Antibiotics and antibiotic resistance in the environment

133 Pages·2016·1.79 MB·English

by  Amábile-Cuevas

Antibiotics and Antibiotic Resistance
in the Environment

Antibiotics and Antibiotic Resistance
in the Environment
Carlos F. Amábile-Cuevas
Fundacio´n Lusara,Mexico City,Mexico
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LibraryofCongressCataloging-in-PublicationData
Names:Amábile-Cuevas,CarlosF.,author.
Title:Antibioticsandantibioticresistanceintheenvironment/CarlosF.
Amábile-Cuevas,FundaciaˆonLusara,MexicoCity,Mexico.
Description:Leiden,TheNetherlands:CRCPress/Balkemaisanimprintofthe
Taylor&FrancisGroup,aninformabusiness,[2016]|Includes
bibliographicalreferencesandindex.|Descriptionbasedonprintversion
recordandCIPdataprovidedbypublisher;resourcenotviewed.
Identifiers:LCCN2015045076(print)|LCCN2015040185(ebook)|
ISBN9781315679419(ebook)|ISBN9781138028395(Hbk:alk.paper)|
ISBN9781315679419(eBook)
Subjects:LCSH:Antibiotics—Environmentalaspects.|Disinfectionand
disinfectants—Environmentalaspects.|Drugresistanceinmicroorganisms.
Classification:LCCTD196.D78(print)|LCCTD196.D78A4342016(ebook)|
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Table of contents
Preface vii
1 Definitions and basic concepts 1
1.1 Antibiotics:originsandactivity 1
1.1.1 Originandmechanismofactionofmainantibioticclasses 2
1.1.2 Antibiotics:chemicalwarfare,intercellularsignaling,
prebioticremains? 6
1.2 Resistance:Whatitisandhowwemeasureit 7
1.2.1 Resistancemechanisms,horizontalgenetransfer,and
adaptiveresponses 9
1.2.1.1 Threemainkindsofresistance:intrinsic,
acquired,andadaptive 9
1.2.1.1.1 Intrinsicresistance 9
1.2.1.1.2 Acquiredresistance 11
1.2.1.1.3 Adaptiveresistance:stressresponses 15
1.2.1.1.4 Adaptiveresistance?Biofilms 17
1.2.1.2 Co-selection:theplotthickens 18
1.2.1.3 Inter-moleculargenemobilization:thegene
“cut&paste’’bacterialkit 19
1.2.1.4 Horizontalgenetransfer:themainmeans
forresistancespread 21
1.2.1.4.1 Transformation 24
1.2.1.4.2 Transduction 26
1.2.1.4.3 Conjugation 28
1.2.2 Detectionofresistanceintheenvironment 30
1.3 Environment 34
1.3.1 Urbanenvironments 34
1.3.2 Ruralenvironments 36
2 Have antibiotics and antibiotic resistance genes always
been out there? 47
2.1 Naturally-occurringantibiotics(andtheirrespective
resistancegenes) 47
2.1.1 Knownresistancegenesfromknownantibioticproducers 48
2.2 Resistance genes of clinical relevance with known environmental
origins 49
vi Table of contents
2.3 Resistancegenesthatwerenot“meant’’forresistance 50
2.4 “Resistance’’genesunrelatedtoantibiotics,andnon-resistance
genesofrelevance 51
3 Human-related release of antibiotics into
the environment 57
3.1 Agriculturaluseofantibiotics 58
3.2 Wastewater 62
3.2.1 Earlyreleaseofantibioticstothesewage 63
3.2.2 Alongthewaytotreatmentorfinalrelease 63
3.2.3 Wastewatertreatmentplants 64
3.2.4 Releasefromtreatmentplants 65
3.3 Soils 65
3.4 Non-antibioticselectivepressures:heavymetals,disinfectants,
otherdrugsandbiocides 67
4 Spread of resistant organisms from human settlements
into the environment 73
4.1 Clinicalenvironmentstourbanenvironmentstoruralenvironments 74
4.1.1 Urbanwastewater 78
4.1.1.1 Wastewatertreatmentplants 78
4.1.1.2 Aftertreatment:releaseintowaterbodies 80
4.1.2 Resistanceinsoils 85
