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Antibiotics in children: a symposium reviews some common problems By Warren E, Wheeler, MD I will examine two aspects of antibiotic the effectiveness of the drugs we use and the attitudes that keep us out of trouble. Most of our patients or their parents now know that colds are caused by viruses and, therefore, do not respond to antibiotics. Despite this, many doctors seem to have the Messiah complex and set out to cure infectious disease. You just can't or shouldn't want to do that. In general it is reserved for surgeons to cure people. A surgeon can ligate a ductus arteriosus and cure the young patient. He restores that child to normal to health. Pediatricians and other physi¬ cians do not often have these oppor¬ tunities for clear-cut intervention. Per¬ haps we have specific antidotes for some poisons and can say we have cured the patient without his participa¬ tion. However, in infectious disease all we do when we give antibiotics is help the patient; we must rely on his defences to carry out the healing process. Think about this and avoid the Mes¬ siah complex, because doctors who feel they have to cure things may get them¬ selves and their patients into a good deal of trouble. Not long ago we admitted a 13-dayold baby to our hospital. The referring doctor sent along his record and a complete account of his treatment to that point. He had given the baby 13 different drugs. Six of them I had never heard of, and, of the 13, I knew enough about only 3 to calculate the dose for a baby that size. You can see what happened. He got panicky and when the first drug didn't work he added the second and the third and the sixth. He was going to cure that patient. We stopped all 13, gave the baby a little supportive care and in a few days he got better. We helped the
therapy:
but we didn't try to cure him. The chief indication for the use of antibiotics is to control a spreading infection. Here antibiotics work well. We all learn quickly that if you ad¬ minister the right antibiotic early, be¬ fore the patient gets too sick, the re¬ sults are much better than if you wait. A spreading infection is not walled off and you are treating the patient at a time when all his defences have not
baby
CMAJ presents a report on a sympo¬ sium organized by the Ontario Medical Foundation, University of Toronto and Physicians9 Services Inc. Foundation on antibiotics in children. The symposium was offered at Women's College Hos¬ pital March 26 this year to help fam¬ ily physicians and pediatricians main¬ tain their competence in this area. This overview of the symposium is presented for the benefit of those unable to at¬ tend. The reports are based on tapes of the presentations by the distinguished US pediatricians named as authors, and the material was compiled by Dr. J.O. Godden.
been mobilized. Therefore, if you re¬ duce the bacterial burden so that the patient's defences can catch up you turn the balance in his favour. You haven't cured him but you have helped him. Another good indication for anti¬ biotics is in prophylaxis. Penicillin in a patient who has had rheumatic fever can prevent streptococcal colonization. That's true prophylaxis, and there are not many instances where you can use antibiotics like this. Most doctors think of prophylaxis in terms of getting there early, as when a recruit comes back on duty and is given penicillin
night on the town". are actually treating his early gonor¬ rhea or syphilis a spreading infec¬ because of "a
However, if he has been exposed you
tion. Do we need bactericidal antibiotics or do we just need a bacteriostatic effect? This is important. Used in a low dose a bactericidal antibiotic can be bacteriostatic and may reduce the bacterial burden by preventing growth and multiplication. This may be all that is needed to turn the tide in the patient's favour. I don't think you need bactericidal concentrations of drugs very often perhaps in osteomyelitis, endocarditis and the more serious invasive types of meningitis. We might get better results with bactericidal concentrations in newborns with gram-negative menin¬ gitis, but bacteriostatic effects often do the trick. This is not to say that you should aim for bacteriostatic effects but that you should guard against the attitude that if some drug is good, twice as much is twice as good and five times as much is five times as
good. My rule of thumb is to use the drug with the narrowest spectrum that is effective against the organism respon¬ sible for the patient's illness. The nor¬ mal flora of the infant's gut, throat and skin have a protective function that we often overlook. When we use broad-spectrum antibiotics that retard or kill Streptococcus viridans, Neisseria and other normal flora in his throat,
and some of the Escherichia coli and anaerobes in his gut, we are depriving him of some of his natural protection. I encourage medical students to study disease by studying patients instead of textbooks; for instance, when a child comes in who has been or is going to
CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113 559
Aldactazide® "The best initial approach ... to the treatment of essential hypertension Pharmacology: Spironolactone effects diuresis by blocking through competitive inhibition, the sodium and water retaining and potassium escreting effects of aldosterone on the distal renal tubule. Hydrochlorothiazide promotes excretion of sodium and water primarily by inhibiting their reabsorption by the cortical diluting segment of the renal tubule. Thus the components of Aldactazide have different and complementary modes of action. In addition, spironolactone minimizes potassium loss characteristically induced by hydrochlorothiazide, thereby reducing the possible serious consequences of potassium depletion. Indications: The treatment of essential hypertension: the edema and ascites of congestive heart failure, cirrhosis of the liver, the nephrotic syndrome and idiopathic edema. Contraindicatlons: Acute renal insufficiency: rapidly progressing impairment of renal function: anuria: hyperkalemia: patients known to be sensitive to thiazides or other sulfonamide-derived drugs: patients with severe or progressive liver disease at the discretion of the physician: nursing mothers: sensitivity to spironolactone. Warnings: Concurrent potassium supplementation is not indicated unless a glucocorticoid is also given. Aldactazide should not be used in conjunction with other potassium conserving agents. Precautions: The most potentially serious electrolyte disturbance is hyperkalemia which is more likely to occur in severely ill patients. If hyperkalemia occurs, discontinue Aldactazide. Hypokalemia may develop. Use cautiously in patients with sodium depletion. Check for signs of fluid or electrolyte imbalance. The most frequent electrolyte disturbance encountered is dilutional hyponatremia. Rarely a true low-salt syndrome may develop. Decrease dosage before diuresis is complete to avoid dehydration. Thiazide diuretics may precipitate hepatic coma. Use with caution in patients subjected to regional or general anesthesia. Discontinue 48 hours prior to elective surgery as both hydrochlorothiazide and spironolactone reduce vascular responsiveness to norepinephrine. Orthostatic hypotension may occur. Thiazides may increase responsiveness to tubocurarine. Pathological changes in the parathyroid glands have been observed. Consider the possibilities of sensitivity reactions in patients with a history of allergy or asthma as well as exacerbation of systemic lupus erythematosus. Thiazides may cause elevation of BUN. Aldactazide may potentiate the effect of other antihypertensives especially the ganglionic blocking agents. The dosage of such drugs should be reduced at least 50% when Aldactazide is added to the regimen. Spironolactone interferes with the assay of plasma cortisol but not the Ertel method. ASA may interfere with the action of spironolactone. Use with caution in patients with hyperuricemia or history of gout. Insulin requirements may be increased, decreased or unchanged in diabetics. Hyperglycemia and glycosuria may be manifested in latent diabetics. Use with caution in women of childbearing age and weigh benefits against the possible hazards to the fetus. Adverse Effects: Nausea or other gastrointestinal disturbances, gynecomastia or mild androgenic manifestations have been reported in some patients. Other side effects including those of hydrochlorothiazide occur less frequently. Overdose: Symptoms of Overdosage: Acute overdosage may be manifested by drowsiness, mental confusion. maculopapular or erythematous rash, nausea, vomiting, dizziness or diarrhea. Rare instances of hypokalemia, hyponatremia, hyperkalemia or hepatic coma may occur. Thrombocytopenic purpura and granulocytopenia have occurred with thiazide therapy. No specific antidote. Treat fluid depletion and electrolyte imbalances as indicated. Dosage: In essential hypertension, a daily dosage of 2 to 4 tablets, in divided doses, will be adequate for most patients, provided the treatment is continued for 2 weeks or longer. Dosage may range from 2108 tablets daily. Dosage should be adjusted according to the response of the patient. In edematous states, a daily dosage of 2 to 4 tablets, in divided doses, will be adequate for most patients but may range from 2 to 8 tablets daily. Dosage should be adjusted according to the response of the patient. Supply: Each round, ivory-coloured tablet contains, spironolactone. 