Central Annals of Clinical and Medical Microbiology

Review Article *Corresponding author Metin Doğan, Department of Microbiology, Necmettin Erbakan University, Turkey, Tel: 90 535 307 16 15; Fax: 90 Overview of b-Lactamases 332 2236384; Email: Submitted: 24 September 2018 and Current Techniques for Accepted: 16 November 2018 Published: 17 November 2018 ISSN: 2578-3629 Detecting Beta-Lactamase Copyright © 2018 Doğan et al. Mediated Resistance OPEN ACCESS Selin Uğraklı and Metin Doğan* Keywords • Beta-lactamase; ESBL; resistance; Department of Microbiology, Necmettin Erbakan University, Turkey Carbapenamases

Abstract Beta-lactam is a major antibiotic group that carries beta-lactam ring in the structure of . Beta-lactam antibiotics are divided into 5 basic classes as , , , and beta-lactamase inhibitors according to the beta-lactam ring side chains and other rings. All beta-lactam antibiotics affect by inhibiting the enzymes ( binding proteins, PBPs) involved in the cross-linking of the layer of the , which is depotentiated, and this leads to osmotic rupture. Beta-lactam antibiotics are one of the most common antibacterial agents used in the treatment of both community and hospital-acquired infections. Due to the widespread use of beta-lactam antibiotics, it is observed that bacteria also develop new resistance mechanisms and their resistance to these antibiotics is increasing. Beta- lactamases are the main responsible for resistance to these antibiotics and the failure of beta-lactam antibiotics in treatment. Therefore, beta-lactamase inhibitors have been developed and combined with beta-lactam antibiotics. These inhibitors are not effective all types of beta-lactamases. In addition, the discovered beta-lactamases are increasing day by day. Characterization of the beta-lactamase type is essential for the detection of the effective antibiotherapy. In this review, the classification of beta-lactamases, the methods used in laboratory detection of beta-lactamases and the current beta-lactamase inhibitors used in treatment will be discussed.

ABBREVIATIONS resistance to beta-lactams is through the production of beta- lactamase enzymes [3]. 6-APA: 6-Aminopenicillanic Acid; EUCAST: The European Committee on Antimicrobial Susceptibility Testing; MBLs: Metallo-Beta-Lactamases; EDTA: Ethylene Diaminetetra Acetic Acid particularlyBeta-lactam/beta-lactamase useful for the treatment inhibitor of combinations infections caused (BLICs), by organismssuch as - that produce beta-lactamases or -clavulanate, [5,6]. are INTRODUCTION BETA-LACTAMASES beta-lactam antibiotic, began with AlexanderFleming [1]. The The beta-lactamases breaks the beta-lactam ring and makes The history of penicillin, which was the first discovered beta-lactamases were intended by the name of the strain beta-lactams ring was the common structure in the developed orthe plasmid antibiotic that inactive produced before them, it reaches an example the PBP that targetInitially persists in cephalosporins,penicillin derivatives. monobactams, The beta-lactam carbapenems nucleus, are 6-APA located proved in the such enzyme names as PC1 or P99. In 1975, the application of beta-lactamto be the key antibiotic in penicillin group synthesis [2]. and modification.Penicillins, isoelectric focusing for beta-lactamase characterization allowed many more enzymes to be differentiated [7-9]. Beta-lactam antibiotics, whose mechanism of action is inhibition of the last stage of bacterial cell wall synthesis, are the largest family of antimicrobial agents and the most widely used in were facilitated by the use of DNA sequencing. While current clinical practice. Unfortunately, increasing resistance to plasmidThe characterization mediated enzymes and are classification generally expressed of beta lactamases in Gram- these antibiotics limits their utility [3]. Mechanisms of resistance

negativeorganisms basicly, chromosomally located inducible to beta-lactams contain the production of efflux pumps, the expression of beta-lactamases is also extensive [10,11]. modification or reduced production of outer membrane suggestsBeta-lactamases four distinct are molecular evaluated classes: by two A, basic B, C classifications and D based productionporins (in Gramof beta-lactamase negative bacteria), (an enzyme alterations able to of break Penicillin- down [12]. The molecular classification proposed by Ambler (in 1980 Binding Proteins (the molecular target of beta-lactams) and the Although classes A, C and D enzymes utilize serine for beta- on the amino acid sequencing and the conserved motifs [13]. beta-lactam ring) [4]. One of the primary mechanisms of bacterial Cite this article: Uğraklı S, Doğan M (2018) Overview of Β-Lactamases and Current Techniques for Detecting Beta-Lactamase Mediated Resistance. Ann Clin Med Microbiol 3(1): 1016. Doğan et al. (2018) Email: [email protected] Central

