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Chapter 6, Part 4

Medical Science Publication No. 4, Volume II

THE DIAGNOSIS AND TREATMENT OF ENTERIC DISEASES*

BERNARD T. GARFINKEL, M. D.

The problem of dysentery among Korean and Chinese prisoners of war was complicated by the presence of many cases of bacillary dysentery which were due to sulfonamide-resistant Shigellae. This finding was based first on clinical observation and was supported later by in vitro sensitivity tests. As a result, the physicians responsible for the care of the men had available only nonspecific, supportive measures. Reports on limited trials of auremoycin, terramycin and chloramphenicol had indicated that they were extremely effective in some cases of sulfonamide-resistant shigellosis. Therefore, their use and careful evaluation seemed urgently indicated. A high incidence of acute amebic dysentery among this group of individuals also gave an unusual opportunity to study the effect of aureomycin and terramycin upon amebiasis.

Patients who complained of diarrhea were seen first by the compound physician. The more seriously ill men, or those who did not respond to treatment, were admitted to the hospital. All studies were carried out in the hospital.

Patients were admitted to a special 100-bed ward. A complete physical examination was done on admission and electrolyte, fluid and symptomatic therapy was begun. Men who were severely ill were immediately begun on specific antibiotic therapy and were not included in the study groups. Immediately after admission diagnostic procedures were also begun. A freshly passed stool specimen was obtained from each man. It was examined for motile trophozoites of E. histolytica and other parasites. A portion was streaked onto an SS (Shigella-Salmonella) agar plate. Stool obtained by the Hardy rectal swab technic was also streaked onto SS agar. Sigmoidoscopic examinations were then carried out and exudate obtained from ulcers or areas of inflammation was aspirated with a 1 cc. pipette and examined for trophozoites of E. histolytica and cultured on SS agar.

A medical officer reviewed the laboratory findings and then assigned each man to the proper treatment group. Only patients with proven


*Presented 29 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington,
D. C.


296

E. histolytica infections were included in the treatment series for amebiasis. Assignments to antibiotic therapy for bacillary dysentery, however, depended upon presumptive diagnoses based upon the appearance of the exudate in the stool and changes in the appearance of the rectal mucosa. Stools from only 60 percent of these men were found to be positive for Shigellae. However, the remaining 40 percent exhibited the characteristic clinical features of Shigella infections. The response to therapy was similar in both groups. Although it was assumed that all of these patients had bacillary dysentery, only the cases with positive cultures were subsequently included in the final study.

The characteristic sigmoidoscopic observations in the patients with bacillary dysentery were those of a diffuse inflammatory process. The lumen of the rectum ordinarily contained large amounts of mucopurulent exudate unmixed with fecal residue. In some cases the mucosa was obscured by a diffuse coating of grayish sticky pus; in others droplets of pus oozed from the mucosal crypts under the pressure of the advancing sigmoidoscope. Ulceration was uncommon, but when seen, the ulcers were shallow, irregular and covered with purulent exudate. They varied from 2 mm. to 2 cm. in diameter. Submucosal ecchymotic areas were often visible in the acute stage but were more striking when the inflammation had subsided. The cellular exudate was composed chiefly of polymorphonuclear leukocytes and some large mononuclear cells. The latter, however, were not sufficiently constant in character to have diagnostic significance.

The sigmoidoscopic observations in the amebic dysentery cases were very different. Ulceration of the rectal mucosa was the most frequent finding and was seen in 87 percent of all patients with intestinal amebiasis. Edema and hyperemia of the mucosa were observed but were less common than in bacillary dysentery. Ordinarily the uninvolved mucosa appeared relatively normal. The typical amebic ulcer was small and discrete. The edges were piled up; the crater was deep and was covered by thin grayish-white exudate. The number of ulcers was often unexpectedly large. Many patients had as many as 100 to 200 varying in size and depth and located principally in the terminal 4 cm. of the rectum. In contrast to the severity of the ulcerations, the patients' general condition was unusually good and their symptoms mild. Material aspirated from these ulcers contained large numbers of actively motile E. histolytica trophozoites which were usually engorged with red blood cells. The cellular exudate was scant, was predominantly hemorrhagic, and contained only rare pus cells.

Evaluation of the effects of treatment was simplified by the uniformity of the affected group. All patients were young or middle-aged adult males who for several months had lived in the same en-


297

vironment. All had received the same type of food in similar amounts. Further comparability was assured by assignment of patients in rotation to predetermined treatment schedules.

