Daptomycin Experience in the Pediatric and Neonatal Population: A Systematic Review

Literature Review.

A literature search was conducted on PubMed MEDLINE (1987–March 2024) using the search terms “daptomycin and pediatrics,” “daptomycin and children,” “cubicin and children,” and “cubicin and pediatrics.” Studies included in the review were limited to those available or translated in English and including patients from birth to 18 years of age. Articles were included if they contained patient data on receiving daptomycin, were randomized controlled trials (RCTs), retrospective analyses (RA), cohort studies, case reports or case series, and patients were less than 18 years of age. Studies performed in vitro or missing dosage information were excluded. A second search was also conducted in Clinicaltrials.gov using the search term “daptomycin,” filtering for subjects 0 to 17 years and completed trials. Article bibliographies from the resulted searches were also reviewed for additional pertinent literature. Assessments of titles, abstracts, and full texts were conducted independently by 2 investigators. Authors worked independently and no automation tools were used. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to identify, screen and select articles.¹¹ See Supplemental Figure.

Data Extraction.

Primary outcome measures of either clinical cure, clinical improvement or microbiological cure were reviewed. Clinical cure was defined based on each study or report’s definition for clinical cure or improvement and was not defined universally or consistently across all studies. Laboratory markers including C-reactive protein (CRP), white blood cells (WBCs), temperature or fever monitoring, and clinical signs and symptoms of infection were all possible factors included in the reported clinical cure. Microbiological cure was defined as the absence of the original microorganism in follow-up cultures or negative cultures. Safety outcomes were also assessed based on the percentage of treatment-related adverse events reported. Laboratory markers such as creatine phosphokinase (CPK) were included if reported. Elevations in CPK due to daptomycin were defined per study. Pharmacokinetic data, dosing and infusion durations were included if provided.

Statistical Analysis.

Data were collected and analyzed using descriptive statistics. For continuous variables, medians, means and ranges were reported where appropriate. Binary variables were described using frequencies and average percentages to show how common each category was reported. Missing data was not included in statistical calculations.

Trials and Retrospective Reviews.

Three randomized controlled trials (RCTs), 2 prospective observational studies, and nine retrospective analyses were included in the review.^12–16 The 3 RCTs compared daptomycin with standard of care (SOC) treatment, most commonly vancomycin.^12–14 As neonatal and infant studies were of particular interest, we identified 7 studies that included children under 1 year of age, 4 of which included neonates.^16–22 Age was typically reported as postnatal age (PNA), with a median age for all studies and case series of 6.5 years. Asfour et al¹⁸ and Mohzari et al¹⁹ were the 2 studies that reported gestational age (GA), of which the median for both studies was 27 weeks.

MRSA and MSSA were the most common organisms with bacteremia and cSSTIs as the most frequently reported types of infection. Other less frequently reported types of infection included bone and joint infections and endocarditis. Dosing ranged from 4 mg/kg/day up to 12 mg/kg/day (including 6 mg/kg/dose twice daily). Dosing varied by age, with most dosing categorized by age similar to FDA-approved prescribing information.¹ While infusion durations were infrequently reported, 4 studies specified infusions consistent with the prescribing information.^1,13–15,18 Tedeschi et al¹⁶ reported using a 3-minute rapid infusion for the 12 patients who received daptomycin. The median duration documented was 12.5 days (range: 1–44 days). Efficacy documented by either improvement or cure across all studies and reviews varied substantially, with a mean of 79.4% (range: 36.7%–100%).

In Bradley et al¹² evaluating the safety and efficacy of daptomycin vs SOC in children with acute hematogenous osteomyelitis, power was not met due to low enrollment to detect noninferiority of clinical improvement by day 5. The RCT by Arrieta et al¹³ evaluated the safety and efficacy of daptomycin vs SOC for children with Staphylococcal bacteremia with safety as the primary outcome. The article by Bradley et al¹⁴ evaluated daptomycin compared with SOC for treatment of cSSTIs. Outcomes were reported for the intention-to-treat (ITT), modified intention-to-treat (mITT), and the clinically evaluable (CE) population.¹⁴ Articles by Arrieta et al¹³ and Bradley et al¹⁴ were both designed with safety as the primary outcome, however these studies were not powered for efficacy or safety.

Of the RCTs reviewed, 87% of patients treated with daptomycin met clinical and/or microbiological cure in the modified intention to treat (mITT) analyses (as defined per study) with a difference in cure rates compared with SOC ranging from −7.9% to 11%. There was no statistically significant difference in efficacy found between daptomycin and the comparator groups among the 3 RCTs.^12–14 Confidence intervals of 95% were reported for primary and secondary outcomes.

