Background Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of gram-negative organisms as a cause of early-onset sepsis and gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs. Methods We analyzed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010. Results Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval 1.21, 1.73], and OR 1.30 [95% CI 1.21, 1.40], respectively). Conclusions This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.

Purpose Extracorporeal Membrane Oxygenation (ECMO) is a cardiopulmonary bypass device that is used to temporarily support the most critically ill of patients with respiratory and/or cardiac failure. Infection and its sequelae may be an indication for ECMO or infections may be acquired while on ECMO, and are associated with a mortality of greater than 50%.1 Effective therapy requires optimal dosing. However, optimal dosing can be different in patients on ECMO, because the ECMO circuit can alter drug pharmacokinetics. This review assessed the current literature for pharmacokinetic data and subsequent dosing recommendations for anti-infective drugs in patients on ECMO. Methods We searched the PubMed and EMBASE databases (1965 to February 2016) and included case reports, case series, or studies that provided pharmacokinetic data for anti-infective drugs including antibiotics, antifungals, and antivirals being used to treat patients of all age groups on ECMO. Pharmacokinetic parameters and dosing recommendations based on these data are presented. Findings The majority of data on this topic come from neonatal studies of antibiotics from the 1980s and 1990s. These studies generally demonstrate a larger volume of distribution (V) due to ECMO and therefore, higher doses are needed initially. More adult data is now emerging, but with a predominance of case reports and case series without comparison to critically ill controls. The available pharmacokinetic analyses do suggest that V and clearance (CL) are unchanged in the adult population and therefore dosing recommendations largely remain unchanged. There are a lack of data in children >1 year of age. The data support the importance of therapeutic drug monitoring (TDM) when available in this population of patients. Implications This review found reasonably robust dosing recommendations for some drugs and scant or no data for other important anti-infectives. In order to better determine optimal dosing on ECMO, a systematic approach is needed. Approaches that combine ex vivo ECMO experiments, animal studies, specialized pharmacokinetic modeling, and human clinical trials are being developed.

ObjectiveHistorically, management of infants with fever without localizing signs (FWLS) has generated much controversy, with attempts to risk stratify based on several criteria. Advances in medical practice may have altered the epidemiology of serious bacterial infections (SBIs) in this population. We conducted this study to test the hypothesis that the rate of SBIs in this patient population has changed over time.Patients and MethodsWe performed a retrospective review of all infants meeting FWLS criteria at our institution from 1997–2006. We examined all clinical and outcome data and performed statistical analysis of SBI rates and ampicillin resistance rates.Results668 infants met criteria for FWLS. The overall rate of SBIs was 10.8%, with a significant increase from 2002–2006 (52/361, 14.4%) compared to 1997–2001 (20/307, 6.5%) (p = 0.001). This increase was driven by an increase in E. coli urinary tract infections (UTI), particularly in older infants (31–90 days).ConclusionsWe observed a significant increase in E. coli UTI among FWLS infants with high rates of ampicillin resistance. The reasons are likely to be multifactorial, but the results themselves emphasize the need to examine urine in all febrile infants <90days and consider local resistance patterns when choosing empiric antibiotics.

f Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of <30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (<32 mg/liter) for 75% of the dosing interval. P iperacillin-tazobactam is approved by the U.S. Food and Drug Administration for the treatment of adults and children of Ͼ2 months of age with infections due to susceptible bacteria; however, the drug is not approved for use in younger infants, including those born prematurely. In spite of this, piperacillin-tazobactam is extensively used "off-label" in young infants for treatment of systemic infections, including bacteremia and complicated intra-abdominal infections, such as necrotizing enterocolitis (1). Because these infections in premature infants are associated with devastating outcomes, such as death and neurodevelopmental impairment (2, 3), appropriate dosing recommendations for agents such as piperacillin-tazobactam are needed. Recommended piperacillin-tazobactam dosing for young infants in sources like Neofax (4) and The Harriet Lane Handbook (5) rely on combinations of birth weight, gestational age, postmenstrual age (PMA), and postnatal age (PNA), which are cumbersome to implement clinically and more importantly are supported by very small and limited clinical trials in this population.The pharmacokinetics (PK) of piperacillin-tazobactam has not been well characterized for premature infants. The drug is primarily renally eliminated by glomerular fi...