Long-term ileoanal pouch survival after pouch urinary tract fistulae.

BACKGROUND: Ileoanal pouch is a demanding procedure with many potential technical complications including bladder or ureteral injury, while inflammation or stricture of the anastomosis or anal transition zone may lead to the formation of strictures and fistulae, including to the adjacent urethra. Pouch urinary tract fistulae are rare. We aimed to describe the presentation, diagnostic workup, and management of patients with pouch urinary at our center. METHODS: Our prospectively maintained pouch registry was queried using diagnostic codes and natural language processing free-text searches to identify ileoanal pouch patients diagnosed with any pouch-urinary tract fistula from 1997 to 2022. Descriptive statistics and pouch survival using Kaplan-Meier curves are presented. Numbers represent frequency (proportion) or median (range). RESULTS: Over 25 years, urinary fistulae were observed 27 pouch patients; of these, 16 of the index pouches were performed at our institution [rate 0.3% (16/5236)]. Overall median age was 42 (27-62) years, and 92.3% of the patients were male. Fistula locations included pouch-urethra in 13 patients (48.1%), pouch-bladder in 12 patients (44.4%), and anal-urethra in 2 (7.4%). The median time from pouch to fistula was 7.0 (0.3-38) years. Pouch excision and end ileostomy were performed in 12 patients (bladder fistula, n = 3; urethral fistula, n = 9), while redo ileal pouch-anal anastomosis (IPAA) was performed in 5 patients (bladder fistula, n = 3; urethral fistula, n = 2). The 5-year overall pouch survival after fistula to the bladder was 58.3% vs. 33.3% with urethral fistulae (p = 0.25). CONCLUSION: Pouch-urinary tract fistulae are a rare, morbid, and difficult to treat complication of ileoanal pouch that requires a multidisciplinary, often staged, surgical approach. In the long term, pouches with bladder fistulae were more likely to be salvaged than pouches with urethral fistulae.

Defining the safety of early ileostomy closure after ileal pouch anal anastomosis.

PURPOSE: The safety of early ileostomy reversal after ileal pouch anal anastomosis (IPAA) has not been established. Our hypothesis was that ileostomy reversal before 8 weeks is associated with negative outcomes. METHODS: This was a retrospective cohort study from a prospectively maintained institutional database. Patients who underwent primary IPAA with ileostomy reversal between 2000 and 2021 from a Pouch Registry were stratified on the basis of timing of reversal. Those reversed before 8 weeks (early) and those reversed from 8 weeks to 116 days (routine) were compared. The primary outcome was overall complications according to timing and reason for closure. RESULTS: Ileostomy reversal was performed early in 92 patients and routinely in 1908. Median time to closure was 49 days in the early group and 93 days in the routine group. Reasons for early reversal were stoma-related morbidity in 43.3% (n = 39) and scheduled closure in 56.7% (n = 51). The complication rate in the early group was 17.4% versus 11% in the routine group (p = 0.085). When early patients were stratified according to reason for reversal, those reversed early for stoma-related morbidity had an increased complication rate compared to the routine group (25.6% vs. 11%, p = 0.006). Patients undergoing scheduled reversal in the early group did not have increased complications (11.8% vs. 11%, p = 0.9). There was a higher likelihood of pouch anastomotic leak when reversal was performed early for stoma complications compared to routinely (OR 5.13, 95% CI 1.01-16.57, p = 0.049). CONCLUSIONS: Early closure is safe but could be delayed in stoma morbidity as patients may experience increased complications.

Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial.

BACKGROUND.: Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. METHODS.: Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h -1 ) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics ® software. Calculations of PTA and FTA were performed for common pathogens. RESULTS.: Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44-80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean ( sd ) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h -1 . Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. CONCLUSIONS.: Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. CLINICAL TRIAL REGISTRATION.: NCT02058979.

Integrated pharmacokinetic-pharmacodynamic modelling to evaluate antimicrobial prophylaxis in abdominal surgery.

