Journal of Antimicrobial Chemotherapy (1999) 44, 133-134
© 1999 The British Society for Antimicrobial Chemotherapy
Correspondence |
Emergence of mefA and mefE genes in beta-haemolytic streptococci and pneumococci in France
J Antimicrob Chemother 1999; 44: 133–134
Laboratoire de Microbiologie, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France
Sir,
Since the early 1990s, most developed countries have experienced a rapid and substantial increase in erythromycin resistance among isolates of Streptococcus pyogenes and Streptococcus pneumoniae, probably related to the increased prescribing of this antibiotic or its novel semisynthetic derivatives. 1 Until recently, the unique mechanism of macrolide resistance recognized in streptococci was target modification by 23S rRNA methylases encoded by erm genes, which convey cross-resistance to macrolides, lincosamides and the streptogramin B compounds (MLS B phenotype). With the increase of erythromycin resistance, a new phenotype designated M, consisting of resistance to 14- and 15-membered macrolides, but susceptibility to 16-membered macrolides, lincosamides and type-B streptogramins, has emerged. The mechanism of this resistance is a proton-dependent efflux system encoded by mef genes: mefA in S. pyogenes, 2 and mefE in S. pneumoniae. 3 S. pyogenes and S. pneumoniae with an M phenotype and/or mef genes have been reported in a number of countries, where their prevalence among erythromycin-resistant isolates has reached very high rates; for S. pyogenes, mainly in Europe 1 (38-97%) and for S. pneumoniae, principally in North America 4 (41-85%). Subsequently, mef genes have been detected in Group C streptococci in Finland, where they represented 95% of the erythromycin-resistant isolates. 5
In France, such an increase in erythromycin resistance has not been observed, at least in our geographical area. The current rate of erythromycin resistance in the South West of France appears to be stabilized around 10% of S. pyogenes and Group C streptococci, 15% of Streptococcusagalactiae and Group G streptococci, and 45% of S. pneumoniae, with high local and temporal variations. Between 1993 and 1998, we collected 18 isolates of S. agalactiae (<1%) with an M phenotype, which have been demonstrated to possess either an mefA or an mefE gene. 6 Over the same period, we have recovered only two S. pyogenes isolates, one Group C streptococcus and two pneumococci with an M phenotype (<0.1%). By the disc diffusion method, these five isolates exhibited a reduced zone of inhibition (diameter 10–20 mm) around the erythromycin disc (15 IU), with neither blunting zones around the discs of spiramycin (100 µg), lincomyin (15 µg) or pristinamycin (15 µg) placed nearby, nor zonal lincomycin resistance, even after prolonged incubation (72 h). MICs of 12 MLS drugs, determined by a agar dilution method in Mueller-Hinton medium supplemented with 5% horse blood, confirmed that these isolates were low-level resistant to erythromycin (2–8 µg/ml) and other 14- and 15-membered macrolides, although the intrinsically more active new ketolide HMR3647 retained a significant activity; in contrast, they remained fully susceptible to 16-membered macrolides, lincosamides, and A (pristinamycin II) and B (pristinamycin I) streptogramin components (Table). The DNA of the five isolates was amplified using primers specific to the mefA or mefE gene as previously described. 6 All isolates except for one (S. pneumoniae No. 4) yielded a PCR product of the expected size (1.2 kb), whereas no amplification was obtained with the DNA of negative control isolates (sensitive or MLS B phenotype isolates). The amplicons were analysed by enzymatic restriction using four endonucleases designed to differentiate mefA and mefE: the ClaI and HindIII enzymes cleave only the mefA gene in two fragments (0.701 and 0.517 kbp for ClaI, and 0.89 and 0.328 bp for HindIII), whereas AccI and HhaI enzymes cleave only the mefE gene in two fragments (0.651 and 0.567 kbp for AccI, and 0.8 and 0.418 kbp for HhaI). The results showed that four isolates carried an mefE gene, whereas the remaining one (S. pyogenes No. 2) possessed an mefA gene (Table). Thus, there is no species-specific distribution of the mefA or mefE gene, and mefE appears to be predominant among streptococci with an M phenotype as previously observed for S. agalactiae 6 and pneumococci. 4 The S. pneumoniae No. 4 isolate carried neither an mef gene nor an erm gene, using PCR with primers specific for ermA (erm1, 5'-TCTAAAAAGCATGTAAAAGAA-3'; erm2, 5'-CTTCGATAGTTTATTAATATTAGT-3'), ermB (erm3, 5'-GAAAAGRTACTCAACCAAATA-3'; erm4, 5'-AGTAACGGTACTTAAATTGTTTAC-3'), ermC (erm5, 5'-TCAAAACATAATATAGATAAA-3'; erm6, 5'-GCTAATATTGTTTAAATCGTCAAT-3') and ermTR (erm7, 5'-TCTCCTTGCCGGTTATAA-3'; erm8, 5'-ATCAATTAAGACAGGTGCTGAAGC-3') (Table). These results suggest the existence of a novel erythromycin resistance gene or mechanism in pneumococci.
