Continuing Education Activity

Penicillin is one of the most commonly used broad-spectrum antibiotics globally and has numerous clinical indications. Penicillin is effective against infections caused by gram-positive cocci, gram-positive rods, most anaerobes, and gram-negative cocci, and it stands as a cornerstone in the management and treatment of various infections within the β-lactam antibiotic class of drugs. Most bacteria feature a peptidoglycan cell wall encasing the bacterial plasma membrane, which prevents osmotic lysis and offers structural stability. This peptidoglycan wall undergoes continuous remodeling during replication and growth. Penicillin functions by inhibiting the cross-linking of peptidoglycan within the cell wall.

Given the rise of resistance, penicillin should be reserved solely for susceptible organisms. This activity encompasses the delineation of penicillin's indications, mechanism of action, administration, adverse event profile, pharmacokinetics, monitoring, and pertinent interactions essential for interprofessional healthcare team members in infection treatment. This activity enhances the clinical team's comprehension of promptly evaluating and administering the appropriate antibiotic for treating several infections, thereby improving patient outcomes.

Objectives:

• Identify the appropriate indications for penicillin therapy based on the specific microbial etiology and clinical presentation.

• Implement evidence-based guidelines for the safe and effective administration of penicillin, considering patient-specific factors such as age, renal function, and comorbidities.

• Select alternative antibiotic therapies in cases of penicillin allergy or resistance, considering the spectrum of activity and susceptibility testing results.

• Coordinate with microbiology and infectious disease specialists to optimize penicillin therapy for complex or resistant infections, utilizing their expertise in antimicrobial management to optimize penicillin therapy.

Indications

Penicillin is one of the most commonly used broad-spectrum antibiotics globally and has numerous clinical indications. Penicillin is effective against infections caused by gram-positive cocci, gram-positive rods, most anaerobes, and gram-negative cocci.[1] Penicillin stands as a cornerstone in the management and treatment of various infections within the β-lactam antibiotic class of drugs. 

Notably, certain bacterial species have developed penicillin resistance, including enterococci. Therefore, due to emerging resistance, penicillin should only be used for susceptible organisms. Enterococci infections are now treated with penicillin, streptomycin, or gentamicin.[2] Specific 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, such as ampicillin and amoxicillin, can penetrate the porin channel, making these drugs effective against Proteus mirabilis, Shigella,  Haemophilus influenzae, Salmonella, and Escherichia coli. Third-generation penicillin, such as carbenicillin, can 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.[4] 

FDA-Approved Indications

Penicillin G: 

• Anthrax caused by Bacillus anthracis

• Actinomycosis caused by Actinomyces israelii

• Clostridium infection in conjugation with antitoxin

• Diptheria caused by Corynebacterium diphtheria with antitoxin

• Fusospirochetosis caused by Fusobacterium species and spirochetes

• Endocarditis caused by sensitive Streptococcus pyogenes 

• Rat bite fever caused by Spirillum minus or Streptobacillus moniliformis [5]

• Tetanus caused by Clostridium tetani with immune globulin and vaccine administration

• Meningitis caused by Listeria monocytogenes,  Meningococcus, and Streptococcus [6]

• Neurosyphilis caused by Treponema pallidum [7]

Penicillin V: 

• Mild-to-moderate infections of the upper respiratory tract infection caused by Streptococcus and Pneumococcus

• Scarlet fever and erysipelas (mild) caused by group A Streptococcus

• Gingivitis caused by Bacillus fusiformis and Borrelia vincentii (along with appropriate dental care) [8]

Benzathine Penicillin:

• Preventing rheumatic fever [9]

• Treating syphilis (primary, secondary, and latent) [10]

Mechanism of Action

Most bacteria feature a peptidoglycan cell wall encasing the bacterial plasma membrane, which prevents osmotic lysis and offers structural integrity. This peptidoglycan wall undergoes continuous remodeling during replication and growth. Penicillin functions by inhibiting the cross-linking of peptidoglycan within the cell wall.[11] 

The catalyst for this reaction is penicillin-binding proteins, such as the enzyme DD-transpeptidase. Penicillin's 4-membered β-lactam ring can bind to DD-transpeptidase to irreversibly inactive it. The bacteria cannot build their cell walls while other proteins break down the wall.[12] 

As the bacteria's 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. Penicillin is combined with a β-lactamase inhibitor such as clavulanic acid to enhance the bactericidal effect. β-lactamase inhibitors prevent the degradation of the β-lactam ring in penicillin, which can occur when certain bacteria express the enzyme β-lactamase.[13]

Pharmacokinetics

Absorption: The potassium salt of penicillin V (oral formulation) is resistant to inactivation by gastric acid; however, penicillin G is destroyed by stomach acid. Benzathine penicillin G has slow hydrolysis and absorption, resulting in a prolonged half-life.

