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Cefazolin

A semisynthetic cephalosporin analog with broad-spectrum antibiotic action due to inhibition of bacterial cell wall synthesis. It attains high serum levels and is excreted quickly via the urine.

Therapeutic use

Mainly used to treat bacterial infections of the skin. It can also be used to treat moderately severe bacterial infections involving the lung, bone, joint, stomach, blood, heart valve, and urinary tract. It is clinically effective against infections caused by staphylococci and streptococci species of Gram positive bacteria. May be used for surgical prophylaxis; if required metronidazole may be added to cover B. fragilis.

Respiratory Tract Infections

Due to S. pneumoniae, S aureus (including β-lactamase−producing strains) and S. pyogenes.
Cefazolin is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of cefazolin in the subsequent prevention of rheumatic fever are not available.

Urinary Tract Infections

Due to E. coli, P mirabilis.

Skin and Skin Structure Infections

Due to S. aureus (including β-lactamase-producing strains), S. pyogenes, and other strains of streptococci.

Biliary Tract Infections

Due to E. coli, various strains of streptococci, P. mirabilis, and S. aureus.

Bone and Joint Infections

Due to S. aureus.

Genital Infections

(i.e., prostatitis, epididymitis) due to E. coli, P. mirabilis.

Septicemia

Due to S. pneumoniae, S. aureus (including β-lactamase-producing strains), P. mirabilis, E. coli.

Endocarditis

Due to S. aureus (including β-lactamase-producing strains) and S. pyogenes.
Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefazolin.

Perioperative Prophylaxis

The prophylactic administration of cefzolin preoperatively, intraoperatively, and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those older than 70 years, with acute cholecystitis, obstructive jaundice, or common duct bile stones).
The perioperative use of cefazolin may also be effective in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty).
The prophylactic administration of cefazolin should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.
If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that appropriate therapy may be instituted.

Dosage and Administration

Controlled studies on adult normal volunteers, receiving 1 gram 4 times a day for 10 days, monitoring CBC, SGOT, SGPT, bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, indicated no clinically significant changes attributed to Cefazolin.

Usual Adult Dosage

 

Type of Infection

Dose

Frequency

Moderate to severe infections

500 mg to 1 gram

every 6 to 8 hrs.

Mild infections caused by susceptible gram-positive cocci

250 mg to 500 mg

every 8 hours

Acute, uncomplicated urinary tract infections

1 gram

every 12 hours

Pneumococcal pneumonia

500 mg

every 12 hours

Severe, life-threatening infections (e.g., endocarditis, septicemia)*

1 gram to 1.5 grams

every 6 hours

*In rare instances, doses of up to 12 grams of ANCEF per day have been used.

Perioperative Prophylactic Use

To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are:

a. 1 gram IV or IM administered 1/2 hour to 1 hour prior to the start of surgery.

b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV or IM during surgery (administration modified depending on the duration of the operative procedure).

c. 500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively.

It is important that the preoperative dose be given just (1/2 to 1 hour) prior to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision; and  cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.
In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

Dosage Adjustment for Patients With Reduced Renal Function

Cefazolin may be used in patients with reduced renal function with the following dosage adjustments: patients with a creatinine clearance of 55 mL/min. or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min. or serum creatinine of 1.6 to 3.0 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min. or serum creatinine of 3.1 to 4.5 mg % should be given 1/2 the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min. or less or serum creatinine of 4.6 mg % or greater should be given 1/2 the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection.

Pediatric Dosage

In pediatric patients, a total daily dosage of 25 to 50 mg per kg (approximately 2.5 to 5 mg per Kg) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg per kg of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

Pediatric Dosage Guide
Weight 25 mg/kg/day

Divided into 3 Doses

25 mg/kg/day

Divided into 4 Doses

Lbs Kg Approximate Single Dose mg/q8h Vol. (mL) needed with dilution of 125 mg/mL Approximate Single Dose mg/q6h Vol. (mL) needed with dilution of 125 mg/mL
10 4.5 40 mg 0.35 mL 30 mg 0.25 mL
20 9.0 75 mg 0.60 mL 55 mg 0.45 mL
30 13.6 115 mg 0.90 mL 85 mg 0.70 mL
40 18.1 150 mg 1.20 mL 115 mg 0.90 mL
50 22.7 190 mg 1.50 mL 140 mg 1.10 mL
Weight 50 mg/kg/day

Divided into 3 Doses

50 mg/kg/day

Divided into 4 Doses

Lbs Kg Approximate Single Dose mg/q8h Vol. (mL) needed with dilution of 225 mg/mL Approximate Single Dose mg/q6h Vol. (mL) needed with dilution of 225 mg/mL
10 4.5 75 mg 0.35 mL 55 mg 0.25 mL
20 9.0 150 mg 0.70 mL 110 mg 0.50 mL
30 13.6 225 mg 1.00 mL 170 mg 0.75 mL
40 18.1 300 mg 1.35 mL 225 mg 1.00 mL
50 22.7 375 mg 1.70 mL 285 mg 1.25 mL

In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min.), 60 percent of the normal daily dose given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min.), 25 percent of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min.) may be given 10 percent of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

RECONSTITUTION

Preparation of Parenteral Solution

Parenteral drug products should be SHAKEN WELL when reconstituted, and inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded. When reconstituted or diluted according to the instructions below, cefazolin is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5°C). Reconstituted solutions may range in color from pale yellow to yellow without a change in potency.

