Cefuroxime Axetil

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Abstract
Cefuroxime axetil, a prodrug of the cephalosporin cefuroxime, has proven in vitro antibacterial activity against several Gram-positive and Gram-negative organisms, including those most frequently associated with various common community-acquired infections. In numerous randomised, controlled trials, 5 to 10 days’ treatment with oral cefuroxime axetil (250 or 500mg twice daily) was an effective treatment in patients with upper (URTI) and lower respiratory tract infections (LRTI) as assessed by clinical and bacteriological criteria. The drug was as effective as several other cephalosporins, quinolones, macrolides and amoxicillin/clavulanic acid. Shorter courses (5 to 10 days’) of cefuroxime axetil were at least as effective as a 10 day course. Furthermore, sequential therapy with intravenous cefuroxime (750mg 2 or 3 times daily for 2 to 5 days) followed by oral cefuroxime axetil (500mg twice daily for 3 to 8 days) proved an effective treatment in adult patients with community-acquired pneumonia (CAP). This approach provided similar efficacy to intravenous ampicillin/sulbactam followed by oral amoxicillin/clavulanic acid, a full parenteral course of cefuroxime, or intravenous then oral azithromycin or clarithromycin. Additionally, cefuroxime axetil was an effective treatment in patients with genitourinary, skin and soft-tissue infections, and erythema migrans associated with early stage Lyme disease. The drug is well tolerated by adult and paediatric patients, with adverse effects that are consistent with those of other cephalosporins. The majority of adverse events (primarily gastrointestinal disturbances) were mild to moderate in intensity and reversible upon discontinuation of treatment, with very few serious adverse events reported. Conclusions: Cefuroxime axetil is a broad spectrum antibacterial agent with a pharmacokinetic profile that permits convenient twice-daily administration. The drug is an effective and well tolerated treatment in patients with various infections, including otitis media, pharyngitis, sinusitis, CAP and acute exacerbations of chronic bronchitis. Cefuroxime axetil proved effective as a component of intravenous/oral sequential therapy in the treatment of CAP, although there are currently no dosage recommendations available for this regimen in some countries. Cefuroxime axetil may be considered as an empirical therapy for a range of community-acquired infections, including those in which β-lactamase-producing strains of common respiratory pathogens are identified as the causative organisms. In an era of rapidly emerging bacterial resistance, empirical treatment with agents such as cefuroxime axetil may ensure the appropriate use of newer antibacterial agents, potentially preventing the emergence of bacterial resistance to these newer drugs. Cefuroxime axetil, a cephalosporin antibacterial agent, prevents bacterial growth primarily by inhibiting penicillin-binding protein 3, resulting in bacterial elongation and leakage and, eventually, cell death. The drug shows good activity against a broad range of Gram-positive and Gram-negative bacteria in vitro, including those most commonly associated with respiratory tract infections [e.g. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, S. pyogenes and methicillin-sensitive Staphylococcus aureus (MSSA)]. Against Gram-positive bacteria, cefuroxime is active against penicillin-susceptible strains of S. pneumoniae [mean minimal inhibitory concentrations required for 90% of strains (MIC90) range ≤0.06 to ≤0.25 mg/L], shows some activity against isolates of S. pneumoniae that are intermediately susceptible to penicillin (mean MIC90 range 2 to 4 mg/L), but has no activity against penicillin-resistant S. pneumoniae (mean MIC90 2 to ≥8 mg/L). In a recent study, against S. pyogenes isolates, cefuroxime (mean MIC90≤0.25 mg/L) antibacterial activity was comparable with that of other cephalosporins. Mean MIC90 values for cefuroxime axetil against MSSA ranged from 2 to 4 mg/L worldwide. Like most other β-lactam antibiotics, cefuroxime has no activity against methicillin-resistant strains of Staphylococcus species (including MRSA). Cefuroxime also shows good activity against several Gram-negative bacteria, including β-lactamase-positive and -negative strains of H. influenzae (mean MIC90 range 1 to 2 and 2 to 4 mg/L, respectively), M. catarrhalis (mean MIC90 2 and 0.5 mg/L) and Neisseria gonorrhoeae (mean MIC90 0.125 and 0.06 mg/L). In recent studies, ≥95% of H. influenzae and ≥99% of M. catarrhalis isolates were susceptible to cefuroxime. The drug also exhibited activity against the common urinary tract pathogen Escherichia coli, with mean MIC90 values of 4 and 8 mg/L in 2 recent studies. However, in a recent worldwide