Antibiotic drugs Among the hundreds of compounds produced by microorganisms that have inhibitory action on other microorganisms, only a relatively small number have a favorable therapeutic index. These are the clinically useful antibiotics. In the present discussion, particular attention will be paid to the potency, antibacterial spectrum, metabolism, and mode of action of these various antibiotic drugs. Penicillin is a highly effective bactericidal antibiotic which has very low toxicity. If it were not for penicillin allergy, the antibiotic would approach perfection for infections caused by susceptible organisms. Penicillin is obtained from cultures of Penicillin chrysogenum. The semisynthetic penicillins are made by modification of the mold product. Penicillin is an organic acid. Its sodium, potassium, and procaine salts are commonly used. There are several other naturally occurring penicillins that differ from penicillin G in having a side chain other than benzyl. Some of these are penicillin F, dihydro F (amylpenicillin), and also K and X. None of these naturally occurring compounds has a significant advantage over penicillin G, and some, such as K, may be much less effective in vivo because of a high degree of plasma protein binding. Although several biosynthetic penicillins have been prepared by adding various precursors of the side chain to the Penicillium culture medium, more recently anew procedure has opened up a field for the preparation of new penicillins. A key intermediate, 6-aminopenicillanic acid, is produced by fermentation, and new penicillins are prepared by adding various groups to this intermediate. Penicillin has been completely synthesized through cooperative efforts of several groups of workers. Total synthesis is much too difficult for commercial production. The available penicillins may be placed in several groups. Penicillin G, or benzylpenicillin, is the prototype. Semisynthetic penicillins, which have a broader antibacterial spectrum but are still susceptible to penicillinase, represent an important group. Other semisynthetic penicillins are resistant to penicillinase and are sometimes called antistaphylococcal penicillins. Minor modifications of penicillin G yielded penicillin V, which is more acid resistant but has no great advantages over penicillin G. The “broad spectrum” penicillins have a greater effect on many gram-negative organisms. They include ampicillin, amoxicillin, carbenicillin, and ticarcillin. This group is still susceptible to penicillinase. The penicillinase-resistant penicillins include oxacillin, cloxacillin, dicloxacillin, methicillin, and nafcillin. Penicillin preparations are standardized on the basis of their growth-inhibition potency against test organisms such as Bacillus subtilis or staphylococci. Activity is expressed in units and is measured in comparison with a standard preparation by determining the zone of inhibition of bacterial growth on an inoculated agar plate. The amount of activity represented by 1 unit is sufficient to prevent multiplication of a susceptible organism such as Bacilus subtilis or certain staphylococci in as much means that 1 unit is equivalent to 0.6 μg of penicillin G. The enormous activity of penicillin may be appreciated from the fact that if 1 mg of the antibiotic were placed in about 5 gallons of broth, the growth of several susceptible organisms would be prevented by the resulting minute concentration of the antibiotic .By contrast it would be necessary to add 2 to 20g of a sulfonamide to this volume of culture medium to obtain similar growth inhibition. Microorganisms inhibited by less than 1 unit of penicillin/ml may be considered moderately susceptible. The highly susceptible infective agents are usually inhibited by less than 0.1 unit/ml. Blood levels of 0.1 to 1.0 unit/ml can be achieved without difficulty in clinical practice. Penicillin is a bactericidal antibiotic that inhibits the synthesis of the cell wall of susceptible bacteria. Its basic action is on a transpeptidase in bacteria. The bactericidal activity of penicillin is quite different from that of the common disinfectants. Penicillin does not kill bacteria rapidly on contact. It apparently produces some alteration in the bacteria that makes them more susceptible to death and disruption. It has been established that rapidly multiplying bacteria are most susceptible to the killing effect of penicillin. The absorption of penicillin G from the gastrointestinal tract is incomplete and variable. To obtain comparable blood levels it is usually necessary to administer five times as much of the antibiotic by the oral route as by intramuscular injection. The reasons for this incomplete absorption are inactivation of the drug by the gastric juice and, once it reaches the large intestine, by bacteria as well. Some of the newer penicillin preparations such as penicillin V are fairly resistant to an acid environment. The absorption of penicillin following oral administration is greatly influenced by the presence of food in the stomach and the rate of gastric emptying. More predictable results are obtained if the drug is taken on an empty stomach. Blood levels obtained following administration of 100,000 units of penicillin G sodium by various routes are shown in Fig.53-1. It is clear that very transient high levels reaching 2 to 4 units/ml can be obtained by either the intravenous or intramuscular route. The same dose given orally produces a blood level of only about 0.4 units/ml, but demonstrable activity remains for a longer time. The rapid decline of penicillin blood levels results from rapid renal clearance of the antibiotic. It has been well established that penicillin is actively secreted by the renal tubules, apparently by the same mechanism as p-aminohippurate or iodopyracet (Diodrast). Drugs have been developed that can block this tubular secretory mechanism. One of these is probenecid (Benemid), which is quite effective. It is of little use in penicillin therapy, however , since it is just as easy to use larger doses of penicillin as to administer a second drug for the purpose of preventing its excretion. Probenecid, on the other hand, has an important clinical application as a uricosuric drug. A number of repository preparations of penicillin are available for the purpose of producing sustained blood levels. Procaine penicillin G and benzathine