The first investigation of AAC(6’)-Ib enzyme in carbapenem-resistant enterobacteriaceae isolated from Indonesian patients

  • Beauty Novianty Faculty of Medicine, Sriwijaya University, Palembang
  • Ella Amalia Department of Microbiology, Faculty of Medicine, Sriwijaya University, Palembang
  • Ziske Maritska Department of Biology, Faculty of Medicine, Sriwijaya University, Palembang
  • Yuwono Department of Microbiology, Faculty of Medicine, Sriwijaya University, Palembang
  • Lusia Hayati Department of Biology, Faculty of Medicine, Sriwijaya University, Palembang
Keywords: AAC(6’)-Ib, Carbapenem Resistant Enterobacteriaceae, Carbapenemase

Abstract

Background: Over the past decade, numbers of Carbapenemase Producing-Carbapenem Resistant Enterobacteriaceae (CP-CRE) has been increasing worldwide and it has been becoming a threat because of its resistance against carbapenem which is considered as the “last resort” antibiotic. Therapy options for its infection are still limited. Aminoglycoside serves as one of the most commonly used antibiotics, but the resistance against it has already been presented for a long time. Aminoglycoside Modifying Enzyme (AME) is the most important resistance mechanism against aminoglycoside. AAC(6’)-Ib enzyme is one of the most common AME produced by the gram-negative bacteria.

Objectives: This study wished to identify the gene of this enzyme among CRE isolated from infected Indonesian patients in Dr. Mohammad Hoesin Hospital Palembang.

Methods: Twenty-eight isolates collected from CRE-infected patients identified by Vitek 2 Compact (bioMerieux, USA) in dr. Mohammad Hoesin Hospital Palembang during September—November 2017. AAC(6’)-Ib gene was identified using PCR method, then visualize by electrophoresis. The result is then analyzed by comparing it with a susceptibility test.  

Results: Out of 28 samples, AAC(6’)-Ib is identified in 22 (78.57%) samples. Samples with AAC(6’)-Ib showed to be less resistant to various antibiotics, significantly to amikacin (p=0.023).

Conclusion: AAC(6’)-Ib gene is found in most of samples implying its frequent occurrence in Indonesian patients.

References

Torres JA, Villegas MV, Quinn JP. Current concepts in antibiotic-resistant gram-negative bacteria. Expert Rev Anti Infect Ther. 2007;5(5):833-43. https://doi.org/10.1586/14787210.5.5.833

Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis. 2016;3(1):15-21. https://doi.org/10.1177/2049936115621709

Xu Y, Gu B, Huang M, Liu H, Xu T, Xia W, et al. Epidemiology of carbapenem resistant Enterobacteriaceae (CRE) during 2000-2012 in Asia. J Thorac Dis. 2015;7(3):376.

Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment options for carbapenem-resistant Enterobacteriaceae infections. In: Open forum infectious diseases. Oxford University Press; 2015. https://doi.org/10.1093/ofid/ofv050

Liana P, Patricia V. Pola kuman dan kepekaan terhadap antibiotik RSUP Dr. Mohammad Hoesin Palembang 2017.

Haidar G, Alkroud A, Cheng S, Churilla TM, Churilla BM, Shields RK, et al. Association between presence of aminoglycoside modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin and plazomicin against KPC and ESBL-producing Enterobacter spp. Antimicrob Agents Chemother. 2016;AAC - 00869. https://doi.org/10.1128/AAC.00869-16

Kim Y-T, Jang J-H, Kim H-C, Kim H, Lee K-R, Park KS, et al. Identification of strain harboring both aac (6)-Ib and aac (6)-Ib-cr variant simultaneously in Escherichia coli and Klebsiella pneumoniae. BMB Rep. 2011;44(4):262-6. https://doi.org/10.5483/BMBRep.2011.44.4.262

Vakulenko SB, Mobashery S. Versatility of aminoglycosides and prospects for their future. Clin Microbiol Rev. 2003;16(3):430-50. https://doi.org/10.1128/CMR.16.3.430-450.2003

Poirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis. 2011;70(1):119-23. https://doi.org/10.1016/j.diagmicrobio.2010.12.002

Vetting MW, Park CH, Hegde SS, Jacoby GA, Hooper DC, Blanchard JS. Mechanistic and structural analysis of aminoglycoside N-acetyltransferase AAC (6′)-Ib and its bifunctional, fluoroquinolone-active AAC (6′)-Ib-cr variant. Biochemistry. 2008;47(37):9825-35. https://doi.org/10.1021/bi800664x

