Cefuroxime: A Review of its Antibacterial Activity, Pharmacological Properties and Therapeutic Use

Summary

Synopsis: Cefuroxime¹ is a new semisynthetic cephalosporin for parenteral administration. It is resistant to destruction by β-lactamases produced by staphylococci and most Gram-negative aerobic bacteria and is active against many bacteria resistant to cephalothin. Cefuroxime is the most active of the cephalosporins against gonococci and Haemophilus influenzae particularly against β-lactamase producing strains. Given by intramuscular or intravenous injection cefuroxime is effective against a wide variety of infections caused by Gram-positive or Gram-negative aerobes, but has no effect against infections caused by Pseudomonas aeruginosa or B. fragilis. Cefuroxime is of value in the treatment of respiratory infections due to Haemophilus influenzae and Streptococcus pneumoniae and is useful against cephalosporin-resistant Klebsiella and Enterobacter infections. Cefuroxime is an alternative to spectinomycin for the treatment of β-lactamase producing Neisseria gonorrhoeae infections. It is generally well tolerated and appears not to be nephrotoxic when given alone at usual dosages.

Antibacterial Activity: At therapeutic concentrations cefuroxime is active in vitro against Staphylococcus aureus, and epidermidis including β-lactamase producing isolates, Streptococcus pneumoniae viridans and pyogenes, but is generally less active than cephaloridine or than benzylpenicillin against non β-lactamase producing strains. Cefuroxime is less active than cephaloridine, cephalothin or cefamandole against methicillin-resistant Staphylococcus aureus. Cefuroxime is stable against most β-lactamases produced by Gram-negative bacteria and is thus active against a wide range of organisms including Escherichia coli, Klebsiella sp., Proteus mirabilis, Salmonella sp., Shigella sp., Haemophilus influenzae, including ampicillin resistant strains, Neisseria meningitidis, Neisseria gonorrhoeae, including penicillin insensitive strains, and most Enterobacter cloacae as well as some strains of Providencia (P. inconstans), Serratia marcescens, indole-positive Proteus and Acinetobacter sp. Pseudomonas aeruginosa are resistant to cefuroxime, as are many strains of Bacteroides fragilis. Cefuroxime is active in vitro against many strains of Gram-negative bacteria resistant to cephalothin and this is supported by its greater activity in vivo against experimental infection in rats and mice. The minimum bactericidal concentration (MBC) of cefuroxime is generally equal to or twice the minimum inhibitory concentration (MIC).

The inhibitory effect of cefuroxime in vitro is not generally influenced by changes in inoculum size between 10³ and 10⁵ viable cells per ml except for some strains of Serratia sp. and |P. morganii which produce β-lactamases able to hydrolyse cefuroxime, but is often affected when the inoculum size is increased to 10⁷ viable cells per ml. Generally, the osmolarity and conductivity of the culture medium does not affect in vitro activity of the drug.

Pharmacokinetics: Peak serum concentration after a bolus intravenous injection of 750mg is about 53 to 73μg/ml and about 26 to 34μg/ml after the same dose intramuscularly. Although peak serum concentration is not directly proportional to dosage, the area under the serum concentration time curve more closely approaches this situation. Serum levels are elevated by concomitant administration of oral probenecid. The volume of distribution is about 15L. Cerebrospinal fluid concentration is low when the meninges are normal, but preliminary observations suggest that it attains therapeutic levels in meningitis. Bile levels vary considerably between individuals, but appear to be lowest in patients with a non-functioning gall bladder. Cefuroxime concentration in sputum and bronchial secretion is generally low relative to serum levels, but are higher than with cephalothin or cefazolin and usually exceed the MIC of respiratory pathogens. Cefuroxime is 33% bound to serum protein and is metabolised to a negligible degree. Half-life is just over 1 hour in subjects with normal renal function, but increases in the presence of renal impairment, particularly when the glomerular filtration rate falls below 20ml/min. In neonates, serum cefuroxime concentrations tend to be higher in those with low birth weight, and serum half-life is inversely related to age, being 5.6 hours in day old neonates and 4 hours in those 14 days old. Cefuroxime is excreted almost wholly in the urine unchanged, resulting in high urinary concentrations.

