Evaluation of pharmacokinetic pharmacodynamic target attainment of meropenem in pediatric patients.

BACKGROUND: Meropenem is a widely used carbapenem for treating severe pediatric infections. However, few studies have assessed its pharmacokinetics/pharmacodynamics (PK/PD) in pediatric patients. This study aimed to evaluate the proportion of Saudi pediatric patients achieving the PK/PD target of meropenem. METHODS: A prospective observational study was conducted at King Saud University Medical City from July to September 2022. Pediatric patients receiving meropenem for suspected or proven infections were included in the study. The primary outcome was the percentage of patients achieving the recommended PK/PD target for critically ill or non-critically ill pediatric patients. RESULTS: The study included 30 patients (nine neonates and 21 older pediatric patients). All neonates were critically ill. Among them, 55 % achieved the PK/PD target of 100 % free time above the MIC. In older ICU pediatric patients, only 11 % attained this target, whereas 58 % of older pediatrics in the general wards achieved the PK/PD target of 50 % free time above the MIC. Augmented renal clearance (ARC) was identified in 57 % of our pediatric patient population, none of whom achieved the recommended PK/PD targets. The median trough concentrations in patients with and without ARC were 0.75 and 1.3 µg/mL, respectively (P < 0.05). CONCLUSIONS: The majority of patients in our cohort did not achieve the PK/PD target for meropenem. ARC emerged as a major risk factor for target attainment failure in both critically ill and non-critically ill pediatric patients.

Population pharmacokinetics of vancomycin in very low birth weight neonates.

Introduction: Vancomycin dosing in very low birth weight (VLBW) neonates is challenging. Compared with the general neonatal population, VLBW neonates are less likely to achieve the vancomycin therapeutic targets. Current dosing recommendations are based on studies of the general neonatal population, as only a very limited number of studies have evaluated vancomycin pharmacokinetics in VLBW neonates. The main aim of this study was to develop a vancomycin population pharmacokinetic model to optimize vancomycin dosing in VLBW neonates. Methods: This multicenter study was conducted at six major hospitals in Saudi Arabia. The study included VLBW neonates who received vancomycin and had at least one vancomycin serum trough concentration measurement at a steady state. We developed a pharmacokinetic model and performed Monte Carlo simulations to develop an optimized dosing regimen for VLBW infants. We evaluated two different targets: AUC0-24 of 400-600 or 400-800 µg. h/mL. We also estimated the probability of trough concentrations >15 and 20 µg/mL. Results: In total, we included 236 neonates, 162 in the training dataset, and 74 in the validation dataset. A one-compartment model was used, and the distribution volume was significantly associated only with weight, whereas clearance was significantly associated with weight, postmenstrual age (PMA), and serum creatinine (Scr). Discussion: We developed dosing regimens for VLBW neonates, considering the probability of achieving vancomycin therapeutic targets, as well as different toxicity thresholds. The dosing regimens were classified according to PMA and Scr. These dosing regimens can be used to optimize the initial dose of vancomycin in VLBW neonates.

Evaluation of vancomycin individualized model-based dosing approach in neonates.

BACKGROUND: Vancomycin is commonly used to treat methicillin-resistant staphylococcal infections in neonates. Consensus on its ideal dosing in neonates has not been achieved. Model-based dosing recently has evolved as an important tool to optimize vancomycin initial dosing. The aim of this is to evaluate a population pharmacokinetic model-based approach in achieving the vancomycin therapeutic target of an AUC0-24 400 as recommended by the recent IDSA treatment guidelines. This model was implemented as a simple Excel calculator to individualize and optimize vancomycin initial dosing in neonates. METHODS: An Excel calculator was developed using a previously published population pharmacokinetic model in neonates. It was evaluated using retrospectively retrieved data. For each patient, the initial empiric dose was calculated using the proposed Excel model and the most widely used neonatal dosing references. The probability of achieving the target AUC0-24 of >400 mg h/L using the model-based method was calculated and compared with that of the empiric doses using other references. RESULTS: This analysis included 225 neonates. The probability of achieving the target AUC0-24 >400 was 89% using our model-based approach compared with 11%-59% using tertiary neonatal dosing references (p < 0.01 for all comparisons). CONCLUSION: These innovative personalized dosing calculators are promising to improve vancomycin initial dosing in neonates and are easily applicable in routine practices.

