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Frequency Determination of Carbapenem-Resistant Klebsiella Pneumoniae (CRKP) Isolated from hospitals in Isfahan of Iran and Evaluation of Synergistic Effect of Colistin and Meropenem on them
Corresponding Author(s) : Hossein Fazeli
Cellular and Molecular Biology,
Vol. 64 No. 1: Issue 1
Abstract
Overuse and misuse of Carbapenems among Klebsiella pneumoniae isolates have caused Carbapenem-Resistant Klebsiella Pneumonia (CRKP) during recent years. Colistin is one of the last available options, and there are increasing concerns about the dosage and resistance to this agent in long-term monotherapies. This study was designed to identification of carbapenemase producing isolates of K. pneumoniae via phenotypic and genotypic methods as well as evaluation of colistin-meropenem combination therapy potential. This study was carried out in Isfahan, of Iran on 100 samples from Alzahra and Khorshid hospitals in 2017. The Modified Hodge Test (MHT) was used to investigate the carbapenemase presence. The minimum inhibitory concentration (MIC) and the Fractional Inhibitory Concentration (FIC) were determined using broth macrodilution and checkerboard assays (respectively) for both meropenem and colistin. The bla-KPC gene was studied by polymerase chain reaction (PCR).The highest and the lowest rate of resistance were observed for piperacillin (84%) and ertapenem (50%) respectively. 68 isolates by MHT were CRKP, but None of them were positive for bla-KPC gene. 21 isolates from CRKP cases were high resistant to used antimicrobial agents in the study that both MIC and FIC results showed significant synergy for this antibiotics in checkerboard test (p-value < 0.05). 21 resistant isolates from CRKP cases showed statistically significant synergy potential for meropenem and colistin. The meropenem-colistin combination therapy can be applied as a suitable antibiotic synergy but it requires further investigation in clinical assay. Regarding to our findings, Probably other mechanisms of resistance to Carbapenems ,except bla-kpc genes are involved.
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- Gupta A, Ampofo K, Rubenstein D, Saiman L. Extended spectrum [beta] lactamase- producing Klebsiella pneumoniae infections: a review of the literature. J Perinatol. 2003; 23:439.
- Chen LF, Chopra T, Kaye KS. Pathogens resistant to antibacterial agents. Infect Dis Clin North Am. 2009; 23:817-45.
- Patel G, Bonomo RA. Status report on carbapenemases: challenges and prospects. Expert Rev Anti Infect Ther. 2011; 9:555-70.
- Bialvaei AZ, Kafil HS, Asgharzadeh M, Yousef Memar M, Yousefi M. Current methods for the identification of carbapenemases. J Chemother. 2016; 28:1-19.
- Bahar MA, Jamali S, Samadikuchaksaraei A. Imipenem-resistant Pseudomonas aeruginosa strains carry metallo-β-lactamase gene bla VIM in a level I Iranian burn hospital. Burns. 2010; 36:826-30.
- Bedenić B, Plećko V, Sardelić S, Uzunović S, Godić Torkar K. Carbapenemases in gram-negative bacteria: laboratory detection and clinical significance. Biomed Res Int. 2014; 2014.
- Munoz-Price LS, Quinn JP. Deconstructing the infection control bundles for the containment of carbapenem-resistant Enterobacteriaceae. Curr Opin Infect Dis. 2013; 26:378-87.
- Bergen PJ, Li J, Nation RL. Dosing of colistin”back to basic PK/PD. Curr Opin Pharmacol. 2011; 11:464-9.
- Miyakis S, Pefanis A, Tsakris A. The challenges of antimicrobial drug resistance in Greece. Clin Infect Dis. 2011; 53:177-84.
- Meletis G, Tzampaz E, Protonotariou E, Sofianou D. Emergence of Klebsiella pneumoniae carrying blaVIM and blaKPC genes. Hippokratia. 2010; 14:139.
- Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011; 17:1791.
- da Silva RM, Traebert J, Galato D. Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae: a review of epidemiological and clinical aspects. Expert Opin Biol Ther. 2012; 12:663-71.