and early cefalosporin such as and cephalothin, lactam hydrolysis, class B metalloenzymes that require divalent subgroup 2b contain the TEM-1, TEM-2, and SHV-1 enzymes [19]. zincThe ions second (metal schemeion) for issubstrate named ashydrolysis Bush, Jacoby, [10]. and Medeiros and are strongly inhibited by and tazobactam. The Subgroup 2be: Include enzymes that are capable of functional classification, which groups different beta-lactamases correlatesaccording to the their beta-lactamases substrate and with inhibitor phenotypes profiles, in was clinical first inactivating third-generation cephalosporins (, isolatesattempted [13]. in Based 1989 and on the then differences improved among in1995. the This enzymes method in generationcefotaxime, cefalosporins and ) they are as named well Extended as monobactams Spectrum (). Because of their board activity against third an important reason for therapy failure with cephalosporins and these groups, they were further divided into several subgroups Beta-lactamases (ESBLs). Organisms that produce ESBLs proceed [14]. The three major groups of enzymes are described by their cephalosporinasessubstrate and inhibitor and profiles: broad spectrumgroup 1 cephalosporinases beta-lactamases that [21].have serious consequences for infection control [20]. Most ESBLs are not well inhibited by clavulanic acid; group 2 penicillinases, can be divided into three groups: TEM, SHV, and CTX-M types TEM types ESBLs: thatare generallyhydrolyze inhibitedpenicillins, by cephalosporins active site-directed and carbapenems beta-lactamase and phenotype. Although TEM-typeTEM-3, beta-lactamases originally reported are most in 1989,often thatinhibitors; are poorly and the inhibited group by 3 almost metallo-beta-lactamases all beta-lactamcontaining (MBLs) foundwas the in firstE. coli TEM-type and K. pneumoniae, beta-lactamase they that are displayedalso found the in otherESBL moleculesGroup 1 Cephalosporinase[14,15]. speciesSHV of type Gram-negative ESBLs: bacteria with increasing frequency [22]. Group 1 enzymes are cephalosporinases belonging to are shown under the amino acids of SHV-1[22]. molecular class C. AmpC enzymes encoded by both chromosomal Substitutions found in SHV-type derivatives • CTX-M type ESBLs: Because of its predominant acquiredand plasmid genes genes for are AmpC also enzymes,evolving to hence hydrolyze transferable broad-spectrum between activity and the location of its isolation species.cephalosporins These enzymes more efficiently. appeared in Transmissible Enterobacteriaceae plasmids that have lack (Munich) was named CTX-M. These enzymes are not chromosomal AmpC enzymes (Proteus mirabilis, Salmonella spp. ithvery these closely two related commonly to TEM isolated or SHV beta-lactamases and Klebsiella in that they share only approximately 40% identity like Escherichia coli and Shigella spp [16]. spp) or only express low basal level of AmpC [23]. CTX-M type ESBLs possess extraordinary high anotherhydrolytic genuine activity characteristic against cefotaxime of these than enzymes ceftazidime is that suchAmpC as beta-lactamases and ; are active oxyiminocephalosporins on penicillins but evensuch they[24]. areIn additioninhibited to better the rapidby the hydrolysis beta-lactamase of cefotaxime, inhibitor asmore ceftazidime, active on cephalosporins cefotaxime, and and . can hydrolyze They cephamycins are usually

• tazobactamSubgroup 2br:than byBroad-spectrum and beta-lactamasesclavulanat [25]. that [17].resistant to inhibition by clavulanic acid [15]. They have a high affinity for aztreonam, in contrast to the class A cephalosporinases • Subgroup 2ber: Contains TEM enzymes that combine an AmpC beta-lactamases encoded by chromosomal are have acquired resistance to clavulanic acid do not paytake to beta-lactam resistance, but in some organisms aminoextended acid spectrum substitutions with relative common resistance to both the to clavulanicESBL and (expressedSerratia marcescens, principally atCitrobacter very low grades.These freundii, Morganella enzymes morganii,generally acid inhibition. These group includesTEM-50, which had Providencia stuartii and especially Enterobacter cloacae inhibitor-resistant TEMs, was recently identified. This ) they can it also conferred a slight resistance to the expanded- spectrumenzyme was cephalosporins resistant to [26]. inhibition by clavulanate, but acidbe provaked ]. The indicuble under certainenzymes situations cause clinical such resistanceas the existence and failure of a beta-lactam [as amoxicillin, , , and clavulanic Subgroup 2c: These beta-lactamases are able to ofGroup treatment 2 Serine [18]. Beta-Lactamases as . These penicillinases are generally easily hydrolyze or at least % 60 as rapidly Functional group 2 beta-lactamases, containing molecular classes A and D, represent the largest group of beta-lactamases, inhibited• Subgroup by clavulanic 2ce: acid Includes or tazobactam the recently [15]. named extended-

