Imipenem Resistance in <i>Clostridium difficile</i> Ribotype 017, Portugal

Isidro, Joana; Santos, Andrea; Nunes, Baltazar; Borges, Vítor; Silva, Catarina; Vieira, Luı́s; Mendes, Aristides L.; Serrano, Mònica; Henriques, Adriano O.; Gomes, João Paulo; Oleastro, Mónica

doi:10.3201/eid2404.170095

Cited by 30 publications

(42 citation statements)

References 13 publications

(18 reference statements)

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“…According to a pan-European study, most clinical isolates in Europe are susceptible to imipenem, although ribotype 027 showed elevated MICs compared to other ribotypes (Freeman et al, 2015). Similarly to another clone of ribotype 017 that we described recently (Isidro et al, 2018), the clone characterized in the present study also showed a high-level resistance to imipenem (MIC >32 mg/L).…”

Section: Discussionsupporting

confidence: 82%

“…Furthermore, we found the mutation 2162G > C in the homolog of locus CDM68_RS05670, which codes for a penicillin-binding protein (PBP), PBP3 (Isidro et al, 2018). This mutation, which leads to the amino acid substitution Cys721Ser, occurs in the PBP transpeptidase domain, the target of carbapenems action (Papp-Wallace et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…Three strains (A, B, and K; Figure 1) were selected for WGS in order to identify putative determinants of resistance and assess clonal relationship. WGS was performed as previously described (Isidro et al, 2018). Nextera XT libraries were subjected to paired-end sequencing on an Illumina Miseq platform (Illumina Inc., San Diego, CA, United States).…”

Section: Methodsmentioning

confidence: 99%

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Genomic Study of a Clostridium difficile Multidrug Resistant Outbreak-Related Clone Reveals Novel Determinants of Resistance

et al. 2018

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Background: Clostridium difficile infection (CDI) is prevalent in healthcare settings. The emergence of hypervirulent and antibiotic resistant strains has led to an increase in CDI incidence and frequent outbreaks. While the main virulence factors are the TcdA and TcdB toxins, antibiotic resistance is thought to play a key role in the infection by and dissemination of C. difficile.Methods: A CDI outbreak involving 12 patients was detected in a tertiary care hospital, in Lisbon, which extended from January to July, with a peak in February, in 2016. The C. difficile isolates, obtained from anaerobic culture of stool samples, were subjected to antimicrobial susceptibility testing with Etest®strips against 11 antibiotics, determination of toxin genes profile, PCR-ribotyping, multilocus variable-number tandem-repeat analysis (MLVA) and whole genome sequencing (WGS).Results: Of the 12 CDI cases detected, 11 isolates from 11 patients were characterized. All isolates were tcdA-/tcdB+ and belonged to ribotype 017, and showed high level resistance to clindamycin, erythromycin, gentamicin, imipenem, moxifloxacin, rifampicin and tetracycline. The isolates belonged to four genetically related MLVA types, with six isolates forming a clonal cluster. Three outbreak isolates, each from a different MLVA type, were selected for WGS. Bioinformatics analysis showed the presence of several antibiotic resistance determinants, including the Thr82Ile substitution in gyrA, conferring moxifloxacin resistance, the substitutions His502Asn and Arg505Lys in rpoB for rifampicin resistance, the tetM gene, associated with tetracycline resistance, and two genes encoding putative aminoglycoside-modifying enzymes, aadE and aac(6′)-aph(2″). Furthermore, a not previously described 61.3 kb putative mobile element was identified, presenting a mosaic structure and containing the genes ermG, mefA/msrD and vat, associated with macrolide, lincosamide and streptogramins resistance. A substitution found in a class B penicillin-binding protein, Cys721Ser, is thought to contribute to imipenem resistance.Conclusion: We describe an epidemic, tcdA-/tcdB+, multidrug resistant clone of C. difficile from ribotype 017 associated with a hospital outbreak, providing further evidence that the lack of TcdA does not impair the infectious potential of these strains. We identified several determinants of antimicrobial resistance, including new ones located in mobile elements, highlighting the importance of horizontal gene transfer in the pathogenicity and epidemiological success of C. difficile.

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genomic Study of a Clostridium difficile Multidrug Resistant Outbreak-Related Clone Reveals Novel Determinants of Resistance

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“…C. difficile has nine PBPs identified of which only one is of Class A, three of Class B and five LMW PBPs ( Figure 5C and Table 2). Note that the numbering of the C. difficile PBPs used herein is based on the nomenclature used in a recent study [152]. Strain M68, a recent representative of RT017 [153], has an additional Class B PBP, referred to as PBP5, which may have been recently acquired by horizontal gene transfer.…”

Section: Penicillin-binding Proteinsmentioning

confidence: 99%

“…Through WGS of the endemic clone, we have identified two mutations affecting the transpeptidase domain of two penicillin-binding protein genes (pbp1 and pbp3; see Figure 5A and B). The mutations are therefore likely to be associated with imipenem resistance possibly by reducing the affinity of the drug to one or both proteins [152]. The emergence of resistance to carbapenems in multiresistant clones of C. difficile might lead to the fast spread of these strains in hospital settings, in an analogy with the initial spreading of the fluoroquinolone-resistant strains, and thus deserves urgent and continuous surveillance.…”

Section: Antibiotic Resistance and The Emergence And Spreading Of Epimentioning

confidence: 99%

Overview of Clostridium difficile Infection: Life Cycle, Epidemiology, Antimicrobial Resistance and Treatment

Isidro¹,

Mendes²,

Serrano³

et al. 2017

Clostridium Difficile - A Comprehensive Overview

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The use of antimicrobial agents and acquired resistances explains in part the emergence and spreading of epidemic strains of Clostridium difficile. Continued use of antimicrobial therapy still represents an acute danger in triggering the emergence and spreading of new resistant and multiresistant strains including against first-line antibiotics. We examine the pathway of peptidoglycan synthesis in this organism and associated resistances, as well as resistance to other classes of antibiotics. The life cycle of C. difficile involves growth, spore formation and germination. Spores endow the organism with a formidable capacity of persistence in the environment and in the host, resistance, dissemination and infectious potential. Highly resistant spores produced by antibiotic-resistant/multiresistant strains may be one of the most serious challenges we face in what concerns the containment of C. difficile. Finally, we review recent developments in the treatment and prevention of C. difficile infection.

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