Dosage guidance:
Dosing: Dose is based on amoxicillin component.
Dosage form information: Not all products are interchangeable; using a product with the incorrect amoxicillin:clavulanate ratio could result in subtherapeutic clavulanate concentrations or severe diarrhea. Incidence of diarrhea appears to increase with clavulanate dose; some experts recommend not exceeding 10 mg clavulanate/kg/day when possible (Ref).
General dosing:
Oral: Neonates: 15 mg amoxicillin/kg/dose every 12 hours.
IV [Canadian product; not available in United States]: Neonates:
5:1 formulation: IV: 25 mg amoxicillin/kg/dose every 12 hours.
10:1 formulation: IV: 50 mg amoxicillin/kg/dose every 12 hours.
High-dose regimen for oral step-down treatment (eg, culture-negative sepsis, susceptible Escherichia coli infection):
Neonates weighing ≥2 kg: Oral: 25 mg amoxicillin/kg/dose every 8 hours (Ref). Note: In the clinical study, the product used was the 4:1 amoxicillin:clavulanate ratio product; however, this resulted in daily clavulanate doses of 18.75 mg/kg/day; changes in defecation patterns were noted in 24% of patients in both the amoxicillin/clavulanate and the IV antibiotics groups (Ref).
Dosage guidance:
Dosing: Dose is based on amoxicillin component; not all products are interchangeable; using a product with the incorrect amoxicillin:clavulanate ratio could result in subtherapeutic clavulanic acid concentrations or severe diarrhea. Incidence of diarrhea increases with clavulanate dose; some experts recommend not exceeding 10 mg clavulanate/kg/day or 125 mg clavulanate/dose (Ref).
Formulation should be chosen based on dosing strategy:
"Standard-dose" regimens (ie, ≤45 mg/kg/day):
2:1 formulations: amoxicillin 250 mg/clavulanate 125 mg. Note: Per the manufacturer, the amoxicillin 250 mg/clavulanate 125 mg tablet should only be used in patients ≥40 kg, due to the amoxicillin to clavulanate ratio.
4:1 formulations:
• amoxicillin 125 mg/clavulanate 31.25 mg
• amoxicillin 250 mg/clavulanate 62.5 mg
• amoxicillin 500 mg/clavulanate 125 mg.
7:1 formulations:
• amoxicillin 200 mg/clavulanate 28.5 mg
• amoxicillin 400 mg/clavulanate 57 mg
• amoxicillin 875 mg/clavulanate 125 mg.
"High-dose" regimens (ie, 80 to 90 mg/kg/day):
14:1 formulations: amoxicillin 600 mg/clavulanate 42.9 mg.
16:1 formulations (extended release): amoxicillin 1,000 mg/clavulanate 62.5 mg.
General dosing: Note: See indication-specific dosing; recommended doses may vary. General dosing determined by formulation amoxicillin:clavulanate ratio.
Immediate-release formulations:
Infants, Children, and Adolescents:
4:1 formulation: Oral: 20 to 40 mg amoxicillin/kg/day in divided doses every 8 hours; maximum daily dose: 1,500 mg/day (Ref).
7:1 formulation: Oral: 25 to 45 mg amoxicillin/kg/day in divided doses every 12 hours; maximum daily dose: 1,750 mg/day (Ref).
14:1 formulation: Oral: 90 mg amoxicillin/kg/day in divided doses every 12 hours; maximum daily dose: 4,000 mg/day (Ref).
Extended-release formulation (16:1): Children and Adolescents ≥40 kg: Oral: 2,000 mg amoxicillin every 12 hours (Ref).
Impetigo: Infants, Children, and Adolescents: Oral: 25 to 45 mg amoxicillin/kg/day in divided doses every 8 to 12 hours for 7 days. Maximum dose: Every-8-hour dosing: 500 mg amoxicillin/dose; every-12-hour dosing: 875 mg amoxicillin/dose (Ref).
Osteoarticular infection, acute (eg, septic [bacterial] arthritis, osteomyelitis): Step-down therapy following parenteral treatment (targeted therapy for susceptible pathogen): Limited data available:
Infants, Children, and Adolescents: Oral: 120 mg amoxicillin/kg/day in divided doses every 6 to 8 hours; maximum daily dose: 3,000 mg amoxicillin/day; do not exceed 125 mg of clavulanate per dose (Ref). Minimum total duration (IV plus oral therapy) is 2 to 3 weeks for septic arthritis and 3 to 4 weeks for osteomyelitis; however, duration should be individualized based on several factors including causative pathogen, response to therapy, and normalization of inflammatory markers (Ref).
Otitis media, acute (AOM):
High-dose regimen: Note: Preferred in the United States and when activity against penicillin-nonsusceptible Streptococcus pneumoniae is desired (Ref).
Infants ≥3 months, Children, and Adolescents: Oral suspension (600 mg per 5 mL; 14:1 ratio product): Oral: 80 to 90 mg amoxicillin/kg/day divided every 12 hours. Maximum dose has not been established for AOM; however, 4,000 mg/day has been suggested (Ref).
Standard-dose regimen: Note: Only for use in areas where rates of penicillin-nonsusceptible S. pneumoniae are known to be low (Ref).
Infants ≥3 months, Children, and Adolescents: Standard formulations (4:1 or 7:1 ratio products): Oral: 40 to 45 mg amoxicillin/kg/day in divided doses every 8 to 12 hours. Maximum daily dose: 1,750 mg/day (Ref).
Duration of therapy: For patients with severe or recurrent AOM, tympanic membrane perforation, or who are <2 years of age, treat for 10 days; for patients ≥2 years of age with mild to moderate, nonrecurrent disease without tympanic membrane perforation, shorter durations of 5 to 7 days may be sufficient (Ref).
Canadian recommendations: Note: A higher-ratio amoxicillin and clavulanate product (ie, 14:1 ratio, the amoxicillin 600 mg and clavulanate 42.9 mg per 5 mL product) is not available in Canada; the following dosing is recommended to target middle ear concentrations similar to those achieved with the high-dose regimen (Ref).
Infants ≥6 months and Children:
≤35 kg: Oral suspension (amoxicillin 400 mg and clavulanate 57 mg per 5 mL): Oral: 45 to 60 mg amoxicillin/kg/day in divided doses every 8 hours (Ref).
>35 kg: Tablet (amoxicillin 500 mg and clavulanate 125 mg per tablet): Oral: 500 mg amoxicillin every 8 hours (Ref).
