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WH O/BVI/PHA/ ANT /82.1
WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE
WHODOC
,
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ANTIMICROBIAL RESISTANCE
Report of a Scientific Working Group Geneva, 23-27 November 1981
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WORLD HEALTH ORGANIZATION ORGANISATION MONDlALE DE LA SANTE
ORIGINAL:
ENGLISH
ANTIMICROBIAL RESISrANCE REPORT OF SCIENrIFIC WORKING GROUP Geneva, 23-27 November 1981
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List of participants
1.
Introduction . . Antibiotic resistance in bacteria pathogenic for men
5 5 5 6 8
2.
2.1 2.2
Historical background . . . . . . . . The. present situation . . . . . . . . Consequences of widespread antibiotic resistance
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2.3
3.
The use of antibiotics in man 3.1 Social pressures favouring the excessive or inappropriate UB~
8 of antibiotics 8
3.2
The
miSl,lSe
of antibiotics .
8 8 9 9
3.2.1
In hospital practice
3.2.1.1 3.2.1.2
Antibiotic treatment Antibiotic prophylaxis
3.2.2
In primary nealtn Care
9
4.
Antibiotic usage in animals 4.1 4.2 Antibiotic usage for growth promotion Prophylactic and therapeutic uSe of antibiotics
10
12 12 12
5.
Measures to control the prevalence of antibiotic-resistant bacteria
5.1
Surveillance of antibiotic resistance
<2 12 13 13 13
• 5.2
5.1.1
5.1.2
Ibe need for surveillance Requirements for surveillance
5.1.2.1 5.1.2.2 5.1.2.3
Surveillance of resistance in human pathogens Surveillance of resistance determinants in the general population Analysis of surveillance data
14 14 14 14 14 15 15 15
Control of antibiotic use in hospitals
5.2.1
Hospital antibiotic policy . . . 5.2.1.1
5.2.1.2 5.2.1.3 5.2.1.4 5.2.1.5
General strategy " " . . Tactical modifications of antibiotic policy Improving the quality of antibiotic prescribing Role of the laboratory Role of the pharmaCist . . . . . . . . . . . .
The
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of or
this document does not constitute
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document
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consthue pi;l5 une publici;ltion. 01,.1
formal the
publication. Quoted for Health
It should without views Organization.
not be reviewed, the aweement of Authors in alone signed
II ne resume
do it faire I"objet d"aucun compte rendu ni
abstr;;tl;ted World
d'aucune citation sans I"autorisation de
rOrganisation mondiale de la Sante. les opinions
are
I't:!sponsible
expressed
anic;ies.
exprimees d,lns leurs, auteurs,.
les artic;:les signes n'engagent Que
WHO/BV1/PHA/ANT/S2.1 page 2
5.2.1.6 5. 2.l. 7 5.2.1.8 5.2.2 5.3
Restriction of contact between pharmaceutical representatives and physician.s Educa·tion . . . . . . .
.
Monitoring antibiotic use
15 15 15 16
Hospital hygiene and antibiotic resistance
Alternatives to the use of antibiotics
16 17 17 17 17
5.3.1 5.3.2
Immunoprophylaxis . . . . + • • The use of chemical disinfectants
6.
Research and development 6.1 Bacteriological . .
6.1.1 6.1. 2 6.1. 3 6.1. 4
Rapid methods of diagnosis of infection and antibiotic-sensitivity testing . . . . . . . . . . . . . . . . . . . . . . New means of
attacking the resistance mechanisms of bacteria . . Alternatives to the use of antibiotics . . . . . . . . + • • • • Alternatives to antibiotics for growth~promotion in fa~ animals
17 17
IS 18 18
6.2
Clinical 6.2.1 6.2.2 Minimal effective dosage Anttbiotic prophylaxis
IS 18 18 18
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6.3
Epidemiological.
6.3.1 6.3.2
6.3.3 6.4 7.
Surveillance 0.£ antibiotic resistance and of resistance determinants Effects of ceasing to administer antibiotics Non-human sources of resistance plasrnids
IS 19 19 19 19 19 19 20 21
Health service research. and recomme.ndations
C01'lc:b~$i[)n
7.1
7.2 7.3 7.4 7.5 References
Gene>:al. . . . . . . . . Surveillance of bacterial resistance National surveillance of antibiotic use Emergency action . . . . . . Veterinary use of antibiotics
Annex - Guidelines for the appropriate use of antibiotics
26
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WHO/BVI/PHA/A,'lT/S2.l page 3 LIST OF PARTICIPANTS
Members
Professor J. F. ACAR, Service de Microbiologie Medicale1 H8pital Saint-Joseph, Paris, France Professor J. FLEURETTE, Laboratoire de Bacteriologie-Virologie, Faculte de Medeclne Alexis Carrel~ Lyon, France Professor E. H. KAMPELMACHER J Rijksinstituut voor de VOlksgezondheid, Bilthoven, Holland
Professor C. M. KUNIN, Depa.rtment of Medicine, University Hospital, Colom.bl,ls, Ohio, United States of Americ.a
Dr J. KUPERSZTOCH; Departmento de Genetic8, Centro da Investigacion y de Estud1os, Mexico City, Mexico Professor S. B. LEVY, Departments of Medicine, and of Mol@cular Biology and Microbiology; Tufts University School of M~dicine, Boston, Massachusetts, United States of America Dr I. LIND, Neisseria Department, Statens Seruminstitut, Copenhagen, Denmark Dr A. H. LINTON, Department of Microbiology, University of Bristol Medical School, Bristol~
England
Dr A. MANTEN, Chemotherapy Laboratory, Rijksinstituut voor de Volksgezondheik, Bilthoven, Holland Professo~
D. G. MONTEFIORE, DepaLtment of Medical Microbiology, University College Hospital, Ibadan, Nigeria
Dt' R_ L. NICHOLS, Departme.nt of Microbiology, Harvard School of Public. Health, Boston, Massachusetts, United States of America Dr T. F. 0' BRIEN; Harvard Me.dical School; Boston, Massachusetts, United States of Americ.a
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Dr M. T. PARKER, fc~erly Cross-Infection Reference Laboratory, Central Public Health Laboratory, London, England Professor V. I. POKROVSKI, Central Institute of Epidemiology, Moscow, USSR Professor K. B. SHARMA, Department of Microbiology, Lady Hardinge Medical COllege; Ne.w Delhi, India ?~ofessor E. A. VEDMINA, Central Institute of Advanced Medical Training, Moscow, USSR
Dr F. VYMOLA, Chief, Research Unit on Bacterial Resistance to Antibiotics and Reference Laboratory toJ:;' the Control of Che.motherapy, Institute of Hygie.n.e and Epidemiology, Prague, Czechoslovakia Dr Hu ZHEN, Institute of Epidemiology and Microbiology, Chinese Academy of Medical Scienc.es, Beijing, China
Observers Professor B. GEDEK, Institut fUr Medizinische Mikrobiologie, Ludwig-Maximilians-Universit~t, MUnchen, Federal Republic of Germany
WtlO/BVI/l'IlA/ANT/82. 1 page 4
WHO Secretariat
Dr C. M. ANTAL, Medical Di8eases~ WHO
Office~, Bacterial
and Venereal Infections, Division of Communicable
Dr J. F. DUNNE, Seni"r Medical Officer~ Pharmaceuticals, Division of DiagnostiC, lberapeutic
and Rehabilitative Technology, WHO Dr G. Y. CAUSSE, alief Medical Officer, Bacterial and Venereal Infections, Division of Co~nunicable Diseases, WHO (Sec~e.tary) Dr L. HOUANG, Acting Chief Me.dical Officer, Health Laboratory Technology, Division of Di,9,gr'l,oatic ~ Therape.utic and Rehabilitative Technology, WHO D'r T.
KERESELIDZE, Medical Officer, Bacterial and Venereal Infections, Division of c()mrnunicable. Diseases, WHO
Dr Z. MATYAS, Chief Medical Officer, Veterinary Public Health, Division of Communicable Diseases, WHO Dr A. H. W. WAHBA, Director, Developme.nt of Comprehensive Health Service:; WHO, Regional Office tor Europe~ Copenhagen~ Denmark
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W1iO/BVI/PHA/ANl!82.1
page 5 A WHO Scientific Working GroLip on antimic.robial resistance met in Geneva from 23-27 November 1981. Dr I. D. Ladnyi, AssJ.stant Director-General of the World Health Organization, opened the me.eCLng on behalf of the Director-General. 1. INTRODUCTION
a The c(mstant e.xpos!).re of the body flora of ~na.n and animals to antibiotics- ba.s led to the selection and wide dissemin;-Hion of antibiotic-resistant bacte.ria, and the transfer of resistance genes betw<I!E!n str.ains in a seleC'.t.ive environment has widened the range: of bacteria in which resistances are prevale.nt.
