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Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması

Year 2018, Volume: 8 Issue: 1, 1 - 6, 30.04.2018
https://doi.org/10.26650/experimed.2018.377256

Abstract

Amaç: Genişlemiş spektrumlu beta laktamaz (GSBL) üreten Enterobactericeae kökenleri ile gelişen enfeksiyonların tedavisinde karbapenemlerin sıklıkla kullanılması beraberinde karbapenem direnci gelişmesine neden olmuştur. Bu nedenle çalışmamızda karbapenemlerin mutant engelleme konsantrasyonlarının (MEK) saptanması ve tedavi sırasında gelişen dirence GSBL üretiminin herhangi bir etkisinin olup olmadığının belirlenmesi amaçlanmıştır.
Gereç ve Yöntem: Bu çalışmaya test grubu olarak, imipenem ve meropenem MİK=<1mg/L olan, fenotipik ve genotipik yöntemlerle GSBL enzimlerinden en az birine sahip olan (n=56) ve kontrol grubu olarak araştırılan enzimlerden hiçbirini içermeyen (n=19) Escherichia coli ve Klebsiella pneumoniae kökeni dahil edilmiştir. Kökenlerin imipenem, meropenem, ertapenem ve doripenem minimal inhibitör konsantrasyonları (MİK) ve mutant engelleme konsantrasyonları (MEK) agar dilüsyon yöntemiyle çalışılmıştır.
Bulgular: GSBL (-) kökenlerin MEK90 değerleri duyarlı sınırlarda kalır iken, GSBL üreten kökenlerde MEK90 değerleri 2-8μg/mL’ye kadar çıkmıştır. GSBL(+) kökenlerde karbapenem MEK değerleri GSBL(-) kökenlere kıyasla 2-9 kat daha yüksek bulunmuş ancak GSBL enzim türlerinin (TEM, SHV, CTX-M) bu dirence katkı açısından aralarında bir farklılık olmadığı saptanmıştır. GSBL(+) kökenlerde imipenem ve meropenem 0,015-0,06 μg/mL gibi çok düşük MİK değerlerinde bile yaklaşık %50 oranında mutant seçimine neden olmaktadır.
Sonuç: Bu verilere göre; i) Köken karbapenem duyarlı olsa da GSBL üretimi karbapenem dirençli mutant seçimine neden olabilir gibi gözükmektedir. ii) Doripenem ve ertapenem en az, imipenem ve meropenem en fazla mutant seçen karbapenemlerdir

