Evaluation of Ceftaroline Use in Pediatric Patients: A Retrospective Case Series

Abstract

Background/Objectives: Ceftaroline (CPT) is a broad-spectrum, fifth-generation cephalosporin with in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and drug-resistant Streptococcus pneumoniae. Real-world data on its use in pediatric patients remain limited. This study aimed to the describe clinical characteristics and outcomes associated with CPT use in pediatric patients at a pediatric academic medical center. Methods: This retrospective case series evaluated patients under 18 years of age who received CPT between November 2016 and August 2023. The primary outcome was clinical success, defined as a composite of 30-day survival, absence of microbiological recurrence within 30 days, and/or resolution of acute infection signs and symptoms without therapy modification due to clinical failure. The secondary outcomes included adverse effects potentially attributable to CPT and the clinical rationale guiding its use. Results: Among 25 patients, most were male (68%) with a median (IQR) age of 3.4 (1.4–14.3) years. The indications for use commonly included respiratory infections (48%), bacteremia (16%), and/or skin and soft tissue (12%) infections. The frequently used dosing regimens included 12 mg/kg (36%) and 8 mg/kg (28%) q8hr, with a median (IQR) duration of therapy of 4.6 (1.7–10.0) days. Clinical success was achieved in 96% of patients. No adverse effects attributable to CPT were observed and CPT was commonly used for escalation (40%) and/or issues with alternative therapies (36%). Conclusions: CPT use was associated with high clinical success rates and no observed adverse effects in this pediatric report. These findings support its use as a therapeutic option when the alternatives are limited. Larger multicenter studies are needed to further evaluate the clinical outcomes and safety of CPT use in pediatric patients.

1. Introduction

Antimicrobial resistance (AMR) represents a mounting global health crisis, and its impact on pediatric populations is increasingly evident. Younger children remain particularly vulnerable, with infectious diseases (IDs) and their complications continuing to be a leading cause of morbidity and mortality worldwide [1,2]. Despite advances in antimicrobial development, pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and drug-resistant Streptococcus pneumoniae (DRSP) continue to pose significant risks to both adult and pediatric patients and are both classified as serious threats by the Centers for Disease Control and Prevention (CDC) [3,4,5,6]. Although vancomycin remains a first-line parenteral agent for invasive infections, its use is complicated by the need for therapeutic drug monitoring to ensure efficacy and to minimize nephrotoxicity [7]. Second-line agents, such as daptomycin and linezolid, are also associated with notable adverse drug reactions and other limitations [6,8,9,10,11]. These challenges underscore the urgent need for pediatric-specific data to guide antimicrobial selection, dosing strategies, and clinical outcome optimization in the treatment of resistant Gram-positive infections [6].

Ceftaroline fosamil, the prodrug of ceftaroline (CPT), represents a paradigm shift within the beta-lactam class as a fifth-generation cephalosporin exhibiting a uniquely broad-spectrum of activity, including against MRSA [12,13,14,15,16]. CPT’s distinctiveness is attributed to its unique structure, which enables binding to penicillin-binding protein 2a (PBP2a), the modified PBP responsible for conferring beta-lactam resistance in MRSA [12]. CPT also demonstrates potent in vitro activity against DRSP, some Enterobacterales, Haemophilus influenzae, and Moraxella catarrhalis [12,14,15,16]. Approved by the United States (U.S.) Food and Drug Administration (FDA) in 2010, CPT was initially indicated in adults for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Its pediatric indications followed in 2016 and 2019, extending its use to children at least 34 weeks gestational age and 12 days postnatal age for ABSSSIs and two months of age and older for CABP [17]. Since its approval, CPT use in pediatric patients has progressively increased due to its potent in vitro activity and favorable efficacy and safety compared to conventional first- and second-line agents [12,13,14,15,16,17,18,19,20,21,22].

While extensive real-world evidence supports CPT use in adults, the data characterizing its utilization and clinical success in pediatric patients remain limited [19,20,21,22,23,24,25,26]. Therefore, this study aimed to characterize contemporary CPT use, including the clinical features and treatment outcomes of pediatric patients treated with CPT.

2. Results

A total of 25 patients were included in this evaluation, who were predominantly white (11/25, 44%) and male (17/25, 68%), with the median (IQR) age of patients being 3.4 (1.4–14.3) years. Most of the patients were admitted to the intensive care unit (ICU), with 14/25 (56%) receiving care in the pediatric intensive care unit. Notably, 15/25 (60%) patients had at least one risk factor for MRSA, with prior antibiotic exposure within 12 months and long-term central venous access within 12 months being the most common, both present in 11/25 (44%) patients. Respiratory infections constituted the most frequent primary diagnosis (12/25, 48%), followed by bacteremia (4/25, 16%) and skin and soft-tissue infections (3/25, 12%). Source control procedures were performed and achieved in nearly half of the population (11/25, 44%), including debridement in 3/25 (12%) and incision and drainage procedures in 2/25 (8%). All the baseline characteristics and diagnoses can be found in

Table 1. Baseline characteristics.

