Penicillins

• Introduction
• Mode of action [video]
• Side effects [infographic]
• Penicillins classification
• Natural penicillins
• Antistaphylococcal penicillins
• Aminopenicillins
• Carboxypenicillins and Ureidopenicillins

Based on "Basic and Clinical Pharmacology"
written by Bertram G. Katzung, MD, PhD

Introduction to Penicillins

Penicillins are a class of beta-lactam antibiotics. Penicillin was the world's first antibiotic, which was produced from the mold Penicillium notatum by Alexander Fleming in 1928.

The basic structure of penicillins is a nucleus consisting of a beta-lactam ring (4 membered cyclic amide) and a side chain. The beta-lactam ring is necessary for antibacterial activity, and the side chain determines the antibacterial spectrum and pharmacologic properties.

Beta-lactamases (also called penicillinases) are enzymes that deactivate penicillins by destroying the beta-lactam ring via hydrolysis. Beta-lactamases allow bacteria to be resistant to penicillin.

Various penicillins differ mainly by the structure of the side chain. In addition to their structural differences, the penicillins differ in their antimicrobial spectrum, pattern of β-lactamase resistance (susceptibility to penicillinase), the ability to penetrate the outer membrane of gram-negative bacteria, bioavailability (stability in gastric acid), and behavior within the body (e.g. absorption, metabolism, distribution).

Mode of action

Penicillins are bactericidal. They hinder bacterial cell wall synthesis leading to bacterial cell death.

The penicillins inhibit bacterial transpeptidase enzymes which are involved in the synthesis of the bacterial cell wall. These enzymes are called "penicillin-binding proteins" (PBPs). Penicillins prevent these enzymes from creating cross-links between peptide chains in the cell wall. Penicillins subsequently activate the bacteria’s endogenous autolytic system leading to cell lysis and death.

Organisms that are not actively multiplying or do not have a cell wall are NOT susceptible to penicillins.

Side effects & Toxicity

The penicillins have minimal toxicity and are among the safest antibiotics. The most serious side effect of penicillins is allergy.

Penicillin Hypersensitivity

Hypersensitivity is one of the most important adverse reactions to penicillins. The frequency of allergic reactions to all penicillins ranges from 0.7% to 10%. The manifestations of penicillin allergy include maculopapular or morbilliform rash, fever, urticaria, exfoliative dermatitis, swelling of the throat, difficulty breathing, eosinophilia, serum sickness, Stevens-Johnson syndrome, and anaphylactic shock (0.004% to 0.015%)5.

Anaphylactic shock is the most dangerous form of drug allergy. A fatality rate from anaphylaxis is about 0.0015-0.002%. Severe allergic reactions are more likely with benzylpenicillin than with other penicillins.

In contrast to the classic hypersensitivity reaction, ampicillin may cause a nonallergic rash.

Cross-sensitivity exists among all penicillins and even other β-lactams. The hypersensitivity is related to the basic penicillin structure and therefore a person allergic to one penicillin will be allergic to all of them.

Gastrointestinal side effects

Penicillins, particularly the broad spectrum, can disrupt the normal balance of the intestinal microflora and lead to superinfection (including candidiasis, diarrhea, Clostridium difficile-associated colitis, candidal infections of the mouth and vagina).

Many persons who take penicillins experience diarrhea, nausea, and vomiting.

Hepatotoxicity (cholestatic hepatitis) most commonly occurs with oxacillin, nafcillin, and flucloxacillin6.

Hematologic side effects

Neutropenia (low level of neutrophils), leukopenia (low level of white blood cells), and hemolytic anemia (abnormal breakdown of red blood cells) are most common with nafcillin, oxacillin, and carbpenicillin.

Other reactions

Neurologic sequelae (convulsions, encephalopathy) can occur after large amounts of parenteral penicillins, especially in patients with renal dysfunction7.

Ticarcillin can also cause hypokalemic metabolic alkalosis.

Interstitial nephritis: especially with methicillin or nafcillin.

Classification

The penicillins can be classified according to their antibacterial activity:

• Natural penicillins
• Antistaphylococcal penicillins (also called penicillinase-resistant penicillins)
• Aminopenicillins
• Extended spectrum penicillins: carboxypenicillins and ureidopenicillins

Natural penicillins

• Penicillin G (Benzylpenicillin)
• Penicillin V

Natural penicillins, the first agents in the penicillin family, are obtained directly from the Penicillium mold and do not require further modification.

Penicillin G is the prototype of the class and the most potent of all penicillins against susceptible gram-positive bacteria. It is sensitive to stomach acids and requires intravenous or intramuscular administration.

Penicillin G is short acting, but its salts, procaine and benzathine, have extended duration of action because they can distribute into storage tissues to be released slowly.

Probenecid blocks tubular secretion of penicillin and has been used to increase the serum concentration and prolong the half-life of penicillin G and other penicillins.

The natural penicillins are very susceptible to inactivation by beta-lactamases.

Spectrum: The natural penicillins are active against non β-lactamase–producing gram-positive cocci (Pneumococci, Staphylococci, Streptococci), few gram-negative cocci (meningococci and gonococci), gram-positive bacilli (Bacillus anthracis, Bacillus perfringens, Bacillus diphtheriae), anaerobes (Clostridum perfringens, C. tetani), and spirochetes (Treponema pallidum, T. pertenue and Leptospira).

