Therapeutic Notes

NOTES ON SOME REMEDIES

VI. SULPHON AMIDES

II

By R. N. CHAUDHURI, m.b. (Cal.), m.r.c.p. (Edin.), t.d.d. (Wales), F.S.M.F.

Professor of Tropical Medicine, School of Tropical Medicine, Calcutta

General considerations

Good and sometimes spectacular results with sulphonamides are obtained usually in the acute infections, but in the main these drugs do little good in chronic conditions. For example, in acute gonorrhoea this therapy works wonders in 4 or 5 days, whereas in chronic gonorrhceal arthritis little or no response can be expected. Best results are obtained if they are given early when the infecting organisms are still small in number : in pneumonia, specially, treatment should be begun before the development of the classical signs. Under-dosage is still far too frequent; if there is a real indication, they

78 THE INDIAN MEDICAL GAZETTE [Feb., 1947

should be used boldly in adequate amount with- out the physician's mind being fixed on the rare event of agranulocytosis. On the other hand they are not to be given indiscriminately in

every low grade infection which heals up

spontaneously. The importance of rapid raising of blood concentration has already been stressed. In severe infections this should be ascertained

during the first two or three days or even earlier if possible; this may go far to explain failure and to suggest the next move in therapy. Like-

wise, the course of diseases like meningitis and septicaemia is best controlled by bacteriological examination. But if such examinations are

not possible the drugs can still be used with reasonable safety and success, provided that the instructions here outlined are applied with common sense. In this connection it should be noted that the sulphonamides can inhibit bacterial growth in pathological fluids, so in

sending a specimen, the bacteriologist should be informed that the patient is receiving these drugs, so that he may use the special culture medium required. Relapses can be treated with renewal of the drugs, but before doing so a white blood cell count should be made.

Ancillary treatment is as important as in any other therapy. Sulphonamides may not be a

substitute for surgery and operative treatment should never be unduly delayed because they have been used. Virus infections, with the possible exceptions of trachoma and fymphogranuloma inguinale, do not respond to these drugs, but there is evidence that they have a definite place in the treatment of secondary bacterial condi- tions. Finally, there are no special contraindi- cations to their use except severe hepatitis and advanced renal disease, especially with nitrogen retention. Some caution is required in pregnant and lactating women as these drugs are slightly excreted in milk and they pass through the

placenta into the fcetal circulation, though they need not be withheld for that reason. Racial

susceptibility is worth remembering.

Therapeutic uses In this section only some of the essential

points are given and it has not been possible to give greater details within the limited space.

1. Hemolytic streptococcal infections, e.g. cellulitis, erysipelas, septicaemia, etc.

In septicemia sulphanilamide is very effective. If the response is not satisfactory, small blood transfusions (200 to 300 c.c.) are indicated.

Any septic focus will require adequate treat-

ment, but abscesses should not be incised until fully ripened, and care must be taken not to

open up fresh channels of infection. Excellent results have been obtained in erysipelas; the

spread of the lesion is stopped in 48 hours and the fever subsides in 3 to 4 days. Treatment should be continued with reduced dosage for a further period of seven days to prevent relapse. In puerperal sepsis sulphonamides have greatly reduced the mortality, the best results being

obtained with high blood concentrations. Quick relief follows in acute otitis media and mastoiditis both of which should be treated as severe infections, but the symptoms are liable to be masked and careful watch must be kept on the drum-head and mastoid bone as surgical intervention may be necessary. Treatment should be continued for a week to prevent relapse. If purulent discharge sets in, the infec- tion rapidly becomes a mixed one of strepto- cocci and staphylococci, when sulphathiazole or sulphadiazine should be preferred. Careful local treatment is necessary. The great majority of non-hsemolytic strepto-

cocci are insensitive to sulphonamides. 2. Staphylococcal infections.?In severe

cases sulphonamides should not be relied on

if penicillin is available, particularly in acute osteomyelitis, cavernous sinus thrombosis, severe carbuncle, septicemia and staphylococcal pneumonia and meningitis. In its absence sul-

