The Division of Geographic Medicine and Infectious Disease, New England Medical Center and Tufts University School of Medicine, 750 Washington Street, Boston, MA 02111, USA
Sir,
Leuconostoc spp. are Gram-positive vancomycin-resistant pathogens that are emerging as a rare cause of bacteraemia in severely ill and immunocompromised hosts.1 Daptomycin is a novel lipopeptide antibiotic that is undergoing investigational use for the treatment of infections with Gram-positive bacteria, including those resistant to vancomycin.2 We describe the use of daptomycin for successful treatment of Leuconostoc bacteraemia in two neutropenic bone marrow transplantation (BMT) patients who failed to respond to a vancomycin-containing empirical antibiotic regimen.
Subjects were enrolled into a study to evaluate the efficacy of daptomycin in the treatment of vancomycin-resistant Gram-positive infections. The study was approved by the Human Investigation Review Committee. MICs for all antibiotics were determined by the broth microdilution method, except for cefepime, which was determined by Etest (AB Biodisk, Solna, Sweden).3 MBCs were determined by subculturing the clear broth microdilution tubes. Greater than a 3-log reduction in colony counts was considered evidence of bactericidal activity.3 PFGE was performed on the two Leuconostoc isolates to determine DNA strain relatedness.3
Case 1: an 18-year-old woman was admitted for treatment of recurrent Hodgkin's lymphoma. Ciprofloxacin, trimethoprimsulphamethoxazole and acyclovir prophylaxis was initiated and high-dose chemotherapy was administered, followed by allogeneic BMT on hospital day 8. Six days post-transplantation she developed high fever, nausea and right shoulder pain, and was started on imipenem and
vancomycin. Low-grade fever persisted and on post-BMT day 11 imipenem was discontinued due to a rash. Vancomycin was continued; cefepime and amphotericin B were added. She developed grade 2 graft versus host disease for which hydrocortisone was initiated. On day 15 post-BMT she developed fever of 40°C followed by septic shock. Blood cultures obtained from peripheral veins and central catheters grew Leuconostoc mesenteroides, which was susceptible to daptomycin (Table). Vancomycin was discontinued. All central catheters were removed. Hickman catheter cultures grew 1550 cfu of L. mesenteroides. Following informed consent she received a 400 mg loading dose of iv daptomycin followed by 4.5 mg/kg every 36 h, adjusted for a creatinine clearance of 55 mL/min, for 8 days. Recovery of renal function occurred on day 9 of daptomycin. The dose was subsequently increased to 6 mg/kg qds for a total course of 15 days. The fever subsided 2 days after the initiation of daptomycin, and she remained afebrile until her discharge on day 42. All subsequent blood cultures were negative. Early in the course of therapy, the patient developed severe facial and oral oedema in the setting of receiving amphotericin B, cefepime, daptomycin and platelet transfusions. Diphenhydramine hydrochloride was started, and the oedema resolved. She tolerated the remainder of her therapy without incident.
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Blood cultures were drawn, and cefepime and vancomycin were started. Blood cultures grew L. mesenteroides susceptible to daptomycin (Table). Penicillin was avoided due to history of allergy. After informed consent he was started on iv daptomycin, 6 mg/kg qds. Within 2 days the fever subsided and the blood cultures became sterile. Three days after the initiation of daptomycin, lumbar puncture was performed to assess for the presence of leukaemic meningitis. CSF culture was positive for Staphylococcus epidermidis and daptomycin was discontinued. Vancomycin and penicillin were initiated and cefepime was continued. Three days after the discontinuation of daptomycin the patient redeveloped fever and rash. His blood cultures, obtained from a peripheral vein and a central catheter, again grew L. mesenteroides. CSF cultures were negative. Daptomycin was restarted, vancomycin and penicillin were discontinued, and all central catheters removed. Within 2 days the fever resolved and subsequent blood cultures were sterile. The Hickman catheter tip cultures grew 1550 cfu of Leuconostoc spp. Daptomycin was continued for 3 weeks without adverse events. The patient died a month later due to complications of leukaemia.