study, the susceptibility of E. coli (4509 isolates) to cefuroxime in different regions of the world was generally lower than this and showed greater variation, with mean MIC90 values ranging from 8 to 32 mg/L (median MIC90 16 mg/L). Cefuroxime showed limited activity against Klebsiella pneumoniae strains (mean MIC90 range 16 to >16 mg/L). In addition, cefuroxime shows limited or no activity against most other Enterobacteriaceae, including Citrobacter spp. and Serratia marcescens, or against Pseudomonas aeruginosa and Acinetobacter spp. The spectrum of pathogens susceptible to cefuroxime axetil has not changed substantially over the last decade, with the exception of some nosocomial isolates of Enterobacteriaceae (notably K. pneumoniae and E. coli) that have developed resistance to cefuroxime and other cephalosporins by producing TEM and SHV extended spectrum β-lactamases. Cefuroxime has shown stability to the most common plasmid-mediated β-lactamases TEM-1, TEM-2, OXA-1 and OXA-2 produced by E. coli, and to SHV-1-producing K. pneumoniae. Pharmacodynamic/pharmacokinetic analyses suggest that the time cefuroxime concentrations are above the MIC90 values for relevant pathogens (e.g. S. pneumoniae isolates that are susceptible or intermediately-susceptible to penicillin, and β-lactamase-positive and -negative H. influenzae isolates) exceeds 50% of the dosage interval in most situations. The lipophilic acetoxyethyl-ester prodrug cefuroxime axetil is well absorbed from the gastrointestinal tract and is rapidly hydrolysed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime and the ester group. The mean absolute oral bioavailability of cefuroxime axetil was 67.9% (n = 12). The extent of absorption was increased from 36 to 52% when the drug was coadministered with food. The pharmacokinetic profile of cefuroxime after oral cefuroxime axetil (administered immediately after a meal) is linear over the 125 to 1000mg dose range. The peak plasma concentration (Cmax) ranged from 2.1 to 13.6 mg/L over this dose range while the corresponding values for elimination half-life (t½), time to Cmax (tmax) and area under the plasma concentration time-curve (AUC) were 2.2 to 3 hours, 1.2 to 1.3 hours and 6.7 to 50 mg/L · h, respectively, when the drug was administered as an oral tablet. After ingestion of cefuroxime axetil 250mg in either tablet or suspension form following a meal, there was little difference in the t½ or tmax of cefuroxime; however, both the AUC (10.22 vs 14.02 mg/L · h) and the Cmax (2.48 vs 4.04 mg/L) were significantly lower after ingestion of the suspension than after the tablet (p = 0.001 for both comparisons). Thus the 2 formulations are not bioequivalent. The protein binding of cefuroxime after oral cefuroxime axetil has not been studied, but the plasma protein binding of cefuroxime after intravenous injection of cefuroxime has been variously reported as 33% and 50%. The volume of distribution of cefuroxime is ≈0.25 to 0.3 L/kg. The highest levels of penetration of cefuroxime after oral cefuroxime axetil (single dose of 375 or 500mg) are seen in sinus tissue (38.1 to 106% with tissue levels of 0.4 to 2.4 mg/kg). Penetration into bronchial mucosa and tonsil tissue was also good (35 to 90%). In addition, after a single dose of cefuroxime axetil 250mg or 15 mg/kg to children with acute otitis media, cefuroxime was shown to penetrate into middle ear effusion. Mean tissue concentrations in these patients were 1.2 and 1.3 mg/kg and in 1 of these studies 29.8% tissue penetration was reported. Penetration into aqueous humor was 13.8% and the mean concentration of cefuroxime obtained (0.5 mg/L) was below the MIC90 for most, but not all, of the organisms frequently involved in intraocular infections. Cefuroxime is released from cefuroxime axetil by de-esterification, but is not metabolised further and approximately 50% of the drug is eliminated unchanged in the urine within 12 hours. In healthy adult volunteers who received a single oral dose of cefuroxime axetil 250mg urinary recovery ranged from 42.8 to 57%. Because cefuroxime axetil is eliminated renally the ty, increases with decreasing renal function. The pharmacokinetics of cefuroxime in elderly volunteers who received the suspension formulation of cefuroxime axetil were similar to those in younger volunteers who received the same preparation. Upper respiratory tract infections: In adult and adolescent patients with acute sinusitis, randomised controlled trials have shown that cefuroxime axetil (250mg twice daily for 8 to 10 days) provided comparable clinical and bacteriological efficacy to that of 7 to 10 days’ treatment with a quinolone agent, including moxifloxacin, gemifloxacin, sparfloxacin and ciprofloxacin. In clinically evaluable patients, satisfactory clinical responses occurred in 83 to 90% of