Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

INTRODUCTION: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. AIM: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. METHODS: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 µg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. RESULTS: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. CONCLUSION: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Population pharmacokinetic/pharmacodynamic target attainment of ceftriaxone 2 g once daily in non-critically ill hospitalized adult patients during the acute phase of infection.

AIMS: Pharmacokinetic/pharmacodynamic target attainment of ceftriaxone is compromised in intensive care unit (ICU) patients and non-ICU hospitalized patients in Beira, Mozambique. Whether this also accounts for non-ICU patients in a high-income setting is unknown. We therefore assessed the probability of target attainment (PTA) of the currently recommended dosing regimen of 2 g every 24 h (q24h) in this patient group. METHODS: We performed a multicentre population pharmacokinetic study in hospitalized non-ICU adult patients empirically treated with intravenous ceftriaxone. During both the acute phase of infection (i.e. first 24 h of treatment) and convalescence, a maximum of 4 random blood samples were obtained per patient for ceftriaxone total and unbound concentration measurements. PTA was calculated using NONMEM and was defined as the percentage of patients of which the unbound ceftriaxone concentration exceeded the minimum inhibitory concentration (MIC) for >50% of the first dosing interval of 24 h. Monte Carlo simulations were performed to determine PTA for different estimated glomerular filtration rates (eGFR; CKD-EPI) and MICs. PTA >90% was considered adequate. RESULTS: Forty-one patients provided 252 ceftriaxone total and 253 unbound concentrations. The median eGFR was 65 mL/min/1.73 m2 (5th to 95th percentile 36-122). With the recommended dose of 2 g q24h, PTA >90% was achieved for bacteria with an MIC ≤2 mg/L. Simulations showed that PTA was insufficient for an MIC of 4 mg/L in case the eGFR was 122 mL/min/1.73 m2 (PTA 56.9%) and for an MIC of 8 mg/L regardless of eGFR. CONCLUSION: The PTA of 2 g q24h ceftriaxone dosing is adequate for common pathogens during the acute phase of infection in non-ICU patients.

An Unusual Case of Low Vancomycin Exposure Despite Extremely High Vancomycin Doses Accompanied by Renal Toxicity: A Grand Round.

ABSTRACT: This grand round describes the case of a patient who received 10 grams (143.5 mg/kg) of vancomycin every 24 hours via continuous infusion, in whom the highest observed level was only 15.4 mg/L. Despite subtherapeutic levels, renal impairment was encountered, which resolved after the discontinuation of vancomycin. Glomerular hyperfiltration was found through nuclear glomerular filtration rate measurement, which likely explains the need for high doses (>6 grams per 24 hours continuous infusion) without reaching therapeutic serum levels.

Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Assay for the Determination of Total and Unbound Ciprofloxacin Concentrations in Human Plasma.

BACKGROUND: Although unbound ciprofloxacin is responsible for antibacterial effects, assays measuring the unbound drug plasma concentrations are scarce. This study aimed to develop and validate a rapid, reproducible, and sensitive liquid chromatography-tandem mass spectrometry assay for the determination of total and unbound ciprofloxacin plasma concentrations. METHODS: The determination of total ciprofloxacin concentrations required a 10 µL sample, while for unbound ciprofloxacin concentrations, it was 100 µL. Unbound ciprofloxacin was separated from protein-bound ciprofloxacin through ultrafiltration. A deuterated internal standard was used, and the sample preparation involved protein precipitation. The method was fully validated over a concentration range of 0.02-5.0 mg/L, according to the US Food and Drug Administration guidelines. In addition, its clinical application was demonstrated. RESULTS: The total run time was 1.5 minutes. For total ciprofloxacin plasma concentrations, the mean accuracy ranged from 94.5% to 105.0% across the validated range, the intraday imprecision was ≤7.6%, and the interday imprecision was ≤9.8%. For unbound ciprofloxacin plasma concentrations, the mean accuracy ranged from 92.8% to 102.1% across the validated range, the intraday imprecision was ≤7.0%, and the interday imprecision was ≤9.6%. Ciprofloxacin in plasma and ultrafiltrate remained stable for at least 96 hours at room temperature, at least 4 years at -80°C, and at least 3 freeze/thaw cycles (-80°C), with a minimum interval of 24 hours. CONCLUSIONS: The presented method is precise and accurate. It has been implemented in clinical care and research projects at a university hospital, permitting rapid determination of total and unbound ciprofloxacin.

Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock-a two-centre randomised clinical trial.

BACKGROUND: Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation. METHODS: In this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury. RESULTS: After inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4-1173.78, p < 0.001). Furthermore, target attainment was faster (26 h, CI 18-42 h, p < 0.001) and better (65% increase, CI 49-84%, p < 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure. CONCLUSIONS: In critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin. TRIAL REGISTRATION: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.

Why we should sample sparsely and aim for a higher target: Lessons from model-based therapeutic drug monitoring of vancomycin in intensive care patients.

AIMS: To explore the optimal data sampling scheme and the pharmacokinetic (PK) target exposure on which dose computation is based in the model-based therapeutic drug monitoring (TDM) practice of vancomycin in intensive care (ICU) patients. METHODS: We simulated concentration data for 1 day following four sampling schemes, Cmin , Cmax + Cmin , Cmax + Cmid-interval + Cmin , and rich sampling where a sample was drawn every hour within a dose interval. The datasets were used for Bayesian estimation to obtain PK parameters, which were used to compute the doses for the next day based on five PK target exposures: AUC24 = 400, 500, and 600 mg·h/L and Cmin = 15 and 20 mg/L. We then simulated data for the next day, adopting the computed doses, and repeated the above procedure for 7 days. Thereafter, we calculated the percentage error and the normalized root mean square error (NRMSE) of estimated against "true" PK parameters, and the percentage of optimal treatment (POT), defined as the percentage of patients who met 400 ≤ AUC24 ≤ 600 mg·h/L and Cmin ≤ 20 mg/L. RESULTS: PK parameters were unbiasedly estimated in all investigated scenarios and the 6-day average NRMSE were 32.5%/38.5% (CL/V, where CL is clearance and V is volume of distribution) in the trough sampling scheme and 27.3%/26.5% (CL/V) in the rich sampling scheme. Regarding POT, the sampling scheme had marginal influence, while target exposure showed clear impacts that the maximum POT of 71.5% was reached when doses were computed based on AUC24 = 500 mg·h/L. CONCLUSIONS: For model-based TDM of vancomycin in ICU patients, sampling more frequently than taking only trough samples adds no value and dosing based on AUC24 = 500 mg·h/L lead to the best POT.

Systematic review: the bioavailability of orally administered antibiotics during the initial phase of a systemic infection in non-ICU patients.

BACKGROUND: The systemic response to an infection might influence the pharmacokinetics of antibiotics. To evaluate the desired possibility of an earlier (< 24 h) IV-to-oral switch therapy in febrile non-ICU, hospitalized patients, a systematic review was performed to assess the effect of the initial phase of a systemic infection on the bioavailability of orally administered antibiotics in such patients. METHODS: An electronic search was conducted in MEDLINE and Embase up to July 2020. Studies were selected when outcome data were collected during the initial stage of a febrile disease. Outcome data were (maximum) serum concentrations, time of achieving maximum serum concentration, and the area-under-the-plasma-concentration-time curve or bioavailability of orally administered antibiotics. Risk of bias was assessed. RESULTS: We identified 9 studies on 6 antibiotics. Ciprofloxacin was the most frequently studied drug. Outcomes of the studies were heterogeneous and generally had a high risk of bias. Three small studies, two on ciprofloxacin and one on clarithromycin, compared the pharmacokinetics of febrile patients with those of clinically recovered patients and suggested that bioavailability was not altered in these patients. Other studies either compared the pharmacokinetics in febrile patients with reported pharmacokinetic values from earlier studies in healthy volunteers (n = 2), or provided no comparison at all and were non-conclusive (n = 4). CONCLUSION: There is a clear knowledge gap regarding the bioavailability of orally administered antibiotics in non-ICU patients during the initial phase of a systemic infection. Well-designed studies on this topic are necessary to elucidate whether patients can benefit from the advantages of an earlier IV-to-oral switch.

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations.

BACKGROUND: Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. OBJECTIVES: To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. METHODS: First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. RESULTS: A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. CONCLUSIONS: For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

Optimizing Predictive Performance of Bayesian Forecasting for Vancomycin Concentration in Intensive Care Patients.

