The Open Infectious Diseases Journal




ISSN: 1874-2793 ― Volume 11, 2019
REVIEW ARTICLE

A Global Overview of β-lactam Resistance Genes in Klebsiella pneumoniae



Yone da Silva1, Rafaela Ferrari3, Victor Augustus Marin2, Carlos Adam Conte Junior1, 3, 4, *
1 Faculty of Veterinary Medicine of Universidade Federal Fluminense – UFF, Niterói, Brazil
2 Department of Food Science, School of Nutrition, Federal University of the State of Rio de Janeiro - UNIRIO, Rio de Janeiro, Brazil
3 Institute of Chemistry, Federal University of Rio de Janeiro - UFRJ, Rio de Janeiro, RJ, Brazil
4 National Institute of Health Quality Control, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil

Abstract

Klebsiella pneumoniae is a gram-negative bacillus of the Enterobacteriaceae family, commonly associated with nosocomial infections. This pathogen is a serious public health problem as some of its strains are resistant to about 95% antimicrobials of the pharmaceutical market. This resistance is promoted by the production of the β-lactamase extended spectrum (ESBL) enzymes, one of the major causes of therapeutic failure. This review evaluated the incidence and distribution of resistance genes from Klebsiella pneumoniae to β-lactams worldwide. Our study was conducted with the subject the organism K. pneumoniae and β-lactamic resistance. The most reported genes were blaSHV-12, blaCTX-M-2 and blaSHV-5; with blaSHV-12 being the most described. The last two were present in all continents, characterizing its cosmopolitan profiles. The greatest genetic diversity was observed in the Asian and Oceania, where 41 different genes were isolated. Additionally, our review points out the coexistence of different classes of β-lactamases in a single bacterial isolate. Finally, knowledge of mechanisms associated with resistance of K. pneumoniae is of great public interest and the verification of resistance genes shows a variation over time and location highlights the importance of evaluating the mechanisms or strategies by which these variations occur.

Keywords: Antibiotic resistance, Enterobacteria, β-lactamase, Global distribution, Antimicrobial Resistance, Klebsiella Preumonia.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 11
First Page: 22
Last Page: 34
Publisher Id: TOIDJ-11-22
DOI: 10.2174/1874279301911010022

Article History:

Received Date: 13/03/2019
Revision Received Date: 17/05/2019
Acceptance Date: 28/05/2019
Electronic publication date: 30/06/2019
Collection year: 2019

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© 2019 Junior et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Institute of Chemistry, Federal University of Rio de Janeiro - UFRJ, Rio de Janeiro, RJ, Brazil; Tel: +55-21-3938-7825; E-mail: carlosconte@id.uff.br





1. INTRODUCTION

Klebsiella pneumoniae is a microorganism found in humans and other mammals, colonizing intestine, skin, nasopharynx and, several environmental niches. A constituent of the human intestinal microbiota, this bacterium, considered harmless, has gained notoriety by being identified as an opportunistic pathogen. This is responsible for a variety of diseases in humans and animals, such as urinary tract infection, pneumoniae, intra-abdominal infection, bloodstream infection, meningitis, pyogenic liver abscess and is a prominent nosocomial pathogen [1Yu VL, Hansen DS, Ko WC, et al. Virulence characteristics of Klebsiella and clinical manifestations of K. pneumoniae bloodstream infections. Emerg Infect Dis 2007; 13(7): 986-93.
[http://dx.doi.org/10.3201/eid1307.070187] [PMID: 18214169]
, 2Brisse S, Fevre C, Passet V, et al. Virulent clones of Klebsiella pneumoniae: identification and evolutionary scenario based on genomic and phenotypic characterization. PLoS One 2009; 4(3)e4982
[http://dx.doi.org/10.1371/journal.pone.0004982] [PMID: 19319196]
]. Moreover, the occurrence and global spread of hypervirulent and MDR (multidrug-resistant) K. pneumoniae are increasingly reported in community-acquired and nosocomial infections [3El Salabi A, Walsh TR, Chouchani C. Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in Gram-negative bacteria. Crit Rev Microbiol 2013; 39(2): 113-22.
[http://dx.doi.org/10.3109/1040841X.2012.691870] [PMID: 22667 455]
], and the use of antimicrobials in the treatment of infections has become progressively more difficult [4Matzov D, Bashan A, Yonath A. A bright future for antibiotics? Annu Rev Biochem 2017; 86(7): 1–7-.17.
[http://dx.doi.org/10.1146/annurev-biochem-061516-044617]
, 5Moradigaravand D, Martin V, Peacock SJ, Parkhill J. Evolution and epidemiology of multidrug-resistant Klebsiella pneumoniae in the United Kingdom and Ireland. MBio 2017; 8(1): 01976-16.
[http://dx.doi.org/10.1128/mBio.01976-16] [PMID: 28223459]
]. However, despite there has been an increase in the number of vulnerable populations to MDR pathogens, in addition to a renewed interest in the Klebsiella pneumoniae, many questions about this pathogen are still unknown, as to how resistance genes spread out and how they reach humans [6Broberg CA, Palacios M, Miller VL. Klebsiella: a long way to go towards understanding this enigmatic jet-setter. F1000Prime Rep 2014; 6: 64-76.
[http://dx.doi.org/10.12703/P6-64] [PMID: 25165563]
].

Over time, bacteria have developed several mechanisms by which they can withstand antimicrobials, rendering the action of these substances ineffective [3El Salabi A, Walsh TR, Chouchani C. Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in Gram-negative bacteria. Crit Rev Microbiol 2013; 39(2): 113-22.
[http://dx.doi.org/10.3109/1040841X.2012.691870] [PMID: 22667 455]
]. The resistance mechanisms of a gram-negative bacterium include: efflux pump; membrane permeability; production of β-lactamases; modification of antibiotic targets; and, acquisition of alternative metabolic pathways to those inhibited by the antibiotic [4Matzov D, Bashan A, Yonath A. A bright future for antibiotics? Annu Rev Biochem 2017; 86(7): 1–7-.17.
[http://dx.doi.org/10.1146/annurev-biochem-061516-044617]
, 6Broberg CA, Palacios M, Miller VL. Klebsiella: a long way to go towards understanding this enigmatic jet-setter. F1000Prime Rep 2014; 6: 64-76.
[http://dx.doi.org/10.12703/P6-64] [PMID: 25165563]
]. One of the most important mechanisms of resistance in bacteria is the Extended Spectrum β-lactamase (ESBL) production [7Güzel M, Genç Y, Aksoy A, et al. Antibiotic resistance and metallo-beta-lactamase positivity in carbapenem-resistant non-fermentative Gram negative bacilli. Turk Hij Deney Biyol Derg 2015; 72: 131-8.]. The first β-lactamase with the ability to hydrolyze β-lactam was described in 1983 in a K. ozaenae isolated in Germany and designated as SHV-2 (Sulfhydryl variable) [8Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 2001; 14(4): 933-51.
[http://dx.doi.org/10.1128/CMR.14.4.933-951.2001] [PMID: 11585 791]
, 9Kliebe C, Nies BA, Meyer JF, Tolxdorff-Neutzling RM, Wiedemann B. Evolution of plasmid-coded resistance to broad-spectrum cephalosporins. Antimicrob Agents Chemother 1985; 28(2): 302-7.
[http://dx.doi.org/10.1128/AAC.28.2.302] [PMID: 3879659]
]. However, the initial outbreaks were related only in 1985 in France and the late ‘80s in the United States. Currently, over one hundred and fifty different ESBLs types have been identified. These classes of enzymes have a distinct spectrum of action and are classified as: Extended Spectrum β-lactamase (ESBL); Metalo-β-lactamase (MBL); and, β-lactamase Class C (AmpC) [8Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 2001; 14(4): 933-51.
[http://dx.doi.org/10.1128/CMR.14.4.933-951.2001] [PMID: 11585 791]
].

