3.5 response to chloramphenicol in the treatment of thypoid fever.kenneth c.watson, m.b

8/12/2019 3.5 Response to Chloramphenicol in the Treatment of Thypoid Fever.kenneth c.watson, m.b

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1054 S.A. MEDICAL JOURNAL 21 ~ o v m rthis up with a description of the size, shape, and colourof the pathological lesion. The diagnosis should alwayscome last; otherwise if you reach the wrong conclusion,you will inevitably lose everything. When i t comes to descr ib ing the colour of the normal organs of the bodymost men are singularly bad. It is scarcely possible topersuade a candida te to say that the suprarenal cortexis golden-yellow, the medulla slaty-grey, and the normalthyroid red-brown. But scattered through examinationscripts one sees such confusing descriptions as the colourof a daffodi l, an iris, a rose, a marigold, or a plum.Because some med ical schools still h ave museum specimens which are bleached in alcohol, a method 50 yearsout of date, the censors are instructed in wri ting not topenalize candidates who cannot iden tify specimens inbottles. It is therefore a mistake to get agitated overthis part of the examinat ion. Besides the censors a re ou tto help you. I once showed a good candidate a specimenof an enlarged thyroid gland uniformly beset throughoutboth lobes and isthmus with adenomata and cysts. Hesaid it was a horseshoe kidney. I then asked him howone could account for all the swellings, and with a suddeninspiration and a bright smile he said, Oh It s a congenital cystic horseshoe kidney. I gave im an extramark on the principle that the capacity to improvise indifficult circumstances is an essential quality in a doctor .Fun for the Censor From time to time a censor getshis fun out of the examination. One candidate wrote,Examination of the fundus oculi reveals papal.oedema,and another t is said that the face of a cretin is likethat of a constipated owl, but perhaps this is a slightexaggeration. examiner is occasionally privileged togive an extra mark to a candidate with exceptional powersof human underst anding, such as the man who said ofthe treatment of insomnia, An attractive and agreeablemarriage partner is advocated by many. At one timea question was asked on anthrax, but it is not recordedwhat mark was given for the statement that in case ofan outbreak of anthrax the animal must be burned orburied alive and the woolsorter must be boiled. Neither

do we know what marks were allowed to the mawrote, In scarlet fever the patient should beisolated and should have connexion with no-onethe nurse.Sometimes, I understand, a number of examscripts contain a remarkable answer which can onlcome from a whole class of men hav ing misunda lecturer. The famous example is that in answequestion on the treatment of haematemesis, whereless candidates said that the patient must be givensoup. This was traced to a lecturer lately importeGlasgow who to ld them to give the patient ice toOne cannot dismiss this subject without quoting thment of a very earnest candidate who obtainedmarks throughout the whole examination- inglycaemia it is possible by the judicious use of adto restore the patient sufficiently towards consciothat he can swallow himself.

he Second Oral Examination In the seconexamination be p repared for questions on the histoclassical literature of medicine. On the whole theof today despairs of meeting a really erudite canOne hot summer, during the July examinatrepeated ly asked who was the author of n EssayShaking Palsy No answer was forthcoming, andend the President pointed out tha t in this modern ashould not expect to meet a candida te who haanything more than a text-book.

In conclusion, lest be accused of being fastidiopedantic, I wish it to be clear that the purposeremarks is to stimulate in you a desire for learnits own sake. In the pract ice of your professinfluential members of the community you will sureto behave as educated men and women. Begin tlea rn ing to speak and to write the Queen s Englisthis I mean the beaut ifu l language of Shakespeare aBible. It is explained fo r you in the OxfordDictionary which, probably, you ve never evenStrive always to master the Queen s English windeed a precious heritage.

RESPONSE TO CHLORAMPHENICOL IN THE TREATMENTOF TYPHOID FEVERKENNETH C. WATSON M.B., CH.B. (ABER.)

