Mandol (Cefamandole)

MANDOL®

Lilly

Cefamandole Nafate

Antibiotic

Action And Clinical Pharmacology: Cefamandole, a semisynthetic cephalosporin antibiotic, possesses properties similar to other members of this group, but has a broader spectrum of activity particularly with respect to the treatment of Gram-negative bacillary infections.

Cefamandole has been shown to be active against the following organisms in vitro:

Gram-positive: b-hemolytic and other strains of streptococci including S. pneumoniae (many strains of S. faecalis are resistant), Staphylococci, both penicillin-resistant and sensitive including S. epidermidis and many methicillin-resistant strains.

Gram-negative: H. influenzae including ampicillin-resistant strains. E. coli. Enterobacter sp. (many strains of E. cloacae are resistant). K. pneumoniae. P. mirabilis. Indole-positive Proteus sp., including P. morganii, P. rettgeri and some strains of P. vulgaris. Salmonella sp. including S. typhosa. Serratia sp. (many strains of S. marcescens and other Serratia sp. are resistant).

Anaerobic Organisms: Bacteroides, Clostridia, Peptococci, Peptostreptococci.

High concentrations of cefamandole may be required for clinical efficacy against some strains of Proteus, Enterobacter, Serratia, and Bacteroides.

Pseudomonas organisms are resistant to cefamandole.

b-Lactamase Stability: Cefamandole is resistant to hydrolysis by b-lactamase from S. aureus (penicillinase), and by b-lactamases (sometimes referred to as cephalosporinases) from certain members of the Enterobacteriacae family.

Susceptibility testing continues to be the most effective method to determine the usefulness of a specific antibiotic in treating an infection.

The O-formyl group of cefamandole nafate is rapidly hydrolyzed to cefamandole sodium when a solution is prepared using an appropriate diluent. The sodium carbonate in Mandol enhances the hydrolysis rate and does not affect cefamandole serum concentrations after i.v. or i.m. administration. In vivo studies have demonstrated that cefamandole sodium is the major circulating antibiotic (85 to 89% of total plasma concentration). No apparent differences in cefamandole serum concentration and total urinary excretion were observed when cefamandole nafate was compared with cefamandole sodium.

Cefamandole nafate i.m. administration to normal subjects resulted in detectable cefamandole concentrations within 15 minutes. Mean peak concentrations of approximately 13 and 25 µg/mL were attained after 0.5 and 1.0 g i.m. doses, respectively. The time to achieve peak concentrations ranged from 30 to 120 minutes. Cefamandole was excreted in urine, with approximately 43 to 77% of the dose being recovered in 0 to 8 hours. Results for cefamandole disposition were comparable between adult patients and infants or children whose ages ranged from 3 months to 13 years, respectively.

I.V. administration of a single 1 g cefamandole nafate dose resulted in a mean cefamandole serum concentration of 139 µg/mL at 10 minutes. This concentration declined to 0.8 µg/mL at 4 hours. Following single doses of 2, 3 and 4 g, serum concentrations were 240, 533 and 666 µg/mL respectively at 10 minutes and these declined to 2.2, 2.9 and 3.9 µg/mL respectively at 4 hours. Assayable concentrations were present for 8 hours after 2 and 4 g doses. Multiple dose studies performed on normal subjects receiving 4 g of cefamandole nafate on various regimens for 4 or 5 days or even longer periods produced no evidence of accumulation.

Cefamandole’s half-life is dependent on the administration route, e.g., 34 minutes and 59 minutes after i.v. and i.m. administration, respectively.

Cefamandole is excreted by glomerular filtration as well as by active tubular secretion. Since 65 to 80% of an i.m. or i.v. dose is excreted over an 8 hour period, high urinary concentrations result, i.e., an average of 359 µg/mL following a 500 mg i.m. dose and 816 µg/mL after a 1 g i.v. dose. Probenecid slows tubular excretion and doubles the peak serum concentration and the duration of measurable serum concentrations.

