EVALUATION OF TREATMENT OF

TYPHOID FEVER

By S. L. MALHOTRA, m.h.c-p. (Lond.), d.c.h. (Eng.)

(From hn>, Medical Department oj Great Indian

Peninsula Railway)

Many attempts have been made in the past to discover an ideal treatment for typhoid fever. The first promising attempt in this direction was made by McSweeney in 1946 who published reports of 5 cases of typhoid fever treated with large doses of penicillin and sul-

phathiazole (McSweeney, 1946). Earlier in the same year Bigger (1946) had observed that the growth of Salmonella typhi in cultures was

prevented by a combination of penicillin and

sulphathiazole, although acting independently these agents had little effect on the organisms. McSweeney in 1946 described the treatment

of typhoid fever with penicillin and sulpha- thiazole. He used two courses of this combined

therapy. Each course consisted of 10 mega units of penicillin and 34 gm. of sulphathiazole given in equally divided doses for 4 days. The second course was given by McSweeney after an interval of 2 to 3 days and he believed that this was necessary to allow the persisting bacteria to grow after the first course so that these could be dealt with by the second course.

A detailed account of this will be found in a letter published by McSweeney in 1948.

McSweeney's work attracted much attention and it was given trials at various centres. The

experience of such trials in the Middle East has been summed up by Parsons in his unequivocal paper published in 1948. Parsons' paper, based on the impressions of the ' Middle East' medical specialists, condemned this new

approach. The opinions expressed were so

strongly phrased that a contemplated field trial was abandoned. Bevan in a report to the M.R.C. on the Welsh cases treated at various centres also stated that the treatment was

disappointing. There have been other trials such as that

by Dana (1948) which gave valuable support to McSweeney's work. But on the whole

McSweeney's method has been described as

disappointing and most workers have felt it

necessary to warn against the indiscriminate use of this treatment,

190 THE INDIAN MEDICAL GAZETTE [May, 1951

The second notable advance in the treatment of typhoid fever came with the discovery of

chloramphenicol. Since Smadel et al. (1950) and Woodward

et al. (1950) reported on the beneficial effect of chloramphenicol in the treatment of typhoid fever, this antibiotic has been used extensively all over the world (Douglas, 1949, 2 cases; Lomax, 1949, 1 case; Vakil, 1949, 14 cases; Shah, 1949, 33 cases;, Patel et al., 1949, 6 cases; El

Ramli, 1950, 200 cases; and Rankin and Grimble, 1950, 18 cases). The position up to date is that both Chloro-

mycetin and to a lesser extent aureomycin favourably influence the course of the disease and are able to sterilize the blood stream, but that neither antibiotic in the doses given can be counted upon to eradicate the bacilli from the

gastro-intestinal tract, or to prevent complica- tions and relapses. It is also possible that the introduction of chloramphenicol may increase the carrier rate.

Woodward et al. (1950) are using the inter- rupted treatment in typhoid : The drug is

given for the first five days and is omitted for the second five days after which the original course is repeated. They had no relapses in the 8 cases given this treatment. The present paper reviews cases of typhoid

fever treated by the writer since August 1948 and 11 cases treated during the year 1950 with chloramphenicol. During this period altogether 38 cases of

typhoid fever were treated by using various

therapeutic regimens as follows :? Two cases in 1948 treated on McSweeney's

plan which was followed rigidly using a slightly higher dosage of penicillin (12 mega units per course). One case of typhoid fever treated with peni-

cillin and sulphathiazole in which McSweeney's courses could not be completed as the patient refused to take any more injections. Two cases in 1949 treated with streptomycin. Twenty cases of typhoid treated with quinine

iodo-bismuthate (1948, 1949 and 1950). Four (P. G. D.) and 7 (S. L. M.) cases treated

with chloramphenicol. Two cases of typhoid treated on orthodox methods (1948).

Methods and dosage scheme 1. McSweeney's.?Patient was put on 2-

hourly penicillin injections concurrently with 4 daily doses of sulphathiazole. At least 4 pints of fluid intake daily and liberal feeding on high protein diet.

2. Quinine iodo-bismuthate.?Twenty cases in this group were treated on the high protein diet. 3.5 cc. of Rubyl supplied by Messrs. May & Baker (India), Ltd. were injected into the gluteal muscles every second day for a total of three doses. If the temperature did not come down

to normal after the third injection, it was

regarded as a failure.

Rubyl is quinine iodo-bismuthate. Its exact mode of action on typhoid is not understood.

3. Streptomycin.?It was given by intra- muscular injection every 8 hours, 1 gm. each time. Total quantity used in the first case was 20 gm., and in the second case 12 gm.

4. Chloromycetin.?It was given orally in the following dosage : Two capsules (0.5 gm.) to start with, and one capsule (0.25 gm.) every hour for the next 4 doses, later on one capsule (0.25 gm.) every two hours until the temperature came down to normal, followed by one capsule (0.25 gm.) every 4 hours for the next 48 hours and afterwards one capsule 4 times daily for 5 days.