Quality appraisal of antibiotic prophylaxis guidelines to prevent infective endocarditis following dental procedures: a systematic review.

OBJECTIVE: To assess the quality of clinical practice guidelines (CPGs) for the use of antimicrobial prophylaxis to prevent infective endocarditis in indicated dental procedures. STUDY DESIGN: We searched on Medline/OVID, CINAHL/EBSCO, and EMBASE from January 2011 to January 2022. We included de novo guidelines and excluded adapted or adopted guidelines, and guidelines published before 2011. The guidelines were independently appraised by 4 reviewers using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) Instrument. RESULTS: Four eligible CPGs were appraised: the European Society of Cardiology, the American Heart Association, the National Institute of Health and Care Excellence (NICE), and the Japanese Circulation Society (JCS). Their AGREE II first overall assessments (OA1) were 63%, 58%, 92%, and 71%, respectively. Both NICE and JCS scored the highest in OA1 (>70%), Domain 3 Rigor of Development (85%, 65%), and Domain 5 Applicability (76%, 48%), respectively. The second overall assessment (OA2) of using the CPGs in daily practice was not significantly variable (recommended for use with modifications). CONCLUSION: Three out of 4 CPGs support that the benefits of prevention of infective endocarditis outweigh the risks of antibiotic resistance.

International alliance and AGREE-ment of 71 clinical practice guidelines on the management of critical care patients with COVID-19: a living systematic review.

OBJECTIVE: We aimed to systematically identify and critically assess the clinical practice guidelines (CPGs) for the management of critically ill patients with COVID-19 with the AGREE II instrument. STUDY DESIGN AND SETTING: We searched Medline, CINAHL, EMBASE, CNKI, CBM, WanFang, and grey literature from November 2019 - November 2020. We did not apply language restrictions. One reviewer independently screened the retrieved titles and abstracts, and a second reviewer confirmed the decisions. Full texts were assessed independently and in duplicate. Disagreements were resolved by consensus. We included any guideline that provided recommendations on the management of critically ill patients with COVID-19. Data extraction was performed independently and in duplicate by two reviewers. We descriptively summarized CPGs characteristics. We assessed the quality with the AGREE II instrument and we summarized relevant therapeutic interventions. RESULTS: We retrieved 3,907 records and 71 CPGs were included. Means (Standard Deviations) of the scores for the 6 domains of the AGREE II instrument were 65%(SD19.56%), 39%(SD19.64%), 27%(SD19.48%), 70%(SD15.74%), 26%(SD18.49%), 42%(SD34.91) for the scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, editorial independence domains, respectively. Most of the CPGs showed a low overall quality (less than 40%). CONCLUSION: Future CPGs for COVID-19 need to rely, for their development, on standard evidence-based methods and tools.

AUC- vs. Trough-Guided Monitoring of Vancomycin in Infants.

OBJECTIVE: Improving vancomycin therapy with therapeutic drug monitoring is recommended. Over the past few years, a few studies have demonstrated that trough concentrations may not be the optimal parameter for monitoring vancomycin concentration and Area under the curve (AUC) should be used instead. In this study authors evaluate two methods to estimate the AUC. The first method is based on linear regression using only a trough concentration. The second method uses a simplified two-sample equation-based strategy to estimate the AUC. METHODS: Data from 70 infant patients were collected retrospectively from their medical records at King Saud University Medical City. The prediction accuracy for vancomycin therapy monitoring was optimized by comparing the two methods for the AUC calculation, the simple linear regression and simplified two-sample equation-based strategy. RESULTS: The target AUC > 400 µg × h/ml was achieved in 10%, 71%, and 100% of patients with trough concentration ranges of 5-10, 10-15, and > 15 µg/ml, respectively. There was a strong correlation between the predicted and observed AUC calculated using the simplified two-sample equation-based strategy (R2 = 0.91, bias = -3.9%, precision =12%). CONCLUSIONS: The target AUC > 400 µg × h/ml can be achieved at trough concentrations <15 µg/ml in most patients. Targeting trough concentrations >15 can lead to overdoing and increase risk of nephrotoxicity. The authors recommend estimating the AUC using the simplified two-sample equation strategy for more precise dosing of vancomycin. Using AUC-guided dosing instead of the trough-guided approach can prevent over dosing and reduce the risk of nephrotoxicity.

Correction to: Vitamin D status and vitamin D receptor gene polymorphism in Saudi children with acute lower respiratory tract infection.

