Penicillin is one of the most commonly used antibiotics in the world, 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 penicillins such as carbenicillin and ticarcillin are 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]

Most bacteria have a peptidoglycan cell wall that surrounds the bacterial plasma membrane and prevents 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.[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 lactamases 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]

Penicillin V and G both can have adverse effects that include 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 reaction or penicillin and its derivatives. Penicillin is also contraindicated in patients who have had Stevens-Johnson syndrome after the administration of 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.