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Drug Resistance in SalmonellasIN salmonellas, antimicrobial drug resistance is

dispersed in cells by the dissemination of transposons,in strains by the transfer of plasmids, and in human andanimal hosts by the spread of resistant strains.Whatever the method of acquisition, resistance insalmonellas can affect the treatment and ultimately thehealth of both individuals and communities.

In Britain, drug resistance in salmonellas has reacheda critical level. Salmonella typhimurium is not only thepredominant serotype in food-poisoning, but is alsothe serotype in which drug resistance is most common.S. typhimurium infection is primarily a zoonosis and inmost instances resistance is acquired in the animal hostbefore transmission of the strain to man. In 1970 a banwas put on the use, in food animals, of therapeuticantibiotics for growth promotion, but the impact of thislegislation has been uncertain. In the early 1970s therewas a decline in the incidence of isolations of drug-resistant S. typhimurium, 2 but since 1976 strainsresistant to up to seven antimicrobial drugs have spreadin calves and have caused infections in man, some ofthem fatal.3-5 A limited number of strains wereimplicated in these outbreaks. These strains have

sequentially acquired resistance plasmids, which inturn have acquired additional resistance transposons.There is reason to believe that it was the use ofantimicrobial drugs in the treatment and prophylaxisof disease in cattle which resulted in the appearance ofthese multiresistant strains, and that practices in thecalf-distribution trade ensured their widedissemination. As yet, there is no legislation whichrestricts the use of therapeutic antimicrobials for theprophylaxis of disease in food animals.In developing countries of the Middle East, Far East,

South America, and Africa, multiresistant salmonellas

1. Hepner E. Food poisoning and salmonella infections in England and Wales,1976-1978. Publ Health (Lond) 1980; 94: 337-49.

2. Rowe B, Threlfall EJ. Multiply-resistant clones of Salmonella typhimurium in Britain:epidemiological and laboratory aspects. In: Levy SB, Clowes RC, Koenig EL, eds.Molecular biology, pathogenicity and ecology of bacterial plasmids. New York:Plenum Press, 1981. 567-73.

3. Threlfall EJ, Ward LR, Rowe B. Epidemic spread of a chloramphenicol-resistant strainof Salmonella typhimurium phage type 204 in bovine animals in Britain Vet Rec

1978; 103: 438-40.4. Threlfall EJ, Ward LR, Rowe B. Spread of multiresistant strains of Salmonella

typhimurium phage types 204 and 193 m Britain. Br Med J 1978; ii: 997.5. Threlfall EJ, Ward LR, Ashley AS, Rowe B. Plasmid-encoded trimethoprim resistance

in multiresistant epidemic Salmonella typhimurium phage types 204 and 193 inBritain Br Med J 1980; i: 1210-11.

have caused extensive outbreaks. These outbreaks havebeen characterised by the severity of clinical symptomsand an unusually high incidence of septicaemia anddeath. Most of the outbreaks have been in paediatricunits, although infections in older children and adultsand amongst the community have been reported.Several serotypes have been implicated-S.typhimurium in South America, the Middle East, andIndia; S. wien in North Africa, Southern Europe, andparts of the Middle East; S. johannesburg in HongKong; S. oranienburg in Indonesia and Brazil; S.

saintpaul in Venezuela; S. ngbvport in Peru; and S.isangi in Central Africa. In all outbreaks the strainswere resistant to at least six antibiotics and resistanceswere plasmid-specified. 6,7 In strains ofS. typhimuriumfrom the Middle East and India, resistance to

ampicillin, chloramphenicol, gentamicin, kanamycin,streptomycin, sulphonamides, tetracyclines, and

trimethoprim has been observed, and these resistanceswere coded for by a single plasmid.8,9 Outbreaks haveoccurred over wide areas but genetic studies haveshown involvement of only a few multiresistant clones.In contrast to the situation with S. typhimurium inBritain, there is no evidence of animal involvementeither in the acquisition of resistance by the strains or intheir dissemination. The main method of spread seemsto have been person-to-person cross infection, andresistances have arisen as a result of the use of anti-biotics in human medicine in the countries concerned.

S. typhi must be regarded as a special case. Before1970, resistance in this serotype was rarelyencountered, but the situation changed in 1972 when astrain with plasmid-encoded resistance to

chloramphenicol, streptomycin, sulphonamides, andtetracyclines caused an enormous epidemic in Mexico,with many fatalities. 10 Resistances were specified by aplasmid of a compatibility group which appears to havea particular affinity for the typhoid bacillus.

