Stewardship Challenges, PK/PD Evidence, and Prescribing Appropriateness of Recently Approved Antibiotics in Pediatric Practice

1. Introduction

1.1. A Dire Need

Rising antimicrobial resistance represents one of the most consequential threats to child health worldwide. Over the past two decades, the incidence and clinical impact of multidrug-resistant (MDR) bacterial infections in pediatric populations have increased across different geographic regions and care settings [1]. Carbapenem-resistant Enterobacterales (CRE) [2], extended-spectrum beta-lactamase–producing (ESBL) Enterobacterales [3], and methicillin-resistant Staphylococcus aureus (MRSA) [4] now account for a growing share of severe community-acquired and healthcare-associated infections in neonates, infants, and older children [5].

These organisms are associated to higher morbidity and mortality, longer hospital stays, greater need for intensive care and invasive support, and substantially increased healthcare costs compared with susceptible pathogens. In low- and middle-income countries the burden is worsened by limited access to diagnostics, intensive care, and newer therapeutic agents, producing stark disparities in outcomes between regions [6]. Despite the rising need of new therapeutic agents in the pharmacological armamentarium to treat MDR infections in younger patients, a persistent “pediatric gap” exists in the antimicrobial pipeline approval.

1.2. The Pediatric Gap

Historically, antibiotics, just like most classes of drugs, are developed and approved first in adult population, with pediatric indication and/or formulations often following years later.

Nonetheless, over the past 30 years, regulatory requirements have required and incentivized pediatric research: FDA enacted the Pediatric Research Equity Act in 2003, and EMA established the Paediatric Regulation in 2007. Regulatory agencies have been using the colloquially known scheme of the “carrot and the stick” approach: they require pediatric studies for certain new drugs and biologic products, as well as new indications that are likely to be used in children, while sponsors and pharmaceutical companies may apply for incentives, such as a 6-month extension of market exclusivity of the drugs for voluntarily conducting requested pediatric trials (in the United States), as well as a 2 year extension of market exclusivity for pediatric orphan drugs that fully comply with the EMA’s Paediatric Investigation Plan (in Europe) [7,8].

Nevertheless, many new agents still lack timely pediatric pharmacokinetic (PK), safety, and dosing data at the time of adult approval, as they are often granted a deferral for pediatric studies until there are sufficient data to demonstrate the safety and efficacy of the products in an adult population: this happens in practice in over 80% of cases [9]. This time lag means clinicians often must rely on extrapolated adult data, off-label use, or compassionate-use programs to treat children with MDR infections. The consequence is either delayed access to potentially superior agents or empiric use of older, less safe drugs with suboptimal efficacy.

And while extrapolation of adult efficacy data remains important to minimize the need for pediatric efficacy trials, indication-specific, dose-finding and safety pediatric trials are still crucial to offer the best standard of care in the youngest patients, who deserve population-specific high-quality evidence.

1.3. Uniquely Pediatric Challenges and How to Do Better

Pediatric trials aside, many challenges to precise pediatric dosing definition remain. From a developmental standpoint, maturation of absorption, distribution, metabolism, and excretion (ADME) systems varies markedly from the preterm neonate through adolescence, needing age-stratified PK and pharmacodynamic (PD) studies. Although physiological maturation continues throughout childhood and adolescence, the most pronounced differences from adults are observed during the neonatal and infant periods.

Renal function, in particular, exhibits marked day-to-day maturation variability: glomerular filtration rate increases rapidly during the first two weeks of life, followed by a more gradual rise, reaching adult values between 8 and 12 months of age [10]. Similarly, tubular secretion is immature at birth and progressively matures throughout the first year of life.

Total body water and extracellular fluid volume are higher in neonates (>70%), influencing hydrophilic drug distribution) [11,12], while fat composition rises with age and affects lipophilic drug distribution and absorption. Plasma protein binding is reduced in neonates, which can increase free (active) drug fractions. Hepatic enzyme systems (cytochrome P450 isoforms) and excretion systems (UGTs) mature at different rates, producing non-linear and age-dependent changes in clearance that may hinder and complicate simple weight-based scaling from adult doses [13]. In addition, disease-specific factors — such as sepsis-associated capillary leak, altered organ perfusion, or concurrent illnesses [12,14,15]— further modify pharmacokinetics in acutely ill children.

Safety profiling also requires age-tailored approaches. Dose-limiting toxicities observed in adults may present differently in children, and developmental toxicity (for example, effects on bone growth or neurodevelopment) can have long-term consequences that are not evident in short adult trials. Short-term clinical endpoints used in adult antibiotic trials (time to clinical stability, 28-day mortality) may be less informative in pediatric studies where baseline mortality is lower, and functional outcomes, growth, and developmental milestones may be more relevant [16].