Therapeutic Trials: Cefuroxime given mainly by the intramuscular route has been used successfully to treat a wide range of infections caused by Gram-positive and Gram-negative aerobic bacteria. A dosage of 750mg 8-hourly has been used most frequently. Cefuroxime is effective against infections due to cephalothin resistant bacteria. In open trials in patients with pneumonia, acute exacerbation of chronic bronchitis or bronchiectasis, treatment with cefuroxime has resulted in complete clinical remission or an improvement in 62.5 to 100% of patients. An apparently low relapse rate in patients with acute exacerbation of chronic bronchitis has been reported, but suitably designed trials comparing cefuroxime with other effective regimens are necessary to confirm this impression.

Cefuroxime has been used successfully to treat urinary tract infections which in many instances have been either in elderly patients or in those with underlying urological conditions or chronic pyelonephritis. Cefuroxime has usually been ineffective in infections caused by bacteria with limited susceptibility to the drug in vitro and superinfection with S. faecalis or Pseudomonas sp. has been reported in several instances. However, cefuroxime has been effective in urinary tract infections caused by Klebsiella resistant to most other antibiotics.

Meningococcal and Haemophilus meningitis in children have been treated with cefuroxime in conjunction with ampicillin, chloramphenicol and sulphadimidine, but the contribution of cefuroxime to the successful outcome is not clear. In combination with an aminoglycoside, cefuroxime has been used successfully to treat confirmed or suspected septicaemia, whilst cefuroxime alone has been effective in paediatric upper and lower respiratory tract infection and urinary tract infection.

In postoperative respiratory tract infection in patients receiving physiotherapy there was a tendency for cefuroxime to alleviate symptoms and eliminate radiological abnormalities in a larger proportion of patients than placebo, but differences were not statistically significant. In open studies cefuroxime has been used successfully to treat postoperative infections of wounds and of the respiratory and urinary tracts.

A cure rate of 97 to 100% has been reported in males and females with uncomplicated acute gonorrhoea treated with a single intramuscular injection of cefuroxime with or without probenecid. A 750mg dose with probenecid has been consistently effective, as have doses of 1g or 1.5g with or without oral probenecid. It has still to be determined which dose is optimum. To date there have been no formal comparative studies of cefuroxime and penicillin G. The role of cefuroxime in treatment of gonorrhoea due to β-lactamase producing strains is being investigated.

Side Effects: Cefuroxime has generally been well tolerated. Pain at the site of intramuscular injection has been reported with varying frequency, but has mostly been moderate or slight and of short duration. There have been only rare reports of thrombophlebitis with intravenous administration. Skin rash has occurred in about 1 % of patients in published reports although the incidence in the total clinical experience may be lower. Most patients known to be allergic to penicillin have been treated with cefuroxime without any skin reaction, but in a few penicillin-allergic patients skin rash has occurred.

Alteration in liver enzymes, largely minor and transient, have occurred in about 5 % of patients, but these have often involved only one enzyme and have not been reported to be of significance in subsequent clinical management.

Changes indicative of a decrease in renal function have occurred rarely, but the contribution of cefuroxime to these changes has not been clear. As cefuroxime is likely to be used in conjunction with an aminoglycoside in some clinical situations, further data on the renal effects of such a combination are needed before the safety of such combined therapy can be determined.

Precautions: As there is evidence of cross-allergenicity between the cephalosporins and the penicillins and cephamycins, cefuroxime should be given with caution to patients who have experienced an anaphylactic reaction to β-lactam antibiotics.

Dosage: Cefuroxime may be administered intramuscularly or intravenously. The usual adult dosage is 750mg 8-hourly. In infections requiring higher dosages of antibiotics, up to 6g daily may be given in divided doses.

In the presence of reduced renal function the maintenance dosage should be reduced in accordance with the degree of renal impairment.