ANTIMICROBIAL AGENTS Summary of a Round Table Discussion

By Mark H. Lepper, M.D., and Harris D. Riley, Jr., M.D. Department of Preventive , University of Illinois (M.H.L.), and Department of Pediatrics, University of Oklahoma (H.D.R.)

NTIMKROBIAL agents have had an espe- sistance of the host to . (The effect cially great impact in pediatrics. Al- of cortisone on stneptococcal in though many diseases have been conquered the rabbit was cited : 58 out of 66 rabbits easily with proper antimicrobial therapy, pnetreated with cortisone died; 5 of 60 con- there still remain difficulties and failures. trol animals died.) Instances of empyema Dr. Leppen opened the session with a dis- developing during treatment of pneuimo- cussion of some of the failures of antimi- coccal pneumonia with both antibiotics and crobial therapy. ACTH were described. The discussants agreed that at no time should adrenal con- HYPERACUTE INFECTIONS ticosteroids be used in the treatment of in- Hyperacute infections, i.e., infections fectious processes without simultaneoums ad- which are often fatal within 24 hours from ministration of adequate amounts of appro- the onset of symptoms, and resistant strains pniate antibiotics. of organisms, account for the vast majority Dr. Lepper reviewed some of the salient of failures in the use of antibiotics. A few facts in connection with the use of cortisone cases cannot be classified into either cate- and allied substances in the treatment of gory and remain as unexplained failures. overwhelming infections, including menin- The magnitude of the problem of hypen- gococcemia and the Waterhouse-Fnidenich- acute infections can be judged by the fact sen syndrome. In the period before conti- that in a contagious disease hospital about sone was readily available, it was used in a third of the fatalities from nontubercu- half of all such patients who died (death bus, bacterial infectious diseases occur rate, 5%). With the liberal umse of cortisone within the first 24 hours from the onset of between 1952 and 1954, there was no dem- symptoms. Meningitis due to meningococ- onstrable change in the death rate from cus on pneumococcus, or meningococcemia, overwhelming infections. Then, because of are most commonly encountered in this the danger of superimposed infection, the group. In Dr. Lepper’s experience, those use of cortisone was restricted-again with- patients who will die within 24 hours from out a change in the death rate. For the pa- onset of symptoms can be predicted early tients treated with cortisone, the death from clinical observations, and they com- rates in these three periods were: 100, 81 mand “heroic therapy.” and 100%, respectively. A lively discussion of the use of adrenal In an effort to elucidate more subtle dif- corticosteroids as pant of “heroic therapy” ferences which might occur from the use in hyperacute infections ensued. Dr. Riley of cortisone, Dr. Lepper conducted con- pointed out that they are useful agents but trolled studies with four types of meningi- have serious side effects and definite haz- tis : Hemophilus influienzal, meningococcal, ards. They are known to decrease the re- pneumococcal, and tuberculous. In 57 pa-

Presented at the Annual Meeting of the American Academy of Pediatrics, October 20, 1958. Summary prepared by Margaret Lyman, M.D. ADDRESS: (M.H.L.) Department of Preventive Medicine, University of Illinois, 840 S. Wood Street, Chicago 12, Illinois. PEDIATRICS, June 1959 1192

