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 y 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
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
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 I 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 ug 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
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 f 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 in complete absorption are inactivation of the drug by the gastric juice and, once
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 predicta ble 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 Fig53-1. 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 secretor mechanism. One of these is probenecid(Benemid), which is quite effective. It is of little use in penicillin therapy
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, demonstra ble 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 prev ention of streptococcal infections and prophylaxis of rheumatic fever. [ru: maetik] (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. [seribrau'spa inal [pa: mia biliti
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%o 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. Tkaeta ian], 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. ypersensitivity reactions are seen most often following
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 n 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, penicillate, 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
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, Larotiddiffers from ampicillin only in producing somewhat higher serum
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 a bsorbed 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 m eq 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) closely related 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
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