Amoxicillin
amoxicillin trihydrate — formerly marketed as Amoxil
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Upper respiratory tract infections (otitis media, sinusitis, pharyngitis/tonsillitis) | Adults and children | Monotherapy | FDA Approved |
| Lower respiratory tract infections (community-acquired pneumonia, acute bronchitis with bacterial superinfection) | Adults and children | Monotherapy | FDA Approved |
| Genitourinary tract infections (uncomplicated UTI) | Adults and children | Monotherapy | FDA Approved |
| Skin and skin structure infections | Adults and children | Monotherapy | FDA Approved |
| H. pylori eradication (with clarithromycin + lansoprazole or lansoprazole alone) | Adults only | Combination (triple or dual therapy) | FDA Approved |
Amoxicillin is effective only against beta-lactamase-negative organisms. In infections where beta-lactamase-producing bacteria are suspected, amoxicillin-clavulanate should be used instead. For Streptococcus pyogenes pharyngitis, a minimum 10-day course is recommended to prevent acute rheumatic fever. Amoxicillin remains the first-line treatment for Group A streptococcal pharyngitis and acute otitis media per current IDSA and AAP guidelines.
Endocarditis prophylaxis — AHA recommends amoxicillin 2 g orally 30–60 min before dental procedures in high-risk patients. Evidence quality: High (guideline-based).
Lyme disease (early localized) — IDSA recommends amoxicillin 500 mg TID for 14–21 days as an alternative to doxycycline. Evidence quality: High.
Anthrax post-exposure prophylaxis — CDC recommends amoxicillin 500 mg TID for 60 days as an alternative when ciprofloxacin/doxycycline cannot be used. Evidence quality: Moderate.
Dental abscess — Commonly used at 500 mg TID for 5–7 days; widely supported by dental practice guidelines. Evidence quality: Moderate.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild-moderate ear/nose/throat, skin, or GU infection | 500 mg q12h or 250 mg q8h | Same | 1000 mg/day | Continue 48–72 h beyond symptom resolution FDA PI Table 1 |
| Severe ear/nose/throat, skin, or GU infection | 875 mg q12h or 500 mg q8h | Same | 1750 mg/day | Also use severe dosing for organisms with intermediate susceptibility FDA PI Table 1 |
| Lower respiratory tract infection (any severity) | 875 mg q12h or 500 mg q8h | Same | 1750 mg/day | All lower respiratory infections use the severe dosing regimen FDA PI Table 1 |
| Streptococcal pharyngitis (GAS) | 500 mg q12h or 250 mg q8h | Same for 10 days minimum | 1000 mg/day | 10 days minimum to prevent acute rheumatic fever (FDA PI) IDSA 2012 guideline first-line |
| H. pylori — triple therapy | 1 g q12h | + clarithromycin 500 mg q12h + lansoprazole 30 mg q12h | 2 g/day amoxicillin | 14-day course FDA PI |
| H. pylori — dual therapy | 1 g q8h | + lansoprazole 30 mg q8h | 3 g/day amoxicillin | 14-day course; use when clarithromycin cannot be used FDA PI |
| Endocarditis prophylaxis (off-label) | 2 g single dose | Single pre-procedure dose | 2 g | 30–60 min before dental procedure in high-risk patients AHA 2021 guideline |
| Lyme disease — early localized (off-label) | 500 mg q8h | Same for 14–21 days | 1500 mg/day | Alternative to doxycycline (preferred in pregnant women and children <8 years) IDSA/AAN/ACR 2020 guideline |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild-moderate ear/nose/throat, skin, GU (≥3 months, <40 kg) | 25 mg/kg/day q12h or 20 mg/kg/day q8h | Same | 25 mg/kg/day | Use weight-based dosing until child reaches 40 kg FDA PI Table 1 |
| Severe infection or lower respiratory (≥3 months, <40 kg) | 45 mg/kg/day q12h or 40 mg/kg/day q8h | Same | 45 mg/kg/day | High-dose regimen for severe or resistant infections FDA PI Table 1 |
| Acute otitis media — high-dose regimen (off-label) | 80–90 mg/kg/day divided q12h | Same for 10 days (≤2 yrs) or 5–7 days (≥2 yrs) | 90 mg/kg/day | AAP 2013 guideline for AOM in high-resistance areas Exceeds FDA PI — guideline-directed high-dose |
| Neonates and infants ≤3 months | 30 mg/kg/day divided q12h | Same | 30 mg/kg/day | Upper dose limit due to immature renal function FDA PI Section 2.3 |
Renal Impairment Dosing
| GFR (mL/min) | Dose | Frequency | Notes | Source |
|---|---|---|---|---|
| ≥30 | Standard dose | Standard | No adjustment needed | FDA PI |
| 10–30 | 500 mg or 250 mg | Every 12 hours | Do NOT use 875 mg tablet | FDA PI Table 2 |
| <10 | 500 mg or 250 mg | Every 24 hours | Do NOT use 875 mg tablet | FDA PI Table 2 |
| Hemodialysis | 500 mg or 250 mg | Every 24 hours | Additional dose during and at end of dialysis | FDA PI Table 2 |
Amoxicillin, like all beta-lactams, exhibits time-dependent bactericidal activity — efficacy correlates with the duration that free drug concentrations remain above the MIC (fT>MIC), not with peak concentration. This means dividing the total daily dose into more frequent intervals (e.g., TID rather than BID) may improve efficacy for infections with organisms near the susceptibility breakpoint, at the cost of adherence. For most community infections, BID dosing provides adequate fT>MIC and better compliance.