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tients with H. influenzae meningitis, 28 re- DR. LEPPER: This has not been demon- ceived cortisone, 29 did not. Tile only dif- strated. I do not believe cortisone is mdi- ference noted was a significantly greater Cate(1 routinely in the treatment of tiliS ds- imlcidence of sui)dumral effusions in those Pa- ease. tients who received cortisone. From this it Q UESTION: What is the mechanism of ac- was concluded that cortisone is not imidi- tion of steroids in infections? cated as an adjumnct in the treatment of H. DR. LEPPER: The fundamental action is influenzae meningitis. Of 56 patients with not known, but they suppress the inflam- meningococcal meningitis, half received matory response which is one mechanism cortisone (7 patients with Waterhouse-Fnid- of defense. With long-term use of steroids, enichsen syndrome were excluded from this there will usually be a decrease in the pa- group) and half did not. No significant tient’s antibody titer. difference could be detected in the two Q UESTION: With the decrease in antibody groups. In the patients with Waterhouse- titer, will there be an increase in the rate Fnidenichsen syndrome, all received sten- of recurrence of infections? oids; the mortality rate was comparable to DR. LEPPER: In our series, there was no that given in the literature. Dr. Lepper statistically significant difference in tile re- noted that none of these patients had evi- currence rate; however, cortisone was not dence of adrenal insufficiency after re- used for long enough periods of time to covery. In the group with pneuimococcal demonstrate reduced antibody titers. meningits, 14 patients received steroids, Q UESTION: What dosages of steroids were 14 did not. There was one death in each used? group; the value of steroids was not estab- DR. LEPPER: Hydnocortisone, 2.5 mg/kg lished for this disease. Similarly in tuber- intravenously, for 5 days. Decreasing doses culous meningitis, it was difficult to estab- were then used for 3 days, and ACTH was lish definite value for the use of the sten- given intramuscularly for 2 days prior to oids. cessation of all steroid therapy. The requiirement of large nummbers of Q UESTION: The New England Journal of cases of any given disease to demonstrate Medicine (258:639, March 27, 1958) ne- small differences was stressed. A current cently reported a series of patients with study in five centers, using double-blind meningococcemia treated with steroids and technique, may prove helpful. The group concluded that there was no good reason was cautioned against generalizing from for their use in this disease. What is your one infection to another, or from one form comment on this report? of tubenculous infection to another. They DR. LEPPER: I am inclined to agree with were urged to avoid the routine use of the authors; however, considerable pres- adrenal steroids in serious infections; to se- sure will be brought to bean to use the lect the patients who are to receive sten- steroids in this disease because of its high oids carefully; and to avoid the rationali- fatality rate. I believe at present that cniti- zations of “maybe I can get away with it” cism will be greater if it is not used than and “it doesn’t seem to do any harm.” if it is. The present literature does not

Q UESTION: Has the use of adrenal ster- contain satisfactory evidence for not using oids in acute laryngotracheobronchitis low- steroids in meningococcemia. ered the incidence of tracheotomy? RESISTANT ORGANISMS DR. LEPPER: To my knowledge, there is no study available with sufficient numbers The second factor responsible for failures of patients upon which to base an opinion. in antibiotic therapy, strains of organisms Q UESTION: Is there more likelihood of re- resistant to available agents, was discussed current laryngotnacheobnonchitis when con- primarily by Dr. Harris Riley. Some or- tisone is used? ganisms are naturally resistant and some,

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while predominantly sensitive, may develop growth of resistant organisms. Or, supenim- resistance. The premature or young infant, posed infection may occumn from exogenoums the extremely old patient, or some under- spread, such as may be produmced by im- lying serious disease predisposing to infec- proper catheterization during the diagnosis tion, share, in common, characteristics of of urinary tract disease. A genuine super- the host which favor infections by resistant imposed infection was not noted by Dr. strains of organisms. Some antimicrobial Lepper in a series of nine patients with in- agents eradicate sensitive strains, allowing dwelling catheters when multiple cultures resistant ones to grow; thus treatment itself were obtained before treatment was started. may produce resistant strains. Dr. Leppen Thus, in these nine patients, all had mixed illustrated this with a brief discussion of the infections which could be misinterpreted as staphylococcus : The per cent of all staphy- superimposed infections. He concludes that lococci resistant to erythromycin rose rap- probably infections of the genito-urimlary idly soon after it became widely used, while tract have a mixture of organisms at the on- the pen cent resistant to penicillin slowly set of therapy more often than is commonly decreased. However, when erythromycin appreciated. Thus, it is essential to treat the was used less abundantly, there was a rapid patient, not the bacteria, for the patient decline in the per cent of resistant strains may well tolerate one organism better than at first, and then the per cent resistant, just another which may emerge as the resuilt of as with penicillin, has declined much more therapy. slowly. The “back-mutation” rate varies Q UESTION : How much reliance do you! with different antibiotics but it would prob- place on laboratory determination of sensi- ably take many years for staphylococci to tivity of various organisms to different anti- become sensitive to most antibiotics once biotics? again if their use were discontinued. DR. LEPPER: There are many variables in Considerable variation in the degree of the determination of resistance and sensi- resistance of staphylococci will be found in tivity. The present disc method is highly different hospitals and in different commu- variable but efforts are being made to nities. In Oklahoma City, for example, most standardize it. However, it will always be of the strains are still sensitive to erythro- only an approximation. Species identifica- mycin. It seems clearly related to the use tion is more important than testing for sen- of particular antibiotics-those communi- sitivity or resistance. Occasionally, an anti- ties and hospitals in which erythnomycin biotic will be effective despite the labora- enjoys popular use will have predominantly tory statement of “resistant.” Bacteriology strains of staphylococci resistant to enyth- may be able to tell you what to use, buit romycin. never when to use it. Clinical judgment re- mains the important factor in the proper SUPERIMPOSED INFECTIONS selection of antibiotic therapy. What appears to be a second infection NEW ANTIMICROBIAL AGENTS arising in association with antibiotic treat- ment is sometimes in reality a mixed infec- Amphotericin (Fungizone#{174}_Squibb) tion in which two organisms were present Amphotenicin, a member of the nystatin initially, but only one was recognized in family, is the first real breakthrough in the pre-treatment cultures; the other is free to treatment of systemic mycotic infections, grow. True superimposed infections may according to Dr. Lepper. It has limited use- come about as the result of autogenous fulness because of the necessity for intra- spread; for example, infection in the kidney venous administration; this could prove to may be cured but a new, resistant organism be an advantage by delaying the emergence may spread from the gastrointestinal tract, of resistant organisms so frequently seen where antibiotic treatment favors the when an antibiotic is abundantly uised.

