Türkiye’ de plazmit aracılı kinolon direnci

Kinolonlar tıpta ve veterinerlikte çeşitli infeksiyonların tedavisinde kullanılan geniş spektrumlu antibiyotiklerdir. Bu ilaçların yaygın kullanımı bakterilerde kinolon direnci gelişimine büyük ölçüde neden olmuştur. Bakterilerdeki kinolon direnci, genellikle topoizomerazları kodlayan kromozomal genlerde meydana gelen mutasyonlar sonucunda ortaya çıkmakta, ayrıca geri atım pompaları ve porinlerin kaybı kinolon direnci gelişmesine katkıda bulunmaktadır. Bununla birlikte son yıllarda yapılan çalışmalar kinolon direncinin yayılması ve artışının plazmit aracılı olabileceğini göstermiştir. Bugüne kadar plazmit aracılı kinolon direnci ile ilgili qnr, aac(6’)-Ib-cr, qepA olmak üzere üç gen tanımlanmıştır. 1998’de Martinez-Martinez ve ark. çoklu dirençli bir Klebsiella pneumoniae suşunda florokinolonların bakteriyel topoizomerazlar üzerine etkisini bloke eden, tekrarlayan pentapeptit protein ailesine ait 218 aminoasitlik bir proteini kodlayan plazmit aracılı kinolon direnci genini (qnrA) bildirmişlerdir. QnrA proteini, kinolonlara dirence, florokinolonların da MİK’lerinde artışa neden olmaktadır. Dünya genelinde Enterobacteriaceae ailesinden birçok bakteride saptanan qnrA genini, diğer plazmit aracılı kinolon direnci genleri olan qnrS, qnrB, qnrC, qnrD takip etmiştir. 2006 yılında farklı bir plazmit aracılı kinolon direnç geni olan aac(6’)-Ib-cr keşfedilmiştir. aac(6’)-Ib’nin -cr varyantı olan bu gen norfloksasin ve siprofloksasin gibi bazı kinolonların enzimatik inaktivasyonu yoluyla duyarlılıklarında azalmaya yol açan bir aminoglikozit asetiltransferazı kodlar. Diğer plazmit aracılı kinolon direnç geni olan qepA ise Japonya ve Belçika’da Escherichia coli suşlarında tanımlanmıştır. 14 transmembran geri atım pompasıyla ilişkili olan 511 aminoasitlik bir proteini kodlayan qepA norfloksasin ve siprofloksasin gibi hidrofilik kinolonların hücre dışına pompalanması yoluyla atılmasına neden olarak, bu antibiyotiklerin MİK’lerini arttırmaktadır. Çok yakın zamanda Serratia marcescens suşlarında smaqnr isminde kromozom kaynaklı yeni bir gen bildirilmiştir. S.marcescens Db11 suşundaki Smaqnr proteininin QnrB1 ile % 80 oranında benzerlik gösterdiği saptanmıştır. Türkiye’de plazmit aracılı kinolon direnç geni olan qnrA, ilk kez 2005 yılında SHV-7 beta-laktamazı üreten Enterobacter cloacae ile VEB-1 ve OXA-48 beta-laktamazı üreten Citrobacter freundii suşlarında saptanmıştır. qnrA’nın ardından, son yıllarda yapılan çalışmalarla ülkemizde diğer plazmit aracılı kinolon direnci genlerinden qnrB, qnrS ve aac(6’)-Ib-cr’nin varlığı da gösterilmiştir. Bu makalede kinolonların genel özelliklerine kısaca değinildikten sonra plazmit aracılı kinolon direnci genlerinin keşfi ve bu konuda Türkiye’de yapılan çalışmalar gözden geçirilmiştir.

Plazmid-mediated quinolone resistance in Turkey

Quinolones are broad spectrum agents for treatment of a variety of clinical and veterinary infections. Widespread use of these agents has largely contributed to the rise of bacterial quinolone resistance. Bacterial resistance to quinolones usually results from mutations in the chromosomal genes encoded topoisomerases and as well the expression of efflux pumps and loss of porines contributed to development of quinolone resistance. However recent studies have shown that the spread and increase of quinolone resistance due to plasmid-mediated mechanism. Since today, three plasmid mediated quinolone resistance mechanisms, qnr, aac(6’)-Ib-cr, qepA, have been described. In 1998, Martinez-Martinez et al reported a plasmid mediated resistance determinant (qnrA) encodes 218 aminoacid which belongs to pentapeptide repeat family of proteins block the action of flouroquinolones on bacterial topoisomerases in a multiresistant Klebsiella pneumoniae. QnrA protein confers resistance to quinolones and increases MICs of floroquinolones. qnrA determinants have been detected in worldwide in many enterobacterial species and followed by other plasmid mediated quinolone determinants, qnrS, qnrB, qnrC, qnD. In 2006, a different plasmid mediated quinolone resistance determinant, aac(6’)-Ib-cr is discovered. The -cr variant of aac(6’)-Ib encodes of an aminoglycoside acetyltransferase cabaple of enzymatic inactivation of certain quinolones as norfloxacin and ciprofloxacin and conferring reduced susceptibility. Another plasmid mediated quinolone resistance determinant, qepA has been recently identified in Escherichia coli strains in Japan and Belgium. qepA encodes 511 aminoacid protein belonging to 14 transmembran segment efflux pumps, causes to pump out hydropilic quinolones such as norfloxacin and ciprofloxacin and increases the MICs of these agents. Very recently, a new chromosome-encoded quinolone resistance determinant, named smaqnr, from Serratia marcescens strains is reported. 80 % amino acid identity was detected between Smaqnr protein in S.marcescens Db11 and QnrB1. In Turkey, plasmid mediated quinolone resistance determinant, qnrA was first detected in two strains, a SHV-7 beta-lactamase producing E.cloacae and a VEB-1 and OXA-48 beta-lactamase producing Citrobacter freundii in 2005. After detection of qnrA, other plasmid mediated determinants qnrB, qnrS and aac(6’)-Ib-cr were reported in Turkey. In this article the discovery of plasmid mediated quinolone resistance determinants and studies related with this subject in Turkey are reviewed after mentioning briefly about general characteristics of quinolones.

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