Chloramphenicol-resistant strains ofS. typhi caused anepidemic in Kerala, South India, in 197211 and seem tobe endemic in many countries of South-East Asia.12 InBangladesh, the first isolation of a chloramphenicol-resistant strain has lately been reported. 13 In all

6. O’Brien TF, Acar JF, Falkow S, Threlfall EJ, Lacey RW, Thornsberry C. Globaldeployment of antibiotic resistance genes. In: Nelson JD, Grassi C, eds. Proceedingsof the 11th International Congress of Chemotherapy, 19th Interscience Conferenceon Antimicrobial Agents and Chemotherapy, vol. 1. Washington DC: AmericanSociety for Microbiology, 1980 46-49.

7. Rowe B. Problems of drug resistance in intestinal bacteria in developing countries. In:Pohl P, Leunen J, eds. Resistance and pathogenic plasmids. Brussels: NationalInstitute for Veterinary Research, 1982: 175-78.

8. Rowe B, Frost JA, Threlfall EJ, Ward LR. Spread of a multiresistant clone ofSalmonella typhimurium phage type 66/122 in South-East Asia and the Middle East.Lancet 1980, i: 1070-71

9. Frost JA, Rowe B, Ward LR, Threlfall EJ. Characterisation of resistance plasmids andcarried phages in an epidemic clone of multiresistant Salmonella typhimurium inIndia. J Hyg 1982; 88: 193-204.

10. Anderson ES. The problem and implications of chloramphenicol resistance in thetyphoid bacillus. J Hyg 1975; 74: 1-11.

11. Paniker CK, Vimala KN. Transferable chloramphenicol resistance in Salmonella typhi.Nature 1972; 239: 109-10.

12. Herzog C New trends in the chemotherapy of typhoid fever. Acta Tropica 1980; 37:275-80.

13. Huq I, Samadi AR. Chloramphenicol-resistant Salmonella typhi Vi phage type Aisolated from patients in Bangladesh. Lancet 1982; i: 1125.

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instances, the plasmid which specifiedchloramphenicol resistance was indistinguishablefrom that in the Mexican strain in 1972. In Britain,chloramphenicol resistance in S. typhi is rarelyencountered and for the most part is confined toisolations from patients who have returned from areaswhere chloramphenicol-resistant strains are endemic.However, monitoring for antibiotic resistance shouldbe continued after a patient with drug-sensitive S. typhihas been treated, since resistance can be acquired invivo and can affect treatment. This was conclusivelydemonstrated in a typhoid patient who was treated firstwith chloramphenicol and then with co-trimoxazole.The strain rapidly acquired plasmids which conferredresistance to both these drugs and it was suggested thatthe genes which coded for trimethoprim resistance hadbeen acquired by transposition from a plasmid in astrain of Klebsiella from the patient. 14With drug-resistant salmonellas, a sinister

possibility is that drug resistance may be associatedwith other factors which enhance the virulence or

communicability of host strains. In the recent S.

typhimurium outbreaks in calves in Britain there weremany reports of a disease of unusual severity and thesefeatures were also evident when the strain was spread tocalves in Holland. It may be relevant that a resistance

plasmid similar to one of those in the S. typhimuriumstrains has been shown in calves to increase the

colonising properties of Escherichia coli strains. 15Similarly, plasmids related to that in the strains of S.typhimurium’and S. wien which have caused extensiveoutbreaks in man in the Middle East, India, or

Southern Europe, have been shown to be involved inthe iron uptake system of invasive strains of E. coli 16and to be necessary for the virulence of Shigellasonnei. l7 Although more experimental evidence is

necessary, we are now faced with the possibility notonly that the use of drugs in human and veterinarymedicine has contributed to the advent of resistantsalmonellas and has provided selective pressure whichhas assisted in their dissemination, but also that thevirulence or communicability of these strains hasincreased.

Epidemiology of CataractCATARACT is the commonest cause of blindness in

the world, with a tally of over 17 million. In India alonea million operations are done each year; and even inEngland this is the sixth commonest surgical foray,with more than 20 000 on waiting-lists for extraction.Senile cataract remains the great enigma in

ophthalmology: we do not know what causes the ageing14 Datta N, Richards H, Datta C. Salmonella typhi in vivo acquires resistance to both

chloramphenicol and co-trimoxazole. Lancet 1981; i: 1181-83.15. Linton AH. R plasmids in micro-organisms found on food. In: Pohl P, Leunen J, eds.

Resistance and pathogenic plasmids. Brussels: National Institute for VeterinaryResearch, 1982 75-100.