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However, there is no docummentation of the ous staphylococcal infections resistant to development on spread of strains resistant other antibiotics. However, complete cross- to amphotenicin as yet. Amphotenicin is resistance is noted with neomycin; i.e., or- utseful in cutaneoums and systemic candidia- ganisms resistant to neomycin will also be sis, histoplasmosis and cryptococcosis when resistant to kanamycin. In Dr. Riley’s opin- given intravenously, and will eradicate Can- ion, kanamycmn has a greater margin of dida albicans from the stool when given safety than neomycin and it should prob- orally. The dosage recommended for in- ably replace neomycin. The use of a topical travenous use is 0.25 mg/kg/24 hours, in- preparation of kanamycin will considerably creasing to 1 to 1.5 mg/kg/24 hours as die- enhance the emergence of resistant strains, tated by the severity of the infection. It is as has been the case with neomycin, and is usually possible to administer it for only 1 to he decried. Kanamycin and neomycin month to 6 weeks because of the technical may be used in preoperative preparation of problem of administration. The most re- the gastrointestinal tract; there is vmntumally cent preparations have not seemed to pro- no absorption of the drugs when taken duice renal complications as were noted orally, but this is not recommended because with the earlier, presumably less pure, of the development of resistant strains. forms. Q uestion: Is there an aerosol form? Dr. Riley: Yes. It has been used in bron- Kanamycin (Kantrex#{174}BristoI) chiectasis and cystic fibrosis of the pancreas Dr. Riley pointed out that kanamycin is with results similar to those obtained with similar in its properties and action to neo- neomycin. mycin and streptomycin. It has the same Q uestion: Is kanamycmn effective orally in general range of effectiveness against gram- E. coli entenitis and is it preferable to neo- negative rods; and it has some anti-staphy- mycin? lococcal activity which is particularly im- Dr. Riley: I have had no experience with pontant in those strains resistant to other oral administration in diarrhea due to path- antibiotics. In general, it is not effective ogenic E. coli, but parenteral administration against pseudomonas, pertussis, tularemia, has been effective in several cases. Because streptococcus; effectiveness is equivocal in of fewer toxic effects it is preferred to pa- typhoid fever and salmonella infections. renteral neomycin. The preparation is available for intra- Ristocetin (Spontin#{174}.Abbott) muscular . Pain is noted at the site of injection, and abscesses have been noted Ristocetin is available for intravenous umse to develop. The dosage suggested is 25 only and is effective against staphylococci mg/kg/day for less serious infections; 50 and enterococci. There is no good evidence mg/kg/day in 2 doses is the usual quantity that adequate blood levels are obtained administered. For severe infections, 100 from its use intramuscularly. It is some- mg/kg/day for the first day or two days what more toxic than another new anti- of treatment may be given, then decreasing biotic, vancomycin. Ristocetin has produced to the lower quantities subsequently. thrombocytopenia and leukopenia in 5% of Toxicity may be noted in the form of patients treated, as well as deafness with deafness, as with streptomycin, and renal prolonged administration. In Dr. Lepper’s complications : casts, albumin and elevation experience, no strains of staphylococci have of the blood urea nitrogen. Toxic effects been found to develop resistance to this will probably not occur if the dose of 50 dnumg. However, experience with the use of mg/kg/day for 10 days is not exceeded. this agent is still limited. Abnormalities in the urine disappear com- Vancomycin (Lilly) pletely upon discontinuation of the drug. Dr. Riley described good results in seni- Vancomycin will soon be available com-

