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Practical Application of Newer Antibiotics
Practical Application of Newer Antibiotics From the Department of Medicine, Ohio State University College of Medicine, and the University Hospital, Columbus.
SAMUEL SASLAW, M.D., PH.D., F.A.C.P. Professor of Medicine and Bacteriology, Ohio State University; Director of Division of Infectious Diseases.
DURING the second decade of the antibiotic era, the increasing number of new agents or modifications of "older" drugs has created additional problems for the practicing physician. The temptation to substitute a new drug for an older drug is great. Often, this occurs before extensive controlled critical evaluations have been made, and the late realization may come that some patients not only did not benefit from the prescribed therapy, but may have suffered unnecessary untoward side reactions. Certain fundamental principles apply to the treatment of infectious diseases regardless of the type of antimicrobial agent employed. These include first of all establishing the necessity for an antimicrobial agent, and then selecting the proper drug in adequate dosage for a sufficient duration of time. Proper application is based on good clinical judgment and understanding the pathogenesis of a disease, two attributes of the physician which obviate juggling and changing of antimicrobial agents because a patient is still symptomatic or febrile when he should be expected to be so with his particular disease process. It is not the purpose of this paper to cover the whole area of antibiotics and antibiotic therapy but to discuss the newer antibiotics which have appeared in the past five years.
NEW PENICILLINS
In recent years many different biosynthetic or synthetic penicillin preparations have appeared on the market. The variety of claims and counterclaims has been somewhat confusing to the practicing physician.2. 4. 5. 6. 9. 14 839
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Phenoxymethyl penicillin or penicillin V (Pen-Vee, V-Cillin) and potassium phenoxymethyl penicillin or potassium penicillin V (Compocillin-VK, Pen-Vee K, V-Cillin K) have similar actions and uses. This type of preparation, because of its stability in acid environments and ready absorption from the gastrointestinal tract, is admirably suited for oral administration. The antibacterial spectrum is similar to that of penicillin G, but unless administered in larger doses penicillin V is not as effective as parenterally injected aqueous preparations of penicillin G, which is preferred in severe acute infections. Dosage for moderately severe infections such as streptococcal or susceptible staphylococcal infections is 200,000 units four times a day. For pneumonias 400,000 to 600,000 units as an initial dose is followed by 400,000 to 600,000 units every four hours. For rheumatic fever prophylaxis 200,000 to 400,000 units are administered daily. As with other penicillins, varying degrees of sensitivity reactions can occur, but they have been relatively infrequent. Cross sensitivity to penicillin G may occur. Diarrhea may occur, as with all orally administered antibiotics. Phenoxyethyl penicillin (phenethicillin) has been marketed under the trade names of Alpen, Broxil, Chemipen, Darcil, Dramacillin S, Maxipen and Syncillin. Earlier claims that this product elicits no sensitivity reactions in penicillin-sensitive patients and produces higher serum levels and greater antibacterial activity, especially to staphylococci resistant to other penicillins, have not been borne out. This product, like penicillin V, is resistant to stomach acid, but its absorption is considerably reduced when it is taken with or shortly after food. In this respect it is inferior to penicillin V, which is not affected by meals. Likewise, early claims that orally administered phenethicillin was superior to intramuscularly injected penicillin G have not been substantiated. Dosage and indications are similar as for penicillin V except that this drug should be given half an hour before or two hours after meals. Staphcillin (Bristol) and Celbenin (Beecham) are the trade names of a recent synthetic penicillin, 6-(2,6 dimethoxybenzamide) penicillinate monohydrate. These preparations show considerable promise in the treatment of staphylococcal infections resistant to other antibiotics by virtue of the fact that they are not appreciably inactivated by penicillinase. 1 , 6,15 However, they have a narrow range of effectiveness and less antibacterial activity against penicillin-sensitive staphylococci or other organisms than the "ordinary" penicillins. Staphcillin should be reserved, therefore, for the treatment of resistant staphylococcal soft tissue infections, boils, abscesses, infected burns, osteomyelitis, pneumonia, lung abscesses, empyema, septicemia, endocarditis, pyelonephritis and staphylococcal arthritis. This drug is unstable in acid media; it is therefore unsuitable for oral administration and must be given intravenously or intramuscularly in doses of 1 to 2 grams every four to six hours. In children the dose is 100 mg. per kg. per day in divided doses.
