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    Penicillinase-Resistant Penicillin Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Semisynthetic antistaphylococcal penicillin. Stable against penicillinase. Main use is for treating infections caused penicillinase-producing S. aureus, including bacteremia, skin and soft-tissue infections, respiratory tract infections, bone and joint infections, and UTIs.

    HOW SUPPLIED

    Oxacillin/Oxacillin Sodium Intramuscular Inj Pwd F/Sol: 1g, 2g, 10g
    Oxacillin/Oxacillin Sodium Intravenous Inj Pwd F/Sol: 1g, 2g, 10g
    Oxacillin/Oxacillin Sodium Intravenous Inj Sol: 1g, 2g, 50mL

    DOSAGE & INDICATIONS

    For the treatment of bacteremia, skin and skin structure infections (e.g., cellulitis), and bone and joint infections (e.g., osteomyelitis, infectious arthritis) caused by penicillinase-producing Staphylococcus sp..
    Intravenous dosage (Intermittent IV Infusion) or Intramuscular dosage
    Adults

    0.25 to 0.5 g IV or IM every 4 to 6 hours for mild to moderate infections and 1 g IV or IM every 4 to 6 hours for severe infections is the FDA-approved dosage. Alternately, 6 g/day IV or IM divided every 4 hours for moderate infections and 9 to 12 g/day IV or IM divided every 4 hours for severe infections is suggested.

    Children and Adolescents weighing 40 kg or more

    100 to 200 mg/kg/day IV or IM divided every 4 to 6 hours (Max: 12 g/day). The FDA-approved dosage is 0.25 to 0.5 g IV or IM every 4 to 6 hours for mild to moderate infections and 1 g IV or IM every 4 to 6 hours for severe infections.

    Infants, Children, and Adolescents weighing less than 40 kg

    100 to 200 mg/kg/day IV or IM divided every 4 to 6 hours. The FDA-approved dosage is 50 mg/kg/day IV or IM divided every 6 hours for mild to moderate infections and 100 mg/kg/day IV or IM divided every 4 to 6 hours for severe infections.

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IV or IM every 6 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV or IM.

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IV or IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV or IM.

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IV or IM every 8 hours is recommended by the American Academy of Pediatrics (AAP).  The FDA-approved dosage for all neonates is 25 mg/kg/day IV or IM.

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IV or IM every 12 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV or IM.

    Intravenous dosage (Continuous IV Infusion)†
    Adults

    12 g/day continuous IV infusion. In a retrospective review of patients with MSSA infective endocarditis, oxacillin continuous IV infusion (CI) over 24 hours (n = 78) was compared to intermittent infusion (II) oxacillin (n = 28). The 30-day mortality (8% CI vs. 10% II, p = 0.7) and length of stay (20 days CI vs. 25 days II, p = 0.4) were similar between groups; however, data suggest an improved 30-day microbiological cure with CI (94% CI vs. 79% II, p = 0.03).[42284] In another retrospective review of burn patients with cellulitis, 26 patients CI oxacillin. A treatment success rate of 73% with CI oxacillin was comparable to 11 patients who received other antibiotic regimens (75%); however, the treatment course with CI oxacillin was shorter (5.16 days CI oxacillin vs. 6.45 days).[42285]

    For the treatment of infective endocarditis.
    Intravenous dosage (Intermittent IV Infusion)
    Adults

    12 g/day IV divided every 4 to 6 hours is recommended by guidelines. The FDA-approved dosage for severe infections is 1 g IV every 4 to 6 hours. Guidelines recommend oxacillin for 6 weeks for uncomplicated left-sided native valve endocarditis (NVE) and for at least 6 weeks for complicated left-sided NVE due to methicillin-susceptible S. aureus. For MSSA prosthetic valve endocarditis (PVE), treat with oxacillin plus rifampin for at least 6 weeks; add gentamicin for the first 2 weeks.

