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

Quinupristin-dalfopristin

Quinupristin-dalfopristin became commercially available in the United States in September 1999.[4] It consists of a 30 : 70 ratio of two different semisynthetic streptogramin antibiotics.[5] Each component binds to sequential sites located on the 50S subunit of the bacterial ribosome.[6] Dalfopristin binding causes a conformational change in the ribosome that subsequently increases the binding of quinupristin.[7] The combination is active in vitro against vancomycin-resistant E. faecium, with an MIC90 of 1 μg/ml;[8,9] however, the agent is inactive against E. faecalis. An efflux pump conferring resistance to dalfopristin appears to be intrinsic to E. faecalis.[10] The abbreviation VRE is used in the following sections discussing quinupristin-dalfopristin, even though we are specifically referring to vancomycin-resistant E. faecium.

Pharmacokinetic Data

Quinupristin-dalfopristin inhibits the metabolism of drugs cleared through cytochrome P450 3A4 enzymes, including tacrolimus and cyclosporine[11] and may result in elevated plasma concentrations of these agents.[11] Quinupristin-dalfopristin is conjugated in the liver and excreted in the bile.[12]Underlying hepatic dysfunction may potentially result in increased plasma concentrations of quinupristin-dalfopristin,[13] although the manufacturer has made no recommendations for dosage reduction for patients with hepatic impairment.[5] Similarly, the manufacturer has not set guidelines for dosage reduction when renal impairment is present.[5]

The pharmacokinetics of quinupristin-dalfopristin has not been evaluated in the pediatric population. In adults, a dose of 7.5 mg/kg/dose intravenous (i.v.) every 8 h is FDA approved for the treatment of complicated skin and skin structure infections.[5] Observational data consisting of 27 children, including infants as young as 1 month of age, indicate that the adult labeled dose of 7.5 mg/kg/dose i.v. every 8 h may provide reasonable efficacy and limited toxicities in children (Table 1).[14,15]

Clinical Outcomes Data

Because the clinical development of quinupristin-dalfopristin coincided with an increased incidence of VRE in the United States, much of the initial published experience with this agent was derived from reports from emergency use programmes initiated in 1993. Two, prospective, noncomparative, emergency-use studies evaluating almost 800 patients, including 23 pediatric patients, with VRE infections from a variety of sources treated with quinupristin-dalfopristin found a clinical response rate of approximately 70% in the evaluable subset.[16,17] Patients with underlying liver disease or dialysis-dependency exhibited the lowest response rates.[17]

The outcomes of 20 patients with VRE bacteremia treated with quinupristin-dalfopristin were compared with a historical cohort of 42 patients with VRE bacteremia treated with other agents.[18] The recurrence rate of VRE bacteremia was 50% in the control group compared with 25% in the quinupristin-dalfopristin group. Similarly, patients in the control group were more likely to have died as a result of VRE infection compared with patients in the quinupristin-dalfopristin group (40 vs. 25%).[18] Significant limitations exist in this study including small sample size, lack of adjustment for possible confounders, heterogeneous agents grouped together in the control group (including several agents known to be inactive against VRE), and limited data on source control measures.[18] The pediatric experience with the use of quinupristin-dalfopristin for the treatment of VRE bacteremia is limited to two small case series.[14,15] Comparative studies of quinupristin-dalfopristin and linezolid are described in subsequent sections of this review. Published studies comparing clinical outcomes of patients receiving quinupristin-dalfopristin vs. daptomycin for the treatment of VRE bacteremia are lacking.

Adverse Events

Myalgias and arthralgias, reported in 10 to 50% of adults receiving quinupristin-dalfopristin has led to limited use of this agent.[11,12,16,17,19–24] The onset of symptoms generally occurs in the first week of therapy and resolves a mean of 4 days after drug termination.[24] Symptoms may improve with dosage reduction to 5 mg/kg/dose i.v. every 8 h, but i.v. analgesics or discontinuation of quinupristin-dalfopristin are frequently needed.[24]

In a case series of 11 children receiving quinupristin-dalfopristin at 7.5 mg/kg/dose i.v. every 8 h, four children required drug discontinuation because of resultant arthralgias and/or myalgias. All four children needed analgesics; three required narcotic analgesics of whom two required continuous morphine infusion.[25] Arthralgias and myalgias attributable to quinupristin-dalfopristin are likely underreported in the pediatric literature because of an inability to verbalize complaints at younger ages.[14,15]

A high incidence of phlebitis often precludes administration of quinupristin-dalfopristin through a peripheral vein. In one study, 42% of patients receiving quinupristin-dalfopristin as peripheral venous infusions developed local venous intolerability.[17] If moderate or severe venous irritation occurs following peripheral venous administration of quinupristin-dalfopristin, consideration should be given to increasing the infusion volume, changing the infusion site, or infusing the drug via a central catheter.[11]

Notable laboratory derangements associated with quinupristin-dalfopristin include elevations in transaminases (1.5%)[17] and a conjugated bilirubin more than five times normal (5.5%).[11] An isolated conjugated hyperbilirubinemia appears to be a consequence of competition for excretion between quinupristin-dalfopristin and bilirubin; therefore, an isolated, hyperbilirubinemia is not necessarily an indication to stop therapy with quinupristin-dalfopristin, but should be evaluated carefully in the context of the entire clinical picture.[11]

Resistance

Although quinupristin-dalfopristin resistant E. faecium isolates have been recovered in almost 60% of retail chickens,[26] data from several large series indicate that in isolates infecting humans, E. faecium resistance to quinupristin-dalfopristin remains rare – approximately 4%.[16,17,27] Similarly, superinfection with E. faecalis seems to occur in approximately 4% of patients treated with quinupristin-dalfopristin.[16] When resistance does occur, it is primarily mediated by three mechanisms: drug inactivation by enzymes, efflux pumps, and conformational alterations in ribosomal target binding sites.[6,28]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....