Antimicrobial therapy in theory and practice. I. Clinical pharmacology

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November, 1969 The Journal of P E D I A T R I C S

MEDICAL

PROGRESS

Antimicrobial therapy in theory and practice I. Clinical pharmacology George H. McCracken, Jr., Heinz F. Eichenwald,* and John D. Nelson DALLAS, TEXAS

I

N T R O D U C T I O N S

to

articles on anti-

microbial therapy tend to follow standard and predictable patterns. The authors piously decry the overuse of antibiotic agents, they stress the limitations and dangers of uncontrolled therapy, and comment on the tendency of physicians to experiment with the "latest" drugs touted by the pharmaceutical industry. All these criticisms are, unhappily, justified, but their frequent reiteration has not changed medical practice. Moreover, human nature being what it is, it is likely that such repetitive exhortation only irritates the reader. Therefore, we will avoid this psychosocial aspect of physician education. Rather, in the present communication we will present a reasonably factual summary of the pharmacology (in its broadest sense) of antimicrobial agents and then illustrate how knowledge of the basic properties of these d r u g s can be applied to the rational therapy of a number of infectious clinical syndromes.

From the Department of Pediatrics, University of Texas Southwestern Medical School at Dallas. Supported in part by Research Grants Nos. CC 00131 and CC 00132 of The National Communicable Disease Center, Atlanta, Ga., and The John A. Hartford Foundation. "~Address: Department of Pediatr{es, Un{verslty of Texas Southwestern Medical School at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75285. Vol. 75, No. 5, pp. 742-757

Per force, we cannot deal exhaustively with the subject. Furthermore, we must confess that our personal prejudices are reflected to some extent; this is not surprising in a field in which practice is dictated often by prejudice or by an individual's uncontrolled "clinical experience" (the terms are, of course, synonymous). Nevertheless, we hope that an understanding of the more commonly employed antimicrobial agents will be helpful to the physician in his treatment of children with infection.

BACITRACIN Bacitracin, one of the oldest antibiotics, is bactericidal to all gram-positive cocci, gram-positive bacilli, clostridia, corynebacteria, and spirochetes. It is largely inactive against gram-negative organisms with the exception of H. influenzae and some Neisseria. It was useful in the past chiefly because of its activity against penicillinresistant staphylococci. An increasing number of resistant strains of this organism have been encountered and thus the drug has been largely replaced by the antistaphylococcal penicillins. Bacitracin's usefulness is further limited by its toxicity, which in older children and adults consists of impairment of both glomemlar and renal tubular function, mani-

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fested initially by proteinuria, hematuria, and cylinduria, and followed eventually by increased nitrogen retention. Toxicity of bacitracin is related to the total daily dose as well as to the duration of administration. Other side effects consist of anorexia, nausea, skin rashes, and irritation at the site of injection. It is of some interest that toxicity appears to be less in the infant than in the older child and in the adult. In the past, the authors have treated nearly 200 babies with staphylococcal pneumonia and empyema with this drug without evidence of significant renal toxicity. CEPHALOTHIN AND CEPHALORIDINE

Cephalothin, usually produced as the sodium salt, is a semisynthetic agent which is chemically closely related to penicillin. Its nucleus is, however, not degraded by penicillinase. Cephalothin and related compounds act by interfering with bacterial cell wall synthesis in a manner quite analogous to that of penicillin. The drugs are highly active against most cocci, with the minimal inhibitory concentration ranging from 0.05 to 1.0 ~g per milliliter. However, some species of streptococci such as Streptococcus faecalis, enterococci, and susceptible gramnegative bacteria are often considerably more resistant and may not be killed until levels of 50 ~g per milliliter are reached. Most Proteus rnirabilis, Salmonella, and Shigella organisms are susceptible in the laboratory, as are many strains of E. coIi, but an increasing number of strains of the Klebsiella-Aerobacter group has natural or acquired resistance. Many H. influenzae, most Proteus vulgarls, and nearly all Pseudomonas are highly resistant. For these reasons, cephalothin cannot be considered a broadspectrum .agent: It is highly effective against gram-positive cocci, but its range against gram-negative bacteria is spotty and unpredictable. If such infections are to be treated with cephalothin , it is first necessary to determine the degree of bacterial susceptibility. The main use of the cephalosporins is in the treatment of infections caused by gram-

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positive bacteria, particularly penicillinresistant staphylococci, but only when the patient is known to be allergic to penicillin and sufficiently ill to be hospitalized. Other agents are generally more effective against gram-negative organisms. Specificially, cephalosporins must not be used alone in the therapy of sepsis neonatorum, since many of the bacteria causing this condition are resistant. Because the drugs are poorly absorbed after oral administration they must be administered intramuscularly or intravenously. Cephalothin is very irritating; large doses or repeated injections produce severe pain, local induration, and, on occasion, sterile abscesses. Intravenous administration of the drug readily produces local thrombophlebitis. Other adverse effects are similar to those observed with the penicillins; a variety of skin rashes including urticaria, eosinophilia, fever, and quite rarely neutropenia or leukopenia may occur. Increased S G O T levels have been reported in some children but these have been transient. When the drug is administered to a pregnant woman, her infant's cord blood may show a falsely positive Coombs' test without evidence of increased hemolysis. Superinfection, particularly with Pseudomonas and Aerobacter, occurs quite frequently, particularly in the urinary tract. The great majority of individuals allergic to penicillin can tolerate cephalothin. However, considering the chemical resemblance of these two agents, it is not surprising that an occasional penicillin-hypersensitive patient has demonstrated anaphylaxis and other allergic reactions following the initial use of cephalothin. Thus, the drug should not be used with impunity in patients known to be allergic to penicillin; initial doses should be given with caution and never intravenously. Cephalothin is rapidly absorbed from an intramuscular site and is excreted predominantly by the renal tubules. About 50 per cent of a given dose is excreted within 6 hours. As with penicillin, probenecid blocks the tubular excretion of the drug. Cephalo-

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The Journal o[ Pediatrics November 1969

thin diffuses rather poorly into body cavities; levels in cerebrospinal and synovial fluids remain low. Because of its rapid renal excretion, the drug must be administered every 4 to 6 hours if adequate plasma levels are to be maintained. Another derivative of cephalosporin (cephaloridine, has been recently marketed. The substance possesses approximately the same range of antimicrobial activity as eephalothin, but is less irritating upon injection; therapeutic blood levels persist longer. However, unlike cephalothin, cephaloridine has been shown to be nephrotoxic when administered in large doses.

