Merck Manual

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Brian J. Werth

, PharmD, University of Washington School of Pharmacy

Reviewed/Revised May 2022
Topic Resources

Penicillins are beta-lactam antibiotics Beta-Lactams Beta-lactams are antibiotics that have a beta-lactam ring nucleus. Subclasses include Carbapenems Cephalosporins and cephamycins (cephems) Clavams Monobactams read more Beta-Lactams that are bactericidal by unknown mechanisms but perhaps by activating autolytic enzymes that destroy the cell wall in some bacteria.





Natural penicillins

Penicillin G (parenteral/aqueous)


Penicillin G benzathine


Penicillin G procaine


Penicillin V potassium




Oral or parenteral







Penicillinase-resistant penicillins




Oral or parenteral


Oral or parenteral

Broad-spectrum (antipseudomonal) penicillins









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 Enterobacterales (formerly 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 Enterobacterales. 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 Monobactams Monobactams are parenteral beta-lactam bactericidal antibiotics. Aztreonam is currently the only available monobactam. Aztreonam has activity similar to that of ceftazidime against Enterobacterales... read more . 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. Procaine salts have increased bioavailability, which results in faster clearance of the drug; for example, penicillin G procaine can only be detected in the blood for 1 week versus penicillin G benzathine, which can be detected for 30 days (1 Pharmacokinetics reference Penicillins are beta-lactam antibiotics that are bactericidal by unknown mechanisms but perhaps by activating autolytic enzymes that destroy the cell wall in some bacteria. (See also Overview... read more ).

Pharmacokinetics reference

Indications for Penicillins

Penicillin G–like drugs

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

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.

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

Amoxicillin and ampicillin

These drugs are more active against

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

Piperacillin and piperacillin/tazobactam have activity against

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 or KPC and may only partially inhibit ESBL produced by some K. pneumoniae, E. coli, and other Enterobacterales. 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)

  • Gastrointestinal discomfort including nausea, vomiting, and diarrhea

Other adverse effects occur less commonly.

Oral penicillin may cause black hairy tongue, which occurs because of irritation of the glossal surface and keratinization of the superficial layers. This is a rare and harmless condition that resolves after the drug is stopped.


Most adverse effects are hypersensitivity reactions:

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 Skin testing Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally... read more may be done. Desensitization Desensitization Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally... read more 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.

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.

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 antistaphylococcal penicillins (eg, nafcillin, oxacillin, cloxacillin, dicloxacillin), 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.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

  • Zagursky RJ, Pichichero ME: Cross-reactivity in β-lactam allergy. J Allergy Clin Immunol Pract 6(1):72–81.e1, 2018. doi: 10.1016/j.jaip.2017.08.027

Drugs Mentioned In This Article

Drug Name Select Trade
Azactam, Cayston
Amoxil, Dispermox, Moxatag, Moxilin , Sumox, Trimox
Bicillin L-A, Permapen
Beepen VK, Veetids
Garamycin, Genoptic, Genoptic SOP, Gentacidin, Gentafair, Gentak , Gentasol, Ocu-Mycin
No brand name available
Zosyn, Zosyn Powder
No brand name available
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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