16. Williams PH, Warner PJ. Col V plasmid-mediated, colicin V-independent iron uptakesystem of invasive strains of Escherichia coli. Infect Immun 1980; 29: 411-16.

17. Sansonetti PJ, Kopecko DJ, Formal SB Shigella sonnei plasmids: evidence that a largeplasmid is necessary for virulence. Infect Immun 1981; 34: 75-83.

lens to become cloudy; and there is no known way ofretarding cataract formation or of dispersing the

opacities that have formed, short of physicallyremoving the opaque lens out of the line of sight. Thisoperation can claim to be the first surgical procedureever practised; and 5000 years later, although boguscataract solvents abound, it remains the only effectivetreatment. Over the past century evidence hasaccumulated for a host of potential aetiological factors;cataracts can be produced experimentally from a widevariety of poisons or physiological disturbances, andare features of many different systemic disorders,patterns of heredity, and environments. But the greatmajority of cataracts arise as a simple senile change. Acampaign has been coordinated by the Group onAgeing of the Crystalline Lens of EURAGE to assess indepth the possible factors and therapies; and shafts oflight from many E.E.C. centres are beginning to

resolve the mass of often conflicting evidence. At thisearly stage the following points have emerged:

1. "Senile" cataract is significantly associated with diastolic

hypertension.I-3 This is consistent with the evidence of cataractdeveloping in many of the Framingham population,4 of differentages, who had systolic hypertension 20 years previously. There isalso an association between antihypertensive drug taking andcataract.

1-3

2. Senile cataract has a long-accepted association with diabetes,and a higher fasting plasma glucose has been noted in the cataractpopulation than in the controls.I-3 This too is consistent with

Framingham observations of an association between cataract andraised casual blood sugar in the 52-64 age-group, again with the20-year delay between the latter finding and the former.

3. There was a significantly higher proportion of "major"tranquilliser takers in the cataract group than in the controls."Major" means barbiturates, monoamine oxidase inhibitors,tricyclic antidepressants, and phenothiazines. The validity of thatassociation is the more convincing because no difference was foundfor minor tranquillisers (diazepam, chlordiazepoxide).

4. The lower plasma calcium in the cataract group than incontrols 1-3 was expected, because hypocalcaemia associated withhypoparathyroidism is a known cause of cataract. 5,6 There is anintriguing inconsistency between that low plasma calcium level andthe high calcium level actually in cataractous lenses, which may bepartly explained away by the low serum albumin 1-3 also observed.

5. The low total protein and low cholesterol (GoswAMY et al.7found a low protein but a high cholesterol), low total CO2, and highurea were all statistically significant but not easy to explain.Meanwhile there is no dearth of sporadic evidence

emerging from other continents and other eras. Thusone of the earliest aetiological theories, attributing

1. Clayton RM, Cuthbert J, Phillips CI, Bartholomew RS, Stokoe NL, ffytche T, ReidJM, Duffy J, Seth J, Alexander M. Analysis of individual cataract patients and theirlenses: a progress report. Exp Eye Res 1980; 31: 553-66.

2. Phillips CI, Bartholomew RS, Clayton RM, Duffy J, Seth J, Reid JM, Cuthbert J,Alexander M. Cataracts: a search for associations or causative factors. Symposiumon The Lens, Montpellier. Amsterdam: Excerpta Medica, 1980.

3. Bartholomew RS, Clayton RM, Cuthbert J, Duffy J, Phillips CI, Reid JM, Seth J,Truman DES, Wilson C, Yim S-M. Analysis of individual cataract patients andtheir lenses: preliminary observations on a population basis In: Regnault F,Hockwin O, Courtois Y, eds. Ageing of the lens Amsterdam: Elsevier, NorthHolland, 1980: 241-61.

4. Kahn HA, Leibowitz HM, Ganley JP, Kim MM, Colton T, Nickerson RS, DawberTR. The Framingham Eye Study. II. Association of ophthalmic pathology withsingle variables previously measured in the Framingham Heart Study. Am JEpidemiol 1977; 106: 33-41.

5. Duke-Elder S. System of ophthalmology, vol. XI. St. Louis Mosby, 1961: 175-82.6. Ireland AW, Hornbrook JW, Neale FC, Posen S. The crystalline lens in chronic

surgical hypoparathyroidism. Arch Intern Med 1968; 122: 408-11.7. Goswamy S, Mathur RL, Agarwal LP. Lipoproteins of the crystalline lens and serum

factors in senile cataract. Indian J Med Res 1971; 59: 1460-66.