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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.

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

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 β-lactam antibiotic/β-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.

Aim: To determine the prevalence of extended-spectrum β-lactamase (ESBL) and metallo-β-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.

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.

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 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%.

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.

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00344-5.

Background and Objective: Combination therapy may be a treatment option against carbapenem-resistant Acinetobacter baumannii (CR-AB) infections. In this study, we explored the utility of fosfomycin...

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.

Unbound ceftriaxone pharmacokinetics in adult patients have been poorly characterised. The objective of this study is to determine the ceftriaxone dose that achieves an unbound trough concentration ≥ 0.5 mg/L in > 90% of adult patients receiving once-daily dosing presenting to the emergency department (ED) with sepsis. We performed a prospective single-centre pharmacokinetic study. A single unbound plasma ceftriaxone concentration was obtained from each patient using blood collected as part of routine clinical practice within the first dosing interval. Samples were analysed using a validated ultra-high pressure liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. A ceftriaxone concentration obtained throughout the first dosing interval was available for fifty adult patients meeting sepsis criteria. Using this concentration time-curve data, a pharmacokinetic model was developed with acceptable predictive performance per the visual predictive check. Simulations show that a 1-g once-daily dose is unlikely to achieve the minimum therapeutic ceftriaxone exposure in > 90% patients with a creatinine clearance ≥ 60 mL/min. However, a 2-g once-daily dose will provide a therapeutic exposure for target pathogens infecting patients with a creatinine clearance ≤ 140 mL/min. Ceftriaxone administered as a 1-g once-daily dose is unlikely to achieve a therapeutic exposure in > 90% of patients presenting to the ED with sepsis. Increasing the ceftriaxone dose to 2 g once daily will likely achieve the desired exposure against target pathogens. Future clinical trials are required to determine any potential clinical benefit of optimised ceftriaxone dosing.

Administering β-lactam antibiotics via prolonged infusions for critically ill patients is mainly based on preclinical evidence. Preclinical data on this topic have not been systematically reviewed before. The aim of this study was to describe the pharmacokinetic/pharmacodynamic (PK/PD) indices and targets reported in preclinical models and to compare the bactericidal efficacy of intermittent and prolonged infusions of β-lactam antibiotics. The MEDLINE and EMBASE databases were searched. To compare the bactericidal action of β-lactam antibiotics across different modes of infusion, the reported PK/PD outcomes, expressed as the percentage of time (T) that free (f) β-lactam antibiotic concentrations remain above the minimal inhibitory concentration (MIC) (%fT>MIC) or trough concentration (Cmin)/MIC of individual studies, were recomputed relative to the area under the curve of free drug to MIC ratio (fAUC24/MIC). A linear mixed-effects meta-regression was performed to evaluate the impact of the β-lactam class, initial inoculum, Gram stain, in vivo or in vitro experiment and mode of infusion on the reduction of bacterial cells (in colony-forming units/mL). Overall, 33 articles were included for review, 11 of which were eligible for meta-regression. For maximal bactericidal activity, intermittent experiments reported a PK/PD target of 40–70% fT>MIC, while continuous experiments reported a steady-state concentration to MIC ratio of 4–8. The adjusted effect of a prolonged as opposed to intermittent infusion on bacterial killing was small (coefficient 0.66, 95% confidence interval − 0.78 to 2.11). Intermittent and prolonged infusions of β-lactam antibiotics require different PK/PD targets to obtain the same level of bacterial cell kill. The additional effect of a prolonged infusion for enhancing bacterial killing could not be demonstrated.

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.

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 based 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.

