PENICILLIN G AND V
Penicillin G and V
Penicillin G and V are first generation penicillins that are used widely to treat infections due to susceptible organisms and have been linked rarely and only weakly with idiosyncratic liver injury.
Penicillin G benzathine, potassium, procaine and sodium are currently available in the United States in parenteral formulations for intravenous or intramuscular use. Penicillin V potassium (also called phenoxymethyl penicillin) is a more acid stable and can be administered orally. Both Penicillin G and V are available in multiple generic formulations. The natural penicillins are indicated as therapy for mild-to-severe infections caused by susceptible organisms including (but not limited to) streptococcal infections and pneumonia, enterococcal and non-enterococcal endocarditis, diphtheria, anthrax, bacterial meningitis, Lyme disease, gonorrhea, syphilis, actinomycosis, botulism and others. The first generation penicillins are susceptible to inactivation by beta-lactamase, and resistance is relatively common. The usual doses of intravenous penicillin G are 300,000 to 4 million units every 6 to 8 hours. Benzathine penicillin G is given in a one time dose of 2.4 million units intramuscularly as therapy of primary or secondary syphilis, and as three weekly doses for syphilis of longer duration; it is also used as prophylaxis against rheumatic fever. Penicillin V is available in tablets of 250 and 500 mg and is usually given in doses of 250 to 500 mg every 6 to 8 hours for 7 to 20 days. It is also available as an oral solution. Side effects of penicillin G and V include nausea, diarrhea, gastrointestinal upset, headache, dizziness, rash and hypersensitivity reactions.
Rare instances of idiosyncratic liver injury have been reported in persons receiving the first generation penicillins. Many case reports predated availability of serologic testing for viral hepatitis and many described patients with multiple reasons for having liver disease (such as sepsis) and who were receiving other potentially hepatotoxic agents. Three distinct forms of liver injury can occur with the first generation penicillins: (1) transient, asymptomatic elevations in serum aminotransferase levels with prolonged high doses of parenteral penicillin, (2) minor liver injury associated with severe hypersensitivity reactions, and (3) idiosyncratic, delayed cholestatic hepatitis. These three forms of injury probably occur with all forms of penicillin, some being more common with one form of penicillin than another.
High doses of intravenous and intramusclar penicillin can be associated with serum aminotransferase elevations that are usually asymptomatic and resolve rapidly with stopping therapy or switching to another antibiotic (Case 1). Jaundice and elevations in alkaline phosphatase are usually absent or mild. This type of hepatotoxicity is most common with oxacillin and carbenicillin, but can occur with parenteral forms of the first generation penicillins as well.
Patients with severe hypersensitivity reactions to penicillin, such as Stevens-Johnson syndrome or anaphylaxis, may have an accompanying liver injury and jaundice, but it is not clear whether this represents true penicillin hepatotoxicity or a complication of hyperthermia, shock and generalized immune reactivity. Generalized allergic reactions to penicillin may be accompanied by granulomas in the liver, spleen and kidney, but are usually without evidence of specific hepatitis injury. Virtually all of the penicillins are associated with hypersensitivity reactions, but liver injury is usually overshadowed by the allergic complications (rash, fever, anaphylaxis).
Finally, isolated case reports have shown that the first generation penicillins can cause a delayed cholestatic hepatitis. Symptoms of nausea, abdominal discomfort, jaundice and pruritus generally arise 1 to 4 weeks after starting therapy, and often a few days or weeks after completing a course. The serum enzyme pattern is usually cholestatic, but may be hepatocellular if tested soon after onset. Immunoallergic features are common, but autoantibody formation is rare. Most cases are mild-to-moderate in severity and resolve rapidly (Case 2). This delayed form of idiosyncratic cholestatic hepatitis is typical of many penicillins, varying in frequency with the specific form. Idiosyncratic, cholestatic hepatitis is quite rare with the natural penicillins, more common with certain broad spectrum penicillins (cloxacillin, flucloxacillin) and is most common with amoxicillin with clavulanic acid.
Mechanism of Injury
The cause of the idiosyncratic, cholestatic liver injury associated with penicillin is probably hypersensitivity or allergy. No cases of rechallenge or reexposure have been reported. The serum aminotransferase elevations that occur with high doses of parenteral penicillin are likely due to direct hepatotoxicity.
Outcome and Management
The asymptomatic rise in serum aminotransferase levels that occurs with high dose penicillin therapy usually resolves rapidly once penicillin is stopped. These patients may tolerate another form of penicillin without recurrence. In the few cases of cholestatic hepatitis that have been described with the first generation penicillins, patients have recovered although recovery was slow in some instances (2 to 6 months). Fatal cases of penicillin associated liver injury have been described, but usually in association with severe allergic reactions such as Stevens-Johnson syndrome in which shock and ischemic hepatitis may have contributed to the outcome. Patients with idiosyncratic liver injury attributed to penicillin should not be reexposed to other penicillins.
References to hepatotoxicity of penicillin G and V are provided in the Overview of the First Generation Penicillins.
|Medication:||Penicillin G benzathine (5 MU iv every 6 hours)|
|Pattern:||Hepatocellular (no alkaline phosphatase elevations)|
|Severity:||1+ (serum enzyme elevations without jaundice)|
|Recovery:||Somewhat more than 3 weeks|
|Other medications:||Ibuprofen, ranitidine, low molecular weight heparin, chloral hydrate, diazepam and, on day 21, propofol and alfentanil anesthesia.|
|Time After Starting||Time After Stopping||ALT* (U/L)||Alk P (U/L)||Bilirubin (mg/dL)**||Other|
|Benzylpenicillin (5 MU iv q 6 hr) started for Streptococcal pyogenic vertebral spondylitis|
|General anesthesia with propofol and alfentanil for minor surgery (~ day 26)|
|29 days||423||101||0.5||13% eosinophils|
|40 days||0||680||Penicillin stopped and Ceftriaxone started|
|45 days||4 days||600|
|48 days||7 days||400|
|56 days||15 days||230|
|2 months||1 month||160|
|Medication:||Oral penicillin (200,000 U)|
|Severity:||3+ (jaundice and hospitalization)|
|Recovery:||More than 3 months|
|Other medications:||None mentioned|
|Time After Starting||Time After Stopping||AST (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|Took a single table of penicillin for sore throat|
|4 days||3 days||96||105||7.3||Fever to 40 deg C|
|8 days||7 days||48||82||3.6|
|25 days||24 days||31||51||3.1|
|2 months||2 months||17||58||1.9|
|3 months||3 months||9||56||0.8|
|5 months||5 months||9||69||0.6|
|11 months||11 months||9||68||1.9|
|DRUG||CAS REGISTRY NO||MOLECULAR FORMULA||STRUCTURE|