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Penicillin for Gonorrhœa

THE LANCETLONDON: SATURDAY, APRIL 15, 1950 0

THE tests of time and experience seldom justify theenthusiasm which new remedies so often arouse.

Penicillin provides an exception to the rule ; for fewwould have ventured to predict that it would be aswidely useful as it has proved. In the treatment

of gonorrhoea, for example, it rapidly abolishes theobvious symptoms and signs ; the complications,once frequent and intractable, are now relativelyuncommon ; and there is no evidence that strainsof gonococci have become penicillin-resistant. Theseresults have been achieved with dosage which seemsabsurdly small, and there are no dangers except forthe occasional possibility that the signs of earlysyphilis acquired at the same time may be masked ordelayed. Perhaps, indeed, the real trouble about thismethod of treatment is that it has been too effective,and has therefore filled patient and doctor with aconfidence which no remedy has ever justified. Withpatients it could hardly be otherwise : they are

concerned with symptoms and signs, and these arepromptly suppressed ; the doctors who treat themhave no doubts about the outcome ; and, after all,penicillin has been hailed in the popular press as

" the wonder drug." Of the series of 1788 male

patients treated by KING, CURTIS, and NicOL, whodescribe their results in our present issue, only 403stayed to complete three months’ observation aftertreatment, and no fewer than 341 did not attend againafter treatment had been given. The women weremore faithful, yet only 265 out of 481 completedobservation and 49 did not attend again after treat-ment. But the doctors who give treatment bear amuch more serious responsibility, and it may well bethat this responsibility is often taken too lightly.Whatever may have been the case some years ago,

the treatment of gonorrhoea is not now limited to

specialists : many general practitioners treat such

patients and some receive treatment in other specialdepartments. Nothing has happened in the past threeyears which need modify our view that this may beadvantageous to the patients concerned, provided thosewho treat maintain certain standards and acceptcertain obligations. But there are disquieting reportsthat the standards then recommended are not

generally observed. Far too many patients with dis-charges receive large doses of penicillin without anyattempt at bacteriological diagnosis ; and if thesymptoms subside, as they often do, no attempt ismade to establish cure by observation and tests.KING and his colleagues contend that some of thecures claimed are apparent rather than real, and

though the evidence with which they support theircontention is not absolute it is highly suggestive. Ifthe remedy is as fully effective as is generally supposed,it is certainly odd that the incidence of the disease

1. Lancet, 1947, ii, 248.

has fallen so little in communities where the infectedalmost all seek treatment. In the United States it is

reported that, though the incidence of early syphilishas shown a satisfactory fall, the incidence of gonor-rhoea has actually risen in recent years. In this

country it is true that the figures for patients attendingthe public clinics with acute gonorrhoea have shownsome decline, but this decline is much less satisfactorythan that of early syphilis. The following figurestaken from the annual reports of the chief medicalofficer of the Ministry of Health give a basis for

comparison of the incidence of gonorrhoea after thefirst world war and after the late war. In 1920,the year of highest incidence after the first war, thefigure was 40,284 ; in 1921 it was 32,433, and in 1922it was 29,477. The peak year after the late war was1946, when the figure was 47,343 ; in 1947 the reportedincidence was 36,666, and in 1948 it was 30,312. Itdoes not seem likely that this decline owes much to afully effective remedy, especially when due allowanceis made for the fact that so many cases are treatedelsewhere than at the public clinics and are thereforenot included in the figures of incidence. If thesedoubts are well founded, it seems that much latentinfection is being set free among the population ; andwe know that such infection carries a serious late

legacy of incapacitating illness, both mental and

physical.Clearly the time has come for reassessment, and

the plea for care and conservatism should not be

ignored. Formerly gonorrhoea suffered from neglect,through indifference or despair; and it would beunfortunate if equal harm were now done throughover-confidence.