The correct affiliations for all authors are as given below.

Optimizing Gentamicin Dosing in Pediatrics Using Monte Carlo Simulations.

Gentamicin is known to have concentration-dependent bactericidal activity, and its nephrotoxic effect is well described. We developed a population pharmacokinetic/pharmacodynamic model to optimize gentamicin dosing in pediatrics. Data were retrospectively collected for pediatric patients 1 month to 12 years of age, admitted to general pediatric wards or intensive care units and received gentamicin for suspected or proven Gram-negative infections at King Saud University Medical City, Riyadh, Saudi Arabia. A total of 306 gentamicin peak and trough concentrations sets from 107 patients were analyzed with mean (±standard deviation) patient age and weight of 4.5 ± 3.5 years and 16.7 ± 10.8 kg, respectively. Gentamicin pharmacokinetics were adequately described with a one compartment system (R = 0.82, bias = 1.75% and precision = 88% for population predictions and R = 0.94, bias = 5% and precision = 29% for individual predictions). The gentamicin pharmacokinetic parameters were as follows: volume of distribution = 8.9 L, total body clearance = 2.8 L/h for a 20-kg patient. Monte Carlo simulations showed that doses of 5-6 mg/kg/dose once daily are adequate only to treat infections with Gram-negative organisms having minimal inhibitory concentration less than 1 µg/mL. While, at minimal inhibitory concentration of 1 µg/mL, higher doses (7-8 mg/kg/dose once daily) are needed to maximize the efficacy of gentamicin. However, at minimal inhibitory concentration of 2 µg/mL, even a 10 mg/kg dose showed poor target attainment (52%). The finding of this study highlights the need to reevaluate the current breakpoints of gentamicin and also to assess the safety of higher doses of gentamicin in pediatrics.

Vitamin D status and vitamin D receptor gene polymorphism in Saudi children with acute lower respiratory tract infection.

There is a significant association exists between vitamin D deficiencies, low respiratory tract infections, and certain types of VDR gene polymorphism. Various studies are being conducted to prove any such link between the different clinical conditions due to disturbed vitamin D regulation and VDR gene polymorphisms. The present study analyzed the presence of vitamin D receptor (VDR) gene polymorphisms (ApaI and TaqI) in Saudi pediatric patient suffering from acute lower respiratory tract infection (ALRTI) cases. Fifty children (50) with ALRTI admitted at King Saud University Medical City, Riyadh/Saudi Arabia were included in addition to seventy-three (73) apparently healthy children who were considered as the control group. Genomic DNA from whole blood was extracted and subjected to polymerase chain reaction (PCR) targeting TaqI and ApaI VDR polymorphisms. RFLP-PCR genotyping was performed to determine the allelic frequency within the VDR gene. In the whole sample, the allelic frequency of ApaI polymorphism in the VDR gene was 58.5%, 17.9%, and 23.6% for AA, Aa, and aa respectively (p = 0.11), while it was 48%, 19%, and 33% for TT, Tt, and tt respectively (p = 0.33) with regards to the frequency of TaqI polymorphism in the VDR gene. VDR ApaI Aa and aa genotypes and VDR TaqI Tt and tt genotypes were not associated with increased risk of ALRTI in children (OR 0.87, 95% CI 0.33-2.28, p = 0.77; OR 0.56, 95% CI 0.23-1.4, p = 0.21; OR 1.15, 95% CI 0.44-2.99, p = 0.77; OR 0.73, 95% CI 0.32-1.68, p = 0.46 respectively). To conclude, neither vitamin D status nor VDR gene polymorphisms such as ApaI and TaqI is associated with increased susceptibility to ALRTI. Linkage disequilibrium was not detected between ApaI and TaqI VDR gene polymorphisms as in the case of serum vitamin D status in ALRTI patients versus apparent healthy children.

Optimizing Amikacin Dosage in Pediatrics Based on Population Pharmacokinetic/Pharmacodynamic Modeling.

