What to Know About Penicillins

Penicillin is an antibiotic used to treat certain types of bacterial infections. Common side effects include diarrhea and stomach upset, and some people may have an allergic reaction to penicillin—the effects can range from mild to severe.

Penicillin is available in oral form to be taken by mouth, or by intravenous (IV, into a vein) injection, or intramuscular (IM, in a large muscle) injection. And there are different types of penicillin with different mechanisms of action.

Background

All forms of penicillin are derived, at least in part, from a fungus known as Penicillium chrysogenum.

Scottish scientist Alexander Fleming is credited with discovering penicillin in 1929 when he realized that bacterial cultures accidentally contaminated with "mold juice" were being killed by the fungus. It wasn't until 1941 that scientists were able to successfully isolate, purify, and test the drug in their first patient, ushering in the age of antibiotics.

By the 1960s, scientists were able to develop the first semisynthetic penicillin drugs able to treat a broader range of bacterial infections. It was about the same time that they began to recognize the threat of penicillin resistance, in which mutant bacterial strains resistant to the antibiotic began to emerge and be passed throughout a population.

Today, there is a growing number of bacterial infections that are either fully or partially resistant to the original penicillin drugs, including Neisseria gonorrhoeae (gonorrhea) and methicillin-resistant Staphylococcal aureus (MRSA).

Streptococcal pneumoniae (a type of bacterial pneumonia) and certain types of Clostridium and Listeria bacteria have become less responsive to these antibiotics as well.

The overuse of antibiotics in livestock to promote growth is known to increase the risk of resistant bacteria, including superbugs, all along the food chain. As a result of this growing global concern, the United States banned the use of antibiotics for growth promotion in animals in 2017.

Types

Penicillins belong to a larger family of drugs known as beta-lactam antibiotics. These drugs share a similar molecular structure and are comprised of a ring of four atoms, referred to as beta-lactam. Each type of penicillin has additional side chains that determine its activity.

Penicillins work by binding to molecules on the walls of bacteria called peptidoglycan. When the bacteria divide, penicillin prevents proteins in the cell wall from reassembling properly, causing the bacterial cell to rupture and quickly die.

Natural penicillins are those directly derived from P. chrysogenum fungi. There are two natural penicillins.

Semisynthetic penicillins are produced in a lab to resemble chemical substances found in P. chrysogenum. There are four classes of semisynthetic penicillins, including such commonly prescribed antibiotics like amoxicillin and ampicillin.

Natural
  • Penicillin G (benzylpenicillin)

  • Penicillin V (phenoxymethylpenicillin)

Semisynthetic
  • Aminopenicillins (ampicillin, amoxicillin, and hetacillin)

  • Antistaphylococcal penicillins (cloxacillin, dicloxacillin, nafcillin, and oxacillin)

  • Broad-spectrum penicillins (carbenicillin, mezlocillin, piperacillin, ticarcillin)

  • Beta-lactamase inhibitor (clavulanic acid)

Each of these types has a slightly different molecular structure and may be administered differently than the others.

Some penicillins don't have direct antibacterial activity. They are used in combination therapy to help overcome penicillin resistance. For example, clavulanic acid blocks an enzyme secreted by antibiotic-resistant bacteria (beta-lactamase) that inhibits the activity of beta-lactam antibiotics.

Uses

Penicillins are used for treating bacterial infections—and they don't treat viral, fungal, or parasitic infections. The drugs are generally active against gram-positive bacteria, a group of bacteria that has peptidoglycan on the outside of the cell wall. With gram-negative bacteria, the peptidoglycan layer is buried beneath a layer of lipid cells, making it harder for the drug to access the molecule.

The list of gram-positive bacteria that are treatable by penicillins includes those of the Clostridium, Listeria, Neisseria, Staphylococcal, and Streptococcal genus.

Natural penicillins—penicillin G and penicillin V—are still used today and are appropriate for the treatment of certain common and uncommon bacterial infections.