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To date no serious toxicity has been observed, although fever and skin rashes have been occasionally encountered. In short-term in vitro studies and clinical trials, staphylococci have not acquired significant resistance. Further experience is needed to see wh()ther such a promising situation will exist in the future. At the present time it appears that Staphcillin is the treatment of choice in staphylococcal infections resistant to other more commonly used antibiotics. TETRACYCLINES
Considerable interest has been centered in recent years on modifications of the tetracyclines, of which the prototypes were Aureomycin (chlortetracycline) and Terramycin (oxytetracycline) . Various preparations with claimed enhancement of blood levels have been marketed, but there has been no proof to date that certain drugs offer any improvement over plain tetracycline (Achromycin, Panmycin, Polycycline, Tetracyn).3, 7,13 Thus there seems to be no therapeutic advantage to be gained with the following types of preparations: (1) tetracycline phosphate complex (Comycin, Panmycin Phosphate, Sumycin, Tetrex), (2) tetracycline hydrochloride with citric acid (Achromycin V), (3) tetracycline hydrochloride with glucosamine hydrochloride (CosaTetracyn). On the other hand, studies with demethylchlortetracycline (Declomycin) 8, 11, 12 have shown that this drug has a very high degree of resistance to acid or alkali. It is more slowly excreted than the other tetracyclines and thus appears to sustain blood levels longer. On the basis of these properties an equivalent therapeutic effect may be anticipated from a smaller dose than with tetracycline. Declomycin has the same spectrum and application as all tetracyclines. For moderately severe infections 150 mg. every six hours is given. In our experience, severe infections require 300 mg. every six hours. The usual side reactions which may be observed with any of the tetracyclines such as diarrhea, nausea, skin eruptions and fever can occur in certain patients. One disturbing reaction peculiar to Declomycin is phototoxicity to sunlight. Persons who develop phototoxicity may experience severe sunburn in a short while. Discontinuation of the drug removes further sensitivity to sunlight. Regardless of which present-day tetracycline preparation is selected, it should be remembered that all have a similar antibacterial and antirickettsial spectrum and also show complete cross resistance. OLEANDOMYCIN
Oleandomycin (Matromycin) exhibits in vitro antimicrobial activity against gram-positive organisms such as streptococci, pneumococci and
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staphylococci and certain gram-negative organisms such as Hemophilus influenzae, meningococci and gonococci, rickettsii and large viruses. In all respects it is similar to but inferior to erythromycin. There is a high incidence of cross resistance between erythromycin and oleandomycin so that therapy with oleandomycin in an erythromycin-resistant infection is often valueless. Thus in staphylococcal infections erythromycin would be preferred if the organism is sensitive to both agents. Against the other gram-positive infections penicillin, erythromycin or tetracyclines are preferable. This antibiotic is frequently included in fixed combinations with tetracyclines which are not desirable for optimum results. The usual adult dose is 250 to 500 mg. orally every six hours. TRIACETYLOLEANDOMYCIN
Some of the objections to oleandomycin have been overcome by triacetyloleandomycin (Cyclamycin, Tao) which is the triacetyl ester of oleandomycin. The same basic spectrum of organisms is susceptible as with oleandomycin. However, this ester is more rapidly absorbed after oral dosage and consequently achieves higher levels. This type of preparation parallels erythromycin in effect more closely than oleandomycin. lo The cross-reactivity of the two types of agents still requires more analysis. Triacetyloleandomycin is certainly to be preferred and recommended over plain oleandomycin. Dosage is 250 to 500 mg. orally every six hours. In children the usual dose is 30 mg. per kg. per day divided into four to six doses. Side reactions include skin rashes, nausea, diarrhea and fever. NOVOBIOCIN
Novobiocin (Albamycin, Cathomycin) is an antibiotic whose clinical usefulness is primarily in the treatment of staphylococcal infections. Because of the ease with which resistance develops to this agent and because of its side effects it should be reserved for use when there is resistance to other more commonly used antibiotics. It is advisable to use this agent in combination with another antibiotic to which the staphylococcus is sensitive to decrease the incidence of the development of resistant strains. Because novobiocin has a high degree of binding to serum protein, which limits its in vivo activity, it has been our experience that oral doses of at least 500 mg. every six hours should be given. This in turn increases the incidence of allergic skin or fever reactions. In children the dosage varies from 15 to 45 mg. per kg. On occasions it may be necessary to give the drug parenterally. The intramuscular route causes pain and irritation at the injection site and is not recommended. For intravenous use, a freshly prepared solution of 500
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mg. in 5 ml. of water is mixed with 30 ml. of saline and injected slowly every 12 hours over a five- to ten-minute period to avoid thrombophlebitis. Instead the drug may be dissolved in 1 liter of saline, Ringer's or Darrow's solution and infused slowly. In children the dose should be about 15 mg. per kg. in two divided doses. Preparations containing novobiocin in fixed combinations with tetracycline or with penicillin are not acceptable in our practice. It certainly is preferable to adjust the dose of each drug independently of the other when treating a patient in whom combination therapy is desired. Novobiocin also inhibits proteus species in vitro, but ill our experience resistance develops rapidly in proteus infections, particularly in urinary tract infections. Again, as with staphylococcal infections, it should he used with another effective agent rather than alone. RISTOCETIN