In the presence of renal impairment, urinary excretion of cefamandole is slower. A study comparing 14 patients with normal kidney function to 9 patients with impaired renal function showed that, after a 500 mg i.m. dose, total urinary excretion values over 7.5 hours were significantly lower in the patients with renal impairment. Following a 1 g dose, a difference was still apparent but considered to be not significant. In one study, serum half-life of cefamandole in patients with normal renal function averaged 1.7 hours, whereas the average half-life in patients with varying degrees of kidney impairment (serum creatinine >1.6 mg/100 mL) was 3 hours. On the basis of these data, and because cefamandole is excreted almost exclusively by the kidneys, the dosage should be adjusted according to the degree of renal impairment.

The antibiotic reaches therapeutic concentrations in pleural and joint fluids and in bile and bone.

Indications And Clinical Uses: Cefamandole may be indicated in the treatment of the following infections caused by susceptible organisms: lower respiratory tract infections such as pneumonia and pulmonary complications resulting from cystic fibrosis; urinary tract infections; septicemia; soft tissue and postsurgical infections such as peritonitis, cellulitis, abscesses, wound infections; bone and joint infections.

Perform appropriate culture and susceptibility studies. On the basis of clinical judgment and anticipated bacteriological findings, therapy may be instituted before results of susceptibility studies are obtained. Antibiotic treatment may be modified once these results become available.

Contra-Indications: Hypersensitivity to cephalosporin antibiotics.

Manufacturers’ Warnings In Clinical States: Before therapy with cefamandole is instituted, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins or other drugs. Cephalosporin C derivatives should be given with caution to penicillin-sensitive patients.

Antibiotics including cefamandole should be administered with caution, and then only when absolutely necessary, to any patient who has demonstrated some form of allergy, particularly to drugs.

As is the case with all new drugs, patients should be followed carefully so that adverse reactions or unusual manifestations of drug idiosyncrasy may be detected. If an allergic reaction to cefamandole occurs, the drug should be discontinued and the patient treated with the usual agents (e.g., epinephrine, antihistamines, pressor amines or corticosteroids).

In newborn infants, accumulation of cephalosporin-class antibiotics (with a resulting prolongation of drug half-life) has been reported.

Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics, including cefamandole. Therefore, it is important to consider its diagnosis in patients administered cefamandole who develop diarrhea. Such colitis may range in severity from mild to life-threatening.

Treatment with broad-spectrum antibiotics including cefamandole may alter the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is one primary cause of antibiotic-associated colitis.

Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, management should include sigmoidoscopy, appropriate bacteriologic studies, and fluid, electrolyte, and protein supplementation. When the colitis does not improve after the administration of cefamandole has been discontinued, or when it is severe, consideration should be given to the administration of oral vancomycin.

Precautions: Pregnancy: Cefamandole’s safety in the treatment of infections during pregnancy has not been established. Therefore, if the drug’s administration to pregnant patients is considered necessary, weigh the potential benefits against the possible hazards to the fetus.

Although cefamandole rarely produces alterations in kidney function, evaluation of renal status is recommended, especially in seriously ill patients receiving high doses. Place patients with impaired renal function on the special dosage schedule (see Dosage), because doses in these individuals are likely to produce excessive serum concentrations.

Studies suggest that the concurrent use of potent diuretics such as furosemide and ethacrynic acid may increase the risk of renal toxicity with cephalosporins. Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

In a few patients receiving cefamandole, nausea, vomiting and vasomotor instability with hypotension and peripheral vasodilation occurred following ingestion of ethanol. These effects are probably due to the inhibition of acetaldehyde dehydrogenase which causes accumulation of acetaldehyde when ethanol is administered concomitantly.

Hypoprothrombinemia, with or without bleeding, has been reported rarely, but it has been promptly reversed by administration of vitamin K. Such episodes usually have occurred in elderly, debilitated, or otherwise compromised patients with deficient stores of vitamin K. Treatment of such individuals with antibiotics possessing Gram-negative and/or anaerobic activity is thought to alter the number and/or type of intestinal bacterial flora, with consequent reduction in synthesis of vitamin K. Prophylactic administration of vitamin K may be indicated in such patients, especially when procedures such as intestinal sterilization are performed.

Erythropenia and decreases in hematocrit values and hemoglobin concentrations have been observed.

Prolonged use of cefamandole may result in the overgrowth of nonsusceptible organisms. Constant patient observation is essential. If superinfection occurs during therapy, take appropriate measures.