Parameters	n = 25
Male	17 (68)
Age, years, median (IQR)	3.4 (1.4–14.3)
Age < 2 years	8 (32)
Age 2–11 years	10 (40)
Age 12–17 years	7 (28)
Weight, kg, median (IQR)	15.7 (10.7–54.4)
Race
White	11 (44)
Black	9 (36)
ICU Admission
PICU	14 (56)
PCICU	1 (4)
NICU	1 (4)
MRSA Risk Factors
Hospitalization within 12 months	9 (36)
Antibiotic exposure within 12 months	11 (44)
MRSA colonization or infection within 12 months	0 (0)
Invasive procedures within 12 months	6 (24)
Long-term central venous access within 12 months	11 (44)
Prior ABSSSI within 12 months	0 (0)
Vital Signs and Laboratory Values *, median (IQR)
Temperature, °Celsius	37.2 (36.7–37.9)
HR, beats per minute	126.0 (115.0–155.0)
RR, breaths per minute	26.0 (24.0–36.0)
WBC, ×109/L	8.2 (6.2–17.0)
CRP, mg/L ^	12.8 (11.8–17.2)
Procalcitonin, ng/mL ^^	0.4 (0.3–3.9)
SCr, mg/dL ^^^	0.5 (0.3–0.7)

Data reported as n (%) unless otherwise noted. * Time of index culture collection or antibiotic initiation (whichever occurred sooner). ^ Data reported for seven patients. ^^ Data reported for six patients. ^^^ Data reported for 23 patients. IQR: interquartile range; kg: kilograms; ICU: intensive care unit; PICU: pediatric ICU; PCICU: pediatric cardiac ICU; NICU: neonatal ICU; MRSA: methicillin-resistant Staphylococcus aureus; ABSSSI: acute bacterial skin and skin structure infection; HR: heart rate; RR: respiratory rate; WBC: white blood cell count; CRP: C-reactive protein; SCr: serum creatinine.

and Figure 1, respectively.

Among those patients with positive cultures, MRSA and Streptococcus species were commonly isolated organisms (Figure 2). Antimicrobial susceptibility testing revealed a vancomycin minimum inhibitory concentration (MIC) of 1 mg/L in all MRSA isolates, while CPT susceptibility was only reported for a single MRSA isolate that exhibited an MIC of 0.5 mg/L.

All the patients received a consultation from pediatric ID, with most CPT initiations (22/25, 88%) being recommended by pediatric ID. Prior to CPT administration, 22/25 (88%) patients had been treated with other antibiotics and the median (IQR) duration of antibiotic therapy prior to CPT initiation was 73.0 (20.9–139.8) hours. Most patients received CPT 12 mg/kg q8h (9/25, 36%) or 8 mg/kg q8h (7/25, 28%) for a median (IQR) total treatment duration of 4.6 (1.7–10.0) days. All other infection and treatment characteristics can be found in

Table 2. Infection and treatment characteristics.

Parameters	n = 25
Hospital length of stay, days, median (IQR)	10.0 (7.8–34.8)
Pediatric ID consult	25 (100)
CPT recommended from pediatric ID	22 (88)
Antibiotics received prior to CPT initiation	22 (88)
Total duration of antibiotics prior to CPT initiation (hours), median (IQR)	73.0 (20.9–139.8)
CPT 12 mg/kg q8h	9 (36)
CPT 8 mg/kg q8h	7 (28)
Duration of CPT, days, median (IQR)	4.6 (1.7–10.0)
Concomitant antibiotics	16 (64)
CPT at discharge	4 (16)

ID: infectious disease; IQR: interquartile range; CPT: ceftaroline.

.

The primary outcome of composite clinical success was achieved in most patients (24/25, 96%), with a single case of 30-day mortality in a patient that underwent a previous hematopoietic stem cell transplantation with bacteremia caused by Rothia mucilaginosa who received combination antibiotic therapy. Furthermore, no adverse events attributable to CPT were identified during the study period. The clinical rationale for CPT utilization is shown in Figure 3.

3. Discussion

This retrospective, real-world study evaluated the clinical use and associated outcomes in children treated with CPT for serious infections. These findings demonstrate that CPT was associated with high rates of clinical success and was found to be safe. These results reinforce CPT’s emerging role as an antimicrobial option in children, particularly when historical first-line agents are limited by toxicities, drug–drug interactions, contraindications, and/or clinical failure.

Vancomycin remains the gold-standard first-line therapy for most invasive Gram-positive infections in both adult and pediatric patients [27,28,29]. However, complications of vancomycin include nephrotoxicity, infusion-related reactions, and the need for therapeutic drug monitoring [28]. Daptomycin represents an effective alternative to vancomycin; however, its use in certain populations is constrained by several factors, including its inactivation by pulmonary surfactant, rendering it ineffective for the treatment of pneumonia, as well as the risk of myopathy, which necessitates the regular monitoring of creatine phosphokinase levels [8]. Although linezolid is frequently employed in the management of resistant Gram-positive infections, its use is constrained by adverse effects linked to prolonged therapy, as well as some clinician hesitation regarding its bacteriostatic activity and potential interactions with serotonergic medications [9,10,11]. These limitations underscore the need for efficacious alternatives with more favorable profiles.

