Name of the medicine
Cephazolin (as cephazolin sodium). https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSCEPSOD.gif
Description
Chemical name: 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)-thio] methyl]-7-[2-(1H-tetrazol-1-yl) acetamido]-3-cephem-4-carboxylic acid, sodium. Kefzol (cephazolin sodium) is a semisynthetic cephalosporin for parenteral administration. The sodium content is 48.3 mg per g of cephazolin sodium. Cephazolin sodium is a white to off white crystalline powder with a solubility in water of ≥ 100 mg/mL.
Actions
Microbiology In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. Kefzol is active against the following organisms in vitro: Staphylococcus aureus (penicillin sensitive and penicillin resistant); group A β-haemolytic Streptococci and other strains of Streptococci (many strains of Enterococci are resistant); Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella sp., Enterobacter aerogenes, Haemophilus influenzae. Most strains of Enterobacter cloacae and indole-positive Proteus (P. vulgaris, P. morganii, P. rettgeri) are resistant. Methicillin resistant Staphylococci, Serratia, Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea sp.) are almost uniformly resistant to cephazolin.
Human pharmacology Table 1 demonstrates the blood levels and duration of cephazolin following intramuscular administration.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/KEFZOL1.gif Clinical pharmacology studies in patients hospitalised with infections indicate that cephazolin produces mean peak serum levels approximately equivalent to those seen in normal volunteers.
In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for one hour (approximately 250 mg) and 1.5 mg/kg for the next two hours (approximately 100 mg) cephazolin produced a steady serum level at the third hour of approximately 28 microgram/mL. Table 2 shows the average serum concentration after intravenous injection of a single 1 g dose; average half-life was 1.4 hours.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/KEFZOL2.gif Controlled studies on adult normal volunteers receiving 1 g four times daily for ten days, monitoring complete blood count, AST, ALT, bilirubin, alkaline phosphatase, serum urea, creatinine and urinalysis, indicated no clinically significant changes attributed to cephazolin.
Cephazolin is excreted unchanged in the urine. Following intramuscular injection of 500 mg, 56 to 89% of the administered dose was recovered within six hours and 80 to nearly 100% was recovered in 24 hours. Cephazolin achieves peak urine concentrations greater than 1,000 and 4,000 microgram/mL, respectively, following 500 mg and 1 g intramuscular doses.
When cephazolin is administered to patients with unobstructed biliary tracts, high concentrations, well over serum levels, occur in the gall bladder tissue and bile. In the presence of obstruction, however, concentration of the antibiotic in bile is considerably lower than the serum level.
Cephazolin readily crosses an inflamed synovial membrane and the concentration of the antibiotic achieved in the joint space is comparable to levels measured in serum.
Cephazolin readily crosses the placental barrier into the cord blood and amniotic fluid. Cephazolin is present in very low concentrations in the milk of breastfeeding mothers.
Disc susceptibility tests. Quantitative methods that require measurements of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure* has been recommended for use with discs for testing susceptibility to cephalosporin class antibiotics. Interpretations correlate diameters of the disc test with minimum inhibitory concentration (MIC) values for Kefzol. With this procedure, a report from the laboratory of ‘susceptible’ indicates that the infecting organism is likely to respond to therapy. A report of ‘resistant’ indicates that the infecting organism is not likely to respond to therapy. A report of ‘intermediate susceptibility’ suggests that the organism would be susceptible if high dosage is used, or if the infection is confined to tissues and fluids (e.g. urine) in which high antibiotic levels are attained.
Indications
Treatment of the following serious infections due to susceptible organisms.
Respiratory tract infections due to Strep. pneumoniae, Klebsiella sp., H. influenzae, Staph. aureus (penicillin sensitive and penicillin resistant) and group A β-haemolytic Streptococci.
Injectable benzathine penicillin is considered to be the drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever.
Kefzol is effective in the eradication of Streptococci from the nasopharynx; however, data establishing the efficacy of Kefzol in the subsequent prevention of rheumatic fever are not available at present.
Genitourinary tract infections due to E. coli, P. mirabilis, Klebsiella sp. and some strains of Enterobacter and Enterococci.
