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Continuing Education Activity

Penicillin is a medication used in the management and treatment of a wide range of infections. It is in the beta-lactam antibiotic class of drugs. This activity describes the indications, action, and contraindications for penicillin as a valuable agent in treating infection. This activity will 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 members of the interprofessional team in the treatment of infection.


  • Identify the mechanism of action of penicillin.
  • Describe the adverse effects of penicillin.
  • Describe the administration of penicillin.
  • Discuss interprofessional team strategies for improving care coordination and communication to advance penicillin administration and improve outcomes.


Penicillin is one of the most commonly used antibiotics globally, as it has a wide range of clinical indications. Penicillin is effective against many different types of infections involving gram-positive cocci, gram-positive rods (e.g., Listeria), most anaerobes, and gram-negative cocci (e.g., Neisseria).[1] Importantly, certain bacterial species have obtained penicillin resistance, including enterococci.  Enterococci infections now receive treatment with a combination of penicillin and streptomycin or gentamicin.[2] Certain gram-negative rods are also resistant to penicillin due to penicillin’s poor ability to penetrate the porin channel.[3] 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 as well as Klebsiella, enterococci, Pseudomonas aeruginosa, and Bacteroides fragilis.[4]

Mechanism of Action

Most bacteria have a peptidoglycan cell wall that surrounds the bacterial plasma membrane, prevents osmotic lysis, and provides structural integrity.  The peptidoglycan wall is continually remodeling during replication and growth. Penicillin inhibits the cross-linking of peptidoglycan in the cell wall.[5] 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.[6] 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. The penicillins can also be combined with a beta-lactamase inhibitor such as clavulanic acid to enhance its effects. 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.[7]


Penicillin G administration can be either intravenously or intramuscularly. 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 an orally administered form.[8] As with any antibiotic, patients must receive counsel to finish the full course of medicine to prevent bacterial resistance. Oral vs. injection will have different bioavailabilities. Penicillin G degrades more easily by stomach acid and has a bioavailability of less than 30%. Therefore, it is a parenterally administered drug. 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. Penicillin demonstrates limited crossing of the blood-brain barrier and can only treat some bacterial meningitis. Most penicillin derivatives are not metabolized much by the liver. They are rapidly excreted in the urine as they are water-soluble, and some of the drug is excreted in bile. Penicillin has a relatively short half-life of about 2 hours.[9]

Adverse Effects

Penicillin V and G both can have adverse effects, including nausea, vomiting, diarrhea, rash, abdominal pain, and urticaria. Penicillin G can have additional effects of muscle spasms, fever, chills, muscle pain, headache, tachycardia, flushing, tachypnea, and hypotension. GI symptoms were the most common and were reported in over 1% of patients, while hypotension, urticaria, and anaphylaxis are severe but rare side effects. Symptoms of rash can appear a week after initiating therapy.[10] The penicillins can also cause acute interstitial nephritis, a disease characterized by inflammation of the tubules and interstitium of the kidneys[11]. Acute interstitial nephritis can also present with hematuria, fever, and rash. In this situation, the recommendation is to withdraw the drug as the disease could lead to renal failure. 


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. Although renal impairment is not a contraindication for penicillin, doses will have to be adjusted given end-stage renal disease. These patients will receive a full loading dose and then half a loading dose every 8 to 10 hours or 4 to 5 hours, depending on the glomerular filtration rate.[12] Penicillin has an antagonistic effect with tetracycline and reportedly can lead to 2.6 times greater risk for mortality when treating pneumococcal meningitis compared to using penicillin alone.[13] Penicillin requires bacterial cell wall synthesis to be active to be effective. 


Generally, the monitoring of patients on penicillin is not required. However, one study recommended therapeutic drug monitoring during endocarditis treatment caused by enterococci to determine penicillin exposure and dosing better. This vigilance will decrease the chance of antibiotic resistance while improving therapeutic impact.[14] 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 5g/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.[15]

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 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. [Level 5]

Should a patient have difficulty obtaining drugs for either financial or logistical reasons, a social worker may help assure that the patient receives his or her 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 drug 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.

Article Details

Article Author

Derek Yip

Article Editor:

Valerie Gerriets


9/30/2021 6:55:32 PM

PubMed Link:




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