Eosinophils and Surgical ShockTHE use of adrenal cortical hormones in ’surgical

or traumatic shock is based on SELYE’S concept ofthe " stress reaction." Under the influence of stressthe pituitary gland releases adrenocorticotropic hor-mone (A.C.T.H.), which in turn stimulates the adrenalcortex to release its steroid hormones, particularlythe so-called 11-17 oxysteroids. Adrenalectomisedanimals and patients with Addison’s disease are

specially liable to develop shock, even fatal shock,after relatively minor operations ; but, by givingthem large quantities of the appropriate adrenalhormones beforehand, the shock can be prevented.Furthermore, in patients with properly functioningadrenals there is a considerable increase of ketosteroidexcretion in the urine after surgical operations. If,therefore, we could find a way of assessing the functionof the adrenal cortex before such operations, we mightdetect the patients likely to have a troublesome

postoperative course, and we could also tell how muchof the postoperative shock is really due to adreno-cortical deficiency. With this end in view, RoCHEand his colleagues 1 have been studying the eosinopeniathat characteristically follows the administration ofA.C.T.H. if adrenal function is normal.The connection of lack of eosinophils in the blood

with severe illness was noted as long ago as 1907by LAMS,2 who also observed that the eosinophillevel returns to normal or above when convalescence

1. Roche, M. Thorn, G. W., Hills, A. G. New Engl. J. Med. 1950,242, 307.

2. Lams, H. C.R. Soc. Biol. Paris, 1907. 62, 489.

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sets in ; eosinophilia, in his view, is a good prognosticsign. RocHE and his colleagues have used the modernwet count of eosinophils, which is much quicker andmore accurate than indirect estimation from a

differential count on a stained film. They confirmedthat a surgical operation is soon followed by a

profound fall, and often a complete disappearance, ofeosinophils in the blood. This eosinopenia is mostsevere 5-8 hours after the operation begins, and it

persists for some hours; but usually by 24 hoursrecovery has begun and the eosinophils rise again,often reaching levels above the normal in the next7 days. Xow, as a rule the level of eosinophils in theblood at any one time means little ; it is the changein that level under different conditions that matters.But it is clear that if in the period from 4 to 24 hoursafter the start of a surgical operation the patient’seosinophil level is very low, it can be assumed thatthe adrenal cortex is functioning properly, and evenif the patient is shocked there is no indication for

giving adrenal cortex hormone. The only cautionsare that the patient must not have an aplastic bone-marrow, or an allergic eosinophilia. To illustratetheir point, RoCHE and his colleagues quote a verystriking case. In 12 normally reacting patients, theeosinophil levels in the blood 10 hours after operationwere about 0-5 per c.mm. The unusual patient wasa man operated on for a suspected lesion of the

sigmoid colon who was profoundly shocked afterwards ;his blood eosinophils 10 hours postoperatively were260 per c.mm. ; the patient died in spite of theadministration of adrenal cortex hormones, and atthe necropsy he was found to have tuberculosis ofboth adrenal glands, only a little functioning glandremaining.

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It is evidently important that we should know thestate of the patient’s adrenocortical reserves beforeoperation. so RocHE and his co-workers have devisedtwo tests to provide this information. The first usesA.c.T.H. : after blood for the eosinophil-count hasbeen taken, 25 mg. of A.C.T.H. is injected intramuscu-larly and 4 hours later the eosinophil-count is repeated ;the fall must be at least 50% to indicate thatadrenocortical reserves are normal. The second testis based on the observation that a small dose-0-3 mg.-of adrenaline will also cause a fall in circulatingeosinophils ; it is thought that the adrenaline actson the hypothalamus or the pituitary which in turnstimulates the adrenal cortex. The test is thus oneof pituitary-adrenocortical reserves. It is carriedout by injecting 0-3 mg. of adrenaline subcutaneouslyand counting the blood eosinophils 4 hours later ;again a fall of 50% or more indicates normal reserves.