penicillin G are two such preparations. With the latter preparation, demonstrable penicillin blood levels can be maintained for as long as 20 days. It is important to keep in mind, however, that demonstrable blood levels are often defined as 0.03 unit/ml or more. This low concentration of the antibiotic may not suffice in many infections, although it may be beneficial in prevention of streptococcal infections and prophylaxis of rheumatic fever. []（prevention） Distribution of penicillin in the body is far from uniform. First, the antibiotic is partially bound to plasma proteins. Under normal circumstances it penetrates poorly into the cerebrospinal fluid, aqueous humor, and joint fluids. On the other hand, inflammation at these various sites greatly increases the permeability to penicillin. [] [] The cumulative urinary excretion of sodium penicillin G following its oral and intramuscular administration is shown in Fig. 53-2. As much as 80% of the intramuscularly administered dose may be recovered in the urine in less than 4 hours. Only about 20% is usually recovered following the oral administration of the antibiotic. With oral administration, this difference results from lack of absorption of much of the administered dose. [],Na+ The inherent toxicity of penicillin as determined in animal experiments is extremely low. In several animal species the acute toxicity of penicillin is so low that death from overdosage has been attributed to the cation rather than to penicillin itself. Unfortunately, however, a significant percentage of the human population shows hypersensitivity reactions to penicillin. These reactions are of many different types, ranging from immediate anaphylactic reactions to late manifestations of the serum sickness type. It is believed that several hundred severe anaphylactic reactions have occurred following penicillin injections, many terminating fatally. Hypersensitivity reactions are seen most often following topical use of penicillin and most rarely after oral administration. The incidence of such reactions has been estimated to vary from 1% to 8% in the general population. Skin tests for the determination of penicillin allergy are unreliable and dangerous when penicillin G itself is injected in small quantities intracutaneously. On the other hand, preparations are available, at least for experimental purposes, in which penicilloylpolylysine (PPL) is suitable for testing allergy to the major determinant. Also, a mixture of penicillin, penicilloate, and other products is suitable for testing allergy to the minor determinants. Despite these refinements in diagnosing penicillin allergy, tests are mot completely reliable. As a consequence, the history of previous reactions is very important, and even in the presence of a negative intradermal test, it is best to be prepared for the possibility of anaphylactic reaction whenever the antibiotic is injected. In addition to hypersensitivity reactions, penicillin is capable of producing other adverse effects. Neural tissue may be susceptible to penicillin, particularly when vulsive phenomena have been noted following such procedures. There is seldom any reason for injecting penicillin intrathecally. Ampicillin (Penbritin, Omnipen, Polycillin) differs from penicillin G mainly in having a greater effect on many gram-negative microorganisms. Also the drug is more acid resistant and is absorbed better following oral administration. Ampicillin is effective in the treatment of urinary tract infections caused by Escherichia coli and Proteus mirabilis（susceptible strains）. The antibiotic is also effective in the treatment of respiratory infections and meningitis caused by susceptible Hemophilus strains. Ampicillin may cause skin rash in 10% of patients, especially if the patient has infectious mononucleosis. Some rashes produced by ampicillin may not be allergic. Ampicillin is available in capsules, 250 and 500 mg. The sodium salt is available for intramuscular and intravenous administration. Amoxicillin trihydrate (Amoxil, Larotid)differs from ampicillin only in producing somewhat higher serum concentrations, and it may be better absorbed in children. Carbenicillin disodium (Geopen) differs from ampicillin in its greater activity against Pseudomonas aeruginosa and Bacteroides fragilis. Also it may be active against strains of Hemophilus and Proteus that are resistant to ampicillin . A special feature of carbenicillin is its high sodium content. Since 1 g of the antibiotic contains 6 mEq of sodium, large doses may cause sodium overload in renal and cardiac patients. Carbenicillin disodium (Geopen) should not be given orally, since it is not absorbed. Carbenicillin indanyl sodium (Geocillin) is available in tablets for oral administration but is not commonly used. Ticarcillin disodium (Ticar) is closely related to carbenicillin and is available for intramuscular and intravenous use. It may have somewhat greater potency against the difficult gram-negative bacilli than carbenicillin. The penicillinase-resistant penicillins are very useful in the treatment of infections caused by organisms that are resistant to penicillin G, such as hospital-acquired staphylococcal infections. If the organism turns out to be susceptible to penicillin G, it is best to switch because of its lower cost and some other advantages. Although these penicillins are resistant to staphylococcal penicillinase, a few strains appeared, which developed “methicillin resistance” not based on penicillinase. Methicillin was the first penicillinase-resistant penicillin and is still used. However, nafcillin is the most potent antibiotic in this group. Methicillin sodium (Staphcillin) is administered intramuscularly or intravenously, and the drug is quite unstable in solution. Its only advantage is in infections caused by staphylococci that are resistant to penicillin G. The antibiotic may have some nephrotoxic potential. Nafcillin sodium (Unipen, Nafcil) may be administered orally, intramuscularly, or intravenously. It is more potent than methicillin, it may penetrate the spinal fluid better, and it is largely excreted in the bile. Oxacillin sodium (Prostaphlin, Bactocill) is very similar in actions and indications to nafcillin. It may be given orally or parenterally. Cloxacillin sodium (Tegopen, Cloxapen) and Dicloxacillin sodium (Dynapen, Dycill) are very similar to oxacillin