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 wascomplicated by the presence of many cases of bacillary dysentery whichwere due to sulfonamide-resistant Shigellae. This finding was based firston clinical observation and was supported later by in vitro sensitivitytests. As a result, the physicians responsible for the care of the menhad available only nonspecific, supportive measures. Reports on limitedtrials of auremoycin, terramycin and chloramphenicol had indicated thatthey 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 individualsalso gave an unusual opportunity to study the effect of aureomycin andterramycin upon amebiasis.
Patients who complained of diarrhea were seen first by the compoundphysician. The more seriously ill men, or those who did not respond totreatment, were admitted to the hospital. All studies were carried outin the hospital.
Patients were admitted to a special 100-bed ward. A complete physicalexamination was done on admission and electrolyte, fluid and symptomatictherapy was begun. Men who were severely ill were immediately begun onspecific antibiotic therapy and were not included in the study groups.Immediately after admission diagnostic procedures were also begun. A freshlypassed stool specimen was obtained from each man. It was examined for motiletrophozoites of E. histolytica and other parasites. A portion wasstreaked onto an SS (Shigella-Salmonella) agar plate. Stool obtained bythe Hardy rectal swab technic was also streaked onto SS agar. Sigmoidoscopicexaminations were then carried out and exudate obtained from ulcers orareas of inflammation was aspirated with a 1 cc. pipette and examined fortrophozoites of E. histolytica and cultured on SS agar.
A medical officer reviewed the laboratory findings and then assignedeach 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 seriesfor amebiasis. Assignments to antibiotic therapy for bacillary dysentery,however, depended upon presumptive diagnoses based upon the appearanceof the exudate in the stool and changes in the appearance of the rectalmucosa. Stools from only 60 percent of these men were found to be positivefor Shigellae. However, the remaining 40 percent exhibited the characteristicclinical features of Shigella infections. The response to therapy was similarin both groups. Although it was assumed that all of these patients hadbacillary dysentery, only the cases with positive cultures were subsequentlyincluded in the final study.
The characteristic sigmoidoscopic observations in the patients withbacillary dysentery were those of a diffuse inflammatory process. The lumenof the rectum ordinarily contained large amounts of mucopurulent exudateunmixed with fecal residue. In some cases the mucosa was obscured by adiffuse coating of grayish sticky pus; in others droplets of pus oozedfrom the mucosal crypts under the pressure of the advancing sigmoidoscope.Ulceration was uncommon, but when seen, the ulcers were shallow, irregularand 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 weremore striking when the inflammation had subsided. The cellular exudatewas composed chiefly of polymorphonuclear leukocytes and some large mononuclearcells. The latter, however, were not sufficiently constant in characterto have diagnostic significance.
The sigmoidoscopic observations in the amebic dysentery cases were verydifferent. Ulceration of the rectal mucosa was the most frequent findingand was seen in 87 percent of all patients with intestinal amebiasis. Edemaand hyperemia of the mucosa were observed but were less common than inbacillary dysentery. Ordinarily the uninvolved mucosa appeared relativelynormal. The typical amebic ulcer was small and discrete. The edges werepiled up; the crater was deep and was covered by thin grayish-white exudate.The number of ulcers was often unexpectedly large. Many patients had asmany as 100 to 200 varying in size and depth and located principally inthe 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 activelymotile E. histolytica trophozoites which were usually engorged withred 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 uniformityof the affected group. All patients were young or middle-aged adult maleswho 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 rotationto predetermined treatment schedules.