Duration of therapy: For patients with severe or recurrent AOM, tympanic membrane perforation, or who are <2 years of age, treat for 10 days; for patients ≥2 years of age with mild to moderate, nonrecurrent disease without tympanic membrane perforation, shorter durations of 5 to 7 days may be sufficient (Ref).
Pneumonia, community-acquired:
Infants ≥3 months, Children, and Adolescents:
Empiric therapy: Oral: 90 mg amoxicillin/kg/day in divided doses every 12 hours; maximum daily dose: 4,000 mg amoxicillin/day (Ref).
H. influenzae, beta-lactamase-positive strains; mild infection or step-down therapy:
Standard-dose regimen: Oral: 45 mg amoxicillin/kg/day in divided doses every 8 hours (Ref).
High-dose regimen: Oral: 90 mg amoxicillin/kg/day in divided doses every 12 hours (Ref).
Duration of therapy: For outpatient treatment of uncomplicated disease in patients who respond to therapy, 5 days of therapy is likely adequate (Ref). Longer duration (eg, total course of 7 to 10 days) may be necessary in patients who do not respond quickly to therapy or who have underlying comorbidities (eg, lung disease, immunosuppression) (Ref).
Rhinosinusitis, acute bacterial:
Infants ≥3 months: Oral: 45 mg amoxicillin/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours.
Children and Adolescents:
Standard-dose regimen: Oral: 45 mg amoxicillin/kg/day in divided doses every 12 hours; maximum dose: 875 mg amoxicillin/dose (Ref).
High-dose regimen: Note: Recommended for patients who live in areas with high endemic rates of penicillin-nonsusceptible S. pneumoniae, have moderate to severe infections, attend daycare, are <2 years of age, were recently hospitalized, received antibiotics within the past month, or are immunocompromised, and/or if initial therapy fails (Ref).
Oral: 80 to 90 mg amoxicillin/kg/day in divided doses every 12 hours; maximum dose: 2,000 mg amoxicillin/dose (Ref).
Duration of therapy: Limited data exist to determine optimal duration; historically 10 days has been recommended, but recently some have suggested a duration as short as 5 days; some patients may require extended therapy (ie, 14 to 21 days) based on clinical resolution (Ref).
Streptococcus, group A; chronic carriage: Limited data available: Note: Most individuals with chronic carriage do not require antibiotic treatment (Ref).
Children and Adolescents: Oral: 40 mg amoxicillin/kg/day in divided doses every 8 hours for 10 days; maximum daily dose: 2,000 mg amoxicillin/day (Ref).
Urinary tract infection: Infants ≥2 months, Children, and Adolescents: Oral: 20 to 50 mg amoxicillin/kg/day in divided doses every 8 to 12 hours; maximum daily dose: 1,750 mg/day (Ref). Duration of therapy should be individualized based on patient age, severity/extent of infection, and clinical response; typical duration is 7 to 14 days, though it may be as short as 3 to 5 days (eg, for uncomplicated cystitis in patients ≥2 years of age) (Ref).
IV dosing (Canadian labeling; not available in United States):
Note: Choice of formulation depends upon desired dosages of amoxicillin and clavulanate; for higher daily doses of amoxicillin (as may be used in the empiric coverage of Streptococcus pneumoniae), the 10:1 formulation is preferred to avoid unnecessary high clavulanate exposure.
5:1 formulation:
Infants <3 months or weighing <4 kg: IV: 25 mg amoxicillin/kg/dose every 12 hours.
Infants ≥3 months weighing ≥4 kg, Children, and Adolescents: IV: 25 mg amoxicillin/kg/dose every 8 hours; maximum dose: 1,000 mg amoxicillin/dose.
10:1 formulation:
Infants <3 months or weighing <4 kg: IV: 50 mg amoxicillin/kg/dose every 12 hours.
Infants ≥3 months, Children, and Adolescents weighing 4 to <40 kg: 50 mg amoxicillin/kg/dose every 8 hours; maximum dose: 2,000 mg amoxicillin/dose.
Children and Adolescents weighing ≥40 kg: 2,000 mg amoxicillin every 8 to 12 hours.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral:
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, the following has been used by some clinicians (Ref). The manufacturer recommends to avoid the 875 mg immediate-release tablets and extended-release tablets if GFR <30 mL/minute.
Standard-dose regimens: Dosing based on 20 to 40 mg amoxicillin/kg/day divided every 8 hours or 25 to 45 mg amoxicillin/kg/day divided every 12 hours:
GFR ≥30 mL/minute/1.73 m2: No adjustment required.
GFR 10 to 29 mL/minute/1.73 m2: Oral: 8 to 20 mg amoxicillin/kg/dose every 12 hours.
GFR <10 mL/minute/1.73 m2: Oral: 8 to 20 mg amoxicillin/kg/dose every 24 hours.
Hemodialysis: Oral: 8 to 20 mg amoxicillin/kg/dose every 24 hours; give after dialysis.
Peritoneal dialysis: Oral: 8 to 20 mg amoxicillin/kg/dose every 24 hours.
High-dose regimens: Dosing based on 80 to 90 mg amoxicillin/kg/day divided every 12 hours:
CrCl >30 mL/minute/1.73 m2: No adjustment required.
CrCl 10 to 29 mL/minute/1.73 m2: Oral: 20 mg amoxicillin/kg/dose every 12 hours.
CrCl <10 mL/minute/1.73 m2: Oral: 20 mg amoxicillin/kg/dose every 24 hours.
Hemodialysis: Oral: 20 mg amoxicillin/kg/dose every 24 hours; give after dialysis.
Peritoneal dialysis: Oral: 20 mg amoxicillin/kg/dose every 24 hours.
IV [Canadian product]:
5:1 formulation:
Infants, Children, and Adolescents weighing <40 kg:
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: IV: 25 mg amoxicillin/kg every 12 hours.
CrCl <10 mL/minute: IV: 25 mg amoxicillin/kg every 24 hours.
Hemodialysis: IV: 25 mg amoxicillin/kg every 24 hours; give an additional dose of 12.5 mg amoxicillin/kg at the end of each dialysis session.
Children and Adolescents weighing ≥40 kg:
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: IV: 1,000 mg amoxicillin followed by 500 mg amoxicillin every 12 hours.
CrCl <10 mL/minute: IV: 1,000 mg amoxicillin followed by 500 mg amoxicillin every 24 hours.