    Children and Adolescents weighing 40 kg or more

    200 mg/kg/day IV divided every 4 to 6 hours (Max: 12 g/day) is recommended by guidelines. The FDA-approved dosage for severe infections is 1 g IV every 4 to 6 hours. Oxacillin is an alternative therapy for penicillin-susceptible staphylococcal native valve endocarditis (NVE). Oxacillin is a preferred therapy for penicillin-resistant, methicillin-sensitive S. aureus (MSSA) NVE; may consider adding gentamicin for the first 3 to 5 days. Treat NVE for at least 4 to 6 weeks. For MSSA prosthetic valve endocarditis (PVE), treat with nafcillin plus rifampin for 6 weeks; add gentamicin for the first 2 weeks.

    Children and Adolescents weighing less than 40 kg

    200 mg/kg/day IV divided every 4 to 6 hours (Max: 12 g/day) is recommended by guidelines. The FDA-approved dosage for severe infections is 100 mg/kg/day IV divided every 4 to 6 hours. Oxacillin is an alternative therapy for penicillin-susceptible staphylococcal native valve endocarditis (NVE). Oxacillin is a preferred therapy for penicillin-resistant, methicillin-sensitive S. aureus (MSSA) NVE; may consider adding gentamicin for the first 3 to 5 days. Treat NVE for at least 4 to 6 weeks. For MSSA prosthetic valve endocarditis (PVE), treat with nafcillin plus rifampin for 6 weeks; add gentamicin for the first 2 weeks.

    Infants

    100 to 200 mg/kg/day IV divided every 4 to 6 hours. The FDA-approved dosage is 100 mg/kg/day IV divided every 4 to 6 hours for severe infections.

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IV every 6 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IV every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IV every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IV every 12 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Intravenous dosage (Continuous IV Infusion)†
    Adults

    12 g/day continuous IV infusion. In a retrospective review of patients with MSSA infective endocarditis, oxacillin continuous IV infusion (CI) over 24 hours (n = 78) was compared to intermittent infusion (II) oxacillin (n = 28). The 30-day mortality (8% CI vs. 10% II, p = 0.7) and length of stay (20 days CI vs. 25 days II, p = 0.4) were similar between groups; however, data suggest an improved 30-day microbiological cure with CI (94% CI vs. 79% II, p = 0.03).[42284]

    For the treatment of bacterial meningitis.
    Intravenous dosage
    Adults

    2 g IV every 4 hours is recommended by guidelines for methicillin-sensitive S. aureus meningitis. The FDA-approved dosage for severe infections is 1 g IV every 4 to 6 hours.

    Infants, Children, and Adolescents weighing 40 kg or more

    200 mg/kg/day IV divided every 6 hours (Max: 12 g/day) is recommended for methicillin-sensitive S. aureus meningitis by guidelines. The FDA-approved dosage for severe infections is 1 g IV every 4 to 6 hours.

    Infants, Children, and Adolescents weighing less than 40 kg

    200 mg/kg/day IV divided every 6 hours (Max: 12 g/day) is recommended for methicillin-sensitive S. aureus meningitis by guidelines. The FDA-approved dosage for severe infections is 100 mg/kg/day IV divided every 4 to 6 hours.

    Neonates older than 7 days weighing more than 2 kg

    50 mg/kg/dose IV every 6 hours is suggested. Alternately, guidelines recommend 150 to 200 mg/kg/day IV divided every 6 to 8 hours for methicillin-sensitive S. aureus meningitis. The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Neonates older than 7 days weighing 2 kg or less

    50 mg/kg/dose IV every 8 hours is suggested. The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Neonates 0 to 7 days weighing more than 2 kg

    50 mg/kg/dose IV every 8 hours is suggested. Alternately, guidelines recommend 75 mg/kg/day IV divided every 8 to 12 hours. The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    Neonates 0 to 7 days weighing 2 kg or less

    50 mg/kg/dose IV every 12 hours is suggested. The FDA-approved dosage for all neonates is 25 mg/kg/day IV.

