Ceforanide

Summary

Synopsis

Ceforanide¹ is a ‘second generation’ cephalosporin administered intravenously or intramuscularly. It is similar to cefamandole and cefonicid in its in vitro superiority to ‘first generation’ cephalosporins against several species of Enterobacteriaceae as well as its activity against Haemophilus influenzae, including β- lactamase- producing strains. Its activity against Staphylococcus aureus is less than that of cefamandole, cefuroxime and first generation cephalosporins. The in vitro activity against Neisseria gonorrhoeae is excellent. Pseudomonas, Acinetobacter and Serratia species, and Bacteroides fragilis are resistant, as are many strains of Proteus and Providencia species.

The elimination half- life is relatively long, although shorter than that of cefonicid, and in most clinical trials ceforanide has been administered twice daily. It appeared to be comparable in therapeutic efficacy to procaine penicillin and cephazolin in the treatment of patients with community- acquired pneumonia, to cephazolin in the treatment of skin and soft tissue infections due to S. aureus or β- haemolytic streptococci and to cefapirin in S. aureus endocarditis in parenteral drug abusers. Also, it was comparable in efficacy to cephalothin in the prophylaxis of infection in patients undergoing open heart surgery or vaginal hysterectomy, and to cephazolin in patients undergoing cholecystectomy.

Thus, ceforanide is an alternative to first and certain other second generation cephalosporins in several important therapeutic and prophylactic situations. It has no advantage over other cephalosporins with regard to spectrum of antibacterial activity, but has a longer half- life than other second generation cephalosporins, except cefonicid, and can be administered according to a twice daily dosage schedule.

Antibacterial Activity

Ceforanide has a spectrum of in vitro antibacterial activity which most closely resembles those of cefamandole and cefonicid. Most isolates of Staphylococcus aureus (except methicillin-resistant strains) are susceptible or moderately susceptible to ceforanide, but ceforanide is a less potent inhibitor of staphylococci than cephazolin, cephalothin, cefamandole or cefuroxime. In common with other cephalosporins, ceforanide is a potent inhibitor of most species of streptococci, excluding enterococci. The activity of ceforanide against Escherichia coli is similar to that of cefamandole and cefoxitin and greater than that of cephazolin and cephalothin. Citrobacter diversus is very susceptible to ceforanide but other Citrobacter species, including C. freundii, are generally resistant. The comparative inhibitory activity of ceforanide, cefamandole and cefoxitin against Klebsiella species and K. pneumoniae varied between studies, with ceforanide generally being the most potent. Salmonella species are very susceptible to ceforanide while Shigella species are moderately susceptible. In general, Enterobacter, Proteus, Providencia and Serratia species are resistant to ceforanide. Neisseria gonorrhoeae and Neisseria meningitidis, including penicillinase-producing strains, and Haemophilus influenzae, including β-lactamase-producing strains are susceptible to ceforanide. However, Pseudomonas and Acinetobacter species are resistant. Ceforanide is less active than cefoxitin against anaerobic bacteria; Bacteroides fragilis is resistant but Clostridium species and Gram-positive anaerobic cocci are susceptible. The activity of ceforanide against Clostridium difficile has not been reported.

In general, increases in the inoculum size up to 10⁵ colony-forming units (cfu) has little effect on the minimum inhibitory concentration (MIC) of ceforanide. However, when the size of the inoculum is increased to 10⁶ cfu or greater considerable increases occur in the MIC, particularly with the Enterobacteriaceae. This may be the result of hydrolysis of the drug by β-lactamases with such large inocula. Ceforanide MICs generally are not affected by use of different growth media, the presence of human serum or pH changes.

Minimum bactericidal concentrations (MBC) of ceforanide are equivalent to or no more than 2-fold higher than MICs for most bacterial species. However, bactericidal concentrations against strains of Enterobacter species, indole-positive Proteus species, staphylococci and streptococci may exceed inhibitory concentrations by several-fold.

No significant synergism has been reported for ceforanide and other antibacterial agents.

Ceforanide is resistant to hydrolysis by the type IIa β-lactamase and the penicillinase of S. aureus. In addition, ceforanide is similar in stability to cephradine against the RTEM enzyme (type IIIa) and type IVa β-lactamase. The selection of resistant isolates occurred more frequently in ceforanide-treated mice than in mice treated with other cephalo-sporins; cross-resistance was complete between ceforanide and cefamandole, partial between ceforanide and cephalothin, but rare with cefoxitin.

Pharmacokinetics

Following intravenous administration the plasma concentration profile of ceforanide is best characterised by a first-order, 2-compartment open model. Average peak plasma concentrations in healthy adults generally ranged from 135 to 140 mg/L following a single 30-minute intravenous infusion or rapid intravenous bolus injection of 1g, and increased approximately linearly with dose. Ceforanide is 100% bioavailable following intramuscular administration, producing a peak plasma concentration, after 1 hour, of 50 to 60% of the peak concentration after intravenous infusion. Results of multiple-dose studies indicate no significant drug accumulation after up to 11 days’ administration of ceforanide.

The mean apparent volume of distribution in healthy adult volunteers is 8 to 13L. Ceforanide concentrations likely to afford sufficient activity against susceptible organisms are achieved in most tissues and fluids, including bone, cardiac tissue, female pelvic organ tissues, abscess fluid, gallbladder tissue and bile and urine. However, penetration into synovial fluid and saliva is poor. Ceforanide is approximately 80% bound to plasma proteins, but the significance of this to its clinical potential is unclear since its antibacterial activity in vitro is influenced little by human serum.