The rates of antibiotic resistance in Gram-negative bacteria are increasing. One method to minimize resistance emergence may be optimization of antibiotic dosing regimens to achieve drug exposure that suppress the emergence of resistance. The aim of this systematic review was to describe the antibiotic exposures associated with suppression of the emergence of resistance for Gram-negative bacteria. We conducted a search of four electronic databases. Articles were included if the antibiotic exposure required to suppress the emergence of resistance in a Gram-negative bacterial isolate was described. Among studies, 57 preclinical studies (in vitro and in vivo) and 2 clinical studies 59 included investigated the monotherapy of antibiotics against susceptible and/or intermediate Gram-negative bacteria. The pharmacokinetic/pharmacodynamic (PK/PD) indices reported to suppress the emergence of antibiotic resistance for various classes were β-lactam antibiotic minimum concentration to minimum inhibitory concentration (Cmin/MIC) ≥ 4; aminoglycoside maximum concentration to MIC (Cmax/MIC) ratio ≥ 20; fluoroquinolones, area under the concentration-time curve from 0 to 24 h to mutant prevention concentration (AUC24/MPC) ≥ 35; tetracyclines, AUC24 to MIC (AUC24/MIC) ratio ≥ 50; polymyxin B, AUC24/MIC ≥ 808; and fosfomycin, AUC24/MIC ≥ 3136. However, the exposures required to suppress the emergence of resistance varied depending on the specific antibiotic tested, the duration of the experiment, the bacterial species and the specific bacterial isolate tested. Importantly, antibiotic exposures required to suppress the emergence of resistance generally exceeded that associated with clinical efficacy. The benefits of implementing such high PK/PD targets must be balanced with the potential risks of antibiotic-associated toxicity.

Vancomycin is commonly used for the management of severe infections; however, vancomycin dosing may be challenging in critically ill patients. This observational study aims to describe the population pharmacokinetics of vancomycin in adult patients with sepsis or septic shock. A single-centre retrospective review of adult patients with sepsis or septic shock receiving vancomycin with therapeutic drug monitoring was undertaken. Blood samples taken 1 h after the vancomycin infusion cessation and 30 min prior to the next dose were assayed using the Vitros Crea Slide method. Vancomycin concentrations determined on different days were included. A pharmacokinetic model was developed using Pmetrics for R. Monte Carlo dosing simulations were performed using the final model. Vancomycin concentrations were available for 27 adult patients admitted to the intensive care unit with sepsis or septic shock. A one-compartment pharmacokinetic model with inter-occasion variability of clearance and volume of distribution before and after 72 h adequately described the data. Creatinine clearance normalized to body surface area was included as a covariate on vancomycin clearance. The clearance and volume of distribution within 72 h of admission were 7.29 L/h and 54.20 L, respectively. Monte Carlo simulations suggested that for patients with a creatinine clearance of ≥ 80 mL/min/1.73 m2, vancomycin doses of ≥ 2 g every 8 h are required to consistently achieve key therapeutic targets. Vancomycin doses ≥ 2 g every 8 h in adult patients with sepsis or septic shock with a creatinine clearance ≥ 80 mL/min/1.73 m2 are likely needed to achieve an optimal therapeutic exposure.

Background Knowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with Gram-negative bacillary ventilator-associated pneumonia (VAP). Objective To compare: (1) the ELF:serum penetration ratio of antibiotics in patients with pneumonia, including VAP, with that in healthy study participants; and (2) the ELF and/or tracheal aspirate antibiotic concentrations following intravenous and nebuliser delivery. Methods Web of Science, EMBASE and PubMed databases were searched and a systematic review undertaken. Results Fifty-two studies were identified. ELF penetration ratios for aminoglycosides and most β-lactam antibiotics administered intravenously were between 0.12 and 0.57, whereas intravenous colistin may be undetectable in the ELF. In contrast, estimated mean fluoroquinolone ELF penetration ratios of up to 1.31 were achieved. Importantly, ELF penetration ratios appear reduced in critically ill patients with pneumonia compared with in healthy volunteers receiving intravenous ceftazidime, levofloxacin and fosfomycin; thus, dose adjustment is likely to be required in critically ill patients. In contrast to the systemic administration route, nebulisation of antibiotics achieves high ELF concentrations. Nebulised 400 mg twice-daily amikacin resulted in a median peak ELF steady-state concentration of 976.01 mg/L (interquartile range 410.3–2563.1 mg/L). Similarly, nebulised 1 million international units of colistin resulted in a peak ELF concentration of 6.73 mg/L (interquartile range 4.80–10.10 mg/L). Conclusion Further pharmacokinetic studies investigating the mechanisms for ELF penetration in infected patients and healthy controls are needed to guide antibiotic dosing in VAP and to determine the potential benefits of nebulised therapy.

Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates.Synergism of FOS/SUL against 50 clinical CR-AB isolates were screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill and 2-log kill after 24-hours with combination therapy.The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased four- to eight-fold, compared to the monotherapy MIC50 and MIC90 In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate, at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam 4 g every 8 hours, demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69-76%, as compared to ∼15-30% with monotherapy regimens at the highest doses.The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

Purpose of Review Early identification of infection in the critically ill patient and initiation of appropriate treatment is key to reducing morbidity and mortality. On the other hand, the indiscriminate use of antimicrobials leads to harms, many of which may be exaggerated in the critically ill population. The current method of diagnosing infection in the intensive care unit relies heavily on clinical gestalt; however, this approach is plagued by biases. Therefore, a reliable, independent biomarker holds promise in the accurate determination of infection. We discuss currently used host biomarkers used in the intensive care unit and review new and emerging approaches to biomarker discovery. Recent Findings White cell count (including total white cell count, left shift, and the neutrophil-leucocyte ratio), C-reactive protein, and procalcitonin are the most common host diagnostic biomarkers for sepsis used in current clinical practice. However, their utility in the initial diagnosis of infection, and their role in the subsequent decision to commence treatment, remains limited. Novel approaches to biomarker discovery that are currently being investigated include combination biomarkers, host ‘sepsis signatures’ based on differential gene expression, site-specific biomarkers, biomechanical assays, and incorporation of new and pre-existing host biomarkers into machine learning algorithms. Summary To date, no single reliable independent biomarker of infection exists. Whilst new approaches to biomarker discovery hold promise, their clinical utility may be limited if previous mistakes that have afflicted sepsis biomarker research continue to be repeated.

Given that aminoglycosides, such as amikacin, may be used for multi-drug resistant infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible to inform ventilator-associated pneumonia and sepsis treatment choices.A hollow-fibre infection model with two isolates (MIC 2 and 8 mg/L) with an initial inoculum ∼10 colony-forming unit/mL was used to test different amikacin dosing regimens. Three regimens (15, 25 and 50 mg/kg) simulating a blood exposure and a 30 mg/kg regimen simulating the epithelial lining fluid (ELF) for potential respiratory tract infection were tested. Data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole genome sequencing was used to identify mutations associated with resistance emergence.While bacterial density was reduced by >6-logs within the first 12 h in simulated blood exposures, following this initial bacterial kill, there was amplification of a resistant sub-population with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (

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 MIC

Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two P. aeruginosa isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼10(8) CFU/ml was used to test different amikacin dosing regimens. Three regimens (15, 25, and 50 mg/kg) were tested to simulate a blood exposure, while a 30 mg/kg regimen simulated the epithelial lining fluid (ELF) for potential respiratory tract infection. Data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole-genome sequencing was used to identify mutations associated with resistance emergence. While bacterial density was reduced by >6 logs within the first 12 h in simulated blood exposures following this initial bacterial kill, there was amplification of a resistant subpopulation with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (

Unbound ceftriaxone pharmacokinetics in adult patients have been poorly characterised. The objective of this study is to determine the ceftriaxone dose that achieves an unbound trough concentration ≥ 0.5 mg/L in90% of adult patients receiving once-daily dosing presenting to the emergency department (ED) with sepsis.We performed a prospective single-centre pharmacokinetic study. A single unbound plasma ceftriaxone concentration was obtained from each patient using blood collected as part of routine clinical practice within the first dosing interval. Samples were analysed using a validated ultra-high pressure liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R.A ceftriaxone concentration obtained throughout the first dosing interval was available for fifty adult patients meeting sepsis criteria. Using this concentration time-curve data, a pharmacokinetic model was developed with acceptable predictive performance per the visual predictive check. Simulations show that a 1-g once-daily dose is unlikely to achieve the minimum therapeutic ceftriaxone exposure in90% patients with a creatinine clearance ≥ 60 mL/min. However, a 2-g once-daily dose will provide a therapeutic exposure for target pathogens infecting patients with a creatinine clearance ≤ 140 mL/min.Ceftriaxone administered as a 1-g once-daily dose is unlikely to achieve a therapeutic exposure in90% of patients presenting to the ED with sepsis. Increasing the ceftriaxone dose to 2 g once daily will likely achieve the desired exposure against target pathogens. Future clinical trials are required to determine any potential clinical benefit of optimised ceftriaxone dosing.

