ii intensive treatment of gonorrhwea and non …toxic manifestations were of a minor character...

BRITISH JOURNAL OF VENEREAL DISEASES

17. MCLEOD, J. W., COATES, J. C., HAPPOLD, J. C., PRIESTLEY, D. P.,and WHEATLEY, B.: Cultivation of the Gonococcus as a Method in theDiagnosis of Gonorrhea, with Special Reference to the OxydaseReaction and to the Value of Air Reinforced in its Carbon DioxideContent, J. Path. and Bact., 39, 22I, July, I934.

i8. RoSE, DONALD L., KENDELL, H. WORLEY, and SIMPSON,WALTER M. : A Plasma-Agar Medium for Cultivation of the Gonococcus,Amer. J. Clin. Path., 10, 59, May, 1940.

9. THOMPSON, L.: A Simple Method of Supplying Carbon Dioxidein Jars for Bacteriological Cultures, Amer. J. Clin. Path., 5, 3I3, July,'935.

20. GORDON, J., and McLEoD, J. W.: The Practical Application ofthe Direct Oxvdase Reaction in Bacteriology, J. Path. and Bact., 31,I85, April, i928.

II

INTENSIVE TREATMENT OF GONORRHWEAAND NON-SPECIFIC URETHRITIS WITH

SULPHAPYRIDINE * tBy LIEUTENANT-COLONEL A. J. KING, Royal Army Medical Corps,

and MAJOR D. I. WILLIAMS, Royal Army Medical Corps.THE effectiveness of sulphapyridine in the treatment of

gonorrhoea has never been seriously questioned. Fromthe first results were universally good and led naturallyto a spirit of extreme optimism which has now givenplace to the realisation that there are problems still tobe solved, not the least of which is the difficult problemof dosage. From the many and varied schemes oftreatment which are used it is clear that there is nogeneral agreement as to the routine dosage which willproduce the highest proportion of good results while yetavoiding undue toxic effects. Most workers in the subjectnow stress the importance of a high constant Jevel ofblood sulphapyridine maintained by giving larger dosesat first followed by smaller doses at short intervals; andcertainly the general experience is that to give smalldoses at first is to risk disaster in the form of the resistantor " sulphonamide-fast" case. Bowie, Anderson, Dawsonand Mackay (I939) were the first to record their experi-

* A paper read to the Medical Society for the Study of Venereal Diseases inLondon on 25th March, 1941.

t Reprinted by permission of the authors and of the editor of the Journal of theRoyal .4rinv Medical Ccrps.

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ences with massive initial dosage followed by rather largedoses over a short period. In the course of review ofexperience with various schemes of dosage they describedthe effects on 23 men with gonorrhoea of the followingtreatment:

4 grams of sulphapyridine at once; 2 grams of sulpha-pyridine after four hours, then i gram every four hoursduring the waking periods, the total dosage spread overseventy-two hours, making a total of from I5 to 20 grams.This has been called the " 8-4-2" treatment, from thenumber of tablets administered at successive intervals,and also the " Aberdeen method." Treatment given bythis or similar schemes will be referred to in this paperas " Intensive Treatment." Of the 23 patients in thisseries twenty were cured without further treatment andone was probably so cured. In this group there was ahigh incidence of unpleasant although not serious toxicreactions and, although these patients were actuallytreated as out-patients, the desirability of strict controlof such treatment under in-patient conditions is clear.This probably accounts for the fact that there are fewrecords in the literature of the use of this treatment.It was to be anticipated that a method which, underconditions of strict observation and control, promisedto give rapid and efficient results would be of considerableinterest to the fighting services and, in fact, the other twopublications which we have traced came from thissource. Buist and Simon (I940) treated 20 men sufferingfrom fresh uncomplicated gonorrhoea according to thescheme of dosage outlined above. All responded to thetreatment and the average length of stay in hospital was5.3 days. During periods of observation and testsvarying from two to three months one relapse occurred.

Petro (I940) treated I00 patients, 27 of them with acourse almost identical with that first used by theAberdeen school, in which the period of treatment wasseventy-two hours and the tablets were given during theday only, the total sulphapyridine in each case amountingto i6 grams. The remaining 73 received a preliminarydose of vaccine consisting of twenty million gonococcigiven intradermally, followed by a course of sulpha-pyridine consisting of 4, 2, i grams at intervals of fourhours and then one gram four-hourly day and night for atotal of forty-four hours. The amount of sulphapyridine

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administered in each case was again i6 grams. In thefirst group the average time taken to achieve clinicalcure was 9-07 days. Three failed to respond but, in afollow up period of two months, there were no relapsesin the successful cases. In the second group the averagetime before clinical cure was 6-7 days; two failed torespond and there was one relapse after apparent success.Toxic manifestations were of a minor character exceptin two cases, in one of which haematuria occurred and inthe other renal colic with microscopic evidence of bloodand crystals in the urine. In both cases the symptomssubsided promptly when the drug was discontinued.Failures were attributed to faulty drainage resultingfrom narrow external urinary meatus, from " pocketing "

of infection in Littre's glands or from urethral stricturedue to past infection.

