Horizontal gene transmission of thecfrgene to MRSA andEnterococcus: role ofStaphylococcus epidermidisas a reservoir and alternative pathway for the spread of linezolid resistance

Cafini, Fabio; Nguyen, Le Thuy Thi; Higashide, Masato; Román, Federico; Prieto, J.; Morikawa, Kazuya

doi:10.1093/jac/dkv391

Cited by 60 publications

(39 citation statements)

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“…Structural modifications in the molecule result in enhanced binding to the 23S rRNA target and provide enhanced activity of tedizolid compared to that of linezolid; furthermore, tedizolid potency is not affected by strains harboring the transmissible cfr resistance gene (1,2,6).…”

mentioning

confidence: 99%

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014

Pfaller

Flamm

Jones

et al. 2016

Antimicrob Agents Chemother

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bTedizolid and linezolid in vitro activities against 3,032 Gram-positive pathogens collected in Asia-Pacific, Eastern European, and Latin American medical centers during 2014 were assessed. The isolates were tested for susceptibility by the current reference broth microdilution methods. Due to concern over the effect of MIC endpoint criteria on the results of testing the oxazolidinones tedizolid and linezolid, MIC endpoint values were read by two methods: (i) reading the MIC at the first well where the trailing began without regard for pinpoint trailing, according to CLSI M07-A10 and M100-S26 document instructions for reading linezolid (i.e., 80% inhibition of growth; these reads were designated tedizolid 80 and linezolid 80), and (ii) at 100% inhibition of growth (designated tedizolid 100 and linezolid 100). All Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, and Enterococcus faecalis isolates were inhibited at tedizolid 80 and 100 MIC values of 0.25 and 0.5, 0.25 and 0.25, 0.25 and 0.5, 0.12 and 0.25, and 0.5 and 1 g/ml, respectively. Generally, MIC 50 and MIC 90 results for tedizolid 80 and linezolid 80 were one doubling dilution lower than those read at 100% inhibition. Tedizolid was 4-to 8-fold more potent than linezolid against all the isolates tested regardless of the MIC endpoint criterion used. Despite the differences in potency, >99.9% of isolates tested in this survey were susceptible to both linezolid and tedizolid using CLSI and EUCAST interpretive criteria. In conclusion, tedizolid demonstrated greater in vitro potency than linezolid against Gram-positive pathogens isolated from patients in medical centers across the Asia-Pacific region, Eastern Europe, and Latin America. Tedizolid is an oxazolidinone derivative that exhibits greater potency and a broader spectrum than linezolid when tested against a broad array of Gram-positive cocci, including those with drug-resistant phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), and linezolid-resistant phenotypes (1, 2). Tedizolid was approved by the U.S. Food and Drug Administration (FDA) in 2014 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and is undergoing phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP) (2).Numerous in vitro surveys have demonstrated that tedizolid is 4-to 8-fold more potent than linezolid against species of staphylococci, enterococci, and streptococci, including those with multidrug-resistant (MDR) phenotypes, such as MRSA, VRE, and linezolid-resistant S. aureus and enterococci (3-5). Structural modifications in the molecule result in enhanced binding to the 23S rRNA target and provide enhanced activity of tedizolid compared to that of linezolid; furthermore, tedizolid potency is not affected by strains harboring the transmissible cfr resistance gene (1,2,6).Whereas the vast majority of in vitro st...

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confidence: 99%

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014

Pfaller

Flamm

Jones

et al. 2016

Antimicrob Agents Chemother

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“…Mobilization of MGEs, though possible [46], would require specific host determinants which might be absent in our donor strains tested In accordance, some studies also report about ineffective transfer from Enterococcus spp. to staphylococci or vice versa [18, 47]. Thus, the questions of whether or not the cfr(B) variant could to be disseminated amongst enterococci by conjugation requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Detection of a cfr(B) Variant in German Enterococcus faecium Clinical Isolates and the Impact on Linezolid Resistance in Enterococcus spp.