References

  • 1. Clinical and Laboratory Standard Institute. Performance of standards for antimicrobial susceptibility testing; Twenty-two Information Supplement M100-S22, 2012, Wayne, PA: Clinical and Laboratory Standard Institute.
  • 2. Credito K, Kosowska-Shick K, Appelbaum PC. Mutant prevention concentrations of four carbapenems against gram-negative rods. Antimicrobial Agents And Chemotherapy, 2010, 54(6): 2692-2695.
  • 3. D'Andrea MM, Giani T, Arena F, Borgianni L, Gesu G, Li Bergoli M, Manso E, Mussap M, Sambri V, Sarti M, Luzzaro F, Rossolini GM. Multifocal emergence of ESBL-producing Klebsiella pneumoniae clone with differential non-carbapenemase-mediated resistance to carbapenems in Italian hospitals. 19th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, 16 - 19 May, 2009, P1700
  • 4. Drlica K. The mutant selection window and antimicrobial resistance. Journal of Antimicrobial Chemotherapy, 2003, 52(1): 1-17.
  • 5. Drlica K, Zhao X, Blondeau JM, Hesje C. Low correlation between MIC and mutant prevention concentration. Antimicrob Agents Chemother, 2006, 50(1): 403-4.
  • 6. Drlica K, Zhao X. Mutant selection window hypothesis updated. Clinical Infectious Diseases, 2007, 44(5): 681-688.
  • 7. Falagas ME, Karageorgopoulos DE. Extended-spectrum beta-lactamase-producing organisms. J Hosp Infect, 2009, 73(4): 345-354.
  • 8. Gür D, Hascelik G, Aydin N, Telli M, Gültekin M, Ogülnç D, Arikan OA, Uysal S, Yaman A, Kibar F, Gülay Z, Sumerkan B, Esel D, Kayacan CB, Aktas Z, Soyletir G, Altinkanat G, Durupinar B, Darka O, Akgün Y, Yayla B, Gedikoglu S, Sinirtas M, Berktas M, Yaman G. Antimicrobial resistance in gram-negative hospital isolates: results of the Turkish HITIT-2 Surveillance Study of 2007. J Chemother, 2009, 21:383-389.
  • 9. Hansen G, Blondeau JM. Comparison of the minimum inhibitory, mutant prevention, and minimum bactericidal concentrations of ciprofloxacin, levofloxacin, and garenoxacin against enteric gram-negative urinary tract infection pathogens. J Chemother, 2005, 17(5): 484-492.
  • 10. Jesús Oteo, Delgado Iribarren I, Dolores Vega, Verónica Bautista, María Cruz Rodríguez, María Velasco, José María Saavedra, María Pérez-Vázquez, Silvia García-Cobos, Luis Martínez-Martínez, José Campos. Emergence of imipenem resistance in clinical Escherichia coli during therapy. International Journal of Antimicrobial Agents, 2008, 32(6): 534-537.
  • 11. Kaczmarek FM, Dib-Hajj F, Shang W, Gootz TD. High-level carbapenem resistance in a Klebsiella pneumoniae clinical isolate is due to the combination of bla ACT-1 beta lactamase production, porin OmpK35/36 insertional inactivation, and down-regulation of the phosphate transport porin PhoE. Antimicrobial Agents and Chemotherapy, 2006, 50(10): 3396–3406.
  • 12. Lee K, Yong D, Choi YS, Yum JH, Kim JM, Woodford N, Livermore DM, Chong Y. Reduced imipenem susceptibility in Klebsiella pneumoniae clinical isolates with plasmid-mediated CMY-2 and DHA-1 beta-lactamases co-mediated by porin loss. Int. J. Antimicrob Agents, 2007, 29: 201-206.
  • 13. Nordmann P, Dortet L, Poirel L. Carbapenem resistance in Enterobacteriaceae: here is the storm. Trends Mol Med. 2012 May;18(5):263-72
  • 14. Öksüz L, Gürler N. Typing of extended-spectrum beta-lactamases in Escherichia coli and Klebsiella spp. strains and analysis of plasmid profiles. Mikrobiyol Bul, 2009, 43(2): 183-94.
  • 15. Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. International Journal of Medical Microbiology, 2010, 300(6): 371–379.
  • 16. Poirel L, Heritier C, Spicq C, Nordmann P. In vivo acquisition of high-level resistance to ımipenemin Escherichia coli. Journal of Clinical Microbiology, 2004, 42(8): 3831–3833.
  • 17. Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance: What’s dosing got to do with it? Crit Care Med, 2008, 36(8): 2433-40.
  • 18. Sindelar G, Zhao X, Liew A, Dong Y, Lu T, Zhou J, Domagala J, Drlica K. Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrobial Agents of Chemotherapy, 2000, 44(12): 3337-43.
  • 19. Smith HJ, Nichol KA, Hoban DJ, Zhanel GG. Stretching the mutant prevention concentration (MPC) beyond its limits. Journal of Antimicrobial Chemotherapy, 2003, 51(6): 1323-5
  • 20. Song W, S.B, Choi JY, Jeong SH, Jeon EH, Lee YK, Hong SG, Lee K. In vivo selection of carbapenem-resistant Klebsiella pneumoniae by OmpK36 loss during meropenem treatment. Diagn Microbiol Infect Dis, 2009, 65(4): 447-449.
  • 21. Xilin Zhao, Drlica K. A unified anti-mutant dosing strategy. Journal of Antimicrobial Chemotherapy, 2008, 62(3): 434-436.
  • 22. Zhao X, Drlica K. Restricting the Selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clinical Infectious Diseases, 2001, 33(Suppl 3): 147-156.

Determination of Mutant Prevention Concentration in Extended Spectrum Beta Lactamases Producing Enterobacteriaceae

Year 2018, Volume: 8 Issue: 1, 1 - 6, 30.04.2018
https://doi.org/10.26650/experimed.2018.377256