Antistaphylococcal penicillins

• Cloxacillin
• Dicloxacillin
• Oxacillin
• Nafcillin
• Methicillin

The antistaphylococcal penicillins (also called the "penicillinase-resistant penicillins") have bulky side chains that prevent their inactivation by the staphylococcal β-lactamases. These penicillins are useful in treating infections caused by Staphylococcus aureus and Staphylococcus epidermidis.

Methicillin was the first member of this group, followed by oxacillin, nafcillin, cloxacillin and dicloxacillin. Methicillin was the first penicillin developed through rational drug modification. Since then all bacteria which are resistant to any type of penicillin are designated as methicillin resistant (e.g MRSA - methicillin-resistant S. aureus).

Due to the bulky side group, all of the antistaphylococcals have difficulty penetrating the cell membrane and have a poor range of activity compared to other penicillins.

Spectrum: Antistaphylococcals have a very narrow spectrum as they were developed solely for killing β-lactamase producing staphylococci. Their major clinical indications are susceptible S. aureus and S. epidermidis infections.

Note: Antistaphylococcals are the only penicillins that by themselves are resistant to penicillinases. Their rank order of resistance is methicillin > cloxacillin = dicloxacillin > oxacillin.

Aminopenicillins

• Ampicillin
• Amoxicillin
• Bacampicillin
• Cyclacillin
• Hetacillin

The aminopenicillins have a wider range of activity than natural or antistaphylococcal penicillins. However, they lack the bulky side groups and are susceptible to inactivation by beta-lactamases. Aminopenicillins have additional hydrophilic groups, allowing the drug to penetrate into Gram-negative bacteria via the porins.

Advantages of aminopenicillins include higher oral absorption, higher serum levels, and longer half-lives. Aminopenicillins are resistant to gastric acids so can be administered orally.

Bacampicillin is more expensive but it does not have any significant advantages over the other aminopenicillins.

Spectrum: Aminopenicillins are similar to penicillin G in the activity against Gram-positive organisms but are slightly weaker than the latter. Aminopenicillins are more active against enterococci and Listeria monocytogenes compared to penicillin G.

Gram-negative spectrum includes Haemophilus influenzae, Salmonella, Shigella, Escherichia coli, Proteus mirabilis, N. gonorrhoeae, N. meningitidis.

Extended-spectrum penicillins (Antipseudomonals)

• Carbenicillin
• Ticarcillin
• Piperacillin
• Azlocillin
• Mezlocillin

Extended-spectrum penicillins (also called antipseudomonals) include both carboxypenicillins (carbenicillin and ticarcillin) and ureidopenicillins (piperacillin, azlocillin, and mezlocillin). Antipseudomonal penicillins are similar to the aminopenicillins in structure but have either a carboxyl group or urea group instead of the amine.

In general, the antipseudomonal penicillins have greater activity than do other penicillins against gram-negative bacteria (especially Pseudomonas and Proteus) due to enhanced penetration through the cell wall of these bacteria.

The principal advantage of carboxypenicillins is their activity against Pseudomonas aeruginosa (one of the major pathogens responsible for nosocomial pneumonia) and certain indole-positive Proteus species that are resistant to aminopenicillins. Ticarcillin is stronger against P. aeruginosa and Enterobacter species than carbenicillin.

Against anaerobes and Gram-positive organisms, carboxypenicillins generally have the same spectrum of activity as penicillin G. However, they are substantially weaker in comparison with penicillin G.

Ureidopenicillins have greater activity against P. aeruginosa compared to carbenicillin and ticarcillin. Piperacillin is the most potent of the extended-spectrum penicillins against Pseudomonas. The spectrum of piperacillin and mezlocillin is extended to include Klebsiella, Enterobacter, Citrobacter.

All antipseudomonals are destroyed by β-lactamases.

The extended-spectrum penicillins are not used in the treatment of infections caused by Gram-positive bacteria because penicillin G and aminopenicillins are more potent against these organisms.

Antipseudomonals penicillins may be used in combination with Aminoglycosides.

ß-lactamase inhibitors

• clavulanic acid
• sulbactam
• tazobactam

The ß-lactamase inhibitors act as suicide inhibitors of the ß-lactamases. These compounds are very slowly released after attack of the penicillinase resulting in irreversible inhibition of the enzyme, i.e. the enzyme remains acylated. This protects the penicillins from degradation and expands their utility.

Further reading

• Types of Antibiotics
• Amoxicillin comparison
• Penicillin comparison

References & Resources

• 1. Chambers HF. Penicillins. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 6th ed. New York: Churchill Livingstone; 2005:281–293
• 2. Mandell G.L., Petri W.A. (1996): Antimicrobial agents: Penicillins, cephalosporins, and other beta-lactam antibiotics. In : Gilman A.G., Goodman L.S., Rall T.W., Murad F. (eds.): Goodman and Gilman’s The Pharma- cological Basis of Therapeutics. 9th ed. McGraw-Hill Companies, New York. 1073–1101.
• 3. The antimicrobial drugs. Eric Michael Scholar, William B. Pratt; 87-90.
• 4. Kelley's Essentials of Internal Medicine. H. David Humes; 544-545
• 5. Idsoe O., Guthe T., Willcox Rr, De Weck Al. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968; 38: 159-188. PubMed
• 6. Hautekeete ML. Hepatotoxicity of antibiotics. Acta Gastroenterol Belg. 1995 May-Aug;58(3-4):290-6.
• 7. Fossieck B Jr, Parker RH. Neurotoxicity during intravenous infusion of penicillin. J Clin Pharmacol. 1974 Oct;14(10):504-12.

Published: January 2012
Last updated: September 03, 2017