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Journal of Clinical Microbiology, December 2007, p. 4090-4091, Vol. 45, No. 12
0095-1137/07/$08.00+0     doi:10.1128/JCM.01213-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

In Vivo Emergence of High-Level Macrolide Resistance in Streptococcus pneumoniae following a Single Dose of Azithromycin

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Resistance to macrolides in the pneumococcus is generally by virtue of an efflux pump (encoded by the mefA or mefE gene) or the presence of a ribosomal methylase (encoded by the ermB or, rarely, the ermA gene). Horizontal spread of these genes can occur through inter- and intraspecies recombination (2). Exposure of the pneumococcus to macrolides can also lead to the spontaneous generation of resistant mutants in vivo and in vitro (9); mutations in the 23S rRNA and ribosomal proteins L4 and L22 have been described (12). A recent randomized controlled study clearly demonstrated the effect of macrolide use on selection of resistant strains of pharyngeal streptococci (7).

The extent of macrolide use in remote indigenous communities in Australia is not well documented. Mass azithromycin treatment campaigns for trachoma eradication have been linked to selection of macrolide-resistant pneumococcal strains in the nasopharynx (5, 6) and conjunctiva (3). However, in populations where macrolide resistance was rare among pneumococci, selection for resistant strains following azithromycin administration for trachoma control was not evident (1).

As a part of a pneumococcal carriage study of young children in remote indigenous communities, we report nasopharyngeal carriage of serial serotype 22F pneumococcal isolates in a 2.5-month-old indigenous infant. The 22F isolate developed resistance to azithromycin (while remaining sensitive to penicillin, tetracycline, chloramphenicol, and cotrimoxazole) after the infant received a single dose of azithromycin (125 mg) as routine prophylaxis following a trachoma contact. As shown in Table 1, the pre- and posttreatment isolates had identical BOX typing (13) patterns and multilocus sequence types (4). The mefA/E and ermB genes and mutations in the ribosomal protein L4 and L22 genes (8, 10-12) were not found in the isolates. However, the previously described 23S rRNA A2059G mutation (Escherichia coli numbering) (12) was detected in the posttreatment isolate.

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TABLE 1. Analysis of serial serotype 22F pneumococcal isolates from nasal swabs collected from an indigenous child given a single dose of azithromycin

Each subsequent monthly nasal swab from the child over the following 8 months cultured macrolide-susceptible isolates of serotype 16F or presumptive nonencapsulated pneumococci. Five percent of the pneumococcal carriage isolates in the study were macrolide resistant (erythromycin MIC, >2 µg/ml). However, the resistant 22F clone was not detected again despite intensive surveillance in that community.

The A2059G mutation in pneumococcal passaged mutants was previously shown to decrease susceptibility to macrolides; changes at two alleles were associated with an increase in the azithromycin MIC from 0.02 µg/ml to >200 µg/ml (12). This mutation is also believed to slow the replication rate (12) and would potentially provide a fitness cost.

In another case of de novo development of resistance, a serotype 3 pneumococcus developed resistance to erythromycin, azithromycin, and quinupristin-dalfopristin (MIC, 2 to 4 µg/ml) during azithromycin treatment for pneumococcal pneumonia, with a fatal outcome. The mechanism of resistance was reported to be a mutation in ribosomal protein L22 (9).

Our findings and those of others have important implications for practice. Strains highly resistant to azithromycin can arise de novo in a previously sensitive strain, independently and in the absence of azithromycin resistance in the population. Although this may be an unusual occurrence, an important consideration during empirical azithromycin treatment for a pneumococcal infection is that clinical failure may occur even when the risk of selecting a preexisting azithromycin-resistant strain is low.

 
Published ahead of print on 17 October 2007.

H.C.S.-V. and R.L.M. contributed equally to this study.