Assistant Pathologist Natal Provincial AdministrationSince Woodward et al 9 (1948) published the first reportson the treatment of typhoid fever with cWoramphenicolthere has been a spate of publications demonstrating thesuperiority of the drug to any other. In almost every seriesreported chloramphenicol has cut short the illness, terminat ing the pyrexia after 3-4 days, and has resulted ina considerable r educt ion in the mortali ty and morbidityrates.In a recent series of 398 cases, El Ramli 5 records anaverage durat ion o f 3.7 days pyrexia after cOj1lmencingtreatment, and in a previous series of 200 cases, of 3.5

days.-t Occasionally however this response does noand the following cases, selected f rom the la st 90 ctyphoid fever treated in Grey s Hospital, Pietermaripresent cer ta in interesting features.(All 90 cases were t rea ted wi th chlorampheni caverage dosage being 500 mg. 6-hourIy in adults amg. in children. In the remaining 84 cases the rein general was similar to that described by othersaverage durat ion of pyrexia following the commenof chloramphenicol treatment was 4 1 days. Tosymptoms cleared up along with the fever. Resp


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21 ovember 1953 S.A. T Y S K R I F VIR G E N E E S K U N E 1055and neurological symptoms and signs cleared up quickly.Abdominal dis tension was usually the l as t fe atur e to disappear. Similar observations were made by Marmion.10 )

BACTERIOLOGICAL METHODSAll blood cultures were done by adding 5-10 rnl of bloodto 35 rnl of bi le -salt b ro th . Subcu ltures were made onWilson and Blair s bismuth sulphite medium. Widalexaminations were performed with s tandar d 0-901 andH-901 st rains as antigens. Clot cul ture s were pe rfo rmedby adding the clot from the Widal specimen to 10 ofbile-salt broth containing 100 units per ml. of streptokinase,the fibrinolytic enzyme derived from certain strains ofhaemolytic streptococci. is supplied by Messrs. Lederle(American Cyanamid Company in the form of alyophilized powder containing 100,000 units of streptokinase and 25,000 units of streptodornase per vial. Wehave had considerable success with this method and theresults will be published separately. All blood culturesand clot cultures were i ncubated for 3 weeks beforebeing discarded. Faeces were plated on Desoxycholatecitrate agar and i nto selenite F medium. Urine depositswere plated directly on Wilson and Blair s med ium andon McConkey agar. All positive cultures were checkedfor biochemical and serological reactions, and the phagetyping of each was done by P rofes sor Pijper of theUniversity of Pretoria.

CASE 1 E., a Nat ive female aged 15. Admitted on 20 February1953 with a 6-day his to ry of headache, generalized musclepains, abdominal pain, fever and anorexia. There wasno history of diarrhoea or constipation. Past history andfamily history were negative.On examination she was extremely toxic and ill looking.Temperature 101.0 0 F pulse 120, blood pressure 95/50.The dorsum of the tongue was furred with raw edges.Respiratory and cardiovascular systems were normal. Theabdomen was tender all over and both liver and spleenwere palpable one f inger-breadth below the costal margin.Physical examination otherwise was negative.

Laboratory nvestigations Blood culture: negative onthe 1st day of incubation, bu t positive on the 12th dayof incubation.White blood cells: 3,600, differential count normal.Widal : S. typhi 1/640. H 1/640.Clot culture: growth of S. typhi on the 1st day.Faeces and urine : repeatedly negative.Treatment was commenced with 500 mg. chloramphenicol every 6 hou rs f rom the day of admission. A studyof the temperature chart shows no response at all.Clinically he r condi tion deter io ra ted rap id ly and on23 February she was delirious and unable to t ake fluid bymouth. She was given 0.85 saline and 5 glucosesaline by intravenous drip. On 24 February her conditionbecame worse , she became hyperpyrexial and died.CASE 2J M., a Nat ive female aged 28. Admitted on 3 March1953 with a 14-day history of severe frontal headache,generalized weakness, anorexia and fever. Fo r 3 daysshe had had abdominal pain, unaccompanied by vomitingor abnormal bowel symptoms. Past history and familyhistory were negative.