Four antibiotics were compared with therapeutic agents previously available for the treatment of bacillary dysentery. The first task was to determine whether or not standard dosages of chloramphenicol, aureomycin terramycin and polymyxin-B were more effective than sulfadiazine or supportive therapy alone. Preliminary observations indicated that chloramphenicol, aureomycin and terramycin were all highly effective. More complete studies were then done to establish a minimum effective dose. Four dosage schedules were used: (1) 10 gm. total, 2 gm. given at once, and 0.5 gm., four times a day for 4 days; (2) 4 gm. total, 0.5 gm. given at once, and 0.25 gm. twice a day for 7 days; (3) 4 gm. total, 2 gm. given at once, and 1 gm. after 12 and 24 hours; (4) 2 gm. as a single dose. Sulfadiazine was used in two dosages, each with 2 gm. given immediately and: (1) with 1 gm. four times a day for 4 days, (2) with 2 gm. three times a day for 5 days. Polymyxin-B was given orally in two dosage schedules: (1) 50 mg. a day for 7 days, (2) 100 mg. four times a day for 5 days.

Cultures were taken on the first, second, fourth and seventh days after the start of treatment. Observations were continued for 2 weeks after the completion of therapy and during this time four additional cultures were made. A case was recorded as continuously positive if the Shigella isolated in the pretreatment culture was found in any subsequent culture, even though intervening tests were negative. A case was counted as culturally negative only when all subsequent examinations during the hospital admission failed to isolate the type of organism found.

The bacteriological findings are summarized in Table 1. All but 29 percent of the patients on supportive therapy had negative cultures

Table 1. Bacteriological Response to Therapy in Acute Bacillary Dysentery


Treatment

Number of patients treated

Cases culturally positive at intervals after beginning of treatment, percent

0* days

2 days

4 days

7 days

Supportive

224

100

73

42

29

Sulfadiazine

146

100

55

35

25

Polymyxin B

135

100

45

22

12

Chloramphenicol

321

100

12

5

1

Aureomycin

308

100

5

2

1

Oxytetracycline

274

100

7

3

0

*Immediately prior to start of therapy.
Source: Garfinkel, B. T., Martin, G. M., Watt, J., Payne, F. J., Mason, R. P., and Hardy, A. V., J. A. M. A. 151 : 1157, 4 April 1953.


298

on the seventh day of treatment and continued to have negative cultures thereafter. There was a gradual decline throughout the week in the proportion of positive cases. Sulfadiazine did not modify this course to a significant degree. Response to polymyxin-B was likewise unimpressive. The drug modified only slightly the course of the disease. The three antibiotics, aureomycin, chloramphenicol and terramycin, were considerably more effective. Most striking was the rapid reversion of the stool cultures from positive to negative. On the seventh day all cases treated with terramycin, and almost all treated with aureomycin and chloramphenicol were culturally negative; they remained so for the follow-up period. As previously indicated, the three antibiotics were used at four dosage levels. As shown in table 2, each schedule effected a similar bacteriological response. All the dosages, even the 2 gm. single dose, appeared to be adequate even for these severe enteric infections.

Table 2. Relative Efficacy of Three Antibiotics at Varying Dosage Levels in Acute Bacillary Dysentery


Medicament


Dosage

Total number of patients

Cases culturally positive at intervals after beginning of treatment, percent

0* days

2 days

4 days

7 days

Aureomycin

10 gm. in 4 days

96

100

8

4

1

Chloramphenicol

10 gm. in 4 days

85

100

14

13

1

Oxytetracyline

10 gm. in 4 days

94

100

13

5

0


Total


275


100


12


7


1

Aureomycin

2 gm. single dose

36

100

3

3

3

Chloramphenicol

2 gm. single dose

39

100

18

10

5

Oxytetracycline

2 gm. single dose

48

100

6

4

0


Total


123


100


9


6


2

Aureomycin

4 gm. in 7 days

51

100

2

2

2

Chloramphenicol

4 gm. in 7 days

41

100

12

0

0

Oxytetracycline

4 gm. in 7 days

48

100

2

0

0


Total


140


100


5


1


1

Aureomycin

4 gm. in 24 hr

125

100

3

0

0

Chloramphenicol

4 gm. in 24 hr

156

100

9

1

1

Oxytetracycline

4 gm. in 24 hr

84

100

2

1

0


Total


365


100


6


1


(†)

*Immediately preceding the start of treatment.
†Less than 0.5.

SOURCE: Garfinkel, B. T., Martin, G. M., Watt, J., Payne, F. J., Mason, R. P., and Hardy, A. V.: J. A. M. A. 151 : 1157 (4 April), 1953.


299

The clinical responses, however, did not coincide with the changes in the bacteriological tests. Sigmoidoscopic examinations done on the fourth day of treatment were used to evaluate further the therapeutic response in 499 cases (table 3). About one-half of the patients who did not receive specific therapy had evidence of continuing active colitis. The proportion dropped to 42 percent when sulfonamides or polymyxin-B were used. Results were significantly better with aureomycin, terramycin and chloramphenicol. Active lesions were seen in only 20 percent when small doses were used and 4 gm. given in the first 24 hours caused healing in all but 4 percent of the cases.

