Cefuroxime and Clavulanic Acid Formulations, Tablets, Products, Syrup, Suspension from Leading Contract Manufacturers of India

MICROBIOLOGY^6,7:

The in vivo bactericidal activity of cefuroxime axetil is due to cefuroxime's binding to essential target proteins and the resultant inhibition of cell-wall synthesis.

Cefuroxime has bactericidal activity against a wide range of common pathogens, including many beta-lactamase–producing strains. Cefuroxime is stable to many bacterial beta-lactamases, especially plasmid-mediated enzymes that are commonly found in enterobacteriaceae.

Cefuroxime has been demonstrated to be active against most strains of the following microorganisms:

Aerobic Gram-Positive Microorganisms:
Staphylococcus aureus (including beta-lactamase–producing strains)
Streptococcus pneumoniae
Streptococcus pyogenes

Aerobic Gram-negative Microorganisms:
Escherichia coli
Haemophilus influenzae (including beta-lactamase–producing strains
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis (including beta-lactamase–producing strains)
Neisseria gonorrhoeae (including beta-lactamase–producing strains)

Spirochetes:
Borrelia burgdorferi

Cefuroxime has been shown to be active in vitro against most strains of the following microorganisms; however, the clinical significance of these findings is unknown.

Cefuroxime exhibits in vitro minimum inhibitory concentrations (MICs) of 4.0 mcg/mL or less (systemic susceptible breakpoint) against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of cefuroxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-negative Microorganisms:

Aerobic Gram-Positive Microorganisms:
Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus agalactiae

NOTE: Listeria monocytogenes and certain strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cefuroxime. Methicillin-resistant Staphylococci are resistant to cefuroxime.

Anaerobic Gram-positive Microorganisms:

Morganella morganii
Proteus inconstans
Proteus mirabilis
Providencia rettgeri

NOTE:Pseudomonas spp., Campylobacter spp., Acinetobacter calcoaceticus, Legionella spp., and most strains of Serratia spp. and Proteus vulgaris are resistant to most first- and second-generation cephalosporins. Some strains of Morganella morganii, Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins.

Anaerobic Microorganisms:

Peptococcus niger

NOTE: Most strains of Clostridium difficile and Bacteroides fragilis are resistant to cefuroxime.

IN-VITRO AND IN-VIVO SUMMARY / CLINICAL TRIAL SUMMARY: ^1-5:

Early Lyme disease: Two adequate and well-controlled studies were performed in patients with early Lyme disease. In these studies all patients had to present with physician-documented erythema migrans, with or without systemic manifestations of infection. Patients were randomized in a 1:1 ratio to a 20-day course of treatment with cefuroxime axetil 500 mg twice daily or doxycycline 100 mg 3 times daily. Patients were assessed at 1 month posttreatment for success in treating early Lyme disease (Part I) and at 1 year post treatment for success in preventing the progression to the sequelae of late Lyme disease (Part II).

A total of 355 adult patients (181 treated with cefuroxime axetil and 174 treated with doxycycline) were enrolled in the 2 studies. In order to objectively validate the clinical diagnosis of early Lyme disease in these patients, 2 approaches were used: 1) blinded expert reading of photographs, when available, of the pretreatment erythema migrans skin lesion; and 2) serologic confirmation (using enzyme-linked immunosorbent assay [ELISA] and immunoblot assay [“Western” blot]) of the presence of antibodies specific to Borrelia burgdorferi, the etiologic agent of Lyme disease. By these procedures, it was possible to confirm the physician diagnosis of early Lyme disease in 281 (79%) of the 355 study patients. The efficacy data summarized below are specific to this “validated” patient subset, while the safety data summarized below reflect the entire patient population for the 2 studies.

Secondary Bacterial Infections of Acute Bronchitis: Four randomized, controlled clinical studies were performed comparing 5 days versus 10 days of CEFUROXIME-CLAV for the treatment of patients with secondary bacterial infections of acute bronchitis. These studies enrolled a total of 1,253 patients (CAE-516 n = 360; CAE-517 n = 177; CAEA4001 n = 362; CAEA4002 n = 354). The protocols for CAE-516 and CAE-517 were identical and compared CEFUROXIME-CLAV 250 mg twice daily for 5 days, CEFUROXIME-CLAV 250 mg twice daily for 10 days, and AUGMENTIN® 500 mg 3 times daily for 10 days. These 2 studies were conducted simultaneously. CAEA4001 and CAEA4002 compared CEFUROXIME-CLAV 250 mg twice daily for 5 days, CEFUROXIME-CLAV 250 mg twice daily for 10 days, and CECLOR® 250 mg 3 times daily for 10 days. They were otherwise identical to CAE-516 and CAE-517 and were conducted over the following 2 years. Patients were required to have polymorphonuclear cells present on the Gram stain of their screening sputum specimen, but isolation of a bacterial pathogen from the sputum culture was not required for inclusion.

