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Rapid Development of Resistance to Clarithromycin Following Monotherapy for
Disseminated Mycobacterium chelonae Infection in a Heart Transplant Patient
Pablo Tebas, Faisal Sultan, Richard J. Wallace, Jr.,* and
Victoria Fraser
From the Infectious Diseases Division, Department of Medicine,
Washington University School of Medicine, St. Louis, Missouri
Mycobacterium chelonae (formerly known as M. chelonae subspecies chelonae) is a rapidly
growing mycobacterium that can cause disseminated infections, especially in immunocompromised hosts. The bacterium is typically resistant to antimicrobial agents; less than 20% of M.
chelonae isolates are susceptible to trimethoprim-sulfamethoxazole, doxycycline, erythromycin,
or ciprofloxacin. Findings in a recent study suggested that clarithromycin may be the drug of
choice for the treatment of cutaneous (disseminated) disease due to M. chelonae. We describe a
60-year-old heart transplant patient with disseminated M. chelonae infection for whom monotherapy with clarithromycin failed because of the rapid development of resistance to the drug.
Case Report
A 60-year-old male underwent orthotopic heart transplantation on 1 December 1992 because of severe ischemic cardiomyopathy. After transplantation, he received treatment
with prednisone, cyclosporin A, and azathioprine as immunosuppressive agents and trimethoprim-sulfamethoxazole
(TMP-SMZ) as prophylaxis against Pneumocystis carinii. On
Received 3 March 1994; revised 23 May 1994.
* Current affiliation: Department of Microbiology, University of Texas
Health Center, Tyler, Texas.
Reprints or correspondence: Dr. Pablo Tebas, Infectious Diseases Division, Washington University, Box 8051, 660 South Euclid, St. Louis, Missouri 63110.
Clinical Infectious Diseases 1995;20:443-4
© 1995 by The University of Chicago. All rights reserved.
1058-4838/95/2002-0032$02.00
28 December 1992 he had an episode of acute rejection that
was treated with three boluses of 5 methyl-prednisolone (500
mg each). On 30 March 1993 he presented with multiple,
red, nontender subcutaneous nodules. A nodule had appeared on his right hand 6 weeks before presentation, and
similar lesions subsequently developed on both arms. He denied having fever or any systemic symptoms except fatigue.
A physical examination revealed multiple subcutaneous
nodules (1 cm in diameter), primarily on the arms and legs;
two of the lesions were pustular. The white blood cell count
was 5,700/mm 3 , and the creatinine level was 2.3 mg/dL.
Examination of an aspirate of the nodules showed an acidfast, gram-positive, branching filamentous organism. The
patient began treatment with high-dose TMP-SMZ for suspected nocardiosis. The organism was subsequently identified as M. chelonae, and treatment with clarithromycin (500
mg twice a day) was initiated. The dosage of TMP-SMZ was
reduced to one double-strength pill every day. The nodules
disappeared while the patient was receiving clarithromycin
therapy (the drug susceptibilities of the organism are shown
in table 1).
In June 1993 the patient developed new nodular lesions
on the forearms and general malaise. Examination of a skin
biopsy specimen again showed acid-fast, branching filamentous organisms. M. chelonae was identified, but the isolate
was now highly resistant to clarithromycin. Immunosuppressive drugs were reduced to the minimum dosage possible,
and intravenous therapy with imipenem and tobramycin was
started; the patient's clinical condition improved. Tobramycin therapy was discontinued 4 weeks later because of nephrotoxicity.
In October 1993, after 14 weeks of imipenem monotherapy, the patient had another relapse. Culture of a skin lesion
yielded M. chelonae; the isolate's susceptibility pattern was
similar to those of the two previous isolates except for a onedilution rise in the MIC of imipenem (MIC = 16 tig/mL), an
increase in the MIC of the aminoglycosides, and development of clinically significant resistance to clarithromycin.
With the agreement of the patient, all antibiotic therapy was
discontinued because of his lack of response, the increase in
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Mycobacterium chelonae (formerly known as M. chelonae
subspecies chelonae) is a rapidly growing mycobacterium
that causes skin and soft tissue infections; these infections
may disseminate, especially in immunocompromised hosts.