cefuroxime axetil recipients versus 83 to 97% of patients receiving a quinolone comparator agent. Overall presumed or documented bacteriological eradication paralleled satisfactory clinical response rates, with eradication occurring in 89 to 95% of microbiologically evaluable cefuroxime axetil recipients versus 94 to 97% of those receiving a quinolone. Cefuroxime axetil also provided comparable clinical efficacy to that of clarithromycin or amoxicillin/clavulanic acid as assessed by clinical and bacteriological criteria. Furthermore, clinical (85 vs 87% of patients) and bacteriological response rates (89 vs 91%) indicated that 5 days’ treatment with cefuroxime axetil (250mg twice daily) was as effective as 10 days’ treatment in a double-blind trial. In children and adults with group A β-haemolytic streptococcal (GABHS) tonsillopharyngitis, clinical (95 to 96% vs 94 to 98% of patients) and bacteriological (88 vs 92% of evaluable patients) response rates were similar with either 5 or 10 days’ treatment with cefuroxime axetil (250 or 500 mg/day, or 20 mg/kg/day) in 2 comparative randomised trials. Additionally, a 5-day course of cefuroxime axetil (500 mg/day or 20 mg/kg/day) was superior to 10 days’ treatment with phenoxymethylpenicillin (50 000 IU/kg/day) in a large phase IV, non-blind, multicentre study in children and adolescents (as assessed using a 2-sided analysis). At 7 to 8 weeks’ follow-up, asymptomatic carriage of GABHS occurred at an equivalent rate in both treatment groups (11.1% of cefuroxime axetil recipients vs 13.8%). At 12 months’ follow-up, no cefuroxime axetil recipients had experienced serious sequelae (e.g. glomerular nephritis or rheumatic fever) and 1 incident of glomerular nephritis had occurred in a patient who had received phenoxymethylpenicillin. Cefuroxime axetil was also as effective as cefpodoxime proxetil, cefaclor or clarithromycin in treating children (aged ≤12 years) with acute otitis media (≥93% satisfactory clinical response in each treatment group). Notably, short-course (5 days) cefuroxime axetil treatment was as effective as 10 days’ treatment with the drug or 8 to 10 days’ of amoxicillin/clavulanic acid in terms of either clinical or bacteriological criteria. Lower respiratory tract infections: Cefuroxime axetil was efficacious in patients with acute bronchitis or acute exacerbations of chronic bronchitis (AECB). The drug was as effective as cefixime, cefpodoxime proxetil, cefprozil, cefdinir, ciprofloxacin, levofloxacin, telithromycin, clarithromycin, roxithromycin and amoxicillin/clavulanic acid. In clinically evaluable patients, clinical response rates (cure or improvement) at the end of therapy in cefuroxime axetil (250 or 500 mg twice daily) recipients ranged from 66 to 94% and were generally similar to those achieved in recipients of comparator drugs (range 74 to 95%). Overall, at the end of treatment, bacteriological eradication (presumed or documented) rates with cefuroxime axetil (60 to 93% of patients) were generally comparable to those achieved with comparator antibacterial drugs (69 to 96%) in microbiologically evaluable patients. In a randomised, double-blind trial, significantly fewer cefuroxime axetil recipients achieved a successful clinical response than gatifloxacin-treated (400mg once daily) patients (77 vs 89% of patients; p < 0.035). In adult patients with community-acquired pneumonia (CAP), oral cefuroxime axetil (with or without erythromycin) provided similar clinical and bacteriological efficacy to that of oral trovafloxacin. Sequential therapy with intravenous cefuroxime followed by oral cefuroxime axetil (with or without erythromycin) was as clinically effective as intravenous ampicillin/sulbactam followed by oral amoxicillin/clavulanic acid, a full parenteral course of cefuroxime, intravenous then oral azithromycin or intravenous then oral clarithromycin in adult patients with CAP. 85 to 94% of cefuroxime axetil recipients achieved a satisfactory clinical response versus 90 to 94% of patients treated with comparator agents in per-protocol analyses. In a large non-blind study, clinical (90 vs 96% of patients; 95% CI -10.7, -1.3) and bacteriological (85 vs 98%; 95% CI -21.6, -4.8) success rates were significantly (no p-values reported) lower in evaluable patients receiving combinations of intravenous ceftriaxone (1 to 2g once or twice daily) and/or oral cefuroxime axetil (500mg twice daily) than those in recipients of intravenous and/or oral levofloxacin (500mg once daily). In paediatric patients with CAP, cefuroxime axetil was as effective as cefpodoxime proxetil or ampicillin/sulbactam. Furthermore, cefuroxime axetil proved clinically effective as a second-line therapy in children who had failed previous antibacterial therapy. Notably, significantly more cefuroxime axetil than ceftibuten