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By Hans P. Schlecht, MD, MSc, Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases & HIV Medicine, Drexel University College of Medicine
Christopher Bruno, MD, Assistant Professor of Medicine, Division of infectious Diseases & HIV Medicine, Drexel University College of Medicine

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Patient Education

Penicillins (see Table: Penicillins) are β-lactam antibiotics that are bactericidal by unknown mechanisms but perhaps by activating autolytic enzymes that destroy the cell wall in some bacteria.




Penicillin G–like drugs

Penicillin G

Oral or parenteral

Penicillin G benzathine


Penicillin G procaine


Penicillin V


Ampicillin-like drugs


Oral or parenteral

Ampicillin plus sulbactam




Amoxicillin plus clavulanate


Penicillinase-resistant penicillins




Oral or parenteral


Oral or parenteral

Broad-spectrum (antipseudomonal) penicillins





Piperacillin plus tazobactam




Ticarcillin plus clavulanate



Some bacteria produce β-lactamases, which inactivate β-lactam antibiotics; this effect can be blocked by adding a β-lactamase inhibitor (clavulanate, sulbactam, or tazobactam). However, available β-lactamase inhibitors do not inhibit ampC β-lactamases, commonly produced by Enterobacter, Serratia, Citrobacter, Providencia, and Morganella spp or by Pseudomonas aeruginosa, and these drugs may only partially inhibit extended-spectrum β-lactamase (ESBL) produced by some Klebsiella pneumoniae, Escherichia coli, and other Enterobacteriaceae.

Carbapenemases, which can inactivate all β-lactam antibiotics, have become increasingly common in Klebsiella sp, other Enterobacteriaceae, P. aeruginosa, and Acinetobacter sp. Currently, there are no carbapenemase inhibitors available, although some are being developed.


Food does not interfere with absorption of amoxicillin, but penicillin G should be given 1 h before or 2 h after a meal. Amoxicillin has generally replaced ampicillin for oral use because amoxicillin is absorbed better, has fewer GI effects, and can be given less frequently.

Penicillins are distributed rapidly in the ECF of most tissues, particularly when inflammation is present.

All penicillins except nafcillin are excreted in urine and reach high levels in urine. Parenteral penicillin G is rapidly excreted (serum half-life 0.5 h), except for repository forms (the benzathine or procaine salt of penicillin G); these forms are intended for deep IM injection only and provide a tissue depot from which absorption takes place over several hours to several days. Benzathine penicillin reaches its peak level more slowly and is generally longer-acting than procaine penicillin.


Penicillin G–like drugs

Penicillin G–like drugs (including penicillin V) are primarily used against

  • Gram-positive bacteria

  • Some gram-negative cocci (eg, meningococci)

A minority of gram-negative bacilli are also susceptible to large parenteral doses of penicillin G. Most staphylococci, most Neisseria gonorrhoeae, many anaerobic gram-negative bacilli, and about 30% of Haemophilus influenzae are resistant.

Penicillin G is the drug of choice for syphilis, for certain clostridial infections, and, with gentamicin, for endocarditis due to susceptible enterococci.

Benzathine penicillin G is available as pure benzathine penicillin, a mixture of equal amounts of benzathine and procaine penicillin G, and a mixture of 0.9 million units benzathine and 0.3 million units procaine penicillin G. Of the 3 products, only pure benzathine penicillin is recommended for treating syphilis and preventing rheumatic fever. Whether the mixture of equal amounts is effective in treating syphilis is unknown. Pure benzathine penicillin and the mixture of equal amounts are indicated for treating URIs and skin and soft-tissue infections caused by susceptible streptococci.

Amoxicillin and ampicillin

These drugs are more active against

  • Enterococci

  • Certain gram-negative bacilli, such as non-β-lactamase–producing H. influenzae, E. coli, and Proteus mirabilis; Salmonella sp; and Shigellasp

The addition of a β-lactamase inhibitor allows use against methicillin-sensitive staphylococci, H. influenzae, Moraxella catarrhalis, Bacteroides sp, E. coli, and K. pneumoniae.