Single-Dose Vials

For IM injection, IV direct (bolus) injection or IV infusion, reconstitute with Sterile Water for Injection according to the following table. SHAKE WELL.
Vial Size Amount of Diluent Approximate

Concentration

Approximate

Available Volume

1 gram 2.5 mL 330 mg/mL 3.0 mL

“Piggyback” Vials

Reconstitute with 50 to 100 mL of Sodium Chloride Injection or other IV solution uled under ADMINISTRATION. When adding diluent to vial, allow air to escape by using a small vent needle or by pumping the syringe. SHAKE WELL. Administer with primary IV fluids, as a single dose.

ADMINISTRATION

Intramuscular Administration

Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved. cefazolin should be injected into a large muscle mass. Pain on injection is infrequent with cefazolin.

Intravenous Administration

Direct (bolus) injection: Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see ul below).

I
ntermittent or continuous infusion

Dilute reconstituted cefazolin in 50 to 100 mL of one of the following solutions:

Sodium Chloride Injection, USP

5% or 10% Dextrose Injection, USP

5% Dextrose in Lactated Ringer’s Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

5% Dextrose and 0.45% Sodium Chloride Injection, USP

5% Dextrose and 0.2% Sodium Chloride Injection, USP

Lactated Ringer’s Injection, USP

Invert Sugar 5% or 10% in Sterile Water for Injection

Ringer’s Injection, USP

5% Sodium Bicarbonate Injection, USP

Toxicology

 

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
dog LD50 intravenous 2200mg/kg (2200mg/kg)   Arzneimittel-Forschung. Drug Research. Vol. 29, Pg. 424, 1979.
dog LD50 subcutaneous 4gm/kg (4000mg/kg) GASTROINTESTINAL: NAUSEA OR VOMITING

GASTROINTESTINAL: CHANGES IN STRUCTURE OR FUNCTION OF SALIVARY GLANDS

GASTROINTESTINAL: "HYPERMOTILITY, DIARRHEA"
Chemotherapy Vol. 18, Pg. 528, 1970.
human TDLo intramuscular 14mg/kg/D (14mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, ALLERGIC: AFTER SYSTEMIC EXPOSURE"

GASTROINTESTINAL: NAUSEA OR VOMITING

GASTROINTESTINAL: CHANGES IN STRUCTURE OR FUNCTION OF SALIVARY GLANDS
Japan Medical Gazette. Vol. 8(8), Pg. 10, 1971.
mouse LD50 intraperitoneal 6200mg/kg (6200mg/kg)   Drugs in Japan Vol. 6, Pg. 404, 1982.
mouse LD50 intravenous 3900mg/kg (3900mg/kg)   Journal of Infectious Diseases. Vol. 128, Pg. S379, 1973.
mouse LD50 oral > 11gm/kg (11000mg/kg)   Chemotherapy Vol. 18, Pg. 528, 1970.
mouse LD50 subcutaneous 7600mg/kg (7600mg/kg)   Journal of Infectious Diseases. Vol. 128, Pg. S379, 1973.
rabbit LD50 intravenous 2500mg/kg (2500mg/kg)   Arzneimittel-Forschung. Drug Research. Vol. 29, Pg. 424, 1979.
rabbit LD50 subcutaneous > 6gm/kg (6000mg/kg)   Chemotherapy Vol. 18, Pg. 528, 1970.
rat LD50 intraperitoneal 7400mg/kg (7400mg/kg)   Drugs in Japan Vol. 6, Pg. 404, 1982.
rat LD50 intravenous 2760mg/kg (2760mg/kg) BEHAVIORAL: ATAXIA

BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD

LUNGS, THORAX, OR RESPIRATION: DYSPNEA
Chemotherapy Vol. 35(Suppl,
rat LD50 oral > 11gm/kg (11000mg/kg)   Chemotherapy Vol. 18, Pg. 528, 1970.
rat LD50 subcutaneous 10gm/kg (10000mg/kg) BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD

GASTROINTESTINAL: "HYPERMOTILITY, DIARRHEA"

BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)
Japan Medical Gazette. Vol. 8(8), Pg. 10, 1971.
women TDLo intravenous 660mg/kg/11D- (660mg/kg) BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD Nephron. Vol. 45, Pg. 72, 1987.

CONTRAINDICATIONS

CEFAZOLIN IS CONTRAINDICATED IN PATIENTS WITH KNOWN ALLERGY TO THE CEPHALOSPORIN GROUP OF ANTIBIOTICS.