|
This is the first description of mefE in S. pyogenes, and the first report of S. pyogenes, Group C streptococci and S. pneumoniae from France with an M phenotype and mef genes. The reason why this mechanism of erythromycin resistance remains more uncommon in France than in other European countries, and why S. agalactiae is more frequently implicated than other streptococcal species, remains to be explained. Our findings emphasize the importance of preparing cultures and carrying out susceptibility testing whenever streptococcal infections are suspected; antibiograms should include not only erythromycin, but also representatives of the 16-membered macrolides, lincosamides, streptogramins and ketolides when these latter drugs become available.
Notes
* Corresponding author. Tel: +33-5-57-57-10-75; Fax:
+33-5-56-90-90-72; E-mail: claudine.quentin{at}bacterio.u-bordeaux2.fr 
References
1
.
Seppälä, H., Nissinen, A., Yu, Q. &
Huovinen, P. (1993). Three different phenotypes of erythromycin-resistant Streptococcus pyogenes in Finland. Journal of Antimicrobial Chemotherapy 32, 885–91.
2 . Clancy, J., Petitpas, J., Did-Hajj, F., Yuan, W., Cronan, M., Kamath, A. V. et al. (1996). Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA, from Streptococcus pyogenes. Molecular Microbiology 22, 867–79.[Web of Science][Medline]
3
.
Tait-Kamradt, A., Clancy, J., Cronan, M., Did-Hajj, F., Wondrack, L., Yuan, W. et al.
(1997). mefE is necessary for the erythromycin-resistance M phenotype
in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 41, 2251–5.
4
.
Johnston, N. J., De Azavedo, J. C., Kellner, J. D. & Low, D. E. (1998). Prevalence
and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance
in isolates of Streptococcus pneumoniae. Antimicrobial Agents and
Chemotherapy 42, 2425–6.
5
.
Kataja, J., Seppälä, H., Skurnik, M., Sarkkinen, H. & Huovinen, P. (1998). Different erythromycin resistance mechanisms in Group C and Group G streptococci. Antimicrobial Agents and Chemotherapy 42, 1493–4.
6
.
Arpin, C., Daube, H., Tessier, F. & Quentin, C. (1999). Presence of mefA
and mefE genes in Streptococcus agalactiae. Antimicrobial Agents
and Chemotherapy 43, 944–6.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. E. Varaldo, M. P. Montanari, and E. Giovanetti Genetic Elements Responsible for Erythromycin Resistance in Streptococci Antimicrob. Agents Chemother., February 1, 2009; 53(2): 343 - 353. [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Amezaga and H. McKenzie Molecular epidemiology of macrolide resistance in {beta}-haemolytic streptococci of Lancefield groups A, B, C and G and evidence for a new mef element in group G streptococci that carries allelic variants of mef and msr(D) J. Antimicrob. Chemother., March 1, 2006; 57(3): 443 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. W. Klaassen and J. W. Mouton Molecular Detection of the Macrolide Efflux Gene: To Discriminate or Not To Discriminate between mef(A) and mef(E) Antimicrob. Agents Chemother., April 1, 2005; 49(4): 1271 - 1278. [Full Text] [PDF]
|
|
|
|
|
|
A. K. Wierzbowski, D. Swedlo, D. Boyd, M. Mulvey, K. A. Nichol, D. J. Hoban, and G. G. Zhanel Molecular Epidemiology and Prevalence of Macrolide Efflux Genes mef(A) and mef(E) in Streptococcus pneumoniae Obtained in Canada from 1997 to 2002 Antimicrob. Agents Chemother., March 1, 2005; 49(3): 1257 - 1261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ardanuy, F. Tubau, J. Linares, M. A. Dominguez, R. Pallares, R. Martin, and The Spanish Pneumococcal Infection Study Network Distribution of Subclasses mefA and mefE of the mefA Gene among Clinical Isolates of Macrolide-Resistant (M-Phenotype) Streptococcus pneumoniae, Viridans Group Streptococci, and Streptococcus pyogenes Antimicrob. Agents Chemother., February 1, 2005; 49(2): 827 