The definition of ESBLs is not consensual, however, some authors propose that an ESBL is any β-lactamase, generally acquired and not inherent in a species, that hydrolyzes rapidly or confers resistance to oxyimino-β-lactam chain, broad-spectrum cephalosporins, penicillins, and monobactams and is inhibited by clavulanate, sulbactam and tazobactam [10Tal Jasper R, Coyle JR, Katz DE, Marchaim D. The complex epidemiology of extended-spectrum β-lactamase-producing Enterobacteriaceae. Future Microbiol 2015; 10(5): 819-39.
[http://dx.doi.org/10.2217/fmb.15.16] [PMID: 26000652]
, 11Shaikh S, Fatima J, Shakil S, Rizvi SM, Kamal MA. Antibiotic resistance and extended spectrum beta-lactamases: Types, epidemiology and treatment. Saudi J Biol Sci 2015; 22(1): 90-101.
[http://dx.doi.org/10.1016/j.sjbs.2014.08.002] [PMID: 25561890]
]. Since the discovery of these enzymes, an increase of K. pneumoniae resistant to several antimicrobials has been reported such as aminoglycosides and even carbapenems [12Souli M, Galani I, Giamarellou H. Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill 2008; 13(47): 19045.
[PMID: 19021957]
, 13EARSS – European Antimicrobial Resistance Surveillance System EARSS Annual report 2008. 2008.]. These latter are considered to be one of the most important antibiotics classes in the fight against ESBL-producing microorganisms due to their stability against the hydrolytic activity of this enzyme and also for the ability to penetrate the bacterium [14Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 2012; 25(4): 682-707.
[http://dx.doi.org/10.1128/CMR.05035-11] [PMID: 23034326]
].

β-lactam antibiotics interact with diverse groups of bacterial enzymes. The enzymes, such as TEM-1 (Temoniera), TEM-2 and SHV-1, encoded by plasmids and widely distributed among enterobacteria, can hydrolyze a wide variety of penicillins and third generation of cephalosporins, which were originally developed as drugs capable of overcoming bacterial resistance. These enzymes have emerged as one of the most successful resistance mechanisms, which limit therapeutic options for treating various human infections, including Klebsiella [15Campos AC, Albiero J, Ecker AB, et al. Outbreak of K pneumoniae carbapenemase–producing: A systematic review. Am J Infect Control 2016; 44: 1374-80.
[http://dx.doi.org/10.1016/j.ajic.2016.03.022] [PMID: 27156198]
, 16Antimicrobial resistance: global report on surveillance. World Health Organization 2014.].

Given the therapeutic limitations caused by resistance mechanisms, several research groups have followed the distribution and susceptibility profile of the genus Klebsiella spp., to monitor possible outbreaks and set up the sensitivity profile in different regions [12Souli M, Galani I, Giamarellou H. Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill 2008; 13(47): 19045.
[PMID: 19021957]
, 13EARSS – European Antimicrobial Resistance Surveillance System EARSS Annual report 2008. 2008.]. Based on the global dissemination of ESBL-producing Klebsiella pneumoniae and limitations of the current treatments, the implementation of prevention and control measures has become extremely important [13EARSS – European Antimicrobial Resistance Surveillance System EARSS Annual report 2008. 2008.].

Considering the recognition of the genus Klebsiella spp. as an important pathogen involved in infections, its variations in the antibiotic resistance profile, and its emerging mechanisms of resistance, reinforces the need to know the local or regional characteristics of this genus, as well as the evolution of its resistance. Thus, monitoring of the resistance and prevalence of antimicrobial resistance determinants are urgently needed and may contribute to better targeting and use of antimicrobials. In this context, the present review focuses on the main aspects related to the distribution of resistance genes to β-lactam antibiotics associated with Klebsiella pneumoniae found in the scientific literature.

2. MATERIALS AND METHOD

The searches were conducted between February and June of 2018 in online health databases, and date delimitation was set as between 2000 and 2018. Editorials, letters, and Ph.D. theses were excluded. The following databases were used for the research: PubMed, SCOPUS, Science Direct, Latin American and Caribbean Literature in Health Sciences (LILACS), Virtual Electronic Scientific Library (SCIELO) and Portal of Periodicals of the Coordination for the Upper Level (Capes Newspapers). Additionally, the descriptors to perform the searches were: Klebsiella pneumoniae, Klebsiella pneumoniae resistance factors, Klebsiella pneumoniae with resistance to β-lactam antimicrobials, broad-spectrum β-lactamases, and extended-spectrum β-lactamase. There was no restriction of sample size for evaluation of publications and the articles selected were only in the English language. Exclusion criteria were: studies that exclusively investigated resistance to non-β-lactam antibiotics and non-human studies. Some studies considered essential to compose the review not included in any of the research bases were added (i.e., articles addressing pathologies in humans, characteristics of the bacterium and, some studies published earlier than the year 2000 due to the importance of it to a specific country and to better contextualize a finding).

3. RESULTS AND DISCUSSION

The descriptors and databases used allowed the identification of 84 scientific articles that fully met the inclusion criteria of the study. It should be noted that several studies found despite the treatment of β-lactam antibiotic resistance associated with K. pneumoniae did not present all relevant information for our review, e.g., resistance genes and/or sites where the microorganism was isolated, which consequently had to be excluded. Finally, not all the countries that constitute the different continents were considered since until the conclusion of our review no results were published between 2000 and 2018.

3.1. Antimicrobial Resistance

Antimicrobial resistance is a growing worldwide iatrogenic complication, which currently constitutes a major public health problem and is responsible for a significant increase in patients' morbidity and mortality [10Tal Jasper R, Coyle JR, Katz DE, Marchaim D. The complex epidemiology of extended-spectrum β-lactamase-producing Enterobacteriaceae. Future Microbiol 2015; 10(5): 819-39.
[http://dx.doi.org/10.2217/fmb.15.16] [PMID: 26000652]
, 17Albrich WC, Angstwurm M, Bader L, Gärtner R. Drug resistance in intensive care units. Infection 1999; 27(Suppl. 2): S19-23.
[http://dx.doi.org/10.1007/BF02561665] [PMID: 10885822]
].

As commented above, the Enterobacteriaceae family has several mechanisms of resistance recognized. This group has also received special attention in recent years as being among the most isolated microorganisms in the laboratory routine [12Souli M, Galani I, Giamarellou H. Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill 2008; 13(47): 19045.
[PMID: 19021957]
]. Belonging to this family, one of the important pathogens for humans, with well-known and powerful mechanisms of resistance, is the genus Klebsiella spp [12Souli M, Galani I, Giamarellou H. Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. Euro Surveill 2008; 13(47): 19045.
[PMID: 19021957]
, 13EARSS – European Antimicrobial Resistance Surveillance System EARSS Annual report 2008. 2008.].

In recent years, increased antibiotic resistance in Enterobacteriaceae has become a major concern worldwide. Although β-lactam antibiotics have been widely used as the first treatment of severe infections, resistance to these drugs due to the acquisition of resistance genes has emerged and spread worldwide since the early 2000s, thus increasing concern about the occurrence of infections of hospital origin where these bacteria are widespread [18Miriagou V, Cornaglia G, Edelstein M, et al. Acquired carbapenemases in Gram-negative bacterial pathogens: detection and surveillance issues. Clin Microbiol Infect 2010; 16(2): 112-22.
[http://dx.doi.org/10.1111/j.1469-0691.2009.03116.x] [PMID: 20085 605]
].

