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Superbugs are strains of bacteria resistant to several types of antibiotics. Their main characteristic is that they are capable of mutating their DNA throughout generations to become resistant to the most common drugs, which is why they represent a serious global health problem that has been contributed by the indiscriminate use of antibiotics, due to poor administration by the doctor, or by the self-medication to which the population frequently incurs, is added to this the pharmaceutical industry, the cattle ranch and the agriculture. Objective: To carry out an updated review on the “superbugs”, causes and mechanisms, and the importance of the emergence of a policy that regulates the indiscriminate use of antibiotics as well as the social and environmental factors that favor their emergence. Material and Methods: A bibliographic search was carried out in different databases on the subject of microbial resistance and referring to “superbugs”. Results: Only the most relevant original articles were used with respect to the subject in question, whose date of publication was lower 10 years ago and from them, the most pertinent information was extracted regarding the subject that concerns us. Conclusions: One must think about each and every one of the three causes that are at the origin of the problem (human, animal and industrial) with respect to the emergence of the “superbugs” since doing nothing will become one of the worst nightmares of Public Health in the years to come.
Keywords: superbusgs; multiresistance; antibiotic-resistance mechanisms
TheWorldHealthOrganization(WHO)describes“super bacteria”or“superbugs”asagroupofGram-negative bacteriathathavetheinnateabilitytoresisttreatments andhavetheabilitytotransmitgeneticmaterialsthat allowotherbacteriatobecomedrug-resistant[1].
MicrobiologyofAutonomousUniversityofGuerrero, Mexico.
Itisimportanttonotethattheterm“superbacteria” isnotsynonymouswithmultidrugresistancebecause withmultidrugresistancethereexistsachanceofdevelopinganewdrug,whilewhenitcomestoa“superbug” thereisnothingthatcanbedonetominimizetheireffects[2].InGeneva,onthe27thofFebruary2017WHO reportedtothepresstheresultsofresearchconducted byexpertsfromtheDivisionofInfectiousDiseasesat theUniversityofTübingen,Germany,reportingthat AntimicrobialResistanceisaseriousproblemthroughouttheworld,andrankedthepriorityofthebacteria havinganurgentneedfordevelopmentofnewantibioticsascritical,highormedium[1](Figure1showing multiresistance).
Superbugs,accordingtotheWHO,areresponsiblefor 700,000deathsannuallyintheworldrepresentinga lossofbetween2%and3.5%ofGDP.Shouldthistrend continueitisexpected10milliondeathsintheyear 2050[3]. InLatinAmericacountriessuchasBolivia, Cuba, Ecuador, El Salvador, Honduras, and the DominicanRepublicareworkinginpartnershipwiththe UnitedNationsOrganizationforFoodandAgriculture (FAO)withthepurposeofmitigatingtheemergenceof multidrug-resistantbacteriaandlimittheirspreadin thesectorsoffoodandagriculture.Thisorganization seestheemergenceofmultidrug-resistantbacteriaas one“moreurgent[threats]facinghumanitytoday”and constitutesapriorityproblemforpublichealth[4]. In Mexico, in 2010, the Secretary of Health (SSA) reportedthatupto60percentofMexicansshowedresistancetomajorantibioticsinthemarket,sothatinAugustofthissameyearbyanagreementpublishedinthe OfficialJournaloftheFederation(DOF)wasenacted forthesaleofantibioticundermedicalsupervisionand withaprescriptiononly[5].
Mexicoranksfifthamongcountrieswithahighriskof antimicrobialresistance.Accordingtostudiescarried out, E.Coli showedthehighestresistancetoaminopenicillins,Pakistanranksfirstwith93%,followedbyIndia with92%,China88%,Kenya86%andMexicowith85% [6].
“Superbugs”originatedduetoaseriesofphenomena ranging from inadequate medical prescription, selfmedication,andothercircumstancessuchastheagricultural practices and the generation of “superbug” throughthesoilandwaterbyusingthewastestreams assewage, animalmanure, andrunofffromagricultural. The environmentis also key inthe resistance toantibioticsbecausethebacteriathatareinthesoil, riversandseawatercandevelopresistancebycoming into contact with other resistant bacteria and disinfectingagentswhicharereleasedbecauseofhuman activity,therefore,humansandlivestockareexposed toincreasinglyresistantbacteria[6].