and are available in capsules for oral administration. The cephalosporins are β-lactam antibiotics obtained originally from a cephalosporium mold. These antibiotics have the same mechanism of action as the penicillins, but differ in antibacterial spectrum, in resistance to β-lactamase, and also in pharmacokinetics. Whereas the penicillins are derivatives of 6-aminopenicillanic acid, the cephalosporins are derivatives of 7-aminocephalosporanic acid. The related cephamycins have a 7-α-methoxy group, which may increase their resistance to β-lactamases. The antibacterial spectrum of the cephalosporins is similar to that of the penicillinase-resistant penicillins, except that they are less effective against Hemophilus influenzae, and they are ineffective against Pseudomonas, several species of Proteus, Klebsiella, B. fragilis, and enterococci. Because of their broad antibacterial spectrum and resistance to β-lactamase, the cephalosporins are being greatly overused in clinical situations in which the penicillins would be just as effective and less costly. For example, the cephalosporins do not penetrate well into the cerebrospinal fluid even in meningitis and they do not enter ocular fluids well. The cephalosporins are eliminated both by glomerular filtration and tubular secretion. Probenecid prolongs the half-life of these drugs as does renal impairment. The cephalosporins may cause bone marrow depression and some of them, particularly cephaloridine, may cause renal tubular necrosis. The cephalosporins are best classified on the basis of their mode of administration. The orally administered members of the group include cephalexin monohydrate (Keflex), cephaloglycin dihydrate (Kafocin), cefaclor (Ceclor), and cefadroxil monohydrate (Duricef), The parenteral cephalosporins include cephalothin sodium (Keflin), sterile cephapirin sodium (Cefadyl), Cephacetrile sodium (Celospor), sterile cefazolin sodium (Ancef, Kefzol), cefamandole nafate (Mandol), and the cephamycin cefoxitin sodium(Mefoxin). Finally, cephradine (Anspor,Velosef) can be administered either orally or parenterally. The increasing number of cephalosporins are basically similar in their indications and uses. A physician could become familiar with one oral and one parenteral drug without having to learn about all members of the group. It should be remembered that these antibiotics should not be considered drugs of first choice in most infections, although they may be very useful in the prevention of infections in surgery. However, for this indication, the cephalosporins should not be given for prolonged periods before and after surgery. Cephalothin and cephapirin are not significantly different as regards pharmacokinetics, ptency, and indications. Cefazolin gives higher serum levels, although it is bound to proteis to a greater extent and has a serum half-life of 1.8 hours compared to 0.5 hour for cephalothin. It is also claimed to penetrate human tissues, such as bone and bile more effectively, although ie does not penetrate int the cerebrospinal fluid. The newer cephalosporis, cefamandole and cefoxitin (a cephamycin), may have somewhat greater effectiveness in certain gram-negative bacillary infections but are less active against penicillinase-producing staphylococci. Cefoxitin is the most active drug in this class against B.fragilis. There is clearly a clinical equivalence between cephalexin and cephradine, and cephalothin and cephapirin. The newer cephalosporins, cefamandole and cefoxitin, should be reserved for situations in which they offer clear-cut advantages. The aminoglycoside antibiotics-streptomcin, neomycin, kanamycin, gentamicin, and tobtamycin-are bactericidal drugs, which are indicated for the treatment of serious infections caused by many gram-negative bacilli and some gram-positive organisms. However, for the latter indications penicillin and the cephalosporins may be preferable. The aminoglycosides have a broad antibacterial spectrum, but streptococci, pneumococci, clostridia, Bacteroides, and fungi are usually resistant. The essential features of several aminoglycosides are shown in Table 53-2. The aminoglycosides include streptomycin, gentamicin, kanamycin, neomycin, tobramycin, paromomycin, and spectinomycin. The most commonly used antibiotic in this group is gentamicin. The aminoglycosides are not absorbed well following oral administration. For that reason they are generally administered intramuscularly or intravenously except in the case of neomycin and paromomycin, which have some usefulness in decreasing the intestinal flora. The aminoglycosides are not greatly bound to serum proteins and are well distributed in the body. However, their penetration into the spinal fluid may not be good enough for some therapeutic purposes. The aminoglycosides are excreted by glomerular filtration without tubular reabsorption. Nephrotixicity may range from proteinuria to severe azotemia but is usually reversible. Since the aminoglyxosides are excreted by the kidney, preexisting renal damage calls for caution and readiustment of dosage schedules. The neuromuscular blocking effect of the aminoglycosides may lead to apnea, particularly in myasthenia gravis or with certain general anesthetics and neuromuscular blocking agents. Intravenous calcium gluconate is effective in antagonizing neuromuscular effects of the aminoglycosides and neostigmine may be useful. Resistance develops rapidly to the antibacterial action of streptomycin and more slowly to the other aminoglycosides, Resistance to one aminoglycoside does not necessarily mean resistance to all. Plasmids mediate resistance in most cases. They induce the production of enzymes that acetylate or phosphorylate the aminoglycoside. These enzymes may be specific for some but not all of the aminoglycosides. For example, some organisms, such as the Pseudomonas, may be resistant to gentamicin but may be susceptible to amikacin. Streptomycin, discovered in 1944, differs from penicillin in being an organic base rather than an acid. It is not absorbed from the gastrointestinal tract, has a much broader antibacterial spectrum although a generally lower potency, and has direct toxic effects in the mammal. At present the main usefulness of this antibiotic is in the treatment of tuberculosis and in combination with penicillin, in which the synergism between the two drugs may be of great importance