recipients experienced a satisfactory clinical response in a randomised multicentre trial in 140 children with CAP (93 vs 80% of patients; p = 0.04), with similar bacteriological eradication rates in both treatment groups (32 vs 36% of patients). Genitourinary tract infections: Cefuroxime axetil (250mg twice daily), administered for 10 to 12 days, provided similar clinical (92 vs 95% of patients) and bacteriological (no numerical data reported) response rates to those of ofloxacin (200mg twice daily) in adult outpatients with uncomplicated pyelonephritis. In the treatment of 832 adult patients with uncomplicated gonorrhoea, a single oral dose of cefuroxime axetil 1g or ciprofloxacin 500mg produced similar rates of bacteriological eradication from the cervix of women and urethra of men infected with penicillinase-producing strains of N. gonorrhoeae (≥96% of patients in all treatment groups). In female patients, overall bacteriological eradication rates (i.e. for all N. gonorrhoeae isolates) from the cervix were also similar (≥97% in all treatment groups). However, in male patients, overall eradication rates from the urethra were significantly lower with cefuroxime axetil than with ciprofloxacin (93 vs 100% of patients; p < 0.001). Other infections: Cefuroxime axetil (250mg twice daily for 10 to 12 days) also appears to be an effective treatment in patients with uncomplicated skin and soft tissue infections, providing similar clinical and bacteriological efficacy to that of cefpodoxime proxetil and cefditoren pivoxil. Additionally, cefuroxime axetil 30 mg/kg/day for 14 days was as effective as 14 days’ treatment with phenoxymethylpenicillin 100 000 IU/kg/day in children with erythema migrans associated with early stage Lyme disease. Pharmacoeconomic analyses of cefuroxime axetil have generally considered costs associated with treatment only from an institutional perspective. Indirect and societal costs have not been assessed to date. Resource utilisation costs associated with cefuroxime axetil were compared with those associated with comparator antibacterial agents in 2 studies using data collected from trials conducted in the US and Canada in patients with CAP. In 1 study, a sensitivity analysis excluding patients receiving treatment for 0.001); this cost difference reflected the reduced costs of oral compared with parenteral therapy. In a US cost-minimisation analysis in hospitalised patients with CAP, the mean length of stay in hospital was significantly (p < 0.05) reduced in those receiving 2 days’ compared with 5 days’ intravenous cefuroxime prior to switching to oral cefuroxime axetil or in those receiving a full parenteral course of cefuroxime (mean length of stay of 6, 8 and 11 days, respectively). A reduction in the standard 13-day hospital stay to 6 days would potentially result in a 53.9% reduction in the cost of treatment of CAP in US Veterans Affairs facilities. Oral cefuroxime axetil 250mg or 500mg twice daily for 5 to 10 days was generally well tolerated in children and adults with various bacterial infections. The majority of adverse events were mild to moderate in intensity and reversible upon discontinuation of treatment, with very few serious adverse events reported. Less than 1 to 6% of patients withdrew because of adverse events attributable to cefuroxime axetil treatment. Most adverse events that occurred during treatment with cefuroxime axetil were of gastrointestinal nature (diarrhoea, nausea, vomiting), although headache, dizziness and skin reactions were also occasionally reported. In recent clinical trials, the most common drug-related adverse events were diarrhoea (2 to 10.2% of patients), nausea (0 to 5%), vomiting (1 to 5%), abdominal pain (2 to 2.8%), dizziness (0.8 to 3%), headache (1 to 3.7%), vaginitis (1 to 2%), and skin rash (3%). The nature and incidence of adverse events was similar with either 5 or 10 days’ treatment with cefuroxime axetil. Comparative studies indicated that the tolerability profile of cefuroxime axetil appeared to be generally similar to that of a broad range of comparator antibacterial agents, including cephalosporins (cefpodoxime proxetil and cefprozil), quinolones (sparfloxacin, ciprofloxacin, trovafloxacin, levofloxacin, gatifloxacin and moxifloxacin), clarithromycin, telithromycin and phenoxymethylpenicillin. Notably, the tolerability of cefuroxime axetil was superior to that of amoxicillin/clavulanic acid in investigations that included patients with upper and lower respiratory tract infections. Both the overall incidence of gastrointestinal adverse events and the incidence of nausea and vomiting were markedly lower in the cefuroxime axetil than amoxicillin/clavulanic acid groups. Stevens-Johnson syndrome and toxic dermal necrolysis,...

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