Distribution: Penicillin V and penicillin G have approximately 80% and 60% plasma protein binding, respectively. Tissue levels are highest in the kidneys. The concentration of penicillin in abscesses, synovial, and peritoneal fluids is higher in the presence of inflammation. However, penicillin G does have poor distribution in polymorphonuclear leukocytes. 

Metabolism: Penicillin derivatives are minimally metabolized by the liver. Organic anion transporter-3 plays a vital role in renal excretion.[14]

Elimination: These agents are rapidly excreted in the urine as they are water-soluble, and others are excreted in bile. Penicillin has a relatively short half-life of about 2 hours. Penicillin is excreted rapidly by tubular excretion, which is inhibited by probenecid.[15][16][17]

Administration

Available Dosage Forms, Strengths, and Dosages

Penicillin G can be administrated by intravenous (IV) or intramuscular (IM) route. Penicillin G potassium for injection USP vial is available in 1 million units, 5 million units, and 20 million units per vial. Because of the short half-life, penicillin G is usually administered in divided doses 4 to 6 hours apart via the IV or IM route. Penicillin G benzathine administration ensures a continuous low dose of penicillin G over 2 to 4 weeks. FDA has also approved a procaine penicillin G combination of antibiotics and local anesthetics.[7]

Penicillin V and its potassium salt derivative, penicillin VK, are accessible in orally administered forms, including solutions for reconstitution (125 mg/5 mL and 250 mg/5 mL) and tablets (250 mg and 500 mg).[18] Penicillin V is best administered to a fasting patient as it degrades in stomach acid. Based on the clinical indication and patient weight, the usual dosage ranges from 125 to 500 mg every 6 to 8 hours.

As with any antibiotic, patients should be advised to finish the treatment course to prevent bacterial resistance. Penicillin demonstrates limited crossing of the blood-brain barrier. According to the Infectious Diseases Society of America (IDSA), penicillin G is recommended for bacterial meningitis caused by susceptible organisms such as Propionibacterium acnes.[19] According to the Centers for Disease Control and Prevention (CDC), penicillin should not be used as first-line therapy for treatment or postexposure prophylaxis for anthrax until susceptibility results.[20]

Specific Patient Populations

Hepatic impairment: Hepatic impairment warrants caution, particularly in cirrhosis cases, due to hypoalbuminemia.[21]

Renal impairment: Although renal impairment is not a contraindication for penicillin, doses must be adjusted given end-stage renal disease. Depending on the glomerular filtration rate, these patients will receive a full loading dose and half a loading dose every 8 to 10 or 4 to 5 hours.[22]

Pregnancy considerations: Penicillin G belongs to the FDA pregnancy category B drug. No severe adverse events are observed with penicillin G. Eliminating 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. According to the American College of Obstetricians and Gynecologists (ACOG) guidelines, penicillin G is recommended for group B Streptococcus (GBS) prophylaxis. The recommendation is a loading dose of 5 million units followed by 2.5 to 3 million units every 4 hours till delivery.[23][24]

Breastfeeding considerations: According to the literature, penicillin G and penicillin V are found in milk at low levels that are unexpected to cause adverse reactions in breastfed infants. Some research has reported that penicillin can disrupt the infant's gastrointestinal flora, causing diarrhea or thrush; however, these adverse effects have not been adequately evaluated. The use of penicillin G or penicillin V is acceptable for nursing mothers.[25][26]

Pediatric patients: The pediatric dose of penicillin is calculated based on the body surface area and weight. The CDC recommends Benzathine penicillin G 50,000 units/kg IM, up to 2.4 million units in a single dose for treating primary and secondary syphilis.[10]

Older patients: Older patients should exercise caution when using due to the potential for reduced glomerular filtration rate.[27]

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 type of reaction occurs within 20 minutes after administering the drug and is characterized by urticaria, pruritis, edema, laryngospasm, bronchospasm, hypotension, vascular collapse, and death.

• Delayed onset: This type of reaction occurs within 1 to 2 weeks of treatment, is rare, and is characterized by fever, malaise, urticaria, myalgia, arthralgia, abdominal pain, and skin rashes.[28]

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

Hematologic reactions: If the dose exceeds 10 million units per day and a patient has received a higher dose previously, then those patients can precipitate Coombs-positive hemolytic anemia and neutropenia, resolved when therapy is stopped.