OBJECTIVES: To use Monte Carlo simulation with an integrated pharmacokinetic-pharmacodynamic (PK-PD) model to evaluate guideline-recommended antimicrobial prophylaxis (AP) regimens with anaerobic coverage in abdominal surgery. METHODS: AP regimens were tested in simulated subjects undergoing elective abdominal surgery using relevant PK models and pathogen distributions in surgical site infections (SSIs). Predicted cumulative target attainment was the percentage of simulated subjects with free (unbound) antimicrobial plasma concentrations above the MICs for potential SSI pathogens. RESULTS: Cefazolin plus metronidazole covered SSI aerobes in 70% and the Bacteroides fragilis group in 99% of subjects, whereas cefoxitin only covered aerobes and anaerobes in 63% and 27% of cases, respectively. The broad-spectrum ceftriaxone plus metronidazole covered aerobes in 82% and anaerobes in 99% of simulations, while ertapenem covered aerobes in 88% and anaerobes in 90% of cases. Clindamycin covered the B. fragilis group in only 11% of cases. For cefazolin, 2 g doses maintained target attainment in simulated subjects from 80 to 120 kg, whereas 1 g doses were associated with lower target attainment against potential Gram-negative pathogens even in those <80 kg. For gentamicin, 3 mg/kg doses were comparable to the suggested 5 mg/kg, but superior to the traditional 1.5 mg/kg. CONCLUSIONS: This study demonstrates the use of PK-PD to inform decisions regarding AP in abdominal surgery. In this case, the findings support avoiding cefoxitin, avoiding clindamycin for anaerobic coverage, selecting 2 g doses of cefazolin even in patients <80 kg and using 3 mg/kg doses of gentamicin.

Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration.

OBJECTIVES: Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). METHODS: Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. RESULTS: Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. CONCLUSIONS: During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.

Antibiotic dose optimization in critically ill patients.

The judicious use of existing antibiotics is essential for preserving their activity against infections. In the era of multi-drug resistance, this is of particular importance in clinical areas characterized by high antibiotic use, such as the ICU. Antibiotic dose optimization in critically ill patients requires sound knowledge not only of the altered physiology in serious infections - including severe sepsis, septic shock and ventilator-associated pneumonia - but also of the pathogen-drug exposure relationship (i.e. pharmacokinetic/pharmacodynamic index). An important consideration is the fact that extreme shifts in organ function, such as those seen in hyperdynamic patients or those with multiple organ dysfunction syndrome, can have an impact upon drug exposure, and constant vigilance is required when reviewing antibiotic dosing regimens in the critically ill. The use of continuous renal replacement therapy and extracorporeal membrane oxygenation remain important interventions in these patients; however, both of these treatments can have a profound effect on antibiotic exposure. We suggest placing emphasis on the use of therapeutic drug monitoring and dose individualization when optimizing therapy in these settings.

Core competencies in critical care for general medical practitioners in South Africa: A Delphi study.

Background: Despite a high burden of disease that requires critical care services, there are a limited number of intensivists in South Africa (SA). Medical practitioners at district and regional public sector hospitals frequently manage critically ill patients in the absence of intensivists, despite these medical practitioners having had minimal exposure to critical care during their undergraduate training. Objectives: To identify core competencies in critical care for medical practitioners who provide critical care services at public sector hospitals in SA where intensivists are not available to direct patient management. Methods: A preliminary list of core competencies in critical care was compiled. Thereafter, 13 national and international experts were requested to achieve consensus on a final list of core competencies that are required for critical care by medical practitioners, using a modified Delphi process. Results: A final list of 153 core competencies in critical care was identified. Conclusion: The core competencies identified by this study could assist in developing training programmes for medical practitioners to improve the quality of critical care services provided at district and regional hospitals in SA. Contribution of the study: The study provides consensus on a list of core competencies in critical care that non-intensivist medical practitioners managing critically ill patients in healthcare settings in South Africa, especially where intensivists are not readily available, should have. The list can form the core content of training programmes aimed at improving critical care competence of general medical practitioners, and in this way hopefully improve the overall outcomes of critically ill patients in South Africa.

Pharmacodynamics of ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus: is it a viable treatment option?

