A 2024 systematic review and meta-analysis evaluated the efficacy and safety of extended infusion of beta-lactams and glycopeptides in pediatric patients. Following Cochrane standards, the analysis included randomized controlled trials and observational studies comparing continuous infusion (COI) or prolonged infusion (PI) to intermittent administration (IA) of these antibiotic classes. The primary outcomes assessed were mortality, clinical success, and microbiological eradication. Five studies met the inclusion criteria for mortality, investigating meropenem, piperacillin/tazobactam, cefepime, or combinations of these agents. The pooled relative risk estimate for mortality was 0.48 (95% CI 0.26 to 0.89; p= 0.02), indicating a statistically significant reduction in mortality with extended infusion of beta-lactams. No significant differences were observed for clinical success or microbiological eradication. Despite these promising results, the overall certainty of evidence was rated as very low due to methodological limitations, including the predominance of non-randomized studies. Future randomized controlled trials focusing on critically-ill pediatric patients are necessary to further validate the observed benefits of extended infusion strategies. [1]
Another 2024 systematic review and meta-analysis evaluated the impact of prolonged beta-lactam infusions on clinical outcomes in children with suspected or confirmed bacterial infections. The analysis included 13 studies encompassing 2,945 pediatric patients, with five randomized controlled trials (RCTs) and eight observational studies. Eligible studies involved children under 18 years receiving beta-lactam extended or continuous infusions (cefepime, cefotaxime, piperacillin/tazobactam, meropenem) compared to standard intermittent infusions. The included populations varied widely, encompassing critically ill patients, febrile neutropenia, bacteremia, late-onset neonatal sepsis, cystic fibrosis exacerbations, and multidrug-resistant Gram-negative infections. A meta-analysis of RCTs involving 1,464 children demonstrated no significant reduction in mortality with prolonged infusions (risk ratio [RR] 0.93, 95% CI 0.71-1.21), while observational data from 833 pediatric patients suggested a potential mortality benefit (RR 0.43, 95% CI 0.19-0.96). No significant differences were identified in hospital length of stay (LOS) (mean difference -0.13 days, 95% CI -3.64 to 3.37). Heterogeneous definitions of microbiological and clinical cure precluded pooled analyses. Some individual studies reported improved clinical and microbiological outcomes with prolonged infusions, particularly in critically ill neonates with Gram-negative sepsis and children with multidrug-resistant infections. However, substantial variability in study designs, inclusion criteria, and definitions of outcomes limited the strength of conclusions. Of note, five studies involved piperacillin/tazobactam either as monotherapy or in combination with other beta-lactams in intervention arm (see Table 1). [2]
Additional studies have evaluated population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in pediatric patients. A 2015 study utilized a Monte Carlo simulation to estimate pharmacokinetic profiles of various dosing regimens using serum samples from children hospitalized in an intensive care unit. Patients were administered piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 hours infused over 4 hours. Assessed dosing regimens included 80 to 100 mg/kg of piperacillin component given every 6 to 8 hours and infused over 0.5, 3, or 4 hours. The analysis revealed weight to be significantly associated with clearance of piperacillin, while both weight and sex were associated with clearance of tazobactam. For piperacillin and tazobactam, respectively, clearance was calculated to be 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, while volume of distribution was 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg. All extended-infusion regimens achieved probability of target attainment (PTA) > 90% at minimum inhibitory concentration (MICs) of ≤16 mg/liter. Results concluded piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 hours and infused over 4 hours are likely to result in adequate pharmacodynamic exposures in critically ill children. [3]
Another study was conducted in 79 children with normal renal function who were prospectively studied after receiving piperacillin-tazobactam dose of 80 mg/kg of body weight every 6 hours infused over 2 hours (for those aged 2 to 5 months) or a dose of 90 mg/kg every 8 hours infused over 4 hours (ages 6 months to 6 years). In this study, optimal dosing regimens based on the piperacillin component, were 75 mg/kg/dose every 4 hours infused over 0.5 hours in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 hours infused over 4 hours in children ages >6 months to 6 years, with MICs up to 16 mg/liter. Finally, another prospective randomized study compared the plasma piperacillin concentrations at the mid-dosing intervals (Cmid, 50% fT) and the proportion of patients achieving 50% fT>MIC between extended infusion and intermittent bolus in 90 pediatric patients. Piperacillin-tazobactam was dosed at 100 mg/kg intravenously every 8 hours, administered over either 4 hour infusion or 30 min infusion. Extended infusion was associated with a higher-trending proportion of patients who achieved 50% fT>4xMIC compared to intermittent bolus (72.7% vs. 30.0%; p= 0.06). While the difference was not significant, results suggest piperacillin-tazobactam administered over extended infusion may be beneficial in settings with increased piperacillin MICs. [4], [5]
Other studies investigate the efficacy of continuous infusion of piperacillin-tazobactam, albeit not specifically denoted as an extended infusion. One 2019 randomized controlled trial in a Mexican pediatric hospital compared continuous (300 mg/kg/day piperacillin at a fixed rate over 24 hours) versus intermittent piperacillin/tazobactam infusion in children with febrile neutropenia, analyzing 176 episodes and finding no significant differences in treatment failure (21% vs. 13%; p= 0.15), fever resolution within 48 hours (45%), clinical improvement by 72 hours (80% vs. 73%), or mortality (one death per group), suggesting no clear therapeutic advantage of continuous infusion over intermittent infusion despite pharmacokinetic benefits. However, a 2022 Danish pharmacokinetic study in 38 pediatric oncology patients found that continuous infusion (300 mg/kg/day piperacillin at a fixed rate over 24 hours) achieved optimal probability of target attainment (PTA) of 100% fT above MIC at 300–400 mg/kg/day, whereas intermittent and extended infusion failed, reinforcing continuous infusion’s pharmacokinetic superiority for optimizing β-lactam exposure against less susceptible pathogens in this high-risk population. [6], [7]