Metabolic reactions: The salt form of penicillin G may cause electrolyte imbalances, such as hyperkalemia, when given IV in a large dose.

Nervous system: Neurological manifestations include hyperreflexia, myoclonic cramps, seizures, and coma after IV doses and are more likely in patients with impaired renal function.[29]

Urogenital system: Urological manifestations with large IV doses include renal tubular damage. Penicillins can also cause acute interstitial nephritis, a disease characterized by inflammation of the tubules and interstitium of the kidneys.[30] 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. 

Other reactions: Jarisch- Herxheimer reaction is precipitated when penicillin is administered in patients with syphilis due to rapid lysis of spirochetes and release of endotoxins.[31] Procaine reactions (1 in 500 patients) are due to immediate toxic reactions to procaine due to large single-dose administration. Procaine may cause a pseudoanaphylactic reaction.[32] Procaine can also cause methemoglobinemia.[33] 

Drug-Drug Interactions

• Concurrent sulfonamides, erythromycin, and chloramphenicol (bacteriostatic drugs) should be avoided due to antagonistic effects.[34]

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

• Drugs such as aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide, furosemide, and ethacrynic acid increase the half-life of penicillin by competing with tubular secretion.[35]

Contraindications

Contraindications of penicillin include a previous history of severe allergic reactions to penicillin or its derivatives. Penicillin is also contraindicated in patients with a prior history of Stevens-Johnson syndrome after administering penicillin or a penicillin derivative. In addition, penicillin has an antagonistic effect with tetracyclines and can lead to a 2.6 times higher mortality risk when treating pneumococcal meningitis than penicillin alone. However, penicillins are relatively safe to use during pregnancy and lactation.[36] 

Nearly all antibacterial agents have been linked to Clostridium difficile–associated diarrhea (CDAD), including penicillin, with severity ranging from mild diarrhea to fatal colitis. Antibacterial agents alter the colon's normal flora, causing the overgrowth of C difficile. This strain produces toxins A and B that contribute to the development of CDAD. During infections caused by hypertoxin-producing strains of C difficile, the morbidity and mortality rate is increased since these infections are often resistant to antimicrobial treatments and may require colectomy. Antibiotic treatment is recommended when CDAD is suspected or confirmed. Depending on clinical need, protein supplementation, fluid and electrolyte management, antibiotic treatment, and surgical evaluation are implemented.[37]

Monitoring

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. This vigilance will decrease the chance of antibiotic resistance while improving therapeutic impact.[38] Prolonged administration of penicillin requires monitoring hematologic, renal, and hepatic function.

Toxicity

Signs and Symptoms of Overdose

Penicillin has a small risk of toxicity. Clinicians can administer penicillin at relatively high doses compared to other drugs without harming patients. Estimates are that it would take 5 g/kg body weight IV to cause convulsions in a patient. However, penicillin can cause local toxicity due to high-dose injections at sensitive sites such as the eye's anterior chamber or the subarachnoid space. Reports show 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.[39] 

Management of Overdose

Neurotoxicity of penicillin requires discontinuation of the offending penicillin. Penicillins are hypothesized to have an inhibitory effect on GABA transmission; consequently, IV benzodiazepines and electroencephalogram (EEG) monitoring may be necessary in refractory cases.[40]

Enhancing Healthcare Team Outcomes

Before prescribing penicillin to a patient, the prescribing clinician and consulting team should confirm that the underlying infection is likely the result of bacteria sensitive to penicillin. The prescriber, pharmacist, and nurse should also counsel the patient on any adverse drug effects that should prompt a return visit, such as prolonged diarrhea or severe rash. Clinicians should notify the CDC if the zoonotic disease is suspected, and infectious disease consultation should be obtained. In an outpatient setting, communication between the clinician and the pharmacist will allow the drug to be dispensed appropriately to the patient.

Pharmacists 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. A retrospective study concluded that a team approach between infectious disease pharmacists with advanced pharmacy practice experience improves antimicrobial stewardship interventions.[41]

If a patient has difficulty obtaining drugs for financial or logistical reasons, a social worker may help ensure 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 has no contraindications to penicillin use.

If any immediate severe 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, current antibiogram data, and any other medications the patient is prescribed. Furthermore, a flattened hierarchy approach should be in place to ensure that reporting mistakes to a superior can take place without resistance. Utilizing the entire healthcare team is critical to ensure the patient is comfortable and has the best medical outcome with the lowest chance of complications. Interprofessional coordination and collaboration among physicians, nurse practitioners, physician assistants, pharmacists, and nurses can improve patient outcomes while using penicillin for treating susceptible infections.