JAC Advance Access published online on August 2, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm273
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Macrolide resistance mechanisms among Streptococcus pneumoniae isolated over 6 years of Canadian Respiratory Organism Susceptibility Study (CROSS) (1998–2004)
1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada 2 Department of Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada 3 Institute of Antimicrobial Chemotherapy, Smolonsk, Russian Federation
* Corresponding author. Tel: +1-204-787-4684; Fax: +1-204-787-4699; E-mail: aw75{at}shaw.ca
Received 1 February 2007; returned 11 March 2007; revised 14 June 2007; accepted 1 July 2007
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Abstract |
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Background: Resistance to macrolides in Streptococcus pneumoniae arises primarily due to Erm(B) or Mef(A). Erm(B) typically confers high-level resistance to macrolides, lincosamides and streptogramin B (MLSB phenotype), whereas Mef(A) confers low-level resistance to macrolides only (M phenotype). The purpose of this study was to investigate the incidence of macrolide resistance mechanisms in Canadian isolates of S. pneumoniae obtained between 1998 and 2004. Furthermore, the genetic relatedness, serotype distribution and antibiotic susceptibility profile among S. pneumoniae isolates with dual erythromycin ribosomal methylase [Erm(B)] and efflux pump [Mef(A)] were analysed.
Methods: A total of 865 macrolide-resistant (erythromycin MIC 
1 mg/L) S. pneumoniae isolates were collected from the Canadian Respiratory Organism Susceptibility Study (CROSS) from 1998 to 2004. The presence of erm(B) and mef(A) was determined for each isolate by PCR; mutations in the genes coding for L4 and L22 ribosomal proteins and for 23S rRNA were identified by DNA sequencing. Each isolate containing both erm(B)- and mef(A)-mediated macrolide resistance was genotyped by PFGE and serotyped using the Quellung reaction with antisera.
Results: Of the 865 isolates studied, 404 (46.7%) were mef(A)-positive, 371 (42.9%) were erm(B)-positive, 50 (5.8%) were positive for both mef(A) and erm(B) and 40 (4.6%) were negative for both mef(A) and erm(B). Of the macrolide-resistant isolates negative for both mef(A) and erm(B), 22 (2.5%) contained 23S rRNA A2058G, A2059G or A2059C mutations, 7 (0.8%) contained 23S rRNA A2058G or A2059G mutations along with an S20N mutation in L4 ribosomal protein, and 1 isolate contained an E30K ribosomal protein mutation alone. Of the macrolide-resistant strains positive for both mef(A) and erm(B), 36 (72%) were multidrug-resistant (macrolide-, penicillin- and trimethoprim/sulfamethoxazole-resistant), 39 (78%) isolates belonged to serotype 19A or 19F and 36 (72%) belonged to one clonal complex (80% genetic relatedness) genetically related to the Taiwan 19F-14 clone.
Conclusions: The prevalence of efflux-based macrolide resistance in S. pneumoniae in Canada remained steady between 1998 and 2004. Macrolide resistance due to erm(B) decreased over the same time period, with a rapid increase in isolates with both erm(B) and mef(A) macrolide resistance.