4.2 Resistantbacteriainanimals 86
4.3 Organisms,genes,routes:morethan“just’’resistance 90
5 Impact of antibiotics and resistance in non-clinical
settings 101
5.1 Immediaterisks 102
5.2 “Hotspots’’forresistanceselectionandHGT-mediated
rearrangements 103
5.3 Ecologicalimpactuponsoilbacteria 105
5.4 Potentialecologicalandclinicalimpactofresistanceinwildlife 108
5.5 Icebergtips,knownknowns,andunknownunknowns 110
5.6 Allthisisveryinterestingbut… 112
5.7 Concludingremarks 116
Subjectindex 121
Preface
Antibioticresistanceistrendyonceagain.Duringthelastfewyears,theWorldHealth
Organization,andtheUSandEuropeanCentersforDiseaseControlandPrevention,
have all issued reviews on the subject, and stern calls to do something about it. The
Infectious Diseases Society of America launched the 10ב20 initiative, calling for a
global commitment to have ten new antibiotics by the year 2020; even the US White
HouseissuedaNationalActionPlanforCombatingAntibiotic-ResistantBacteria.The
findingofanewantibioticproducedbysoilbacteria,somethingthatwouldhavebeen
publishedinanobscurejournal,ifatall,hadithappenedduringthelastcentury,ended
upasafullpaperinNature,andmostnewsoutletsworldwideafterwards.Isbacterial
resistance to antibiotics something new? Was its emergence unexpected? Is it out of
controlasneverbefore?Curiouslyenough,theanswertoallthreequestionsis‘no’.
Penicillin,theveryfirstantibiotic,haditsmajorclinicaldebutin1942;itwasused
onthevictimsoftheinfamousfireatthe“CocoanutGrove’’nightclubinBoston.That
veryyear,RammelkampandMaxonreportedthedevelopmentofresistanceinStaphy-
lococcusaureusafterlong-termculturinginincreasingconcentrationsofpenicillin;and
foundthesamephenotypeinfourclinicalisolatesobtainedduringthecourseofpeni-
cillin treatments (Exp Biol Med 51: 386–389). Three years later, Alexander Fleming
himself, in his Nobel Lecture, warned that it was “not difficult to make microbes
resistanttopenicillininthelaboratory’’,andthat“ignorantmen’’underdosingthem-
selves, would make microbes resistant to the drug. By 1981, antibiotic abuse was so
rampant,andantibioticresistancesocommon,thatStuartLevyfoundedtheAlliance
forthePrudentUseofAntibiotics.AntibioticresistancemadethecoverofNewsweek
inMarch, 1994(“Antibiotics–theendofthemiracledrugs?’’) and, halfayearlater,
of Time (“Revenge of the killer microbes – are we losing the war against infectious
diseases?’’).However,nothingspectaculardidhappenafterwards;mortalityratesdue
toincreasedbacterialresistancekeptrising,atacontinuousbutnotdramaticpace.It
wasn’tuntiltheendof2007,whena“18,650’’figureatthebottomofabusytablein
aJAMApaper,createdanewboomforresistance.Thatwastheestimatednumberof
yearly deaths caused by methicillin-resistant S. aureus, MRSA; that number, it turns
out, was larger than the yearly deaths caused by AIDS. It was shocking: an obscure
pathogen,unknowntomostpeople,waskillingmorethanthewell-knownHIV.Dur-
ing 2008, most US newspapers carried some information on antibiotic resistance at
least once a week; Dr. House had a patient infected by MRSA, and a crucial witness
inLaw&OrderdiedbecauseofanMRSAinfectionbeforetestifyingincourt.Butthe
viii Preface
MRSAcrisismoreorlesssubsided,onlytobereplacedbyCRE,carbapenem-resistant
enterobacteria.AntibioticresistanceisagaintrendypartiallythankstoCRE.
