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    Penicillin and Beta-Lactamase Inhibitor Combination Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Contains amoxicillin and clavulanic acid; clavulanic acid is a beta-lactamase inhibitor that reestablishes amoxicillin's activity against beta-lactamase-producing bacteria; drug combination has good activity against beta-lactamase producing H. influenzae and penicillinase-producing anaerobes; used commonly for upper respiratory infections, otitis media and sinusitis.

    COMMON BRAND NAMES

    Amoclan, Augmentin, Augmentin ES, Augmentin XR

    HOW SUPPLIED

    Amoclan/Amoxicillin Trihydrate, Clavulanate Potassium/Amoxicillin, Clavulanate Potassium/Augmentin/Augmentin ES Oral Pwd F/Recon: 5mL, 125-31.25mg, 200-28.5mg, 250-62.5mg, 400-57mg, 600-42.9mg
    Amoxicillin Trihydrate, Clavulanate Potassium/Amoxicillin, Clavulanate Potassium/Augmentin Oral Tab Chew: 200-28.5mg, 400-57mg
    Amoxicillin Trihydrate, Clavulanate Potassium/Amoxicillin, Clavulanate Potassium/Augmentin Oral Tab: 250-125mg, 500-125mg, 875-125mg
    Amoxicillin Trihydrate, Clavulanate Potassium/Amoxicillin, Clavulanate Potassium/Augmentin XR Oral Tab ER: 1000-62.5mg

    DOSAGE & INDICATIONS

    For the treatment of acute otitis media.
    NOTE: Amoxicillin; clavulanic acid is the preferred initial therapy for children who have received amoxicillin within the past 30 days, who have concurrent conjunctivitis, or those for whom coverage of beta-lactamase-positive H. influenzae and M. catarrhalis is desired.
    Oral dosage (immediate-release formulations and non-ES suspensions, standard dose therapy)
    Adults

    500 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; or 125 mg/5 mL or 250 mg/5 mL suspension) or 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 875 mg tablet or 200 mg/5 mL or 400 mg/5 mL suspension) for 10 days.

    Children and Adolescents weighing 40 kg or more

    500 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; or 125 mg/5 mL or 250 mg/5 mL suspension) or 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 875 mg tablet or 200 mg/5 mL or 400 mg/5 mL suspension) for 10 days.

    Infants 3 months and older, Children, and Adolescents weighing less than 40 kg

    Due to the higher clavulanic acid content in regular formulations (i.e., chewable tablets, non-ES suspensions) and the need for high-dose therapy (i.e., 90 mg/kg/day), these formulations are not recommended for the treatment of AOM. The formulation containing 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL (e.g., ES-600) is recommended for high-dose therapy. The FDA-approved dose is 45 mg/kg/day amoxicillin component PO divided every 12 hours (using 200 mg/5 mL or 400 mg/5 mL suspension; 200 mg or 400 mg chewable tablets) or 40 mg/kg/day amoxicillin component PO divided every 8 hours (using 125 mg/5 mL or 250 mg/5 mL suspension; 125 mg or 250 mg chewable tablets; or 500 mg regular tablets) for 10 days.

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours. Due to limited data supporting the use of other formulations, the 125 mg/5 mL suspension is recommended for use in this age group.

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours. Due to limited data supporting the use of other formulations, the 125 mg/5 mL suspension for use in this age group.

    Oral dosage (ES-600; 600 mg amoxicillin and 42.9 mg clavulanic acid per 5 mL suspension, high-dose therapy)
    Children 6 years and older

    90 mg/kg/day amoxicillin component PO divided every 12 hours for 5 to 7 days for mild to moderate disease and 10 days for severe disease.

    Children 2 to 5 years

    90 mg/kg/day amoxicillin component PO divided every 12 hours for 7 days for mild to moderate disease and 10 days for severe disease.

    Infants and Children 6 to 23 months

    90 mg/kg/day amoxicillin component PO divided every 12 hours for 10 days.

    Infants 3 to 5 months

    90 mg/kg/day amoxicillin component PO divided every 12 hours for 10 days.

    For the treatment of acute bacterial sinusitis.
    Oral dosage (immediate-release formulations and non-ES suspensions, standard dose therapy)
    Adults

    500 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; or 125 mg/5 mL or 250 mg/5 mL suspension) or 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 875 mg tablet or 200 mg/5 mL or 400 mg/5 mL suspension) for 5 to 10 days as first-line therapy. High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, patients older than 65 years, those with recent hospitalization, antibiotic use within the past month, and who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    Children and Adolescents weighing 40 kg or more

    500 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; or 125 mg/5 mL or 250 mg/5 mL suspension) or 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 875 mg tablet or 200 mg/5 mL or 400 mg/5 mL suspension) for 10 to 14 days as first-line therapy. The every 12 hour regimen is preferred because it associated with less diarrhea than the every 8 hour regimen.  High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, children who attend daycare, those with recent hospitalization, antibiotic use within the past month, and who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    Infants, Children, and Adolescents 3 months to 17 years weighing less than 40 kg

    40 mg/kg/day amoxicillin component PO divided every 8 hours (using 125 mg/5 mL or 250 mg/5 mL suspension; 125 mg or 250 mg chewable tablets; or 500 mg regular tablets) or 45 mg/kg/day amoxicillin component PO divided every 12 hours (using 200 mg/5 mL or 400 mg/5 mL suspension; 200 mg or 400 mg chewable tablets) for 10 to 14 days as first-line therapy for most patients. The every 12 hour regimen is preferred because it associated with less diarrhea than the every 8 hour regimen. High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, children who attend daycare, children younger than 2 years, children with recent hospitalization, those with antibiotic use within the past month, and those who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours for 10 to 14 days as first-line therapy. Due to limited data supporting the use of other formulations, the 125 mg/5 mL suspension is recommended for use in this age group.

