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. 1996 Aug;40(8):1817–1824. doi: 10.1128/aac.40.8.1817

Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system.

J Sutcliffe 1, A Tait-Kamradt 1, L Wondrack 1
PMCID: PMC163423  PMID: 8843287

Abstract

Macrolide-resistant Streptococcus pyogenes isolates from Finland, Australia, and the United Kingdom and, more recently, Streptococcus pneumoniae and S. pyogenes strains from the United States were shown to have an unusual resistance pattern to macrolides, lincosamides, and streptogramin B antibiotics. This pattern, referred to as M resistance, consists of susceptibility to clindamycin and streptogramin B antibiotics but resistance to 14- and 15-membered macrolides. An evaluation of the macrolide-lincosamide-streptogramin B resistance phenotypes among our streptococcal strains collected from 1993 to 1995 suggested that this unusual resistance pattern is not rare. Eighty-five percent (n = 66) of the S. pneumoniae and 75% (n = 28) of the S. pyogenes strains in our collection had an M phenotype. The mechanism of M resistance was not mediated by target modification, as isolated ribosomes from a pneumococcal strain bearing the M phenotype were fully sensitive to erythromycin. Further, the presence of an erm methylase was excluded with primers specific for an erm consensus sequence. However, results of studies that determined the uptake and incorporation of radiolabeled erythromycin into cells were consistent with the presence of a macrolide efflux determinant. The putative efflux determinant in streptococci seems to be distinct from the multicomponent macrolide efflux system in coagulase-negative staphylococci. The recognition of the prevalence of the M phenotype in streptococci has implications for sensitivity testing and may have an impact on the choice of antibiotic therapy in clinical practice.

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Selected References

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  1. Andremont A., Gerbaud G., Courvalin P. Plasmid-mediated high-level resistance to erythromycin in Escherichia coli. Antimicrob Agents Chemother. 1986 Mar;29(3):515–518. doi: 10.1128/aac.29.3.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Appelbaum P. C. Antimicrobial resistance in Streptococcus pneumoniae: an overview. Clin Infect Dis. 1992 Jul;15(1):77–83. doi: 10.1093/clinids/15.1.77. [DOI] [PubMed] [Google Scholar]
  3. Arthur M., Andremont A., Courvalin P. Distribution of erythromycin esterase and rRNA methylase genes in members of the family Enterobacteriaceae highly resistant to erythromycin. Antimicrob Agents Chemother. 1987 Mar;31(3):404–409. doi: 10.1128/aac.31.3.404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arthur M., Autissier D., Courvalin P. Analysis of the nucleotide sequence of the ereB gene encoding the erythromycin esterase type II. Nucleic Acids Res. 1986 Jun 25;14(12):4987–4999. doi: 10.1093/nar/14.12.4987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Arthur M., Molinas C., Mabilat C., Courvalin P. Detection of erythromycin resistance by the polymerase chain reaction using primers in conserved regions of erm rRNA methylase genes. Antimicrob Agents Chemother. 1990 Oct;34(10):2024–2026. doi: 10.1128/aac.34.10.2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barthélémy P., Autissier D., Gerbaud G., Courvalin P. Enzymic hydrolysis of erythromycin by a strain of Escherichia coli. A new mechanism of resistance. J Antibiot (Tokyo) 1984 Dec;37(12):1692–1696. doi: 10.7164/antibiotics.37.1692. [DOI] [PubMed] [Google Scholar]
  7. Bechhofer D. H. Triple post-transcriptional control. Mol Microbiol. 1990 Sep;4(9):1419–1423. doi: 10.1111/j.1365-2958.1990.tb02051.x. [DOI] [PubMed] [Google Scholar]
  8. Breiman R. F., Butler J. C., Tenover F. C., Elliott J. A., Facklam R. R. Emergence of drug-resistant pneumococcal infections in the United States. JAMA. 1994 Jun 15;271(23):1831–1835. [PubMed] [Google Scholar]
