The treatment of infantile diarrhea with a new combination of antibiotics

T H E T R E A T M E N T OF I N F A N T I L E D I A R R H E A W I T H A N E W C O M B I N A T I O N OF A N T I B I O T I C S EL~IER R.

KADISON, M . D . , AND MAXWELL

P.

BOROVSKu

M.D.

CHICAGO, ILL.

G RinE AtheT p rtor egar et ms se nhast ofbeend i aachieved r r h e a in i n f a n t s a n d children d u r i n g the p a s t fifteen years. The recognition and a p p l i c a t i o n of basic principles of fluid bMance a n d electrolyte m e t a b olism 1, 2, 8, 4, 5 h a v e been, perhaps, the most r e v o l u t i o n a r y contributions to the m o d e r n m a n a g e m e n t of sueh disorders. The i n t r o d u c t i o n of the sulfonamides and of the antibiotic drugs, however, afforded a direct app r o a c h to t r e a t i n g the causes of the fluid and electrolyte disturbances, i.e., the infected and inflamed gastrointestinal tract. The p r e s e n t s t u d y concerns itself w i t h the t r e a t m e n t of infantile diarr h e a with a c o m b i n a t i o n of two new antibiotics, n e o m y c i n and bacitracin. The isolation of b a e i t r a e i n 6 p r e s e n t e d a new d r u g which in vitro and in vivo showed p r o m i s i n g action against gram-positive cocci a n d bacteria, a f e w l a r g e r viruses, and E n d a m o e b a h i s t o l y t i c a , r Neomycin, discovered b y Waksman, s a p p e a r e d to be effective against few gram-positive but m a n y gram-negative bacteria, the tubercle bacillus, and E . h i s t o l y t i c a . 7 A synergistic effect is achieved w h e n neom y c i n and b a e i t r a c i n are administered s i m u l t a n e o u s l y 2 The combination of n e o m y c i n and b a e i t r a e i n will hencef o r t h be r e f e r r e d to as " N e o b a c i n . " I n view of the f a v o r a b l e results obt a i n e d in vitro and in e x p e r i m e n t a l

animals, it was felt t h a t a clinical s t u d y should be u n d e r t a k e n to det e r m i n e the effectiveness of Neobaein against infantile d i a r r h e a as comp a r e d with p r e v i o u s l y used treatments. The s t u d y consisted of a series of fifty-three infants u n d e r 1 y e a r of age who were either admitted to the hospital because o,f diarrhea or developed such a condition while hospitalized for a different reason. The stools of all p a t i e n t s were cult u r e d for p a t h o g e n i c b a c t e r i a and e x a m i n e d f o r protozoa. 1~ No viral studies were p e r f o r m e d . Rectal swabs were placed in t e t r a t h i o n a t e broth, and a f t e r t w e n t y - f o u r h o u r s ' incubation s t r e a k e d to L e v i n e ' s eosin methylene blue agar, sodium azide blood plate, a n d Shigella-Sa]monella (S.S.) agar. A f t e r t w e n t y - f o u r hours, two more S.S. plates were inoculated front the t e t r a t h i o n a t e broth. The p a r a sitologic e x a m i n a t i o n was carried out b y e x a m i n i n g f r e s h stools within t w e n t y minutes a f t e r evacuation, followed b y zinc flotation and hematoxylin-stained p e r m a n e n t slides.

