CID 1996;24 (January)
Brief Reports
with quinupristin/dalfopristin plus another agent with in vitro activity against enterococci may prevent the emergence of moreresistant isolates during treatment. Although the frequency of
emergence of an E. faecium isolate that is relatively resistant to
quinupristin/dalfopristin during therapy with this antimicrobial
agent remains unknown, it would seem prudent for clinicians to
be vigilant for this phenomenon while treating patients with
E. faecium bacteremia.
Joseph W. Chow, Susan M. Donabedian,
and Marcus J. Zervos
Wayne State University School of Medicine and Department of Veterans
Affairs Medical Center, Detroit; and William Beaumont Hospital,
Royal Oak, Michigan
Superinfection with Enterococcus faecalis During
Quinupristin/Dalfopristin Therapy
Quinupristin/dalfopristin (RP59500; Synercid, RhOne-Poulenc
Rorer, Collegeville, PA) is a new semisynthetic antimicrobial agent
from the streptogramin family; it is composed of two compounds
that work synergistically. The agent has good in vitro inhibitory
activity against many staphylococci and enterococci [1], two organisms that have become increasingly resistant to antibiotic therapy.
Quinupristin/dalfopristin has been under study in particular for treatment of infections with methicillin-resistant Staphylococcus aureus
and vancomycin-resistant Enterococcus faecium. However, the
agent has poor in vitro activity against most strains of Enterococcus
faecalis [1, 2]. We describe two patients who developed E. faecalis
bacteremia while being treated with quinupristin/dalfopristin.
The first patient was a 66-year-old man who underwent fourvessel bypass surgery. He subsequently developed methicillinresistant S. aureus endocarditis and was treated with intravenous
vancomycin. However, he developed a severe allergy to vancomycin, which resulted in erythematous edema and sloughing of his
skin. Treatment with vancomycin was discontinued, and that with
intravenous quinupristin/dalfopristin (7.5 mg/kg q8h) was begun;
24 days after quinupristin/dalfopristin therapy was initiated, the
patient developed hypotension and had a fever (temperature to
39.2°C).
Three sets of three blood cultures yielded E. faecalis that was
resistant to quinupristin/dalfopristin (MIC = 8.0 sg/mL). Four
days later two sets of two blood cultures also yielded an isolate
of E. faecalis that was resistant to quinupristin/dalfopristin. This
isolate was susceptible to ampicillin (MIC = 0.5 big/mL), vancomycin (MIC = 1.0 Ag/mL), and gentamicin (MIC = 4 sg/mL).
Culture of the central catheter tip also yielded E. faecalis with the
same antibiotic susceptibility pattern.
Financial support: This work was supported in part by the William Beaumont
Hospital Research Institute and the Metropolitan Detroit Research and Education Foundation.
Reprints or correspondence: Dr. Joseph W. Chow, Division of Infectious
Diseases, 4160 John R, Suite 2140, Detroit, Michigan 48201-2021.
Clinical Infectious Diseases 1997; 24:91-2
© 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2401 — 0023$02.00
91
References
1. Donabedian SM, Chow JW, Boyce JM, et al. Molecular typing of ampicillinresistant, non-O-lactamase-producing Enterococcus faecium isolates from
diverse geographic areas. J Clin Microbiol 1992; 30:2757-61.
2. Collins LA, Malanoski GJ, Eliopoulos GM, Wennersten CB, Ferraro MJ,
Moellering RC Jr. In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms.
Antimicrob Agents Chemother 1993; 37:598-601.
3. Johnson CC, Slavoski L, Schwartz M, et al. In vitro activity of RP59500
(quinupristin/dalfopristin) against antibiotic-resistant strains of Streptococcus pneumoniae and enterococci. Diagn Microbiol Infect Dis 1995;
21:169-73.
4. Freeman C, Robinson A, Cooper B, Mazens-Sullivan M, Quintiliani R,
Nightingale C. In vitro antimicrobial susceptibility of glycopeptide-resistant enterococci. Diagn Microbiol Infect Dis 1995;21:47-50.