OBJECTIVE: Our objective was to determine the population pharmacokinetic parameters of amikacin in pediatric patients to contribute to the future development of a revised optimum dose and population-specific dosing regimens. METHODS: We performed a retrospective chart review in non-critical pediatric patients (aged 1-12 years) who received amikacin for suspected or proven Gram-negative infection at a university hospital. The population pharmacokinetic models were developed using Monolix 4.4. Pharmacokinetic/pharmacodynamic (PK/PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. RESULTS: The analysis included 134 amikacin plasma concentrations from 67 patients with a mean ± standard deviation age of 4.1 ± 3.9 years and bodyweight of 15 ± 8.4 kg. The patients received an amikacin total daily dose (TDD) of 23 ± 7.3 mg/kg, which resulted in peak and trough concentrations of 20.65 ± 7.6 and 2.4 ± 1.7 mg/l, respectively. The estimated pharmacokinetic parameters for amikacin were 1.2 l/h and 6.5 l for total body clearance (CL) and the volume of distribution (V), respectively. Dosing simulations showed that the standard dosing regimen (15 mg/kg/day) of amikacin achieved the PK/PD target of peak serum concentration (Cpeak)/minimum inhibitory concentration (MIC) ≥ 8 for an MIC of 2 mg/l; higher doses were required to achieve higher MIC values. CONCLUSION: The simulation results indicated that amikacin 20 mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily. In addition, combination therapy is recommended for pathogens with an MIC of ≥ 8 mg/l.

Optimizing Vancomycin Monitoring in Pediatric Patients.

BACKGROUND: Several studies have reported that trough levels may not be optimal for monitoring vancomycin therapy, because of overexposure and nephrotoxicity risks. Therefore, we developed a population pharmacokinetic model to optimize vancomycin dosing and monitoring in pediatrics. METHODS: Data were retrospectively collected on 76 pediatric patients 1-12 years of age, admitted to general pediatric wards or intensive care units at King Saud University Medical City, Riyadh, Saudi Arabia. The predictability of 3 methods for calculating the area under the curve (AUC) at steady state was assessed for optimum vancomycin therapy monitoring. The 3 methods were simple linear regression, Bayesian approach and the 2-sample pharmacokinetic equation method. We also used Monet Carlo simulations to evaluate the dosing of vancomycin. RESULTS: A 1-compartment model adequately described the data. A strong correlation occurred between the observed and predicted AUC from 0 to 24 hours (AUC0-24h) calculated using the Bayesian approach with a trough sample only or pharmacokinetic equations based on 2 measured samples (R = 0.93 and 0.92, respectively). For the simple linear regression method with a trough sample only, the predicted AUC0-24h at steady state with vancomycin trough levels of 10, 15 and 20 µg/mL were 413, 548 and 714 µg·hour/mL, respectively. The target AUC0-24h above 400 was achieved in 46% and 95% of individuals with trough values of 7-11 and 11-15 µg/mL, respectively. Monte Carlo simulations showed that 60-80 mg/kg/d doses are needed to optimize vancomycin therapy. CONCLUSIONS: In conclusion, targeting vancomycin trough levels above 15 µg/mL in pediatrics would overshoot the target AUC0-24h above 400 and expose them to unnecessary adverse events.

Pediatric acute kidney injury induced by concomitant vancomycin and piperacillin-tazobactam.

BACKGROUND: Vancomycin is very commonly used in combination with piperacillin-tazobactam (PTZ) as the initial empiric treatment for moderate-severe infection, whenever coverage for both methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa is required. The combination of vancomycin and PTZ in adults has recently been reported to significantly increase the risk of acute kidney injury (AKI) relative to vancomycin monotherapy; such reports in pediatrics, however, are sparse. METHODS: A retrospective chart review was conducted of pediatric patients, aged 0-14 years, who were admitted to the general wards or intensive care unit and developed AKI after receiving vancomycin and PTZ concomitantly for >48 h. AKI is defined as a decrease in estimated glomerular filtration rate ≥50% from baseline. Cases were identified by reviewing the Adverse Drug Reaction program database at King Saud University Medical City in Saudi Arabia from January 2015 to June 2016. RESULTS: Eight children admitted to the present hospital and who received concomitant vancomycin and PTZ treatment for pneumonia (n = 7) or febrile neutropenia (n = 1) developed drug-induced nephrotoxicity. Drug Interaction Probability Scale (DIPS) score for causation assessment was 9 in all cases (highly probable). CONCLUSION: Caution in utilizing the combination of vancomycin and PTZ is warranted in pediatric patients. Health-care professionals should be vigilant if this combination is to be initiated, and ensure close monitoring of renal function. Antibiotic therapy de-escalation should be considered as soon as culture results are available.