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1. Batt, S. L., B. M. Charalambous, A. W. Solomon, C. Knirsch, P. A. Massae, S. Safari, N. E. Sam, D. Everett, D. C. Mabey, and S. H. Gillespie. 2003. Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 47:2765-2769.[Abstract/Free Full Text]
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2. Cerdá Zolezzi, P., L. M. Laplana, C. R. Calvo, P. G. Cepero, M. C. Erazo, and R. Gomez-Lus. 2004. Molecular basis of resistance to macrolides and other antibiotics in commensal viridans group streptococci and Gemella spp. and transfer of resistance genes to Streptococcus pneumoniae. Antimicrob. Agents Chemother. 48:3462-3467.[Abstract/Free Full Text]
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3. Chern, K. C., S. K. Shrestha, V. Cevallos, H. L. Dhami, P. Tiwari, L. Chern, J. P. Whitcher, and T. M. Lietman. 1999. Alterations in the conjunctival bacterial flora following a single dose of azithromycin in a trachoma endemic area. Br. J. Ophthalmol. 83:1332-1335.[Abstract/Free Full Text]
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4. Enright, M. C., and B. G. Spratt. 1998. A multilocus sequence typing scheme for Streptococcus pneumoniae: identification of clones associated with serious invasive disease. Microbiology 144:3049-3060.[Abstract/Free Full Text]
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5. Gaynor, B. D., J. D. Chidambaram, V. Cevallos, Y. Miao, K. Miller, H. C. Jha, R. C. Bhatta, J. S. Chaudhary, H. S. Osaki, J. P. Whitcher, K. A. Holbrook, A. M. Fry, and T. M. Lietman. 2005. Topical ocular antibiotics induce bacterial resistance at extraocular sites. Br. J. Ophthalmol. 89:1097-1099.[Abstract/Free Full Text]
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6. Leach, A. J., T. M. Shelby-James, M. Mayo, M. Gratten, A. C. Laming, B. J. Currie, and J. D. Mathews. 1997. A prospective study of the impact of community-based azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin. Infect. Dis. 24:356-362.[Medline]
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7. Malhotra-Kumar, S., C. Lammens, S. Coenen, K. Van Herck, and H. Goossens. 2007. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 369:482-490.[CrossRef][Medline]
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8. Montanari, M. P., I. Cochetti, M. Mingoia, and P. E. Varaldo. 2003. Phenotypic and molecular characterization of tetracycline- and erythromycin-resistant strains of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 47:2236-2241.[Abstract/Free Full Text]
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9. Musher, D. M., M. E. Dowell, V. D. Shortridge, R. K. Flamm, J. H. Jorgensen, P. Le Magueres, and K. L. Krause. 2002. Emergence of macrolide resistance during treatment of pneumococcal pneumonia. N. Engl. J. Med. 346:630-631.[Free Full Text]
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10. Sutcliffe, J., T. Grebe, A. Tait-Kamradt, and L. Wondrack. 1996. Detection of erythromycin-resistant determinants by PCR. Antimicrob. Agents Chemother. 40:2562-2566.[Abstract]
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11. Sutcliffe, J., A. Tait-Kamradt, and L. Wondrack. 1996. Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system. Antimicrob. Agents Chemother. 40:1817-1824.[Abstract]
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12. Tait-Kamradt, A., T. Davies, M. Cronan, M. R. Jacobs, P. C. Appelbaum, and J. Sutcliffe. 2000. Mutations in 23S rRNA and ribosomal protein L4 account for resistance in pneumococcal strains selected in vitro by macrolide passage. Antimicrob. Agents Chemother. 44:2118-2125.[Abstract/Free Full Text]
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13. van Belkum, A., M. Sluijter, R. de Groot, H. Verbrugh, and P. W. M. Hermans. 1996. Novel BOX repeat PCR assay for high-resolution typing of Streptococcus pneumoniae strains. J. Clin. Microbiol. 34:1176-1179.[Abstract]

						H. C. Smith-Vaughan* Child Health Division Menzies School of Health Research Building 58, Royal Darwin Hospital Darwin 0810, Australia R. L. Marsh P. S. Morris A. J. Leach Menzies School of Health Research Institute of Advanced Studies Charles Darwin University Northern Territory, Australia
						* Phone: 61-889228871 Fax: 61-889275187 E-mail: heidi{at}menzies.edu.au

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Journal of Clinical Microbiology, December 2007, p. 4090-4091, Vol. 45, No. 12
0095-1137/07/$08.00+0     doi:10.1128/JCM.01213-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This Article Full Text (PDF) 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 Google Scholar Google Scholar Articles by Smith-Vaughan, H. C. Articles by Leach, A. J. Search for Related Content PubMed PubMed Citation Articles by Smith-Vaughan, H. C. Articles by Leach, A. J.