phathiazole is the drug of choice. Septicemia due to this cause is a serious condition with a

high mortality. Give maximal or still higher dosage, even at the risk of toxic reactions. To avoid relapse or recrudescence, treatment should not be interrupted unless a pronounced clinical

improvement or a dangerous toxic reaction occurs. The minimal dose should be 12 to 18 gm. a day (2 or 3 tablets two hourly) for three days, followed by 2 gm. four hourly for a further four days. If necessary the treatment should be continued for a longer period. Blood cultures are helpful as a guide to dosage and the length of the course. A colony of 20 or over per c.cm. is a bad prognostic sign. A co-existing focal lesion such as abscess or osteomyelitis is of

good omen. Small repeated blood transfusions are of great value. Both in streptococcal and staphylococcal

septicaemia full doses of sulphonamide and

penicillin would seem the most promising combination, since some strains of streptococcus and staphylococcus are resistant to one or other of the drugs.

Sulphathiazole given early in acute osteo-

myelitis not only controls the systemic infection but also limits the bone infection, but it has to be combined with surgery when there is

already bone damage and abscess formation. Treatment should not be stopped after the first few days when the disease may appear to be under control. The affected part should be immobilized. The cause of death is usually staphylococcal septicemia and the patient should be treated as a case of severe infection. In impetigo contagiosa the drug is applied as

a 5 per cent cream or paste twice in the day and night after removing the crusts and scabs. The condition gets almost cured in 5 or 6 days, but quicker results have been reported with 15 per cent suspension of microcrystalline sul-

phathiazole. Treatment should not be continued

longer than 5 days, as patients are liable to

develop hypersensitivity.

Feb., 1947 J SULPHONAHIDES : CHAUDHUHI 79

. 3. Meningococcal injections (cerebrospinal

lever).?Chemotherapy has greatly reduced the Mortality from this disease. It is vital to secure adequate blood concentration at the earliest possible moment and to maintain it for several days. Another point that is likely to be overlooked is the need for giving sufficient fluid to comatose patients. The initial dose or doses, except in mild cases, should be given intra-

venously as soon as lumbar puncture has shown [he fluid to be turbid and without waiting for bacteriological examination. The fluid may not

always be purulent, but the presence of even ?ne or two polymorphonuclear cells should arouse suspicion. The dosage is higher than

usual, no infant should be given less than 3 gm. oaily during the first two days of treatment, *or adults during this period 12 gm. daily !s an appropriate dose and for children an

mtermediate amount. Intravenous (or intra-

muscular) injections may have to be repeated lf. the clinical condition "does not improve within 2 or 3 days. When repeating lumbar Puncture only a small quantity of fluid should "e removed (5 c.c.) to prevent loss of sul-

fonamide. With clinical improvement the dose is reduced but the drug should be continued

about 10 days. Meningitis due to pneumococci, staphylococci

and H. influenza, etc., is relatively resistant to sulphonamide treatment. In most cases the infection is secondary to a primary focus else-

where in the body such as pneumonia, otitis and sinusitis. Examination of the spinal fluid should be made at frequent intervals so that

relapse which is much more common in these

infections may be detected at the earliest stage and appropriately treated with renewal of high dosage. The drug should be continued for at

least a week after the temperature has subsided and for a longer period in H. influenza infec- tion which is specially liable to relapse. Remarkably good results have been obtained by combined sulphonamide and penicillin therapy in pneumococcal meningitis in which the case

mortality before the advent of chemotherapy was a little short of 100 per cent. The same

combination should be adopted for all these

types of meningitis, although H. influenza are

relatively more resistant to penicillin. 4. Pneumonia.?In pneumococcal infection

temperature usually comes down within 48

hours, but the treatment should be continued tor 5 days more. Resolution occurs rather

slowly and physical signs may persist for as

long as a fortnight, but the drugs should not be given longer than 7 days. Age is an

important factor in prognosis, and in the aged sulphonamides are not nearly so effective as

earlier in life. Parenteral injections should be given in severely toxic patients or where the

clinical response is poor. In some cases the

drug has no effect when penicillin is indicated.