Abstract

Objectives: The use of carbapenems for treating infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae has increased. Consequently, this practice has resulted in the emergence of carbapenem resistance. In this study, we aimed to determine mutant prevention concentrations (MPCs) of carbapenems and the development of carbapenem resistance in infections caused by ESBL-producing bacteria.
Material and Method: The test group included isolates of Escherichia coli and Klebsiella pneumonia that produced imipenem and meropenem minimum inhibitor concentration (MIC)=<1mg/L and at least one of the ESBL (n=56). Negatives isolates (n=19) for all tested enzymes comprised the control group. Carbapenems included in the study were imipenem, meropenem, doripenem, and ertapenem. The MIC and MPC values of these drugs were determined using the agar dilution method for all tested organisms.
Results: In ESBL-negative isolates, the MPC90 values were in the susceptible range. In contrast, in the ESBL positive isolates, MPC90 value increased to 2–8 mg/L. The MPC values were 2- to 9-fold higher in the ESBL-producing strains compared with the non-ESBL strains. However, the mutant selection rate was not affected by the ESBL enzymes types (TEM, SHV, and CTX-M). In ESBL-positive strains, imipenem and meropenem, even at very low MICs (0.015–0.06 µg/mL), showed selective carbapenem-resistant mutants at a rate of 50%.
Conclusion: Our results suggest the following conclusions. i) ESBL production seems to increase carbapenem resistance in mutant strains, even though these are carbapenem susceptible in routine tests. ii) Among carbapenems, doripenem and ertapenem have the least potential for mutant selection whereas imipenem and meropenem have the most potential. 

References

  • 1. Clinical and Laboratory Standard Institute. Performance of standards for antimicrobial susceptibility testing; Twenty-two Information Supplement M100-S22, 2012, Wayne, PA: Clinical and Laboratory Standard Institute.
  • 2. Credito K, Kosowska-Shick K, Appelbaum PC. Mutant prevention concentrations of four carbapenems against gram-negative rods. Antimicrobial Agents And Chemotherapy, 2010, 54(6): 2692-2695.
  • 3. D'Andrea MM, Giani T, Arena F, Borgianni L, Gesu G, Li Bergoli M, Manso E, Mussap M, Sambri V, Sarti M, Luzzaro F, Rossolini GM. Multifocal emergence of ESBL-producing Klebsiella pneumoniae clone with differential non-carbapenemase-mediated resistance to carbapenems in Italian hospitals. 19th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, 16 - 19 May, 2009, P1700
  • 4. Drlica K. The mutant selection window and antimicrobial resistance. Journal of Antimicrobial Chemotherapy, 2003, 52(1): 1-17.
  • 5. Drlica K, Zhao X, Blondeau JM, Hesje C. Low correlation between MIC and mutant prevention concentration. Antimicrob Agents Chemother, 2006, 50(1): 403-4.
  • 6. Drlica K, Zhao X. Mutant selection window hypothesis updated. Clinical Infectious Diseases, 2007, 44(5): 681-688.
  • 7. Falagas ME, Karageorgopoulos DE. Extended-spectrum beta-lactamase-producing organisms. J Hosp Infect, 2009, 73(4): 345-354.
  • 8. Gür D, Hascelik G, Aydin N, Telli M, Gültekin M, Ogülnç D, Arikan OA, Uysal S, Yaman A, Kibar F, Gülay Z, Sumerkan B, Esel D, Kayacan CB, Aktas Z, Soyletir G, Altinkanat G, Durupinar B, Darka O, Akgün Y, Yayla B, Gedikoglu S, Sinirtas M, Berktas M, Yaman G. Antimicrobial resistance in gram-negative hospital isolates: results of the Turkish HITIT-2 Surveillance Study of 2007. J Chemother, 2009, 21:383-389.
  • 9. Hansen G, Blondeau JM. Comparison of the minimum inhibitory, mutant prevention, and minimum bactericidal concentrations of ciprofloxacin, levofloxacin, and garenoxacin against enteric gram-negative urinary tract infection pathogens. J Chemother, 2005, 17(5): 484-492.
  • 10. Jesús Oteo, Delgado Iribarren I, Dolores Vega, Verónica Bautista, María Cruz Rodríguez, María Velasco, José María Saavedra, María Pérez-Vázquez, Silvia García-Cobos, Luis Martínez-Martínez, José Campos. Emergence of imipenem resistance in clinical Escherichia coli during therapy. International Journal of Antimicrobial Agents, 2008, 32(6): 534-537.
  • 11. Kaczmarek FM, Dib-Hajj F, Shang W, Gootz TD. High-level carbapenem resistance in a Klebsiella pneumoniae clinical isolate is due to the combination of bla ACT-1 beta lactamase production, porin OmpK35/36 insertional inactivation, and down-regulation of the phosphate transport porin PhoE. Antimicrobial Agents and Chemotherapy, 2006, 50(10): 3396–3406.
  • 12. Lee K, Yong D, Choi YS, Yum JH, Kim JM, Woodford N, Livermore DM, Chong Y. Reduced imipenem susceptibility in Klebsiella pneumoniae clinical isolates with plasmid-mediated CMY-2 and DHA-1 beta-lactamases co-mediated by porin loss. Int. J. Antimicrob Agents, 2007, 29: 201-206.
  • 13. Nordmann P, Dortet L, Poirel L. Carbapenem resistance in Enterobacteriaceae: here is the storm. Trends Mol Med. 2012 May;18(5):263-72
  • 14. Öksüz L, Gürler N. Typing of extended-spectrum beta-lactamases in Escherichia coli and Klebsiella spp. strains and analysis of plasmid profiles. Mikrobiyol Bul, 2009, 43(2): 183-94.
  • 15. Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. International Journal of Medical Microbiology, 2010, 300(6): 371–379.
  • 16. Poirel L, Heritier C, Spicq C, Nordmann P. In vivo acquisition of high-level resistance to ımipenemin Escherichia coli. Journal of Clinical Microbiology, 2004, 42(8): 3831–3833.
  • 17. Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance: What’s dosing got to do with it? Crit Care Med, 2008, 36(8): 2433-40.
  • 18. Sindelar G, Zhao X, Liew A, Dong Y, Lu T, Zhou J, Domagala J, Drlica K. Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrobial Agents of Chemotherapy, 2000, 44(12): 3337-43.
  • 19. Smith HJ, Nichol KA, Hoban DJ, Zhanel GG. Stretching the mutant prevention concentration (MPC) beyond its limits. Journal of Antimicrobial Chemotherapy, 2003, 51(6): 1323-5
  • 20. Song W, S.B, Choi JY, Jeong SH, Jeon EH, Lee YK, Hong SG, Lee K. In vivo selection of carbapenem-resistant Klebsiella pneumoniae by OmpK36 loss during meropenem treatment. Diagn Microbiol Infect Dis, 2009, 65(4): 447-449.
  • 21. Xilin Zhao, Drlica K. A unified anti-mutant dosing strategy. Journal of Antimicrobial Chemotherapy, 2008, 62(3): 434-436.
  • 22. Zhao X, Drlica K. Restricting the Selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clinical Infectious Diseases, 2001, 33(Suppl 3): 147-156.
There are 22 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Makale
Authors