Ceftriaxone is a broad-spectrum cephalosporin that may be one option to treat methicillin-susceptible Staphylococcus aureus (MSSA). Although MSSA may be susceptible to ceftriaxone, the minimum inhibitory concentration (MIC) is generally two- to four-fold higher than other susceptible bacterial pathogens. This study aimed to explore the pharmacodynamics of ceftriaxone against MSSA and to determine the likely optimal dose. A hollow-fibre infection model was used with one clinical MSSA isolate (MIC = 4 mg/L) at an initial inoculum of 1 × 106 CFU/mL. Ceftriaxone dosing regimens of 1 g once and twice daily and 2 g once and twice daily were simulated. Ceftriaxone 1 g dosing regimens did not substantially impact bacterial killing within the first 12 h. Conversely, when administered as a 2 g dose either once or twice daily, an approximate 1-log10 bacterial reduction was observed where it plateaued for up to 96 h. No resistance was identified. Only a high ceftriaxone dose of 2 g twice daily achieves bacterial killing and sustained inhibition of bacterial growth. Ceftriaxone at routinely used doses is unsuitable for the treatment of MSSA infections and alternative agents should be preferentially used.

The role of surveillance cultures in the prediction of susceptibility patterns of Gram-negative bacilli in the intensive care unit.

Surveillance cultures may detect colonisation with drug-resistant Gram-negative bacteria and can be hypothesised to guide appropriate initial antibiotic treatment for intensive care unit (ICU) patients. We investigated the microbiological data of 228 episodes of nosocomial bloodstream infection (BSI) due to Gram-negative bacteria in an ICU in which piperacillin/tazobactam or meropenem was used empirically for serious infections, to evaluate the contribution of surveillance cultures to an appropriate choice of initial antibiotic therapy. Surveillance cultures were taken in advance of BSI in 218 (95.6%) of 228 episodes. Concordant organisms with identical identification and susceptibilities were found in prior surveillance cultures and subsequent blood cultures in 65 (29.8%) of 218 episodes. Surveillance cultures predicted resistance in 52.9% and 51.4% of BSIs caused by resistant pathogens to piperacillin/tazobactam and meropenem, respectively. The negative predictive value of surveillance cultures negative for a resistant organism also exceeded 90% for piperacillin/tazobactam and meropenem. Given that the overall resistant rates of BSI pathogens of our study were 11.3% to piperacillin/tazobactam and 16.4% to meropenem, surveillance cultures in our setting may provide important information on the probability of drug resistance of the causative pathogens and some utility in aiding empiric antibiotic therapy for ICU patients who subsequently develop BSI.

Determining authorship in multicenter trials: a systematic review.

The practical and ethical issues in determining authorship in multicenter trials raise significant and unique challenges. This systematic review examines methods of assigning authorship in multicenter clinical trials. A literature search (October 2009) was conducted to identify articles with the terms 'authorship' and 'clinical trial,' 'multicenter' or 'multicentre.' Abstracts were reviewed for potential relevance and the complete manuscript was obtained where indicated. Additional articles were identified by a review of the reference list from sourced articles. Methods for determining authorship were reviewed in terms of practicality, fairness and the time course for decision-making. Eight methods for determining authorship were identified: four used a scoring system, two articles contained guidelines with reference to scoring systems and two articles outlined general guidelines. All methods attempted to provide a fair and practical approach and appeared to achieve this to varying degrees. No one method was applicable across all multicenter trials. The authors propose a guide for determining authorship based on the methods identified and the number of collaborators and anticipated publications. For smaller collaborative groups (e.g. <10 persons), byline inclusion of all authors based on relative contributions is recommended. For larger collaborations (e.g. ≥ 10 persons), authorship guidelines should be explicit from the outset of the trial with consideration of relevant scoring systems.

Pitfalls of using estimations of glomerular filtration rate in an intensive care population.

BACKGROUND: Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing. AIMS: Recently, an estimation of GFR (eGFR) was suggested as a method of estimating GFR. How well this formula predicts GFR in unwell patients with normal initial serum creatinine concentrations has not been examined. METHODS: The accuracy of the eGFR (before and after adjustment for actual body surface area (BSA)) was compared with measured and with estimated creatinine clearance using the Cockcroft Gault (CG) formula adjusted for total and lean body weight. RESULTS: A total of 237 observations was recorded in 47 subjects. These were initially analysed independently, and then using the first observation only. Overall the mean difference between measured creatinine clearance and eGFR was -12 mL/min (95% confidence interval (CI) -20 to -3), between measured creatinine clearance and CG +17 mL/min (95% CI 9-24), between measured creatinine clearance and CG adjusted for ideal body weight +12 mL/min (95% CI 4-21) and between measured creatinine clearance and eGFR 'unadjusted' for BSA 5 mL/min (95% CI -2-13). CONCLUSIONS: Using either eGFR or CG formulae to estimate renal function in ICU subjects with normal serum creatinine concentrations is inaccurate. Although correcting for BSA improves the eGFR, this requirement to measure height and weight removes a major attraction for its use. We suggest that eGFR should not be automatically calculated in the ICU setting.

