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CeFAZolin


General


Pronunciation

(sef A zoe lin)


Indications


Use: Labeled Indications

Biliary tract infections: Treatment of biliary tract infections due to Escherichia coli, various strains of streptococci, Proteus mirabilis, Klebsiella species and Staphylococcus aureus.

Bone and joint infections: Treatment of bone and joint infections due to S. aureus.

Endocarditis, treatment: Treatment of endocarditis due to S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci (S. pyogenes).

Genital infections: Treatment of genital infections (ie, prostatitis, epididymitis) due to E. coli, P. mirabilis, and Klebsiella species.

Perioperative prophylaxis: To reduce the incidence of certain postoperative infections in patients undergoing surgical procedures.

Respiratory tract infections: Treatment of respiratory tract infections due to S. pneumoniae, Klebsiella species, Haemophilus influenzae, S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.

Septicemia: Treatment of septicemia due to Streptococcus pneumoniae, S. aureus (penicillin-sensitive and penicillin-resistant), P. mirabilis, E. coli and Klebsiella species.

Skin and skin structure infections: Treatment of skin and skin structure infections due to S. aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci and other strains of streptococci.

Urinary tract infections: Treatment of urinary tract infections due to E. coli, P. mirabilis, Klebsiella species and some strains of enterobacter.


Contraindications


Hypersensitivity to cefazolin, other cephalosporin antibiotics, penicillins, other beta-lactams, or any component of the formulation.


Dosing and Administration


Dosing: Adult

Usual dosage range: IM, IV: 1 to 1.5 g every 8 hours, depending on severity of infection; maximum: 12 g daily

Cholecystitis, mild-to-moderate: IV: 1 to 2 g every 8 hours for 4 to 7 days (provided source controlled)

Endocarditis, treatment: IV:

Manufacturer 's labeling: 1 to 1.5 g every 6 hours

Alternate dosing (AHA [Baddour 2015]): MSSA in penicillin-allergic (nonanaphylactoid) patients:

Native valve: 2 g every 8 hours for 6 weeks

Prosthetic valve: 2 g every 8 hours for a minimum of 6 weeks (in combination with rifampin for entire course of therapy and gentamicin for the first 2 weeks)

Group B streptococcus (neonatal prophylaxis): IV: 2 g once, then 1 g every 8 hours until delivery (CDC 2010)

Intra-abdominal infection, complicated, community-acquired, mild-to-moderate (in combination with metronidazole): IV: 1 to 2 g every 8 hours for 4 to 7 days (provided source controlled)

Moderate to severe infections: IV: 500 mg to 1 g every 6 to 8 hours

Mild infection with gram-positive cocci: IV: 250 to 500 mg every 8 hours

Perioperative prophylaxis:

Manufacturer 's labeling: IM, IV: 1 to 2 g initiated 30 to 60 minutes prior to surgery; may repeat after 2 hours if procedure is lengthy with 500 mg to 1 g intraoperatively, followed by 500 mg to 1 g every 6 to 8 hours for 24 hours postoperatively.

Guideline recommendations (off-label): IV: Note: For most surgical procedures, joint clinical practice guidelines from the American Society of Health-System Pharmacists, Infectious Diseases Society of America, Surgical Infection Society, and Society for Healthcare Epidemiology of America (ASHP/IDSA/SIS/SHEA) recommend a dose of 2 g within 60 minutes prior to surgical incision (for nonobese patients weighing <120 kg). For procedures requiring anaerobic coverage (eg, appendectomy, small bowel surgery with intestinal obstruction, colon procedures), combine cefazolin with metronidazole as an alternative to a second generation cephalosporin with anaerobic activity (eg, cefoxitin or cefotetan). Cefazolin doses may be repeated intraoperatively in 4 hours if procedure is lengthy or if there is excessive blood loss (Bratzler 2013).

Obesity: The ASHP/IDSA/SIS/SHEA guidelines recommend that for patients weighing ≥120 kg, a dose of 3 g within 60 minutes prior to surgical incision should be administered (Bratzler 2013). Alternatively, for patients with BMI >40 kg/m2, a single 2 g dose may be sufficient for common general surgical procedures lasting <5 hours; patients enrolled in this multigroup study had a BMI up to a group mean of 55.7 kg/m2 (Ho 2012).

