Penicillin is a medication used to manage and treat a wide range of infections. It is in the beta-lactam antibiotic class of drugs. 

We will describe penicillin’s indications, action, and contraindications as a valuable agent in treating infection. In addition, to highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for interprofessional team members in the treatment of infection.


  • Penicillin is one of the most commonly used antibiotics globally, it has a wide range of clinical indications. Penicillin is effective against many different infections involving gram-positive cocci, gram-positive rods (e.g., Listeria), most anaerobes, and gram-negative cocci (e.g., Neisseria).
  • Importantly, certain bacterial species have obtained penicillin resistance, including enterococci. Enterococci infections now receive treatment with a combination of penicillin and streptomycin or gentamicin.
  • Certain gram-negative rods are also resistant to penicillin due to penicillin’s poor ability to penetrate the porin channel.
  • However, later generations of broad-spectrum penicillins are effective against gram-negative rods. Second-generation penicillins (ampicillin and amoxicillin) can also penetrate the porin channel, making these drugs effective against Proteus mirabilis, Shigella, H. influenzae, Salmonella, and E. coli. Third-generation penicillin such as carbenicillin is also able to penetrate gram-negative bacterial porin channels. Fourth-generation penicillins such as piperacillin are effective against the same bacterial strains as third-generation penicillins and Klebsiella, enterococci, Pseudomonas aeruginosa, and Bacteroides fragilis.

Mechanism of Action

Most of bacteria have a peptidoglycan cell wall surrounding the bacterial plasma membrane, preventing osmotic lysis and providing structural integrity. The peptidoglycan wall is continually remodeling during replication and growth. Penicillin inhibits the cross-linking of peptidoglycan in the cell wall.The catalyst for this reaction is penicillin-binding proteins, such as the enzyme DD-transpeptidase. Penicillin’s four-membered β-lactam ring can bind to DD-transpeptidase to irreversibly inactive it. The bacteria, therefore, are unable to build their cell walls even while other proteins continue to break down the wall.As the bacteria cell wall continues to weaken, osmotic pressure pushes water into the cell and kills the cell. Peptidoglycan fragments further destroy the cell wall as these fragments can activate autolysins and hydrolases. To enhance its effects, the penicillins can also be combined with a beta-lactamase inhibitor such as clavulanic acid. Beta-lactamase inhibitors prevent the degradation of the beta-lactam ring in penicillin that can occur when certain species of bacteria express the enzyme beta-lactamase.

Most penicillin derivatives are not metabolized much by the liver. Oral vs. injection will have different bioavailabilities. They are rapidly excreted in the urine as they are water-soluble, and some of the drugs are excreted in bile. Penicillin has a relatively short half-life of about 2 hours.


Penicillin G administration can be either intravenously or intramuscularly. Penicillin G potassium for injection USP vial is available in 1 million units, 5 million units, and 20 million units per vial. Penicillin G degrades more easily by stomach acid and has less than 30% bioavailability; therefore, it is a parenterally administered drug. Because of the short half-life, penicillin G is usually administered in divided doses 4 to 6 hours apart via the intravenous or intramuscular route. Penicillin G benzathine administration ensures a continuous low dose of penicillin G over 2 to 4 weeks.

Penicillin V and penicillin VK (potassium salt of penicillin V) is available in orally administered forms as a solution for reconstitution (125 mg/5 mL, 250 mg/5 mL) and tablets (250 mg and 500 mg). Penicillin V has a bioavailability of around 65% after passing stomach acid. Penicillin V is best administered to a fasting patient as it degrades in stomach acid. The normal dose ranges from 125 mg to 500 mg every 6 to 8 hours based on the clinical indication and patient weight.

As with any antibiotic, patients must receive counsel to finish the full medicine course to prevent bacterial resistance. Penicillin demonstrates limited crossing of the blood-brain barrier and can only treat some bacterial meningitis.

Specific Patient Population

Pregnant Women: Penicillin G belongs to FDA pregnancy category B. No severe adverse events are observed with penicillin G. Elimination of penicillin V is increased during pregnancy, requiring dose adjustment with an increased dose of the standard dosing interval or shorter dosing intervals of the standard dose.

Breastfeeding Women: According to literature, penicillin G and penicillin V can be found in milk at low levels that are unexpected to cause adverse reactions in breastfed infants. It is sometimes reported that penicillin can disrupt the infant’s gastrointestinal flora, causing diarrhea or thrush; however, these side effects have not been adequately evaluated. The penicillin G or penicillin V use is acceptable for nursing mothers.

Pediatric Population: The pediatric dose of penicillin is calculated based on their body surface area and weight.

Patients with Renal Impairment: Although renal impairment is not a contraindication for penicillin, doses will have to be adjusted given end-stage renal disease. Depending on the glomerular filtration rate, these patients will receive a full loading dose and then half a loading dose every 8 to 10 hours or 4 to 5 hours.

Adverse Effects

Penicillin V and G can have adverse effects, including nausea, vomiting, diarrhea, rash, abdominal pain, and urticaria. In addition, Penicillin G can have other adverse reactions, including muscle spasms, fever, chills, muscle pain, headache, tachycardia, flushing, tachypnea, and hypotension.

Hypersensitivity Reactions: The commonly encountered adverse drug reaction with penicillin is hypersensitivity of immediate onset or delayed onset.

Immediate onset: This kind of reaction occurs within 20 minutes post-administration. It is characterized by urticaria, pruritis, edema, laryngospasm, bronchospasm, hypotension, vascular collapse, and death.