Ampicillin is indicated primarily for infections typically caused by susceptible gram-negative bacteria:

  • UTIs

  • Meningococcal meningitis

  • Biliary sepsis

  • Respiratory infections

  • Listeria meningitis

  • Enterococcal infections

  • Some typhoid fever and typhoid carriers

Penicillinase-resistant penicillins

These drugs are used primarily for

  • Penicillinase-producing methicillin-sensitive Staphylococcus aureus

These drugs are also used to treat some Streptococcus pneumoniae, group A streptococcal, and methicillin-sensitive coagulase-negative staphylococcal infections.

Broad-spectrum (antipseudomonal) penicillin

These drugs have activity against

  • Bacteria susceptible to ampicillin

  • Some strains of Enterobacter and Serratia spp

  • Many strains of P. aeruginosa

Ticarcillin is less active against enterococci than piperacillin. The addition of a β-lactamase inhibitor enhances activity against β-lactamase–producing methicillin-sensitive S. aureus, E. coli, K. pneumoniae, H. influenzae, and gram-negative anaerobic bacilli, but not against gram-negative bacilli that produce ampC β-lactamase, and may only partially inhibit ESBL produced by some K. pneumoniae, E. coli, and other Enterobacteriaceae. Broad-spectrum penicillins exhibit synergy with aminoglycosides and are usually used with this class to treat P. aeruginosa infections.


Penicillins are contraindicated in patients who have had serious allergic reactions to them.

Use During Pregnancy and Breastfeeding

Penicillins are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not).

Penicillins enter breast milk in small amounts. Their use is usually considered compatible with breastfeeding.

Adverse Effects

Adverse effects include

  • Hypersensitivity reactions, including rashes (most common)

Other adverse effects occur less commonly.


Most adverse effects are hypersensitivity reactions:

  • Immediate reactions: Anaphylaxis (which can cause death within minutes), urticaria and angioneurotic edema (in 1 to 5/10,000 injections), and death (in about 0.3/10,000 injections)

  • Delayed reactions (in up to 8% of patients): Serum sickness, rashes (eg, macular, papular, morbilliform), and exfoliative dermatitis (which usually appears after 7 to 10 days of therapy)

Most patients who report an allergic reaction to penicillin do not react to subsequent exposure to penicillin. Although small, risk of an allergic reaction is about 10 times higher for patients who have had a previous allergic reaction. Many patients report adverse reactions to penicillin that are not truly allergic (eg, GI adverse effects, nonspecific symptoms). If patients have a vague or inconsistent history of penicillin allergy and taking alternative antibiotics is not effective or convenient, skin testing may be done (see Drug Hypersensitivity : Skin testing). Desensitization may be attempted in patients with a positive skin test if there is no alternative to a penicillin-type drug. However, patients with a history of anaphylaxis to penicillin should not be given any β-lactam again (including for skin testing), except in very rare circumstances when no substitute can be found. In such cases, special precautions and desensitization regimens are required (see Drug Hypersensitivity : Desensitization).


Rashes occur more often with ampicillin and amoxicillin than with other penicillins. Patients with infectious mononucleosis often develop a nonallergic rash, typically maculopapular, usually beginning between days 4 and 7 of treatment.

Other adverse effects

Penicillins can also cause

  • CNS toxicity (eg, seizures) if doses are high, especially in patients with renal insufficiency

  • Nephritis

  • C. difficile–induced diarrhea (pseudomembranous colitis—see Clostridium difficile –Induced Diarrhea)

  • Coombs-positive hemolytic anemia

  • Leukopenia

  • Thrombocytopenia

Leukopenia seems to occur most often with nafcillin. Any penicillin used in very high IV doses can interfere with platelet function and cause bleeding, but ticarcillin is the most common cause, especially in patients with renal insufficiency.

Other adverse effects include pain at the IM injection site, thrombophlebitis when the same site is used repeatedly for IV injection, and, with oral formulations, GI disturbances. Rarely, black tongue, due to irritation of the glossal surface and keratinization of the superficial layers, occurs, usually when oral formulations are used.

Ticarcillin in high doses may cause Na overload because ticarcillin is a disodium salt. Ticarcillin can also cause hypokalemic metabolic alkalosis because the large amount of nonabsorbable anion presented to the distal tubules alters H+ ion excretion and secondarily results in K+loss.

Dosing Considerations

Because penicillins, except nafcillin, reach high levels in urine, doses must be reduced in patients with severe renal insufficiency. Probenecid inhibits renal tubular secretion of many penicillins, increasing blood levels. It is sometimes given concurrently to maintain high blood levels.

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