DESCRIPTION OF CLINICAL MATERIAL

In our series the total number of patients treatedintensively was 502 including 397 whose urethral smearsshowed gonococci and 98 in whom the gonococcus wasnot found. Seven were suffering from infections such ascystitis which are not relevant to the present investiga-tion.

Of the 397 patients with gonorrhoea i6 had had recentgonorrhoea treated with sulphonamide preparations andwere presumed to have relapsed. Thirty-nine othersgave the history of an attack of gonorrhoea in previousyears. Five had received small doses of sulphonamidepreparations before admission to hospital; but thedosage given was insufficient to produce any beneficialeffect and all continued to show gonococci in smears.

Of the 98 patients diagnosed as suffering from non-specific urethritis 2o admitted to a previous attack ofgonorrhoea and IO to previous attacks of non-specificurethritis. One had had inadequate treatment withsulphonamide before admission. Most of the men in this,group admitted having taken a risk of infection.Almost all these patients reported sick at once when

symptoms appeared and were immediately admitted tohospital for treatment. Of 397 men with gonorrhoea only3I had had symptoms for more than one week. Of 98men with non-specific urethritis I4 had had symptoms

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for more than a week. The remainder in each categoryhad noticed symptoms for periods varying from a fewhours to seven days, but in the large majority treatmentwas instituted within the first three days.Under these circumstances the number of patients.

with complications before treatment was started wassmall, as might be expected.Among the patients with gonorrhoea there were:

6 cases of epididymitis; i infection of Tyson's gland; Iinfection of a para-urethral duct.Among the patients with non-specific urethritis there

were: 5 cases of epididymitis; i case of fibrositis.

DETAILS OF TREATMENTThe broad outlines of our scheme of treatment remained

unchanged throughout the four months in which we usedthis intensive course; but as our experience of the toxiceffects of the drug grew a number of modifications weremade. From the first all patients were kept strictly inbed during the seventy-two hours in which thev weretaking sulphapyridine, on a " milk diet " consisting oftwo to three pints of milk daily with rice, bread andbutter or margarine. Temperature was taken morningand evening. In 402 cases an initial dose of 8 tablets ofsulphapyridine was followed by 4 tablets in four hours'time and thereafter by 2 tablets every four hours day andnight to the seventy-second hour when the last dose wasgiven-a total of 23 grams. IOO patients were treatedby an 8-6-4-2 tablets scheme, a total of 25 grams.In all cases the actual taking of tablets was supervisedso that doses could not be missed. In most cases thetablets were swallowed whole and a large drink of watergiven immediately afterwards. It was soon evident thatas far as the patient was concerned the most troublesomeeffect of the treatment was the high incidence of vomiting.The suggestion was made that constipation might be apredisposing factor and therefore, in all later cases a" No. 9" pill, consisting of calomel grains ii, compoundrhubarb pill grains ii, compound colocynth pill grains ii,.was given at the beginning of the treatment. It seemedthat the incidence of vomiting was slightly less in conse-quence. At first the possibility of severe damage to thebone marrow was feared and daily white cell counts were

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done. Later the cell count on the second day was givenup, and finally a count was done on the third morningof treatment only unless there was some special indicationat another time. Early morning smears and urine wereexamined daily during treatment. No urethral irrigationsor other local treatments were given.The incidence of certain renal complications-to be

discussed later-brought in its train further additionsto the routine. The daily fluid intake and output weremeasured, alkali was given by mouth, at first in the formof sodium bicarbonate, i drachm to the pint of water,in as large quantities as the patients could be persuadedto take (Long and Bliss, I939)-and later as potassiumor sodium citrate grains xxx two-hourly throughout thetwenty-four hours, since sodium bicarbonate of itselfseemed to encourage vomiting in some cases and was sounpalatable that difficulty was experienced in ensuringthat it was taken in adequate quantities. Patients wereof course examined daily and carefully questioned as toabdominal symptoms, particularly pain. The urine waswatched for macroscopic and, in certain cases, for micro-scopic evidence of blood.

PROCEDURE FOR OBSERVATION AND TESTS OF CURE

At the end of the three-day course of treatment patientswere allowed up and were usually fit to perform light wardduties. After treatment close observation under in-patient conditions extended over a period of at leastseven days and longer if there was doubt about clinicalcure. In each case on three or four occasions during thisperiod an attempt was made to obtain and examine aurethral smear before the first morning specimen ofurine was passed. At the same time the first morningspecimens of urine were examined by naked eye, and thepersistent presence of leucocytes in the smear duringthe period of observation, or of haziness or pus threadsin the urine, was accepted as evidence that cure was notcomplete and that further observation or treatmentwas required. The repeated naked-eye examination ofsuch all night specimens of urine by the experiencedobserver, supported bv microscopic examination of threadswhen necessary, is probably the most reliable of allsingle tests for latency of gonorrhoea. This test is still

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more reliable if alcohol is taken beforehand. If at theend of seven days morning smears and urine were satis--factory the following tests were performed

(i) Rectal examination.(2) Microscopic examination of a prostatic bead.(3) Naked-eye examination of the urine after the-

prostatic massage.(4) Urethroscopy.These tests were followed by another examination of

morning smear and urine on the day after instrumenta-tion. If all the tests were satisfactory the patient wasdischarged from hospital.

