Diet in Relation to Antimicrobial Therapy

DIET IN RELATION TO

ANTIMICROBIAL THERAPY ROBERT Z. EANES, M.D.

The introduction of sulfonamides in the 1930's brought to the medical profession a new era of relatively specific and effective therapy for microbial infection. Since that time a large number of antimicrobial agents have been added, and indeed the number is still increasing. These chemical compounds have given the means whereby many previously fatal infectious disease processes may be controlled, and at the same time they have contributed to a change in man's microbial environment. These facts are well recognized and reported throughout the recent medical literature. But it must not be forgotten that these same compounds also interact with the molecular processes which give the human organism life. Some of these interactions relate to man and his nutrition. These will be discussed here. THE CHEMICAL NATURE OF ANTIMICROBIAL COMPOUNDS

The ability of antimicrobial compounds to stop or retard the growth of microorganisms indicates that these agents must have chemical constitutions which are active at the molecular level. Examination of their several structures reveals the presence of oxygen, nitrogen, sulfur and chlorine appearing individually or combined in radical groups to yield "electrically" active structures. These active structures cannot be expected to remain inert within the environment of the biologic world, where many reactive components exist. One manifestation of this ability is readily seen in the association which takes place between serum albumin and several of the antimicrobial agents, including penicillin, the sulfonamides, chloramphenicol, and others. IB • 23 These associations can competitively interfere with the normal carrier functions of these proteins. The chelating ability of these agents 6 can influence their effectiveness as microbial agents or their distribution and biological life in the organism. Chelation of isoniazid with copper may increase its potency towards the tubercle 10 33

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bacillus. In man isoniazid-copper chelation may inhibit histamine destruction by a copper-catalyzed enzyme. The tetracyclines chelate heavy metals and also bind calcium in bone, where they may be deposited for long periods of timeP Antimicrobial ability to interfere with enzymatic reactions in the metabolizing cell should not be excluded. The similarity of peniciUin and glutathione enables high concentrations of peniciUin to inhibit competitively hydrolysis of glutathione in liver preparations. 20 Transpeptidation reactions involving glutathione may also be inhibited. Tetracyclines uncouple aerobic phosphorylation in liver and kidney preparations at high concentrations. This process might again be related to their ability to chelate magnesium in the mitochondrion, where they have been observed to accumulate. 9 Chloramphenicol has been a useful agent in the prevention of protein synthesis in biochemical systems containing ribonucleic acids. Its action apparently affects the transfer of the amino acid to the growing protein molecule somewhere beyond the activation step of the amino acid. 1 All the foregoing examples illustrate interactions among an antimicrobial agent, a protein molecule and some nutritive factor. In order to block the inhibition, an increase in the concentration of the nutritive factor and/or a decrease in the concentration of the antimicrobial agent must be effected. Such considerations are important primarily in the infant, in whom diet may limit the intake of nutrients, and excretory and metabolic abilities may limit the disposal of the antimicrobial. In addition, the concentration of the enzyme itself may impose certain limitations on the ability to carry out a reaction. S ANTIMICROBIAL SOURCES IN THE PEDIATRIC PATIENT

Although the most common antimicrobial source of the pediatric patient is direct administration by the physician, other less readily conceived sources are available. The fetus in utero is exposed to many of the drugs given the mother via placental transfer. On the whole, drugs whose molecular weight is less than 1000 can cross the placenta.2 Sulfapyridine, sulfacetamide, sulfathiazole, sulfamerazine, sulfamethoxypyridazine and several other sulfonamides cross the placenta freely, and equilibrium between the maternal and fetal blood occurs within three hours. Sulfadiazine has been shown to give the highest concentrations in fetal blood. Other antibiotics which reach the fetus in therapeutic concentrations when given the mother include penicillin, tetracycline, chloramphenicol, erythromycin, vancomycin, cycloserine, isoniazid and probably streptomycin. After birth the child may be subjected to antimicrobial agents which by chance are presented to him in his diet. A mother who is breastfeeding may give her infant antibiotics included in her postpartum therapy. Tetracyclines, chloramphenicol, sulfonamides and penicillin are probably all secreted to greater or lesser degree in the breast milk. 25