  9. Brisson-Noël A., Delrieu P., Samain D., Courvalin P. Inactivation of lincosaminide antibiotics in Staphylococcus. Identification of lincosaminide O-nucleotidyltransferases and comparison of the corresponding resistance genes. J Biol Chem. 1988 Nov 5;263(31):15880–15887. [PubMed] [Google Scholar]
  10. Clewell D. B., Franke A. E. Characterization of a plasmid determining resistance to erythromycin, lincomycin, and vernamycin Balpha in a strain Streptococcus pyogenes. Antimicrob Agents Chemother. 1974 May;5(5):534–537. doi: 10.1128/aac.5.5.534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Coonan K. M., Kaplan E. L. In vitro susceptibility of recent North American group A streptococcal isolates to eleven oral antibiotics. Pediatr Infect Dis J. 1994 Jul;13(7):630–635. doi: 10.1097/00006454-199407000-00009. [DOI] [PubMed] [Google Scholar]
  12. Devriese L. A. Two new types of resistance to lincomycin in pathogenic staphylococci from animals. Ann Microbiol (Paris) 1980 Nov-Dec;131B(3):261–266. [PubMed] [Google Scholar]
  13. Dubnau D. Translational attenuation: the regulation of bacterial resistance to the macrolide-lincosamide-streptogramin B antibiotics. CRC Crit Rev Biochem. 1984;16(2):103–132. doi: 10.3109/10409238409102300. [DOI] [PubMed] [Google Scholar]
  14. Eady E. A., Ross J. I., Tipper J. L., Walters C. E., Cove J. H., Noble W. C. Distribution of genes encoding erythromycin ribosomal methylases and an erythromycin efflux pump in epidemiologically distinct groups of staphylococci. J Antimicrob Chemother. 1993 Feb;31(2):211–217. doi: 10.1093/jac/31.2.211. [DOI] [PubMed] [Google Scholar]
  15. Feigin R. D., Keeney R. E., Nusrala J., Shackelford P. G., Lins R. D. Efficacy of clindamycin therapy for otitis media. Arch Otolaryngol. 1973 Jul;98(1):27–31. doi: 10.1001/archotol.1973.00780020031008. [DOI] [PubMed] [Google Scholar]
  16. Fernandez-Munoz R., Monro R. E., Torres-Pinedo R., Vazquez D. Substrate- and antibiotic-binding sites at the peptidyl-transferase centre of Escherichia coli ribosomes. Studies on the chloramphenicol. lincomycin and erythromycin sites. Eur J Biochem. 1971 Nov 11;23(1):185–193. doi: 10.1111/j.1432-1033.1971.tb01607.x. [DOI] [PubMed] [Google Scholar]
  17. Fogel S., Sypherd P. S. Extraction and isolation of individual ribosomal proteins from Escherichia coli. J Bacteriol. 1968 Aug;96(2):358–364. doi: 10.1128/jb.96.2.358-364.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Friedland I. R., Shelton S., Paris M., Rinderknecht S., Ehrett S., Krisher K., McCracken G. H., Jr Dilemmas in diagnosis and management of cephalosporin-resistant Streptococcus pneumoniae meningitis. Pediatr Infect Dis J. 1993 Mar;12(3):196–200. doi: 10.1097/00006454-199303000-00004. [DOI] [PubMed] [Google Scholar]
  19. Gerber M. A. Antibiotic resistance in group A streptococci. Pediatr Clin North Am. 1995 Jun;42(3):539–551. doi: 10.1016/s0031-3955(16)38978-7. [DOI] [PubMed] [Google Scholar]
  20. Girard A. E., Girard D., Gootz T. D., Faiella J. A., Cimochowski C. R. In vivo efficacy of trovafloxacin (CP-99,219), a new quinolone with extended activities against gram-positive pathogens, Streptococcus pneumoniae, and Bacteroides fragilis. Antimicrob Agents Chemother. 1995 Oct;39(10):2210–2216. doi: 10.1128/aac.39.10.2210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Goffic F. L., Capmau M. L., Bonnet D., Cerceau C., Soussy C., Dublanchet A., Duval J. Plasmid-mediated pristinamycin resistance. PAC IIA: a new enzyme which modifies pristinamycin IIA. J Antibiot (Tokyo) 1977 Aug;30(8):665–669. doi: 10.7164/antibiotics.30.665. [DOI] [PubMed] [Google Scholar]
  22. Hagman K. E., Pan W., Spratt B. G., Balthazar J. T., Judd R. C., Shafer W. M. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology. 1995 Mar;141(Pt 3):611–622. doi: 10.1099/13500872-141-3-611. [DOI] [PubMed] [Google Scholar]