Arrangements were made with the man's unit for himto attend at hospital once a week for three weeks for-urethral and prostatic smear and for examination of theurine. Finally, three months after discharge fromhospital, each patient was re-admitted and all testsrepeated with the addition of a complement fixation testfor gonorrhcea on the blood serum. If the tests remainedsatisfactory the patient was discharged as cured.The difficulties of maintaining these standards under

war-time conditions are obvious. Units are moved fromplace to place, from Command to Command and overseas..As far as possible these men have been followed throughtheir period of three months' observation but there arelarge gaps in the information and these will be indicated.It may be argued that three months is too short a time forobservation in view of the fact that relapses after treat-ment with sulphonamides have been described after-longer intervals. The force of this criticism must beadmitted but it is not possible to provide for everycontingency in a disease so variable in its outcome asgonorrhoea and, probably, the standards of observationand testing were as high as could be attained in thecircumstances. The question of relapse is in any case adifficult one. No method of hard and fast distinctionbetween relapse and reinfection has yet been devised.Histories are misleading and even the certain knowledgethat sexual intercourse has taken place is no sure evidencethat reinfection has occurred. It is well known that inter--course is one of the common factors which may convertlatent into declared infection.

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IMMEDIATE RESULTS OF TREATMENTFor the purpose of assessing the effectiveness of this

scheme of treatment in producing clinical cure each groupis divided into three sub-groups according to the amountof treatment ultimately required and in each sub-groupthe average length of time that these patients were detainedin hospital is indicated. This last is in many respects aninaccurate index of the success or failure of this treatment.In using a scheme of dosage with which we were un-familiar it was a natural tendency to prolong ratherthan to shorten the period of observation. This alsodepended to a great extent, as it proved, upon the viewof the individual medical officer. The facts that thesemen were drawn from a large and scattered Commandand that units were often situated many miles from theCommand treatment centre, had to be taken into con-sideration and demanded longer observation than wouldhave been necessary in a compact area.The sub-grouping is as follows:Gonorrhcea.-The total number of patients was 397.(i) Patients requiring no further treatment after three

days' intensive treatment numbered I95, or 49 per cent.*of the total. The period of stay in hospital varied fromII to 28 days, the average time being I3 days.

(2) Patients requiring a small amount of extra treat-ment such as one intravenous injection of T.A.B. vaccineor urethral irrigations for a few days only numberedto, or I5 per cent. of the total. In-patient stay variedfrom I5 to 38 days and the average was 23 days.

(3) Patients requiring a further course of sulphonamide,irrigations and T.A.B. combined, or other combinationsof these treatments numbered I42, or 36 per cent. of thetotal. Five of these patients in sub-group 3 are still inhospital after treatment for periods of from 83 to iio days.The remaining I37 were in hospital for an average timeof 44 days, the shortest period being i8 days and thelongest II4 days.

" Sulphonamide Resistance."-Fourteen patients in thisseries were suffering from infections which proved" sulphonamide-resistant " in that gonococci were stillpresent in the urethral secretions when the intensivecourse of treatment was finished and persisted forvariable periods from the fourth day up to three months.Bowie and his co-workers state, in their original article

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that, in a few cases, gonococci were present in a mucoidsecretion at the end of intensive treatment but disappearedat once, the patient making a prompt and satisfactoryrecovery. In our series this occurred in only one case,which is included in the first and most satisfactory group,since no further treatment was required and the patientwas discharged from hospital after fourteen days. Oneother made a prompt recovery after an additionalintravenous injection of T.A.B. and is included in thesecond group. The remaining twelve were very resistantand required prolonged treatment. They are includedin the third group and one is among the five patients stillin hospital.

COMPARISON WITH PATIENTS SUFFERING FROMGONORRHZEA AND TREATED WITH A ROUTINE NON-

INTENSIVE COURSEFor the purposes of this comparison the records were

taken at random of an identical number of cases, 397,treated with a fourteen-day course of sulphapyridineconsisting of 4 grams daily for three days followed by 3grams daily for eleven days without irrigations. Thestandards of observation and tests were identical. Thefollowing is the result of assessment of these cases underthe same headings:

(i) I98 or 50 per cent. required no additional treatment.The length of stay in hospital varied from I2 to 37 daysand the average was 30 days.

(2) 62 or i6 per cent. required a small amount of addi-tional treatment. Stay in hospital varied from I4 days (ina patient whose course was curtailed through toxic effects),to 29 days. The average length of stay was 20 days.

(3) I37 or 34 per cent. required considerably moretreatment. Stay in hospital varied from 20 to 223 days,with an average of 56 days. Twenty-six of these cases, allincluded in sub-group 3, proved " sulphonamide fast."

NON-SPECIFIC URETHRITIS TREATED INTENSIVELYThe total number of patients was 98; of these two

became seriously ill as a result of treatment, one withfatal outcome, and are not included in this assessment.

(I) 27 or 28 per cent. of the total (96) required noadditional treatment. The length of stay in hospitalvaried from 9 to 23 days and the average was I3 days.

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(2) 7 or 7 per cent. required a small amount of addi-tional treatment. Stay in hospital varied from i8 to30 days, and the average was 23 days.