Drug  Administration Conditions Commonly Treated
Penicillin G Intravenous or intramuscular injection •Anthrax
Bacterial endocarditis
Bacterial meningitis
Cellulitis
Diphtheria

Gangrene
Necrotizing enterocolitis
Pneumococcal pneumonia
Strep throat
Syphilis (advanced disseminated or congenital)
Tetanus
Tonsillitis
Penicillin V By mouth  Anthrax
Cellulitis
Dental abscess
Erysipelas
Rheumatic fever
Strep throat
Streptococcal skin infections
Tonsillitis

By contrast, semisynthetic antibiotics like amoxicillin—one of the most commonly prescribed antibiotics today—can be used to treat a broad spectrum of respiratory infection, skin, and bacterial infections like H. pylori, Lyme disease, and acute otitis media.

Off-Label

The off-label use of penicillins is common, albeit more often with drugs like amoxicillin and ampicillin than natural penicillins. Off-label use includes treatment of critical care patients with sepsis or newborns with acute respiratory distress. In neither instance are the drugs indicated for such use, but they are often considered necessary when no other treatment options are available.

Penicillin G is sometimes used off-label to treat prosthetic joint infections, Lyme disease, and leptospirosis. Penicillin V is occasionally used off-label to treat Lyme disease and otitis media, or to prevent infections in people undergoing stem cell transplant.

Before Taking

Penicillin can be very effective if used appropriately. Even so, there are instances when the drug is not effective in clearing an infection. In such cases, antibiotic susceptibility testing (also known as antibiotic sensitivity testing) may be used to determine if a person's infection is responsive to penicillin.

The test starts by culturing bacteria taken from a swab of body fluid, then directly exposing the bacteria to various penicillin types in a lab. Antibiotic susceptibility testing is often used for people with community-acquired pneumonia who are at high risk of severe illness or death.

Precautions and Contraindications

Penicillins are contraindicated if you've had a prior allergy to any drug in the penicillin family. It should also be used with extreme caution if you have ever had a severe drug hypersensitivity reaction in the past, including anaphylaxis, Stevens-Johnson syndrome (SJS), or toxic epidermal necrosis (TEN).

If you have had an allergic reaction to penicillin G or penicillin V in the past, you may be—but are not necessarily—allergic to semisynthetic penicillins like amoxicillin or ampicillin.

Other beta-lactam antibiotics should be used with caution in people with penicillin allergy as there is a risk, albeit slight, of a cross-reactive allergy. This includes cephalosporin antibiotics like Keflex (cephalexin), Maxipime (cefepime), Rocephin (ceftriaxone), and Suprax (cefixime).

If you are concerned that you may be allergic to penicillin, you can have skin allergy testing to see if you react to a minute amount of the drug placed under the skin.

Penicillin should also be used with extreme caution if you have acute renal (kidney) failure. Penicillin is mainly excreted through the kidneys, and diminished kidney function can cause the drug to accumulate to toxic levels. The ensuing overdose of penicillin can lead to symptoms of agitation, confusion, stupor, abnormal twitches, and, in rare cases, coma.

Dosage

The recommended dosage of penicillin G and penicillin V can vary depending on the disease, its disease, and the age of the person being treated.

The doses are measured in several different ways depending on the formulation. In adults, the drug is usually measured in units or milligrams (mg). In children, the dose may be calculated by milligrams per kilograms of body weight per day (mg/kg/day) or units per kilogram of body weight per day (units/kg/day).

Drug Indication Recommended Dose
Penicillin G Anthrax Minimum 8 million units per day in four divided doses
  Diphtheria Adults: 2 to 3 million units per day in divided doses for 10 to 12 days
Children: 150,000 to 250,000 units/kg/day in four divided doses for 7 to 14 days
  Endocarditis Adults: 15 to 20 million units per day for 4 weeks
Children: 150,000 to 300,000 units/kg/day in four to six divided doses (duration varies by the severity of the illness)
  Gangrene 20 million units per day
  Meningitis Adults: 14 to 20 million units per day for 2 weeks
Children: 150,000 to 300,000 units/kg/day in four to six divided doses (duration varies by the severity of illness)
  Pneumonia Adults: 5 to 24 million units per day in four to six divided doses (duration varies by the severity of illness)
  Syphilis Adults: 12 to 24 million units per day every four hours for 10 to 14 days
Children: 200,000 to 300,000 units/kg/day in four to six divided doses for 10 to 14 days
Penicillin V Dental abscess 250 to 500 mg every 6 hours for 5 to 7 days
  Erysipelas 500 mg every 6 hours as needed
  Rheumatic fever Adults: 250 mg every 12 hours as needed
Children: 125 to 250 mg every 12 hours as needed
  Strep throat Adults: 500 mg every 12 hour or 250 every 6 hours for 10 day
Children: 250 to 500 mg every 8 to 12 hours for 10 days
  Staphylococcal skin infections 250 to 500 mg every 6 to 8 hours (duration varies by the severity of illness)

