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REVIEW

MED JOUBNAL;I5(2)53-67 r-ir,A]lt,Al{l -r-ltE- ZX)3

Antinibticresistancein bacteria an emergingpublic health problem 0OKomolafe Departmentof Microbiology, Collegeof MedicineUniversityof Malawi,P,/bag360'.Blantyre3 fax no: +265- 1 - 672644,tel: +265- 1 - 671911 e-mail: [email protected],

The discovery and eventual introduction of anti'microbial agents to clinical medicine was one of the greatest medical triumphs of the twentieth century that revolutionized the treatment of bacterial diseases. However, the gradual emer' gence of populations of antibiotic-resistant bacteria resulting from use, misuse and outright abuse of antibiotics has today

Abstract

become a major public health problem of global proportions. This review paper examines the origins and molecular epidemiology of resistance genes' global picture of antibacterial resistance, factors that favour its spread, strategies for its control, problems of control and the consequencesof failure to contain antibiotic resistance in bacteria-

intrinsic resistanceis a naturally occurring trait arising from the resistance in The discovery of antibiotics must surely rank-asone of the great- biology of the organism e.g. vancomycin occurs when a bacterium est medical triumphs of the twentieth century. Starting with the Escherichia coli1), acquitedresistance develops resistintroduction into medical practice of the sulphonamidesin the which was previously sensitive to antibiotics or by acquisition of i930s, penicillin and streptomycinin the 1940s,the broad spec- ance. This frequently happensby mutation as the commonest trum bacteriostatic antibiotics during the 1950s, followed by new DNA(e). Mutation is now recognised in bacteria especially in bactericidal antibiotics in the 1960s,together with other impor- mechanism of resistancedevelopment and it occurs regardless of tant synthetic chemicals and highly specific narrow spectrum Mycobacterium tuberculosls('o) genesproduced in the antibiotics during these years, one might have thought that the whether antibiotic is present. Resistance in-contact individuals to transferred and replicated are process of bacterial stagehad been set for revolutionizing the treatment in the emergence of resulting transposons and plasmids via was however, diseases(').Steadilytrailing these developments, now been identifred has which tuberculosis, resistant multi-drug bacthe gradual emergenceof populations of antibiotic-resistant countries("). 100 over in antibiotics teria occasionedby use, misuse and outright abuseof have developeda diverse array by humans such that drug-resistantbacteria has today become a In addition to mutation, bacteria for ensuring the evolution systems genetic and biochemical of major global public health problem. These include resistance(7). of antibiotic dissemination The phenomenonof antimicrobial resistancehas prompted two and with the target react not it does that such modification WHO meetings in the last four years, the United StatesInstitute antibiotic cleave enzymatically which in b-lactamases occurs as such of Medicine occasioned a report on emerging infections by site inacantibiotic the rendering ring, b-lactam four-membered and it has also been debated by the antimicrobial resistance(2) tive(t'). British House of Lords€). Within the last two yearsthe European bacteria may protect the target Union has conveyedthree scientific sessionsin addition to sev- In some cases,antibiotic resistant uptake and/or a quick antibiotic reducing by action review of antibiotic eral review arlicles on antimicrobial resistance.(4-6)This antibiotics and Gram b-lactam between happens it, as of article is an attempt to draw attention to an emerging public efflux antibiotic action the target Furthermore, bacteria(to). health problem that may negatively impact healthcare delivery negative e'g' the ineffective antibiotic the rendering thus altered be particularly in developing countries should the situation be may to cephalosporins(tt). of enterococci resistance allowed to escalate. The final mechanism by which bacteria may protect themselves of an alternative target Originsand molecularepidemiologyof resistance from antibiotic action is the production by the antibiinhibition to resistant is that (usually an enzyme) genes sensioriginal the produce to continue Antibiotic resistanceshould be defined in terms of clinical out- otic while the organisms of selecthe face in survive to bacteria allows This come rather than by laboratory methods(t)and in the medical in tive target. antibithe of effect the bypasses enzyme alternative vlvo setting therefore, a resistant microbe is one which is not tion as the is the alternativepenicillin buildkilled by an antimicrobial agent after a standardcourse of treat- otic. The best-known example in addition to the normal produced (PBP2a) is which ment(8). The use of antimicrobials for any infection, real or ing protein methicillin resistant by proteins feared, in any dose over a period of time, forces microbes to penicillin building not uncommon however It is (MRSA). adapt or die (selectivepressure)and it is the surviving microbes Staphyloccoccusaureus these mechaof one than more which carry drug resistancegenes which may be transferred to to find a bacterium exhibiting other strainswithin their own genusand speciesand acrossthem nisms(t). Clinical resistanceis therefore even to other unrelated species(t). a complex phenomenoninvolving interaction between the type Globalpicture of antibacterialresistance of bacterium, its location in the body, the distribution of the Resistanceto antimicrobials is a global problem with geographantibiotic in the body and its concentration at the site of infec- ical variation. Acquired bacterial resistanceis common in isotion, and the immune statusof the patient(7). lates from apparently healthy but carrier individuals and from Resistancein bacteria can be intrinsic or acquired. While

