CASE REPORT
DAPTOMYCIN-RESISTANT ENTEROCOCCUS FAECIUM
Daptomycin-Resistant Enterococcus faecium in a
Patient With Acute Myeloid Leukemia
JENNIFER K. LONG, PHARMD; TONI K. CHOUEIRI, MD; GERALDINE S. HALL, PHD; ROBIN K. AVERY, MD;
AND MIKKAEL A. SEKERES, MD, MS
Daptomycin is a lipopeptide antimicrobial used for the treatment
of aerobic gram-positive skin and soft tissue infections. We de-
scribe a patient with acute myeloid leukemia whose febrile neutro-
penia was treated with daptomycin and who later developed
daptomycin-resistant Enterococcus faecium infection. Deferves-
cence and negative blood cultures ensued after treatment with
linezolid. Guidelines for testing daptomycin susceptibilities of
enterococci include breakpoints only for vancomycin-susceptible
Enterococcus faecalis, making interpretation of minimum inhibi-
tory concentrations for common clinical infections difficult. No
enterococcal cross-resistance has been reported among
daptomycin, linezolid, or quinupristin-dalfopristin, and these
agents may be viable alternatives.
Mayo Clin Proc. 2005;80(9):1215-1216
MIC = minimum inhibitory concentration; VRE = vancomycin-resistant
Enterococcus faecium
D aptomycin is the first lipopeptide antimicrobial to be
approved by the US Food and Drug Administration
for the treatment of complicated skin and soft tissue infec-
tions.1 It has significant in vitro bactericidal activity against
aerobic gram-positive organisms, including glycopeptide-
and oxazolidinone-resistant enterococci and methicillin-
resistant Staphylococcus aureus.2 To date, no mechanism
for resistance to daptomycin has been identified, although
2 cases of resistant organisms were reported in more than
1000 subjects enrolled in phase 2 and phase 3 clinical
trials—1 case of S aureus and 1 of Enterococcus faecalis in
patients receiving lower drug doses than are used cur-
rently.3 We report a case of daptomycin-resistant Entero-
coccus faecium infection in a patient undergoing treatment
of acute myeloid leukemia.
REPORT OF A CASE
A 37-year-old woman presented to our hospital with fever,
fatigue, and pancytopenia. Circulating blasts were noted in
her peripheral blood smear. A bone marrow biopsy speci-
men contained 80% blasts of myeloid origin, and acute
myeloid leukemia was diagnosed. Remission-induction
chemotherapy consisting of idarubicin and cytarabine was
initiated. The patient became severely neutropenic and
transfusion dependent, and fever developed 1 week after
initiation of chemotherapy. Broad-spectrum antibiotics, in-
cluding piperacillin-tazobactam, gentamicin, and vanco-
Mayo Clin Proc. • September 2005;80(9):1215-1216
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
mycin, were administered intravenously. The fever per-
sisted, and amphotericin B was added. A severe maculo-
papular rash prompted replacement of vancomycin with
daptomycin (6 mg/kg), with resolution of the rash.
Additional chemotherapy consisting of cytarabine,
etoposide, and mitoxantrone was initiated 3 weeks after the
first course for persistent leukemia. Seven days later, when
the patient had been neutropenic for approximately 4
weeks and had been receiving daptomycin for 17 days, she
became febrile, with temperatures as high as 38.9oC for 5
consecutive days. Computed tomography revealed pansi-
nusitis, and nasal sinus cultures were positive for Aspergil-
lus fumigatus, thought to be a contaminant because the
fever did not abate in response to amphotericin B and later
voriconazole. Within 24 hours, 1 of 3 blood cultures grew
vancomycin-resistant E faecium (VRE), which was not
susceptible to daptomycin (zone diameter, 8.7 mm; suscep-
tible, ≥11 mm). This was determined
with use of the Kirby-Bauer disk diffu- For editorial
sion test performed according to stan- comment, see
dard Clinical and Laboratory Standards page 1122
Institute (CLSI—formerly the National
Committee for Clinical Laboratory Standards [NCCLS])
methods for daptomycin susceptibility.4 A microdilution
test yielded a minimum inhibitory concentration (MIC) of
greater than 8 µg/mL. Additional susceptibility patterns
were as follows: ampicillin, greater than 16 µg/mL (resis-
tant); linezolid, 1 µg/mL (susceptible); quinupristin-
dalfopristin, 0.5 µg/mL (susceptible); chloramphenicol, 4.0
µg/mL (susceptible); and gentamicin and streptomycin,
high-level resistance demonstrated.
The isolate was sent to a reference laboratory, where
microdilution and Kirby-Bauer disk diffusion tests con-
firmed nonsusceptibility (MIC, >32 µg/mL; zone diameter,
From the Department of Pharmacy (J.K.L.), Department of Hematology and
Medical Oncology (T.K.C., M.A.S.), Clinical Microbiology Section, Department
of Pathology (G.S.H.), and Department of Infectious Diseases and Transplant
Center (R.K.A.), The Cleveland Clinic Foundation, Cleveland, Ohio.