Hemodialysis: IV: 1,000 mg amoxicillin followed by 500 mg amoxicillin every 24 hours; give an additional 500 mg at the end of each dialysis session.
10:1 formulation:
Infants, Children, and Adolescents:
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Use not recommended due to lack of data; preferred formulation is 5:1 with this level of kidney impairment.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Use is contraindicated in patients with a history of amoxicillin and clavulanate-associated hepatic dysfunction.
(For additional information see "Amoxicillin and clavulanate: Drug information")
Dosage guidance:
Dosing: Dose is based on the amoxicillin component.
Dosage form information: Dose and frequency are product specific; not all products are interchangeable. For adults who have difficulty swallowing the tablets, oral suspension in the appropriate amount may be given.
Usual dosing range:
Oral: Immediate release: 500 mg every 8 to 12 hours or 875 mg every 12 hours; Extended release: 2 g every 12 hours.
IV [Canadian product]: 1 g every 8 hours or 2 g every 8 to 12 hours; surgical prophylaxis: 1 to 2 g at induction of anesthesia for procedures <1 hour (for procedures >1 hour may administer up to 2 additional doses in 24 hours; do not exceed 3 g in 24 hours).
Bite wound infection, prophylaxis or treatment (animal or human bite) (off-label use): Oral: Immediate release: 875 mg every 12 hours (Ref). For prophylaxis, duration is 3 to 5 days (Ref); for treatment of established infection, duration is typically 5 to 14 days and varies based on clinical response and patient-specific factors (Ref).
Bronchiectasis, acute exacerbation: Oral: 500 mg every 8 hours or 875 mg every 12 hours for up to 14 days (Ref).
Chronic obstructive pulmonary disease, acute exacerbation: Note: Some experts reserve for patients with risk factors for poor outcomes (eg, ≥65 years of age, FEV1 <50% predicted, frequent exacerbations, major comorbidities), but low risk of Pseudomonas infection (Ref).
Oral: Immediate release: 500 mg every 8 hours or 875 mg every 12 hours for 5 to 7 days (Ref).
Diabetic foot infection (off-label use): Note: May be used alone for mild infections or after clinical response to parenteral therapy in patients without risk factors or concern for infection caused by Pseudomonas aeruginosa (Ref).
Oral: Immediate release: 875 mg every 12 hours (Ref). Duration of therapy depends on severity and clinical response; most patients with infection limited to skin and soft tissue respond to 1 to 2 weeks of therapy (Ref).
Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure (off-label use):
Diverticulitis, acute (for uncomplicated infection that meets criteria for outpatient therapy or as step-down therapy after clinical improvement on initial parenteral therapy):
Note: Some experts suggest deferring antibiotics in otherwise healthy patients who are immunocompetent with mild disease (Ref).
Immediate release: Oral: 875 mg every 8 hours (Ref).
Extended release: Oral: 2 g every 12 hours (Ref).
Other intra-abdominal infection, step-down therapy (when clinically improved and able to tolerate oral therapy) : Oral: Immediate release: 875 mg 2 to 3 times daily (Ref).
Duration: Total duration of therapy is 4 to 5 days following adequate source control (Ref). For diverticulitis or uncomplicated appendicitis managed without intervention, duration is 10 to 14 days (Ref); for perforated appendicitis managed with laparoscopic appendectomy, 2 to 4 days may be sufficient (Ref).
Neutropenic fever, low-risk patients with cancer (empiric therapy) (off-label use): Oral: Immediate release: 500 mg every 8 hours (Ref) or 875 mg every 12 hours (Ref). Combine either dosing regimen with oral ciprofloxacin; continue until resolution of fever and neutropenia. Note: Avoid in patients who have received fluoroquinolone prophylaxis. Administer first dose in the health care setting (after blood cultures are drawn); observe patient for ≥4 hours before discharge (Ref).
Odontogenic infection (off-label use):
Acute simple gingivitis, plaque-associated: Note: Reserve systemic therapy for patients with rapidly progressive disease, severe pain, or immunocompromising conditions (Ref).
Oral: Immediate release: 875 mg every 12 hours or 500 mg every 8 hours for 5 to 7 days (Ref).
Periodontitis, severe, plaque-associated: Oral: Immediate release: 875 mg every 12 hours or 500 mg every 8 hours for 14 days or until clinical resolution, whichever is longer; use in addition to periodontal debridement (Ref).
Pyogenic odontogenic soft tissue infection (initial therapy for mild infection or step-down therapy after parenteral treatment): Oral: Immediate release: 875 mg every 12 hours; continue until clinical resolution, typically for 7 to 14 days. Use in addition to appropriate surgical management (eg, drainage and/or extraction) (Ref).
Otitis media, acute:
Immediate release: Oral: 875 mg twice daily (Ref) or 500 mg every 8 hours (Ref).
Extended release: Oral: 1 or 2 g twice daily, based on weight and severity of infection; some experts prefer the extended release formulation for patients at high risk of severe infection or resistant S. pneumoniae (Ref).
Duration: 5 to 7 days for mild to moderate infection and 10 days for severe infection (Ref).
Peritonsillar cellulitis or abscess (off-label-use): Note: For step-down therapy after parenteral treatment. Limited data available; dosing based on expert opinion. Oral: Immediate release: 875 mg every 12 hours to complete a total of 14 days of therapy (Ref).
Pneumonia:
Aspiration pneumonia (community acquired [mild]):
Immediate release: Oral: 875 mg twice daily (Ref).
Extended release: Oral: 2 g twice daily (Ref).
Duration of therapy: Generally 5 days (Ref).
Community-acquired pneumonia:
Note: For empiric therapy in outpatients with comorbidities or oral step-down therapy following initial parenteral therapy in patients who are hospitalized (Ref).
Immediate release: Oral: 500 mg 3 times daily or 875 mg twice daily as part of an appropriate combination regimen (Ref).
Extended release: Oral: 2 g twice daily as part of an appropriate combination regimen (Ref).
Duration of therapy: Minimum of 5 days; patients should be clinically stable with normal vital signs before therapy is discontinued (Ref).
Rhinosinusitis, acute bacterial:
Note: In uncomplicated acute bacterial rhinosinusitis, initial observation and symptom management without antibiotic therapy is appropriate in most patients. Reserve antibiotic therapy for poor follow-up or lack of improvement over the observation period (Ref).
Standard dose: Oral: Immediate release: 500 mg every 8 hours or 875 mg every 12 hours for 5 to 7 days (Ref).