The main application of ristocetin (Spontin) is in the treatment of systemic staphylococcal or enterococcal infections resistant to the more commonly used antibiotics. Although it is active against other grampositive cocci, Actinomyces bovis and the tubercle bacillus, there are better and less toxic agents. Spontin is not absorbed from the gastrointestinal tract and therefore should be administered intravenously in doses of 50 mg. per kg. divided into two 12-hour doses. It should be injected slowly (30 to 45 minutes) with the required dose dissolved in 100 to 150 ml. of 5 per cent dextrose in water or by giving not more than 1 gram in 40 ml. of 5 per cent dextrose in water by syringe slowly over a period of five to ten minutes. A very frequent and disturbing side reaction is thrombophlebitis at the site of injection. Depression of neutrophils and platelets has been observed; blood counts should be done about three times weekly. Fever, skin eruptions, nephrotoxicity and ototoxicity are not rare. VANCOMYCIN
The principal application of vancomycin (Vancocin) is also in the treatment of systemic staphylococcal infections in which the organism is resistant to the more commonly employed antibiotics. Although vancomycin is active against hemolytic streptococci, enterococci, pneumococci, gonococci, diphtheria and tetanus bacilli, its use in infections by these agents is usually not indicated. Vancomycin is not absorbed from the gastrointestinal tract and therefore must be given intravenously in doses of 0.5 to 1 gram every six hours. The higher dose is particularly more desirable in staphylococcic meningitis or endocarditis. Since in the latter types of disease therapy
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must be continued for at least two and four weeks, respectively, the high incidence of pain and thrombophlebitis at the site of injection is particularly disturbing. There are also some nephrotoxic properties which are reflected by the appearance of casts and albumin in the urine; on occasion decreased renal function and azotemia may occur. Biweekly blood urea nitrogen determinations are advised. Ototoxicity is also not rare and checks should be made for tinnitus and auditory acuity. Morbilliform eruptions are also occasionally observed. KANAMYCIN
Kanamycin (Kantrex), a drug closely related to neomycin, should be reserved for judicious use only when infections can not be treated by less toxic and more commonly used antibiotics. This agent is active against staphylococci, tubercle bacilli and certain gram-negative bacteria such as the coliforms. It is not effective against streptococci, pneumococci, clostridia or most strains of proteus and pseudomonas. Clinically this drug has been most useful in certain urinary tract infections, gram-negative bacteremias, peritonitis and systemic staphylococcal infections. Given by mouth, it has also been used for reduction of intestinal flora because of its poor absorption. About 15 mg. per kg. per day divided into three doses is given intramuscularly every eight hours. The duration of treatment must be carefully controlled and patients questioned daily for tinnitus. Checks on hearing should also be made weekly, and blood urea nitrogens checked twice weekly. As one approaches a total dose of over 20 grams, side reactions may be more likely. Toxicity is even more likely in patients over 45 years of age or in patients with impaired kidney function, pre-renal azotemia or dehydration. The drug should be discontinued if there is a rising blood urea nitrogen or oliguria. One should also avoid concomitant or sequential use with other ototoxic drugs such as streptomycin, vancomycin or neomycin. Additional reactions include skin eruptions and pain at the injection site. For bowel preparation, 4 to 12 grams are given orally but it is contraindicated in the presence of bowel obstructions or azotemia since even the small amounts absorbed from the gastrointestinal tract may reach toxic levels. ANTIBIOTIC COMBINATIONS
There are certain types of infections in which a combination of antibiotics is superior to a single agent. For example, a combined therapy regimen of streptomycin and para-aminosalicylic acid and/or isonicotinic acid in pulmonary tuberculosis is well accepted. Streptomycin and penicillin in enterococcus endocarditis and tetracycline and strep-
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tomycin in brucellosis are also effective combinations. Unfortunately, there have appeared on the market many combinations of antimicrobial agents which have actually, in our opinion, been detrimental to the practice of good medicine. The principal objection is the same as one would make to anti-anemic preparations containing every conceivable ingredient required in the treatment of an anemia. This type of "shotgun" approach may not only mask underlying disease, but may actually reduce the therapeutic value of individual components. In addition, one may overtreat with one component while undertreating with another which is combined in fixed dosage. One may argue that one of the ingredients may not be therapeutic but "prophylactic." Present experience indicates that indiscriminate "prophylaxis" is not only ineffective, but may actually result in more serious infections with resistant organisms as well as increasing sensitization of patients to antibiotics. It is fitting, then, that the physician have the privilege of determining the dosage of each antimicrobial when more than one is indicated rather than prescribe one already "fixed" in a combination that may be unsuitable for the particular patient under treatment. GENERAL COMMENTS
The principles of good antibiotic therapy are fundamentally the same as those in any other phase of therapy. First, one must ascertain that a treatable infection is present. To date, we have no proved specific agent effective against the ordinary virus infections encountered. The effecttiveness of broad-spectrum antibiotics, for example, in infections due to "large viruses" such as psittacosis and lymphogranuloma venereum is not carried over to influenza, enterovirus infections, measles, mumps, etc. Once one has ascertained the etiology of an infection either by classic signs and symptoms or by laboratory tests, the selection of antibiotic should be based on known general effectiveness in the type of infection encountered, assisted particularly in the more severe infections by sensitivity testing in the laboratory. This latter procedure is particularly helpful in gram-negative, staphylococcal and enterococcal infections. The least toxic better known antibiotic agents which have stood the test of time should be used whenever possible. This choice is governed by such other factors as mode of administration, nature of the disease and allergic history of the patient. Thus the "older" antibiotics such as penicillin, streptomycin, the tetracyclines, chloramphenicol and erythromycin as well as the sulfonamides afford an excellent first line of defense in the armamentarium of the physician cognizant of their potentialities, limitations and toxicities. Among the "older" drugs polymyxin, bacitracin and neomycin, if reserved for special cases only, and with an awareness of their toxic manifestations, can be useful agents.