Cardiothoracic surgery: IV: 1 g (see Note") initiated 30 to 60 minutes prior to surgery (usually at the time of anesthetic induction); repeat dose if the duration of operation exceeds 3 hours (Hillis 2011). The ASHP/IDSA/SIS/SHEA guidelines recommend the use of 2 g (single dose) administered within 60 minutes prior to surgical incision (Bratzler 2013). May either continue for ≤48 hours postoperatively or administer as a single dose preoperatively (may be preferred due to reduced cost and potential for antimicrobial resistance) (Bratzler 2013; Bucknell 2000; Douglas 2011; Edwards 2006; Hillis 2011).

Note: For patients weighing >60 kg, the Society of Thoracic Surgeons recommends a preoperative dose of 2 g administered within 60 minutes of skin incision. If the surgical incision remains open in the operating room, follow with 1 g every 3 to 4 hours unless cardiopulmonary bypass is to be discontinued within 4 hours then delay administration (Engelman 2007).

Peritonitis, treatment (off-label route; Li 2010): Intraperitoneal:

Intermittent exchange: 15 mg/kg per exchange every 24 hours in the long dwell ( ≥6 hours)

Continuous exchange: Loading dose: 500 mg per liter of dialysate. Maintenance: 125 mg per liter of dialysate.

Note: If patient has residual renal function (eg, >100 mL/day urine output), empirically increase each dose by 25%

Automated peritoneal dialysis: 20 mg/kg every 24 hours in the long day dwell; Note: Guidelines suggest nighttime levels of intraperitoneal cefazolin may fall below the MIC of most organisms and adding cefazolin to each exchange may be warranted

Pneumococcal pneumonia: IV: 500 mg every 12 hours

Prophylaxis against infective endocarditis (off-label use): IM, IV: 1 g 30 to 60 minutes before procedure. Intramuscular injections should be avoided in patients who are receiving anticoagulant therapy. In these circumstances, orally administered regimens should be given whenever possible. Intravenously administered antibiotics should be used for patients who are unable to tolerate or absorb oral medications.

Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA.

Prophylaxis in total joint replacement patients undergoing dental procedures which produce bacteremia (off-label use): IM, IV: 1 g 1 hour prior to procedure (ADA/AAOS 2003). Note: In general, patients with prosthetic joint implants do not require prophylactic antibiotics prior to dental procedures. In planning an invasive oral procedure, dental consultation with the patients orthopedic surgeon may be advised to review the risks of infection (Sollecito 2015).

Prosthetic joint infection,Staphylococcal (oxacillin-susceptible): IV: 1 to 2 g every 8 hours for 2 to 6 weeks (in combination with rifampin) followed by oral antibiotic treatment and suppressive regimens (Osmon 2013)

Severe infection: IV: 1 to 1.5 g every 6 hours

Skin and soft tissue infection due to MSSA, including pyomyositis: IV: 1 g every 8 hours for 7 to 14 days; treat pyomyositis for 14 to 21 days (IDSA [Stevens 2014])

Skin and soft tissue necrotizing infection due to MSSA (off-label use): IV: 1 g every 8 hours; continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014])

Streptococcal skin infections: IV: 1 g every 8 hours (IDSA [Stevens 2014])

Surgical site infection (trunk or extremity [away from axilla or perineum]) (off-label use): IV: 500 mg to 1 g every 8 hours (IDSA [Stevens 2014])

UTI (uncomplicated): IM, IV: 1 g every 12 hours


Dosing: Geriatric

Refer to adult dosing.


Dosing: Pediatric

Usual dosage range: IM, IV: Infants >1 month, Children, and Adolescents: 25 to 100 mg/kg/day divided every 6 to 8 hours; maximum: 6 g daily

Community-acquired pneumonia (CAP) (IDSA/PIDS 2011), moderate-to-severe infection, S. aureus (methicillin-susceptible) (preferred): Infants >3 months and Children: IM, IV: 150 mg/kg/day divided every 8 hours

Perioperative prophylaxis (off-label use): Children ≥1 year: IV: Note: For most surgical procedures, joint clinical practice guidelines from the American Society of Health-System Pharmacists, Infectious Diseases Society of America, Surgical Infection Society, and Society for Healthcare Epidemiology of America (ASHP/IDSA/SIS/SHEA) recommend a dose of 30 mg/kg (maximum dose: 2,000 mg) administered within 60 minutes prior to surgical incision. For procedures requiring anaerobic coverage (eg, appendectomy, small bowel surgery with intestinal obstruction, colon procedures), combine cefazolin with metronidazole as an alternative to a second generation cephalosporin with anaerobic activity (eg, cefoxitin or cefotetan). Cefazolin doses may be repeated intraoperatively in 4 hours if procedure is lengthy or if there is excessive blood loss (Bratzler 2013).