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Other sources in the food supply can come from the consumption of the meats, poultry and dairy products derived from animals whose feed has contained one or more of these agents.37 Antimicrobials have long been recognized as useful agents in promoting growth of animals raised for human consumption.24 The unlimited use of antimicrobial agents in women during pregnancy might be harmful. Some experimental work done in animals and a few observations in man suggest this.2 Sulfanilamide given to pregnant rats caused a high death rate in the intrauterine and neonatal periods, and a high proportion of the offspring were stunted in growth. Streptomycin given to a woman during her pregnancy may rarely result in damage to the fetal eighth nerve. In the latter case, however, other reports have shown eighth nerve damage in the mother without apparent effect in the offspring. Many toxic effects of large doses of antibiotics given in the immediate neonatal period have been reported. These will be discussed subsequently. The relatively small doses of antibiotic obtained by the infant in his food may be of little importance to him, since many are poorly absorbed with food intake. Nevertheless small quantities of antibiotic ingested in the food do assume importance when given to allergic subjects. At least four cases of allergic reaction to penicillin ingested with dairy products have been reported in adults. 46 The foregoing examples may be readily related to the nutrition of the individual. Antimicrobial use during the development of the fetus may affect the functioning of enzyme systems through their competition with coenzymes, metals or substrates at the reactive site. Retardation of growth or development may result if the effect is prolonged. The indirect inclusion of these agents in foods may render them unsatisfactory for the use of the allergic population. What effect they may have in promoting allergy remains to be seen. RELATION OF NUTRITION TO THE INTESTINAL FLORA3o,34

The adverse effects of intestinal pathogens on the maintenance of fluid balance and nutrition are self-evident and will not be discussed here. Instead, the factors which the normal intestinal flora produce that may be of value in human nutrition will be discussed. The early work in nutrition quickly showed that diets could be devised which would cause rats to lose weight and become coprophagous. It was in turn noted that deficient rats, given liberal access to their own feces or, preferably, to the fecal material from normal rats, would again begin to gain weight. Subsequently various thermostable factors were found, to which the general name of vitamin has been applied. After these growth factors had been described, it was of interest to define man's requirements, and more especially to determine whether these were fulfilled through intestinal bacterial synthesis followed by ab-

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sorption. Balance studies were therefore carried out, and the results are of interest here. Thiamine (vitamin B1 ), the antiberiberi factor, was excreted in the feces and urine of human subjects who were studied while receiving diets low in thiamine content. The excretion exceeded intake, and three months of low intake was incapable of producing thiamine deficiency in at least one case. But thiamine intake of less than 30 micrograms resulted in deficiency. Diet was found to influence thiamine synthesis significantly. A synthetic diet containing Dextri-maltose was associated with an output in excess of 250 micrograms daily. Replacement of the Dextri-maltose with rice resulted in a drop in the excretion to 36 micrograms daily. GeneraUy, dextrin and dextrin-containing carbohydrates, milk curds and vitamin C seem to stimulate or at least promote more favorable conditions for the synthesis of vitamin Bl in the gastrointestinal tract by the microbial flora. Unfortunately, however, synthesis seems to take place largely in the colon, and although some absorption does seem to occur, the amount absorbed does not fulfi11 the needs of bodily nutrition under aU conditions. Riboflavin (vitamin B2) was shown to be synthesized in substantiaUy greater quantities in the gastrointestinal tract than was thiamine. As with thiamine and aU the remaining vitamins to be described, it is primarily synthesized in the colon. Najjar et a1. 33 studied 12 adolescent males who were fed a diet containing 70 to 90 micrograms of B2 daily. Urinary excretion feU during the first two weeks of therapy, but thereafter remained stable over a three-month period at twice the ingested quantity. The fecal excretion meanwhile contained five to six times the intake. An increase in bulk of the diet or inclusion of dextrin-containing carbohydrates promoted the synthesis. Present evidence indicates that absorption of riboflavin synthesized within the alimentary canal is limited. Niacin, the vitamin whose lack is associated with pe11agra, apparently is synthesized in the alimentary canal in relatively large amounts. Early studies relating to its absorption, however, were in error, since many of these studies did not recognize that tryptophan could act as a precursor for this compound. Dextrin, glucose and galactose aU seemed to stimulate or at least favor a flora which would synthesize it, but it is doubtful at present whether any niacin is provided to man from this source. Pantothenic acid, the vitamin which participates in the formation of coenzyme A, is synthesized within the human alimentary tract, but there has been no good evidence presented for the absorption of the synthesized product. Dietary protein and vitamin C in addition to dextrin and cornstarch seem to increase its intestinal biosynthesis in the rat. Biotin and folic acid have been associated with pantothenic acid metabolism. Deficiencies of biotin and folic acid have been associated with impaired pantothenic acid metabolism. Dextrin is capable of promoting the bacterial synthesis of both biotin: and folic acid within

