<p>Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.</p>

<p>Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage.: Male Sprague-Dawley rats (n=125) were randomized to receive 150 to 400 mg/kg/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 hours prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic curves (ROC) were employed to assess urinary biomarker performance of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologic defined VIKI (using a national standard pathologic assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL according to sensitivity and specificity. For the earliest injury, urinary KIM-1 (AUC 0.662, p&lt;0.001) and clusterin (AUC 0.706, p&lt;0.001) were most sensitive to predicting even low-level histopathologic damage at 24 h when compared to NGAL. KIM-1 and clusterin are earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin and OPN define the extent of damage best.</p>

<p><strong>BACKGROUND: </strong>Acute kidney injury (AKI) commonly occurs after cardiac arrest. Those subsequently treated with vancomycin are at additional risk for drug-induced kidney injury.</p>

<p><strong>OBJECTIVE: </strong>We aimed to determine whether opportunities exist for improved drug monitoring after cardiac arrest.</p>

<p><strong>METHODS: </strong>This was a retrospective cohort study of children aged 30&nbsp;days-17&nbsp;years treated after cardiac arrest in an intensive care unit from January 2010 to September 2014 who received vancomycin within 24&nbsp;h of arrest. Vancomycin dosing and monitoring were compared between those with and without AKI, with AKI defined as pRIFLE (pediatric risk, injury, failure, loss, end-stage renal disease) stage 2-3 AKI at day 5 using Schwartz formula-calculated estimated glomerular filtration rate (eGFR).</p>

<p><strong>RESULTS: </strong>Of 43 children, 16 (37%) had AKI at day 5. Age, arrest duration, median time to first vancomycin dose, and the number of doses before and time to first vancomycin concentration measurement were similar between groups. Children with AKI had higher initial vancomycin concentrations than those without AKI (median 16 vs. 7&nbsp;mg/L; p = 0.003). A concentration was not measured before the second dose in 44% of children with AKI. Initial eGFR predicted day 5 AKI. In children with AKI, the initial eGFR was lower in those with than those without a concentration measurement before the second dose (29&nbsp;mL/min/1.73&nbsp;m [interquartile range (IQR) 23-47] vs. 52 [IQR 50-57]; p = 0.03) but well below normal in both.</p>

<p><strong>CONCLUSIONS: </strong>In children with AKI after cardiac arrest, decreased vancomycin clearance was evident early, and early monitoring was not performed universally in those with low initial eGFR. Earlier vancomycin therapeutic drug monitoring is indicated in this high-risk population.</p>

<p>Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G&gt;T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G&gt;T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.</p>

<p><strong>OBJECTIVES: </strong>To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes.</p>

<p><strong>DESIGN: </strong>Observational cohort study of HIV infected adults initiating efavirenz-based regimens in Botswana.</p>

<p><strong>METHODS: </strong>The primary endpoint was a composite of death or loss to care or HIV RNA&gt;25 copies/ml at 6 months. CYP2B6 516G&gt;T and 983T&gt;C genotyping was done with Taqman Open Array platform. Adverse experiences were measured using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint.</p>

<p><strong>RESULTS: </strong>801 individuals included 406 (51%) males, median age 37 years, median baseline CD4 count 195 cells/mm and plasma HIV RNA 4·9 log10 copies/ml. 277 (35%) reached the endpoint including 34 (4%) deaths, 151 (19%) lost to care, and 92 (11%) with plasma HIV RNA&gt;25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences.</p>

<p><strong>CONCLUSIONS: </strong>Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate CNS toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.</p>

<p><strong>BACKGROUND: </strong>CYPB2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYPB2B6 516G&gt;T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana.</p>

<p><strong>SETTING: </strong>We performed a case-control study that included 1,338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART). Patients were approached for enrollment during regular visits at one of the outpatient HIV clinics between 7/2013-4/2014.</p>

<p><strong>METHODS: </strong>Cases experienced late HIV failure, defined as plasma HIV RNA &gt;1000 copies/mL after maintaining viral suppression (&lt;400 copies/mL) for at least 6 months. For each case, a total of 4 control patients were randomly sampled from the same population. Controls had plasma HIV RNA &lt;400 copies/mL on ART for at least 6 months. Logistic regression was used to determine the adjusted odds of late HIV failure by 516G&gt;T genotype.</p>

<p><strong>RESULTS: </strong>After adjustment for the confounding variables age and CD4 count, the CYPB2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95%CI 0.50-0.97.</p>

<p><strong>CONCLUSION: </strong>The CYPB2B6 516 T-allele was protective against late virologic breakthrough in patients with initial (6 month) HIV RNA suppression on EFV-based ART. Future studies are needed to assess long-term viral benefits of identifying and offering EFV containing ART to black African HIV-infected patients with CYPB2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.</p>

<p><strong>BACKGROUND: </strong>Surgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery.</p>

<p><strong>METHODS: </strong>This prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4-15.4] yr and a median weight of 60.6 (IQR 50.8-66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated.</p>

<p><strong>RESULTS: </strong>Skeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8-40.0) µg ml(-1) within 30-60 min after the first cefazolin 30 mg kg(-1) dose. For patients who received a second 30 mg kg(-1) dose, the peak concentrations reached a median of 40.5 (IQR 30.8-45.7) µg ml(-1) within 30-60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively.</p>