Modifications

If you have kidney disease, you may need a lower penicillin dose to prevent drug toxicity. A dose reduction is typically recommended when the creatinine clearance (a measure of kidney function) is less than 10 milliliters per minute (mL/min).

On the other hand, if you are treated with hemodialysis, you may need a higher dose because hemodialysis can speed the clearance of penicillin from the blood.

How to Take and Store

Penicillin G

Penicillin G is available as either a premixed solution or a powder that is reconstituted with sterile water for injection. The premixed solution can be stored in the refrigerator or freezer, while the powder formulation can be kept safely at room temperature. 

Penicillin G injections are not self-administered.

Penicillin V

Penicillin V is available as an oral tablet or a cherry-flavored powder mixed with water. Both can be safely stored at room temperature. Once the powder is reconstituted, it should be stored in the refrigerator and discarded after 14 days.

Penicillin V should be taken on an empty stomach to ensure maximum absorption. It should be taken at least one hour before a meal or at least two hours after a meal.

If you miss a dose of penicillin V, take it as soon as you remember. If it is near the time of your next dose, skip the dose and continue as normal. Never double up on doses.

Use As Directed

Always take penicillin as directed and to completion. Do not stop because you feel well. You need to take the entire course so that all bacteria are eradicated. Small amounts of remaining bacteria can proliferate once treatment is stopped.

Side Effects

Most penicillin side effects are mild and transient and will resolve on their own without treatment. But sometimes side effects can be severe—and even life-threatening—and require emergency care.

Common

The most common side effects of penicillins (affecting at least 1% of users) are:

Fever and angioedema (tissue swelling) can also occur but are less common.

Severe

One of the most serious concerns associated with the use of penicillin is the risk of a potentially life-threatening, whole-body allergy known as anaphylaxis. True penicillin-induced anaphylaxis affects around one to five of every 100,000 people.

Anaphylaxis can reap serious harm if it is left untreated. It can lead to shock, coma, respiratory or cardiac failure, and even death.

When to Call 911

Seek emergency care if you experience some or all of the symptoms of anaphylaxis after receiving a dose of penicillin:

  • Shortness of breath
  • Wheezing
  • Dizziness, lightheadedness, or fainting
  • Severe rash or hives
  • Rapid or irregular heartbeat
  • Swelling of the face, tongue, or throat
  • A feeling of impending doom

On rare occasions, penicillins can cause acute interstitial nephritis, an inflammatory kidney condition most often caused by an abnormal immune reaction to medications. Symptoms include nausea, rash, fever, drowsiness, diminished urine output, fluid retention, and vomiting. Most cases are mild, but some can turn serious and cause an acute kidney injury.

Penicillins, like all antibiotics, are associated with an increased risk of Clostridium difficile diarrhea. This is caused when bacteria that are normally present in the gut are obliterated by antibiotics, allowing C. difficile bacteria to proliferate. Most cases are mild and readily treatable, but C. difficile has been known on rare occasions to cause severe fulminant colitis, toxic megacolon, and death.

Warnings and Interactions

Penicillins are generally considered safe during pregnancy and breastfeeding. With that said, the drugs are classified as Pregnancy Category B drugs, meaning that animal studies have shown no risk of fetal harm but evidence in humans is lacking.

If you are pregnant, planning to get pregnant, or breastfeeding, speak with your doctor to fully understand the benefits and risks of using penicillin.

