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  • CLASSES

    1st Generation Cephalosporin Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral first-generation cephalosporin. Compared to other first-generation cephalosporins cefazolin has greater gram-positive coverage, requires less frequent dosing, and achieves higher blood levels after IM/IV administration .

    COMMON BRAND NAMES

    Ancef, Kefzol

    HOW SUPPLIED

    Ancef/Cefazolin/Cefazolin Sodium/Kefzol Intramuscular Inj Pwd F/Sol: 1g, 10g, 20g, 500mg
    Ancef/Cefazolin/Cefazolin Sodium/Kefzol Intravenous Inj Pwd F/Sol: 1g, 2g, 10g, 20g, 500mg
    Cefazolin Sodium, Dextrose/Cefazolin, Dextrose Intravenous Inj Sol: 20-4g

    DOSAGE & INDICATIONS

    For the treatment of upper respiratory tract infections, lower respiratory tract infections (e.g. pneumonia), skin and skin structure infections, bone and joint infections, and biliary tract infections caused by susceptible organisms.
    Intravenous or Intramuscular dosage
    Adults

    For mild infections, 250—500 mg IM or IV every 8 hours. For moderate to severe infections, 500—1000 mg IM or IV every 6 to 8 hours. Maximum dose is 12 g/day.

    Infants, Children, and Adolescents


    25—50 mg/kg/day IV or IM divided every 8 hours for mild to moderate infections; 100 mg/kg/day IV or IM divided every 8 hours (Max: 6 g/day) for severe infections.

    Premature and Term Neonates 8—28 days and weighing > 2 kg†

      25 mg/kg/dose IV or IM every 8 hours.

    Premature Neonates < 29 days and weighing <= 2 kg† and Term Neonates <= 7 days†

      25 mg/kg/dose IV or IM every 8 hours.

    For the treatment of urinary tract infection (UTI).
    For treatment of a complicated urinary tract infection (UTI).
    Intramuscular or Intravenous dosage
    Adults

    For mild infection with gram-positive cocci: 250—500 mg IM or IV every 8 hours. For moderate to severe infection: 500—1000 mg IM or IV every 6 to 8 hours. Maximum dose is 12 g/day.

    Infants > 1 month, Children, and Adolescents

    For mild to moderate infections, 50 mg/kg/day IM or IV divided every 8 hours. For severe infections, 75—100 mg/kg/day IM or IV divided every 6—8 hours. Maximum dose is 6 g/day.

    Neonates > 7 days and > 2000 g†

    60 mg/kg/day IM or IV divided every 8 hours.

    Premature Neonates and Neonates > 7 days and <= 2000 g†

    40 mg/kg/day IM or IV divided every 12 hours.

    Premature Neonates and Neonates <= 7 days (all weights)†

    40 mg/kg/day IM or IV divided every 12 hours.

    For treatment of an uncomplicated urinary tract infection (UTI).
    Intramuscular or Intravenous dosage
    Adults

    1 g IM or IV every 12 hours.

    Infants > 1 month, Children, and Adolescents

    25—50 mg/kg/day IM or IV in 3—4 equally divided doses. Maximum dose is 6 g/day.

    For the treatment of endocarditis or septicemia.
    Intramuscular or Intravenous dosage
    Adults

    1—1.5 g IV or IM every 6 hours. A maximum dose of 12 g/day has been used rarely in severe, life threatening infections. Clinical practice guidelines recommend 2 g IV every 8 hours for the treatment of native or prosthetic valve staphylococcal endocarditis (oxacillin-susceptible strains) in penicillin-allergic (nonanaphylactoid-type) patients. For native valve infections, the duration of treatment is 6 weeks with the optional addition of 3—5 days of gentamicin. For prosthetic valve infections, the duration of treatment is >= 6 weeks with the addition of rifampin for >= 6 weeks and gentamicin for the initial 2 weeks of treatment.

    Infants > 1 month, Children, and Adolescents

    100 mg/kg/day IV or IM divided every 8 hours (Max: 6 g/day). A maximum dose of 12 g/day has been used rarely in severe, life-threatening infections. Cefazolin is recommended for the treatment of native or prosthetic valve staphylococcal endocarditis (oxacillin-susceptible strains) in penicillin-allergic (nonanaphylactoid-type) patients.

    Premature and Term Neonates 8—28 days and weighing > 2 kg†

    25 mg/kg/dose IV or IM every 8 hours.