Drs Long and Hall are on an advisory board for Cubist Pharmaceuticals, Inc.
Drs Choueiri, Avery, and Sekeres report no conflicts of interest.
Individual reprints of this article are not available. Address correspondence to
Mikkael A. Sekeres, MD, MS, Department of Hematology and Medical Oncol-
ogy, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk R35, Cleveland,
OH 44195 (e-mail: sekerem@ccf.org).
© 2005 Mayo Foundation for Medical Education and Research
• www.mayoclinicproceedings.com 1215
DAPTOMYCIN-RESISTANT ENTEROCOCCUS FAECIUM
9 mm). Daptomycin was discontinued, the patient was
treated with linezolid, and defervescence with subsequent
negative blood cultures ensued. Two months later, the pa-
tient received a matched unrelated allogeneic bone marrow
transplant and had a recurrence of VRE bacteremia with the
same antimicrobial susceptibility pattern identified in 4
sets of blood cultures. Her Hickman catheter was removed,
and echocardiography showed no evidence of vegetations.
DISCUSSION
Daptomycin is a novel antimicrobial developed in the early
1980s. Daptomycin’s exact mechanism of action has not
been fully elucidated, but research has shown that it binds
to the cytoplasmic membrane of gram-positive bacteria in a
calcium-dependent manner. Once bound, the lipopeptide
tail of the molecule is inserted into the bacterial cell mem-
brane. This tail serves as an ion channel through which an
efflux of potassium, and potentially other ions, can pass,
thereby causing the bacterial cell to depolarize rapidly and
ultimately resulting in cell death.1,5 Daptomycin’s activity
depends on the presence of calcium ions, a factor that
influences the conditions required for in vitro testing. Con-
cerns about skeletal muscle toxicity led to voluntary sus-
pension of clinical trials of daptomycin in 1991. Prompted
by the perceived increased need for new gram-positive
agents in the late 1990s, further investigations were under-
taken.1 Subsequent in vitro studies showed daptomycin to
be rapidly bactericidal for all gram-positive organisms,
including drug-resistant strains. Concentration-dependent
activity and a strong postantibiotic effect have been identi-
fied, indicating that higher doses such as 4 to 6 mg/kg
administered once daily may improve efficacy and mini-
mize the risk of skeletal muscle toxicity, which is thought
to be related to high drug trough levels.
Guidelines for testing daptomycin susceptibilities of en-
terococci include breakpoints only for vancomycin-suscep-
tible E faecalis (MIC, ≤4 µg/mL or a zone diameter of ≥11
mm). No interpretive criteria for intermediate or resistant
breakpoints have been proposed because of the lack of
resistant isolates.5 Furthermore, no interpretive criteria for
E faecium exist. In vitro studies have shown a slightly
higher MIC90 (concentration at which 90% of strains are
inhibited) for E faecium compared with E faecalis (4 µg/
mL vs 1 µg/mL), yet most isolates would still be consid-
ered susceptible using E faecalis breakpoints.6 In addition,
a previous report of daptomycin-resistant E faecium indi-
cated that disk diffusions may not reliably detect resis-
tance.7 In that case, the isolate was determined to be resis-
tant by broth microdilution but not by disk diffusion. In
practice, however, clinicians may choose daptomycin for
the treatment of VRE infections because other available
1216 Mayo Clin Proc. • September 2005;80(9):1215-1216
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
therapies such as linezolid and quinupristin-dalfopristin
have adverse effects that may be considered prohibitively
toxic (eg, bone marrow suppression and myalgias, respec-
tively). For example, linezolid was avoided initially in our
patient because of concerns about the risk of hematologic
adverse effects of the drug in an already compromised host.
In addition, daptomycin has been shown to be bactericidal
against enterococci, whereas most therapies are only
static.2 Inasmuch as no guidelines are available for inter-
preting E faecium MIC data for daptomycin and clinical
trials of daptomycin for treatment of such infections are not
available, it is difficult for clinicians to interpret and apply
existing MIC data to patient care.
Daptomycin is a new addition to the armamentarium of
agents available for the treatment of resistant gram-positive
infections. Its rapid bactericidal activity, once-daily dos-
ing, and safety profile make it an attractive alternative for
the treatment of gram-positive infections. Clinicians
should be aware that currently MIC breakpoints have been
determined only for vancomycin-sensitive E faecalis. Fur-
ther studies correlating pharmacokinetic parameters and in
vitro data are needed to identify appropriate clinical
breakpoints for daptomycin and to optimize dosing regi-
mens for patients with VRE infections.
Daptomycin pharmacokinetics are linear and concentra-
tion dependent; therefore, higher dosages may provide ad-
equate coverage for organisms with elevated MICs. No
enterococcal cross-resistance has been reported among
daptomycin, linezolid, or quinupristin-dalfopristin. Thus,
these agents may also be viable alternatives for dapto-
mycin-nonsusceptible isolates. Until breakpoints for E
faecium are defined, clinicians should consider a change in
therapy when a daptomycin MIC of greater than 4 µg/mL
or a zone diameter of less than 11 mm occurs.
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