Downloaded from www.aappublications.org/news by guest on September 26, 2021 1196 ANTIMICROBIAL AGENTS other preparations of sulfonamides lies in mercially, also only in a form for intra- venous use. It appears to be effective the fewer number of daily doses required. against all staphylococci. Because of the COMBINATIONS OF ANTIBIOTICS high incidence of venous thrombosis and phlebitis, it should be reserved for the more A number of attributes, desirable and un- serious staphylococcal or entenococcal in- desirable, have been ascribed to combina- fections such as subacute bacterial endo- tions of antibiotics, two or more agents carditis. Hearing impairment may be en- used either separately but simultaneously, countered with prolonged uise. Improved on in fixed proportions. Dr. Lepper dis- refining is expected to decrease the mci- cussed the pros and cons in a frank and dence of toxic manifestations. Vancomycin helpful manner. has had insufficient use to make valid com- It has been held that combinations of panisons with nistocetin as to relative effec- antibiotics delay the development of re- tiveness butt at present is believed to be a sistant organisms. This has been cleanly safer agent. demonstrated in the treatment of cavitary tubencumlosis with streptomycin and iso- Sulfamethoxypyridazine (Kynex#{174} niazid. It has not yet been conclusively Lederle) shown that this is true for staphylococcal This drug may be compared in its activity infections using combinations of , and usefulness to other preparations of erythromycmn and chlonamphenicol (any sulfonamides. No organisms resistant to sul- two of the three). Dr. Lepper reported 22 fonamides will be sensitive to suffamethoxy- cases of staphylococcal septicemia success- pynidazine. However, it differs in the rate of fully treated in this manner without the excretion and therefore high, prolonged development of resistant strains. concentrations in the blood may be ob- The use of two agents favors the over- tamed with single doses. The drug must be growth of doubly resistant organisms in the used correctly to avoid undesirable compli- normal flora of the respiratory, urinary and cations. The dosage recommended is as fol- gastrointestinal tracts and increases the in- lows : 40 to 50 mg/kg/day is given orally cidence of doubly resistant organisms in the in one or two doses for the first 3 or 4 days environment. of therapy; thereafter, the dose is decreased The case for increased effectiveness of to 25 or 30 mg/kg/day for the remainder combinations of antibiotics is less well sub- of the course. The prolonged levels-as long stantiated. Combinations of bacteniostatic as a week after the last dose, some of the and bactericidal agents are potentially an- drug may be detected in the blood-make tagonistic, but this is probably a limited the treatment of toxic manifestations a phenomenon in vivo. To demonstrate true problem. Toxicity would be expected to be antagonism, it is necessary to give the bac- comparable to that observed with other tenicidal agent in less than adequate dose preparations of sulfonamides. and the bacteniostatic agent first. However,

Dr. Lepper cautioned that the use of sul- it remains more desirable to umse two bac- famethoxypynidazine in the prophylaxis of tenicidal or two bacteniostatic agemlts if com- nileumatic fever has not received sufficient binations are to be used. study to recommend a change from the Synergy, i.e., enhanced activity beyond a present penicillin regimen. Studies using simple additive effect, is often claimed for

30 mg/kg once a week are being made; two particular agents butt is probably by some of the drumg has been detected in the and large a myth. In the treatment of seri- blood at the end of the week at this dosage ous and difficult infections, some additional in 80% of patients. antibacterial activity may be obtained with The chief advantage of this drug oven two or more drugs, but only if each drug

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is given in the maximum tolerated dose. continuous concentration. I am a “continu- Commercially-available combinations of ous level” man. Concentrations of antibi- antibiotics have the major disadvantage of otics beyond the level required to kill the fixed proportions, making it impossible to bacteria have not been shown to be of any alter the dose of one agent without alter- advantage unless there is a particular prob- ing the dose of the other. Combiotic#{174} is a lem of penetration into the tissues. classic example: it contains a relatively ex- Q uEsTmoN: What do you use in treating cessive amount of streptomycin, especially phanyngitis and otitis media when bac- for adumlts with infections for which a com- teniologic studies are not available? l)ination of penicillin and streptomycin may DR. LEPPER: Our studies show that peni- i)e indicated. The indiscniminant use of this cillin will be effective in all but about 2-4% combination of agents has severely jeop- of cases; therapy will have to be changed in ar(lized the effectiveness of streptomycin that per cent because of resistant staphylo- i)ecaumse of the continuted favoring of spread cocci or H. influenzae. Tetracycline and of resistant organisms. Dr. Lepper stated erythromycmn will each be effective in all tilat, in his opinion, there is no rationale but about 3%, the staphylococci again being whatsoever for the use of some combinations the reason one will have to change to an- with fixed ratios in single-dose forms, such other agent. Resistant staphylococci are