Subgroup 2a: These beta-lactamases represent penicillinase due primarily to the increasing identification of ESBLs [19]. spectrum carbenicillinase RTG-4 (CARB-10) with • expandedSubgroup activity 2d: beta-lactamases against distinguished and by [27]. their ability to hydrolyze or and thereby activity. They are the predominant beta-lactamases in Gram- positive cocci. Subgroup 2a beta-lactamases are inhibited by subgroup are inhibited by NaCl. clavulanic acid and tazobactam. These beta-lactamases have are known as OXA enzymes. Many beta-lactamases in this insufficientSubgroup activtiy 2b: Comprises on cefalosporins. enzymes that hydrolyze penicilin • Subgroup 2de: Are cloxacillin or oxacillin hydrolyzing

Ann Clin Med Microbio 3(1): 1016 (2018) 2/6 Doğan et al. (2018) Email: [email protected] Central

enzymes with an extended spectrum that includes Ambler class B. MBLs are a group of featured enzymes that can

including . They are separated from the other oxyimino-beta-lactams but not carbapenems. OXA-11, serineinactivate carbapenemases most commonly by their used requirement beta-lactambased for zinc antibiotics ion to be OXA-14 and OXA-15 beta-lactamases are in this group. • Subgroup 2df: They have most often been found in Turkey and France. hydrolytic capability for monobactams and are not inhibited by used in their active site. The MBLs have insufficient affinity or type beta-lactamases2df beta-lactamases confer resistance are OXA to ampicillin enzymes andwith cephalothin.They carbapenem-hydrolyzing are characterized activities. by The their OXA- high clavulanic acid or tazobactam. The MBLs are inhibitedBacillus by cereus, metal Aeromonasion chelators spp. such and as EDTA S. maltophilia, and dipicolinic which acid.The are chromosomal first metallo- beta-lactamases identified and studied were hydrolytic activity against oxacillin and cloxacillin and enzymes found in opportunistic pathogenic bacteria [36]. The most common metallo-beta-lactamase families include arethe fact usually that producedthey are poorly by genes inhibited that areby clavulanic located on acid. the In Acinetobacter baumannii, OXA type beta-lactamases the enzymes VIM, IMP, GIM and SIM which are included in the

chromosome [28]. However, OXA-23 and OXA-48, which cassettes. These integrons can be easily transferred between by genes on plasmids [29]. various integron constructs in which they are included as gene have been identified in Enterobacteriaceae, are aquired bacteria by plasmids or transposons [37]. Rapidly spreading • Subgroub 2e: Characteristics of the subgroup 2e cephalosporinases include the ability to hydrolyze epidemiologically. The importance of metallo-beta-lactamases in extended-spectrum cephalosporins and to be inhibited by theantibiotic rapid spreadof resistance resistance is a major has recently problem increased. both clinically The newly and