lntroduction

Malawi Medical Journal

&rttfiurhiotuf, Fesistance in bacteria

I _-_: I ":'n :Lh.Lrrnmunitr-acquiredinfectionsin both developedr+rused for human therapy in 1994,24000kg of active avopammr ..-: i.,,;lurprin: countries particularly where the demand for (vancomycin equivalence in veterinary practice) was used "rr ::-:lr,li.s is driren b1' high incidenceof infectious disease('2).feed additivesfor animals('?7). In Austria, between 1992 and 1996^ f :: ir are increasingly S:'. .,1';-parho,sens developingresistance, an annual average of 582kg of vancomycin was imported fcrr ::nicularlr to trrst-line inexpensivebroad-spectrumantibiotics medical pulposes and 62,242kg of avoparcin for animal huiT;b,le I r. uhile the introduction of new drugs (e.g. fluoro_ bandry(T). As expectedvancomycin resistantEnterococcus faequrnolones)has been relatively quickly followed by the emer- cium (VRE) of animal origin has been detected in humans} ,senceand disseminationof resistant strain(rs).As resistance through consumption of contaminated meat(2e.303') thus makins ,lelelops. outbreaksoccur which may result in high mortality. the treatment of theseinfections, difficult. When avoparcin u ar. -\cute respiratorytract infections,for example,cause3.5 million bannedin Denmark (1995), Germany (1996) and rhe whole of deathsin childreneachyearrr6) and the most importantpathogens EuropeanUnion countries(1997), the net effect was a dramaric associatedwith pneumoniaparticularly in pre-schoolchildren reduction in the incidence of VRE, in humans(rr)suggesting thar are Haemophilus influenz.ae and Streptococcus pneumoniae. antimicrobial resistancecan be controlled through prudent use Penicillin resistantpneumococci were first reported in Australia of antibiotics.(33) and PapuaNew Guineain the 1960s(,')and are now worldwide in distribution. In a study of carriage of pneumococci in Misuse of antibiotics by physicians Malawian children,22Voand237oof clinical and cariage pneu- Misuse of antibioticsby physiciansis commonplaceand worldwide('*)especiallyin the intensivecare unit (ICU) in hospitals mococci isolateswere found to be penicillin resistant(,8). Typhoid is also endemicin the developingworld where an esti- which are fast becoming a breeding ground for the development mated 16 million cases occur each year resulting in some and spreadof antimicrobial resistancedue to exposureof heavl' 700,000deaths('e). Unfortunatelymultidrug resistantSalmonella antibiotic use in a high density patient population(35).When n'phi emergedin 1987 and has spreadthroughout the Indian sub- patients are discharged to continue medication at home, it furcontinent, south east Asia, and sub-saharan Africa(r0). ther facilitates antibiotic resistance spread to other in-contact Furihermore, in two separatestudies on non-typhoidal salmo_ humans. nellae (NTS) bacteraemiain Malawian children, in vitro resist- The unnecessaryprescription of antibiotics seen in industrialalthough for different reasons has also been ance to the commonly availableantibiotics was J6Vo and 79Vo ized nations(313637) (ampicillin), 72Vo (co-trimoxazole),TlVo (timethoprim - sul- documentedin many developingcountries.(3e3e) While the overfamethoxazole) and 557o (gentamicin) while an increasing use of antibiotics in developedcountries(33) among other reasons is patient-driven, in developing countries where laboratory diagresistance(207o)to chlorampenicolwas also observed.(2r:2) Isolates from burn patients have not been sparedfrom the con- nostic facilities are scarce, this has led to the introduction of sequencesof the development of antibiotic resistance,in fact; empiric, pragmatic and problem oriented managementstrategies immuno-compromised burn patients, who receive multiple for the administration of antimicrobials which inevitably results thus placing antibiotic-resistantbacteria at a antibiotics are essentially incubators for antibiotic resistant in over treatment('e) strains which can manifest rapidly€r. For example, susceptible competitive advantage. Either way there is need for physicians Enterobacternotoriously generatesresistanceto third generation to prudently use/prescribeantibiotics to stem the tide of drug cephalosporinseven within a single courseof treatment(ra). In a resistancein bacteria. recent study(")of the bacteriology of burns in the Burns Unit at Misuse by unskilled practitioners and general public the QECH, Blantyre, a general broadspectrumresistance(< This is a major problem in developing countries where qualified 1A0Vo)to panelsof antibioticsused was observedin 20Voof all and well-trained health personnel are scarce and ill-trained or bacterialisolates. self-trainedquacks paradethemselvesas medical personnelin Even more alarming has been the emergenceof multidrug resist_ rural areas(a0). While many of them are semi-literates,do not preant tuberculosis, spreadingrapidly and threatening to spiral out serve their drugs appropriately, are unaware of the deleterious of control(11). The HIV/AIDS pandemic,acting as a catalyst,has effects of antibiotic misuse and care less about inappropriate increasedthe impact of tuberculosisand may have led to a gradprescription, they seem to have an antibiotic for every human ual increasein resistanceto antituberculosisdrugs. In Russia, ailment(a).For example,pharmacytechniciansin Thailand preEstonia and other hotspots,spanningover 100 countries scatscribe rifampicin for urethritis and tetracycline for young chiltered round the world, the multidrug resistant tuberculosis dren(") while their counterparts in Nigeria and elsewhere pre(MDR-TB) is reachingunprecedented heightsr"r.While TB and scribe antibiotics for headache,dyspnoeaand to prevent sexual- MDR-TB have traditionally been viewed as a scourge of the ly transmitted diseasesamong prostitutes(a2.a3). In these and other poor, a study commissionedby philanthropist George Soros developingcountries,self medicationis common and antibiotics Open Society Institute has traced the spreadof MDR-TB not to are readily available acrossthe counter in pharmaceuticalstores, the peri-urban slums of the third world but to Westem Europe market stalls, by the roadside, and from hawkers. This practice and Norlh America(e).Unless checkmated,MDR-TB poses the usually leads to antibiotic underuse(sub-optimaldosages)that greatestthreat to public health in the new millennium.('u) invariably increasesselective pressureand antimicrobial resistance.