(3) 62 or 65 per cent. required considerably moretreatment, for 57 of these the stay in hospital variedfrom 20 to ii2 days and the average was 48 days. Theother 5 are still in hospital after 75, 83, IOO, I05 andI24 days respectively.

COMPARISON WITH PATIENTS SUFFERING FROM NON-SPECIFIC URETHRITIS TREATED WITH ROUTINE NON-

INTENSIVE COURSEThe records of 98 patients with non-specific urethritis

who had received the routine fourteen-day coursewithout urethral irrigations were taken at random.

(I) 34 or 35 per cent. of the total required no additionaltreatment. Stay in hospital varied from I5 to 32 daysand the average was 2i days.

(2) 6 or 6 per cent. required a small amount of addi-tional treatment. Stay in hospital varied from 2o to32 days, the average being 26 days.

(3) 58 or 59 per cent. required considerably moretreatment. Stay in hospital varied from 32 to I30 days;the average was 6o days.

THE EFFECT OF DURATION OF THE INFECTION UPON THERESULTS OF TREATMENT

As previously stated the very large majority of thesemen began treatment during the first week followingthe onset of symptoms. Those with discharge for morethan one week were only 27 in number and fall into theappropriate sub-groups as follows: (I) I4 or 52 per cent.;(2) 2 or 7 per cent. ; (3) II or 4I per cent.The average time of stay in hospital for all these cases

was 27 days. Obviously conclusions cannot be drawnfrom this small number of cases but, for what the evidenceis worth, there appears to be no difference between thisgroup and the majority.

COMPLICATIONS OF INFECTION ARISINGDURING TREATMENT

Gonorrhcea Treated Intensively.-The following com-plications occurred: i case of epididymitis supervenedon the third day, i case of arthritis of knee on the fourth

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day, i case of multiple arthritis on the seventh day andi case of latent prostatitis was discovered as the resultof tests for cure.

Control Cases of Gonorrhcea.-There were 9 cases ofsoft stricture of the urethra and in one case a fibrousstricture was found at final test five months later in aman with no history of previous gonorrhoea. In additionthere was one case of periurethral abscess and one ofepididymitis occurring on the eighth day.

Non-Specific Urethritis Treated Intensively.-The follow-ing complications occurred: i case of subacute prostatitisoccurring after 42 months; i case of arthritis of theknee on the tenth day; i case of epididymitis in theseven*th week; i case of multiple arthritis beginning onthe fourth day.

Control Cases of Non-Specific Urethritis.-Soft strictureswere found subsequently in 5 cases; there was i case ofepididymitis on the sixth day and also I case of meta-tarsalgia on the eighth day.

ULTIMATE RESULTS OF TREATMENTThe difficulties of carrying this investigation to its

ultimate conclusion have been indicated. As regardscontrol patients it has been impossible to obtain figureswhich would be of any value. Every effort has beenmade to obtain details of the later history of patientstreated with the intensive method. Many are servingoverseas and details are not yet available. Others didnot start their treatment until the end of December andearly January and, at the time of writing, are not yetdue for their final tests. Of the patients with gonorrhoeaI27 are known to have passed all their tests satisfactorily-78 from group (i), I9 from group (2), and 30 fromgroup (3).

Of the patients with non-specific urethritis there arerecords of i6, 9 in group (i), one in group (2), and 6 ingroup (3), who have passed all tests.Relapses.-From the group of patients with gonorrhoea

2i are known to have relapsed. Of these I5 were ingroup (I), 7 of these having positive smears; I ingroup (2), having a positive smear; 5 were in group (3),,2 of these having a positive smear.From the cases with non-specific urethritis, i from

group (i) is known to have relapsed and 2 from group (3)-V.D. 2II


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These results are still coming in and the ultimateassessment will include a considerable proportion of thetotal number treated.

THE COMPLICATIONS OF TREATMENTMinor Toxic Effects.-Most of the complications were

of a minor character although unpleasant and oftendistressing to the patient. These occurred in the followingorder of frequency: vomiting, headache, nausea andfeeling of distension, anorexia, persistent low backache,insomnia, depression, leucopenia, skin rashes. Vomitingwas the only symptom of this character which assumedimportant proportions. It occurred in more than 6o percent. and in half of these it was severe enough to causeconsiderable distress and to handicap treatment. Never-theless, in no case was treatment stopped on account ofit. The administration of alkalies in the form of sodiumbicarbonate, I drachm to the pint of water, or of potas-sium or sodium citrate grains xxx two-hourly, seemed tocontrol vomiting to some small extent. All patientswere free from these minor complaints within twenty-four hours of the termination of the treatment.White cell counts did not fall below 5,ooo per c.mm. in

any case; but in one instance in which the total countwas 5,200 per c.mm. the percentage of polymorpho-nuclear leucocytes fell to 43 and it was thought advisableto stop treatment after i8 grams of sulphapyridine hadbeen taken.

