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in the plant concerned and in other plants. Indeedit is urgent that such investigations are carried outin other plants since WHORTON and his colleaguesfound that airborne concentrations of D.B.C.P. inthe factory concerned were below the 1 p.p.m. limitrecommended by TORKELSON et al. on the basis ofwork in animals. Of special interest will be the fol-low-up of the aspermic men. In animals, the steri-lity induced by D.B.c.P. has proved to be reversible.But this welcome information is offset by the

finding that D.B.c.P. is carcinogenic in laboratoryrats and mice. OLSON and his colleagues3 reportedthe early occurrence of mammary tumours andsquamous carcinomas of the stomach in rats

exposed to the maximum tolerated dose (24mg/kg/day) of D.B.c.P. by once-daily gavage incorn oil, or half the M.T.D. administered in thesame way. In a parallel study in mice daily dosesby gavage of up to 260 mg/kg/day gave rise tosquamous carcinomas of the stomach only. LaterROSENKRANZ4 found D.B.C.P. to be a bacterial

mutagen.Chlordecone (’Kepone’) is another organochlor-

ine pesticide which has attracted attention becauseof an effect on the testis. J. R. TAYLOR and his col-leagues in the United States5 observed signs of toxi-city affecting the nervous system, the liver, and thetestis in workers heavily exposed to kepone. Theeffects on the testis were limited to oligospermiaand hypomobility of sperm. This seems to be anexample of the sort of poor occupational hygienewhich unjustifiably gives pesticides a bad name.The toxic effects relate to the levels of chlordeconein the tissues, and without treatment these fall onlyvery slowly.6 An important advance in this connec-tion was a report earlier this year of the value ofthe anion-exchange resin, cholestyramine, in thedetoxification of people exposed to chlordecone orother lipophilic toxins such as D.D.T. Cholestyra-mine acts by binding with chlordecone excreted inthe bile and preventing its reabsorption from thegut. The status of chlordecone in relation to car-

cinogenicity is uncertain. Tremors, skin lesions,and liver tumours were seen in rats and mice

exposed orally to M.T.D. of chlordecone for 80weeks in a study sponsored by the U.S. NationalCancer Institute.8 But in neither species was therean excess of tumours at any other site and someauthorities are reluctant to accept that such resultsfrom M.T.D. exposure studies are unequivocally in-

‘

dicative of hazard at much lower levels of expo-sure.

The debate on the risk-benefit equation for pesti-

3. Olson, W. A., Habermann, R. T., Weisburger, E. K., Ward, J. M., Weis-burger, J. H. J. natn. Cancer Inst. 1973, 51, 1993.

4. Rosenkranz, H. S. Bull. envir. Contam. Tox. 1975, 14, 8.5. Taylor, J. R., Selhorst, J B., Houff, S. A., and others Neurology, (in the

press).6. Hayes, W J. Toxicology of Pesticides; p. 379 Baltimore, 1975.7. Cohn, W. J., Boylan, J. J., Blanke, R. V., Fariss, M. W., Howell, J. R., Guze-

lian, P. S. New Engl. J. Med. 1978, 298, 243.8 National Cancer Institute Technical Report, 1976.

cides attracts many voices. Some stress the dangersof toxicity-including carcinogenicity, teratogeni-city, and mutagenicity for man-while others aremore concerned with potential ecological effects.These voices sometimes almost drown the remon-strations of those who have knowledge of the

ravages which pests can bring if not controlled.The debate will long continue and rightly so.

Meanwhile, and whatever its outcome, there can beno excuse for exposing factory workers to toxiclevels of any pesticide.

Antibiotic Antagonism and SynergyAs many as a fifth of patients with infections in

hospital receive two or more antibacterial agentsconcurrently. What are the proper grounds forcombined antibiotic therapy? Certainly two antibi-otics may be necessary in the initial therapy ofsevere undiagnosed infection, and for treatment ofmixed infections where the pathogens do not sharean antibiotic susceptibility. Combined therapy mayprevent the development of resistance to certaindrugs; for example, penicillin may be given withfusidic acid to prevent emergence of fucidin-resis-tant mutants. Dose-related toxicity of certain drugsmay be reduced by administration of a second

agent permitting smaller doses to be used: 5-fluoro-cytosine is sometimes given with amphotericin Bfor this reason. Two antibacterial drugs may begiven in the hope of achieving synergy-a greaterantimicrobial activity than the sum of the singleagents. The clinical relevance of synergy is oftendifficult to prove, and results of in-vitro tests maynot always predict the activity of antibiotics in

