1 July 2001

Clarithromycin Resistance in Mycobacterium abscessus

We read with interest the article by Sanguinetti et al. titled “Fatal Pulmonary Infection Due to Multidrug-ResistantMycobacterium abscessus in a Patient with Cystic Fibrosis,” which appeared in the February 2001 issue (5). We would like to point out some additional information relating to the authors' comment, “to our knowledge, this is the first evidence of true resistance to clarithromycin, which is considered the most active drug against M. chelonae.” First, the case report involves Mycobacterium abscessus, notM. chelonae. The two names are not synonymous and should not be used interchangeably (10). The organisms have different biologies, are readily differentiated in the laboratory, and have different drug susceptibilities (2, 3, 6, 8). (Essentially all cases of chronic lung disease caused by rapidly growing mycobacteria in the setting of cystic fibrosis are due to M. abscessus [3].)
Second, there have been several previous reports of acquired clarithromycin resistance in isolates of M. abscessus and the closely related M. chelonae, and the genetics of this resistance have been well characterized (7, 9, 11). We would especially call the authors' attention to an article describing the study of clarithromycin resistance in a series of 800 isolates ofM. chelonae and M. abscessus. Eighteen of 800 clinical isolates (2.3%) submitted for susceptibility testing between 1990 and 1995 were found to be resistant to clarithromycin; 10 of these isolates were M. abscessus (9). The underlying conditions most commonly associated with the development of macrolide resistance in M. abscessus following clarithromycin therapy were cystic fibrosis (as in the case reported by the authors) and disseminated cutaneous disease. Sequencing studies of the 23S rRNA gene revealed that 94% of the clarithromycin-resistant isolates had a mutation involving the adenine at position 2058 or 2059 (Escherichia coli numbering system). Selected laboratory mutants resistant to clarithromycin had the same mutations, as have other species of mycobacteria and bacteria with acquired clarithromycin resistance (1, 4). The study also revealed that M. chelonae and M. abscessus have only a single copy of the ribosomal operon in their genome and hence demonstrate susceptibility to a single point mutation resulting in high-level (clinical) resistance.

AUTHOR’S REPLY

Maurizio Sanguinetti, Giovanni Fadda
Istituto di Microbiologia
Università Cattolica del S. Cuore
L. go F. Vito 1, 00168 Rome, Italy

AUTHORS' REPLY

We thank Dr. Wallace and Dr. Brown-Elliott for their interest in our article, and we appreciate their comments, which were occasioned by the following sentence: “To our knowledge, this is the first evidence of true resistance to clarithromycin, which is considered the most active drug against M. chelonae.” Regarding the first comment, M. chelonae is different from M. abscessus; therefore, the use of the term M. chelonae was a mistake, due to the fact that M. abscessus was formerly designated M. chelonaesubsp. abscessus. It is known that M. abscessus is the rapidly growing mycobacterial species most frequently involved in infections of patients with cystic fibrosis (1-3, 1-4), but M. chelonae (1-1) andM. fortuitum (1-2) also cause severe lung disease in these patients. With regard to the second comment, our intention was to stress the concept that the described case was the first fatal case of M. abscessus infection in a cystic fibrosis patient being associated with a multidrug resistance pattern (including resistance to clarithromycin). In fact, even though there are some reports of infections caused by M. chelonae and M. abscessus resistant to clarithromycin, as underlined by Dr. Wallace and Dr. Brown-Elliott, only infections caused by M. chelonae (1-5, 1-7) have been clinically well defined. On the other hand, while Wallace et al. (1-6) interestingly reported the insurgence of clinical resistance to clarithromycin in rapidly growing mycobacteria, such as M. abscessus andM. chelonae, isolated from patients with disseminated or chronic lung disease, no mention of the outcome of disease for any patient was made. However, in our report we highlighted the fatal outcome of the M. abscessus infection associated with the multidrug resistance pattern of the isolate. In conclusion, we apologize for our inappropriate sentence, recognizing that it should have read as follows: “To our knowledge, this is the first evidence of a fatal infection due to a M. abscessus isolate resistant to several drugs, including clarithromycin, which is considered the most active drug against rapidly growing mycobacteria.”