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As can be seen from the general text of this paper, most of the newer antibiotics have been predominantly antistaphylococcal agents which should be reserved for use when the more common and safer antibiotics are not effective. Agents such as ristocetin, vancomycin and kanamycin are antibiotics of approximately comparable activity 16 which exhibit significant ototoxicity and nephrotoxicity as well as other effects described above. Their use should be reserved for situations in which the toxic reactions are a necessary, calculated risk. The synthetic penicillin Staphcillin at present shows considerably more promise in respect to efficacy and lesser toxicity, and is preferred by us for systemic staphylococcic infections resistant to the more common antibiotics. The wide variety of penicillin preparations with various claimed advantages is confusing. In essence it has been our experience, particularly in the severely ill patient, that intramuscular penicillin G is the most effective and practical preparation to use. In moderately ill patients who can take medication by mouth, oral penicillin preparations are effective, and there is no significant outstanding advantage of one synthetic penicillin over another if given a half hour before or two hours after meals. Oral penicillin G likewise can be effective if the higher dose factor necessary because of lower resistance to stomach acids is employed. The difficulty with oral medication is dependence upon the patient to continue therapy for the prescribed period. Similarly, the various tetracycline preparations do not offer significant differences in therapeutic response in most susceptible infections. Although Declomycin gives higher and more sustained blood levels than the other tetracyclines, it has been our experience that severe infections require 2 capsules (300 mg.) every six hours as compared to 2 capsules (500 mg.) of other tetracycline preparations; in addition, the incidence of phototoxicity is not so low that one can disregard this side reaction. SUMMARY
The proper utilization of new antibiotics as they appear on the market requires first of all a critical analysis of their therapeutic and toxic properties. "Older" antibiotics which have stood the test of time should not be traded in for "new models" if the infection under consideration is due to organisms sensitive to the older preparations. When antibioticresistant organisms are encountered which require the use of a relatively more toxic antimicrobial, some risk is then justified. Unfortunately, there is no short cut to keeping up with the fluid field of antibiotics. Just as with any other phase of medicine, current literature must be carefully followed and appraised. There is no panacea apparent upon the horizon, no omnibiotic effective against all infectious agents. There is still no substitute for good clinical judgment in the selection and application of antimicrobial agents, new or old.
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REFERENCES 1. Branch, A., Rodger, K. C., Lee, R. W. and Power, E. E.: Clinical and Laboratory
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Experiences with A New Synthetic Penicillin-2,6-Dimethoxyphenyl Penicillin. Canad. M. A. J. 83: 991, 1960. Breese, B. B. and Disney, F. A.: Penicillin in Treatment of Streptococcal Infections: Comparison of Effectiveness of Five Different Oral and One Parenteral Form. New England J. Med. 259: 57,1958. Boger, W. P. and Gavin, J. J.: An Evaluation of Tetracycline Preparations. New England J. M. 261: 827, 1959. Cronk, G. A. and Wheatley, W. B.: Penicillin: Oral or Intramuscular? Am. J. M. Sc. 240: 722, 1960. Editorial: New "Synthetic" Penicillin. New England J. Med. 263: 361, 1960. Editorial: "Resistant" Staphylococci and the New Synthetic Penicillins. Canad. M. A. J. 83: 822, 1960. Finland, M.: Antibiotic Blood Level Enhancement. Antibiotic Med. 5: 359,1958. Finland, M. and Garrod, L. P.: Demethylchlortetracycline. Brit. M. J. 2: 959, 1960. Geronimus, L. H.: Inoculum Size and Apparent Sensitivity of Staphylococci to Penicillins. New England J. Med. 263: 349, 1960. Hirsch, H. A. and Finland, M.: Effect of Food on Absorption of Erythromycin Propionate, Erythromycin Stearate and Triacetyloleandomycin. Am. J. M. Sc. 237: 693, 1959. Hirsch, H. A. and Finland, M.: Comparative Activity of Four Tetracycline Analogues against Pathogenic Bacteria In Vitro. Am. J. M. Sc. 239: 288, 1960. Kunin, C. M., Dornbush, A. C. and Finland, M.: Distribution and Excretion of Four Tetracycline Analogues in Normal Young Men. J. Clin. Invest. 38: 1950,1959. Kunin, C. M., Jones, W. F. and Finland, M.: Enhancement of Tetracycline Blood Levels. New England J. Med. 259: 147, 1958. McCarthy, C. G. and Finland, M.: Absorption and Excretion of Four Penicillins: Penicillin G, Penicillin V, Phenethicillin and Phenylmercaptomethyl Penicillin. New England J. Med. 263: 315, 1960. Symposium: A New Synthetic Penicillin-Experiences in the Therapy of Resistant Staphylococcal Disease. State University of New York, Upstate Medical Center, Syracuse, N. Y. Syracuse University Press, 1960. Waisbren, B. A., Kleinerman, L., Skemp, J. and Bratcher, G.: Comparative Clinical Effectiveness and Toxicity of Vancomycin, Ristocetin and Kanamycin. A.M.A. Arch. Int. Med. 106: 179, 1960.