F r o m the Children's Division and from the Hektoen Institute for N[edical Research of the Cook County Hospital. 576

All p a t i e n t s t r e a t e d w i t h Neobacin as well as the controls received w e a k tea or w a t e r by m o u t h for the first twelve to t w e n t y - f o u r hours. This was followed b y the addition of a f o r m u l a consisting of one p a r t of boiled skim milk to one p a r t of water. W h o l e boiled skim m i l k to which Casee was a d d e d was given to the

]~ADISON AND B O R O V S K Y :

I N F A N T I L E DIARRHEA AND ANTIBIOTICS

infants within the next twenty-four to forty-eight hours. After a period of two to three days, the patients received a dilute evaporated milk formula to which carbohydrate was gradually added. One teaspoon of Xaopeetate q. 4 h., and 5 gr. of calcium lactate t.i.d, were given to all patients who had liquid stools. Seriously ill patients constituted 54 per cent of the infants. They were severely dehydrated and were given parenteral fluids, plasma, Amigen, and blood transfusions. Three of them had hypopotassemia and received, therefore, potassium chloride, 1 Gin. daily subcutaneously for two to three days. Thirty-two of the infants were started on su]fadiazine (1 gr. per pound of body weight daily), streptomycin (100,000 to 200,000 units q. 6 h. orally), and procaine penicillin (150,000 to 300,000 units daily intramuscularly) alone or in combinations. Neobacin ~ was given to the other infants in dosage of one tablet q. 6 h. orally. Three who had amebiasis received two tablets of Neobacin q. 6 h. Five of the patients were on a different schedule. They received 2,500 units of neomycin and bacitracin each, q. 6 h. orally. As the study progressed, it became apparent that twenty-three infants of the control group were doing poorly on the sulfadiazine, streptomycin, and penicillin combinations. It was decided, therefore, to place them later on Neobaein therapy. RESULTS

Table I demonstrates the study o,f nine cases of amebiasis in infants be*Each t a b l e t c o n t a i n e d 10,000 u n i t s of n e o m y c i n a n d 2,000 u n i t s of b a c i t r a c i n a n d w a s s u p p l i e d t h r o u g h t h e c o u r t e s y of t h e C o m m e r c i a l S o l v e n t s Co., T e r r e H a u t e , I n d .

577

tween 2 and 9 months of age. Five were admitted to the hospital with severe diarrhea, dehydration, and acidosis. Three had chronic persistent diarrhea with intermittent periods of dehydration. One had a history of cramps and irritability without diarrhea. Six of the nine infants had been treated with sulfadiazine, streptomyein, and penicillin alone or in combinations before E. histolytiea was isolated from the stools. The results were poor. One infant had been previously treated with bacitraein alone. Although the diarrhea subsided under this treatment, E. histolytica was still present prior to Neobacin therapy. The dosage of Neobaein used in seven of the nine patients was one tablet q. 6 h. for fourteen days. Three of them required a second course of Neobaein, two tablets q. 6 h. for fourteen days. Two infants were on different treatment schedules, having received 2,500 units each of neomycin and bacitraein q. 6 h. for five days. After the institution of Neobaein therapy, the diarrhea subsided in one to four days, on the average in 1.86 days. Two of the infants continued to harbor E. histolytica in their stools, but did not have diarrhea. All patients were proetoseoped, and showed considerable improvement after the treatment. Table II represents nine infants between three weeks and 10 months of age with acute diarrhea. Seven of these were dehydrated and required parenteral fluids and blood transfusions on admission. Five had Proteus morganii in their stools on admission. One of them con-

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tinued to h a r b o r Pr. morganii and another Pseudomonas aeruginosa a f t e r Neobacin therapy, though diarrheic and general s y m p t o m s disappeared during the course. None of these infants had previous therapy. Neobaein was administered one tablet q. 6 h. for f o u r to seven days. The results were satisfactory. The average duration of the diarrhea was 3.22 days. No recurrences were noted a f t e r Neobacin treatment. Table I I I shows diarrhea in thirteen infants between 11 days and 11 mouths of age who had been previously treated with sulfadiazine, s t r e p t o m y c i n , and penicillin alone or in combinations, with p o o r results. Three of the patients showed an encouraging initial response while on such t r e a t m e n t but had a r e c u r r e n c e of the d i a r r h e a in spite of the m e d i c a t i o n . Six of these p a t i e n t s h a r b o r e d Ps. aeruginosa and one i n f a n t had Pr. morganii in the stools before and after therapy. Five of the patients had persistently negative stool cultures. All of the patients were asymptomatic a f t e r t r e a t m e n t with NeobacinTen infants in this group were given Neo.bacin 1 tablet q. 6 h. f r o m four to seven days. To three patients, 2,500 units each of neomycin and baeitracin q. 6 h. for four days were given. The average duration of the diarrhea was 2.8 days. Table I V represents thirteen infants between 9 days and 9 months of age with diarrhea. F o u r had been treated with sulfadiazine, streptomycin, and penicillin unsuccessfully. A f t e r this, the patients were treated with Neobaein and penicillin. Penicillin was used because of complicating u p p e r respirat o r y tract infections or bronchopneumonia.