Ceftaroline has demonstrated potent in vitro activity with high rates of susceptibility noted against various Gram-positive organisms, including MRSA and DRSP [15,16]. Importantly, previous population pharmacokinetic modeling studies have further supported CPT’s use in pediatrics, with comparable exposure profiles to adult regimens [30,31]. Furthermore, several pediatric trials have evaluated CPT use, including in ABSSSI and CABP. These trials, which included children aged 2 months to 17 years, demonstrated similar efficacy and safety outcomes between CPT and comparator agents [32,33,34].

Although CPT has been studied in children with cystic fibrosis, robust real-world data in the broader pediatric population remain notably limited [19,20,21,22]. In one retrospective chart review involving 180 cystic fibrosis patients (50% receiving CPT) aged 0 to 21 years, CPT was compared to vancomycin, with no significant differences observed between the two agents in terms of mean change in forced expiratory volume in one second (FEV₁) or hospital readmissions [19]. In another study of 16 pre-term infants with late-onset staphylococcal sepsis that failed vancomycin therapy, clinical success rates were approximately 70%, with no severe adverse drug reactions reported [20]. In contrast, there are numerous, large, real-world studies in adult populations that have provided supportive evidence of CPT’s effectiveness in treating complicated ABSSSIs, pneumonia, and bloodstream infections, with high clinical response rates observed [23,24,25,26].

Although limited by its retrospective design, single-center setting, and absence of a comparator group, this study offers valuable insights into the high clinical success rates, safety, and current prescribing practices of CPT at a pediatric academic medical center. Other limitations include potential overestimation of clinical success due to untracked readmissions at external facilities, the lack of a minimum CPT duration of therapy, and relatively high rates of combination antimicrobial therapy, which may have inflated the attribution of positive outcomes to the therapy. Furthermore, only one isolate had formal CPT susceptibility testing, yet high clinical success rates were still achieved, which is consistent with the data showing CPT’s potent in vitro activity against commonly encountered drug-resistant Gram-positive organisms [15,16]. Despite these findings, the lack of real-world pediatric studies assessing CPT use outside of clinical trials remains a significant gap. This study contributes novel data on CPT utilization patterns, clinical decision-making, and outcomes in children with serious infections.

4. Materials and Methods

This was a retrospective case series of pediatric patients (age < 18 years) that was conducted at the Medical University of South Carolina (MUSC) Health. Pediatric patients who received CPT at the Children’s Hospital between November 2016 and August 2023 were eligible for inclusion. The decision to initiate CPT, as well as its duration, was made at the discretion of the treating clinician(s), based on the presumed overall clinical picture, as well as the suspected or confirmed pathogen(s) and infectious source(s). The dosing of CPT was based off the prescribing information, adjusted for age, weight, renal function, and indication, at the discretion of the treating provider(s) [17].

The primary outcome was a composite measure of clinical success, defined by 30-day survival, the absence of microbiologic recurrence within 30 days, and/or the resolution of acute infection signs and symptoms without modifications in therapy due to clinical failure. Modifications for de-escalation or oral step-down therapy were not considered clinical failures. The secondary outcomes included adverse effects and the clinical rationale regarding CPT use. Adverse effects were identified and recorded through review of clinical documentation in the patients’ medical records. Additional variables potentially related to the outcomes were collected and included gender, age, weight, race, intensive care unit admission, MRSA risk factors, vital signs and laboratory values at index culture or initial antibiotic administration (whichever occurred sooner), and hospital length of stay [35,36,37]. The treatment-related variables included prior antibiotic use, CPT dosing and duration, concomitant antibiotic use, and CPT discharge prescriptions.

The rationale for CPT use was categorized based on the documentation provided by the treating clinician(s) and/or the clinical judgement of data abstractors at the time of review. Empiric therapy was defined as the administration of CPT for the treatment of a suspected infection; issues with alternative therapy included variables such as toxicity, drug interactions, and/or contraindications; escalation of care was defined as initiation of CPT in the setting of presumed failure of empiric or targeted therapy; use for potential synergistic effects was based off in vitro data; and consolidation of therapy included when CPT was selected as a continuation agent following initial therapy for streamlining purposes and therapeutic simplification [38,39].

Proportions were used to describe the categorical variables and medians with IQRs were used for the continuous variables. Statistical analyses were performed using Microsoft Excel (version 2502; Microsoft Corporation; Redmond, Washington, DC, USA). The study protocol was submitted to the local institutional review board and was determined to be exempt from full board review.

5. Conclusions

CPT appears to be a well-tolerated and promising therapeutic option in pediatric patients, particularly when conventional therapies are not viable or ideal. Further multicenter, comparative studies are essential to better define the role of CPT in pediatric practice, guide stewardship efforts, and inform evidence-based prescribing in this vulnerable population.