410 West 10th Avenue Columbus 10, Ohio
SAMUEL SASLAW, M.D., PH.D., F.A.C.P. Professor of Medicine and Bacteriology, Ohio State University; Director of Division of Infectious Diseases.
DURING the second decade of the antibiotic era, the increasing number of new agents or modifications of "older" drugs has created additional problems for the practicing physician. The temptation to substitute a new drug for an older drug is great. Often, this occurs before extensive controlled critical evaluations have been made, and the late realization may come that some patients not only did not benefit from the prescribed therapy, but may have suffered unnecessary untoward side reactions. Certain fundamental principles apply to the treatment of infectious diseases regardless of the type of antimicrobial agent employed. These include first of all establishing the necessity for an antimicrobial agent, and then selecting the proper drug in adequate dosage for a sufficient duration of time. Proper application is based on good clinical judgment and understanding the pathogenesis of a disease, two attributes of the physician which obviate juggling and changing of antimicrobial agents because a patient is still symptomatic or febrile when he should be expected to be so with his particular disease process. It is not the purpose of this paper to cover the whole area of antibiotics and antibiotic therapy but to discuss the newer antibiotics which have appeared in the past five years.
NEW PENICILLINS
In recent years many different biosynthetic or synthetic penicillin preparations have appeared on the market. The variety of claims and counterclaims has been somewhat confusing to the practicing physician.2. 4. 5. 6. 9. 14 839
840
SAMUEL SASLAW
Phenoxymethyl penicillin or penicillin V (Pen-Vee, V-Cillin) and potassium phenoxymethyl penicillin or potassium penicillin V (Compocillin-VK, Pen-Vee K, V-Cillin K) have similar actions and uses. This type of preparation, because of its stability in acid environments and ready absorption from the gastrointestinal tract, is admirably suited for oral administration. The antibacterial spectrum is similar to that of penicillin G, but unless administered in larger doses penicillin V is not as effective as parenterally injected aqueous preparations of penicillin G, which is preferred in severe acute infections. Dosage for moderately severe infections such as streptococcal or susceptible staphylococcal infections is 200,000 units four times a day. For pneumonias 400,000 to 600,000 units as an initial dose is followed by 400,000 to 600,000 units every four hours. For rheumatic fever prophylaxis 200,000 to 400,000 units are administered daily. As with other penicillins, varying degrees of sensitivity reactions can occur, but they have been relatively infrequent. Cross sensitivity to penicillin G may occur. Diarrhea may occur, as with all orally administered antibiotics. Phenoxyethyl penicillin (phenethicillin) has been marketed under the trade names of Alpen, Broxil, Chemipen, Darcil, Dramacillin S, Maxipen and Syncillin. Earlier claims that this product elicits no sensitivity reactions in penicillin-sensitive patients and produces higher serum levels and greater antibacterial activity, especially to staphylococci resistant to other penicillins, have not been borne out. This product, like penicillin V, is resistant to stomach acid, but its absorption is considerably reduced when it is taken with or shortly after food. In this respect it is inferior to penicillin V, which is not affected by meals. Likewise, early claims that orally administered phenethicillin was superior to intramuscularly injected penicillin G have not been substantiated. Dosage and indications are similar as for penicillin V except that this drug should be given half an hour before or two hours after meals. Staphcillin (Bristol) and Celbenin (Beecham) are the trade names of a recent synthetic penicillin, 6-(2,6 dimethoxybenzamide) penicillinate monohydrate. These preparations show considerable promise in the treatment of staphylococcal infections resistant to other antibiotics by virtue of the fact that they are not appreciably inactivated by penicillinase. 1 , 6,15 However, they have a narrow range of effectiveness and less antibacterial activity against penicillin-sensitive staphylococci or other organisms than the "ordinary" penicillins. Staphcillin should be reserved, therefore, for the treatment of resistant staphylococcal soft tissue infections, boils, abscesses, infected burns, osteomyelitis, pneumonia, lung abscesses, empyema, septicemia, endocarditis, pyelonephritis and staphylococcal arthritis. This drug is unstable in acid media; it is therefore unsuitable for oral administration and must be given intravenously or intramuscularly in doses of 1 to 2 grams every four to six hours. In children the dose is 100 mg. per kg. per day in divided doses.