the group 1 AmpC enzymes or with ESBLs because they mayclavulanic appear acid in or similar tazobactam. organisms They and can withbe confused comparable with identified New Delhi MBL 1 (NDM-1) is a novel member of this family that is capable of hydrolysing a broad variety of clinically important antibiotics [38]. resistance profiles. Subgroup 2e enzymes can be blaNDM-1 was a Klebsiella pneumoniae from a Swedish patient of The first bacterial isolate carrying the MBL later designated differentiated from AmpC enzymes by their poor affinity Subgroupfor aztreonam 2f: Include [30]. serine carbapenemases from ambler Indian origin who traveled to New Delhi and acquired a urinary tractThe infection bla-NDM-1 there [39,40] gene was found on a resistance- conferring genetic element that was easily passed on to other toclass hydrolyze A. Carbapenemases penicillins, cephalosporins,are beta-lactamases monobactams that have and the activity of hydrolyzing carbapenems. They have the ability carbapenems. This group enzymes can be inhibited better by resistance regions such as containing a gene encoding CMY- Enterobacteriaceae and that implicated a variety of other tazobactam than by clavulanic acid. a serine-based hydrolytic mechanism, whereas molecular class B NDM-14 (a broad-spectrum can hydrolyze beta-lactamase) all beta-lactams and except genes inactivating aztreonam. The beta-lactamases in which molecular classes A and D have ciprofloxacin, erythromycin rifampicin, and chloramphenicol. beta-lactamasesThe class A serine are all carbapenemases metalloenzymes contain with an the active-site NMC (for zinc. “not Bacterial infections producing NDM-1 are difficult to treat. There areSubgroup many antibiotic 4 resistances except [39,41]. metalloenzyme carbapenemase” ), IMI (imipenem-hydrolyzing incompletely characterized. beta-lactamase”), SME (for “Serratia marcescens enzyme”), This group contains enzymes that have as yet been chromosomallyGES (Guiana-Extended-Spectrum) encoded enzymes [31]. and KPC (Klebsiella DETECTION OF BETA-LACTAMASE-MEDIATED pneumoniae carbapenemase) . Of these, SME, NMC and IMI are RESISTANCE Recommended methods for detection of ESBLs in AlthoughKPC and KPCs GES are are associated plasmid-encoded with K. group pneumoniae, 2f enzymes. this Theenzyme first Enterobacteriaceae KPC-producing K pneumoniae isolate was reported in 2001 [32]. It is recommended ormandatory to determine the ESBL to [33]. KPCs are encoded by the blaKPC gene that interprets take infection precautions in many places.The recommended has also been identified in other several gram negative bacteria transitions between species. Global spring is largely explained method for detecting ESBL-producing Enterobactericae is based on non-susceptibility to indicator oxyimino-cephalosporins, may appear to be susceptible to imipenem and in followed the application of phenotypic tests. Broth dilution, agar by its location in the Tn3-type transposon, Tn4401 [34]. KPCs automated routine susceptibility testing, leading to misdiagnosis dilution, disk diffusion or an automated system can be used for ESBL-screening in Enterobacteriaceae. It is needed that both and making it difficult to diagnose. cephalosporins. KPC carbapenemases have been associated with outbreaks cefotaxime (or ceftriaxone) and ceftazidime are used as indicator especially in US [35]. Phenotypic confirmation methods due to multidrug resistant Gram negative bacterial infection, Subgroup 3 The common phenotypic methods are the combination

This group include MBLs which is is also classified in disk test (CDT), the double-disk synergy test (DDST), the ESBL Ann Clin Med Microbio 3(1): 1016 (2018) 3/6 Doğan et al. (2018) Email: [email protected] Central gradient test, and the broth microdilution test that based on