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Sweeney, J. Dave, P. A. Chambers, and J. Heritage Antibiotic resistance in general dental practice--a cause for concern? J. Antimicrob. Chemother., April 1, 2004; 53(4): 567 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Montanari, M. Mingoia, I. Cochetti, and P. E. Varaldo Phenotypes and Genotypes of Erythromycin-Resistant Pneumococci in Italy J. Clin. Microbiol., January 1, 2003; 41(1): 428 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Amezaga, P. E. Carter, P. Cash, and H. McKenzie Molecular Epidemiology of Erythromycin Resistance in Streptococcus pneumoniae Isolates from Blood and Noninvasive Sites J. Clin. Microbiol., September 1, 2002; 40(9): 3313 - 3318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nagai, P. C. Appelbaum, T. A. Davies, L. M. Kelly, D. B. Hoellman, A. T. Andrasevic, L. Drukalska, W. Hryniewicz, M. R. Jacobs, J. Kolman, et al. Susceptibility to Telithromycin in 1,011 Streptococcus pyogenes Isolates from 10 Central and Eastern European Countries Antimicrob. Agents Chemother., February 1, 2002; 46(2): 546 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Naber, M. Hammer, M. Kinzig-Schippers, C. Sauber, F. Sorgel, E. A. Bygate, A. J. Fairless, K. Machka, and K. G. Naber Urinary Excretion and Bactericidal Activities of Gemifloxacin and Ofloxacin after a Single Oral Dose in Healthy Volunteers Antimicrob. Agents Chemother., December 1, 2001; 45(12): 3524 - 3530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nagai, T. A. Davies, L. M. Ednie, A. Bryskier, E. Palavecino, M. R. Jacobs, and P. C. Appelbaum Activities of a New Fluoroketolide, HMR 3787, and Its (Des)-Fluor Derivative RU 64399 Compared to Those of Telithromycin, Erythromycin A, Azithromycin, Clarithromycin, and Clindamycin against Macrolide-Susceptible or -Resistant Streptococcus pneumoniae and S. pyogenes Antimicrob. Agents Chemother., November 1, 2001; 45(11): 3242 - 3245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Fluit, M. R. Visser, and F.-J. Schmitz Molecular Detection of Antimicrobial Resistance Clin. Microbiol. Rev., October 1, 2001; 14(4): 836 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Weber, J. Filipecki, E. Bingen, F. Fitoussi, G. Goldfarb, J. P. Chauvin, C. Reitz, and H. Portier Genetic and phenotypic characterization of macrolide resistance in group A streptococci isolated from adults with pharyngo-tonsillitis in France J. Antimicrob. Chemother., August 1, 2001; 48(2): 291 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Firsov, I. Y. Lubenko, Y. A. Portnoy, S. H. Zinner, and S. N. Vostrov Relationships of the Area under the Curve/MIC Ratio to Different Integral Endpoints of the Antimicrobial Effect: Gemifloxacin Pharmacodynamics in an In Vitro Dynamic Model Antimicrob. Agents Chemother., March 1, 2001; 45(3): 927 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Santagati, F. Iannelli, M. R. Oggioni, S. Stefani, and G. Pozzi Characterization of a Genetic Element Carrying the Macrolide Efflux Gene mef(A) in Streptococcus pneumoniae Antimicrob. Agents Chemother., September 1, 2000; 44(9): 2585 - 2587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ball Quinolone generations: natural history or natural selection? J. Antimicrob. Chemother., July 1, 2000; 46(90003): 17 - 24. [Abstract] [Full Text]
|
|
|
|
|
|
E. Bingen, F. Fitoussi, C. Doit, R. Cohen, A. Tanna, R. George, C. Loukil, N. Brahimi, I. Le Thomas, and D. Deforche Resistance to Macrolides in Streptococcus pyogenes in France in Pediatric Patients Antimicrob. Agents Chemother., June 1, 2000; 44(6): 1453 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. T. Hannan and G. Woodnutt In vitro activity of gemifloxacin (SB 265805; LB20304a) against human mycoplasmas J. Antimicrob. Chemother., March 1, 2000; 45(3): 367 - 369. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||