Safety data were analyzed descriptively in all 3 studies.^12–14 Treatment-related adverse events were reported with an average of 28.8% with daptomycin and 37% in the SOC comparator studies (8.25% difference). In the RCT by Bradley et al¹² comparing safety of daptomycin (n = 74 patients) with SOC (n = 72 patients) in pediatric patients with osteomyelitis, patients with treatment-related adverse events occurred 6.8% in the daptomycin group vs 18.1% in the comparator group. Patients who discontinued treatment due to at least 1 adverse effect were 1.4% in the daptomycin group vs 9.7% in the SOC group. There were no serious treatment-related adverse effects in the daptomycin group, while 4.2% of the comparator group experienced serious adverse effects such as pyrexia, drug reaction with eosinophilia and systemic symptoms (DRESS) and red man syndrome.¹² Arrieta et al¹³ reported an increase in blood CPK concentrations above the normal range (reported as 39 to 308 U/L) in 7.3% of patients receiving daptomycin (n = 55) vs no increase in CPK concentrations in the SOC (n = 27) group (values ranged from 19 to 545 U/L) however, it was deemed that only 2 cases (3.6%) were attributed to daptomycin therapy. Bradley et al¹⁴ reported increased serum CPK concentrations in 14 (5.5% of daptomycin patients) and 7 (5.3% of the SOC patients). Only 1 case of elevated serum CPK concentration was deemed to be related to daptomycin. In Bradley et al¹² increases in CPK blood concentrations following treatment were reported in 7 (11%) daptomycin patients and 4 (6%) SOC patients, however all were less than or equal to 2.5 times the upper limit of normal and resolved during or following treatment.

In summary of all prospective and retrospective studies, treatment-related or possible adverse effects were reported in 13 of the 14 articles. Adverse effects occurred in an average of 10.2% (range: 0%–65.5%) of patients. Whereas 7 of the 8 studies that included infants (n = 7) and/or neonates (n = 4) reported an average of 4.2% of treatment-related adverse events (range: 0%–11.1%). A significant increase in CPK concentrations as defined per study, was reported an average of 2.8%. Significant increases in CPK varied per study from greater than 1 to greater than 2.5 times the upper limit of normal (ULN) from baseline during daptomycin therapy. A rise in CPK was not confirmed to be caused by daptomycin in any of the patients.^12–25

Case Reports.

Twenty-seven case reports (Table 2) were identified for this review.^{26–33,36–52} Of the 27 published case reports, 13 (48%) were of children under 1 year of age. The median age reported was 1.73 years (range 13 days–16 years). If GA was reported, it was included within Table 2. The most common organisms identified were MRSA (n = 11), VRE (n = 8) and CoNS (n = 7), specifically S epidermidis (n = 5) and the most treated infections were bacteremia (n = 16), endocarditis (n = 7), and cSSTIs (n = 5). Median daptomycin dosing used was 10 mg/kg/day (range: 4–15 mg/kg/day). In the subset of children less than 1 year of age, the most common dose of daptomycin was 12 mg/kg/day, typically divided into 6 mg/kg IV every 12 hours (n = 5). Infusion durations were only reported in 1 case report of a neonate who received up to 15 mg/kg as a 40-minute intravenous infusion.³⁵ The median duration of daptomycin therapy was 21 days (range: 3–59 days). Time to clinical improvement was noted to be an average of 6.2 days (1–18 days) with a median of 4 days and clinical cure was reported in 25 of the 27 case reports (92.5%).

Safety was reported in 18 of the 27 case reports.^{26,28–31,33–36,38–41,43–46,52} Of the 18 reports, 1 patient developed eosinophilia and daptomycin was discontinued, although the cause of the eosinophilia was not determined.²⁸ One patient started with a baseline CPK of 29 U/L measured on day of life 25 (DAP treatment day 12) which increased to 405 U/L on day of life 53 (DAP treatment day 40 and LZD treatment day 8).²⁶ Daptomycin was not discontinued in this case and continued through day 72. The last follow-up CPK concentration was 308 on day 67 of therapy with no mention of adverse effects. The remaining 17 case reports reported CPK concentrations within normal limits.