Ramirez MS, Nikolaidis N, Tolmasky M. Rise and dissemination of aminoglycoside resistance: the aac (6′)-Ib paradigm. Front Microbiol. 2013;4:121. https://doi.org/10.3389/fmicb.2013.00121

Shaw KJ, Rather PN, Hare RS, Miller GH. Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Rev. 1993;57(1):138-63. https://doi.org/10.1128/mr.57.1.138-163.1993

Shmara A, Weinsetel N, Dery KJ, Chavideh R, Tolmasky ME. Systematic analysis of a conserved region of the aminoglycoside 6′-N-acetyltransferase type Ib. Antimicrob Agents Chemother. 2001;45(12):3287-92. https://doi.org/10.1128/AAC.45.12.3287-3292.2001

Casin I, Bordon F, Bertin P, Coutrot A, Podglajen I, Brasseur R, et al. Aminoglycoside 6′-N-acetyltransferase variants of the Ib type with altered substrate profile in clinical isolates of Enterobacter cloacae and Citrobacter freundii. Antimicrob Agents Chemother. 1998;42(2):209-15. https://doi.org/10.1128/AAC.42.2.209

Kim S-Y, Park Y-J, Yu JK, Kim YS. Aminoglycoside susceptibility profiles of Enterobacter cloacae isolates harboring the aac (6')-Ib gene. Korean J Lab Med. 2011;31(4):279-81. https://doi.org/10.3343/kjlm.2011.31.4.279

Machuca J, Ortiz M, Recacha E, Díaz-De-Alba P, Docobo-Perez F, Rodríguez-Martínez J-M, et al. Impact of AAC (6′)-Ib-cr in combination with chromosomal-mediated mechanisms on clinical quinolone resistance in Escherichia coli. J Antimicrob Chemother. 2016;71(11):3066-71. https://doi.org/10.1093/jac/dkw258

Garneau-Tsodikova S, Labby KJ. Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives. Medchemcomm. 2016;7(1):11-27. https://doi.org/10.1039/C5MD00344J

Subramanian G, Gnanasoundari P, Chakraborty S, Krishnan P. Occurrence of aac (6')-Ib variants among Enterobacteriaceae: Is aac (6')-Ib-cr the most predominant variant? Indian J Med Microbiol. 2016;34(3). https://doi.org/10.4103/0255-0857.188378

Frasson I, Cavallaro A, Bergo C, Richter SN, Palù G. Prevalence of aac (6')-Ib-cr plasmid-mediated and chromosome-encoded fluoroquinolone resistance in Enterobacteriaceae in Italy. Gut Pathog. 2011;3(1):12. https://doi.org/10.1186/1757-4749-3-12

Redgrave LS, Sutton SB, Webber MA, Piddock LJ V. Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol. 2014;22(8):438-45. https://doi.org/10.1016/j.tim.2014.04.007

García-Fulgueiras V, Bado I, Mota MI, Robino L, Cordeiro NF, Varela A, et al. Extended-spectrum β-lactamases and plasmid-mediated quinolone resistance in enterobacterial clinical isolates in the paediatric hospital of Uruguay. J Antimicrob Chemother. 2011;66(8):1725-9. https://doi.org/10.1093/jac/dkr222

Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55(7):943-50. https://doi.org/10.1093/cid/cis588

Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin Infect Dis. 2008;46(4):567-70. https://doi.org/10.1086/526775

Cunha BA. Pharmacokinetic considerations regarding tigecycline for multidrug-resistant (MDR) Klebsiella pneumoniae or MDR Acinetobacter baumannii urosepsis. J Clin Microbiol. 2009;47(5):1613. https://doi.org/10.1128/JCM.00404-09

Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009;9(4):228-36. https://doi.org/10.1016/S1473-3099(09)70054-4

Food and Drug Administration. FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. 2013; Available from: https://www.fda.gov/Drugs/DrugSafety/ucm369580.htm

Sbrana F, Malacarne P, Viaggi B, Costanzo S, Leonetti P, Leonildi A, et al. Carbapenem-sparing antibiotic regimens for infections caused by Klebsiella pneumoniae Carbapenemase-Producing K. Pneumoniae in intensive care unit. Clin Infect Dis. 2012;56(5):697-700. https://doi.org/10.1093/cid/cis969

Published
2019-06-30
How to Cite
Novianty, B., Amalia, E., Maritska, Z., Yuwono, & Hayati, L. (2019). The first investigation of AAC(6’)-Ib enzyme in carbapenem-resistant enterobacteriaceae isolated from Indonesian patients. Acta Biochimica Indonesiana, 2(1), 8-14. https://doi.org/10.32889/actabioina.v2i1.32