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours for 10 to 14 days as first-line therapy. Due to limited data supporting the use of other formulations, the 125 mg/5 mL suspension is recommended for use in this age group.

    Oral dosage (extended-release tablets containing 1,000 mg amoxicillin and 62.5 mg clavulanate, high-dose therapy)
    Adults

    2,000 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours for 5 to 10 days as first-line therapy. High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, patients older than 65 years, those with recent hospitalization, antibiotic use within the past month, and who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    Children and Adolescents weighing 40 kg or more

    2,000 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours for 10 to 14 days as first-line therapy.   High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, children who attend daycare, those with recent hospitalization, antibiotic use within the past month, and who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    Oral dosage (ES-600; 600 mg amoxicillin and 42.9 mg clavulanic acid per 5 mL suspension, high-dose therapy)†
    Adults

    2,000 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours for 5 to 10 days. High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, patients older than 65 years, those with recent hospitalization, antibiotic use within the past month, and who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    Infants, Children, and Adolescents

    90 mg/kg/day amoxicillin component PO divided every 12 hours (Max: 2,000 mg amoxicillin/125 mg clavulanic acid/dose) for 10 to 14 days as first-line therapy. High-dose therapy is recommended as initial empiric therapy for patients from geographic areas with high rates of penicillin-resistant S. pneumoniae, those with severe infection, children who attend daycare, children younger than 2 years, children with recent hospitalization, those with antibiotic use within the past month, and those who are immunocompromised. High-dose therapy is also recommended after initial treatment failure.

    For the treatment of lower respiratory tract infections (LRTIs), including community-acquired pneumonia (CAP).
    For the treatment of nonspecific lower respiratory tract infections (LRTIs).
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours.[43200]

    Children and Adolescents weighing 40 kg or more

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours.[43200]

    Infants, Children, and Adolescents 3 months to 17 years and weighing less than 40 kg

    45 mg/kg/day amoxicillin component PO divided every 12 hours or 40 mg/kg/day amoxicillin component PO divided every 8 hours. The every 12-hour regimen is associated with less diarrhea.[43200]

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours. The 125 mg/5 mL suspension is recommended.[43200]

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours. The 125 mg/5 mL suspension is recommended.[43200]

    For the treatment of community-acquired pneumonia (CAP).
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for at least 5 days as part of combination therapy for outpatients with comorbidities. Guide treatment duration by clinical stability.[34362] [43200] [64669]

    Adolescents weighing 40 kg or more

    500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for 5 to 10 days as an alternative to high-dose amoxicillin for mild infections or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[34362] [43200] [46963] In HIV-infected patients, amoxicillin; clavulanate is recommended as part of combination therapy for outpatients.[34362]

    Adolescents weighing less than 40 kg

    45 mg/kg/day amoxicillin component PO divided every 8 hours for 5 to 10 days as an alternative to high-dose amoxicillin for mild infections or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[34362] [43200] [46963] In HIV-infected patients, amoxicillin; clavulanate is recommended as part of combination therapy for outpatients.[34362]

    Children weighing 40 kg or more

    500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for 7 to 10 days as an alternative to high-dose amoxicillin for mild infections or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[43200] [46963]

    Infants and Children 3 months to 12 years and weighing less than 40 kg

    45 mg/kg/day amoxicillin component PO divided every 8 hours for 7 to 10 days as an alternative to high-dose amoxicillin for mild infections or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[43200] [46963]

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours. The 125 mg/5 mL suspension is recommended.[43200] If a lower respiratory tract infection is suspected in a young infant, full evaluation and careful clinical workup are warranted. Infants younger than 3 to 6 months are likely to benefit from hospitalization.[46963]

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours. The 125 mg/5 mL suspension is recommended.[43200] If a lower respiratory tract infection is suspected in a neonate, full evaluation and careful clinical workup are warranted. Neonates are likely to benefit from hospitalization.[46963]

    Oral dosage (extended-release tablets containing 1,000 mg amoxicillin and 62.5 mg clavulanate per tablet)
    Adults

    2,000 mg amoxicillin with 125 mg clavulanate PO every 12 hours for at least 5 days as part of combination therapy for outpatients with comorbidities. Guide treatment duration by clinical stability.[34356] [34362] [64669] FDA-approved labeling recommends treatment for 7 to 10 days.[34356]

    Adolescents weighing 40 kg or more

    2,000 mg amoxicillin with 125 mg clavulanate PO every 12 hours for 5 to 10 days as an alternative to amoxicillin for empiric therapy in outpatients, for mild infections, or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[34356] [34362] [46963] In HIV-infected patients, amoxicillin; clavulanate is recommended as part of combination therapy for outpatients.[34362]

    Children weighing 40 kg or more

    2,000 mg amoxicillin with 125 mg clavulanate PO every 12 hours for 7 to 10 days as an alternative to amoxicillin for empiric therapy in outpatients, for mild infections, or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[34356] [46963]

    Oral dosage (ES-600; suspension containing 600 mg amoxicillin and 42.9 mg clavulanate per 5 mL)†
    Adolescents

    90 mg/kg/day amoxicillin component PO divided every 12 hours (Max: 2,000 mg amoxicillin with 125 mg clavulanate per dose) for 5 to 10 days as an alternative to amoxicillin for empiric therapy in outpatients, for mild infections, or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.[34362] [46963] In HIV-infected patients, amoxicillin; clavulanate is recommended as part of combination therapy for outpatients.[34362]

    Infants and Children 3 months to 12 years

    90 mg/kg/day amoxicillin component PO divided every 12 hours (Max: 2,000 mg amoxicillin with 125 mg clavulanate per dose) for 7 to 10 days as an alternative to amoxicillin for empiric therapy in outpatients, for mild infections, or as step-down therapy for infections due to beta-lactamase-producing H. influenzae.

