Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T.MIC) (for efficacy purposes and 100% T.4×MIC and 100% T.5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T.MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T.MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T.4×MIC and 100% T.5×MIC are desired.</p

Population Pharmacokinetics of Ganciclovir in Critically Ill Patients

Item does not contain fulltex

The impact of trimethoprim-sulfamethoxazole as Pneumocystis jiroveci pneumonia prophylaxis on the occurrence of asymptomatic bacteriuria and urinary tract infections among renal allograft recipients: a retrospective before-after study

The international guidelines recommend the administration of trimethoprim-sulfamethoxazole (TMP-SMX) as Pneumocystis jiroveci pneumonia (PJP) prophylaxis for six months after transplantation. The aim of this study is to evaluate the influence of TMP-SMX prophylaxis on the occurrence of asymptomatic bacteriuria (ASB) and urinary tract infections (UTIs) as cystitis and allograft pyelonephritis (AGPN) and its impact on the antimicrobial resistance pattern of causative microorganisms. We have conducted a retrospective before-after study in adult renal allograft recipients with one year follow-up after transplantation. We compared the ("after") group that received TMP-SMX as PJP prophylaxis to the ("before") group that did not receive it. In total, 343 renal allograft recipients were analysed, of whom 212 (61.8 %) received TMP-SMX as PJP prophylaxis. In this study, 63 (18.4 %) did only develop ASB without UTI, 26 (7.6 %) developed cystitis and 43 (12.5 %) developed AGPN. The remaining 211 (61.5 %) renal allograft recipients did not develop any bacteriuria at all. Multivariable Cox proportional regression analysis indicated that TMP-SMX as PJP prophylaxis was not associated with reduced prevalence of ASB (Hazard ratio (HR) = 1.52, 95 % CI = 0.79-2.94, p = 0.213), nor with reduced incidence of cystitis (HR = 2.21, 95 % CI = 0.76-6.39, p = 0.144), nor AGPN (HR = 1.12, 95 % CI = 0.57-2.21, p = 0.751). Among the group receiving TMP-SMX as PJP prophylaxis there was a trend was observed in increase of both amoxicillin (86 % versus 70 %) and TMP-SMX (89 % versus 48 %) resistance which already appeared within the first 30 days after TMP-SMX exposure. Among renal allograft recipients, administration of TMP-SMX as PJP prophylaxis does not prevent ASB nor UTI, however it is associated with tendency towards increased amoxicillin and TMP-SMX resistanc

Performance of Kiestra total laboratory automation combined with MS in clinical microbiology practice

Microbiological laboratories seek technologically innovative solutions to cope with large numbers of samples and limited personnel and financial resources. One platform that has recently become available is the Kiestra Total Laboratory Automation (TLA) system (BD Kiestra B.V., the Netherlands). This fully automated sample processing system, equipped with digital imaging technology, allows superior detection of microbial growth. Combining this approach with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MS) (Bruker Daltonik, Germany) is expected to enable more rapid identification of pathogens. Early growth detection by digital imaging using Kiestra TLA combined with MS was compared to conventional methods (CM) of detection. Accuracy and time taken for microbial identification were evaluated for the two methods in 219 clinical blood culture isolates. The possible clinical impact of earlier microbial identification was assessed according to antibiotic treatment prescription. Pathogen identification using Kiestra TLA combined with MS resulted in a 30.6 hr time gain per isolate compared to CM. Pathogens were successfully identified in 98.4% (249/253) of all tested isolates. Early microbial identification without susceptibility testing led to an adjustment of antibiotic regimen in 12% (24/200) of patients. The requisite 24 hr incubation time for microbial pathogens to reach sufficient growth for susceptibility testing and identification would be shortened by the implementation of Kiestra TLA in combination with MS, compared to the use of CM. Not only can this method optimize workflow and reduce costs, but it can allow potentially life-saving switches in antibiotic regimen to be initiated soone

Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria

The aim of this study was to describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven Gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial MICs found in this population. Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care Unit (NICU) at the Academic Medical Center (AMC), Amsterdam, The Netherlands. A single nonlinear mixed-effects regression analysis (NONMEM) was performed to describe the population PK of gentamicin. Dosage regimens based upon gestational age (GA) were generated using Monte Carlo simulations with the final model. Target values were based on the MIC distribution in our patient population. In total, 136 gentamicin concentrations from 65 (pre)term neonates were included. The PK was best described by an allometric 2-compartment model with postmenstrual age (PMA) as a covariate on clearance (Cl). The MIC distribution (median, 0.75 [range, 0.5 to 1.5] mg/liter) justified a gentamicin target peak concentration of 8 to 12 mg/liter. This study describes the PK of gentamicin in (pre)term neonates. Dosage regimens of 5 mg/kg of body weight every 48 h, 5 mg/kg every 36 h, and 5 mg/kg every 24 h for patients with GAs of <37 weeks, 37 to 40 weeks, and ≥40 weeks, respectively, are recommende

Inadequate vancomycin therapy in term and preterm neonates: a retrospective analysis of trough serum concentrations in relation to minimal inhibitory concentrations