WARNINGS

BEFORE THERAPY WITH ANCEF IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFAZOLIN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO ANCEF OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefazolin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an oral antibacterial drug clinically effective against C. difficile colitis.

ADVERSE REACTIONS

The following reactions have been reported:

Gastrointestinal

Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia, and pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Nausea and vomiting have been reported rarely.

Allergic

Anaphylaxis, eosinophilia, itching, drug fever, skin rash, Stevens-Johnson syndrome.

Hematologic

Neutropenia, leukopenia, thrombocytopenia, thrombocythemia.

Hepatic

Transient rise in SGOT, SGPT, and alkaline phosphatase levels has been observed. As with other cephalosporins, reports of hepatitis have been received.

Renal

As with other cephalosporins, reports of increased BUN and creatinine levels, as well as renal failure, have been received.

Local Reactions

Rare instances of phlebitis have been reported at site of injection. Pain at the site of injection after intramuscular administration has occurred infrequently. Some induration has occurred.

Other Reactions

Genital and anal pruritus (including vulvar pruritus, genital moniliasis, and vaginitis).

Pharmacokinetic

After intramuscular administration of ANCEF to normal volunteers, the mean serum concentrations were 37 mg/mL at 1 hour and 3 mg/mL at 8 hours following a 500-mg dose, and 64 mg/mL at 1 hour and 7 mg/mL at 8 hours following a 1-gram dose. Studies have shown that following intravenous administration of ANCEF to normal volunteers, mean serum concentrations peaked at approximately 185 mg/mL and were approximately 4 mg/mL at 8 hours for a 1-gram dose. The serum half-life is approximately 1.8 hours following IV administration and approximately 2.0 hours following IM administration. In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin produced a steady serum level at the third hour of approximately 28 mg/mL. Studies in patients hospitalized with infections indicate that ANCEF produces mean peak serum levels approximately equivalent to those seen in normal volunteers.

Bioavailability 0%
Protein binding 74-86%
Metabolism not metabolized
Half-life 1.8 hrs
Cmax (mg/ml) 64 mg/mL (1g IM)

185 mg/mL (1g iv)

tmax (hrs) 1-2 hrs (i.m.)
Distribution volume Vd (l)  
Excretion Urinary

Absorption

Not absorbed from GI tract. Must be administered parenterally. Peak serum concentrations attained 1-2 hours post intramuscular injection.

Distribution

Bile levels in patients without obstructive biliary disease can reach or exceed serum levels by up to 5 times; however, in patients with obstructive biliary disease, bile levels of ANCEF are considerably lower than serum levels (<1.0 mg/mL).
In synovial fluid, the level of ANCEF becomes comparable to that reached in serum at about 4 hours after drug administration.
Studies of cord blood show prompt transfer of ANCEF across the placenta. ANCEF is present in very low concentrations in the milk of nursing mothers.


Excretion

Cefazolin is present in very low concentrations in the milk of nursing mothers. Cefazolin is excreted unchanged in the urine. In the first six hours approximately 60% of the drug is excreted in the urine and this increases to 70%-80% within 24 hours. Cefazolin achieves peak urine concentrations of approximately 2,400 mg/mL and 4,000 mg/mL respectively following 500-mg and 1-gram intramuscular doses.

Metabolism

Not metabolized.

Mechanism of Action

In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, it inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins.

Other pharmacological effects

 


Medicinal Chemistry

CAS number:   27164-46-1   EINECS: 247-362-8
 

Molecular Formula:  C14H14N8O4S3

Average mass:  454.507202 Da

Monoisotopic mass: 454.029999 Da

Systematic name: (6R,7R)-3-{[(5-Methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-8-oxo-7-[(1H-tetrazol-1-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

SMILES: CC1=NN=C(S1)SCC2=C(N3[C@@H]([C@@H](C3=O)NC(=O)CN4C=NN=N4)SC2)C(=O)O

Std. InChI: 1S/C14H14N8O4S3/c1-6-17-18-14(29-6)28-4-7-3-27-12-9(11(24)22(12)10(7)13(25)26)16-8(23)2-21-5-15-19-20-21/h5,9,12H,2-4H2,1H3,(H,16,23)(H,25,26)/t9-,12-/m1/s1

CD/LogP: 1.13±0.57 # of Rule of 5 Violations: 1
ACD/LogD (pH 5.5): -1.71 ACD/LogD (pH 7.4): -2.58
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 12 #H bond donors: 2
#Freely Rotating Bonds: 7 Polar Surface Area: 234.93 Ĺ2
Index of Refraction: 1.961 Molar Refractivity: 109.8±0.5 cm3
Molar Volume: 225.4±7.0 cm3 Polarizability: 43.5±0.5 10-24cm3
Surface Tension: 107.7±7.0 dyne/cm Density: 2.0±0.1 g/cm3
Flash Point: °C Enthalpy of Vaporization: kJ/mol
Boiling Point: °C at 760 mmHg Vapour Pressure: mmHg at 25°C

 

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility:

Stability:

 


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