diameter < 25mm (with 10 µg disks) and MIC >0,125mg/L, the in vitro inhibition ofESBL activity by clavulanic acid are tomeropenem carbapenems screening in routine cut-off susceptibilityfor zone diameter testing; < 28mm phenotypic (with Combination disk test (CDT): The basis of this method is to recommended for ESBL confirmation [20,42]. methods10 µg disks) should and beMIC applied >0,125mg/L. to detect Isolates carbapenemases. of reduced sensitivity Combination disk testing: The requirements for the evaluate the inhibition zone around a disk of and around a disk of the same cephalosporin plus clavulanate. The test is positive if the inhibition zone diameter is ≥5 mm larger inhibitors.combination Class disc A test carbapenemases method are commercially are inhibited available by boronic from withDouble-disk clavulanic acid synergy than without test [43]. (DDST): Disks containing many manufacturers. The disks include meropenem ± several cephalosporins (cefotaxime, ceftazidime, cefepime; each of acid. Class B carbapenemases (MBLs) are inhibited by dipicolinic them 30 µg) are applied to medium either side of one containing acid and ethylenediaminetetraacetic acid (EDTA). There are no clavulanic acid (amoxicillin-clavulanic acid;containing 10 µg of appropriate inhibitors for OXA-48-like enzymes. OXA-48-like carbapenemase producers exhibit high resistance( >128 mg/L, anyclavulanate) of the cephalosporinpositioned at a disksdistance are of augmented 20 mm (centre or thereto centre). is a A positive result is indicated when the inhibition zones around zone diameter) to , but this is not specific enough to be a phenotypic marker The main disadvantage of CDT is that it Biochemical (colorimetric) tests: The CarbaNP test will ‘keyhole’ in the direction of the disk containing clavulanic acid takes a long time (overnight incubation) [45]. Gradient test method: [20]. yellow with phenol red solution. The test uses isolated bacterial ESBL gradient tests have been give rise to a pH-change resulting in a colour shift from red to developed in order to quantify the synergy between extended- spectrum cephalosporins and clavulanate. The test is positive if colonies and is based on in vitro hydrolysis of a carbapenem, ≥ eightfold (more than three doubling dilution steps) reduction imipenem. The advantages of the test are that it is rapid (<2hours) andCarbapenem cheaper than molecular inactivation methods method: [46]. The basis of this is evaluated in the MIC of the cephalosporin combined with method is to determine enzymatic hydrolysis by incubating a clavulanic acid compared with the MIC of the cephalosporin Interpreting results of the ESBL gradient test strips is delicate carbapenem with a bacterial suspension. andalone requires or if a phantom training. zone In addition, or deformed ESBL ellipse detection is present by gradient [43]. still not clear and it takes a long time. The main disadvantages of this technique that the negative predictive value of the test is test may fail when the MIC values for cephalosporins fall outside Detection of carbapenem hydrolysis with MALDI-TOF the Brothrange ofMICs microdilution: available on Mueller-Hinton the test strip [40]. broth containing serial twofold dilutions of cefotaxime, ceftazidime, aztreonam, With the use of molecular methods in the field of microbiology, An eightfold or greater decrease in the MIC of any of the or cefepime with or without clavulanic acid was prepared. there have been many advances in this area. As one of the important products of these advances that ’matrix-assisted laser cephalosporins in the presence of clavulanic acid was considered desorbtion / ionization time-of-flight mass spectrometry (MALDI- a positive result for ESBL. TOF MS) has been used in recent years to examine microbiological materials [47]. The basis is to determine in a mass spectrometry Indeterminate test results and false-negative test results appliance (MALDI TOF) the decrease or disappearance of definite testsmay resultbased fromon the the detection overproduction of cephamycin of AmpC hydrolysis beta-lactamases, or AmpC specific peaks of carbapenems in a mass spectra when a bacterial inhibitionwhich mask will the distinguish occurrence AmpC of ESBLs. beta-lactamases Phenotypic confirmatory from ESBLs. suspension is in advance incubated with the carbapenem. The method has been demostrated in various studies to have good hydrolyzed by AmpC beta-lactamases. Cefepime may be used in assaysensitivity are required and specificity for each [48].Thedrug–enzyme disavantage combination of this separately. tecnique allCefepime the CDT, (used DDST, as gradient indicator test cefalosporin) or broth dilution is generally test formats. not that optimization and standardization of the MALDI-TOF MS

Furthermore, it requires expert knowledge for evaluation Alternative approach contain use of cloxacillin, which is a good becauseCurrent the overview mass spectrum of carbapenemases of each antibiotic is different [49]. inhibitorGenotypic of AmpC confirmation: enzymes [44]. The globalemerge of carbapenem-resistant Enterobacteriace- Conventional polymerase chain approachreaction (PCR) would can be be of time great consuming help in and detecting exhaustive simultaneously due to the wide variety of mutations in ESBL-encoding genes. A microarray asae (CRE)one of has the become most urgent a major antimicrobial-resistance threat to public health. threats.The Centers The transmissionfor Disease Control of CPE andoccur Prevention by plasmids, have or recentlytransposons classified from perCPE- severalRecommended enzyme-encoding methods genes from a for single strain detection [44]. of son to person, with such transmission existing predominantly in carbapenemases in Enterobacteriaceae United States, it has emerge rapidly other countries including It- healthcare institutions. Since KPC was identified in 1996 in the preferredMeropenem in routine is the susceptibility carbapenem tests. which According provides to the EUCAST best balance of sensitivity and specificity and thus it is usually aly, Colombia and the United Kingdom. At present, OXA-48 is the most prevalent and is widespread in Klebsiella pneumoniae in methodology [46]; screening cut-off for zone Turkey, the Middle-East, North Africa and Europe. On account of Ann Clin Med Microbio 3(1): 1016 (2018) 4/6 Doğan et al. (2018) Email: [email protected] Central