High dose: Oral: Extended release: 2 g every 12 hours for 5 to 7 days. Note: Recommended for patients at risk for poor outcome or pneumococcal resistance based on the following features: ≥65 years of age, recent hospitalization or antibiotic use, multiple comorbidities, high endemic resistance (Ref).
Urinary tract infection (alternative agent):
Note: Use only when preferred first-line agents cannot be used; limited evidence suggests inferior efficacy of oral beta-lactams (Ref).
Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract, prostate, or systemic infection) : Oral: Immediate release: 500 mg twice daily (Ref) for 5 to 7 days (Ref).
Urinary tract infection, complicated (including pyelonephritis) : Oral: Immediate release: 875 mg twice daily for 10 to 14 days (Ref); for patients with symptomatic improvement within the first 48 to 72 hours of therapy, some experts recommend shorter courses of 7 to 10 days (Ref). Note: Oral beta-lactam therapy should generally follow appropriate parenteral therapy (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Oral:
Note: Renally adjusted dose recommendations are based on the amoxicillin component of the amoxicillin 250 mg/clavulanate 125 mg and amoxicillin 500 mg/clavulanate 125 mg tablets. Avoid IR 875 mg tablet or ER tablets in patients with CrCl <30 mL/minute.
Altered kidney function: Note: Although the manufacturer's labeling for some products utilizes the term GFR to present dose adjustment cutoffs, pharmacokinetic studies utilized CrCl measurements (Ref).
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 10 to <30 mL/minute: 250 to 500 mg every 12 hours.
CrCl <10 mL/minute: 250 to 500 mg every 12 to 24 hours (Ref).
Hemodialysis, intermittent (thrice weekly): Dialyzable (30% to 47% [amoxicillin component], 34% [clavulanic acid] with low-flux filters (Ref)): 250 to 500 mg every 12 to 24 hours (Ref). If utilizing a 24-hour dosing interval, administer dose after dialysis or give an additional dose after dialysis on dialysis days.
Peritoneal dialysis: 250 to 500 mg every 12 hours (Ref).
IV [Canadian product]: Note: Dose based on amoxicillin component.
Altered kidney function:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: Initial: 1 g followed by 500 mg every 12 hours.
CrCl <10 mL/minute: Initial: 1 g followed by 500 mg every 12 to 24 hours (Ref).
Hemodialysis, intermittent (thrice weekly): Dialyzable (30% to 47% [amoxicillin component] with low-flux filters (Ref)): Initial: 1 g followed by 500 mg every 12 to 24 hours. If utilizing a 24-hour dosing interval, administer dose after dialysis or give an additional 500 mg dose after dialysis on dialysis days (Ref).
Peritoneal dialysis: Initial: 1 g followed by 500 mg every 12 hours (Ref).
The hepatic dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST, Jeong Park, PharmD, MS, BCTXP, FCCP, FAST, Arun Jesudian, MD, Sasan Sakiani, MD.
Note: Amoxicillin is minimally metabolized while clavulanic acid is primarily metabolized by the liver. Both are eliminated in the kidney (Ref). In patients with cirrhosis with ascites, the combination of amoxicillin/clavulanic acid distributes extensively into ascitic fluid, is minimally protein bound, and has a prolonged elimination half-life (Ref).
Hepatic impairment prior to treatment initiation: Note: Amoxicillin/clavulanic acid is contraindicated in patients who previously developed liver injury (eg, cholestasis) associated with exposure to this antimicrobial combination.
Child-Turcotte-Pugh class A through C: No dosage adjustment necessary (Ref).
Hepatic impairment developing in patients already receiving amoxicillin/clavulanic acid:
Acute hepatotoxicity during treatment (eg, requiring hospitalization):
Progression from baseline to Child-Turcotte-Pugh class A through C: No dosage adjustment necessary (Ref). Discontinue use if amoxicillin/clavulanic acid–induced liver injury is suspected (Ref).
GI effects range from antibiotic-associated [non-Clostridioides difficile] diarrhea (AAD), nausea, and vomiting. Most cases of AAD are mild and self-limiting (Ref). However, Clostridioides difficile may account for as many as >20% of cases in children, adolescents, and adults (discussed separately) (Ref). Diarrhea is more common with amoxicillin/clavulanic acid than with amoxicillin or ampicillin alone (Ref).
Mechanism: Dose- and time-related. In addition to antibiotic disruption of indigenous gut microbiota, clavulanic acid appears to stimulate small-bowel motility (Ref).
Onset: Varied; mean time to onset of AAD is 3 to 18 days for adult patients and 2 to 6 days for pediatric patients. The majority of AAD cases occur during (versus after) antibiotic therapy in pediatric patients (Ref).
Risk factors:
• More frequent dosing (eg, 3 times daily versus twice daily) and higher amounts of clavulanic acid (eg, high-dose amoxicillin/clavulanate) may increase risk in pediatric patients (Ref)
• Longer duration of therapy (Ref)
• Age (pediatric patients <2 years of age and older adults) (Ref)
• Longer length of hospitalization or ICU stay (Ref)
• Longer duration of proton pump inhibitor use (Ref)
• Parenteral nutrition (Ref)
• Combined administration of antibiotics (Ref)
Clostridioides difficile infection (CDI) has occurred, including Clostridioides difficile associated diarrhea and Clostridioides difficile colitis. (Ref)
Mechanism: Dose- and time-related; related to cumulative antibiotic exposure. Amoxicillin may cause disruption of the intestinal microbiota resulting in the overgrowth of pathogens, such as C. difficile (Ref).
Onset: Varied; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).
Risk factors:
• Antibiotic exposure (highest risk factor), especially prolonged use (Ref)
• Type of antibiotic (penicillin combination antibiotics, including amoxicillin and clavulanate, have been associated with increased risk) (Ref)
• Long durations in a hospital or other healthcare setting (recent or current) (Ref)
• Older adults (Ref)
• Immunocompromised conditions (Ref)
• A serious underlying condition (Ref)
• GI surgery/manipulation (Ref)
• Antiulcer medications (eg, proton pump inhibitors and H2 blockers) (Ref)
• Chemotherapy (Ref)
• In pediatric patients, community-acquired CDI was associated with amoxicillin/clavulanate, cephalosporins, or clindamycin use in the prior 12 weeks, as well as non-Hispanic race, more health care visits, and prior positive Clostridioides difficile test in the past 6 months (Ref).