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'Th.is e.xposure to antibiotics is a con.sequence of Cheir use (1) in human and vete:t:'inary medicine for the treatment or prevention of disease (2) in animal husbandry for th~ promot.ic:m of growth or (3) in various other ways fot· disease control in agriculture. The use of antibiotics other than in human medicine has been reviewed in previous WHO publication~,1,2,3 and vaI.'iol.ls proposals were made to limit its impact on bacteria pathogenic for man. It was accepted in these public.ations that the administ:t:ation of antibiotics to the human popt~lation was a major cause of the accumulation of resistant ba.cteria in its flora, but rneasure~ designed to limit this usage we.re not discussed in detail. The Working Group decided, therefore, to COnc.entrate its attention on the uSe of antibiotics in human medicine, and to (1) conside.r what types of antibiotic use iNE:!re inappropriate, (2) provide general guidelines for the appropriate use of antibiotics, and (3) suggest measures to improve the quality of antibiotic treatment. The Group also decided to review briefly the operation of restriction on the use of antibiotics in animal husbandry and veterinary medicine and to suggest improvements in their clinical use in animals. 2. ANTIBIOTIC RESISTANCE IN BACTERIA PATHOGENIC FOR MAN
2.1
Historical
backg~ound
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The first clinically serious consequences of antibiotic resistance. to attract widespread attention was the "Wide disseminatioJ'i in hospitals of strains of StaphYlococcus aure.U$ tha.t Vere resistant to penicillin by virtue of their ability to form an antibiotic-destroying en%.yme, pe.n-i,c i llinase- ( p ~ lac tamase) ~ a.nd subse.quencly acquired res is tance to seve.ral 0 t:her chemically unrelated antibiotics. Some but by no means all of these other resistances were also mediated by tl.~ pn"'lduction of antibiotic-destroying e.nzymes. From the early 1950s onwa~ds these so-calle.d. IImultiple~antibioticll resistant staphYlococci became endemically established in most hospitals throughout the world and were for some. years the main cause of hospital-acquired septic infe.ction. Many of the genetic determinants for resistance in these strains of: S. aureus were extrachromosomal pieces of DNA, called plasmidn (R factors), most of which coded for ~esistance to only one. antibiotic or group of related antibiotics; multiple antibiotic resistance bad thus arisen as a result of several genetic events. The wide dissemination of multiple-antibiotic :resistant strains was attributable to their spread from patient to patie.nt in populations e.xposed to several of the antibiotics to which they were resistant.
In the early 19505 it was also observed 4 that certain gram-negative organisms, notably strains of Klebsiella t Proteus and Pseudomonas aeruginosa that we.re naturally insusceptible to currently available antibiotics, were assuming a great importanc.e as causes of septic. infec.tions in hospitals. This prt)CeS5 continued into the 1960s~ by which time a numbet' of other gramnegative organisms ~ some of them derived from the natural environment - had been added to the list of important "hospital ll pathogens, and the e.stablished gram-negative pathogens were acquiring additional resistances to more recently introduced antibiotics. Resistance in gram~negat;.ive organisffi8 differed from that in S. aureus in that (1) it was in :many cases determined by R plasmids that coded for resistance to several unrelated antibiotics and which
~ This term is used to include both antibiotics and synthetic chemicals with a similar selective antibacte.rial activity.
,IHO/RVJ/J'H,yANT/82.1 page 6
could be easily transferred as a single genetic event between bacterial strains and (2) R plasmids were transferable not only between members of a single species but also between members of many geneta of gram~negative bacilli and c.occi.
As a result of the.se changes, the gram-negative bacilli had by the early
1970$
replace.d
S. aureus as the most important cause of hospital-acquired septic infections, and, at least in a number of developed countries, widespread endemic: prevalences of multiple-antibiotic resistant strains of S. aureus had become rather uncommon. S The serious clinical consequences of antibiotic resis,tanc.e became apparent considerably later in the. general population than in hospitals. Penicillin resistance in S. aureus~ which had become common in hO$pital~acquired stra.ins by 1950 J did not reach a similar frequency in the outside population for another ten ye:aX's or more; and, apart from some. "ovet"flow" of exceptionally virulent hospital stra;ns in the years 1955-1960, multJ.p1e-anUbiotic resistant strai.ns have se.ldom been very prevale.nt in the general population. Multiple-antibiotic resistartt strains of g~oup-A streptococci became very cOmmon in same countries in the 19605 but the clintca.l significance was limited by their continued sensitivity to penicillin. A more serious situation developed when antibiotic X'esistance became a commOn cause of treat.ment failu:t:'e in diarrhoeal and enteric diseases. P1asm:f.d-determined transferable resi.stance was detected with increasing frequency among shigellae and salmonellae during the 196Qs, and a few years later there were widespread epidemics of severe bacillary dysentery and of typhoid fever caused by strains that were X'esistant to several antibiotics~3 including the agents of choice for the treatment of these infections. In 1974, a plasmid~determined fJ -lactamase ('rEM 1) identic.al with that found in many enterobacteria appeared in Haemophilus. influenzae.6,7~8 In 1976 plasmid borne en2~-mediated chloramphenicol resistance in H. influenzae was discovered 9 and emergence of multiple resistant stt'ains carrying re.sistance to ampicillin, chloramphenicol and tetracycline (antibiotics of first choice for the therapy of of infections) have been reported since.IO,ll For most of the organisms so far discussed, the number of carriers greatly exceeds the number of clinical infections, so that exposure of the whole population to antibiotics might be expected to select for resistance. With tubercle bacilli, and until recently gonococci, the situation is different: c.linically infected persons are the main source of the organism., and high-case finding rates and the elimination of treatment-failure thus aSSume exceptional i,mportance in c.ontrolling resistanc.e. The resistance of gonococci to penicillin increased slo'W'ly over many years, but treatment failure could be prevented by suitably increased doses of penicillin. This resistance was chromosomal and non~enzymic; in 1976, however~ plasrnids determining the production of the TEM 1 p-laetarnase appeared in gonococci J 12~ 13,14,15 which then exhibited total resistance to penicillin. (For reviews of the development of resistance in gonoc.oc.ciJ see rcfel;'ences l6 J 17, 18.)
.. ..
2.2
The present situation
The Working Group reviewed the prevale.nce of antibiotic X'esistance in man since. the last WHO Repurt on th~s subject*3 in this re.port it was noted tha.t information about its dis~ribution was patchy; it was particularly deficient in developing countries and was often difficult to interpret because. the. methods used for testing $usc.eptibility to antibiotic.a Wc:":re uften not sta.ndardized. The present Working Group considered the information now ~vailable, and c.oncluded that, a.lthough the frequency of resistance in individual pathogens, ~nd the patterns of multiple resistance varied considerably between countries and often in differcnt parts of the same: countryJ the situation had in a number of respects worsened in the last fe.w ye.ars. In most developed countt:'ies endemic hospital infection caused by multiple-antibiotic resistant strains of S. aureus contiliued to present less urgent problems than infections with cer.tain members of the gt"am-negative bacilli. There was~ however, recent evidence from Britain, th~ USA and Australia of an irtct"easing number of local outbreaks of infection caused by staphylococcal strains with a very broad spectrum of resistance to antibiotics~ including
WllO/BVI/PHA/ANT/82.1 page 7 'd 19,20,21,22,23,2/, methicillin and aminoglycOSl es. S . Orne report,:: from. developing countr:i.€!S indicaced that strains of S. aureuS resistant to locally available antibiotics were ~til1 a
major cause cf serious infections in hospitals. TIle. Working Group noted that there had been a further dissemination of strains of gonococci and of H. influenzae that possessed the l'EM 1 j3~lactarnase, and that an additional type of /1-1actamase had been reported in H. influenzae~ 25 that multiple antibtotic tesist,:ant strains of the latter organism had been found, 26, 27 and that H. inEluen2,a,e type b resistant t.~) both ampicillin and chloramphenic.ol had c..;l\,lsed an ()utbre<:;l,k of meningitis with three deaths in an orphanage in Tha.iland. 28 Clinical failure in the treatment of meningitis caused by H. inf1uenzae with ampicillin has nOw been reported with considerable frequency. In recent ye.c:I.'I:·s, pe.nicillinase-forming gonococci have shown considerable spread worldwide, 29, 30,.11 and several diffe't'ent p-lact.amase: plasmids have. be.en ide.~'tified among them • .32 A penicillinase~ producing gonococcus with a high level of resistance to spectinornycin has been described,33,34 but such strains appear to be still uncgmmon. Dec.r.eased susceptibility to the ne.wer cephalosporins has also been described.'S Penicillin resistant strains of pneumococci had become locally preva.lent in South Africa,36 where they caused treatment failure and the death of infants. 1his resistance was non-enzymatic and chromosomally de.termine.d, and was oft(~n accompanied by resistance to other antibiotics, including chlol:amphe.nic.ol and tett'"acycU.n€! . Pneumococci with clinically significant levels of penicillin resistance were also COll'lI~\On in Papua. New Guinea)7 and had been found occasionally elsewhere. Antibiotic resistanc€! in Bacteroides has been on the increase for some years, and a transferable R factor for clindarnycin had now been reporte.d. 38 Until quite recently chole.t;'a vibrios with R factors coding ft.>r multipl<:::-antibiotic resistance were. se.en infrequently* Extensive epidemics of c.hclera have now been reported from Tanzania 39 and Bangladesh40 in whic.h an initially sensitive strain became predominantly resistant within a few months; the R factors re.sponsible for this specified re.sistance. for several antibi.oti.c.s; including tetracycline, the: CUrl,'c.nt drug of first choice (or treatment. Clinically significant resistances may be mediated by antibiotic inactivating enzymes or by other resistance mechanisms; and they may be determine.d genetically On a plasmid Or on the chromosome. Multiple~antibiotic resistance may be specified by a single plasmid or by a number of distinct resistance genes~ some on plasmids and others on the ch"':"omosome:. Evidence continues to accumulate of the genetic adaptability of many of the: R plasmids .41 The.y m8.y be self-transferable: or may be. accompanied by other plasmids that mobilize. the:m for' t:ranstet". Many of them can move as distinct genetic ele.ments c.i::l.lled "transposons lT from a plasmid to the chromosome, or to a phage. This permits modi.fication of the pattern of resistance c.onfe.rred, and the bringing together of resistance de.terminants and transfer mechanisms appropriate for a fresh host bacterium. T"t"ansposition:may also lead to the association 0"["\ the $a.m~ plasmid of resistance determinants and ge.nes for coloni2ation, toxin production and other so-called ,tvirulence fac:. torslT. When an infection is tre.ated with an antibiotic to which the causal agent is initially susceptible, resistance may appear as a result of the transfer of an R plasmid or its transposable: resistance determinant from another organism in the patient's flora. 42 NumerDus instances have been reported in which an R plasmid, after being introduced into a hospital in Ol'le gram-nega.tive organism, is subsequently transferred to another strain of the same Qr a different species, which then spreads extensively among the patients. Preliminary evidence from surveillance. data presented ti) the Working Group indicated that serious consequences of antibiotic resist.ance Were no longer confined tn urban hospitals but were being encounte.re.d increasingly in the general population. It also showed a greater prevalence in deve.loping countries of resistance to easily available antibiotics such as ampicillin, tctracyc:.line., chlm:amphe.nicol and sulfonamides~ than is known to OCCt1t" in develope.d count.ries* Surveys of fJ~lactamases in enterobacteria from developing ~:otlntries revealed a correspondingly greater variety of types, and of instances of multiple fi~lactamases in the same isolate. Patients in developing countries were thus in a situation in which only the cheaper antibiotics were available to them and these agents were bec.oming progressively less effective.. In the absence of local laboratory support and of up-to~date in.(or~ation
•
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WIiO/BVlhHAj ANl!82.1 pag" R about the prevalence of resistance] th~ choice of an appropriate antibiotic was becoming a gamble against worsening odds. It was clear that the uncontt'olled importation of the e}l".pensive nnew" antibiotics now available in developed countries, even if economically feasible, would cause only a temporary improvement in the situation.