et al. 2016

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The National Reference Centre for Staphylococci and Enterococci in Germany has received an increasing number of clinical linezolid-resistant E. faecium isolates in recent years. Five isolates harbored a cfr(B) variant gene locus the product of which is capable of conferring linezolid resistance. The cfr(B)-like methyltransferase gene was also detected in Clostridium difficile. Antimicrobial susceptibility was determined for cfr(B)-positive and linezolid-resistant E. faecium isolates and two isogenic C. difficile strains. All strains were subjected to whole genome sequencing and analyzed with respect to mutations in the 23S rDNA, rplC, rplD and rplV genes and integration sites of the cfr(B) variant locus. To evaluate methyltransferase function, the cfr(B) variant of Enterococcus and Clostridium was expressed in both E. coli and Enterococcus spp. Ribosomal target site mutations were detected in E. faecium strains but absent in clostridia. Sequencing revealed 99.9% identity between cfr(B) of Enterococcus and cfr of Clostridium. The methyltransferase gene is encoded by transposon Tn6218 which was present in C. difficile Ox3196, truncated in some E. faecium and absent in C. difficile Ox3206. The latter finding explains the lack of linezolid and chloramphenicol resistance in C. difficile Ox3206 and demonstrates for the first time a direct correlation of elevated linezolid MICs in C. difficile upon cfr acquisition. Tn6218 insertion sites revealed novel target loci for integration, both within the bacterial chromosome and as an integral part of plasmids. Importantly, the very first plasmid-association of a cfr(B) variant was observed. Although we failed to measure cfr(B)-mediated resistance in transformed laboratory strains the occurrence of the multidrug resistance gene cfr on putatively highly mobile and/or extrachromosomal DNA in clinical isolates is worrisome with respect to dissemination of antibiotic resistances.

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“…Among the studied strains, one S. aureus strain did not share a similar plasmid proile. Plasmid sequence analysis demonstrated the existence of identical 39.3 kb pSCFS3-like plasmids in one S. epidermidis and S. aureus isolates [6]. As pSCFS3 plasmids were considered as non-conjugative vectors [94], this indirect demonstration of plasmid transmission questioned the nature of the HGT involved in the spread of these plasmids.…”

Section: Dissemination Of Cfrmentioning

confidence: 98%

“…Our group answered this question demonstrating an alternative mechanism for cfr spread based on phage transduction among MRSA [6]. By using a S. aureus N315 derivate strain harboring a pSCFS7-like vector obtained by conjugation from one clinical S.…”

Section: Dissemination Of Cfrmentioning

confidence: 99%

Mechanisms of Horizontal Gene Transfer

Cafini¹,

Romero²,

Morikawa³

2017

The Rise of Virulence and Antibiotic Resistance in ≪i>Staphylococcus AureusSelf Cite

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Horizontal gene transfer plays important roles in the evolution of S. aureus, and indeed, a variety of virulence factors and antibiotic resistance genes are embedded in a series of mobile genetic elements. In this chapter, we review the mechanisms of horizontal gene transfer, including recent indings on the natural genetic competence. Then, we consider the transfer of two important antibiotic resistance genes: the methicillin resistance gene, mecA (in Staphylococcal Cassete Chromosome) and the linezolid resistance gene, cfr (in plasmid). In either case, distinct mechanisms driving the gene dissemination support the prominent evolutionary ability of this important human pathogen.

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Horizontal gene transmission of thecfrgene to MRSA andEnterococcus: role ofStaphylococcus epidermidisas a reservoir and alternative pathway for the spread of linezolid resistance

Abstract: Linezolid resistance mediated by cfr vectors, such as pSCFS7-like plasmids, can be efficiently transferred to clinical MRSA in Japanese isolates. After reaching the staphylococcal pool, the cfr gene could be spread among MRSA strains by either conjugation or transduction.

Cited by 60 publications

References 29 publications

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014

Detection of a cfr(B) Variant in German Enterococcus faecium Clinical Isolates and the Impact on Linezolid Resistance in Enterococcus spp.

Mechanisms of Horizontal Gene Transfer

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