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At least 19 recordsLinked to original sources
PubMed2004

Distribution across the USA of macrolide resistance and macrolide resistance mechanisms among Streptococcus pneumoniae isolates collected from patients with respiratory tract infections: PROTEKT US 2001-2002.

BACKGROUND: Resistance to the macrolides has increased rapidly among isolates of Streptococcus pneumoniae from community-acquired respiratory tract infections (CARTIs). METHODS: A total of 10 012 S. pneumoniae isolates were submitted from 46 US states and the territory of Puerto Rico in the PROTEKT US Year 2 (2001-2002) surveillance study. Antimicrobial susceptibilities were determined according to NCCLS guidelines and genes encoding common macrolide resistance mechanisms were sought by PCR. RESULTS: Overall, 27.9% (n=2793) of S. pneumoniae isolates were macrolide (erythromycin) resistant; the highest prevalence was recorded in Louisiana (48.2%). Of the 2738 genotyped macrolide-resistant S. pneumoniae, 68.7% possessed mef(A) (state range: Delaware 40.0%-Georgia 84.8%), 16.8% of isolates harboured erm(B) (Georgia 6.1%-Idaho and Rhode Island both 36.4%) and 12.2% possessed erm(B) + mef(A) (Arkansas and Rhode Island 0%-South Dakota 32.9%). Five isolates possessed an erm(A) subclass erm(TR) gene (from California, Illinois, Missouri, Pennsylvania and Virginia), while the mechanisms for 56 isolates were not definable by the methods used in this study. Susceptibility to telithromycin was high, irrespective of macrolide resistance mechanism, with > or =96.4% of the macrolide-resistant isolates susceptible. CONCLUSIONS: The prevalence of macrolide resistance and the resistance mechanisms among S. pneumoniae isolates are highly variable among the US states. Telithromycin may represent an effective treatment option for CARTIs caused by macrolide-resistant pneumococci.

Anti-Bacterial Agents↗
PubMed1997

The role of ribosomal RNAs in macrolide resistance.

Macrolides are bacteriostatic antibiotics which interfere with the peptidyltransfer function of the ribosome. We have investigated the molecular mechanisms underlying macrolide resistance in Mycobacterium smegmatis, an eubacterium carrying two rRNA operons. Surprisingly, drug resistance was associated not with alterations in ribosomal proteins, but with a single point mutation in the peptidyltransferase region of one of the two 23S RNA genes, i.e. A2058-->G or A2059-->G. This mutation resulted in a heterozygous organism with a mutated and a wild-type rRNA operon respectively. Reverse transcriptase sequencing indicated the expression of both wild-type and mutated rRNAs. The mutated operon was introduced into genetically engineered rrn- strains of M. smegmatis carrying a single functional rRNA operon and into parental M. smegmatis with two chromosomal rRNA operons, using gene transfer as well as gene replacement techniques. The results obtained demonstrate the dominant nature of resistance. As exemplified in our results on macrolide resistance, a complete set of genetic tools is now available, which allows questions of dominance vs. recessivity and gene dosage effects in eubacterial ribosomal nucleic acids to be addressed experimentally in vivo.

Alleles↗
PubMed2005

Prevalence of inducible clindamycin resistance in macrolide-resistant Staphylococcus spp.

Between January 2002 and December 2003, macrolide-resistant isolates of Staphylococcus aureus (n = 45) and coagulase-negative staphylococci (CoNS; n = 75) from a Greek hospital were examined phenotypically for inducible clindamycin resistance. The constitutive macrolide resistance phenotype predominated (60%) in S. aureus, followed by the inducible (35%) and the clindamycin-susceptible (5%) phenotypes. In CoNS, the inducible phenotype was more common than the constitutive phenotype (50% vs. 41%). There was a significant incidence of inducible clindamycin resistance, and screening of all staphylococci is necessary in order to differentiate inducibly resistant isolates from those that are truly sensitive.

Anti-Bacterial Agents↗
PubMed1977

Macrolide resistance in Staphylococcus aureus: inducers of macrolide resistance.

Several macrolide-, lincosamide-, and streptogramin B-type (MLS) antibiotics were tested as inducers of erythromycin A (EM)-resistant [(14)C]leucine incorporation. Only 14-membered-ring macrolides having a glycosidically linked 6-deoxy sugar at the C-3 position of the lactone ring and the structurally dissimilar lincosamide, celesticetin, showed inducer activity. Modifications of EM at the C-4'' position of cladinose can apparently destroy the inducer property but do not affect the inhibitory properties of the antibiotic. The findings clearly show that inducer and inhibitor activities can be dissociated and are consistent with the concept that distinct binding/receptor sites are utilized for inhibition of ribosome function and induction of resistance.