Drug-induced enterocolitis syndrome (DIES) has been reported with the amoxicillin component of amoxicillin/clavulanate; most cases have occurred in patients ≤18 years of age. DIES is a non–IgE-mediated hypersensitivity reaction defined by major criteria (ie, protracted vomiting occurring in the 1- to 4-hour period after drug ingestion in the absence of classic IgE-mediated skin or respiratory symptoms), plus at least three additional minor criteria (eg, extreme lethargy, marked pallor, need for emergency department visit, need for IV fluid support, diarrhea in 24 hours after ingestion of the drug [usually 5 to 10 hours], hypotension, hypothermia, leukocytosis with elevated neutrophils) (Ref).
Mechanism: Not clearly established, non-IgE-mediated hypersensitivity reaction; sharing mechanistic similarities with food-protein enterocolitis syndrome, alterations of intestinal mucosa may favor entry of drug antigens with subsequent activation of immune cells with release of proinflammatory cytokines and histamine (Ref).
Onset: Rapid; 1 to 4 hours after drug ingestion (Ref).
Although rarely fatal, drug-induced liver injury has been reported. The most frequent presentation is cholestatic hepatitis (Ref). Most patients recover after drug discontinuation, but there are reports of death or patients who require liver transplantation (Ref)
Mechanism: Non-dose-related; primarily immunologic, mediated by T-cells (Ref). Genetic variation at human leukocyte antigen class I & II loci has been shown to be associated with amoxicillin/clavulanic acid induced liver jury (Ref). Unknown whether the liver injury is due to amoxicillin or clavulanic acid or both (Ref).
Onset: Varied; most cases occur within 12 weeks after initial drug exposure (Ref).
Risk factors:
• Older male patients, most often of Caucasian race (Ref)
• Serious underlying disease
• Higher number of concurrent medications (Ref)
• Repeated courses of therapy (Ref)
Immediate hypersensitivity reactions, including urticaria, angioedema and anaphylaxis (Ref), and delayed hypersensitivity reactions have been reported in all ages (Ref). Delayed hypersensitivity reactions range from maculopapular skin rash to rare severe cutaneous adverse reactions (SCARs), including acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis in all ages (Ref). Drug-induced enterocolitis syndrome (discussed separately) has also been reported (Ref).
Mechanism: Non–dose-related; immunologic. Immediate hypersensitivity reactions (eg, anaphylaxis, urticaria) are IgE-mediated. Delayed hypersensitivity reactions, including maculopapular rash and SCARs are T-cell-mediated (Ref). In patients with reactions to amoxicillin/clavulanic acid, the reaction can be mediated by the amoxicillin or clavulanic acid component (Ref), or some patients may be sensitized independently to both amoxicillin and clavulanic acid (Ref). Approximately 30% of patients have selective reactions to clavulanic acid (Ref).
Onset: Immediate hypersensitivity reactions: Rapid; generally occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref). Delayed hypersensitivity reactions: Maculopapular reactions: Intermediate; occur 7 to 10 days after initiation. Other reactions (including SCARs): Variable; occur after 7 to 14 days up to 3 months) (Ref).
Risk factors:
• Rash may develop in 9% to 23% of patients with Epstein-Barr virus (EBV) infection (infectious mononucleosis) who are not on antibiotics. Although previous studies indicated that concomitant administration of an aminopenicillin, specifically ampicillin or amoxicillin, may increase the risk of rash in these patients, more recent studies suggest that amoxicillin/clavulanic acid may not increase the risk of rash. In one study, 12.5% of EBV-infected patients who used amoxicillin/clavulanic acid developed a rash (Ref).
• Cross-reactivity between beta-lactams (related to side chain similarity) (Ref). No cross-reactivity reported between clavulanic acid and penicillins, likely due to differences in chemical structures (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see Amoxicillin.
>10%: Gastrointestinal: Diarrhea (3% to 34%)
1% to 10%:
Dermatologic: Candidal diaper rash (4% to 6%), diaper rash (4%), skin rash (≤3%), urticaria (≤3%)
Gastrointestinal: Nausea (2% to 3%), vomiting (1% to 2%)
Genitourinary: Vaginal mycosis (3%), vaginitis (1%)
Infection: Candidiasis (1%)
<1%:
Gastrointestinal: Abdominal distress, flatulence
Hematologic & oncologic: Thrombocytosis
Nervous system: Headache
Postmarketing:
Dermatologic: Acute generalized exanthematous pustulosis (Hioki 2019), bullous dermatitis (linear IgA) (Panasiti 2009), erythema multiforme (Peng 2013), exfoliative dermatitis (Barni 2018), fixed drug eruption (Perez-Ezquerra 2010), pruritus, Stevens-Johnson syndrome (Mori 2017), Sweet syndrome (histiocytoid) (Yuksek 2022), toxic epidermal necrolysis (Rodriguez-Martin 2019)
Gastrointestinal: Clostridioides difficile colitis, Clostridioides difficile-associated diarrhea (Brown 2020; Slimings 2014), dyspepsia, enterocolitis (including drug-induced enterocolitis syndrome [DIES]) (Freundt Serpa 2020), gastritis, glossitis, hemorrhagic colitis (Youn 2018), melanoglossia, mucocutaneous candidiasis, pancreatitis (Chams 2018), staining of tooth (Garcia-Lopez 2001), stomatitis
Genitourinary: Crystalluria (van Noord 2012), hematuria (Asim 2021)
Hematologic & oncologic: Agranulocytosis (Armas Villalba 2019), anemia, eosinophilia, hemolytic anemia, immune thrombocytopenia, leukopenia, thrombocytopenia (Mansour 2014)
Hepatic: Acute hepatic failure (Fontana 2005), cholestatic hepatitis (Chalasani 2021; deLemos 2016), hepatocellular hepatitis (Chalasani 2021; deLemos 2016), jaundice (deLemos 2016)
Hypersensitivity: Anaphylaxis (including Kounis syndrome) (Moloney 2019), angioedema (Salvo 2007), drug reaction with eosinophilia and systemic symptoms (van Kester 2018), hypersensitivity angiitis, nonimmune anaphylaxis, serum sickness-like reaction (Patterson-Fortin 2016), type IV hypersensitivity reaction (Copaescu 2020)
Nervous system: Agitation, anxiety, aseptic meningitis (Chandler 2019), behavioral changes (Macknin 1987), confusion, dizziness, insomnia, myoclonus (Viloria-Alebesque 2020), reversible hyperactivity
Renal: Interstitial nephritis (including acute interstitial nephritis; can be hemorrhagic) (Asim 2021)
Hypersensitivity to amoxicillin, clavulanic acid, other beta-lactam antibacterial drugs (eg, penicillins, cephalosporins), or any component of the formulation; history of cholestatic jaundice or hepatic dysfunction with amoxicillin/clavulanate potassium therapy.