<p><strong>CONCLUSIONS: </strong>For children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens.</p>

<p><strong>OBJECTIVES: </strong>Polypharmacy is common in hospitalized children in the United States and has been identified as a major risk factor for exposure to potential drug-drug interactions. Little is known about the characteristics and prevalence of exposure of pediatric patients to polypharmacy and potential drug-drug interactions in PICUs.</p>

<p><strong>DESIGN: </strong>Retrospective cohort study using the Pediatric Health Information System database.</p>

<p><strong>SETTING: </strong>Forty-two freestanding children's hospitals throughout the United States.</p>

<p><strong>PATIENTS: </strong>A total of 54,549 patients less than 18 years old cared for in PICUs in 2011. Patients in neonatal ICUs were not included.</p>

<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>PICU patients were on average exposed to 10 distinct drugs each hospital day and to 20 drugs cumulatively during their hospitalization. Seventy-five percent of patients were exposed to greater than or equal to one potential drug-drug interaction regardless of severity level, 6% to greater than or equal to one contraindicated potential drug-drug interaction, 69% to greater than or equal to one major potential drug-drug interaction, 57% to greater than or equal to one moderate potential drug-drug interaction, 19% to greater than or equal to one minor potential drug-drug interaction. Potential drug-drug interaction exposures were significantly associated with specific diagnoses (p &lt; 0.001), presence of complex chronic conditions (p &lt; 0.001), increasing number of total distinct drugs used (p &lt; 0.001), increasing length of stay in PICU (p &lt; 0.001), and white race (p &lt; 0.001).</p>

<p><strong>CONCLUSIONS: </strong>Many PICU patients are exposed to substantial polypharmacy and potential drug-drug interactions. Future research should identify the risk of adverse drug events following specific potential drug-drug interaction exposures, especially the risk of adverse drug events due to multiple potential drug-drug interaction exposures, and determine the probability and magnitude of the actual harm (if any) for each specific potential drug-drug interaction, especially for multiple potential drug-drug interaction exposures.</p>

<p><strong>BACKGROUND: </strong>Surgical site infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts.</p>

<p><strong>AIM: </strong>The purposes of this study were to determine the plasma and tissue concentrations with standard of care, perioperative cefazolin dosing in an immature porcine model of pediatric cardiac surgery, and to determine the feasibility of this model.</p>

<p><strong>METHODS: </strong>Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB + DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of the skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, noncompartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed.</p>

<p><strong>RESULTS: </strong>Following the first intravenous dose, maximal cefazolin concentrations in the subcutaneous tissue and skeletal muscle were similar between groups with peak tissue concentrations 15-30 min after administration. After the second cefazolin dose given with the initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle- and subcutaneous-unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed subcutaneous and skeletal muscle concentrations of cefazolin &gt;16 μg·ml(-1) while this percentage was 78-79% for the CPB + DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP + DHCA (P = 0.03).</p>

<p><strong>CONCLUSIONS: </strong>The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of the cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.</p>

<p><strong>OBJECTIVES: </strong>Care for the pediatric patient with acute renal failure who requires hemodialysis (including continuous renal replacement therapy) is made more complex, as this intervention may significantly affect drug clearance, potentially altering, to a degree that is largely unknown, the effectiveness and safety of the multiple medications used to manage this complex patient population. This study aims to describe patterns of drug utilization among a large cohort of pediatric patients requiring hemodialysis and to document the easily accessible existing data available for dosing guidance of frequently prescribed medications.</p>

<p><strong>STUDY DESIGN: </strong>Retrospective cohort using the Pediatric Health Information System database.</p>

<p><strong>SETTING: </strong>Forty freestanding children's hospitals throughout the United States.</p>

<p><strong>PATIENTS: </strong>Two thousand seven hundred thirty-eight pediatric patients with acute renal failure treated with hemodialysis from 2007 to 2011.</p>

<p><strong>INTERVENTION: </strong>A retrospective review of all patients requiring hemodialysis from 2007 to 2011 was conduction using the Pediatric Health Information System Database.</p>

<p><strong>MAIN RESULTS: </strong>Over 6% of pediatric patients with acute renal failure treated with hemodialysis were exposed to hemodialysis for over 2 weeks. Cumulative exposure to distinct drugs increased substantially with more prolonged courses of hemodialysis. Of the 50 most frequently prescribed medications in the cohort with acute renal failure treated with hemodialysis, 10% have readily available and easily accessible information to guide dosing adjustments with the use of hemodialysis. Furthermore, only 18% of these medications have clear recommendations for dosing in pediatric patients of all age groups with renal failure.</p>

<p><strong>CONCLUSIONS: </strong>Pediatric patients with acute renal failure managed with hemodialysis are exposed to a broad variety of medications, with a high prevalence of polypharmacy. There is a trend for longer courses of hemodialysis in these patients, which leads to an increase in cumulative drug exposure, complexity of drug interactions, and potential toxicity. For the vast majority of medications that are being used to treat this complex patient population, pediatric dosing guidance is not easily accessible. These findings underscore the need for targeted pharmacologic studies of medications used in the pediatric population managed with hemodialysis.</p>