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Preface to Penicillins (Monograph)

Drug class: Penicillins

Classification of Penicillins Based on Spectra of Activity

Penicillins are natural or semisynthetic antibiotics produced by or derived from certain species of the fungus Penicillium.10 61 62 70 10 The drugs are β-lactam antibiotics structurally and pharmacologically related to other β-lactam antibiotics, including cephalosporins and cephamycins.10 61 62 64 89 575 Penicillins contain a 6-aminopenicillanic acid (6-APA) nucleus, which is composed of a β-lactam ring fused to a 5-membered thiazolidine ring .61 62 63 64 70 72 89 Although the 6-APA nucleus has little antibacterial activity itself, it is a major structural requirement for antibacterial activity of penicillins.62 63 64 88 89 In currently available penicillins, cleavage at any point in the penicillin nucleus, including the β-lactam ring, results in complete loss of antibacterial activity.62 A free carboxyl group in the thiazolidine ring and one or more substituted amino side chains at R are also essential for antibacterial activity.62 89

Addition of various side chains at R on the penicillin nucleus results in penicillin derivatives with differences in spectra of activity, stability against hydrolysis by β-lactamases, acid stability, GI absorption, and protein binding.62 63 64 67 88 89 575

Currently available penicillins can be divided into 4 groups based principally on their spectra of activity:61 62 63 64 575

NATURAL PENICILLINS

penicillin G

penicillin V

Natural penicillins are produced by fermentation of mutant strains of Penicillium chrysogenum.61 64 70 72 89 575 Natural penicillins with different side chains at R are produced by altering the composition of the culture media of Penicillium.61 64 68 70 89 Although various natural penicillins have been produced (e.g., penicillins F, G, N, O, V, X), only penicillin G and penicillin V are used clinically.64 68 70 89 575

Natural penicillins are active in vitro against many gram-positive aerobic cocci including nonpenicillinase-producing Staphylococcus aureus and S. epidermidis,8 9 10 11 12 18 19 20 21 61 64 70 71 72 88 116 205 Streptococcus pneumoniae,8 9 10 11 18 19 20 21 61 64 71 72 88 177 206 215 581 S. pyogenes (group A β-hemolytic streptococci; GAS),3 4 5 7 8 9 11 12 18 19 20 21 61 S. agalactiae (group B streptococci; GBS),61 174 other β-hemolytic streptococci (e.g., groups C, G, H, L, R),3 4 5 7 8 9 10 11 12 18 19 20 21 61 64 72 173 174 181 205 212 215 261 viridans streptococci,18 19 20 21 61 72 88 173 and nonenterococcal group D streptococci.61 116 173 205 Although some strains of enterococci are susceptible to penicillin G in vitro, many strains are resistant and penicillin tolerance has been reported.61 116 288 Natural penicillins are readily hydrolyzed by staphylococcal penicillinases and are therefore inactive against penicillinase-producing strains of S. aureus and S. epidermidis.3 4 5 7 8 9 10 11 12 18 19 20 21 61 64 116 The drugs are active in vitro against some gram-positive aerobic bacilli including Bacillus anthracis,8 9 11 12 18 19 20 21 61 64 72 88 116 Corynebacterium diphtheriae,8 9 11 12 18 19 20 21 61 64 72 88 116 Erysipelothrix rhusiopathiae,61 and Listeria monocytogenes.8 9 11 12 18 19 20 21 61 64 72 88

Natural penicillins also are active in vitro against some gram-negative aerobic cocci including Neisseria meningitidis.8 9 11 12 61 64 71 72 88 Although natural penicillins may be active in vitro against strains of nonpenicillinase-producing N. gonorrhoeae,8 9 11 12 61 64 71 72 88 penicillinase-producing strains of N. gonorrhoeae (PPNG) are resistant.61 171 172 176 The drugs are active in vitro against some gram-negative aerobic bacilli including some strains of Haemophilus influenzae,61 71 116 205 Pasteurella multocida,61 64 183 Streptobacillus moniliformis,61 64 213 and Spirillum minus.61 However, Pseudomonas61 116 210 and most Enterobacteriaceae61 64 71 72 88 89 116 are resistant to natural penicillins.