PURPOSE: Bayesian forecasting is crucial for model-based dose optimization based on therapeutic drug monitoring (TDM) data of vancomycin in intensive care (ICU) patients. We aimed to evaluate the performance of Bayesian forecasting using maximum a posteriori (MAP) estimation for model-based TDM. METHODS: We used a vancomycin TDM data set (n = 408 patients). We compared standard MAP-based Bayesian forecasting with two alternative approaches: (i) adaptive MAP which handles data over multiple iterations, and (ii) weighted MAP which weights the likelihood contribution of data. We evaluated the percentage error (PE) for seven scenarios including historical TDM data from the preceding day up to seven days. RESULTS: The mean of median PEs of all scenarios for the standard MAP, adaptive MAP and weighted MAP method were - 7.7%, -4.5% and - 6.7%. The adaptive MAP also showed the narrowest inter-quartile range of PE. In addition, regardless of MAP method, including historical TDM data further in the past will increase prediction errors. CONCLUSIONS: The proposed adaptive MAP method outperforms standard MAP in predictive performance and may be considered for improvement of model-based dose optimization. The inclusion of historical data beyond either one day (standard MAP and weighted MAP) or two days (adaptive MAP) reduces predictive performance.

Population Pharmacokinetics of Ganciclovir in Critically Ill Patients.

BACKGROUND: The pharmacokinetic (PK) data of ganciclovir (GCV), a first-line antiviral treatment for cytomegalovirus infections, in critically ill patients are limited. This study aimed at characterizing GCV population PK and interindividual variability (IIV) in intensive care unit (ICU) patients. Secondary objectives were to identify patient characteristics responsible for IIV and simulate GCV exposure for different dosing regimens. METHOD: In this retrospective observational study, clinical data and serum GCV levels were collected from ICU patients on intravenous GCV. PK modeling, covariate analyses, and explorative Monte Carlo dosing simulations (MCS) were performed using nonlinear mixed-effects modeling. Bootstrap and visual predictive checks were used to determine model adequacy. RESULTS: In total, 128 GCV measurements were obtained from 34 patients. GCV PK conformed to a 1-compartment model with first-order elimination. After multivariate analyses, only the estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (P < 0.001) was included as a covariate. In the final model, the estimated clearance (CL) and volume of distribution (V1) were 2.3 L/h and 42 L, respectively, for a patient with the median CKD-EPI of the population (65 mL/min per 1.73 m). The association between CKD-EPI and CL decreased the residual variability from 0.56 to 0.43 and V1-IIV from 114% to 80%, whereas CL-IIV changed from 43% to 47%. MCS revealed that a substantial number of patients may not achieve the GCV PK/pharmacodynamic target trough level (>1.5 mg/L) when administering the label-recommended dose reductions for patients with CKD-EPI <50 mL/min. CONCLUSIONS: A large IIV was observed in GCV PK among ICU patients. CKD-EPI could partially explain the IIV, although a large part of the variability remains unclear. MCS suggested that recommended dose reductions for CKD-EPI <50 mL/min may lead to subtherapeutic plasma GCV levels in these patients.

Population Pharmacokinetics with Monte Carlo Simulations of Gentamicin in a Population of Severely Ill Adult Patients from Sub-Saharan Africa.

In sub-Saharan Africa (SSA), gentamicin is commonly used for severe infections in non-intensive-care-unit (ICU) settings, but pharmacokinetic and pharmacodynamic data for this specific population are lacking. We performed a population pharmacokinetic study in an adult Mozambican non-ICU hospital population treated with gentamicin (n = 48) and developed a pharmacokinetic model using nonlinear mixed-effects modeling. Simulations showed that non-ICU patient populations in SSA may be at substantial risk for underexposure to gentamicin during routine once-daily dosing.

External Evaluation of Population Pharmacokinetic Models of Vancomycin in Large Cohorts of Intensive Care Unit Patients.