Anti-Bacterial Agents↗
PubMed1977

Macrolide resistance in Staphylococcus aureus: induction of macrolide-resistant protein synthesis.

Induction of resistance to macrolide-, lincosamide-, and streptogramin B-type antibiotics in Staphylococcus aureus was studied by monitoring the appearance of erythromycin A (EM)-resistant [(14)C]leucine incorporation. Examination of the induction process revealed saturation kinetics and a time course much like that reported for penicillinase in gram-positive bacteria. Induction kinetics in exponentially growing cells were sigmoidal and appeared to reach a maximum and constant rate when growth reached stationary phase. Since the induction of EM-resistant colony-forming ability was complete within 60 min, ribosome modification cannot be limited to a fraction of the population and must occur in essentially every cell. However, EM-resistant growth was expressed in cells where less than half the [(14)C]leucine-incorporating activity was resistant to EM. This suggests that resistance requires that only a threshold level of ribosome modification be exceeded and that, once exceeded, resistance is dominant to sensitivity.

Anti-Bacterial Agents↗
PubMed2001

Antibiotic resistance rates and macrolide resistance phenotypes of viridans group streptococci from the oropharynx of healthy Greek children.

A total of 200 isolates of viridans group streptococci isolated from the oropharynx of healthy Greek children were studied. Vancomycin, rifampicin, fluoroquinolones and dalfopristin/quinupristin were active against all tested isolates. High level resistance to gentamicin was not seen. Intermediate and high-level penicillin resistance was present in 28.5 and 14.5% isolates, respectively, with 41.3% of the latter group, being also resistant to cefotaxime. Resistance rates to other antimicrobials were as follows - erythromycin 38.5%, clarithromycin 33.5%, clindamycin 7.5% and tetracycline 23%. Penicillin resistance occurred more frequently in Streptococcus mitis isolates, while macrolide resistance was more frequent in S. oralis. MLSB resistance phenotype M was dominant (74%) among erythromycin resistant isolates, with phenotypes IR and CR being represented by 6 and 20% of isolates, respectively.

Adolescent↗
PubMed2004

Oropharyngeal carriage of macrolide-resistant viridans group streptococci: a prevalence study among healthy adults in Belgium.

OBJECTIVES: Viridans group streptococci (VGS) are gaining significance as reservoirs of resistance determinants for respiratory tract pathogens. Our aim was to investigate healthy adults for oropharyngeal carriage of VGS that are resistant to macrolides, as well as to other common antibiotics. METHODS: Macrolide-resistant VGS were isolated from throat samples of 154 healthy Belgian adults, and phenotyped and genotyped for erm(A), erm(B) and mef(A). In vitro susceptibilities to 10 antimicrobials and the presence of tetracycline resistance genes were also determined. RESULTS: Carriage was detected in 71% of the population screened, from whom 157 unique, macrolide-resistant VGS were isolated. A constitutive (cMLS) phenotype was present in 105 isolates, of which 102 isolates carried either erm(B) or erm(B) + mef(A). The remaining three isolates did not present with any of the genes studied. All 45 isolates showing the M phenotype carried mef(A). The least abundant inducible (iMLS) isolates (n = 7) carried either erm(B) or erm(B) + mef(A). The most abundant macrolide-resistant VGS species was Streptococcus mitis (51%). Co-resistance to tetracycline was identified in 114 isolates, of which tet(M) was present in 105, tet(O) in two and both tet(M) and tet(O) in one, while the remaining six isolates did not present with either gene. tet(M) was also present in four tetracycline susceptible and two intermediately resistant isolates. Fluoroquinolone resistance (ciprofloxacin MIC > or = 4 mg/L) was detected in 16 isolates. Resistance to telithromycin, penicillin and chloramphenicol was appreciably low. CONCLUSIONS: This study highlights a high oropharyngeal carriage of macrolide-resistant VGS and its co-resistance to tetracycline and fluoroquinolones among healthy Belgian adults.

Adolescent↗
PubMed2002

Clinical and public health implications of macrolide-resistant Streptococcus pneumoniae.

Macrolide resistance among Streptococcus pneumoniae is a growing global concern, although its specific impact on public health is not currently well defined. A Consensus Working Group was convened in March 2001 to address whether credible, scientific data substantiate macrolide resistance in S. pneumoniae as: (i) producing significant morbidity; (ii) creating attendant health and economic burdens; (iii) constituting a public health threat; and (iv) warranting intervention, including development of new antibiotics with efficacy against these strains. Despite the limitations of available clinical data, concern about the possibility of treatment failure with macrolides is being expressed in clinical practice and in formal treatment guidelines, threatening the important role of these agents in the treatment of respiratory tract infections. Further studies are required to monitor and control macrolide resistance and evaluate settings in which macrolide treatment failures are occurring, and new therapeutic interventions are needed.