    For the treatment of skin and skin structure infections, including impetigo, cellulitis, erysipelas, animal or human bite wounds, leg ulcer, and diabetic foot ulcer.
    For the treatment of impetigo.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours for 5 to 7 days.

    Children and Adolescents weighing 40 kg or more

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours for 5 to 7 days.

    Infants, Children, and Adolescents 3 months to 17 years weighing less than 40 kg

    25 mg/kg/day amoxicillin component PO divided every 12 hours for 5 to 7 days.

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours for 5 to 7 days. Due to limited data supporting the use of other formulations, the FDA-approved labeling recommends the 125 mg/5 mL suspension for use in this age group.

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours for 5 to 7 days. Due to limited data supporting the use of other formulations, the FDA-approved labeling recommends the 125 mg/5 mL suspension for use in this age group.

    For the treatment of animal bite wounds.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours. In setting of a cat or dog bite, preemptive early antimicrobial therapy for 3 to 5 days is recommended for patients who are immunocompromised, asplenic, have advanced liver disease, have edema of the bite area, have moderate to severe injuries, particularly of the hand or face, or have penetrating injuries to the periosteum or joint capsule.

    Children and Adolescents weighing 40 kg or more

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours. In setting of a cat or dog bite, preemptive early antimicrobial therapy for 3 to 5 days is recommended for patients who are immunocompromised, asplenic, have advanced liver disease, have edema of the bite area, have moderate to severe injuries, particularly of the hand or face, or have penetrating injuries to the periosteum or joint capsule.

    Infants, Children, and Adolescents 3 months to 17 years weighing less than 40 kg

    25 to 45 mg/kg/day amoxicillin component PO divided every 12 hours. In setting of a cat or dog bite, preemptive early antimicrobial therapy for 3 to 5 days is recommended for patients who are immunocompromised, asplenic, have advanced liver disease, have edema of the bite area, have moderate to severe injuries, particularly of the hand or face, or have penetrating injuries to the periosteum or joint capsule.

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours. Due to limited data supporting the use of other formulations, the FDA-approved labeling recommends the 125 mg/5 mL suspension for use in this age group. In setting of a cat or dog bite, preemptive early antimicrobial therapy for 3 to 5 days is recommended for patients who are immunocompromised, asplenic, have advanced liver disease, have edema of the bite area, have moderate to severe injuries, particularly of the hand or face, or have penetrating injuries to the periosteum or joint capsule.

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours. Due to limited data supporting the use of other formulations, the FDA-approved labeling recommends the 125 mg/5 mL suspension for use in this age group. In setting of a cat or dog bite, preemptive early antimicrobial therapy for 3 to 5 days is recommended for patients who are immunocompromised, asplenic, have advanced liver disease, have edema of the bite area, have moderate to severe injuries, particularly of the hand or face, or have penetrating injuries to the periosteum or joint capsule.

    For the treatment of nonpurulent skin infections, such as cellulitis and erysipelas.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 to 12 hours or 250 mg amoxicillin with 125 mg clavulanate PO every 8 hours for 5 to 14 days.

    Children and Adolescents weighing 40 kg or more

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 to 12 hours or 250 mg amoxicillin with 125 mg clavulanate PO every 8 hours for 5 to 14 days.

    Infants, Children, and Adolescents 3 months to 17 years weighing less than 40 kg

    25 to 45 mg/kg/day amoxicillin component PO divided every 12 hours or 20 to 40 mg/kg/day amoxicillin component PO divided every 8 hours for 5 to 14 days.

    Infants 1 to 2 months

    30 mg/kg/day amoxicillin component PO divided every 12 hours for 5 to 14 days. Due to limited data supporting the use of other formulations, the FDA-approved labeling recommends the 125 mg/5 mL suspension for use in this age group.

    Neonates

    30 mg/kg/day amoxicillin component PO divided every 12 hours for 5 to 14 days. Due to limited data supporting the use of other formulations, the FDA-approved labeling recommends the 125 mg/5 mL suspension for use in this age group.

    For the treatment of leg ulcer.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for 7 days.

    For the treatment of mild diabetic foot ulcer.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for 7 to 14 days for mild infections in patients with recent antibiotic exposure or moderate or severe infections with no complicating features or with ischemic limb/necrosis/gas forming. Continue treatment for up to 28 days if infection is improving but is extensive and resolving slower than expected or if patient has severe peripheral artery disease.

    For the treatment of human bite wounds.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours.

    For the treatment of urinary tract infection (UTI), including cystitis.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults (every 12 hour regimens)

    500 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; 125 mg/5 mL or 250 mg/5 mL suspension) for mild/moderate infections and 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 875 mg regular tablets; 200 mg or 400 mg chewable tablets; 200 mg/5 mL or 400 mg/5 mL suspension) for severe infections.

    Adults (every 8 hour regimens)

    250 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 250 mg regular tablets) for mild/moderate infections and 500 mg PO with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; 125 mg/5 mL or 250 mg/5 mL suspension) for severe infections.

    Children and Adolescents weighing 40 kg or more (every 12 hour regimens)

    500 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; 125 mg/5 mL or 250 mg/5 mL suspension) for mild/moderate infections and 875 mg amoxicillin with 125 mg clavulanic acid PO every 12 hours (using 875 mg regular tablets; 200 mg or 400 mg chewable tablets; 200 mg/5 mL or 400 mg/5 mL suspension) for severe infections.

    Children and Adolescents weighing 40 kg or more (every 8 hour regimens)

    250 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 250 mg regular tablets) for mild/moderate infections and 500 mg PO with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; 125 mg/5 mL or 250 mg/5 mL suspension) for severe infections.