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the lower alimentary canal. In addition, folic acid synthesis is promoted by vitamins B6, B12 and C and decreased by a diet high in fats. Although balance studies would indicate that both these vitamins can be synthesized and absorbed in sufficient quantity from the gastrointestinal canal, only biotin appears to be adequately provided in all cases to date. Vitamin B6 (pyridoxine and its derivatives) is an important coenzyme in the metabolism of amino acids. It actively participates in transamination, deamination and decarboxylation reactions. Adults have active bacterial synthesis of this vitamin, and it would appear that it is available to the body by absorption. Reports4 of the vitamin B6 deficiency convulsive syndrome in infants, however, would seem to indicate that little of this vitamin is available to the infant after it has been synthesized. Vitamin B12 is synthesized in the lower part of the alimentary canal in man and is excreted in large quantities, provided cobalt is present in the diet. It is uncertain how much B12 is provided by this source, but probably little if any is available to the body through the bowel wall. As with vitamin B6 and the other B vitamins, dextrin in the diet considerably promotes its synthesis. Little information was found about the bacterial synthesis of vitamins A and D in the alimentary tract of man. Vitamin E is apparently neither synthesized nor destroyed in man, both of which are important factors in suggesting possible vitamin therapy for the newborn whose vitamin E levels are known to be low. 19 The synthesis of vitamin K by bacterial activity in the human intestinal tract would appear to provide man's needs. It is not known exactly, however, what the total contribution of this synthesis of vitamin K is to the human being. In the case of neonatal nutrition, hypoprothrombinemia of the newborn can be corrected by as little as 1 microgram of K daily. The relation between the body stores of vitamin K and the prothrombin levels is not completely understood at present. Intraintestinal bacterial vitamin synthesis in man may be antagonized in certain cases by bacterial catabolism. The most notable example of this has been found in Japan, where an analysis of intestinal bacteria indicated that approximately 3 per cent of the population of Kobe had bacteria which split thiamine into an inactive form. Signs of vitamin Bl deficiency were associated with this group, and the feeding of lactic acid bacterial cultures resulted in the elimination of at least one of the bacteria for as long as a month. A culture of Staphylococcus aureus which actively split thiamine has been isolated from the gastric contents of a man with severe polyneuritis. Vitamins C and folic acid have also been shown to be destroyed by intestinal bacteria. In the case of vitamin C, gastric achlorhydria has been associated with a variety of vitamin C-splitting bacteria in the contents of the stomach and colon. Vitamin B12 is known to be absorbed in large quantity by both Escherichia coli and Lactobacillus casei, but as yet no evidence is available that this in any way leads to B12 deficiency. A normally functioning bowel in an infant or child with a well estab-

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DIET IN RELATION TO ANTIMICROBIAL THERAPY

lished vitamin-synthesizing bacterial flora may be assumed to absorb the body requirement for vitamin K and biotin and at least part of the requirement for vitamin B6 • Significantly lesser amounts of the other B vitamins and vitamins A, D and E are provided from this source in meeting the body need. In all cases the diet may be assumed to affect the quantity and qualitative nature of this synthesis. The presence of certain bacteria in the gastrointestinal tract may alter the total quantity of vitamin available from ingested and synthesized sources. This latter possibility is most frequently associated with abnormal circumstances existing in the upper gastrointestinal tract and may be assumed to give rise to symptoms relatively infrequently. ANTIMICROBIAL AGENTS-THEIR RELATION TO ABSORPTION AND BACTERIAL SYNTHESIS OF VITAMINS