ministration of small doses for short periods of time, as well as after prolonged therapy. Other toxic effects consist of skin rashes and gastrointestinal and neurologic reactions, including optic and peripheral neuritis. Furthermore, the drug inhibits protein synthesis and is capable of suppressing anamnestic as well as primary antibody responses by blocking the ribosomal binding sites for messenger RNA. Even in average dosage, chloramphenicol produces varying degrees of arrest of red cell maturation. In individuals with shortened red cell survival or with anemias of other types, this temporary decrease in red cell formation may rapidly result in serious and profound anemias. In the premature and young infants, a peculiar form of cardiovascular collapse known as the "gray syndrome" has been observed when the drug is given in recommended or even low dosage. This syndrome is related to diminished glucuronide conjugation of chloramphenicol resulting in accumulation of drug in the serum. Chloramphenicol is rapidly absorbed from the gastrointestinal tract, a maximal blood level being attained within 2 hours following administration. Because of its small molecular size, it is efficiently distributed throughout most body tissues; it passes particularly readily into the cerebrospinal fluid, into the aqueous and vitreous humor of the eye and into joint spaces. The drug is mainly excreted in the urine, chiefly in a conjugated, inactive form. The sodium succinate salt is similar to the parent compound but is considerably more soluble in water. Because of poor absorption and ineffective serum levels, the succinate salt is given by the intravenous route only. No satisfactory intramuscular preparation is available. The sodium succinate salt itself has no antibacterial activity; its effectiveness depends on hydrolysis to the parent compound. The palmitate ester of chloramphenicol represents a satisfactory liquid preparation for oral administration, since it is essentially tasteless. However, in young and particularly

744

CHLORAMPHENIGOL

Chloramphenicol has the distinction of being the first antibiotic of broad antimicrobial range introduced into clinical use. However, the subsequent development of more potent and much less toxic agents has nearly eliminated the need for this drug in clinical practice. In general, chloramphenlcol should be used only for the treatment of typhoid fever, occasionally of other salmonelloses not responding to ampicillin, as an alternate drug in the treatment of rickettsial disease, occasionally in urinary tract infections, and, perhaps, in infections involving the interior of the eye. While widely used in patients with cystic fibrosis, there is no evidence that under these circumstances it is superior to other safer drugs. Rarely, it is necessary to use chloramphenicol in the treatment of infections of the meninges, and then only when the patient is allergic to more effective agents or has not clinically responded because of drug resistance. In general, the drug should not be employed in the treatment of infections unless the etiologic agent has been identified and has been shown not to be susceptible to other less potentially dangerous agents. Chloramphenicol has a wide range of toxic effects, the most serious of which is aplastic anemia with pancytopenia; occasionally erythroid hypoplasia without pancytopenia, or isolated thrombocytopenia occur. Aplastic anemia has developed after ~he ad-

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Antimicrobial therapy. I

in acutely ill children, blood levels following its administration are sometimes erratic. Because better and less toxic drugs exist for nearly all conditions, chloramphenicol should be reserved for hospital use and then only for a very limited number of conditions. During recent years, we have rarely found it necessary to employ this drug in premature and young infants. COLISTIN

AND POLYMYXINS

Colistin is a cyclic polypeptide probably identical to polymyxin E and thus very closely related to polymyxin B. It is available as the sulfate salt, which is marketed as an oral preparation useful only in certain elateritides, and as its sodium sulfomethyl derivative, sodium colistimethate, a preparation for intramuscular use. Polymyxin B is sold for parenteral use as the sulfate salt. Oral tablets are also available. The antibacterial spectra of colistin and polymyxin B are identical: in the laboratory these agents are active against a number of gram-negative bacteria including E. coli, Pseudomonas, Klebsiella, Aerobacter, Salmonella, Shigella, and Hemophilus but not against Proteus or gram-positive bacteria. Of greatest clinical importance is the activity of colistin and polymyxin B against most strains of Pseudomonas; here they are uniquely bactericidal, resembling in their action those chemical disinfectants that have a lytic effect on bacteria. Thus, polymyxin B and colistimethate are most useful in the treatment of Pseudomonas infections, since other less toxic and equally effective agents can be utilized in the therapy of most other conditions. Both drugs are potentially nephrotoxic; these reactions may be manifested by a diminishing urinary output and a rising blood urea nitrogen. These agents must be used cautiously in patients with impaired renal function; under such conditions increased plasma levels of the drug result in further diminution of renal function and an increased incidence of neurotoxic effects. Numbness of the extremities, transient circumoral paresthesias, dizziness, ataxia, nys-

745

tagmus, muscular weakness, and on occasion, respiratory arrest can all occur, particularly when the drugs are administered intravenously. Following intramuscular injection, the polymyxins are relatively slowly absorbed, 40 to 60 per cent of the drug being excreted in the inactive form in the urine within 8 hours. The lack of active drug in the urine may account for the fact that urinary tract infections often do not respond favorably to these drugs, despite demonstrated susceptibility of the causative organism. Neither drug penetrates well into tissue and both enter cerebrospinal fluid poorly, even in the presence of inflammation. Thus, in the therapy of pseudomonas meningitis, it is usually necessary to instil polymyxin B intrathecally in addition to its administration intramuscularly. Sodium colistimethate must not be given intrathecally since available preparatiofis contain dibucaine. Colistin sulfate or polymyxin B sulfate are used orally in infants and children in the treatment of diarrhea caused by polymyxinsusceptible but neomycin-resistant pathogenic serotypes of E. coli. There is no evidence that shigellosis or salmonellosis will respond favorably to the oral administration of these compounds. Although absorption is poor following oral administration, as much as 10 per cent of the drug may be absorbed in small infants. Thus, excessive amounts given by mouth may occasionally result in systemic toxicity. ERYTHROMYCIN

Erythromycin is a member of the macrolid group of antimicrobial agents, a name derived from the fact that these drugs possess a large lactone ring as a structural characteristic. Novobiocin and oleandomycin are members of the same group, but, of these agents, erythromycin is the only one possessing clinically useful characteristics. Erythromycin is most active against grampositive bacteria, including many penicillinresistant strains of staphylococci. In the laboratory, it is effective against Listeria, most strains of Hemophilus and Neisseria,

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The Journal o[ Pediatrics November 1969

many enterococci, some strains of Bordetella and occasional other gram-negative species. It is active against Mycoplasma pneurnoniae, as well as certain strains of Rickettsia and Actinomyces. Because erythromycin is an agent of only modest potency, its use should be limited to the therapy of relatively minor and easily treatable infections of the respiratory tract, particularly those caused by group A beta~ hemolytic streptococci or pneumococci in patients allergic to penicillin. It has been used successfully in the treatment of staphylococcal infections due to susceptible strains of penicillin-resistant staphylococci, but at present erythromycin should be used only against those staphylococcal diseases which are essentially self-limiting. The drug is claimed to be moderately effective in the treatment of primary atypical pneumonia in adults. However, no reliable data have been presented which would indicate that erythromycin is useful in the treatment of Eaton agent infections in children. For reasons which are not quite clear, erythromycin is the drug of choice in the antimicrobial therapy of acute diphtheria and in the eradication of the carrier state of Corynebacterium

demned. In general, if the patient is too sick to tolerate orally administered erythromycin, he should be receiving a more potent drug.