Background: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In the intensive care unit (ICU), organ dysfunction is common. The challenge lies in determining when organ dysfunction can be attributed to infection. We aimed to retrospectively determine what proportion of patients commenced on antibiotics for presumed sepsis in a mixed ICU had blood-culture positive sepsis, blood-culture negative sepsis, or an aseptic mimic.Methods: One hundred antibiotic naïve ICU patients who were clinically deemed to have an infection were enrolled. Retrospective interpretation of clinical history, biochemical, and microbiological data was performed by three clinicians from the fields of intensive care and infectious disease who aimed to differentiate infective from non-infective insults.Results: There was good interrater reliability amongst clinician assessors using this approach (Krippendorf’s alpha 0.868) for the retrospective diagnosis of infection. In the examined cohort, 35 percent of patients met the criteria of blood culture positivity and an additional 41 percent of patients were assessed as having probable blood culture negative sepsis. Twenty-four percent of patients were retrospectively determined to not have had sepsis.Conclusions: Misdiagnosis of infection as a cause for organ dysfunction in the ICU is common. The false attribution of organ dysfunction to infection in the ICU has significant clinical and research implications, and highlights the need for accurate point-of-care sepsis diagnostic tools.

Background - This study aims to compare the bacterial killing and suppression of resistance emergence of intermittent and prolonged infusions of piperacillin/tazobactam (PTZ) against clinical K. pneumoniae isolates. Methods - Two clinical isolates, CTX-M-14 producing #69 (MIC 1 mg/L), and DHA-1, SHV-106 producing #68 (MIC 8 mg/L), were studied in a dynamic hollow-fiber infection model over 7 days (initial inoculum 107 CFU/mL). Three piperacillin doses (4/0.5g over 0.5h, and 4h infusion 8 hourly; 12/1.5g continuous infusion 24h) against #69, and six dosages of piperacillin (4/0.5g over 0.5h, and 4h infusion 8 hourly, and 12/1.5g continuous infusion 24h; 4/0.5g over 0.5h, and 3h infusion 6 hourly, and 16/2g continuous infusion 24h) against #68 were tested. The total and less-susceptible bacterial populations were determined. Results - For all PTZ dosing regimens against #69, there were ∼4 logs of bacterial killing over 8h. The amplification of less-susceptible subpopulation were associated with intermittent infusion (T>MIC 90%, Cmin/MIC = 0.4) after 24h, and with extended infusion (T>MIC 100%, Cmin/MIC = 2.76) after 72h. However, continuous infusion (Cmin/MIC = 35) prevented drug resistance amplification and sterilized the model system. For #68, there was a similar initial bacterial killing profile; however, all regimens were associated with the emergence of a resistant subpopulation after 8h. The MIC of resistant subpopulations exceeded 256 mg/L. Conclusions – To maximize bacterial killing and suppress the emergence of resistance of multiple-beta-lactamases producing K. pneumoniae isolates with higher MIC alternative therapeutic strategies are required.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (V-p) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (K-m) and the maximum elimination rate for Michaelis-Menten elimination (V-max) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for K-m and V-max were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for K-m lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

The scourge of antibiotic resistance threatens modern healthcare delivery. A contributing factor to this significant issue may be antibiotic dosing, whereby standard antibiotic regimens are unable to suppress the emergence of antibiotic resistance. This article aims to review the role of pharmacokinetic and pharmacodynamic (PK/PD) measures for optimising antibiotic therapy to minimise resistance emergence. It also seeks to describe the utility of combination antibiotic therapy for suppression of resistance and summarise the role of biomarkers in individualising antibiotic therapy. Scientific journals indexed in PubMed and Web of Science were searched to identify relevant articles and summarise existing evidence. Studies suggest that optimising antibiotic dosing to attain defined PK/PD ratios may limit the emergence of resistance. A maximum aminoglycoside concentration to minimum inhibitory concentration (MIC) ratio of > 20, a fluoroquinolone area under the concentration–time curve to MIC ratio of > 285 and a β-lactam trough concentration of > 6 × MIC are likely required for resistance suppression. In vitro studies demonstrate a clear advantage for some antibiotic combinations. However, clinical evidence is limited, suggesting that the use of combination regimens should be assessed on an individual patient basis. Biomarkers, such as procalcitonin, may help to individualise and reduce the duration of antibiotic treatment, which may minimise antibiotic resistance emergence during therapy. Future studies should translate laboratory-based studies into clinical trials and validate the appropriate clinical PK/PD predictors required for resistance suppression in vivo. Other adjunct strategies, such as biomarker-guided therapy or the use of antibiotic combinations require further investigation.