in selected cases. Gentamicin sulfate (Garamycin) and tobramycin sulfate (Nebcin) are very similar chemically and pharmacologically. Their main difference is the greater potency of tobramycin against Pseudomonas aeruginosa. The major usefulness of gentamicin and tobramycin is in the treatment of systemic infections caused by susceptible gram-negative bacteria. Streptococci, pneumococci, anaerobic bacteria, and fungi are resistant. In the clinical use of these drugs, renal elimination, nephrotoxicity, ototoxicity, and neuromuscular dysfunction should be taken into consideration. In addition, gentamicin should not be mixed with carbnicillin or heparin. Gentamicin sulfate (Garamycin) is available in solutions containing 20 mg/ml and in disposable syringes. Tobramycin sulfate (Nebcin) is available in solutions containing 10 or 40 mg/ml and in disposable syringes. The dosage for adults with normal renal function of either drug is 3 to 5mg/kg daily in divided doses administered intramuscularly or intravenously. Amikacin sulfate (Amikin) is a chemically modified semisynthetic aminoglycoside. The chemical modification confers resistance to the inactivating effect of enzymes that are capable of destroying the activity of gentamicin and tobramycin. Amikacin is actually a derivative of kanamycin. The drug is available for the treatment of infections caused by gram-negative bacteria in solutions containing 50 and 250 mg/ml for intramuscular and intravenous administration. Neomycin sulfate (Mycifradin sulfate) is quite toxic and should be used only topically or orally. When given orally, only a small percentage of the dose is absorbed, and reduction of intestinal flora may be beneficial in the treatment of hepatic coma. Kanamycin sulfate (Kantrex) may be useful in the treatment of gram-negative bacillary infections, but many resistant strains have appeared and gentamicin is generally preferred. Oral administration may be useful for reduction of ammonia production by the intestinal flora. Paromomycin may be used orally for the treatment of intestinal amebiasis. It is discussed on p.681. The tetracyclines are broad-spectrum bacteriostatic antibiotics, which inhibit protein synthesis in bacteria by blocking the combination of aminoacyl transfer ribonucleic acid(RNA) with messenger RNA. These antibiotics are highly effective in the treatment of brucellosis, Mycoplasma pneumoniae, and cholera, and they may be useful as alternatives in many infections in which the drug of choice cannot be used. Being bacteriostatic, the tetracyclines occasionally interfere with the killing effect of a bactericidal antibiotic such as penicillin. The three tetracycline antibiotics, chlortetracycline (Aureomycin), oxytetracycline (Terramycin), and tetracycline were discovered as a result of extensive screening ex[periments on antibiotics produced by soil organisms. These drugs are characterized by a wide antibacterial spectrum, effectiveness of oral administration,and a very favorable therapeutic index. They are essentially bacteriostatic drugs, except in very high concentrations. Their use may in some cases modify the infection rather than eradicate it completely. Their characteristics are summarized in Table 53-3. Tetracycline is a true broad-spectrum antibiotic and for that reason it is probably overused. Such excessive use has led to the development of many resistant strains of bacteria and to superinfections, which in some series have been as high as 20% of patients. In general, broad-spectrum agents are more conducive to superinfections than are antibiotics having a narrow spectrum. Tetracycline hydrochloride is widely used in the treatment of infections cause by Mycoplasma pneumoniae, or chlamydiae, in cholera, in various infections related to the respiratory tract such as mucoviscidosis, in rickettsial infections, and in the management of skin infections such as acne and many others. In addition to the three well-known tetracycline antibiotics, other derivatives have been introduced. Demeclocycline (Declomycin) was introduced a few years ago. Although certain advantages have been claimed for this drug, some cases of photosensitization have been reported following its use. Its ultimate status in relation to the other tetracyclines cannot be stated at present Methacycline (Rondomycin) resembles demeclocycline in its pharmacology. Doxycycline monohydrate (Vibramycin monohydrate) differs from other tetracyclines in that less frequent administration is effective because the drug is less readily excreted. It may cause phototoxicity. Rolitetracycline (Syntetrin) is a very soluble derivative of tetracycline and is suitable for parenteral administration. I t may be injected intravenously or intramuscularly. Another slowly excreted member of the tetracycline family is minocycline (Minocin). The slowly excreted tetracyclines, such as demeclocycline, methacycline, and minocycline, may accumulate in the body and produce toxicity when renal function is impaired. Doxycycline is slowly excreted also but appears to be safer in renal failure. Problem 53-1. The causative agent in a stubborn urinary tract infection was found to be most susceptible to the tetracyclines. The physician selected doxycycline because of the convenience of twice-daily administration. Was this a good choice? No, because doxycycline is not excreted in the urine to the same extent as some other tetracyclines. All these drugs are absorbed rapidly but incompletely from the gastrointestinal tract. Calcium salts and gastric antacids prevent their absorption. Variable amounts may remain in the large intestine, and the bacterial flora of the intestinal contents may be altered considerably. The development of serious staphylococcal gastroenteritis during therapy with one of the tetracycline has been attributed to the phenomenon of superinfection, with micrococci producing exitoxin. Oral administration of 250 mg of tetracycline will produce a serum level of about 0.7 μg/ml in less than 2 hours (Fig.53-3). This level will decline very gradually to about half this value in approximately 12 hours. This slow decline may be explained by the low renal clearance of the drug. During the first 12 hours only about 10% to 20% of the dose appears in the urine. The drug is widely distributed in the various tissues and probably penetrates into cells, but its level in the cerebrospinal