diphtheriae. Numerous erythromycin salts are on the market which, while differing in absorption and blood levels, have few differences in clinical efficacy. The toxicity of the salts is also similar; in general, erythromycin is the least toxic antibiotic known. Minor gastrointestinal disturbances and mild allergic reactions such as urticaria and other skin rashes represent the major toxic effects. Erythromycin estolate may produce jaundice during or after therapy, apparently due to intrahepatie cholestasis caused by hypersensitivity to the preparation. This toxic effect occurs infrequently and is usually reversible but, because of it, erythromycin estolate should not be used in patients with impaired liver function. An ethylsuccinate ester of erythromycin in available for intramuscular use. This preparation is highly irritating and extremely painful; its u s e in children is to "be con-

GENTAMICIN Gentamicin, an aminoglycoside antibiotic derived from Micromonospora species, has structural and antimicrobial similarities to the streptomycin-neomycin-kanamycin family. Its broad range of antimicrobial effectiveness includes most gram-positive and gram-negative bacteria, Myocoplasma and mycobacteria. It is not effective against viruses, yeasts, and fungi. Unlike the Streptomyces-derived drugs, gentamicin is inhibitory to virtually all Pseudomonas species. For local use, the drug is available as a 0.1 per cent cream or ointment. Because significant absorption from the skin occurs, caution should be employed when it is applied to large areas, especially in patients with reduced renal function. So far, no toxic systemic reactions from cutaneous absorption have been reported. A parenteral form of gentamicin has recently been made available. Of greatest clinical interest is its effectiveness against infections caused by Pseudomonas, staphylococci, Klebsiella-Aerobacter, and E. coll. Pseudomonas species are susceptible in vitro to < 3 /~g per milliliter. Most enteric gram-negative bacilli are susceptible to < 5 #g per milliliter, although a significant proportion of Protetis species are resistant. Approximately 95 per cent of staphylococci are susceptible to ( 1.25 t~g per milliliter. At the recommended dosage of 0.8 mg. per kilogram of body weight intramuscularly every 8 or 12 hours, peak serum levels in the range of 2 to 4/~g per milliliter are usually achieved. Because it is excreted in the urine in active form, one half the recommended dose is sufficient for treatment of urinary tract infections. Ototoxicity consisting of either vertigo or decreased hearing or both has usually been associated with serum levels above 12 /~g per milliliter in instances when the drug was given in large doses, or in ordinary doses to patients with reduced renal function. The

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drug causes destruction of cochlear hair cells and of the vestibular sensory cells; thus deafness produced by it is irreversible. The drug has also been associated with proteinuria and increase in blood urea nitrogen in a few patients. Very little gentamicin is absorbed after oral administration. It has been used in an oral dosage of 20 to 30 mg./Kg./day in the treatment of diarrheal disease, with equivocal results. The drug has also been administered intrathecally in a dosage of 1 rag. daily, combined with intramuscular administration, in patients with gram-negative meningitis. Insufficient clinical experience exists at present to assess the usefulness of parenteral gentamicin. Because of the relatively narrow range between effective serum levels and those that can produce serious ototoxicity, dosage will have to be carefully monitored. Thus, the drug must be used with great caution, if at all, in patients with reduced renal function. No adequate toxicity or efficacy data exist to justify its use in infants except under most unusual circumstances; in fact, no dosage recommendations can be given for infants at this time. In other individuals, however, gentamicin provides an alternative to the polymyxins in the treatment of serious Pseudomonas infections and, in the event of increasing resistance of gramnegative enteric bacilli to kanamycin, it may possibly find more widespread use. KANAMYCIN

Kanamycin sulfate is one of the numerous antibiotics derived from species of streptomyces and is, at present, the single most useful drug in the therapy of infections caused by enteric bacteria. Its antimicrobial spectrum closely resembles that of the chemically related drug neomycin, but, because of its lesser toxicity, kanamycin can be used parenterally with reasonable safety. In vitro, the drug is bactericidal against many gram-negative bacteria including nearly all strains of E. coli producing systemic disease in infants, as well as against Klebsiella-Aerobacter, most strains of

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Shigella and Salmonella and some strains of Proteus and Pseudomonas. Kanamycin is active also against mycobacteria, Staphylococcus aureus, and other common gram-positive organisms, but is clinically not useful against this latter group of bacteria. Like several of the other membrane-active antimicrobial agents, "he drug's toxicity is manifest by renal and central nervous system (chiefly auditory nerve) reactions. Renal toxicity is evidenced initially by proteinuria, followed by hematuria, cylinduria, diminished renal clearances, and nitrogen retention. Though these toxic effects are observed relatively frequently in older children and adults, they are rarely encountered during infancy. Eighth nerve damage may occur following prolonged kanamycin therapy and is often preceded by tinnitus and dizziness; patients with diminished renal clearances are at the greatest risk. Hearing loss and renal damage occur relatively less frequently in patients with good urinary outputs. Thus, it is desirable to keep a child well hydrated during therapy. Other side effects of the drug include pain at the site of injection, eosinophilia, and occasional evidence of neuromuscular blockade when the drug is given soon after anesthesia or concomitantly with muscle relaxants. Kanamycin is rapidly absorbed after intramuscular injection; peak serum levels are attained within one hour. The drug is usually completely cleared from the serum in 12 hours. It is poorly absorbed when administered orally. Because kanalnycin is uniquely effective against nearly all gram-negative organisms that produce serious infections during the neonatal period, it generally represents the drug of choice in the therapy of infections caused by them, except when disease is caused by Pseudomonas. The agent is useful in the therapy of urinary tract infections due to organisms resistant to those antimicrobial agents having less nephrotoxicity, but should then be used with caution. Despite laboratory evidence of activity against Shigella and Salmonella, kanamycin has not been useful in the treatment of diseases caused by