The progression of resistance of Klebsiella pneumoniae to antibiotics has caused great concern since the 1980s with the emergence of K. pneumoniae ESBL-producing [19Boszczowski I, Nicoletti C, Puccini DM, et al. Outbreak of extended spectrum beta-lactamase-producing Klebsiella pneumoniae infection in a neonatal intensive care unit related to onychomycosis in a health care worker. Pediatr Infect Dis J 2005; 24(7): 648-50.
[http://dx.doi.org/10.1097/01.inf.0000168844.55898.8f] [PMID: 15999012]
]. Since them, other β-lactamases were discovered, for example, the carbapenemase. This enzyme was discovered in the United States in 2001 in K. pneumoniae and has expanded remarkably, being able to confer resistance to all β-lactams, even those associated with β-lactamase inhibitors [20McGettigan SE, Hu B, Andreacchio K, Nachamkin I, Edelstein PH. Prevalence of CTX-M beta-lactamases in Philadelphia, Pennsylvania. J Clin Microbiol 2009; 47(9): 2970-4.
[http://dx.doi.org/10.1128/JCM.00319-09] [PMID: 19587301]
]. Another important β-lactamase is the MBL, which degrades all β-lactams except aztreonam (monobactam) in vitro, whereas AmpC, in turn, can hydrolyze penicillins, monobactams, and cephalosporins until the third generation [21Philippon A, Arlet G, Jacoby GA. Plasmid-determined AmpC-type β-lactamases. Antimicrob Agents Chemother 2002; 46(1): 1-11.
[http://dx.doi.org/10.1128/AAC.46.1.1-11.2002] [PMID: 11751104]
].

The β-lactamase type enzymes can be classified into two distinct ways, the molecular classification of Ambler [22Ambler RP. The structure of β-lactamases. Philos Trans R Soc Lond B Biol Sci 1980; 289(1036): 321-31.
[http://dx.doi.org/10.1098/rstb.1980.0049] [PMID: 6109327]
] and the functional classification Bush & Jacoby [23Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev 2009; 22(1): 161-82.
[http://dx.doi.org/10.1128/CMR.00036-08] [PMID: 19136439]
]. The first classifies the β-lactamases into four classes (A, B, C, and D), grouped according to the similarity between the amino acid sequences. Classes A, C, and D are considered serine β-lactamase because they have the site of action composed of serine. Class B, also called MBL, uses zinc (Zn) as a cofactor [24Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother 2010; 54(3): 969-76.
[http://dx.doi.org/10.1128/AAC.01009-09] [PMID: 19995920]
].

The most current classification is from Bush & Jacoby, based on the activity of the enzyme, that is, on functional groups and correlates the properties of each enzyme with the resistance profile of each isolate [23Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev 2009; 22(1): 161-82.
[http://dx.doi.org/10.1128/CMR.00036-08] [PMID: 19136439]
, 24Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother 2010; 54(3): 969-76.
[http://dx.doi.org/10.1128/AAC.01009-09] [PMID: 19995920]
]. In this way, enzymes are classified into three groups: group 1, which is the group of cephalosporinases. Enzymes belonging to molecular class C, from Ambler, which are more active against cephalosporins and are not inhibited by β-lactamase inhibitors, such as clavulanic acid and tazobactam. Group 2 comprises the serine β-lactamases, enzymes belonging to group A and D, of Ambler, represented by the largest group of β-lactamases. It is divided into subgroups (2a and 2b) according to the action spectrum of each enzyme. Group 3 includes the enzymes that require the zinc ion at its site of action to produce antimicrobial activity (Fig. 1). They are the MBLs that can hydrolyze carbapenems and are inhibited by ion chelators, such as EDTA [23Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev 2009; 22(1): 161-82.
[http://dx.doi.org/10.1128/CMR.00036-08] [PMID: 19136439]
, 24Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother 2010; 54(3): 969-76.
[http://dx.doi.org/10.1128/AAC.01009-09] [PMID: 19995920]
].

The AmpC-type β-lactamases are chromosomal β-lactamases but can be found on both the bacterial chromosome and inserted into mobile plasmids. There are various types of plasmid-mediated AmpC β-lactamases: the CMY, MIR, MOX, LAT, FOX, DHA, ACT, ACC and CFE. They are capable of hydrolyzing penicillins, monobactams, and cephalosporins of up to the third generation, with resistance to cefoxitin being the main marker of AmpC expression. AmpC-producing bacteria are commonly also resistant to non-β-lactam drugs, such as aminoglycosides, chloramphenicol, quinolones, sulfonamides, tetracyclines and trimethoprim [21Philippon A, Arlet G, Jacoby GA. Plasmid-determined AmpC-type β-lactamases. Antimicrob Agents Chemother 2002; 46(1): 1-11.
[http://dx.doi.org/10.1128/AAC.46.1.1-11.2002] [PMID: 11751104]
, 23Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev 2009; 22(1): 161-82.
[http://dx.doi.org/10.1128/CMR.00036-08] [PMID: 19136439]
].

Chromosomal origin AmpC can occur in two forms: inducible and constitutive. Thus, the exposure of bacteria to β-lactam antibiotics leads to an increase in the production of enzymes. This stimulus may occur at different levels of β-lactamase production, depending on the type of antimicrobial. In both cases, hyperproduction or hyperinduction of the enzyme can be attributed to a mutation in the AmpC regulatory genes [21Philippon A, Arlet G, Jacoby GA. Plasmid-determined AmpC-type β-lactamases. Antimicrob Agents Chemother 2002; 46(1): 1-11.
[http://dx.doi.org/10.1128/AAC.46.1.1-11.2002] [PMID: 11751104]
, 23Jacoby GA. AmpC β-lactamases. Clin Microbiol Rev 2009; 22(1): 161-82.
[http://dx.doi.org/10.1128/CMR.00036-08] [PMID: 19136439]
, 25Ghafourian S, Sadeghifard N, Soheili S, Sekawi Z. Extended spectrum beta-lactamases: definition, classification and epidemiology. Curr Issues Mol Biol 2015; 17: 11-21.
[PMID: 24821872]
].

Another important factor to be highlighted is the ability to transfer genes that determine antimicrobial resistance. The genes encoding ESBLs are usually located on plasmids that are highly mobile and can harbor resistance genes to several other unrelated classes of antimicrobials [26Baudry PJ, Nichol K, DeCorby M, et al. Mechanisms of resistance and mobility among multidrug-resistant CTX-M-producing Escherichia coli from Canadian intensive care units: the 1st report of QepA in North America. Diagn Microbiol Infect Dis 2009; 63(3): 319-26.
[http://dx.doi.org/10.1016/j.diagmicrobio.2008.12.001] [PMID: 19216943]
]. Carattoli [27Carattoli A. Resistance plasmid families in Enterobacteriaceae. Antimicrob Agents Chemother 2009; 53(6): 2227-38.
[http://dx.doi.org/10.1128/AAC.01707-08] [PMID: 19307361]
] and Zhang [28Zhang X, Lü X, Zong Z. Enterobacteriaceae producing the KPC-2 carbapenemase from hospital sewage. Diagn Microbiol Infect Dis 2012; 73(2): 204-6.
[http://dx.doi.org/10.1016/j.diagmicrobio.2012.02.007] [PMID: 22463 869]
] identified in Klebsiella pneumoniae isolates, transconjugants of blaCTX-M-type antibiotic resistance genes, blaSHV, blaVIM, blaDHA. Of these, about 67.7% of the transconjugants harbored at least two resistance classes and 32.2% identified three classes of resistance determinants.

Fig. (1)
β-lactamases of major clinical importance according to the classification of Ambler and Bush & Jacoby. AmpC: β-lactamases resistant to extended-spectrum of cephalosporins. ESBLs: Extended-spectrum β-lactamase. MBLs: Metallo-β-lactamases.


