Amoxicillin-Clavulanate
amoxicillin / clavulanate potassium — marketed as Augmentin
Indications
| Indication | Key Pathogens (beta-lactamase-producing) | Therapy Type | Status |
|---|---|---|---|
| Lower respiratory tract infections | H. influenzae, M. catarrhalis | Monotherapy | FDA Approved |
| Acute bacterial otitis media | H. influenzae, M. catarrhalis | Monotherapy | FDA Approved |
| Acute bacterial sinusitis | H. influenzae, M. catarrhalis | Monotherapy | FDA Approved |
| Skin and skin structure infections | S. aureus (MSSA), E. coli, Klebsiella spp. | Monotherapy | FDA Approved |
| Urinary tract infections | E. coli, Klebsiella spp., Enterobacter spp. | Monotherapy | FDA Approved |
Amoxicillin-clavulanate extends the spectrum of amoxicillin to cover beta-lactamase-producing organisms that would otherwise be resistant. When susceptibility testing indicates the organism is susceptible to amoxicillin alone (no beta-lactamase production), plain amoxicillin should be used instead. The IDSA recommends amoxicillin-clavulanate as first-line empiric therapy for acute bacterial rhinosinusitis and as an option for community-acquired pneumonia in patients with comorbidities.
Animal and human bite wounds — First-line oral agent for empiric coverage of Pasteurella, Eikenella, and anaerobes. Widely guideline-supported. Evidence quality: High.
Diabetic foot infections (mild) — IDSA 2012 diabetic foot guidelines list amoxicillin-clavulanate as an oral option for mild soft-tissue infections. Evidence quality: Moderate.
Dental infections with abscess — Commonly used when beta-lactamase-producing anaerobes are suspected. Evidence quality: Moderate.
Community-acquired pneumonia (outpatient with comorbidities) — ATS/IDSA 2019 guidelines include high-dose amoxicillin-clavulanate as an option combined with a macrolide. Evidence quality: High.
Dosing
Two 250/125 mg tablets are NOT equivalent to one 500/125 mg tablet — they deliver the same amoxicillin but double the clavulanate (250 mg vs 125 mg), increasing GI side effects. Similarly, the 250 mg tablet (contains 125 mg clavulanate) is NOT interchangeable with the 250 mg chewable tablet (contains 62.5 mg clavulanate). Always verify the amoxicillin:clavulanate ratio when prescribing or substituting formulations.
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild-moderate infection (skin, UTI) | 500/125 mg q12h or 250/125 mg q8h | Same | 1000/250 mg/day (amox/clav) | q12h regimen has less diarrhea FDA PI §2.1 |
| Severe infection or respiratory tract (sinusitis, LRT, otitis media) | 875/125 mg q12h or 500/125 mg q8h | Same | 1750/250 mg/day or 1500/375 mg/day | Use severe dosing for all lower respiratory infections FDA PI §2.1 |
| Animal / human bite wound (off-label) | 875/125 mg q12h | Same for 5–7 days | 1750/250 mg/day | First-line oral therapy for bite wounds covering Pasteurella, Eikenella, anaerobes IDSA bite wound guidelines |
| CAP outpatient with comorbidities (off-label) | 2000/125 mg q12h (Augmentin XR) | Same for 7–10 days | 4000/250 mg/day | High-dose extended-release formulation + macrolide for CAP ATS/IDSA 2019 CAP guideline |
Pediatric Dosing (based on amoxicillin component)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild-moderate infection (≥3 months, <40 kg) | 25 mg/kg/day q12h or 20 mg/kg/day q8h | Same | 25 mg/kg/day | q12h regimen associated with significantly less diarrhea FDA PI Table 1; use 200 or 400 mg/5 mL suspension for q12h dosing |
| Severe infection, otitis media, sinusitis, LRT (≥3 months, <40 kg) | 45 mg/kg/day q12h or 40 mg/kg/day q8h | Same for 10 days (AOM) | 45 mg/kg/day | High-dose for otitis media recommended for 10 days FDA PI Table 1 |
| Recurrent/resistant AOM (off-label, high-dose) | 90 mg/kg/day divided q12h | Same for 10 days | 90 mg/kg/day | Use Augmentin ES-600 (600/42.9 per 5 mL) formulation AAP 2013 AOM guideline; 14:1 ratio formulation |
| Neonates and infants <3 months | 30 mg/kg/day divided q12h | Same | 30 mg/kg/day | Use 125/31.25 mg per 5 mL suspension only FDA PI §2.2; limited experience with other formulations in this age group |
Renal Impairment Dosing
| GFR (mL/min) | Dose | Frequency | Notes | Source |