It appears that none of the antibiotics studied thus far is able to inhibit directly the absorption of any of the vitamins from the upper intestinal tract. Nevertheless their occasional influence upon appetite by causing gastrointestinal irritation with associated nausea or diarrhea may indirectly precipitate such a deficiency state, especially if symptoms are prolonged and nutrition is impaired in a patient with borderline disease. Little information is available about the effect of antimicrobial agents on bacterial synthesis of vitamins in the alimentary tract of man. Sulfonamides apparently have little or no effect upon the synthesis of riboflavin, pyridoxine, biotin or pantothenic acid. They decrease the synthesis of folic acid and spare the dietary requirement of thiamine. Aureomycin has had no effect upon synthesis of niacin or pantothenic acid and has not affected vitamin K as measured by blood prothrombin levels. The association of cheilosis, stomatitis and painful tongue with Aureomycin therapy27 has suggested that it may have some effect on the synthesis or utilization of one or more of the B vitamins. No clearcut answer to this question has been formulated. Chloramphenicol has no effect upon pantothenic acid or thiamine synthesis, and penicillin, though not affecting pantothenic acid synthesis, has some sparing activity on thiamine. Early studies in rats receiving specially selected diets indicated that sulfonamides were extremely effective in precipitating the various B vitamin deficiencies, presumably through their activity in preventing vitamin synthesis. It should be remembered that an antimicrobial agent may have a similar effect in any patient receiving a borderline or low vitamin intake. Deficient or relatively deficient diets as sometimes prescribed for allergy treatment occasionally contribute to full-blown vitamin-deficiency disease. 7 The onset of disease conceivably could be spared or provoked by the wise or unwise choice of an antibiotic for therapy of an associated infection in such a patient. Although antimicrobial agents have not been associated particularly with increased vitamin synthesis in the alimentary canal, they may

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nevertheless have certain nutritional effects which may be of value to the young infant or child. Prophylactic Aureomycin given in 25- to 50mg. doses per kilogram of body weight daily has been noted to promote weight gain and growth in prematures, while lowering their morbidity.24 In addition, 75 mg. of Aureomycin administered twice daily has promoted significantly better weight gains in groups of mentally defective 1- to 3-year-old children when compared to similar controls. Good responses by pernicious anemia patients to administered Aureomycin or penicillin have been reported. The beneficial effect of oral antibiotic therapy in the treatment of the patient with hepatic coma is well known. ADVERSE EFFECTS OF ANTIMICROBIALS ON INTESTINAL ABSORPTION AND NUTRITION

Several antimicrobials have been associated with the appearance ofsteatorrhea. Merliss and Hoffman 28 described several cases of steatorrhea and mild diarrhea developing after oral therapy with combinations of chloramphenicol, Aureomycin, Terramycin and a penicillin-sulfonamide combination. Penicillin and sulfonamide seemed to provoke the syndrome only when used together. In every case the diarrhea was increased by fat in the diet. Neomycin is now known to produce a malabsorption syndrome in adults 14 (see also p. 983). Oral doses of 8 to 12 Gm. daily have caused decreascd absorption of carotene, vitamin B12 , d-xylose, glucose, cholesterol and J131-labeled trioleate. Jejunal biopsies taken from patients with the syndrome have shown histologic pictures resembling early sprue. Recently therapeutic doses in the range of 4 to 6 Gm. daily have caused malabsorption of d-xylose, carotene and fats. 22 This syndrome can occur in the pediatric age group, and caution should be used in prescribing this drug for children. The direct effect on the intestinal flora which chronic oral antimicrobial therapy may have must not be forgotten. Woods et a1. 44 suggested that replacement of the normal flora by monilia was a possible cause for the diarrhea which they noted in their patients. Changes in bacterial flora within the gut are often noted during administration of oral antibiotics,17 These changes are frequently associated with an increase in volume and frequency of the stools, which contain greater quantities of undigested food and fibrous material. In tetracycline therapy this was paralleled by an initial decrease in the flora followed by a rebound of colony counts at the end of nine days' treatment. Generally tetracyclines brought about few significant alterations in the bacterial flora, whereas polymyxin B and bacitracin in combination profoundly altered it. It is not clear whether the increase in undigested food can be explained completely by a decline in destructive bacterial activity. It is conceivable that the antibiotics may have acted to decrease intestinal digestion. In any case the oral administration of Aureomycin and oxytetracycline