PHARMACOKINETICS⁶:

After oral administration cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolysed in the body to release cefuroxime into the circulation. Approximately 60% of an administered dose is absorbed. Optimum absorption occurs when it is administered after a light meal. Absorption is not decreased by drugs which affect gastrointestinal motility e.g. loperamide, diphenoxylate or castor oil. However, absorption is decreased by concurrent administration of drugs such as ranitidine.

The mean peak serum level of cefuroxime following a 250 mg dose in normal healthy adults, after food, was 4.1 mg/L and occurred two to three hours after dosing. Serum levels were significantly higher in the elderly, apparently due to slower excretion. Unhydrolysed drug was not detected in the serum but 1-2% of the administered dose is excreted in the urine in a form which indicates that small amounts of the intact ester are absorbed into circulation. The mean serum half life of cefuroxime is approximately 1.2 hours. Protein binding has been variously stated as 33-50% depending on the methodology used. Cefuroxime is not metabolized to any significant extent.

Excretion occurs mainly through the kidney both by glomerular filtration and tubular secretion. Approximately 49% of an administered dose, after food, is recovered in the urine in 24 hours; urinary recovery is significantly reduced if the drug is taken on an empty stomach.

After 250 mg dose urinary concentrations at 0-6 and 6-12 hours were 227 mcg/mL (range 92-515) and 35.3 mcg/mL (range 7.6-102) respectively.

Concurrent administration of probenecid prolongs the terminal half life of cefuroxime. Serum levels of cefuroxime are reduced by haemodialysis.

ADVERSE EVENTS^8-9:

Adverse reactions to cefuroxime axetil have been generally mild and transient in nature. The following adverse reactions to cefuroxime axetil have been reported. However, the possibility of the occurrence of other adverse reactions, seen with the cephalosporin class of antibiotics, should be borne in mind.

Major adverse reactions which may occur are diarrhea/loose motions, nausea/vomiting, transient elevation in AST, ALT, LDH, Eosinophilia.
Other adverse events that may occur are abdominal pain, abdominal cramps, flatulence, indigestion, headache, vaginitis, vulvar itch, rash, hives, itch, dysuria, chills, chest pain, shortness of breath, mouth ulcers, swollen tongue, sleepiness, thirst, anorexia.

WARNINGS / PRECAUTIONS^1-3:

TABLETS AND ORAL SUSPENSION ARE NOT BIOEQUIVALENT AND ARE THEREFORE NOT SUBSTITUTABLE ON A MILLIGRAM-PER-MILLIGRAM BASIS
Before therapy with CEFUROXIME-CLAV is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins or other drugs.
Because cefuroxime is excreted in human milk, consideration should be given to discontinuing nursing temporarily during treatment with cefuroxime.
Prescribing CEFUROXIME-CLAV in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Cephalosporins, including cefuroxime, should be given with caution to patients receiving concurrent treatment with potent diuretics because these diuretics are suspected of adversely affecting renal function.
Cefuroxime, as with other broad-spectrum antibiotics, should be prescribed with caution in individuals with a history of colitis.

DRUG INTERACTIONS^1-2:

Probenecid: Concomitant administration of probenecid with cefuroxime axetil tablets increases the area under the serum concentration versus time curve by 50%. The peak serum cefuroxime concentration after a 1.5-g single dose is greater when taken with 1 g of probenecid (mean = 14.8 mcg/mL) than without probenecid (mean = 12.2 mcg/mL).

Antacids: Drugs that reduce gastric acidity may result in a lower bioavailability of CEFUROXIME-CLAV compared with that of fasting state and tend to cancel the effect of postprandial absorption.

Oral contraceptives: In common with other antibiotics, cefuroxime axetil may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone.

REFERENCES

Prescribing information for Cefuroxime.
Prescribing information for Clavulanic acid
Perry CM, Brogden RN. Cefuroxime axetil. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1996, 52, 125-58.
Tartaglione, T. A. and Polk, R. E. Review of the new second-generation cephalosporins: cefonicid, ceforanide, and cefuroxime. Drug Intelligence & Clinical Pharmacy, 1985, 19, 188-198.
Brambilla, C.; Kastanakis, S.; Knight, S. and Cunningham, K. Cefuroxime and cefuroxime axetil versus amoxicillin plus clavulanic acid in the treatment of lower respiratory tract infections, Eur. J. Clin. Microbiol. Infect. Dis., 1992, 11, 118-24.
National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 3rd ed. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25. Villanova, Pa: NCCLS; 1993.
National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. 4th ed. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7. Villanova, Pa: NCCLS; 1990.
Mayorga C, Torres M, Blanca M. Cephalosporin allergy. N Engl J Med 2002; 236:380–381
Norrby S. Side effects of cephalosporins. Drug 1987; 34(Suppl 2):105–120.