Rashes occurred in only three patients. One developedan urticarial rash with swelling of the eyelids, on thethird day of treatment. The other two developed rashesof the morbilliform type on the fifth and sixth days afterthe start of treatment respectively.Major Toxic Effects.-The complications in this group

were all of renal origin. Cases of renal intolerance tosulphapyridine are relatively uncommon but the subjectis one which has accumulated a considerable literature.No less than 45 articles on this subject were found. Thegeneral experience seems to have been remarkablyuniform and corresponds closely with our own. Themanifestations of intolerance tend to occur early, usuallyon or about the second or third day of treatment, and areof sudden onset. They have been described with bothintensive and non-intensive dosage but seem to be more

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common with the former. Heematuria is the mostconstant and in many cases the first symptom of renaldamage. Other symptoms are severe lumbar pain, oftenunilateral at first, which may require morphia for itsrelief, true renal colic, oliguria and anuria which, in somecases, in spite of treatment goes on to uraemia. Vomitingis usually persistent and severe. In several of our casesthere was a marked abdominal distension, a symptomto which there appears to be no reference in the literature.In all cases sheaves of jagged crystals consisting of theacetyl derivative of sulphapyridine were found in theurine. There are records of ten fatalities and post-mortem investigation of some of these showed blockageof the vesical ends of both ureters with concretionsformed of this crystalline deposit of acetylated sulpha-pyridine.

In our series of 502 patients treated intensively therewere 5 cases of anuria. Two of these developed uroemiaand one died in consequence. A description of both thesecases will be given including details of post-mortemexamination of the patient who died, which gave evidenceof blockage of the vesical ends of both ureters althoughno actual concretions were found. All these patients hadhaematuria and lumbar pain. Two other cases of haema-turia and two of severe lumbar pain occurred but anuriadid not supervene. It is possibly significant that fourcases of anuria, including the two in which uraemiadeveloped, one of hoematuria and one of lumbar painoccurred in patients receiving the 8, 6, 4, 2 (tablets)dosage as opposed to the routine 8, 4, 2 dosage whichthe others were given. The records of over 2,000 patientstreated by non-intensive therapy with sulphapyridineduring the past year show that there have been twocases of anuria and three of heematuria. The twopatients who suppressed were receiving three grams ofthe drug daily when the complication occurred.The causes of this serious and potentially dangerous

complication are not fully understood, but there isevidence to suggest (Baines and Wien, I939) that,whereas many if not all patients excrete up to 50 percent. of their sulphapyridine in the acetylated form, inonly few patients does massive precipitation occur in thecourse of excretion. This may be due to idiosyncrasybut it seems clear that diminution of fluid excretion with

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zonsequent increased tubular concentration of sulpha-pyridine or its acetyl derivative, and perhaps acidity ofthe urine, increase the likelihood of deposition of crystals.It is interesting to note that renal complications, whichdeveloped in six patients receiving the 8, 6, 4, 2 dosage,occurred in rapid succession in a group of patients whowere in the same ward at the same time. Previouslygo men had been treated similarly without mishap.Investigation of the circumstances showed that thesemen objected to, and either evaded or surreptitiouslydisposed of the sodium bicarbonate solution which theywere ordered to drink. In the light of experience gainedit seems probable that too much faith was placed in theadministration of alkali with failure to make certain thatsufficient fluid was taken. The bicarbonate solution, wasunpalatable and these men were convinced that it madethem vomit. In neglecting to take the bicarbonatesolution they also failed to take sufficient fluids. After-wards this difficulty was adjusted satisfactorily by givingpalatable fluids, such as barley water and lemonade inlarge quantities, and by giving alkali in small bulk in theform of sodium citrate solution grains xxx to the dosetwo-hourly.The following precautionary measures are recom-

mended for patients undergoing intensive treatment inaddition to those mentioned in the details of treatment.

(I) The urine should be tested for albumin before thetreatment is begun.

(2) Large quantities of fluid should be given by mouthin palatable form.

(3) Some of these men are not used to taking largequantities of fluid and constant supervision is essentialto see that they do so.

(4) Alkali should be given in the form of potassium orsodium citrate grains xxx two-hourly. The value ofalkali in preventing renal complications has been ques-tioned and is uncertain. It was decided to continuegiving it until further evidence was obtained as- to itsefficacy; but certainly it is of less importance than theforcing of fluids. The reaction of the urine should betested each morning, acidity of the urine being an indica-tion for more energetic use of alkalis. In most of ourpatients the reaction of the morning urine was neutral.

(5) The total quantity of urine passed each day by2I4


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each patient should be measured. Diminution of theamount in a patient known to be taking and retaininglarge quantities of fluids would be an indication to stoptreatment.

(6) In cases of persistent vomiting fluids should begiven by the intravenous drip method if the treatment isto continue.

(7) The following are indications for stopping thedrug: (a) Haematuria. (b) Severe lumbar pain. (c) In-tractable vomiting. (d) Diminished excretion of fluids.

(8) If anuria supervenes operative treatment as outlinedbelow should not be delayed for more than I2 to 24 hours.The following is a description of the two cases in which

uraemia developed: the early stages of their conditionresemble closely those found in the other cases of anuria.