Dosing of vancomycin is often guided by therapeutic drug monitoring and population pharmacokinetic models in the intensive care unit (ICU). The validity of these models is crucial, as ICU patients have marked pharmacokinetic variability. Therefore, we set out to evaluate the predictive performance of published population pharmacokinetic models of vancomycin in ICU patients. The PubMed database was used to search for population pharmacokinetic models of vancomycin in adult ICU patients. The identified models were evaluated in two independent data sets which were collected from two large hospitals in the Netherlands (Amsterdam UMC, Location VUmc, and OLVG Oost). We also tested a one-compartment model with fixed values for clearance and volume of distribution, in which a clinical standard dosage regimen (SDR) was mimicked to assess its predictive performance. Prediction error was calculated to assess the predictive performance of the models. Six models plus the SDR model were evaluated. The model of Roberts et al. (J. A. Roberts, F. S. Taccone, A. A. Udy, J.-L. Vincent, F. Jacobs, and J. Lipman, Antimicrob Agents Chemother 55:2704-2709, 2011, https://doi.org/10.1128/AAC.01708-10) performed satisfactorily, with mean and median values of prediction error of 5.1% and -7.5%, respectively, for Amsterdam UMC, Location VUmc, patients, and -12.6% and -17.2% respectively, for OLVG Oost patients. The other models, including the SDR model, yielded high mean values (-49.7% to 87.7%) and median values (-56.1% to 66.1%) for both populations. In conclusion, only the model of Roberts et al. was able to validly predict the concentrations of vancomycin for our data, whereas other models and standard dosing were largely inadequate. Extensive evaluation should precede the adoption of any model in clinical practice for ICU patients.

Current dosing practices for perioperative factor VIII concentrate treatment in mild haemophilia A patients result in FVIII levels above target.

BACKGROUND: In patients with haemophilia A (HA) perioperative dosing of factor VIII (FVIII) concentrate is based on body weight, historical FVIII level, in vivo recovery and FVIII level target values. In moderate and severe HA patients, this dosing regimen frequently leads to perioperative FVIII levels below and above target. This has not yet been evaluated in mild HA patients. OBJECTIVES: To evaluate perioperative FVIII concentrate treatment in mild HA patients and to assess the frequency of FVIII levels below or above target. PATIENTS/METHODS: This retrospective single-centre study collected data from medical files of mild HA patients undergoing surgery and treated with FVIII concentrate. FVIII levels were compared to their target ranges and predictive factors for levels outside the target ranges were determined by logistic regression. RESULTS: Fifty surgeries performed in 34 patients were evaluated. Median age was 47 years and median historical FVIII level was 0.14 IU/mL. Preoperative peak FVIII level was above or below the target range in 80% and 6.7% of surgeries, respectively. Postoperatively, the percentages above and below target trough ranges were 55.8% and 12.8%. Patients with blood group 0 had the highest risk on the preoperative peak FVIII level being above target. In addition, patients who had a preoperative baseline FVIII level of >0.10 IU/mL higher than their historical FVIII level had a higher preoperative peak FVIII level than patients without this increase. CONCLUSIONS: Dosing above FVIII target ranges with FVIII concentrates occurs frequently during perioperative treatment of mild HA patients. These results underline the necessity for better patient-tailored treatment.

Strategies for Individualized Dosing of Clotting Factor Concentrates and Desmopressin in Hemophilia A and B.

Hemophilia A and hemophilia B are hereditary bleeding disorders, caused by a deficiency of clotting factor VIII or clotting factor IX, respectively. To treat and prevent bleedings, patients can administer clotting factor concentrates (hemophilia A and B) or desmopressin (hemophilia A). Both clotting factor concentrates and desmopressin are currently dosed according to the patients' body weight. However, clotting factor concentrates exhibit considerable pharmacokinetic (PK) variability. Therefore, several alternative dosing strategies to individualize dosing of clotting factor concentrates and desmopressin in hemophilia A and B have been proposed. In this study, a review of the existing literature on the individualization of dosing based on PK guidance was performed. In total, 79 articles were included. The methods to individualize dosing were divided into 3 categories: (1) methods using clinical parameters, (2) empirical individual PK-guided methods, and (3) maximum a posteriori (MAP) Bayesian estimation methods. The clinical parameter mainly used to individualize dosing is bleeding phenotype. Dosing based on bleeding phenotype may decrease clotting factor consumption. However, with this method, it is not possible to individualize on-demand dosing during bleeding events or in the perioperative setting. Empirical individual PK-guided methods can be used both for prevention and treatment of bleedings. These methods include dose individualization using a nomogram and individualized in vivo recovery. In the perioperative setting, adjustment of the rate of continuous infusion can be applied to obtain a specific target level. The final category, MAP Bayesian estimation methods, relies on the availability of a population PK model. In total, 22 population PK models describing clotting factor concentrate or desmopressin dosing are currently available in literature. MAP Bayesian estimates can be used to calculate the individualized doses required to achieve or maintain a target level in every setting. The application of PK-guided and pharmacodynamic-guided dosing of clotting factor concentrates and desmopressin seems promising, although further investigation is warranted. Prospective studies analyzing its potential benefit are on the way.