Gülşen Altınkanat Gelmez

Güner Söyletir

Publication Date April 30, 2018
Published in Issue Year 2018 Volume: 8 Issue: 1

Cite

APA Altınkanat Gelmez, G., & Söyletir, G. (2018). Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması. Deneysel Tıp Araştırma Enstitüsü Dergisi, 8(1), 1-6. https://doi.org/10.26650/experimed.2018.377256
AMA Altınkanat Gelmez G, Söyletir G. Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması. Deneysel Tıp Araştırma Enstitüsü Dergisi. April 2018;8(1):1-6. doi:10.26650/experimed.2018.377256
Chicago Altınkanat Gelmez, Gülşen, and Güner Söyletir. “Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması”. Deneysel Tıp Araştırma Enstitüsü Dergisi 8, no. 1 (April 2018): 1-6. https://doi.org/10.26650/experimed.2018.377256.
EndNote Altınkanat Gelmez G, Söyletir G (April 1, 2018) Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması. Deneysel Tıp Araştırma Enstitüsü Dergisi 8 1 1–6.
IEEE G. Altınkanat Gelmez and G. Söyletir, “Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması”, Deneysel Tıp Araştırma Enstitüsü Dergisi, vol. 8, no. 1, pp. 1–6, 2018, doi: 10.26650/experimed.2018.377256.
ISNAD Altınkanat Gelmez, Gülşen - Söyletir, Güner. “Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması”. Deneysel Tıp Araştırma Enstitüsü Dergisi 8/1 (April 2018), 1-6. https://doi.org/10.26650/experimed.2018.377256.
JAMA Altınkanat Gelmez G, Söyletir G. Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması. Deneysel Tıp Araştırma Enstitüsü Dergisi. 2018;8:1–6.
MLA Altınkanat Gelmez, Gülşen and Güner Söyletir. “Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması”. Deneysel Tıp Araştırma Enstitüsü Dergisi, vol. 8, no. 1, 2018, pp. 1-6, doi:10.26650/experimed.2018.377256.
Vancouver Altınkanat Gelmez G, Söyletir G. Genişlemiş Spektrumlu Beta Laktamaz Üreten Enterobacteriaceae’larda Mutant Engelleme Konsantrasyonunun Saptanması. Deneysel Tıp Araştırma Enstitüsü Dergisi. 2018;8(1):1-6.