Finally, practical challenges — such as limited blood volume available for PK sampling and lower prevalence of target infections in single centers — complicate trial logistics and increase the need for novel trial designs, such as sparse sampling, population PK modeling, adaptive trials, and international multicenter collaboration [13].

The convergence of a rising pediatric MDR burden, delayed pediatric access to new antimicrobials, and unique developmental pharmacology creates an urgent need for strategies that accelerate safe pediatric evaluation and access. These strategies include earlier inclusion of pediatric cohorts at least during late efficacy or phase IIIb trials (to also monitor potential pediatric-specific safety concerns), use of innovative PK/PD algorythms and modeling approaches to inform dosing, and harmonized regulatory requirements across jurisdictions and countries.

Addressing these gaps is essential to ensure that children may benefit at least from the same modern scientific and therapeutic advances as their adult counterparts, hopefully tailored to their unique needs.

2. Advanced Cephalosporins

2.1. Ceftaroline Fosamil

Ceftaroline is known as a novel “fifth-generation” cephalosporin that shows in vitro bactericidal activity against MRSA [17], and is also active against other common bacteria in the pediatric population, such as S. pneumoniae, S. pyogenes, Haemophilus influenzae and Moraxella catarrhalis [18]. Nevertheless, it does not exhibit activity against Gram-negative bacteria producing ESBL or carbapenemase [19].

It was initially approved in the European Union and the United States for the treatment of adults with complicated skin and soft tissue infection (cSSTI)/acute bacterial skin and skin structure infection (ABSSSI) and community acquired pneumonia (CABP) [20,21]. These approvals were subsequently extended, based on additional pediatric studies as part of the PIP, to include pediatric patients aged ≥ 2 months and, more recently, neonates (with ABSSSI only in the United States). [20,21]. European labeling has recently further extended to include high-dose recommendations for pediatric patients aged ≥ 2 months with cSSTI [21].

Ceftaroline has undergone extensive clinical trials in pediatric patients (birth-<18 years), including single-dose PK studies and multiple-dose safety and efficacy studies, though the trials’ primary endpoint was safety, and they were not powered for comparative interferential efficacy analysis. Across phase II/III-IV trials in patients aged ≥ 2 months to less than 18 years with CABP, complicated CABP, or ABSSSI, ceftaroline fosamil demonstrated generally similar clinical efficacy to standard comparator treatments, as well as adverse events incidence and therapeutic failure rates [22]. No new safety concerns were identified, and patterns of treatment-emergent adverse events were similar to those reported in pooled analysis of the trials in adults [23]. In a phase II, open-label, non-comparative trial in children <2 months of age with late-onset sepsis, the safety and tolerability of ceftaroline fosamil was consistent with previous data in older children and adults [24].

A recent study carried out on a population of 20 children with cystic fibrosis showed, through 160 measured serum concentrations and 119 urine concentrations, that pediatric patients with cystic fibrosis have a higher ceftaroline clearance than those without, and may therefore benefit from higher doses, though no standard regimen has been established yet [25]. Further studies would be useful to establish a specific optimal dosing, as S. aureus is the most commonly isolated organism in the early course of the disease and therefore ceftaroline may be an interesting candidate for such population.

In line with other beta-lactam antibiotics, the percentage of time that free drug concentrations are above the bacteria MIC during a dose interval (fT > MIC) has been shown to be the PK/PD index associated with efficacy [26].

Although ceftaroline standard dose regimens (6 mg/kg every 8 h by 60-minute infusion) are appropriate for most patients, in Europe, adult and pediatric high-dose regimens with longer 2 h infusions are approved for patients aged ≥ 2 months with cSSTI caused by rare S. aureus isolates with ceftaroline fosamil MICs of 2-4 mg/L [21]. In addition, the European label, but not the United States label, includes recommended ceftaroline dose adjustments for pediatric patients with impaired kidney function (estimated creatinine clearance ≤ 50 mL/min [21]. Finally, a high-dose regimen (15 mg/kg, or 600 mg if weighing >40 kg infused over 120 minutes every 8 hours) for treatment of hematogenously acquired S. aureus osteomyelitis has been studied in children aged 1 to 17 years [27], though this indication is currently off-label.

In fact, ceftaroline has long been used, both in adult and pediatric populations, for off-label indications, such as bacteremia, osteomyelitis, septic arthritis, sepsis, endocarditis, meningitis, device infections, nosocomial pneumonia [28], with clinical success.