    For the treatment of lower respiratory tract infections (LRTIs), including community-acquired pneumonia (CAP).
    For the treatment of nonspecific lower respiratory tract infections (LRTIs).
    Intravenous or Intramuscular dosage
    Adults

    250 to 500 mg IV or IM every 4 to 6 hours for mild to moderate infections and 1 g IV or IM every 4 to 6 hours for severe infections is the FDA-approved dose. Alternately, 6 g/day IV or IM divided every 4 hours for moderate infections and 9 to 12 g/day IV or IM divided every 4 hours for severe infections is suggested.

    Children and Adolescents weighing 40 kg or more

    150 to 200 mg/kg/day IV or IM divided every 4 to 6 hours (Max: 2 g/dose). The FDA-approved dose is 250 to 500 mg IV or IM every 4 to 6 hours for mild to moderate infections and 1 g IV or IM every 4 to 6 hours for severe infections.

    Infants, Children, and Adolescents weighing less than 40 kg

    150 to 200 mg/kg/day IV or IM divided every 4 to 6 hours (Max: 2 g/dose).[63245] The FDA-approved dose is 50 mg/kg/day IV or IM divided every 6 hours for mild to moderate infection and 100 mg/kg/day IV or IM divided every 4 to 6 hours for severe infections.[46797]

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IV or IM every 6 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose is 25 mg/kg/day IV or IM.

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IV or IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose is 25 mg/kg/day IV or IM.

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IV or IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose for all neonates is 25 mg/kg/day IV or IM.

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IV or IM every 12 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose for all neonates is 25 mg/kg/day IV or IM.

    For the treatment of community-acquired pneumonia (CAP).
    Intravenous or Intramuscular dosage
    Infants 4 to 11 months, Children, and Adolescents

    150 to 200 mg/kg/day IV or IM divided every 4 to 8 hours (Max: 2 g/dose) for 10 days. Guidelines recommend a semisynthetic penicillin for hospitalized patients with infections due to methicillin-susceptible S. aureus.

    For the treatment of mastitis.
    Intravenous dosage
    Adults

    1 to 2 g IV every 4 hours for 10 to 14 days.

    For the treatment of neonatal mastitis.
    Intravenous dosage
    Infants 1 to 2 months

    100 to 200 mg/kg/day IV divided every 4 to 6 hours.

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IV every 6 hours.

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IV every 12 hours.

    MAXIMUM DOSAGE

    Adults

    6 g/day IV/IM is the FDA-approved dosage; however, 12 g/day IV/IM has been used off-label.

    Geriatric

    6 g/day IV/IM is the FDA-approved dosage; however, 12 g/day IV/IM has been used off-label.

    Adolescents

    weight 40 kg or more: 6 g/day IV/IM is the FDA-approved dosage; however, up to 200 mg/kg/day IV/IM (Max: 12 g/day) has been used off-label.
    weight less than 40 kg: 100 mg/kg/day IV/IM is the FDA-approved dosage; however, up to 200 mg/kg/day IV/IM has been used off-label.

    Children

    weight 40 kg or more: 6 g/day IV/IM is the FDA-approved dosage; however, up to 200 mg/kg/day IV/IM (Max: 12 g/day) has been used off-label.
    weight less than 40 kg: 100 mg/kg/day IV/IM is the FDA-approved dosage; however, up to 200 mg/kg/day IV/IM has been used off-label.

    Infants

    100 mg/kg/day IV/IM is the FDA-approved dosage; however, up to 200 mg/kg/day IV/IM has been used off-label.