Four antibiotics were compared with therapeutic agents previously availablefor the treatment of bacillary dysentery. The first task was to determinewhether or not standard dosages of chloramphenicol, aureomycin terramycinand polymyxin-B were more effective than sulfadiazine or supportive therapyalone. Preliminary observations indicated that chloramphenicol, aureomycinand terramycin were all highly effective. More complete studies were thendone to establish a minimum effective dose. Four dosage schedules wereused: (1) 10 gm. total, 2 gm. given at once, and 0.5 gm., four times aday for 4 days; (2) 4 gm. total, 0.5 gm. given at once, and 0.25 gm. twicea day for 7 days; (3) 4 gm. total, 2 gm. given at once, and 1 gm. after12 and 24 hours; (4) 2 gm. as a single dose. Sulfadiazine was used in twodosages, each with 2 gm. given immediately and: (1) with 1 gm. four timesa day for 4 days, (2) with 2 gm. three times a day for 5 days. Polymyxin-Bwas 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 afterthe start of treatment. Observations were continued for 2 weeks after thecompletion of therapy and during this time four additional cultures weremade. A case was recorded as continuously positive if the Shigella isolatedin the pretreatment culture was found in any subsequent culture, even thoughintervening tests were negative. A case was counted as culturally negativeonly when all subsequent examinations during the hospital admission failedto isolate the type of organism found.
The bacteriological findings are summarized in Table 1. All but 29 percentof the patients on supportive therapy had negative cultures
Table 1. Bacteriological Response to Therapyin Acute Bacillary Dysentery
| 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 culturesthereafter. There was a gradual decline throughout the week in the proportionof positive cases. Sulfadiazine did not modify this course to a significantdegree. Response to polymyxin-B was likewise unimpressive. The drug modifiedonly slightly the course of the disease. The three antibiotics, aureomycin,chloramphenicol and terramycin, were considerably more effective. Moststriking was the rapid reversion of the stool cultures from positive tonegative. On the seventh day all cases treated with terramycin, and almostall treated with aureomycin and chloramphenicol were culturally negative;they remained so for the follow-up period. As previously indicated, thethree 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 severeenteric infections.
Table 2. Relative Efficacy of Three Antibioticsat Varying Dosage Levels in Acute Bacillary Dysentery
|
| 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 | |
|
|
|
|
|
| ||
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 | |
|
|
|
|
|
| ||
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 | |
|
|
|
|
|
| ||
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 | |
|
|
|
|
|
| ||
*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 (4April), 1953.
299
The clinical responses, however, did not coincide with the changes inthe bacteriological tests. Sigmoidoscopic examinations done on the fourthday of treatment were used to evaluate further the therapeutic responsein 499 cases (table 3). About one-half of the patients who did not receivespecific therapy had evidence of continuing active colitis. The proportiondropped to 42 percent when sulfonamides or polymyxin-B were used. Resultswere significantly better with aureomycin, terramycin and chloramphenicol.Active lesions were seen in only 20 percent when small doses were usedand 4 gm. given in the first 24 hours caused healing in all but 4 percentof the cases.
Table 3. Efficacy of Various Methods of Therapyas Determined by Sigmoidoscopic Examination on
Fourth Day of Therapy in 499 Culturally Positive Cases
| 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 (4April), 1953.
Other criteria of therapeutic response were also studied. The characterof each stool was observed and recorded. Information on the decrease inthe diarrhea and the disappearance of exudate was available. The physicians'daily notes also indicated the clinical status of the patient. All theseobservations paralleled the sigmoidoscopic findings. The results of therapywere also analyzed according to the species of Shigella isolated. No significantvariation was noted.
These studies, therefore, indicated that terramycin, aureomycin andchloramphenicol were effective agents in treating sulfonamide-resistantshigellosis in Korea. Four grams in three doses in 24 hours gave as satisfactoryresults as the larger doses ordinarily employed. Polymyxin-B was much lesseffective.
The patients who had amebic dysentery were treated in accordance withthe predetermined schedules shown in table 4. Standard amebacides, emetine,carbarsone, chiniofon, milibis and chloroquine, were used singly or incombination. Terramycin, aureomycin and chloramphenicol were given; terramycinwas used with the other amebacides, and aureomycin was combined with chloroquine.