2.2. Ceftobiprole

Ceftobiprole medocaril is a broad-spectrum fifth-generation cephalosporin with activity against both Gram-positive and Gram-negative bacteria. Its activity against methicillin-resistant Staphylococcus aureus (MRSA) is mediated by high-affinity binding to PBP2a, and its spectrum also includes Pseudomonas aeruginosa, Streptococcus pneumoniae, and Enterococcus faecalis. This dual coverage supports its use in selected severe infections in which simultaneous activity against resistant Gram-positive and Gram-negative pathogens is clinically relevant [29].

As with other beta-lactams, the primary pharmacodynamic determinant of ceftobiprole efficacy is the percentage of the dosing interval during which free-drug concentrations remain above the minimum inhibitory concentration (%fT>MIC). The conservative PK/PD target used in pediatric development was based on maintaining free-drug concentrations above an MIC of 4 mg/L, corresponding to the EUCAST non-species-specific PK/PD breakpoint [30,31].

Pediatric phase III and pharmacokinetic (PK) studies have included neonates, infants, children, and adolescents. Across these studies, ceftobiprole showed low protein binding, minimal metabolism, and predominantly renal elimination. As in adults, peak plasma concentrations were achieved at the end of infusion, and accumulation after repeated administration was minimal because of its relatively short elimination half-life [30,32]

A randomized phase III trial involving hospitalized patients aged 3 months to <18 years with CAP or HAP found ceftobiprole has a clinical response comparable to standard-of-care cephalosporins [33]. This led to the support of the pediatric use of ceftobiprole. It has been demonstrated that pediatric exposure profiles are generally comparable to those observed in adults. Across pediatric age groups, median half-life values ranged from approximately 1.9 to 2.9 hours, whereas overall exposure overlapped substantially with adult values. Importantly, the lowest observed %fT>MIC remained above 50%, suggesting adequate PK/PD target attainment throughout childhood [32].

Population pharmacokinetic modelling subsequently integrated data from patients from birth to 17 years of age. Body weight and renal function were identified as the main determinants of interindividual variability. Model-informed simulations suggest that 15 mg/kg every 12 hours in neonates and infants younger than 3 months, and every 8 hours in older pediatric patients, leads to exposures comparable to those observed in adults while maintaining adequate PK/PD target attainment [34,35]

Despite encouraging clinical and PK data, several limitations remain. Pediatric development has primarily focused on pneumonia, leaving limited to no evidence for invasive infections such as bacteremia, endocarditis, osteoarticular infections, and infections occurring in critically ill children receiving extracorporeal support. Furthermore, many pediatric dosing recommendations rely on exposure matching and pharmacometric extrapolation from adult populations rather than large efficacy-driven trials [34].

Overall, ceftobiprole is among the most extensively characterized advanced cephalosporins for pediatric use. Its combined anti-MRSA and antipseudomonal activity, favorable safety profile, and robust PK/PD characterization make it a valuable option when both spectrum components are clinically justified [36,37,38]. Nevertheless, its clinical positioning is less defined in the most complex clinical settings. TDM should be performed in such cases to tailor antibiotic therapy to each specific case and in order to gather further clinical information [32,34].

2.3. Cefiderocol

Cefiderocol is a novel siderophore-conjugated cephalosporin that utilizes a unique “Trojan horse” mechanism, exploiting bacterial active iron transport systems to penetrate the outer membrane of multidrug-resistant (MDR) and carbapenem-resistant Gram-negative pathogens. As a time-dependent antibiotic, its primary PD driver is the percentage of time the free drug concentration remains above the minimum inhibitory concentration (%fT>MIC) [39]. Data from the PEDI-CEFI phase 2 trial (NCT04335539) indicate that weight-adjusted dosing—60 mg/kg (<34 kg) or 2000 mg (≥34 kg) via a 3-hour infusion every 8 hours—achieves steady-state plasma exposures in patients aged 3 months to <18 years comparable to those in adults. These regimens consistently maintain trough concentrations above susceptibility breakpoints, ensuring a high probability of target attainment (100% T>MIC) [40,41].

Further investigations, including the APEKS-PEDI [42] and the neonatal NEO-CEFI [43] studies, are ongoing to refine dosing across pediatric subpopulations, with model-based approaches highlighting the importance of postmenstrual age for PK optimization in neonates [42,43].

Regarding safety, cefiderocol appears well tolerated in children, with a profile consistent with the beta-lactam class. Systematic reviews and trial data report no drug-related serious adverse events, significant hepato-renal toxicity, or clinical laboratory abnormalities [40,44]. A unique, benign pediatric phenomenon is the “red wine urine syndrome”, resulting from cefiderocol’s interaction with iron from blood products [45]. Collective evidence from case reports and systematic reviews suggests that cefiderocol is an effective off-label salvage therapy for life-threatening carbapenem-resistant infections [46,47,48,49], even during extracorporeal support (ECMO/CRRT) [50], though clinicians should remain vigilant regarding pre-existing resistance among metallo-β-lactamase producers and the risk of microbiological relapse in complex settings [51,52].