Theobjectiveofthepresentresearchistoperforman updatedreviewonthe“superbugs”causesandmechanisms,andthesignificanceoftheemergenceofapolicyregulatingtheindiscriminateuseofantibioticsas wellassocialandenvironmentalfactorsthatfavorthe emergenceofthese.
Abibliographicsearchwascarriedoutindifferentdatabases onthesubjectofmicrobialresistanceandrelatingto “superbugs”,apolicyofantimicrobialuse,environmental policies, pharmaceutical industry, agro-industry, andhospital-acquiredinfectionsorassociatedtohealthcare.Thesearchwasconductedinaframeworkofthe past10years.Textsthatmetahigherlevelofscientific evidencewereselected.Atotalof100articleswereobtained,ofwhich,accordingtotheinterestofthisarticle, only40wereselected,fromwhichtheinformationwas obtained.
Superbugsarestrainsofbacteriathatareresistantto severaltypesofantibiotics.Theresistancemaybeintrinsicaswithbacteriathatcarrygenesthatallowthem tosurviveexposuretoantibiotics,oracquiredthrough natural selection such as random changes or mutationsthatoccuringenesofindividualbacterialcells andthegenethatcarryantibioticresistanceispassed betweenbacteria.Theresultisthecreationofbacteriathatcarriesresistancegenestomultipleantibiotics, thesebacteriaareknownassuperbugsorsuperbacteria[7].
Superbugsareorganismsresistanttodifferentclasses ofantimicrobialstestedinthemicrobiologicalexaminations,includingtherestrictedusebytheCommissionofControlofInfectionHospital(CCIH)andtheconsideredofcontrolleduse,accordingtotheWHO;these multidrug-resistantmicroorganismsarethreateninga numberoftreatments,additionallytheyincreasethe timethatpeoplearesick,increasethemorbidityand mortality,andtheuseofcostlytreatmentstotheinstitutions[8].
Antibioticresistancecanbenatural(intrinsic),unique toeachfamily,genusorbacterialspecies,oracquired whichisvariableandtypicalofastrainofabacterial species.Thebacteriacanacquirethesemechanisms ofresistanceduetotheirgeneticvariabilityeitherby mutationsorbyhorizontaltransferofgeneticmaterial betweenbacteriaofrelated(ordifferent)species.The genescanbeencodedinthegeneticmaterial, chromosomalorextrachromosomal(plasmids).Thisresistanceistheonethatleadstothefailureofantibiotics [9].
The mechanisms of resistance to antibiotics can be groupedintofourcategories: • Enzymeinactivation:bacteriaexpressenzymes thatcancreatechangesinthestructureofthe antibioticcausingittoloseitsfunctionality.The mainmechanismofinactivationishydrolysis,as occurswiththeβ -lactamases,butnon-hydrolytic modificationscanalsooccur,suchasacetylation, adenylationorphosphorylationinactivatingthe antibiotic[10].
• Changesinthepermeabilityoftheoutermembrane:throughalterationsofbacterialmembranes resultinchangesinthelipidbilayerbyaltering thepermeability.Alterationsintheinputofantibioticsthatareenergy-dependent, orbythe presenceofeffluxpumpsthatincreasetheexpulsionofantibiotics[11].
• Overproductionoralterationofthetargetsiteof theantibioticforexample,thealterationsofthe PBPS(penicillin-bindingproteins)orhyperproductionoftheenzymedihydrofolatereductase. Theemergenceofnewmetabolicpathways:alternativeroutestothetargetsiteofactionofthe antibiotic. Althoughtherehavebeenmanyeffortstochemicallymodifytheformulationsof theantibioticstherealityisthattheevolutionof thedynamicsofthebacterialgenomeandthe acquisitionofnewgenesthroughprocessesof geneticrecombinationhasmadethisstrategy ineffectiveandinefficient[10].
• Effluxpumps.Operatebytakingtheantibioticin theperiplasmicspaceandexpellingittotheoutsidepreventingtheantibioticfromreachingits siteofaction.Thisisthemechanismfrequently usedforGram-negativebacteria[11].