DIARRHEA AND ANTIBIOTICS

581

Two infants had Paraeolobactra and two had Pr. morganii before and a f t e r Neobacin treatment. Six patients had persistently negative stool cultures. The dosage of Neobaein was one tablet q. 6 h. f r o m f o u r to nine days. Procaine penicillin was given, 150,000 to 300,000 units intramuscularly, f r o m two to nine days. The average duration of the diarrhea was four days. No recurrences were noted a f t e r this treatment. Table V represents nine patients between 2 weeks and 10 months of age with acute diarrhea.. These infants were treated initially with sulfadiazine, streptomycin, and penicillin alone or in combinations. Three infants had Pr. morganii, three had Paracolobactra, and one had Pr. vulgaris in their stools. The average duration o,f diarrhea in these patients was 6.44 days. Two had relapses and required f u r t h e r treatment. D!SCUSSION

One of the problems frequently enc o u n t e r e d in the s t u d y of diarrheic disorders is the role played by members of the Proteus, Paracolobactrum (paraeolon) and Pseudomonas genera of microorganisms, especially in infants and children. Neter and Clark ~1 felt that Paraco,lobaetra m a y be the p r i m a r y cause of diarrhea in infants and children but stated t h a t these organisms m a y be present as saprophytic, harmless organisms, or be associated with enteric p a t h o g e n s and p l a y a s e c o n d a r y p a r t as ineitants of d i a r r h e a l diseases. Felsenfeld and Y o u n g 12 showed a higher incidence of P r o t e i and P a r a e o l o b a e t r a in adults with d i a r r h e a t h a n in h e a l t h y individuals. Levinson and R a y e r a f t ~a