2.3
Consequences of widespread antibiotic resistance
1. Antibiotic resistance limits the therapeutic efficacy of antibiotics against pathogens that a.re initially resistant to t.hern or acquire a transferable resistance: from another organism in tha patient' s flora during treatment. Widespr~ad use of antibiotics encourages the overgrowth of other resistant bacteria in the f:lc)ra of the treated patient. '!his process ("superinfection't), may have important clinic.al consequences, especially in hospital patients, many of whom have an increased susc.eptibility to i.ofec.tion by organisms that seldom invade healthy persons. In such patients these organisms are frequently responSible for respit'atory or septicaemic. complications that ~ly be a greater hazard than the infection for which antibiotic treatment was given.
2.
3. Wide spectra or antibiotic resistance in p:t'evalent bacteria set'iously limit the possibility of controlling the f~lrther spread of resist.ant. organisms by the selective use of antibiotics. 3. TIUl USE OF ANTllllOTlCS IN MAN
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Antibiotic resistance in human pathogens is widely attributed to the "misuse" of antibioi;, Lc.s for treatment Or prophylaxis in :man. Before making proposals for the more rational uSe of antibiotics~ the Working Group considered the nature and extent of this misuse.
3.1
Social p~essures favouring Che excessive or inappropriate use of antibiotics
The decision to use an antibiotic may be influenced by social pressures that outweigh the: medical indic.ations ./-l-.3 When antibiotics are available On the open maX'ket, the attitude of the patient and his family is decisive. The desire to do the best for the patient in a situat.ion of fear and anxiety] coupled with public ignorance about the efficacy of antibiotics in particular diseaaes~ encourage unnecessary and sometimes damaging tt'eatme.nt. Poor choice of antibiotics is encouraged by the beWildering multiplicity of names under which they are m...1.rkete:d~ by the promotion in developing countries of antibiotics that are obsolete or in other ways inappropriatc,44 notably unjustified fixed combinations of drugs~ and by misleading advertising material.
Jo.:ven when the physician is the only oX' the preferred source of antibiotics, he may find it to resist pt:"E!ssure from the patient ot" the family. He is also motivated to do the h~:$t for the patient; unless he has a good knowledge of the management of micX'obial infections, of antibiotic action, and of the Current local state of susceptibility of pathogens to anti~ biot:I.c~) he :may be tempt.ed to give unnecessary treatment. He may feel that even if an antibj,oti.c is ~lnlikely to do good it will do nO harm] or he may attempt to ensure the efficacy of treatment by giving largeX' doses Or mOre prolonged treatment than is necessary. For similar reasonS he may employ broad-spectrum agents or antibiotic combinations as a routine to covar the possibility of infection by unusual organisms. All of these practices will be particularly difficult to resist if laboratory and other diagnostic support are not available. dirfh~t,llt
a
:3.2 3.2.1
The misuse. of antibiotics In hospital p~actice
Recent S~lrveys in North America and BX'ita1n indicate that about one-2uarter of all patii:!nt:s rec.:eive One or more courses of antibiotic. whilst in hospital~45~ 6~47~48J49J50J51 though the rates vary somewhat between hospitals and even mOre between hospital departments. In Britain, some 20% of all patients in general hospitals On anyone day are receiving antibiotics. About one-third of all CQut'ses of antibiotic are given for prophylaxis. 50 A Ijimilar situation exists in many other advanced countries.
WHO/BVI/PHA/ANT/82.1 page 9 Several workers have claimed that the administration of antibiotics ~a5 irrational or inappropriate in a considerable proportion of patients~ variously estimated at 38_66%.45,46,47,51,52,53 In a ,et,ospective Canadian survey in 1976,46 only 41% of all courses of antibiotics were considered to be "rationalllj "questionahle" • 3.2.1.1 Antibiotic treatment 38% were "irrational", and 22"/~
were
Antibiotic therapy is inappropriate if it is unnecessary, Or if the agent used is unsuitable Or given in incorrect dosage. This may be attributable in various dcg~ees to (1) POOl;'
c.linical decision-taking j
(2) absence or failure to make use of laboratory support,
(3) ignorance of the types of bacteria mOst likely to cause particular infections and lack of inforn~tion about the current susceptibility of the suspected causal agent to antibiotics, and (4) inadequate knowledge about the pharmaco,kinetic properties of antibiotics. An example. of the analysis of ant'.ibiotic use for treatment is shown in the investigation carriad out in a London hospital provided with a well run laboratory service. Antibiotic use was monitored at the time of administration by an independent team of experts; it was concluded Sl that in this hospital the most frequent form of therapeutic misuse was giving unnecessary courses of antibiotics. The most common reaSOns for giving antibiotic treatment were infections and suspected infections of the lower respirato~ tract (39%) and of the urinary tract (20%). Reconsideration of the clinical, bacteriological and radiologic.al findings led to the conc.lusion that there was no significant e.vidence of pneumonia. in 40% of the patients treated for this disease. Nearly 40% of all patients aged more than 80 years who were admitted to the: hospital received antibiotics for "chest infection". In patients given antibiotics for suspected infection of the urinaty tract, nO justification c.Quld be Irrational treatment was: (1) giving an antibiotic, or found for the treatment in 49%. failing to stop treat~nt~ when the initial urine specimen showed nO evidence of bacteriuria (33%), and (2) treating bacteriu'ria 'in the absence of relevant symptoms in patients on continuous catheterization or when the only evidence of infection 'Was a "significant l, number of bac.teria in a single routine mids'tream urine specimen (16%). There was thus very considerable. OVeruse of ant'ibiotics attributable to poor clinical decision~taking~ notably inadequate. diagnostic criteria for infection and uncritical interpretation of chest X~ray films and laboratory repor'ts. In this hospital the. choice of antibiotics for infections confirmed by laboratory examination 'Was in general good, but there was disturbing ev:tdence that~ in the absence of a significant laborato~ report~ physicians had little idea of the most likely microbial cause of an infection and its probable susceptibility to antibiotics, and so often gave inappropriate treatment . 3.2.1.2 Antibiotic prophyla~is
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•
The widesp~ead use of antibiotics prophylactically bas undoubtedly contributed greatly to the spread of resistant organisms in hospitals. On the other hand, antibiotic prophylaxis significantly reduce:s the risk DE certain types of surgical ope1;'ation, notably those of the intestinal Or urogenital traet J 5 and its use in these circumstances must be considered justifiable. Misuse Can be defined as using prophylaxis when there is no clear evidence that this will prevent serious clinical infection or using a prophylactic regimen that unnecessarily selects resistant organisms. Guidelines for the appropriate prophylactic use of antibiotics are given in the Anne~.
3.2.2
In prima<y health care
There is little quantitative information about antibiotic-prescribing habits in primary health care, and this mainly concerns practice in developed countries. It suggests considerable misuse in the treatment of mild upper-respiratory~tract infections~ febrile episodas and diarrhoea. In One survey in the USA;S5 nearly 60% of physicians used antibiotics to treat the COmmon cold. Until quite recently, considerable quantities of chloramphenicol continued to be used mainly by older physicians and in rural areas for the treat~nt of infections of the upper-respiratory tract despite'repeate.d official condemnation of the practic.e. 56 ,57 Tetracycline was also Widely used for respiratory~tract infec.tions in children. 58 There has 1
WHO/BVI/PHAjANT/82.1 page 10
been considerable overuse of tetracycline in B~ita1n for many years; treatment of ~elapsea in chronic bronchitis with this drug, in which it is nOW believed to be ineffectiv@~ accounted fo~ much of this. There are now few COmmOn diseases in non-tropical areas in which tetra~ cycline is the drug of first choice 59 but it continues to be widely used in family practice in Brita.in. Richmond & Li~ton60 concluded th.et this was the main cause of the prevalence of tetracycline-resistant strains of Escherichia coli, many of which were also ampicillin resistant, in the faeces of members of the general population of Bristol.