25 mg and hydrochlorothiazide. 25 mg. Available in bottles of 100, 1,000 and 2.500 tablets. Complete prescribing information available on request. References 1. Cecil-Loeb, Textbook of Medicine, P. B. Beeson & W. McDermott, eds. W. B. Saunders, Philadelphia, 1971. 13th edition, pp. 1050-1062. 2. Mendlowitz. M.: "Systemic Arterial Hypertension Charles C. Thomas, Springfield, Illinois: (1974). 3, Hollander, W. and Wilkins, R. W.: Progr. Cardiovasc. Dis., 8: 291-318 (Jan.) 1966. 4, Gantt, C. H.: "Diuretic Therapy". Rational Drug Therapy 6. No. B (Aug.) 1972. 5, Dustan, H. P. in Page, I. H. (Moderatorand Editor): Dustan, H. P.: Freis, E. 0.: Stamler, J.. and Wilkins, R. W. (Discussants): Symposium of Hypertension, Mod, Med. 49: 74-113 (March 20) 1972. Copies of all clinical reprints available on request.
. Searle Pharmaceuticals Oakville, Ontario
be taking ampicillin, I ask the student to determine how long it will be before his stool flora become predominantly Kiebsiella (average, 3 days). This and similar exercises give him an appreciation of what he does to these helpful organisms when he prescribes broadspectrum antibiotics. After entering hospital a child becomes a carrier of penicillinase-producing staphylococci much later when given penicillin - even though the organism is penicillin-resistant - than when given tetracycline, according to Ehrenkranz and colleagues. There are many things antibiotics cannot do; for example, they cannot cure abscesses. Four years ago a 13year-old girl came to our hospital. Her illness had started with a high fever and a backache. Her doctor gave her penicillin and put her in hospital. The high fever and backache persisted, so he doubled the dose of penicillin and then quadrupled it. After 2 weeks she still had the high fever and backache so he decided to use one of the newer antibiotics - cephalothin. That didn't do much, so he doubled the dose and then quadrupled it. After a month in hospital she wasn't getting any better, so he sent her to us. Our chief resident palpated the lower part of her back; it was fluctuant. He aspirated about 150 ml of pus, which started her on her way to recovery. The pus from this deep-seated abscess grew staphylococci and tiny colonies of group A streptococci. By the Millipore filter technique we demonstrated a bactericidal concentration of the antibiotic against both organisms in the pus. Why, then, were we able to recover live organisms from it? Simply, the organisms survived in the low oxygen concentration inside the pus, and the pH of the pus was 5, a level at which penicillin and some other antibiotics do not work well. The doctor was expecting the antibiotic to work in an unfavourable environment. He apparently hadn't looked at her back; had he done so he would have discovered the abscess and tried to drain it (one reason for doing so is that the abscess wall is a barrier to the antibiotic). Many other clinical situations are similar to this such as an infection behind an obstruction or associated with a foreign body. I once saw a child who had had a shunt implanted for hydrocephalus. He had been doing well for 2 years and then suddenly signs of "leukemia" developed - generalized petechiae and enlargement of his liver and spleen. When he arrived at hospital the youngster had had a fever for some time. He was a happy little fellow. His temperature was 39.40C but he sat up in bed and talked, and
didn't seem very sick. Staphylococcus aureus was repeatedly cultured from blood samples. The referring doctor had given him penicillin, but despite intensive therapy he didn't get better. We then persuaded the neurosurgeon that infection in association with a foreign body required him to remove the foreign body. He wanted to order tremendous doses of penicillin in addition, but we finally convinced him not to. There wasn't any need: there was no evidence of toxicity and he had adequate defences against staphylococci once removal of the foreign body gave them a chance to work (he had the highest gamma globulin level I had ever seen). So the surgeon took the shunt out. The next day the temperature was somewhat lower; the blood culture was still positive. The 2nd day the temperature was normal; the blood culture was negative and remained so without penicillin. Another pitfall is that the organisms seem to change. You start off treating one and you wind up with another, especially in the urinary tract and in burns and other surface infections. The underlying truth in all this is that nature abhors a bacteriologic vacuum, and, with all your treatment, you can't maintain one. If you kill the predominant organism and the lesion is exposed to air another organism will take its place, probably one that is resistant to the drug you're using. The situation so produced may be much worse than the original infection because, in many instances, surfaces like mucosa and granulating wounds are colonized by relatively nonpathogenic bacteria; if you get rid of these benign organisms you lay the wound open to invasion by "true" pathogens that otherwise would have been excluded. In addition, we sometimes expect drugs to work where they are at a disadvantage. The pH inside an abscess is low and the pH of normal urine is about 6.5; and streptomycin, for example, is 20 times more effective at a pH of 8 than it is at one of 6.8. These are some of the considerations that underlie the general use of antibiotics. In my experience the least common reason for failure of therapy is that the organism you started to treat has become resistant to the antibiotic you are using. If it's on the surface it may be replaced by another organism - that's superinfection. But the development of antibiotic resistance in deep-seated infections, in my experience, is rare. I emphasize this to caution against changing drugs too readily. I once saw a 7-year-old boy with osteomyelitis who was being treated with erythromycin. The drug seemed to be effective: his temperature
CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
561
decreased and he felt much better. But on the 5th day he was sick again with a temperature of 400C. The orthopedic surgeon attributed this to resistance. So he changed the antibiotic. I came along soon after and found a red streak coming up from his intravenous needle - he had thrombophlebitis, not antibiotic resistance. My point is that if the patient doesn't do well, instead of first thinking about changing the antibiotic, look at the patient and see if there is some reason why he isn't getting better. In both outpatient and office practice, the most common reason children don't respond to an antibiotic in the way you expect them to is that the mother isn't giving the drug the way you want. A doctor has two jobs: first, to come to an agreement with the mother as to what is wrong with the child, and second, to come to an agreement with her as to what should be done about it. For example, a young child arrives in our emergency room at night with a temperature of 400C. His mother says he has an upset stomach. The resident looks in the child's ear and sees a red-hot bulging drum. He tells the mother that the child has otitis, prescribes an antibiotic and tells her to come back in 4 days. Thirty minutes later the same mother with the same child appears at the emergency room of another hospital. She tells them that she took her child to the university and the doctor over there didn't understand the situation because he didn't do anything about the child's upset stomach. The second doctor could take a little interest in the mother's concern and, after he has examined the infant, point out to her that although the baby has an upset stomach, this is caused by an infection - the abscess in the ear. He could assure her that if she gives him this medicine the child will feel much better quickly, but she is to continue the medicine so that the abscess will heal completely. This type of counselling takes longer but is much more effective.