Because the patient had a history of severe allergy to penicillin
as well as vancomycin, he did not receive treatment with ampicillin; he was treated instead with intravenous tobramycin for 4 days
and intravenous gentamicin for 14 days. The patient became afebrile 1 day after the initiation of aminoglycoside therapy and the
removal of the central venous catheter. Six subseqUent blood cultures did not yield enterococci. The patient died 1 month later of
multiple medical complications, including gastrointestinal hemorrhage, pneumonia, respiratory failure, acute renal failure, and
S. aureus bacteremia.
The second patient was a 36-year-old man who was undergoing
hemodialysis for diabetes-induced end-stage renal disease and who
was hospitalized for a right-upper-extremity wound infection. He
had been receiving intravenous vancomycin for 13 days (partly as
an outpatient) for previous bacteremia due to E. faecalis, S. aureus,
and a coagulase-negative Staphylococcus species. On admission,
treatment with intravenous vancomycin was continued, and ampicillin was added to the regimen. One set of four blood cultures performed on admission yielded a coagulase-negative Staphylococcus
species. One set of three blood cultures performed 3 days after
admission yielded E. faecium that was resistant to vancomycin, ampicillin, and gentamicin. Treatment with vancomycin and ampicillin
was discontinued, and quinupristin/dalfopristin therapy was begun.
After 20 days of quinupristin/dalfopristin therapy, the patient had
an acute drop in blood pressure accompanied by mental confusion
and an elevated WBC count of 18,700/mm 3 . One set of two blood
cultures yielded E. faecalis that was resistant to quinupristin/dalfopristin (MIC = 8.0 ktg/mL) and gentamicin (MIC, >2,000 pg/mL)
but susceptible to ampicillin (MIC = 0.5 ,ug/mL) and vancomycin
(MIC = 1.0 .tg/mL). Treatment with quinupristin/dalfopristin was
discontinued, and vancomycin therapy was begun. The patient died
of a sudden cardiac arrest 12 days later in the intensive care unit.
Quinupristin/dalfopristin shows promise in treating infections due
to S. aureus and E. faecium. The agent has been reported to be
successful for treating S. aureus bacteremia and E. faecium peritonitis
[3, 4]. Treatment with quinupristin/dalfopristin was a good alternative
for the first patient, who was infected with methicillin-resistant
S. aureus and who had a severe allergy to vancomycin. The second
patient's case is typical of infection with multiresistant E. faecium
for which no good alternative therapy is available. Quinupristin/
dalfopristin is a promising antimicrobial agent in these situations.
Unfortunately, it has poor in vitro activity against many strains of
E. faecalis. The findings in these two cases illustrate that clinicians
CID 1997;24 (January)
Brief Reports
92
should be aware of the potential for E. faecalis superinfection, including bacteremia, in patients treated with quinupristin/dalfopristin.
Joseph W. Chow, Alma Davidson, Edward Sanford III,
and Marcus J. Zervos
Department of Veterans Affairs Medical Center and Wayne State
University School of Medicine, Detroit; and William Beaumont Hospital,
Royal Oak, Michigan
References
1. Collins LA, Malanoski GJ, Eliopoulos GM, Wennersten CB, Ferraro MJ,
Moellering RC Jr. In vitro activity of RP59500, an injectable strepto-
Clarithromycin-Associated Digoxin Toxicity in the
Elderly
Clarithromycin has become an essential component of treatment
regimens for infections due to Mycobacterium avium complex
(MAC). Drug interactions are an important consideration with the
use of clarithromycin because it is both an inhibitor and a substrate
for the cytochrome P-450 system. An interaction that is not well
appreciated involves inhibition of the colonic inactivation of digoxin, resulting in subsequent digoxin toxicity. We describe a
patient in whom this interaction occurred.
A 91-year-old male with MAC lung disease and atrial fibrillation
presented with a 5-day history of abdominal cramps and pain,
nausea, vomiting, and anorexia. Nine days previously, the patient
had started receiving daily treatment with clarithromycin (1,000
mg), rifabutin (300 mg), and ethambutol (1,400 mg) for recurrence
of MAC lung disease. (He had previously received treatment with
the latter two medicines with no side effects.) The patient was also
gramin antibiotic, against vancomycin-resistant Gram-positive organisms. Antimicrob Agents Chemother 1993; 37:598-601.
