Molecular Epidemiology of Macrolide-Resistant Isolates of Streptococcus pneumoniae Collected from Blood and Respiratory Specimens in Norway

Abstract

Norway has a low prevalence of antimicrobial resistance, including macrolide-resistant Streptococcus pneumoniae (MRSP). In a nationwide surveillance program, a total of 2,200 S. pneumoniae isolates were collected from blood cultures and respiratory tract specimens. Macrolide resistance was detected in 2.7%. M-type macrolide resistance was found in 60% of resistant isolates, and these were mainly mef(A)-positive, serotype-14 invasive isolates. The erm(B)-encoded macrolide-lincosamide-streptogramin B (MLS B ) type dominated among the noninvasive isolates. One strain had an A2058G mutation in the 23S rRNA gene. Coresistance to other antibiotics was seen in 96% of the MLS B -type isolates, whereas 92% of the M-type isolates were susceptible to other commonly used antimicrobial agents. Serotypes 14, 6B, and 19F accounted for 84% of the macrolideresistant isolates, with serotype 14 alone accounting for 67% of the invasive isolates. A total of 29 different sequence types (STs) were detected by multilocus sequence typing. Twelve STs were previously reported international resistant clones, and 75% of the macrolide-resistant isolates had STs identical or closely related to these clones. Eleven isolates displayed 10 novel STs, and 7/11 of these "Norwegian strains" coexpressed MLS B and tetracycline resistance, indicating the presence of Tn1545. The invasive serotype-14 isolates were all classified as ST9 or single-locus variants of this clone. ST9 is a mef-positive M-type clone, commonly known as England 14 -9, reported from several European countries. These observations suggest that the import of major international MRSP clones and the local spread of Tn1545 are the major mechanisms involved in the evolution and dissemination of MRSP in Norway.Antimicrobial resistance is an increasing problem worldwide, and several countries have implemented surveillance systems in recent years. The Norwegian surveillance program for antimicrobial resistance (NORM) was established in 1999 and has reported yearly on the epidemiology of antimicrobial resistance and the usage of antimicrobial agents. Antimicrobial susceptibility data on common pathogens such as Escherichia coli, Klebsiella spp., Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes confirm that antimicrobial resistance is still a limited problem in Norway (28). The prevalence of macrolide-resistant S. pneumoniae (MRSP) has increased dramatically in several European countries (16) but is still relatively low in Northern Europe (31, 34). In Norway, macrolide resistance in S. pneumoniae blood culture isolates has increased from 2.4% in 2000 to 4.8% in 2002 and 6.0% in 2003 (28). Macrolides are used as second-line alternatives in the treatment of respiratory tract infections, because the prevalence of non-penicillin-susceptible S. pneumoniae is below 3% in Norway. They are recommended only for patients who are allergic to penicillin or are suspected of having atypical pneumonia. Thus, the increase in MRSP is of clinical concern as we...

Expression of the mef (E) Gene Encoding the Macrolide Efflux Pump Protein Increases in Streptococcus pneumoniae with Increasing Resistance to Macrolides

“…In fact, the increasing rates of macrolide resistance in the United States in recent years have been directly linked to the emergence of efflux-mediated resistance (8). Although once not very common, efflux-mediated macrolide resistance is not only now present at significant rates in Germany and Italy (6,16,20) but also predominates in European countries, such as Greece, Norway, and Scotland (1,15). Recent work has shown that the efflux mechanism of resistance in S. pneumoniae responsible for acquired macrolide resistance can be distinguished as either mef(E) or mef(A) (6,8,25).…”

“…Since it has been reported that both mef(A) and mef(E) genes are located on different genetic elements in S. pneumoniae that may influence the dissemination of M-phenotype macrolide resistance among streptococcal and other species, it has been suggested that the two genes remain separate (11). Generally, mef(A) predominates in Europe (1,2,6,15) and mef(E) predominates in North America and Asia (5,25). However, countries such as The Netherlands and Italy have reported that as many as 30% to 40% of macrolide-resistant S. pneumoniae isolates contain mef(E) (17).…”

Macrolide-Resistant Streptococcus pyogenes in Norway: Population Structure and Resistance Determinants

“…Forty-four strains (2.7%) showed reduced susceptibility to erythromycin (MIC Ն 1 mg/liter) and were further investigated. Antimicrobial susceptibility testing and determination of macrolide resistance phenotype and genotype and tetracycline resistance genotype was performed as previously described (9,16,25,32,33,37,38). Subtyping of mef was achieved by BamHI digestion of the 346-bp mef amplicon (22).…”

“…The regional dissemination of the M type ST39 clone in both high-and low-consumption countries is intriguing, and the selective advantage of this clone warrants further studies. Furthermore, mef(A) was recently shown to predominate among macrolide resistant S. pneumoniae in Norway (16). The evolutionary mechanism(s) for the successful spread of this efflux mechanism between streptococci remain(s) to be elucidated.…”

Phenotypic and Genotypic Characterization of Streptococcus pneumoniae Strains Colonizing Children Attending Day-Care Centers in Norway

“…However, resistance to erythromycin in systemic pneumococcal isolates has increased from 2.7% in 2002 to 12.4% in 2006 (33). This rapid increase in erythromycin resistance was found to be caused mainly by the spread of the England 14 -9 clone, carrying the mef(A) gene (29,44).…”