|Country or Region||Years||# isol||% Erythromycin Resistance||Reference|
|USA - Philadelphia, UPHS||2000||135||22||This web site|
|USA - Nationally||1997-1999||4193||18||CID 2001;32:S82|
|China - Hong Kong||1994-1998||197||80||AAC 2001;45:1578|
|Latin America||1999||257||13||AAC 2001;45:1463|
|Country or Region||Year||# Isol.||% Erythromycin Resistance||Citation|
|USA||1994-1997||2.6||Ped Inf Dis J 1999;18:1069|
|San Francisco, USA||1994-1997||157-invasive strains||32||JCM 1999;37:1727|
|San Francisco||1994-1997||149 -pharyngitis strains||9||same as above|
|Pittsburgh, USA||2000-2001||100- non-invasive||38||NEJM 2002;346:1200|
|Philadelphia, USA||2002 (April)||100 - pharyngitis||1||unpublished, Univ Penn Med System|
|Italy||180||38||Emerg Inf Dis 2000;6:180|
|Sweden||1998-1999||3.7||Int J. Clin Pract 2000;54:585|
There are two major recognized resistance phenotypes, "MLSB" and "M"
MLSB - Resistant to macrolides, lincosamides, and streptogramin B. Conferred by methylation of a single adenine in the bacterial 50s ribosome that binds to erythryomycin, erm. Can be either inducible (iMLSB) or constitutive (cMLSB)
M -Resistant to macrolides, but not lincosamides or streptograminB. Conferred by macrolide efflux pump, mef.
Very recently, two novel mechanisms of macrolide resistance of pneumococci have been described, which complicate the inference of the genetic mechanism of resistance based on the phenotype. These two mechanisms are mutations in Domain V (Roman numeral V, not the letter "V") of the 23s rRNA, and mutations of two different ribosomal proteins that constitute part of the assembled 50s rRNA, ribosomal protein L4 and ribosomal protein L22. These mutations appear to result in two different phenotypes, ML and MSB, which can be confused with the phenotypes produced by erm and mef, respectively. These phenotypes can be differentiated from the M and MLSB phenotypes by inclusion of a streptogramin B and clindamycin in the testing.
The table below gives an example of typical susceptibility patterns for the various phenotypes
The genes classes that encode for the phenotypes are also of two main types, "erm" and "mef"
erm - The bacterial gene class coding for erythromycin ribosomal methylase, which methylates a single adenine in 23S rRNA, itself a component of 50S rRNA. Multiple erm gene types are recognized, and the nomenclature is very confusing. However a new nomenclature system may help (Antimicrob. Agents Chemother 1999;43:2823-2830)
The erm classes that are important for resistance of streptococci are class A and class B. Most authors refer to erm(TR) and erm(AM) for designating streptococcal erm
|Class||Proposed new gene name||Includes these genes|
|B||erm(B)||erm(AM), erm(B), erm(AMR), erm(BC), erm(P), erm(BP), erm(IP), erm(Z), erm, erm(2)|
To make matters even more confusing there can be both constitutive (always on) and inducible variants of erm, the phenotypes of which are designated as either cMLSB or iMLSB, respectively. erm gene regulation is complex and may involve more than one mechanism.
mef macrolide efflux pump. There are two recognized streptococcal mef types, mef(A) and mef(E), the former described in S. pyogenes and the latter in S. pneumoniae. mef(A) and mef(E) are 90% homologous, and it has been proposed that both be referred to as mef(A). mef actively pumps out macrolides (14 and 15 ring , but not 16 ring), but not lincosamides, streptogramins, or ketolides.
