Penicillins (see table Penicillins Penicillins Penicillins (see table Penicillins) are beta-lactamantibiotics that are bactericidal by unknown mechanisms but perhaps by activating autolytic enzymes that destroy the cell wall in some bacteria... read more ) are beta-lactam Beta-Lactams Beta-lactams are antibiotics that have a beta-lactam ring nucleus. Subclasses include Cephalosporins and cephamycins (cephems) Clavams Carbapenems Monobactams read more antibiotics Overview of Antibacterial Drugs Antibacterial drugs are derived from bacteria or molds or are synthesized de novo. Technically, “antibiotic” refers only to antimicrobials derived from bacteria or molds but is often (including... read more that are bactericidal by unknown mechanisms but perhaps by activating autolytic enzymes that destroy the cell wall in some bacteria.
Resistance
Some bacteria produce beta-lactamases, which inactivate beta-lactam antibiotics; this effect can be blocked by adding a beta-lactamase inhibitor.
However, traditional beta-lactamase inhibitors (eg, clavulanate, sulbactam, tazobactam) do not reliably inhibit the following:
AmpC beta-lactamases, commonly produced by Enterobacter, Serratia, Citrobacter, Providencia, and Morganella species or by Pseudomonas aeruginosa
Extended-spectrum beta-lactamases (ESBLs) produced by some Klebsiella pneumoniae, Escherichia coli, and other Enterobacteriaceae
Carbapenemases
Novel, non–beta-lactam beta-lactamase inhibitors, such as avibactam, relebactam, and vaborbactam, do have activity against AmpC, ESBLs, and even some carbapenemases such as the Klebsiella pneumoniae carbapenemases (KPCs), which have become increasingly common in Klebsiella species and other Enterobacteriaceae. However, there are no currently available beta-lactamase inhibitors active against metallo-beta-lactamases (MBLs), such as NDM-1 (New Delhi MBL-1), VIMs (Verona integron–encoded MBLs), and IMP (imipenem)-types, which can inactivate all beta-lactam antibiotics except for aztreonam Monobactams Monobactams are parenteral beta-lactam bactericidal antibiotics. Aztreonam is currently the only available monobactam. Aztreonam has activity similar to that of ceftazidime against Enterobacteriaceae... read more . However, many strains that produce MBLs also produce other beta-lactamases that can hydrolyze aztreonam.
Pharmacokinetics
Food does not interfere with absorption of amoxicillin, but penicillin G should be given 1 hour before or 2 hours after a meal. Amoxicillin has generally replaced ampicillin for oral use because amoxicillin is absorbed better, has fewer gastrointestinal effects, and can be given less frequently.
Penicillins are distributed rapidly in the extracellular fluid of most tissues, particularly when inflammation is present.
All penicillins are at least partially excreted in urine, and most reach high levels in urine. Parenteral penicillin G is rapidly excreted (serum half-life 0.5 hour), except for repository forms (the benzathine or procaine salt of penicillin G); these forms are intended for deep IM injection only and provide a tissue depot from which absorption takes place over several hours to several days. Benzathine penicillin reaches its peak level more slowly and is generally longer-acting than procaine penicillin.
Indications for Penicillins
Penicillin G–like drugs
Penicillin G–like drugs (including penicillin V) are primarily used against
Gram-positive bacteria
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 Syphilis Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential clinical, symptomatic stages separated by periods of asymptomatic latent infection. Common manifestations... read more 
, for certain clostridial infections Overview of Anaerobic Bacteria Bacteria can be classified by their need and tolerance for oxygen: Facultative: Grow aerobically or anaerobically in the presence or absence of oxygen Microaerophilic: Require a low oxygen concentration... read more , and, with gentamicin, for endocarditis Infective Endocarditis Infective endocarditis is infection of the endocardium, usually with bacteria (commonly, streptococci or staphylococci) or fungi. It may cause fever, heart murmurs, petechiae, anemia, embolic... read more 
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 Rheumatic Fever Rheumatic fever is a nonsuppurative, acute inflammatory complication of group A streptococcal pharyngeal infection, causing combinations of arthritis, carditis, subcutaneous nodules, erythema... read more 
. Pure benzathine penicillin and the mixture of equal amounts are indicated for treating upper respiratory infections and skin and soft-tissue infections Overview of Bacterial Skin Infections Bacterial skin infections can be classified as skin and soft tissue infections (SSTI) and acute bacterial skin and skin structure infections (ABSSSI). SSTI include Carbuncles Ecthyma Erythrasma... read more caused by susceptible streptococci.