On examination, she appeared extremely ill Temperature 103.6 0 F Pulse 120. The tongue was furred andthere were sordes on the lips, which were dry and cracked.Respiratory and cardiovascular systems were norma l.There was generalized abdominal tenderness, but the liverand spleen were not palpable.

aboratory nvestigations Blood culture: negative afterone day s incubation, but yielded a growth of S typhiafter 7 days.White blood cells: 2,800, with a normal differentialcount.Widal: on day of admission, S. ty phi 1/640, H1/640.Clot culture: yielded a growth of S typhi on the firstday.Faeces and urine: repeatedly negative.Treatment Treatment was begun with penicillin300,000 units every 6 hours, and sulphathiazole 1 g every4 hours. This was continued for 3 days beforechloramphenicol was given. On 6 March 500 mg. every6 hours of cWoramphenicol was given. There was noclinical improvement and her temperature remainedbetween 101 0 and 103 0 F. On the 6th day an intravenousdrip of 5 glucose saline was instituted, and the

cWoramphenicol was given by nasal tube. On t he 9th day,i.e. on the 6th day of chloramphenicol therapy, her condit ion deter iorated rapidly, and she became stuporose andhyperpyrexial and died.CASE 3

B S., a Nat ive male aged 14, was admitted on 14 March1953 with a 4-day history of severe frontal headache,genera lized muscle pain, epistax is , cough , anorexia andfever. There was no history of gastro-intestinal upset.Past history was negative. He had a sister in hospi tal atthat time with proved typhoid fever.

On examination, he was not obviously ill in spi te of atemperature of 103.6 F. Pulse was 130. The tongue wasclean and the fauces clear . There was no abdominal tenderness and the liver and spleen were not palpable.Physical examination was otherwise negative.Laboratory nvestigations Blood cul tu re was negativeafter 3 weeks incubation.White blood cells: 3,400, with a normal differentialcount.

Unfortunately treatment was begun with chloramphenicol, 250 mg. every 6 hours, before any further investigat ions were done . On 17 March a specimen of blood forWidal examination gave agglutinin titres of S typhi 1/640 H 1/640. lot culture from this specimen gavea growth of S typhi on the first day of incubation. i.e.after the patient had had 3 g of chloramphenicol.Stool and urine cultures were repeatedly negative.Progress He con tinued to receive 250 mg. every 6hours , bu t rema ined febrile fo r 7 days. Treatment wascontinued for a further 7 days after his temperature fellto normal. His general condi tion was satisfactory throughout , in spite of the pyrexia and he made an uninterruptedrecovery.

CASE 4B L., a ative male aged 14 was admitted on 21 May1953 with a 14-day history of frontal headache, cough,pain in both sides of the chest, generalized abdominal pain,


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1056 S.A. M ED IC AL JO U RN A L 21 Novembean d fever. He was in a delirious state and the historywas obtained from relatives. Hi s sis ter was admitted atth e sam e t ime with similar symptoms.

On examination, he was delirious an d appeared very ill.Temperature was 104.4 F pulse 112. Th e tongue wasf ur re d o n the dorsum. Scattered rhonchi were present atboth lung bases. Th e abdomen was distended, an d bothliver an d sp:een were palpable.

Laboratory investigations Blood was taken from aWidal an d clot culture, a nd t re at me nt begun immediatelyin view of his critical state. Unfortunately a b lood cul tu rewas no t done.

Widal: S typhi 1/640 1/640.Clot cul ture yielded a growth of S. typhi after on e day sincubation. A second clot culture on 23 May, i.e. afterhe ha d ha d 2 g of chloramphenicol was also positive.Stool an d u ri ne cul tures were al l negat ive.Progress After 6 days treatment with 250 mg. every6 hours his condition was still ser ious. On the 6th da y

he was given 1 g. of chloramphenicol followed by 500 mg.every 6 hours. He became afebrile on the 9th day, i.e.3 days after t he increased dosage. Treatment was continued fo r a further 15 days, an d his subsequent recoverywas satisfactory.

CASE 5M. M., a Native male aged 7 Admitted 16 January 1953with a 5-day history of cough, frontal headache an d sorethroat. No further history was obtainable.

On examination, he looked ill an d toxic, temperature103.0 pulse 120. Th e tongue was furred an d bothtonsi ls were inf lamed. There was pu s in the right earan d th e ear-drum was inflamed. Th e tip of th e spleenwas just palpable. There were scattered rhonchi andcrepitations at b ot h l un g bases.