5. Controls.?The 2 cases treated as controls received none of the above therapeutic agents. They were treated on a high calorie, high protein diet. Fever lasted for 12 days in one of these cases and the disease rair a very mild course. The other case proved fatal on the 45th day due to meningeal involvement. These control cases demonstrate amply the variations in the course of the disease.

Selection of cases All the cases had typical clinical features of

typhoid fever. They invariably had rhonchi in both the lungs and the typical temperature- pulse dissociation. Hsemoculture was positive only in 14 cases. Seventeen others showed a

rising titre of Widal. Five showed no significant rise in specific agglutinins throughout the ill- ness and the diagnosis in these was based

entirely on the history and clinical features. Presence of rhonchi in the lungs is regarded by the writer as an essential clinical sign, and this sign was present at some stage of the disease in all his cases.

Culture of urine or stool was not undertaken in this series on any of the cases.

Three groups

1. McSweeney's treatment. It was rigidly followed only in 2 cases and it failed to produce even the slightest difference on the course of the disease. The third patient on whom this treat- ment was to have been tried did not permit us to persevere with the injections. Two cases are indeed insufficient to condemn this form of treatment but the fact that not the slightest difference was produced in them by the treatment had not encouraged one to try it

any further. Penicillin and sulphonamides, of

course, must have their place in the treatment of complications due to sulphonamide-sensitive or penicillin-sensitive organisms.

2. Quinine iodo-bismuthate. It has been tried on 20 cases. No exaggerated claims of its specific efficacy are made. But the fact that 11 out of the 20 cases were definitely improved

May, 1951] TREATMENT OF TYPHOID FEVER : MALHOTRA 191

Q ? , Day on ena which case

number first seen

1 7 2 5 3 10

26 5

27 14 28 10

29 5 30 4

31 19

32 30

33 8 34 4

35 8

36

37 5 38 10

Day on which

treatment started

12 10 13

4 |

17 17

5 15 15 6 3 8 7 7 7

8 18 19 9 5 11 10 3 7 H 9 11

12 ! 4 7 13 4 8 14 14 14 15 28 31 16 36 36 17 3 8 18 4 8 19 I 12 14 20 9 12 21 j 12 16 22 10 | 11

23 13 13

24 5 7 25 14 14

7 14 15 12 7

19

30

15 4

Day on which the fever came

down

Table

Complications, if any Diagnosis established

l

M cSweeney's

Tympanites

Nil

Quinine iod.o-bismutha.te

Remarks

20 Venous thrombosis scalp veins.

| Meningitis 12 | Nil 30 | Relapse occurred on

23rd day and treated with Rubyl.

27 Nil 16 Nil 27 Nil 17 Relapse occurred on

23rd day. 11 Nil 13 Nil 19 Nil 35 Tympanites

21 13 18 14 18 15

16

26 24

26 23 17 14 14 21

33

21 8 10

12

Haemorrhage Nil Diarrhoea Nil Nil Nil Nil

Streptomycin

Nil Diarrhoea

Chloramphenicol Series A (S. L. M.)

Nil Nil Nil Tympanites

ff

Had relapse on 26th

day.

Diarrhoea

Series B (P. G. D.)

Nil Nil Had relapse on 18th day : Chloromycetin re-started and tem-

perature came down on the 20th day. Had another relapse on

23rd day in spite of Chloromycetin which was now stopped.

Controls

Patient expired on 45th day of the fever.

Culture

Widal

Clinically

Widal Culture

Widal Culture

Clinically

Culture

Widal

Clinically Widal Culture Widal

Culture Clinically

Culture

Culture Widal' Culture

Clinically Widal

Widal

Culture Widal and clinically.

Treatment ineffective.

Treatment could not be

followed rigidly.

Effective.

Died. Effective. Relapse cured on 30th

day after 2nd dose.

Effective ? Effective. Ineffective. Relapse controlled on

27th day by a 2nd dose. Treatment effective.

Died on 38th day. Treatment effective.

Treatment effective. Treatment ineffective.

Treatment effective. Treatment ineffective. Treatment effective.

Treatment ineffective. Relapse fever came

down on 30th day. Effective.

Ineffective ? Treatment effective. Treatment ineffective.

Treatment effective.

Chloromycetin was not

available when this

patient was treated.

192 THE INDIAN MEDICAL GAZETTE [May, 1951

by this simple procedure of giving 3 intra- muscular injections, every other day, could not,

fail to impress the author. The response in case nos. 8, 12, 14 and 15 has that dramatic character which would appear extremely promis- ing. Against this are cases in whom Rubyl failed to produce any appreciable effect in the

temperature. Case nos. 10 and 17 were extremely toxemic and although Rubyl proved completely ineffective in cutting down the febrile period, it did reduce the toxjemia. The profound amelioration in the toxsemic condition of these

patients was very convincing. In some of the cases there has been a slight,

increase in the temperature after the first injec- tion and this settles down on the second day and in most of the successful cases the tempera- ture came down after the second injection.