At a genetic level bacterium can generate antibiotic resistanceasaresultofchromosomalmutationsand exchangeofgeneticmaterialfromotherbacteriaor phages(virusesthatusebacteriafortheirdevelopment andreproduction)throughmechanismssuchas[12].
• Conjugation: Exchangeofgeneticmaterialbetweentwobacteria(donorandreceptor)through asexualstrandorphysicalcontactbetweenthe twomediatedbyplasmids,conjugativeelements thathavethepropertytobetransferredfromone celltootherthankstoclosecontactbetweenthe twocellsthroughaporeofconjugationorsex pilus.Theplasmidsaremobilegeneticelements, circularinshape, andtheypossesstheability toself-replicateindependentofthebacterium. They possess gene cassettes coding for bacterialresistance[13].Theyalsoproducedeletions andgenemutationswhichoptimizethebacterial processes[14].
• Transformation:Thetransferorincorporationby abacteriumoffree-extracellularDNAoriginating fromthelysisofotherbacteria[14].
• Itisthetransferofgeneticmaterial,DNA,froma bacteriumtoanotherbyavirusthatinfectsbacteria(bacteriophage). Thisviruscanintegrate intothebacterialgenomeandwhentransferred toanothercellcancarrypartofthegenomeof thisbacterium,andsotransfersgenesincluding antimicrobialresistancegenes[13].
• Transposition: Movement of a section of DNA (transposon)thatmaycontaingenesforresistancetodifferentantibioticsandothergenecassettesworkingtogetherfortheexpressionofa particularpromoter[12].
Antibioticsthatbindtosedimentparticlesdelaytheir biodegradationandexplaintheirlong-termpersistence intheenvironment.Antimicrobialagentsareretained inthesoilbecauseoftheirassociationwithsoilchemicals[15].
Itisoftenassumedthathospitalsarethemostprominentsourceofintroductionofantibioticsandbacteria resistance to municipal wastewater, but it has been reportedthathospitaleffluentscontributelessthan 1%ofthetotalamountpresentandalthoughtheyare notthemainsourceofresistantbacteriaintheenvironmentaquaticenvironment,theydocontributeto thegenerationofthese[15].
Withinthisperspective,itisnotstrangetothinkthat hospitalsandmorespecificallytheirliquiddischarges exertaselectivepressureonthebiotapresentinthe recipientbodiesthatreceivethem,contributingtothe selectionofmicroorganismswithmultipleresistance patternstoantibiotics,andeitherbythepresenceof antibioticsinthedischargesorbythetransmissionof resistancefactorstowardsthebacteriafoundinsurface waters[16].
Thelevelsofconcentrationofveterinaryantibioticsin environmentalcontextssuchassoil, water, andmanure,aswellastheirdestinationandtransportinthe environment, bring a comparison of the ecotoxicity dataavailableinorganismsforsomeofthesedrugs [16].
Thebiggestrisktothehealthofconsumerssurroundingtheuseofantibioticsinanimalsisnotgivenbythe waste,butbythedevelopmentofresistanceinbacteriaofthesameanimals.Theseresistancescanleadto therapeuticfailuresinveterinarytreatments,andto theriskoftransferofresistantbacteriafromanimals toman,orofgenescarryinginformationthatencodes resistanceofbacteriafromanimalstohumanbacteria [17].
Theanimalandhumangastrointestinaltracthasbeen consideredastheplaceofchoiceforresistancetransfers. Otherniches,however,begintobeconsidered asofgreatimportance.Thus,theintestineofwildanimals(rodents),pets,andespeciallyfish;considering commercialfarmsfortheirproduction,theyrepresent placeswherethephenomenonwouldoccuronalarge scale[18].
Theuncontrolledadministrationofantibioticsinevitably leadstoresidualconcentrationsintheexcrement.Therefore,itisnotsurprisingtofindantibioticresiduesin agriculturalsoilseitherasametaboliteororiginalcompound in manure, fertilizer and later in agricultural fields[15].