fluid is less than in plasma. Probably as a consequence of its chelating properties, tetracycline tends to localize in bones and teeth, where it may be detected by its fluorescence. Tetracycline fluorescence is widespread but tends to disappear from normal tissues, except from bones and teeth, in about 24 hours. It tends to remain in inflammatory tissue somewhat longer, whereas it clings to neoplastic tissue for a surprisingly ling time. Problm 53-2. Inhibition of gastrointestinal absorption of tetracycline by gastric antacids is generally attributed to chelation. Would sodium bicarbonate interfere with the absorption of the antibiotic, and if so, by what mechanism? In an experimental study of this problem, it was found that sodium bicarbonate interferes with the dissolution of tetracycline contained in capsules and thus interferes with absorption. Adverse effects caused by tetracyclines include nausea, vomiting, enterocolitis, stomatitis, and superinfections. Phototoxicity may occur after the administration of demeclocycline (Declomycin). Adminstration of the tetracyclines in large doses has produced liver damage in patients, as proved by liver biopsy. Recent evidence suggests that tetracycline in large doses produces a negative nitrogen balance and probably exerts an antianabolic action. Interference with protein synthesis may be the basis of these effects. A similar action may explain the mechanism of its action against bacteria. Chloramphenicol (Chloromycetin) is a broad-spectrum antibiotic having an antibacterial spectrum and potency very similar to those of the tetracyclines. It is not effective, however, against Entamoeba histolytica but is more effective than the tetracyclines in the treatment of typhoid fever. It may be seen from the structural formula of chloramphenicol that this antibiotic is a derivative of nitrobenzene. The drug is well absorbed from the gastrointestinal tract. It is largely metabolized in the body, so that only about 10% of an administered dose appears in the urine in the unchanged form. The mode of action of chloramphenicol is not completely understood. The drug is largely bacteriostatic. Considerable evidence indicates that it interferes with protein synthesis in bacteria and also in human protein-synthesizing systems, at least as demonstrated with human bone marrow cells in tissue culture, Chloramphenicol attaches to the bacterial ribosomes (50S subunits) and prevents the binding of amino acids, thus interfering with the growth of the peptide chain. The acute toxicity of chloramphenicol in experimental animals is about the same as that of the tetracyclines. In clinical usage many minor side effects such as gastrointestinal disturbances, glossitis, skin rash, and superinfection may occur. These are similar to the effects produced by the tetracyclines. On the other hand, it is generally recognized that chloramphenicol has a much greater tendency than have commonly used antibiotics to produce blood dyscrasias such as aplastic anemia. Although the incidence of this serious toxic effect is small, it is sufficient to made physicians very cautious in the use of chloramphenicol. Chloramphenicol is particularly dangerous in infants, in whom it can lead to a symptom complex often referred to as the “gray syndrome.” The gray syndrome occurs in premature and newborn infants when chloramphenicol is administered during the first few days of life. Symptoms consist of cyanosis, vascular collapse, and elevated chloramphenicol levels in the blood. The syndrome results from lack of development of glucuronyl transferase in the liver, which normally detoxifies the antibiotic by changing it to the glucuronide. Since chloramphenicol can cause fatal aplastic anemia in rare cases, it should not be used if there is a suitable alternative. At the same time the antibiotic is not contraindicated if an infection is severe and the drug appears to be the best by susceptibility tests. Chloramphenicol sodium succinate, a water-soluble derivative, is available for parenteral administration. Bacitracin, polymyxin, and colistin are discussed as a group for two reasons. First, all three are nephrotoxic when administered systemically in large enough doses. Second, they are used mostly for special purposes and only rarely as systemic chemotherapeutic agents. Bacitracin, a mixture of polypeptides, was first isolated from cultures of a gram-positive bacillus. Its name was derived from Tracy, the name of the patient from whom the bacillus was isolated. The antibacterial spectrum of bacitracin is remarkably similar to that of penicillin. It is particularly effective against gram-positive organisms, those of the Neisseria group, and spirochetes. The main usefulness of bacitracin is in treating infections of the skin and mucous membranes, where it can be applied topically. When used by intramuscular injection, renal tubular damage regularly occurs in patients or experimental animals if large enough doses are used. The main usefulness of bacitracin is in treating infections of the skin and muxous membranes, where it can be applied topically. When used by intramuscular injection, renal tubular damage regularly occurs in patients or experimental animals if large enough doses are used. The activity of bacitracin is expressed in a unit that represents 26 μg of a standard preparation. For topical use, ointments containing 500 units/g of base are available. Bacitracin is valuable for topical application and, compared to penicillin, has the great advantage of seldom causing sensitivity reactions. The drug is not absorbed from the gastrointestinal tract. Polynyxin B is one of a serous of polypeptide antibiotics produced by Bacillus polymyxa, a soil bacillus. This antibiotic has a potent bactericidal effect on gram-negative bacilli. Unfortunately, when administered to patients in daily doses exceeding 4 mg/kg, it is likely to cause renal tubular damage. This appears to be a direct toxic effect, readily demonstrable in experimental animals. The main usefulness of polymyxin is for topical application. Many preparations for available for this purpose, and the drug is generally combined with either bacitracin or neomycin in order to widen the antibacterial spectrum. The polymyxins are useful in the treatment of severe urinary tract infections. The systemic use of polymyxin is hazardous, and the daily dose should not exceed 