The use of antibiotics to treat suspected infections of the urinary tract in women is certainly excessive. Treatment is commonly given to all women with frequency and dysuria despite the fact that no more than one-half of them have significant bacteriuria. The avidence that very short courses of antibiotic are as effective as longer courses in uncomplicated urinary-tract infection6lj62163 appears to have had little impact yet in primary health cart:!. In highly affluent countries there has been a recent tendency to use new high-cost proprietary agents, such as oral cephalosporins and derivatives of ampicillin, though these are seldom more effective than cheaper alternatives. Evidence from developing countries presented to the Working Group indicated that the consumption of antibiotics was often enormous, but there was little precise information about the purposes fo~ which they had been given. In most such countries, antibiotics are freely available on the open market and are habitually taken without t'\le:dical advice. 1he unexpected finding of widespread trimethoprim resistance in E. coli strains in Mexico is a p~obable consequence of uncontrolled use. 64 Chloramphenicol is widely used in developing countries for the treatment of diarrhoea, which is often attributed to typhoid fever without bacteriological evidence. tot~l
•
TIle prophylactic use of antibiotics On individual patients outside hospital does not appear to make a material contribution to total antibiotic usage, and complications attributable to the overgrowth of resistant organisms a~e infrequent. Mass prophylaxis with narrow~spectrum agents such as penicillin 1 e.g. for the control of group-A streptococcal infection in institutions~ though not always very effective'j appears to have had few untoward consequences. On the other hand, mass prophylaxis with broad~spectrum antibiotics, e.g. tetracycline, for the control of diarrhoeal diseases is likely to contribute mate:t'ially to the hpread of resistant strains. 4. ANTIBIOTIC USAGE IN ANIMALS
It is well recognized that the administration of antibiotics to animals for any purpose prophylaxis or therapy) leads to the accumulation of resistant bacteria in their flora. Antibiotics have been used for each of these purposes over ~ny years and it is difficult tn separate: the contribution made by each to the pool of resistant organisms in animals. The importance of this pool to man are (1) that antibiotic l,"esistant pathogens cormnon to animals and man may reach man by cross-infection and (2) that antibiotic resistant, non-pathogenic organisms in the animal may be passed to and colonize man, thereby carrying R plasmids into the human environment. These R plasmids may be transferred subsequently to hum.an pathogens or to his indigenous flora. (growth~promotion,
Antibiotic resistant animal pathogens Not all animal pathogens cause disease in man. For instance, pathogenic animal staphylococci (in cattle j poultry and dogs) are mainly distinct from those found in man. Antibiotic resistant st~ains which occur in animals, e.g. in staphyloco.cca! mastitis of cows, do not, therefore, present a problem to man. In contrast 1 many of the enteric Gram-negative organisms e.g. Salmonella spp. and/or some stains of Campylobacter infect man as well as aoilna.ls. The larger proportion of salmonella infections in man are derived from eating contaminated roeat and therefore, indirectly, from animal sources. Where strains of anti~ biotic-resistant salmonellae arise in animals, they eventually reach man. 65 1 66,67
WHO/BVI/PHA/ANT/82.1 page 11 The frequency of antibiotic resistance in various salmonella s@rotypes from animals varies from country to count~y. A survey of isolates in the United Kingdom from 1958-197968 revealed that whilst resistance to sulfonamides and st~eptomycin occurred in up to 50% of isolates, multiple-resistance was rarely experienced in most se~otypes. Where this did arise it occurred almost exclusively in one serotype 1 namely Salmonella typhirmurium, and then only
phage type 29 69 and, since 1977, principally in phage types 193 and 204. 66 ,70 Available evidence indicates that the selection of these multiple resistant phag@ types was due to the ~lse of antibiotic.s for treatment ratheX' than for growth promotion. Since epidemics by multiple resistant strains have been relatively few) it must be deduced that the circumstances precipitating th~ genetic events leading to multiple resistance must have been rare in the United Kingdom. Nevertheless, Once selected~ these strains spread rapidly over a wide area by the movement of infected calves as frequently occurs in the calf industry and human infections followed. Higher levels of antibiotic resistance have been experienced in the United States of America. A survey of animal salmonellae in the Northeastern United States of America 7l revealed that the majority of S. tvphimurium~ S. saint-paul, and S. heidelbers were resistant to three or more antibiotics; these included resistance to ampicillin~ kanamycin and te:tracycline, in addition to sulfonamides and streptomycin. Sevex-al authors 65 attribute this~ at least in part) to the continuing widespread use of antibiotics as feed additives and this may be a significant cause since antibiotics are often used in the United States of America at levels considerably higher than those recommended under EEC legislation for growth promotion. The level of multiple resistance of salmonellae in the Netherlands falls between that experienced in the United Kingdom and the United States of America. Multiple ~esistance is found in a wider range of serotypes than in the United Kingdom, including S. dublin and s. panama in addition to S. typhirou~ium. After' a ban on the use of tetracycline in animal feeds in 1974, the incidence of tetracycline resistance in S. typhimurium of porcine origin dropped from about 90% in 1974 to 34% in 1980. The incidence of resistance in human strains concurrently decreased from about 80% in 1974 to 25% in 19BO. These changes suggested strongly that the use of tetracycline fol" gro'Wth prom.otion played a part in the emergence. of drug resistant salmonellae in pigs and their subsequent tx-ansfer to humans in that country. 72~ 73~ 74 Thu5 it is clear that marked differences in antibiotic resistance has been experienced in animal salmonellae in different countries. These may reflect the difference in the use of antibiotics, methods of animal husbandry~ density of animal populations and local topographical factors. Antibiotic resistance in the normal gut flora of animals The antibiotic ~esistance status of the normal gut flo~a of domestic animals is somewhat different. The oral administration of antibiotics (a common route for therapy~ prophylaxis and gro'Wth promotion) invariably selects for a resistant stl"ain pa~ticularly from among the Enterobacteriaceae and other Gram-negative bacilli, which then become predominant. Evidence is now available confirming that these resistant strains reach man via the food chain. The most definitive work has been done with Escherichia coli. The high~st incidence of antibiotic resistant E. coli are found in calves,75 pigs 76 and poultry 77 species in which antibiotics have been widely used. Under commercial slaughter conditions, contamination of carcasses on the slaughter line regularly occurs with strains of E. coli of the same O-serotypes and antibiotic resistance patterns as those found in the gut of the animals being slaughtered. 77 , 78 79 These strains reach the kitchen on meat and meat products, 77 subse.quently colonize the gut of manBO and may be detected in the dominant gut flora for up to 10 days. No evidence has been presented 50 far to indicate that antibiotic resistant E. coli of animal origin cause clinical disease in man such as urinary tract infections, but they obviously form a rich source of R-plasmids that are potentially transferable to a range of Gram~negative bacilli pathogenic for man which may be present in the gut. 1 1
in a few phage. type.s.
In the 1960$ multiple resistance was e.~perienced in S. typhimurium
•
•
WHo/aVI/PHA/ANT/8Z.1 page 12
widesp~ead
The use of antibiotics to prevent food spoilage 1 once a common practice, is now much lesa because the ftequency of antibiotic resistance in contaminating organisms limits its efficacy. It is probably no longer an important consideration. Antibiotic usage for growth p~omotion no antibiotic antibiotic, should this policy would use of the SSme
4.1
The Working Group noted that an earlier WHO Report l had recommend~d that that was of therapeutic value in man, or showed cross-r~sistance with such an be used for growth-promotion. It was the opinion that the i~plementation of have only a limited effect on the prevalence of resistant bacteria unless the antibiotic for prophylaXiS and treatment in animals was also restricted.
4.2
Prophylactic and the~apeutic use of antibiotics
It is not practicable to distinguish between the prophylactic and the therapeutic use of antibiotics in current veterinary practice because antibiotics a~e usually given not only to sick animals but also to their healthy contacts. While recognizing the value of antibiotics for the treatment of bacterial diseases in animals, the Working Group was of the opinion that gove~nments and professional bodies should exert greater control Over the circumstances in which certain agents are administered to animals (see section 7.S).
~'
5 5*1 5.1*1
MEASURES TO CONTROL THE PREVALENCE OF ANTIBIOTIC-RESISTANT BACTERIA Surveillance of antibiotic resistance The need for surveillance
Without reliable infor~ation about the susceptibility to antibiotics of important human pathogens it is impossible to find solutions to the problems created by antibiotic resistance. Surveillance is necessary at several levels. (1) To imp,ove the quality of antibiotic p,escribing for the individual pat.ent: information obtained in the course of routine investigations of patients can be used as a guide for the treatment of other patients with severe infections from whom the causative organism has not yet been isolated* (2)
To influence the pattern of antibiotic usage in the individual hospital.
(3) To assist national governments and inte~national organizations in the formulation of policy for the supply of antibiotics and thei~ uSe in man and animaLs; and to encourage responsible action by antibiotic manufacturers in the ma~keting and promotion of their products in individual countries.
