Mechanisms and development of antimicrobial resistance in Campylobacter with special reference to ciprofloxacin

Minna Hannula

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma

Abstrakti

In industrialized countries, campylobacteriosis is the most common cause of human gastroenteric infection. It is mainly caused by Campylobacter jejuni and Campylobacter coli, but the pathogenic role of other species, such as Campylobacter hyointestinalis, remains unclear. The predominant antimicrobial agents for treating Campylobacter infections are erythromycin and ciprofloxacin. However, during the past few decades resistant C. jejuni and C. coli strains have rapidly emerged. The aim of this thesis was to study the various resistance mechanisms of C. jejuni, C. coli and C. hyointestinalis towards antimicrobial agents.

When susceptibility to 12 different antimicrobials was tested, it was concluded that Finnish C. hyointestinalis strains remain susceptible to most antimicrobials of veterinary importance. All the 24 reindeer strains included in the study proved susceptible, but resistance to streptomycin and sulphonamides was observed in 32% and 24% of the 25 bovine strains, respectively. The difference in the susceptibility profile of the bovine and reindeer strains most probably reflects the veterinary use of these substances in bovine husbandry, but not in reindeer.

Unlike C. jejuni and C. coli, C. hyointestinalis is inherently resistant to nalidixic acid, but the mutations in the quinolone resistance-determining region (QRDR) of gyrA involved in the acquired quinolone resistance of C. jejuni were not present in C. hyointestinalis.

An efflux pump system, CmeABC, has been established to play an important role in the resistance of C. jejuni and C. coli to various antimicrobial agents. The effect of putative efflux pump inducers and inhibitors on the minimum inhibitory concentration (MIC) values of C. jejuni, C. coli and C. hyointestinalis was evaluated. It was concluded that the most potent was an efflux pump inhibitor, PAβN, which decreased inherent resistance of C. hyointestinalis to nalidixic acid 2- to 8-fold, and of C. jejuni and C. coli to rifampicin 8- to 64-fold. It also increased inherent susceptibility of C. jejuni and C. coli to erythromycin 8- to 32-fold. Another inhibitor, NMP, had similar but smaller effect on erythromycin, rifampicin and tetracycline MIC values of C. jejuni and C. coli. The two tested putative efflux pump inducers, sodium salicylate and bile salts, did not have any major effect on the MIC values of the studied antimicrobials.

Since target mutation is an important resistance mechanism in C. jejuni and C. coli, the mutation frequencies of C. jejuni and C. coli strains were determined. The obtained values varied from hypomutable to strongly hypermutable. The relatively large proportion (25%) of hypermutable strains may facilitate the adaptation of C. jejuni and C. coli to selective environments.

When originally ciprofloxacin-susceptible C. jejuni strains were subjected to low-level (0.125 or 1 mg/l) ciprofloxacin, the MIC values for these strains increased up to 32 mg/l. The high MIC values persisted even when the strains were repeatedly subcultured in the absence of ciprofloxacin. Subsequent sequencing of the QRDR revealed multiple peaks at nucleotide positions 256 and 267, but some variants had ciprofloxacin MIC levels of up to 16 mg/l, even though no peaks corresponding to mutated nucleotides in the QRDR were observed; this suggests the presence of a QRDR-independent resistance mechanism in these strains.
Alkuperäiskielienglanti
JulkaisupaikkaHelsinki
Kustantaja
Painoksen ISBN978-952-92-7360-7
Sähköinen ISBN978-952-10-6285-8
TilaJulkaistu - 2010
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)

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