Althoughthetransferofantibiotic-resistantmicroorganisms directly from animals to humans is known, therearen’tvirtuallystudiesdescribingthetransferof resistancetoantimicrobialstovegetablesoranimals rearedinplotstreatedwithsewagesludgewithanintermediate passage through the soil. However, this connection can be made when analyzing that feedingfromcropsandfieldstreatedwithurbansludge orfromanimalscontributestotheacquisitionofthese differentprofilesofresistances. Thepresenceofantibioticresistancegenesinagriculturalsoilstreated withsewagesludgemaybeabundant,althoughthe transfercapacityoftheseresistancesmaybeverylimited.Inthecaseofvegetablesgrowninthistypeofsoil, theonlyresistancetoantibioticsappearsintheplants whentheperiodoftimeindicatedbytheregulations isnotrespected,fromthetimethesludgeisapplied untilharvestingoccurs[19].
TheWHOclassifiedinthreecategoriesthebacteriathat urgentlyrequirenewtreatmentandthatareatriskof runningoutofone;givingthemthefollowingpriority designation:critical,highormedium(seetable1).The criticalprioritygroupincludesmulti-resistantbacteria, whicharealarmingpresentinhospitals,nursinghomes andamongpatientswhoneedtobetreatedwithdevices such as ventilators and intravenous catheters. Suchbacteriaincludethefollowing: , Acinetobacter Pseandseveral suchas domonas Enterobactericie Kleib- , , ,and .Theyarebacteria siella E.coli Serratia Proteus thatcancauseseriousandoftenlethalinfecions,such asbloodstreaminfectionsandpneumonia[1].
Thesebacteriahaveacquiredresistancetoahighnumberofantibiotics,suchascarbapenemsandthird-generation cephalosporins(thebestantibioticsavailabletotreat multi-resistantbacteria)[7].
Thesecondandthirdlevelsofthelist–thehighand mediumprioritycategories–containotherbacteria that exhibit in increased drug resistance and cause common diseases such as gonorrhea or salmonella foodpoisoning[1].
AnotherclassificationdevelopedbytheCenterforDiseaseControlandPrevention(CDC)organizesthesesuper bacteria according to the impact they cause on PublicHealthinthreelevels:urgent,seriousandworrisome. Microorganisms withan urgent threat level are Clostridiumdifficile, Enterobacteriaceae resistant tocarbapenem, Neisseriagonorrhoeae drug-resistant; thisgrouphasthepotentialtospreadinthepopulation andisaseriousthreattopublichealth,soitrequires measurestolimititsgrowth[7].
Microorganismswithaseriousthreatlevelare Acinetobacter multi-drugresistant, Campylobacter drug-resistant, Candida resistanttofluconazole,Extendedspectrum β -lactamases (ESBLs), vancomycin-resistant Enterococcus multi-drugresistant Pseudomonasaeruginosa, drug-resistantnon-toxic ,drug-resistant Salmonella Salmonella typhi,drug-resistant Shigella,methicillin-resistant Staphy- twogroups,CarOaandCarOb,whereCarObhasbeen lococcusaureus (MRSA),drug-resistant Streptococcus pneumoniae,drug-resistanttuberculosis(MDRandXDR). Thesearesignificantthreats[20].Somebacteriathough notcurrentlylabeledasurgenthavethepotentialto becomeanightmareifadequatepublichealthsurveillanceandpreventionarenotcarriedoutinatimely manner.Thesearethebacteriacategorizedastheworrisome level of threat such as vancomycin-resistant Staphylococcusaureus (VRSA), StreptococcusgroupA erythromycin-resistant,and clindamycin-narytractinfection,andsofttissueinfection.Thisspecies StreptococcusgroupB resistant[21].
Next,wewillbrieflyexplainthemechanismactionleadingthesebacteriatobeconsideredinthelistofglobal prioritiesofbacteriaresistanttoantibiotics.
ThemechanismofresistancetovancomycininenterococciisestablishedduetotheexistenceofninevancomycinresistantphenotypesthatcontainthevanA,B,C,D,E, G,L,MandvanNgenes.WithvanAphenotypebeing the most predominant worldwide. The mechanism ofactionofvancomycinactsbybindingtothedipeptide D-alanyl-D-alanine terminal of the precursor of thepeptidoglycan,thusinhibitingthesynthesisofthe cellwall. TheVanAproteinisaligasethat,insteadof synthesizingtheterminaldipeptideD-Ala-D-Ala,synthesizesD-Ala-D-lactatewithmuchloweraffinityfor vancomycin.27
Isresponsibleforinfections,suchassepsis,meningitis andurinarytractinfections,andthereforehasacquired greatimportanceinthecontrolofinfectionsbyhealth personnel[22].