therapy, where pharmacokinetic behaviour is alsoimportant. Principles of antibiotic interaction wereformulated in 1952 by JAWETZ and GUNNISON,]whose broad conclusions were that: (1) two bacter-istatic drugs react to produce an additive effect; (2)(2) a bacteristatic and a bactericidal drug togethermay be antagonistic; and (3) two bactericidal drugsmay be synergistic. Penicillin, streptomycin, baci-tracin, and neomycin were drugs then availablewith bactericidal activity (designated group I) andthe tetracyclines, chloramphenicol, and erythromy-cin formed a group whose activity was primarilybacteristatic (group II). DOWLING has observedthat many variations are possible, depending onconcentrations of antibiotics and susceptibilities oforganisms, but these principles are still accepted asthe basis of antimicrobial interaction. In twenty-five years since JAWETZ and GUNNISON proposedtheir classification, many new antimicrobial agentshave been introduced. How do these drugs fit intothe scheme? A paper by RAHAL3 examines this mat-

1. Jawetz, E., Gunnison, J. B. J. Am. med. Ass. 1952, 150, 6932. Dowling, H F. ibid. 1957, 164, 44.3. Rahal, J. J. Medicine, 1978, 57, 179.

81

ter in detail and evaluates the clinical relevance of

synergy and antagonism of today’s antimicrobialdrugs (antituberculous therapy excepted). Group Inow includes the penicillins, cephalosporins,aminoglycosides, polymixins, and combinations ofsulphonamides and trimethoprim; the lincomycinshave been added to the primarily bacteristatic

agents in group II.

Antagonism between penicillin and tetracyclinein treatment of pneumococcal meningitis was

demonstrated by LEPPER and DOWLlNG4 in 19S 1: inpatients treated with penicillin alone mortality was21% compared with 79% in those treated with

penicillin and tetracycline (who were otherwisewell-matched prognostically). JAWETZ et al.5 haveshown that chloramphenicol may antagonise thein-vitro activity of penicillin on streptococci whenconcentrations of penicillin are low. In dogs withexperimental pneumococcal meningitis chloram-

phenicol was antagonistic when given before peni-cillin but less so when given with or after peni-cillin.6 Clinically this antagonism seems to be

irrelevant, whether in pneumococcal meningitistreated with chloramphenicol and penicillin or inHaemophilus influenzae meningitis treated with

chloramphenicol and ampicillin. In endocarditis, asin meningitis, organisms are not very accessible topenicillin. In rabbits with experimental endocar-ditis caused by penicillin-sensitive streptococci,sterilisation of valves took longer when animalswere given chloramphenicol one hour before peni-cillin than when penicillin was given first. In endo-carditis, the cidal activity of penicillin is essentialand may be eliminated by chloramphenicol, whosestatic effect alone is unlikely to eradicate bacteriafrom this site. In-vitro tests have shown anta-

gonism when klebsiellae are exposed to chloram-phenicol before or at the same time as gentamicin,8although there is no clinical information on the useof this combination in gram-negative infections. Inanimals the results vary with different organismsand states of host defence; normal phagocytosismay compensate for chloramphenicol’s inhibitionof cidal activity. Neutropenia renders a host moredependent on the bactericidal activity of antibio-tics ; clearly, therefore, combinations used to treatleucopenic patients must be fully bactericidal. Anantagonistic ratio between cidal and static antibi-otics is unlikely in sites easily penetrated by bothdrugs given in normal doses. Probably the onlysituation where antagonism is important clinicallyis where rapid bacterial killing is essential for re-covery.

Gentamicin and carbenicillin react synergisti-cally against many strains of gram-negative bacil-4. Lepper, M. H., Dowling, H. F. Archs intern. Med. 1951, 88, 489.5. Jawetz, E , Gannison, J. B., Speck, R. S., et al. ibid. 1951, 87, 349.6. Wallace, J. F., Smith, R. H., Garcia, M., et al. J. Lab. clin. Med. 1967, 70,

408

7. Carrizosa, J., Kobusa, W. D., Kaye, D. ibid. 1975, 85, 307.8 D’Alessandri, R M., McNeely, D. J., Kluge, R. M. Antimicrob. Agents

Chemother. 1976, 10, 889.