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To date no serious toxicity has been observed, although fever and skin rashes have been occasionally encountered. In short-term in vitro studies and clinical trials, staphylococci have not acquired significant resistance. Further experience is needed to see wh()ther such a promising situation will exist in the future. At the present time it appears that Staphcillin is the treatment of choice in staphylococcal infections resistant to other more commonly used antibiotics. TETRACYCLINES
Considerable interest has been centered in recent years on modifications of the tetracyclines, of which the prototypes were Aureomycin (chlortetracycline) and Terramycin (oxytetracycline) . Various preparations with claimed enhancement of blood levels have been marketed, but there has been no proof to date that certain drugs offer any improvement over plain tetracycline (Achromycin, Panmycin, Polycycline, Tetracyn).3, 7,13 Thus there seems to be no therapeutic advantage to be gained with the following types of preparations: (1) tetracycline phosphate complex (Comycin, Panmycin Phosphate, Sumycin, Tetrex), (2) tetracycline hydrochloride with citric acid (Achromycin V), (3) tetracycline hydrochloride with glucosamine hydrochloride (CosaTetracyn). On the other hand, studies with demethylchlortetracycline (Declomycin) 8, 11, 12 have shown that this drug has a very high degree of resistance to acid or alkali. It is more slowly excreted than the other tetracyclines and thus appears to sustain blood levels longer. On the basis of these properties an equivalent therapeutic effect may be anticipated from a smaller dose than with tetracycline. Declomycin has the same spectrum and application as all tetracyclines. For moderately severe infections 150 mg. every six hours is given. In our experience, severe infections require 300 mg. every six hours. The usual side reactions which may be observed with any of the tetracyclines such as diarrhea, nausea, skin eruptions and fever can occur in certain patients. One disturbing reaction peculiar to Declomycin is phototoxicity to sunlight. Persons who develop phototoxicity may experience severe sunburn in a short while. Discontinuation of the drug removes further sensitivity to sunlight. Regardless of which present-day tetracycline preparation is selected, it should be remembered that all have a similar antibacterial and antirickettsial spectrum and also show complete cross resistance. OLEANDOMYCIN
Oleandomycin (Matromycin) exhibits in vitro antimicrobial activity against gram-positive organisms such as streptococci, pneumococci and
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staphylococci and certain gram-negative organisms such as Hemophilus influenzae, meningococci and gonococci, rickettsii and large viruses. In all respects it is similar to but inferior to erythromycin. There is a high incidence of cross resistance between erythromycin and oleandomycin so that therapy with oleandomycin in an erythromycin-resistant infection is often valueless. Thus in staphylococcal infections erythromycin would be preferred if the organism is sensitive to both agents. Against the other gram-positive infections penicillin, erythromycin or tetracyclines are preferable. This antibiotic is frequently included in fixed combinations with tetracyclines which are not desirable for optimum results. The usual adult dose is 250 to 500 mg. orally every six hours. TRIACETYLOLEANDOMYCIN
Some of the objections to oleandomycin have been overcome by triacetyloleandomycin (Cyclamycin, Tao) which is the triacetyl ester of oleandomycin. The same basic spectrum of organisms is susceptible as with oleandomycin. However, this ester is more rapidly absorbed after oral dosage and consequently achieves higher levels. This type of preparation parallels erythromycin in effect more closely than oleandomycin. lo The cross-reactivity of the two types of agents still requires more analysis. Triacetyloleandomycin is certainly to be preferred and recommended over plain oleandomycin. Dosage is 250 to 500 mg. orally every six hours. In children the usual dose is 30 mg. per kg. per day divided into four to six doses. Side reactions include skin rashes, nausea, diarrhea and fever. NOVOBIOCIN
Novobiocin (Albamycin, Cathomycin) is an antibiotic whose clinical usefulness is primarily in the treatment of staphylococcal infections. Because of the ease with which resistance develops to this agent and because of its side effects it should be reserved for use when there is resistance to other more commonly used antibiotics. It is advisable to use this agent in combination with another antibiotic to which the staphylococcus is sensitive to decrease the incidence of the development of resistant strains. Because novobiocin has a high degree of binding to serum protein, which limits its in vivo activity, it has been our experience that oral doses of at least 500 mg. every six hours should be given. This in turn increases the incidence of allergic skin or fever reactions. In children the dosage varies from 15 to 45 mg. per kg. On occasions it may be necessary to give the drug parenterally. The intramuscular route causes pain and irritation at the injection site and is not recommended. For intravenous use, a freshly prepared solution of 500
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mg. in 5 ml. of water is mixed with 30 ml. of saline and injected slowly every 12 hours over a five- to ten-minute period to avoid thrombophlebitis. Instead the drug may be dissolved in 1 liter of saline, Ringer's or Darrow's solution and infused slowly. In children the dose should be about 15 mg. per kg. in two divided doses. Preparations containing novobiocin in fixed combinations with tetracycline or with penicillin are not acceptable in our practice. It certainly is preferable to adjust the dose of each drug independently of the other when treating a patient in whom combination therapy is desired. Novobiocin also inhibits proteus species in vitro, but ill our experience resistance develops rapidly in proteus infections, particularly in urinary tract infections. Again, as with staphylococcal infections, it should he used with another effective agent rather than alone. RISTOCETIN