3. Novel Protected Beta-Lactam Combinations

3.1. Ceftolozane/tazobactam and Ceftazidime/avibactam

Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CAZ/AVI) provide activity against P. aeruginosa, including MDR and difficult-to-treat resistant (DTR) phenotypes, and are used when conventional antipseudomonal beta-lactams are no longer reliable [53,54]. However, they should not be considered interchangeable: C/T is primarily a potent antipseudomonal agent, with ceftolozane retaining activity against isolates with AmpC overexpression, efflux pump upregulation, and OprD loss, whereas CAZ/AVI provides a broader beta-lactamase inhibition profile, particularly against class A carbapenemases such as KPC and class D OXA-48-like enzymes, although remaining inactive against MBLs unless combined with aztreonam [55,56]. In CAZ/AVI, activity against resistant P. aeruginosa is mainly driven by avibactam-mediated inhibition of relevant beta-lactamases, including AmpC-derived cephalosporinases [53,54]. These differences are clinically relevant in children with severe infections, especially in ICU settings, where beta-lactam exposure may be difficult to predict due to factors such as augmented renal clearance, expanded volume of distribution, fluid shifts, or extracorporeal support [57,58].

Both agents have followed the traditional pediatric development pathway for new antimicrobials. For C/T, randomized pediatric trials evaluated C/T versus meropenem in complicated urinary tract infections (cUTI) and C/T plus metronidazole versus meropenem in complicated intra-abdominal infections (cIAI), supporting weight-based regimens in neonates, infants, children and adolescents [59,60]. A dedicated neonatal and young-infant phase I subgroup analysis further suggested that single-dose PK profiles were generally comparable to those of older children and that the drug was well tolerated in this vulnerable population, although the small number of enrolled subjects limits definitive conclusions [61].

For CAZ/AVI, pediatric development includes a phase I PK study, two randomized phase II trials in children aged ≥3 months to <18 years with cUTI and cIAI, and population PK analyses supporting exposure matching with adults [62,63,64,65]. In Europe, CAZ/AVI has also been approved from 3 months of age for cUTI, cIAI, HAP including VAP, bacteremia associated with these infections, and infections due to aerobic Gram-negative organisms with limited treatment options, depending on local regulatory wording [66]. This broader formal indication makes CAZ/AVI particularly relevant when the expected pathogen is a carbapenem-resistant Enterobacterales rather than isolated DTR P. aeruginosa.

For both C/T and CAZ/AVI, dosing in children is driven by time-dependent PD, with fT>MIC as the key exposure parameter. Adequate inhibitor exposure is also essential in beta-lactam/beta-lactamase inhibitor combinations to maintain beta-lactam activity. Therefore, dosing cannot rely on body weight alone, especially in critically ill children, who may require higher PK/PD targets and are at risk of reduced target attainment due to augmented renal clearance or extracorporeal support [58,67].

For C/T, age-based and weight-based dosing strategies for cUTI and cIAI are supported by both population PK analyses and pediatric trials [59,60,68]. For CAZ/AVI, population PK modeling suggests that pediatric regimens can achieve exposures comparable to those in adults, but target attainment may be challenging in critically ill patients, especially when renal clearance is high or when the MIC approaches the susceptibility breakpoint [65]. In these circumstances, prolonged or continuous infusion and TDM, when available, may be useful adjuncts to optimize exposure, although pediatric outcome data remain limited.

Adult comparative evidence remains more extensive than pediatric data for DTR P. aeruginosa, with pediatric experience mainly derived from case reports, series, stewardship cohorts, and reviews. C/T has been used as rescue therapy for MDR P. aeruginosa infections in children, including bloodstream infections, endocarditis, and cystic fibrosis pulmonary exacerbations, due to its potent antipseudomonal activity [69,70,71]. Reduced susceptibility to C/T and CAZ/AVI has been reported in cystic fibrosis isolates even without previous exposure, supporting isolate-specific susceptibility testing rather than reliance on expected activity [72]. CAZ/AVI has broader pediatric real-world experience, particularly in carbapenem-resistant infections and immunocompromised patients [66,73,74].

The main limitation of the pediatric evidence is that registrational trials generally enrolled relatively stable children with cUTI or cIAI and were not designed to evaluate outcomes in the patients in whom these agents are most needed: neonates, critically ill children, patients receiving extracorporeal support, children with cystic fibrosis, hemato-oncologic patients, and those with bloodstream, CNS, bone, joint, or endovascular infections. Much of the evidence in these scenarios remains observational and vulnerable to confounding by indication, concomitant therapy, and source control. A 2026 pediatric systematic review and evidence map found that most available studies were case reports or case series, while randomized trials excluded critically ill children and carbapenem-resistant infections; clinical and microbiological cure were generally high, but the certainty of evidence remains limited [73].