Some individuals have developed positive direct Coombs’ test during treatment with cephalosporin antibiotics.

In patients treated with cefamandole, 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 (Glucose Enzymatic Test Strip USP). A false positive test for protein in the urine can occur with acid or denaturization precipitation tests.

Adverse Reactions: Hypersensitivity: Maculopapular rash, urticaria, eosinophilia, anaphylaxis and drug fever have been reported. These reactions are most likely to occur in patients with a history of allergy, particularly to penicillin.

Blood: Thrombocytopenia has been reported rarely. Neutropenia has been reported, especially in long courses of treatment. Some individuals have developed positive direct Coomb’s test during cephalosporin treatment. Erythropenia and decreases in hematocrit values and hemoglobin concentrations have been observed.

Hepatic: Transient increases in AST, ALT, alkaline phosphatase and bilirubin concentrations have been noted. Transient hepatitis or cholestatic jaundice occurred in a few patients.

Renal: BUN increases and decreased creatinine clearance have been reported, particularly in patients with prior renal impairment.

Local: Pain on i.m. injection, phlebitis and thrombophlebitis have occurred infrequently.

Gastrointestinal: Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely. As with some penicillins and some other cephalosporins, transient hepatitis and colistatic jaundice have been reported rarely.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The administration of inappropriately large doses of parenteral cephalosporins may cause seizures, particularly in patients with renal impairment. Dosage reduction is necessary when renal function is impaired (see Dosage). If seizures occur, the drug should be promptly discontinued; anticonvulsant therapy may be administered if clinically indicated. Hemodialysis may be considered in cases of overwhelming overdosage.

Other than general supportive treatment, no specific antidote is known. Although cefamandole is poorly dialyzed, the rate of removal by hemodialysis is slightly better than that by peritoneal dialysis.

Dosage And Administration: After reconstitution, cefamandole may be administered i.v. or i.m. Dosage and route of administration should be determined by the severity of infection, susceptibility of the causative organisms, and condition of the patient.

Adults: The usual daily i.v. or i.m. dosage is 500 mg to 1 g every 4 to 8 hours (i.e., 1.5 to 6 g/day). Higher doses may be required for some bone and joint infections and those infections due to anaerobic organisms. In severe infections, the usual dosage is 1 g every 4 to 6 hours.

In life-threatening infections, doses up to 2 g every 4 hours may be needed (i.e., 12 g/day). The duration of treatment should normally not exceed 2 weeks. Antibiotic therapy for b-hemolytic streptococcal infections should continue for at least 10 days (see Infants and Children).

A dosage of 500 mg every 6 hours is adequate for uncomplicated pneumonia and soft tissue infections.

A dosage of 500 mg every 8 hours is sufficient for mild urinary tract infections. One g may be administered every 8 hours in moderate infections and every 4 to 6 hours in severe infections.

The i.v. route may be preferable for patients with septicemia, localized parenchymal abscesses such as intra- abdominal abscess and peritonitis or other severe or life threatening infections in patients who may be poor risks because of lowered resistance.

For infections in patients with normal renal function, the i.v. dosage is 3 to 12 g/day. In conditions such as septicemia, initiate treatment with 6 to 12 g/day; then, depending on the clinical response and laboratory findings, gradually reduce the dosage.

Infants and Children: Administration of 50 to 100 mg/kg/day in equally divided doses every 4 to 8 hours has been effective in children for most infections susceptible to cefamandole. This may be increased to a total daily dose of 150 mg/kg (not to exceed the maximum adult dose) for serious infections.

Note: As a general principle, antibiotic therapy should be continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended in infections caused by group A beta-hemolytic streptococci in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infections and may be required for several months after therapy has been completed; persistent infections may require longer treatment; doses smaller than those indicated above should not be used.

Impaired Renal Function: For adults, when renal function is impaired, employ a reduced dosage and monitor the serum concentration closely. After an initial loading dose of 1 to 2 g (depending on the severity of infection), calculate the maintenance dosage (see Table I) relative to the degree or renal impairment, severity of infection and susceptibility of the causative organism.

Note: Although cefamandole is poorly dialyzed, the rate of removal by hemodialysis is slightly better than that by peritoneal dialysis.