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The Journal o[ Pediatrics November 1969

these organisms. Because complete crossresistance exists between kanamycin and neomycin, orally administered kanamycin is ineffective in therapy of diarrheas caused by neomycin-resistant enteropathogenic E. coil. For maximum efficacy and minimal toxicity, dosage of kanamycin is critical; the infant and young child should receive 7 ~ mg./Kg, intramuscularly every t2 hours. Satisfactory serum levels are obtained without accumulation with this dosage. If kanamycin is to be used in patients with renal damage, both the dosage and frequency of administration must be reduced. There are now detailed data on toxicity during the neonatal period which confirm kanamycin's safety in this age group when given in appropriate dosage and for periods not in excess of 9 days. Under these circumstances, there is no evidence that either renal damage or hearing loss are produced.

or may develop a rash, pruritus, proctitis, and vaginitis. Occasional cases of jaundice with abnormal liver function tests have been reported; leukopenia or neutropenia have been rarely observed. In terms of antimicrobial potency, lincomycin is approximately equivalent to the macrolid antibiotics. Thus, it is inferior to penicillin and its derivatives, which remain the drugs of choice for serious infections due to gram-positive cocci. When allergy makes penicillin therapy hazardous, cephalothin should be used in moderate to severe infections, particularly when they are caused by penicillin-resistant staphylococci. When an oral drug of moderate activity is indicated, erythromycin remains the preferred alternative to penicillin, because, compared with lincomycin, this drug is generally cheaper, less likely to prove toxic, and possesses at least equal efficacy. Though an increasing number of penicillin-resistant staphylococci are resistant to erythromycin, a similar pattern is emerging for lincomycin. In fact, cross-resistance between these latter two agents has been produced in vitro.

LINCOMYCIN

In vitro, lincomycin inhibits growth of many gram-positive organisms, including strains of penicillinase-producing staphylococci, pneumococci, and Streptococcus pyogenes, but has only little effect upon enterococci, meningococci, and gonococci. It is completely inactive against gram-negative enterobacteria. Thus, while chemically distinct from the macrolid antibiotics, lincomycin has a similar antimicrobial spectrum. The drug is readily absorbed from the gastrointestinal tract; therapeutic serum levels are attained in approximately 2 to 4 hours, and persist for 6 to 8 hours. An intramuscular preparation is well tolerated and produces effective serum levels for 12 hours. Lincomycin diffuses into pleural and peritoneal spaces and into bone, but penetrates the central nervous system poorly. Lincomycin appears to be a relatively nontoxic drug. Intramuscular injection rarely causes much pain or irritation. Use of the oral preparation is occasionally associated with minor gastrointestinal disturbances such as nausea, vomiting, abdominal cramps, and diarrhea. Some patients complain of dizziness, headache, or generalized aching,

NALIDIXIC

ACID

Nalidixic acid is a synthetic chemical useful only in the treatment of acute and chronic urinary tract infections. The drug has been tried in newborn infants with sepsis but insufficient data concerning efficacy or toxicity exist to support any recommendations in favor of such use. Nalidixic acid is readily absorbed from the gut; within 8 hours, most of it is excreted in the urine. Approximately four fifths of the excreted material is conjugated and biologically inactive. Serum levels ranging from 4 to 30 /xg per milliliter are found during oral therapy, but most of the drug is tightly bound to protein and this appears to decrease its activity. Only traces of the active chemical are detectable in spinal fluid or milk. In vitro, nalidixic acid inhibits many gram-negative bacteria in concentrations ranging from 2 to 50 /~g per milliliter. It is especially active against E. coli and several Proteus species, but less so against Aero-

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bacter, Klebsiella, and Pseudomonas. It is relatively ineffective against enterococci and gram-positive bacteria. I'n the laboratory, resistant strains can be produced rapidly and easily. It is therefore not surprising that this also happens clinically, severely limiting the usefulness of the drug. Nalidixic acid causes a variety of side effects. Most commonly noted are nausea, vomiting, rash, and urticaria. Diarrhea and fever, eosinophilia, and photosensitivity occur less frequently. A few patients have developed gastrointestinal bleeding while on therapy, but the relationship to the drug remains unknown. The most important toxic reactions consist of neurologic disturbances which include headache, malaise, drowsiness, dizziness, hallucinations, muscular weakness, and myalgia. In an occasional individual with a history of grand mal seizures, convulsions have been precipitated, especially when larger than normal doses were given or when the drug was not well excreted because of renal insufficiency. Clinical data indicate that results obtained with nalidixic acid are no better and usually worse than those found with wellestablished and safer antibacterial agents. Thus, except for an occasional Proteus urinary tract infection resistant to other forms of therapy, naladixic acid has few if any uses. NEOMYCIN

Neomycin, closely related chemically and biologically to kanamycin, possesses an identical antibacterial spectrum but has only limited clinical usefulness because of its toxicity. A considerable proportion of patients treated parenterally with therapeutic doses develop signs of renal and eighth nerve toxicity. Because the drug is only poorly absorbed from the gastrointestinal tract, it has been employed effectively and safely in the treatment of epidemic diarrhea of the newborn infant caused by susceptible strains of enteropathogenie E. coll. In newborn and premature infants, care must be taken not to administer excessively large doses for long

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periods of time; approximately Jrl per cent of the administered dose may be absorbed and, with decreased renal function, sufficient drug may accumulate in the serum to produce toxic effects. In addition, a malabsorption syndrome may result from prolonged administration. NITROFURANTOIN

Nitrofurantoin is used orally and, as a sodium salt, intravenously for the treatment of bacterial infections of the urinary tract. The drug is effective against both grampositive and gram-negative bacteria, including E. coli, Aerobacter, a few strains of Proteus and rarely Pseudomonas. Bacterial resistance develops slowly and then only to a limited degree. The oral preparation is readily absorbed but rapidly excreted by the kidney, resulting in insignificant serum levels. Should the patient have decreased renal function, the drug may accumulate in the serum, giving rise to such toxic effects as peripheral neuropathies. When nitrofurantoin is administered orally or intravenously, nausea and vomiting are the most common side effects. A variety of skin rashes have also been reported. Furthermore, the drug may cause hemolytic anemias in patients with congenital deficiencies of erythrocytic glucose-6-phosphate dehydrogenase. For this and other reasons it is recommended that nitrofurantoin not be used in infants under 3 months of age and in persons known or suspected to have these enzyme defects. Rarely patients on this drug have developed peculiar, possibly allergic, pneumonias. Because of acceptably low toxicity, wide range of activity, and slow development of resistance, nitrofurantoin represents an excellent choice when a drug is required for long-term suppression of urinary tract infections. It is particularly useful for prolonged therapy in patients with chronic bacteriuria. In general, acute pyelonephritis with systemic manifestations is best treated with drugs producing more reproducible tissue levels, such as the sulfonamides, ampicillin, etc.