The main application of ristocetin (Spontin) is in the treatment of systemic staphylococcal or enterococcal infections resistant to the more commonly used antibiotics. Although it is active against other grampositive cocci, Actinomyces bovis and the tubercle bacillus, there are better and less toxic agents. Spontin is not absorbed from the gastrointestinal tract and therefore should be administered intravenously in doses of 50 mg. per kg. divided into two 12-hour doses. It should be injected slowly (30 to 45 minutes) with the required dose dissolved in 100 to 150 ml. of 5 per cent dextrose in water or by giving not more than 1 gram in 40 ml. of 5 per cent dextrose in water by syringe slowly over a period of five to ten minutes. A very frequent and disturbing side reaction is thrombophlebitis at the site of injection. Depression of neutrophils and platelets has been observed; blood counts should be done about three times weekly. Fever, skin eruptions, nephrotoxicity and ototoxicity are not rare. VANCOMYCIN
The principal application of vancomycin (Vancocin) is also in the treatment of systemic staphylococcal infections in which the organism is resistant to the more commonly employed antibiotics. Although vancomycin is active against hemolytic streptococci, enterococci, pneumococci, gonococci, diphtheria and tetanus bacilli, its use in infections by these agents is usually not indicated. Vancomycin is not absorbed from the gastrointestinal tract and therefore must be given intravenously in doses of 0.5 to 1 gram every six hours. The higher dose is particularly more desirable in staphylococcic meningitis or endocarditis. Since in the latter types of disease therapy
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must be continued for at least two and four weeks, respectively, the high incidence of pain and thrombophlebitis at the site of injection is particularly disturbing. There are also some nephrotoxic properties which are reflected by the appearance of casts and albumin in the urine; on occasion decreased renal function and azotemia may occur. Biweekly blood urea nitrogen determinations are advised. Ototoxicity is also not rare and checks should be made for tinnitus and auditory acuity. Morbilliform eruptions are also occasionally observed. KANAMYCIN
Kanamycin (Kantrex), a drug closely related to neomycin, should be reserved for judicious use only when infections can not be treated by less toxic and more commonly used antibiotics. This agent is active against staphylococci, tubercle bacilli and certain gram-negative bacteria such as the coliforms. It is not effective against streptococci, pneumococci, clostridia or most strains of proteus and pseudomonas. Clinically this drug has been most useful in certain urinary tract infections, gram-negative bacteremias, peritonitis and systemic staphylococcal infections. Given by mouth, it has also been used for reduction of intestinal flora because of its poor absorption. About 15 mg. per kg. per day divided into three doses is given intramuscularly every eight hours. The duration of treatment must be carefully controlled and patients questioned daily for tinnitus. Checks on hearing should also be made weekly, and blood urea nitrogens checked twice weekly. As one approaches a total dose of over 20 grams, side reactions may be more likely. Toxicity is even more likely in patients over 45 years of age or in patients with impaired kidney function, pre-renal azotemia or dehydration. The drug should be discontinued if there is a rising blood urea nitrogen or oliguria. One should also avoid concomitant or sequential use with other ototoxic drugs such as streptomycin, vancomycin or neomycin. Additional reactions include skin eruptions and pain at the injection site. For bowel preparation, 4 to 12 grams are given orally but it is contraindicated in the presence of bowel obstructions or azotemia since even the small amounts absorbed from the gastrointestinal tract may reach toxic levels. ANTIBIOTIC COMBINATIONS
There are certain types of infections in which a combination of antibiotics is superior to a single agent. For example, a combined therapy regimen of streptomycin and para-aminosalicylic acid and/or isonicotinic acid in pulmonary tuberculosis is well accepted. Streptomycin and penicillin in enterococcus endocarditis and tetracycline and strep-
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tomycin in brucellosis are also effective combinations. Unfortunately, there have appeared on the market many combinations of antimicrobial agents which have actually, in our opinion, been detrimental to the practice of good medicine. The principal objection is the same as one would make to anti-anemic preparations containing every conceivable ingredient required in the treatment of an anemia. This type of "shotgun" approach may not only mask underlying disease, but may actually reduce the therapeutic value of individual components. In addition, one may overtreat with one component while undertreating with another which is combined in fixed dosage. One may argue that one of the ingredients may not be therapeutic but "prophylactic." Present experience indicates that indiscriminate "prophylaxis" is not only ineffective, but may actually result in more serious infections with resistant organisms as well as increasing sensitization of patients to antibiotics. It is fitting, then, that the physician have the privilege of determining the dosage of each antimicrobial when more than one is indicated rather than prescribe one already "fixed" in a combination that may be unsuitable for the particular patient under treatment. GENERAL COMMENTS
The principles of good antibiotic therapy are fundamentally the same as those in any other phase of therapy. First, one must ascertain that a treatable infection is present. To date, we have no proved specific agent effective against the ordinary virus infections encountered. The effecttiveness of broad-spectrum antibiotics, for example, in infections due to "large viruses" such as psittacosis and lymphogranuloma venereum is not carried over to influenza, enterovirus infections, measles, mumps, etc. Once one has ascertained the etiology of an infection either by classic signs and symptoms or by laboratory tests, the selection of antibiotic should be based on known general effectiveness in the type of infection encountered, assisted particularly in the more severe infections by sensitivity testing in the laboratory. This latter procedure is particularly helpful in gram-negative, staphylococcal and enterococcal infections. The least toxic better known antibiotic agents which have stood the test of time should be used whenever possible. This choice is governed by such other factors as mode of administration, nature of the disease and allergic history of the patient. Thus the "older" antibiotics such as penicillin, streptomycin, the tetracyclines, chloramphenicol and erythromycin as well as the sulfonamides afford an excellent first line of defense in the armamentarium of the physician cognizant of their potentialities, limitations and toxicities. Among the "older" drugs polymyxin, bacitracin and neomycin, if reserved for special cases only, and with an awareness of their toxic manifestations, can be useful agents.