Delayed onset: This reaction occurs within 1 to 2 weeks of treatment. It is rare and is characterized by fever, malaise, urticaria, myalgia, arthralgia, abdominal pain, and skin rashes.

Gastrointestinal System: GI symptoms were the most common and were reported in over 1% of patients, including nausea, vomiting, stomatitis, which are commonly observed with oral administration. Pseudomembranous colitis is also observed during or after the treatment.

Hematologic Reactions: If the dose is exceeded 10 million units/day and if a patient has received a higher dose previously, then those patients can precipitate Coombs positive hemolytic anemia and neutropenia, which is resolved when therapy is stopped.

Metabolic Reactions: The salt form of penicillin G may cause electrolyte imbalances, i.e., hyperkalemia when given IV in a large dose.

Nervous System: Neurological manifestations include hyperreflexia, myoclonic twitches, seizures, and coma after IV doses and are more likely in patients with impaired renal function.

Urogenital System: Urological manifestations with large IV doses include renal tubular damage. The penicillins can also cause acute interstitial nephritis, a disease characterized by inflammation of the tubules and interstitium of the kidneys. Acute interstitial nephritis can also present with hematuria, fever, and rash. The recommendation is to withdraw the drug as the disease could lead to renal failure in this situation. 

Other: Jarisch- Herxheimer reaction is precipitated when penicillin is administered in patients with syphilis.

Drug-Drug Interactions

Concurrent sulfonamides, erythromycin, chloramphenicol should be avoided due to antagonistic effects.

Tubular secretion of penicillin G can be blocked by probenecid- higher and longer plasma concentrations are achieved. Probenecid also decreases the volume of distribution of penicillin.

Drugs like aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide, furosemide, and ethacrynic acid increase the half-life of penicillin by competing with tubular secretion.


Contraindications of penicillin include a previous history of severe allergic reactions or penicillin and its derivatives. Penicillin is also contraindicated in patients who have had Stevens-Johnson syndrome after administering penicillin or a penicillin derivative. The penicillins are safe to use during pregnancy and nursing, as the drug appears at a low concentration in breastmilk. Penicillin has an antagonistic effect with tetracycline and reportedly can lead to 2.6 times greater risk for mortality when treating pneumococcal meningitis than using penicillin alone. Penicillin requires bacterial cell wall synthesis to be active to be effective. 

Nearly all antibacterial agents have been linked to Clostridium difficile associated diarrhea (CDAD), including penicillin, with severity ranging from mild diarrhea to fatal colitis. The use of antibacterial agents alters the normal flora of the colon, causing the overgrowth of C. difficile. This strain produces toxins A and B that contribute to the development of CDAD. During infections caused by hyper toxin-producing strains of C. difficile, the rate of morbidity and mortality can be increased since these infections are often resistant to antimicrobial treatments and may require colectomy. When C. difficile-associated diarrhea (CDAD) is suspected or confirmed, ongoing antibiotic treatment is recommended to stop. Depending on clinical need, protein supplementation, fluid and electrolyte management, antibiotic treatment, and surgical evaluation should be implemented.


Generally, the monitoring of patients on penicillin is not required. However, one study recommended therapeutic drug monitoring during endocarditis treatment caused by enterococci to better determine penicillin exposure and dosing. This vigilance will decrease the chance of antibiotic resistance while improving therapeutic impact. With long-term administration of penicillin, it may be necessary to monitor hematologic, renal, and hepatic function.


Penicillin has a small risk of toxicity. Compared to other biologically active substances, clinicians can administer these drugs at relatively high doses without harming patients. Estimates are that it would take 5 g/kg body weight intravenously to cause convulsions in a patient. However, penicillin can cause local toxicity due to high dose injections at sensitive sites such as the anterior chamber of the eye or the subarachnoid space. There are reports that pure preparations of penicillin cause no harm to the lungs and veins. Other reports indicate that topical penicillin can prevent coagulation in dental cavities.

Enhancing Healthcare Team Outcomes

Before prescribing penicillin to a patient, the clinician and healthcare team should confirm that the underlying infection is likely the result of a bacteria that is sensitive to penicillin. The clinician, pharmacist, and/or nurse should also tell the patient of any side effects of the drug that should prompt a return visit, such as prolonged diarrhea or serious rash. In an outpatient setting, communication between the clinician and the pharmacist will allow the drug to be dispensed appropriately to the patient. The pharmacist should consult the patient on how best to administer the penicillin and remind them that they should complete the entire course of the antibiotic. This interprofessional approach will optimize therapeutic results while minimizing adverse effects.

Should a patient have difficulty obtaining drugs for either financial or logistical reasons, a social worker may help assure that the patient receives their medications. In an inpatient setting, communication between the clinician and the nurse will allow the patient to receive the drug. The healthcare team can work together to confirm that the patient does not have any contraindications to penicillin use. If any immediate serious adverse effects occur after administering penicillin, such as anaphylaxis, the healthcare team should receive notification and treat the acute condition immediately. A board-certified infectious disease pharmacist can also consult on the case to confirm if penicillin is the best choice given the patient’s diagnosis and any other medications that the patient might be taking. Furthermore, a flattened hierarchy approach should be in place to ensure that reporting mistakes to a superior can take place without resistance. Utilization of the entire healthcare team is critical to ensure that the patient is comfortable and has the best medical outcome with the lowest chance of complications.


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