Natural penicillins are active in vitro against many gram-positive anaerobic bacteria, includingActinomyces israelii,8 9 11 12 18 19 20 21 61 64 72 88 Clostridium (C. botulinum, C. perfringens, and C. tetani),8 9 11 12 18 19 20 21 61 194 Cutibacterium acnes (formerly Propionibacterium acnes),61 179 Eubacterium,61 Lactobacillus,61 Peptococcus,116 194 and Peptostreptococcus.61 116 Gram-negative anaerobic bacteria vary in their susceptibility to the drugs.61 64 72 88 116 194 Although penicillin G is active in vitro against some strains of Fusobacterium,61 116 194 209 Veillonella,116 194 and Bacteroides oralis, the B. fragilis group (e.g., B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus) require high penicillin G concentrations for in vitro inhibition and usually are resistant.61 72 88 116 194 211

The drugs also are active against spirochetes, including Treponema pallidum subsp pallidum,3 4 5 7 8 9 11 12 61 T. pallidum subsp pertenue,61 T. carateum,3 Leptospira,8 9 11 12 18 19 20 21 61 Borrelia burgdorferi (causative agent of Lyme disease),61 220 221 224 B. hermsii,61 and B. recurrentis.178

PENICILLINASE-RESISTANT PENICILLINS

dicloxacillin

oxacillin

nafcillin

Penicillinase-resistant penicillins are semisynthetic derivatives of 6-APA that are stable against hydrolysis by staphylococcal penicillinases.61 62 63 64 68 69 72 88 89 97 These penicillins have bulky side chains at R on the 6-APA nucleus that result in steric hindrance and help to prevent attachment of penicillinases to the β-lactam ring.62 68 69 72 88 89 575

Because penicillinase-resistant penicillins are not hydrolyzed by most staphylococcal penicillinases, these drugs are active in vitro against many penicillinase-producing strains of S. aureus27 28 29 61 88 97 222 223 224 and S. epidermidis61 88 97 223 that are resistant to natural penicillins, aminopenicillins, and extended-spectrum penicillins.

Penicillinase-resistant penicillins also have some in vitro activity against other gram-positive bacteria61 64 68 69 72 88 97 116 222 223 224 225 226 227 228 and some gram-negative bacteria61 69 72 88 97 116 224 and spirochetes;88 however, the drugs generally are less active on a weight basis against these organisms than natural penicillins,61 62 74 88 97 427 and use of penicillinase-resistant penicillins generally is limited to the treatment of infections caused by susceptible penicillinase-producing staphylococci.27 28 34 35 61 64 67 80 97 203 406 427 865

AMINOPENICILLINS

amoxicillin

ampicillin

Aminopenicillins are semisynthetic derivatives of 6-APA which have a free amino group at the α-position at R on the penicillin nucleus.61 62 68 74 76 88 575 Partly because of this polar group, aminopenicillins have enhanced activity against gram-negative bacteria compared with natural penicillins and penicillinase-resistant penicillins.62 68 74 88 575

In vitro, aminopenicillins are generally active against gram-positive aerobic cocci and gram-positive aerobic bacilli that are susceptible to natural penicillins.61 63 64 73 116 205 226 228 However, with the possible exception of enterococcal infections, natural penicillins are generally the penicillins of choice for the treatment of infections caused by gram-positive cocci that are susceptible to both natural penicillins and aminopenicillins.10 63 64 67 80 Like natural penicillins and extended-spectrum penicillins, aminopenicillins are readily hydrolyzed by staphylococcal penicillinases and are therefore inactive against penicillinase-producing strains of S. aureus and S. epidermidis.36 37 38 39 61 64 68 75 76 116 226 228

Aminopenicillins are generally active in vitro against gram-negative aerobic cocci,61 116 228 gram-negative aerobic bacilli,61 116 183 205 and anaerobic bacteria61 68 116 that are susceptible to natural penicillins. In addition, aminopenicillins are active in vitro against some Enterobacteriaceae including some strains of Escherichia coli,61 73 76 116 226 228 Proteus mirabilis,61 76 116 226 228 Salmonella,61 76 116 226 228 and Shigella.61 76 116 226 228 Aminopenicillins are generally inactive against other Enterobacteriaceae,61 63 116 226 B. fragilis,61 63 and Pseudomonas.61 73 116 226 228