as tetracycline and oleandomycin ( Signe- somewhat more frequent with these drugs mycin#{174}). Dr. Riley suggested that, when than with penicillin. The sulfonamides have two antimicrobial agents are to be used not been as effective, in my experience, simultaneously, it is preferable to give ade- against the streptococci as have antibiotics. qumate amounts of each drug rather than to Sulfonamides will keep streptococci away rely on a fixed, commercially-prepaned com- in rheumatic fever prophylaxis but they are i)ination of the two drugs. not as good at getting rid of them once in- The use of two or more antibiotics is in- fections starts. (heated in tumbercumlosis (isoniazid and strep- DR. RILEY I am reluctant to use penicillin tomiiycin), brucellosis (tetracycline and strep- alone in the treatment of acute suppurative tomycin), and subacute bacterial endocandi- otitis because of the high incidence of H. tis (penicillin and streptomycin). Dr. Leppen influenzae as the causative organism.

does not employ two on more antibiotics in Q UESTION: What do you recommend for the treatment of meningitis (chlorampheni- prophylaxis of rheumatic fever? col on tetracycline for gram-negative rods, DR. LEPPER: I believe the American Heart penicillin for gram-positive organisms, any Association’s recommendation of oral peni- of these agents for meningococci). cillin, 250,000 units twice daily, is at present The umse of two on more antibiotics simul- the preferred method. tamleoumsiy is not indicated for routine treat- DR. RILEY : The use of benzathine peni- nlent of most infectioums processes or for sys- cillin intramuscuilarly at monthly intervals temic prophylaxis. Nor is is indicated in the was much more economical, was quite effec- treatment of stable tllough incumrable situa- tive, and the only disadvantage was the tiomis such as cystic fibrosis of the pancreas discomfort associated with the injection. ‘hen tile patient is doing moderately well. Q UESTION: Are there significant differ- Q UESTION: Would you comment on the ences among the oral penicillin prepara- relation between blood levels and therapeu- tions? tic effect? DR. LEPPER: Oral penicillin V is better DR. LEPPER: Tile answer will depend than penicillin G; potassium penicillin V 111)011 %vlletiler one holds that “peaks and provides a higher 1-hour concentration in valleys” in tile concentration of antibiotic the blood than other forms, but a somewhat in tile blood are more desirable than a lower concentration at 3 hours. Therefore,

Downloaded from www.aappublications.org/news by guest on September 26, 2021 1198 ANTIMICROBIAL AGENTS it has no advantage and perhaps is some- erythromycin in all affected patients until what inferior. May I caution the group not the epidemiology, and sensitivity of the to rely upon oral penicillin in the treatment organisms, can be determined. Then appro- of acute illness. The danger of vomiting is pniate changes in therapy may be made as always present and also 5 to 10% of patients indicated. will not obtain adequate concentrations in DR. RiLEY: I think scrupulous asepsis and the blood with the doses usually employed. education of all personnel associated with And there is no way of knowing which of the infants are of the greatest importance. your patients will be in that group. Q UESTION: Do you use continuouts or in-

Q UESTION: How long do you continue termittent antibiotic therapy in tile milder antibiotic therapy in the usual infections? cases of cystic fibrosis of the pancreas? DR. RILEY: If the antibiotic is indicated at DR. LEPPER: In limited experience, I have all, it must be continued at least 4 days noted no difference in the clinical coumrse after a satisfactory clinical response has with either regimen. Empirically I vouild been obtained, as judged by subsidence of prefer intermittent therapy. tile inflammatory process, and general well- DR. RILEY: We are using in most of the being of the child, not just by the return of patients with cystic fibrosis of the pan- the temperature to normal. creas continuous antibiotic therapy, but use Q UESTIONS How do you manage outbreaks a schedule of rotation of agents. of staphylococcal infections in a newborn Q UESTION: What is your opinion of the use nursery? of gamma-globulin to potentiate the effec- DR. LEPPER: Antibiotics should be used tiveness of antibiotics? only as a stop-gap and must not replace DR. LEPPER: I have not ilad experience proper epidemiologic study and appropriate with it but I do know the clinical reports control measures. I recommend the use of are not statistically valid.

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1959 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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