Skin and skin structure infections due to Staph. aureus (penicillin sensitive and penicillin resistant) and group A β-haemolytic Streptococci and other strains of Streptococci.
Bone and joint infections due to Staph. aureus.
Septicaemia due to Strep. pneumoniae, Staph. aureus (penicillin sensitive and penicillin resistant), P. mirabilis, E. coli and Klebsiella sp.
Endocarditis due to Staph. aureus (penicillin sensitive and penicillin resistant) and group A β-haemolytic Streptococci.
Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to Kefzol.
Contraindications
Known allergy to the cephalosporin group of antibiotics or previous experience of a major allergy to penicillin (see Precautions).
Precautions
Before cephazolin therapy is instituted, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins and penicillin. Cephalosporin C derivatives should be given cautiously in penicillin sensitive patients.
Serious acute hypersensitivity reactions may require adrenaline and other emergency measures.
There is some clinical and laboratory evidence of partial cross allergenicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both drugs.
Antibiotics, including Kefzol, should be administered cautiously to any patient who has demonstrated some form of allergy, particularly to drugs.
If an allergic reaction to Kefzol occurs, the drug should be discontinued and the patient treated with the usual agents (e.g. adrenaline or other pressor amines, antihistamines or corticosteroids).
Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including Kefzol. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, appropriate therapy with a suitable oral antibacterial agent effective against Cl. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated.
Drugs that delay peristalsis, e.g. opiates and diphenoxylate with atropine (e.g. Lomotil), may prolong and/or worsen the condition and should not be used.
Prolonged use of Kefzol may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
When Kefzol is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required (see Dosage and Administration).
The intrathecal administration of Kefzol is not an approved route of administration for this antibiotic; in fact, there have been reports of severe CNS toxicity including seizures when cephazolin was administered in this manner.
Use in pregnancy. (Category B1)
Safety of this product for use during pregnancy has not been established.
Use in infants. Safety for use in premature infants and infants under 1 month of age has not been established.
Interactions
Laboratory test interactions A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution or with Clinitest tablets, but not with Tes-Tape (urine sugar analysis paper, Lilly).
Adverse effects
The following reactions have been reported.
Hypersensitivity. Drug fever, skin rash, vulvar pruritus, eosinophilia, itching and Stevens-Johnson syndrome have occurred.
Blood. Neutropenia, leucopenia, thrombocythaemia, thrombocytopenia and positive direct and indirect Coombs' tests have occurred.
Hepatic and renal. Isolated transient rises in AST, ALT, serum urea and alkaline phosphatase levels have been observed without evidence of renal or hepatic impairment.
Gastrointestinal. Nausea, anorexia, vomiting, diarrhoea and oral candidiasis (oral thrush) have been reported. As with other broad spectrum antibiotics, colitis, including rare instances of pseudomembranous colitis, has been reported in conjunction with therapy with Kefzol (see Precautions).
Other. Pain at the site of injection after intramuscular administration has occurred, some with induration. Phlebitis at the site of injection has been noted. Other reactions have included genital and anal pruritus, genital candidiasis and vaginitis.
Dosage and Administration
Kefzol may be administered intramuscularly or intravenously after reconstitution.
The intrathecal administration of Kefzol is not an approved route of administration for this antibiotic; in fact, there have been reports of severe CNS toxicity including seizures when cephazolin was administered in this manner.
Intramuscular administration. Reconstitute with sterile water for injections, bacteriostatic water for injections, or sodium chloride 0.9% injection according to the dilution table (Table 3). Shake well until dissolved. To facilitate putting the product into solution, the vial should be warmed in the hands while shaking. Do not use the reconstituted injection solution if there is any sign of turbidity. Kefzol should be injected into a large muscle mass.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/KEFZOL3.gif Intravenous administration. Kefzol may be administered by direct intravenous injection or by intermittent or continuous infusion. Total daily dosages are the same as with intramuscular injection.
Direct intravenous injection. Dilute the reconstituted Kefzol 1 g in a minimum of 10 mL of sterile water for injections. Inject solution slowly over three to five minutes. It may be administered directly into a vein or through the tubing for a patient receiving one of the following intravenous solutions: sodium chloride 0.9% injection, glucose 5 or 10% injection, glucose 5% in lactated Ringer's injection, glucose 5% and sodium chloride 0.9% injection (also may be used with glucose 5% and sodium chloride 0.4 or 0.2% injection), lactated Ringer's injection, invert sugar 5 or 10% in sterile water for injections, Ringer's injection, Normosol-M in glucose 5%, Ionosol B with glucose 5%, Plasma-Lyte with glucose 5%.
