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Brian J. Werth

, PharmD, University of Washington School of Pharmacy

Last full review/revision May 2020| Content last modified May 2020
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Penicillins (see table Penicillins) are beta-lactamantibiotics 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 beta-lactamases, which inactivate beta-lactam antibiotics; this effect can be blocked by adding a beta-lactamase inhibitor.

However, traditional beta-lactamase inhibitors (eg, clavulanate, sulbactam, tazobactam) do not reliably inhibit the following:

  • AmpC beta-lactamases, commonly produced by Enterobacter, Serratia, Citrobacter, Providencia, and Morganella species or by Pseudomonas aeruginosa

  • Extended-spectrum beta-lactamases (ESBLs) produced by some Klebsiella pneumoniae, Escherichia coli, and other Enterobacteriaceae

  • Carbapenemases

Novel, non–beta-lactam beta-lactamase inhibitors, such as avibactam, relebactam, and vaborbactam, do have activity against AmpC, ESBLs, and even some carbapenemases such as the Klebsiella pneumoniae carbapenemases (KPCs), which have become increasingly common in Klebsiella species and other Enterobacteriaceae. However, there are no currently available beta-lactamase inhibitors active against metallo-beta-lactamases (MBLs), such as NDM-1 (New Delhi MBL-1), VIMs (Verona integron–encoded MBLs), and IMP (imipenem)-types, which can inactivate all beta-lactam antibiotics except for aztreonam. However, many strains that produce MBLs also produce other beta-lactamases that can hydrolyze aztreonam.


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

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

All penicillins are at least partially excreted in urine, and most reach high levels in urine. Parenteral penicillin G is rapidly excreted (serum half-life 0.5 hour), 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.

Indications for Penicillins

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 a long-acting formulation that is available as

  • Pure benzathine penicillin

  • A mixture of equal amounts of benzathine and procaine penicillin G

  • A 3:1 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. Pure benzathine penicillin and the mixture of equal amounts are indicated for treating upper respiratory infections and skin and soft-tissue infections caused by susceptible streptococci.

Amoxicillin and ampicillin

These drugs are more active against

The addition of a beta-lactamase inhibitor (clavulanate or sulbactam) allows use against methicillin-sensitive staphylococci, H. influenzae, Moraxella catarrhalis, Bacteroides species, E. coli, and K. pneumoniae.

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

Penicillinase-resistant penicillins

These drugs (dicloxacillin, nafcillin, cloxacillin, flucloxacillin, and oxacillin) 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

Ticarcillin is less active against enterococci than piperacillin. The addition of a beta-lactamase inhibitor enhances activity against beta-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 beta-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.

Contraindications to Penicillins

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

Use During Pregnancy and Breastfeeding

Penicillins are among the safest antibiotics during pregnancy. Animal reproduction studies with penicillin have not shown risk to the fetus. Data related to pregnancy in humans are limited. If medically indicated, penicillins can be used during pregnancy. Penicillin G is effective for preventing maternal transmission of syphilis to the fetus and for treating fetal and maternal infection.

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

Adverse Effects of Penicillins

Adverse effects of penicillins 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, gastrointestinal 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. 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 other penicillins or any beta-lactam with similar side chains (including for skin testing), except in very rare circumstances when no substitute can be found and the drug can be given under supervision in a controlled environment. In such cases, special precautions and desensitization regimens are required.


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

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, gastrointestinal 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 and carbenicillin in high doses may cause sodium overload, especially in patients with heart or kidney failure, because both are disodium salts. Ticarcillin and carbenicillin 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 potassium loss.

Dosing Considerations for Penicillins

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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