Key Words: pneumococci , Canada , S. pneumoniae
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Introduction |
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Streptococcus pneumoniae is a key pathogen of community-acquired respiratory tract infections including community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute bacterial sinusitis and acute otitis media.1,2 The clinical management of these infections has been complicated by the worldwide emergence and spread of resistance in S. pneumoniae to commonly used antibiotics, particularly ß-lactams and macrolides.1,2 Macrolide resistance in S. pneumoniae is mediated by two major mechanisms: methylation of the ribosomal macrolide target site, encoded by the erm(B) gene, and drug efflux, encoded by the mef(A) gene.3–5
The methylation of the ribosomal target [erm(B)] results in resistance to 14-, 15- and 16-membered macrolides, lincosamides and streptogramin B (MLSB phenotype),3 whereas drug efflux [mef(A)] results in resistance to 14- and 15-membered-ring macrolide resistance only (M phenotype).4,5 The prevalence of efflux and target site methylation mechanisms among macrolide-resistant S. pneumoniae varies geographically.6 The efflux mechanism is the predominant form of macrolide resistance in North America,2,6,7 whereas target site modification predominates in Europe and Asia.8–12 Recently, however, some European countries such as Germany, Norway and Austria have reported an increasing incidence of the efflux mechanism, similar to rates in North American centres.13–16
In addition to these major mechanisms, S. pneumoniae isolates positive for both erm(B) and mef(A) are becoming rapidly more common worldwide and have been identified in many countries, including the USA, South Korea, China, Japan, Mexico and Hungary.8,17–24 In the USA, these strains have increased in prevalence from 9.7% in 2000–01 to 16.4% in 2002–03.19,20 In some regions, these isolates account for more than 20% of all macrolide-resistant strains.19,20 These dual erm(B)-positive/mef(A)-positive S. pneumoniae isolates have been shown to belong to one major clonal complex and show high rates of resistance to multiple antibiotic classes.18,23,24 Consequently, their potential spread is of serious concern and may have clinical implications for treatment failure. Pneumococcal resistance to macrolides may also be a result of ribosomal mutations (genes encoding 23S rRNA and riboproteins L4 and L22); however, reports to date of such ribosomal mutations among macrolide-resistant S. pneumoniae are rare.25–27
The objective of this study was to investigate the prevalence of macrolide resistance mechanisms in clinical S. pneumoniae isolates obtained across Canada from the Canadian Respiratory Organism Susceptibility Study (CROSS) between 1998 and 2004. In addition, in the light of the recent emergence of S. pneumoniae isolates with dual erm(B) and mef(A) mechanisms, the serotype distribution and genotypic relatedness of 50 erm(B)-positive/mef(A)-positive S. pneumoniae isolates collected during the 1998–2004 CROSS were also examined.
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Pneumococcal isolates
S. pneumoniae isolates (n = 9286) were collected between September 1998 and November 2004 as part of an ongoing national surveillance study (CROSS).6,28 Twenty-five medical centres in 9 of the 10 Canadian provinces contributed S. pneumoniae respiratory tract isolates to the surveillance study undertaken at the Health Sciences Centre (Winnipeg, Manitoba, Canada). Consecutive isolates, one per patient, were collected form respiratory tract specimens only. Isolates were identified by a conventional methodology by individual laboratory protocols. All isolates were shipped to a central laboratory (Health Sciences Centre) on Amies charcoal swabs. The identity of each S. pneumoniae was confirmed by the central laboratory using the CLSI (formerly NCCLS) Abbreviated Identification of Bacteria and Yeast: Approved Guideline M35 (2002). According to the CLSI guidelines; positive bile (either 2% or 10%) solubility on the plate is accurate for identification of S. pneumoniae organisms. Furthermore, the guideline does acknowledge a limitation: some S. pneumoniae may not be bile soluble. All of the S. pneumoniae isolates included in this study were confirmed as bile soluble.
Antibiotic susceptibilities were determined using the CLSI M7-A7 (2006) microbroth dilution technique.29 Antibiotics tested included erythromycin, clarithromycin, azithromycin, clindamycin and telithromycin. MIC interpretive standards were defined according to the CLSI breakpoints (M100-S17, 2007).29a Susceptibility to penicillin, amoxicillin/clavulanate, levofloxacin, doxycycline and trimethoprim/sulfamethoxazole was determined for isolates with dual erm(B) and mef(A) mechanisms of resistance in order to determine a multidrug resistance phenotype. S. pneumoniae ATCC 49619 was used as a control.
Determination of macrolide resistance mechanism
A total of 865 erythromycin-resistant (MIC 1 mg/L) S. pneumoniae isolates collected in CROSS were analysed for the presence of mef(A) and erm(B) resistance genes using a previously described PCR assay with primers described by Sutcliffe et al.30 Macrolide-resistant isolates of S. pneumoniae that were both mef(A)-negative and erm(B)-negative (40; 4.6%) were assessed for mutations in the genes coding for ribosomal proteins L4 and L22 and 23S rRNA using primers and conditions as described by Tait-Kamradt et al.27
The genetic relatedness among 50 macrolide-resistant S. pneumoniae isolates containing both erm(B) and mef(A) was examined by PFGE, as described previously.31,32 Isolates that differed by one to three bands were considered clonally related. SmaI restriction patterns were digitized for analysis using BioNumericsTM version 3.5 (Applied Maths, Austin, TX, USA) software. A dendrogram was calculated by the unweighted pair group method with arithmetic averages. Isolates were compared with the internationally described clones of the pneumococcal molecular epidemiology network.