- their point mutant analogues with ESBLs, OXA-48–type produc Functional Diversity of Extended Spectrum Beta-Lactamases,” Biomed 7. Zapun A, Contreras-Martel C, Vernet T. Penicillin binding proteins and ers are among the most difficult carbapenemase producers to be Research International. 2018; 18. characterised. Therefore, their true prevalence rates are difficult to estimate [50]. β-LactamsDocquier JD, resistance. Mangani S.FEMS An update Microbiol on Rev. 2008; 32: 361-385. Since NDM was first reported in India [41], the sequences of 8. β-lactamase inhibitor discovery Treatment of bacterial infections with the spread of NDM- 9. and Matthew development. A, Harris Drug AM, Resist Marshall Updat. MJ, 2018;Ross GW36:13-29.. The use of analytical producing18 NDM variants bacteria (NDM-19 around the unpublished) world is becoming have been increasingly reported. . J

isoelectric focusing for detection and identification of β-lactamases GenBush Microbiol. K, Jacoby 1975; G. Nomenclature 88: 169-178. of TEM lactamases. J Antimicrob difficult with antibiotics being ineffective. Unfortunately, very Chemother.1997; 39: 1-3. few reseach on NDM variants focus on animal-derived bacterial 10. 11. Jacoby GA. Nomenclature. Antimicrob Agents Chemother. describedisolates. NDM-17 in anEscherichia was discovered coli strain in an isolated E. coli strain from isolateda swine from[52]. a chicken [51]. Recently, a novel NDM variant, NDM-20, was β-Lactamase The current situation in global antibiotic resistance 12. 2006;Ambler 50: RP. 1123-1129. The structure of b-lactamases. Philos Trans R Soc Lond B

13. BiolFernandes Sci. 1980; R, 289:Amador 321-331. P, Prudencio, Cristina. : chemical The European Antimicrobial Resistance Surveillance Network (EARS-Net) has published its 2017 report with the β-Lactams structure, mode of action and mechanisms of resistance. Rev Med thatparticipation antimicrobial of data resistance from 30 Europeanremains a Union serious (EU) threat and in European Europe. Microbiol. 2013; 1: 7-17. Economic Area (EEA) countries. EARS-Net data for 2017 show -lactamases and its correlation with molecular structure. Antimicrob 14. Bush K, Jacoby G, Medeiros A. A functional classification scheme for β antimicrobial agents is especially important and is one of the single Agents Chemother. 1995; 39: 1211-1233. For invasive bacterial infections, prompt treatment with effective 15. -Lactamase. For Escherichia coli and Klebsiella pneumoniae, combined most effective interventions to reduce the risk of fatal outcome. Bush K, Jacoby GA. Updated Functional Classification of β 16. AntimicrobRodríguez-Ba Agentsño J, MirChemother.ó E, Villar 2010; M, Coelho 54: 969-976. A, Gozalo M, Borrell N, et al. Colonization and infection due to Enterobacteriaceae producing resistance to various antimicrobial groups was frequent, andK. plasmid-mediated AmpC pneumoniaeextended-spectrum than in beta-lactamase E. coli. While (ESBL) carbapenem production resistance was 17. β-lactamases. J Infect. 