Adjuvants like oxygen, good nursing, etc., must, not be forgotten.

In an average case of pneumonia, there is little to choose between the sulphonamides and penicillin so far as the end result is concerned, but there is a small percentage of patients over 40 for whom penicillin represents a definite advance on the sulphonamides. Generally the indications for its use are extensive pulmonary involvement, severe cyanosis and dyspnoea, heavy bacteremia and lack of leucocytosis. Pneumonia due to streptococcus or Fried-

lander's bacillus responds well to sulphon- amides, although not so dramatically as in the pneumococcal disease. In staphylococcal pneumonia which is a very fatal disease

penicillin is the drug of choice. Broncho-

pneumonia is caused by a wide variety of

agents, against some of which sulphonamides may fail, but the difference in response seems to be more apparent at the extremes of life when the resistance to infection is poor. They are of value in influenzal pneumonia, provided the viral infection itself is not too severe; a leucocytosis favours the chance of a good response.

5. Intestinal injections.?Sulphonamide ther- apy has been strikingly successful in bacillary dysentery. In severe Shiga infections, the

clinical response to ̂ sulphaguanidine is remark-

able?abdominal pain and tenesmus are relieved in 1 to 2 days and the number of stools reduced to normal in a few days. Blood rapidly dis-

appears although mucus persists for some time. Doses of 3 gm. four times a day for three days and then two or three times a day for four days are effective in all but the most severe infections in which the unit dose may be increased to 5 gm. Best results are obtained if treatment is started in 24 to 36 hours of the onset. In fulminating cases 50,000 to 100,000 units of concentrated

anti-dysenteric serum (Shiga) should be given intravenously to combat the toxaemia. Flexner infections also respond very well, doses of 3 gm. being usually sufficient. Convalescent carriers are common among untreated patients, and these

together with symptomless carriers can usually be cured by a course of sulphaguanidine. Sonne

dysentery is rather resistant but it is a mild infection and the treatment is that of a con-

valescent carrier. Succinyl sulphathiazole (sul- phasuccinyl) is reported to be equally effective and may be given in daily 10 gm. dosage, divided into five doses, but there has not been enough experience with it owing to short supply. Although sulphaguanidine as a rule produces

no toxic complications, large doses such as 24

gm. a day as originally used may result in high concentration in the body and if the drug is continued for more than 8 days, toxic symptoms become common. Succinyl sulphathiazole on

the other hand is so poorly absorbed that it seems to be free from this danger. These two drugs have been introduced on the

hypothesis that, being poorly ̂ absorbed, they

produce a higher concentration in the faeces and

80 THE INDIAN MEDICAL GAZETTE [Feb., 1947

hence are more effective than drugs which arc

well absorbed. If this hypothesis is correct, then succinyl sulphathiazole should be the best drug, but so far this has not been the case.

Paulley (1942) suggested that it is not the con- centration of the drug in the intestinal contents but the concentration in the blood which is the important factor. It is argued that bacillary dysentery is a systemic disease with focal intestinal manifestations and treatment should be more effective when the absorbable drugs such as sulphadiazine or sulphathiazole are used. This seems to be borne out by the fact that these drugs have given as good, or even better results, presumably because, besides having some local action, they are in a better position to act on the organisms lying in the mucosa.

