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Defining the breakpoint for resistance to rifampicin in Neisseria meningitidis by rpoB sequencing
Örebro universitet, Hälsoakademin.
Visa övriga samt affilieringar
2009 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Clinical isolates of Neisseria meningitidis resistant to rifampicin are important to identify asthey lead to failure of chemoprophylaxis of meningococcal disease. However, theidentification of these isolates is hindered by the absence of a harmonized breakpoint despiteefforts of standardization. In the present study, a large number (n=352) of clinical N.meningitidis isolates from 12 mainly European countries and spanning over 25 years (1984 to2009) were examined. The collection comprised all clinical isolates with MIC 0.25 mg/lreceived by the national reference laboratories for meningococci in the participating countries(n=161). In addition, representative isolates displaying MIC of rifampicin <0.25 mg/l wereexamined (n=191). Phenotyping and genotyping of isolates were performed and a 660 bpDNA fragment of the rpoB gene was sequenced in all the included isolates. Sequencesdiffering by at least one nucleotide were defined as a unique rpoB allele (n=55). Geometricmeans of MIC were calculated for isolates displaying the same allele. All the clinical isolatesdisplaying MIC >1 mg/l of rifampicin possessed rpoB alleles with critical mutations (in total21 alleles), resulting in substitutions at the codon H552 and less frequently at nearby codons(S548 and S557). These alterations were absent in the alleles (n=34) found in all isolates withMIC 1 mg/l. Based on these findings, rifampicin susceptible isolates could be defined asthose with MIC 1 mg/l. A new web site was created based on the data from this work (http://neisseria.org/nm/typing/rpoB). The rifampicin resistant isolates belonged to diversegenetic lineages and provoked lower bacteremia levels in mice. This biological cost mayexplain the non-expansion of the rifampicin resistant isolates.

Ort, förlag, år, upplaga, sidor
2009.
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Medicin
Identifikatorer
URN: urn:nbn:se:oru:diva-8655OAI: oai:DiVA.org:oru-8655DiVA, id: diva2:278354
Tillgänglig från: 2009-11-25 Skapad: 2009-11-25 Senast uppdaterad: 2017-10-18Bibliografiskt granskad
Ingår i avhandling
1. Antibiotic susceptibility and resistance in Neisseria meningitidis: phenotypic and genotypic characteristics
Öppna denna publikation i ny flik eller fönster >>Antibiotic susceptibility and resistance in Neisseria meningitidis: phenotypic and genotypic characteristics
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Neisseria meningitidis, also known as the meningococcus, is a globally spread obligate human bacterium causing meningitis and/or septicaemia. It is responsible for epidemics in both developed and developing countries. Untreated invasive meningococcal disease is often fatal, and despite modern intensive care units, the mortality is still remarkably high (approximately 10%). The continuously increasing antibiotic resistance in many bacterial pathogens is a serious public health threat worldwide and there have been numerous reports of emerging resistance in meningococci during the past decades.

In paper I, the gene linked to reduced susceptibility to penicillins, the penA gene, was examined. The totally reported variation in all published penA genes was described. The penA gene was highly variable (in total 130 variants were identified). By examination of clinical meningococcal isolates, the association between penA gene sequences and penicillin susceptibility could be determined. Isolates with reduced susceptibility displayed mosaic structures in the penA gene. Two closely positioned nucleotide polymorphisms were identified in all isolates with reduced penicillin susceptibility and mosaic structured penA genes. These alterations were absent in all susceptible isolates and were successfully used to detect reduced penicillin susceptibility by real-time PCR and pyrosequencing in paper II. In papers III and IV, antibiotic susceptibility and characteristics of Swedish and African meningitis belt meningococcal isolates were comprehensively described. Although both populations were mainly susceptible to the antibiotics used for treatment and prophylaxis, the proportion of meningococci with reduced penicillin susceptibility was slightly higher in Sweden. A large proportion of the African isolates was resistant to tetracycline and erythromycin. In paper V, the gene linked to rifampicin resistance, the rpoB gene, was examined in meningococci from 12 mainly European countries. Alterations of three amino acids in the RpoB protein were found to always and directly lead to rifampicin resistance. A new breakpoint for rifampicin resistance in meningococci was suggested. The biological cost of the RpoB alterations was investigated in mice. The pathogenicity/virulence was significantly lower in rifampicin resistant mutants as compared with susceptible wild-type bacteria.

Ort, förlag, år, upplaga, sidor
Örebro: Örebro universitet, 2009. s. 94
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 38
Nyckelord
Neisseria meningitidis, meningococcal disease, antibiotic resistance, antibiotic susceptbility, biological cost, PCR, sequencing
Nationell ämneskategori
Cell- och molekylärbiologi Mikrobiologi inom det medicinska området Mikrobiologi inom det medicinska området Mikrobiologi inom det medicinska området
Forskningsämne
Biomedicin; Medicin
Identifikatorer
urn:nbn:se:oru:diva-8652 (URN)978-91-7668-702-4 (ISBN)
Disputation
2009-12-18, Wilandersalen, Universitetssjukhuset Örebro, Örebro, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-11-25 Skapad: 2009-11-25 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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Thulin Hedberg, SaraUnemo, Magnus

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