Optimizing Therapy for VRE Bacteremia in Children

Abstract and Introduction

Abstract

Purpose of review Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used.

Recent findings Quinupristin-dalfopristin, linezolid, and daptomycin, all approved between 1999 and 2003, represent the mainstays of therapy for VRE bacteremia, although only linezolid has been specifically approved by the United States Food and Drug Administration for this indication. The main objective of this review is to compare the relative efficacies, dosing strategies, and side-effect profiles of quinupristin-dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population. A brief description of recently approved broad-spectrum Gram-positive agents that may have a role in the management of VRE bacteremia in upcoming years is also provided.

Summary Linezolid, despite its bacteriostatic activity against VRE, may be the most versatile of the available drugs. It has activity against both Enterococcus faecalis and E. faecium, can be administered orally, and resistance appears to be less of a concern with linezolid compared with the other agents. Additionally, the results of two recent meta-analyses demonstrate more favorable outcomes with linezolid compared with daptomycin for the treatment of VRE bacteremia. The clinical pharmacokinetics of linezolid have been well described in children. The most notable concern with linezolid, however, is toxicities associated with prolonged use. Until more prospective data are available, we favor linezolid as first-line therapy for the treatment of VRE bacteremia in children.

Introduction

The preferred treatment for vancomycin-resistant enterococci (VRE) bacteremia is ampicillin if the isolate is susceptible to this agent. However, the majority of vancomycin-resistant Enterococcus faecium isolates (80–95%) are resistant to ampicillin.^[1,2] In contrast, vancomycin-resistant E. faecalis are usually susceptible to ampicillin, as are E. gallinarum and E. casseliflavus, both of which are intrinsically resistant to vancomycin.

The optimal therapy for VRE bacteremia in the setting of ampicillin resistance is unclear. Quinupristin-dalfopristin, linezolid, daptomycin, and tigecycline, all approved between 1999 and 2005, represent the mainstays of therapy for invasive VRE infections, although only linezolid has been specifically approved by the United States Food and Drug Administration (FDA) for this indication. Given concerns regarding the achievement of adequate tigecycline serum drug concentrations,^[3] we do not recommend tigecycline for the treatment of VRE bacteremia. The main objective of this review is to compare the relative efficacies and side-effect profiles of quinupristin-dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population.

Table 1. Suggested antimicrobial agents for the treatment of vancomycin-resistant enterococcal (VRE) bacteremia in children
Agent	Dosing specific for VRE bacteremia	Potential adverse events^a
Quinupristin/dalfopristin	7.5 mg/kg/dose i.v. every 8h	Drug-drug interactions with medications metabolized through CYP450 enzymes
Adjustment for renal impairment: none	Myalgias and arthralgias
	Phlebitis
	Transaminitis, conjugated hyperbilirubinemia
Linezolid	Neonates <34 weeks gestation:	Serotonin syndrome
<7days old: 10 mg/kg/dose i.v./p.o. every 12 h	Thrombocytopenia, anemia
≥7days old: 10 mg/kg/dose i.v./p.o. every 8 h	Lactic acidosis
	Peripheral or optic neuropathy
Neonates ≥34 weeks gestation: 10 mg/kg/dose i.v./p.o. every 8 h
Infants/children <12 years old: 10 mg/kg/dose i.v./p.o. every 8 h; maximum 600 mg/dose
Adolescents ≥12 years old: 600 mg i.v./p.o. every 12
Adjustment for renal impairment: none
Daptomycin^b	Neonates: 6mg/kg/dose i.v. every 12 h, based on limited data (doses as high as 15 mg/kg/dose i.v. every 12 h¥ have been reported)	Creatine phosphokinase elevation and myopathy
Infants and children: 8 to 10 mg/kg/dose i.v. every 24 h¥	Rhabdomyolysis (rare)
Adolescents/adults: 8 to 10 mg/kg/dose IV every 24 h. Adjustment for renal impairment: interval adjustment to every 48 h recommended for creatinine clearance <30 ml/min	Eosinophilic pneumonia (rare)

Table 1. Suggested antimicrobial agents for the treatment of vancomycin-resistant enterococcal (VRE) bacteremia in children

Agent

Dosing specific for VRE bacteremia

Potential adverse events^a

Quinupristin/dalfopristin

7.5 mg/kg/dose i.v. every 8h

Drug-drug interactions with medications metabolized through CYP450 enzymes

Adjustment for renal impairment: none

Myalgias and arthralgias

Phlebitis

Transaminitis, conjugated hyperbilirubinemia

Linezolid

Neonates <34 weeks gestation:

Serotonin syndrome

<7days old: 10 mg/kg/dose i.v./p.o. every 12 h

Thrombocytopenia, anemia

≥7days old: 10 mg/kg/dose i.v./p.o. every 8 h

Lactic acidosis

Peripheral or optic neuropathy

Neonates ≥34 weeks gestation: 10 mg/kg/dose i.v./p.o. every 8 h

Infants/children <12 years old: 10 mg/kg/dose i.v./p.o. every 8 h; maximum 600 mg/dose

Adolescents ≥12 years old: 600 mg i.v./p.o. every 12

Adjustment for renal impairment: none

Daptomycin^b

Neonates: 6mg/kg/dose i.v. every 12 h, based on limited data (doses as high as 15 mg/kg/dose i.v. every 12 h¥ have been reported)

Creatine phosphokinase elevation and myopathy

Infants and children: 8 to 10 mg/kg/dose i.v. every 24 h¥

Rhabdomyolysis (rare)

Adolescents/adults: 8 to 10 mg/kg/dose IV every 24 h. Adjustment for renal impairment: interval adjustment to every 48 h recommended for creatinine clearance <30 ml/min

Eosinophilic pneumonia (rare)