In countries with well developed laboratory facilities a great deal of valuable information about antibiotic susceptibility accumulates in hospital records. In some hospitals this is analysed periodically for local use, and in a few countries a comprehensive scheme of surveillance) based on hospital-laboratory data, is in operation. At least one informal international collaborative study has been made of resistance in a range of important human pathogens. 81 To these sources of information must be added several special schemes for the surveillance of resistance in individual pathogens, notably enteric pathogens and gonOCOCCi, by WHO reference centres. Information from these sources though valuable, is f~ from comprehensive. Earlier WHO reports have urged the establishment ot national and regional centres for the surveillance of resistance. The Working Group is of the opinion that such a scheme to cover a wide ~ange of impo~tant human pathogens is now required. 1
WHO/BVI/PHA/ANT/S2.L paga
n
.5 .1.2 5.1.2.1
Requirements for surveillance
Surveillance of resistance in human pathogens
The primary objective of this is to prOVide: informaCion about resistance in bacteria that
are responsible for infection. microbiolo~y
The most readily available source of these is the clinical
laboratory. There is thus a very strong case for basing a surveillance scheme on the selection of routine isolates from this source. Considerable advantages would be gained it the: results of routine se.nsitivity tests pe.X'forme.d in the local laboratorie5 w~r~ made use of in this scheme. The role of the national centre would be (1) to organize the
selection by pat:"ticipating labol"atories of strains to be inc.luded in thE:! surveillance, "~"r'ld (2) to enSu,e that laboratory testing is performed reliabLy and by a standard method. This ,'":H·rangem~nt would keep the" woX'k-load of the national centre within reasonable limit5 and would tend to upgrade the quality of routine sensitivity testing in local labo~atories. The scheme for selecting test results for inclusion in the surveillance would be standardized internationally. Sampling should be designed to include adequate numbers of each important pathoge.n from a series of specified clinical source.s (e.g. blood, pus, faeces, significant urinary-cract infection) in each pa~ticipating laboratory in an agreed period of time. Participating labo~ato~ies should be those in which standard methods are employed and aX'e moni toX'ed, and a:t:'e as re.presentative as possible of majot' geographica.1 regions of the country. The national centre would specify acceptable methods for sensitivity testing according to the guidelines given in requirements for antimicrobic susceptibility tests~ and would monitor their performance in participating laboratories regularly by a system of external quality control. It should also evaluate commercially available reagents (antibiotic discs, sensitivity-test media), and if necessary specify locally produced alternatives, and provide standard cultures for use in internal quality-control tests. National centres would, in collaboration with WHj0 specify which pathogenic bact€tia should be tested and with which antibiotics. In the first instance it would be wise to limit surveillance to common and easily identifiable pathogens. Later, consideration roight be given to extending surveillance to other organisms for which special testing methods a~e required. The national laboratory ce.ntre should be prepared also to examine "problem" cultures from local laboratories, including stX'ains thought to exhibit "ne.w" resistances. It is not enVisaged that such centres would undertake advanced research on the biochemical basis of resistance or on genetics; this should be left to academic centres in the same or other countries. However, they would be expected to make use of simple procedures foX' the recognition and characterization of R plasmids. They would have an important role in providing bacterial strains suspected of containing ne.w or unusual R factors to speCialized laboratories for further s,tudy. 5.1.2.2 Surveillance of resistance determinants in the general population
•
•
The Working Group considered that information about the prevalence of R plasmids in the bacterial flora of the general population would be of great assistance in forecasting future changes in the resistance of pathogens. A programme should therefore be initiated for national centres to monitor periodically the R factors in coliform bacteria in the faecal flora of healthy persons. Faecal samples would be plat~d by a serial-dilution method on, for example, MacConkey IS medium. Replication on to plates of the same me:.diu\'1'I e.ach containing one of a serie.s of clinically important antibiotics would be used to enumel."ate: colonies resistant to one or more antibiotics, and simple methods would be used to examine. selected colonias for pLasmid DNA.
~ Document WHO/BS/Sl.L337 Rev.l.
WHO /BVI/PHA/ANT/82.1 page 14
Information about the prevalence of R plasmids in the faecal flora is already available in many countries. The value of the proposed surveillance would therefore be greatest in countries - mainly in the developing world - in which this sort of information i5 otherwise unlikely to be obtained. H~W'ever) information about the prevalenc.e of R plasmids in faecal coliform bacteria is unlikely to be of much use unless the current situation in clinically important pathogens is also known. 5.1.2.3 Analysis of surveillance data
'rhe methods of analysis of the results of surveillance should be: so chosen that they can conveniently be applied successively at each level - local, national and global. Hand or ~imple mechanical sorting may be appropriate to give early information locally but computer assistance will be essential for analysis of national and global data. Regional cooperation i.n the ~lse of computer facilities might help to me:et deficiencies in individual countries. 5.2 5.2.1 Control of antibiotic use in hospitals Hospital antibiotic policy •
The decision to administer an antibiotic to a patient is taken by the doctor responsible for his care. In many hospitalsj however, attempts have been made to influence such decisions by the development of an antibiotic policy, ag.eed u~on by the heads of the main clinical d~partments in collaboration with the microbiologist. This policy may be given official status by the Hospital Infection Control Co~ittee or Committee of Consultants. It may conveniently be codified in a booklet issued to all medical memhe~s of the staff. This booklet may begin by setting out basic information about the action of common antibiotics, dosage sChedules) etc., but its main pu~pose is to outline agreed principles for the rational u::;f! of antibiotic.5 (see Annex). It should not seek to establish rigid rules because. (1) the ultimate right of the doctor to decide upon the treatment appropriate for his patient must be pr~servedj (2) alternative courses of action may be acceptable in the present state of knowledge) and (3) changing ci~cumstances, e.g. increasing resistance in an important pathogen, intl"oduction of a new antibiotic, may from time to time dictate. modifications. Thus, the antibiotic policy should seek only to define limits within which antibiotic prescribing is justifiable and appropriate. The heads of individual departments may establish more precise rules) within these guidelines to which junior doctors are expected to adhere. 1
5.2.1.1
General stratesy
Th~ following is an outline of th~ general advice to be given in an antibiotic policy~ which can be elaborated~ with suitable examples according to local circumstances. Antibiotic. treatment should be based on precise clinical diagnosis of the nature of the infective p~ocess. It is directed against specific pathogens identified by culture O~~ when this is not practicab1e j inferred from the site and nature of the infection. The antibiotic is chosen, wheneve~ possible) in accordance with results of susceptibility tests (with advice f~om the l.aboratory); when immediate tre.atment is deemed necessary, this should be reviewed when the test results become available. When no pathoge.ns are isolated, a suitable. antibiotic for the inferred pathogen should be chosen with reference to the known susceptibility of recent local i~olates of the species. In all cases, an effective antibiotic with the narrowest po~sible spectrum of ac.tivity should be c.hosen. (For an elaboration of this strategy, and for indications for the prophylactic use of antibiotics see. the Annex.) 1
5.2.1.2
Tactical modifications of antibiotic policy 1
Decisions to restrict the use of individual antibiotics for greater or lesser periods of time, have often been employed as elements in a hospital antibiotic policy. The ultimate measure) withdrawal of allot nearly all antibiotics~ was successful in controlling one local outbreak of surgical wound infection caused by a multiple-antibiotic resistant klebsiella infection. 82 Less stringent measur@s of selective restriction have been practised, often for long periods of time. This restriction may be practised to minimize the use of antibiotics
WHO/BVI/PHA/ANT/S2.1 page 15 that are useful for the treatment of serious infections, so delaYing the appea~ance
of
resistance to them ("keeping antibiotics in re.serve."). Other justifia.ble gl,"ounds for re:stl"icting the use of paX'tic.ular agents include: high costJ particularly if equally effective altf!:l;'n.atives exist; fl"eque.ncy of toxic reactions; and a tendency to disturb the natural flora. of the patient. Temporary restric'tion of a single antibiotic, e.g. carbenicillin,83 has on occasion resulted in the disappearance of organisms resistant to it from a ho.spital~ but such a satisfactory outcome. c.annot always be e.xpected~ paX'tic.ularly when the organism is re.sistaIH:
to othe.r antibiotics that continue to be used. Restrictive policies can be used effectively only when close surveillance of resistance in tho hospital is practised. Provision muSt also be made for the release of the restricted agents under exceptional circumstances by ,jrequiring justifications ,j84 for this to an outside authoritYJ e.g~ the infection-control officer or the infectious~disease physician. Another option is the release of the antibiotic if the patient is transferred to an isolation unit.
5.2.1.3
Improving the quality of antibiotic prescribing
•
It is generally easy to obtain the agreement of senior hospital staff to establish a policy for antibiotic administration; securing general adherence to it presents greater difficulties . 5.2.1.4 Role of the laboratory
The. effe.ct of good laboX'atory reporting on the. appropriate choice of antibiotics i.s likely to be most effective when the medical microbiologist has convinced his clinical colleague.s of his competence. to advise on antibiotic treatment (see Annex J section 2.2). 5.2.1.5 Role of the pharmacist
The appropriate hospital authority should agree upon a limited formulary comprising the minimum number of antibiotics required for effective treatment. The pharmacist should under normal circumstances dispense antibiotics only from this list, and ~hould operate rules (or the automatic substitution of the least expensive and the most effective of a class of suitable agents. The conditions under which he may depart from these rules should be: carefully de.fined by the authority. Generic names should be required to be used in all prescriptions and in labelling. The pharmacist has an important role in monitoring the: hospital's policy for the rest~icted use of individual antibiotics (see section 5.2.1.2).
•
5.2.1.6
Restriction of contact between
pha~maceutical
representatives and physicians
The hospital authorities should enforce the following rules: (1) all r~pre:sentatives should report to the pharmacy for registration; (2) they should visit physicians only by appointment, and should not in general enter the patient-care areas of the hospital; (3) they should be permitted to mount displays of their products only for limited times and in designated places; (4) offe.rs to sponsor speakers at scientific meetings and to provide free samples, test kits, etc. should be accepted with caution and only after consultation with senior staff.
5.2.1.7
Education
The hospital authority has a responsibility to oX'ganize a continuing programme of postgraduate education for medical staff on all matters concerning antibiotic use. It must be admitted~ howeve~J that the relative effect of different types of educational presentation on subsequent practice is not known (see section 5.4). 5.2.1.8 Monitoring antibiotic use
Perhaps the most valuable means of influencing the pattern of antibiotic use is to obtain information re.trospectively about antibiotic consumption and use this to stimulate discu~sion between physicians about their practices.