Themechanismsofresistanceinvolvetheenzymatic degradationofdrugs,themodificationorprotection ofthepharmacologicalreceptoranddecreaseinthe permeabilityofprotonpumpsofantibioticsthatoften worksynergistically.Resistancetocarbapenemsin A. baumannii hasbeengloballyrelatedtonumerousenzymes,includingOXA-typecarbapenemase(OXA-51, OXA-23,OXA-24,andOXA-58)andMetallo-β -lactamase (IMPandNDM)[21].Oxacillinisa β -lactamgroupthat preferentiallyhydrolyzesoxacillinonbenzylpenicillin. Inaddition,theycaneffectivelyinactivateaminopenicillins,methicillinsand,toalesserextent,somefirstgenerationcephalosporins[23].
Thelossofmembranepermeability,duetochangesin theprimarystructure,orlossofCarO(outermembrane proteinassociatedwithcarbapenem),isclassifiedinto
showntobethedoubleofspecificforimipenemthan forCarOa[21].
Thesearecurrentlythecausesthatbestexplainthe resistancetocarbapenemicsof A.baumannii [21].
is one of the main oppor- Pseudomonas aeruginosa tunisticpathogensthatcausealargenumberofnosocomial infections, including sepsis, pneumonia, uri-
isfrequentlyisolatedinimmunocompromisedpatients whounderwentorgantransplantation,invasiveprocedure,immunosuppressivetherapyorintensivecare [24].
P. aeruginosa is one of the most important bacteria withdocumentedresistancetomultipleclassesofantimicrobials,includingβ -lactams,carbapenems,aminoglycosides,fluoroquinolones,andpolymyxins[25].Due toitisintrinsicandacquiredantimicrobialresistance, onlyafewclassesofantibioticsareeffectiveforthe treatmentof P.aeruginosa infections.Amongthevariousmechanismsofantimicrobialresistanceistheproduction of carbapenemase, one of the most importantmechanismsbywhich P.aeruginosa acquiresresistancetocarbapenemics.Manycarbapenemaseshave beenidentifiedin P.aeruginosa [26].
Amongthedifferentcarbapenem-resistantorganisms, carbapenemase-producing enterobacteria (CPE)are posingathreattoglobalhealthduetoitshastydissemination,madepossiblethroughthehorizontaltransfer ofgenes. Currently,thedrugsthataremostusedto treat Enterobacteriaceae (CRE)infectionsresistantto carbapenemonlyincludetigecycline,aminoglycosides andseveralolderantibioticssuchasFosfomycinand colistin[27].
MCR-1(“MobileColistinResistance”)isthefirstplasmidmediated colistin resistance gene that can be transferredhorizontallythroughplasmids.Thisgenecodes foraphosphorylethanolaminetransferase,whoseeffectisthemodificationofthelipidAofthebacterial outermembranethuspreventingtheinteractionofthe bacteriumwiththepolymyxins.Therelevanceofthis geneliesinitshighhorizontaldisseminationcapacity [26].
Table 1. WHOlistofprioritypathogensfortheI+Dof newantibiotics
,resistanttocarbapen- Acinetobacterbaumannii ems ,resistanttocarbapen- Pseudomonaaeruginosa ems Enterobacteriace,resistanttocarbapenems,producersofESBL
Enterococcusfaecium,resistanttovancomycin Staphylococcus aereus, reistant to methicillin, withintermediatesensivityandresistancetovancomycin Helicobacterpylori,resistanttoclarithromycin Campylobacterspp.,Resistanttofluorquinolones Samonellae,resistanttofluorquinolones Neisseriagonorrhoeae,reistenttocephalosporin, resisntanttofluorquinolones
Streptococcus pneumoniae, without sesivity to penicillin Haemophilusinfluenza,resistanttoampicillin Source:OwnelaborationfromtheWHOpublishesde listofbacteriaforwichnewantibioticsareurgently needed.
isamongthemaincausesofinfectionssuch E.faecium assepticemia,endocarditis,urinarytractinfections, woundinfections,neonatalsepsis,andmeningitis[27].