3 to 4 mg/kg in adults. In addition to nephrotoxic action, systemic use of polymyxin can produce CNS effects such as vertigo and paresthesia. Polymyxin B is not absorbed significantly from the gastrointestinal tract and may occasionally be used by mouth for intestinal chemotherapy. When the drug is applied to open wounds, absorption may take place and the total quantity applied in a day should not exceed 3 to 4 mg/kg. Colistin is a polypeptide antibiotic very similar in antibacterial spectrum and toxicity to polymyxin B. Although some investigators believe that the drug is less neurotoxic and is not as likely to produce paresthesia, others question the superiority of this drug over polymyxin B. It is available as sodium colistimethate (Coly-Mycin), used in daily doses of 2 to 5 mg/kg by intramuscular injection. Since penicillin and the broad-spectrum antibiotics became available, several important additional discoveries have been made in the fight against gram-positive organisms, such as the introduvtion of erythromycin, the discovery of newer antibiotics effective against resistant micrococci (staphylococci), and the development of the newer penicillins. Erythromycin (Ilotycin), a macrolide antibiotic, was isolated from a strain of Streptomyces. It is an organic base having a molecular weight of about 700. This antibiotic is particularly effective against gram-positive microorganisms, although gonococci, Hemophilus organisms, and the large viruses of the lymphogranuloma venereum group are somewhat affected by it. Its antibacterial spectrum is between that of penicillin and of the tetracyclines, but the gram-negative bacilli such as Escherichia coli and Salmonella organisms are not inhibited by it . Its mode of action appears to be largely bacteriostatic, since it has a true killing effect only at very high concentrations. Erythromycins are among the safest antibiotics commonly used for respiratory infections, particularly in patients allergic to penicillin. Erythromycins should not be used in serious staphylococcal infections or in the treatment of gonococal infections because better drugs are available. Gastric juice tends to destroy erythromycin, but enteric-coated preparations and the erythromycin stearate are well absorbed. It is given in doses of 0.5g every 6 hours, and blood levels of 2μg/ml or more can be obtained. Many gram-positive organisms are inhibited by levels below this amount. Erythromycin estolate (Ilosone) is stable in acid, is well absorbed, and is excreted in lesser amounts in bile. Thus, when taken with food, it gives faster, higher, and longer lasting blood levels than comparable doses of erythromycin. Cholestatic jaundice has been reported following the use of this drug and other esters of erythromycin. Although this occurs rarely, caution is necessary in its use. In addition to erythromycin estolate (Ilosone), the antibiotic is also available as erythromycin base (Ilotycin), the stearate, erythromycin ethylsuccinate (Pediamycin), erythromycin gluceptate (Ilotycin Gluceptate), and erythromycin lactobionate (Erythrocin Lactobionate). In general the erythromycin base is rapidly destroyed by gastric juice and the stearate is more stable but is not absorbed as well as the esters. Vancomycin hydrochloride (Vancocin hydrochloride) is a glycopeptide that is highly toxic but bactericidal against gram-positive cocci. It should only be used orally to treat staphylococcal enteritis and in severe infections caused by gram-positive cocci when other antibiotics may be ineffective or the patient is allergic to them. Vancomycin can cause permanent deafness and fatal uremia. Novobiocin (Albamycin) has a narrow antibacterial spectrum, being effective against gram-positive cocci. The main disadvantage of this antibiotic is the high incidence of adverse reactions, probably based on sensitization. Skin rashes, fever, and blood dyscrasias are caused in such a high percentage of patients that novobiocin should probably never be used. Lincomycin (Lincocin) is structurally unrelated to previously discussed antibiotics. Its antibacterial spectrum resembles that of erythromycin. It is effective against gram-positive organisms, Neisseria, and Bacteroides. It is administered by mouth, intramuscularly, or intravenously. Its usual adult dose is 0.5g every 6 to 8 hours. Side effects from lincomycin include gastrointestinal manifestations, skin rashes, and anaphylactoid reactions. Clindamycin (Cleocin) is closely related to lincomycin structurally. In fact, it differs only in a chloro substitution of the 7-hydroxyl group. The spectrum of activity of the drug includes gram-positive organisms (not Neisseria or enterococci), Actinomyces, and B.fragilis. The drug is administered by mouth in a usual adult dose of 150 to 450 mg every 6 hours. The drug may be either bactericidal or bacteriostatic and acts by inhibiting protein synthesis in the 50 S subunit of the ribosome. Adverse effects caused by clindamycin include gastrointestinal manifestations, neutropenia, eosinophilia, rashes, and elevated serum glutamic-oxaloacetic transaminase (SGOT) levels. Although clindamycin has produced excellent results in the treatment of anaerobic infections, severe hemorrhagic colitis has occurred in some patients following the use of the antibiotic. This serious complication may limit the usefulness of clindamycin. Clindamycin hydrochloride (Cleocin hydrochloride) is available in capsules, 75 and 150 mg. Clindamycin palmitate is available in granules for suspension, 75 mg/5 ml. Clindamycin phosphate (Cleocin phosphate) is available in injectable solutions containing 150 mg/ml. Nystatin (Mycostatin) and amphotericin B (Fungizone) are also called polyene antibiotics. This name refers to the fact that these antibiotics contain a large ring with a conjugated double-bond system. There is evidence to indicate that the polyene antibiotics injure the membrane of the fungi, perhaps by complexing with sterols that occur in these membranes. Because of this interaction, sterols protect yeasts against the action of these antibiotics. Bacterial membranes are not injured by the polyenes. On the other hand, the hemolytic anemia sometimes caused by the polyene antibiotics may be a consequence of injury of the red cell membrane, which is known to contain cholesterol. Nystatin is effective against Candida albicans and some other fungi. It