WHO /EVI /PHA/ANT/82.1 page 16
The simplest and cheapest form of monitoring is one based on pharmacy records. It will produce good information if these records are based on unit doses J if issues to individual wards ara identifie.d~ and if issues fo~ inpatients and outpatients are recorded sepa~ately. It will provide secular trends in the use of particular agents and may identify unusual prsctices in some departments and stinlulate fruitful discussion of these. Comparison of the pattern of antibiotic use in comparable departments in different hospitals are possible if recording methods are standardized. More elaborate surveys of particular fotms of antibiotic use j
made by retrospective
f.~xamination of patients' records J are more expensive but very valuable.. These. inc.lude studies (1 f the usc: of antibiotics prophylactically for different types of surgical operation by different surgeons, and of therapeutic p~actice in groups of patients indentified by discharge
diagnOSiS. Collaborative schemes for monitoring the effects of t~eatment in relation to the in vitro susceptibility of the causative organism for exampl~, in gonococcal infection, have contributed mate. r i.a.lly to preventing the sprea.d of resistant stra1ns .. 85j86 The value of ~etrospective monitoring depends on the use made of the results. The (:(mcept of "pe.e.r assessment" of their practloes by groups of physic.ians or surgeons must first be a.ccepted; the potentiality for profitable. "feed-back" to pt:'ac:tie.e and to the education programme is very great. 5.2.2 Hospital hygiene and antibiotic resistance
.,
TIle very high fr~quency of antibiotic:~re5istant pathogens in the bacterial flora of hospital patients is attributable not only to frequent ~~posure to antibiotics but also to the many opportunities that exist in hospital for the transmission of bacteria between patients, However successful we are in contrOlling antibiotic misuse, the amount of antibiotic used in hospi tals wi 11 continue to be conSiderable, particularly in some departments. For example, Ca.sewell and his colleagU2s87 concluded from a careful study in a urological ward that 24% of a.ll the patients admitted had received courses of antibiotics that had been prescribed on strictly rational grounds. There is little doubt that the use of antibiotics on such a scale would lead to serious antibiotic-resistance troubles unless the highest standards of hygie.ne. .::l.re maintained. Thus an active programne for the c.ontrol of hospital-acquired infection can be looked upon as an itnportant element in "antibiotic policy". The proviSion of adequa.te facilities fot' the isolation of patients J 88 and sufficient trained staff to work in theIn, are particularly relevant to controlling the spread of resistant organisms in parts of the hospital where antibiotic usage is heavy ~ Source isolation is needed to accommodate patients "Who are heavy dispersers of resistant organiSl'n8 and protective isolation for uninfected patients in whom the prolonged administration of broad-spectrum antibiotics is considered to be justifiable. j
•
Close epidemiological surveillance of the: spread of identifiable strains of resistant pathoge.ns in the hospital is an important part of the work of the Infection-Control Team,89 who should advise about spec.ial measures needed to deal with individual incidents J whether or not these have yet r~sulted in clinical infections. These measures ~y include the detection al"'ld elimination of hygienic lapses, the transfer of patients to isolation accommodation, and tacti~~al changes in antibiotic policy. 5.3 Alternatives to the use of antibiotics
The prevention of disease by means other than the use nf antibiotic.s is an important means of reducing antibiotic consumption. Improved hygienic conditionsJ notably in the quality of d~inking water in de~eloping countries, would lessen the use of antibiotics £o~ t.reatment and :t'educe pressure foX' their prophylactic use.. Many other examples cOl,lld be quoted. Certain more: specific mea.sures might be expected to have a s1tnil.sr effect ..
WllO/BVI/PHA/Al'lT/82.1
page
17
5.3.1
Imrnunoprophylaxi$
Immunization in Che. general popula.tion would ix'I. SOme instances reduce antibiotic consumption; I:'!.g. the use of me.ningococcal vaccines in high-inc.idence areas. The developme.nt of re.ally effective vaccines against enteric bacterial pathogens, and thaiX' widespre.ad e.mployment~
would also re.duce one of the major uses of antibiotics in developing countries.
Opportuniti€!$ for the successful deployment of immunoprophylaXiS to protect hospital patients tIt c;pecial risk of infection are unfortunately less common. In many cases the
increased susceptibility of the patient is of acute
onset~
and there is insufficient time [or
.'l.!;tive immunity to cevelop before the infection appears. The proven efficacy of pse.uuomc..'I'l..:L$ va.ccine when given .:Lfter burning in preventing invasive: infe.ction by Pseudomonas ae.rl.lgino$.::l. is an almost unique e.xc.eption to this, and certainly lessens the justification for bro,ad-Spf!(:t:rum antibiotic prophylClxis in burned patients. If the onset of susceptibility can be predicted~ as in pregnant women and their babies, there may be time for the development of active immunity. There is evide.nce that giving staphylococcal vaccines to pregnant women reduces somewhat the frequency of puerperal mastitis and l1eonatal skin se.psis~ but the present infrequency of these conditions in most countries hardly justifies the p~actice. A similar procedure for preventing neonatal sroup~B streptococcal infection by means of a polysaccharide vaccine is under investigation. Acute iIrtmunization may be of value in protecting certain categories of patients with an established susc.eptibility to Cl single bacterial pathoge.n~ e..g. to the pneumococcl,!s in asph::!ni,c. persons. However~ some other pCltients with a similar susc.eptibility may give a poor re~ponse to the vacc:.ine. and caution should theX'e.fore be exercised in .abandoning long-term antibiotic. prophylaxies in fClvOUl," of vaccinati.on.
•
5.3.2
The use of chemical disinfec.tants
The topical Clpplicat.ion of relatively non-to'Xic disinfectants such a ... chlo:rhexidine and iodophors provide.s a possible alternative: to antibiotic prophyla.xis in surgery and the prevention of neonatal skin sepsis. Its most clear success to date is in the prevention of catheter-borne urinary-tract infection. 90 Mention must be made of the speci.fic effe.ct of silver salts in preventing the. invasion of burns by P. aeX'Ugin05a, but pla.smid-borne resistaI'H.:e to silver has developed in some gram-negative bacteria.
•
6.
RESEARCH Al'lD DEVEWPl1ENT
The Workin~ Group identified a number of areas in which Chis might lead to improvements in antibiotic use and in methods for the containment of resistance.
6.1 6.1.1
Bacteriological Rapid methods of diagnosis of infection and antibiotic-sensitivity testing
Many new methods are under investigaCion; the most urgent nee.ds are roX' tht~ development of inexpensive methods applicable to a. number of different pathogens and their integrCltion into routine laboratory practice.
6.1.2
New means of attacking the resistance mechanisms of bacteria
Chemical substance.s that inhibit the ac.tion of antibiotic-destroying en~ymes may restore the usefulne.ss of antibiotics at present rendered ineffec.tive. by the pre.valence of enzyme.~ mediated re.sistance. ~-lactamase inhibitors (e.g. clavulanic acid) are now available; their therape.utic value in combination with various penicillins and cephalosporins, their range. of activity agrtinst various £-lactamases, and their potential impact on the pattern of antibiotic usage; are all matters of great interest. Chemical substances that inhibit other antibioticdestroying enzymes would be. of gr~at. potential value. Non-toxic substances that eliminate plasmids from bacte.ria ~ithin the animal and human body might be useful in p~eventing the spread of resist~nce in the natural flora.
WIlO/BVl/PHA/ANT/82.1 pag~ 18
6.1.3
Alternatives to the use of antibiotics
Of 3vailable methods of 1~unological prophylaxis, the use of pseudomonas vaccine is of: the greatest interest; study of the tlearlytl immunity elicited by it may have: implications for preventing infections by other gram-negative bacteria. The topical application of mild disinfectants is a promising method of preventing bacterial infection from specified sites. The extent of which it could replace: antibiotic prophylaxisjI and optimal methods of deploying it, require further study by controlled t~ials. 6.1.4 Alternatives to antibiotics for growth-promotion in farm animals
Pressure to use: antibiotics for growth promotion, especially where this is not effectively controlled by government action, might be lessened if effective and cheap chemical agents with a similar action could be: found. (,.2 CHnical
6.2.1 ~)[
Minimal effective dosage ~
In some infections, for ex~ple of the urinary tract~ smaller dosage or a shorter course treatment may perhaps be as effective as those currently e:mployed in effecting c.linical cure. Recent experience with uncomplicated urinary-tract infection supports this view; some other infections merit reconsideration. 6.2.2 Antibiotic prophyla~is
The guidelines given in the: Annex represent a general consenSuS of current vie:ws~ but uncertainty eJ!;ists on some points, e.g. about the relative efficacy of individual antibiotics and the liability of ce.rtain proposed regimens to cause undesirable changes in patients flora when given by differe:nt routes. The justification for longer courses of prophylaxis in ce.rtain non-surgical conditions, such as underweight neonates and immunodeficient pa.tients, is a subject [or c.ontroversy. Critical evaluation of their consequences for the patient and otheX's in the unit, and the extent to which these are influenced by various systems of patient-isolation, are needed. I
6.3 6.3.1
Epidemiological Surveillance of antibiotic resistance and of resistance determinants
The need for establishing an integ~ated system of suX'veil1ance~ under the general direction of WHO, to obtain information on a global Bcale about the frequency and nature of antibiotic resistance in pathogenic bacteria as well as proposals on limited study of the: R plasmids in I.:ht·! faec.al flora of the general population of the respective countries have been made and d~guments in favour of these schemes have been given by the group (see section 5.1). 6.3.2 Effects of ceasing to administer antibiotics
~
There is insufficient information about the effect of the reduced use of individual antibiotics, either as a result of a planned policy or restriction or as a consequence of the introduc.tion of new antibiotics, on the prevalence of resistant bacteria and of clinical infect.ions caused by them. Some can found in published papers, but the findings of workers l,r) different hospitals are often difficult to compare. Guidelines for recording relevant info'tmation are urgent.ly needed. The introduction of detailed schemes for the monitoring of antibiotic use in many hospitals should provide a good starting point for improved studies. The effect of the duration of antibiotic administ~at1on~ in communities and individuals~ on the persistence: of resistant flo1"a after the antibiotic has been withdrawn requires fw:the:r study.