Peritonitis, treatment (off-label route; Warady 2012): Infants, Children, and Adolescents: Intraperitoneal:

Intermittent exchange: 20 mg/kg every 24 hours in the long dwell

Continuous exchange: Loading dose: 500 mg per liter of dialysate. Maintenance: 125 mg per liter of dialysate.

Prophylaxis against infective endocarditis (off-label use): Infants and Children: IM, IV: 50 mg/kg 30 to 60 minutes before procedure; maximum dose: 1,000 mg. Intramuscular injections should be avoided in patients who are receiving anticoagulant therapy. In these circumstances, orally administered regimens should be given whenever possible. Intravenously administered antibiotics should be used for patients who are unable to tolerate or absorb oral medications.

Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA.

Skin and soft tissue infection due to MSSA, including pyomyositis: Infants and Children: IV: 50 mg/kg/day divided every 8 hours for 7 to 14 days; treat pyomyositis for 14 to 21 days (IDSA [Stevens 2014])

Skin and soft tissue necrotizing infections due to MSSA (off-label use): Infants and Children: IV: 33 mg/kg every 8 hours; continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014])

Streptococcal skin infections: Infants and Children: IV: 33 mg/kg every 8 hours (IDSA [Stevens 2014])


Dosing: Renal Impairment

Adults:

CrCl ≥55 mL/minute: No dosage adjustment necessary

CrCl 35 to 54 mL/minute: Administer full dose in intervals of ≥8 hours

CrCl 11 to 34 mL/minute: Administer 50% of usual dose every 12 hours

CrCl ≤10 mL/minute: Administer 50% of usual dose every 18 to 24 hours

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Dialyzable (20% to 50%): 500 mg to 1 g every 24 hours or use 1 to 2 g every 48 to 72 hours (Heintz 2009) or 15 to 20 mg/kg (maximum dose: 2 g) after dialysis 3 times weekly (Ahern 2003; Sowinski 2001) or 2 g after dialysis if next dialysis expected in 48 hours or 3 g after dialysis if next dialysis is expected in 72 hours (Stryjewski 2007).

Note: Dosing dependent on the assumption of 3 times weekly, complete IHD sessions.

Peritoneal dialysis (PD): IV: 500 mg every 12 hours

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 2 g followed by 1 to 2 g every 12 hours

CVVHD/CVVHDF: Loading dose of 2 g followed by either 1 g every 8 hours or 2 g every 12 hours. Note: Dosage of 1 g every 8 hours results in similar steady-state concentrations as 2 g every 12 hours and is more cost effective (Heintz 2009).

Infants >1 month, Children, and Adolescents:

CrCl >70 mL/minute: No dosage adjustment necessary.

CrCl 40 to 70 mL/minute: 60% of usual daily dose divided every 12 hours

CrCl 20 to 40 mL/minute: 25% of usual daily dose divided every 12 hours

CrCl 5 to 20 mL/minute: 10% of usual daily dose every 24 hours

Intermittent hemodialysis (IHD): 25 mg/kg per dose every 24 hours (Aronoff 2007)

Peritoneal dialysis (PD): 25 mg/kg per dose every 24 hours (Aronoff 2007)

Continuous renal replacement therapy (CRRT): 25 mg/kg per dose every 8 hours (Aronoff 2007)


Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturers labeling.


Reconstitution

Dilute 500 mg vial with 2 mL SWFI and 1 g vial with 2.5 mL SWFI; reconstituted solution may be directly injected after further dilution with 5 mL SWFI or further diluted for IV administration in 50 to 100 mL compatible solution; 10 g vial may be diluted with 45 mL to yield 1 g/5 mL or 96 mL to yield 1 g/10 mL.


Administration

IM: Inject deep IM into large muscle mass.

IV: Inject direct IV over 3 to 5 minutes or may infuse as an intermittent infusion over 30 to 60 minutes.

Some penicillins (eg, carbenicillin, ticarcillin and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.


Dietary Considerations

Some products may contain sodium.


Storage

Store intact vials at room temperature and protect from temperatures exceeding 40 ‚ °C. Reconstituted solutions of cefazolin are light yellow to yellow. Protection from light is recommended for the powder and for the reconstituted solutions. Reconstituted solutions are stable for 24 hours at room temperature and for 10 days under refrigeration. Stability of parenteral admixture in D5W, D5LR, D51/4NS, D51/2NS, D5NS, D10W, LR, or NS at room temperature (25 ‚ °C) is 48 hours. Stability of parenteral admixture at refrigeration temperature (4 ‚ °C) is 14 days.