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The ]ournal o[ Pediatrics November 1969

Furazolidone. Furazolidone, a nitrofuran, is active in vitro against a variety of gramnegative and gram-positive enteric organisms, including Salmonella, Shigella, and E. coll. The drug is partly absorbed from the gut and then rapidly excreted in the urine in a form which may color it brown. Most of the clinical studies undertaken with furazolidone are uncontrolled. Since bacterial diarrheas are usually self-limiting diseases, it is not possible to ascribe the improvement observed in these patients to the use of the drug. As with other agents, treatment of acute enteric infections with this material is often followed by the development of a carrier state, unaffected by further therapy. In the treatment of Giardia lamblia infections, furazolidone is highly effective; one week of therapy eradicates this protozoan from nearly all patients. Side effects are similar to those of nitrofurantoin and consist primarily of nausea, vomiting, and a variety of skin rashes. In a single patient, there was evidence of neuropathy. Hemolytic anemias may develop in patients with glucose-6-phosphate dehydrogenase deficient erythrocytes.

It is well absorbed after intramuscular injection; because of the diminished renal function found during the neonatal and premature periods, high and prolonged blood levels result. The long duration of blood levels obtained with penicillin G in infants during the first weeks of life and the occasional occurrence of sterile abscesses following administration of procaine penicillin have led us to abandon the use of the latter preparation in this age group. Instead, the baby is given an intramuscular injection every 12 hours of approximately 50,000 units of aqueous penicillin G per kilogram of body weight. The intravenous route of administration is rarely indicated in infants. If it is used, care should be taken to inject the drug slowly and in moderate dosage, especially if the potassium salt is employed. Procaine penicillin suspension is widely used because the slow absorption of this relatively insoluble salt results in more prolonged blood levels. However, it should be recognized that the price paid for this effect consists of blood levels which are often lower than those obtainable with orally administered penicillins. For this reason, procaine penicillin G should be employed only for therapy of conditions due to highly susceptible bacteria such as group A beta-hemolytic streptococci and pneumococci. A preparation which produces initial high blood levels with overalI duration of activity similar to that of procaine penicillin is fortified procaine penicillin G U.S.P., in which aqueous penicillin G is mixed with 3 times its quantity of procaine penicillin. Benzathine penicillin G suspension (Bicillin) produces very prolonged but extremely low blood levels, even when it is "fortified." It can be recommended only for the therapy of proved beta-hemolytic streptococcal infections, as well as for the prophylaxis of rheumatic fever. Benzathine penicillin G and its various combinations with soluble penicillin salts are not suitable substitutes for other forms of penicillin in regular practice. Furthermore, these preparations are quite painful; in general, oral penicillin is to be preferred.

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PENICILLIN AND RELATED MODIFICATIONS

Proved effectiveness, low cost, and a wide margin of safety continue to make penicillin G the antibiotic of choice for infections due to pneumococci, Group A beta-hemolytic streptococci, non-penicillinase-producing staphylococci, meningococci, and gonococci. Although other antimicrobial agents are active against these organisms, they are less effective and usually more costly, and their toxic effects, particularly in the newborn and the pregnant woman, are generally more frequent and severe. A detailed discussion of penicillin G (benzyl penicillin) is unnecessary, since this remarkable agent is familiar to all physicians. Its use in small infants, however, differs from that in older children. Penicillin G has proved particularly useful in this age group because of its high potency and low toxicity.

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Under ordinary circumstances, oral administration avoids the trauma and hazard of injection, and is effective if infection is caused by such highly susceptible bacteria as group A beta-hemolytic streptococci and pneumococci, and the patients are reasonably cooperative. Various oral penicillins differ little in efficacy; in general, phenoxymethyl penicillin (penicillin V) or phenethicillin will give satisfactory blood levels in approximately 90 per cent of patients. A somewhat smaller proportion of individuals will have equivalent but less predictable blood levels after ingesting buffered penicillin G. Penicillinase-reslstant penicillins. The first important semisynthetic analogues to be marketed were the antistaphylococcal penicillins. The great efficacy which these drugs have in vitro is not entirely borne out in clinical practice. The reasons for this difference appear to be twofold: (1) the tissue levels achieved are often low, and (2) these penicillins are more toxic than the parent molecule, and thus dosage must be limited. Nevertheless, these drugs are far more effective against staphylococci than the bacteriostatic antimicrobial agents such as erythromycin, lincomycin, kanamycin, chloramphenicol, etc. Methicillin. This was the first of the parenterally administered antistaphylococcal penicillins available for use. The dosages of this agent generally recommended for use in children are too low to give adequate penetration into infected tissue. In children, and particularly in infants with severe staphylococcal disease, the optimum dosage is approximately 250 to 300 mg./Kg./day, divided into 6 doses in children, and into 4 doses in infants. Smaller amounts may result in relatively poor therapeutic effects; a dose significantly larger will occasionally produce a measurable but apparently reversible diminution of renal function, as well as, on occasion, hematuria. In addition to the same allergic reactions which occur with the parent penicillin molecule, methicillin has been shown to cause transient bone marrow depression in some patients. Long continued

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use should therefore be accompanied by hematologic studies. A disadvantage of methicillin over oxacillin and nafcillin is that it is very unstable in solutions of glucose in water or in saline. Either rapid infusion or alkalinization of the solution used for continuous drip is thus essential. Methicillin-resistant strains are encountered occasionally in the laboratory; approximately 0.5 per cent of coagulase-positive staphylococci are resistant in vitro. In Europe, where the drug has been employed for a longer period than in this country, methicillin-resistant staphylococcal disease has been encountered with increasing frequency. Since the advent of methicillin, a number of other penicillinase-resistant penicillins have been developed. These include oxacillin, cloxacillin, dicloxacillin, diphenicillin, and nafcillin. Unlike methicillin, these compounds are acid stable and absorbed more or less well from the gastrointestinal tract; thus they may be administered orally. When given parenterally, none of them is clearly superior to methicillin. Oxacillin. It is 5 to 8 times as active as methicillin against staphylococci in vitro and is absorbed satisfactorily in approximately 90 per cent of children after oral administration. The advantage of greater activity is possibly offset by the fact that it is bound to serum proteins to a much greater extent than methicillin (80 to 90 per cent versus less than 20 per cent). The clinical significance of protein binding is unknown; some doubt that this is a disadvantage at all. In any event, direct measurements have shown that methicillin diffuses into joints, cerebrospinal fluid, and bone in higher concentrations than oxacillin, suggesting that the former drug might be preferable for infections involving these sites. In general, however, clinical studies comparing parenteral oxacillin to parenteral methicillin have failed to show significant differences in either efficacy or toxicity. Oxacillin is well absorbed following intramuscular administration; a dose of 100 to 150 mg./Kg./day (given at 6 hour intervals)