    For surgical infection prophylaxis.
    For ophthalmic surgical infection prophylaxis†.
    Intraocular dosage
    Adults

    100 mg by subconjunctival injection or 1 to 2.5 mg by intracameral injection is optional at the end of the procedure. Perioperative antisepsis with povidone-iodine is recommended. The necessity of continuing topical antimicrobials postoperatively has not been established.

    Intramuscular or Intravenous dosage
    Adults

    1 g IM or IV or 2 g IV as a single dose within 30 to 60 minutes prior to the surgical incision. For lengthy operations (e.g., 2 hours or longer), additional doses of 0.5 to 1 g IM or IV may be given during the procedure and postoperatively every 6 to 8 hours for 24 hours. Where the occurrence of infection may be particularly devastating (e.g. open-heart surgery, prosthetic arthroplasty), prophylaxis may be continued for up to 3 to 5 days. Clinical practice guidelines suggest 2 g IV, and for patients weighing 120 kg or more, 3 g IV. For gynecologic procedures, the American College of Obstetricians and Gynecologists (ACOG) recommends 1 g IV, and for women with a body mass index (BMI) more than 35 or weight more than 100 kg, 2 g IV. Intraoperative redosing 4 hours from the first preoperative dose and duration of prophylaxis less than 24 hours for most procedures is suggested by clinical practice guidelines. A longer prophylaxis duration of 48 hours for certain cardiothoracic procedures is controversial. Cefazolin is FDA-approved for contaminated or potentially contaminated procedures, including vaginal hysterectomy and cholecystectomy in high-risk patients, as well as in surgical patients in whom infection at the operative site would present a serious risk (e.g. open-heart surgery, prosthetic arthroplasty). Clinical practice guidelines recommend cefazolin monotherapy for cardiothoracic, gastrointestinal, biliary tract, hernia repair, clean head and neck with prosthesis, neurosurgical, urogynecology, orthopedic, vascular, certain transplantation, and plastic surgery procedures. Cefazolin is recommended as part of combination therapy for appendectomy, obstructed GI, colorectal, clean-contaminated head and neck, and urologic with prosthesis or clean-contaminated procedures.

    Infants†, Children†, and Adolescents†

    30 mg/kg IM or IV as a single dose (Max: 2 g/dose) within 60 minutes prior to the surgical incision. Repeat dose intraoperatively 4 hours after preoperative dose if surgery still in progress. Depending on the procedure, 30 mg/kg/dose (Max: 2 g/dose) IV may be given postoperatively every 8 hours for 24 hours. A longer prophylaxis duration of 48 hours for certain cardiothoracic procedures is controversial.

    Neonates†

    30 mg/kg IM or IV as a single dose within 60 minutes prior to the surgical incision is reasonable based on the usual dose for neonates and surgical prophylaxis recommendations in other populations.

    For the treatment of prostatitis and epididymitis due to susceptible organisms .
    Intravenous and Intramuscular dosage
    Adults

    For mild infections, 250—500 mg IM or IV every 8 hours. For moderate to severe infections, 500—1000 mg IM or IV every 6 to 8 hours. Maximum dose is 12 g/day. The CDC does not recommend for the treatment of sexually transmitted epididymitis.

    Infants, Children, and Adolescents

    25—50 mg/kg/day IV or IM divided every 8 hours for mild to moderate infections; 100 mg/kg/day IV or IM divided every 8 hours (Max: 6 g/day) for severe infections. The CDC does not recommend for the treatment of sexually transmitted epididymitis.

    Premature and Term Neonates 8—28 days and weighing > 2 kg†

    25 mg/kg/dose IV or IM every 8 hours.

    Premature Neonates < 29 days and weighing <= 2 kg† and Term Neonates <= 7 days†

    25 mg/kg/dose IV or IM every 12 hours.