rRNA and ribosomal protein mutations The rRNA mutations are all in Domain 5 ("V") of 23S rRNA, very close to, or at the same location as the adenine that gets methylated by ermA ("A2058"), either at position 2058, 2059, or 2611, and are all adenine to guanine mutations. This region of Domain V is at the active translation site (peptidyl transferase region) of the 50S rRNA subunit (see Science 2000;289:905, or this link for more on ribosomal structure). There are four copies of rRNA in pneumococci, and these mutations have to occur in at least two of the ribsomes; the degree of resistance probably depends on whether the mutations are in 2, 3, or all 4 rRNAs. The ribosomal protein mutations have been mutations in either the L4 or L22 proteins, with a variety of changes, including substitutions, deletions, and additions (AAC 2002;46:371; AAC 2000;44:3395; AAC 2000;44:2118).
macrolide - erythromycin (more properly erythromycin A), clarithromycin, azithromycin (more properly an azalide) [all of these are either 14 or 15 ring compounds]. Rokitamycin is a 16 ring macrolide.
lincosamide - lincomycin and clindamycin
streptogramin B - quinupristin, a component of dalfopristin/quinupristin, or Synercid. Dalfopristin is a streptogramin A compound. Also pristinimycin IA is a streptogramin B compound, while pristinamycin IIA is a streptogramin A compound, both of which are components of the combination antimicrobial agent, pristinamycin .
ketolide - a macrolide which has been chemically modified. Telithromycin is one example of a ketolide.
Examples of macrolide resistance phenotypes of S. pyogenes**
|genotype||mef(A)||erm(TR)||erm(B)||mutations in 23S rRNA, or in L4 or L22 ribosomal proteins|
|erythromycin (14 ring)||0.03||4||1||>32||>32||>32|
|azithromycin (15 ring, azalide)||0.125||4||4||>32||>32||>32|
|clarithromycin (14 ring)||0.03||4||0.25||>32||>32||>32|
|roxithromycin (15 ring)||0.06||8||4||>32||>32||>32|
|telithromycin (ketolide)||0.03||0.25||0.06||1 to 16||0.01||0.1|
|clindamycin after exposure of bacteria to erythromycin||0.03||0.03||>32||>32||?||?|
|rokitamycin (16 ring macrolide)||0.25||0.25||4||>32||>32||>32|
Portions of this table modified very liberally from Antimicrob.
Agents Chemother 2000;44:2999-3002, and from AAC
** Note that in the case of S. pneumoniae the ketolides retain activity for the vast majority of cMLSB producers
Testing of streptococcal isolates with erythromycin and clindamycin disks applied close together can often yield phenotypic information, although it is not always possible to differentiate between phenotypes using this method. See J. Clin. Microbiol 2001;39:1311-1315 for details of this method for phenotypic analysis of S. pneumoniae. The figures below are taken from that paper, with some major modifications made to simplify this discussion; see the paper for the real and more complicated story.
iMLSB- the clindamycin zone is blunted towards the erythromycin because the erythromycin induces clindamycin resistance
cMLSB- no zone around either erythromycin or clindamycin because erm is fully expressed at all times
M- no change in the clindamycin zone induced by erythromycin because mef does not pump out clindamycin regardless of erythromycin presence
A= clindamycin and B=erythromycin
|Examples of triple disk testing of rRNA or ribosomal protein mutants. Disk on left is clindamycin, middle is erythromycin, and right is streptogramin B. All bacteria are S. pneumoniae. Plate A shows ML (rRNA mutation), plates B and C show MSB (Both L4 mutations). Taken from AAC 2000;44:3395.|
Percent Prevalence of Macrolide Resistance Phenotypes/Genotypes
|Country||Years||# isol||M||iMLSB||cMLSB||cMLSB & M||Other||rRNA, L22 or L4 mutation||Ref.|
|UK, Ireland||1997-1998||83||62||35||2||1||JAC 2001;48:541|
|Slovak Rep||1999-2000||28||0||39||61||AAC 2002;46:371|
|Eastern, Central Europe||1999-2000||180||14||70||16||AAC 2002;46:371|
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Written by Paul H. Edelstein 1/25/02.Modified 4/29/03. If you spot any errors, please let me know.