2012; 64:176-183. remainedextensive. rare Resistance in E. coli percentages were mostly higher in K. Pneumoniae (Figure Jacoby GA. AmpC beta lactamases. Clin Microbiol Rev. 2009; 22: 161- , several countries reported carbapenem 182.Bush K, Tanaka SK, Bonner DP, Sykes RB. Resistance caused by resistance percentages above 10% for decreased penetration of antibiotics into Enterobacter aeruginosa and Acinetobacter species, and at higher percentages 18. cloacae compared1.1). Carbapenem with K. Pneumoniaresistance was[53]. also common in Pseudomonas β-lactam 19. Matthew. Antimicrob M. Plasmid Agents mediated Chemother. 1985; 27: 555-556. DISCUSSION AND CONCLUSION bacteria: properties and distribution. J. Antimicrob Chemother. 1979; 5: β-lactamases of gram-negative whole world. If emergency measures are not put into practice, an Paterson349-358. DL, Bonomo RA. Extended-spectrum : a clinical Antibiotic resistance has reached levels that threaten the : 20. β-lactamases the spread of resistance and control of infections, countries need 21. update.Pitout JD, Clin Laupland Microbiol KB. Rev. Extended-spectrum2005; 18 657-686. beta-lactamase-producing increase in infection-related deaths is possible. In order to prevent Enterobacteriaceae: an emerging public-health concern. Lancet Infect is needed. In order to reduce the propagation of resistance genes, to establish urgent action plans and a global surveillance system we should also take steps to control the resistance in animal 22. Dis.Bradford 2008; PA. 8:159-166. Extended-Spectrum in the 21st Century: Characterization, Epidemiology, and Detection of This Important β-Lactamases food-borneREFERENCES reservoirs. 23. Resistance Threat. Clin Microbiol Rev. 2001; 14: 933-951. 1. : an emerging group of extended-spectrum enzymes. Int special reference to their use in the isolation of B. influenzae. Br J Exp Tzouvelekis LS, Tzelepi E, Tassios PT, Negakis NJ. CTX-M-type Fleming A. On the antibacterial action of cultures of a penicillium, with β-lactamases JChen Antimicrob Y, Delmas Agents. J, Sirot 2000; J, 14: Shoichet 137-142. B, Bonnet R. Atomic resolution 2. Pathol.Sheehan 1929; JC, Henery-Logan 10: 226-236. KR. A general synthesis of the penicillin’s. J 24. structures of CTX-M beta-lactamases: extended spectrum activities 3. Am Chem Soc. 1959; 81: 5838-5839. Inhibitors: An from increased mobility and decreased stability. J Mol Biol. 2005; 348: . 25. 349-362. Bush K, Bradford PA. Β-Lactams and β-Lactamase Bush K, Macielag MJ. New antibiotics and Overview. Cold Spring Harb Perspect Med. 2016; 6: a025247 outbreakBrandford of PA, Salmonella Yang Y, Sahmtyphimurium D, Grope I, Gardovska D, Storch G. inhibitors. . CTX-M-5, a novel cefotaxime-hydrolyzing β-lactamase from an 4. β-Lactam β-lactamase in Latvia. Antimicrob Agents 5. ExpertBeta-lactamase Opin Ther Pat induction2010; 20: and 1277-1293. cell wall metabolism in 26. Chemother. 1998; 42: 980-1894. Zeng X, Lin J. Robin F, Delmas J, Chanal C, Sirot D, Sirot J, Bonnet R. TEM-109 (CMT- 6. Gram-negativeRahman S, Ali T, bacteria. Ali I, Khan Front N, HanMicrobiol. B, Gao 2013;J, “The 4: Growing 128. Genetic and 5), a natural complex mutant of TEM-1 beta-lactamase combining the amino acid substitutions of TEM-6 and TEM-33 (IRT-5). Antimicrob Ann Clin Med Microbio 3(1): 1016 (2018) 5/6 Doğan et al. (2018) Email: [email protected] Central