  23. Higgins C. F., Hyde S. C., Mimmack M. M., Gileadi U., Gill D. R., Gallagher M. P. Binding protein-dependent transport systems. J Bioenerg Biomembr. 1990 Aug;22(4):571–592. doi: 10.1007/BF00762962. [DOI] [PubMed] [Google Scholar]
  24. Jánosi L., Nakajima Y., Hashimoto H. Characterization of plasmids that confer inducible resistance to 14-membered macrolides and streptogramin type B antibiotics in Staphylococcus aureus. Microbiol Immunol. 1990;34(9):723–735. doi: 10.1111/j.1348-0421.1990.tb01050.x. [DOI] [PubMed] [Google Scholar]
  25. Klugman K. P., Koornhof H. J. Drug resistance patterns and serogroups or serotypes of pneumococcal isolates from cerebrospinal fluid or blood, 1979-1986. J Infect Dis. 1988 Nov;158(5):956–964. doi: 10.1093/infdis/158.5.956. [DOI] [PubMed] [Google Scholar]
  26. Klugman K. P., Koornhof H. J., Kuhnle V. Clinical and nasopharyngeal isolates of unusual multiply resistant pneumococci. Am J Dis Child. 1986 Nov;140(11):1186–1190. doi: 10.1001/archpedi.1986.02140250112045. [DOI] [PubMed] [Google Scholar]
  27. Kono M., O'Hara K., Ebisu T. Purification and characterization of macrolide 2'-phosphotransferase type II from a strain of Escherichia coli highly resistant to macrolide antibiotics. FEMS Microbiol Lett. 1992 Oct 1;76(1-2):89–94. doi: 10.1016/0378-1097(92)90369-y. [DOI] [PubMed] [Google Scholar]
  28. Kreiswirth B. N., Löfdahl S., Betley M. J., O'Reilly M., Schlievert P. M., Bergdoll M. S., Novick R. P. The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophage. Nature. 1983 Oct 20;305(5936):709–712. doi: 10.1038/305709a0. [DOI] [PubMed] [Google Scholar]
  29. Lai C. J., Weisblum B. Altered methylation of ribosomal RNA in an erythromycin-resistant strain of Staphylococcus aureus. Proc Natl Acad Sci U S A. 1971 Apr;68(4):856–860. doi: 10.1073/pnas.68.4.856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lampson B. C., von David W., Parisi J. T. Novel mechanism for plasmid-mediated erythromycin resistance by pNE24 from Staphylococcus epidermidis. Antimicrob Agents Chemother. 1986 Nov;30(5):653–658. doi: 10.1128/aac.30.5.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Le Goffic F., Capmau M. L., Abbe J., Cerceau C., Dublanchet A., Duval J. Plasmid mediated pristinamycin resistance: PH 1A, a pristinamycin 1A hydrolase. Ann Microbiol (Paris) 1977 Nov-Dec;128B(4):471–474. [PubMed] [Google Scholar]
  32. Leclercq R., Brisson-Noël A., Duval J., Courvalin P. Phenotypic expression and genetic heterogeneity of lincosamide inactivation in Staphylococcus spp. Antimicrob Agents Chemother. 1987 Dec;31(12):1887–1891. doi: 10.1128/aac.31.12.1887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Leclercq R., Courvalin P. Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob Agents Chemother. 1991 Jul;35(7):1267–1272. doi: 10.1128/aac.35.7.1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Leclercq R., Courvalin P. Intrinsic and unusual resistance to macrolide, lincosamide, and streptogramin antibiotics in bacteria. Antimicrob Agents Chemother. 1991 Jul;35(7):1273–1276. doi: 10.1128/aac.35.7.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lewis K. Multidrug resistance pumps in bacteria: variations on a theme. Trends Biochem Sci. 1994 Mar;19(3):119–123. doi: 10.1016/0968-0004(94)90204-6. [DOI] [PubMed] [Google Scholar]
  36. Matsuoka M., Endou K., Saitoh S., Katoh M., Nakajima Y. A mechanism of resistance to partial macrolide and streptogramin B antibiotics in Staphylococcus aureus clinically isolated in Hungary. Biol Pharm Bull. 1995 Nov;18(11):1482–1486. doi: 10.1248/bpb.18.1482. [DOI] [PubMed] [Google Scholar]
  37. Matsuoka M., Jánosi L., Endou K., Saitoh S., Hashimoto H., Nakajima Y. An increase of 63 kDa-protein present in the cell membranes of Staphylococcus aureus that bears a plasmid mediating inducible resistance to partial macrolide and streptogramin B antibiotics. Biol Pharm Bull. 1993 Dec;16(12):1288–1290. doi: 10.1248/bpb.16.1288. [DOI] [PubMed] [Google Scholar]
