) infusion dosing regimens of piperacillin/tazobactam against two Escherichia coli clinical isolates in a dynamic hollow-fibre infection model (HFIM). METHODS: Three piperacillin/tazobactam dosing regimens (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion) against a ceftriaxone-susceptible, non-ESBL-producing E. coli 44 (Ec44, MIC 2 mg/L) and six piperacillin/tazobactam dosing regimens (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion; 4/0.5 g 6 hourly as 0.5 and 3 h infusions and 16/2 g/24 h continuous infusion) were simulated against a ceftriaxone-resistant, AmpC- and ESBL-producing E. coli 50 (Ec50, MIC 8 mg/L) in a HFIM over 7 days (initial inoculum ∼107 cfu/mL). Total and less-susceptible subpopulations and MICs were determined. RESULTS: All simulated dosing regimens against Ec44 exhibited 4 log10 of bacterial killing over 8 h without regrowth and resistance emergence throughout the experiment. For Ec50, there was the initial bacterial killing of 4 log10 followed by regrowth to 1011 cfu/mL within 24 h against all simulated dosing regimens, and the MICs for resistant subpopulations exceeded 256 mg/L at 72 h. CONCLUSIONS: Our study suggests that, for critically ill patients, conventional intermittent infusion, or prolonged infusions of piperacillin/tazobactam may suppress resistant subpopulations of non-ESBL-producing E. coli clinical isolates. However, intermittent, or prolonged infusions may not suppress the resistant subpopulations of AmpC- and ESBL-producing E. coli clinical isolates. More studies are required to confirm these findings.

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Meropenem in Neurocritical Care Patients: a Prospective Two-Center Study.

Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.

Multicenter Population Pharmacokinetic Study of Unbound Ceftriaxone in Critically Ill Patients.

The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized dosing regimens. Total and unbound ceftriaxone concentrations were obtained from two pharmacokinetic studies and from a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit. Population pharmacokinetic analysis and Monte Carlo simulations were used to assess the probability of achieving a free trough concentration/MIC ratio of ≥1 using Pmetrics for R. A total of 474 samples (267 total and 207 unbound) were available from 36 patients. A two-compartment model describing ceftriaxone-albumin binding with both nonrenal and renal elimination incorporating creatinine clearance to explain the between-patient variability best described the data. An albumin concentration of ≤20 g/L decreased the probability of target attainment (PTA) by up to 20% across different dosing regimens and simulated creatinine clearances. A ceftriaxone dose of 1 g twice daily is likely therapeutic in patients with creatinine clearance of <100 mL/min infected with susceptible isolates (PTA, ~90%). Higher doses administered as a continuous infusion (4 g/day) are needed in patients with augmented renal clearance (creatinine clearance, >130 mL/min) who are infected by pathogens with a MIC of ≥0.5 mg/L. The ceftriaxone dose should be based on the patient's renal function and albumin concentration, as well as the isolate MIC. Hypoalbuminemia decreases the PTA in patients receiving intermittent dosing by up to 20%.

Evaluating Mono- and Combination Therapy of Meropenem and Amikacin against Pseudomonas aeruginosa Bacteremia in the Hollow-Fiber Infection Model.

Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied the extent of bacterial killing by and the emergence of resistance to meropenem and amikacin as monotherapies and as a combination therapy against susceptible and resistant P. aeruginosa isolates from bacteremic patients using the dynamic in vitro hollow-fiber infection model. Three P. aeruginosa isolates (meropenem MICs of 0.125, 0.25, and 64 mg/L) were used, simulating bacteremia with an initial inoculum of ~1 × 105 CFU/mL and the expected pharmacokinetics of meropenem and amikacin in critically ill patients. For isolates susceptible to amikacin and meropenem (isolates 1 and 2), the extent of bacterial killing was increased with the combination regimen compared with the killing by monotherapy of either antibiotic. Both the combination and meropenem monotherapy were able to sustain bacterial killing throughout the 7-day treatment course, whereas regrowth of bacteria occurred with amikacin monotherapy after 12 h. For the meropenem-resistant P. aeruginosa isolate (isolate 3), only the combination regimen demonstrated bacterial killing. Given that tailored antibiotic regimens can maximize potential synergy against some isolates, future studies should explore the benefit of combination therapy against resistant P. aeruginosa. IMPORTANCE Current guidelines recommend that aminoglycosides should be used in combination with ß-lactam antibiotics as initial empirical therapy for serious infections, and otherwise, patients should receive ß-lactam antibiotic monotherapy. Given the challenges associated with studying the clinical effect of different antibiotic strategies on patient outcomes, useful data for subsequent informed clinical testing can be obtained from in vitro models like the hollow-fiber infection model (HFIM). Based on the findings of our HFIM, we propose that the initial use of combination therapy with meropenem and amikacin provides some bacterial killing against carbapenem-resistant P. aeruginosa isolates. For susceptible isolates, combination therapy may only be of benefit in specific patient populations, such as critically ill or immunocompromised patients. Therefore, clinicians may want to consider using the combination therapy for the initial management and ceasing the aminoglycosides once antibiotic susceptibility results have been obtained.

Association Between Urine Output and Mortality in Critically Ill Patients: A Machine Learning Approach.

OBJECTIVES: Current definitions of acute kidney injury use a urine output threshold of less than 0.5 mL/kg/hr, which have not been validated in the modern era. We aimed to determine the prognostic importance of urine output within the first 24 hours of admission to the ICU and to evaluate for variance between different admission diagnoses. DESIGN: Retrospective cohort study. SETTING: One-hundred eighty-three ICUs throughout Australia and New Zealand from 2006 to 2016. PATIENTS: Patients greater than or equal to 16 years old who were admitted with curative intent who did not regularly receive dialysis. ICU readmissions during the same hospital admission and patients transferred from an external ICU were excluded. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty-one thousand nine hundred forty patients were included with a mean urine output of 1.05 mL/kg/hr and an overall in-hospital mortality of 7.8%. A urine output less than 0.47 mL/kg/hr was associated with increased unadjusted in-hospital mortality, which varied with admission diagnosis. A machine learning model (extreme gradient boosting) was trained to predict in-hospital mortality and examine interactions between urine output and survival. Low urine output was most strongly associated with mortality in postoperative cardiovascular patients, nonoperative gastrointestinal admissions, nonoperative renal/genitourinary admissions, and patients with sepsis. CONCLUSIONS: Consistent with current definitions of acute kidney injury, a urine output threshold of less than 0.5 mL/kg/hr is modestly predictive of mortality in patients admitted to the ICU. The relative importance of urine output for predicting survival varies with admission diagnosis.

A personalised approach to antibiotic pharmacokinetics and pharmacodynamics in critically ill patients.

Critically ill patients admitted to intensive care unit (ICU) with severe infections, or those who develop nosocomial infections, have poor outcomes with substantial morbidity and mortality. Such patients commonly have suboptimal antibiotic exposures at routinely used antibiotic doses related to an increased volume of distribution and altered clearance due to their underlying altered physiology. Furthermore, the use of extracorporeal devices such as renal replacement therapy and extracorporeal membrane oxygenation in these group of patients also has the potential to alter in vivo drug concentrations. Moreover, ICU patients are likely to be infected with less-susceptible pathogens. Therefore, one potential contributing cause to the poor outcomes observed in critically ill patients may be related to subtherapeutic antibiotic exposures. Newer concepts include the clinician considering optimised dosing based on a blood antibiotic exposure defined by pharmacokinetic modelling and therapeutic drug monitoring, combined with a knowledge of the antibiotic penetration into the site of infection, thereby achieving optimal bacterial killing. Such optimised dosing is likely to improve patient outcomes. The aim of this review is to highlight key aspects of antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in critically ill patients and provide a PK/PD approach to tailor antibiotic dosing to the individual patient.

A Systematic Review of Intravenous ß-Hydroxybutyrate Use in Humans - A Promising Future Therapy?