Compliance Pediatrics' January issue had a good review of compliance. It described a shake mixture of ampicillin prescribed for children who had otitis media. A surprising number never did complete their course of medication, and only about two thirds of the families got the size of bottle of ampicillin from the pharmacy that was ordered. Furthermore, a large percentage of the bottles didn't have any shake labels on them and no one cautioned the mothers to keep the suspension in the refrigerator. In addition, many children spat
ALDOMET (methyldapa, MSD Std.)
Indications: Sustained moderate through severe hypertension. Dosage Summary: Start usually with 250 mg two or three times daily during the tirst 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. In the presence of impaired renal function smaller doses may be needed. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease and may be avoided by reducing the dose. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. Contraindications: Active hepatic disease such as acute hepatitis and active cirrhosis; known sensitivity to methyldopa; unsuitable in mild or labile hypertension responsive to mild sedation or thiazides alone; pheochromocytoma; pregnancy. Use cautiously if there is a history of liver disease or dysfunction. Precautions: Acquired hemolytic anemia has occurred rarely. Hemoglobin and/or hematocrit determinations should be performed when anemia is suspected. If anemia is present, determine if hemolysis is present. Discontinue methyldopa on evidence of hemolytic anemia. Prompt remission usually results on discontinuation alone or the initiation of adrenocortical steroids. Rarely, however, fatalities have occurred. A positive direct Coombs test has been reported in some patients on continued therapy with methyldopa, the exact mechanism and sigpificance of which is not established. Incidence has varied from 10 to 20%. If a positive test is to develop it usually does within 12 months following start of therapy. Reversal of positive test occurs within weeks to months after discontinuation of the drug. Prior knowledge of this reaction will aid in crosa matching blood for transfusion. This may result in incompatible minor cross match. If the indirect Coombs test is negative, transfusion with otherwise compatible blood may be carried out. If positive, advisability of transfusion should be determined by a hematologist or expert in transfusion problems. Reversible leukopenia with primary effect on granulocytes has been seen rarely. Rare cases of clinical agranulocytosis have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Occasionally fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur also, with onset usually within first 2 or 3 months of therapy. Rare cases of fatal hepatic necrosis have been reported. Liver biopsies in several patients with liver dysfunction showed a microscopic focal necrosis compatible with drug hypersensitivity. Determine liver function, leukocyte and differential blood counts at intervals during the first six to twelve weeks of therapy or whenever unexplained fever may occur. Discontinue if fever, abnormalitiesinliverfunctiontests, or jaundiceoccur. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on ALDOMET*. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. Hypertension occasionally noted after dialysis in patients treated with ALDOMET* may occur because the drug is removed by this procedure.
562 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
Rarely involu ntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, discontinue therapy. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. Methyldopa will not serve as a diagnostic test for pheochromocytoma. Usage in Pregnancy: Because clinical experience and follow-up studies in pregnancy have been limited, the use of methyldopa when pregnancy is present or suspected requires that the benefits of the drug be weighed against the possible hazards to the fetus. Adverse Reactions: Cardiovascular: Angina pectons may be aggravated; reduce dosage if symptoms of orthostatic hypotension occur; bradycardia occurs occasionally. Neurological: Symptoms associated with effective lowering of blood pressure occasionally seen include dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency. Sedation, usually transient, seen during initial therapy or when dose is increased. Similarly, headache, asthenia, or weakness may be noted as early, but transient symptoms. Rarely reported: paresthesias, parkinsonism, psychic disturbances including nightmares, reversible mild psychoses or depression, and a single case of bilateral Bells palsy. Gastrointestinal: Occasional reactions generally relieved by decrease in dosage: mild dryness of the mouth and gastrointestinal symptoms including distention, constipation, flatus, and diarrhea; rarely, nausea and vomiting. Hemafological: Positive direct Coombs test, acquired hemolytic anemia, leukopenia and rare cases of thrombocytopenia. Toxic and Allergic: Occasional drug related fever and abnormal liver function studies with jaundice and hepatocellular damage, (see PRECAUTIONS) and a rise in BUN. Rarely, skin rash, sore tongue or black tongue", pancreatitis and inflammation of the salivary glands. Endocrine and Metabolic: Rarely, breast enlargement, lactation, impotence, decreased libido; weight gain and edema which may be relieved by administering a thiazide diuretic. If edema progresses or signs of pulmonary congestion appear, discontinue drug. Miscellaneous: occasionally nasal stuffiness, mild arthralgia and myalgia; rarely, darkening of urine after voiding. Detailed information available on request. How Supplied: Tablets ALDOMET* are yellow, filmcoated, biconvex shaped tablets, supplied as f ollows: Ca 8737 - each tablet containing 125 mg of methyldopa, marked MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290 - each tablet containing 250 mg of methyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733 - each tablet containing 500 mg of methyldopa, marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293 - Injection ALDOMET* Ester hydrochloride, a clear colourless solution containing 250 mg methyldopate hydrochloride per 5 ml, supplied in 5 ml ampoules. (MC-949a)
C
ERCK I SHARP I & DOHME CANADA LIMITED/LIMIT.E
A Leader In Cardiovascular Medicine
out some of the medicine when the mother tried to give it, so that half the mothers decided the medicine was not agreeing with their children and stopped it. This does happen, and unless you take time to talk to a mother to get some ideas of how she looks upon the child's illness, she is going to stop the medicine as soon as the temperature decreases and the child feels better. To counteract these failures in compliance I wonder if we might try to teach students something about communication. For many years, when I have had a patient on the ward about to be discharged, I have tried to get to the medical student and say to him "Don't be there when the house staff talks to the mother. Make it a point to be around the corner, and after the house staff leaves go to her, all out of breath, and say 'I wanted to hear
what Dr. So-and-So had to say about your baby but I couldn't make it. What did he say? What did he say was wrong with your baby? What are you going to do?'" It's a great way to teach the student communication because for him it's the other guy who goofs. He is just checking up. It is a tremendous learning experience for a student when he realizes that otherwise-good doctors, whom he respects, can fail when they commit a basic human slip. In your own practice, your nurse or receptionist can get this kind of feedback. When the patient comes out she can ask "What did the doctor say was wrong with the baby? What did he tell you to do? How are you going to do that?" They could be trained to find out how mothers give medicines at home and in the process encourage them to do the right thing.
