Penicillins

1. 1. Centers for Disease Control and Prevention (CDC): Inadvertent use of Bicillin C-R to treat syphilis infection—Los Angeles, California, 1999-2004. MMWR Morb Mortal Wkly Rep 54(9):217–219, 2005. PMID: 15758893

Penicillin G–like drugs (including penicillin V) are primarily used against

• Gram-positive bacteria

• Some gram-negative cocci (eg, meningococci)

A minority of gram-negative bacilli are also susceptible to large parenteral doses of penicillin G. Most staphylococci, most Neisseria gonorrhoeae, many anaerobic gram-negative bacilli, and about 30% of Haemophilus influenzae are resistant.

Penicillin G is the drug of choice for syphilis, for certain clostridial infections, and, with gentamicin, for endocarditis due to susceptible enterococci.

Benzathine penicillin G is a long-acting formulation that is available as

• Pure benzathine penicillin

• A mixture of equal amounts of benzathine and procaine penicillin G

• A 3:1 mixture of 0.9 million units benzathine and 0.3 million units procaine penicillin G

Of the 3 products, only pure benzathine penicillin is recommended for treating syphilis and preventing rheumatic fever. Pure benzathine penicillin and the mixture of equal amounts are indicated for treating upper respiratory infections and skin and soft-tissue infections caused by susceptible streptococci.

These drugs are more active against

• Enterococci

• Certain gram-negative bacilli, such as non-beta-lactamase–producing H. influenzae, E. coli, and Proteus mirabilis; Salmonella species; and Shigella species

The addition of a beta-lactamase inhibitor (clavulanate or sulbactam) allows use against methicillin-sensitive staphylococci, H. influenzae, Moraxella catarrhalis, Bacteroides species, E. coli, and K. pneumoniae.

Ampicillin is indicated primarily for infections typically caused by susceptible gram-negative bacteria:

• Urinary tract infections

• Meningococcal meningitis

• Biliary sepsis

• Respiratory infections

• Listeriameningitis

• Enterococcal infections

• Some typhoid fever and typhoid carriers

These drugs (dicloxacillin, nafcillin, cloxacillin, flucloxacillin, and oxacillin) are used primarily for

• Penicillinase-producing methicillin-sensitive Staphylococcus aureus

These drugs are also used to treat some Streptococcus pneumoniae, group A streptococcal, and methicillin-sensitive coagulase-negative staphylococcal infections.

Piperacillin and piperacillin/tazobactam have activity against

• Bacteria susceptible to ampicillin

• Some strains of Enterobacter and Serratia species

• Many strains of P. aeruginosa

The addition of a beta-lactamase inhibitor enhances activity against beta-lactamase–producing methicillin-sensitive S. aureus, E. coli, K. pneumoniae, H. influenzae, and gram-negative anaerobic bacilli but not against gram-negative bacilli that produce AmpC beta-lactamase or KPC and may only partially inhibit ESBL produced by some K. pneumoniae, E. coli, and other Enterobacterales. Broad-spectrum penicillins exhibit synergy with aminoglycosides and are usually used with this class to treat P. aeruginosa infections.

Most adverse effects are hypersensitivity reactions:

• Immediate reactions: Anaphylaxis (which can cause death within minutes), urticaria and angioneurotic edema (in 1 to 5/10,000 injections), and death (in about 0.3/10,000 injections)

• Delayed reactions: Serum sickness, rashes (eg, macular, papular, morbilliform), and exfoliative dermatitis (which usually appears after 7 to 10 days of therapy)

Most patients who report an allergic reaction to penicillin do not react to subsequent exposure to penicillin. Although small, risk of an allergic reaction is about 10 times higher for patients who have had a previous allergic reaction. Many patients report adverse reactions to penicillin that are not truly allergic (eg, gastrointestinal adverse effects, nonspecific symptoms).

If patients have a vague or inconsistent history of penicillin allergy and taking alternative antibiotics is not effective or convenient, skin testing may be done. Desensitization may be attempted in patients with a positive skin test if there is no alternative to a penicillin-type drug. However, patients with a history of anaphylaxis to penicillin should not be given other penicillins or any beta-lactam with similar side chains (including for skin testing), except in very rare circumstances when no substitute can be found and the drug can be given under supervision in a controlled environment. In such cases, special precautions and desensitization regimens are required.

Rashes occur more often with ampicillin and amoxicillin than with other penicillins. Patients with infectious mononucleosis often develop a nonallergic rash, typically maculopapular, usually beginning between days 4 and 7 of treatment.

Penicillins can also cause

• Central nervous system toxicity (eg, seizures) if doses are high, especially in patients with renal insufficiency

• Nephritis

• Clostridioides (formerly Clostridium) difficile–induced diarrhea (pseudomembranous colitis)

• Coombs-positive hemolytic anemia

• Leukopenia

• Thrombocytopenia

Leukopenia seems to occur most often with nafcillin. Any penicillin used in very high IV doses can interfere with platelet function and cause bleeding.

Other adverse effects include pain at the IM injection site, thrombophlebitis when the same site is used repeatedly for IV injection, and, with oral formulations, gastrointestinal disturbances.

Ticarcillin and carbenicillin in high doses may cause sodium overload, especially in patients with heart or kidney failure, because both are disodium salts. Ticarcillin and carbenicillin can also cause hypokalemic metabolic alkalosis because the large amount of nonabsorbable anion presented to the distal tubules alters H+ ion excretion and secondarily results in potassium loss.