Isolates were serotyped by the Quellung reaction with antisera obtained from the Statens Serum Institut (Copenhagen, Denmark). Isolates described as non-typeable did not react with the omni-serum provided by the Statens Serum Institut and therefore were considered ‘rough’ strains.
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Mechanism of macrolide resistance
Of the 865 macrolide-resistant S. pneumoniae isolates tested, 775 (89.6%) carried either mef(A) (n = 404; 46.7%) or erm(B) (n = 371; 42.9%) (Table 1). Fifty isolates (5.8%) contained both mef(A) and erm(B), whereas the remaining 40 isolates (4.6%) did not have either mef(A) or erm(B) (Table 1). Of the macrolide-resistant isolates negative for both mef(A) and erm(B), 22 (2.5%) contained 23S rRNA A2058G, A2059G or A2059C mutations, 7 (0.8%) contained 23S rRNA A2058G or A2059G mutations along with an S20N mutation in L4 ribosomal protein and 1 isolate contained an E30K ribosomal protein mutation alone.
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The majority of the mef(A)-positive isolates demonstrated lower erythromycin MICs (MIC90, 4 mg/L) than the erm(B)-positive isolates (MIC90, 128 mg/L) (Table 1); however, it is important to note that some mef(A)-positive isolates exhibited higher than usual MICs of macrolides (MICs, 128 mg/L). Interestingly, although the majority of mef(A)-positive isolates were susceptible to clindamycin (MIC90, 0.25 mg/L), 12.4% demonstrated clindamycin MICs in the intermediate and resistant range (0.5–128 mg/L) (Table 1). These isolates will be investigated in the future for the presence of additional mechanisms of resistance, such as mutations within the 23S rRNA or ribosomal proteins. The majority (97%) of the erm(B)-positive isolates were resistant to clindamycin (MIC90, 32 mg/L). The erythromycin and clindamycin MIC90s for isolates with both mef(A) and erm(B) were 128 and 32 mg/L, respectively; identical to the results for erm(B)-positive isolates. The majority of the isolates (58%) that were negative for both mef(A) and erm(B) demonstrated an erythromycin MIC90 of 128 mg/L, along with an MIC90 of clindamycin of 4 mg/L (Table 1).
Susceptibility to telithromycin
Among the macrolide-resistant S. pneumoniae, the susceptibility to telithromycin was 98.3%. Fifteen (1.7%) of the macrolide-resistant isolates had an intermediate telithromycin MIC of 2 mg/L. Lower MICs of telithromycin were found among isolates carrying the erm(B) gene than among isolates carrying the mef(A) gene, with the majority (MIC90) of isolates being inhibited by MICs of 0.03 and 0.25 mg/L, respectively (Table 1). The activity of telithromycin against isolates positive for both mef(A) and erm(B) and those negative for both mef(A) and erm(B) was similar to mef(A)-positive isolates, with the majority of isolates (MIC90) inhibited at 0.25 and 0.12 mg/L, respectively (Table 1).
Incidence of macrolide resistance mechanisms over the 6 year study period
The incidence of mef(A)-positive S. pneumoniae isolates changed from 40% (1998) to 45% (2004), whereas the incidence of erm(B)-positive S. pneumoniae changed from 55% (1998) to 38% (2004) (Figure 1). Isolates containing both mef(A) and erm(B) resistance genes increased from 4% (1998) to 12% (2004), whereas isolates negative for both mef(A) and erm(B) increased from 1% (1998) to 5% (2004) (Figure 1).