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As can be seen from the general text of this paper, most of the newer antibiotics have been predominantly antistaphylococcal agents which should be reserved for use when the more common and safer antibiotics are not effective. Agents such as ristocetin, vancomycin and kanamycin are antibiotics of approximately comparable activity 16 which exhibit significant ototoxicity and nephrotoxicity as well as other effects described above. Their use should be reserved for situations in which the toxic reactions are a necessary, calculated risk. The synthetic penicillin Staphcillin at present shows considerably more promise in respect to efficacy and lesser toxicity, and is preferred by us for systemic staphylococcic infections resistant to the more common antibiotics. The wide variety of penicillin preparations with various claimed advantages is confusing. In essence it has been our experience, particularly in the severely ill patient, that intramuscular penicillin G is the most effective and practical preparation to use. In moderately ill patients who can take medication by mouth, oral penicillin preparations are effective, and there is no significant outstanding advantage of one synthetic penicillin over another if given a half hour before or two hours after meals. Oral penicillin G likewise can be effective if the higher dose factor necessary because of lower resistance to stomach acids is employed. The difficulty with oral medication is dependence upon the patient to continue therapy for the prescribed period. Similarly, the various tetracycline preparations do not offer significant differences in therapeutic response in most susceptible infections. Although Declomycin gives higher and more sustained blood levels than the other tetracyclines, it has been our experience that severe infections require 2 capsules (300 mg.) every six hours as compared to 2 capsules (500 mg.) of other tetracycline preparations; in addition, the incidence of phototoxicity is not so low that one can disregard this side reaction. SUMMARY
The proper utilization of new antibiotics as they appear on the market requires first of all a critical analysis of their therapeutic and toxic properties. "Older" antibiotics which have stood the test of time should not be traded in for "new models" if the infection under consideration is due to organisms sensitive to the older preparations. When antibioticresistant organisms are encountered which require the use of a relatively more toxic antimicrobial, some risk is then justified. Unfortunately, there is no short cut to keeping up with the fluid field of antibiotics. Just as with any other phase of medicine, current literature must be carefully followed and appraised. There is no panacea apparent upon the horizon, no omnibiotic effective against all infectious agents. There is still no substitute for good clinical judgment in the selection and application of antimicrobial agents, new or old.
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Experiences with A New Synthetic Penicillin-2,6-Dimethoxyphenyl Penicillin. Canad. M. A. J. 83: 991, 1960. Breese, B. B. and Disney, F. A.: Penicillin in Treatment of Streptococcal Infections: Comparison of Effectiveness of Five Different Oral and One Parenteral Form. New England J. Med. 259: 57,1958. Boger, W. P. and Gavin, J. J.: An Evaluation of Tetracycline Preparations. New England J. M. 261: 827, 1959. Cronk, G. A. and Wheatley, W. B.: Penicillin: Oral or Intramuscular? Am. J. M. Sc. 240: 722, 1960. Editorial: New "Synthetic" Penicillin. New England J. Med. 263: 361, 1960. Editorial: "Resistant" Staphylococci and the New Synthetic Penicillins. Canad. M. A. J. 83: 822, 1960. Finland, M.: Antibiotic Blood Level Enhancement. Antibiotic Med. 5: 359,1958. Finland, M. and Garrod, L. P.: Demethylchlortetracycline. Brit. M. J. 2: 959, 1960. Geronimus, L. H.: Inoculum Size and Apparent Sensitivity of Staphylococci to Penicillins. New England J. Med. 263: 349, 1960. Hirsch, H. A. and Finland, M.: Effect of Food on Absorption of Erythromycin Propionate, Erythromycin Stearate and Triacetyloleandomycin. Am. J. M. Sc. 237: 693, 1959. Hirsch, H. A. and Finland, M.: Comparative Activity of Four Tetracycline Analogues against Pathogenic Bacteria In Vitro. Am. J. M. Sc. 239: 288, 1960. Kunin, C. M., Dornbush, A. C. and Finland, M.: Distribution and Excretion of Four Tetracycline Analogues in Normal Young Men. J. Clin. Invest. 38: 1950,1959. Kunin, C. M., Jones, W. F. and Finland, M.: Enhancement of Tetracycline Blood Levels. New England J. Med. 259: 147, 1958. McCarthy, C. G. and Finland, M.: Absorption and Excretion of Four Penicillins: Penicillin G, Penicillin V, Phenethicillin and Phenylmercaptomethyl Penicillin. New England J. Med. 263: 315, 1960. Symposium: A New Synthetic Penicillin-Experiences in the Therapy of Resistant Staphylococcal Disease. State University of New York, Upstate Medical Center, Syracuse, N. Y. Syracuse University Press, 1960. Waisbren, B. A., Kleinerman, L., Skemp, J. and Bratcher, G.: Comparative Clinical Effectiveness and Toxicity of Vancomycin, Ristocetin and Kanamycin. A.M.A. Arch. Int. Med. 106: 179, 1960.
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