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f o u n d t h a t 41.3 per cent of their cases cases one to f o u r hours a f t e r the inof infantile d i a r r h e a h a r b o r e d Protei, gestion of Neobacin. Thus, renal P a r a c o l o b a e t r a and Ps. aeruginosa. d a m a g e t h r o u g h the excretion of neoOther authors 1~, 15, 16 have found Ps. m y c i n or b a e i t r a c i n did not h a v e to be aeruginosa in outbreaks of infantile feared. diarrhea. There is a trend in public Neobacin was well tolerated. The health laboratories 17 to recognize these tablets were crushed a n d given with bacteria as incitants in diarrheic dis- applesauce or jelly. None of the inorders. One m a y suppose that eases f a n t s who received it p e r os developed of infantile diarrhea m a y be due to vomiting. No other side effects were these microorganisms. I n this study, observed. Neobacin was also easily however, Ps. aeruginosa was cultured combined w i t h the routine antidiarf r o m five patients and Pr. morganii rheic d i e t a r y regimen. f r o m two a f t e r successful t r e a t m e n t The a v e r a g e d u r a t i o n of d i a r r h e a and when the infants were already in infants t r e a t e d w i t h N e o b a c i n (inasymptomatic, whereas before t h e r a p y eluding those t r e a t e d w i t h Neobacin the stool cultures did not reveal these and procaine penicillin ) was 3.34 organisms. Thus we have to be days, as c o m p a r e d w i t h 6.44 d a y s in the control group. A f t e r Neobaein cautious in the evaluation of the role of Protei, Paracolobactra and Pseudo,- t r e a t m e n t , moreover, no r e c u r r e n c e s monades in the present series. were observed. Nine p a t i e n t s h a d 'There have been numerous reports u n u s u a l weight gains d u r i n g treaton the use of sulfonamides in the m e n t in spite of low calorie intake. t r e a t m e n t of specific and nonspecific Stool counts on p a t i e n t s receiving diarrheas of infants. ~8, 19 Sulfadiazine Neobacin showed a m a r k e d depresappears to be p r e f e r r e d to the other sion of both the gram-positive and sulfonamides. g r a m - n e g a t i v e intestinal flora. 2~ One The use of oral strepto,mycin in diarm a y expect Neobacin to be of value in rheal disorders ~~ a p p e a r e d to be bene- infantile d i a r r h e a because of this ficial. Seligman and associates ~1 effect. found, however, that this antibiotic is I t is difficult to evaluate t r e a t m e n t merely baeteriostatie. Stable and of diarrheic disorders because of the Philpott ~ stated that i n t r a m u s c u l a r l y seasonal v a r i a t i o n of bacterial strains administered streptomycin a p p e a r e d and the v a r i a b i l i t y of their response to control the Salmonella bacteremia in to specific d r u g t h e r a p y . their patients but had no effect on the I t is believed that antibiotic t h e r a p y enteroeolitis. does p l a y an i m p o r t a n t p a r t in the W e observed a recurrence of the t r e a t m e n t of diarrhea but we feel t h a t diarrhea in eight infants in o u r series, the early administration of fluids and four to seven days a f t e r the sulfa- electrolytes is of p a r a m o u n t impordiazine and streptomycin t r e a t m e n t tance. The role of antibiotics is to was discontinued, which necessitated depress the intestinal flora and f a u n a the institution of t h e r a p y with a dif- and to shorten the duration of diarf e r e n t drug. rhea, so t h a t f u r t h e r disturbances of I n the doses given b y us, no blood the electrolyte balance cannot take levels were obtained in the e x a m i n e d place.

KADISON AND BOROVSKY : INFANTILE DIARRHEA AND ANTIBIOTICS SUMMARY

A study of fifty-three patients with infantile diarrhea was carried out in order to determine the effectiveness of a combination of neomycin and baeitraein, called Neobaein, as comp a r e d with a control group t r e a t e d with sulfadiazine, streptomycin, and penicillin alone or in combinations. All infants r.eeeivcd th.e same general supportive and d i e t a r y therapy.

The Neobaein-treated group of infants showed a significant reduction in the duration of diarrhea, as compared with the control group. In addition, no recurrence of the diarrhea was observed itt the patients receiving Neobaein. REFERENCES 1. Hartmann, A . F . : Therapy of St. Louis C h i l d r e a ' s Hospital: T r e a t m e n t of Severe Diarrhea in I n f a n t s and Children, Washington Univ. M. Alumni Quart. 6: 45, 1942. 2. Rapoport, S., Dodd, K., Clark, M., and Sylemn, F.: Fostacidotie State in Infantile Diarrhea, Symptoms and Chemical D a t a : Postacidotic Hypocalcemia and Associated Decreases in Levels of Potassium and Phosphorus in Serum, Am. J. Dis. Child. 73: 391, 1947. 3. ])arrow, D . C . : R e t e n t i o n of Electrolyte During R e c o v e r y F r o m Severe Dehydration 1)ue to Diarrhea, J. PEmAT. 28: 515, 1946. 4. Fleet, J. Jr., P r a t t , E. L., and Darrow, D.C.: Methods in ~t~reatmer~t of Diarrhea, P e d i a t r i c s 4: 604, 1949. 5. Oovan, C. D., and Darrow, D. C.: tlse of Potassium Chloride in T r e a t m e n t of D e h y d r a t i o n of D i a r r h e a in I n f a n t s j J. PEDIAT. 28: 541, 1946. 6. Johnson, B. A., Anker, tI., and Meleney, F. L. : :Bacitracin: A New Antibiotic Produced by a Member of the B. subtilis Group, Science 102: 376, 1945. 7. Felsenfeld, O., Volini, I. F , Ishihara, S. J., Bachman, M. C., and Young, V. M.: A Study of the Effect of Neomycin and Other Antibiotics on Bacteria., Viruses, and Protozoa, J. Lab. & 0Iin. Ned. 35: 428, 1950. 8. Waksman, S. A., and Lechevalier, It. A.: Neomycin: A New A n t i b i o t i c Active A g a i n s t S t r e p t o m y e i n - g e s l s t a n t Bacteria, Including Tuberculosis Organisms, Science 109: 305~ 1949.