Antibioticsaredrugsand,assuch,mostpeoplebelievethattheyaremostlyusedto
treat ill people and other animals. Exposure of bacteria to such compounds should,
following this logic, occur only in clinical settings. Resistance hinders the ability of
antibiotics to effectively cure infections; other than that, in most people’s thoughts,
resistance has little or no impact. Therefore, resistance is defined not based on the
biologicalchangeenablingbacteriatosurviveandeventhriveinantibioticconcentra-
tionspreviouslylethaltothem;butonlyintermsofwhetherornotitcanberelatedto
therapeuticfailurewhenusingsuchantibiotic.Allthenotionsaboveareplaguedwith
misconceptionsthathadseriouslylimitedresearchonantibioticresistanceoutsidethe
clinical settings. Why would sub-clinical concentrations of antibiotics, and low-level
resistance,beofanyrelevance?Whylookforantibioticresistanceintheenvironment?
Who cares if an obscure bacteria from a lake, or from the gut of a wild animal, is
resistant to an antibiotic? It is the purpose of this book to answer those questions
anddispelthosemisconceptions.Thefieldofantibioticresistanceintheenvironment
is, however, hardly new: a paper dated more than 40 years ago, warned about the
dangersofhavingresistantcoliformsinwatersupplies,followedbydescriptionsofall
sortsofenvironmentalbacteriaresistanttothedrugsofthattime(e.g.,chlorampheni-
col, tetracycline, ampicillin, nalidixic acid). Looking at more recent papers, the only
things that have changed are the resistance figures (always higher) and the names of
antibiotics(alwaysstranger).ItfeelslikeAndréGidewasright:“Everythinghasbeen
said before. But since nobody listens we have to keep going back and begin all over
again’’.However,therehasbeenaninterestingtwistrecently.Thearrivalofpowerful
moleculartechnologiesenabledustolookforresistancegeneswithoutculturingbac-
teria(whichisimportant,aslessthan1%ofsoilbacteriahavebeencultured),andto
detect minute quantities of such genes. Using these technologies, a swarm of papers
reported resistance genes of all kinds in samples from soil, water, feces … even very
oldpermafrost.Thesepapersgavetherightnotionthatresistanceiseverywhereandis
ancient;butthisnotionbecamedistortedastosignifythatitisthereforenotworrisome
to find resistance to, for instance, a new, synthetic drug, in an enteric bacteria from
wildlife or a lake sediment. Something very akin to stating that climate has always
changed – therefore human influence is irrelevant, an argument so popular amongst
thosethatdonotunderstandthedifferencebetweenclimateandweather.Interestingly,
manyofthosepapersemergedwhenpeoplestartedtoworryaboutresistance,alarmed
also by the lack of new antibiotics – and by the lack of interest from pharmaceutical
companies to develop them; only to give room for the grim reports mentioned at the
beginning of this preface – including a forecast for a dramatic rise in yearly mortal-
ity due to resistance, from 700,000 to 10 million by 2050, along with a 100-trillion
US dollars GDP loss, now that everybody seems convinced of the need for financial
“incentives’’forpharmacompaniestoengageinantibioticR&D.Curioustiming.
Anyway, this book will ride the new wave of interest on antibiotic resistance. A
(disproportionatelylong)introductoryfirstchapterwillestablishworkingdefinitions
ofantibiotics,resistanceandenvironment,aswellasbrieflydescribetheknownmech-
anisms underlying resistance and its spread, and the methods used to investigate the
presenceofantibioticsandantibioticresistanceintheenvironment.Fromthere,itwill
reviewavailableevidenceofthecausesandmagnitudeoftheproblem;andwhyitisa
Preface ix
veryseriousproblemindeed.Iwouldtrytodosoinawaythatisaccessibleformost
readers, requiringonlybasicnotionsofeachoftheinvolvedtopics. Asthesubjectof
antibioticsandenvironmenthasrepercussionsonhumanandanimalmedicine,micro-
biology, ecology, public health, environmental protection, pharmaceutical discovery
andpolicymaking,tomentionafew,thisbookwilltrytoprovideabasicbackground
foreverybodytounderstanditscontent.Obviously,toachievethisgoal,somesections
willbeboringtosomereaders,andsomeoversimplificationswouldhavetobedone.