Augmentin XR: Additional contraindications: Severe renal impairment (CrCl <30 mL/minute) and patients on hemodialysis.
Canadian labeling: Additional contraindications (not in the US labeling): Suspected or confirmed mononucleosis.
Concerns related to adverse effects:
• Superinfection: Prolonged use may result in fungal or bacterial superinfection.
Dosage form specific issues:
• Clavulanic acid content: Due to differing content of clavulanic acid, not all formulations are interchangeable; use of an inappropriate product for a specific dosage could result in either diarrhea (which may be severe) or subtherapeutic clavulanic acid concentrations leading to decreased clinical efficacy.
• Phenylalanine: Some products contain phenylalanine.
Diarrhea has been reported with amoxicillin and clavulanate; incidence increases with clavulanate dose. Some experts recommend not exceeding 10 mg clavulanate/kg/day, 5 mg clavulanate/kg/dose, or 125 mg clavulanate/dose (Yu 2022). In a study of patients 6 to 23 months of age with acute otitis media (n=112), patients who received amoxicillin 80 mg/kg/day and clavulanate 2.85 mg/kg/day (novel formulation not currently available) experienced less diarrhea and diaper dermatitis but similar efficacy as compared to historical controls receiving amoxicillin 90 mg/kg/day and clavulanate 6.4 mg/kg/day (Hoberman 2017). Minimum dose requirement for optimal inhibition of beta-lactamases and pharmacodynamic predictor of efficacy for clavulanate have not been defined (Crass 2019). Dosing per manufacturer's labeling for patients <40 kg results in a clavulanate dose of 3.6 to 10 mg/kg/day (4:1 ratio formulations: 5 to 10 mg/kg/day; 7:1 ratio formulations: 3.6 to 6.4 mg/kg/day; 14:1 formulation: 6.4 mg/kg/day).
IV [Canadian product]: 500 mg, 1 g, and 2 g vials contain 31.4 mg (1.4 mmoL), 62.9 mg (2.7 mmoL), and 125.9 mg (5.5 mmoL) of sodium and 19.6 (0.5 mmoL), 39.3 mg (1 mmoL) and 39.3 mg (1 mmoL) of potassium, respectively.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Suspension Reconstituted, Oral:
Augmentin: Amoxicillin 250 mg and clavulanate potassium 62.5 mg per 5 mL (75 mL [DSC], 100 mL [DSC], 150 mL [DSC]); Amoxicillin 125 mg and clavulanate potassium 31.25 mg per 5 mL (75 mL [DSC], 100 mL [DSC], 150 mL [DSC]) [contains saccharin sodium]
Augmentin: Amoxicillin 125 mg and clavulanate potassium 31.25 mg per 5 mL (100 mL, 150 mL) [contains saccharin sodium; banana flavor]
Augmentin ES-600: Amoxicillin 600 mg and clavulanate potassium 42.9 mg per 5 mL (75 mL [DSC], 125 mL [DSC], 200 mL [DSC]) [contains aspartame; strawberry cream flavor]
Generic: Amoxicillin 200 mg and clavulanate potassium 28.5 mg per 5 mL (50 mL, 75 mL, 100 mL); Amoxicillin 250 mg and clavulanate potassium 62.5 mg per 5 mL (75 mL, 100 mL, 150 mL); Amoxicillin 400 mg and clavulanate potassium 57 mg per 5 mL (50 mL, 75 mL, 100 mL); Amoxicillin 600 mg and clavulanate potassium 42.9 mg per 5 mL (75 mL, 125 mL, 200 mL)
Suspension Reconstituted, Oral [preservative free]:
Augmentin ES-600: Amoxicillin 600 mg and clavulanate potassium 42.9 mg per 5 mL (200 mL) [contains aspartame; strawberry cream flavor]
Tablet, Oral:
Augmentin: Amoxicillin 500 mg and clavulanate potassium 125 mg
Generic: Amoxicillin 250 mg and clavulanate potassium 125 mg, Amoxicillin 500 mg and clavulanate potassium 125 mg, Amoxicillin 875 mg and clavulanate potassium 125 mg
Tablet Chewable, Oral:
Generic: Amoxicillin 200 mg and clavulanate potassium 28.5 mg, Amoxicillin 400 mg and clavulanate potassium 57 mg
Tablet Extended Release 12 Hour, Oral:
Generic: Amoxicillin 1000 mg and clavulanate potassium 62.5 mg
Yes
Chewable (Amoxicillin-Pot Clavulanate Oral)
200-28.5 mg (per each): $3.08
400-57 mg (per each): $5.88
Suspension (reconstituted) (Amoxicillin-Pot Clavulanate Oral)
200-28.5 mg/5 mL (per mL): $0.36 - $0.39
250-62.5 mg/5 mL (per mL): $0.86 - $0.88
400-57 mg/5 mL (per mL): $0.69 - $0.74
600-42.9 mg/5 mL (per mL): $0.49 - $0.68
Suspension (reconstituted) (Augmentin ES-600 Oral)
600-42.9 mg/5 mL (per mL): $5.49
Suspension (reconstituted) (Augmentin Oral)
125-31.25 mg/5 mL (per mL): $7.21
Tablet, 12-hour (Amoxicillin-Pot Clavulanate ER Oral)
1000-62.5 mg (per each): $8.43
Tablets (Amoxicillin-Pot Clavulanate Oral)
250-125 mg (per each): $5.92
500-125 mg (per each): $3.78 - $6.00
875-125 mg (per each): $5.05 - $9.00
Tablets (Augmentin Oral)
500-125 mg (per each): $11.57
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Intravenous:
Generic: Amoxicillin 1000 mg and clavulanate potassium 200 mg (1 ea); Amoxicillin 2000 mg and clavulanate potassium 200 mg (1 ea); Amoxicillin 500 mg and clavulanate potassium 100 mg (1 ea)
Suspension Reconstituted, Oral:
Clavulin: Amoxicillin 400 mg and clavulanate potassium 57 mg per 5 mL (70 mL); Amoxicillin 200 mg and clavulanate potassium 28.5 mg per 5 mL (70 mL)
Clavulin-125F: Amoxicillin 125 mg and clavulanate potassium 31.25 mg per 5 mL (100 mL, 150 mL)
Clavulin-250F: Amoxicillin 250 mg and clavulanate potassium 62.5 mg per 5 mL (100 mL, 150 mL)
Generic: Amoxicillin 250 mg and clavulanate potassium 62.5 mg per 5 mL (100 mL); Amoxicillin 400 mg and clavulanate potassium 57 mg per 5 mL (70 mL)
Tablet, Oral:
Clavulin: Amoxicillin 875 mg and clavulanate potassium 125 mg [DSC]
Clavulin-500F: Amoxicillin 500 mg and clavulanate potassium 125 mg [DSC]
Generic: Amoxicillin 250 mg and clavulanate potassium 125 mg, Amoxicillin 500 mg and clavulanate potassium 125 mg, Amoxicillin 875 mg and clavulanate potassium 125 mg
Oral: Immediate-release formulations may be given without regard to meals; however, administer at the start of a meal to decrease the frequency or severity of GI side effects and improve absorption; administer extended-release tablet at the start of a meal. Shake suspension well before use.