Pharmacology
Mechanism of Action
Amoxicillin is a semi-synthetic aminopenicillin that exerts bactericidal activity by irreversibly binding to penicillin-binding proteins (PBPs), particularly PBP1A, PBP1B, and PBP3, on the inner surface of the bacterial cell membrane. This binding inhibits the transpeptidation step of peptidoglycan cross-linking during cell wall synthesis. The resulting structural weakness in the cell wall triggers autolytic enzymes that lyse and destroy the bacterial cell. Amoxicillin is effective against a range of gram-positive and gram-negative organisms but only those that do not produce beta-lactamases. When combined with clavulanic acid (a beta-lactamase inhibitor), the spectrum extends to beta-lactamase-producing strains of H. influenzae, M. catarrhalis, E. coli, and others.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; bioavailability ~75–90%; Tmax 1–2 h; food does not significantly reduce extent of absorption | Can be taken with or without food; taking at the start of a meal reduces GI intolerance per FDA PI |
| Distribution | Vd ~0.3 L/kg (~20 L); protein binding ~20%; good penetration into respiratory tract, middle ear, sinuses, skin, urinary tract; poor CSF penetration unless meninges inflamed | Low protein binding means most drug is free and pharmacologically active; excellent tissue penetration supports use across multiple infection sites |
| Metabolism | Partially hepatic via oxidation, hydroxylation, and deamination; majority excreted unchanged | Minimal hepatic metabolism means no dose adjustment needed in hepatic impairment and minimal drug-drug metabolic interactions |
| Elimination | t½ ~1–1.5 h; ~60% excreted unchanged in urine within 6–8 h via glomerular filtration and tubular secretion; removable by hemodialysis | Short half-life requires BID–TID dosing; dose reduction required in severe renal impairment (GFR <30); probenecid blocks tubular secretion, prolonging half-life |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea / loose stools | ~3–5% (FDA PI: >1%; up to 9% with clavulanate co-formulation) | Most frequently reported effect; rate is lower for amoxicillin alone than amoxicillin-clavulanate; usually mild and self-limiting; evaluate for C. difficile if persistent or bloody |
| Rash (non-allergic maculopapular) | ~3% | Distinguish from true penicillin allergy; incidence dramatically higher (~70–100%) in mononucleosis patients — avoid amoxicillin with mono |
| Nausea | ~3% | Reduced by taking at the start of a meal; dose-related |
| Vomiting | ~1% | More common in pediatric patients and with higher doses |
| Vulvovaginal candidiasis | ~1% | Due to disruption of normal vaginal flora; treat with topical or oral antifungals if symptomatic |
| Headache | 6–7% (H. pylori triple/dual therapy trials) | Reported at higher rates in combination regimens; may relate to lansoprazole component |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis | ~0.01–0.05% (1 in 2,000–10,000) | Minutes to hours after dose; can occur on first exposure | Discontinue immediately; epinephrine, airway management; do not rechallenge; document penicillin allergy |
| Severe cutaneous adverse reactions (SJS, TEN, DRESS, AGEP) | Very rare | Days to weeks | Discontinue immediately; dermatology consult; supportive care; do not rechallenge |
| Clostridioides difficile-associated diarrhea (CDAD) | ~0.5–2% | During or up to 2 months after treatment | Stop amoxicillin; test for C. difficile toxin; treat with vancomycin or fidaxomicin if confirmed; avoid antiperistaltic agents |
| Drug-induced enterocolitis syndrome (DIES) | Rare (mostly pediatric) | 1–4 hours post-dose (vomiting); diarrhea within 24 h | Discontinue; IV fluids if hypotensive; recognize as non-IgE mediated reaction; avoid re-exposure |
| Hemolytic anemia / agranulocytosis / thrombocytopenia | Very rare | Variable | Discontinue; CBC with differential; usually reversible on cessation |
| Hepatic dysfunction (cholestatic jaundice, hepatitis) | Very rare | Weeks | Discontinue; monitor LFTs; usually reversible |
| Seizures | Very rare (primarily in renal impairment with high doses) | Variable | Discontinue or reduce dose; manage seizure; assess renal function |
| Crystalluria | Rare (reported in overdose) | Hours to days at high doses | Maintain adequate hydration; reduce dose; monitor urine output and renal function |
A high percentage of patients with infectious mononucleosis (EBV infection) who receive amoxicillin develop a widespread erythematous maculopapular rash. This occurs in up to 70–100% of mono patients given amoxicillin and is thought to be immune-complex mediated, not a true penicillin allergy. However, it is clinically indistinguishable from allergic rash in the acute setting. The FDA PI explicitly states that amoxicillin should not be administered to patients with mononucleosis. Always consider mono in the differential before prescribing amoxicillin for pharyngitis, particularly in adolescents and young adults.