The most common prior antibiotics used were vancomycin (n = 20) and linezolid (n = 8). The majority (n = 17) of patients had overlap of antibiotics during daptomycin treatment with linezolid (n = 6), rifampin (n = 5), and gentamicin (n = 4) overlapping most frequently. Most frequently reported reasons for switch to daptomycin included clinical and microbiological failure on prior treatment (n = 6), microbiological failure (n = 7), and documented culture and sensitivity data showing resistance (n = 5). Antimicrobial resistance data was infrequently reported. PVL-positive ST80 MRSA phenotypic resistance was reported in 2 cases.^35,48 Of the VRE strains, CC17-ST412 clonal complex was reported in 1 case report.⁵⁰ Susceptibilities to daptomycin were reported in 19 of the 27 case reports with a median MIC of 1 mcg/mL (range: 0.064–2 mcg/mL) across a range of Gram-positive bacteria.^{26,28,30,31,33–35,37–39,41–44,46,49–52} Pharmacokinetic data were infrequently reported and, therefore, not included within Table 2. Three case reports (aged 15 days, 28 days and roughly 2 months of age) reported daptomycin serum peak concentrations using a dosing strategy of 6 mg/kg every 12 hours ranging from 27.26 mcg/mL to 51.9 mcg/mL.^30,34,38

Daptomycin Treatment Success and Rational for Daptomycin Use.

Since the most recent review in pediatrics, 3 RCTs have been added to the literature on the use of daptomycin in pediatrics.¹⁰ There has also been an increase in studies, case reports, including use in neonates and infants. Of the 3 RCTs published, clinical success of daptomycin was reported as an average of 85.5%, with an overall success of 79.4% within the retrospective analyses, prospective studies and RCTs combined. As the RCTs did not meet power for efficacy nor were they designed to prove efficacy, noninferiority or superiority as the primary outcome, no inferences on the results compared with SOC can be made. Pooled data indicate that daptomycin achieved clinical success in most patients. Among the RCTs there was no significant difference in defining clinical success, clinical cure, or test-of-cure.

In summary of the case reports, clinical cure was achieved in 92.5% of the reports. Case reports indicated switches to daptomycin due to clinical or microbiological failure, adverse event to prior treatment, less invasive monitoring, and subtherapeutic vancomycin troughs. These factors emphasize daptomycin’s role in therapy, particularly once first-line agents fail or with documented or suspected antimicrobial resistance. Active surveillance for increasing vancomycin resistance patterns such as those associated with sequence type (ST) 80 MRSA and clonal complex (CC) 17-ST412 VRE can be used to support an early switch to daptomycin to prevent treatment failure.⁵⁵ There was no significant difference in defining clinical success or clinical cure between the case reports.

Dosing and Pharmacokinetic Considerations.

This review also aimed to explore dosing strategies used in neonates and infants. For infants and neonates, the most common dose of daptomycin was 6 mg/kg IV every 12 hours (12 mg/kg/day). Within the case report by Gawronski et al³³ dosing and pharmacokinetic parameters for several case reports were summarized. In preterm neonates with normal renal function between 27 and 80 days post-natal age, daptomycin 6 mg/kg/dose every 12 hours yielded peaks ranging from 22.9 to 41.7 mg/dL, compared with older full-term neonates which yielded lower peaks ranging from 10.9 to 17.7 mg/dL, yet similar troughs as preterm neonates.²³ This suggests a highly variable and inverse relationship with distribution and clearance in preterm neonates vs term infants in line with what was also summarized in a previous review article reporting on pharmacokinetics of 11 studies, including infants and neonates.¹⁰ In the case of a full-term infant, pharmacokinetic monitoring was used to adjust daptomycin dosing from 4 mg/kg to 6 mg/kg every 36 hours based on a low daptomycin serum peak (6.19 mcg/mL). Following dosage adjustment, blood cultures became negative.³⁹ Doses as high as 15 mg/kg daily over 40 minutes in a 23-day-old neonate were reported with pharmacokinetic and safety monitoring and no reported adverse effects.³⁵

Concentration-dependent nerve toxicity was observed in preclinical trials in juvenile dogs, providing rationale for using prolonged infusion times for young children in clinical trials, and the basis for the infusion recommendations in the daptomycin prescribing information. Nerve toxicity was observed at significantly lower daptomycin peak concentrations in juvenile dogs compared with adults and therefore, longer infusion times were used in children up to 6 years of age in pediatric studies to theoretically reduce peak concentrations while not affecting the overall AUC.^1,8,56 In the prospective observational study by Tedeschi et al,¹⁶ a 3-minute daptomycin rapid infusion of 8 mg/kg was administered to 12 patients with no adverse effects. This is the only study that reported an infusion duration in neonates and infants although it is unclear how many patients were less than 1 year of age.¹⁶ In a phase 1 single-dose pharmacokinetic safety study by Bradley et al,⁵⁶ daptomycin was administered over 30 minutes at 4 mg/kg in patients 3 to 12 months and 6 mg/kg in patients 13 to 24 months with no significant adverse effects. Given limited reports in the literature and no published studies directly comparing daptomycin infusion durations with adverse effects in pediatric patients, clinicians should consider daptomycin pharmacokinetics, weighing the risks and benefits of a shorter infusion until more evidence is available.