7 5 2 McCracken, Eichenwald, and Nelson

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in young infants and 150 to 200 mg./Kg./day (given at 4 hour intervals) in older infants and children produces adequate therapeutic responses. Cloxacillin. Cloxacillin is closely related to oxacillin and is similar in serum binding, but has greater activity in vitro against the few staphylococci that are resistant to methicillin. Serum concentrations after oral administration are at least twice as high as with oxacillin. Even after parenteral administration of equivalent doses of cloxacillin as compared with oxacillin, the serum concentrations of cloxacillin are higher. This may in part be related to more rapid destruction of oxacillin by the liver. At present, cloxaeillin is available only in an oral dosage form, limiting its use to moderately ill patients. The recommended dose is 50 mg,/ Kg./day, given at 6 hour intervals. Like other penicillins, cloxacillin is best absorbed when given 3 or more hours after meals. Dicloxacillin. It produces higher blood levels than cloxacillin after oral administration and has as high an in vitro activity. The toxicity of dicloxacillin and cloxacillin appears to be equivalent to that of oxacillin, but their greater activity and lower cost, combined with better blood levels after oral administration, would seem to indicate that these two drugs should replace oxacillin. NafeilIin. It is somewhat more active in vitro and less bound by serum protein than oxacillin and cloxacillin. Intramuscular administration of nafcillin and oxacillin resuits in approximately the same order of activity in the serum; however, nafcillin produces generally lower blood levels after oral administration than does cloxacillin. Comparative clinical studies are difficult to perform, but it would seem that parenteral nafcillin and methicillin, or oral nafcillin and oxacillin are approximately equal in efficacy. Diphenicillin has been used in Europe but is not available commercially in the United States. It is clearly inferior in clinical efficacy to methicillin or oxacillin. The antistaphylococcal penicillins are most useful in the treatment of severe and moderately severe penicillin-resistant staphylo-

coccal disease. They are sufficiently active against such organisms as group A betahemolytic streptococci and pneumococci to provide adequate initial therapy for these penicillin G-susceptible infections, but do not represent optimum therapy. If a patient is suspected of having a severe staphylococcal disease, it is preferable to initiate therapy with one of the penicillinaseresistant penicillins and await bacteriologic data. If the staphylococcus in question is found subsequently to be penicillin G susceptible, this drug should be used in preference to its semisynthetic derivatives, since it is more effective, less toxic, and far less expensive. Oral therapy is generally less satisfactory than parenteral therapy. Seriously ill patients or patients with deep tissue infections should not be treated with these agents administered by the oral route: Not every patient develops adequate serum levels and the range of serum levels varies considerably from child to child. Furthermore, it has been shown that the therapeutic failure rate of oxacillin given orally in cases of osteomyelitis is high, even after an initial course of parenteral methicillin. For these reasons, all potentially serious infections should be treated parenterally despite the convenience of oral administration. AmpiciUin. Ampicillin is a semisynthetic penicillin with a broader antimicrobial range than the parent molecule. It is nearly as effective against penicillin G-susceptible gram-positive organisms as penicillin G, but it is destroyed by penicillinase and is therefore ineffective against penicillinase-producing staphylococci. Ampicillin is also bactericidal against a variety of gram-negative organisms, including H. influenzae, B. pertussis, Listeria, gonococci, meningococci, Proteus mirabilis, and many strains of E. coli, Shigella, and Salmonella. The agent is, however, ineffective against other Proteus species, the Klebsiella-Aerobacter group of organisms, and Pseudomonas. Because not all enteric bacteria are susceptible t o ampicillin, the drug should not be used alone without laboratory confirmation of bacterial

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susceptibility if serious infection with one of these organisms is suspected. Adverse reactions to ampicillin include rubella-like skin rashes which occur quite frequently, pruritis, urticaria, and, with oral use, gastrointestinal disturbances (nausea, vomiting, diarrhea). The appearance of a maculopapular rash does not necessarily imply that the patient is allergic to the drug; usually, ampicillin may be safely continued Very large doses administered parenterally may increase excitability of the nervous system sufficiently to produce convulsions. Eosinophilia commonly occurs. Elimination of normal flora from the gastrointestinal and respiratory tracts, permitting the overgrowth of organisms such as Pseudomonas and monilia, is a relatively constant finding. A few instances of moderate transaminase elevation have been observed, particularly in newborn infants. Therapeutic blood levels are readily achieved after intramuscular or intravenous administration. The recommended dosage for the treatment of severe, systemic infection (sepsis, meningitis, etc.) is 150 to 200 mg./Kg./day given parenterally in 4 divided doses. A smaller oral dose (100 m g . / K g . / day) is satisfactory when treating urinary tract infections, shigellosis or more trivial diseases. In general, considerable variation in blood levels is found when the drug is administered orally, and therefore it should not be employed in situations in which reproducible and predictable blood levels are desirable. Ampicillin has been found useful in the treatment of meningitis beyond the newborn period, typhoid fever (including the chronic typhoid excreter), salmonellosis, listeriosis, pertussis, and certain urinary tract infections, and represents the drug of choice in all types of H. influenzae infections and shigellosis. Ampicillin should not be employed as routine, broad-spectrum therapy for upper respiratory infections, pneumonia, and diarrheal disease of undetermined etiology. Penicillin G remains the preferred antibiotic in the treatment of most bacterial pneumonias.

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While ampicillin is widely used in the therapy of otitis media and pharyngitis, no data indicate that it is more effective than the much less expensive Penicillin V. Hetacillin. Hetacillin is prepared by the reaction of ampicillin with acetone. It has an antimicrobial spectrum similar to that of ampicillin and, aside from improved stability, offers no apparent advantages over the latter drug. However, its clinical effectiveness and toxicity in small children have not been adequately determined. Carbenicillin. Carbenicillin is structurally closely related to ampicillin and possesses approximately the same order of activity against gram-positive and gram-negative organisms. It is, however, also active against most indol-positive Proteus species and is bactericidal to Pseudomonas at in vitro concentrations ranging from 12.5 to 200 /zg per milliliter. These levels can only be reached with very large doses. Following intramuscular injection, peak serum levels are attained in one hour. The drug is very rapidly excreted in active form by the kidney; little serum activity remains after 4 hours. Serum levels can be raised and prolonged by simultaneous administration of probenecid. Oral administration does not result in measurable blood or urine levels. In a few patients with pseudomonas meningitis, the drug has been administered intrathecally. So far, the only toxic effects noted with carbenicillin have been a variety of drug rashes similar to those produced by ampicillin. In the absence of signs of serum sickness or urticaria, these rashes do not necessitate the discontinuation of carbenicillin. Carbenicillin is still classified as an investigational drug but will probably be available to the practicing physician in the future. At the present moment, it can be recommended only for the treatment of Pseudomonas septicemia, meningitis, pneumonia, or urinary tract infections, as well as disease caused by indol-positive Proteus species. Patients with cystic fibrosis who harbor Pseudomonas in their respiratory tree have shown clinical improvement, but carbenicillin therapy has

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not eliminated the organism from the sputum. Presently, the recommended dosage for the treatment of Pseudomonas or Proteus urinary tract infections is 50 to 100 mg./ Kg./day administered in 4 divided doses intralnuscularly or intravenously. When serious systemic infections due to Pseudomonas are to be treated, doses in the range of 100 to 300 mg./Kg./day in 6 divided doses have been employed; under some unusual circumstances as much as 1,000 mg./Kg./day have been administered without serious toxicity.