Antibiotics in the newborn By George H. McCraken, Jr., MD I will discuss the pharmacologic considerations underlying antimicrobial therapy, particularly dosage recommendations for antibiotics in common use in the newborn and the young infant. The selection of appropriate antimicrobial therapy in these young patients depends on a number of factors. The first is the historical experience in a nursery of organisms encountered. This information is important in guiding initial therapy before the pathogen has been identified. The second factor is the, antimicrobial susceptibility of common pathogens to routinely used drugs; that is, you would not use an antibiotic to which common pathogens, such as Escherichia coli, are resistant. Third, the physician who is managing patients must have some familiarity with the pharmacologic properties of an antimicrobial agent; that is, peak concentrations attainable in serum, cerebrospinal fluid (CSF) and urine and the relation between these peak values and the organism's susceptibility (minimal inhibitory concentration [MId). Surveillance data collected in Dallas from August 1963 to August 1974 showed that E. coli isolated from neonates became resistant to kanamycin after extensive use over 6 or 7 years. This resistance, first observed in 1968, persisted for 3 years in the face of continued use of the drug. In January 1971 we stopped routinely using kanamycin, and for the next 3 years used gentamicin in our neonatal units. In 1971 the in vitro effectiveness of kanamycin declined even further (70% of strains were resistant) and then slowly
returned to its original level; now about 90% of E. ccli strains are susceptible to 10 ,.g/ml of kanamycin or less. Thus, during the period of limited use the drug's effectiveness returned, and when kanamycin was reintroduced into our nurseries in January 1974 the susceptibility of E. coli did not change. This is what would have been expected. During the 3-year period we had eliminated resistant clones or strains of E. ccli, so when kanamycin was reintroduced there was no selective pressure for the rapid emergence of resistant strains. These data suggest that alternating antibiotics on an annual or biannual basis to prevent the emergence of resistance may avoid the necessity of using newer and potentially more toxic drugs that we have not had adequate time to test in the laboratory and in clinical trials. Our experience is not peculiar to Dallas. We have looked at similar surveillance data over a 3- to 6-year period at the University of Utah in Salt Lake City, and we have data from Winnipeg and Montreal as well as from 17 other centres in North, Central and South America. These studies show that most E. ccli strains isolated from neonates are susceptible to kanamycin. These data demonstrate the importance of antimicrobial surveillance studies not only in the local institution but on a regional and national basis. The pharmacokinetic properties of antibiotics in newborn and young infants did not receive adequate attention until about a decade ago. Consequently, our young patients were exposed
564 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
The modifier of digestive behaviour
Classification:MAXERAN5 (metoclopramide monohyd rochloride) is a modifier of upper gastrointestinal tract motility. Indications: Sub-acute gastritis, chronic gastritis, gastriG sequellae of surgical procedures such as vagotomy and pyloroplasty. Under these conditions, when gastric emptying is delayed, Maxeran may relieve such symptoms as nausea, vomiting, epigastric distress, bloating, etc. Small bowel intubat,on: Maxeran may facilitate ano accelerate small bowel intubation.
Side-effects: Drowsiness and, more rarely, insomnia,
fatigue, headaches, dizziness and bowel disturbances have been reported. Parkinsonism and other extra-pyramidal syndromes have been reported infrequently. An increase in the frequency and severity of seizures has been reported in conjunction with the administration of Maxeran to epileptic patients.
Precautions: Drugs with atropine-like action should not be used simultaneously with Maxeran since they have a tendency to antagonize effect of this drug on gastrointestinal motility. Maxeran should not be used in conjunction with potent ganglioplegic or neuroleptic drugs since potentiation of effects might occur. Maxeran should not be used in patients with epilepsy and extrapyramidal syndromes, unless its expected benefits outweigh the risk of aggravating these symptoms. In view of the risk of extrapyramidal manifestations, metoclopramide should not be used in children unless a clear indication has been established. The recommended dosage of Maxeran should not be exceeded since a further increase in dosage will not produce a corresponding increase in the clinical response. The dosage recommended for children should not be exceeded. Contraindications: Maxeran should not be administered to patients in combination with MAO inhibitors, tricyclic antidepressants, sympathomimetics and foods with high tyramine content, since safety of such an association has not yet been established. As a safety measure, a twoweek period should elapse between using Maxeran and administration of any of these drugs. The safety of use of Maxeran in pregnancy has not been established. Therefore Maxeran should not be used in pregnant women, unless in the opinion of the physician the expected benefits to the patient outweigh the potential risks to the fetus. Dosage and administration:
For delayed gastric emptying Adults Tablets: Liquid: Injectable:
Children: Liquid:
/2 to 1 tablet (5 - 10 mg) three or four times a day before meals. 5 - 10 ml (5 - 10 mg) three or four times a day before meals. When parenteral administration is required, 1 ampoule (10 mg) IM. or IV. (slowly) to be repeated 2 or 3 times a day if necessary. (5 to 14 years): 2.5 to 5 ml (2.5 - 5 mg)
For small bowel intubation: Adults:
Children:
One ampoule (10 mg) IV. - 15 minutes before intubation. Other routes (oral or IM.) may be used but with a greater period of latency. (5 to 14 years):
2.5 to 5 ml (2.5 - 5 mg) Availability: Tablets:
Liquid:
Injectable:
Each white scored compressed tablet contains 10 mg of Metoclopramide Monohydrochloride. Bottles of 50 & 500 tablets. Each ml contains 1 mg of Metoclopramide Monohydrochloride. Available in bottles of 110 ml and 450 ml. Each 2 ml ampoule contains 10 mg of Metoclopramide Monohydrochloride in a clear colourless solution. Keep away from light and heat. Available in boxes of 5 and 50 ampoules. Product monograph available upon request.
rT. fl . HARMACEUTIQUES LT.E tOi II HARMACEUTICALS LTD L.IJ . .II. i..' U LavalQue. Canada.