27. AgentsPotron A,Chemother. Poirel L , Croiz 2005;é J,49: Chanteperdrix 4443-4447. V, Nordmann P. Genetic and Med.Raghunath 2010; 363: D. New 2377-2379. metallo -lactamase NDM-1. Indian J Med Res. Biochemical Characterization of the First Extended-Spectrum CARB- Type ß-Lactamase Acinetobacter baumannii. Antimicrob 40. β 2010;Yong 132: D, Toleman 478-481. MA, Giske CG, Cho HS, Sundman K, Lee K. , RTG-4, from 41. AgentsRamussen Chemotherapy. JW, Hø 2009; 53: 3010-3016. StructureCharacterization in Klebsiella of a New pneumoniae Metallo-beta-Lactamase Gene, bla(NDM-1), 28. iby N. OXA-type carbapenemases, J Antimicrob and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic 29. Chemother. 2006; 57: 373-383. Sequence Type 14 from India. Mediated Resistance to Imipenem in Klebsiella pneumoniae. AntimicrobPlatteel TN, Agents Cohen Chemother. Stuart JW, 2009; de Neeling 53: 5046-5054. AJ, Voets GM, Scharringa Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of Oxacillinase- 42. extended spectrum detection guideline in the routine AntimicrobBush K. Characterization Agents Chemother. of 2004;beta-lactamases 48: 15-22.. Antimicrob Agents J, van de Sande N, Fluit AC Multi-centre evaluation of a phenotypic Chemother. ; 33: 259-263. β-lactamase 30. Drieux L, Brossier F, Sougakoff W, Jarlier V. Phenotypic detection of 31. . Clin setting. Clin Microbiol Infect. 2013; 19: 70-76. 1989 extended-spectrum beta-lactamase production in Enterobacteriaceae: 43. Queenan AM, Bush K. Carbapenemases: the versatile β-lactamases 32. MicrobiolYigit H, Queenan Rev. 2007; AM, 20: Anderson 440-458. GJ, Domenech-Sanchez A, Biddle JW, reviewThomson and bench KS. Extended-spectrum-guide. Clin Microbiolbeta-lactamase Infect. 2008; 14:, 21-24. AmpC, and KPC-1 from a carbapenem-resistant strain of Klebsiella pneumoniae. 44. Steward CD, et al. Novel carbapenem-hydrolyzing beta-lactamase CarbapenemaseHartl R, Widhalm issues. S, J KerschnerClin Microbiol. H, 2010; Apfalter 48: P.1019-1025. Temocillin and meropenem to discriminate resistance mechanisms leading to 33. Bratu S, Landman D, Alam M, Tolentino E, Quale J. Detection of Antimicrob Agents Chemother. 2001; 45: 1151-1161. 45. KPC Carbapenem-Hydrolyzing Enzymes in spp. from Enterobacter Enterobacteriaceae decreased carbapenem susceptibility with focus on OXA-48 in Nordmann P, Poirel. ClinL, Dortet Microbiol L. Rapid Infect. detection 2013; 19: of Edition carbapenemase- 230-232. Brooklyn, New York. Antimicrob Agents Chemother. 2005; 49: 776- producing Enterobacteriaceae 778.Arnold RS, Thom KA, Sharma S, Phillips M, Kristie Johnson J, Morgan 46. DJ. Emergence of Klebsiella pneumoniae carbapenemase-producing . Emerg Infect Dis. 2012; 18:1503-1507. 34. 47. Doğan M. Use of matrix-assisted laser desorbtion / ionization time- 35. bacteria.Bradford SouthPA, Bratu Med S,J. 2011;Urban 104: C, Visalli 40-45. M, Noriel Mariano N, Landman of-flight mass spectrometry (MALDI-TOF MS)’ systems in virology. D, et al. Emergence of Carbapenem Resistant Klebsiella Species Altındiş M(Ed). Basic, Clinical and Diagnostic Medical Virology. Nobel Possessing Class A Carbapenem Hidrolyzing KPC-2 and Inhibitor Publishers: 2018; 419-25. öttcher A, Sleghel betalactamases F, Colonization of residents and staff of a longterm-care facility and 48. March A, Aschbacher R, Dhanji H, Livermore DM, B Resistant Tem-30 in New York. Clin InfectDis. 2004; 36. 39:Walsh 55-60. T, The emergence and implications of metallo- in adjacent acute-care hospital geriatric unit by multiresistant bacteria. Clin Microbiol Infect. 2010; 16: 934-944. β-lactamases (Basel) 37. Gram-negative bacteria. Clin Microbiol Infect. 2005; 11: 2-9. 49. Codjoe FS, Donkor ES. Carbapenem Resistance: A Review. Med Sci Liu Z, Wang. 2017; Y, 6:1. Walsh TR, Liu D, Shen Z, Zhang R, et al. Plasmid- Zheng F, Sun J, Cheng C, Rui Y. Resistant Gram-Negative Bacteria in blaNDM-17 Gene Encoding a Carbapenemase with Southern China. Microbial Drug Resistance. 2015: 21. 50. Escherichia coli Strain. Antimicrobial Delhi metallo- , Struct Mediated Novel 38. Green VL, Verma A, Owens RJ, Phillips SE, Carr SB. Structure of New Enhanced Activity in a ST48 β-lactamase 1 (NDM-1). Acta Crystallogr Sect F 51. 39. Moellering RC JR. NDM-1-A Cause for Worldwide Concern. N Engl J Agents Chemotherapy. 2017; 61: 02233-22316. Biol Cryst Commun. 2011; 67: 1160-1164. Metallo- Escherichia coli. Front Microbiol. LiuZ, LiJ, WangX, LiuD, Ke Y, Wang Y, et al. Novel Variant of New Delhi β-lactamase, NDM-20, in 2018; 9: 248.

Cite this article Uğraklı S, Doğan M (2018) Overview of Β-Lactamases and Current Techniques for Detecting Beta-Lactamase Mediated Resistance. Ann Clin Med Microbiol 3(1): 1016.

Ann Clin Med Microbio 3(1): 1016 (2018) 6/6