Daptomycin for Treating Gram-Positive Infections in Children

In This Article

Abstract and Introduction

Abstract

Background: This subgroup analysis of the European Cubicin Outcomes Registry Experience evaluated the safety and effectiveness of daptomycin in children and adolescent patients (<18 years).

Methods: Clinical outcomes at the end of therapy were assessed as success (cured or improved), failure or nonevaluable. Safety was assessed for up to 30 days post treatment.

Results: Eighty-one children and adolescent patients were included in this study. The most common primary infections were bacteremia (19.8%), complicated skin and soft-tissue infection (18.5%), osteomyelitis (13.6%), endocarditis (12.3%), foreign body/prosthetic infection (12.3%), uncomplicated skin and soft-tissue infection (9.9%) and other (13.6%). Daptomycin doses ranged from 4 to >10 mg/kg/day. Median duration of therapy was 12.5 (interquartile range, 7–25; mean, 16.7; standard deviation, 12.8) days. Staphylococcus aureus (46.7%) was the most commonly isolated pathogen (23.8% methicillin-resistant S. aureus). Forty-nine (60.5%) patients completed daptomycin therapy without further antibiotics, 27 (33.3%) switched to another antibiotic, 4 (4.9%) discontinued because of adverse events (AEs) and 1 (1.2%) discontinued because of other reason. Overall, 75 (92.6%; 95% confidence interval: 95.2–100.0%) patients achieved clinical success; 39 of 41 (95.1%) patients receiving daptomycin monotherapy and 36 of 40 (90.0%) patients receiving concomitant antibiotics. Six (7.4%) patients reported AEs, including 1 patient with increased blood creatine phosphokinase. Three (3.7%) patients had serious AEs; 1 (1.2%) had a serious AE possibly related to daptomycin.

Conclusion: Daptomycin, alone or combined with other antibiotics and/or surgery, demonstrated high clinical success rates against a wide variety of infections and was well tolerated in children and adolescents.

Introduction

Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), are known to be common pathogens in children and adolescents in both healthcare and community-associated infections.^[1–3] Treatment of resistant pathogens including MRSA and vancomycin-resistant enterococci remains challenging even with standard antimicrobial protocols.^[4–6] Higher mortality has been reported because of MRSA infections than infections caused by methicillin-susceptible S. aureus.^[7,8] Several treatment options are available for the management of MRSA infections in adults; however, these options are limited for pediatric patients owing to a lack of sufficient safety and efficacy data.^[1] Clindamycin, vancomycin and linezolid are currently the only antibiotics approved by the US Food and Drug Administration for the management of MRSA infections in pediatric patients.^[1]

Daptomycin is a cyclic lipopeptide that is active against a wide range of Gram-positive bacteria. Its mechanism of action involves calcium-dependent binding to the bacterial cell membrane, resulting in rapid depolarization of the membrane potential and bacterial cell death, without cell lysis and release of inflammatory mediators.^[9,10] Daptomycin is a concentration-dependent bactericidal agent indicated for the treatment of adult patients with complicated skin and soft-tissue infection (cSSTI), right-sided endocarditis caused by S. aureus, and bacteremia associated with cSSTI or right-sided endocarditis.^[11]

Daptomycin is not approved for the treatment of pediatric patients,^[12] and limited data are currently available regarding its use in the treatment of Gram-positive infections in this population.^[1] A few case reports and retrospective studies have described that use of daptomycin is beneficial in treating Gram-positive infections in children.^[2,12]

The European Cubicin Outcomes Registry and Experience (EU-CORE^SM) study was a retrospective, noninterventional registry developed to collect real-world data on the use of daptomycin in the treatment of patients with Gram-positive infections. This subgroup analysis evaluated the safety and effectiveness of daptomycin in children and adolescent patients from the EU-CORE study.

Table 1. Baseline Demographics and Clinical Characteristics
Parameters	N = 81 n (%)*
Age, yrs
Median (IQR)	13.0 (8–16)
Age group, yr
0 to <1	2 (2.5)
1 to <2	3 (3.7)
2 to <7	10 (12.3)
7 to <12	20 (24.7)
12 to <18	46 (56.8)
Gender
Male	53 (65.4)
Female	28 (34.6)
Race
Caucasian	74 (91.4)
Asian	1 (1.2)
Black	1 (1.2)
Other	4 (4.9)
Unknown	1 (1.2)
Body weight, kg
Median (IQR)	46.5 (27–60)
Underlying diseases/conditions†	44 (54.3)
Oncologic (hematologic and solid organ cancer)	18 (22.2)
Cardiovascular	11 (13.6)
Immunosuppressed state	4 (4.9)

*Unless otherwise indicated.
†Data presented for any disease/condition with >3 patients. Some patients had more than 1 underlying condition.