Antibiotics in children: a symposium reviews some common problems By Warren E, Wheeler, MD I will examine two aspects of antibiotic the effectiveness of the drugs we use and the attitudes that keep us out of trouble. Most of our patients or their parents now know that colds are caused by viruses and, therefore, do not respond to antibiotics. Despite this, many doctors seem to have the Messiah complex and set out to cure infectious disease. You just can't or shouldn't want to do that. In general it is reserved for surgeons to cure people. A surgeon can ligate a ductus arteriosus and cure the young patient. He restores that child to normal to health. Pediatricians and other physi¬ cians do not often have these oppor¬ tunities for clear-cut intervention. Per¬ haps we have specific antidotes for some poisons and can say we have cured the patient without his participa¬ tion. However, in infectious disease all we do when we give antibiotics is help the patient; we must rely on his defences to carry out the healing process. Think about this and avoid the Mes¬ siah complex, because doctors who feel they have to cure things may get them¬ selves and their patients into a good deal of trouble. Not long ago we admitted a 13-dayold baby to our hospital. The referring doctor sent along his record and a complete account of his treatment to that point. He had given the baby 13 different drugs. Six of them I had never heard of, and, of the 13, I knew enough about only 3 to calculate the dose for a baby that size. You can see what happened. He got panicky and when the first drug didn't work he added the second and the third and the sixth. He was going to cure that patient. We stopped all 13, gave the baby a little supportive care and in a few days he got better. We helped the
therapy:
but we didn't try to cure him. The chief indication for the use of antibiotics is to control a spreading infection. Here antibiotics work well. We all learn quickly that if you ad¬ minister the right antibiotic early, be¬ fore the patient gets too sick, the re¬ sults are much better than if you wait. A spreading infection is not walled off and you are treating the patient at a time when all his defences have not
baby
CMAJ presents a report on a sympo¬ sium organized by the Ontario Medical Foundation, University of Toronto and Physicians9 Services Inc. Foundation on antibiotics in children. The symposium was offered at Women's College Hos¬ pital March 26 this year to help fam¬ ily physicians and pediatricians main¬ tain their competence in this area. This overview of the symposium is presented for the benefit of those unable to at¬ tend. The reports are based on tapes of the presentations by the distinguished US pediatricians named as authors, and the material was compiled by Dr. J.O. Godden.
been mobilized. Therefore, if you re¬ duce the bacterial burden so that the patient's defences can catch up you turn the balance in his favour. You haven't cured him but you have helped him. Another good indication for anti¬ biotics is in prophylaxis. Penicillin in a patient who has had rheumatic fever can prevent streptococcal colonization. That's true prophylaxis, and there are not many instances where you can use antibiotics like this. Most doctors think of prophylaxis in terms of getting there early, as when a recruit comes back on duty and is given penicillin
night on the town". are actually treating his early gonor¬ rhea or syphilis a spreading infec¬ because of "a
However, if he has been exposed you
tion. Do we need bactericidal antibiotics or do we just need a bacteriostatic effect? This is important. Used in a low dose a bactericidal antibiotic can be bacteriostatic and may reduce the bacterial burden by preventing growth and multiplication. This may be all that is needed to turn the tide in the patient's favour. I don't think you need bactericidal concentrations of drugs very often perhaps in osteomyelitis, endocarditis and the more serious invasive types of meningitis. We might get better results with bactericidal concentrations in newborns with gram-negative menin¬ gitis, but bacteriostatic effects often do the trick. This is not to say that you should aim for bacteriostatic effects but that you should guard against the attitude that if some drug is good, twice as much is twice as good and five times as much is five times as
good. My rule of thumb is to use the drug with the narrowest spectrum that is effective against the organism respon¬ sible for the patient's illness. The nor¬ mal flora of the infant's gut, throat and skin have a protective function that we often overlook. When we use broad-spectrum antibiotics that retard or kill Streptococcus viridans, Neisseria and other normal flora in his throat,
and some of the Escherichia coli and anaerobes in his gut, we are depriving him of some of his natural protection. I encourage medical students to study disease by studying patients instead of textbooks; for instance, when a child comes in who has been or is going to
CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113 559
Aldactazide® "The best initial approach ... to the treatment of essential hypertension Pharmacology: Spironolactone effects diuresis by blocking through competitive inhibition, the sodium and water retaining and potassium escreting effects of aldosterone on the distal renal tubule. Hydrochlorothiazide promotes excretion of sodium and water primarily by inhibiting their reabsorption by the cortical diluting segment of the renal tubule. Thus the components of Aldactazide have different and complementary modes of action. In addition, spironolactone minimizes potassium loss characteristically induced by hydrochlorothiazide, thereby reducing the possible serious consequences of potassium depletion. Indications: The treatment of essential hypertension: the edema and ascites of congestive heart failure, cirrhosis of the liver, the nephrotic syndrome and idiopathic edema. Contraindicatlons: Acute renal insufficiency: rapidly progressing impairment of renal function: anuria: hyperkalemia: patients known to be sensitive to thiazides or other sulfonamide-derived drugs: patients with severe or progressive liver disease at the discretion of the physician: nursing mothers: sensitivity to spironolactone. Warnings: Concurrent potassium supplementation is not indicated unless a glucocorticoid is also given. Aldactazide should not be used in conjunction with other potassium conserving agents. Precautions: The most potentially serious electrolyte disturbance is hyperkalemia which is more likely to occur in severely ill patients. If hyperkalemia occurs, discontinue Aldactazide. Hypokalemia may develop. Use cautiously in patients with sodium depletion. Check for signs of fluid or electrolyte imbalance. The most frequent electrolyte disturbance encountered is dilutional hyponatremia. Rarely a true low-salt syndrome may develop. Decrease dosage before diuresis is complete to avoid dehydration. Thiazide diuretics may precipitate hepatic coma. Use with caution in patients subjected to regional or general anesthesia. Discontinue 48 hours prior to elective surgery as both hydrochlorothiazide and spironolactone reduce vascular responsiveness to norepinephrine. Orthostatic hypotension may occur. Thiazides may increase responsiveness to tubocurarine. Pathological changes in the parathyroid glands have been observed. Consider the possibilities of sensitivity reactions in patients with a history of allergy or asthma as well as exacerbation of systemic lupus erythematosus. Thiazides may cause elevation of BUN. Aldactazide may potentiate the effect of other antihypertensives especially the ganglionic blocking agents. The dosage of such drugs should be reduced at least 50% when Aldactazide is added to the regimen. Spironolactone interferes with the assay of plasma cortisol but not the Ertel method. ASA may interfere with the action of spironolactone. Use with caution in patients with hyperuricemia or history of gout. Insulin requirements may be increased, decreased or unchanged in diabetics. Hyperglycemia and glycosuria may be manifested in latent diabetics. Use with caution in women of childbearing age and weigh benefits against the possible hazards to the fetus. Adverse Effects: Nausea or other gastrointestinal disturbances, gynecomastia or mild androgenic manifestations have been reported in some patients. Other side effects including those of hydrochlorothiazide occur less frequently. Overdose: Symptoms of Overdosage: Acute overdosage may be manifested by drowsiness, mental confusion. maculopapular or erythematous rash, nausea, vomiting, dizziness or diarrhea. Rare instances of hypokalemia, hyponatremia, hyperkalemia or hepatic coma may occur. Thrombocytopenic purpura and granulocytopenia have occurred with thiazide therapy. No specific antidote. Treat fluid depletion and electrolyte imbalances as indicated. Dosage: In essential hypertension, a daily dosage of 2 to 4 tablets, in divided doses, will be adequate for most patients, provided the treatment is continued for 2 weeks or longer. Dosage may range from 2108 tablets daily. Dosage should be adjusted according to the response of the patient. In edematous states, a daily dosage of 2 to 4 tablets, in divided doses, will be adequate for most patients but may range from 2 to 8 tablets daily. Dosage should be adjusted according to the response of the patient. Supply: Each round, ivory-coloured tablet contains, spironolactone. 