3.2. Carbapenem-Based Combinations

3.2.1. Imipenem/cilastatin/relebactam

Imipenem/cilastatin/relebactam (IMI/REL) is a combination of a carbapenem, a renal dehydropeptidase-I inhibitor, and a novel diazabicyclooctane β-lactamase inhibitor designed to protect imipenem from degradation by Ambler class A (including KPC) and class C (AmpC) β-lactamases, while also restoring activity against certain imipenem-resistant P. aeruginosa strains [74,75]. Pediatric PK and PD evidence has recently advanced through Phase Ib and Phase II/III trials, which collectively established weight-based dosing regimens from birth to <18 years designed to achieve target exposures [76,77,78,79].

In these studies, imipenem achieved a geometric mean percentage of time where unbound plasma concentrations exceeded the MIC (%fT>MIC) of 56.5%–93.7%, consistently surpassing the ≥30% target (at an MIC of 2 μg/mL), while relebactam exposures exceeded the PK/PD target of a free drug AUC/MIC ratio ≥8.0 [78]. Geometric mean AUC₀₋₂₄ values for imipenem and relebactam ranged from 610 to 795 μM⋅hr and 399 to 634 μM⋅hr, respectively, across pediatric cohorts [79]. These PK/PD data support the clinical efficacy observed against multidrug-resistant (MDR) and KPC-producing Enterobacterales, where IMI/REL maintains high in vitro susceptibility (93.5%–100% for KPC-positive isolates) [74,75,76,77,78,79]. Regarding safety, IMI/REL was generally well-tolerated across all pediatric age groups, with a profile comparable to active comparators and consistent with adult safety data [78,79,80]. The majority of reported adverse events were mild to moderate in intensity—most commonly gastrointestinal symptoms such as vomiting and diarrhea—and no study-related deaths or significant new safety signals were identified [80]. These data confirm that weight-based dosing provides a robust PK/PD profile and a safety margin that supports its therapeutic role in treating pediatric resistant infections [78,79,80].

3.2.2. Meropenem/vaborbactam

Meropenem/vaborbactam (MER/VAB) is a combination of a carbapenem and a cyclic boronic acid-based beta-lactamase inhibitor specifically designed to inhibit carbapenemases, such as KPC, thereby protecting meropenem from degradation and restoring its activity against CRE [81,82]. PK characterization in the pediatric population (ranging from 3 months to 18 years) indicates that both moieties follow two-compartment models with first-order elimination, where body weight and creatinine clearance serve as significant covariates [81]. To achieve a probability of target attainment (PTA) ≥90%, current modeling supports a dosing regimen of 40 mg/kg (up to 2 g) administered as a 3.5-hour intravenous infusion every 8 hours for children aged ≥3 months; for neonates and infants under 3 months, extrapolated data suggest a dose of 20 mg/kg [81]. Real-world PK data from a 4-year-old patient confirmed a volume of distribution of 0.59 L/kg and a clearance of 13.1 ml/min/kg, achieving 100% target attainment (T > MIC for 40% of the interval) with a 6-hour dosing frequency [82]. Regarding safety, clinical evidence from pediatric case series and reports—including patients treated for bloodstream infections and intra-abdominal abscesses—indicates the drug is well-tolerated, with no identified adverse drug events or complications reported during treatment or follow-up [82,83]. Ongoing Phase II/III trials, specifically TANGO-KIDS, VABOR-KIDS (NCT06828848), and ML-VAB-201-3248-2 (NCT06672978) are currently further evaluating the safety, PK, and tolerability of the drug in children with complicated urinary tract infections, with further results expected in the near future [84,85,86].