    Infants, Children, and Adolescents 3 months to 17 years weighing less than 40 kg (every 12 hour regimens)

    25 mg/kg/day amoxicillin component PO divided every 12 hours for mild/moderate infections and 45 mg/kg/day amoxicillin component PO divided every 12 hours for severe infections (using 200 mg/5 mL or 400 mg/5 mL suspension; 200 mg and 400 mg chewable tablets). The every 12 hour regimen is preferred in children because it causes less diarrhea.

    Infants, Children, and Adolescents 3 months to 17 years weighing less than 40 kg (every 8 hour regimens)

    20 mg/kg/day amoxicillin component PO divided every 8 hours for mild/moderate infections and 40 mg/kg/day amoxicillin component PO divided every 8 hours for severe infections (using 125 mg/5 mL or 250 mg/5 mL suspension; 125 mg and 250 mg chewable tablets; 500 mg regular tablets). The every 12 hour regimen is preferred in children because it causes less diarrhea.

    Neonates and Infants 2 months and younger

    30 mg/kg/day amoxicillin component PO divided every 12 hours is the FDA-approved dosage. Due to limited data supporting the use of other formulations, the FDA-approved labeling states that only the 125 mg/5 mL suspension is recommended for this age group. Neonates and infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. UTIs should be treated as presumed pyelonephritis in these patients. 20 to 40 mg/kg/day amoxicillin component PO divided every 8 hours is recommended by the American Academy of Pediatrics (AAP) for the initial treatment of UTI in febrile infants 2 months and older.

    For the treatment of dental infection†, including dentoalveolar infection†, periodontitis†, and pericoronitis†.
    For adolescent aggressive periodontitis† or adult refractory chronic periodontitis† after scaling and root planing.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    250 or 500 mg PO 3 times daily for 10 days.

    Children and Adolescents

    20 to 40 mg/kg/day PO in equally divided doses given 3 times daily (Max: 500 mg/dose) for 10 days (using 125 mg/5 mL or 250 mg/5 mL suspension; 125 mg or 250 mg chewable tablets; or 500 mg regular tablets). The 250 mg regular tablets should not be used until the child reaches 40 kg.

    For pericoronitis†.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    For preoperative prophylaxis, 2 g PO single dose 1 hour before surgical intervention. If surgical intervention unable to be performed, treat suppurative acute phase pericoronitis with 2 g PO every 12 hours for 7 days.

    For the treatment of actinomycotic mycetoma† caused by susceptible strains of Nocardia brasiliensis.
    Oral dosage
    Adults

    500 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours for 5—6 months.

    For use as oral maintenance therapy in the treatment of melioidosis† due to Burkholderia pseudomallei†.
    Oral dosage
    Adults, Adolescents, Children

    Following initial parenteral treatment for melioidosis, oral maintenance therapy with amoxicillin; clavulanic acid 30 mg/kg/day divided into 3 doses is given for 3—6 months as a second-line agent in adults and as a first-line agent in children and pregnant women.

    For the empiric treatment of febrile neutropenia† in low risk patients.
    Oral dosage
    Adults

    Guidelines recommend amoxicillin; clavulanate in combination with ciprofloxacin as a first line option in low-risk patients. These recommendations are supported by several studies. Doses of 500 mg (amoxicillin component) PO every 8 hours or 1000 mg (amoxicillin component) PO twice daily have been used, with ciprofloxacin, in studies.

    For group A streptococci chronic pharyngeal carriage eradication†.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    40 mg/kg/day amoxicillin component PO divided every 8 hours (Max: 2 g/day) for 10 days. Most chronic streptococcal carriers do not need antimicrobial therapy. Treatment may be considered during a community outbreak of acute rheumatic fever, acute poststreptococcal glomerulonephritis or invasive group A streptococcal (GAS) infection; during an outbreak of GAS pharyngitis in a closed or partially closed community; in the presence of a family or personal history of acute rheumatic fever; in a family with excessive anxiety about GAS infections; or when tonsillectomy is being considered only because of carriage.

    Infants, Children, and Adolescents

    40 mg/kg/day amoxicillin component PO divided every 8 hours (Max: 2 g/day) for 10 days. Most chronic streptococcal carriers do not need antimicrobial therapy. Treatment may be considered during a community outbreak of acute rheumatic fever, acute poststreptococcal glomerulonephritis or invasive group A streptococcal (GAS) infection; during an outbreak of GAS pharyngitis in a closed or partially closed community; in the presence of a family or personal history of acute rheumatic fever; in a family with excessive anxiety about GAS infections; or when tonsillectomy is being considered only because of carriage.

    For the treatment of drug-resistant tuberculosis infection† paired with a carbapenem as part of combination therapy.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    500 mg amoxicillin with 125 mg clavulanate PO every 8 to 12 hours or 1 g amoxicillin with 250 mg clavulanate PO every 8 hours.

    Infants, Children, and Adolescents

    75 mg/kg/day amoxicillin component PO divided every 8 hours or 80 mg/kg/day amoxicillin component PO divided every 12 hours (Max: 3 g amoxicillin component/day).

    Oral dosage (extended-release tablets containing 1,000 mg amoxicillin and 62.5 mg clavulanate per tablet)
    Adults

    2,000 mg amoxicillin with 125 mg clavulanate PO every 12 hours.

    Oral dosage (ES-600; suspension containing 600 mg amoxicillin and 42.9 mg clavulanate per 5 mL)
    Infants, Children, and Adolescents

    80 mg/kg/day amoxicillin component PO divided every 12 hours (Max: 3 g amoxicillin component/day). 

    For the treatment of intraabdominal infections†, including peritonitis†, appendicitis†, intraabdominal abscess†, complicated diverticulitis†, and peritoneal dialysis catheter-related infection†.
    For the oral step-down treatment of complicated intraabdominal infections† or for the treatment of complicated diverticulitis†.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours or 500 mg amoxicillin with 125 mg clavulanate PO every 8 hours for a total treatment duration of 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    Infants, Children, and Adolescents

    40 mg/kg/day amoxicillin component (Max: 1,500 mg/day) PO divided every 8 hours for a total treatment duration of 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.

