SULPHONAMIDE INTOLERANCE · SULPHONAMIDE INTOLERANCE administration of sodium bicarbonate or a mild...

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SULPHONAMIDE INTOLERANCE

By DAVID ERSKINE, M.D., D.P.H. (Medical Officer, Guy's Hospital-and Canterbury V.D. Clinics, and Dermatologist to the Seamen'sDreadnought Hospital, Greenwich).

THE considerable incidence of intolerance to sulphon-amide therapy causes many difficulties in treatment; itis important that the symptoms resulting from thisintolerance should be well recognised and their significanceappreciated, for it is not always necessary to discontinuethe drug. In view of the reported toxicity, there is atendency among practitioners to give small and ofteninadequate doses of the compounds with the result thatclinical response is often delayed or absent while,frequently, a degree of intolerance still occurs. Thereis evidence that a resistance to the drug occurs when thedosage is at first small and in many of these casestherapeutic effect is not obtained by a later full dosage.Further, an essential of efficient medication is that thedosage should be evenly spaced so that the blood contentcan be maintained, as nearly as possible, constant; thatis to say, 8 hourly and not " Three times a day " or6 hourly and not " Four times a day." It is also wellrecognised that sulphonamide therapy should continuefor an optimum period after apparent cure as otherwisemorbid conditions are liable to recur.The degree of intolerance appears to bear a relationship

to the therapeutic efficiency of the particular compoundemployed; certain individuals also appear to be moresusceptible to the drugs, possibly exhibiting an idiosyn-crasy, and show a higher degree of intolerance. Manypatients complain of malaise when commencing treat-ment with sulphonamides, but the symptoms usuallydiminish after forty-eight hours and most patients canthen continue medication without difficulty.The more common minor manifestations of intolerance

are headache, indigestion, malaise and nausea. Thesesymptoms occur early in treatment and are usually ofshort duration. They can frequently be relieved by the

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administration of sodium bicarbonate or a mild gastricsedative, but the more persistent cases, occasionally withsevere gastritis, vomiting and enteritis, may causeconsiderable anxiety and require administration of thecompounds by the injection of one of the soluble solutions.A frequent symptom reported by patients under treat-ment with sulphanilamide is a mild tingling of the handsand feet usually with no objective evidence of an organiclesion; this symptom may, however, be related to theoccasional occurrence of peripheral neuritis which is nowwell recognised after the administration of a certaincompound of the group.

Undesirable effects of the drugs on the bone marrowhave been reported by several workers and appear tooccur to a greater or lesser degree with all compounds ofthe group. Attention to the occurrence of a polymorpho-neuclear leucopaenia in a proportion of cases was madeby Britton and Howkins (I938) and Lloyd, Erskine andJohnson (1938); the latter writers were of opinion thatwith treatments of short duration this effect was not aserious contra-indication to chemotherapy, as a normalblood condition was apparently rapidly regained afterdiscontinuation of treatment. Cases of agranulocytosishave been ascribed to sulphonamide compounds, usuallyafter very high dosage (Nicol and Freedman, I939), andColebrook (1939) collected 35 cases in a complete reviewof the literature over two years; he stated that he knewof other cases which had not been reported and suggestedthat, as the angina syndrome occurred in only about oneof 5 cases of agranulocytosis, it was probable that furthercases had occurred but had not been diagnosed. He, too,observed that most cases had occurred after compara-tively high doses and drew attention to the narrowmargin of safety which appeared to exist between thenecessary therapeutic dose and that which was liable tocause serious damage to the bone marrow. He stressedthe importance of frequent blood examinations in casesundergoing prolonged chemotherapy and referred to thedanger of continuing administration in cases which didnot show an early response to the drug.

It is probable that certain unexplained cases of " DrugFever " may in reality be cases of an abortive type ofagranulocytosis and the occurrence of Drug Fever, inview of its symptom similarity to the onset of the more

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BRITISH JOURNAL OF VENEREAL DISEASES

serious condition, should in all cases be considered anindication for a complete blood examination.The effect of the drug on the red marrow is less marked,

but a diminution of the heemoglobin percentage has beenobserved and cases of hoemolytic anaemia are reported(Jennings and Southwell-Sander, I937). Cyanosis, withand without methaemoglobinaemia and sulphhaemo-globinaemia, is a manifestation of intolerance which hasreceived considerable attention by several workers, butwhich would appear to occur less frequently during theadministration of sulfapyridine. A urinary excess ofurobilin, hepatitis and jaundice have occasionally beenobserved and McCann (I939) and others have drawnattention to the occurrence of haematuria.