The disseminated form of the disease usually presents as multiple subcutaneous nodules that involve the extensor surfaces of the arms and legs [1, 2]. The bacterium is typically
resistant to antimicrobial agents, and <20% of M. chelonae
isolates are susceptible to trimethoprim-sulfamethoxazole,
doxycycline, erythromycin, or ciprofloxacin [3-6]. Findings
in a recent study suggest that clarithromycin may be the drug
of choice for treatment of cutaneous (disseminated) disease
due to M. chelonae [7]. In an open noncomparative trial in
which 14 patients who had M. chelonae disease received
monotherapy with clarithromycin, 11 patients had an excellent response, 2 patients died of unrelated conditions, and 1
patient who did not comply with the regimen initially responded (this last patient then relapsed; the M. chelonae isolated was resistant to clarithromycin) [7].
We describe a second patient with disseminated M. chelonae infection for whom clarithromycin monotherapy failed
because of the rapid development of resistance to the drug;
the findings in this case question the value of single-drug
therapy for M. chelonae infection.
444
Tebas et al.
Table 1. Summary of susceptibilities of Mycobacterium chelonae
isolated from a heart transplant recipient with disseminated infection.
MIC of M. chelonae (AgImL)
First isolate
(4/15/93)
Second isolate
(6/4/93)
Third isolate
(11/8/93)
Amikacin
Tobramycin
Clarithromycin
Doxycycline
Cefoxitin
Imipenem
Sulfamethoxazole
Ciprofloxacin
Azithromycin
32
<2
0.125
>16
>256
8
>32
8
1
32
2
>128
16
>256
8
>32
8
>32
>64
8
>128
>16
>256
16
>32
8
>128
NOTE. All tests were performed at the Mycobacterial/Nocardia Research Laboratory at the University of Texas Health Center in Tyler, Texas.
antibiotic resistance, and the necessity of maintaining prolonged intravenous access. The patient received no treatment for 8 months and remained stable; the few relapses that
occurred were self-limited. He died of cardiac disease in September 1994. An autopsy revealed evidence of ongoing M.
chelonae infection, but this infection did not directly contribute to his death.
Discussion
The spectrum of infections produced by M. chelonae has
recently been described [8]. More than 50% of patients who
are infected with M. chelonae have disseminated cutaneous
infections. Disseminated infections are usually seen in immunocompromised hosts, and the chronic use of steroids
seems to be the most important factor predisposing to disseminated infection [8]. One-third of patients who are infected
with M. chelonae have localized infections in the skin or
bone, which usually occur in immunocompetent hosts following minor trauma. Approximately 10% of these patients
have catheter-related infections.
Clinical data on antibiotic susceptibility and resistance for
M. chelonae have not been well defined, and the National
Committee for Clinical Laboratory Standards has not determined breakpoints for this bacterium. To determine MICs
for M. chelonae, most laboratories use the breakpoints for
aerobic bacteria with slight modifications. According to recent studies, clarithromycin is the drug most active against
M. chelonae; the MICs of clarithromycin for most isolates
were <0.25 Ag/mL [4].
The findings in this case demonstrate the difficulties in
managing patients with disseminated infections due to M.
chelonae. Although clarithromycin is a promising drug for
the treatment of infections due to this organism, rapid emergence of resistance can be a problem even for patients who
comply with the treatment regimen. Rapid development of
resistance has also been reported for other drugs (e.g., ciprofloxacin) that have been used as monotherapy in the treatment of other rapidly growing mycobacteria (e.g., Mycobacterium fortuitum) [6].
Because of the rarity of disseminated infection due to M.
chelonae, prospective comparative studies of other potential
therapies will be difficult. On the basis of the findings in this
report and experience with other mycobacterial infections,
the use of at least two drugs (one of which should be clarithromycin) should be considered for treatment of M. chelonae infections, especially in immunosuppressed patients.
Potential agents to use in combination (which were efficacious at least temporarily in this case) include imipenem
and tobramycin. These drugs could be given initially as part
of induction therapy. Therapy for disseminated M. chelonae
infections in immunocompromised hosts should be continued for at least 6 months [7, 9].
Resistance to clarithromycin and other drugs may still develop in patients with disseminated M. chelonae infection
who have received treatment. If resistance develops, treatment with a realistic potential for cure would not be available; thus, the patient's only option may be symptomatic
therapy including drainage of obvious fluid collections.
References
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Drug
CID 1995;20 (February)