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Antimicrobial Agents and Chemotherapy, April 2005, p. 1664-1665, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1664-1665.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Emergence of Daptomycin Resistance in Enterococcus faecium during Daptomycin Therapy

Top Letter References

 
Daptomycin is a cyclic lipopeptide antibiotic that has been available in the United States since September 2003. We report a clinical and bacteriological failure of daptomycin therapy for enterococcal bacteremia. Briefly, a 22-year-old man with Hodgkin's lymphoma, subsequent acute myelogenous leukemia, and nonseminomatous testicular carcinoma developed neutropenic fever during chemotherapy in 2004. A urine culture at hospital admission yielded 50,000 to 100,000 CFU of Enterococcus faecium/ml that were resistant to vancomycin (VRE) but susceptible to daptomycin (MIC = 2 µg/ml) and doxycycline. The patient initially received doxycycline, cefepime, metronidazole, and vancomycin. Two days later, a urine culture grew <10,000 CFU of VRE/ml. Computed tomography of the abdomen revealed bilateral wedge-shaped renal hypodensities compatible with a diagnosis of focal pyelonephritis. All blood cultures obtained during early hospitalization were negative, and on hospital day (HD) 8 the patient's urine culture was negative. Due to persistent fever, daptomycin (6 mg/kg of body weight/day) was used in place of doxycycline and vancomycin beginning on HD 9 and continuing until HD 26, for 17 days of therapy. When chemotherapy was again initiated, the fever returned, and blood cultures at that time grew Escherichia coli, for which meropenem was initiated. The patient continued to be febrile, and a blood culture revealed VRE. Susceptibility testing performed by the broth microdilution method with calcium-supplemented Mueller-Hinton broth and by the disk diffusion procedure (5, 6) indicated a daptomycin MIC of greater than 32 µg/ml and a reduced disk diffusion zone diameter (Table 1). While the daptomycin MIC reflected resistance, the zone of inhibition was within the range indicative of susceptibility (i.e., 11 mm) by the recently published breakpoints (3). Daptomycin was discontinued and linezolid was initiated at 600 mg intravenously twice daily. The fever persisted, and daptomycin-resistant VRE again grew from two blood cultures obtained 5 days after linezolid was initiated. Linezolid was continued with the addition of doxycycline, and the catheter was removed. The fever abated, and all further blood cultures were negative. Pulsed-field gel electrophoresis of SmaI digests of chromosomal DNA of the four VRE isolates indicated that they were highly related.

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TABLE 1. MICs of selected antibiotics against pre- and postdaptomycin therapy VRE isolates

Daptomycin is a new agent for treating serious methicillin-resistant Staphylococcus aureus (MRSA) and enterococcal infections (1, 2). Its value has been due in part to the fact that resistance of MRSA and VRE to linezolid has already been encountered, and quinupristin-dalfopristin resistance of VRE has been widely reported (7, 8, 9). A previous examination of a collection of unrelated VRE from several geographic areas of the United States did not reveal any isolates with daptomycin MICs that exceeded 8 µg/ml (4). This appears to represent the first description of a clinical and bacteriological failure of an invasive VRE infection due to the emergence of high-level daptomycin resistance during therapy. However, a recent report has illustrated the emergence of resistance in MRSA isolates during daptomycin therapy (K. Rezai, J. P. Quinn, R. Hayes, K. Lolans, R. A. Weinstein, and M. K. Hayden, Abstr. 44th Intersci. Conf. Antimicrob. Agents Chemother., abstr. K-97a, 2004). Clinicians and microbiologists should be aware of the possibility of the emergence of daptomycin resistance and closely monitor the susceptibilities of subsequent isolates that might be recovered during therapy. However, the present breakpoints for the disk diffusion test do not appear to be reliable for the detection of resistance.

 
We thank the staff of the University Hospital Microbiology Laboratory, Cynthia Kelly, and M. Leticia McElmeel for valuable contributions to this report.

Top Letter References

 

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1. Arbeit, R. D., D. Maki, F. P. Tally, E. Campanaro, and B. I. Eisenstein. 2004. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin. Infect. Dis. 38:1673-1681.[CrossRef][Medline]
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2. Cha, R., and M. Rybak. 2003. Daptomycin against multiple drug-resistant staphylococcus and enterococcus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Diagn. Microbiol. Infect. Dis. 47:539-546.[CrossRef][Medline]
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3. Clinical and Laboratory Standards Institute. 2005. Performance standards for antimicrobial susceptibility testing. Supplement M100-S15. Clinical and Laboratory Standards Institute, Wayne, Pa.
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4. Jorgensen, J. H., S. A. Crawford, C. C. Kelly, and J. E. Patterson. 2003. In vitro activity of daptomycin against vancomycin-resistant enterococci of various Van types and a comparison of susceptibility testing methods. Antimicrob. Agents Chemother. 47:3760-3763.[Abstract/Free Full Text]
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5. NCCLS. 2003. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A6. NCCLS, Wayne, Pa.
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6. NCCLS. 2003. Performance standards for antimicrobial disk susceptibility tests. Approved standard M2-A8. NCCLS, Wayne, Pa.
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7. Raad, I. I., H. A. Hanna, R. Y. Hachem, T. Dvorak, R. B. Arbuckle, G. Chaiban, and L. B. Rice. 2004. Clinical-use-associated decrease in susceptibility of vancomycin-resistant Enterococcus faecium to linezolid: a comparison with quinupristin-dalfopristin. Antimicrob. Agents Chemother. 48:3583-3585.[Abstract/Free Full Text]
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8. Rahim, S., S. K. Pillai, H. S. Gold, L. Venkataraman, K. Inglima, and R. A. Press. 2003. Linezolid-resistant, vancomycin-resistant Enterococcus faecium infection in patients without prior exposure to linezolid. Clin. Infect. Dis. 36:E146-E148. [Online.][CrossRef][Medline]
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9. Tsiodras, S., H. S. Gold, G. Sakoulas, G. M. Eliopoulos, C. Wennersten, L. Venkataraman, R. C. Moellering, Jr., and M. J. Ferraro. 2001. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 358:207-208.[CrossRef][Medline]

						Kathryn Sabol Jan E. Patterson South Texas Veterans Affairs Healthcare System James S. Lewis II Pharmacy Service, University Health System,  and Department of Pharmacology and Clinical Pharmacy Aaron Owens Departments of Medicine, Division of  Infectious Diseases Jose Cadena Department of Medicine James H. Jorgensen* Department of Pathology The University of Texas Health  Science Center San Antonio, TX 78229
						* Phone: (210) 567-4088,Fax: (210) 567-2367,E-mail: jorgensen{at}uthscsa.edu

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Antimicrobial Agents and Chemotherapy, April 2005, p. 1664-1665, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1664-1665.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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This Article Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sabol, K. Articles by Jorgensen, J. H. Search for Related Content PubMed PubMed Citation Articles by Sabol, K. Articles by Jorgensen, J. H.