    Neonates

    25 mg/kg/day IV/IM is FDA-approved for all neonates; however, the following doses have been used off-label:
    older than 7 days weighing more than 2 kg: up to 200 mg/kg/day IV/IM.
    older than 7 days weighing 2 kg or less: up to 150 mg/kg/day IV/IM.
    0 to 7 days weighing more than 2 kg: up to 150 mg/kg/day IV/IM.
    0 to 7 days weighing 2 kg or less: up to 100 mg/kg/day IV/IM.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. However, oxacillin is significantly eliminated by the kidneys and dosage adjustments may be necessary in patients with renal impairment.

    ADMINISTRATION

     
    NOTE: For severe infections, a 4-hour dosing interval is recommended to avoid subtherapeutic serum concentrations at the end of the dosing interval.

    Injectable Administration

    Oxacillin may be administered intramuscularly (IM) or by intermittent IV injection or infusion.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Direct IV Push:
    Vials: To provide a solution containing 50 mg/mL reconstitute 250 mg with 5 mL of Sterile Water for Injection, 0.45% Sodium Chloride Injection, or 0.9% Sodium Chloride Injection. To provide a solution containing 100 mg/mL reconstitute 500 mg, 1 g, 2 g, 4 g with 5, 10, 20, or 40 mL, respectively, of Sterile Water for Injection, 0.45% Sodium Chloride Injection, or 0.9% Sodium Chloride Injection. Vigorously shake vials until solution is clear.
    Inject appropriate dose slowly directly into a vein over 10 minutes. To minimize vein irritation, inject as slowly as possible.
    Intermittent IV infusion:
    Vials: The reconstituted powder (see Direct Intermittent above) may be further diluted to concentrations of 0.5 to 40 mg/mL with a compatible IV solution. For peripheral vein infusion, a concentration of <= 20 mg/mL is preferred to help lessen the possibility of phlebitis, unless fluid restrictions are necessary for the patient.
    Pharmacy bulk packages: reconstitute 10 grams with 93 mL of Sterile Water for Injection to give a concentration of 100 mg/mL. Withdraw appropriate dose and further dilute as recommended in a compatible IV solution.
    Frozen bags: Thaw at room temperature. Do not force thaw. No reconstitution necessary.
    ADD-Vantage vials: for IV infusion only. Reconstitute only with 0.9% Sodium Chloride Injection or 5% Dextrose Injection in the appropriate flexible diluent container.
    Infuse appropriate dose at a rate to ensure that the entire dose is given before 10% or more of the drug is inactivated by the IV solution. Because oxacillin may cause phlebitis, slow IV infusion is recommended; many infuse the drug over a 1 hour administration time. Care should particularly be taken with the elderly and with peripheral vein infusion.
    Continuous IV infusion:
    In one study, 10 g of oxacillin was mixed in 500 mL of 5% Dextrose Injection. The dose, 12 g/day continuous IV infusion, was administered at a rate of 500 mg/hour (25 mL/hour) via a peripheral or central venous catheter.

    Intramuscular Administration

    Vials: Reconstitute 250 mg, 500 mg, 1 g, 2 g, 4 g with 1.4, 2.8, 5.7, 11.4, or 21.8 mL, respectively, of Sterile Water for Injection, 0.45% Sodium Chloride Injection, or 0.9% Sodium Chloride Injection to give a concentration of 167 mg/mL (250 mg/1.5 mL). Vigorously shake vials until solution is clear.
    Inject deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh). Care should be taken to avoid sciatic nerve injury.

    STORAGE

    Generic:
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins and using Benedict's solution, Fehling's solution and Clinitest(R) tablets. However, this has not been observed with Tes-tape (glucose Enzymatic Test Strip, USP, Lilly).
     
    Antibiotic therapy can result in superinfection or suprainfection of non-susceptible organisms. Overgrowth of non susceptible organisms can occur with penicillin therapy. Patients should be monitored closely during therapy.

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

    Oxacillin, a penicillin, should not be used in patients with penicillin hypersensitivity. Oxacillin should be used cautiously in patients with carbapenem hypersensitivity, or cephalosporin hypersensitivity. These patients are more susceptible to hypersensitivity reactions during oxacillin therapy. Patients with allergies or allergic conditions including asthma, eczema, hives, or hay fever may have a greater risk for hypersensitivity reactions to penicillins.