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DIET IN RELATION TO ANTIMICROBIAL THERAPY

significantly decreases the nitrogen balance by causing an increase in urinary nitrogen excretion. This is paralleled by increased urinary output of riboflavin. A similar effect has been described for oral tetracycline,13 but not for chloramphenicoP2 Aureomycin administration earlier was noted to promote a diffuse increase of fat in approximately 40 per cent of patients with chronic liver disease. 39 This peculiar effect of the tetracyclines in the patients reported may ultimately be related to their chelating ability. Their concentration in the liver mitochondria and their ability to bind magnesium may promote uncoupling of oxidative phosphorylation to the extent of causing increased fatty acid and protein catabolism. SPECIFIC BINDING OF A VITAMIN BY AN ANTIBIOTIC

Vitamin B6 is a vitamin intimately associated with the metabolism of amino acids through its coenzyme activity in transaminations, deaminations and decarboxylations. Its deficiency in young infants is associated with a clinical syndrome of irritability and repeated seizures of short duration precipitated by stimulation from movement, feeding or extraneous sound. Pyridoxine-deficient infants frequently are associated with an inability to handle tryptophan, as exhibited by elevated urinary xanthurenic acid excretion after an oral tryptophan load. The central nervous system manifestations are the result of impaired ability to decarboxylate 1-glutamic acid to form gamma-amino butyric acid, a compound which apparently functions as a moderator or regulator of neuronal activity.lo This compound is present principally in the tissues of the nervous system, particularly the gray matter. It is now recognized that isoniazid can combine with pyridoxal or pyridoxal phosphate, the active forms of the vitamin. It forms a hydrazide which renders B6 inactive at the enzyme level. In the brain the resultant decrease in the level of 1-glutamic acid decarboxylase lowers the gammaaminobutyric acid concentration, and seizure activity is initiated. Reduced levels of 1-glutamic acid decarboxylase produced by such inhibition have been directly related to seizure activity in isolated cortical, normal cortical and subcortical tissues. 26 The effect is completely reversed by administration of B6. The result is interesting in that the enzyme affected shows a ready dissociation of B6 coenzyme from the protein apoenzyme. Other enzymes are probably also affected. Xanthurenuria can be produced in dogs by administering isoniazid in a dose roughly equivalent to that required to produce a convulsant effect.45 Toxically high doses of isoniazid produce convulsions in children. 21 Peripheral neuritis may occur in up to 40 per cent of adults receiving 20 mg. per kilogram of body weight per day.r. A special case is seen in the pediatric group demonstrating impaired B6 utilization.4, 40 Here the infant requires an abnormally large quantity of B6 daily to prevent the convulsive symptomatology even though xanthurenic acid excretion may remain normal with lower intakes. Recently the acute convulsive effects

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of an overdose of isoniazid in mice have been prevented by the use of pyruvate. 3 This compound, a normal product of the glycolytic pathway, reacts with isoniazid to inactivate it as the corresponding hydrazone . THE NEWBORN-A. SPECIAL RELATION TO ANTIMICROBIAL THERAPY