3.3. Aztreonam/avibactam

Aztreonam/avibactam (ATM/AVI) is a fixed-dose combination of a monobactam and a non-β-lactam β-lactamase inhibitor specifically engineered to circumvent resistance in metallo-β-lactamase (MBL)-producing Gram-negative bacteria [87]. At present, clinical data regarding the use of ATM/AVI in pediatric patients are extremely limited. A primary prospective, randomized trial designed to evaluate its efficacy and safety in serious MBL-producing infections (NCT03580044) was terminated prematurely due to recruitment challenges and, according to final results, enrolled no subjects under 18 years of age [88]. Despite this clinical gap, microbiological surveillance through the INFORM Program (2019–2023) demonstrates that ATM/AVI is highly potent against pediatric isolates, inhibiting >99.9% of Enterobacterales at a MIC ≤8 mg/L across various infection types, including pneumonia and UTIs [89]. From a PK/PD perspective, the current dosing framework utilizes a loading dose followed by 3-hour extended infusions to maximize the time-above-MIC, with maintenance doses adjusted every 6 to 8 hours based on renal function (creatinine clearance) [88,90]. The ongoing study NCT05639647 is currently recruiting pediatric participants (9 months to <18 years) to characterize essential population PK parameters, including AUC, clearance, and volume of distribution [90]. Regarding safety, evidence from the adult cohort in NCT03580044 showed that 91.7% of subjects experienced treatment-emergent adverse events (TEAEs), with 41.7% experiencing serious adverse events (SAEs), although many were associated with the underlying disease severity [88]. For the pediatric population, the NCT05639647 protocol specifically monitors the proportion of participants reporting liver injury and acute kidney injury, alongside clinically significant laboratory and vital sign abnormalities, to establish a robust safety profile across different age cohorts [90]. Ongoing pediatric development is guided by the European Medicines Agency’s Paediatric Investigation Plan (PIP) and regulatory requirements to bridge these data gaps and establish formal dosing for children [88,90,91].

4. Long-Acting Glycolipopeptides

Long-acting lipoglycopeptides are increasingly relevant in pediatric infectious diseases because their prolonged half-lives may simplify parenteral treatment, reduce the burden of repeated intravenous administration, and support earlier discharge in selected patients with Gram-positive infections [92,93,94].

Dalbavancin and oritavancin are long-acting lipoglycopeptides whose prolonged half-lives create a clear theoretical advantage for pediatric outpatient parenteral antimicrobial therapy. Among the two agents, dalbavancin has the more robust evidence base, including pediatric population pharmacokinetic modeling, PK/PD target attainment analyses, a phase 3 ABSSSI study, systematic review data, and real-world case series suggesting early discharge and reduced hospitalization [93,94,95]. Oritavancin is also pharmacologically attractive and supported by early pediatric pharmacokinetic data, but its role in children remains investigational due to comparable clinical outcome evidence being still limited [94].

4.1. Dalbavancin

Dalbavancin is the pediatric long-acting lipoglycopeptide with the most substantial evidence base for outpatient parenteral antimicrobial therapy-oriented use. Its main pharmacologic advantage is the prolonged terminal half-life, which supports infrequent dosing and makes it attractive when the clinical goal is to reduce intravenous treatment burden and shorten hospitalization [96]. The recommended dose of dalbavancin is a single dose based on the patient’s age and weight: 22.5 mg/kg up to 6 months old and 18 mg/kg between 6 and 18 years old (maximum 1,500 mg).

The pediatric pharmacokinetic study included 43 children aged 3 months to 11 years and analyzed 311 concentration samples using a three-compartment population pharmacokinetic model. Simulations identified pediatric regimens that achieved adult-like exposure, supporting the feasibility of adult-referenced PK/PD target attainment in children [92,93,97].

This pharmacologic rationale is supported by clinical data. In the pediatric phase 3 ABSSSI study, favorable clinical response at 48-72 hours was observed in 97.4% of children receiving the single-dose regimen and 98.6% receiving the two-dose regimen, with no new safety signals identified [95]. A 2025 systematic review concluded that dalbavancin may be a valuable alternative for pediatric ABSSSIs and selected off-label indications, with the potential to minimize hospital stay [92].

Real-world pediatric reports are consistent with this positioning. A 2024 case series of five children with ABSSSI described dalbavancin as effective and emphasized its role in facilitating early discharge and reducing healthcare burden [98]. Another 2024 report found dalbavancin to be a safe, effective, and convenient alternative in selected children with complicated non-ABSSSI infections [99]. A more recent pediatric series suggested that dalbavancin may also be useful when inpatient or outpatient parenteral therapy is difficult to maintain [100].

Overall, dalbavancin can be positioned in pediatric review articles as the long-acting lipoglycopeptide with the most mature integration of PK, PK/PD, and clinical data. Its greatest practical value appears in ABSSSI/cSSTI and in selected consolidation strategies where simplified dosing may reduce length of stay, facilitate outpatient parenteral antimicrobial therapy, and limit the need for prolonged vascular access [92,93,95,98]

4.2. Oritavancin

Oritavancin shares the same conceptual appeal as dalbavancin because it is also a long-acting lipoglycopeptide with sustained activity against Gram-positive pathogens. Its terminal half-life is approximately 245 hours, which makes it theoretically suitable for outpatient parenteral antimicrobial therapy and for reducing the need for prolonged hospitalization. The recommended dose of oritavancin is 15 mg/kg given as a single dose via intravenous infusion over 3 hours (maximum 1,200 mg).