Case i.-Lance-Corporal M., admitted December 9, I940, withrelapsing non-specific urethritis this being the fourth attack sinceI938. On examination a thin mucoid urethral discharge showingleucocytes, secondary organisms and epithelial cells was found. Hewas given intensive treatment (8, 6, 4, 2, 2, 2, 2, 2, 2, 2 tablets),i6 grams in thirty-six hours. After thirty-six hours he developedheematuria and pain in the right loin which required morphia for itsrelief. The urine contained crystals of acetyl sulphapyridine. Tabletswere stopped at once, but suppression of urine supervened and continuedfor some days in spite of treatment. During the night of Decem-ber I5-I6 his condition deteriorated rapidly and marked greyishcyanosis, dyspncea, with sighing respirations, cough and frothy blood-stained discharge from the nose were present. He was unconsciousand had epileptiform convulsions. Face and neck were puffy butthere was no actual pitting cedema. There were signs of right heartdilatation and failure with cedema of the lungs and distended veins inthe neck. The blood urea rose from 63 mgm. per I00 c.c. on Decem-ber I2 to 400 mgm. per I00 c.c. on December i6, the systolic blood-pressure was i8o and the total white cell count rose to 2I,200 perc.mm. Marked leucocytosis was a feature of all cases in which renalcomplications occurred. The following treatment was given:

Continuous oxygen by nasal tube; lavage of the lower bowel followedby rectal infusion of 30 per cent. magnesium sulphate solution;venesection with withdrawal of I4 Oz. of blood followed after two anda half hours by the removal of another pint of blood and intravenousinfusion of 4-286 per cent. sodium sulphate and I0 per cent. glucosein normal saline. That evening (December I6) he began to pass urineand voided 9 pints during the succeeding twelve hours. From thispoint he made an excellent recovery and on December 2I the bloodurea was 35 mgm. per I00 c.c., the patient was normal in appearanceand felt well. The urine showed a faint cloud of albumin but therewere no pus, red-blood-cells or casts seen in the centrifuged specimen.On December 28 he was discharged from hospital and returned earlyin February looking and feeling well, the urine showed no abnormality,

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the blood urea was 34 mgm. per I00 c.c. and the urea concentrationtest showed normal renal function.

Case 2.-Corporal B., admitted on December i8, 1940 with non-specific urethritis. He was given intensive treatment (8, 6, 4, 2, 2, 2,2, 2, 2, 2, 2 tablets), I7 grams in forty hours, but after forty hours(December 2I) he complained of severe colicky pains in the loins andlower abdomen and the drug was discontinued. Morphia was requiredto relieve the pain. The patient vomited periodically; there was noabdominal distension. The total white cell count of the blood was12,800 per c.mm. rising later to I7,200 (on December 23). During thetwenty-four hours that followed several small specimens of urine,heavily stained with blood, and containing crystals of acetyl sulpha-pyridine, were passed at intervals. On December 22 the blood ureawas 73 mgm. per Ioo c.c., rising to 94 on the following day and reaching300 on the day of death. Treatment was given as outlined in theprevious case, but without success. He became drowsy with puffvface, sighing respirations, frequent vomiting and fits. He died onDecember 27.

The pathological findings in this case form the subjectof a separate communication by Major N. T. Whitehead,R.A.M.C., to which reference should be made, but thefollowing is a summary of his report and of his suggestionsas to the probable sequence of events.Death in this case was due to the blocking of both

ureters by " altered" blood with subsequent anuria andurnemia.

Sulphapyridine crystals were formed in the tubulesand were then either forced through the walls of thetubules into the surrounding interstitial tissue or elsepassed down the tubules into the renal pelvis and thenceinto the ureters. Many of those crystals which wereside-tracked into the kidney substance damaged adjacentblood capillaries and caused a number of small haemor-rhages. Some of the extravasated blood found its waydown the tubules into the ureters. The crystals whichreached the renal pelvis 'continued their journey downinto the bladder but in so doing damaged the walls of theureters causing subepithelial haemorrhages. This wasparticularly so at the ureteral orifices whose lumina weremuch reduced in consequence. The narrowed lumina andthe sludge-like " altered " blood were held to account forthe blockage of the ureters and the fatal consequences.

In the light of after knowledge it is clear that thecorrect procedure in these cases was to catheterise theureters and wash out the kidney pelves and ureters in anattempt to clear the obstruction. Unfortunately, we had

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little knowledge of this complication and its pathologyat this time, and this procedure, which might have savedthe second patient, was not carried out.

Toxic EFFECTS IN THE CONTROL GROUP OF 495 CASESTREATED WITH THE ROUTINE FOURTEEN-DAY COURSE

OF SULPHAPYRIDINEThe toxic effects of treatment of this type are now

common knowledge, but the details in this group ofcases are included for purpose of direct comparison.Most of these patients suffered to a minor degree from

insomnia, anorexia, depression, headache and vagueabdominal discomfort. While nausea was the rule,vomiting was unusual and in only three cases was treat-ment stopped for this reason; in three others who werevomiting, the dose of sulphapyridine had to be reduced.Toxic rashes were the most marked feature occurring in95 or I9-2 per cent. of the cases; these eruptions were ofthe morbilliform or scarlatiniform type with, rarely, anurticarial element. They were associated with anincrease in the severity of the general toxic reactions,frequently with pyrexia and sometimes with a low gradepharyngitis. In i8 of the cases with rashes treatmentwith sulphapyridine was stopped; in 55 the course wascompleted with the same doses of sulphanilamide; inthe remaining 22 treatment with sulphapyridine wascontinued to the end of the course. There was one caseof haematuria and none of agranulocytosis.