    Electrolyte imbalance, heart failure, hypertension

    Use oxacillin cautiously in patients with fluid and electrolyte imbalance and those who are particularly sensitive to sodium intake (e.g., patients with heart failure or hypertension). The amount of sodium and/or potassium can vary between oxacillin products. For example, oxacillin injection by Baxter Healthcare contains 92.4 mg (4.02 mEq) of sodium per gram. At the usual recommended doses, patients would receive between 92.4 and 554 mg/day (4.02 and 24.1 mEq) of sodium. The elderly may respond to sodium loading with a blunted natriuresis which may be clinically important in regard to such diseases as congestive heart failure. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    Renal failure, renal impairment

    Oxacillin should be used cautiously in patients with renal impairment because it is known to be substantially excreted by the kidney. The risk of adverse reactions to this drug may be greater in patients with renal dysfunction. Seizures are possible if excessively large doses are administered to patients with renal failure.

    Hepatic disease

    Hepatotoxicity has been associated with oxacillin therapy. Oxacillin should be used cautiously in patients with preexisting hepatic disease.

    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 oxacillin, 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.

    Pregnancy

    Use of penicillins in human pregnancy has not shown any evidence of harmful effects on the fetus. Animal data have also not demonstrated any evidence of impaired fertility or harmful fetal effects. However, there are no adequate and well-controlled studies in pregnant women showing conclusively that harmful effects of penicillins on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, oxacillin should be used in pregnant women only if clearly needed.

    Infants, neonates

    Oxacillin should be used with caution in neonates and infants. Transient hematuria, albuminuria, and azotemia have been reported in neonates and infants receiving large doses of oxacillin (150—175 mg/kg/day).

    Breast-feeding

    Penicillins are excreted in breast milk. Use caution when oxacillin is administered to a breast-feeding woman. After oral doses of oxacillin, concentrations in breast milk ranged from 0.04 to 0.68 mg/L. After IV or IM doses of oxacillin, concentrations in breast milk ranged from 0.18 to 0.68 mg/L. In a study in which 10 women received 3 g/day of oxacillin orally for 5 to 6 days, oxacillin was detectable in the urine in 5 of the 6 breast-fed infants with concentrations ranging from 0.2 to 3.7 mg/L. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in breast-feeding infants. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy; the infant should be observed for potential effects.

    Geriatric

    Because geriatric patients are more likely to have decreased renal function, care should be taken in oxacillin dose selection, and it may be useful to monitor renal function. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities. According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    ADVERSE REACTIONS

    Severe

    serum sickness / Delayed / 0-5.0
    interstitial nephritis / Delayed / 0-1.0
    renal tubular necrosis / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-0.1
    laryngospasm / Rapid / 0-0.1
    laryngeal edema / Rapid / 0-0.1
    angioedema / Rapid / 0-0.1
    bronchospasm / Rapid / 0-0.1
    anaphylactoid reactions / Rapid / 0-0.1
    C. difficile-associated diarrhea / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 1.0-10.0
    hepatitis / Delayed / 1.0-10.0
    stomatitis / Delayed / 2.0-5.0
    neutropenia / Delayed / 0-1.0
    hypotension / Rapid / 0-0.1
    proteinuria / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    superinfection / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / 0-5.0
    myalgia / Early / 0-5.0
    fever / Early / 0-5.0
    rash / Early / 0-5.0
    malaise / Early / 0-5.0
    pruritus / Rapid / 0-5.0
    tongue discoloration / Delayed / 2.0-5.0
    diarrhea / Early / 2.0-5.0
    nausea / Early / 2.0-5.0
    vomiting / Early / 2.0-5.0
    abdominal pain / Early / 2.0-5.0
    urticaria / Rapid / Incidence not known
    injection site reaction / Rapid / 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; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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.
    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; Dihydrocodeine: (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.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and oxacillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including oxacillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    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.
    Erythromycin; Sulfisoxazole: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    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.
    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.
    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.
    Methotrexate: (Major) Penicillins may reduce the renal clearance of methotrexate. Increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with concurrent administration of high or low doses of methotrexate and penicillins. Patients should be carefully monitored while receiving this combination.
    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 oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    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.
    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 oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfasalazine: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfisoxazole: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Sulfonamides: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Tetracyclines: (Major) Avoid the coadministration of tetracycline antibiotics with penicillins as tetracyclines may interfere with the bactericidal action of penicillins.
    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