appears to be useful against those monilial infections that can be reached by topical application. The drug is inactivated by gastric juice, and no systemic effects can be expected when it is administered orally although it has been incorporated in tetracycline preparations. Amphotericin B appears to be the most effective antibiotic against deep-seated mycotic infections. The usefulness of the antibiotic has been demonstrated against histoplasmosis, cryptococcosis, blastomycosis, and coccidiodomycosis. It has also proved to be effective in systemic infections caused by Candida albicans. The drug is administered intravenously but can cause thrombophlebitis at the site of injection and may also produce some renal damage, skin rash, and gastrointestinal upset. Test doses of 1 to 5 mg are injected first. If there is no untoward reaction, these may be followed by daily doses of 20 to 50 mg. Although amphotericin B is obviously a dangerous drug, its use may be justified in severe systemic fungous infections. Its intravenous LD50 in mice is of the order of 5 mg/kg. The drug is poorly absorbed from the intestine. Griseofulvin represents an interesting development in the treatment of certain dermatomycoses. The antibiotic is produced by a Penicillium mold. When given orally for long periods of time, it is apparently incorporated into the skin, hair, and nails and exerts a fungistatic activety against various species of Microsporum, Trichophyton, and Epidermophyton. Prolonged administration is necessary because ring-worm of the skin may require several weeks for improvement. In fungal infectons of the nails, treatment may have to be continued for several months. The most common side effects consist of gastric discomfort, diarrhea, and headache. Urticaria and skin rash may also occur. Griseofulvin (Fulvicin, Grifulvin V, Grisactin) is available in tablet form containing 125,250, or 500 mg. Several other antifungal agents are available, mostly for topical application. These include candicidin, miconazole, clotrimazole, flucytosine, haloprogin, tolnaftate, iodochlorhydroxyquin, and undecylenic acid. Candicidin (Candeptin, Vanobid) is a polyene antibiotic available in ointments and capsules or tablets to be inserted in the vagina. Miconazole nitrate (Monistat, Micatin) is an imidazole derivative, which may act on the fungal plasma membrane. Although the drug can be used intravenously for the treatment of infections caused by Candida albicans, Cryptococcus, and Aspergillus, its main usefulness is its topical application for dermatophytosis and candidal infections. Clotrimazole (Lotrimin) is related to miconazole and is used primarily as a topical fungicide in the form of creams or vaginal tablets. Flucytosine (Ancobon) is a simple fluorinated compound available for the treatment of systemic infections caused by Candida or Cryptococcus neoformans. Although the drug is less toxic than amphotericin B, it may cause blood dyscrasias and CNS toxicity. Flucytosine (Ancobon) is available in 250 and 500 mg capsules. Haloprogin (Halotex) is a synthetic topical antifungal agent used for the treatment of skin infections caused by a variety of fungi. Tolnaftate (Tinactin) is a synthetic topical, somewhat selective antifungal agent. Although it is effective in epidermophytosis, it does not eliminate candidal organisms. The drug is not adequate for fungal infections of the nails, scalp, and soles. Iodochlorhydroxyquin (clioquinol; Vioform) is useful in epidermophytosis. The drug has antibacterial effects also. It should be used topically on the skin, avoiding areas around the eyes. Undebylenic acid is a harmless topical agent for mild epidermophytosis. Several developments have taken place in the chemotherapy of viral diseases during the last few years (Table 53-5). The inhibitor of nucleic acid synthesis, idoxuridine, has produced spectacular results by topical application in herpetic keratitis, and the new drug amantadine has providede a new approach to the prevention of influenza A2 infections. Amantadine blocks the penetration of the virus into the host cell. In addition to these approaches, there is great interest in the stimulation of interferon production by synthetic polyanions of defined composition such as pyran copolymer. Idoxuridine (5-iodo-2’deoxyuridine; IDU; Stoxil) is a pyrimidine analog that blocks the synthesis of nucleic acids. It is applied topically in a 0.1% solution to the conjunctiva every 1 to 2 hours in the treatment of herpetic keratitis caused by the herpes simplex virus. This is an important therapeutic advance because herpetic keratitis can lead to blindness. No effective treatment existed prior to the introduction of idoxuridine. Unfortunately the drug is ineffective by systemic administration, probably because of rapid destruction. Nevertheless, the drug has been used systemically in the treatment of herpes simplex encephalitis and varicella-zoster infections. Some of the toxic effects of idoxuridine are bone marrow depression, alopecia, gastric ulcers, loss of fingernails, and hepatotoxicity. Amantadine (Symmetrel) is a new synthetic drug of unusual structure that inhibits the penetration of certain viruses into the host cell. In vitro it is effective against influenza and rubella viruses. In humans its effectiveness as a chemoprophylactic measure against influenza A2 (Asian) virus has been demonstrated. Amantadine reduced the number of clinical illnesses and also diminished the serological response to influenza infection. Mice could be protected against several strains of influenza A2 virus even when treatment was delayed as much as 72 hours after inoculation. Amantadine is available in capsules containing 100mg of the drug and also as a syrup. The adult daily dose is 200mg. Although amantadine appears to be quite nontocic on the basis of animal experiments, it can produce CNS stimulation and even convulsions when given in large doses. Nervousness, dizziness, hallucinations, and even grand mal convulsions have been associated with the use of the drug in humans. These adverse reactions are not common, however, and are more likely to occur following the administration of large doses. Amantadine is a new approach to viral diseases. Its ultimate place in chemoprophylaxis in comparison with immunization procedures is a matter of debate. Amantadine has some therapeutic effect in parkinsonism (p.158). Methisazone, or n-methylisatin-β-thiosemicarbazone, shows some therapeutic promise against the poxyviruses such as smallpox and complications of vaccination. Vidarabine (Vira-A) or adenine arabinoside inhibits DNA viruses, such as herpes simplex, and varicella agents. Topically, vidarabine may be used for the treatment of ocular herpes simplex, although results in genital herpes infections have been poor. Vidarabine may be administered intravenously for the treatment of herpes encephalitis. For intravenous infusion vidarabine (Vira-A) is available as a suspension containing 200 mg of the drug. Systemic use may cause many adverse effects and should be undertaken only in grave illnesses. Acyclovir is an important investigational agent, which is active against herpes virus infections. It is a nucleoside analog, 9-(2-hydroxymethyl) guanine. Cells infected with herpes simplex phosphorylate the drug much faster than uninfected cells. This phosphorylation yields acycloguanosine triphosphate, which inhibits preferentially virus-specified DNA polymerase. Investigational antiviral agents include immunopotentiating compounds, such as levamisole and methisoprinol (Isoprinosine), and other antimetabolites, such as 2-deoxyglucose or purine and pyrimidine analogs. Interferon inducers represent a novel approach to antiviral chemotherapy. Interferon is an antiviral protein produced by cells as a consequence of virus infections. Not only viruses but also bacteria and their products are capable of inducing shown that chemically defined substances such as a polyanionic pyran copolymer or double-stranded RNA from a synthetic source can also act as interferon inducers. Early trials in human beings and animals indicate that these synthetic materials may induce demonstrable serum interferon levels. Clinical experience with chemotherapeutic agents in a wide variety of infections allows certain generalizations regarding the best choice. These will be summarized, based on a more extensive report. There may be exceptions to these recommendations in individual cases in which susceptibility tests reveal resistance or the causative agent to a drug that ordinarily would be a good choice (Table 53-6). With the availability of effective weapons against infection, it is inexcusable not to cure an infection that would be curable with optimal treatment. Some of the causes of failure of anti-infective therapy are unavoidable. Others, however, may be iatrogenic. Some of the causes of failure are as follows: Incorrect clinical or bacteriological diagnosis Improper selection of drugs Improper method of administration or inadequate dose Futile prophylaxis Alteration in bacterial flora and superinfection Inaccessible lesion Drug resistance Deficiency in host defenses Drug toxicity and hupersensitivity The possible effects of antibiotics on the gastrointestinal tract are of two types. They may alter the bacterial flora or they may have direct toxic effects unrelated to the bacterial flora. Alteration of the bacterial flora is deliberately sought when antibiotics are used prior to bowel surgery. The nonabsorbable antibiotics such as neomycin, kanamycin, and certain sulfonamides have often been employed for this purpose. Despite some enthusiastic proponents of such a prophylactic measure, many investigators believe that it has no advantages over the preoperative cleansing of the bowel. Staphylococcal enterocolitis has occurred in patients who received oxytetracycline, neomycin, multiple antibiotics, or preoperative bowel antisepsis. Candidiasis is commonly seen in patients who receive long-term treatment with broad-spectrum antibiotics. The number of yeasts in the stools can be diminished by the simultaneous use of nystatin, but it is not certain that the gastrointestinal symptoms are caused by the yeasts. The condition improves if the antibiotic is discontinued. Prophylaxis of hepatic coma is an indication for the use of neomycin, kanamycin, or paromomycin, a closely related drug. The mode of action of these antibiotics in the prevention of hepatic coma is explained by their inhibitory effect on ammonia production in the intestine. Malabsorption syndrome may reault from the continued oral administration of neomycin. Changes in the jejunal mucosa and interference with the absorption of fat, glucse, D-xylose, iron, and vitamin B12 have been demonstrated. Liver disease may be induced by some antibiotics. Large doses of intravenously administered tetracycline are quite hepatotoxic. Erythromycin estolate and triacetyl-oleandomycin can produce an obstructive hepatitis. Novobiocin can increase serum bilirubin in newborns by inhibiting the enzyme glucuronyl transferase. Effectiveness and safety of antibiotic therapy depend on several host factors that will be summarized briefly. Defense mechanisms of the host have much to do with the success or failure of treatment. Debilitating diseases or the administration of large doses of corticosteroids or immunosuppressant drugs may interfere with antibiotic therapy. The age of the patient influences both the effectiveness and the safety of antibiotic therapy. Infants in the first month of life excrete penicillin more slowly, presumably because of less developed tubular secretory mechanism. Older infants and children require larger doses of penicillin than adults. Tetracycline may be deposited in tooth enamel and dentin and perhaps also in the bones of children. Chloramphenicol can cause the “gray syndrome” when given to infants during the first month of life. Undeveloped glucuronide conjugation by the liver makes chloramphenicol more hazardous. Pregnancy is a contraindication to the use of many drugs. Tetracyclines can cause dental defects in the fetus. Liver disease may be aggravated by chloramphenicol, the tetracyclines, novobiocin, and erythromycin. Defective renal function would cause the accumulation of sulfonamides, tetracycline, and other antibiotics that are largely cleared by the kidney. Urinary obstructions in any part of the urinary tract are a most important host factor in making the eradication of the infection very difficult. Pharmacogenetic defects such as glucose-6-phosphate dehydrogenase deficiency may predispose an individual to hemolytic anemia from various antimicrobial drugs such as sulfamethoxypyridazine, sulfadimethoxine, sulfisoxazole, nitrofurantoin, and chloramphenicol.