- Petersen PJ, Labthavikul P, Jones CH, Bradford PA. In vitro antibacterial activities of tigecycline in combination with other antimicrobial agents determined by chequerboard and time-kill kinetic analysis. J Antimicrob Chemother. 2006; 57:573-6.
- Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases.
- Clin Microbiol Rev. 2007; 20:440-58.
- Fallah F, Taherpour A, Vala MH, Hashemi A. Global Spread of New Delhi mettallo-beta-lactamase-1 (NDM-1). Clin Infect Dis. 2012; 6:171-7.
- Deshpande LM, Rhomberg PR, Sader HS, Jones RN. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999–2005). Diagn Microbiol Infect Dis. 2006; 56:367-72.
- Krishnappa LG, Marie MAM, Al Sheikh YA. Characterization of carbapenem resistance mechanisms in Klebsiella pneumoniae and in vitro synergy of the colistin–meropenem combination. J Chemother. 2015; 27:277-82.
- Shanmugam P, Meenakshisundaram J, JayaraMan P. blaKPC gene detection in clinical isolates of carbapenem resistant Enterobacteriaceae in a tertiary care hospital. J Clin Diagn Res. 2013; 7:2736.
- Agha-Seyed Hosseini M, Firoozeh F, Piroozmand A, Gilasi HR. Carbapenemase-producing Klebsiella pneumoniae strains among clinical specimens in Kashan (2014-2015). Feyz. 2016; 20:267-73.
- Roudbari F QK Fh, Nqndr k, with AJ, et al. Frequency of Klebsiella Pneumoniae Producing Carbapenemase KPC in Clinical specimens of Mashhad during 2014. Med. J Mashhad Univ Med Sci. 2015; 58:322-9.
- Bina M, Pournajaf A, Mirkalantari S, Talebi M, Irajian G. Detection of the Klebsiella pneumoniae carbapenemase (KPC) in K. pneumoniae Isolated from the Clinical Samples by the Phenotypic and Genotypic Methods. Iran J Pathol. 2015; 10:199.
- Shokri D, Mobasherizadeh S, Baruq MN, Yaran M. Isolation and Identification of Carbapenemase KPC Producing Strains of Enterobacteriaceae and Determination of Their Antibiotic Susceptibility Patterns. J Isfahan Med Sch. 2013; 31.
- Bratu S, Tolaney P, Karumudi U, Quale J, Mooty M, Nichani S, et al. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother. 2005; 56:128-32.
- Castanheira M, Sader HS, Deshpande LM, Fritsche TR, Jones RN. Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase-and metallo-β-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2008; 52:570-3.
- Chen S, Hu F, Xu X, Liu Y, Wu W, Zhu D, et al. High prevalence of KPC-2-type carbapenemase coupled with CTX-M-type extended-spectrum β-lactamases in carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China. Antimicrob Agents Chemother. 2011; 55:2493-4.
- Anderson K, Lonsway D, Rasheed J, Biddle J, Jensen B, McDougal L, et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J. Clin. Microbiol. 2007; 45:2723-5.
- Flonta M, Lupse M, Craciunas C, Almas A, Carstina D. Ertapenem resistance among extended-spectrum-β-lactamase producing Klebsiella pneumoniae isolates. Therapeu Pharmacol Clin Toxicol. 2011; 15:121-5.
- Nagaraj S, Chandran S, Shamanna P, Macaden R. Carbapenem resistance among Escherichia coli and Klebsiella pneumoniae in a tertiary care hospital in south India.
- Indian J Med Microbiol. 2012; 30:93.
- Shibl A, Al-Agamy M, Memish Z, Senok A, Khader SA, Assiri A. The emergence of OXA-48-and NDM-1-positive Klebsiella pneumoniae in Riyadh, Saudi Arabia.
- Int J Infect Dis. 2013; 17:e1130-e3.
- Uz Zaman T, Aldrees M, Al Johani SM, Alrodayyan M, Aldughashem FA, Balkhy HH. Multi-drug carbapenem-resistant Klebsiella pneumoniae infection carrying the OXA-48 gene and showing variations in outer membrane protein 36 causing an outbreak in a tertiary care hospital in Riyadh, Saudi Arabia.