  38. McCracken G. H., Jr Emergence of resistant Streptococcus pneumoniae: a problem in pediatrics. Pediatr Infect Dis J. 1995 May;14(5):424–428. doi: 10.1097/00006454-199505001-00004. [DOI] [PubMed] [Google Scholar]
  39. Meier A., Kirschner P., Springer B., Steingrube V. A., Brown B. A., Wallace R. J., Jr, Böttger E. C. Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994 Feb;38(2):381–384. doi: 10.1128/aac.38.2.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Milton I. D., Hewitt C. L., Harwood C. R. Cloning and sequencing of a plasmid-mediated erythromycin resistance determinant from Staphylococcus xylosus. FEMS Microbiol Lett. 1992 Oct 1;76(1-2):141–147. doi: 10.1016/0378-1097(92)90377-z. [DOI] [PubMed] [Google Scholar]
  41. Nelson C. T., Mason E. O., Jr, Kaplan S. L. Activity of oral antibiotics in middle ear and sinus infections caused by penicillin-resistant Streptococcus pneumoniae: implications for treatment. Pediatr Infect Dis J. 1994 Jul;13(7):585–589. doi: 10.1097/00006454-199407000-00001. [DOI] [PubMed] [Google Scholar]
  42. Nikaido H. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science. 1994 Apr 15;264(5157):382–388. doi: 10.1126/science.8153625. [DOI] [PubMed] [Google Scholar]
  43. Nikaido H., Thanassi D. G. Penetration of lipophilic agents with multiple protonation sites into bacterial cells: tetracyclines and fluoroquinolones as examples. Antimicrob Agents Chemother. 1993 Jul;37(7):1393–1399. doi: 10.1128/aac.37.7.1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Noguchi N., Emura A., Matsuyama H., O'Hara K., Sasatsu M., Kono M. Nucleotide sequence and characterization of erythromycin resistance determinant that encodes macrolide 2'-phosphotransferase I in Escherichia coli. Antimicrob Agents Chemother. 1995 Oct;39(10):2359–2363. doi: 10.1128/aac.39.10.2359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. O'Hara K. Application of nuclear magnetic resonance spectrometry to measure the activity of bacterial macrolide esterase. Microbios. 1994;79(321):231–239. [PubMed] [Google Scholar]
  46. O'Hara K., Kanda T., Ohmiya K., Ebisu T., Kono M. Purification and characterization of macrolide 2'-phosphotransferase from a strain of Escherichia coli that is highly resistant to erythromycin. Antimicrob Agents Chemother. 1989 Aug;33(8):1354–1357. doi: 10.1128/aac.33.8.1354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ounissi H., Courvalin P. Nucleotide sequence of the gene ereA encoding the erythromycin esterase in Escherichia coli. Gene. 1985;35(3):271–278. doi: 10.1016/0378-1119(85)90005-8. [DOI] [PubMed] [Google Scholar]
  48. Pan W., Spratt B. G. Regulation of the permeability of the gonococcal cell envelope by the mtr system. Mol Microbiol. 1994 Feb;11(4):769–775. doi: 10.1111/j.1365-2958.1994.tb00354.x. [DOI] [PubMed] [Google Scholar]
  49. París M. M., Shelton S., Trujillo M., Hickey S. M., McCracken G. H., Jr Clindamycin therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother. 1996 Jan;40(1):122–126. doi: 10.1128/aac.40.1.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Pernodet J. L., Boccard F., Alegre M. T., Blondelet-Rouault M. H., Guérineau M. Resistance to macrolides, lincosamides and streptogramin type B antibiotics due to a mutation in an rRNA operon of Streptomyces ambofaciens. EMBO J. 1988 Jan;7(1):277–282. doi: 10.1002/j.1460-2075.1988.tb02810.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Phillips G., Parratt D., Orange G. V., Harper I., McEwan H., Young N. Erythromycin-resistant Streptococcus pyogenes. J Antimicrob Chemother. 1990 Apr;25(4):723–724. doi: 10.1093/jac/25.4.723. [DOI] [PubMed] [Google Scholar]
  52. Ross J. I., Eady E. A., Cove J. H., Baumberg S. Identification of a chromosomally encoded ABC-transport system with which the staphylococcal erythromycin exporter MsrA may interact. Gene. 1995 Feb 3;153(1):93–98. doi: 10.1016/0378-1119(94)00833-e. [DOI] [PubMed] [Google Scholar]