WHO/BVI/PHA/ANT/82.1 page 19 6.3,3 Non-human sources of resistance plasmids
There ;8 still considerable doubt about the relacive exposl're of human subjects by the oral route to faecal coliform bacteria derived, directly or indirectly, from meat and other 8nimal products, from vegetables, and from other sources. This is very difficult to
investigate because the organisms from the various sources are at present indistinguishable in the labQ';r;'atory. ~nd
A combination of indirect methods, e.g. quantitative studies of raw products 8:
of the foods actually ingested, and the use of bacterial and non-bacterial markers, might general picture.
e.ventu.::!.1, ly yield
6.4
Health service research
•
Opinions differ about optimal methods of education on matters concerned with the administration of antibiotics. Studies of the effects of various types of education in imparting information and in affecting prescribing practice are indicated~ and perhaps also of the effects of internship experi~nc~ in different types of hospital department_ The attitudes of physicians to the objective assessment of their prescribing habits~ and ways of encouraging ac.ce.ptance of "peer ass~ssrne.nt" ~ need investigation • 7. 7.1
CONCLUSIONS AND RECOMMENDATIONS ~eral
The increasing frequency of acquired resistance to antibiotics among bacteria of medical is a worldwide health p~oblem that demands international attention. The World HCCllth Organization has kept the: situation under revieW' for twenty years, during which time it h.:l.S pt"omoted research into various aspects of the pl."oblem. However~ the. rapidity with which new resistances are appearing and existing t'esistances are be.coming mOre prevalent indicate. the. need for more precise information about the situation and for action to control it. impo~tance
The importance of antibiotics to health care in all countries is reflected in the composition of the WHO Model List of Essential Drugs j 91 and, potentiallYj the Organization has an important coordinating role to play in ensuring that these drugs are used everywhe~e to optimum advantage. 7.2 Surveillance of bacterial resistance
•
The group is in full agreement with the emphasis placed by previous WHO meetings 1 ,2 J 3 on surveillance of bacterial resistance at both the national and the international level with a view to providing health authorities~ doctors and pha~maceutical companies with data on which the use and futu~e development of antibiotics may be rationalized. Efficient integration of surveillance activities internationally will depend upon the establishment of regio~al and national reference centres J and their subsequent collaboration both in standardizing methods of antibiotic susceptibility testing, and training personnel working in peripheral laboratories and institutes of quality control; WHO could play an important role. in promoting the.se ac.tivi.ties. 7.3 National surveillance of antibiotic use
Information is urgently needed about the pattern of antibiotic use in each country with the objective of assessing the extent of overuse) misuse (and underuse) of various ag~nts in the common clinical situations encountered in the country. The extent to which the: ,:1,dvertising of produ~ts in the lay and medical press contributes to this requires investigatiorr. Th~ expecte.d effect of various regulatory measures, the provision of reliable informati~n~ cost, etc., on the quality of antibiotic use should be studied. Areas should be defined in '!.l'hic.h furthe~ investigations are ne.ede.d to determine. the relative efficacy, in X'elation to cost;:~ and the safe:ty~ of regimens of antibiotic administration currently employed in the various countries.
WIl0/nVL/PtlA/ANT/82.1 page 20
(a)
Importation and manufacture of antibiotics
Countries should dev~lop their own schemes for antibiotic manufacture and import control what antibiotics are: manufactured in the country or imported into it. Countries should inl;:rodl,.lce a st.rong and we.ll designed nat.ional formulary for antibiotics and update this regularly on the advice of pharmacologists and microbiologists; WHO provides guidance. for this. 91 Special ~e.ntion must be made of the widespread use, particularly in developing count~ies~ of p~eparations containing two or more antibiotics in fixed ratios. Their spectrum of activity is often so wide that they have undesirable effects on the body flora~ few of them have notable the~apeutic advantages~ and they are generally costly. Only the few such CQ~binations that are of clinically proven value, should be available. I.)f
(1))
AvaUabiUty of antl.bi.otl.cs
The un~est~1cted sale of antibiotics to the general pub1ic encourages excessive and l.nappropriate use. Legislation making them available only on prescription by designated classes of professional persons (e.g. medical and veterinary practitioners) is therefore highly desirable and strongly recommended; however, such laws have proved very difficult to enforce in some countries. A possible solution to this difficulty may be through limiting the routes by which antibiotics are distributed to the hospitals, the government pri~ry health care service, and registered pharmacists, coupled with increased supervision of pharmacists who provide antibiotics directly to the public and attempts to educate th~ in the indications for antibiotic use. In countries with an acute shortage of doctors in pr~ry health care it may be necessary to empower health workers who have received little formal training to administer antibiotics. High priority should be given to the in-service training of these workers in the use of antibiotics and to monitoring their prescribing practices. Consideration should be given, in countries in which the control of antibiotic uSe i8 particularly diff1cult~ to restricting the supply of certain antibiotics required for the treatMent of very serious infections to hospitals, or even to selected hospitals.
(c)
Education
Countries should provide, through their programme of health education for the general simple advice about the types of illness in which the use. of antibiotics is not indlcat~d. They have a responsibility to ensure that the correct use of antibiotics receives adeq\late attention in the training not only of medical students but of all categories of health wo'('ke~6 who may be concerned in the administration of antibiotics. Adequate facilities should be provided for the continuing postgraduate education of medical practitioners~ whether or not they are in the gove~nment service. Countries should also diss~1nate reliable and up-to-date information to all ~dical practitioners about the efficacy of~ indication for; and contra~ indications to~ and unwanted side effects from the use of individual antibiotics by means of a periodical publication (see. the British "Prescriber's Journal" and "Drugs and Therapeutics Bulletin't, and the American "AMA Drug Evaluations"). pl.lblic~
~
'
Manufacturers and importers of antibiotics should be required to p~ovide the same to users in all countries in which their products are sold; this should always include the gene:ric name of the produet~ the indications and contrindicat1ons for use, and the side effects.. The Working Group welcomed the efforts of WHO's Expert Committe.e on ~ssential Drusa to prepare data sheets for international use. 91 It is the duty of countries to ensure that evidence is obtained through the existing WHO certification scheme for drugs moving in international commerce. The same standards should be enfo~ced in respect of drugs manufactured in the country. Countries should monitor the claims made by antibiotic manufacturers and distributors in advertisements in the ~dical and lay pX'ess. (d) info~mation
7.4
Emergency actions
The Working Group considered lines of action that ~ight be taken if an epidemic of severe infections caused by an o~ganism resistant to all available antibiotics occurred in a developing country. To meet such an emergency~ manufacturers of "newt! antibiotics should be invIted to contribute a limited supply of these to the WHO Emergency Relief Office, where they would be held in reserve £o~ prompt iBsue~ under WHO coordination, to the government of the affected country.
WHO/BVI/PHA/ANT/SZ.' page H
7.5
Veterinary use of antibiotics Since the use of antibiotics is an important means of treating bacterial diseases in
•
animals, as in human medicine, (a) antibiotics for this purpose should be avnilable only on prescriptior'l by a licensed person; national aut.horities should organize t.he. education of these persons in the prope.r use of antibiotics; (b) countries should be encouraged to prohibit. the therapeutic use in animals of ce.rtain newer antibiotics of value for the. tt"eatment of serious infections in man (e:.g. gentamicin and related aminoglycosides, spectinolnycin, rifampicin); (c) the re:connnendation of an earlier WHO Working GX'oupl that chlQramphenicol should be: re.served for use. in man i;; endorsed. However, it is :recognized that this antibiotiG is still widely used for the oral treatment of salmo~el1osis in animals. In order to restrict its use to the treatment of infected animals under the care of a. veterinary sut"geoTI, this drug should be available for veterinary use only as a parenteral preparation; (d) large number~ of antibiotic preparations for intramammary administration in cases of mastitis arc being marketed. Often these are mixtures of severa.l antibiotic.s. For reaSOns given earl", (section 4.2)~ the use of fixed-ratio combinations of antibiotics, other than a few of proven efficacY1 should be discouraged, if necessary by a.dministrative action; (e) the routine use of antibiotic prophylaxis in the. absence of proven infection is no s1,1bs't.itute for good hygiene in animal rearing establishments .
•
W Hoj1lVljl'HAjANTjeZ.1 page 22 REFERENCES 1. World Health Organization (1974) The Public Health Aspects of Antibiotics in Foodstuffs. Report on a Working Group, Bremen~ 1-5 October 1973, WHO Regional Office for Europe 1 Copenhagen World Health Organization (1976) Public Health Aspects of Antibiotic-resistant Bacteria in the environment~ Reporl;. on a consultation meeting, Brussels, 9~12 December 1975, ~IO Regional Office for Europe, Copenhagen World Health Organ;.zation (1978) Surveillance for the prevention and control of health hazards due to antibiotic-resistant e:nterobacteria~ Techn. Rep. Ser. t No. 624 McGowan, J. E., Barnes, M. W. & Finland, M. (1975) J. Infect. Dis .. 132, 316 Parker, M. T. et a1. (1974) Ann. N.Y. Acad. Sci., 236, 466 Elwell, L. P. et a1. (1975) Infect. and IllIIIlun ..