    For bacterial endocarditis prophylaxis†.
    NOTE: Cardiac conditions which are considered having the highest risk of adverse outcomes from endocarditis and in which prophylaxis is considered reasonable by The American Heart Association (AHA) guidelines include prosthetic cardiac valve or prosthetic material used for cardiac valve repair, cardiac transplantation recipients who develop cardiac valvulopathy, and congenital heart disease (CHD). The only CHD conditions for which endocarditis prophylaxis is recommended consist of: unrepaired cyanotic CHD, including palliative shunts and conduits; completely repaired congenital heart defects with prosthetic material or device during the first 6 months after the procedure; or repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device.
    For bacterial endocarditis prophylaxis† in cardiac patients who are unable to take oral medications, are allergic to amoxicillin, ampicillin, and penicillin, and are undergoing dental procedures that involve: manipulation of either gingival tissue or the periapical region of teeth or perforation of the oral mucosa; invasive procedures of the respiratory tract that involve incision or biopsy of the respiratory mucosa (i.e., tonsillectomy and adenoidectomy); procedures that involve infected skin, skin structure, or musculoskeletal tissue; or genitourinary/gastrointestinal procedures in patients that have an established genitourinary/gastrointestinal infection.
    NOTE: AHA guidelines do not recommend endocarditis prophylaxis: for patients with moderate cardiac risk factors; for general procedures of the respiratory tract, including bronchoscopy, unless there is incision of the respiratory tract mucosa; solely to prevent endocarditis in genitourinary/gastrointestinal procedures, including diagnostic esophagogastroduodenoscopy or colonoscopy (patients with an established genitourinary/gastrointestinal infection may be reasonable candidates).
    NOTE: Do not use cephalosporins in patients with immediate-type hypersensitivity reaction to penicillins.
    Intramuscular or Intravenous dosage
    Adults and Adolescents unable to take oral medications

    1 g IM or IV within 30 minutes before procedure.

    Infants > 1 month and Children unable to take oral medications

    50 mg/kg (up to 1 g) IM or IV within 30 minutes before procedure.

    For perinatal Group B streptococcal bacterial infection prophylaxis† in patients allergic to penicillin.
    Intravenous dosage
    Pregnant adult females

    At the time of labor or rupture of membranes, intrapartum doses of 2 g IV then 1 g IV every 8 hours should be administered until delivery in patients allergic to penicillin. Penicillin is the agent of choice for preventing Group B streptococcal disease. Antibiotics administered for at least 4 hours before delivery have been found to be highly effective at preventing the transmission of Group B Streptococcus.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    12 g/day IV.

    Elderly

    12 g/day IV.

    Adolescents

    12 g/day IV.

    Children

    100 mg/kg/day IV, not to exceed 6 g/day IV for most indications; 2 g single dose max IV.

    Infants

    > 1 month: See individualized weight-based dosing by indication.
    <= 1 month: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Cefazolin is primarily eliminated by the kidneys and is not metabolized by the liver. No dosage adjustments are required in patients with hepatic impairment.

    Renal Impairment

    Adults:
    CrCl > 54 mL/min: no dosage adjustment needed.
    CrCl 35—54 mL/min: reduce frequency to at least every 8 hours.
    CrCl 11—34 mL/min: after a loading dose, reduce maintenance dose by 50% and administer every 12 hours.
    CrCl < 10 mL/min: after a loading dose, reduce the recommended dose by 50% and administer every 18—24 hours.
     
    Children:
    CrCl > 70 mL/min: no dosage adjustment needed.
    CrCl 40—70 mL/min: after an initial loading dose, reduce maintenance dose to 7.5—30 mg/kg IM or IV and administer every 12 hours.
    CrCl 20—39 mL/min: after an initial loading dose, reduce maintenance dose to 3.125—12.5 mg/kg IM or IV and administer every 12 hours.
    CrCl 5—19 mL/min: after an initial loading dose, reduce maintenance dose to 2.5—10 mg/kg IM or IV and administer every 24 hours.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Vials: Reconstitute powder with Sterile Water for Injection. Use 2 mL for 500 mg vial (resultant concentration = 225 mg/mL) and 2.5 mL for 1 g vial (resultant concentration = 330 mg/mL).
    Storage: Reconstituted solutions are stable for 24 hours at room temperature or for 10 days if stored under refrigeration. Reconstituted solutions may range in color from pale yellow to yellow without a change in potency.
    Pharmacy bulk package: Reconstitute 10 g vial with 45 mL or 96 mL of Sterile Water for Injection, Bacteriostatic Water for Injection, or 0.9% Sodium Chloride Injection for a resultant concentration of 200 mg/mL and 100 mg/mL, respectively. Reconstitute 20 g vial with 87 mL of diluent for a resultant concentration of 200 mg/mL.
    Storage: Bulk vials should be used within 4 hours of initial entry.
    ADD-Vantage vials: Should only be reconstituted in 50 or 100 mL flexible containers with 0.9% Sodium Chloride Injection or 5% Dextrose Injection. ADD-Vantage vials are not to be used for direct IV injection or IM injection.
    Storage: ADD-Vantage vials should be reconstituted immediately before administration; however, the solution is stable for 24 hours at room temperature.
     
