Amoxicillin is one of the most commonly used antibiotics in the primary care setting. It is an amino-penicillin, created by adding an extra amino group to penicillin, to battle antimicrobial resistance. Amoxicillin covers a wide variety of gram-positive bacteria, with some added gram-negative coverage compared to penicillin. Similar to penicillin, it covers most Streptococcus species and has improved coverage of Listeria monocytogenes and Enterococcus spp. It also has coverage over Haemophilus influenzae, some Escherichia coli, Actinomyces spp., Clostridium species, Salmonella spp., Shigella spp., and Corynebacteria spp. 

Amoxicillin is FDA approved for the treatment of genitourinary tract infections, ear, nose, and throat infections, lower respiratory tract infections, Helicobacter pylori infections, pharyngitis, tonsillitis, and skin and skin structure infections. It is recommended as the first-line treatment by the Infectious Disease Society of America (IDSA), for acute bacterial rhinosinusitis and as one of the treatments for community-acquired pneumonia.[1] For this, it is often in combination with a macrolide antimicrobial. The Centers for Disease Control and Prevention (CDC) recommends its use for post-exposure prophylaxis for anthrax inhalation.[2] It also has other off-label uses, such as erysipeloid, Lyme disease (if doxycycline contraindications are present), and infectious endocarditis prophylaxis, as well as prophylaxis in patients with prosthetic joints undergoing dental procedures. It can be effective in periodontitis in combination with metronidazole and is one of the first-line treatments for group A streptococcus pharyngitis.

Amoxicillin is in the class of beta-lactam antimicrobials. Beta-lactams act by binding to penicillin-binding proteins that inhibit a process called transpeptidation (cross-linking process in cell wall synthesis), leading to activation of autolytic enzymes in the bacterial cell wall. This process leads to lysis of the cell wall, and thus, the destruction of the bacterial cell. This type of activity is referred to as bactericidal killing.

Amoxicillin administration can also be in combination with a beta-lactamase inhibitor. Some examples of these are clavulanic acid and sulbactam. These beta-lactamase inhibitors work by binding irreversibly to the catalytic site of an organism’s beta-lactamase enzyme, which causes resistance to the original beta-lactam ring of amoxicillin. These drugs do not have inherent bactericidal activity; however, when combined with amoxicillin, they may broaden amoxicillin's spectrum to organisms that produce the beta-lactamase enzyme.[3]

Bactericidal antimicrobials, such as amoxicillin, often are most effective in a “time-dependent” manner, rather than a “concentration-dependent” manner. Time-dependent refers to the time that serum concentrations exceed the minimum-inhibitor-concentration (MIC) for the microorganism. Therefore, they are often dosed more frequently, rather than the concentration-dependent drugs, which can be dosed, for example, daily. The more “around-the-clock” dosing provides less variation in peak and trough serum concentrations.

Amoxicillin is an oral antimicrobial; whereas, ampicillin (which is structurally similar) can be given orally, intravenously, or intramuscularly. Amoxicillin comes in immediate-release or extended-release tablets. It also comes in a chewable tablet or a suspension. If given in suspension, it may be mixed (after thouroughly shaking) and administered with formula, milk, water, fruit juice, ginger ale, or other cold drinks. Administration should take place immediately after mixing. Extended-release tablets should not be crushed, and the administration should be within 1 hour after finishing a meal. Amoxicillin is sometimes preferred over penicillin in children because of its taste.

It is important to note that it is excreted by in the majority of people by the kidney, and some renal adjustment and extra caution may be necessary for renal insufficiency. It is reported to be partially dialyzable, and therefore, immediate-release tablets can be an option for dosing after hemodialysis. There are no guidelines for hepatic dosing or geriatric dosing. It was a pregnancy category B drug under the old FDA classification system, which means there have been no studies demonstrating clear risk. It has also been reported to get excreted in breast milk.

Amoxicillin is well-tolerated, but some common complaints can be gastrointestinal (GI) symptoms, such as nausea, vomiting, and diarrhea. Superinfections, as with fungi or Clostridioides difficile colitis, are also important complications. Crystalluria, nephritis, and hemolytic anemia can happen with prolonged administration. Of note, patients who take amoxicillin may have less diarrhea than those who take ampicillin, which may lead to better absorption in the gut.

Another significant complication to be aware of is hypersensitivity reactions. Amoxicillin can lead to type-I, II, III, or IV reactions. It is important to differentiate between a type-I and type-IV hypersensitivity reaction because one may be more dangerous than the other. A type-I reaction is an IgE-mediated hypersensitivity to a sensitized patient that triggers widespread histamine release leading to an urticarial like pruritic rash or even more severe systemic symptoms, such as anaphylaxis. A type-IV hypersensitivity reaction does not get mediated by histamine release, and is more papular or morbilliform and often not itchy. Professionals suggest that almost all patients that receive amoxicillin inadvertently for infectious mononucleosis develop a maculopapular rash caused by a type IV-mediated hypersensitivity reaction. These types of reactions are not known to lead to anaphylaxis.

Any previous anaphylactic reaction or serious skin reaction (for example, Stevens-Johnson syndrome) to amoxicillin or any other beta-lactam is a significant contraindication to amoxicillin. These reactions may have crossover sensitivity with cephalosporins or carbapenems. It is important to note that newer data has suggested a much lower cross-reactivity with cephalosporins and carbapenems than once suspected. Another important consideration is to determine if the patient’s allergic rash is a type-I or a type-IV hypersensitivity reaction. Occasionally patients will report a childhood allergy to amoxicillin, which is, in fact, a type-IV-mediated hypersensitivity reaction, often in the setting of infectious mononucleosis; this is not a contraindication to giving repeat amoxicillin. A type-1 mediated hypersensitivity reaction is, however, a contraindication given that a repeat exposure puts the patient at risk for anaphylaxis. Skin testing has been approved to help assist in hypersensitivity to penicillins. Reports are that the risk of an allergic reaction in a patient with a positive skin test is roughly four percent, whereas a negative skin test has a relatively high sensitivity in ruling out a type-I hypersensitivity reaction.[4]