    For the treatment of peritoneal dialysis catheter-related infection†.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    875 mg amoxicillin with 125 mg clavulanate PO every 12 hours for at least 14 days to 21 days.

    For the treatment of bartonellosis†, including uncomplicated Oroya fever†.
    Oral dosage (immediate-release formulations and non-ES suspensions)
    Adults

    1 g amoxicillin with 250 mg clavulanate PO every 12 hours for 14 days with or without chloramphenicol as second-line therapy.

    Pregnant or Breast-feeding Persons

    1 g amoxicillin with 250 mg clavulanate PO every 12 hours for 14 days with or without chloramphenicol as first-line therapy.

    Infants, Children, and Adolescents

    20 mg/kg/dose amoxicillin component (Max: 1 g amoxicillin component/dose) PO every 12 hours for 14 days with or without chloramphenicol as first-line therapy.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    regular tablets, chewable tablets, or suspension: up to 1750 mg/day amoxicillin component PO; XR tablets: 4000 mg/day amoxicillin component PO depending on formulation.

    Geriatric

    regular tablets, chewable tablets, or suspension: up to 1750 mg/day amoxicillin component PO; XR tablets: 4000 mg/day amoxicillin component PO depending on formulation.

    Adolescents

    40 kg or more: regular tablets, chewable tablets, or suspension: up to 1750 mg/day amoxicillin component PO depending on formulation; XR tablets: 4000 mg/day amoxicillin component PO; ES-600 suspension: safety and efficacy have not been established; however, 90 mg/kg/day amoxicillin component PO (Max: 4000 mg/day amoxicillin component) is used off-label.
    less than 40 kg: 90 mg/kg/day amoxicillin component PO using ES-600 suspension; 40 to 45 mg/kg/day amoxicillin component PO for regular suspension and chewable tablets depending on formulation for most indications.

    Children

    40 kg or more: regular tablets, chewable tablets, or suspension: up to 1750 mg/day amoxicillin component PO depending on formulation; XR tablets: 4000 mg/day amoxicillin component PO; ES-600 suspension: safety and efficacy have not been established; however, 90 mg/kg/day amoxicillin component PO (Max: 4000 mg/day amoxicillin component) is used off-label.
    less than 40 kg: 90 mg/kg/day amoxicillin component PO using ES-600 suspension; 40 to 45 mg/kg/day amoxicillin component PO for regular suspension and chewable tablets depending on formulation for most indications.

    Infants

    3 months and older: 90 mg/kg/day amoxicillin component PO using ES-600 suspension; 40 to 45 mg/kg/day amoxicillin component PO for regular suspension depending on formulation for most indications.
    younger than 3 months: 30 mg/kg/day amoxicillin component PO.

    Neonates

    30 mg/kg/day amoxicillin component PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dose amoxicillin; clavulanic acid with caution in those patients with pre-existing hepatic disease and monitor liver function during therapy. No specific dosage adjustment recommendations are available. The amoxicillin component is not appreciably metabolized in the liver and does not undergo biliary secretion.

    Renal Impairment

    NOTE: The 875-mg tablet is not recommended in patients with renal impairment. The extended-release formulation is contraindicated in patients with a CrCl 30 mL/min or less.
     
    Adult and Pediatric Patients Weighing More Than 40 kg
    Dosage adjustments are needed for amoxicillin, but clavulanic acid pharmacokinetics are not changed by the presence of renal impairment unless CrCl is less than 10 mL/min. The manufacturer recommended dosage adjustments for adults are listed below.
    CrCl 30 mL/min or more: No dosage adjustment necessary.
    CrCl 10 to 30 mL/min: 250 to 500 mg PO amoxicillin component every 12 hours, depending on the severity of the infection.
    CrCl less than 10 mL/min: 250 to 500 mg PO amoxicillin component every 24 hours, depending on the severity of the infection.
     
    Pediatric Patients
    The following dose adjustments are based on the usual dose in pediatric patients of 20 to 40 mg/kg/day amoxicillin component PO divided every 8 hours, 25 to 45 mg/kg/day amoxicillin component PO divided every 12 hours, or 80 to 90 mg/kg/day PO divided every 12 hours (high dose; ES-600 formulation) :
    CrCl 30 mL/min/1.73 m2 or more: No dosage adjustment necessary.
    CrCl 10 to 29 mL/min/1.73 m2: 8 to 20 mg/kg/dose amoxicillin component (20 mg/kg/dose for high dose) PO every 12 hours.
    CrCl less than 10 mL/min/1.73 m2: 8 to 20 mg/kg/dose amoxicillin component (20 mg/kg/dose for high dose) PO every 24 hours.
     
    Intermittent hemodialysis
    For adults and children receiving the adult dosage, 250 to 500 mg PO amoxicillin component every 24 hours, depending on the severity of the infection. According to the manufacturer, a supplemental dose should be administered both during and at the end of a dialysis session. For pediatric patients, the recommended dose is 8 to 20 mg/kg/dose amoxicillin component (20 mg/kg/dose for high dose) PO every 24 hours, after dialysis.
     
    Peritoneal dialysis
    For adults and children receiving the adult dosage and receiving continuous ambulatory peritoneal dialysis (CAPD), 250 to 500 mg PO amoxicillin component every 24 hours, depending on the severity of the infection. For pediatric patients, the recommended dose is 8 to 20 mg/kg/dose amoxicillin component (20 mg/kg/dose for high dose) PO every 24 hours.