25 mg and hydrochlorothiazide. 25 mg. Available in bottles of 100, 1,000 and 2.500 tablets. Complete prescribing information available on request. References 1. Cecil-Loeb, Textbook of Medicine, P. B. Beeson & W. McDermott, eds. W. B. Saunders, Philadelphia, 1971. 13th edition, pp. 1050-1062. 2. Mendlowitz. M.: "Systemic Arterial Hypertension Charles C. Thomas, Springfield, Illinois: (1974). 3, Hollander, W. and Wilkins, R. W.: Progr. Cardiovasc. Dis., 8: 291-318 (Jan.) 1966. 4, Gantt, C. H.: "Diuretic Therapy". Rational Drug Therapy 6. No. B (Aug.) 1972. 5, Dustan, H. P. in Page, I. H. (Moderatorand Editor): Dustan, H. P.: Freis, E. 0.: Stamler, J.. and Wilkins, R. W. (Discussants): Symposium of Hypertension, Mod, Med. 49: 74-113 (March 20) 1972. Copies of all clinical reprints available on request.
. Searle Pharmaceuticals Oakville, Ontario
be taking ampicillin, I ask the student to determine how long it will be before his stool flora become predominantly Kiebsiella (average, 3 days). This and similar exercises give him an appreciation of what he does to these helpful organisms when he prescribes broadspectrum antibiotics. After entering hospital a child becomes a carrier of penicillinase-producing staphylococci much later when given penicillin - even though the organism is penicillin-resistant - than when given tetracycline, according to Ehrenkranz and colleagues. There are many things antibiotics cannot do; for example, they cannot cure abscesses. Four years ago a 13year-old girl came to our hospital. Her illness had started with a high fever and a backache. Her doctor gave her penicillin and put her in hospital. The high fever and backache persisted, so he doubled the dose of penicillin and then quadrupled it. After 2 weeks she still had the high fever and backache so he decided to use one of the newer antibiotics - cephalothin. That didn't do much, so he doubled the dose and then quadrupled it. After a month in hospital she wasn't getting any better, so he sent her to us. Our chief resident palpated the lower part of her back; it was fluctuant. He aspirated about 150 ml of pus, which started her on her way to recovery. The pus from this deep-seated abscess grew staphylococci and tiny colonies of group A streptococci. By the Millipore filter technique we demonstrated a bactericidal concentration of the antibiotic against both organisms in the pus. Why, then, were we able to recover live organisms from it? Simply, the organisms survived in the low oxygen concentration inside the pus, and the pH of the pus was 5, a level at which penicillin and some other antibiotics do not work well. The doctor was expecting the antibiotic to work in an unfavourable environment. He apparently hadn't looked at her back; had he done so he would have discovered the abscess and tried to drain it (one reason for doing so is that the abscess wall is a barrier to the antibiotic). Many other clinical situations are similar to this such as an infection behind an obstruction or associated with a foreign body. I once saw a child who had had a shunt implanted for hydrocephalus. He had been doing well for 2 years and then suddenly signs of "leukemia" developed - generalized petechiae and enlargement of his liver and spleen. When he arrived at hospital the youngster had had a fever for some time. He was a happy little fellow. His temperature was 39.40C but he sat up in bed and talked, and
didn't seem very sick. Staphylococcus aureus was repeatedly cultured from blood samples. The referring doctor had given him penicillin, but despite intensive therapy he didn't get better. We then persuaded the neurosurgeon that infection in association with a foreign body required him to remove the foreign body. He wanted to order tremendous doses of penicillin in addition, but we finally convinced him not to. There wasn't any need: there was no evidence of toxicity and he had adequate defences against staphylococci once removal of the foreign body gave them a chance to work (he had the highest gamma globulin level I had ever seen). So the surgeon took the shunt out. The next day the temperature was somewhat lower; the blood culture was still positive. The 2nd day the temperature was normal; the blood culture was negative and remained so without penicillin. Another pitfall is that the organisms seem to change. You start off treating one and you wind up with another, especially in the urinary tract and in burns and other surface infections. The underlying truth in all this is that nature abhors a bacteriologic vacuum, and, with all your treatment, you can't maintain one. If you kill the predominant organism and the lesion is exposed to air another organism will take its place, probably one that is resistant to the drug you're using. The situation so produced may be much worse than the original infection because, in many instances, surfaces like mucosa and granulating wounds are colonized by relatively nonpathogenic bacteria; if you get rid of these benign organisms you lay the wound open to invasion by "true" pathogens that otherwise would have been excluded. In addition, we sometimes expect drugs to work where they are at a disadvantage. The pH inside an abscess is low and the pH of normal urine is about 6.5; and streptomycin, for example, is 20 times more effective at a pH of 8 than it is at one of 6.8. These are some of the considerations that underlie the general use of antibiotics. In my experience the least common reason for failure of therapy is that the organism you started to treat has become resistant to the antibiotic you are using. If it's on the surface it may be replaced by another organism - that's superinfection. But the development of antibiotic resistance in deep-seated infections, in my experience, is rare. I emphasize this to caution against changing drugs too readily. I once saw a 7-year-old boy with osteomyelitis who was being treated with erythromycin. The drug seemed to be effective: his temperature
CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
561
decreased and he felt much better. But on the 5th day he was sick again with a temperature of 400C. The orthopedic surgeon attributed this to resistance. So he changed the antibiotic. I came along soon after and found a red streak coming up from his intravenous needle - he had thrombophlebitis, not antibiotic resistance. My point is that if the patient doesn't do well, instead of first thinking about changing the antibiotic, look at the patient and see if there is some reason why he isn't getting better. In both outpatient and office practice, the most common reason children don't respond to an antibiotic in the way you expect them to is that the mother isn't giving the drug the way you want. A doctor has two jobs: first, to come to an agreement with the mother as to what is wrong with the child, and second, to come to an agreement with her as to what should be done about it. For example, a young child arrives in our emergency room at night with a temperature of 400C. His mother says he has an upset stomach. The resident looks in the child's ear and sees a red-hot bulging drum. He tells the mother that the child has otitis, prescribes an antibiotic and tells her to come back in 4 days. Thirty minutes later the same mother with the same child appears at the emergency room of another hospital. She tells them that she took her child to the university and the doctor over there didn't understand the situation because he didn't do anything about the child's upset stomach. The second doctor could take a little interest in the mother's concern and, after he has examined the infant, point out to her that although the baby has an upset stomach, this is caused by an infection - the abscess in the ear. He could assure her that if she gives him this medicine the child will feel much better quickly, but she is to continue the medicine so that the abscess will heal completely. This type of counselling takes longer but is much more effective.