Administration of quinine iodo-bismuthate is

simple and devoid of any ill effects. In the author's opinion it deserves more extensive trials on well-controlled series. The cost of treatment as compared to chloramphenicol is

negligible. 3. Chloramphenicol. It is a fact that Chloro-

mycetin brings down the temperature quickly. The response, however, has been variable, the temperature coming down on the second day in some cases and on the eighth day in others. One of the cases relapsed and the relapse proved more resistant to treatment. Case no. 31 had two relapses and the second relapse was quickly /controlled by quinine iodo-bismuthate.

Discussion

The writer has experienced that both quinine iodo-bismuthate and chloramphenicol bring down the temperature quickly and relieve toxaemia. There is no doubt that some un-

explainable diversities in the action of both the drugs exist, some cases responding more quickly than others: He is also of the opinion that diarrhoea is no contra-indication to the exhibi- tion of chloramphenicol. On the whole, judging from his own experience and that of others, it is true that chloramphenicol is very effective. However, it seems to have no appreciable effect on the incidence of relapse. In his own series out of 11 cases two had relapse in spite of continued therapy. The cost of the drug is prohibitive for routine

use and therefore until it is more freely avail- able it will remain beyond the reach of a poor patient.

Quinine iodo-bismuthate in kis experience has been very satisfactory, although it must be said that the response in some cases is either

very poor or none at all. In other cases the

response has been dramatic. It is difficult to

explain such discrepancies in the action of both Rubyl and chloramphenicol. It is possible that

this variability of the response may be due to :?

1. A difference in the nature of the fever itself depending on the type strain of the bacillus and some other undetermined factors.

2. The possibility that a secondary infection or a pre-infection with heterologous organisms may modify the course of the disease depend- ing on the bacterial allergy produced. It is an

interesting speculation how far such alterations of reactivity as may be produced by pre-infec- tion with other organisms may be responsible for the existence of variations in the clinical

types of typhoid fever. The author is now

observing the role of such heterogeneous pre- infections or secondary infections on the clinical course of typhoid fever and tuberculosis.

Conclusions

Chloramphenicol is in short supply and its cost is prohibitive for general use. Until more

experience is accumulated it is suggested that quinine iodo-bismuthate should be used soon

after the diagnosis is established and chlor-

amphenicol used only in those cases that have failed to respond to quinine iodo-bismuthate.

Summary 1. Treatment of 38 cases of typhoid fever is

reviewed with special reference to McSweeney's plan, quinine iodo-bismuthate and chlor-

amphenicol. 2. Variability in the action of both quinine

iodo-bismuthate and chloramphenicol is pointed out.

3. It is suggested that quinine iodo- bismuthate may prove a drug of second choice to chloramphenicol in the treatment of typhoid fever.

My thanks are due to Dr. P. G. Dalai, District Medical Officer, G. I. P. Railway, Bhusawal, for permis- sion to use his case notes on 4 of the Chloromycetin cases (nos. 33 to 36), and to Dr. P. N. Kapur, f.r.c.p.

(Edin.), F.C-C.P., for permission to communicate the

paper.

Some of the quinine iodo-bismuthate used in this study was supplied through the courtesy of Messrs. May & Baker (India), Ltd., to whom the author's thanks are also due.

Addendum

The writer has observed marked glossitis and pharyngitis in fact inflammation of the whole of the oral mucosa coming on in some cases after the use of chloramphenicol. The antibiotic destroys certain organisms

ordinarily present in the oral cavity, leaving others unaffected so that these latter overgrow rapidly once the normal floral equilibrium is disturbed.

May, 1951] TREATMENT OF GUINEA-WORM INFECTION : BHAJEKAR 193

Another explanation which appears more

rational is that the inflammation is due to the

deficiency of vitamin B particularly nicotinic acid and folic acid. The antibiotic destroys the normal flora in the intestine which is respons- ible for the biosynthesis of this vitamin.

This view is supported by the fact that the oral inflammation subsides with folic acid administration.

Whatever the explanation of the condition, one moral emerges from it, that large doses of vitamin B particularly folic acid and nicotinic acid must be given with chloramphenicol.

REEERENCES

Bigger, J. W. (1946) .. Lancet, i, 81.

Dana, R. (1948) .. IbicL., i, 692.

Douglas, A. D. M. Ibid., i, 858. (1949).

El Ramli, A. H. (1950). Ibid., i, 618.

Lomax, W. (1949) .. Brit. Med. J., ii, 911.

McSweeney, C.J. (1946). Lancet, ii, 114.

Idem (1948). Ibid., i, 691.

Parsons, C. G. (1948). Ibid., i, 510.

Patel, J. C., Banker, Ibid., ii, 908. D. D., and Modi, C. J. (1949).

Rankin, A. L. K., and Ibid., i, 615. Grimble, A. S. (1950).

Shah, M. J. (1949) .. Indian Physician, 8, 192.

Smadel, J. E., Bailey, Ann. Intern. Med., 33, 1.

C. A., and Lethwaite, R. (1950).

Vakil, R. J. (1949) .. Indian Physician, 8, 185.

Woodward, T. E., Smadel, J. Clin. Invest., 29, 87. J. E., and Ley, H. L. (1950).

^