The unfortunate experiences with the use of chloramphenicol in the newborn 38 have done much to promote re-examination of the use of antimicrobial agents in this period of life. Experiments in rats carried out by Michael and Sutherland29 indicate that other antibiotics may be dangerous when used for this age group. Novobiocin, tetracycline and penicillin G were shown to be more toxic in the newborn rat than in the older animal. Comparable results were obtained for chloramphenicol. Some of these effects probably are due to the inability of the newborn organism to excrete these compounds effectively by either glomerular or tubular mechanisms. The resulting increase of the concentration of antimicrobial in the blood secondary to the infant's limited excretory capacity statistically increases the chances for the enzymatic inhibitory effects previously described. The very nature of deranged metabolic systems implies inefficient cellular metabolism with concomitant disruption of cellular function. Severe derangements could conceivably cause death. The salt form of the agent is also important in this respect. The potassium and magnesium salts of penicillin exhibit an intravenous toxicity four times greater than do the corresponding lithium and sodium salts. 32 The toxicity is directly related to the metal. Several of the enzyme systems in the newborn are functionally immature when compared to those of the adult. 8 The glucuronating system of the liver has limited abilities for performing this function at birth. As a result the newborn finds himself in a delicate state of balance between bilirubin production and conjugation. Since unconjugated bilirubin cannot be excreted and is itself toxic to the metabolizing tissue, the infant must be protected from drugs which might disturb what conjugating mechanism there is available. A variety of drugs have been shown to interfere with this conjugative ability. These include both sulfonamides and chloramphenicol, which may be glucuronized before excretion. Each of these, through its ability to compete. with bilirubin for the enzyme system, might be expected to upset the delicate balance in the newborn and thereby promote hyperbilirubinemia. In addition to their enzyme-blocking effect, the sulfonamides have been noted to exhibit a second effect, entirely unrelated to the former. Silverman et aU1 noted an increase in the incidence of death in their infants given sulfonamide and penicillin as a prophylactic regimen. The cause was related to the sulfonamide and associated with an increased incidence of kernicterus. Oddly enough, there was no particular difference between the serum bilirubin in the group receiving sulfonamide and that group given another antibiotic. Since this report, the effect produced by sulfonamide has been related to its ability to displace bilirubin from

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carrier serum albumin. The released bilirubin concentrates in the tissues to produce its toxic effect. Other antibiotics can bind serum albumin in a similar fashion. Recently work on Gunn rats has suggested that high concentrations of penicillin, tetracycline and chloramphenicol acid succinate also are capable of producing similar effects.23 The difficulty with which the newborn handles bilirubin is compounded by the suscepibility of his erythrocytes to hemolysis in the presence of large concentrations of menadione sodium bisulfite.47 Doses as high as 40 mg. have resulted in hemolytic anemia in the newborn. Zinkham 47 found that the hemolytic effect and associated glutathione instability were prevented when adequate concentrations of glucose were provided in the in vitro system which he used. Blood glucose levels decrease in the newborn shortly after birth 15 and remain low with a gradual rise throughout the first week of life.35 , 36 This, combined with an increased rate of glycolysis in the red blood cell during this period, predisposes the erythrocyte to hemolysis in the presence of large concentrations of the vitamin. Hyperbilirubinemia in the newborn has been reported as a complication of novobiocin therapy.42 Here the antibiotic appears to compete with the excretory function of the liver for excreting bilirubin glucuronide. The competition promotes bilirubin retention with resultant jaundice It appears therefore that early supplementation of glucose may provide a means of decreasing the adverse affects of reduced bilirubin conjuga tion and red blood cell hemolytic tendency in the neonatal period Promotion of an adequate serum glucose level during this period woukl be expected to promote maximum efficiency of the bilirubin-conjugating mechanism by aiding in the saturation of the enzyme system with one of its substrates. In addition, the prevention of glycogen depletion from the liver would be expected to prevent fatty acid mobilization and resultant decrease in blood pH, both of which favor dissociation of bilirubin from carrier albumin. Finally, saturation of the erythrocyte glycolytic enzyme system would help to stabilize the red blood cell glutathione, which is necessary for erythrocyte longevity. The use of salt-free serum albumin in cases of active hemolytic anemia or in prematures with low serum protein levels is a reserve measure which may be of considerable value in preventing kernicterus in the seriously ill infant. Finally, the ability of the liver to acetylate compounds for excretion also is impaired in the neonatal period. Sulfonamides are acetylated at a limited rate,16 and isoniazid may be poorly detoxified by acetylation in a similar mechanism. Glucose might be expected to play an indirect role in promoting acetylation by supplying additional substrate for the reaction. ANTIMICROBIALS-THEIR RELATION TO THE PATIENT WITH AN ERROR OF METABOLISM