li,9 but paradoxically gentamicin is inactivated bycarbenicillin when both are mixed in vitro; the twodrugs should not be infused together. When renalfunction is adequate this reaction is not clinicallyimportant because inactivation in serum is slowerthan excretion of both drugs.1O It may, however, berelevant in patients with renal failure, and whenantibiotic turnover is slow at the site of infec-

tion--e.g., cerebrospinal or pleural fluid.Synergy between penicillin and aminoglycosides

is usefully exploited in the treatment of enterococ-cal endocarditis;1I,12 the synergy found in vitro cor-relates well with clinical response.13 Enterococciare somewhat impermeable to aminoglycosides,and the penicillin probably eases their entry intobacteria by interfering with cell-wall biosynthesis. 14These days some strains of enterococci are veryhighly resistant to streptomycin and there is no

synergy with penicillin; such mutant strainsaccounted for 41% of blood-culture isolates in

MOELLERING’S series. IS None are highly resistant togentamicin, and it is clear that gentamicin shouldnow replace streptomycin for use with penicillin inthe treatment of enterococcal endocarditis.16 Peni-cillin and streptomycin also act synergisticallyagainst the viridans group of streptococci, althoughpenicillin alone is often given, with good results, topatients with endocarditis caused by these

organisms. In rabbits with experimental endocar-ditis a combination of penicillin and an aminogly-coside produces more rapid sterilisation of valvesinfected by penicillin-sensitive streptococci thandoes penicillin alone. 17

These are not the only mechanisms of synergyexploited by combination chemotherapy. Sequen-tial block of steps in a metabolic sequence is theexplanation of synergy between sulphonamides andtrimethoprim, which both inhibit folate synthesis,and trimethoprim and rifampicin are also said to besynergistic against a wide range of bacteria.18 Thesynergy shown by mecillinam with other &bgr;-Iactamantibiotics against many gram-negative bacillimerits further evaluation.I9 One drug may protectanother from enzymic destruction; an example isthe activity of ampicillin against &bgr;-Iactamase-pro-ducing gram-negative bacilli, which is oftenenhanced by cloxacillin and cephalosporins. Thehigh affinity of &bgr;-Iactamase-stable drugs for these

9. Klastersky, J. (editor) Clinical Use of Combinations of Antibiotics. London,1975.

10. Riff, L. J., Jackson, G. G. Archs intern. Med. 1972, 130, 887.11. Jawetz, E., Gunnison, J. B.J. Lab. clin. Med. 1950, 35, 488.12. Mandell, G. L., Kaye, D., Levison, M. E., et al. Archs intern. Med. 1970,

125, 258.13. Standiford, H. D., de Maine, J. B., Kirby, W. M. H. ibid. 1970, 126, 255.14. Moellenng, R. C., Wennersten, C., Weinberg, A. N. J. Lab. clin. Med. 1971,

77, 821.15. Moellering, R. C., Wennersten, C. Medrek, T., et al. Antimicrob. Agents

Chemother. 1970, p. 335.16. Weinstein, A. J., Moellering, R. C.J. Am. med. Ass. 1973, 223, 1038.17. Durack, D. T., Pelletier, L. L., Petersdorf, R. G. J. clin. Invest. 1974, 53,

829.18. Kerry, D. W., Hamilton-Miller, J. M. T., Brumfitt, H. W. J. antimicrob.

Chemother. 1975, 1, 417.19. Neu, H. C. ibid. 1977, 3, suppl. B, p. 43.

82

enzymes prevents inactivation of ampicillin. 20 WISEand others21 have lately reported inhibition of

P-lactamases by clavulanic acid, and the results ofclinical work with this compound should be inter-esting.

Clinical evidence of synergy or antagonism tendsto be elusive even when the experimental data areconvincing. Having reviewed an extensive range ofliterature on this subject, RAHAL’s conclusion is that"an optimistic view of the validity of antibioticsynergy and antagonism would hold that synergy ismore likely to affect therapeutic results than antag-onism. Nonetheless, antibiotics should not be com-bined for purposes of synergy unless therapeuticresults with one of the drugs [are] known to be unsat-isfactory". The possibility that bacterial resistanceto antibiotics may one day seriously limit ourchoice of therapy cannot be dismissed; we shouldperhaps seek more ingenious ways of deployingexisting agents, and a new role for antibiotic com-binations may emerge. Meanwhile, the unwantedeffects of combined therapy-broader suppressionof normal flora, increased risk of secondary infec-tion caused by resistant organisms, obscured diag-nosis, and adverse drug reactions-should temperour enthusiasm for antibiotic combinations.