Drug Interactions
Amoxicillin has a relatively favorable drug interaction profile due to its minimal hepatic metabolism. Interactions are predominantly pharmacokinetic (renal excretion) or pharmacodynamic (antagonism with bacteriostatic agents). The FDA PI identifies four key interactions.
Amoxicillin may cause false-positive urine glucose results when using copper sulfate-based tests (Clinitest). Glucose tests based on enzymatic glucose oxidase reactions (Clinistix) are recommended instead. Amoxicillin may also cause a transient decrease in plasma estriol, estradiol, and conjugated estrone levels in pregnant women, which could interfere with certain prenatal monitoring assays.
Monitoring
Amoxicillin does not require routine laboratory monitoring for most short-course treatments in healthy patients. Monitoring focuses on clinical response, signs of hypersensitivity, and potential complications in prolonged or high-dose regimens.
-
Clinical response
48–72 h after initiation
Routine Assess for symptom improvement. If no clinical response by 48–72 hours, reconsider diagnosis, obtain cultures if not already done, and consider treatment change. Continue treatment at least 48–72 h beyond symptom resolution. -
Renal function
Baseline in at-risk patients; before prolonged courses
Trigger-based Obtain creatinine/eGFR before prescribing in elderly, patients with known renal disease, or when high-dose or prolonged therapy is planned. Adjust dose for GFR <30 mL/min. -
Allergic reactions
Throughout treatment
Routine Counsel patients to report rash, urticaria, swelling, or breathing difficulty immediately. Distinguish non-allergic maculopapular rash (common, especially with viral infections) from true hypersensitivity. -
GI symptoms / C. difficile
Throughout and up to 2 months post-treatment
Trigger-based Evaluate new-onset watery or bloody diarrhea for C. difficile infection. CDAD can present during or up to 2 months after treatment. -
INR (with warfarin)
Within 3–5 days of starting amoxicillin
Trigger-based Check INR early in course if patient is on warfarin. Adjust anticoagulant dose as needed; re-check after amoxicillin is completed. -
CBC, LFTs
Only for prolonged courses (>2 weeks)
Trigger-based Monitor periodically during prolonged use (e.g., endocarditis treatment) for hematologic abnormalities (leukopenia, eosinophilia) and hepatic dysfunction (elevated AST/ALT). Usually reversible on discontinuation.
Contraindications & Cautions
Absolute Contraindications
- History of serious hypersensitivity to amoxicillin or other beta-lactams — including anaphylaxis, SJS, TEN. Cross-reactivity with cephalosporins is estimated at 1–2%, primarily with first-generation cephalosporins sharing similar R1 side chains.
Relative Contraindications (Specialist Input Recommended)
- Infectious mononucleosis — the FDA PI states amoxicillin should not be administered to patients with mono due to the very high incidence of rash. While not a true allergy, it can confound future penicillin allergy assessments.
- History of mild penicillin rash (non-severe) — consider penicillin allergy testing before re-exposure; many patients labeled “penicillin allergic” can safely receive amoxicillin after evaluation.
Use with Caution
- Severe renal impairment (GFR <30 mL/min) — dose reduction required; avoid 875 mg tablet.
- Phenylketonuria — chewable tablets contain aspartame (phenylalanine). Oral suspension and standard tablets do not contain phenylalanine.