The adverse effects of antimicrobial agents on serum bilirubin may be magnified in certain inborn errors of metabolism. The association of hyperbilirubinemia with the neonatal period may present special diffi-

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culties to the child born of a diabetic mother. Here early feeding of glucose has helped to reduce the serum bilirubin levels.4~ Glycogen storage disease may cause hypoglycemia with resultant acidosis; any of the problems described in the previous section might be expected to arise. The importance of the recognition of galactosemia in the newborn period need not be overemphasized. The necessity for the elimination of galactose-containing sugars from the diet has been discussed (see p. 955). An adequate supply of glucose is essential here in preventing the hyperbilirubinemia associated with this disease in the neonatal period. The added dangers of hyperbilirubinemia through inappropriate drug administration need no further elaboration. Sulfonamides, Furadantin derivatives and para-aminosalicylic acid represent a potential threat to the patient with a deficiency of glucose-6-phosphate dehydrogenase at all times. The production of acute hemolytic anemia in a newborn with this deficiency by the administration of any of these drugs could be disastrous. Toxicity of isoniazid in the human being might be expected to increase in any metabolic defect which renders him incapable of acetylating and thereby detoxifying this compound; the report of Evans et alP indicates that such hereditary defects are possible. It will be interesting to see how many other defects in antimicrobial metabolism will appear in the next few years. SUMMARY

The relations between antimicrobial agents and nutrition have been considered. Few specific contraindications to the more commonly used drugs have been described. Toxic and nutritional abnormalities have been noted to occur with greatest frequcncy in the neonatal period, in which metabolic and excretory limitations were recognized. In all cases the avoidance of excessive dosage of the appropriate drug 25 associated with a diet requisite for the age is recommended. The chemical nature of the antimicrobial agent precludes its use as a panacea for diseases in which microorganisms play no obvious part. REFERENCES

1. AIl frey, V. G., and Mirsky, A. E.: Amino Acid Transport into the CeIl Nucleus and Reactions Governing Nuclear Protein Synthesis; in R. J. C. Harris, ed.: Protein Biosynthesis. New York, Academic Press, 1961. 2. Baker, J. B. E.: Effects of Drugs on the Fetus. Pharmacol. Rev., 12:37, 1961. 3. Barreto, R. C. R., and Mano, D. B.: Prevention of the Convulsant and Lethal Effects of Isonicotinic Acid Hydrazide by Pyruvic Acid. Biochem. Pharmacol., 8:409,1961. 4. Bessey, O. A., Adam, D. J. D., and Hansen, A. E.: Intake of Vitamin Bs and Infantile Convulsions: A First Approximation of Requirements of Pyridoxine in Infants. Pediatrics, 20:33,1957. 5. Biehl, J. P., and Vilter, R. W.: Effect of Isoniazid on Vitamin B6 Metabolism; Its Possible Significance in Producing Isoniazid Neuritis. Proc. Soc. Exper. Biol. '" Med., 85:389, 1954.