Because clavulanic acid and sulbactam are β-lactamase inhibitors that can inhibit certain β-lactamases that inactivate aminopenicillins, fixed combinations of amoxicillin and clavulanate potassium (amoxicillin/clavulanate) and fixed combinations of ampicillin sodium and sulbactam sodium (ampicillin/sulbactam) are active in vitro against many β-lactamase-producing organisms that are resistant to the aminopenicillin alone.40 41 61 117 118 119 120 311 312 314 316 318

EXTENDED-SPECTRUM PENICILLINS

piperacillin

ticarcillin (no longer commercially available in the US)

Extended-spectrum penicillins are semisynthetic derivatives of 6-APA that have a wider spectra of activity than natural penicillins, penicillinase-resistant penicillins, and aminopenicillins.55 61 64 68 103 202 208 593

The group of extended-spectrum penicillins is composed of 2 different subgroups: Acylaminopenicillins (piperacillin) and α-carboxypenicillins (ticarcillin; no longer commercially available in the US).61 64 68 102 202 208 518 593 Acylaminopenicillins have basic groups on the side chain at R on the penicillin nucleus202 208 and α-carboxypenicillins have a carboxylic acid group at the α-position at R on the penicillin nucleus.68 88 99 103 202 575 Partly because of these polar groups, extended-spectrum penicillins are more active against gram-negative aerobic and gram-negative anaerobic bacilli than aminopenicillins,68 88 99 103 202 575 and use of extended-spectrum penicillins is generally limited to the treatment of serious infections caused by susceptible gram-negative bacilli78 100 102 570 953 or mixed aerobic-anaerobic bacterial infections.100 102 593 955

In vitro, extended-spectrum penicillins are generally active against gram-positive and gram-negative aerobic cocci that are susceptible to natural penicillins and aminopenicillins.78 99 100 116 205 215 Like natural penicillins and aminopenicillins, extended-spectrum penicillins are hydrolyzed by staphylococcal penicillinases and are therefore inactive when used alone against penicillinase-producing strains of S. aureus and S. epidermidis.67 78 79 100 102 205 219 Extended-spectrum penicillins have some activity against gram-positive aerobic and gram-positive anaerobic bacilli, but the drugs are generally less active in vitro on a weight basis against these organisms than are natural penicillins and aminopenicillins.100 116

Extended-spectrum penicillins are generally active in vitro against gram-negative bacilli that are susceptible to aminopenicillins.61 67 68 78 79 99 116 198 The drugs are also active against many Enterobacteriaceae and some Pseudomonas that are resistant to other currently available penicillins.61 67 68 78 79 99 198 204 215 237 α-Carboxypenicillins are active in vitro against some strains of E. coli,61 99 197 198 Morganella morganii,61 78 198 215 P. mirabilis,78 99 198 215 P. vulgaris,61 78 99 215 Providencia rettgeri,78 198 215 Salmonella,78 99 Shigella,78 and Ps. aeruginosa.61 78 99 116 204 219 239 240 302 In addition to these organisms, acylaminopenicillins are generally active in vitro against some strains of Citrobacter,61 237 Enterobacter,61 237 Klebsiella,61 64 219 237 and Serratia.61 Extended-spectrum penicillins are more active in vitro against B. fragilis than other currently available penicillins.61 78 79 219 246

The only extended-spectrum penicillin commercially available in the US is piperacillin sodium in fixed combination with tazobactam sodium (piperacillin/tazobactam).55 Because tazobactam has a high affinity for and irreversibly binds to certain β-lactamases that can inactivate extended-spectrum penicillins, piperacillin/tazobactam is active against many β-lactamase-producing bacteria that are resistant to piperacillin alone.56 57

Related Monographs

For more complete information on the spectra of activity of penicillins and additional information on the drugs, see the General Statements on Natural Penicillins, Aminopenicillins, and Penicillinase-Resistant Penicillins and the individual monographs in 8:12.16.04, 8:12.16.08, 8:12.16.12, and 8:12.16.16.

AHFS DI Essentials™. © Copyright 2025, Selected Revisions January 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

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