A number of drugs can also interact with penicillin, oftentimes by competing for clearance in the kidneys. This can increase penicillin concentrations in the blood as well as the risk of side effects and drug toxicity. Other medications can speed the clearance of penicillin from the body and reduce the drug's effectiveness.

Among the drugs that are likely to interact with penicillin are:

To avoid interactions, always let your doctor know about any drugs you are taking, whether they are prescription, over-the-counter, nutritional, herbal, or recreational.

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  1. Lobanovska M, Pilla G. Penicillin's discovery and antibiotic resistance: Lessons for the future?. Yale J Biol Med. 2017;90(1):135-45.

  2. Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. P T. 2015;40(4):277-83.

  3. Founou LL, Founou RC, Essack SY. Antibiotic resistance in the food chain: A developing country-perspective. Front Microbiol. 2016;7:1881. doi:10.3389/fmicb.2016.01881

  4. Centers for Disease Control and Prevention. Food and food animals. Updated February 10, 2020.

  5. Pandey N, Cascella M. Beta lactam antibiotics. In: StatPearls. Updated July 4, 2020.

  6. Blum JK, Deaguero AL, Perez CV, Bommarius AS. Ampicillin synthesis using a two-enzyme cascade with both α-amino ester hydrolase and penicillin G acylase. ChemCatChem. 2010;2(8):987-91 doi:10.1002/cctc.201000135

  7. Evans J, Hannoodee M, Wittler M. Amoxicillin clavulanate. In: StatPearls. Updated April 20, 2020.

  8. Sizar O, Unakal CG. Gram positive bacteria. In: StatPearls. Updated June 27, 2020.

  9. Mukattash TL, Hayajneh WA, Ibrahim SM, et al. Prevalence and nature of off-label antibiotic prescribing for children in a tertiary setting: A descriptive study from Jordan. Pharm Pract (Granada). 2016;14(3):725. doi:10.18549/PharmPract.2016.03.725

  10. Gartlan WA, Rahman S, Reti K. Benzathine penicillin. In: StatPearls. Updated June 2, 2020.

  11. Rashidi A, Wangjam T, Bhatt AS, Weisdorf DJ, Holtan SG. Antibiotic practice patterns in hematopoietic cell transplantation: A survey of blood and marrow transplant clinical trials network centers. Am J Hematol. 2018;93(11):E348-50. doi:10.1002/ajh.25236

  12. Zafar A, Hasan R, Nizamuddin S, et al. Antibiotic susceptibility in Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes in Pakistan: A review of results from the Survey of Antibiotic Resistance (SOAR) 2002-15. J Antimicrob Chemother. 2016;71 Suppl 1:i103-9. doi:10.1093/jac/dkw076

  13. Patterson RA, Stankewicz HA. Penicillin allergy. In: StatPearls. Updated on June 27, 2020

  14. Yuson CL, Katelaris CH, Smith WB. ‘Cephalosporin allergy’ label is misleading. Aust Prescr. 2018 Apr;41(2):37-41. doi:10.18773/austprescr.2018.008

  15. Bayer Healthcare LLC. Penicillin G potassium injection, USP. Updated July 2016.

  16. Smyth B, Jones C, Saunders J. Prescribing for patients on dialysis. Aust Prescr. 2016;39(1):21-4. doi:10.18773/austprescr.2016.008

  17. Cleveland Clinic. Penicillin V powder for oral solution. 2020.

  18. Sandoz Pharmaceuticals. Penicillin VK USP tablets. Updated August 2012.

  19. Yip DW, Gerriets V. Penicillin. In: StatPearls. Updated May 12, 2020.

  20. Finnigan NA, Bashir K. Allergic interstitial nephritis (AIN). In: StatPearls. Updated on March 18, 2020.

  21. Mada PK, Alam MU. Clostridium difficile. In: StatPearls. Updated on June 26, 2020.

  22. Kuscu F, Ulu A, Inal AS, et al. Potential drug-drug interactions with antimicrobials in hospitalized patients: A multicenter point-prevalence study. Med Sci Monit. 2018;24:4240-7. doi:10.12659/MSM.908589