Recently, the suggestion that encephalomyelitis occur-ring in two patients after treatment with sulphanilamidemay be a toxic manifestation of the drug (Fisher andGilmour, I939) shows that our knowledge of the dangersattendant on the administration of these compounds isnot yet complete. It should however be recognised thatthese manifestations of toxicity are comparatively rareand are not contra-indications to the administration ofthe drugs for conditions in which they are indicated;they do however indicate the importance of carefulobservation in all cases which are undergoing treatmentso that these undesirable side effects can be minimised byearly corrective treatment.Apart from the gastric cases already mentioned, the

most frequent manifestation of intolerance to these drugsis the appearance of a sulphonamide dermatitis. Con-siderable attention has recently been drawn to theseskin rashes and their variation in tvpe. It seems probablethat cases of sensitisation and of drug retention occur, butthe factors are so variable and the incidence so frequentthat a brief description of illustrative cases will be ofinterest. These rashes may occur during the first courseof treatment or only on subsequent courses; they mayoccur with every course of treatment, and with all or onlyone of the compounds of the group. The only constantfactor is the tendency for the rash to occur between theeighth and fourteenth day of administration, so that when-ever possible from a clinical consideration the restrictionof therapy to seven days will almost entirely remove thiscomplication which the patient finds so distressing.

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TYPICAL CASESCase I.-MORBILLIFORM ERUPTION.-Male,

took 30 gm. of M. & B. 693 in ten days. At t

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aged 23,this stage

FIG. i.-Case I. Morbilliform Type of Eruption due to M & B 693; photo-graphed on the second day of rash.

he complained of generalised irritation of the skin, andone day later developed a profuse morbilliform eruptionon the trunk, face, neck and thighs with a rather less

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profuse rash on the arms and legs. The eruption wasslightly bluish-red in colour and tended to be papular.There was mild pyrexia and malaise. The drug wasdiscontinued and the rash faded in one day.

Case 2.-SCARLATINIFORM ERUPTION.-Female, aged29. After 35 gm. of Sulphanilamide in eleven days, shewas found to be covered with a non-irritating punctateerythema; the rash was intense on the forearms andouter aspects of the upper arms, but rather fainter on thechest and back, while the face was clear. This eruptionhad been preceded by one day of malaise and shivering.

Case 3.-URTICARIAL ERUPTION.-.A female, aged 20,had felt " dopey " while taking 20 gm. of M. & B. 693 inten days. She then developed irregular patches ofirritating erythema. The drug was continued and furtherlesions tended to occur for a day or two, but after thefourth day no further patches were observed.

Case 4.-Male, aged 39. 42 gin. of Sulphanilamide infourteen days. He developed an acute generalisedurticaria and was treated (in the Casualty Department)with adrenalin. Seven days later, he was given furthersulphonamide treatment and took 72 gm. of the samedrug in five days without intolerance.

Case 5.-.PAPULAR ERUPTION.-Male, aged 37, hadtaken 24 gmi. of M. & B. 693 in eight days when a rashappeared at the bend of the elbow after a blood test. Therash was seen on the following day; it was a fine, discretepapular eruption on the arms and trunk, and it appearedto be causing severe irritation. The drug was discon-tinued and the rash completely disappeared in twodays.

Case 6.-LIGHT SENSITISATION TYPE.-Male, aged 43,took 30 gm. of Sulphanilamide in ten days, and thendeveloped an cedematous, urticarial erythema of thehands and face with many bulle on grossly cedematousears. The cedema and eruption were limited to theexposed areas. The drug was discontinued and thecondition subsided in three days. Five weeks later,i gm. of M. & B. 693 three times a day was prescribed,and on the eighth day of this course he again developedan exactly similar eruption on the exposed areas whichfaded four days after discontinuing the drug. The urinewas dark, and there was a weakly positive indirect Vanden Berg reaction. One year later, chemotherapy was

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again administered and on the third day he noticedgeneralised irritation of the skin as on the previousoccasions. The drug was immediately stopped and nofurther symptoms occurred.

FIG. 2.-Case 6. Light Sensitisation Eruption, photographed on secondday. Showing medema and limitation to the exposed areas.

Case 7. SENSITISATION TO THE COMPOUNDS. A male,aged 2I years, took 34 gm. of M. & B. 693 in fourteendays. On the tenth day he complained of a sore throat,and this was followed by a period of malaise; on thefourteenth day, his private doctor diagnosed scarlet feverand sent him to a Fever Hospital where the diagnosis wasin doubt, partly on account of the rash being severelyirritating. Three weeks later, he took one tablet of

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M. & B. 693 and within a few hours developed a sorethroat and generalised scarlatiniform rash which lastedonly one day. Two months later a single tablet againreproduced the same evidence of immediate intolerance.