|---|---|---|---|---|
| ≥30 | Standard dose | Standard | No adjustment needed | FDA PI |
| 10–30 | 500/125 mg or 250/125 mg | Every 12 hours | Do NOT use 875/125 mg tablet | FDA PI §2.3 |
| <10 | 500/125 mg or 250/125 mg | Every 24 hours | Do NOT use 875/125 mg tablet | FDA PI §2.3 |
| Hemodialysis | 500/125 mg or 250/125 mg | Every 24 hours | Additional dose during and at end of dialysis | FDA PI §2.3 |
Clavulanate is the primary driver of GI side effects (especially diarrhea) in amoxicillin-clavulanate. The clavulanate dose is capped at 125 mg per adult tablet regardless of the amoxicillin dose, which is why the q12h regimen (which delivers less total daily clavulanate than q8h) is associated with significantly less diarrhea. Taking the medication at the start of a meal further enhances clavulanate absorption and reduces GI intolerance.
Pharmacology
Mechanism of Action
Amoxicillin-clavulanate combines two complementary mechanisms. Amoxicillin is a bactericidal aminopenicillin that binds to penicillin-binding proteins (PBPs) and inhibits transpeptidation during cell wall synthesis, leading to cell lysis and death. However, many bacteria produce beta-lactamase enzymes that hydrolyze amoxicillin’s beta-lactam ring, rendering it inactive. Clavulanic acid is a beta-lactam compound produced by Streptomyces clavuligerus that acts as a “suicide inhibitor” — it irreversibly binds to the catalytic site of beta-lactamase enzymes, depleting them and protecting amoxicillin from degradation. Clavulanate has minimal intrinsic antibacterial activity of its own. This combination extends amoxicillin’s spectrum to include beta-lactamase-producing strains of H. influenzae, M. catarrhalis, S. aureus (MSSA), E. coli, Klebsiella, and Bacteroides fragilis.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Both well absorbed orally (~60% bioavailability); Tmax ~1.5 h; food minimally affects amoxicillin but enhances clavulanate absorption | Take at start of meal to optimize clavulanate absorption and reduce GI intolerance; no PK interaction between components |
| Distribution | Amoxicillin: protein binding ~18%, Vd ~0.3 L/kg; Clavulanate: protein binding ~25%, Vd ~0.24 L/kg; both distribute well to tissues; detected in middle ear effusions; poor CNS penetration unless meninges inflamed | Low protein binding for both means most drug is free and active; excellent tissue penetration supports use across respiratory, skin, and urinary infection sites |
| Metabolism | Amoxicillin: primarily excreted unchanged; Clavulanate: extensively hepatically metabolized | Amoxicillin dosing driven by renal function; clavulanate clearance depends on hepatic function — monitor LFTs in hepatic impairment |
| Elimination | Amoxicillin: t½ 1.3 h; 50–70% excreted unchanged in urine within 6 h; Clavulanate: t½ 1.0 h; 25–40% excreted unchanged in urine; both removable by hemodialysis | Short half-lives require BID–TID dosing; dose reduction for amoxicillin in severe renal impairment (GFR <30); probenecid blocks amoxicillin tubular secretion but does not affect clavulanate excretion |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea / loose stools | 9% | Most common effect; driven primarily by clavulanate; dose-related and increases with higher doses; q12h regimen causes significantly less diarrhea than q8h; evaluate for C. difficile if persistent/bloody |
| Nausea | 3% | Reduced by taking at start of a meal |
| Skin rashes / urticaria | 3% | Distinguish from true penicillin allergy; dramatically higher in mononucleosis patients |
| Vomiting | 1% | More common in pediatric patients |
| Vaginitis | 1% | Due to disruption of normal vaginal flora; treat with antifungals if symptomatic candidiasis develops |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Cholestatic jaundice / hepatitis | ~1 in 2,000–2,500 prescriptions (LiverTox); more common in elderly and males | During treatment or up to several weeks after discontinuation; mean onset ~31 days | Discontinue immediately; monitor LFTs; usually reversible but deaths reported; future Augmentin use contraindicated (FDA PI §4.2) |