The family of SVH-type enzymes appears to be closely related to Klebsiella spp. SHV-1 isthe parent of the SHV-type enzyme class, and most of these enzymes are found in strains of K. pneumoniae [8Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 2001; 14(4): 933-51.
[http://dx.doi.org/10.1128/CMR.14.4.933-951.2001] [PMID: 11585 791]
, 29Livermore DM. Fourteen years in resistance. Int J Antimicrob Agents 2012; 39(4): 283-94.
[http://dx.doi.org/10.1016/j.ijantimicag.2011.12.012] [PMID: 22386 741]
]. There are a few derivatives of SHV-1, and the changes that occurred in the gene to give rise to its variations were characterized by the substitution of serine for glycine [8Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 2001; 14(4): 933-51.
[http://dx.doi.org/10.1128/CMR.14.4.933-951.2001] [PMID: 11585 791]
].

TEM-1 enzyme is the β-lactamase most commonly found in gram-negative bacteria. Its first derivative is TEM-2, where the only difference is the amino acid substitution from the original β-lactamase. The amino acid substitutions occurring within the TEM enzyme occur in a limited number of positions. Combinations of these amino acid changes result in several subtle alterations in ESBL phenotypes, such as the ability to hydrolyze specific oxyimino-cephalosporins, such as ceftazidime and cefotaxime, or a change in isoelectric points [30Liebana E, Batchelor M, Hopkins KL, et al. Longitudinal farm study of extended-spectrum β-lactamase-mediated resistance. J Clin Microbiol 2006; 44(5): 1630-4.
[http://dx.doi.org/10.1128/JCM.44.5.1630-1634.2006] [PMID: 16672 386]
]. More than 150 different variants of TEM and SHV that generate resistant have been described in the literature. Among these genes, TEM-3 causes a high rate of resistance concomitant with such antibiotics, being the most reported. The CTX-M enzymes have been recognized as the most prevalent among Enterobacteriaceae and other ESBLs, such as GES, PER, and EBV, have been described as having a lower prevalence [31Walsh TR. Combinatorial genetic evolution of multiresistance. Curr Opin Microbiol 2006; 9(5): 476-82.
[http://dx.doi.org/10.1016/j.mib.2006.08.009] [PMID: 16942901]
].

During the 1990s, TEM and SHV were dominant; however, the last decade was marked by the rapid and massive spread of β-lactamases of the CTX-M type, which are currently the most prevalent ESBL in Enterobacteriaceae in Europe and other parts of the world [32Belbel Z, Chettibi H, Dekhil M, Ladjama A, Nedjai S, Rolain JM. Outbreak of an armA methyltransferase-producing ST39 Klebsiella pneumoniae clone in a pediatric Algerian Hospital. Microb Drug Resist 2014; 20(4): 310-5.
[http://dx.doi.org/10.1089/mdr.2013.0193] [PMID: 24475919]
]. The existence of the CTX-M enzyme was discovered at the end of the '80s and, more than 100 variations have been identified [33Bonnet R. Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother 2004; 48(1): 1-14.
[http://dx.doi.org/10.1128/AAC.48.1.1-14.2004] [PMID: 14693512]
]. Its origin is different from the TEM, and SHV enzymes, the ESBL of CTX-M were acquired by horizontal transfer of genes from other bacteria by translocation or conjugative plasmid, whereas TEM and SHV ESBLs originate from the substitution of the amino acids of parental enzymes [34Olson AB, Silverman M, Boyd DA, et al. Identification of a progenitor of the CTX-M-9 group of extended-spectrum beta-lactamases from Kluyvera georgiana isolated in Guyana. Antimicrob Agents Chemother 2005; 49(5): 2112-5.
[http://dx.doi.org/10.1128/AAC.49.5.2112-2115.2005] [PMID: 15855 541]
, 35Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother 2004; 48(1): 15-22.
[http://dx.doi.org/10.1128/AAC.48.1.15-22.2004] [PMID: 14693513]
]. They are classified into five groups based on their amino acid sequence: CTXM-1, CTX-M-2, CTX-M-8, CTX-M-9, and CTX-M-25 [33Bonnet R. Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother 2004; 48(1): 1-14.
[http://dx.doi.org/10.1128/AAC.48.1.1-14.2004] [PMID: 14693512]
]. The diversity of CTX-M enzymes from clinical isolates, described today, grossly underestimate the diversity that exists in nature. The rapid global spread of the CTX-M enzyme poses a threat to current antimicrobial therapy strategies, which rely heavily on third-generation cephalosporins to control gram-negative bacterial infections [33Bonnet R. Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother 2004; 48(1): 1-14.
[http://dx.doi.org/10.1128/AAC.48.1.1-14.2004] [PMID: 14693512]
].

3.2. Epidemiology

Our results indicate that the population of K. pneumoniae is highly diversified and that in some cases resistant strains seem to have spread throughout the country over time. In addition, we found evidence that some strains independently acquired antimicrobial resistance genes, presumably in response to antimicrobial treatment [5Moradigaravand D, Martin V, Peacock SJ, Parkhill J. Evolution and epidemiology of multidrug-resistant Klebsiella pneumoniae in the United Kingdom and Ireland. MBio 2017; 8(1): 01976-16.
[http://dx.doi.org/10.1128/mBio.01976-16] [PMID: 28223459]
].

The spectrum of infections and the epidemiology of K. pneumoniae changed drastically from the 1970s when this microorganism was identified in a hospital environment. In addition to the considerable colonization efficiency, the antimicrobial resistance allowed K. pneumoniae to spread rapidly in health care settings [14Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 2012; 25(4): 682-707.
[http://dx.doi.org/10.1128/CMR.05035-11] [PMID: 23034326]
]. The frequency of the association of the bacteria with cases of hospital infections, as well as the high mortality rates caused by K. pneumoniae justify their monitoring [36Landman D, Bratu S, Kochar S, et al. Evolution of antimicrobial resistance among Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae in Brooklyn, NY. J Antimicrob Chemother 2007; 60(1): 78-82.
[http://dx.doi.org/10.1093/jac/dkm129] [PMID: 17490999]
]. There are reports in the literature of the increasing number of genes associated with the production of ESBLs in K. pneumoniae. Among these, the precursors of SHV and TEM enzymes, as well as CTX-M are isolated in numerous countries, alerting to the occurrence of more than one resistance gene in the same strain [37Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 2005; 18(4): 657-86.
[http://dx.doi.org/10.1128/CMR.18.4.657-686.2005] [PMID: 16223 952]
]. In this study, blaCTX-M-15 and blaSHV-5 genes were identified in 4 of the 7 (57%) of the European countries that were part of this research, both of which were identified in France, Italy, Spain, and Portugal. With featured on France and Spain, where the gene blaCTX-M-15 was isolated twice in rectal swab in both countries (Table 1). Concomitant with the use of antibiotic, the prevalence of Klebsiella pneumoniae strains producing CTX-M-type ESBLs has increased worldwide [46Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int J Med Microbiol 2010; 300(6): 371-9.
[http://dx.doi.org/10.1016/j.ijmm.2010.04.005] [PMID: 20537585]
]. The blaCTX-M-15 gene is predominantly present on the European continent due to the spread of isolates initially identified in France and Italy, which have spread to other countries [46Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int J Med Microbiol 2010; 300(6): 371-9.
[http://dx.doi.org/10.1016/j.ijmm.2010.04.005] [PMID: 20537585]
].

