Mandol® (Cefamandole Nafate for Injection, USP) is a semisynthetic broad-spectrum cephalosporin antibiotic for parenteral administration. It is 5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(formyloxy)phenylacetyl]amino]-3-[[(1-methyl-1 H -tetrazol-5-yl)thio]methyl]-8-oxo-, monosodium salt, [6 R- [6(alpha),7(beta)( R *)]]. Cefamandole has the empirical formula C ₁₉ H ₁₇ N ₆ NaO ₆ S ₂ representing a molecular weight of 512.49.

Mandol also contains 63 mg sodium carbonate/g of cefamandole activity. The total sodium content is approximately 77 mg (3.3 mEq sodium ion) per g of cefamandole activity. After addition of diluent, cefamandole nafate rapidly hydrolyzes to cefamandole, and both compounds have microbiologic activity in vivo. Solutions of Mandol range from light-yellow to amber, depending on concentration and diluent used. The pH of freshly reconstituted solutions usually ranges from 6.0 to 8.5.

Mandol is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below:

Lower respiratory infections, including pneumonia, caused by S. pneumoniae, H. influenzae, Klebsiella spp., S. aureus (penicillinase- and non-penicillinase-producing), (beta)-hemolytic streptococci, and P. mirabilis

Urinary tract infections caused by E. coli, Proteus spp. (both indole-negative and indole-positive), Enterobacter spp., Klebsiella spp., group D streptococci (Note: Most enterococci, eg, E. faecalis, are resistant), and S. epidermidis

Peritonitis caused by E. coli  and Enterobacter spp.

Septicemia caused by E. coli, S. aureus (penicillinase- and non-penicillinase-producing), S. pneumoniae, S. pyogenes (group A (beta)-hemolytic streptococci), H. influenzae, and Klebsiella spp.

Skin and skin structure infections caused by S. aureus (penicillinase- and non-penicillinase-producing), S. pyogenes (group A (beta)-hemolytic streptococci), H. influenzae, E. coli, Enterobacter spp., and P. mirabilis

Bone and joint infections caused by S. aureus (penicillinase- and non-penicillinase-producing)

Clinical microbiologic studies in nongonococcal pelvic inflammatory disease in females, lower respiratory infections, and skin infections frequently reveal the growth of susceptible strains of both aerobic and anaerobic organisms. Mandol has been used successfully in those infections in which several organisms have been isolated. Most strains of B. fragilis are resistant in vitro; however, infections caused by susceptible strains have been treated successfully.

Specimens for bacteriologic cultures should be obtained in order to isolate and identify causative organisms and to determine their susceptibilities to cefamandole. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly.

In certain cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, Mandol may be used concomitantly with an aminoglycoside ( see Precautions ). The recommended doses of both antibiotics may be given, depending on the severity of the infection and the patient's condition. The renal function of the patient should be carefully monitored, especially if higher dosages of the antibiotics are to be administered.

Antibiotic therapy of (beta)-hemolytic streptococcal infections should continue for at least 10 days.

Preventive Therapy  The administration of Mandol preoperatively, intraoperatively, and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures that are classified as contaminated or potentially contaminated (eg, gastrointestinal surgery, cesarean section, vaginal hysterectomy, or cholecystectomy in high-risk patients such as those with acute cholecystitis, obstructive jaundice, or common-bile-duct stones).

In major surgery in which the risk of postoperative infection is low but serious (cardiovascular surgery, neurosurgery, or prosthetic arthroplasty), Mandol may be effective in preventing such infections.

If signs of infection occur, specimens for culture should be obtained for identification of the causative organism so that appropriate antibiotic therapy may be instituted.

Dosage Adults:   The usual dosage range for cefamandole is 500 mg to 1 g every 4 to 8 hours.

In infections of skin structures and in uncomplicated pneumonia, a dosage of 500 mg every 6 hours is adequate.

In uncomplicated urinary tract infections, a dosage of 500 mg every 8 hours is sufficient. In more serious urinary tract infections, a dosage of 1 g every 8 hours may be needed.

In severe infections, 1-g doses may be given at 4 to 6-hour intervals.

In life-threatening infections or infections due to less susceptible organisms, doses up to 2 g every 4 hours (ie, 12 g/day) may be needed.