ThemechanismofresistancetovancomycininenterococciisestablishedduetotheexistenceofninevancomycinresistantphenotypesthatcontainthevanA,B,C,D,E, G,L,MandvanNgenes.WithvanAphenotypebeing the most predominant worldwide. The mechanism ofactionofvancomycinactsbybindingtothedipeptide D-alanyl-D-alanine terminal of the precursor of thepeptidoglycan,thusinhibitingthesynthesisofthe cellwall. TheVanAproteinisaligasethat,insteadof synthesizingtheterminaldipeptideD-Ala-D-Ala,synthesizesD-Ala-D-lactatewithmuchloweraffinityfor vancomycin[27].
Gram-negativeaerobicbacteriaisthecausativeagent of gonorrhea. Three genetic mutations cause a decreaseinsusceptibilityandchromosomalresistance tob-lactamantibiotics[28].
• The penA gene encodes changes in penicillinbindingproteinstype2PBP2(penicillin-binding protein2).Thisalterationinitsactivesiteleads toalossoftheaffinityofthisfortheantibiotic. AlterationsinPBP-2andinPBP-1decreasethe affinityforpenicillinandthesusceptibilityofthe microorganismtopenicillin[28].
• ThemtrRgenegeneratesonexpressedflowpumps thatexpelcytoplasmmoleculesfromtheb-lactams, especiallyceftriaxonemolecules,changingthis genecanalsostimulatethepenBmutation[29]. • ThepenBgenealterstheoutermembraneporins (porB1b), preventingthecephalosporinsfrom penetratingthebacterialcell[29].
Currently,thebacteriumhasgeneratedageneticvariation,themecAgene.Thisgeneallowsthebacterium tomodifythestructureofitspenicillin-bindingprotein (PBP2a),whichpreventsmethicillinfromadheringto thereceptor,thuspreventingthedrugfromactingto blockthetranspeptidaseenzyme,preventingthebacteriumtheabilitytoformthebacterialwall.ThismechanismgivesStaphylococcusaureusresistanceagainst semi-synthetic penicillins (Methicillin and Oxacillin) andfirstandsecondgenerationCephalosporins[26]. Somestrainsof S.aureus havedecreasedtheirsensitivitytomethicillinduetotheincreaseintheproductionof β -lactamases,whichincludethemodificationof PBP.ThisgrouphasbeencategorizedasGoldenStaphylococcuswithResistancelimitedtoOxacillin(BORSA for its acronym in English). This group has little response to treatment with semi-synthetic Penicillins and cephalosporins but does respond to Imipenem (Carbapenem)[25].
Theresistanceofthisbacteriumisrelatedtoachange inthestructureoftheSubunit(23SrRNA);sincethis subunitisthepharmacologicaltargetofclarithromycin. Thestructuralchangeof23SrRNAisduetoasingle nucleotidepolymorphism(SNP)ofthe23SrRNAgene [30].
Themechanismofresistanceformutations(adenine → guanine, adenine → cytokine) at positions 2142 (A2142G,A2142C)and2143(A2143G)areassociated withthelossofbindingofclarithromycintoribosomes.31 Atpresent, thisisofgreatimportanceinthephenotypicdeterminationofresistantstrainsbymeansof PCR”[31]
Thefirst-lineantibiotictreatmentintheUSfor salmonella isusuallyciprofloxacin,athird-generationcephalosporin orfolicacidpathwayinhibitorscanalsobeused.FluoroquinolonesinhibittwobacterialenzymesDNAgyraseandtopoisomeraseIV,theseplayanimportant roleinDNAreplication. Theternarytopoisomerasequinolone-DNAcomplexleadstothegenerationofa doublestrandofDNA;quinolonesblocktheprogress ofDNAreplicationinthisenzymecomplex,resultingin bacterialDNAdamageandbacterialcelldeath[32]. Mostofthesemutationsoccurinthequinoloneresistancedeterminingtheregion(QRDR).Mutationsinthe QRDRsofthesegenesmayconferreducedsusceptibilityorresistancetofluoroquinolones,dependingonthe numberofmutationsacquired.Asinglepointmutation inthechemicalconformationofthisregionconfersresistancetonalidixicacidanddecreasessusceptibility tociprofloxacin.Twoormoremutationsinthegeneor othergenesofthetopoisomerasecanconfercomplete resistancetociprofloxacin[33].