Table 3. Efficacy of Various Methods of Therapy as Determined by Sigmoidoscopic Examination on
Fourth Day of Therapy in 499 Culturally Positive Cases


Therapy

Number of patients observed

Continuing active colitis

Number

Percent

Supportive

86

42

49

Sulfonamide

60

25

42

Polymyxin-B

106

45

42

Antibiotics: 2 gm. single dose

56

11

20

Antibiotics: 4 gm. in 7 days

91

20

22

Antibiotics: 4 gm. in 24 hr.

100

4

4

SOURCE: Garfinkel, B. T., Martin, G. M., Watt, J., Payne, F. J., Mason, R. P., and Hardy, A. V.: J. A. M. A. 151 : 1157 (4 April), 1953.

Other criteria of therapeutic response were also studied. The character of each stool was observed and recorded. Information on the decrease in the diarrhea and the disappearance of exudate was available. The physicians' daily notes also indicated the clinical status of the patient. All these observations paralleled the sigmoidoscopic findings. The results of therapy were also analyzed according to the species of Shigella isolated. No significant variation was noted.

These studies, therefore, indicated that terramycin, aureomycin and chloramphenicol were effective agents in treating sulfonamide-resistant shigellosis in Korea. Four grams in three doses in 24 hours gave as satisfactory results as the larger doses ordinarily employed. Polymyxin-B was much less effective.

The patients who had amebic dysentery were treated in accordance with the predetermined schedules shown in table 4. Standard amebacides, emetine, carbarsone, chiniofon, milibis and chloroquine, were used singly or in combination. Terramycin, aureomycin and chloramphenicol were given; terramycin was used with the other amebacides, and aureomycin was combined with chloroquine.


300

Table 4. Drugs and Dosage Schedules Used in 538 Cases of Acute Amebic Dysentery

Treatment agent

Dosage

Standard Amebacides:

1. Emetine

0.03 gm. twice a day for 4 days.

2. Carbarsone

0.25 gm. three times a day for 7 days.

3. Chiniofon

1.0 gm. three times a day for 7 days.

4. Chloroquine base

0.3 gm. twice a day for 2 days or more.
0.3 gm. three times a day for 19 days.

5. Emetine, carbarsone, and chiniofon, given concurrently.

0.03 gm. twice a day for 4 days.
0.25 gm. three times a day for 7 days.
1.0 gm. three times a day for 7 days.

6. Bismuth glycolylarsanilate, and chloroquine diphosphate.

0.5 gm. three times a day for 7 days.
0.15 gm. three times a day for 7 days.

Antibiotics:

7. Oxytetracycline

a. 2 gm. initially, 0.5 gm. every 6 hr. for 10 days.
b. 2 gm. initially, 0.5 gm. three times a day for 10 days
c. 2 gm. initially, 0.5 gm. every 6 hr. for 5 days.

8. Aureomycin

2 gm. initially, 0.5 gm. every 6 hr. for 10 days.

9. Chloramphenicol

2 gm. initially, 0.5 gm. every 6 hr. for 10 days.

Antibiotics and Amebacides Combined:

10. Oxytetracycline with

2 gm. initially, 0.5 gm. three times a day for 10 days.

a. Emetine

0.03 gm. twice a day for 4 days.

b. Carbarsone

0.25 gm. three times a day for 7 days.

c. Chiniofon

1.0 gm. three times a day for 7 days.

d. Bismuth glycolylarsanilate and chloroquine diphosphate.

0.5 gm. three times a day for 7 days.
0.15 gm. three times a day for 7 days.

e. Chloroquine

0.3 gm. twice a day for 2 days; 0.3 gm. per day for 5 days.

11. Oxytetracycline with chloroquine.

2 gm. initially, 0.5 gm. every 6 hr. for 5 days.
0.3 gm. twice a day for 2 days; 0.3 gm. per day for 3 days.

12. Aureomycin with chloroquine

2 gm. initially, 0.5 gm. every 6 hr. for 10 days.
0.3 gm. twice a day for 2 days; 0.3 gm. per day for 5 days.

Supportive Therapy

Bed rest and nutritional supplements.

SOURCE: Martin, G. M., Garfinkel, B. T., Brooke, M. M., Weinstein, P. P., and Frye, W. W.: J. A. M. A. 151 : 1055, 28 March 1953.


301

Patients with amebic dysentery were followed for 6 weeks after treatment was begun. Saline preparations of stool specimens were examined on the first, second, fourth and sixth days, and once a week thereafter. Before discharge each patient was given a saline cathartic, and the specimens were searched for amebae. The zinc sulfate centrifugal floatation technic was used to find E. histolytica cysts 2 weeks, 5 weeks and 6 weeks after onset of therapy. The sigmoidoscopic examination, bacteriological and parasitological tests were repeated once a week. Criteria for cure were absence of diarrhea, exudate and amebae, lack of sigmoidoscopic evidence of colitis, and subsidence of significant symptoms. Treatment failures varied in degree. No significant improvement was noted in some patients; others had a favorable clinical and parasitological response only to have E. histolytica reappear in their stools. Attempts were made to keep patients under observation for at least 2 weeks before changes in therapy were ordered. Assignments to different treatment were made only by the responsible doctor.