Vancomycin is effective against gram-positive bacteria and the first-line antibiotic for treatment of proven coagulase-negative staphylococcal infections. The aim of this study is bipartite: first, to assess the percentage of therapeutic initial trough serum concentrations and second, to evaluate the adequacy of the therapeutic range in interrelationship with the observed MIC-values in neonates. In this study, preterm and term neonates admitted at a tertiary NICU in the Netherlands from January 2009 to December 2012 and treated with vancomycin for a proven gram-positive infection were included. Trough serum concentrations were measured prior to administration of the 5th dose. Trough concentrations in the range of 10 to 15 mg/L were considered therapeutic. Staphylococcal species minimal inhibitory concentrations (MIC's) were determined using the E-test method. Species identification was performed by matrix-assisted laser desorption/ionisation mass spectrometry. Of the 112 neonates, 53 neonates (47%) had sub-therapeutic initial trough serum concentrations of vancomycin, whereas 22% had supra-therapeutic initial trough serum concentrations. In all patients doses were adjusted on basis of the initial trough concentration. In 40% (23/57) of the neonates the second trough concentration remained sub-therapeutic. MIC's were determined for 30 coagulase-negative Staphylococcus isolates obtained from 19 patients. Only 4 out of 19 subjects had a trough concentration greater than tenfold the MIC. Forty-seven percent of the neonates had sub-therapeutic initial trough serum concentrations of vancomycin. The MIC-data indicate that the percentages of underdosed patients may be greater. It may be advisable to increase the lower limit of the therapeutic range for European neonate

De ziekte van Chagas in Nederland: een schatting van het aantal patiënten

A total of 8-10 million persons are infected worldwide with Trypanosoma cruzi, the causative parasite of Chagas disease, most of whom are inhabitants of Latin America. Due to the increased migration of peoples, Chagas disease has been on the uprise outside Latin America, including in Europe. The course of Chagas, also called American trypanosomiasis, runs in 2 phases: an acute phase lasting approximately 2 months, and a chronic phase in which symptoms may appear years after infection. Without treatment, the patient will remain infected for life. The acute phase is usually asymptomatic; in the chronic phase of American trypanosomiasis, severe gastro-intestinal and cardiac abnormalities may develop, finally with fatal course. In the Netherlands, the number of immigrants who would serologically test positive for American trypanosomiasis is estimated to be between 726 and 2929. Healthcare providers in the Netherlands may encounter patients who have Chagas disease more and more frequently. The screening of pregnant women and blood donors at risk for American trypanosomiasis should be considere

Predictive performance of a gentamicin population pharmacokinetic model in two western populations of critically ill patients

External validation of population pharmacokinetic (PK) models is warranted before they can be clinically applied to aid in antibiotic dose selection. The primary objective of this study was to assess the predictive performance of a gentamicin population PK model in intensive care unit (ICU) patients in two independent western populations of critically ill patients. Methods: Data were collected from the ICU where the model was developed (Academic Medical Centre, Amsterdam [AMC]) and from the Centre Hospitalier Universitaire de Nîmes (CHU Nîmes). Primary endpoints were bias and accuracy. The model was regarded as valid if bias was not significantly different from 0 and accuracy was equal to or less than 2.5 mg/L. Non-linear mixed-effects modelling (NONMEM) was used for data analysis. Results: The AMC validation dataset consisted of 192 samples from 66 ICU patients and the CHU Nîmes dataset of 230 gentamicin samples from 50 ICU patients. The structural model predicted the gentamicin plasma concentrations in the AMC population with a non-significant bias (0.35, 95%CI: -0.11–0.81) and a sufficient accuracy of 2.5 mg/L (95%CI: 2.3–2.8). The gentamicin plasma concentrations were overpredicted in the CHU Nîmes population with a significant bias of 4.8 mg/L (95%CI: 4.00–5.62) and an accuracy of 5.5 mg/L (95%CI: 4.7–6.2). Conclusion: The model is valid for use in the AMC ICU population but not in the CHU Nîmes ICU population. This illustrates that caution is needed when using a population PK model in an external population

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of short-term empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy

Determinants of gentamicin concentrations in critically ill patients: a population pharmacokinetic analysis

When treating critically ill patients with gentamicin for severe infection, peak concentrations (C-max) determine clinical efficacy and trough concentrations (C-min) determine toxicity. Despite administration of body weight-standardised starting doses, a wide range of Cmax is generally observed. Furthermore, in therapeutic drug monitoring, several measures of renal function are used to predict appropriate Cmin and gentamicin dosing intervals, but the most accurate predictor is not known. This study aimed to quantify the impact of several patient parameters on gentamicin Cmax values and to determine which measure of renal function best predicts gentamicin clearance (CL). Clinical data and serum gentamicin levels were retrospectively collected from all critically ill patients treated with gentamicin at our intensive care unit between 1 January and 30 June 2011. Data were analysed using non-linear mixed-effects modelling (NONMEM v.7.1.2). A two-compartmental model was developed based on 303 gentamicin concentration-time data from 44 critically ill patients. Serum albumin levels explained 25% of interindividual variability in the volume of distribution (V-d). Creatinine clearance calculated from the creatinine concentration in a 6-h urine portion (CalcCL(Cr)) resulted in acceptable estimation of gentamicin CL, whilst serum creatinine (SCr) and creatinine clearance estimated by the Cockcroft-Gault formula (CGCL(Cr)) overestimated gentamicin CL and therefore underestimated C-min. In conclusion, low albumin concentrations resulted in a larger Vd and lower Cmax of gentamicin. These results suggest that use of a higher gentamicin starting dose in critically ill patients with hypoalbuminaemia may prevent underdosing. Urinary CalcCLCr is a better predictor of C-min than SCr or CGCL(Cr). (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserve