Glycopeptide-resistant Enterococcus faecium infections in paediatric liver transplant recipients: safety and clinical efficacy of quinupristin/dalfopristin

Anita Vermaa,*, Anil Dhawanb, John Philpott-Howarda, Mohamed Relac, Nigel Heatonc, Giorgina Mieli Verganib and Jim Wadea

a Dulwich Public Health Laboratory & Medical Microbiology, King's College Hospital; b Paediatric Liver Service and c Liver Transplant Surgery, King's College Hospital, London, SE5 9RS, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
We describe our experience of quinupristin/dalfopristin for glycopeptide-resistant Enterococcus faecium (GREF) infections in 19 paediatric liver transplant recipients. The median patient age was 2 years and all were receiving immunosuppressive regimens. Quinupristin/ dalfopristin was well tolerated and complete resolution of infection was seen in 74% of patients. Side-effects included reversible elevation of serum alkaline phosphatase, skin rash, itching, diarrhoea and vomiting, but therapy was not withdrawn from any patient. Quinupristin/ dalfopristin appears safe and efficacious in critically ill immunocompromised children with renal or hepatic impairment.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
Infection with glycopeptide-resistant Enterococcus faecium (GREF) has become a significant problem in high-dependency patients.1 Most physicians would wish to treat E. faecium bloodstream infection in critically ill, compromised patients with signs of sepsis. Unfortunately, the therapeutic options for GREF infections are limited.1,2 Quinupristin/dalfopristin is a novel injectable streptogramin active against Gram-positive bacteria.3 There is little published experience of use of quinupristin/dalfopristin in children, particularly in the immunocompromised or those at risk of impaired hepatic or renal function. We describe our experience of quinupristin/dalfopristin for treating serious GREF infections in paediatric liver transplant patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
Quinupristin/dalfopristin was available through the Rhône– Poulenc Rorer compassionate use programme. Written informed consent was obtained for all patients.

GREF identification and susceptibility testing

E. faecium was identified by standard methods4 and API STREP galleries (bioMérieux SA, Marcy-l'Etoile, France). Disc susceptibility testing was performed on Diagnostic Sensitivity Testing agar (Oxoid, Basingstoke, UK) using discs of ampicillin (10 µg), erythromycin (5 µg), rifampicin (5 µg), tetracycline (10 µg), gentamicin (10 and 200 µg), vancomycin (5 and 30 µg), chloramphenicol (10 µg) and quinupristin/dalfopristin (15 µg disc, containing 5 µg quinupristin and 10 µg dalfopristin). MICs of ampicillin, teicoplanin, vancomycin, gentamicin, chloramphenicol, ciprofloxacin, doxycycline, rifampicin and quinupristin/ dalfopristin were determined by microbroth dilution.5

Definitions of GREF infection

An episode of GREF infection was defined as isolation of GREF with two or more clinical criteria (see below). Bloodstream infection (BSI) was defined by recovery of GREF from multiple blood cultures, or one blood culture with another culture-positive source of infection other than intravascular device tips. In the absence of another source, isolation from both blood and intravascular device tips was termed catheter-related bacteraemia (CRB). GREF urinary tract infection was defined by repeated isolation from urine, including after catheter removal with pyuria. Recovery of GREF from other sterile fluids was considered to represent infection. Clinical criteria included: white blood cell count (WBC) >10 000/mm3 or <4000 mm3; tachycardia and tachypnoea more than two standard deviations above age normal; mechanical ventilator dependence; inadequate organ perfusion or function; vasopressor dependence; systolic blood pressure more than two standard deviations below mean for age, or altered mental status.6

Quinupristin/dalfopristin therapy

The following were recorded at inclusion and every 2–3 days thereafter: WBC and platelet counts, serum urea, creatinine, aspartate transaminase, alkaline phosphatase, alanine transaminase, {gamma}-glutamyltranspeptidase, total bilirubin and direct bilirubin. Follow-up cultures were performed in all patients routinely and when clinically indicated. Patients received 7.5 mg/kg quinupristin/dalfopristin (without adjustment for renal or hepatic function) by slow infusion through a central venous catheter, every 8 h or 12 h. Severity of infection and response dictated duration of treatment; patients were followed for response and adverse events for 2 weeks after discontinuation.

Definitions of response

Complete response was defined as resolution of fever, leucocytosis and other signs of sepsis with subsequent negative cultures (except from superficial sites or faeces). A partial response was defined as abatement of the above parameters but without complete resolution. Failure was defined as no abatement of, or deterioration in, any clinical parameter, with persistently positive cultures (except from superficial sites or faeces). Uncertain response included intermittent or recurrent symptoms and signs of infection not attributable to GREF. Recurrence of infection was defined as recovery of GREF after initial negative cultures whilst on treatment.


    Results and discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
GREF was recovered from 33 paediatric liver transplant recipients between 1996 and 1999, 21 of whom were deemed to be infected. Fifteen patients yielded isolates resistant to all clinically appropriate antimicrobials and received quinupristin/dalfopristin, as did four of six patients with GREF infection unresponsive to chloramphenicol. Most of the patients had complications requiring surgical intervention or invasive diagnostic procedures (TableGo). All were receiving other antimicrobials, though only two had confirmed concurrent infections: one with herpes simplex virus and one with Candida spp.