Meropenem dosing in critically ill patients with sepsis receiving high-volume continuous venovenous hemofiltration.

Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (> or = 4 liters/h); secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter); and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood samples and ultrafiltrate and urine samples. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0); terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3); trough concentration, 7.7 mg/liter (6.2 to 12.9); total clearance, 6.0 liters/h (5.2 to 6.2); hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem (R(2) = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei.

Objective evaluation of the performance of surgical trainees on a porcine model of open colectomy.

BACKGROUND: Evaluation of surgical trainee operative performance is rarely objective. A rating system is proposed that assesses trainee performance objectively and quantifies technical improvement. METHODS: General surgery trainees were evaluated while performing porcine segmental colectomy. Initial instruction was provided for the critical operative steps. Evaluations were later repeated without additional instruction. Performance in 17 critical areas was scored. RESULTS: Twenty-three trainees were evaluated. Performance was divided into thirds, with a significant difference detected between tertiles (P < 0.001). Postgraduate year 2 trainees scored lower than those in years 3 and 4 (P < 0.001), but there was no difference between year 3 and 4 trainees (P = 0.557). Mean repeat scores were improved by 35 per cent, with most improvement at postgraduate year 2 level (71 per cent). Mean time taken to complete the operation was reduced by 23 per cent, with the largest reduction in the year 2 group. CONCLUSION: The results support the use of this rating system as a tool for the objective evaluation of trainee operative skill. Instruction in the performance of segmental colectomy using deconstructed, step-by-step direction improved the ability of junior trainees to complete the operation. This evaluation system may be useful in the assessment, instruction and technical development of surgical trainees.

When not to start antibiotics: avoiding antibiotic overuse in the intensive care unit.

BACKGROUND: Most intensive care unit (ICU) patients receive broad-spectrum antibiotics. While lifesaving in some, in others these treatments may be unnecessary and place patients at risk of antibiotic-associated harms. OBJECTIVES: To review the literature exploring how we diagnose infection in patients in the ICU and address the safety and utility of a 'watchful waiting' approach to antibiotic initiation with selected patients in the ICU. SOURCES: A semi-structured search of PubMed and Cochrane Library databases for articles published in English during the past 15 years was conducted. CONTENT: Distinguishing infection from non-infectious mimics in ICU patients is uniquely challenging. At present, we do not have access to a rapid point-of-care test that reliably differentiates between individuals who need antibiotics and those who do not. A small number of studies have attempted to compare early aggressive versus conservative antimicrobial strategies in the ICU. However, this body of literature is small and not robust enough to guide practice. IMPLICATIONS: This issue will not likely be resolved until there are diagnostic tests that rapidly and reliably identify the presence or absence of infection in the ICU population. In the meantime, prospective trials that identify clinical situations wherein it is safe to delay or withhold antibiotic initiation in the ICU until the presence of an infection is proven are warranted.

A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: do current studies supply sufficient data?

BACKGROUND: Drug dosing for septic patients with acute renal failure receiving continuous renal replacement therapy (CRRT) is complicated, and failure to correctly dose may result in either drug toxicity or treatment failure and development of antibiotic resistance. The aim of this study was to establish an ideal dataset that needs to be reported when presenting pharmacokinetic data for these patients and review current literature for completeness of this dataset. METHODS: An ideal dataset was established of the parameters that should be reported when calculating a drug dosing regimen from first principles. A Medline search was performed of relevant literature producing 64 citations from which completeness of the specified criteria was examined. RESULTS: None of the studies analysed presented the full dataset that we established as necessary. Of concern, basic pharmacokinetic parameters such as volume of distribution (V(d)) and clearance (CL) were specified in only 79% and 81% of studies, respectively. CONCLUSIONS: A large proportion of current studies do not report key information necessary to devise a rational dosing regimen for patients with acute renal failure receiving CRRT, and we hope this dataset will be a useful guide when reporting future pharmacokinetic data.

