Öz
Giriş: Çalışmamızda seftazidim-avibaktam (CZA) ve seftolozan-tazobaktamın (C/T) çoklu ilaca dirençli (ÇİD) Klebsiella pneumoniae izolatlarındaki in vitro etkinliklerinin incelenmesi amaçlanmıştır. Ayrıca karbapenem direncinden sorumlu tutulan karbapenemaz enzim tiplerinin belirlenerek, bu enzimlere göre CZA ve C/T etkinliğinin karşılaştırılması amaçlanmıştır.
Gereç ve Yöntem: İncelenen 22 ÇİD K. pneumoniae izolatının tanımlama ve antibiyotik duyarlılık çalışmaları VITEK 2® (BioMérieux, Fransa) otomatize sistemi kullanılarak yapılmıştır. Seftolozan-tazobaktam ve CZA etkinliği gradiyent strip test (Liofilchem MIC strip test, İtalya) ile tespit edilmiştir. Karbapenemaz enzimi kodlayan blaIMP-1, blaKPC, blaNDM-1, blaOXA-48 ve blaVIM gen bölgeleri Xpert CARBA-R test kitleri (Cepheid, Sunnyvale, CA, USA) kullanılarak araştırılmıştır.
Bulgular: CZA direnci; altı (%27) izolatta görülürken, C/T direnci; 21 (%95) izolatta tespit edilmiştir. Moleküler yöntemle 22 K. pneumoniae izolatının üçünde NDM-1, ikisinde NDM-1+OXA-48, sekizinde OXA-48 ve dokuzunda KPC geni tespit edilmiştir. VIM ve IMP-1 gen bölgeleri hiçbir izolatta saptanmamıştır. Sadece OXA-48 üreten sekiz K. pneumoniae izolatı arasında; yedi izolat C/T’ye karşı dirençli iken, CZA tüm izolatlarda duyarlı bulunmuştur. OXA-48 üretiminin yanında NDM-1 üretimi de saptanan izolatlarda ise C/T ve CZA’ya karşı yüksek minimum inhibitör konsantrasyon (MİK) düzeylerinde direnç (MİK ≥256 µg/ml) saptanmıştır. NDM-1 üretimi saptanan izolatların tümünde C/T ve CZA’nın her ikisine yüksek MİK düzeylerinde direnç (MİK >256 µg/ml) saptanmıştır. KPC üreten K. pneumoniae izolatlarının tümü C/T’ye dirençli tespit edilirken, CZA’ya karşı sadece bir izolatta direnç saptanmıştır. KPC üreten ÇİD K. pneumoniae izolatlarında CZA çok etkili bulunurken, C/T’nin etkili olmadığı tespit edilmiştir.
Sonuç: Çalışmamızdaki ÇİD K. pneumoniae izolatlarında CZA’nın in vitro antibakteriyel etkinliği, C/T’den daha fazla bulunmuştur. OXA-48 ve KPC üreten ÇİD K. pneumoniae izolatlarında CZA çok etkili bulunurken, C/T’nin etkinliğinin düşük olduğu tespit edilmiştir. Avibaktamın KPC tipi karbapenemazları inhibe edebilmesi, CZA kombinasyonunun KPC tipi karbapenemaz üreten izolatlarda etkili bir seçenek olacağını düşündürmektedir. Ancak NDM tipi karbapenemaz üreten izolatlarda, CZA’nın etkinliğinin olmadığı görülmüştür.
Anahtar Kelimeler: Klebsiella pneumoniae, çoklu ilaca dirençli, seftazidim-avibaktam, seftolozan-tazobaktam, karbapenemaz enzimleri
Kaynakça
Goodlet KJ, Nicolau DP, Nailor MD. Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections. Ther Clin Risk Manag. 2016;12:1811-26.
Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12). J Antimicrob Chemother. 2014;69:2713-22.
Rodríguez-Núñez O, Ripa M, Morata L, de la Calle C, Cardozo C, Fehér C, Pellicé M, Valcárcel A, Puerta-Alcalde P, Marco F, García-Vidal C, Del Río A, Soriano A, Martínez-Martínez JA. Evaluation of ceftazidime/avibactam for serious infections due to multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa. J Glob Antimicrob Resist. 2018;15:136-9.
Liscio JL, Mahoney MV, Hirsch EB. Ceftolozane/tazobactam and ceftazidime/ avibactam: two novel beta-lactam/beta-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. Int J Antimicrob Agents. 2015;46:266-71.
Humphries RM, Hindler JA, Wong-Beringer A, Miller SA. Activity of Ceftolozane-Tazobactam and Ceftazidime-Avibactam against Beta-Lactam-Resistant Pseudomonas aeruginosa Isolates. Antimicrob Agents Chemother. 2017;61:e01858-17.
van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016;63:234-41.
Yin D, Wu S, Yang Y, Shi Q, Dong D, Zhu D, Hu F, China Antimicrobial Surveillance Network (CHINET) Study Group. Results from the China Antimicrobial Surveillance Network (CHINET) in 2017 of the In Vitro Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2019;63:e02431-18.
Alatoom A, Elsayed H, Lawlor K, AbdelWareth L, El-Lababidi R, Cardona L, Mooty M, Bonilla MF, Nusair A, Mirza I. Comparison of antimicrobial activity between ceftolozane-tazobactam and ceftazidime-avibactam against multidrug-resistant isolates of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Int J Infect Dis. 2017:62:39-43.
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18:268-81.
Wayne P. Performance standards for antimicrobial susceptibility testing, 11th ed. CLSI supplement M100. Clinical and Laboratory Standards Institute; 2018.
EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. EUCAST document version 6.0. European Committee on Antimicrobial Susceptibility Testing, 2016. Available from: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_6.0_Breakpoint_table.pdf
Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012;56:2108-13.
Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55:943-50.
Petrosillo N, Giannella M, Lewis R, Viale P. Treatment of carbapenemresistant Klebsiella pneumoniae: the state of the art. Expert Rev Anti Infect Ther. 2013;11:159-77.
Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015;2:ofv050.
Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, Mussini C, Leibovici L. Combination therapy for carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother. 2014;69:2305-9.
Sader HS, Castanheira M, Shortridge D, Mendes RE, Flamm RK. Antimicrobial Activity of Ceftazidime-Avibactam Tested against Multidrug-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Isolates from U.S. Medical Centers, 2013 to 2016. Antimicrob Agents Chemother. 2017;61:e01045-17.
Shortridge D, Pfaller MA, Castanheira M, Flamm RK. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013-2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program. Diagn Microbiol Infect Dis. 2018;92:158-63.
Tato M, Garcia-Castillo M, Bofarull AM, Canton R, CENIT Study Group. In vitro activity of ceftolozane/tazobactam against clinical isolates of Pseudomonas aeruginosa and Enterobacteriaceae recovered in Spanish medical centres: results of the CENIT study. Int J Antimicrob Agents. 2015;46:502-10.
Livermore DM, Mushtaq S, Meunier D, Hopkins KL, Hill R, Adkin R, Chaudhry A, Pike R, Staves P, Woodford N; BSAC Resistance Surveillance Standing Committee. Activity of ceftolozane/tazobactam against surveillance and ‘problem’ Enterobacteriaceae, Pseudomonas aeruginosa and non-fermenters from the British Isles. J Antimicrob Chemother. 2017;72:2278-89.
Pfaller MA, Bassetti M, Duncan LR, Castanheira M. Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing urinary tract and intraabdominal infections in Europe: report from an antimicrobial surveillance programme (2012-15). J Antimicrob Chemother. 2017;72:1386-95.
Hirsch EB, Zucchi P, Cheung N, Krevolin K, Emery C, Bias T. Activity of Ceftolozane/tazobactam (C/T) and Ceftazidime/avibactam (CZA) against Extended-spectrum Beta-lactamase (ESBL)-producing Enterobacteriaceae and Multidrug-resistant (MDR) Pseudomonas aeruginosa Isolates. IDWeek press conferences. 2017;P:1231.
Seifert H, Körber-Irrgang B, Kresken M; German Ceftolozane/Tazobactam Study Group. In-vitro activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates recovered from hospitalized patients in Germany. Int J Antimicrob Agents. 2018;51:227-34.
Jean SS, Lu MC, Shi ZY, Tseng SH, Wu TS, Lu PL, Shao PL, Ko WC, Wang FD, Hsueh PR. In vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, and other comparable agents against clinically important Gram-negative bacilli: results from the 2017 Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART). Infect Drug Resist. 2018;11:1983-92.
Shields RK, Clancy CJ, Pasculle AW, Press EG, Haidar G, Hao B, Chen L, Kreiswirth BN, Nguyen MH. Verification of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Susceptibility Testing Methods against Carbapenem-Resistant Enterobacteriaceae and Pseudomonas aeruginosa. J Clin Microbiol. 2018;56:e01093-17.
Van Horn KG, Sneed D, Goldstein EJC. Comparative “real world” in vitro activity of two new antimicrobials (ceftolozane-tazobactam and ceftazidime-avibactam) against ceftazidime non-susceptible Pseudomonas aeruginosa and resistant Enterobacteriaceae from california long term acute care hospitals. Clin Microbiol Infect Dis. 2018;3:1-4.
Shortridge D, Pfaller MA, Castanheira M, Flamm RK. Antimicrobial Activity of Ceftolozane-Tazobactam Tested Against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2013-2016) as Part of the Surveillance Program: Program to Assess Ceftolozane-Tazobactam Susceptibility. Microb Drug Resist. 2018;24:563-77.
Castanheira M, Duncan LR, Mendes RE, Sader HS, Shortridge D. Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae Isolates Collected from Respiratory Tract Specimens of Hospitalized Patients in the United States during 2013 to 2015. Antimicrob Agents Chemother. 2018;62:e02125-17.
Pfaller MA, Shortridge D, Sader HS, Castanheira M, Flamm RK. Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in the Asia-Pacific region (minus China, Australia and New Zealand): report from an Antimicrobial Surveillance Programme (2013-2015). Int J Antimicrob Agents. 2018;51:181-9.
Evans SR, Tran TTT, Hujer AM, Hill CB, Hujer KM, Mediavilla JR, Manca C, Domitrovic TN, Perez F, Farmer M, Pitzer KM, Wilson BM, Kreiswirth BN, Patel R, Jacobs MR, Chen L, Fowler VG Jr, Chambers HF, Bonomo RA, Antibacterial Resistance Leadership Group (ARLG). Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam against Pseudomonas aeruginosa: PRIMERS IV. Clin Infect Dis. 2019;68:1823-30.
Demiray T, Aydemir Ö, Kilic U, Yilmaz K, Koroglu M, Altindis M. Karbapenem Dirençli Klebsiella pneumoniae İzolatlarında Karbapenemaz Saptanmasında Karbapenemaz İnaktivasyon Testinin Kullanımı. Türk Mikrobiyol Cem Derg. 2017;47:78-82.
Wang X, Zhang F, Zhao C, Wang Z, Nichols WW, Testa R, Li H, Chen H, He W, Wang Q, Wang H. In Vitro Activities of Ceftazidime-Avibactam and Aztreonam-Avibactam against 372 Gram-Negative Bacilli Collected in 2011 and 2012 from 11 Teaching Hospitals in China. Antimicrob Agents Chemother. 2014;58:1774-8.