300
Table 4. Drugs and Dosage Schedules Used in538 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. |
5. Emetine, carbarsone, and chiniofon, given concurrently. | 0.03 gm. twice a day for 4 days. |
6. Bismuth glycolylarsanilate, and chloroquine diphosphate. | 0.5 gm. three times a day for 7 days. |
Antibiotics: | |
7. Oxytetracycline | a. 2 gm. initially, 0.5 gm. every 6 hr. for 10 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. |
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. |
12. Aureomycin with chloroquine | 2 gm. initially, 0.5 gm. every 6 hr. for 10 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 March1953.
301
Patients with amebic dysentery were followed for 6 weeks after treatmentwas begun. Saline preparations of stool specimens were examined on thefirst, second, fourth and sixth days, and once a week thereafter. Beforedischarge each patient was given a saline cathartic, and the specimenswere searched for amebae. The zinc sulfate centrifugal floatation technicwas used to find E. histolytica cysts 2 weeks, 5 weeks and 6 weeksafter onset of therapy. The sigmoidoscopic examination, bacteriologicaland parasitological tests were repeated once a week. Criteria for curewere absence of diarrhea, exudate and amebae, lack of sigmoidoscopic evidenceof colitis, and subsidence of significant symptoms. Treatment failuresvaried in degree. No significant improvement was noted in some patients;others had a favorable clinical and parasitological response only to haveE. histolytica reappear in their stools. Attempts were made to keeppatients under observation for at least 2 weeks before changes in therapywere ordered. Assignments to different treatment were made only by theresponsible doctor.
The responses to therapy as assessed at the end of 6 weeks in 538 casesare shown in table 5. Standard amebacides used individually were inadequatetherapeutic agents. Patients treated with emetine responded symptomatically;only 2 of the 22 patients required re-treatment before the end of the follow-upperiod. However, 10 others had E. histolytica in their stools atthe end of 6 weeks. One of them had a recurrence of clinical symptoms.Carbarsone and chiniofon treatment resulted in 33 failures as comparedwith 13 successes. There were 18 failures in 31 cases in which chloroquinewas 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 didnot recur, four of the patients suffered a parasitological relapse.
The combination of milibis and chloroquine diphosphate gave satisfactoryearly clinical response in 18 of 22 cases. In addition to the four casesregarded as clinical failures, the stools of seven others failed to remainnegative.
Terramycin proved to be the most effective of the antibiotics. A totalof 104 patients were treated with this drug alone in varying dosages; allresponded clinically. Six relapsed, however, three in the early follow-upperiod and three later. One of the six had clinical amebic hepatitis. Theremaining 98 were well at the end of 6 weeks. Aureomycin produced a goodinitial response in all but 3 of 41 cases. However, E. histolytica reappearedin 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 theywere re-treated
302
Table 5. Therapeutic Response in 538 Casesof Acute Amebic Dysentery Assessed at End of Six Weeks
|
| Therapeutic response |
| Failures followed for 6 weeks | |||
|
| Number with E. histolytica in stools at 6 weeks |
| 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 fivestandard amebacides. Only 4 failures occurred in 97 cases.
Sixty-six patients were followed without specific therapy. Thirty-ninewere eventually assigned to a specific treatment schedule before the endof the 6 weeks. At the end of the follow-up period 11 of the remaining27 men who received no treatment had no clinical or parasitological evidenceof amebic infection. These patients were well according to the criteriapreviously established.
A group of 16 patients treated with terramycin or aureomycin were followedin greater detail to determine the rapidity with which ulcers healed andamebae disappeared from the lesions. Sigmoidoscopic examinations were donedaily. Material was aspirated from ulcers and searched for amebae. Theaverage time required for the disappearance of E. histolytica was48 hours, the minimum being 36 and the maximum 72. Hyperemia and mucusdecreased in 18 hours as did the white exudate covering the ulcers. Within48 to 72 hours epithelization had begun. Many discrete, shallow ulcershad 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 withterramycin called attention to a possible limitation of the form of antibiotictherapy. Since terramycin seemed to control most effectively the intestinalinfection, it was concluded that chloroquine, a drug of proven value inamebic hepatitis, should also be given to prevent hepatic complications.