Table 2. Types of Monoinfections and Mixed Infections by Type of Primary Infection
Primary Infection	Total No. of Patients, N	Culture Positive, n (%)	Monoinfection, n (%)*	Mixed Infection, n (%)†
Bacteremia	16	12 (75.0)	12 (100.0)	—
Complicated skin and soft-tissue infection	15	8 (53.3)	5 (62.5)	3 (37.5)
Osteomyelitis	11	5 (45.5)	4 (80.0)	1 (20.0)
Endocarditis	10	6 (60.0)	6 (100.0)	—
Foreign body/prosthetic infection	10	6 (60.0)	5 (83.3)	1 (16.7)
Uncomplicated skin and soft-tissue infection	8	3 (37.5)	3 (100.0)	—
Septic arthritis	3	1 (33.3)	1 (100.0)	—
Urinary tract infection	3	3 (100.0)	3 (100.0)	—
Other‡	5	1 (20.0)	1 (100.0)	—

*Only 1 pathogen identified in culture source of primary pathogen.
†More than 1 pathogen identified in culture source of primary pathogen.
‡Includes surgical antibiotic prophylaxis (n = 2) and primary infection not otherwise specified (n = 3).

Table 3. Culture Results—Overall and By Age Groups
Culture Results/Pathogens	Overall n (%)	Age Group (Yrs)
	Overall n (%)	<2, n (%)	≥2 to <12, n (%)	≥12 to <18, n (%)
	N = 81	N = 5	N = 30	N = 46
Culture available	63 (77.8)	5 (100.0)	21 (70.0)	37 (80.4)
Negative culture	18 (28.6)	1 (20.0)	7 (33.3)	10 (27.0)
Positive culture	45 (71.4)	4 (80.0)	14 (66.7)	27 (73.0)
Staphylococci
Staphylococcus aureus	21 (46.7)	—	6 (42.9)	15 (55.6)
MSSA	14 (31.1)	—	4 (28.6)	10 (37.0)
MRSA	5 (11.1)	—	1 (7.1)	4 (14.8)
Methicillin susceptibility unknown	2 (4.4)	—	1 (7.1)	1 (3.7)
CoNS
Staphylococcus epidermidis	10 (22.2)	1 (25.0)	3 (21.4)	6 (22.2)
Methicillin resistant	10 (22.2)	1 (25.0)	3 (21.4)	6 (22.2)
Staphylococcus spp., coagulase-negative	5 (11.1)	1 (25.0)	1 (7.1)	3 (11.1)
Methicillin resistant	3 (6.7)	1 (25.0)	—	2 (7.4)
Methicillin susceptible	1 (2.2)	—	—	1 (3.7)
Methicillin susceptibility unknown	1 (2.2)	—	1 (7.1)	—
Staphylococcus spp., coagulase not specified	1 (2.2)	—	—	1 (3.7)
Enterococci
Enterococcus faecium	3 (6.7)	2 (50.0)	1 (7.1)	—
Vancomycin susceptibility unknown	3 (6.7)	2 (50.0)	1 (7.1)	—
Enterococcus faecalis	2 (4.4)	—	1 (7.1)	1 (3.7)
Non-VRE	1 (2.2)	—	—	1 (3.7)
Vancomycin susceptibility unknown	1 (2.2)	—	1 (7.1)	—
Other	3 (6.7)	—	2 (14.3)	1 (3.7)

Proportions of pathogens are based on the number of patients with a positive culture.
CoNS indicates coagulase-negative Staphylococcus species; MSSA, methicillin-susceptible Staphylococcus aureus; and VRE, vancomycin-resistant enterococc

Table 4. Safety of Daptomycin in Children and Adolescents
Parameter	N = 81, n (%)
Any AE	6 (7.4)
Any SAE	3 (3.7)
SAEs related to study medication*	1 (1.2)
Death†	1 (1.2)
AEs leading to permanent drug discontinuation	4 (4.9)
AEs related to study medication‡	4 (4.9)
Individual AEs reported
Rash	2 (2.5)
Anaphylactic reaction	1 (1.2)
Blood CPK increased	1 (1.2)
Dyspnea	1 (1.2)
Hypersensitivity	1 (1.2)
Osteosarcoma	1 (1.2)
Renal failure acute	1 (1.2)
Pulmonary hemorrhage	1 (1.2)
Tachycardia	1 (1.2)

*One (1.2%) patient each had tachycardia, anaphylactic reaction, dyspnea and rash.
†An 11-year-old girl whose death was caused by pulmonary hemorrhage, which was deemed to be unrelated to the study drug.
‡Two (2.5%) patients had rash, and 1 (1.2%) patient each had tachycardia, anaphylactic reaction, hypersensitivity, blood CPK increased and dyspnea.

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Clinical Experience With Daptomycin for the Treatment of Gram-Positive Infections in Children and Adolescents

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