Laboratory investigations Blood cul tu re sterile after3 weeks incubation.White blood cells: 3,900, with a normal differential

count.Widal: S typhi nil, nil.C l ot c ul tu re : sterile.Treatment Penicil lin 100,000 units every 6 hours and

sulphatriad 1 g. every 4 hours were given fo r his ea r condition. Temperature fell to normal over a period of 7days an d clinically he was much better. Eight days later,on 1 February his temperature rose suddenly to 102.0 F.

Blood cul ture was repeated an d was again steri le, an dWidal titres showed no rise. Clot culture however yieldeda growth of S typhi

Chloramphenicol 250 mg. every 6 hours was started,an d penicillin stopped. Th e response was poor an d heremained pyrexial fo r 7 days before there was an y signof clinical improvement. Treatment was continued fo ra further 4 days with 250 mg. 3 times a day and fo ranother 8 days with 250 mg. twice daily. Recovery wasthen satisfactory.

CASE 6This case was on e which relapsed. On both occasionsth e response t o t re atm en t was satisfactory, bu t it is included because of several interest ing features. _

N. Z., a Native female aged 12. Admitted 18 February

1953 wi th a ll-day history of cough, sore throat cotion, an d severe frontal headache. Her sister was adat th e same time wi th a s imi la r hi story.

On examination, an obviously ill girL Tempe103.0 F. Pulse 114. Th e tongue was furred an d tdry, cracked an d covered with sordes. Both tonsilinflamed. Scattered r ho nc hi a n d crepitations were pthroughout both lungs. Th e abdomen was tender al iver was palpable, bu t th e spleen could no t be fel t.Laboratory nvestigations Blood culture: steril3 weeks.

White blood cells: 2,900.Widal: S typhi 1/640 1/640.Clot culture was negative.Treatment In view of th e clinical diagnosis of tfever, chloramphenicol was begun on 19 e ~ r u r y250 mg. every 6 hours. Four d ay s l at er th e t e l ~became no rm al an d clinically she was much imp

On 27 February i.e. a ft er h av in g ha d 8 g. of chphenicol, clot culture from a r ep ea t W id al specimea gr owt h o f S typhi He r temperature when thismen wa s t aken was 98.0 F. Treatment was stopp10 March i.e. 16 days after she became afebrile.March while she was undergoing faeces an dclearance tests, the temperature rose to 103.0 F.culture an d clot culture were both positive fo r STreatment was recommenced with 250 mg. every 6and again she became afebrile on the 4th. day.sequent progress was satisfactory.All s trains tested belong to Phage type A.

DISCUSSIONChloramphenicol is undoubtedly th e treatment ofin typhoid fever and in genera l the response is ex(SmadeJ,7 John an d Vinayagam 6 This ha s beexperience in an area where typhoid is


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21 ~ o v m r 1953 S.A. T Y S K R I F VIR GENEESKU DE 1057blood cul ture. Cases 3 4, and 6 all gave positive clotcultures after 3, 2, and 8 g. respectively of chloramphenicol had been given. Cook - and Marmion 3 state, Theeffect of chloromycetin seems to -be to arres t the diseaseat whatever stage it has r eached and to sterilize the bloodat the same time . This has not been our experience andwe have records of several cases where a positive clotculture has been obtained after the admin is tration ofchloramphenicol.The positive isolation in case 6 was from a specimentaken when the temperature was normal. is a commonmisconception that positive cultures can only be obtainedwhen the patient is pyrexial. Batty Shaw and HandfieldJones,l and Batty Shaw and Mackay 2 record similarobservations.The relapse in case 6 occurred after treatment had beencontinued for 16 days from the time the temperaturebecame normal. El Rarnli il records a relapse rate of3.9 where treatment was continued for 12 days fromthe day of becoming afebrile, and 26.3 when it wascontinued for only 0-3 days.

SUMMARY1. A number of cases of typhoid fever showing no

response or delayed response to chloramphenicol are presented.2. Positive isolation from blood may be obtained inspite of chloramphenicol having been given-in case 6after as much as 8 g.3. Positive cultures may be obtained in the absence ofpyrexia.4. Isolation of S. typhi from stools and urine has proveddisappointing.