- Int J Infect Dis. 2014; 28:186-92.
- Azimi L, Rastegar-Lari A, Talebi M, Ebrahimzadeh-Namvar A, Soleymanzadeh-Moghadam S. Evaluation of Phenotypic Methods for Detection of Klebsiella Pneumoniae Carbapenemase-Producing K. Pneumoniae in Tehran. J Med Bacteriol. 2015; 2:26-31.
- Eftekhar F, Naseh Z. Extended-spectrum β-lactamase and carbapenemase production among burn and non-burn clinical isolates of Klebsiella pneumoniae.
- Iran J Microbiol. 2015; 7:144.
- Zare A, Akya A, Nejat P. The Frequency of blaVIM, blaIMP, blaKPC and blaNDM Carbapenemase Genes in Clinical Isolates of Klebsiella Pneumoniae in Kermanshah Medical Centers. J Shaheed Sadoughi Univ Med Sci. 2015; 23:760-9.
References
Gupta A, Ampofo K, Rubenstein D, Saiman L. Extended spectrum [beta] lactamase- producing Klebsiella pneumoniae infections: a review of the literature. J Perinatol. 2003; 23:439.
Chen LF, Chopra T, Kaye KS. Pathogens resistant to antibacterial agents. Infect Dis Clin North Am. 2009; 23:817-45.
Patel G, Bonomo RA. Status report on carbapenemases: challenges and prospects. Expert Rev Anti Infect Ther. 2011; 9:555-70.
Bialvaei AZ, Kafil HS, Asgharzadeh M, Yousef Memar M, Yousefi M. Current methods for the identification of carbapenemases. J Chemother. 2016; 28:1-19.
Bahar MA, Jamali S, Samadikuchaksaraei A. Imipenem-resistant Pseudomonas aeruginosa strains carry metallo-β-lactamase gene bla VIM in a level I Iranian burn hospital. Burns. 2010; 36:826-30.
Bedenić B, Plećko V, Sardelić S, Uzunović S, Godić Torkar K. Carbapenemases in gram-negative bacteria: laboratory detection and clinical significance. Biomed Res Int. 2014; 2014.
Munoz-Price LS, Quinn JP. Deconstructing the infection control bundles for the containment of carbapenem-resistant Enterobacteriaceae. Curr Opin Infect Dis. 2013; 26:378-87.
Bergen PJ, Li J, Nation RL. Dosing of colistin”back to basic PK/PD. Curr Opin Pharmacol. 2011; 11:464-9.
Miyakis S, Pefanis A, Tsakris A. The challenges of antimicrobial drug resistance in Greece. Clin Infect Dis. 2011; 53:177-84.
Meletis G, Tzampaz E, Protonotariou E, Sofianou D. Emergence of Klebsiella pneumoniae carrying blaVIM and blaKPC genes. Hippokratia. 2010; 14:139.
Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011; 17:1791.
da Silva RM, Traebert J, Galato D. Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae: a review of epidemiological and clinical aspects. Expert Opin Biol Ther. 2012; 12:663-71.
Petersen PJ, Labthavikul P, Jones CH, Bradford PA. In vitro antibacterial activities of tigecycline in combination with other antimicrobial agents determined by chequerboard and time-kill kinetic analysis. J Antimicrob Chemother. 2006; 57:573-6.
Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases.
Clin Microbiol Rev. 2007; 20:440-58.
Fallah F, Taherpour A, Vala MH, Hashemi A. Global Spread of New Delhi mettallo-beta-lactamase-1 (NDM-1). Clin Infect Dis. 2012; 6:171-7.
Deshpande LM, Rhomberg PR, Sader HS, Jones RN. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999–2005). Diagn Microbiol Infect Dis. 2006; 56:367-72.
Krishnappa LG, Marie MAM, Al Sheikh YA. Characterization of carbapenem resistance mechanisms in Klebsiella pneumoniae and in vitro synergy of the colistin–meropenem combination. J Chemother. 2015; 27:277-82.
Shanmugam P, Meenakshisundaram J, JayaraMan P. blaKPC gene detection in clinical isolates of carbapenem resistant Enterobacteriaceae in a tertiary care hospital. J Clin Diagn Res. 2013; 7:2736.