    ADMINISTRATION

    Oral Administration

    NOTE: The ratio of amoxicillin; clavulanic acid is not equivalent in different formulations of Augmentin (tablets, chewable tablets, extended-release tablets, and suspension). Therefore, except where noted, different dosage forms should not be interchanged.
    All dosage forms: Administer dose at the start of a meal. May be administered without regard to meals, however, oral absorption of amoxicillin and clavulanic acid are enhanced when administered at the start of a light meal. Also, administration with food minimizes gastrointestinal irritation. Avoid high-fat meals as they decrease the absorption of clavulanic acid.

    Oral Solid Formulations

    Chewable tablets: Chew well before swallowing, do not swallow whole.
    Extended-release tablets: Swallow tablet whole. Do not crush or chew. Scored extended-release tablets are available for patients who have difficulty swallowing.

    Oral Liquid Formulations

    Suspension: Shake well prior to each administration. Measure dosage with calibrated spoon, cup, or oral syringe.
    For infants < 3 months of age, the 125 mg/5 mL oral suspension is recommended by the manufacturer.
    The various suspensions of amoxicillin; clavulanic acid are not interchangeable due to differences in the amount of clavulanic acid potassium contained in each product.
     
    Reconstitution method for the oral suspension:
    Prior to reconstitution, tap the bottle several times to loosen the powder. Add approximately 2/3 of the total amount of water and shake well. Add the remainder of the water and shake well.
    Storage after reconstitution: Shake well prior to each use. Store under refrigeration. Discard any unused suspension after 10 days.

    STORAGE

    Amoclan :
    - Discard any unused reconstituted product after 10 days
    - Discard unused portion. Do not store for later use.
    - Reconstituted product is stable for 10 days when refrigerated (36 to 46 degrees F)
    - See package insert for detailed storage information
    - Store at or below 77 degrees F
    - Store reconstituted product in refrigerator (36 to 46 degrees F)
    Augmentin:
    - Discard any unused reconstituted product after 10 days
    - Store at or below 77 degrees F
    Augmentin ES:
    - Discard any unused reconstituted product after 10 days
    - Discard unused portion. Do not store for later use.
    - Reconstituted product is stable for 10 days when refrigerated (36 to 46 degrees F)
    - See package insert for detailed storage information
    - Store at or below 77 degrees F
    - Store reconstituted product in refrigerator (36 to 46 degrees F)
    Augmentin XR:
    - Store at or below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins, such as amoxicillin; clavulanic acid, and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix). Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on amoxicillin; clavulanic acid treatment.

    Asthma, carbapenem hypersensitivity, cephalosporin hypersensitivity, eczema, penicillin hypersensitivity, urticaria

    Amoxicillin is a penicillin and should not be used in patients with a penicillin hypersensitivity. Amoxicillin; clavulanic acid should be used cautiously in patients with cephalosporin hypersensitivity or carbapenem hypersensitivity. These patients are more susceptible to hypersensitivity reactions during therapy with amoxicillin; the incidence of true cross-sensitivity has been estimated at roughly 3—5%. Patients with allergies or atopic conditions including asthma, eczema, hives (urticaria), or hay fever may have a greater risk for hypersensitivity reactions to penicillins.

    Geriatric

    In clinical studies of amoxicillin; clavulanic acid (Augmentin XR and other dosage forms) no overall differences in safety and effectiveness were observed between geriatric subjects and younger adult subjects, and other clinical experience has not reported differences in responses between the elderly and younger patients. A greater sensitivity of some older individuals cannot be ruled out. Because this drug is known to be substantially excreted by the kidney and because the elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function in these patients.

    Dialysis, renal disease, renal failure, renal impairment

    Amoxicillin; clavulanic acid extended-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min), renal failure, and in hemodialysis (dialysis) patients. In general, other formulations of amoxicillin; clavulanic acid should be used with caution in patients with renal impairment or renal disease since the drug is eliminated via renal mechanisms. Adjust the dosage in patients with CrCl <= 30 mL/min and in patients with renal failure. Dosage adjustments are also recommended for patients receiving dialysis.

    C. difficile-associated diarrhea, diarrhea, pseudomembranous colitis

    Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including amoxicillin; clavulanic acid, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

    Children, infants, neonates

    Amoxicillin; clavulanic acid has been used to treat infections in infants < 3 months of age, including neonates. However, dosages must be modified for these age groups compared to infants >= 3 months of age because of incompletely developed renal function. Certain dosage forms are not for use in small children; for example, the safety and effectiveness of amoxicillin; clavulanic acid extended-release tablets and regular tablets have not been established in pediatric patients weighing less than 40 kg. Children less than 40 kg of body weight should be dosed using oral suspension or chewable tablets. Neonates and infants < 3 months should be dosed using the 125 mg/5 mL oral suspension for dosing only.

    Labor, obstetric delivery, pregnancy

    While amoxicillin; clavulanate should be used with caution in pregnancy, penicillins are usually considered safe during pregnancy when clearly needed. The effects of amoxicillin; clavulanic acid on pregnant women or the fetus during labor and obstetric delivery are unknown; however, one study in women with premature rupture of fetal membranes reported that prophylactic therapy with amoxicillin; clavulanic acid may be associated with an increased risk of necrotizing enterocolitis in the neonate. Animal data reveal no teratogenic effects; however, there are no adequate and well-controlled studies in pregnant women.

    Breast-feeding

    According to the manufacturer, amoxicillin; clavulanic acid should be used cautiously during breast-feeding. However, unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy. The American Academy of Pediatrics (AAP) considers amoxicillin a medication that is usually compatible with breast-feeding; however, amoxicillin; clavulanic acid has not been evaluated by the AAP. Amoxicillin; clavulanic acid is excreted in breast milk in small amounts. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in breast-feeding infants. In a study assessing adverse events in breast-fed infants of mothers exposed to antibiotics, 22.3% (15/67) of infants experienced adverse events after exposure to amoxicillin; clavulanic acid. The adverse events included constipation, rash, diarrhea, irritability, and elevated liver enzymes. The rate of adverse events was positively correlated with the dose of amoxicillin; clavulanic acid.. The infant should be observed for potential effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Phenylketonuria

    Amoxicillin; clavulanic acid chewable tablets contain phenylalanine in the amount of 2.1 mg per 200 mg tablet and 4.2 mg per 400 mg tablet. The 200 mg/5mL, 400 mg/5mL and 600 mg/5 mL oral suspensions of amoxicillin; clavulanic acid each contain 7 mg of phenylalanine per 5 mL. These formulations should be used cautiously in patients with phenylketonuria. Patients with phenylketonuria should be warned that these items contain phenylalanine. However, other amoxicillin; clavulanic acid formulations do not contain phenylalanine.