Note: Consider concomitant administration of aminoglycoside antibiotics such as tobramycin in certain cases of sepsis and serious infections, particularly in immunosuppressed patients, as initial therapy while awaiting culture and susceptibility results. Antibiotic treatment may be modified once these results have become available. Monitor renal function carefully especially if high doses are to be given.

Mandol and aminoglycosides should not be mixed in the same vial, infusion container or volume control chamber.

Note: I.M. administration is not recommended for anaerobic infections which require the i.v. administration of about 2 g every 4 to 6 hours to attain adequate concentrations.

Reconstitution: For i.m. use, reconstitute Mandol with sterile water for injection, bacteriostatic water for injection, 0.9% sodium chloride injection or bacteriostatic sodium chloride injection. Use 3 mL for the 1 g vial. Mandol is sometimes difficult to dissolve and requires vigorous shaking. Dissolution is facilitated by keeping the powder at the stopper end of the vial while adding the diluent to the other end of the vial.

Carbon dioxide for sodium carbonate develops inside the reconstituted vial during storage. This pressure may be dissipated prior to withdrawing the vial contents, or the pressure may be used to aid withdrawal by inverting the vial over the syringe needle and allowing the contents to flow into the syringe. Employ proper aseptic techniques at all times. When used as multiple dose containers, reconstitute with bacteriostatic water for injection or bacteriostatic sodium chloride injection.

I.M.: For i.m. administration, inject Mandol into a large muscle mass (such as the gluteus or lateral part of the thigh) to minimize pain.

Direct I.V. (Bolus) Injection: The reconstituted solution should be injected slowly over a period of 3 to 5 minutes.

Intermittent I.V. Infusion: For Mandol administration during the infusion of other i.v. fluids, a Y type administration set or volume control set may be used. During infusion of the solution containing Mandol, discontinue administration of the other solution. Careful attention should be paid to the infused volume of the Mandol solution to ensure administration of the correct dose.

Note: If therapy with cefamandole is carried out in combination with an aminoglycoside antibiotic, either, each of these antibiotics should be administered at different sites, or cefamandole and the aminoglycoside should be administered sequentially by intermittent i.v. infusion. After the administration of 1 of the 2 drugs, the tubing should be flushed very carefully and thoroughly with an approved solution for reconstitution and then administer the other drug solution. An aminoglycoside should not be mixed with cefamandole in the same container.

For i.v. administration, Mandol may be administered by i.v. injection or by either continuous or intermittent infusion. Reconstitute with sterile water for injection or, if required, bacteriostatic water for injection. Shake well until dissolved. The reconstituted Mandol must be further diluted to desired volume with any of the solutions for i.v. infusion.

For direct i.v. injection or intermittent i.v. infusion, reconstitute each g of Mandol with 10 to 20 mL of diluent and administer slowly over a 3- to 5-minute period.

For continuous i.v. infusion, reconstitute each g of Mandol with 10 mL of sterile water for injection. This solution may be added to an i.v. bottle/bag containing any of the solutions for i.v. infusion listed below. The following i.v. infusion fluids are compatible with Mandol and may be used as diluents: 0.9% sodium chloride injection; 5% and 10% dextrose injection; 5% dextrose and 0.9%, 0.45%, or 0.2% sodium chloride injection; lactated Ringer’s and 5% dextrose.

Storage: Reconstituted Mandol Solutions stored at room temperature must be discarded after 24 hours or after 72 hours if stored under refrigeration.

Further diluted infusion mixtures should be prepared immediately before use and any unused portion must be discarded.

Incompatibility: Mandol should not be added to blood products, protein hydrolysates or amino acids. It should not be mixed with an aminoglycoside.

Availability And Storage: Each 10 mL dry powder, rubber stoppered vial contains: 1 g (equivalent to cefamandole 1 g and sodium carbonate 63 mg; sodium content: 3.3 mmol (77 mg)/vial). Each 25 mL rubber stoppered vial contains: cefamandole nafate 2 g (equivalent to cefamandole 2 g and sodium carbonate 126 mg; sodium: 6.6 mmol (154 mg)/vial).

MANDOL® Lilly Cefamandole Nafate Antibiotic

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