However, I hope that, at the end, all readers, regardless of their background, would
get the “big picture’’ behind the issue of antibiotics and antibiotic resistance in the
environment. This is, of course, a big task; and people do not undertake big tasks if
notaffectedbyabitofarrogance(i.e.,“anexaggeratedsenseofone’sownimportance
or abilities’’). So, I confess: I am writing this book believing that a training in phar-
macology, microbiology and molecular biology, a long time dealing with the clinical
sideofbacterialresistance,andsomerecentincursionsinthefieldofresistanceinthe
environment;alongwithalifetimeina–so-called–“developing’’country,doprovide
mewithenoughperspectiveandinsighttoconveyanintegratedviewofthisproblem.
Now,let’sseeifIcandeliver.
MexicoCity,September2015
Chapter 1
Definitions and basic concepts
Whenthinkingof“antibioticsintheenvironment’’,perhapsafirstimagethatcomesto
mindisaclandestinedumpingofantibioticsfromadrugfactoryintoariverinanon-
developed country; and when thinking of “antibiotic resistance in the environment’’,
thenaturalconsequencewouldbetothinkofanaquaticbacteriaundertheselectionof
thedumpedantibioticbecomingresistanttothedrug,andthencausinganoutbreakin
a neighboring town. The actual scenario is far more complicated and complex: com-
plicated,astherearemuchmoreelementsatplay;complex,astheinteractionsofthose
elementsaremanyandmulti-directional.Evenfromthesemanticpointofview,there
couldbeconfusionastowhatwecall“antibiotic’’,“resistance’’or“environment’’,so
itisimportanttobeginwithsomeworkingdefinitions.Althoughsomedefinitionsare
not unanimously agreed upon, it is crucial to frame the content of this book within
thosedefinitions,inordertoavoidmisinterpretation.
In addition to formal definitions, this first section will deal with some concepts
that are relevant and necessary to understand the reach and limitations of our cur-
rent knowledge of the topic at hand. What is the “role’’ of natural antibiotics in
microbial ecology? How is the definition of resistance limiting the perspective view
ofitsemergenceandevolution? Whataretheadvantagesanddisadvantagesofusing
molecular-based or culture-based techniques for assessing resistance in the environ-
ment?Manyoftheseissuesareclearlycontroversial,andtheauthor’sbiaswillbecome
clear; but by actually stating a position, it is hoped that the readers will be able to
reachtheirownconclusionsmuchmoreeasily.
1.1 ANTIBIOTICS: ORIGINS AND ACTIVITY
“Antibiotic’’,accordingtotheMerriam-Websterdictionary,is“asubstanceproduced
byorasemisyntheticsubstancederivedfromamicroorganismandableindilutesolu-
tiontoinhibitorkillanothermicroorganism’’.Thisdefinitionwouldencompassthings
likenaturalpenicillin(aproductofamold)andampicillin(asemisyntheticderivative
of penicillin); exclude entirely synthetic agents such as sulfonamides and quinolones;
and leave in a limbo drugs like chloramphenicol which, although initially discovered
asaproductofsoilbacteria,itisnowproducedentirelybychemicalsynthesis.Awider
definitionfromWikipediastatesthat“antibiotics[...]areatypeofantimicrobialused
inthetreatmentorpreventionofbacterialinfection’’,whereas“antimicrobial’’issim-
ply “an agent that kills microorganisms or inhibits their growth’’, which would also