    Mononucleosis

    According to the manufacturer, amoxicillin; clavulanic acid should not be used in patients with mononucleosis as a high incidence of skin rashes have been reported with amoxicillin in these patients.

    Cholestasis, hepatic disease, jaundice

    Amoxicillin; clavulanic acid is contraindicated for use in any patient with a previous history of drug-induced cholestasis, jaundice, or other hepatic dysfunction induced by this combination of drugs. Amoxicillin; clavulanic acid should be used with caution in those patients with pre-existing hepatic disease. Monitor liver function in these patients during therapy. The amoxicillin component is not appreciably metabolized in the liver and does not undergo biliary secretion. However, hepatic dysfunction due to amoxicillin; clavulanic acid has been reported on rare occasions; occasionally these reactions have been severe.

    Serious rash

    Serious rash events, such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, and exfoliative dermatitis have been reported in patients receiving treatment with amoxicillin; clavulanic acid. If a skin rash occurs, monitor patients closely and discontinue amoxicillin; clavulanic acid if lesions progress.

    ADVERSE REACTIONS

    Severe

    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    C. difficile-associated diarrhea / Delayed / Incidence not known
    aseptic meningitis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    contact dermatitis / Delayed / 5.0-6.0
    candidiasis / Delayed / 3.0-6.0
    vaginitis / Delayed / 1.0-1.0
    thrombocytosis / Delayed / 0-1.0
    hematuria / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    confusion / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    diarrhea / Early / 2.0-34.0
    cough / Delayed / 7.0-12.0
    infection / Delayed / 3.0-9.0
    vomiting / Early / 1.0-8.0
    fever / Early / 4.0-6.0
    diaper dermatitis / Delayed / 5.0-6.0
    rash / Early / 3.0-3.0
    urticaria / Rapid / 3.0-3.0
    nausea / Early / 2.0-3.0
    abdominal pain / Early / 0-1.0
    flatulence / Early / 0-1.0
    headache / Early / 0-1.0
    tooth discoloration / Delayed / 0-1.0
    pruritus / Rapid / Incidence not known
    dyspepsia / Early / Incidence not known
    tongue discoloration / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    insomnia / Early / Incidence not known
    hyperactivity / Early / Incidence not known
    agitation / Early / Incidence not known
    anxiety / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Acetaminophen; Aspirin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Acetaminophen; Aspirin; Diphenhydramine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
    Amiloride: (Major) The administration of amiloride 2 hours before a dose of amoxicillin oral suspension reduced the bioavailability of amoxicillin by 27% and its Cmax by 25%. No change in the renal clearance of amoxicillin was noted. Although the significance of this pharmacokinetic interaction is unclear, clinicians should avoid administering doses of these two drugs within 2 hours of the other. Staggering the administration times further may avoid this interaction.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) The administration of amiloride 2 hours before a dose of amoxicillin oral suspension reduced the bioavailability of amoxicillin by 27% and its Cmax by 25%. No change in the renal clearance of amoxicillin was noted. Although the significance of this pharmacokinetic interaction is unclear, clinicians should avoid administering doses of these two drugs within 2 hours of the other. Staggering the administration times further may avoid this interaction.
    Aspirin, ASA: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Dipyridamole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Oxycodone: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Pravastatin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Caffeine; Sodium Benzoate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
    Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Desogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and amoxicillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including amoxicillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Digoxin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Drospirenone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Estetrol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norgestimate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethacrynic Acid: (Minor) Ethacrynic acid may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norelgestromin: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Etonogestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Furosemide: (Minor) Furosemide may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Indomethacin: (Minor) Indomethacin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Lesinurad; Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
    Leuprolide; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Mafenide: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Mestranol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Methotrexate: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
    Mycophenolate: (Moderate) Drugs that alter the gastrointestinal flora may interact with mycophenolate by disrupting enterohepatic recirculation. Amoxicillin;Clavulanic Acid may decrease normal GI flora levels and thus lead to less free mycophenolate available for absorption. The effect of amoxicillin without clavulantic acid on mycophenolate kinetics is unclear.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norethindrone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norgestimate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Probenecid: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
    Probenecid; Colchicine: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
    Pyrimethamine; Sulfadoxine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites or could displace other highly protein-bound drugs such as penicillins. An enhanced effect of the displaced drug may occur.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Sodium Benzoate; Sodium Phenylacetate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Sulfadiazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfasalazine: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfonamides: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Tetracyclines: (Minor) Consider additional monitoring or alternative antimicrobial therapy for patients with infections in which clinical response is highly dependent upon the rapid, bactericidal activity of penicillins. Bacterostatic antibacterials like tetracyclines may antagonize the bactericidal effects of penicillins which may reduce their efficacy. The clinical relevance of this interaction is poorly defined and for many infections the benefits of combination therapy are likely to outweigh the potential risks.
    Typhoid Vaccine: (Major) Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine.
    Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    While amoxicillin; clavulanate should be used with caution in pregnancy, penicillins are usually considered safe during pregnancy when clearly needed. The effects of amoxicillin; clavulanic acid on pregnant women or the fetus during labor and obstetric delivery are unknown; however, one study in women with premature rupture of fetal membranes reported that prophylactic therapy with amoxicillin; clavulanic acid may be associated with an increased risk of necrotizing enterocolitis in the neonate. Animal data reveal no teratogenic effects; however, there are no adequate and well-controlled studies in pregnant women.