Intermittent intravenous infusion. Kefzol can be administered along with primary intravenous fluid management programs in a volume control set or in a separate, secondary intravenous bottle. Reconstituted Kefzol 1 g may be diluted in sterile water for injections 50 to 100 mL or one of the previously listed parenteral fluids and infused over a period of three to five minutes. If a Y-type administration set is used, it is desirable to discontinue the other solution during the infusion of the solution containing Kefzol.
Continuous intravenous infusion. The total daily dose of Kefzol, diluted and well mixed with at least 50 mL of sterile water for injections, may be added to an intravenous bottle containing one of the previously listed parenteral fluids. The choice of saline or glucose solution and the volume to be employed are dictated by fluid and electrolyte management.
Dosage. In adults, usual dosage for mild Gram positive infections is Kefzol 250 to 500 mg every eight hours. In mild to moderate infections of the respiratory tract caused by Strep. pneumoniae, or mild to moderate infections of the genitourinary tract caused by susceptible organisms, a dosage of 500 mg to 1 g every 12 hours may be used. In moderate or severe infections, the usual adult dosage is Kefzol 500 mg to 1 g every six to eight hours. Kefzol has been administered in dosages of 6 g/day in serious infections such as endocarditis. In patients with renal impairment, cephazolin is not readily excreted. After a loading dose of 500 mg, the recommendations in Table 4 for maintenance dosage may be used as a guide.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/KEFZOL4.gif In children, a total daily dosage of 25 to 50 mg/kg bodyweight, divided into three or four equal doses, is effective for most mild to moderately severe infections (see Table 5). Total daily dosage may be increased to 100 mg/kg bodyweight for severe infections.In children with mild to moderate impairment of renal function (creatinine clearance of 70 to 40 mL/minute), 60% of the normal daily dose given in divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/minute), 25% of the normal daily dose given in divided doses every 12 hours should be sufficient. In children with marked impairment (creatinine clearance of 20 to 5 mL/minute), 10% of the normal daily dose given every 24 hours should be adequate. All dosage recommendations apply after an initial loading dose.
Since safety for use in premature infants and in infants aged under 1 month has not been established, the use of Kefzol in these patients is not recommended.
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/KEFZOL5.gif
Overdosage
Signs and symptoms. Toxic signs and symptoms following an overdose of Kefzol may include pain, inflammation and phlebitis at the injection site.
The administration of inappropriately large doses of parenteral cephalosporins may cause dizziness, paraesthesias and headaches. Seizures may occur following overdosage with some cephalosporins, particularly in patients with renal impairment, in whom accumulation is likely to occur.
Laboratory abnormalities may include elevations in creatinine, serum urea, liver enzymes and bilirubin, a positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leucopenia and prolongation of the prothrombin time.
Treatment. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient.
If seizures occur, the drug should be discontinued promptly; anticonvulsant therapy may be administered if clinically indicated. Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc.
In cases of severe overdosage, especially in a patient with renal failure, combined haemodialysis and haemoperfusion may be considered if response to more conservative therapy fails. However, no data supporting such therapy are available.
Contact the Poisons Information Centre on 131 126 for management of overdose.
Presentation
Powder for injection, 1 g: 10's (vials).
Storage
Store below 30°C and protect from light. Upon reconstitution, Kefzol and dilutions of Kefzol in the recommended intravenous fluids are stable for 24 hours if stored under refrigeration (2 to 8°C). To reduce microbiological hazards, use as soon as practicable after reconstitution. Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.
Reference
• *Bauer, A.W., Kirby, W.M.M., Sherris, J.C., and Turck, M.: Antibiotic Susceptibility Testing by a Standardized Single Disc Method. Am. J. Clin. Path., 45: 493, 1966.
• Standardized Disc Susceptibility Test, Federal Register, 37: 20527–29, 1972; 39: 19182–19184, 1974.