The β-lactamase CTX-M-15, first detected in 1999 in India, is currently recognized as the most widely distributed CTX-M β-lactamase in the world [46Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int J Med Microbiol 2010; 300(6): 371-9.
[http://dx.doi.org/10.1016/j.ijmm.2010.04.005] [PMID: 20537585]
]. CTX-M enzymes, especially CTX-M-15, are related to various epidemiological situations and have spread throughout the continents due to epidemic plasmids and/or epidemic strains [47Ruppé E, Woerther PL, Diop A, et al. Carriage of CTX-M-15-producing Escherichia coli isolates among children living in a remote village in Senegal. Antimicrob Agents Chemother 2009; 53(7): 3135-7.
[http://dx.doi.org/10.1128/AAC.00139-09] [PMID: 19364858]
]. Corroborating this statement, in the present study, the blaCTX-M-15 gene was found in K. pneumoniae in all continents evaluated Table(1-4). Many of the emerging antimicrobial resistance problems of the nineties have been characterized by difficulty in recognition of resistance in the laboratory, particularly by rapid susceptibility-test methods. The emergence of plasmid-encoded ESBLs is a significant evolution in antimicrobial resistance. Outbreaks due to the dissemination of ESBL-producing bacterial strains and to the dissemination of ESBL-encoding plasmids among different species of the family Enterobacteriaceae have been described in hospitals and other health care facilities [46Pfeifer Y, Cullik A, Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens. Int J Med Microbiol 2010; 300(6): 371-9.
[http://dx.doi.org/10.1016/j.ijmm.2010.04.005] [PMID: 20537585]
, 47Ruppé E, Woerther PL, Diop A, et al. Carriage of CTX-M-15-producing Escherichia coli isolates among children living in a remote village in Senegal. Antimicrob Agents Chemother 2009; 53(7): 3135-7.
[http://dx.doi.org/10.1128/AAC.00139-09] [PMID: 19364858]
].

Some authors identified antimicrobial resistance genes in K. pneumoniae and demonstrated the CTX-M-15 and SHV-5 domain isolated from Portuguese hospitals [45Rodrigues C, Machado E, Ramos H, Peixe L, Novais Â. Expansion of ESBL-producing Klebsiella pneumoniae in hospitalized patients: a successful story of international clones (ST15, ST147, ST336) and epidemic plasmids (IncR, IncFIIK). Int J Med Microbiol 2014; 304(8): 1100-8.
[http://dx.doi.org/10.1016/j.ijmm.2014.08.003] [PMID: 25190354]
]. The production of the SHV-type ESBLs in K. pneumoniae is associated with an increased tendency to invade epithelial cells and expression of fimbrial adhesions [48Andrade LN, Vitali L, Gaspar GG, et al. Expansion and evolution of a virulent, extensively drug-resistant (polymyxin b-resistant), QnrS1, CTX-M-2, and KPC-2-producing Klebsiella pneumoniae ST11 international high-risk clone. J Clin Microb 2014; pp. 2530-5.]. The propagation of these genes is influenced by the amplification of the epidemic and international clones of K. pneumoniae and specific types of plasmids. The same authors also highlight the potential for antibiotic resistance and virulence plasmid dissemination [45Rodrigues C, Machado E, Ramos H, Peixe L, Novais Â. Expansion of ESBL-producing Klebsiella pneumoniae in hospitalized patients: a successful story of international clones (ST15, ST147, ST336) and epidemic plasmids (IncR, IncFIIK). Int J Med Microbiol 2014; 304(8): 1100-8.
[http://dx.doi.org/10.1016/j.ijmm.2014.08.003] [PMID: 25190354]
]. The origin of the blaCTX-M-15 gene identified in K. pneumoniae in Portugal is clone ST336, and the most recent occurrence in France, described in the literature, reported a clonal outbreak involving K. pneumoniae isolates recovered from a single hospital in the Picardie region of northern France [45Rodrigues C, Machado E, Ramos H, Peixe L, Novais Â. Expansion of ESBL-producing Klebsiella pneumoniae in hospitalized patients: a successful story of international clones (ST15, ST147, ST336) and epidemic plasmids (IncR, IncFIIK). Int J Med Microbiol 2014; 304(8): 1100-8.
[http://dx.doi.org/10.1016/j.ijmm.2014.08.003] [PMID: 25190354]
, 49Jayol A, Poirel L, Dortet L, Nordmann P. National survey of colistin resistance among carbapenemase-producing Enterobacteriaceae and outbreak caused by colistin-resistant OXA-48-producing Klebsiella pneumoniae, France, 2014. Euro Surveill 2016; 21(37): 30339.
[http://dx.doi.org/10.2807/1560-7917.ES.2016.21.37.30339] [PMID: 27685838]
]. This outbreak was caused by a resistance to colistin with OXA-48 and CTXM-15 which produced K. pneumoniae type ST11 that was susceptible only to cefoxitin. The first identification of the ST11 clone in K. pneumoniae occurred in 1997 in France [49Jayol A, Poirel L, Dortet L, Nordmann P. National survey of colistin resistance among carbapenemase-producing Enterobacteriaceae and outbreak caused by colistin-resistant OXA-48-producing Klebsiella pneumoniae, France, 2014. Euro Surveill 2016; 21(37): 30339.
[http://dx.doi.org/10.2807/1560-7917.ES.2016.21.37.30339] [PMID: 27685838]
]. This clone has been associated to the acquisition of resistance genes to a broad spectrum of antimicrobial agents, as well as to the dissemination of OXA-48, in addition to VIM (Verona Imipenemase), NDM (New Delhi Metallo-β-lactamase) and KPC [40Brañas P, Villa J, Viedma E, Mingorance J, Orellana MA, Chaves F. Molecular epidemiology of carbapenemase-producing Klebsiella pneumoniae in a hospital in Madrid: Successful establishment of an OXA-48 ST11 clone. Int J Antimicrob Agents 2015; 46(1): 111-6.
[http://dx.doi.org/10.1016/j.ijantimicag.2015.02.019] [PMID: 25914088]
, 49Jayol A, Poirel L, Dortet L, Nordmann P. National survey of colistin resistance among carbapenemase-producing Enterobacteriaceae and outbreak caused by colistin-resistant OXA-48-producing Klebsiella pneumoniae, France, 2014. Euro Surveill 2016; 21(37): 30339.
[http://dx.doi.org/10.2807/1560-7917.ES.2016.21.37.30339] [PMID: 27685838]
].

The most recent occurrence of blaCTX-M-15 in other European countries was described by Rodrigues and Brañas [40Brañas P, Villa J, Viedma E, Mingorance J, Orellana MA, Chaves F. Molecular epidemiology of carbapenemase-producing Klebsiella pneumoniae in a hospital in Madrid: Successful establishment of an OXA-48 ST11 clone. Int J Antimicrob Agents 2015; 46(1): 111-6.
[http://dx.doi.org/10.1016/j.ijantimicag.2015.02.019] [PMID: 25914088]
, 45Rodrigues C, Machado E, Ramos H, Peixe L, Novais Â. Expansion of ESBL-producing Klebsiella pneumoniae in hospitalized patients: a successful story of international clones (ST15, ST147, ST336) and epidemic plasmids (IncR, IncFIIK). Int J Med Microbiol 2014; 304(8): 1100-8.
[http://dx.doi.org/10.1016/j.ijmm.2014.08.003] [PMID: 25190354]
]. The first author related finding of the increased incidence of CTX-M-15, SHV and several other types ESBL were observed in a Portuguese hospital associated with the increase of MDR K. pneumoniae epidemic clones, the second reported blaOXA-48 and blaCTX-M-15 as responsible for a major outbreak involving 44 patients at a hospital in Madrid, Spain, 2009 to 2014 [40Brañas P, Villa J, Viedma E, Mingorance J, Orellana MA, Chaves F. Molecular epidemiology of carbapenemase-producing Klebsiella pneumoniae in a hospital in Madrid: Successful establishment of an OXA-48 ST11 clone. Int J Antimicrob Agents 2015; 46(1): 111-6.
[http://dx.doi.org/10.1016/j.ijantimicag.2015.02.019] [PMID: 25914088]
, 45Rodrigues C, Machado E, Ramos H, Peixe L, Novais Â. Expansion of ESBL-producing Klebsiella pneumoniae in hospitalized patients: a successful story of international clones (ST15, ST147, ST336) and epidemic plasmids (IncR, IncFIIK). Int J Med Microbiol 2014; 304(8): 1100-8.
[http://dx.doi.org/10.1016/j.ijmm.2014.08.003] [PMID: 25190354]
].