The responses to therapy as assessed at the end of 6 weeks in 538 cases are shown in table 5. Standard amebacides used individually were inadequate therapeutic agents. Patients treated with emetine responded symptomatically; only 2 of the 22 patients required re-treatment before the end of the follow-up period. However, 10 others had E. histolytica in their stools at the end of 6 weeks. One of them had a recurrence of clinical symptoms. Carbarsone and chiniofon treatment resulted in 33 failures as compared with 13 successes. There were 18 failures in 31 cases in which chloroquine was used. Combinations of standard amebacides proved to be more effective. A combination of emetine, carbarsone and chiniofon was given to 23 patients. All had a satisfactory clinical response. Although clinical symptoms did not recur, four of the patients suffered a parasitological relapse.

The combination of milibis and chloroquine diphosphate gave satisfactory early clinical response in 18 of 22 cases. In addition to the four cases regarded as clinical failures, the stools of seven others failed to remain negative.

Terramycin proved to be the most effective of the antibiotics. A total of 104 patients were treated with this drug alone in varying dosages; all responded clinically. Six relapsed, however, three in the early follow-up period and three later. One of the six had clinical amebic hepatitis. The remaining 98 were well at the end of 6 weeks. Aureomycin produced a good initial response in all but 3 of 41 cases. However, E. histolytica reappeared in the stools of 7 of the remaining 38 patients; 4 of them had symptoms. Chloramphenicol was ineffective. Only 11 of the 41 patients treated responded. Most of those failing to respond had amebae in their stools until they were re-treated


302

Table 5. Therapeutic Response in 538 Cases of Acute Amebic Dysentery Assessed at End of Six Weeks


Treatment agent


Number of cases

Therapeutic response


Number re-treated before 6 weeks

Failures followed for 6 weeks


Success


Failure

Number with E. histolytica in stools at 6 weeks


Number clinically ill

Number with active colitis sigmoid oscopically

Standard Amebacides:

Emetine

22

10

12

2

10

1

1

Carbarsone

22

4

18

12

6

2

3

Chiniofon

24

9

15

6

9

1

1

Chloroquine

31

13

18

5

13

6

5

Emetine, carbarsone, and chiniofon

23

19

4

0

4

0

0

Bismuth glycolylarsanilate and chloroquine diphosphate

22

11

11

4

7

3

0

 

Antibiotics:

Oxytetracycline

104

98

6

3

3

2

3

Aureomycin

41

31

10

3

7

4

2

Chloramphenicol

41

11

30

9

21

10

13

Antibiotics and Amebacides Combined:

Oxytetracycline and standard amebacides for 10 days

97

93

4

2

2

1

1

Oxytetracycline and chloroquine for 5 days

22

20

2

1

1

1

1

Aureomycin and chloroquine for 10 days

23

23

0

0

0

0

0

Supportive Therapy:

Bed rest and nutritional supplements

66

11

55

39

16

8

11

SOURCE: Martin, G. M., Garfinkel, B. T., Brooke, M. M., Weinstein, P. P., and Frye, W. W.: J. A. M. A. 151 : 1055, March 28, 1953.


303

with another drug. Terramycin was given in combination with the five standard amebacides. Only 4 failures occurred in 97 cases.

Sixty-six patients were followed without specific therapy. Thirty-nine were eventually assigned to a specific treatment schedule before the end of the 6 weeks. At the end of the follow-up period 11 of the remaining 27 men who received no treatment had no clinical or parasitological evidence of amebic infection. These patients were well according to the criteria previously established.

A group of 16 patients treated with terramycin or aureomycin were followed in greater detail to determine the rapidity with which ulcers healed and amebae disappeared from the lesions. Sigmoidoscopic examinations were done daily. Material was aspirated from ulcers and searched for amebae. The average time required for the disappearance of E. histolytica was 48 hours, the minimum being 36 and the maximum 72. Hyperemia and mucus decreased in 18 hours as did the white exudate covering the ulcers. Within 48 to 72 hours epithelization had begun. Many discrete, shallow ulcers had healed in 72 hours.

Amebic hepatitis and amebic abscess was encountered, but were not common. The occurrence of hepatic involvement in one patient who was treated with terramycin called attention to a possible limitation of the form of antibiotic therapy. Since terramycin seemed to control most effectively the intestinal infection, it was concluded that chloroquine, a drug of proven value in amebic hepatitis, should also be given to prevent hepatic complications.