For the treatment of nontuberculous infections, the intramuscular dosage is 40 rag./ Kg./day, half of this amount being administered every 12 hours. When urinary output is depressed, the daily dose should be reduced to 30 or 20 mg./day. In infants, these regimens result in good blood levels without evidence of accumulation; if the drug is continued for periods of less than 10 days, no evidence of vestibular, auditory or renal damage has been noted. However, streptomycin may be nephrotoxic, particularly in patients with underlying renal disease. Therefore, in the presence of an elevated blood urea nitrogen or any other sign of renal insufficiency, the drug must be used with great care and in lowered dosage. Damage to the vestibular and auditory portion of the eighth nerve also occurs, particularly on prolonged use. Greatly excessive dosage of streptomycin in infants can produce a form of cardiovascular collapse which is similar to that noted with the gray syndrome produced by chloramphenicol. Finally, drug fevers occur quite frequently in children receiving this drug.

STREPTOMYCIN

Streptomycin, aside from its use in the therapy of tuberculosis, is presently employed infrequently in pediatrics. The drug is effective against a variety of gram-negative organisms, particularly E. coli, as well as some strains of Pseudomonas and Proteus. It also possesses activity against gram-positive bacteria, but this action is much less than that produced by other antimicrobial agents. Not all organisms susceptible in vitro are affected by streptomycin in vivo; for example, treatment of Brucella and Salmonella infections is usually unsuccessful. Resistance to streptomycin develops rapidly; as a result, many strains of the more common enterobacteria and Hemophilus influenzae are no longer susceptible. For this reason, kanamycin has replaced streptomycin in the treatment of most severe gram-negative infections. Streptomycin is occasionally used in urinary tract infections due to organisms susceptible to its action and resistant to other less toxic agents. Since the drug is most active in an alkaline environment, no attempt should be made to acidify the urine of these patients. The drug is rapidly absorbed following intramuscular injection. Most of the injected material is excreted in the urine at a rate considerably slower than that of penicillin. The drug is poorly and erratically absorbed from the gastrointestinal tract; most of the administered dose is excreted unchanged in the stool. The oral preparations of streptomycin are not useful in the therapy of any type of bacterial enteritis.

SULFONAMIDES

As new antibiotics have become available for therapeutic use, the importance of the sulfonamides in the management of human infections has greatly diminished. Many strains of gonococci, meningococci, streptococci, shigella, and coliform organisms have become resistant. The sulfonamides find their major clinical usefulness in the treatment of urinary tract infections and in the suppression of bacteriuria. They may be given to patients with rheumatic fever who are allergic to penicillin and who require prophylactic administration of a drug to combat streptococcal infection. They are no longer the drugs of choice in the treatment of meningococcal infections, bacterial meningitis, or shigellosis. No sulfonamide, including those most recently marketed, should be used for the therapy of group A betahemolytic streptococcal infections. In the therapy of upper respiratory infections, such as otitis media, it has been common practice

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to combine sulfonamides with penicillin or erythromycin. Adequate data indicate that such mixtures offer no advantages over the use of penicillin or erythromycin alone. The so-called triple sulfonamides and sulfisoxazole are relatively safe drugs. In the newborn infant, however, kernicterus occurs with increased frequency after administration of sulfonamides. In other age groups, crystalluria, hematuria, and occasionally renal shutdown have been reported as well as bone marrow depression and hepatic tox~ icity. Other toxic effects include fever, various cutaneous eruptions, and photosensitivity reactions. The use of long-acting sulfonamide preparations (Kynex, Madribon) may occasionally be associated with serious and peculiar reactions such as the Stevens-Johnson and the Ryetl syndromes, thrombocytopenic purpura, myocarditis, and hepatitis. Hemolysis and jaundice have been reported in newborn infants with inborn deficiency of erythrocyte glucose-6-phosphate dehydrogenase following maternal treatment with sulfamethoxypyridazine (Kynex). In general, it is our opinion that the convenience of the longacting sulfonamides does not compensate for their increased toxicity. TETRACYCLINES The tetracyclines are a family of closely related compounds, consisting of tetracycline itself and a bewildering variety of other natural or semisynthetic variations masquerading under many different names. These drugs do not differ from each other in spectrum of activity, toxicity, efficacy, potency, or any other essential characteristic. Thus, the physician should select for use whichever tetracycline can be employed most economically in his area. Actually, the uses of tetracycline in pediatric practice are very few. These drugs are bacteriostatic because of interference w~th synthesis of microbial protein. They have a wide range of antimicrobial activity, including many gram-positive and gram-negative bacteria, rickettsiae, the psittacosis-lymphogranuloma group of pseudoviruses, and the agent of primary atypical

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pneumonia. Clinical resistance occurs in a significant number of instances. Many strains of group A beta-hemolytic streptococci are now resistant, as are most staphylococci, many pneumococci, enterococci, and aerobic enteric gram-negative bacilli. The tetracyclines are absorbed rapidly from the gastrointestinal tract, become widely distributed in the tissues and fluids of the body, and are excreted in the bile, stool and urine. Blood levels obtained in children after oral administration are directly related to the amount of fluid administered concurrently. Approximately 1 c.e. of water per milligram of drug will permit maximal absorption. The recommended dosage is 25 to 50 mg./Kg./day in 4 divided doses. In full-term and premature infants the tetracyclines are absorbed from the gastrointestinal tract poorly; furthermore, their excretion is erratic, and the drugs tend to persist in the blood stream for long periods of time. Because of the toxicity of these agents, and because more effective medications are available, the use of tetracyclines in infants cannot be recommended. These agents may be administered intravenously, but should be used with care, since excessive dosage has led to liver toxicity. Intramuscular administration may be followed by erratic and unpredictable blood levels. All intramuscular preparations are highly irritating, and their use is associated with considerable destruction of muscle. The toxicity of the various members of this family of drugs is essentially identical. Administration of tetracyclines to expectant mothers, infants, and young children may produce a permanent brown-yellow or grayish-black discoloration of both the deciduous and permanent teeth of the children. The deposition of the drug in the enamel and dentine of teeth results in enamel hypopIasia, deformity of the cusps, and greatly increased rate of caries. This effect is determined mainly by the total dose of the drug and the time during dental development when administered, rather than by the duration of exposure. Furthermore, these agents have been shown to produce inhibition of bone