Amoxicillin and ampicillin
These drugs are more active against
Certain gram-negative bacilli, such as non-beta-lactamase–producing H. influenzae Haemophilus Infections The gram-negative bacteria Haemophilus species cause numerous mild and serious infections, including bacteremia, meningitis, pneumonia, sinusitis, otitis media, cellulitis, and epiglottitis... read more , E. coli Escherichia coli Infections The gram-negative bacterium Escherichia coli is the most numerous aerobic commensal inhabitant of the large intestine. Certain strains cause diarrhea, and all can cause infection when they invade... read more , and Proteus mirabilis Proteeae Infections The Proteeae are normal fecal flora that often cause infection in patients whose normal flora have been disturbed by antibiotic therapy. The Proteeae constitute at least 3 genera of gram-negative... read more ; Salmonella Overview of Salmonella Infections The genus Salmonella is divided into 2 species, S. enterica and S. bongori, which include > 2400 known serotypes. Some of these serotypes are named. In such cases, common usage sometimes shortens... read more species; and Shigella Shigellosis Shigellosis is an acute infection of the intestine caused by the gram-negative Shigella species. Symptoms include fever, nausea, vomiting, tenesmus, and diarrhea that is usually bloody. Diagnosis... read more species
The addition of a beta-lactamase inhibitor (clavulanate or sulbactam) allows use against methicillin-sensitive staphylococci Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more 
, H. influenzae, Moraxella catarrhalis Moraxella catarrhalis Infection Moraxella catarrhalis is a gram-negative cocci that causes ear and upper and lower respiratory infections. M. catarrhalis is also known as Branhamella catarrhalis. M. catarrhalis is a frequent... read more , Bacteroides Mixed Anaerobic Infections Anaerobes can infect normal hosts and hosts with compromised resistance or damaged tissues. Mixed anaerobic infections can include both single anaerobic species or multiple anaerobic species... read more species, E. coli, and K. pneumoniae Klebsiella, Enterobacter, and Serratia Infections The gram-negative bacteria Klebsiella, Enterobacter, and Serratia are closely related normal intestinal flora that rarely cause disease in normal hosts. Diagnosis is by culture. Treatment is... read more .
Ampicillin is indicated primarily for infections typically caused by susceptible gram-negative bacteria:
Biliary sepsis
Respiratory infections
Penicillinase-resistant penicillins
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.
Broad-spectrum (antipseudomonal) penicillin
These drugs have activity against
Bacteria susceptible to ampicillin
Some strains of Enterobacter Klebsiella, Enterobacter, and Serratia Infections The gram-negative bacteria Klebsiella, Enterobacter, and Serratia are closely related normal intestinal flora that rarely cause disease in normal hosts. Diagnosis is by culture. Treatment is... read more and Serratia Klebsiella, Enterobacter, and Serratia Infections The gram-negative bacteria Klebsiella, Enterobacter, and Serratia are closely related normal intestinal flora that rarely cause disease in normal hosts. Diagnosis is by culture. Treatment is... read more species
Ticarcillin is less active against enterococci Enterococcal Infections Enterococci are gram-positive, facultative anaerobic organisms. Enterococcus faecalis and E. faecium cause a variety of infections, including endocarditis, urinary tract infections, prostatitis... read more than piperacillin. 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, and may only partially inhibit ESBL produced by some K. pneumoniae, E. coli, and other Enterobacteriaceae. Broad-spectrum penicillins exhibit synergy with aminoglycosides and are usually used with this class to treat P. aeruginosa infections.
Contraindications to Penicillins
Penicillins are contraindicated in patients who have had serious allergic reactions to them.
Use During Pregnancy and Breastfeeding
Penicillins are among the safest antibiotics during pregnancy. Animal reproduction studies with penicillin have not shown risk to the fetus. Data related to pregnancy in humans are limited. If medically indicated, penicillins can be used during pregnancy. Penicillin G is effective for preventing maternal transmission of syphilis to the fetus and for treating fetal and maternal infection.
Penicillins enter breast milk in small amounts. Their use is usually considered compatible with breastfeeding.
Adverse Effects of Penicillins
Adverse effects of penicillins include
Hypersensitivity reactions, including rashes (most common)
Other adverse effects occur less commonly.
Hypersensitivity
Most adverse effects are hypersensitivity reactions:
Immediate reactions: Anaphylaxis Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more (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 (in up to 8% of patients): 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 Skin testing Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally... read more may be done. Desensitization Desensitization Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to severe and include rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing is occasionally... read more 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
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.
Other adverse effects
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 Clostridioides (formerly Clostridium) difficile–Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody, rarely... read more (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, but ticarcillin is the most common cause, especially in patients with renal insufficiency.
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. Rarely, black tongue, due to irritation of the glossal surface and keratinization of the superficial layers, occurs, usually when oral formulations are used.
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.
Dosing Considerations for Penicillins
Because penicillins, except nafcillin, reach high levels in urine, doses must be reduced in patients with severe renal insufficiency. Probenecid inhibits renal tubular secretion of many penicillins, increasing blood levels. It is sometimes given concurrently to maintain high blood levels.
More Information
An article about cross-reactivity in beta-lactam allergy