Point of care measurement of plasma creatinine in critically ill patients with acute kidney injury.

We report the utility of an enzymatic point of care system for estimation of plasma creatinine concentration in critically ill patients with acute kidney injury. Multiple measurements were obtained from a heterogenous population admitted to a multi-disciplinary intensive care unit. The acute kidney injury network guidelines were used to identify and stratify patients based on the creatinine concentration. Central laboratory values were used as comparators to assess the precision and bias of the system. Overall, point of care measurements correlated well with central pathology results (R(2) = 0.991, p < 0.001), although there tended to be a small negative bias in patients with acute kidney injury (3 micromol x l(-1)). The accuracy of point of care measurement is within clinically acceptable limits and given the much shorter turn around time can be used to identify and monitor patients with acute kidney injury in the critical care environment.

Clinical and design factors influence the survivorship of custom flange acetabular components.

AIMS: Custom flange acetabular components (CFACs) are a patient-specific option for addressing large acetabular defects at revision total hip arthroplasty (THA), but patient and implant characteristics that affect survivorship remain unknown. This study aimed to identify patient and design factors related to survivorship. PATIENTS AND METHODS: A retrospective review of 91 patients who underwent revision THA using 96 CFACs was undertaken, comparing features between radiologically failed and successful cases. Patient characteristics (demographic, clinical, and radiological) and implant features (design characteristics and intraoperative features) were collected. There were 74 women and 22 men; their mean age was 62 years (31 to 85). The mean follow-up was 24.9 months (sd 27.6; 0 to 116). Two sets of statistical analyses were performed: 1) univariate analyses (Pearson's chi-squared and independent-samples Student's t-tests) for each feature; and 2) bivariable logistic regressions using features identified from a random forest analysis. RESULTS: Radiological failure and revision rates were 23% and 12.5%, respectively. Revisions were undertaken at a mean of 25.1 months (sd 26.4) postoperatively. Patients with radiological failure were younger at the time of the initial procedure, were less likely to have a diagnosis of primary osteoarthritis (OA), were more likely to have had ischial screws in previous surgery, had fewer ischial screw holes in their CFAC design, and had more proximal ischial fixation. Random forest analysis identified the age of the patient and the number of locking and non-locking screws used for inclusion in subsequent bivariable logistic regression, but only age (odds ratio 0.93 per year) was found to be significant. CONCLUSION: We identified both patient and design features predictive of CFAC survivorship. We found a higher rate of failure in younger patients, those whose primary diagnosis was not OA, and those with more proximal ischial fixation or fewer ischial fixation options. Cite this article: Bone Joint J 2019;101-B(6 Supple B):68-76.

Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion.

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 (Vp) 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 (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax 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 Km 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.

Lessons learnt in the pharmacokinetic analysis of the effect of haemoperfusion for acute overdose with sustained-release diltiazem.

The effect of charcoal haemoperfusion on the pharmacokinetics of diltiazem is described in a patient with severe clinical toxicity following acute overdose. The patient presented within 3 h following acute ingestion of multiple medications including sustained-release diltiazem. Routine resuscitation and supportive care were administered, but hypotension did not resolve despite intravenous fluids and infusions of calcium, adrenaline, noradrenaline and vasopressin. Multiple-doses of activated charcoal, haemodialysis and charcoal haemoperfusion were prescribed to expedite the elimination of diltiazem. The maximum diltiazem concentration (577 microg.l(-1)) was recorded 7 h post ingestion which was followed by an erratic and prolonged elimination phase. The maximum clearance of diltiazem due to haemoperfusion was calculated to be 19.4 and 15.1 ml.min(-1) at different times, equating to removal of approximately 1.5 mg diltiazem during 4 h of haemoperfusion. Haemoperfusion did not appear to remove sufficient diltiazem to recommend its routine use in the treatment of patients with acute diltiazem overdose.

Individualising Therapy to Minimize Bacterial Multidrug Resistance.

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 ß-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.