Pharmacokinetics and Pharmacodynamic Target Attainment of Benzylpenicillin in an Adult Severely Ill Sub-Saharan African Patient Population.

Background: In intensive care (ICU) patients, systemic exposure of ß-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT > MIC ratios. In sub-Saharan African hospitals, benzylpenicillin (PEN) is frequently used for the empiric treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking. Methods: We performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014 through November 2015. Four blood samples/patient were collected for total PEN (PENt) and unbound PEN (PENu) concentration measurement. We developed a PPK model through nonlinear mixed-effects analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios. Results: One hundred twelve participants yielded 387 PENt and 53 PENu concentrations. The median body mass index was 18.3 (range, 10.5-31.3) kg/m2 and the median albumin concentration and creatinine clearance (CrCl) were 29 (range, 12-44) g/L and 80 (range, 3-195) mL/minute, respectively. In a 1-compartment model, CrCl was positively correlated with PENt clearance. For infections with a microorganism with a minimum inhibitory concentration (MIC) of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) every 6 hours, 74.1% would have a PENu concentration greater than the MIC during half of the dosing interval (fT > MIC = 50%), whereas this was 24.8% for the fT > MIC = 100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%, respectively. Conclusions: Severely ill adult sub-Saharan African patients may be at high risk for underexposure to PENu during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility.

Pharmacokinetics and pharmacodynamic target attainment of ceftriaxone in adult severely ill sub-Saharan African patients: a population pharmacokinetic modelling study.

Background: In sub-Saharan Africa (SSA), the highly albumin-bound ß-lactam ceftriaxone is frequently used for the empirical treatment of severe bacterial infections. Systemic drug exposure of ß-lactams can be altered in critically ill ICU patients, but pharmacokinetic and pharmacodynamic data for non-ICU SSA populations are lacking. Methods: We performed a population pharmacokinetic study in an adult hospital population in Mozambique, treated with ceftriaxone for presumptive severe bacterial infection from October 2014 to November 2015. Four blood samples per patient were collected for total ceftriaxone (CEFt) and unbound ceftriaxone (CEFu) concentration measurement. We developed a population pharmacokinetic model through non-linear mixed effect analysis and performed simulations for different patient variable, dosing and pharmacodynamic target scenarios. Results: Eighty-eight participants yielded 277 CEFt and 276 CEFu concentrations. The median BMI was 18.9 kg/m2 and the median albumin concentration was 29 g/L. In a one-compartment model with non-linear protein binding, creatinine clearance was positively correlated with CEFu clearance. For microorganisms with an MIC of 1 mg/L, simulations demonstrated that with a 1 g twice-daily regimen and a 2 g once-daily regimen, 95.1% and 74.8% would have a CEFu concentration > MIC during half of the dosing interval (fT>MIC = 50%), respectively, whereas this was only 58.2% and 16.5% for the fT>MIC = 100% target. Conclusions: Severely ill adult non-ICU SSA patients may be at substantial risk for underexposure to CEFu during routine intermittent bolus dosing, especially when their renal function is intact.

Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review.

BACKGROUND: In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the pharmacokinetics (PK) of antibiotics in this population. The aim of this systematic review was to summarize antibiotic PK data of SSA adult patient populations to clarify whether inappropriate drug concentrations that may also lead to antimicrobial resistance are likely to occur. METHODS: An electronic search was conducted in Ovid MEDLINE, Embase, and the African Index Medicus collecting studies from 1946 to May 2016. Reviewers independently selected studies reporting outcome data on volume of distribution (V), clearance, and half-life. Relevant information was abstracted and quality assessed. RESULTS: Twelve studies were selected, addressing 6 antibiotic classes. There were 6 studies on fluoroquinolones and 1 on ß-lactam antibiotics. Nine out of 12 originated from South Africa and 6 of those dealt with intensive care unit (ICU) populations. The quality of most studies was low. Studies on amikacin, teicoplanin, and ertapenem (n = 4) displayed a pattern of a large V with low drug concentrations. Fluoroquinolone PK changes were less prominent and more diverse whereas the probability of pharmacodynamic target attainment was low for the treatment of tuberculosis in South Africa. Interindividual variability of V was high for 10/12 studies. CONCLUSIONS: Antibiotic PK data of SSA adult patient populations are scarce, but disease-induced inappropriate drug concentrations do occur. Data from non-ICU, severely ill patients, and ß-lactam data are particularly lacking, whereas ß-lactam antibiotics are commonly used, and typically vulnerable to disease-induced PK changes. Studies investigating the PK and pharmacodynamics of ß-lactam antibiotics in severely ill, adult SSA patient populations are needed to improve local antibiotic dosing strategies.