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The .lournai o/ Pediatrics November 19'69

growth in normal premature infants. Another but fortunately unusual side effect is the appearance of signs of increased intracranial pressure (pseudotumor cerebri). The tetracyclines may cause urea nitrogen retention in patients with normal and altered renal function; tubular damage resulting in a Fanconi-like syndrome has been reported to follow the administration of outdated tetracyclines. However, protein metabolism is usually affected even in the normal child; nitrogen balance remains negative as long as the drugs are administered, an obviously undesirable event during an acute or chronic illness. Frequently observed side effects are nausea, vomiting, and diarrhea. Elimination of various normal aerobic and anaerobic flora by these drugs permits overgrowth of highly resistant organisms of various types. Thus, vaginitis or proctitis occur commonly. An alteration in normal flora is undesirable, particularly in hospitalized patients who tend to acquire highly resistant and pathogenic organisms from their environment. Other side effects include various allergic or hypersensitivity reactions, skin eruptions, a phototoxic response to sunlight, and, if the drug is administered intravenously, hepatic damage. In summary, then, the tetracyclines possess an unusually high index of toxicity, and a low order of activity against most of the organisms responsible for common infections in pediatrics. Thus, this group should be relegated to the position of limited purpose drugs, prescribed only if other more effective and less toxic antimierobials cannot be administered, as well as in a few, relatively specialized situations. Certainly, their use is never indicated in the therapy of upper respiratory infections or bacterial pneumonia. Even in hospitalized patients the tetracyclines find limited usefulness. Their use is indicated in rickettsial diseases, occasional infections of the urinary tract, severe, ampicillin-resistant shigellosis, in diseases caused by the psittaeosis-lymphogranuloma group, in certain anaerobic infections, and in a few other unusual circumstances. In illrtesses due

to Eaton agent in children, no data exist to indicate that benefit is obtained from their use. MISCELLANEOUS ANTIMICROBIAL

AGENTS

Several agents more or less useful in the past have become obsolete with the introduction of more potent and less toxic agents. Triacetyloleandomycin belongs to the macrolid group of antibiotics and has the same range of activity as erythromycin. Prior to the introduction of the antistaphylococcal penicillins, it was useful in the therapy of moderately severe staphylococcal disease produced by penicillin- and erythromycinresistant staphylococci. It has been replaced by the antistaphylococcal penicillins and cephalothin. In other respects, erythromycin is a safer and equally effective drug, less likely to be associated with reversible disturbances of liver function, cutaneous hypersensitivity, rectal burning, headache, vomiting, diarrhea, skin rashes, etc. For purely commercial reasons, this drug is available in combination with a tetracycline, an illogical combination whose use identifies the nonthinking physician. Ristocetin was formerly employed for the treatment of severe staphylococcal disease resistant to other forms of therapy, but it is less effective and more toxic than the antistaphylococcal penicillins or cephalothin. Novobiocin is active against gram-positive cocci as well as some gram-negative orga~ nisms. Because of its relatively low order of activity and its high toxicity, manifested by a considerable incidence of skin rashes, drug fevers, the occasional appearance of neutropenia, thrombocytopenia, and liver disturbances, novobiocin no longer has a place in clinical practice. The commercially available combination of novobiocin with tetracycline represents an illogical and a potentially highly toxic combination, whose use can only be condemned in the strongest possible terms. Vancomycin is bactericidal against grampositive cocci and is very active against Staphylococcus aureus. Prior to the introduc-

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tion of the antistaphylococcal penicillins a n d the cephalosporins, the d r u g was useful in the t r e a t m e n t of severe staphylococcal disease caused by penicillin-resistant strains. Its usefulness now is limited to patients with potentially fatal staphylococcal infections who are allergic to penicillin a n d who cannot tolerate the cephalosporins. T h e d r u g m a y also be useful in bacterial endocarditis caused b y enterococci or nonhemolytic streptococci in patients who are u n a b l e to tolerate penicillin. I t must be a d m i n i s t e r e d intravenously. U n f o r t u n a t e l y , the use of vancomycin in children is associated with a high incidence of thrombophlebitis a n d n o t unc o m m o n l y with d a m a g e to the kidney a n d auditory p o r t i o n of the eighth nerve. This p a p e r will be continued in the following issue of the JOURNAL.

Antimicrobial therapy. I

3.

4. 5. 6.

7. 8.

9. 10.

REFERENCES

1. Hunt, A. D., and Fell, M. B.." Streptomycin intramuscular dosages per unit body weight correlated with serum levels in infants and children, Pediatrics 4: 163, 1949. 2. Nord, N. M., and Hoeprich, P. D.: Polymyxin

11. 12.

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B and colistin: A critical comparison, N. England J. Med. 270: 1030, 1964. Kaplan, K., Chew, W. H., and Weinstein, L.: Microbiological, pharmacological and clinical studies of lincomycin, Am. J. M. Sc. 250: 137, 1965. Merrill, S. L., Davis, A., Smolens, B., and Finegold, S. M.: Cephalothin in serious bacterial infection, Ann. Int. Med. 64: 1, 1966. Mann, C. H., editor: Kanamycin: Appraisal after eight years of clinical application, Ann. New York Acad. Sc. 132: 771, 1966. McCracken, G. I-I., and Eichenwald, H. F.: Antimicrobial therapy in infancy and childhood: 1966, Pediat. Clin. North America 13: 231, 1966. Olson, C. A., and Riley, H. D.: Complications of tetracycline therapy, J. P~DIAT. 68: 783, 1966. Mann, C. H., editor: Comparative assessment of the broad-spectrum peniciUins and other antibiotics, Ann. New York Acad. Sc. 145: 207, 1967. Brumfitt, W., Percival, A., and Leigh, D. A.: Clinical and laboratory studies with carbenicillin, Lancet 1: 1289, 1967. Axlene, S. G., Yaffe, S. Y., and Simon, tI. J.: Clinical pharmacology of antimicrobials in premature infants, Pediatrics 39: 97, 1967. Kunin, C. M.: The tetraeyclines, Pedlar. Clin. North America 15: 43, 1968. Holt, R. J.: Gentamicin in urinary infections of children, Arch. Dis. Childhood 43: 329, 1968.