Factors that favour the spread of antimicrobial Poor quali ry anI i biori cs resistance General oyeruse of antibiotics Most antibioticuseis in two areas,that is, in humansin the community and in animals for growth promotion and prophylaxis. It has been found out that 20 * 50Vaantlbiotics used in human and 40 - 80Voin animals(')are unnecessaryand highly questionable. In Denmark for example, while 24kg of active vancomycin was

Antibiotics degraded by exposure to temperatureshigher than 25'Cby hawkers(oo), harshadverseconditionsduring shipmentto the tropicstasror when laid out on the hot pavement, expired drugs which receive new labels, sometimes dumped without labels or donated rather than destroyed are common in developing countriest16,47) all of which promote development and spread of antimicrobialresistancewhen used. Malawi Medical Journal

Antibioticresistancein bacteria 65 "--::mrrre.counterfeitantibioticswith much reducedor no have been identified in \igena. . .' ingredientsat all(o&so) - r,esia.Brazil, Thailand,Bangladesh,Malal sia and tian- :rone African countries. In a potency study of larious for example,S of the l0 brands -:.,:s : availablein Bangladesh, were substandard.Therehavealso beenreportsof : "mpicillin ,.rditionalhealersmixing antibioticswith their concoctionsto potency(52). ::',crease

tt muah tnt re to overcolneits later nlodifications. There is thereloreneL'dt. inren:iir re:e&r.h actirities in the area of [.] nrkethe lr..:ure trtTthe eristineonesand in the antitracteriairntibioti; 13'i:1.Iflc.in L'lcteria. reduce prLrce::

o i r n t i l n l a r i r t i l .rr8l ' 1 ' t r l l . ' i r i r I S u r re i l l ; r n c e :t[.rliLl, ltr'uJ-r'iil- il hli: tt-rbe backedup For anr antinlicrt-bi-ri b1 an efltcient\ur\eill[nce .J.I.lTl ti 'lete'Jt-tlltrnitorand docuin the localre:1\tJnae rri an) :lnllrnlar,rhl.rl ment the emergence ' ' ttre relationship ll. Once 1e', ity, at nationaland internation;.il { rtt'rease in International trav el \urveillance r'ttrbli'he'lheen hare Enormousincreasein internationaltravel in recentyearsmeans betweenuse and resistance "intonnatirrnfor r.11!rn"lrrr lnitiati\e to rhat individuals may be exposedto resistantmicrobes in one datacan then serveas of prescribing and Frrrlttrn{the u