Therapeutic ketosis is traditionally induced with dietary modification. However, owing to the time delay involved, this is not a practical approach for treatment of acute conditions such as traumatic brain injury. Intravenous administration of ketones would obviate this problem by rapidly inducing ketosis. This has been confirmed in a number of small animal and human studies. Currently no such commercially available product exists. The aim of this systematic review is to review the safety and efficacy of intravenous beta-hydroxybutyrate. The Web of Science, PubMed and EMBASE databases were searched, and a systematic review undertaken. Thirty-five studies were included. The total beta-hydroxybutyrate dose ranged from 30 to 101 g administered over multiple doses as a short infusion, with most studies using the racemic form. Such dosing achieves a beta-hydroxybutyrate concentration >1 mmol/L within 15 min. Infusions were well tolerated with few adverse events. Blood glucose concentrations occasionally were reduced but remained within the normal reference range for all study participants. Few studies have examined the effect of intravenous beta-hydroxybutyrate in disease states. In patients with heart failure, intravenous beta-hydroxybutyrate increased cardiac output by up to 40%. No studies were conducted in patients with neurological disease. Intravenous beta-hydroxybutyrate has been shown to increase cerebral blood flow and reduce cerebral glucose oxidation. Moreover, beta-hydroxybutyrate reduces protein catabolism and attenuates the production of counter-regulatory hormones during induced hypoglycemia. An intravenous beta-hydroxybutyrate formulation is well tolerated and may provide an alternative treatment option worthy of further research in disease states.

Dose optimisation of antibiotics used for meningitis.

PURPOSE OF REVIEW: Central nervous system (CNS) infections such as ventriculitis and meningitis are associated with significant morbidity and mortality. In part, this may be due to increased difficulties in achieving a therapeutic antibiotic concentration at the site of infection due to both the pharmacokinetic (PK) changes observed during critical illness and the reduced antibiotic penetration through the blood brain barrier. This paper reviews the pharmacodynamics (PD) and CNS PKs of antibiotics used for Gram-negative bacterial CNS infections to provide clinicians with practical dosing advice. RECENT FINDINGS: Recent PK studies have shown that currently used intravenous antibiotic dosing regimens may not achieve a therapeutic exposure within the CNS, even for reportedly 'susceptible' bacteria per the current clinical meningitis breakpoints. Limited data exist for new ß-lactam antibiotic/ß-lactamase inhibitor combinations, which may be required for multidrug resistant infections. Intraventricular antibiotic administration, although not a new concept, has further evidence demonstrating improved patient outcomes compared with intravenous therapy alone, despite the ongoing paucity of PK studies guiding dosing recommendations. SUMMARY: Clinicians should obtain the bacterial minimum inhibitory concentration when treating patients with CNS Gram-negative bacterial infections and consider the underlying PK/PD principles when prescribing antibiotics. Therapeutic drug monitoring, where available, should be considered to guide dosing. Intraventricular therapy should also be considered for patients with ventricular drains to optimise clinical outcomes.

Pharmacodynamic Evaluation of a Single Dose versus a 24-Hour Course of Multiple Doses of Cefazolin for Surgical Prophylaxis.

The optimal perioperative duration for the administration of cefazolin and other prophylactic antibiotics remains unclear. This study aimed to describe the pharmacodynamics of cefazolin for a single 2 g dose versus a 24 h course of a 2 g single dose plus a 1 g eight-hourly regimen against methicillin-susceptible Staphylococcus aureus. Static concentration time-kill assay and a dynamic in vitro hollow-fibre infection model simulating humanised plasma and interstitial fluid exposures of cefazolin were used to characterise the pharmacodynamics of prophylactic cefazolin regimens against methicillin-sensitive Staphylococcus aureus clinical isolates. The initial inoculum was 1 × 105 CFU/mL to mimic a high skin flora inoculum. The static time-kill study showed that increasing the cefazolin concentration above 1 mg/L (the MIC) did not increase the rate or the extent of bacterial killing. In the dynamic hollow-fibre model, both dosing regimens achieved similar bacterial killing (~3-log CFU/mL within 24 h). A single 2 g dose may be adequate when low bacterial burdens (~104 CFU/mL) are anticipated in an immunocompetent patient with normal pharmacokinetics.

Epidemiology of extended-spectrum ß-lactamase and metallo-ß-lactamase-producing Escherichia coli in South Asia.