REFERENCES

1-1.
Boxerbaum B. Isolation of rapidly growing mycobacteria in patients with cystic fibrosis J. Pediatr. 961 1980 689 -691
1-2.
Efthimou J., Smith M. J., Oddson M. E., and Batten J. C. Fatal pulmonary infection with Mycobacterium fortuitum in cystic fibrosis Br. J. Dis. Chest 78 1984 229 -302
1-3.
Griffith D. E., Girard W. M., and Wallace R. J. Jr. Clinical features of pulmonary disease caused by rapidly growing mycobacteria Am. Rev. Respir. Dis. 147 1993 1271 -1278
1-4.
Olivier K. N., Yankaskas J. R., and Knowles M. R. Nontuberculous mycobacterial pulmonary disease in cystic fibrosis Semin. Respir. Infect. 11 1996 272 -284
1-5.
Tebas P., Sultan F., Wallace R. J. Jr., and Fraser V. Rapid development of resistance to clarithromycin following monotherapy for disseminated Mycobacterium chelonae infection in a heart transplant patient Clin. Infect. Dis. 20 1995 443 -444
1-6.
Wallace R. J. Jr., Meier A., Brown B. A., Zhang Y., Sander P., Onyi G. O., and Böttger E. C. Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus Antimicrob. Agents Chemother. 40 1996 1676 -1681
1-7.
Wallace R. J., Tanner D., Brennan P. J., and Brown B. A. Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae Ann. Int. Med. 119 1993 482 -486

REFERENCES

1.
Alarcón T., Domingo D., Prieto N., and López-Brea M. PCR using 3′-mismatched primers to detect A2142C mutation in 23S rRNA conferring resistance to clarithromycin in Helicobacter pylori clinical isolates.J. Clin. Microbiol.382000923-925
2.
Brown B. A., Wallace R. J. Jr., Onyi G., DeRosas V., and Wallace R. J. III. Activities of four macrolides, including clarithromycin, against Mycobacterium fortuitum, Mycobacterium chelonae, and M. chelonae-like organisms.Antimicrob. Agents Chemother.361992180-184
3.
Griffith D. E., Girard W. M., and Wallace R. J. Jr. Clinical features of pulmonary disease caused by rapidly growing mycobacteria: “Analysis of 154 patients.” Am. Rev. Respir. Dis. 147 1993 1271 -1278
4.
Pina M., Occhialini A., Monteiro L., Doermann H.-P., and Mégraud F. Detection of point mutations associated with resistance of Helicobacter pylori to clarithromycin by hybridization in liquid phase.J. Clin. Microbiol.3619983285-3290
5.
Sanguinetti M., Ardito F., Fiscarelli E., La Sorda M., D'Argenio P., Ricciotti G., and Fadda G. Fatal pulmonary infection due to multidrug-resistant Mycobacterium abscessus in a patient with cystic fibrosis.J. Clin. Microbiol.392001816-819
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Swenson J. M., Wallace R. J. Jr., Silcox V. A., and Thornsberry C. Antimicrobial susceptibility of five subgroups of Mycobacterium fortuitum and Mycobacterium chelonae.Antimicrob. Agents Chemother.281985807-811
7.
Tebas P., Sultan F., Wallace R. J. Jr., and Fraser V. Rapid development of resistance to clarithromycin following monotherapy for disseminated Mycobacterium chelonae infection in a heart transplant patient.Clin. Infect. Dis.201995443-444
8.
Wallace R. J. Jr., Brown B. A., and Onyi G. Skin, soft tissue, and bone infections due to Mycobacterium chelonae subspecies chelonae—importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to oral antimicrobials other than clarithromycin.J. Infect. Dis.1661992405-412
9.
Wallace R. J. Jr., Meier A., Brown B. A., Zhang Y., Sander P., Onyi G. O., and Böttger E. C. Genetic basis for clarithromycin resistance among isolates of Mycobacterium chelonae and Mycobacterium abscessus.Antimicrob. Agents Chemother.4019961676-1681
10.
Wallace R. J. Jr., Silcox V., and Brown B. A. Taxonomy of rapidly growing mycobacteria.Clin. Infect. Dis.181994121-122
11.
Wallace R. J., Tanner D., Brennan P. J., and Brown B. A. Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae.Ann. Int. Med.1191993482-486

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Published In

cover image Journal of Clinical Microbiology
Journal of Clinical Microbiology
Volume 39Number 71 July 2001
Pages: 2745 - 2746
PubMed: 11446360

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Published online: 1 July 2001

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Barbara A. Brown-Elliott
Richard J. Wallace Jr.
Department of Microbiology
The University of Texas Health Center
11937 US Hwy 271
Tyler, TX 75708

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