Case 8.-A male, aged 26, was treated with M. & B. 693,i gm. t.d.s. He took 24 gm. in ten days with no evidenceof intolerance, but there was a delayed clinical response.After an interval of twelve days, he took two tablets(I gm.) of M. & B. 693 and rapidly became " hot all over ";he took further tablets and was seen a few hours later witha generalised scarlatiniform erythema. T. 99-8°;P. IIO; faucial inflammation and suffused conjunctivae.Although the drug was continued, the rash faded intwenty-four hours. A further 24 gmi. of the drug wereadministered and there was no further ill effect. Thispatient has also had two further courses of sulphonamidewithout any drug symptoms.

Case 9.-CEDEMA OF THE LARYNX. A more seriousindication of intolerance was observed in an elderly malepatient with lupus erythematosis. He had been givenSulphanilamide, but this was discontinued after a fewdays on account of symptoms of intolerance. One yearlater it was decided to try the effect of M. & B.. 693 whichwas then available. On account of the previous intoler-ance, an initial dose of one half gram tablet was given;eight hours later he developed dyspncea, swelling of thetongue and face with cyanosis and cedema of the larynx.The condition was relieved by adrenalin and intravenouscalcium gluconate; no further sulphonamide was, ofcourse, administered. A reaction of this type, althoughprobably extremely rare, serves to indicate the danger ofhaphazard treatment with these drugs and the need ofspecial care in treating cases who are thought possibly tobe sensitised to the compounds.The appearance of a sulphonamide dermatitis is not of

serious significance. If medication is stopped, the rashwill probably disappear in a few days. In certain condi-tions, however, cessation of therapy will be undesirablefrom the clinical point of view and it is therefore interest-ing to note that many of the eruptions will rapidly cleareven if the drug is continued in the same or diminisheddosage (Erskine, I939). This is particularly likely whenthere is no drug retention. It has been suggested(Tedder, I939) that the various pictures of sulphonamide

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dermatitis cannot be explained by a single theory ofcausation and that drug retention, sensitisation, libera-tion of toxins (Barber, I938; Erskine, I938) and theappearance of photo-sensitising agents (Rimington andHemmings, I938) all play a part in different cases. Thepossibility of a light sensitisation type of eruption shouldbe remembered and excessive exposure of the patient toreal or artificial sunlight, especially during treatmentwith Sulphanilamide, should be avoided. When thistype of eruption occurs, it is desirable that the drugshould be discontinued. In certain other cases, when theurinary elimination has been found satisfactory (Werner,I939) treatment has been continued with a possibledesensitisation of the patient; these cases frequentlyshow no intolerance on later administration of thecompounds, whereas when the drug has been stopped onaccount of the appearance of an eruption, subsequenteruptions often occur during later courses of treatment.This continuation of therapy should be attempted onlywhen the patient is under continued observation so thatany exacerbation can be immediately controlled.

SUMMARYAlthough the manifestations of intolerance to the

sulphonamide group of drugs are varied and undesirable,they are seldom of serious import; when the extensiveuse of these drugs is considered, it will be realised that theincidence of grave intolerance is rare. It is, however,apparent that the closest observation of cases undertreatment is desirable so that toxic effects can be con-trolled at the earliest indication. Cessation of therapy isnot always indicated when intolerance occurs, indeed itis often not desirable; a proper evaluation of the signsand symptoms will lead to an appreciation of the indica-tions for or against further administration of thecompounds.

REFERENCESBARBER, H. W. (I938) Lancet, 2, 668.BRITTON, C. J. C. & HOWKINS, J. (I938), Lancet, 2, 7I8.COLEBROOK, L (I939) Lancet, 2, 158.COXON, R. V. & FORBES, J. R. (I938) Lancet, 2, I4I2.ERSKINE, D. (1938) Brit. J. vener. Dis., 14, 39.

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ERSKINE, D. (I939) B.M.J., 2, IO4.FISHER, J. H. & GILMOUR, J. R. (I939) Lancet, 2, 30I.JENNINGS, G. H. & SOUTHWELL-SANDER, G. (I937), Lancet, 2, 898.LLOYD, V. E., ERSKINE, D. & JOHNSON, A. G. (I938) Lancet, 2, ii6o.MCCANN, J. S. (I939) Lancet, 2, ioo.NICOL, H. & FREEDMAN, B. (I939) Lancet, 2, 647.RIMINGTON, C. & HEMMINGS, A. W. (I938) Lancet, 1, 770.TEDDER, J. W. (I939) Arch. Derm. Syph. Chicago, 89, 2I7.WERNER, A. E. A. (I939), Lancet, 1, i8.

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SULPHONAMIDE INTOLERANCE · SULPHONAMIDE INTOLERANCE administration of sodium bicarbonate or a mild...

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