- History of GI disease, particularly colitis — increased risk of C. difficile-associated diarrhea.
- Concurrent warfarin therapy — increased INR monitoring required.
- Concurrent allopurinol — increased rash incidence.
Serious and occasionally fatal anaphylactic reactions have been reported in patients on penicillin therapy, including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred with oral penicillins. These reactions are more likely in individuals with a history of penicillin hypersensitivity or sensitivity to multiple allergens. Before initiating therapy, careful inquiry about prior reactions to penicillins, cephalosporins, or other allergens is essential. If an allergic reaction occurs, amoxicillin must be discontinued immediately and appropriate therapy instituted. Severe cutaneous adverse reactions (SJS, TEN, DRESS, AGEP) have also been reported — any progressive rash should prompt immediate discontinuation.
Patient Counselling
Purpose of Therapy
Amoxicillin is an antibiotic used to treat bacterial infections. It does not work against viral infections (such as the common cold or flu). Taking antibiotics when they are not needed contributes to antibiotic resistance — a growing public health concern.
How to Take
Take amoxicillin at evenly spaced intervals (every 8 or 12 hours as prescribed). It may be taken with or without food, though taking it at the start of a meal can reduce stomach upset. Complete the entire prescribed course, even if symptoms improve before the medication is finished. If using the oral suspension, shake well before each dose and measure with a proper dosing device (not a household spoon). Chewable tablets must be chewed completely before swallowing.
Sources
- AMOXIL (amoxicillin) prescribing information. USAntibiotics, LLC. Revised May 2024. FDA Label (PDF) Primary source for all dosing, indications, adverse reactions, drug interactions, and renal adjustment data.
- Amoxicillin capsules prescribing information. Northstar Rx LLC. DailyMed / NLM. FDA Label Current generic capsule labeling with DIES warning added 2024.
- Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):e86-e102. doi:10.1093/cid/cis629 IDSA guideline recommending amoxicillin as first-line treatment for GAS pharyngitis with 10-day course.
- Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131(3):e964-e999. doi:10.1542/peds.2012-3488 AAP guideline recommending high-dose amoxicillin (80–90 mg/kg/day) as first-line for acute otitis media.
- Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020;81(2):266-275. doi:10.1016/j.jinf.2020.05.046 Context for appropriate antibiotic stewardship; demonstrates low co-infection rates challenging empiric amoxicillin use in viral respiratory illness.
- Wilson WR, Gewitz M, Lockhart PB, et al. Prevention of viridans group streptococcal infective endocarditis: a scientific statement from the AHA. Circulation. 2021;143(20):e963-e978. doi:10.1161/CIR.0000000000000969 AHA guideline recommending amoxicillin 2 g as first-line endocarditis prophylaxis before dental procedures in high-risk patients.
- Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical practice guidelines by the IDSA, AAN, and ACR: 2020 guidelines for the prevention, diagnosis, and treatment of Lyme disease. Clin Infect Dis. 2021;72(1):e1-e48. doi:10.1093/cid/ciaa1215 Lyme disease guideline listing amoxicillin 500 mg TID for 14–21 days as alternative to doxycycline for early localized disease.
- Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2017;112(2):212-239. doi:10.1038/ajg.2016.563 ACG guideline for H. pylori eradication including amoxicillin-based triple and quadruple therapy regimens.
- Akhavan BJ, Khanna NR, Vijhani P. Amoxicillin. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. NCBI Bookshelf Comprehensive clinically oriented review of amoxicillin pharmacology, PK parameters (~20% protein binding, t½ ~61 min, ~60% renal excretion), and clinical use.
- Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201. doi:10.1128/CMR.00037-09 Authoritative review of beta-lactamase mechanisms; contextualizes why amoxicillin requires clavulanate for beta-lactamase-producing organisms.
- Paintaud G, Allegaert K, Gras-Champel V, et al. Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints. J Antimicrob Chemother. 2016;71(10):2909-2917. doi:10.1093/jac/dkw237 Population PK analysis demonstrating dose-dependent (saturable) absorption of amoxicillin with implications for dosing regimen selection.
- Spyker DA, Rugloski RJ, Vann RL, O’Brien WM. Pharmacokinetics of amoxicillin: dose dependence after intravenous, oral, and intramuscular administration. Antimicrob Agents Chemother. 1977;11(1):132-141. doi:10.1128/AAC.11.1.132 Early PK study establishing Vd (~0.3 L/kg), oral bioavailability (~77%), and elimination parameters for amoxicillin.