In the United Kingdom and Sweden, the only resistance genes identified were NDM-type, with blaNDM-1 being isolated in both countries (Table 1). Among the NDM isolates identified in the United Kingdom, ST231 was the most common type along with ST147 and ST273. In the case of Sweden, the isolates belonged to four different sequence types, as they were imported from various regions of the world such as India and Iraq [43Giske CG, Fröding I, Hasan CM, et al. Diverse sequence types of Klebsiella pneumoniae contribute to the dissemination of blaNDM-1 in India, Sweden, and the United Kingdom. Antimicrob Agents Chemother 2012; 56(5): 2735-8.
[http://dx.doi.org/10.1128/AAC.06142-11] [PMID: 22354295]
]. Strains of K. pneumoniae NDM-1 positive can exhibit relatively high clonal diversity. In Sweden and the United Kingdom clone ST14 was the most frequently observed type. Clone K. pneumoniae ST14 has been described as a host for the NDM-1 enzyme and is also a frequent host of CTX-M enzymes. In addition, ST14 is a single locus variant (SLV) of ST15, which often encodes the CTX-M type ESBLs. The production of the NDM-1 enzyme by isolates belonging to clone ST11 and complex ST147-ST273 is very relevant information since clone ST11 is a frequent host of CTX-M and KPC and is also an SLV of ST258, making it fundamental for its dissemination [43Giske CG, Fröding I, Hasan CM, et al. Diverse sequence types of Klebsiella pneumoniae contribute to the dissemination of blaNDM-1 in India, Sweden, and the United Kingdom. Antimicrob Agents Chemother 2012; 56(5): 2735-8.
[http://dx.doi.org/10.1128/AAC.06142-11] [PMID: 22354295]
, 50Woodford N, Zhang J, Warner M, et al. Arrival of Klebsiella pneumoniae producing KPC carbapenemase in the United Kingdom. J Antimicrob Chemother 2008; 62(6): 1261-4.
[http://dx.doi.org/10.1093/jac/dkn396] [PMID: 18812425]
].

Of the European countries correlated in this study, Spain stands out as the site where the largest number of different genes (15 in total) was identified, which shows the genetic diversity in relation to the occurrence of K. pneumoniae with resistance to the antibiotic β-lactams (Table 1). This characteristic, from the point of view of the therapeutic of the infection, is a difficult factor, considering that the variation of resistance genes decreases the antimicrobial therapy options.

The country where the lowest gene diversity occurred was Greece, where the only isolated gene was blaKPC-2 in two outbreak cases (Table 1). Considering that the outbreaks were of monoclonal origin and that there was no identification of a common source or an environmental reservoir, the main dissemination mechanism of the blaKPC-2 in these cases was the transmission from patient to patient [41Maltezou HC, Giakkoupi P, Maragos A, et al. Outbreak of infections due to KPC-2-producing Klebsiella pneumoniae in a hospital in Crete (Greece). J Infect 2009; 58(3): 213-9.
[http://dx.doi.org/10.1016/j.jinf.2009.01.010] [PMID: 19246099]
, 42Souli M, Galani I, Antoniadou A, et al. An outbreak of infection due to β-Lactamase Klebsiella pneumoniae Carbapenemase 2-producing K. pneumoniae in a Greek University Hospital: molecular characterization, epidemiology, and outcomes. Clin Infect Dis 2010; 50(3): 364-73.
[http://dx.doi.org/10.1086/649865] [PMID: 20041768]
]. The smallest genetic diversity in Greece, identified in this study, may be related to a low number of publications in this country.

Table 1
Association between resistance genes to β-lactams, geographical areas of occurrence and clinical isolates in the European continent.


In Asia and Oceania, 41 different resistance gene types have been identified in the literature. Of these, the greatest diversity occurred in China, where 14 of the 41 genes were described, corresponding to 41% of the total of related genes in Table 2. The variety of genes in China can be justified by its high population density, associated with intense migrations.

The second country with the greatest diversity of genes was Israel (12 different genes), followed by Turkey (11 genes) and Iran (10 genes). The lowest variety of β-lactam resistance genes occurred in Pakistan (2 genes), according to data in Table 2. Despite the lower diversity, the genes identified in Pakistan, blaKPC, and blaNDM-1, are of great importance for tracking the control of microbial resistance. The first gene is characterized by its wide plasmodial spread, and the second has broad relationships with the globalization and population mobility [63Navon-Venezia S, Leavitt A, Schwaber MJ, et al. First report on a hyperepidemic clone of KPC-3-producing Klebsiella pneumoniae in Israel genetically related to a strain causing outbreaks in the United States. Antimicrob Agents Chemother 2009; 53(2): 818-20.
[http://dx.doi.org/10.1128/AAC.00987-08] [PMID: 19029323]
, 64Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53(12): 5046-54.
[http://dx.doi.org/10.1128/AAC.00774-09] [PMID: 19770275]
]. The blaNDM-1 gene was first identified in 2009 in a Swedish patient of Indian origin, who acquired a urinary tract infection in New Delhi, caused by a strain of K. pneumoniae that showed resistance to β-lactam antibiotics [64Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53(12): 5046-54.
[http://dx.doi.org/10.1128/AAC.00774-09] [PMID: 19770275]
, 65Nordmann P, Poirel L, Toleman MA, Walsh TR. Does broad-spectrum beta-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria? J Antimicrob Chemother 2011; 66(4): 689-92.
[http://dx.doi.org/10.1093/jac/dkq520] [PMID: 21393184]
].

Table 2
Association between resistance genes to β-lactams, geographical areas of occurrence and clinical isolates in Asia and Oceania.


Of the isolates of K. pneumoniae from Singapore, the occurrence of blaCTX type genes predominated, with the blaCTX-M-1 group being more numerous than the others. Literature data report transport of methylase genes in isolated MDR K. pneumoniae strains in Chinese hospitals [52Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J Antimicrob Chemother 2011; 66(2): 307-12.
[http://dx.doi.org/10.1093/jac/dkq431] [PMID: 21131324]
]. In most countries of Asia and Oceania, the blaCTX-M gene, in particular, blaCTX-M-15, was detected in K. pneumoniae, as shown in Table 2. A study published in 2015 reported, for the first time, the isolation of K. pneumoniae CTX-M-15, SHV-11, and KPC belonging to ST336 in Lebanon [62Tokajian S, Eisen JA, Jospin G, Farra A, Coil DA. Whole genome sequencing of extended-spectrum β-lactamase producing Klebsiella pneumoniae isolated from a patient in Lebanon. Front Cell Infect Microbiol 2015; 5: 32.
[http://dx.doi.org/10.3389/fcimb.2015.00032] [PMID: 25905047]
]. The contributors to the dissemination of the blaCTX-M-15 gene highlight the clonal complex 17, among them ST336 [45Rodrigues C, Machado E, Ramos H, Peixe L, Novais Â. Expansion of ESBL-producing Klebsiella pneumoniae in hospitalized patients: a successful story of international clones (ST15, ST147, ST336) and epidemic plasmids (IncR, IncFIIK). Int J Med Microbiol 2014; 304(8): 1100-8.
[http://dx.doi.org/10.1016/j.ijmm.2014.08.003] [PMID: 25190354]
] is related to the presence of this gene in clinical isolates in several countries of the world. In the present study, the occurrence of the blaCTX-M-15 gene is reported in all continents evaluated, except in the African continent, revealing its endemicity and, highlighting the dissemination of this gene at a global level through human mobility. This clone was isolated for the first time from a patient (nurse), 62 years old, with an abdominal tumor and who had recurrent urinary infections. The ST336 epidemic clone belongs to CG17, and studies revealed the prevalence of this strain in France, Germany, Italy, USA and Greece [38Baraniak A, Izdebski R, Fiett J, et al. Comparative population analysis of Klebsiella pneumoniae strains with extended-spectrum β-lactamases colonizing patients in rehabilitation centers in four countries. Antimicrob Agents Chemother 2013; 57(4): 1992-7.
[http://dx.doi.org/10.1128/AAC.02571-12] [PMID: 23403 417]
, 66MacPherson DW, Gushulak BD, Baine WB, et al. Population mobility, globalization, and antimicrobial drug resistance. Emerg Infect Dis 2009; 15(11): 1727-32.
[http://dx.doi.org/10.3201/eid1511.090419] [PMID: 19891858]
]