Compliance Pediatrics' January issue had a good review of compliance. It described a shake mixture of ampicillin prescribed for children who had otitis media. A surprising number never did complete their course of medication, and only about two thirds of the families got the size of bottle of ampicillin from the pharmacy that was ordered. Furthermore, a large percentage of the bottles didn't have any shake labels on them and no one cautioned the mothers to keep the suspension in the refrigerator. In addition, many children spat
ALDOMET (methyldapa, MSD Std.)
Indications: Sustained moderate through severe hypertension. Dosage Summary: Start usually with 250 mg two or three times daily during the tirst 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. In the presence of impaired renal function smaller doses may be needed. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease and may be avoided by reducing the dose. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. Contraindications: Active hepatic disease such as acute hepatitis and active cirrhosis; known sensitivity to methyldopa; unsuitable in mild or labile hypertension responsive to mild sedation or thiazides alone; pheochromocytoma; pregnancy. Use cautiously if there is a history of liver disease or dysfunction. Precautions: Acquired hemolytic anemia has occurred rarely. Hemoglobin and/or hematocrit determinations should be performed when anemia is suspected. If anemia is present, determine if hemolysis is present. Discontinue methyldopa on evidence of hemolytic anemia. Prompt remission usually results on discontinuation alone or the initiation of adrenocortical steroids. Rarely, however, fatalities have occurred. A positive direct Coombs test has been reported in some patients on continued therapy with methyldopa, the exact mechanism and sigpificance of which is not established. Incidence has varied from 10 to 20%. If a positive test is to develop it usually does within 12 months following start of therapy. Reversal of positive test occurs within weeks to months after discontinuation of the drug. Prior knowledge of this reaction will aid in crosa matching blood for transfusion. This may result in incompatible minor cross match. If the indirect Coombs test is negative, transfusion with otherwise compatible blood may be carried out. If positive, advisability of transfusion should be determined by a hematologist or expert in transfusion problems. Reversible leukopenia with primary effect on granulocytes has been seen rarely. Rare cases of clinical agranulocytosis have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Occasionally fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur also, with onset usually within first 2 or 3 months of therapy. Rare cases of fatal hepatic necrosis have been reported. Liver biopsies in several patients with liver dysfunction showed a microscopic focal necrosis compatible with drug hypersensitivity. Determine liver function, leukocyte and differential blood counts at intervals during the first six to twelve weeks of therapy or whenever unexplained fever may occur. Discontinue if fever, abnormalitiesinliverfunctiontests, or jaundiceoccur. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on ALDOMET*. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. Hypertension occasionally noted after dialysis in patients treated with ALDOMET* may occur because the drug is removed by this procedure.
562 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
Rarely involu ntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, discontinue therapy. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. Methyldopa will not serve as a diagnostic test for pheochromocytoma. Usage in Pregnancy: Because clinical experience and follow-up studies in pregnancy have been limited, the use of methyldopa when pregnancy is present or suspected requires that the benefits of the drug be weighed against the possible hazards to the fetus. Adverse Reactions: Cardiovascular: Angina pectons may be aggravated; reduce dosage if symptoms of orthostatic hypotension occur; bradycardia occurs occasionally. Neurological: Symptoms associated with effective lowering of blood pressure occasionally seen include dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency. Sedation, usually transient, seen during initial therapy or when dose is increased. Similarly, headache, asthenia, or weakness may be noted as early, but transient symptoms. Rarely reported: paresthesias, parkinsonism, psychic disturbances including nightmares, reversible mild psychoses or depression, and a single case of bilateral Bells palsy. Gastrointestinal: Occasional reactions generally relieved by decrease in dosage: mild dryness of the mouth and gastrointestinal symptoms including distention, constipation, flatus, and diarrhea; rarely, nausea and vomiting. Hemafological: Positive direct Coombs test, acquired hemolytic anemia, leukopenia and rare cases of thrombocytopenia. Toxic and Allergic: Occasional drug related fever and abnormal liver function studies with jaundice and hepatocellular damage, (see PRECAUTIONS) and a rise in BUN. Rarely, skin rash, sore tongue or black tongue", pancreatitis and inflammation of the salivary glands. Endocrine and Metabolic: Rarely, breast enlargement, lactation, impotence, decreased libido; weight gain and edema which may be relieved by administering a thiazide diuretic. If edema progresses or signs of pulmonary congestion appear, discontinue drug. Miscellaneous: occasionally nasal stuffiness, mild arthralgia and myalgia; rarely, darkening of urine after voiding. Detailed information available on request. How Supplied: Tablets ALDOMET* are yellow, filmcoated, biconvex shaped tablets, supplied as f ollows: Ca 8737 - each tablet containing 125 mg of methyldopa, marked MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290 - each tablet containing 250 mg of methyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733 - each tablet containing 500 mg of methyldopa, marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293 - Injection ALDOMET* Ester hydrochloride, a clear colourless solution containing 250 mg methyldopate hydrochloride per 5 ml, supplied in 5 ml ampoules. (MC-949a)
C
ERCK I SHARP I & DOHME CANADA LIMITED/LIMIT.E
A Leader In Cardiovascular Medicine
out some of the medicine when the mother tried to give it, so that half the mothers decided the medicine was not agreeing with their children and stopped it. This does happen, and unless you take time to talk to a mother to get some ideas of how she looks upon the child's illness, she is going to stop the medicine as soon as the temperature decreases and the child feels better. To counteract these failures in compliance I wonder if we might try to teach students something about communication. For many years, when I have had a patient on the ward about to be discharged, I have tried to get to the medical student and say to him "Don't be there when the house staff talks to the mother. Make it a point to be around the corner, and after the house staff leaves go to her, all out of breath, and say 'I wanted to hear
what Dr. So-and-So had to say about your baby but I couldn't make it. What did he say? What did he say was wrong with your baby? What are you going to do?'" It's a great way to teach the student communication because for him it's the other guy who goofs. He is just checking up. It is a tremendous learning experience for a student when he realizes that otherwise-good doctors, whom he respects, can fail when they commit a basic human slip. In your own practice, your nurse or receptionist can get this kind of feedback. When the patient comes out she can ask "What did the doctor say was wrong with the baby? What did he tell you to do? How are you going to do that?" They could be trained to find out how mothers give medicines at home and in the process encourage them to do the right thing.