DUPLEX: Store at 20 ‚ °C to 25 ‚ °C (68 ‚ °F to 77 ‚ °F); excursions permitted to 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F) prior to activation. Following activation, stable for 24 hours at room temperature and for 7 days under refrigeration.

GALAXY: Store at or below -20 ‚ °C (-4 ‚ °F). Thawed solution stable for 48 hours at room temperature and for 30 days under refrigeration. Do not refreeze.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Generic: 1 g (50 mL); 2 g (100 mL)

Solution Reconstituted, Injection:

Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 20 g (1 ea); 100 g (1 ea); 300 g (1 ea)

Solution Reconstituted, Injection [preservative free]:

Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 20 g (1 ea [DSC])

Solution Reconstituted, Intravenous:

Generic: 1 g (1 ea); 2 g (1 ea)


Compatibility

Stable in D5W, D5LR, D51/4NS, D51/2NS, D5NS, D10W,LR, NS.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, caspofungin, idarubicin, pemetrexed, pentamidine, vinorelbine.


Drug Interactions

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Fosphenytoin: CeFAZolin may decrease the protein binding of Fosphenytoin. Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Phenytoin: CeFAZolin may decrease the protein binding of Phenytoin. Monitor therapy

Probenecid: May increase the serum concentration of Cephalosporins. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Cephalosporins may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy


Monitoring Parameters

Renal function periodically, hepatic function tests, CBC; monitor for signs of anaphylaxis during first dose


Lab Test Interferences


Test Interactions

Positive direct and indirect Coombs, false-positive urinary glucose test using cupric sulfate (Benedict's solution, Clinitest, Fehling's solution), false-positive serum or urine creatinine with Jaffe reaction.

Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential underestimation of aminoglycoside serum concentration.


Adverse Reactions


Frequency not defined.

Cardiovascular: Localized phlebitis

Central nervous system: Seizure

Dermatologic: Pruritus, skin rash, Stevens-Johnson syndrome

Gastrointestinal: Abdominal cramps, anorexia, diarrhea, nausea, oral candidiasis, pseudomembranous colitis, vomiting

Genitourinary: Vaginitis

Hepatic: Hepatitis, increased serum transaminases

Hematologic: Eosinophilia, leukopenia, neutropenia, thrombocythemia, thrombocytopenia

Hypersensitivity: Anaphylaxis

Local: Pain at injection site

Renal: Increased blood urea nitrogen, increased serum creatinine, renal failure

Miscellaneous: Fever


Warnings/Precautions


Concerns related to adverse effects:

- Elevated INR: May be associated with increased INR, especially in nutritionally-deficient patients, prolonged treatment, hepatic or renal disease.

- Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, may occur. If an allergic reaction occurs, discontinue treatment and institute appropriate supportive measures.

- Penicillin allergy: Use with caution in patients with a history of penicillin allergy.

- Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

- Gastrointestinal disease: Use with caution in patients with a history of gastrointestinal disease, particularly colitis.

- Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required.

- Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.


Pregnancy Risk Factor

B


Pregnancy Considerations

Adverse effects have not been observed in animal reproduction studies. Cefazolin crosses the placenta. Adverse events have not been reported in the fetus following administration of cefazolin prior to cesarean section. Cefazolin is recommended for group B streptococcus prophylaxis in pregnant patients with a nonanaphylactic penicillin allergy. It is also one of the antibiotics recommended for prophylactic use prior to cesarean delivery and may be used in certain situations prior to vaginal delivery in women at high risk for endocarditis.

Due to pregnancy-induced physiologic changes, the pharmacokinetics of cefazolin are altered. The half-life is shorter, the AUC is smaller, and the clearance and volume of distribution are increased.


Actions


Pharmacology

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.


Distribution

Widely into most body tissues and fluids including gallbladder, liver, kidneys, bone, sputum, bile, pleural, and synovial; CSF penetration is poor


Excretion

Urine (70% to 80% as unchanged drug)


Time to Peak

Serum: IM: 0.5 to 2 hours; IV: Within 5 minutes


Half-Life Elimination

IM or IV: Neonates: 3 to 5 hours; Adults: 1.8 hours (IV); ~2 hours (IM) (prolonged with renal impairment)


Protein Binding

80% (Marshall 1999)


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience diarrhea or lack of appetite. Have patient report immediately to prescriber severe nausea, severe vomiting, bruising, bleeding, thrush, chills, pharyngitis, loss of strength and energy, seizures, injection site pain or irritation, urinary retention, change in amount of urine passed, vaginitis, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools) (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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