Infants and Children:   Administration of 50 to 100 mg/kg/ day in equally divided doses every 4 to 8 hours has been effective for most infections susceptible to Mandol. This may be increased to a total daily dose of 150 mg/kg (not to exceed the maximum adult dose) for severe infections. ( See recommendations regarding this age group in WARNINGS and Precautions.)

Note:   As with antibiotic therapy in general, administration of Mandol 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 infection and may be required for several months after therapy has been completed; persistent infections may require treatment for several weeks; and doses smaller than those indicated above should not be used.

For perioperative use of Mandol, the following dosages are recommended:

Adults  1 or 2 g intravenously or intramuscularly ¹ / ₂ to 1 hour prior to the surgical incision followed by 1 or 2 g every 6 hours for 24 to 48 hours.

Pediatric Patients (3 months of age and older)  50 to 100 mg/kg/day in equally divided doses by the routes and schedule designated above.

Note:   In patients undergoing prosthetic arthroplasty, administration is recommended for as long as 72 hours.

In patients undergoing cesarean section, the initial dose may be administered just prior to surgery or immediately after the cord has been clamped.

Impaired Renal Function  When renal function is impaired, a reduced dosage must be employed and the serum levels closely monitored. After an initial dose of 1 to 2 g (depending on the severity of infection), a maintenance dosage schedule should be followed (see chart). Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organism.

When only serum creatinine is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

Males:          Weight (kg) x (140 - age)
                   72 x serum creatinine

Females:      0.9 x above value

Modes of Administration  Mandol may be given intravenously or by deep intramuscular injection into a large muscle mass (such as the gluteus or lateral part of the thigh) to minimize pain.

Intramuscular Administration  Each g of Mandol should be diluted with 3 mL of 1 of the following diluents: Sterile Water for Injection, Bacteriostatic Water for Injection, 0.9% Sodium Chloride Injection, or Bacteriostatic Sodium Chloride Injection. Shake well until dissolved.

Intravenous Administration  The intravenous route may be preferable for patients with bacterial septicemia, localized parenchymal abscesses (such as intra-abdominal abscess), peritonitis, or other severe or life-threatening infections when they may be poor risks because of lowered resistance. In those with normal renal function, the intravenous dosage for such infections is 3 to 12 g of Mandol daily. In conditions such as bacterial septicemia, 6 to 12 g/day may be given initially by the intravenous route for several days, and dosage may then be gradually reduced according to clinical response and laboratory findings.

If combination therapy with Mandol and an aminoglycoside is indicated, each of these antibiotics should be administered in different sites. Do not mix an aminoglycoside with Mandol in the same intravenous fluid container.

A SOLUTION OF 1 G OF MANDOL IN 22 ML OF STERILE WATER FOR INJECTION IS ISOTONIC.

The choice of saline, dextrose, or electrolyte solution and the volume to be employed are dictated by fluid and electrolyte management.

For direct intermittent intravenous administration, each g of cefamandole should be reconstituted with 10 mL of Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection. Slowly inject the solution into the  vein  over  a  period  of  3  to  5 minutes, or give it through the tubing of an administration set while the patient is also receiving 1 of the following intravenous fluids:

0.9% Sodium Chloride Injection; 5% Dextrose Injection; 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.2% Sodium Chloride Injection; or Sodium Lactate Injection (M/6).

Intermittent intravenous infusion with a Y-type administration set or volume control set can also be accomplished while any of the above-mentioned intravenous fluids are being infused. However, during infusion of the solution containing Mandol, it is desirable to discontinue the other solution. When this technique is employed, careful attention should be paid to the volume of the solution containing Mandol so that the calculated dose will be infused. If Sterile Water for Injection is used as the diluent, reconstitute with approximately 20 mL/g to avoid a hypotonic solution.

For continuous intravenous infusion, each g of cefamandole should be diluted with 10 mL of Sterile Water for Injection. An appropriate quantity of the resulting solution may be added to an IV bottle containing 1 of the following fluids: 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.2% Sodium Chloride Injection; or Sodium Lactate Injection (M/6).

STABILITY

Reconstituted Mandol is stable for 24 hours at room temperature (25°C) and for 96 hours if stored under refrigeration (5°C). During storage at room temperature, carbon dioxide develops inside the vial after reconstitution. This pressure may be dissipated prior to withdrawal of the vial contents, or it may be used to aid withdrawal if the vial is inverted over the syringe needle and the contents are allowed to flow into the syringe.