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Murray, B. E., Rensi.mor, E. R. Ii< Dupont H. L. (1982) New Engl. J. Med., 306, 130 Lyons, R. W. et a1. (1980) J. Am. Med. Ass., 243, 546 Rowe, B. et a1. (1979) Veterinary Record, 105, 468 Ryder, R. W. et a1. (1980) J. Infect. Dis., 142, 485 Unton, A. H. (1981) Veterinary Record, 108, 328 Anderson, E. S. (1968) Erit. M"d. J.,
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Ho,",,,, K. Ii< Linton, A. H. (1976) J. App1. Bact .. Unton, A. H. (1977) Veterinary Record, 100, 354 Unton, A. H. et a1. (1977c) J. Appl. Bact.,
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Howe, K .. Linton, A. H. & Osborne, A. D. (1976) J. Appl. Bact., 41,37 Linton, A. H. et a1. (1977a) J. App1. llact., 42, 89 Linton, A. H. et a1. (1977b) J. Ape!. Bact.,
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O'Brien, T. F. et at. (1978) J. Am. Med. Ass., 239, 1518 Price, D. J. E. Ii< SloLgh, J. D. (1970) Lancet, ll,. 12D Lowbury, E. J. L., Roe, E. Ii< Babb, J. R. (1972) Lancet, ll,. 941 McGowan, J. E. Ii< Finland, M. (1974) J. Infect. Dis., 130, 165 Guinan, M. E. et al. (1979) Sex. Transm. Dis., ~
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86. 87. 88. 89.
Evans. A. J., ~orrison, G. D. & rrice, D. J. (1970) Brit. J. Vener., 56, 88 Casewell, M. W., Pugh, S. & Dalton, M. J. (1981) J. Hosp. Infect., ~, 55 B~gshawe, K. D., Blowers, R. & Lidwell, O. E. (1978) Brit. Med. J., ~ 609
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Evaluation of aseptic techniques and chlorh@~idine on the rate of catheter-associated urinary tract infections. Lancet, !~ 89 Report of Southampton infection control team (1982)
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Second Report of a
Petrocheilou, V., Richmond, M. H. & Bennett, P. M. (1977) Antimic'Ob. Agents Chemother., li, 219 Petrocheilou, v., Richmond, M. H. & Bennett, P. M. (1979) Antimicrob. Agents Chemother.
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93.
li,
225
t
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WHOjUVIjPJ:lAjAl'ITjS2 .1 page 26
ANNEX GUIDELINES FOR THE APPROPRIATE USE OF Al'ITIBIOTICS 1. Ob iectives
The first of these is the: successful tre.atment of infection in the patient, but treating one patient may increase the. ~isk to others of acquiring an infection with resistant organism~. To m;Lnirnize this risk: (1) the antibiotic used should be the one to which the infecting organism has been shown or, if this is not practicable, to which the putative. infecting
tu be sensitive;
orgaoJ.sm can be e.xpected to be sensitive; (2) (3) it should have as narrow a spectrum of activity as possible; it should be given in dosage and by a route appropl;"iate to effect cure;
and
(4) 2•
it should be used tor the least possible time.
The therapeutic use of antibiotics
The correct use of antibiotics for treat~ent depends on accurate clinical diagnosis supported whenever possible by laboratory evidence of the nature of the infecting organ1sp~ and its susceptibility to antibiotics. 2.1 Good clinical practice
•
Under optimal conditions the physician will obtain assistance in interpreting the paticntls signs and symptoms from ancillary services (laboratory tests, radiographs, and so on). He must know how to deploy these and to interpret their results correctly. In many cases however, it is necessary to begin treatment before the causative organism has been isolated J and in others it may not be possible to obtain laboratory evidence of its identity, "BE-~st-choi(:e" treatment of sevel."e infections must in these circumstances be based on experience .:l[ld on. a knowledge of the current antibiotic susceptibility of the more likely causes (.);f the infe.ct;h>o. Physic.ians without laboX'ato'l"y support, notably those working in developing C:O\.lr'ltrles~ need special tra.ining in the performance of simple. laboratory procedures~ such as the. mic.roscopic examination of cerebrospinal fluid pus and othe.X' exudates, counting of le~lcocytes~ and selected serological tests. 1 1
2.2
Efficient laboratory support
A good laboratory service can do much to improve the quality of antibiotic prescribing. Reporting of results should be as rapid as pOSSible; provisional reports, based on microscopic examination or preliminary cultural and sensitivity tests, if given by telephone with suitable e.xplanation, are particularly valuable in guiding initial treatment in meningiti~, septicaemia and othe.r serious infections. Rapid methods, e.g. of blood culture, detecting ha.<.:tet:"ial antigens in exudates, and antibiotic-sensitivity testing, should be employed whenE!'.ver possible in these infections. The laboratory should re.port only relevant infor~tion; it has a responsibility to 8.ss€.ss the clinical significance of its findings and re.poX't in the. light of this. When the physician does not prOVide: enough clinical infOX'""lnation foX' this to be done, the. laboratory should not hesitate: to seek this iX'om him oX' his staff. Selective reporting of the l:"esl,11ts of antibiotic~sensitivity tests is a useful nte:thod of influencing the choice of antibiotic. RestLlts should be given only in respect of organisms thought to be of clinical Signifia.ance. For significant organisms, results for antibiotics of first choice only are given J thORe for other antibiotics being withheld and release.d only on request from the physician. Generic names of antibiotics should be used.
•
WHO/BVI/PHA/ANT/82.l page 27 Annex
3.
the prophylactic use of antibiotics
a~t1biot1cs should be used prophylactically only when there ~. good evidence that this will significantly reduce the frequency of infection. With a few exceptions that will be noted below, this will be in situa~ions in which the risk of infection is short-lived and it is practicable to give the antibiotic before the infecting organism has multiplied significantly at the expected point of its entry into the body.
3.1
Prophylaxis in surgery Acce.ptable: indications include "contaminated U surg@'t'y when the risk of infection is high,
and "clean" surgery when though the risk of infection is low its consequences would be disastrous. Ther@ is no justification for its use in other classes of "clean" surgery
(e.g. herniography, thy~oideetomy, craniotomy), nor does it appear to be very effective. Many surgeons seek Co compensate fo!." poor hygier~ic conditions in their operating theatre or wards by employing prophylaxis as a routine for IIclean" surgery; this results in excessive antibiotic use and is certainly counterproductive. Clinical trials support the use of antibiotics in relation to the follOWing procedures: limbs~ the insertion of prosthetic devices, and in cardiac surgery; in "contaminated ll surge.ry: abdominal (large bowel, small bowel with blinci loop, gal1-bladde~ in high~risk patients~ p~netrating accidental wounds)j pelViC (vaginal hysterectcrroy~ Caesarian section with ruptured membranes); urological, when the urine is infect@dj recent compound fracturej human bites.
in "clean" surgery, for the amputation of ischaemic
Prophylaxis should be strictly perioperative. It should not begin more than a few hours before the operation. The aim is to maintain high tissue levels of antibiotic for the duration of the operation and for a few hours afterwards. It should not be given for a total period exceeding 24 hours. The presence of a drainage device in the wound does not justify prolonging this period~ The prophylactic agent chosen should be effective against organisms likely to invade from the site of the operation, e.g. gram-positive cocci in cardiac surgery and joint replacement~ g~am-negative aerobes and anaerobes in abdominal surgery~ clostridia in leg amputation. Dosage should be high enough for maximal tissue concentrations to be attained. The systemic ~oute is generally preferred. For intestinal procedures some surgeons prefer to give prophylactic agents orally or by suppository in combination with mechanical cleansing of the bowel. It is particularly important not to begin these forms of prophylaxis too soon.
•
3.2
Non-surgical prophylaxis
There are few clear indications for this in hospital patients J though it is widely practised in hospitals~ with many consequent ill-e:ffe:cts: adverse drug reactions and superinfection in the patient~ infections with resistant organisms in other patients~ and high hospital costs~ FortunatelYJ most of the conditions in which non-surgical prophylaxis is clearly beneficial oceu~ in Single patients or small groups of patients scattered throughout the general population. The adverse consequences of prophylaxis in these circumstances are less. Non-surgical p~ophylaxiB
may be justified tor the following purposes:
(1) Prevention of rh@umatic. fever: (a) "primary" prevention in patients with no pre.vious history of the disease:; and (b) IIsecondary" prevention of subsequent attacks. (2) Ptevention of secondary cases of meningococcal or H. influenzae meningitis in family contacts of caSeS. (3) Prevention of tuberculos.s in high,risk groups.
WHO/BVI/PI!A/ANT/82,1 pag" 28
Annex (4) ~evention of endocarditis in patients with damaged heart valves when dental or genitourinary procedures are performed~ (5) Long-term low-dose administration of cotrimoxazole or certain other agents for the prevention of recur~ent urinary-tract infection in selected patients. Cond~cions for which prophylaxis has not been clearly shown Co be effecttve include the
following: (1) (2)
Cardiac catheterization and the insertion of pacemakers, Prevention of recurrenCeS in acute glomerulonephritis.
(3) Prevention of pneumonia in patients with viral infection of the upper respiratory tract or measles. (4) Prevention of pneumonia and septic complications in patients with a variety of serious medical condit1ons~ including co~~ respiratory failure, congestive heart failure. (5) Prevention of acute exacerbations in chronic bronchitis.
~,
(6) Protection against infection of patients with immuno-deficiency, either natural or therapeutically induced, unless the condition is limited in duration and facilities are available for strict protective isolation of the patient. ),3
Other prophylactic uses of anttbiotic5
The topical application of broad-spectrum antibiotics to chronic skin les1ons~ including varicose and decubitus ulcers and burns~ is a relatively ineffective means of prophylaxis and a potent cause to the dissemination of resistant bacteria; it is believed to have contributed conSiderably to the increasing frequency of aminoglycoside resistance in staphylococci and gram-negative bacteria. It may also induce hypersensitivity with an associated risk of crossallergy to related antibiotics. oral tetracycline is reported to be an effective means of inhibiting the development of acne lesions and is widely used for this purpose. There is evidence that it selects for antibiotic resistance in the natural flora of patients, and that the resistant organisms may be transmitted to fSIDily contacts. The prophylactic use of tetracycline should therefore be considered only in severe cases of acne. 88 , 90
~