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9. Young, V. ~ . , Yoshimura, T., and ]s feld, O.: Synergism of Neomycin and Bacitraein, Spring Meeting, Midwest Society of Parasitology 1950, A n n Arbor, Mich. 10. Felsenfe]d, O., and Young, V . M . : Cornmeats on the Laboratory Diagnosis of Enteric Infections, Am. ft. Digest. Dis. 14: 392, 1947. 11. Neter, E. i%, and Clark, P.: Observations on the Possible Pathogenicity of Paracolon Bacilli as Incitants of Diarrheal Diseases in I n f a n t s and Children, Am. J. Digest. Dis. l l : 356j 194:4. 12. Felsenfeld, O , a n d Young, V. 3s The Correlation of I n t e s t i n a l Protozoa and E n t e r i c Microorganisms of K n o w n and Doubtful P a t h o g e n i c i t y , Am. J. Digest. Dis. 13: 233, 1946. 13. Levinson, J. D., and R a y c r a f t , W. B.: A Study of Three Hundred Cases of Diarrhea in Infants and Children During the Summer and Fall of 1948, J. PEDIAT. 36: 316, I950. 14. Ensign, P. R., and I-lunter, C. A.: An Epidemic of Diarrhea in the l'~ewborn Nursery Caused by a Milk-Borne Epidemic in the Community, J'. PEmAT. 29: 620, 1946. 5. Schaffer, A. J., and Offenheimer, E. It.: Pseudomonas Infections of the Gastrointestinal Tract in I n f a n t s and Children, South. 3/L 5. 41: 460, 1948. 16. Florman, A. L., and Schifrin, N.: Observations on a Small Outbreak of Infantile Diarrhea Associated With Pseudomonas Aeruginosa, J. PEDIAT. 36: 758, 1950. 17. Felsenfeld, O.: Two Surveys of Methods Used by Public Health Laboratories for the Examination of Stool Specimens for Salmonellae, Shige]lae, and Protozoa, Pub. Health Rep. 65: 1075, 1950. 18. Hardy, A . V . : F u r t h e r Observations on the Relation Efficacy of Sulfonamide in Shigella Infections, Pub. H e a l t h Rep. 60: 1037, 1943. 19. Watts, J., and Cummins, S.D.: Studies of Acute Diarrheal Diseases. Further Studies on Relative Efficacy of Sulfonamides in Shigellosis, Pub. H e a l t h Rep. 60: 1355, 1945. 20. James, V., and Kramer, I. R . H . : Infantile Gastro-Eateritis Treated With Streptomycin by Mouth, Lancet 2: 555~ 1948. 21. Seligman, E., Barash, L , and Cohlan, S. Q.: S t r e p t o m y c i n T r e a t m e n t of Salmonella Enteritis in Infants, J. PEDIAT. 30: 182, 1947. 22. Stable, G., and Philpott, I. G. : Epidemic o f Gastroenteritis in I n f a n t s , With Special Reference to Treatment, M. J. Australia 2: 63, 1948. 23. Felsenfeld, O., Ishihara, S. J., and Norsen, ft. : The Influence of Oral Administ r a t i o n of Antibiotics on the Bacterial Flora of the Intestines. I n print.