Solutions of Mandol in Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection that are frozen immediately after reconstitution in the conventional vials in which the drugs are supplied are stable for 6 months when stored at -20°C. If the product is warmed (to a maximum of 37°C), care should be taken to avoid heating it after the thawing is complete. Once thawed, the solution should not be refrozen.

Vials (Dry Powder):

1 g. * 10-mL size (No. 7061) (Traypak ** of 25) NDC 0002-7061-25

2 g, * 20-mL size (No. 7064) (Traypak of 10) NDC 0002-7064-10

*Equivalent to cefamandole activity.

** Traypak ^TM (multivial carton, Lilly).

1. Bauer AW, Kirby WMM, et al: Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol 1966;45:493. Standardized disk susceptibility test. Federal Register 1974;39:19182-19184. National Committee for Clinical Laboratory Standards. Approved Standard: M2-A3 Performance standards for antimicrobial disk susceptibility tests Fourth Edition, December, 1988.
2. Determined by the ICS agar-dilution method (Ericsson HM, Sherris JC: Acta Pathol Microbiol Scand 1971;[suppl 217]:B), or any other method that has been shown to give equivalent results.

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 cholestatic jaundice have been reported rarely.

Hypersensitivity  Anaphylaxis, maculopapular rash, urticaria, eosinophilia, and drug fever have been reported. These reactions are more 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 Coombs' tests during treatment with the cephalosporin antibiotics.

Liver  Transient rise in SGOT, SGPT, and alkaline phosphatase levels has been noted.

Kidney  Decreased creatinine clearance has been reported in patients with prior renal impairment. As with some other cephalosporins, transitory elevations of BUN have occasionally been observed with Mandol; their frequency increases in patients over 50 years of age. In some of these cases, there was also a mild increase in serum creatinine.

Local Reactions  Pain on intramuscular injection is infrequent. Thrombophlebitis occurs rarely.

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BEFORE THERAPY WITH MANDOL IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

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

Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics (including macrolides, semisynthetic penicillins, and cephalosporins); therefore, it is important to consider its diagnosis in patients who develop diarrhea in association with the use of antibiotics. Such colitis may range in severity from mild to life threatening.

Treatment with broad-spectrum antibiotics 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.

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 drug has been discontinued, or when it is severe, oral vancomycin is the drug of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should be ruled out.

General  Although Mandol rarely produces alteration in kidney function, evaluation of renal status is recommended, especially in seriously ill patients receiving maximum doses.

Prolonged use of Mandol may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

A false-positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution or with Clinitest® tablets. There may be a false-positive test for proteinuria with acid and denaturization-precipitation tests.

As with other broad-spectrum antibiotics, 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 significant 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 intestinal sterilization and surgical procedures are performed.

In a few patients receiving Mandol, nausea, vomiting, and vasomotor instability with hypotension and peripheral vasodilatation occurred following the ingestion of ethanol.

Cefamandole inhibits the enzyme acetaldehyde dehydrogenase in laboratory animals. This causes accumulation of acetaldehyde when ethanol is administered concomitantly.

Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Carcinogenesis, Mutagenesis, Impairment of Fertility  Certain (beta)-lactam antibiotics containing the N-methylthiotetrazole side chain have been reported to cause delayed maturity of the testicular germinal epithelium when given to neonatal rats during initial spermatogenic development (6 to 36 days of age). In animals that were treated from 6 to 36 days of age with 1,000 mg/kg/day of cefamandole (approximately 5 times the maximum clinical dose), the delayed maturity was pronounced and was associated with decreased testicular weights and a reduced number of germinal cells in the leading waves of spermatogenic development. The effect was slight in rats given 50 or 100 mg/kg/day. Some animals that were given 1,000 mg/kg/day during days 6 to 36 were infertile after becoming sexually mature. No adverse effects have been observed in rats exposed in utero, in neonatal rats (4 days of age or younger) treated prior to the initiation of spermatogenesis, or in older rats (more than 36 days of age) after exposure for up to 6 months. The significance to humans of these findings in rats is unknown because of differences in the time of initiation of spermatogenesis, rate of spermatogenic development, and duration of puberty.

Usage in Pregnancy  Pregnancy Category B  Reproduction studies have been performed in rats given doses of 500 or 1,000 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to Mandol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers  Caution should be exercised when Mandol is administered to a nursing woman.