IV [Canadian product]: Administer as an infusion over 30 to 40 minutes. In infants ≥3 months, children, and adolescents, 5:1 formulations (500/100 mg and 1,000/200 mg) may also be administered by slow IV injection over 3 to 4 minutes.
Oral: Administer around-the-clock to promote less variation in peak and trough serum levels. Administer with food to increase absorption and decrease stomach upset; shake suspension well before use. ER tablets should be administered with food.
Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not cut, crush, or chew. Switch to IR formulation.
IV [Canadian product]: Administer by slow IV injection over 3 to 4 minutes (500 mg or 1 g dose only) or as an infusion over 30 to 40 minutes.
Oral:
Powder for oral suspension: Store dry powder at or below 25°C (77°F). Reconstituted oral suspension should be kept in refrigerator. Discard unused suspension after 10 days (consult manufacturer's labeling for specific recommendations). Unit-dose antibiotic oral syringes are stable under refrigeration for 24 hours (Tu 1988).
Tablet: Store at or below 25°C (77°F). Dispense in original container.
IV [Canadian product]: Store intact vials at 15°C to 30°C (59°F to 86°F). Store reconstituted solution at 15°C to 30°C (59°F to 86°F) for up to 15 minutes. Solutions diluted for infusion should be used within 1 hour if stored at 25°C (77°F) or within 4 hours if stored at 5°C (41°F); recommendations may vary based on solution used for dilution, refer to manufacturer’s labeling for detailed information.
Treatment of lower respiratory tract infections, acute otitis media, sinusitis, skin and soft tissue infections, and urinary tract infections caused by susceptible bacteria (FDA approved in all ages).
Note: Approved indications and ages may vary by product; consult product-specific labeling for details.
Powder for oral suspension:
Amoxicillin 125 mg/clavulanate 31.25 mg/5 mL (4:1): FDA approved in all ages.
Amoxicillin 200 mg/clavulanate 28.5 mg/5 mL (7:1): FDA approved in ages ≥3 months and adults.
Amoxicillin 250 mg/clavulanate 62.5 mg/5 mL (4:1): FDA approved in ages ≥3 months and adults.
Amoxicillin 400 mg/clavulanate 57 mg/5 mL (7:1): FDA approved in ages ≥3 months and adults.
Amoxicillin 600 mg/clavulanate 42.9 mg/5 mL (14:1): FDA approved in pediatric patients ≥3 months and <40 kg.
Tablet, chewable:
Amoxicillin 200 mg/clavulanate 28.5 mg (7:1): FDA approved in pediatric patients (age not specified).
Amoxicillin 400 mg/clavulanate 57 mg (7:1): FDA approved in pediatric patients (age not specified).
Tablet, oral:
Amoxicillin 250 mg/clavulanate 125 mg (2:1): FDA approved in pediatric patients ≥40 kg and adults.
Amoxicillin 500 mg/clavulanate 125 mg (4:1): FDA approved in pediatric patients ≥40 kg and adults.
Amoxicillin 875 mg/clavulanate 125 mg (7:1): FDA approved in pediatric patients ≥40 kg and adults.
Extended-release tablet: Amoxicillin 1,000 mg/clavulanate 62.5 mg (16:1): FDA approved in pediatric patients ≥40 kg and adults.
Augmentin may be confused with amoxicillin, Azulfidine
Amoxicillin and Clavulanate is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) for use in asymptomatic bacteriuria (O’Mahony 2023).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Acemetacin: May increase the serum concentration of Penicillins. Risk C: Monitor therapy
Allopurinol: May enhance the potential for allergic or hypersensitivity reactions to Amoxicillin. Risk C: Monitor therapy
Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Risk C: Monitor therapy
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy
Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Khat: May decrease the serum concentration of Amoxicillin. Management: Consider administering amoxicillin before, or 2 hours after, khat chewing to avoid reductions in amoxicillin bioavailability. Risk D: Consider therapy modification
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Antibiotics may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be reduced. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Betalactamase Inhibitors. Management: Coadministration of probenecid with amoxicillin/clavulanate is not recommended per official package labeling. Risk D: Consider therapy modification
Sodium Benzoate: Penicillins may diminish the therapeutic effect of Sodium Benzoate. Risk C: Monitor therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Tetracyclines: May diminish the therapeutic effect of Penicillins. Risk C: Monitor therapy
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
May be taken with meals or on an empty stomach; take with meals to increase absorption and decrease GI upset; may mix with milk, formula, or juice. Extended release tablets should be taken with food. Some products may contain sodium. Some products contain phenylalanine. All dosage forms contain potassium.
Both amoxicillin and clavulanic acid cross the placenta (Muller 2009; Weber 1984). An increased risk of necrotizing enterocolitis in neonates or bowel disorders in children may be associated with amoxicillin/clavulanate when exposure occurs near delivery (Kenyon 2001).
Oral ampicillin-class antibiotics are poorly absorbed during labor. Clavulanate does not appear to influence maternal amoxicillin pharmacokinetics following IV administration of amoxicillin/clavulanate prior to delivery (Muller 2009).
As a class, penicillin antibiotics are widely used in pregnant women. Based on available data, penicillin antibiotics are generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Damkier 2019; Lamont 2014; Muanda 2017a; Muanda 2017b).