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Table. Details of GREF infection, coexisting complications, treatment and outcome of paediatric patients treated with quinupristin/dalfopristin
 
Infections were diagnosed at median 18 days (range 9–122 days) after transplant. Disc testing revealed penicillin, ampicillin and rifampicin resistance in all isolates, high-level gentamicin resistance in 15 isolates and chloramphenicol and tetracycline resistance in nine and four isolates, respectively. All isolates had MICs of ampicillin and vancomycin >64 mg/L; MICs of rifampicin and ciprofloxacin >32 mg/L; and MICs of teicoplanin >=8 mg/L; 15 had gentamicin MICs > 500 mg/L. The MIC ranges for other agents were: chloramphenicol, 4–126 mg/L; doxycycline, 0.06–0.12 mg/L; and quinupristin/dalfopristin, 0.25–2 mg/L.

Quinupristin/dalfopristin therapy was instituted at median 10 days (range 3–16 days) after diagnosis of GREF infection. In four patients, serum alkaline phosphatase concentrations increased during therapy (range 456–2766 IU) but returned to normal after completing therapy. Quinupristin/dalfopristin therapy was not withdrawn because of side-effects in any patients. Complete resolution was seen in 14 (74%) patients. Three patients had a partial response with defervescence and negative cultures, but recurrence of pyrexia after discontinuing treatment, with no other identifiable cause. Response was recorded as uncertain in two patients with no clinical improvement but cultures rendered negative. There were no failures or recurrences. Two deaths during the study period were due to graft failure unrelated to quinupristin/dalfopristin.

Prescribing in liver transplantation is difficult as both hepatic and renal function may be impaired. Susceptibility testing and published experience7 suggested that chloramphenicol might be useful, but half our isolates were resistant and four patients had previously failed chloramphenicol therapy. Although isolates from 14 patients were tetracycline susceptible, age was a contraindication for tetracyclines for most patients.

With the exception of two novel agents active against Gram-positive bacteria, namely quinupristin/dalfopristin and the oxazolidinone, linezolid, few other antimicrobials are available for GREF infections. Quinupristin/dalfopristin, a mixture of two streptogramins synergically active against E. faecium, though not Enterococcus faecalis, has been used successfully for GREF infection.8,9 Although our patients appear to have fared better than others with GREF bacteraemia,9,10 these other studies included adult patients with longer intensive care admissions, and higher proportions of polymicrobial infections or patients with renal failure.9,10

None of our patients experienced serious side-effects, and those recorded have been described in adults.8 Arthralgia and myalgia have been reported as common adverse event in adults,8 but were not seen in our patients, because either they were ventilated, too young or too critically ill to report such reactions. Our experience is that quinupristin/dalfopristin can be safely administered with minimal side-effects to critically ill paediatric patients with complex medical and surgical problems predisposing to hepatic and renal impairment.


    Acknowledgments
 
We thank Dr Pim Kon (formerly of Rhône–Poulenc Rorer; now of Aventis) for advice and provision of MIC data. Quinupristin/dalfopristin was provided as part of the Rhône–Poulenc Rorer Emergency-use Programme.


    Notes
 
* Corresponding author. Tel: +44-20-73463213; Fax: +44-20-73463404. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results and discussion
 References
 
1 . Murray, B. E. (2000). Vancomycin-resistant enterococcal infections. New England Journal of Medicine 342, 710–21.[Free Full Text]

2 . Landman, D. & Quale, J. M. (1997). Management of infections due to resistant enterococci: a review of therapeutic options. Journal of Antimicrobial Chemotherapy 40, 161–70.[Abstract]

3 . Collins, L. A., Malanoski, G. J., Eliopoulos, G. M., Wennersten, C. B., Ferraro, M. J. & Moellering, R. C. (1993). In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms. Antimicrobial Agents and Chemotherapy 37, 598–601.[Abstract]

4 . Barrow G. I. & Feltham R. K. (eds) (1993). Cowan and Steel's Manual for the Identification of Medical Bacteria, 3rd edn. Cambridge University Press, Cambridge.

5 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth Edition: Approved Standard M7-A4. NCCLS, Villanova, PA.

6 . Hayden, W. R. (1994). Sepsis terminology in pediatrics. Journal of Pediatrics 124, 657–8.[Medline]

7 . Norris, A. H., Reilly, J. P., Edelstein, P. H., Brennan, P. J. & Schuster, M. G. (1995). Chloramphenicol for the treatment of vancomycin-resistant enterococcal infections. Clinical Infectious Diseases 20, 1137–44.[ISI][Medline]

8 . Moellering, R. C., Linden, P. K., Reinhardt, J., Blumberg, E. A., Bompart, F. & Talbot, G. H. (1999). The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-use Study Group. Journal of Antimicrobial Chemotherapy 44, 251–61.[Abstract/Free Full Text]

9 . Linden, P. K., Pasculle, A. W., McDevitt, D. & Kramer, D. J. (1997). Effect of quinupristin/dalfopristin on the outcome of vancomycin-resistant Enterococcus faecium bacteraemia: comparision with a control cohort. Journal of Antimicrobial Chemotherapy 39, Suppl. A, 145–51.[Abstract/Free Full Text]

10 . Linden, P. K., Pasculle, A. W., Manez, R., Kramer, D. J., Fung J. J., Pinna, A. D. et al. (1996). Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium. Clinical Infectious Diseases 22, 663–70.[ISI][Medline]

Received 23 June 2000; returned 8 August 2000; revised 5 September 2000; accepted 21 September 2000





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