Usage in Infants Mandol has been effectively used in this age group, but all laboratory parameters have not been extensively studied in infants between 1 and 6 months of age; safety of this product has not been established in premature infants and term neonates under 1 month of age. Therefore, if Mandol is administered to infants, the physician should determine whether the potential benefits outweigh the possible risks involved.

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 and Administration ). 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.

Mandol is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.

After intramuscular administration of a 500-mg dose of cefamandole to normal volunteers, the mean peak serum concentration was 13 µg/mL. After a 1-g dose, the mean peak concentration was 25 µg/mL. These peaks occurred at 30 to 120 minutes. Following intravenous doses of 1, 2, and 3 g, serum concentrations were 139, 240, and 533 mcg/mL respectively at 10 minutes. These concentrations declined to 0.8, 2.2, and 2.9 mcg/mL at 4 hours. Intravenous administration of 4-g doses every 6 hours produced no evidence of accumulation in the serum. The half-life after an intravenous dose is 32 minutes; after intramuscular administration, the half-life is 60 minutes.

Sixty-five percent to 85% of cefamandole is excreted by the kidneys over an 8-hour period, resulting in high urinary concentrations. Following intramuscular doses of 500 mg and 1 g, urinary concentrations averaged 254 and 1,357 mcg/mL respectively. Intravenous doses of 1 and 2 g produced urinary levels averaging 750 and 1,380 mcg/mL respectively. Probenecid slows tubular excretion and doubles the peak serum level and the duration of measurable serum concentrations.

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

Microbiology The bactericidal action of cefamandole results from inhibition of cell-wall synthesis. Cephalosporins have in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefamandole is usually active against the following organisms in vitro and in clinical infections:

Gram-positive

Staphylococcus aureus, including penicillinase- and non-penicillinase-producing strains

Staphylococcus epidermidis

(beta)-hemolytic and other streptococci (Most strains of enterococci, eg, Enterococcus faecalis [formerly Streptococcus faecalis ], are resistant.)

Streptococcus pneumoniae

Gram-negative

Escherichia coli

Klebsiella spp.

Enterobacter spp. (Initially susceptible organisms occasionally may become resistant during therapy.)

Haemophilus influenzae

Proteus mirabilis

Providencia rettgeri (formerly Proteus rettgeri )

Morganella morganii (formerly Proteus morganii )

Proteus vulgaris (Some strains of P. vulgaris have been shown by in vitro tests to be resistant to cefamandole and certain other cephalosporins.)

Anaerobic organisms

Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.)

Gram-positive bacilli (including Clostridium spp.)

Gram-negative bacilli (including Bacteroides and Fusobacterium spp.). Most strains of Bacteroides fragilis are resistant.

Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea   spp.), and most Serratia strains are resistant to cefamandole and certain other cephalosporins. Cefamandole is resistant to degradation by (beta)-lactamases from certain members of the Enterobacteriaceae.

Susceptibility Tests  Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure ¹ has been recommended for use with disks to test susceptibility to cefamandole. Interpretation involves correlation of the diameters obtained in the disk test with minimal inhibitory concentration (MIC) values for cefamandole.

Reports from the laboratory giving results of the standardized single-disk susceptibility test ¹ using a 30-mcg cefamandole disk should be interpreted according to the following criteria:

Susceptible organisms produce zones of 18 mm or greater, indicating that the tested organism is likely to respond to therapy.

Organisms of intermediate susceptibility produce zones of 15 to 17 mm, indicating that the tested organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids (eg, urine) in which high antibiotic levels are attained.

Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.

For gram-positive isolates, the test may be performed with either the cephalosporin-class disk (30 mcg cephalothin) or the cefamandole disk (30 mcg cefamandole), and a zone of 18 mm is indicative of a cefamandole-susceptible organism.

Gram-negative organisms should be tested with the cefamandole disk (using the above criteria), since cefamandole has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalosporin-class disk. Gram-negative organisms having zones of less than 18 mm around the cephalothin disk are not necessarily of intermediate susceptibility or resistant to cefamandole.

The cefamandole disk should not be used for testing susceptibility to other cephalosporins.

A bacterial isolate may be considered susceptible if the MIC value for cefamandole ² is not more than 16 mcg/mL. Organisms are considered resistant if the MIC is greater than 32 mcg/mL.

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