    Dilution:
    Intermittent IV injection: Further dilute the reconstituted solution with Sterile Water for Injection to a maximum concentration of 100 mg/mL for direct injection.
    Intermittent IV infusion: Further dilute the reconstituted solution in compatible IV solution to a concentration of 10 to 20 mg/mL.
     
    Thawing Frozen Pre-mixed Bags:
    Frozen GALAXY bags: Thaw frozen container at room temperature or under refrigeration. Do not force thaw by immersion in water baths or by microwave irradiation.
    Storage: The thawed solution remains stable for 30 days under refrigeration or for 48 hours at room temperature. Do not refreeze.
     
    Intermittent IV Injection:
    Inject IV over 3 to 5 minutes.
     
    Intermittent IV Infusion:
    Infuse IV over 10 to 60 minutes.

    Intramuscular Administration

    Reconstitution:
    Reconstitute powder with Sterile Water for Injection. Use 2 mL for 500 mg vial (resultant concentration = 225 mg/mL) and 2.5 mL for 1 g vial (resultant concentration = 330 mg/mL). Reconstituted solutions may range in color from pale yellow to yellow without a change in potency.
    Storage: Reconstituted solution is stable for 24 hours at room temperature or for 10 days refrigerated.
     
    Intramuscular Injection
    Inject deeply into a large muscle. Aspirate to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Discard unused portion. Do not store for later use.
    - Do not refreeze
    - Store frozen product at or below -4 degrees F
    Ancef:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Reconstituted product is stable for 10 days when refrigerated (36 to 46 degrees F)
    - Reconstituted product is stable for 24 hours at room temperature
    - Store unreconstituted product at 68 to 77 degrees F
    Kefzol:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Reconstituted product is stable for 10 days when refrigerated (36 to 46 degrees F)
    - Reconstituted product is stable for 24 hours at room temperature
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Cefazolin may interfere with certain HPLC techniques and effect theophylline serum concentration measurements.
     
    A false-positive reaction for glucose in the urine has been observed in patients receiving cephalosporins, such as cefazolin, 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 cefazolin treatment.
     
    A positive direct Coombs test may develop in some patients. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs test of newborns whose mothers received cefazolin before delivery, clinicians should keep in mind that a positive Coombs test may be due to the drug.

    Antimicrobial resistance, viral infection

    Cefazolin does not treat viral infection (e.g., common cold). Prescribing in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (antimicrobial resistance). Patients should be told to complete the full course of treatment, even if they feel better earlier.

    Cephalosporin hypersensitivity, penicillin hypersensitivity

    Cefazolin is contraindicated in patients with cephalosporin hypersensitivity or cephamycin hypersensitivity. An anaphylactic response to both classes of drugs is possible. Cefazolin should be used cautiously in patients with hypersensitivity to penicillin. The structural similarity between cefazolin and penicillin means that cross-reactivity can occur. Penicillins can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients who have experienced severe penicillin hypersensitivity should not receive cefazolin. Cefazolin induced an allergic reaction in 4% of patients known to have penicillin allergy.

    Renal failure, renal impairment

    Cefazolin should be used with caution in patients with renal impairment or renal failure since the drug is eliminated via renal mechanisms. After an initial loading dose appropriate to the severity of the infection, lower doses should be employed for patients with reduced creatinine clearance; dosage adjustment recommendations are available for adult and pediatric patients.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Pregnancy

    Cefazolin is classified as FDA pregnancy risk category B. Animal data reveal no teratogenic effects. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cefazolin has not been studied for use during labor and delivery. Treatment should be given only if clearly needed.

    Breast-feeding

    Cefazolin distributes into breast milk in low concentrations. The manufacturer recommends that cefazolin should be used with caution during breast feeding and the benefits versus risks should be considered. AA rare potential complication in the nursing infant of a woman taking a cephalosporin is an alteration of gut flora that might result in diarrhea or other related complications (e.g., dehydration). Cefazolin is generally considered compatible for use during breast-feeding by the American Academy of Pediatrics (AAP). 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Coagulopathy, vitamin K deficiency

    All cephalosporins, including cefazolin, may rarely cause hypoprothrombinemia and have the potential to cause bleeding. Cephalosporins which contain the NMTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have been associated with an increased risk for bleeding. Cephalosporins should be used cautiously in patients with a preexisting coagulopathy (e.g., vitamin K deficiency) since these patients are at a higher risk for developing bleeding complications.