In this study, K. pneumoniae with the presence of the blaKPC gene was isolated in all the evaluated continents, as described in Tables 1, 2, 3 and 4. Although it occurs in all continents evaluated, the blaKPC-2 type gene was more prominent in the Asian and American continents (Tables 2 and 3), and is described as the second most frequent gene. The most prevalent β-lactamase in the family Enterobacteriaceae is the type of KPC, which was found in Klebsiella pneumoniae, especially in the United States, Asia, United Kingdom, Israel and Europe [65Nordmann P, Poirel L, Toleman MA, Walsh TR. Does broad-spectrum beta-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria? J Antimicrob Chemother 2011; 66(4): 689-92.
[http://dx.doi.org/10.1093/jac/dkq520] [PMID: 21393184]
]. The propagation of the blaKPC gene to other countries is associated with cases imported from countries where they are endemic [66MacPherson DW, Gushulak BD, Baine WB, et al. Population mobility, globalization, and antimicrobial drug resistance. Emerg Infect Dis 2009; 15(11): 1727-32.
[http://dx.doi.org/10.3201/eid1511.090419] [PMID: 19891858]
]. Besides, population mobility is recognized as a major factor in the spread of microorganisms resistant to antimicrobial drugs. Thus, the emergence of K. pneumoniae producing blaKPC in the United States in 2001 may be associated with the onset of travel-related outbreaks in other countries [63Navon-Venezia S, Leavitt A, Schwaber MJ, et al. First report on a hyperepidemic clone of KPC-3-producing Klebsiella pneumoniae in Israel genetically related to a strain causing outbreaks in the United States. Antimicrob Agents Chemother 2009; 53(2): 818-20.
[http://dx.doi.org/10.1128/AAC.00987-08] [PMID: 19029323]
].

In the literature, the first identification of the blaOXA-48 gene in a K. pneumoniae isolate occurred in Istanbul, Turkey, in 2001, since then the β-lactamase OXA-48 has become an important carbapenemase associated with the Entero bacteriaceae family in Europe, North Africa, and Asia [35Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother 2004; 48(1): 15-22.
[http://dx.doi.org/10.1128/AAC.48.1.15-22.2004] [PMID: 14693513]
, 72Mathers AJ, Hazen KC, Carroll J, et al. First clinical cases of OXA-48-producing carbapenem-resistant Klebsiella pneumoniae in the United States: the “menace” arrives in the new world. J Clin Microbiol 2013; 51(2): 680-3.
[http://dx.doi.org/10.1128/JCM.02580-12] [PMID: 23175248]
].

In the Americas, the highest diversity of β-lactam resistance genes occurred in Brazil, where 12 of the 25 different types of genes identified on the continent were reported, representing 48% of the total genes present in this continent (Table 3). Secondly, in the diversity of resistance genes, the United States of America (USA) presented 10 of the 25 genes identified; followed by Canada (9 different genes) and Argentina (6 different genes). The lowest resistance gene diversity occurred in Mexico (3 different genes), according to data described in Table 3. The smallest variety of genes in Mexico can be justified by the low number of publications on the subject in this country.

The occurrence of β-lactamase gene diversity produced by K. pneumoniae may be closely related to the variety of antimicrobials used in the treatment of infection over the decades. With the evolution of antimicrobial resistance in bacteria, it is necessary to continually re-evaluate the laboratory detection of ESBLs and potential treatment options for organisms that produce ESBLs [1Yu VL, Hansen DS, Ko WC, et al. Virulence characteristics of Klebsiella and clinical manifestations of K. pneumoniae bloodstream infections. Emerg Infect Dis 2007; 13(7): 986-93.
[http://dx.doi.org/10.3201/eid1307.070187] [PMID: 18214169]
].

Among the resistance genes identified in the American continent, blaCTX-M-2, blaSHV-1, blaSHV-5, and blaSHV-2 were isolated from K. pneumoniae in 60% of the American countries listed in this study. The genes blaCTX-M-15, blaCTX-M-1, blaSHV-11, blaSHV-12, blaTEM-1, blaTEM-10 and blaKPC-2 were the second most frequent in the Americas, being found in 40% (Table 3).

TEM-10 was ESBL type TEM which is most frequently detected in K. pneumoniae isolates, being found in different geographic regions (United States, South Africa, and Argentina). The identification of genes encoding the production of TEM-10 β-lactamase isolated from K. pneumoniae in Argentina in 2003 represented the first report of ESBL-type TEM-10 in South America [55Paterson DL, Hujer KM, Hujer AM, et al. Extended-spectrum β-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type β-lactamases. Antimicrob Agents Chemother 2003; 47(11): 3554-60.
[http://dx.doi.org/10.1128/AAC.47.11.3554-3560.2003] [PMID: 14576 117]
]. In Argentina, most ESBLs belong to the CTX-M class, referring to a growing family of ESBLs that shares a single phenotype that confers in vitro resistance to cefotaxime, ceftriaxone and many times to cefepime [74Quinteros M, Radice M, Gardella N, et al. Extended-spectrum beta-lactamases in enterobacteriaceae in Buenos Aires, Argentina, public hospitals. Antimicrob Agents Chemother 2003; 47(9): 2864-7.
[http://dx.doi.org/10.1128/AAC.47.9.2864-2867.2003] [PMID: 12936 986]
].

Table 3
Association between genes of resistance to β-lactams, geographical areas of occurrence and clinical isolates, in American continent.


In Brazil, the first reported case of KPC occurred in 2009. Data from a survey published in 2005 pointed out that the number of ESBL positive strains is increasing worldwide from 30% to 60% of strains of Klebsiella [37Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 2005; 18(4): 657-86.
[http://dx.doi.org/10.1128/CMR.18.4.657-686.2005] [PMID: 16223 952]
]. A major concern emerged in Brazil after the isolation and identification of Klebsiella pneumoniae with concomitant expression of MBL IMP-1 and ESBL CTX-M, since the production of these enzymes together gives the microorganism resistance to all antibiotics available for treatment, including carbapenems [78Lincopan N, McCulloch JA, Reinert C, Cassettari VC, Gales AC, Mamizuka EM. First isolation of metallo-beta-lactamase-producing multiresistant Klebsiella pneumoniae from a patient in Brazil. J Clin Microbiol 2005; 43(1): 516-9.
[http://dx.doi.org/10.1128/JCM.43.1.516-519.2005] [PMID: 15635 033]
]. A study on the antimicrobial resistance of Klebsiella spp., in Brazil, reported the trend of resistance growth in most of the antibiotics tested, indicating the need for new studies to monitor both the evolution of resistance and the emergence of new resistance mechanisms. The rapid spread of ESBL-producing K. pneumoniae is a major clinical and public health concern. These broad-spectrum β-lactamases are increasing in new locations around the world, indicating this to be a continuous process [79Cuzon G, Naas T, Truong H, et al. Worldwide diversity of Klebsiella pneumoniae that produce β-lactamase blaKPC-2 gene. Emerg Infect Dis 2010; 16(9): 1349-56.
[http://dx.doi.org/10.3201/eid1609.091389] [PMID: 20735917]
].