Thepneumococcalresistanceto β -lactamshasbeenattributedtotheexistingalterationsofpenicillin-binding proteins(PBP).Thefirstisolatedcaseofpneumococcusresistanttopenicillinwasreportedin1967froma patientinAustralia,latermorecasesofresistant pneumococci havebeendescribedaroundtheworld[34]. β -lactamantibiotics exert theirbiologicaleffectsby interactingwithPBPs. Currently,theresistanceof βlactamsinpneumococciismediatedbyalteredPBPs, specificallyPBP1a,PBP2x,andPBP2b.Thisincreasein resistancetoantibioticshascometopresentahealth probleminplaceslikeMorocco[34].
The H.influenzae bacteriumencodesfourPBPs, the oneresponsibleforgeneratingresistanceagainstampicillinisthePBP3mutationencodedbytheFTSLgene, whichinturnincludesseveralmutationsaroundthe functionalareasoftheproteinpresentingfourtypes ofmutations. Themainmutationsthatconferresistancearethosethatdecreasetheaffinityintheunion betweentheampicillinmoleculesandthePBP,even generatingresistanceagainstcephalosporins;dueto this,theprevalenceofreportedcasesof H.influenzae resistanttoampicillinindifferentpartsofAsiahasincreased[35].
Aspreviouslymentioned,thegeneticmechanismof the pharmacological resistance of this bacterium is commonlyattributedtomutationsinthequinolone resistancedeterminingregion(QRDR),whichinUltimately,theinteractionbetweentheantimicrobialand itstargetdecreases[33].
Resistancetofluoroquinolonesleadsustoincreasingly reducedtreatmentoptions,placingthosepopulations thatarevulnerabletopresentahigherriskofcomplicationscausedbythisbacteriumandhinderingthe efficientmanagementofoutbreaks.Theseresistance factorshaveplaced Shigella strainsresistanttofluoroquinolonesinthegloballistofprioritypathogensthat urgentlyneedantimicrobialdevelopment[34].
AccordingtostudiesconductedbyaspecialistinEurope,infectionswithsuperbacteriaresistanttomultipleantibioticskillabout33,000peopleeachyearin thatnation.Itisestimatedthatabout70%ofthebacteriathatcancauseaninfectionarealreadyresistanttoat leastanantibioticthatiscommonlyusedtotreatthem. Thishasledtotheevolutionof“superbugs”,whichcan evade one or multiple medications. It is one of the biggestthreatsfacingmedicinetodayduetovariations inthenumberofcasesandtypesofantibiotic-resistant bacteria that cause infections in different countries, preventionandcontrolmeasuresmustbeadjustedto nationalsituations[36].
In2015WHOlaunchedthealertinthissituation,immediatelyengagedinthisprojectwerethousandsof scientistswhodefinedaGlobalActionPlanonantimicrobialresistance.Thiswastheofficialstartingpoint tolaunchvariousstrategiesthatmanagedtoreversea situationthatclaimsmillionsoflivesayear[37].
Theunnecessaryuseofdrugssuchasantibioticsmakes thebacteriadevelopmoreandmoreresistancetothe pointofbecomingakindofunbeatable“superbugs”or “superbacteria”.TheseareparticularlydangeroustopatientsadmittedtotheIntensiveCareUnit,withchronic diseases,surgicallyintervened,sincegeneralpeople withdiseasesoftheimportantbasewhenacquiringa multi-resistantbacterialinfectiontakeslongertoheal becauseitismoredifficulttotreat[38].
Awareoftheseriousnessoftheproblem,boththeWorld HealthOrganizationandthecountriesmostaffectedby thisglobalproblemhavelaunchedmajorawareness campaigns in recent years with the aim of reducing theabuseofantibiotics.However,despitenumerous internationalandnationalefforts,thepresenceofresistantbacteriainMexicoCity,wherethepresenceof Helicobacterpylori,causinggastriccancer,hasbeen alerted,in2005,asourceofsupplyfromXochimilco wasrecordedbytheInstituteofEcology.Inaddition, in2014 Vibriocholerae wasidentifiedinawellinthe SierradeHuejutla,Hidalgo,Mexico[39].