Adolescent↗
PubMed2001

Evaluation of PCR primers to screen for Streptococcus pneumoniae isolates and beta-lactam resistance, and to detect common macrolide resistance determinants.

Pneumococcal isolates (n = 148) from various countries (mostly from the USA) were tested by a primer set for PCR. Thirty-eight (86.4%) of the 44 penicillin G-susceptible isolates (MIC < or = 0.06 mg/L) had unaltered pbps, while six isolates (13.6%) had either one or two alterations in pbps. Of 47 penicillin G-resistant strains (MIC > or = 2 mg/L), 41 isolates (87.2%) had all three pbps altered, six isolates (12.8%) had altered pbp1a + 2x. Various combinations of altered pbp were seen in penicillin G-intermediate isolates. Prevalence of macrolide resistance genes mef(A) and erm(B) in isolates was clearly reflected by their MICs. All isolates were positive for lytA. The primers were useful for screening for Streptococcus pneumoniae and beta-lactam resistance, and for detection of common macrolide resistance determinants.

Anti-Bacterial Agents↗
PubMed1998

Isolation and characterization of two plasmids that mediate macrolide resistance in Escherichia coli: transferability and molecular properties.

Escherichia coli BM2506 is highly resistant to macrolide antibiotics; it produces macrolide 2'-phosphotransferase II [MPH(2')II] which inactivates such drugs. We investigated the localization and the transfer of the macrolide-resistance determinant that encoded the mphB gene for MPH(2')II in strain BM2506. Although we detected no clear band of plasmid DNA after agarose gel electrophoresis, transformation analysis using satellite DNA that corresponded to plasmid DNA after CsCl-ethidium bromide gradient centrifugation and restriction analysis of plasmid DNA in transformants showed that strain BM2506 harbored two plasmids, pTZ3721 (84 kb) and pTZ3723 (24 kb), that specified resistance to macrolides, ampicillin, streptomycin, tetracycline and sulfonamide and to macrolides and ampicillin, respectively. Southern hybridization showed that the mphB gene hybridized to both plasmids. Furthermore, pTZ3721 was transferred by conjugation to another strain of E. coli and pTZ3723 was mobilized with a self-transferable plasmid RP1 to other strains of E. coli. Therefore, it appears that the mphB gene is located on two plasmids in BM2506 and can be transferred to other strains of E. coli by conjugation or mobilization.

Anti-Bacterial Agents↗
PubMed1998

Macrolide resistance.

The macrolides have evolved through four chemical generations since erythromycin became available for clinical use in 1952. The first generation, the 14-membered ring macrolide erythromycin, induced resistance and was replaced by the second generation 16-membered ring macrolides which did not. The inability to induce came at the price of mutation, in the pathogenic target strain, to constitutive expression of resistance. A third generation of macrolides improved the acid-stability, and therefore the pharmacokinetics of erythromycin, extending the clinical use of macrolides to Helicobacter pylori and Mycobacterium tuberculosis. Improved pharmacokinetics resulted in the selection of intrinsically resistant mutant strains with rRNA structural alterations. Expression of resistance in these strains was unexpected, explainable by low rRNA gene copy number which made resistance dominant. A fourth generation of macrolides, the 14-membered ring ketolides are the most recent development. Members of this generation are reported to be effective against inducibly resistant strains, and ketolide resistant strains have not yet been reported. In this review we discuss details of the ways in which bacteria have become resistant to the first three generations of macrolides, both with respect to their biochemistry, and the genetic mechanisms by which their expression is regulated.

Journal Article↗
PubMed2005

Molecular epidemiology of macrolide-resistant isolates of Streptococcus pneumoniae collected from blood and respiratory specimens in Norway.

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 macrolide-resistant 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.

Drug Resistance, Bacterial↗
PubMed2004

Comparative activity of telithromycin against macrolide-resistant isolates of Streptococcus pneumoniae: results of two years of the PROTEKT surveillance study.