Aim: To determine the prevalence of extended-spectrum ß-lactamase (ESBL) and metallo-ß-lactamase (MBL)-producing Escherichia coli in South Asia. Methodology: A systematic review and meta-analysis of data published in PubMed, EMBASE, Web of Science and Scopus. Results: The pooled prevalence of ESBL and MBL-producing E. coli in South Asia were 33% (95% CI: 27-40%) and 17% (95% CI: 12-24%), respectively. The prevalence of blaCTX-M type was 58% (95% CI: 49-66%) with blaCTX-M-15 being the most prevalent (51%, 95% CI: 40-62%) variant. The most prevalent MBL variant was blaNDM-1 (33%, 95% CI: 20-50%). Conclusion: This study suggests a high prevalence of ESBLs and MBLs among E. coli clinical isolates. Comprehensive resistance surveillance is required to guide clinicians prescribing antibiotics in South Asia.

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa.

BACKGROUND: Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing. OBJECTIVE: The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing. METHODS: Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance. RESULTS: In the presence of broth alone, there was rapid and extensive (> 6 - log10) bacterial killing, with emergence of resistance identified in amikacin concentrations < 976 mg/L. In contrast, the rate and extent of bacterial killing was reduced (≤ 5 - log10) when exposed to an acidic pH and mucin. Surfactant did not appreciably impact the bacterial killing or resistance emergence when compared with broth alone for either isolate. The combination of mucin and an acidic pH further reduced the rate of bacterial killing, with the maximal bacterial killing occurring 24 h following initial exposure compared with approximately 4-8 h for either mucin or an acidic pH alone. CONCLUSIONS: Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.

Semi-mechanistic PK/PD modelling of meropenem and sulbactam combination against carbapenem-resistant strains of Acinetobacter baumannii.

Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are commonly used. In this study, we explored the potential efficacy of meropenem-sulbactam combination (MEM/SUL) against CR-AB. The checkerboard method was used to screen for synergistic activity of MEM/SUL against 50 clinical CR-AB isolates. Subsequently, time-kill studies against two CR-AB isolates were performed. Time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Subsequently, Monte Carlo simulations were performed to estimate the probability of 2-log kill, 1-log kill or stasis at 24-h following combination therapy. The MEM/SUL demonstrated synergy against 28/50 isolates. No antagonism was observed. The MIC50 and MIC90 of MEM/SUL were decreased fourfold, compared to the monotherapy MIC. In the time-kill studies, the combination displayed synergistic killing against both isolates at the highest clinically achievable concentrations. At concentrations equal to the fractional inhibitory concentration, synergism was observed against one isolate. The PK/PD model adequately delineated the data and the interaction between meropenem and sulbactam. The effect of the combination was driven by sulbactam, with meropenem acting as a potentiator. The simulations of various dosing regimens revealed no activity for the monotherapies. At best, the MEM/SUL regimen of 2 g/4 g every 8 h demonstrated a probability of target attainment of 2-log10 kill at 24 h of 34%. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that MEM/SUL may potentially be effective against some CR-AB infections.

Pharmacodynamics of once- versus twice-daily dosing of nebulized amikacin in an in vitro Hollow-Fiber Infection Model against 3 clinical isolates of Pseudomonas aeruginosa.

This study aims to compare the bacterial killing of once- versus twice-daily nebulized amikacin against Pseudomonas aeruginosa and to determine the optimal duration of therapy. Three clinical P. aeruginosa isolates (amikacin MICs 2, 8, and 64 mg/L) were exposed to simulated epithelial lining fluid exposures of nebulized amikacin with dosing regimens of 400 mg and 800 mg once- or twice-daily up to 7-days using the in vitro hollow-fiber infection model. Quantitative cultures were performed. Simulated amikacin dosing regimens of 400 mg twice-daily and 800 mg once-daily achieved ≥2-log reduction in the bacterial burden within the first 24-hours of therapy for all isolates tested. No dosing regimen suppressed the emergence of amikacin resistance. No difference in bacterial killing or regrowth was observed between 3- and 7-days of amikacin. Amikacin doses of 800 mg once-daily for up to 3-days may be considered for future clinical trials.