These tests were tried on two patients with pituitarylesions who might well have had a stormy postoperativecourse. The first patient had had intensive X-raytherapy of the pituitary gland for Cushing’s syndrome10 months before she was admitted to hospital fora hysterectomy. With both adrenaline and A.C.T.H.tests there was a significant fall in eosinophils, whichsuggested that the operation could be undertakenwithout undue risk. The operation was duly performed,and recovery was uneventful. The second patient hada chromophobe adenoma causing visual impairment ;with the adrenaline test the eosinophils actually roseslightly, while with the A.c.T.H. test only a 15% fallwas recorded. Difficulties were anticipated and an

attempt to begin the operation failed because of shockcaused by the anaesthetic. She was therefore treatedfor 6 days with large doses of A.C.T.H., by which timethe eosinophils in the blood had fallen 75% and theurinary excretion of ketosteroids had increased from0-9 to 8-9 mg. in 24 hours. The operation was thenperformed without incident, and, though the patienthad a difficult time after the operation, she recoveredsatisfactorily. The number of cases reported byROCHE et al. is small, but their work is sure to berepeated, and if it is confirmed the surgeon will wantto know his patients’ eosinophil-counts. Stimulated

by the work with A.C.T.H. in rheumatoid arthritis, thetechnique of eosinophil counting is being improved.Most laboratories use DuNGAR’s method in some form,but this has disadvantages, especially for large-scaleuse; methods like that of RANDOLPH,3 which usepropylene glycol in the diluting fluid, are cominginto use.

Apart from its immediate importance, there are

two interesting points about this work. It is one ofthe first applications of A.C.T.H. and its effects as a" research tool in conditions other than rheumatoidarthritis. And the results suggest that shock due tofailure of adrenal cortical function is likely to be dis-tinctly rare, so that large amounts of adrenal corticalhormone will be saved for the patients who reallyneed it.

Chloromycetin in Typhoid FeverUNTIL lately typhoid fever had resisted all attempts

at chemotherapy. Most of the sulphonamides intro-duced in the past fifteen years have been tried in thisdisease, but the initially favourable claims for severalof them were soon disproved. The same process hasbeen repeated with each of the antibiotics hithertotried-penicillin, streptomycin, aerosporin (poly-myxin), and Aureomycin ’-and even the promising

results reported with penicillin and sulphonamidescombined have not been repeated. There is goodreason, therefore, for caution in interpreting theremarkable clinical effects of chloramphenicol.

In the last few months an increasing stream ofclinical reports have appeared in this country andabroad confirming the original observations ofWOODWARD and his colleagues 4 with chloromycetinin the treatment of typhoid patients in Malaya. Someof these have already been reviewed in these columns.5The drug’s action on the constitutional symptoms areso striking that the clinicians are unanimous in

acclaiming its value, even though some failures havealso been recorded. Thus, out of 6 severely ill patientstreated in Bombay by PATEL et al., 3 died and 1

relapsed ; and in a series of 63 patients treated inItaly by CONTI and his colleagues there were 4deaths and 9 relapses. DANA et al. 8 have described 5cases treated in Tunis which showed an alarming risein blood-urea ; 3 of these patients died, but the other2 improved when the chloramphenicol was stoppedand they eventually survived. In our correspondencecolumns this week Dr. STEPHENS reports a case from3. Randolph, T. G. J. Lab. clin. Med. 1949, 34, 1696.4. Woodward, T. E., Smadel, J. E., Ley, H. L., Green, R., Mankikar,

D. S. Ann. intern. Med. 1948, 29, 131.5. Lancet, 1949, ii, 1001.6. Patel, J. C., Banker, D. D., Modi, C. J. Brit. med. J. 1919, ii, 908.7. Conti, F., Cassano, A., Monaco, R. Rif. med. 1949, 63, 901.8. Dana, R., Sebag, A., Cohen, J., Borsoni, G. Tunisie med. 1950,

38, 190.