  53. Ross J. I., Eady E. A., Cove J. H., Cunliffe W. J., Baumberg S., Wootton J. C. Inducible erythromycin resistance in staphylococci is encoded by a member of the ATP-binding transport super-gene family. Mol Microbiol. 1990 Jul;4(7):1207–1214. doi: 10.1111/j.1365-2958.1990.tb00696.x. [DOI] [PubMed] [Google Scholar]
  54. Ross J. I., Farrell A. M., Eady E. A., Cove J. H., Cunliffe W. J. Characterisation and molecular cloning of the novel macrolide-streptogramin B resistance determinant from Staphylococcus epidermidis. J Antimicrob Chemother. 1989 Dec;24(6):851–862. doi: 10.1093/jac/24.6.851. [DOI] [PubMed] [Google Scholar]
  55. Scott R. J., Naidoo J., Lightfoot N. F., George R. C. A community outbreak of group A beta haemolytic streptococci with transferable resistance to erythromycin. Epidemiol Infect. 1989 Feb;102(1):85–91. doi: 10.1017/s095026880002971x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Seppälä H., Nissinen A., Järvinen H., Huovinen S., Henriksson T., Herva E., Holm S. E., Jahkola M., Katila M. L., Klaukka T. Resistance to erythromycin in group A streptococci. N Engl J Med. 1992 Jan 30;326(5):292–297. doi: 10.1056/NEJM199201303260503. [DOI] [PubMed] [Google Scholar]
  57. Seppälä H., Nissinen A., Yu Q., Huovinen P. Three different phenotypes of erythromycin-resistant Streptococcus pyogenes in Finland. J Antimicrob Chemother. 1993 Dec;32(6):885–891. doi: 10.1093/jac/32.6.885. [DOI] [PubMed] [Google Scholar]
  58. Shandler L., Gonzales J., Overturf G. D. Recurrence of pneumococcal sepsis caused by an intermediately penicillin-resistant organism treated with loracarbef. Pediatr Infect Dis J. 1996 Apr;15(4):379–380. doi: 10.1097/00006454-199604000-00020. [DOI] [PubMed] [Google Scholar]
  59. Spika J. S., Facklam R. R., Plikaytis B. D., Oxtoby M. J. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal Surveillance Working Group. J Infect Dis. 1991 Jun;163(6):1273–1278. doi: 10.1093/infdis/163.6.1273. [DOI] [PubMed] [Google Scholar]
  60. Stingemore N., Francis G. R., Toohey M., McGechie D. B. The emergence of erythromycin resistance in Streptococcus pyogenes in Fremantle, Western Australia. Med J Aust. 1989 Jun 5;150(11):626-7, 630-1. doi: 10.5694/j.1326-5377.1989.tb136725.x. [DOI] [PubMed] [Google Scholar]
  61. Swendsen C. L., Johnson W. Humoral immunity to Streptococcus pneumoniae induced by a pneumococcal ribosomal protein fraction. Infect Immun. 1976 Aug;14(2):345–354. doi: 10.1128/iai.14.2.345-354.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Weisblum B. Erythromycin resistance by ribosome modification. Antimicrob Agents Chemother. 1995 Mar;39(3):577–585. doi: 10.1128/AAC.39.3.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Weisblum B. Inducible resistance to macrolides, lincosamides and streptogramin type B antibiotics: the resistance phenotype, its biological diversity, and structural elements that regulate expression--a review. J Antimicrob Chemother. 1985 Jul;16 (Suppl A):63–90. doi: 10.1093/jac/16.suppl_a.63. [DOI] [PubMed] [Google Scholar]
  64. Weisblum B. Insights into erythromycin action from studies of its activity as inducer of resistance. Antimicrob Agents Chemother. 1995 Apr;39(4):797–805. doi: 10.1128/aac.39.4.797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Welby P. L., Keller D. S., Cromien J. L., Tebas P., Storch G. A. Resistance to penicillin and non-beta-lactam antibiotics of Streptococcus pneumoniae at a children's hospital. Pediatr Infect Dis J. 1994 Apr;13(4):281–287. doi: 10.1097/00006454-199404000-00007. [DOI] [PubMed] [Google Scholar]
  66. Wondrack L., Massa M., Yang B. V., Sutcliffe J. Clinical strain of Staphylococcus aureus inactivates and causes efflux of macrolides. Antimicrob Agents Chemother. 1996 Apr;40(4):992–998. doi: 10.1128/aac.40.4.992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Youngs E. R. Erythromycin resistant Streptococcus pyogenes in Merseyside. J Infect. 1984 Jan;8(1):86–87. doi: 10.1016/s0163-4453(84)93543-6. [DOI] [PubMed] [Google Scholar]

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