COMMENTThe number of cases is small; the follow-up is incom-

plete and no figures are available for comparison of theend results obtained with the two schemes of dosage.Under these circumstances, no conclusions can be drawnfrom this investigation; but certain interesting factsemerge. While treating the patients the impression wasformed that the intensive method was decidedly superiorto other schemes of treatment which had been used.This impression was probably determined by the promptand clear-cut response to treatment which occurred inthe successful cases, and by the fact that the proportionof immediate, group (I), successes was considerablyhigher in our first IOO cases than in those treated subse-quently. In this first IOO, 69 were clinically cured after

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three days of treatment; and our first " sulphapyridine-fast infection" was not until the II4th case. That thisimpression was not altogether justified is shown fromthe figures which run a close parallel in the intensive andnon-intensive groups.The following advantages may be claimed for the

intensive method, at any rate as far as the treatment ofgonorrhoea is concerned:

(i) The period of stay in hospital is shortened.(2) The unpleasant complications of treatment which

commonly occur on or about the ninth day, namelypyrexia, malaise and toxic eruptions, are eliminated forpractical purposes.

(3) The danger of toxic effects upon the bone marrowis less with a three-day course of treatment than with afull fourteen-day course.

(4) The incidence of " sulphonamide-fastness " and ofurethral infiltrations was markedly diminished. Inpreventing these the addition of urethral irrigations tothe routine fourteen-day course would in all probabilitybe equally effective.

(5) The treatment is more economical in that fewertablets are required and in-patient treatment is curtailed.

Attention is drawn to the following disadvantages:(i) During the short period of treatment many patients

vomited a great deal and felt unwell; on the other handin many cases the malaise was no worse than is commonlyexperienced with routine non-intensive dosage. Thosepatients who had experience of both were questionedand all stated that they preferred the intensive treatmentowing to its short duration.

(2) Renal complications were more common. No doubtthe incidence in this series was exceptionally high and itis believed that with the help of present experience itwould be possible to avoid the more serious effects ofthese complications.

(3) The treatment is not practicable under out-patientconditions.

In view of the fact that we were inexperienced withthe method and deliberately prolonged observation andin-patient stay in these cases, it may be that the scalesof this investigation are to a certain extent weightedagainst the intensive method, and that, with the helpof experience gained, better results could be obtained

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and the period of treatment shortened in those patientswho do not immediately respond to the three-day course.The proportion of immediate successes in patients with

gonorrhcea in both intensive and non-intensive groups isless than that which has been claimed in the largemajority of publications on the subject, although thetotals shown by the combination of groups (i) and (2) arenot far short of the percentages of success which areclaimed by most workers who have used sulphapyridinewithout irrigations. We attribute the difference to theroutine tests involving the examination of the morningsmear and the all-night urine during the period of obser-vation. In previous work in civil clinics it was notpossible to apply these tests as a routine and it is believedthat some latent infections escaped notice and furthertreatment in consequence.

SUMMARY(I) 502 patients, including 397 who were suffering

from gonorrhoea and 98 who were suffering from non-specific urethritis, were treated with a three-day courseof intensive treatment with sulphapyridine, along thelines first suggested by the Aberdeen school.

(2) Of the patients with gonorrhoea 49 per cent.required no further treatment and remained in hospitalan average period of thirteen days; I5 per cent. requireda small amount of extra treatment and remained inhospital an average period of twenty-three days, and36 per cent. required considerably more treatment withan average in-patient stay of forty-four days.

(3) Of the patients with non-specific urethritis 28 percent. required only the initial course and the averagelength of stay in hospital was thirteen days; 7 per cent.required slightly more treatment, remaining in hospitalan average of twenty-three days, and 65 per cent. hadconsiderably more treatment, the in-patient stay amount-ing to an average of forty-eight days.

(4) A comparison with the same number of casestreated non-intensively with a fourteen-day course oftreatment showed that in the two groups there was littledifference in the proportion of successes, although in-patient stay was shortened for patients treated success-fully with intensive dosage.

(5) The complications of the treatment consisted of2I9


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minor toxic effects, of which vomiting was the mostfrequent and troublesome, and of toxic effects on thekidney due to excretion of crystals of the acetyl derivativeof sulphapyridine. In consequence there were twvo cases.of haematuria, two of severe lumbar pain, and five casesof anuria, in two of which uraemia developed, one ter-minating fatally. Methods of avoiding or minimisingthese complications are discussed.We wish to thank Colonel H. L. Howell, O.B.E., M.C.,.

Commanding Royal Victoria Hospital, Netley, for per-mission to publish the result of this investigation,Lieutenant-Colonel T. E. Osmond, R.A.M.C., for helpfuladvice, Dr. Robert Forgan for his kindness in undertakingthe very considerable task of abstracting the literature-on renal complications and Major J. S. Sloper, R.A.M.C.,Medical Specialist to the Royal Victoria Hospital, forpermission to use his clinical notes on the later stages ofthe two cases described in detail.