| Anaphylaxis | ~0.01–0.05% | Minutes to hours | Discontinue; epinephrine; airway management; document allergy; do not rechallenge |
| Severe cutaneous reactions (SJS, TEN, DRESS, AGEP) | Very rare | Days to weeks | Discontinue immediately; dermatology consult; do not rechallenge |
| C. difficile-associated diarrhea (CDAD) | ~0.5–2% | During or up to 2 months after treatment | Stop Augmentin; C. difficile toxin test; vancomycin or fidaxomicin if confirmed |
| Hemolytic anemia / agranulocytosis / thrombocytopenia | Very rare | Variable | Discontinue; CBC; usually reversible; believed to be hypersensitivity-mediated |
| Interstitial nephritis / crystalluria | Very rare (primarily overdose) | Variable | Maintain hydration; discontinue; monitor renal function; usually reversible |
| Seizures | Very rare (renal impairment with high doses) | Variable | Discontinue or reduce dose; seizure management; assess renal function |
Cholestatic jaundice and hepatitis are specifically associated with the clavulanate component and represent a unique risk not seen with amoxicillin alone. The risk is higher in elderly patients, males, and those on prolonged courses. Onset may occur during treatment or several weeks after the antibiotic is stopped. While usually reversible, fatal cases have been reported. A prior episode of Augmentin-associated hepatotoxicity is an absolute contraindication to future use — this is explicitly stated in the FDA PI as a separate contraindication (§4.2), distinct from hypersensitivity.
Drug Interactions
The interaction profile is similar to amoxicillin alone. Notably, probenecid delays amoxicillin excretion but does not affect clavulanate elimination — a key pharmacokinetic distinction.
Amoxicillin may cause false-positive urine glucose with copper sulfate-based tests (Clinitest). Use glucose oxidase-based methods instead. In pregnant women, transient decreases in plasma estriol and related hormones have been noted, potentially affecting prenatal estriol monitoring.
Monitoring
- Clinical response48–72 h after initiation
RoutineAssess symptom improvement. If no response by 48–72 h, reconsider diagnosis and obtain cultures. Continue treatment at least 48–72 h beyond symptom resolution. - Hepatic function (LFTs)At regular intervals in hepatic impairment; baseline if prolonged course planned
Trigger-basedThe FDA PI mandates regular LFT monitoring in patients with hepatic impairment. Cholestatic hepatitis can present during or weeks after therapy. Discontinue if signs of hepatic dysfunction (jaundice, elevated transaminases, dark urine) develop. - Renal functionBaseline in at-risk patients
Trigger-basedObtain creatinine/eGFR in elderly, renal disease, or prolonged/high-dose therapy. Adjust dose for GFR <30; avoid 875 mg formulation. - GI symptoms / C. difficileThroughout and up to 2 months post-treatment
Trigger-basedDiarrhea is common (9%) and usually self-limiting. Test for C. difficile if watery/bloody diarrhea develops. CDAD can present up to 2 months after completion. - INR (with warfarin)Within 3–5 days of starting
Trigger-basedCheck INR early if patient on warfarin. Adjust anticoagulant dose as needed. - Allergic reactionsThroughout treatment
RoutineCounsel patients to report rash, urticaria, swelling, or breathing difficulty immediately. Distinguish non-allergic maculopapular rash from true hypersensitivity.
Contraindications & Cautions
Absolute Contraindications
- Serious hypersensitivity to amoxicillin, clavulanate, or other beta-lactams — including anaphylaxis and SJS (FDA PI §4.1).
- History of cholestatic jaundice or hepatic dysfunction associated with prior Augmentin use — this is a unique, specific contraindication not shared with amoxicillin alone (FDA PI §4.2).
Relative Contraindications (Specialist Input Recommended)
- Infectious mononucleosis — high incidence of rash; avoid Augmentin (FDA PI §5.4).
- Pre-existing hepatic disease — monitor LFTs at regular intervals; hepatotoxicity is more common in this population.
Use with Caution
- Severe renal impairment (GFR <30) — dose adjustment required; do not use 875 mg formulation.
- Elderly patients — hepatotoxicity risk is higher in elderly and males; also more susceptible to renal accumulation.