Untreated urinary tract infections (UTI) during pregnancy are associated with an increased risk of developing pyelonephritis, low birth weight, and preterm labor. Amoxicillin/clavulanate may be an option for the treatment of UTI during pregnancy (Betschart 2020; de Rossi 2020; IDSA [Nicolle 2019]; Usta 2011).
Antibiotics are used in the management of preterm prelabor rupture of membranes (PROM) to prolong pregnancy and reduce the risk of infection. However, due to the possible increased risk of necrotizing enterocolitis, amoxicillin/clavulanate is not recommended for this indication (ACOG 217 2020).
Amoxicillin/clavulanate is considered compatible for the of treatment airway diseases in pregnant women. Use should be avoided in women at risk for preterm delivery (due to association with necrotizing enterocolitis) (ERS/TSANZ [Middleton 2020]).
The routine use of antibiotics prior to an operative vaginal delivery (vacuum or forceps delivery) is not currently recommended. However, amoxicillin/clavulanate IV administered after an operative vaginal delivery may decrease the risk of a maternal infection occurring within 6 weeks postpartum. A single dose may be appropriate in specific cases (Knight 2019; Liabsuetrakul 2020).
With prolonged therapy, monitor renal, hepatic, and hematologic function; monitor for signs of hypersensitivity, including anaphylaxis.
Clavulanic acid binds and inhibits beta-lactamases that inactivate amoxicillin resulting in amoxicillin having an expanded spectrum of activity. Amoxicillin inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
Amoxicillin pharmacokinetics are not affected by clavulanic acid.
Amoxicillin: See individual Amoxicillin monograph.
Clavulanic acid:
Distribution:
Vd: Children ≥2 years and Adolescents ≤14 years: 0.368 ± 0.014 L/kg (Schaad 1983).
Protein binding: ~25%.
Half-life elimination:
Oral:
Infants ≥8 months and Children <12 years: 1.1 ± 0.3 hours.
Adults: 1 hour.
IV:
Children ≥2 years and Adolescents ≤14 years: 0.81 ± 0.04 hours (Schaad 1983).
Time to peak: Oral:
Infants ≥8 months and Children <12 years: Median: 1.1 hours; range: 1 to 4 hours.
Adults: 1.5 hours.
Excretion: Urine (25% to 40% as unchanged drug).
Anti-infective considerations:
Parameters associated with efficacy:
Amoxicillin: Refer to Amoxicillin monograph.
Clavulanate (in combination with amoxicillin): Not defined.
Expected drug exposure in normal renal function:
Pediatric patients, Cmax (peak):
Oral suspension (4:1 ratio); single dose:
Children 2 to 5 years of age: Amoxicillin 125 mg/clavulanate 31.25 mg per 5 mL: Mean dose amoxicillin 9.11 ± 1.83 mg/kg: Amoxicillin 3.45 ± 1.14 mg/L; clavulanate: 1.18 ± 0.63 mg/L (van Niekerk 1985).
Children 6 to 10 years of age: Amoxicillin 250 mg/clavulanate 62.5 mg per 5 mL: Mean dose amoxicillin 12.35 ± 3.11 mg/kg: Amoxicillin: 4 ± 1.65 mg/L; clavulanate: 1.31 ± 0.79 mg/L (van Niekerk 1985).
Oral suspension (14:1 ratio), amoxicillin 600 mg/clavulanate 42.9 mg per 5 mL; steady state:
Infants ≥8 months of age and children ≤11 years of age: Amoxicillin 45 mg/kg/dose every 12 hours: Amoxicillin: 15.7 ± 7.7 mg/L; clavulanate: 1.7 ± 0.9 mg/L.
Oral tablet, extended release; steady state:
Children ≥7 years of age and adolescents ≤15 years of age (weighing ≥40 kg): Amoxicillin 2,000 mg/clavulanate 125 mg every 12 hours: Amoxicillin: 11 ± 3.34 mg/L; clavulanate: 1.17 ± 0.67 mg/L.
IV (5:1 ratio) [Canadian product]; single dose, 2-minute infusion:
Children ≥2 years of age and adolescents ≤14 years of age: Amoxicillin 25 mg/kg/dose: Amoxicillin: 89.4 mg/L; clavulanate: 19.5 mg/L (Schaad 1983).
Adults, Cmax (peak):
Oral tablet; steady state:
Amoxicillin 250 mg/clavulanate 125 mg every 8 hours: Amoxicillin: 3.3 ± 1.12 mg/L; clavulanate: 1.5 ± 0.7 mg/L.
Amoxicillin 500 mg/clavulanate 125 mg every 12 hours: Amoxicillin: 6.5 ± 1.41 mg/L; clavulanate: 1.8 ± 0.61 mg/L.
Amoxicillin 500 mg/clavulanate 125 mg every 8 hours: Amoxicillin: 7.2 ± 2.26 mg/L; clavulanate: 2.4 ± 0.83 mg/L.
Amoxicillin 875 mg/clavulanate 125 mg every 12 hours: Amoxicillin: 11.6 ± 2.78 mg/L; clavulanate: 2.2 ± 0.99 mg/L.
Oral tablet, chewable; single dose:
Amoxicillin 250 mg/clavulanate 62.5 mg: Amoxicillin: 6.9 mg/L; clavulanate: 1.6 mg/L.
Amoxicillin 400 mg/clavulanate 57 mg: Amoxicillin: 6.67 ± 1.37 mg/L; clavulanate: 1.03 ± 0.33 mg/L.
Oral tablet, extended release; single dose:
Amoxicillin 2 g/clavulanate 125 mg: Amoxicillin: 17 ± 4 mg/L; clavulanate: 2.05 ± 0.8 mg/L.
IV [Canadian product]; single dose:
Amoxicillin 500 mg/clavulanate 100 mg, bolus: Amoxicillin: 32.2 mg/L; clavulanate: 10.5 mg/L.
Amoxicillin 1 g/clavulanate 200 mg, bolus: Amoxicillin: 105.4 mg/L; clavulanate: 28.5 mg/L.
Amoxicillin 2 g/clavulanate 200 mg, 30-minute infusion: Amoxicillin: 108 mg/L; clavulanate: 13.9 mg/L.
Postantibiotic effect:
H. influenzae: 0 to <2 hours; S. pneumoniae: 0 to <3 hours; Streptococcus pyogenes: 0 to 3.9 hours; methicillin-susceptible S. aureus: 0 to 2.55 hours; Enterobacterales: 0 to <1 hour (Dubois 2000; Neuhauser 2001; Thorburn 1996).
Do you want to add Medilib to your home screen?