Julie Autmizguine

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin‐structure infections (including those caused by community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA‐MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one‐compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)0.75 × (PMA3.1/(43.63.1 + PMA3.1)); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age‐based dosing.

Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective

Therapeutic drug monitoring (TDM) is necessary for certain drugs to ensure that the levels are sufficient to be effective, but not so high as to cause adverse effects. This review summarizes the literature regarding TDM for newer-generation extended-spectrum triazoles, including when TDM may be necessary for each drug and why, and laboratory techniques used for the measurement of levels of these drugs. The document includes recommendations for the use of TDM for each triazole that is discussed.

Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants

OBJECTIVE: To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants. METHODS: We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort. RESULTS: A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95). CONCLUSIONS: Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.

Staphylococcal infections in infants: updates and current challenges.

Staphylococci are common pathogens in the neonatal period. Increased survival of premature infants leads to prolonged hospital stay with associated risk factors for developing invasive staphylococcal disease. Challenges of diagnosing coagulase-negative staphylococcal infections result in conflicting definitions and inconsistent clinical practice. Resistance to methicillin influences the choice of empirical therapy.

Evaluation of a New Strategy for Clean-Catch Urine in Infants.

BACKGROUND AND OBJECTIVES: A new noninvasive bladder stimulation technique has been described to obtain clean-catch urine (CCU) in infants aged <30 days. Objectives were (1) to determine proportion and predictive factors for successful CCU collections using a stimulation maneuver technique among infants <6 months and (2) to determine the proportion of bacterial contamination with this method. METHODS: A prospective cohort study was conducted in a tertiary pediatric emergency department among infants <6 months needing a urine sample. CCU samples were collected using a standardized stimulation technique. Invasive technique was performed after CCU for three specific conditions. Primary outcomes were proportions of successful CCU specimens and bacterial contamination. We determined associations between successful urine samples and 4 predictive factors (age, sex, low oral intake, and recent voiding). RESULTS: A total of 126 infants were included (64 boys, median age: 55 days). The CCU procedure was effective in 62 infants (49%; median time: 45 seconds). Infants 0 to 29 days; 30 to 59 days, and 60 to 89 days had more successful procedures, compared with infants >89 days (odds ratios [95% confidence interval (CI)]: 4.3 [1.4 to 13.4]; 3.2 [1.2 to 8.4]; and 4.44 [1.5 to 13.3], respectively). The contamination proportion was 16% (95% CI: 8% to 27%) in the CCU group. This proportion was not statistically different compared with the invasive method group (6%, 95% CI: 3% to 15%). CONCLUSIONS: The CCU procedure is a quick and effective noninvasive method in children aged <90 days. Contamination proportions were similar to those reported in the literature for urethral catheterization. Circumstances for which the CCU procedure could be performed are proposed.

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation.

Background: Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK). Methods: To characterize micafungin pharmacokinetics and safety in infants on ECMO, we conducted an open-label pharmacokinetics trial. Infants on ECMO either received intravenous micafungin 4 mg/kg every 24 h for invasive candidiasis prophylaxis or 8 mg/kg every 24 h when a fungal infection was suspected or confirmed. We collected plasma samples after single and multiple micafungin doses. We defined the therapeutic target as the adult exposure associated with efficacy in phase III trials and the prophylactic target as one-half of the therapeutic target. Results: We enrolled 12 infants (124 samples) with a median age of 59 days. Using a 1-compartment model, median weight-normalized volume of distribution and clearance were 0.64 L/kg and 0.041 L/kg/h, respectively. Dose-exposure simulations revealed that doses of 2.5 and 5 mg/kg every 24 h matched exposure targets for prophylaxis and treatment of invasive candidiasis, respectively. We did not observe any drug-related adverse events. Conclusions: In infants on ECMO, micafungin volume of distribution was higher and clearance was in the upper range of previously published values for infants not on ECMO. Based on these data, we recommend dosing of 2.5 and 5 mg/kg every 24 h for prophylaxis and treatment of invasive candidiasis, respectively, to match adult exposure proven effective against Candida spp.

Pharmacokinetics and pharmacodynamics of oral cephalexin in children with osteoarticular infections.

Background: Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection. Methods: Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child’s PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L. Results: Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (T>MIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively. Conclusions: Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.

Posaconazole Plasma Monitoring in Immunocompromised Children

Plasma posaconazole exposure was assessed in 13 children who underwent a hematopoietic stem cell transplant. The median dosage was 12.5 mg/kg per day, divided into 3 doses. Of these 13 patients, 46.2% (6) and 30.8% (4) achieved concentrations higher than 0.7 and 1.25 mg/L, respectively. In children at high risk, a higher dosage might be needed to achieve target concentrations.

Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two of 3 children with a staphylococcal CSF infection had CSF concentrations greater than minimal inhibitory concentration at the end of the dosing interval.

Safety of High-dose Acyclovir in Infants with Suspected and Confirmed Neonatal Herpes Simplex Virus Infections.

Background: Acyclovir is used to treat herpes simplex virus disease in infants. Treatment with high-dose acyclovir, 60 mg/kg/d, is recommended; however, the safety of this dosage has not been assessed in the past 15 years, and this dosage is not currently approved for infants by the US Food and Drug Administration. Methods: We included infants with neonatal herpes simplex virus disease treated with ≥14 days of intravenous acyclovir starting in the first 120 days of life admitted to 1 of 42 neonatal intensive care units managed by the Pediatrix Medical Group between 2002 and 2012. We determined the frequency and proportion of infants with clinical and laboratory adverse events (AEs) as well as the number and proportion of infant days with laboratory AEs occurring during acyclovir exposure. Results: We identified 89 infants during the study period with 1658 days of acyclovir exposure. Almost all received high-dose acyclovir therapy (79/89, 89%). The most common clinical AEs were hypotension and seizure, both occurring in 9% of infants. Thrombocytopenia was the most common laboratory AE occurring in 25% of infants and on 9% of infant-days. Elevated creatinine occurred in 2% of infants and 0.2% of infant-days and no infants developed renal failure requiring dialysis. Overall, 45% of infants had ≥1 AE. Conclusions: In this cohort of infants treated during the high-dose acyclovir era, AEs were common but usually not severe. Many of the AEs reported in this cohort may be related to the underlying infection rather than due to acyclovir exposure.