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Characteristics of isolates with dual erm(B) and mef(A) mechanisms of macrolide resistance
Of the 50 dual erm(B) and mef(A) macrolide-resistant S. pneumoniae isolates, 46 isolates (92%) displayed the typical MLSB phenotype (Table 2), characterized by high-level resistance to macrolides and resistance to clindamycin (MIC90, 16 mg/L). Three isolates (6%) showed low-level resistance to macrolides (clarithromycin MIC, 2–8 mg/L) and were susceptible to clindamycin, typical of an M phenotype. The remaining isolate (2%) was susceptible to clindamycin (MIC, 0.25 mg/L), but showed high-level resistance to the macrolides (erythromycin MIC, 64 mg/L). Among other antimicrobials, the highest resistance was found to trimethoprim/sulfamethoxazole (80%) and penicillin (72%). In addition, resistance rates of 20% and 13%, respectively, were noted for amoxicillin/clavulanate and doxycycline. The genetic relatedness among isolates is shown in Figure 2. Fifteen unique PFGE profiles were observed among the 50 erm(B)-positive/mef(A)-positive S. pneumoniae. Dendrogram analysis identified one major cluster (80% genetic relatedness), containing 36 (72%) of the 50 isolates (Figure 2). Thirty-four (94.4%) isolates within this cluster (68% of all isolates) belonged to serotype 19F, one (2.8% of cluster, 2% of all strains) was serotype 19A and one (2.8% of cluster, 2% of all isolates) was serotype 14. All isolates within this cluster were genetically related to the internationally known Taiwan 19F-14 clone. The remaining 14 isolates were genetically unrelated by PFGE and belonged to serotypes 19F (three isolates, 6%), 23F (two isolates, 4%) or 19A (one isolate, 2%). Eight isolates (16%) were non-typeable.
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Characteristics of isolates with neither erm(B) nor mef(A) mechanism of resistance
Of the 40 mef(A)-negative and erm(B)-negative isolates, mutations in the 23S rRNA or ribosomal L4 proteins were documented for 30 isolates (75% of the 40 strains or 3.5% of all macrolide-resistant isolates). Isolates with these mutations together with their respective MICs of erythromycin, clindamycin and telithromycin are shown in Table 3. Of the 30 isolates, 29 (97%) demonstrated mutations in 23S rRNA, whereas 8 (27%) isolates demonstrated a mutation in the L4 ribosomal protein. Seven isolates (23%) contained both 23S rRNA and L4 ribosomal protein mutations. Isolates with mutations in three or four of the four 23S rRNA alleles were found most commonly. The most common mutation was A2058G, followed by A2059G and A2059C. Among 29 isolates with ribosomal RNA mutations, 69% demonstrated erythromycin MICs 16 mg/L and 59% were susceptible to clindamycin (MIC 
0.25 mg/L). Resistance to clindamycin (MIC 1 mg/L) was noted for six isolates (21%). Four of those isolates had three of the four 23S rRNA alleles mutated and two had all four 23S rRNA alleles mutated. Two ribosomal L4 mutations were found: S20N in seven isolates and E30K present in one isolate. Among the isolates with an S20N L4 mutation, two isolates had a mutation in one 23S rRNA allele, three isolates in three alleles and two isolates in four alleles of the 23S rRNA. All isolates with an S20N ribosomal protein mutation demonstrated an erythromycin MIC of 16 mg/L. The majority of these isolates (71%) were susceptible to clindamycin and only two isolates demonstrated resistance to clindamycin, with MICs of 1 and 4 mg/L. An E30K ribosomal L4 protein mutation was present in one isolate. This isolate had wild-type 23S rRNA and it demonstrated erythromycin and clindamycin MICs of 4 and 0.12 mg/L, respectively. No isolates demonstrated mutations in ribosomal protein L22. The macrolide resistance mechanism remained unresolved [not mef(A) or erm(B) and no mutations in 23S rRNA or ribosomal L4 proteins] in 10 (1.1% of all macrolide-resistant strains) isolates.