However, the pediatric evidence base remains much thinner than for dalbavancin. The principal pediatric study retrieved is the ORKIDS pharmacokinetic study, which evaluated a single 15 mg/kg intravenous dose in children and showed that patients aged 6 to less than 18 years had pharmacokinetic profiles similar to adults, whereas children aged 2 to less than 6 years had lower exposure than the adult target range. These findings indicate that pediatric dose optimization is still evolving, particularly in younger children.

Oritavancin should be presented as a promising pharmacologic option rather than a clinically established pediatric OPAT agent. The available literature supports its pharmacokinetic plausibility, but not yet a mature body of pediatric outcome data comparable to dalbavancin [101].

5. Prescriptive Appropriateness & Positioning

On-Label Vs. Off-Label: Navigating the Legal and Clinical Evidence Framework.

Despite regulatory efforts, off-label prescribing remains common in pediatric antimicrobial therapy, particularly for severe infections, rare pathogens, neonates, and newly introduced agents. Its use may be justified when supported by a sound pharmacological rationale and the best available evidence. Treatment decisions should consider microbiological susceptibility, PK/PD data, disease severity, age-appropriate dosing, organ function, and safety monitoring [102,103].

A practical approach to prescribing novel antibiotics in children should combine the traditional principles of antimicrobial stewardship with pediatric pharmacology. The process can be summarized in five sequential steps (Table 1). Pediatric stewardship programs have been associated with reductions in inappropriate antibiotic use, costs, and antimicrobial resistance, and professional societies emphasize that antibiotics should be used only when necessary and, when needed, with the appropriate agent, dose, duration, and route.

Pharmacokinetic models, TDM and early involvement of clinical pharmacologists can be an additional tool to better adapt the therapeutical choice, especially in extremely complex clinical subsets such as augmented renal clearance, organ dysfunction, extracorporeal membrane oxygenation (ECMO), or continuous renal replacement therapy (CRRT) [58].

6. Antimicrobial Stewardship in Pediatrics

6.1. The 3 Right D’s: Right Drug, Right Dose, Right Duration

The “3 D’s” rule remains a practical framework for pediatric antimicrobial stewardship, emphasizing selection of the right drug, dose, duration, and route to optimize outcomes while minimizing adverse consequences. Drug selection should consider likely pathogens, local resistance patterns, site penetration, toxicity, formulation, and patient-specific factors [104,105]. Dose optimization is particularly challenging because developmental physiology and clinical conditions substantially affect PK, supporting individualized dosing strategies [106,107]. Appropriate treatment duration is equally important to reduce unnecessary drug exposure, microbiome disruption, and antimicrobial resistance, with regular reassessment and early discontinuation when appropriate representing key stewardship practices [108].

6.2. Diagnostic Stewardship: Integrating Rapid Molecular Diagnostics with Bedside Prescribing.

Diagnostic stewardship is a key component of pediatric antimicrobial stewardship, as appropriate prescribing relies on accurate and timely microbiological diagnosis. These complementary strategies improve diagnostic accuracy and optimize antimicrobial use [109]. Stewardship teams play a central role in integrating clinicians, microbiologists, pharmacologists and laboratory specialists to translate diagnostic information into appropriate treatment decisions [110].

In practice, diagnostic stewardship involves selecting the right test for the right patient at the right time, avoiding unnecessary testing, and ensuring appropriate interpretation of microbiological results, including rapid molecular diagnostics.

6.3. Reactive Vs. Proactive TDM

TDM in pediatric infectious diseases has evolved from a toxicity-prevention tool into a precision-medicine strategy aimed at optimizing both efficacy and safety. Modern approaches focus on identifying underexposure and achieving PK/PD targets associated with antimicrobial activity [106,111,112]. Given the high PK variability in children due to age, inflammation, organ function, critical illness, and supportive therapies, TDM is increasingly integrated with physiologic, microbiological, and concentration data to guide individualized treatment [113].

The distinction between reactive and proactive TDM represents a major shift in pediatric clinical pharmacology. Reactive TDM is performed after concerns such as toxicity, lack of efficacy, or abnormal concentrations arise, whereas proactive TDM is implemented early in patients at high risk of PK target non-attainment due to age, clinical instability, organ dysfunction, or high PK variability [114]. This approach moves beyond toxicity prevention toward MIC-targeted efficacy, assessing whether drug exposure is sufficient to achieve the desired PK/PD target according to pathogen susceptibility. This is particularly relevant in critically ill children, where underexposure may remain undetected until treatment failure occurs [112,114].