UNLABELLED: The increase in resistance to macrolides has been linked with increasing use of these agents as empirical therapy for community-acquired respiratory tract infections (CARTIs). As part of the ongoing PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance program, over 7600 Streptococcus pneumoniae isolates were collected worldwide from 1999-2001 and evaluated for macrolide resistance. Globally, macrolide resistance was 31-33%, with considerable inter-country variation (<10-88%) and particularly high prevalence in the Far East (>71%). In Europe, France had the most resistant isolates (>53%). The highest rates of macrolide resistance were seen in 0-2 year olds. Co-resistance to clindamycin (64%) and all beta-lactams (14-79%) was seen among macrolide-resistant isolates, but >99% of these isolates were susceptible to telithromycin, vancomycin and linezolid. There was considerable variation in the prevalence of erm(B) (56-64%) and mef(A) (30-35%): erm(B) was prevalent in Europe and mef(A) in North America. Globally, 5-7% isolates carried both mechanisms (erm(B)+mef(A)); of these, 47-65% were from South Korea. These double resistance isolates were >90% resistant to the beta-lactams, except amoxicillin-clavulanate. Clindamycin was active against >98% mef(A) but poorly active against erm(B) and erm(B)+mef(A) isolates. Telithromycin, vancomycin and linezolid were highly active (>99.5%) across all three genotypes. CONCLUSIONS: In vitro, telithromycin, vancomycin and linezolid are highly active against antibiotic-resistant strains of S. pneumoniae. Telithromycin may be a useful therapeutic alternative to macrolides for the treatment of CARTIs.

Acetamides↗
PubMed2004

Mutation at the position 2058 of the 23S rRNA as a cause of macrolide resistance in Streptococcus pyogenes.

BACKGROUND: In streptococci, three macrolide resistance determinants (erm(B), erm(TR) and mef(A)) have been found. In addition, certain mutations at the ribosomal 23S RNA can cause resistance to macrolides. Mutation at the position 2058 of the 23S rRNA of the Streptococcus pyogenes as a cause of macrolide resistance has not been described before. METHODS: Antibiotic resistance determinations for the clinical S. pyogenes strain ni4277 were done using the agar dilution technique. Macrolide resistance mechanisms were studied by PCR and sequencing. All six rRNA operons were amplified using operon-specific PCR. The PCR products were partially sequenced in order to resolve the sequences of different 23S rRNA genes. RESULTS: One clinical isolate of S. pyogenes carrying an adenine to guanine mutation at the position 2058 of the 23S rRNA in five of the six possible rRNA genes but having no other known macrolide resistance determinants is described. The strain was highly resistant to macrolides and azalides, having erythromycin and azithromycin MICs > 256 microgram/ml. It was resistant to lincosamides (clindamycin MIC 16 microgram/ml) and also MIC values for ketolides were clearly elevated. The MIC for telithromycin was 16 microgram/ml. CONCLUSION: In this clinical S. pyogenes strain, a mutation at the position 2058 was detected. No other macrolide resistance-causing determinants were detected. This mutation is known to cause macrolide resistance in other bacteria. We can conclude that this mutation was the most probable cause of macrolide, lincosamide and ketolide resistance in this strain.

Journal Article↗
PubMed2001

Macrolide resistance gene mreA of Streptococcus agalactiae encodes a flavokinase.

The mreA gene from Streptococcus agalactiae COH31 gamma/delta, resistant to macrolides and clindamycin by active efflux, has recently been cloned in Escherichia coli, where it was reported to confer macrolide resistance (J. Clancy, F. Dib-Hajj, J. W. Petitpas, and W. Yuan, Antimicrob. Agents Chemother. 41:2719--2723, 1997). Cumulative data suggested that the mreA gene was located on the chromosome of S. agalactiae COH31 gamma/delta. Analysis of the deduced amino acid sequence of mreA revealed significant homology with several bifunctional flavokinases/(flavin adenine dinucleotide (FAD) synthetases, which convert riboflavin to flavin mononucleotide (FMN) and FMN to FAD, respectively. High-performance liquid chromatography experiments showed that the mreA gene product had a monofunctional flavokinase activity, similar to that of RibR from Bacillus subtilis. Sequences identical to those of the mreA gene and of a 121-bp upstream region containing a putative promoter were detected in strains of S. agalactiae UCN4, UCN5, and UCN6 susceptible to macrolides. mreA and its allele from S. agalactiae UCN4 were cloned on the shuttle vector pAT28. Both constructs were introduced into E. coli, where they conferred a similar two- to fourfold increase in the MICs of erythromycin, spiramycin, and clindamycin. The MICs of a variety of other molecules, including crystal violet, acriflavin, sodium dodecyl sulfate, and antibiotics, such as certain cephalosporins, chloramphenicol, doxycycline, nalidixic acid, novobiocin, and rifampin, were also increased. In contrast, resistance to these compounds was not detected when the constructs were introduced into E. faecalis JH2-2. In conclusion, the mreA gene was probably resident in S. agalactiae and may encode a metabolic function. We could not provide any evidence that it was responsible for macrolide resistance in S. agalactiae COH31 gamma/delta; broad-spectrum resistance conferred by the gene in E. coli could involve multidrug efflux pumps by a mechanism that remains to be elucidated.

Amino Acid Sequence↗