I am grateful to Professor Pijper of the University ofPretoria for the phage types.REFERE CES

1. Batty Shaw, A and Handfield-Jones, R. P. C. 1948):J. Roy. Army Med. Cps., 91, 189.2. Batty Shaw, A and Mackay, H. A. F. 1951): J. Hyg., 49315.3. Cook, A. T and Marmion, D. E. 949): Lancet, 2 975.4. El Ramli, E. H. 1950): Ibid 1, 618. Idem 1953): Ibid 1,927.6. John, A. T. and Vinayagam, V. S. 1952): Ibid 2, 757.7. Smadel, T. E. 950): Amer. J. Hyg., 51 229.8. Stephens, P. R 1950): Lancet, 1, 731.9. Woodward, T E., Smadel, J. E., Ley, H. L Jr. , Green, R.and Mankikar, D. S. 1948): Ann. Intern. Med., 29 131.10. Marmion, D. E. 1952): Trans. Roy. Soc. Trop. Med.Hyg., 46 619.Since this article was written, there has been another casesimilar to cases 1 and 2: N., a Native female aged 13 was admitted on 2 July1953 with a 10-day history of headache, diarrhoea, abdominalpain, anorexia, cough, and pain in the chest.Temperamre on admission was 103.4 0 F. The tongue wasfurred and the mouth covered with sordes. She was slightlyjaundiced. There was bronchial breathing over the whole ofthe left lung, and crepitations at both bases. The liver waspalpable one finger-breadth below the costal margin. Thespleen could not be felt.Laboratory investigations: White blood count 2 900.Widal-TO 1/200, TH 1/25. Clot culture-positive on thefirst day of incubation. Blood culture was negative after 3weeks incubation. S. typ i was also isolated from the stool.Urine culture was negative.In view of her serious condition she was treated with 500mg. 6-hourly of chloramphenicol, but with no response. Thetemperature remained between 102 e and 104 for 4 days. Shethen developed a terminal hyperpyrexia and died.

ALCOHOL-BARBITURATE SYNERGISMEDMUND H. BURROWS M.B., CH.B. CAPE TOWN)

Assistant Government Pathologist Cape ownThe investigation of two recent deaths has focused ourattention upon the danger of the combined act ion ofethyl alcohol and the barbiturate drugs:Case A middle-aged woman was found dead on thefloor of her flat. She was known to have been a chronicalcoholic, and at the probable time of her death, in thethroes of a severe bout of drinking.- A bottle containingsome Tuinal capsules, a medium-acting barbiturate,was found in the same room. The brain alcohol wasestimated at 0.04 , and barbiturates in the liver10.91 mg., k idneys 1.79 mg. and stomach 1.45 mg.Case 2. A European male pensioner was found dead inbed, and the circumstances of his death indicate that itwas due to an overdose of Tuinal , as he had exhaustedhis a lcohol supply the previous day. The history isinteres ting: his landlady detailed how he was in thehabit of buying a bot tl e of spirits and about 40 Tuinalcapsules each month when he drew his pension. He wouldt hen begin drinking and con ti nu e unti l t he bot tl e wasempty, when he would taper off his hangover with the

capsules. On two occasions she had found him lying quitelimp on his bed, breathing very sof tly and apparentlyunconscious, and she had been unajJle to rouse him untilthe following morning. After the second bout he volunteered to her that he must have overdone i t with thecapsules, and tha t he had a fright.The synergistic action of ethyl alcohol and the barbiturates was first repor ted in experimental animals in 1937,1

and subsequent observations showed a similar synergismto exist i n humans. As these substances a re among thecommonest drugs used by moder n man , this pharmacological phenomenon is of more than forensic interest.Moreover, a certain proportion of the society-group whohabitually use alcohol as an adjuvant to daily activity arepotential candidates fo r barbiturate addiction s thesecases illustrate), and it is from this group that many ofthe recorded fatal cases in the literature spring.Whilst the use of alcohol is one of the most anc ient

human practices on record, barbiturate addiction isentirely a product of the mid-20th century. From the 80

3.5 response to chloramphenicol in the treatment of thypoid fever.kenneth c.watson, m.b

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