The bacteria Vibrio cholerae and Helicobacter pylori havethecapacitytodevelopastateofresistancewhen presentedinanaqueousmediumasasurvivalmechanismoriftheyareinanadverseenvironment.Thus, theyremainactive(metabolism,respiration,infective capacity,genetictranscription,proteinsynthesis,and biomassproduction),buttheyarenotabletoreplicate inaculturemedium, whichimpactsthewaterqualitytestsandgeneratesimprecisioninthetraditional modesofpathogenmeasurement,falsenegativesand anunderestimationoftheirpresence[39].
In2010theconsumptionofantibioticsinMexicoamountedantimicrobialresistance: wemustthinkabouteach to70.5millionboxesperyear, ofwhichtheauthoritiesestimatedthataround40percentwasduetoselfdiagnosisandself-prescription. Thatyear,itwasdecidedthatthistypeofmedicinewouldonlybesold undermedicalprescription,butafter24monthsofthe implementation of that measure, consumption had beenreducedmuchlessthanexpected[40].
InthestudyAsymptomaticcarriersofresistantmethicillinStaphylococcusaureus(MRSA)infishermenand horticulturistsinGuerrero,Mexicodetectedfrom57 fishermenand50horticulturists,onlyfourMRSAThey were detected due to resistance to oxacillin and beingcefoxitinpositive.Fromtheresultsobtainedfrom 57fishermen and50 horticulturists, only fourMRSA strainsweredetectedinfishermen;detectionofthese strainsintheenvironmentcouldbeimportant. The presenceof S.aureus isofepidemiologicalsignificance sinceitcanbetransmittedfrompeopletopeople,food handlersthatcarry,sinceS.aureus,producersofenterotoxins,causefoodpoisoning[41].
As a strategy, and in conjunction with international organizations, MexicopublishedthisJuneintheOfficialGazetteoftheFederationtheNationalStrategy ofActionagainstResistancetoAntimicrobials,which intendstoperformaworkfortheconsciousandresponsibleuseofantimicrobialsforthehealthofhumans,animalsandcropsinordertoreducethespread ofresistancetoantibioticsindifferentsectors.Strains detectedinthehospitalenvironmenthaveanegative impactonthehealthofhospitalizedpatients;therefore,microbiologicalenvironmentalmonitoringand the strategies implemented help maintain a higherqualityhospitalenvironmentandpotentiallyreduce theriskofpatientsdevelopinghealthcare-associated infections(HAIs)[42].
Finally,“theimportanceofenvironmentalmicrobiologicalmonitoring,inwhichsamplingtakenmostlyin intensivecareunits,operatingroomsandotherhospitalareasconsideredhighriskfromdifferentsurfaces, showthatthemicroorganismsfoundareofrisktohealth, the microorganisms identified are mostly Staphylococcusaureus, Acinetobacterbaumannii, Paeruginosa, Klebsiellapneumoniae, Staphylococcus coagulase, Kytococcusspp and Cladosporiumspp, Penicillium and Aspergillusspp,recommendcontinuousmicrobiological monitoringtoidentifytimelycleaninganddisinfection toavoidcrossinfectionsandmulti-resistantstrains” [43].
Thesituationisclearwhenitcomestothefightagainst
andeveryoneofthethreecausesthatareattheoriginoftheproblem(human,animalandindustrial)if wedonotwanttofight.Ithasalreadybeenobserved thatgettingthepharmaceuticalsectortoassumeits responsibilitiesbecomesadifficulttaskandthatboth theinstitutionalpreventioncampaignsandtheinformationfocusarefocusedonthemisuseofantibiotics bydoctorsandpatientsandintheabuseofantibiotics inintensiveagriculture.
Declarationofconflictofinterest. Theauthorsdeclarethatthereisnoconflictofinterestforthepublicationofthisarticle.
Artificialintelligence. Theauthorsdeclarethatno artificialintelligencewasusedinanyofthesections.