Reports are however conflicting and, according to our present knowledge, the following recommendations may be made. In severe cases

sulphaguanidine should be given; in the dosage now employed it hardly ever has unpleasant side- effects and it is not advisable to give drugs which are toxic and easily liable to crystallize out in the urine of a dehydrated patient with oliguria. But as it is rather slowly absorbed it may be preceded by sulphathiazole during the first 24 hours. In other types of the disease, both forms of sulphonamides can be used, the dose of sulphadiazine or sulphathiazole being 2 to 4 gm. followed by 1 gm. 4 hourly, and later 6 hourly. All these drugs are not infallible and a change of drug in unresponsive cases may be an advantage. There is also some evidence that a combination of the two forms of drugs may be more desirable than either type alone in the acute phase of the disease. Succinyl sulphathiazole should be reserved for the treat- ment of Sonne dysentery and dysentery carriers who become bacteriologically negative after a

course of 10 gm. a day for 5 days. It is also

used in the pre- and post-operative stage of

intestinal surgery owing to its marked property of reducing B. coli in the bowel?a property which is more noticeable with phthalyl sulpha- thiazole. A few practical points may here be mentioned.

Purgatives, high enemas and colon irrigations are contra-indicated. Fluid intake must be

sufficient and, if necessary, glucose and saline

injections are given intravenously. Sulphon- amides should not be started in a dehydrated patient until steps have been taken towards restoration and maintenance of normal hydra- tion. Lastly it should be noted that the

dramatic relief of symptoms does not imply healing of the intestinal lesions; this usually takes some time and the convalescence should not be hurried, or there may be relapse. If

possible, sigmoidoscopy and stool cultures should be made before a patient is declared as cured.

In chronic bacillary dysentery and ulcerative colitis reports are as yet inconclusive. In a few

moderately ill patients sulphaguanidine has

given complete remission of symptoms but

severe infections arc unaffected. Full doses should be given, and it is often necessary to

repeat the course. Where oral therapy fails, the use of retention enemata has been advocated, containing 7 to 10 gm. of sulphaguanidine or

succinyl sulphathiazole in 7 ounces of water or mucilage. Such enemata can be retained from 6 to 8 hours, and to assist this, phenobarbitone or morphine is given as a bowel sedative.

Penicillin and sulphasuccinyl have given very promising results in chronic amoebic dysentery which has resisted the usual courses of treatment. An initial dose of 100,000 units of

penicillin intramuscularly is given, followed by 33,000 units every three hours until two million units have been given. At the same time sulpha- succinyl is given until a total of 80 gm. has been taken. This course does not eradicate the amoebic infection but can deal with the

secondary pyogenic organisms that invade the ulcers in the intestine and thus bring about conditions that permit a favourable response to anti-amcebic drugs. In the absence of sulpha- succinyl, sulphaguanidine may be used. Sulphonamide therapy is also of value in non-

specific colitis and in some cases of sprue along with liver injections or folic acid therapy. Chaudhuri and Rai Chaudhuri (1944) found sulphaguanidine very efficacious in controlling the diarrhoea.

In cholera, sulphaguanidine has already given favourable results, but trials are still continuing. Huang (1944) obtained rapid amelioration of

symptoms with an initial dose of 3 gm. followed by 1 gm. every two hours for six hours and then 1 gm. four hourly for 1 to 2 days; In India the report of the Scientific Advisory Board

(1945) records good results with a different method of treatment; sulphaguanidine was given in 3 gm. doses every four hours for 3 days, and then twice a day for 3 days. Such results are not obtained when treatment is started late. In any case usual steps should be taken to combat the dehydration and depletion of salts and colloids.

Finally it should be remembered that certain intestinal organisms synthesize vitamins and that sulphaguanidine and succinyl sulphathiazole given over long periods can reduce the natural flora of the bowel and thus inhibit the synthesis of many factors essential to the host, e.g.

thiamine, members of B2-complex such as folic

acid, riboflavin, nicotinic acid, etc. Further a severe intestinal infection such as bacillary dysentery may in itself precipitate a deficiency state. It is therefore wise to attend to the vitamin B state of the patient when employing '

chemotherapy within the bowel \

REFERENCES

Chaudhuri, R. N., and Indian Med. Gaz., 79, 404. Rai Chaudhuri, M. N. (1944).

Huang, J. S. (1944) .. J. Amer. Med. Assoc., 125, 23.

Pault.ey, J. W. (1942). Lancet, ii, 592.

[To be concluded]