    Use of penicillins in human pregnancy has not shown any evidence of harmful effects on the fetus. Animal data have also not demonstrated any evidence of impaired fertility or harmful fetal effects. However, there are no adequate and well-controlled studies in pregnant women showing conclusively that harmful effects of penicillins on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, oxacillin should be used in pregnant women only if clearly needed.

    Penicillins are excreted in breast milk. Use caution when oxacillin is administered to a breast-feeding woman. After oral doses of oxacillin, concentrations in breast milk ranged from 0.04 to 0.68 mg/L. After IV or IM doses of oxacillin, concentrations in breast milk ranged from 0.18 to 0.68 mg/L. In a study in which 10 women received 3 g/day of oxacillin orally for 5 to 6 days, oxacillin was detectable in the urine in 5 of the 6 breast-fed infants with concentrations ranging from 0.2 to 3.7 mg/L. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in breast-feeding infants. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy; the infant should be observed for potential effects.

    MECHANISM OF ACTION

    Oxacillin, a beta-lactam antibiotic, is mainly bactericidal. It 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 cell wall synthesis 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 oxacillin and other beta-lactams against a particular organism depends on their ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, oxacillin'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.[51465]
     
    Oxacillin, because of its side chain, resists destruction by beta-lactamases. This makes it useful for treating bacteria that resist penicillin due to the presence of penicillinase. Oxacillin is ineffective, however, against methicillin-resistant S. aureus (MRSA). These organisms appear to resist oxacillin and related antistaphylococcal penicillins due to the presence of a relatively insensitive PBP, although this mechanism is not fully understood.[53205]
     
    Beta-lactams, including oxacillin, 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).[34143] [34145] [35436] [35437] [35438] [35439] 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.[35439] 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.[35436] [35437] [35438]
     
    The susceptibility interpretive criteria for oxacillin are delineated by pathogen. The MICs are defined for S. aureus and S. lugdunensis as susceptible at 2 mcg/mL or less and resistant at 4 mcg/mL or more. The MICs are defined for other Staphylococcus sp. as susceptible at 0.5 mcg/mL or less and resistant at 1 mcg/mL or more. [63320] [63321]

    PHARMACOKINETICS

    Oxacillin is administered orally, intravenously, and intramuscularly. Protein binding ranges from 89—94%. Oxacillin is distributed into lungs; bone; bile; sputum; and pleural, pericardial, peritoneal, and synovial fluids. Low levels are attained within the CSF; however, higher concentrations are obtained when the meninges are inflamed. Oxacillin does cross the placenta. Between 45—50% of a dose is metabolized by the liver to active and inactive metabolites. Oxacillin and its metabolites are excreted primarily in the urine via tubular secretion and glomerular filtration. A small percentage may be excreted in breast milk. The elimination half-life of oxacillin is approximately 30 minutes.

    Oral Route

    Approximately 30% of an oral oxacillin dose is absorbed. Peak serum levels of oxacillin occur within 30—120 minutes following an oral dose. Food in the stomach inhibits the rate and extent of absorption, and oxacillin therefore should be taken on an empty stomach, preferably 1 hour prior to or 2 hours following a meal.

    Intramuscular Route

    Peak serum levels of oxacillin occur within 30 minutes following an IM dose.