TRAINING FOR THE SURGICAL LIFE

THE British have a long tradition of craft learning forsurgery backed by the award of a fellowship of one ofthe Royal Colleges after a two-part examination, thefirst in the basic sciences at the outset of training andthe second in the general aspects of surgery at aboutmid-term of apprenticeship. Higher training has grownup somewhat untidily into a system of senior registrar-ships, some rotating, some not, but all in accredited pro-grammes. How effective this is it is impossible to judgeexcept entirely subjectively on the basis of statementsthat range from "we produce the best surgeons in theworld" to "things are not what they were". The finalcertificate of the higher training committees is awardedon the basis of personal report, time served, and rubberstamps.Though senior-registrar accreditation and certifica-

tion were major reforms there has been little stir for

change in the examination system which, by comparisonwith the practice in the U.S.A. and more recently Aus-tralia, sits awkwardly at the gateway to higher trainingand does not assess specialty skills. It can be argued thata formal assessment (particularly by examination) is anaffront to men and women in their thirties, is a brakeon the production of good original work, and in any casehas no proven validity. It can equally well be arguedthat to have assessment sets goals, goes some way to pro-.mote quality, and provides the public with the sameassurances about surgeons as they expect about airlinepilots.

In the past few years two zephyrs of change haveblown. The Edinburgh Royal College of Surgeons has

20. Sutherland, R., Batchelor, F. R. Nature, 1964, 201, 868.21. Wise, R., Andrews, J. M., Bedford, K. A. Antimicrob. Agents Chemother.

1978, 13, 389.

offered its fellows a series of provisional proposals whichwould make the fellowship a yardstick of specialty train-ing and also give the first part a wider role in assessingbasic knowledge of surgery in general. The plan is togive part I the task of assessing a "basic surgeon" fit toenter a specialty training programme (including the spe-cialty of general surgery); the accolade of fellowship willbe bestowed only after a specialist examination at or

about the third year of higher training. Such an examin-ation would include much of the basic science peculiarto that specialty, so lightening the load on the part I andpermitting the introduction of material relevant to thepractice of surgery. These suggestions are still under dis-cussion though, as might be expected in an essentiallyconservative professional climate, there is a tendency towork from Falkland’s axiom "When it is not necessaryto change, it is necessary not to change". Perhaps so farthe most important thing to emerge is that there areclear distinctions between training, examinations, andassessment. It is in this area of educational analysis thatthe other small wind can be sensed. The Australasian

Royal College, already committed to a late-in-trainingspecialty fellowship, has moved on to look at educationalobjectives and technologies. The report of a two-dayconference, orchestrated by a medical educational insti-tute,’ serves notice to sister colleges that the Australiansand New Zealanders are ahead in appreciation of whatthey want their training and assessment to do. The

report outlines goals in specific terms of knowledge andtechnical proficiency, much as some years ago was donefor their part I fellowship.2 The examination system isalso reviewed, with a move toward more in-training as-sessment both by the trainee’s teachers and by others.There are as yet no firm commitments, but here is a realattempt to break from a theoretical and sterile worldinto the open ground of education. No one would claimthat such ground is free from pitfalls and obstacles,amongst which jargon is one of the most important.Nevertheless, analysis makes the framework for a rea-soned discussion and for practical test. We can expect tosee further change in surgical training coming from theantipodes; the older colleges might well need to stirthemselves to make a similar examination of their own

practices-particularly if the Edinburgh proposals donot gain acceptance.

OSTEOSARCOMA: ADVANCES IN TREATMENTOR CHANGING NATURAL HISTORY?

BEFORE 1972, survival-rates for osteogenic sarcomawere universally poor,3,4 with cure-rates of 20% or lesswhether the treatment was primary amputation or irra-diation with delayed amputation. Then came reportsthat the pulmonary metastatic lesions responded favour-ably to high-dose methotrexate with folinic-acid rescue’and to daunorubicin.6 Other groups subsequently triedsimilar regimens and multidrug protocols of adjuvant

1. Surgical Training and Examinations: proceedings of residential seminar onFeb. 25 and 26, 1978, at the Chevron Hotel, Sydney (edited by KennethR. Cox). Royal Australasian College of Surgeons, 1978.

2. Dudley, H. Lancet, 1972, i, 1386.3. Marcove, R. C., Mike, V., Hajek, J. V., Levin, A. G., Huller, R. V. P.J. Bone

Jt. Surg. 1970, 52A, 411.4. Sweetham, R., Knowelder, J., Jedden, H. Br. med. J. 1971, ii, 363.5. Jaffe, N. Cancer, 1972, 30, 1627.6. Cortes, E. P., Holland, J. F., Wang, J. J., Sinks, L. F.J. Am. med. Ass. 1972,

221, 1132.