    Neonates

    The safety and efficacy of cefazolin have not been established in neonates.

    Geriatric

    No overall differences in safety or effectiveness of cefazolin were observed between the older adult and younger adults in clinical trials. Cefazolin is excreted renally; because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents 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

    interstitial nephritis / Delayed / 0-1.0
    serum sickness / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-0.1
    anaphylactoid reactions / Rapid / 0-0.1
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known

    Moderate

    eosinophilia / Delayed / 2.7-8.2
    elevated hepatic enzymes / Delayed / 1.0-7.0
    thrombocytopenia / Delayed / 0-3.0
    hypoprothrombinemia / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    oral ulceration / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    confusion / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known
    vaginitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 1.0-19.0
    nausea / Early / 1.0-6.0
    vomiting / Early / 1.0-6.0
    maculopapular rash / Early / 1.0-3.0
    pruritus / Rapid / 1.0-3.0
    fever / Early / 0.5-0.9
    urticaria / Rapid / Incidence not known
    rash (unspecified) / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    pyrosis (heartburn) / Early / Incidence not known
    flatulence / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known
    weakness / Early / Incidence not known
    drowsiness / Early / Incidence not known
    pruritus ani / Early / Incidence not known

    DRUG INTERACTIONS

    Clofarabine: Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and cefazolin, an inhibitor of OAT1 and OAT3, may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OAT1 and OAT3 inhibitors.
    Ibuprofen lysine: Use caution in combining ibuprofen lysine with renally eliminated medications like cephalosporins, as ibuprofen may reduce renal blood flow.
    Loop diuretics: Nephrotoxicity associated with cephalosporins may be potentiated by concomitant furosemide therapy. Clinicans should be aware that this may occur even in patients with minor or transient renal impairment.
    Oral Contraceptives: 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 picosulfate; Magnesium oxide; Anhydrous citric acid: 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.
    Warfarin: The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the 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. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. 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

    Cefazolin is classified as FDA pregnancy risk category B. Animal data reveal no teratogenic effects. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Cefazolin has not been studied for use during labor and delivery. Treatment should be given only if clearly needed.

    Cefazolin distributes into breast milk in low concentrations. The manufacturer recommends that cefazolin should be used with caution during breast feeding and the benefits versus risks should be considered. AA rare potential complication in the nursing infant of a woman taking a cephalosporin is an alteration of gut flora that might result in diarrhea or other related complications (e.g., dehydration). Cefazolin is generally considered compatible for use during breast-feeding by the American Academy of Pediatrics (AAP). 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Cefazolin, a beta-lactam antibiotic similar to penicillins, 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. Penicillin-binding proteins 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. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of cefazolin as well as other cephalosporins and penicillins against a particular organism depends on their ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, cefazolin'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.

    PHARMACOKINETICS

    Cefazolin is administered parenterally. It is not well absorbed from the GI tract. Approximately 75—85% of circulating drug is protein-bound. It is distributed into most body tissues and fluids including gallbladder, liver, kidney, bone, myocardium, sputum, bile, and pericardial, pleural, and synovial fluids. The drug concentrates in the urine, at levels much higher than peak serum levels. Cefazolin does not reach therapeutic levels within the CSF. Studies of cord blood show prompt transfer of cefazolin across the placenta. Cefazolin distributes into breast milk in low concentrations; a milk:plasma ratio of 0.02 has been reported. Unlike cephalothin, cefazolin is not hepatically metabolized. Cefazolin is largely excreted unchanged into the urine via glomerular filtration and tubular secretion, although tubular secretion appears to be less important for renal clearance of cefazolin than for cephalothin. Approximately 60% of cefazolin is excreted within the first 6 hours, reaching 70—80% within the first 24 hours. Elimination half-life is 1—2 hours in patients with normal renal function.

    Intravenous Route

    Studies have shown that following intravenous (IV) administration of cefazolin to normal adult volunteers, mean peak serum concentrations were roughly 185 mcg/mL and were roughly 4 mcg/mL at 8 hours following a 1-gram dose. The serum half-life for cefazolin is approximately 1.8 hours following IV administration.

    Intramuscular Route

    Peak serum levels of cefazolin occur within 1—2 hours following an intramuscular (IM) dose. After IM administration of cefazolin to normal adult volunteers, the mean serum concentrations were 37 mcg/mL at 1 hour following a 500-mg dose, and 64 mcg/mL at 1 hour following a 1-gram dose. The serum half-life for cefazolin is approximately 2 hours following IM administration.