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6. Chenoweth, M. B.: Chelation as a Mechanism of Pharmacological Action. Pharmacol. Rev., 8:57, 1956. 7. Davis, R. A., and Wolf, A.: Infantile Beriberi Associated with Wernicke's En· cephalopathy. Pediatrics 21:409,1958. 8. Driscoll, S. G., and Hsia, D. V.: The Development of Enzyme Systems during Early Infancy. Pediatrics, 22:785, 1958. 9. DnBuy, H. G., and Showacre, J. L.: Selective Localization of Tetracycline in Mitochondria of Living Cells. Science, 133:196, 1961. 10. Edwards, E., and Kuffier, S. W.: Inhibitory Mechanisms of Gamma-Aminobutyric Acid on Isolated Nerve. Fed. Proc., 16:34, 1957. 11. Evans, D. A. P., Manley, K A., and McKusick, V. A.: Genetic Control of Isoniazid Metabolism in Man. Brit. MI, 2:485, 1960. 12. Faloon, W. W., Noll, J. W., and Collins, K: Metabolic and Histologic Studies in Patients with and without Liver Disease Receiving Chloramphenicol and Oxytetracycline. J. Lab. 6> Clin. Med., 44:75, 1954. 13. Faloon, W. W., Downs, J. J., Duggan, K, and Prior, J. T.: Nitrogen and Electrolyte Metabolism and Hepatic Function and Histology in Patients Receiving Tetracycline. Am. J. M. Sc., 233:563,1957. 14. Faloon, W. W., and Jacobson, E. D.: Malabsorption during Neomycin Administration. Gastroenterology, 40:447, 1961. 15. Farquhar, J. W.: Control of the Blood Sugar Level in the Neonatal Period. Arch. Dis. Childhood, 29:519, 1954. 16. Fichter, E. G., and Curtis, J. A.: Sulfonamide Administration in Newborn and Premature Infants. Pediatrics, 18:50, 1956. 17. Gabuzda, G. J., and others: Some Effects of Antibiotics on Nutrition in Man, Including Studies of the Bacterial Flora of the Feces. A.M.A. Arch. Int. Med., 101:476, 1958. 18. Goldstein, A.: The Interactions of Drugs and Plasma Proteins. Pharmacol. Rev., 1:102,1949. 19. Gordon, H. H., Nitowsky, H. M., Tildon, J. T., and Levin, S.: Studies of Tocopherol Deficiency in Infants and Children. Pediatrics, 21:673,1958. 20. Hunter, F. E., Jr., and Lowry, O. H.: The Effects of Drugs on Enzyme Systems. Pharmacol. Rev., 8:89,1956. 21. Hyatt, H. W.: Acute Poisoning from Overdose of Isoniazid. Am. J. Dis. Child., 102:228, 1961. 22. Jacobson, E. D., and Faloon, W. W.: Some Effects of Antibiotics on Nutrition in Man. A.M.A. Arch. Int. Med., 101:476, 1958. 23. Johnson, L., Garcia, M. L., Figueroa, E., and Sarmiento, F.: Kernicterus in Rats Lacking Glucuronyl Transferase. II. Factors Which Alter Bilirubin Concentration and Frequency of Kernicterus. Am. J. Dis. Child., 101:322, 1961. 24. Jukes, T. H., and Williams, W. L.: Nutritional Effects of Antibiotics. Pharmacol. Rev., 5:381, 1953. 25. Kagan, B. M., Ed.: Symposium on Antimicrobial Therapy. PEDIAT. CLIN. N. AMER., 8:967-1298, 1961. 26. Killam, R. F.: Convulsant Hydrazides, II. Comparison of Electrical Changes and Enzyme Inhibition Induced by the Administration of Thiosemicarbazide. J. Pharmacol. 6> Exper. Therap., 119:263, 1957. 27. Leitner, Z. A.: Vitamin Deficiency and Antibiotics. Brit. M.J., 1:491, 1950. 28. Merliss, R. R., and Hoffman, A.: Steatorrhea Following the Use of Antibiotics. New England J. Med., 245:328, 1951. 29. Michael, A. F., and Sutherland, J. M.: Antibody Toxicity in Newborn and Adult Rats. Am. J. Dis. Child., 101:442, 1961. 30. Mickelsen, 0.: Intestinal Synthesis of Vitamins in the Nonruminant. Vitamins 6> Hormones, 14: 1, 1956. 31. Milch, R. A., Rail, D. P., and Tobie, T. K: Bone Localization of the Tetracyclines. J. Nat. Cancer Inst., 19:87, 1957. 32. Molitor, H., and Graessle, O. E.: Pharmacology and Toxicology of Antibiotics. Pharmacol. Rev., 2:1, 1950. 33. Najjar, V. A., and others: The Biosynthesis of Riboflavin in Man. !.A.M.A., 126: 357, 1944. 34. Najjar, V. A., and Barrett, R.: The Synthesis of B Vitamins by Intestinal Bacteria. Vitamins 6> Hormones, 3:23, 1945.

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