Safdar et al⁵³ reported in previous PK/PD analysis that peak to MIC and 24-hour AUC to MIC ratios best correlated with daptomycin efficacy. Mean daptomycin AUC to MIC ratios reported for 1-log killing were 666 for Staphylococcus aureus and 4.14 to 33.8 for E faecium. Mean peak to MIC ratios reported for 1-log bactericidal activity against S aureus were 129 +/− 24.1 with a range of 86 to 184 and 0.62 to 5.05 for tested E faecium isolates.⁵³ Based on Monte Carlo PK simulations conducted in a study by Wei et al,⁵⁴ higher dosing of 8 to 12 mg/kg in infants and children, specifically 12 mg/kg/day in infants 3 to 12 months was affirmed as being necessary to achieve probable responses to infections caused by S aureus and E faecium. Achieving desired peak to MIC and AUC to MIC concentrations with higher doses is something to consider in overcoming treatment failure due to suboptimal pharmacokinetics and dosing.

Daptomycin Treatment Success and Rational for Daptomycin Use.

Of the 3 RCTs published, clinical success of daptomycin was reported as an average of 87%, with an overall success of 78% within the retrospective analyses and RCTs combined. As the RCTs did not meet power for efficacy nor were they designed to prove efficacy noninferiority or superiority as the primary outcome, no inferences on the results compared to SOC can be made. Pooled data indicate that daptomycin achieved clinical success in most patients.

Of the case reports, clinical cure was achieved in 92.5% of the reports. Case reports indicated switches to daptomycin due to clinical or microbiological failure, adverse event to prior treatment, less invasive monitoring, and subtherapeutic vancomycin trough concentrations. These factors emphasize daptomycin’s role in therapy, particularly once first-line agents fail or exhibit resistance. Active surveillance for increasing vancomycin resistance patterns such as those associated with sequence type (ST) 80 MRSA and clonal complex (CC) 17-ST412 VRE can be used to support an early switch to daptomycin to prevent treatment failure.⁵⁵

Genotyping and Resistance.

This review highlights 2 significant MRSA cases with documented resistance.^34,48 The first, by Erturan et al,⁴⁸ was associated with osteomyelitis, while the second by Tsironi et al,³⁴ was an ophthalmic infection. Both infections were caused by Panton-Valentine Leucocidin (PVL) positive strains belonging to the ST80 lineage.^34,48 These cases demonstrated clinical success after treatment with daptomycin compared to the standard anti-MRSA regimen. This suggests that daptomycin may be a promising treatment option for MRSA infections, especially those caused by PVL-positive ST80 strains. Overall, these findings underscore the importance of considering alternative treatments such as daptomycin for managing MRSA infections, particularly when dealing with strains that exhibit unique genotypic characteristics like PVL positivity and specific clonal types.

Adverse Effects.

Of the 3 RCTs included in the review, treatment-related adverse events occurred 8.3% less often than with SOC, although we cannot confirm statistical significance due to lack of power and statistical reporting. Only 1 case report cited substantially elevated CPK concentrations during daptomycin therapy. Elevated CPK concentrations reported in the daptomycin prescribing information were based on Bradley et al,¹⁴ studying daptomycin for cSSTIs in children. CPK was elevated in 5.5% of patients in the daptomycin group vs 5.3% in the comparator group.^1,14 Bradley et al¹² found no serious treatment-related adverse effects in pediatric patients with osteomyelitis treated with daptomycin. Eight of the studies included in this review were conducted in infants or neonates, showing not only use of daptomycin in this population, but a low percentage of adverse effects (4.2%). Significant CPK elevations were only reported an average of 2.8% across all studies and retrospective analysis. Among the 27 pediatric case reports using daptomycin, only 2 noted adverse effects, with more than half (63%) of cases monitoring and confirming normal CPK concentrations.^26,28 In a population with limited high-quality evidence, the currently summarized observations in this review demonstrate use with little to no reported toxicity compared to what is reported in the product labelling.¹