Agha-Seyed Hosseini M, Firoozeh F, Piroozmand A, Gilasi HR. Carbapenemase-producing Klebsiella pneumoniae strains among clinical specimens in Kashan (2014-2015). Feyz. 2016; 20:267-73.
Roudbari F QK Fh, Nqndr k, with AJ, et al. Frequency of Klebsiella Pneumoniae Producing Carbapenemase KPC in Clinical specimens of Mashhad during 2014. Med. J Mashhad Univ Med Sci. 2015; 58:322-9.
Bina M, Pournajaf A, Mirkalantari S, Talebi M, Irajian G. Detection of the Klebsiella pneumoniae carbapenemase (KPC) in K. pneumoniae Isolated from the Clinical Samples by the Phenotypic and Genotypic Methods. Iran J Pathol. 2015; 10:199.
Shokri D, Mobasherizadeh S, Baruq MN, Yaran M. Isolation and Identification of Carbapenemase KPC Producing Strains of Enterobacteriaceae and Determination of Their Antibiotic Susceptibility Patterns. J Isfahan Med Sch. 2013; 31.
Bratu S, Tolaney P, Karumudi U, Quale J, Mooty M, Nichani S, et al. Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother. 2005; 56:128-32.
Castanheira M, Sader HS, Deshpande LM, Fritsche TR, Jones RN. Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase-and metallo-β-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2008; 52:570-3.
Chen S, Hu F, Xu X, Liu Y, Wu W, Zhu D, et al. High prevalence of KPC-2-type carbapenemase coupled with CTX-M-type extended-spectrum β-lactamases in carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China. Antimicrob Agents Chemother. 2011; 55:2493-4.
Anderson K, Lonsway D, Rasheed J, Biddle J, Jensen B, McDougal L, et al. Evaluation of methods to identify the Klebsiella pneumoniae carbapenemase in Enterobacteriaceae. J. Clin. Microbiol. 2007; 45:2723-5.
Flonta M, Lupse M, Craciunas C, Almas A, Carstina D. Ertapenem resistance among extended-spectrum-β-lactamase producing Klebsiella pneumoniae isolates. Therapeu Pharmacol Clin Toxicol. 2011; 15:121-5.
Nagaraj S, Chandran S, Shamanna P, Macaden R. Carbapenem resistance among Escherichia coli and Klebsiella pneumoniae in a tertiary care hospital in south India.
Indian J Med Microbiol. 2012; 30:93.
Shibl A, Al-Agamy M, Memish Z, Senok A, Khader SA, Assiri A. The emergence of OXA-48-and NDM-1-positive Klebsiella pneumoniae in Riyadh, Saudi Arabia.
Int J Infect Dis. 2013; 17:e1130-e3.
Uz Zaman T, Aldrees M, Al Johani SM, Alrodayyan M, Aldughashem FA, Balkhy HH. Multi-drug carbapenem-resistant Klebsiella pneumoniae infection carrying the OXA-48 gene and showing variations in outer membrane protein 36 causing an outbreak in a tertiary care hospital in Riyadh, Saudi Arabia.
Int J Infect Dis. 2014; 28:186-92.
Azimi L, Rastegar-Lari A, Talebi M, Ebrahimzadeh-Namvar A, Soleymanzadeh-Moghadam S. Evaluation of Phenotypic Methods for Detection of Klebsiella Pneumoniae Carbapenemase-Producing K. Pneumoniae in Tehran. J Med Bacteriol. 2015; 2:26-31.
Eftekhar F, Naseh Z. Extended-spectrum β-lactamase and carbapenemase production among burn and non-burn clinical isolates of Klebsiella pneumoniae.
Iran J Microbiol. 2015; 7:144.
Zare A, Akya A, Nejat P. The Frequency of blaVIM, blaIMP, blaKPC and blaNDM Carbapenemase Genes in Clinical Isolates of Klebsiella Pneumoniae in Kermanshah Medical Centers. J Shaheed Sadoughi Univ Med Sci. 2015; 23:760-9.