Model-informed precision dosing (MIPD) is a major innovation in pediatric antimicrobial optimization, combining population PK models, patient-specific characteristics, and measured drug concentrations to provide individualized dosing recommendations. Through Bayesian forecasting, prior PK predictions are updated with real-world patient data to optimize therapy [106,111]. Studies suggest that MIPD improves target attainment compared with conventional dosing, often requiring dose or infusion adjustments, highlighting the limitations of standard regimens in achieving PK/PD targets in real-world pediatric practice [106,115].

The future development of MIPD is likely to depend on even more advanced modeling approaches. Tanaka et al. (2025), in their review of physiologically based pharmacokinetic modeling of antibiotics in children, argue that PBPK-based approaches may further improve MIPD by incorporating developmental physiology and, potentially, target-site exposure [113]. Additional feasibility data from pediatric intensive care suggest that MIPD is transitioning from a theoretical concept to a practical clinical tool. Its role may be even more relevant in pediatrics than in adults due to limited pharmacological data and greater PK variability. The combination of TDM and reliable prediction software is increasingly recognized as a valuable support for routine antibiotic optimization beyond research settings [116].

Microsampling represents a promising technology for pediatric TDM and pharmacokinetic research, addressing the limitations of standard sampling strategies due to limited blood volume, repeated venipuncture distress, and logistical challenges [117,118]. Techniques such as dried blood spots and volumetric absorptive microsampling allow quantitative analysis from very small blood volumes, although further validation of blood-to-plasma relationships and therapeutic ranges is needed [117,118,119]. From a stewardship perspective, microsampling is important not only for reducing procedural burden but also because it may enable wider implementation of proactive TDM and precision dosing in settings where conventional repeated sampling is impractical. Moreover, it may streamline monitoring pathways and offer potential economic advantages [117,118,119,120].

6.4. The Pediatrician-Pharmacologist Synergy

The increasing complexity of pediatric antimicrobial therapy makes the partnership between pediatricians and pharmacologists increasingly important. Antibiotic choice, dose optimization, TDM interpretation, Bayesian forecasting, and PK/PD target assessment all require the integration of bedside clinical judgment with advanced pharmacologic expertise [109,111,113,115].

This synergy becomes even more critical in critically ill children, where rapidly changing organ function, inflammation, extracorporeal therapies, and fluid shifts may alter drug exposure in ways that are difficult to anticipate using conventional dosing alone [115,116].

7. The Future Pipeline & Conclusions

In March 2026, the World Health Organization (WHO) published three new target product profiles (TPPs) for antibacterial agents targeting severe MDR infections, including Gram-negative and Gram-positive infections and bacterial meningitis in high-risk populations [121]. The 2025 analysis of antibacterial agents in clinical and preclinical development identified 90 agents in development, but only 15 were considered innovative [122]. These TPPs emphasize the need for new antimicrobials addressing underserved populations, including immunosuppressed patients, the elderly, children, neonates, and patients with complex infections.

Currently, the antibacterial pipeline offers cautious optimism, but it still falls short of the urgent clinical needs of children, especially neonates and infants with multidrug-resistant infections.

Among the agents currently being studied, cefepime/taniborbactam and sulbactam/durlobactam also represent important pipeline candidates as they target resistance mechanisms that are especially relevant in neonatal sepsis, including carbapenem-resistant and metallo-β-lactamase-producing organisms [123], while new interesting antibiotics classes that may revolutionize future antibiotic research and use are bacteriophages and antibodies [122].

Future antibiotic research should therefore shift from a sequential model, in which pediatric studies begin only after adult development is complete, to a parallel model that incorporates pediatric pharmacokinetics, safety, dosing, and formulation work much earlier. WHO specifically emphasized that pediatric antibiotic development lags behind adult development by nearly a decade and that lack of investment, weak trial infrastructure, and missing child-friendly formulations continue to slow access. For pediatric populations, especially neonates, this means trials should be designed around age- and weight-specific cohorts, clinically meaningful endpoints, and formulations suitable for real-world use in both high-resource and resource-limited settings [123].

In conclusion, the use of antibiotics in pediatrics is very widespread, even for newly introduced agents, for which real-world clinical data are still often incomplete or lacking. Moreover, further new agents are planned for commercialization in the coming years, though they may often not be studied in pediatrics. Additionally, the pediatric patient is often very complex due to variability in clinical conditions, which differ from one child to another and can rapidly change over time, significantly impacting pharmacokinetics. In this context, the study and implementation of multidisciplinary stewardship strategies, involving pediatricians, infectious disease specialists, microbiologists, and clinical pharmacologists, is essential to ensure correct and optimized therapy, utilizing tools such as TDM and pharmacokinetic models.