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.

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.

Background Combining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice. Objective To determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy. Methods A systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity. Results Four randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63–1.08, P = 0.10, I2 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64–0.99, P = 0.04, I2 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83–2.09, P = 0.40, I2 0%). Conclusions The existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.

Background and Aim Poor bowel preparation results in difficult colonoscopies, missed lesions, and repeat procedures. Identifying patient risk factors for poor bowel preparation, such as prolonged runway time and prolonged cecal intubation, will aid in interventions prior to a procedure. Methods This was a retrospective, single‐center analysis of 3 295 colonoscopies performed between May 2012 and November 2014. Indications for colonoscopy included gastrointestinal bleed and anemia, change in bowel habits, for screening, and others (including planning re‐anastomoses, abdominal distension, family history and angioectasias). Data were collected from medical charts and endoscopy reports. Comparisons between patient factors and runway time were made with adequacy of bowel preparation as the primary outcomes. Results Male and diabetic patients had statistically higher rates of inadequate bowel preparation and prolonged cecal intubation times. A previous history of abdominal surgery also demonstrated prolonged cecal intubation. A runway time of ≤7.63 h was associated with higher rates of adequate bowel preparation by multivariate analysis. The optimal time frame is 3–6 h for the highest success rates. Conclusion Patient risk factors for inadequate bowel preparation or prolonged cecal intubation should signal clinicians to intervene prior to colonoscopy. A runway time between 3 and 6 h is optimal for adequate bowel preparation. This may involve further patient education, along with work flow optimization, to facilitate ideal runway times. Future studies should explore how to avoid repeat endoscopies using protocols enforcing this timeframe., Optimizing runway time plays a critical role in adequate bowel preparation for colonoscopy. Identifying methods of good bowel preparation in patients is ideal to prevent repeat procedures.

Optimized antibiotic dosing regimens improve survival rates in critically ill patients. However, dose optimization is challenging because of fluctuating antibiotic pharmacokinetics both between patients and within a single patient. This study reviews the pharmacokinetic changes that occur in critically ill patients, along with the pharmacodynamics and toxicodynamics of antibiotics commonly used for the treatment of Gram-negative bacterial infections to formulate a recommendation for antibiotic dosing at the bedside. Recent studies highlight that critically ill patients do not achieve therapeutic antibiotic exposures with standard antibiotic dosing. Although dose increases are required, the method of administration, such as the use of β-lactam antibiotic continuous infusions and nebulized aminoglycoside administration, may improve efficacy and limit toxicity. In addition, the increased availability of therapeutic drug monitoring and antibiotic dosing software allow the formulation of individualized dosing regimens at the bedside. When prescribing antibiotic doses, the clinician should consider antibiotic pharmacokinetic and pharmacodynamic principles. Before initiating high-dose antibiotic therapy, therapeutic drug monitoring may be considered to assist the clinician to optimize antibiotic treatment and minimize potential toxicity.

Dear Sir, We read with interest the comments from Ong et al. [1] regarding the need for a well-designed randomized controlled trial (RCT) to provide evidence to guide clinicians regarding the use of combined β-lactam antibiotic and aminoglycoside therapy for the management of critically ill patients with sepsis or septic shock. We would like to highlight the importance of appropriate dosing strategies and the inclusion of pharmacokinetic/pharmacodynamic (PK/PD) sub-studies to provide further evidence about the potential utility of combination therapy.