Optimizing Therapy for Vancomycin-resistant Enterococcal Bacteremia in Children

Pranita D. Tamma; Alice J. Hsu

Disclosures

Curr Opin Infect Dis. 2014;27(6):517-527. 

In This Article

Daptomycin

Daptomycin is a rapidly bactericidal agent derived from the bacterium Streptomyces roseosporus.[108,109] Its unique mechanism of action involves insertion of its lipophilic tail into the bacterial membrane, forming a channel that causes efflux of intracellular potassium with subsequent depolarization of the cell membrane.[110] Although there were insufficient clinical data to support FDA approval for VRE infections, existing data suggest it offers an off-label alternative for the treatment of infections caused by these organisms.[111]

Pharmacokinetics Data

Daptomycin is approved by the FDA at 6 mg/kg/day i.v. for S. aureus bacteremia and right-sided endocarditis.[112,113] However, based on its concentration-dependent activity, higher doses of daptomycin may increase the degree and rapidity of bacterial killing, while reducing the emergence of resistance.[114–116] The clinical response with higher doses is supported by an animal model of infective endocarditis against strains with reduced daptomycin susceptibility.[117] Furthermore, as daptomycin MICs for Enterococcus species are typically higher than those for other Gram-positive organisms, patients with VRE infections may require higher doses of daptomycin for optimal treatment.[118,119]

Tolerability and pharmacokinetics of a single i.v. dose of daptomycin 4 mg/kg in 22 children stratified by age[120] found that although pharmacokinetic variables for adolescents (12–17 years) were comparable with those in adults,[121,122] clearance is increased in younger children (2–6 years of age) and we suggest initiating daptomycin therapy at 8 to 10 mg/kg/dose once daily in this population.[123] Existing pharmacokinetic data suggest that daptomycin clearance in infants 3 months of age to children 2 years of age is similar to those of children 2 to 6 years of age,[124,125] therefore, we also recommend initiating daptomycin at 8 to 10 mg/kg/dose i.v. every 24 h in this age group (Table 1).

It is important to note that the pediatric dosing strategy of 8 to 10 mg/kg/day was intended to mimic the adult dose of 4 to 6 mg/kg/day. However, for adults, many experts recommend initiating daptomycin at higher doses, suggesting that doses higher than 10 mg/kg/day may be needed in children to obtain similar drug exposures to adults receiving 8–10 mg/kg/day. Unfortunately, pharmacokinetic data on dosages more than 10 mg/kg/day are unavailable in the pediatric population. Based on existing pharmacokinetic and clinical outcomes data, we suggest that daptomycin 8 to 10 mg/kg/dose i.v. once daily should be considered in adolescents.[126–130] Because of the increased volume of distribution in burn patients, this population may require further dose adjustment as high as 10 to 12 mg/kg to achieve therapeutic serum values.[131]

Dosing for neonates is less clear. Existing pharmacokinetic data suggest that daptomycin clearance in neonates is similar to that in children 2–6 years of age.[125] Limited data suggests that preterm neonates may require 6 mg/kg/dose i.v. every 12 h, with dose escalation as high as 15 mg/kg/dose reported (ref[132–134]).

Excretion of daptomycin occurs primarily through the renal system with 50% of the administered dose excreted within 24 h as intact drug.[135] Consequently, impairment of renal function influences the clearance of daptomycin and interval adjustment to every 48 h is recommended for creatinine clearance (CrCl) less than 30 ml/min.[122] Although pharmacokinetic data are lacking, a similar adjustment of dosing interval should be considered in children with CrCl less than 30 ml/min.

The high affinity of daptomycin to serum albumin and its small volume of distribution limit its penetration into bone, cerebrospinal fluid, and lungs.[136–139] In addition, it is inactivated by alveolar surfactants, and therefore, should not be used for pulmonary infections.[140]

Clinical Outcomes Data

In 2013, Whang et al.[141] conducted a meta-analysis comparing clinical outcomes of patients receiving linezolid and daptomycin for VRE bacteremia in nine observational studies. There was a trend towards increased survival in patients receiving linezolid therapy (odds ratio [OR], 1.3; 95% confidence interval [CI] 1.1–1.8). More recently, a 2014 meta-analysis by Balli et al.[142] summarized data from 10 observational studies including 967 patients, and compared daptomycin and linezolid for the treatment of VRE bacteremia. Daptomycin was associated with a higher 30-day all-cause mortality (OR, 1.61; 95% CI, 1.08–2.40) and infection-related mortality (OR, 3.61; 95% CI 1.42–9.20).[142] Additionally, there was a trend towards more bacteremic relapses in the daptomycin group (OR, 2.51; 95% CI, 0.94–6.72).

After the publication of the aforementioned meta-analyses, Hayawaka et al.[143] evaluated 168 cases of patients receiving daptomycin or linezolid for VRE bacteremia. After propensity score matching was performed, in-hospital mortality was observed in 41% of patients receiving daptomycin and 31% of patients receiving linezolid. Their findings did not reach statistical significance but it is unknown if notable differences would be observed with a larger sample size.

The majority of patients in clinical studies of VRE bacteremia received daptomycin dosed at 6 mg/kg/dose i.v. every 24 h. Case reports and postmarketing surveillance data suggest that higher doses may be well tolerated and efficacious.[144–147,148] A prospective study including patients receiving higher daptomycin dosages needs to be undertaken. The published clinical experience with daptomycin therapy in pediatrics is limited with a minority of patients receiving this agent for VRE bacteremia.[149–152]

Daptomycin Adverse Events

Skeletal muscle is the principal target of daptomycin toxicity. The incidence of reversible creatine phosphokinase (CPK) elevation has been reported in 2.8% of patients and myopathy in 0.2% of patients using dosages of 4 mg/kg/day.[153] Similar findings have been described in studies evaluating the safety of daptomycin dosed between 8 and 12 mg/kg/day.[111,144,154] There are rare reports of daptomycin-associated rhabdomyolysis.[155] Concerns for clinical or biochemical myositis have prompted the manufacturers to recommend weekly CPK measurements during therapy.[122] It is suggested that daptomycin be discontinued in patients with clinical signs and symptoms of myositis in combination with a CPK level elevation greater than five times the upper limit of normal or a CPK level greater than 10 times the upper limit of normal in an asymptomatic patient.[122] Symptoms generally resolve within 2 to 3 days after discontinuation of the drug, although CPK elevations may persist up to 2 weeks.[130,156,157] Daptomycin-induced eosinophilic pneumonia has been described.[158]

Daptomycin Resistance

Emerging data regarding daptomycin-nonsusceptible enterococci highlight a new problem for this multidrug-resistant pathogen.[159,160] Daptomycin resistance in VRE bloodstream isolates has been reported to be as high as 15% in one US institution.[161] The mechanisms of VRE resistance to daptomycin have not been fully elucidated.[162–165]

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