- History of GI disease — higher baseline diarrhea risk; increased C. difficile susceptibility.
- Phenylketonuria — chewable tablets and some suspension formulations contain aspartame (phenylalanine).
- Concurrent warfarin — increased INR monitoring required.
Hepatic dysfunction including hepatitis and cholestatic jaundice has been associated with Augmentin use. While usually reversible, fatal cases have been reported. Risk factors include elderly age, male sex, and prolonged treatment. Signs may appear during or several weeks after therapy. Serious and occasionally fatal anaphylactic reactions have also been reported. Before initiating therapy, careful inquiry about prior reactions to penicillins, cephalosporins, or other allergens is essential.
Patient Counselling
Purpose of Therapy
Amoxicillin-clavulanate is an antibiotic that combines amoxicillin with a beta-lactamase inhibitor (clavulanic acid) to treat infections caused by bacteria that would be resistant to amoxicillin alone. It does not work against viral infections.
How to Take
Take at the start of a meal to reduce stomach upset and improve absorption. Complete the entire prescribed course. If using the liquid suspension, shake well before measuring each dose with a proper dosing device. Refrigerate the reconstituted suspension and discard after 10 days.
Sources
- AUGMENTIN (amoxicillin/clavulanate potassium) prescribing information. GlaxoSmithKline. Revised January 2013. FDA Label (PDF)Primary source for all dosing, formulation details, adverse reactions (diarrhea 9%, nausea 3%, rash 3%), drug interactions, renal dosing, and hepatotoxicity warnings.
- Amoxicillin clavulanate. StatPearls [Internet]. Updated August 2024. NCBI BookshelfComprehensive review including PK parameters, protein binding (amoxicillin ~18%, clavulanate ~25%), and mechanism of beta-lactamase inhibition.
- 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.2012-3488AAP guideline recommending high-dose amoxicillin-clavulanate (90/6.4 mg/kg/day) for AOM when beta-lactamase coverage is needed.
- Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the IDSA. Clin Infect Dis. 2014;59(2):e10-e52. doi:10.1093/cid/ciu296IDSA guideline listing amoxicillin-clavulanate as first-line oral therapy for animal and human bite wound infections.
- Chow AW, Benninger MS, Brook I, et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012;54(8):e72-e112. doi:10.1093/cid/cir1043IDSA guideline recommending amoxicillin-clavulanate over amoxicillin alone as first-line for acute bacterial rhinosinusitis.
- Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the ATS and IDSA. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581STATS/IDSA 2019 CAP guideline including high-dose amoxicillin-clavulanate + macrolide as outpatient option for patients with comorbidities.
- Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-e173. doi:10.1093/cid/cis346IDSA diabetic foot guideline listing amoxicillin-clavulanate as oral option for mild infections.
- Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201. doi:10.1128/CMR.00037-09Authoritative review of beta-lactamase inhibitor mechanisms including clavulanate’s “suicide inhibitor” binding to beta-lactamase active sites.
- Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013;68(9):1951-1961. doi:10.1093/jac/dkt129Meta-analysis quantifying C. difficile risk with amoxicillin-clavulanate relative to other antibiotics.
- Huttner A, Bielicki J, Clements MN, et al. Oral amoxicillin and amoxicillin-clavulanic acid: properties, indications and usage. Clin Microbiol Infect. 2020;26(7):871-879. doi:10.1016/j.cmi.2019.11.028Comprehensive review of PK differences between amoxicillin and clavulanate, including clavulanate’s hepatic metabolism and GI tolerance implications.
- Gin AS, Dilay L, Karlowsky JA, Walkty A, Rubinstein E, Zhanel GG. Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination. Expert Rev Anti Infect Ther. 2007;5(3):365-383. doi:10.1586/14787210.5.3.365Comparative review of beta-lactam/inhibitor combinations providing context for clavulanate’s PK/PD profile relative to other inhibitors.
- Veeraraghavan B, Bakthavatchalam YD, Sahni RD. Orally administered amoxicillin/clavulanate: current role in outpatient therapy. Infect Dis Ther. 2021;10(1):15-25. doi:10.1007/s40121-020-00374-7Contemporary PK/PD analysis of amoxicillin-clavulanate including Monte Carlo simulations and bioavailability data (~60% for both components).