2. Johnson CC, Slavoski L, Schwartz M, et al. In vitro activity of RP59500
(quinupristin/dalfopristin) against antibiotic-resistant strains of Streptococcus pneumoniae and enterococci. Diagn Microbiol Infect Dis 1995;
21:169-73.
3. Torralba MD, Frey SE, Lagging LM. Treatment of methicillin-resistant
Staphylococcus aureus infection with quinupristin/dalfopristin [letter].
Clin Infect Dis 1995;21:460-1.
4. Lynn WA, Clutterbuck E, Want S, et al. Treatment of CAPD-peritonitis
due to glycopeptide-resistant Enterococcus faecium with quinupristin/
dalfopristin. Lancet 1994;344:1025-6.
Physical examination revealed a blood pressure of 140/72 mm Hg
and a pulse rate of 56. The results of all hepatic and renal function
tests were normal (table 1). An electrocardiogram showed sinus
bradycardia. Repeated testing showed a serum digoxin level of 3.5
ng/mL. Treatment with digoxin and clarithromycin was stopped.
Findings on a repeated electrocardiogram were unchanged. The patient's symptoms resolved within 36 hours; repeated determinations
showed that the serum digoxin levels had decreased to 2.7 ng/mL,
2.5 ng/mL, and then <2.0 ng/mL.
We identified three other cases of clarithromycin-related digoxin
toxicity, all in elderly patients [1-3]. The first case involved a 66year-old male who developed nausea, blurred vision, and supraventricular tachycardia. The patient recovered within 24 hours after
treatment with digoxin and clarithromycin was discontinued [3].
A second 81-year-old patient developed nausea and confusion 4
days after administration of clarithromycin and was hospitalized
with a serum digoxin level of 3.7 ng/mL. Therapy with digoxin and
clarithromycin was again discontinued, and the patient's symptoms
abated within 2 days [1]. A third case report [2] described a
Table 1. Reported cases of digoxin toxicity in elderly patients receiving clarithromycin therapy.
Patient
age
(y)
Dose of digoxin
(mg), day of
week
1 [3]
2 [2]
66
77
3 [1]
4 [PR]
81
91
0.5/d
0.25 M, W, F
0.125 T, Th, S, S
0.25/d
0.25/d
Case
[reference]
Peak serum
level of
digoxin
(ng/mL)
Days from initiation
of clarithromycin
therapy adverse
event
Serum level
of creatinine
(mg/dL)
Serum level of digoxin
before clarithromycin
therapy
(ng/mL)
4.3
3.7
17
4
Normal
Unknown
<0.2
0.5-0.7
3.7
3.5
7
7
0.7
0.8
1.0
1.2
NOTE. PR = present report.
receiving digoxin (0.25 mg daily). A recently determined serum
level of digoxin was 1.2 ng/mL (normal range, 0.9-2.0 ng/mL).
His only other medicine was one aspirin per day.
Reprints or correspondence: Dr. Barbara A. Brown, Department of Microbiology, University of Texas Health Center at Tyler, P.O. Box 2003, Tyler,
Texas 75710.
Clinical Infectious Diseases 1997; 24:92-3
© 1997 by The University of Chicago. All rights reserved.
1058-4838/97/2401-0024$02.00
77-year-old male with gastrointestinal symptoms and a serum digoxin level of 3.7 ng/mL (table 1).
The current package insert for digoxin [4] states that concomitant
coadministration with erythromycin (and possibly other macrolides)
may cause elevated serum levels of digoxin [4]. Approximately
60%-80% of an oral dose of digoxin is absorbed from the gastrointestinal tract, and as much as 40% of the drug is metabolized by colonic
flora [5-7]. Oral erythromycin or tetracycline appears to inhibit these
bacteria, and thus degradation of the drug diminishes, allowing more
active drug to be absorbed [5, 8]. Clarithromycin is believed to have
a similar effect on digoxin [9]. Elevated digoxin levels have not been
reported in clinical trials with azithromycin.