Two patients who developed catheter-associated Leuconostoc bacteraemia after BMT failed to respond to vancomycin and were successfully treated with daptomycin along with removal of iv lines. Both tolerated the drug well. The two isolates showed a similar DNA-fragment pattern (data not shown) suggestive of a common source, which was not determined.
Leuconostoc spp., members of the Streptococcaceae family, are increasingly described as nosocomial pathogens infecting severely ill and immunosuppressed patients.1 While focal infections such as meningitis, pneumonia, endocarditis, osteomyelitis and urinary tract infection were documented, it had been most frequently described as a cause of hospital-acquired bacteraemia.4 Leuconostoc spp. are commonly misidentified as streptococci until susceptibility testing reveals its characteristic resistance to vancomycin.5
Unlike the glycopeptides, daptomycin, a lipopeptide antibiotic derived from a fermentation product produced by Streptomyces roseosporus, disrupts multiple aspects of bacterial plasma membrane function, including peptidoglycan synthesis, lipoteichoic acid synthesis and the bacterial membrane potential, and provides rapid, concentration-dependent killing and prolonged post-antibiotic effect in vitro.2 It has been shown to have in vitro bactericidal activity against all Gram-positive microorganisms including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate-susceptible S. aureus, coagulase-negative staphylococci, vancomycin-resistant enterococci and strains of Leuconostoc, Lactobacillus and Pediococcus, all of which are resistant to vancomycin.2,6 Phase 2 clinical trials demonstrated that daptomycin at doses of 2 mg/kg od and 3 mg/kg bd is efficacious against skin and soft tissue infections and bacteraemia, respectively. Animal toxicity studies demonstrated that reversible, dose-dependent, skeletal muscle damage is the main target organ toxicity. Neural, renal, and gastrointestinal toxicity was also associated with daptomycin. Elevated creatine phosphokinase and muscle weakness were the most common adverse effects in humans receiving this drug.2
Daptomycin was found to be safe and effective in the treatment of catheter-related bacteraemia caused by vancomycin-resistant Leuconostoc. Its future role in the treatment of resistant Gram-positive organisms should be determined according to the results of several ongoing large-scale clinical trials.
Acknowledgments
Part of this manuscript was presented at the Tenth European Congress of Clinical Microbiology and Infectious Diseases, Stockholm, Sweden, May 2000. The daptomycin study, in which both patients described in this manuscript were enrolled, was supported by Cubist Pharmaceuticals, Boston, MA.
Notes
J Antimicrob Chemother 2001; 47: 364365
* Corresponding author. Tel: +1-617-636-5788; Fax: +1-617-636-8525; E-mail: dsnydman{at}lifespan.org
References
1 . Zinner, S. H. (1999). Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on Gram-positive and resistant bacteria. Clinical Infectious Disease 29, 4904.[ISI][Medline]
2 . Tally, P. T., Zeckel, M., Wasilewski, M. M., Carini, C., Berman, C. L., Drusano, G. L. et al. (1999). Daptomycin: a novel agent for gram-positive infections. Expert Opinion on Investigational Drugs 8, 116.
3 . Tenover, F. C. (1999). Antimicrobial agents and susceptibility testing. In Manual of Clinical Microbiology, 7th edn, (Murray, P. R., Baron, E. J., Pfaller, M. A., Tenover, F. C. & Yolken, R. H., Eds), pp. 1467592. American Society for Microbiology, Washington, DC.
4 . Handwerger, S., Horowitz, H., Coburn, K., Kolokathis, A. & Wormser, G. P. (1990). Infection due to Leuconostoc species: six cases and review. Review of Infectious Disease 12, 60210.[ISI][Medline]
5 . Isenberg, H. D., Vellozzi, E. M., Sapiro, J. & Rubin, L. G. (1988). Clinical laboratory challenges in the recognition of Leuconostoc species. Journal of Clinical Microbiology 26, 47983.[ISI][Medline]
6 . de la Maza, L., Ruoff, K. L. & Ferraro, M. J. (1989). In vitro activities of daptomycin and other antimicrobial agents against vancomycin-resistant Gram-positive bacteria. Antimicrobial Agents and Chemotherapy 33, 13834.[ISI][Medline]