    MECHANISM OF ACTION

    Amoxicillin is a semisynthetic antibacterial agent. Beta-lactam antibiotics such as amoxicillin are mainly bactericidal. Like other penicillins, amoxicillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. PBPs are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. PBPs vary among different bacterial species. Thus, the intrinsic activity of amoxicillin, as well as the other penicillins, against a particular organism depends on their ability to gain access to and bind with the necessary PBP. The aminopenicillins are able to penetrate gram-negative bacteria more readily than are the natural penicillins or penicillinase-resistant penicillins due to the presence of a free amino group within the structure. Like all beta-lactam antibiotics, amoxicillin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Prevention of the autolysin response to beta-lactam antibiotic exposure through loss of autolytic activity (mutation) or inactivation of autolysin (low-medium pH) by the microorganism can lead to tolerance to the beta-lactam antibiotic resulting in bacteriostatic activity.
     
    Clavulanic acid is a beta-lactam drug that acts as a competitive inhibitor of bacterial beta-lactamases. This protects amoxicillin from degradation and effectively extends the antibacterial spectrum of amoxicillin. It binds to the enzyme's active site, preventing the beta-lactamase from inactivating the beta-lactam antibiotic; clavulanic acid is also inactivated by this process, earning it the title "suicide" inhibitor. Clavulanic acid can bind with many plasmid- and chromosomally mediated bacterial beta-lactamases. Penetration of the cell wall allows clavulanic acid to bind both bound and extracellular beta-lactamases. Clavulanic acid does not alter the actions of the beta-lactam antibiotics.
     
    Beta-lactams exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T above MIC). This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Penicillins require free drug concentrations to exceed the MIC for 30% of the dosing interval to achieve bacteriostatic activity and 50% of the dosing interval to achieve bactericidal activity.
     
    The susceptibility interpretive criteria for amoxicillin; clavulanic acid are delineated by pathogen. The MICs are defined for Enterobacterales as susceptible at 8/4 mcg/mL or less, intermediate at 16/8 mcg/mL, and resistant at 32/16 mcg/mL or more. The MICs are defined for S. pneumoniae (excluding meningitis) as susceptible at 2/1 mcg/mL or less, intermediate a 4/2 mcg/mL, and resistant at 8/4 mcg/mL or more. The Clinical and Laboratory Standards Institute (CLSI) and the FDA differ on MIC interpretation for H. influenzae. The MICs are defined for H. influenzae by the FDA as susceptible at 4/2 mcg/mL or less and resistant at 8/4 mcg/mL or more; however, the MICs are defined for H. influenzae and H. parainfluenzae by the CLSI as susceptible at 2/1 mcg/mL or less, intermediate at 4/2 mcg/mL, and resistant at 8/4 mcg/mL or more. The MICs are defined for anaerobes as susceptible at 4/2 mcg/mL or less, intermediate at 8/4 mcg/mL, and resistant at 16/8 mcg/mL or more. The breakpoints are based on a dosage of 875 mg amoxicillin with 125 mg clavulanic acid administered every 12 hours or 500 mg amoxicillin with 125 mg clavulanic acid administered every 8 hours when used for treatment of UTIs due to Enterobacterales, completion of therapy for Enterobacterales systemic infections, and for the treatment of S. pneumoniae, H. influenzae, and H. parainfluenzae. Enterococci susceptible to penicillin are predictably susceptible to amoxicillin; clavulanic acid for non-beta-lactamase producing enterococci. Oxacillin-susceptible staphylococci and beta-hemolytic streptococci can be considered susceptible to amoxicillin; clavulanic acid.

    PHARMACOKINETICS

    Amoxicillin; clavulanic acid (clavulanate) is administered orally as tablets, chewable tablets, extended-release tablets, and oral suspension. Protein-binding is approximately 18% for amoxicillin and 25% for clavulanic acid. Amoxicillin and clavulanic acid are distributed into many tissues and body fluids including the liver, gallbladder, prostate, lungs, urine, middle ear effusions, bronchial secretions, maxillary sinus secretions, and synovial, pleural, and peritoneal fluids. Minimal levels are attained within the CSF when meninges are not inflamed; these levels are increased with inflammation. The drugs cross the placenta. Approximately 10% of an amoxicillin dose is metabolized to inactive derivatives; most (50 to 80%) of the drug is eliminated unchanged. Amoxicillin and its metabolites are primarily excreted into the urine primarily via tubular secretion and glomerular filtration. Clearance of clavulanic acid has both a renal (25 to 50%) and a non-renal component. Clavulanic acid appears to be extensively metabolized, although the exact mechanism is not fully established. A small percentage of amoxicillin; clavulanic acid is excreted in breast milk. In patients with normal renal function, the elimination half-lives of amoxicillin and clavulanic acid are roughly 1.3 hours and 1 hour, respectively.
     
    Affected cytochrome P450 isoenzymes: none.

    Oral Route

    Both amoxicillin and clavulanic acid are stable against gastric acid and are well absorbed from the GI tract. Approximately 74 to 92% of a dose of amoxicillin is absorbed. Peak serum levels of both amoxicillin and clavulanic acid occur within 1 to 2.5 hours following an oral dose of either chewable or immediate release tablets or oral suspension. Amoxicillin systemic exposure achieved with extended-release tablets is similar to that produced by the oral administration of equivalent doses of amoxicillin alone. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin; however, absorption of amoxicillin and clavulanate potassium is greater when the drugs are taken with food relative to the fasted state. High-fat meals decrease the absorption of clavulanic acid. In general, all dosage forms are recommended to be taken at the start of a standard meal.