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Resistance to macrolide antibiotics in S. pneumoniae in Canada has typically been mediated equally by the mef(A) and erm(B) genes.6 However, the most recent data from CROSS presented here have shown that the prevalence of high-level erm(B)-mediated macrolide resistance in Canada has decreased by 17% between 1998 and 2004 (P < 0.05). This decrease has coincided with an 8% increase (from 4% to 12%) in isolates containing both erm(B) and mef(A) (P < 0.05). Genetic typing and phenotypic antibiotic testing of dual erm(B)-positive/mef(A)-positive isolates suggest that a multidrug-resistant (MDR) clonal complex, genetically related to the internationally known Taiwan 19F-14 clone of S. pneumoniae, is emerging in Canada. Serotype analysis of dual erm(B)-positive/mef(A)-positive S. pneumoniae isolates showed serotype 19F as the most predominant. Serotype 19A was detected in two isolates. Interestingly, in one study, 11 of 15 isolates belonged to serotype 19A and only 4 were serotype 19F, indicating possible capsular replacement as a result of vaccine usage.20,23 The 7-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal vaccine coverage against these MDR S. pneumoniae isolates was studied. Both vaccinations showed a coverage rate of 80% against these MDR dual mef(A)-positive/erm(B)-positive S. pneumoniae. Several studies have shown that significant cross-reactivity of serotype 19F with serotype 19A occurs.20,23 Assuming the cross-coverage extends to serotype 19A, the coverage increases to 84%. However, significant differences in the cross-reactivity have been noted between different vaccine formulations and to date there is no conclusive evidence that serotype 19A is adequately covered by vaccination.23 Some studies conclude that the introduction of routine immunization has not prevented the spread of non-vaccine serotypes, but rather selects for them, including 19A. Therefore, in the future, we might be seeing vaccine serotypes being replaced by more pathogenic and uncommon non-vaccine serotypes. In Canada, 7-valent pneumococcal conjugate vaccination became part of routine childhood vaccination programmes in the winter of 2004–05; therefore, most of our dual erm(B)-positive/mef(A)-positive isolates came from pre-vaccinated individuals. This may explain the low prevalence of serotype 19A among our patient population. Although this study did not contain invasive disease isolates childhood vaccinations are meant to prevent, studies have shown that conjugate vaccinations control the selection of resistance, as they prevent carriage and lessen the antibiotic pressure of S. pneumoniae and therefore analysis of coverage against respiratory isolates may be of value.33
In conclusion, the emerging MDR S. pneumoniae may have clinical implications such as the increased potential for treatment failure with most antibiotics currently recommended to empirically treat community-acquired respiratory tract infections. Therefore, the continued surveillance of pneumococcal resistance is imperative to ensure accurate detection of MDR clones. In addition, continued serotyping and genotyping of macrolide-resistant pneumococci is necessary to determine whether the introduction of 7-valent conjugate pneumococcal vaccine to routine childhood immunizations will select these clonal, MDR S. pneumoniae with combined erm(B)- and mef(A)-mediated macrolide resistance and whether it will promote serotype replacement over time in the paediatric population. This study also evaluated the activity of telithromycin, the first of the ketolide antimicrobials introduced into clinical practice. Although CROSS surveillance has shown it to be a very effective agent against most macrolide-resistant strains, reduced susceptibility was noted against strains with mef(A)-mediated resistance. The possibility that telithromycin is being affected by a low-level efflux-mediated resistance mechanism is disturbing. It may suggest a possible additive effect to another mechanism or a first step towards acquiring higher resistance levels. Therefore, the use of telithromycin should be carefully considered not only when high-level erm(B)-mediated macrolide resistance is present but also is dependent on the presence of efflux. This finding highlights the ongoing necessity for antimicrobial surveillance studies in S. pneumoniae.
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D. J. H. and G. G. Z. have received research funding from Abbott, Pfizer and Sanofi-Aventis.
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Acknowledgements |
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We thank the participating centres, investigators and laboratory staff for their continued support. The technical assistance of B. Weshnoweski and R. Vashisht, along with the secretarial support of M. Tarka, is appreciated. The financial support of Abbott, Bayer Canada, Bristol-Myers Squibb, Janssen-Ortho Inc., Merck Frosst, Sanofi-Aventis and Wyeth is gratefully acknowledged. This research was in part supported by grants from the Manitoba Health Research Council (MHRC) and from the Manitoba Institute of Child Health (MICH).
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