REFERENCESADALJA (I939) Brit. Med. Journ., 1, 643.ALLISON and MYERS (1939) Journ. Amer. Med. Assoc., 113, i8, I63I.ANTOPOL and ROBINSON (I939) Proc. Soc. Exp. Bio. & Med., 40, 3, 428..ARNETT (1940) Journ. Amer. Med. Assoc., 115, 5, 362.BACKHOUSE (I939) Lancet, 2, 736.BACKHOUSE (1940) Med. J. Austral., 2, I35.BAINES and WIEN (I939) Quart. J. Pharm. & Pharmacol., 12, 4.BANKS (1939) Lancet, 2, I921.BARFORD (I939) ibid., 959.BOWIE, ANDERSON, DAWSON and MACKAY (1939) Brit. Med. Journ., 1,

7II.BROWN, THORNTON and WILSON (1940) Journ. Amer. Med. Assoc., 114,

I6O5.BUIST and SIMON (1940) Journal of the oyal Aiixy Medical Corps,

74, 229.CARROL, SHEA and PIKE (I940) ibid., 114, 5, 4II.DETWEILER et al (1940) Archiv. Int. Med., 65, II44.FINLAND, SPRING, LOWELL and BROWN (1939) Ann. Int. Med., 12, i8i6FINLAY (1940) Med. J. Austral., 2, 409.FLETCHER (194I) Brit. Med. Journ., 1, 242.FLIPPIN (I939) Journ. Amer. Med. Assn., 113, i85I.FLIPPIN et al. (1940) Ann. Int. Med., 13, ii, 2038.GRAHAM et al. (I939) C. M. A. J., 40, 325.GROSS, COOPER and LEWIS (1939) Proc. Soc. Exp. Bio. & Med., 40, 3,

448.GROSS, COOPER and SCOTT (1940) Urolog. and Cutan. Rev., 44, 4.HANSSEN (I939) Lancet, 1, 6i.HEGGLIN (1940) Schweiz. med. Woch., 70, 37, 88i.

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INTENSIVE TREATMENT OF GONORRHWA

HODES, GIMBEL and BURNETT (I939) Journ. Amer. Med. Assoc., 113,I6I4.

JANNEY SMITH (1939) Journ. Amer. Med. Assoc., 113, I85I.KILGOUR (I939) C. M. A. J., 41, 445.KOHLSTAEDT and PAGE (1940) Ann. Int. Med., 14, I29.LONG et al. (1940) Journ. Amer. Med. Assoc., 115, 364.LONG and BLISS (I939) " The Clinical and Experimental Use of Sulph-

anilamide and Sulphapyridine and Allied Compounds."-Special addendum.

LONG and WOOD (I939) Ann. Int. Med., 13, 487.MCCANN (1938) Lancet, 2, IOO.MACLEOD (1939) Journ. Amer. Med. Assoc., 113, I405.NISSEN and ROESGAARD (I939) Ibid., 113, I924.O'MEARA (1940) Journ. Roy. Naval Med. Serv., 26, 3, 284.PEPPER and HOORACK (1940) Am. J. Med. Sci., 199, 674.PETRO (I940) Journ. Roy. Naval Med. Serv., 26, 336.PLUMMER and EMSWORTH (1939) Journ. Amer. Med. Assoc., 113, i847.PLUMMER and MCLELLAN (1940) ibid., 114, 943.RAKE (1940) J. Bact., 39, 45.RAVID and CHESNER (1940) Am. J. Med. Sci., 199, 380.ROBERTSON (1938) Lancet, 2, 728.ROMCKE and VOIGT (I939) ibid., 2, 778.SADUSK et al. (1940) Journ. Amer. Med. Assoc., 115, I968.SMITH, EVELYN and NOLAN (1940) C. M. A. J., 942, 27.SNAPPER, LIu, CHUNG, YU and SUN (1939) Chinese Med. J., 56, i.SOUTHWORTH and COOKE (1939) Journ. Amer. Med. Assoc., 112, I820.STEWART, ROURKE and ALLEN (1938) ibid., 110, I885.TOOMEY (I939) ibid., 113, 3, 250.TSAO et al. (I939) ibid., 113, I3I6.ULLAND (I939) Nord. Medic., 4, 52.

IIIINTENSIVE TREATMENT OF GONORRHCEA-AND NON-SPECIFIC URETHRITIS WITH

SULPHAPYRIDINEDIsCussION

DISCUSSION OF THE PAPER READ BEFORE THE M.S.S.V.D. on 28.3.4IBY LIEUT.-COLONEL A. J. KING AND MAJOR D. I. WILLIAMSMAJOR T. E. ANDERSON said he had used the " intensive " method

of treatment for three years and questioned the statement that itwas unsuitable for out-patient treatment. Dr. Bowie and he hademployed it routinely for a year and a half before the war in out-patient treatment, and Dr. Bowie was still using it without trouble.

Since the beginning of the war he had treated i,8oo cases of gonor-rhcea by this method and had been struck by the contrast in tolerancebetween in-patients (as military circumstances compel service cases

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ii intensive treatment of gonorrhwea and non …toxic manifestations were of a minor character...

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