Therapeutic Drug Monitoring of Gentamicin Peak Concentrations in Critically Ill Patients.

BACKGROUND: Adequate gentamicin peak concentrations (Cmax) are important for optimal clinical efficacy. Within a critically ill patient, substantial variability in Cmax can occur over time, hampering the usefulness of therapeutic drug monitoring (TDM). The aim of this study was to evaluate the effect of gentamicin dosing based on Cmax after the first dose on gentamicin target attainment in critically ill patients. METHODS: From gentamicin-treated critically ill patients, dosing information, clinical parameters, and serum concentrations were collected prospectively. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling to estimate Cmax after each dose. To evaluate the usefulness of routine TDM, percentages of Cmax within (%Cther, 15-20 mg/L), above (>20 mg/L), and below (%Csubther, <15 mg/L) the therapeutic range after the first and second doses were compared. In addition, simulations were performed to evaluate the impact of TDM. RESULTS: Four hundred sixteen measurements from 59 patients receiving 130 gentamicin doses were included. In the 30 patients who received >1 dose, TDM increased %Cther from 40% after a first median dose of 5.0 mg/kg to 50% after the second dose, and decreased %Csubther from 47% to 30%. Simulations using a 5 mg/kg starting dose revealed %Cther after the second dose of 28.4% without and 36.8% with TDM and %Csubther of 56.9% and 29.3%, respectively. Increasing the simulated starting dose to 6 mg/kg increased %Cther after the first dose from 27.7% to 33.5% and decreased %Csubther from 58.6% to 35.6%. TDM after a first dose of 6 mg/kg had no substantial effect on %Cther or %Csubther after the second dose. CONCLUSIONS: Gentamicin dosing based on Cmax after the first dose increased %Cther and decreased %Csubther, but did not result in therapeutic Cmax in half of the patients. When simulating a higher starting dose, %Csubther after the first dose decreased, and TDM showed no additional influence. These data suggest that a starting dose of 6 mg/kg should be considered and that repeated Cmax measurements are not of added value.

Antimicrobial prophylaxis outside the operating theatre, an audit in a university hospital.

BACKGROUND: The prophylactic use of antimicrobial agents to prevent infections in non-surgical situations has hardly been investigated. We investigate the extent, indications and appropriateness of antimicrobial prophylaxis given outside the operating room in a tertiary care hospital. METHODS: Four point-prevalence surveys were conducted in which all inpatients on that day were screened for the use of prophylactic antimicrobials: medical prophylaxis, prophylaxis around non-surgical interventions and surgical prophylaxis given on the ward. The primary endpoint was the extent of prophylaxis relative to the total number of antimicrobial prescriptions. We also investigated per prescription the presence of a (local) protocol and adherence to these protocols. RESULTS: We registered in total 1020 antimicrobial prescriptions, of which 317 (31.1%) were given as prophylaxis. 827/1020 were antibiotic prescriptions. Of these antibiotic prescriptions, 17.0% was medical prophylaxis, 2.7% prophylaxis around non-surgical interventions and 6.9% surgical prophylaxis administered on a ward. For medical antibiotic prophylaxis, a protocol was present in 125 of 141 prescriptions (88.7%); the protocol was followed in 118 cases (94.4%). For prophylaxis around non-surgical interventions and surgical prophylaxis on the wards, protocol presence and adherence rates were 59.1% and 92.3%, and 73.3% and 97.6% respectively. Of the 96 antiviral and 97 antifungal prescriptions, 42.7% and 57.8%, respectively, were medical prophylaxis, of which 95.1 and 96.3% were prescribed according to protocols respectively. CONCLUSIONS: Antimicrobial prophylaxis outside the operating theatre is responsible for a considerable part of total in-hospital antimicrobial use. For most prescriptions there was a protocol and adherence to the protocols was high. The main targets for improvement were prophylaxis around non-surgical interventions and surgical prophylaxis given on the ward.