Ceforanide is primarily excreted by glomerular filtration as unchanged drug, with an average urinary recovery of 83 to 95% over the first 24 hours. Total body clearance approximates 3.0 L/h with a renal clearance of approximately 2.1 to 2.7 L/h. The mean plasma elimination half-life of ceforanide is approximately 2.5 to 3.0 hours in healthy adults.

The plasma and renal clearances of ceforanide decrease linearly as the creatinine clearance decreases. The elimination half-life increased to 25 hours in patients with severe renal insufficiency (creatinine clearance < 5 ml/min). Ceforanide is removed from the body by haemodialysis.

The elimination half-life of ceforanide is somewhat shorter in infants and children than adults, and the extent of protein binding may be reduced in children. The mean peak plasma concentrations attained in women with suspected endometritis after caesarean section were lower than those reported in healthy volunteers and may be due to an increased volume of distribution in this population.

The pharmacokinetics of intramuscularly administered ceforanide were unaltered by concomitant administration of probenecid.

Therapeutic Trials

Ceforanide 0.5 to 2g 12-hourly has proven to be therapeutically effective in several types of infection. Clinical and bacteriological cures are obtained in nearly 100% of patients with pneumonia due to S. pneumonia, while H. influenzae infections may persist after therapy. Randomised comparative trials reveal it is similar in efficacy to procaine penicillin 600,000U 12-hourly and cephazolin 0.5 to lg 8-hourly. In skin and soft tissue infections (mostly cellulitis) due to S. aureus or β-haemolytic streptococci, ceforanide clinical and bacteriological efficacy rates are approximately 95%; randomised clinical trials comparing ceforanide and cephazolin reveal similar efficacy rates for the 2 cephalosporins in these types of infections. Equally high clinical and bacteriological efficacy rates have also been reported for ceforanide in S. aureus endocarditis in parenteral drug abusers; ceforanide appeared to be similar in clinical and bacteriological efficacy to cefapirin 2g 4-hourly. In uncomplicated lower urinary tract infection there was no statistically significant difference in clinical efficacy between a single 1g intramuscular dose of ceforanide and 7 days’ treatment with ampicillin 250mg 4 times daily, although there was a trend towards a higher failure rate with ceforanide (33% and 15%, respectively). Ceforanide has also shown promising therapeutic results in a few patients with osteomyelitis and in paediatric patients with infections of various body sites (excluding the central nervous system).

Several randomised trials have assessed the comparative efficacy of ceforanide and cephalothin in the prophylaxis of infection following open heart surgery or vaginal hysterectomy. In patients undergoing open heart surgery, a single preoperative dose of ceforanide 0.5 to lg, followed by 2 to 4 doses administered 12-hourly after surgery was, in general, similar in efficacy to 6 to 10 doses of cephalothin 1g 6-hourly (beginning with a single preoperative dose). However, in a study which analysed the patients who underwent cardiac artery bypass grafting independently of the patients who underwent grafting plus additional procedures (e.g. valve replacement), the patients in the latter subgroup had a significantly (p=0.001) lower overall infection rate with ceforanide than cephalothin prophylaxis. In patients undergoing vaginal hysterectomy with or without repair there were no statistically significant differences in the rate of infection, or other indices of prophylactic efficacy, between a preoperative dose of ceforanide 0.5g followed by a single postoperative dose 12 hours later and a preoperative (dose of cephalothin followed by 5 postoperative doses 6-hourly. Intrauterine administration of a single 2g dose of ceforanide was not significantly different in efficacy from intravenous administration for the prophylaxis of infection in patients undergoing non-elective caesarean section after rupture of membranes for 3 hours or longer.

There were no postoperative infections among any of the patients undergoing cholecystectomy (with or without additional procedures) who were included in a randomised comparison of prophylaxis with ceforanide 1g (a single preoperative dose alone or followed by a single postoperative dose 12 hours later) or cephazolin 1g (a single preoperative dose followed by 3 postoperative doses 6-hourly). In addition, in noncomparative studies, ceforanide has demonstrated a high rate of prophylactic efficacy in patients undergoing elective gastric bypass surgery, surgery for acute non-perforated appendicitis, and total joint arthroplasty.

Adverse Effects

Significant adverse effects from ceforanide are uncommon. Discomfort or pain associated with intramuscular injection, mild gastrointestinal effects, and skin rash or other hypersensitivity reactions occur occasionally but rarely necessitate discontinuation of therapy. Other untoward effects that have been reported rarely (incidence less than 1%) are lethargy, confusion, headache and hypotension. Mild, transient alterations in laboratory values, similar to those seen with other cephalosporins (eosinophilia, thrombocytosis, elevated liver function test values, serum creatinine and blood urea nitrogen) also occur with ceforanide. The development of positive direct and indirect Coombs’ tests (without haemolysis) occurred in 3 of 52 patients in 1 study.

Dosage and Administration

The recommended adult dosage of ceforanide is 0.5 to 1g administered every 12 hours by intravenous injection over 3 to 5 minutes, infusion over 30 minutes or by deep intramuscular injection. The perioperative prophylactic dose for adults undergoing surgery, where there is presumed contamination or the potential for contamination, is 0.5 to 1g administered 1 hour prior to the initiation of surgery; prophylactic ceforanide may be continued for up to 2 days postoperatively when significant risk of postoperative infection exists, e.g., prosthetic arthroplasty or open heart surgery.

For children the recommended dose of ceforanide is 20 to 40 mg/kg/day in equally divided doses.

The dosage of ceforanide should be reduced in patients with impaired renal function.