Antibiotics in the newborn By George H. McCraken, Jr., MD I will discuss the pharmacologic considerations underlying antimicrobial therapy, particularly dosage recommendations for antibiotics in common use in the newborn and the young infant. The selection of appropriate antimicrobial therapy in these young patients depends on a number of factors. The first is the historical experience in a nursery of organisms encountered. This information is important in guiding initial therapy before the pathogen has been identified. The second factor is the, antimicrobial susceptibility of common pathogens to routinely used drugs; that is, you would not use an antibiotic to which common pathogens, such as Escherichia coli, are resistant. Third, the physician who is managing patients must have some familiarity with the pharmacologic properties of an antimicrobial agent; that is, peak concentrations attainable in serum, cerebrospinal fluid (CSF) and urine and the relation between these peak values and the organism's susceptibility (minimal inhibitory concentration [MId). Surveillance data collected in Dallas from August 1963 to August 1974 showed that E. coli isolated from neonates became resistant to kanamycin after extensive use over 6 or 7 years. This resistance, first observed in 1968, persisted for 3 years in the face of continued use of the drug. In January 1971 we stopped routinely using kanamycin, and for the next 3 years used gentamicin in our neonatal units. In 1971 the in vitro effectiveness of kanamycin declined even further (70% of strains were resistant) and then slowly
returned to its original level; now about 90% of E. ccli strains are susceptible to 10 ,.g/ml of kanamycin or less. Thus, during the period of limited use the drug's effectiveness returned, and when kanamycin was reintroduced into our nurseries in January 1974 the susceptibility of E. coli did not change. This is what would have been expected. During the 3-year period we had eliminated resistant clones or strains of E. ccli, so when kanamycin was reintroduced there was no selective pressure for the rapid emergence of resistant strains. These data suggest that alternating antibiotics on an annual or biannual basis to prevent the emergence of resistance may avoid the necessity of using newer and potentially more toxic drugs that we have not had adequate time to test in the laboratory and in clinical trials. Our experience is not peculiar to Dallas. We have looked at similar surveillance data over a 3- to 6-year period at the University of Utah in Salt Lake City, and we have data from Winnipeg and Montreal as well as from 17 other centres in North, Central and South America. These studies show that most E. ccli strains isolated from neonates are susceptible to kanamycin. These data demonstrate the importance of antimicrobial surveillance studies not only in the local institution but on a regional and national basis. The pharmacokinetic properties of antibiotics in newborn and young infants did not receive adequate attention until about a decade ago. Consequently, our young patients were exposed
564 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
The modifier of digestive behaviour
Classification:MAXERAN5 (metoclopramide monohyd rochloride) is a modifier of upper gastrointestinal tract motility. Indications: Sub-acute gastritis, chronic gastritis, gastriG sequellae of surgical procedures such as vagotomy and pyloroplasty. Under these conditions, when gastric emptying is delayed, Maxeran may relieve such symptoms as nausea, vomiting, epigastric distress, bloating, etc. Small bowel intubat,on: Maxeran may facilitate ano accelerate small bowel intubation.
Side-effects: Drowsiness and, more rarely, insomnia,
fatigue, headaches, dizziness and bowel disturbances have been reported. Parkinsonism and other extra-pyramidal syndromes have been reported infrequently. An increase in the frequency and severity of seizures has been reported in conjunction with the administration of Maxeran to epileptic patients.
Precautions: Drugs with atropine-like action should not be used simultaneously with Maxeran since they have a tendency to antagonize effect of this drug on gastrointestinal motility. Maxeran should not be used in conjunction with potent ganglioplegic or neuroleptic drugs since potentiation of effects might occur. Maxeran should not be used in patients with epilepsy and extrapyramidal syndromes, unless its expected benefits outweigh the risk of aggravating these symptoms. In view of the risk of extrapyramidal manifestations, metoclopramide should not be used in children unless a clear indication has been established. The recommended dosage of Maxeran should not be exceeded since a further increase in dosage will not produce a corresponding increase in the clinical response. The dosage recommended for children should not be exceeded. Contraindications: Maxeran should not be administered to patients in combination with MAO inhibitors, tricyclic antidepressants, sympathomimetics and foods with high tyramine content, since safety of such an association has not yet been established. As a safety measure, a twoweek period should elapse between using Maxeran and administration of any of these drugs. The safety of use of Maxeran in pregnancy has not been established. Therefore Maxeran should not be used in pregnant women, unless in the opinion of the physician the expected benefits to the patient outweigh the potential risks to the fetus. Dosage and administration:
For delayed gastric emptying Adults Tablets: Liquid: Injectable:
Children: Liquid:
/2 to 1 tablet (5 - 10 mg) three or four times a day before meals. 5 - 10 ml (5 - 10 mg) three or four times a day before meals. When parenteral administration is required, 1 ampoule (10 mg) IM. or IV. (slowly) to be repeated 2 or 3 times a day if necessary. (5 to 14 years): 2.5 to 5 ml (2.5 - 5 mg)
For small bowel intubation: Adults:
Children:
One ampoule (10 mg) IV. - 15 minutes before intubation. Other routes (oral or IM.) may be used but with a greater period of latency. (5 to 14 years):
2.5 to 5 ml (2.5 - 5 mg) Availability: Tablets:
Liquid:
Injectable:
Each white scored compressed tablet contains 10 mg of Metoclopramide Monohydrochloride. Bottles of 50 & 500 tablets. Each ml contains 1 mg of Metoclopramide Monohydrochloride. Available in bottles of 110 ml and 450 ml. Each 2 ml ampoule contains 10 mg of Metoclopramide Monohydrochloride in a clear colourless solution. Keep away from light and heat. Available in boxes of 5 and 50 ampoules. Product monograph available upon request.
rT. fl . HARMACEUTIQUES LT.E tOi II HARMACEUTICALS LTD L.IJ . .II. i..' U LavalQue. Canada.