The literature data are still scarce in reporting the problem of ESBLs produced by K. pneumoniae in Africa, especially in sub-Saharan Africa [65Nordmann P, Poirel L, Toleman MA, Walsh TR. Does broad-spectrum beta-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria? J Antimicrob Chemother 2011; 66(4): 689-92.
[http://dx.doi.org/10.1093/jac/dkq520] [PMID: 21393184]
, 80Blomberg B, Jureen R, Manji KP, et al. High rate of fatal cases of pediatric septicemia caused by gram-negative bacteria with extended-spectrum beta-lactamases in Dar es Salaam, Tanzania. J Clin Microbiol 2005; 43(2): 745-9.
[http://dx.doi.org/10.1128/JCM.43.2.745-749.2005]
]. In the present study, the presence of K. pneumoniae presenting blaNDM-1 resistance gene, as described in (Table 4), was identified in Kenya and South Africa. NDM-1 is a type of MBL whose denomination is related to the city of origin, being a common practice in the case of transferable MBLs [81Rolain JM, Parola P, Cornaglia G. New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia? Clin Microbiol Infect 2010; 16(12): 1699-701.
[http://dx.doi.org/10.1111/j.1469-0691.2010.03385.x]
]. Isolates from the Enterobacteriaceae family harboring the blaNDM-1 gene are responsible for causing a variety of infections including urinary tract infections, septicemia, pulmonary infections, diarrhea, peritonitis, device-associated infections, and soft tissue infections [82Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10(9): 597-602.
[http://dx.doi.org/10.1016/S1473-3099(10)70143-2] [PMID: 20705 517]
]. The blaNDM-1 gene is a genetic element found in different plasmids. This gene is characterized by a large capacity of duplication migrating from bacterium to bacterium, which explains its rapid dissemination [64Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53(12): 5046-54.
[http://dx.doi.org/10.1128/AAC.00774-09] [PMID: 19770275]
]. Also, blaNDM-1 is easily disseminated between different bacterial species by lateral transfer. These characteristics make globalization a favorable aspect of gene dissemination, where travel represents a high risk of a global pandemic among Enterobacteriaceae. Since these plasmids also harbor genes that confer resistance to almost all antibiotics, making rapid their spread in clinically relevant bacteria a serious threat to therapy [64Yong D, Toleman MA, Giske CG, et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009; 53(12): 5046-54.
[http://dx.doi.org/10.1128/AAC.00774-09] [PMID: 19770275]
, 81Rolain JM, Parola P, Cornaglia G. New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia? Clin Microbiol Infect 2010; 16(12): 1699-701.
[http://dx.doi.org/10.1111/j.1469-0691.2010.03385.x]
]. The results of the present study report the occurrence of the K. pneumoniae isolated blaNDM-1 gene in all continents, except in the Americas (Table 3).

Although the blaNDM-1 gene isolated from K. pneumoniae in the American continent was not related to the present study (because the articles found did not meet the inclusion criteria), a study identified the first isolate of this gene in South America [83Escobar Pérez JA, Olarte Escobar NM, Castro-Cardozo B, et al. Outbreak of NDM-1-producing Klebsiella pneumoniae in a neonatal unit in Colombia. Antimicrob Agents Chemother 2013; 57(4): 1957-60.
[http://dx.doi.org/10.1128/AAC.01447-12] [PMID: 23357776]
]. However, data from the literature mainly demonstrate the presence of the gene in the Americas isolated from other enterobacteria other than K. pneumoniae. This occurrence demonstrates the ease of dissemination of this gene among different bacterial species by lateral transfer, especially in the Enterobacteriaceae family, as previously described [84Pereira PS, Albano RM, Asensi MD, Carvalho-Assef AP. Draft genome sequences of three NDM-1-producing Enterobacteriaceae species isolated from Brazil. Mem Inst Oswaldo Cruz 2015; 110(4): 580-2.
[http://dx.doi.org/10.1590/0074-02760150081] [PMID: 26061 151]
].

The propagation of NDM-1 shows some problems related to the occurrence of MBLs, which include: the absence of a routine standardized phenotypic test for MBL detection; the consequent high prevalence of unrecognized asymptomatic carriers, allowing international dissemination of these bacteria; the scarcity of effective antibiotics available today; and the possibility of their spread in many different gram-negative bacteria [81Rolain JM, Parola P, Cornaglia G. New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia? Clin Microbiol Infect 2010; 16(12): 1699-701.
[http://dx.doi.org/10.1111/j.1469-0691.2010.03385.x]
]. In addition to NDM-1 β-lactamase, other resistance genes have been identified in South Africa, namely: blaSHV-5, blaSHV-2, blaTEM-10, blaTEM12, blaCTX-M-2 and blaKPC-2, as described in (Table 4). In 2012, the occurrence of K. pneumoniae in South Africa with reduced susceptibility to carbapenems due to ESBL CTX-M was reported. In this study, the blaCTX-M-2 gene was identified in South Africa [55Paterson DL, Hujer KM, Hujer AM, et al. Extended-spectrum β-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type β-lactamases. Antimicrob Agents Chemother 2003; 47(11): 3554-60.
[http://dx.doi.org/10.1128/AAC.47.11.3554-3560.2003] [PMID: 14576 117]
, 76Brink AJ, Coetzee J, Clay CG, et al. Emergence of New Delhi metallo-β-lactamase (NDM-1) and Klebsiella pneumoniae carbapenemase (KPC-2) in South Africa. J Clin Microbiol 2012; 50(2): 525-7.
[http://dx.doi.org/10.1128/JCM.05956-11] [PMID: 22116157]
]. However, there was no isolation in Kenya (Table 4), as well as other types of CTX-M, originating from K. pneumoniae were not reported.

4. CONCLUSION

The content of the present study characterizes the relevance/importance of epidemiological knowledge related to mechanisms of resistance of β-lactam antibiotics associated with the microorganism Klebsiella pneumoniae from the analysis of scientific production. One of the results of great importance in this study is the coexistence of different classes of β-lactamases in the same strain, representing not only a therapeutic challenge but also a challenge in the diagnosis of infectious disease. Among the microbial resistance genes originating from K. pneumoniae and identified in this study, blaSHV-12 – which codes one of the most prevalent ESBLs - was the most frequent in Americas, Europe, and Asia, except in Africa. Otherwise, blaCTX-M-2 and blaSHV-5 genes, the second most reported, were found in all continents, characterizing their cosmopolitan distribution. The highest genetic diversity was observed in Asian and Oceania continents, where 41 different types of genes were reported. Additionally, the verification of resistance genes shows a variation over time and location, which highlights the importance of evaluating the mechanisms or strategies by which these variations occur. Finally, understanding the occurrence and distribution of these genes may generate possibilities of future interference in this process with the production of new drugs which are more efficient and specific, thereby providing results that allow assisting the health team in the most appropriate therapy.

Table 4
Association between genes of resistance to β-lactams, geographical areas of occurrence and clinical isolates in Africa.


CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This work was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro process no. E-26/201.577/2018 and E-26/201.185/2014. Conselho Nacional de Desenvolvimento Científico e Tecnológico (process no. 311422/2016-0, CNPq, Brazil).

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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