Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. E, 93-101
Cefpodoxime proxetfl: dosage, efficacy and tolerance in adults suffering from respiratory tract infections CSafran
The efficacy of cefpodoxime proxetil has been studied in ten clinical trials conducted in adults suffering from- lower respiratory tract infections (pneumonia, acute bronchitis or acute on chronic bronchitis) and upper respiratory tract infections (tonsillitis/pharyngitis or sinusitis). All the trials were controlled, randomized, multicentre and international and seven were double-blind, double-dummy designed. Over a period of 18 months from July 1988 to December 1989, 2448 patients were included. Among them, 2429 (99%) were evaluated for tolerance, 2101 (86%) for tolerance and clinical efficacy and 1018 (42%) for tolerance and clinical and bacteriological efficacy. The clinical response was judged satisfactory in 1205/1263 (95-4%) patients treated with cefpodoxime proxetil and in 788/838 (94%) patients treated with comparative antibiotics. The bacteriological response was judged satisfactory for 662/699 (95%) pathogens for cefpodoxime proxetil treatment versus 427/463 (92, 2%) for comparators. Cefpodoxime proxetil has been given to 7351 patients in the course of its international development with no severe side-effect being observed. Common reactions have been noted with a similar frequency to that seen with the other /Mactams. No pseudomembranous colitis has been observed during clinical trials. On this basis, cefpodoxime proxetil appears to be efficacious and well tolerated and could be an antibiotic of first choice in the treatment of lower and upper respiratory tract infections in adults and adolescents.
Introduction
The development of parenteral third-generation cephalosporins represented a major scientific advance in antibiotic therapy. These drugs are characterized by considerably greater activity against Gram-negative bacilli (10-100-fold that of first- and secondgeneration cephalosporins) and increased resistance to /Mactamases. They have an important role in the treatment of severe infections by virtue of their high degree of efficacy and their good tolerance. The development of the oral third-generation cephalosporins is a further important advance. It has proved difficult to combine the remarkable antibacterial activity of third-generation compounds with a good intestinal uptake but the creation of prodrugs by the addition of an ester increasing the lipophilicity of the compound, has facilitated their intestinal absorption. The third-generation oral derivatives thus provide the clinician with a major advance because they constitute an effective, well tolerated, empirical broad-spectrum treatment of several types of infections in outpatients, and because they may be used as an early replacement of, or even an alternative to, parenteral antibiotics. 93 03O5-7453/9O/26EO93 + 09 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 6, 2015
Roussel-Uclaf Institute, 93230 Romainville, France
94
CSafran
Determination of the dose Various studies have shown that the bactericidal action of the cephalosporins is time-dependent (Drugeon et al., 1988) and this mode of action has been confirmed for cefpodoxime (Dabernat, Avril & Boussougant, 1990). It therefore appeared essential to establish the optimal dose for phase 2 trials by performing human pharmacokinetic studies which would ensure that plasma concentrations between doses remained above the MICs of the principal target pathogens. This objective was in theory attained with doses of 100 and 200 mg (expressed as mg cefpodoxime) administered every 10-12 h to fasting healthy volunteers, as indicated in Figure 1 and Table I, particularly as cefpodoxime had been shown to possess a postantibiotic effect against Gram-positive cocci preventing in-vivo bacterial multiplication at least 2h after the antibiotic concentrations have fallen below the MIC (Siebor et al., 1990). In order to define the optimum dosage, a phase 2 clinical trial comparing 200 and 400 mg of cefpodoxime proxetil (expressed as mg cefpodoxime) administered in two daily doses for five to ten days was undertaken (Sieling et al., 1989). In this comparative double-blind study 200 patients hospitalized for communityacquired infectious pneumonia confirmed by parenchymatous changes on chest X-ray were recruited. Bacterial pneumonia was adopted for study as it has a highly stereotyped clinical and X-ray picture in 85% of cases (Tilghman & Finland, 1973) and thus
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 6, 2015
Cefpodoxime pTOxetil (RU 51807) is one of the first oral third-generation cephalosporins to have been developed clinically. The compound is a semisynthetic cephalosporin characterized by: (1) an O-methyloxime function conferring on it a very high degree of stability to hydrolysis by /J-lactamases while maintaining good antistaphylococcal activity; (2) a methoxymethyl radical in position 3 of the thiazide nucleus enhancing gastro-intestinal absorption; (3) an esterification of the carboxyl function in position 4 of the thiazide nucleus by a complex hydroxylated residue (isopropyloxycarbonyloxyethyl) which enables the antibiotic to be absorbed by the enterocytes where the host's non-specific esterases release active cefpodoxime, which then enters the blood and tissues. Cefpodoxime proxetil is thus the inactive prodrug of cefpodoxime. Cefpodoxime is, bactericidal, highly stable to hydrolysis by /Mactamases and has a suitable antibacterial spectrum for the treatment of infections of the upper and lower respiratory tract with MIC*, (Jones & Barry, 1987; Fass & Helsel, 1988; Chin & Neu, 1988; Wise et al., 1990) from 0-01-006 mg/1 for Streptococci^ pneumoniae, 006-
Cefpodoxime proxetfl: dosage, efficacy and tolerance in adults suffering from respiratory tract infections CSafran
The efficacy of cefpodoxime proxetil has been studied in ten clinical trials conducted in adults suffering from- lower respiratory tract infections (pneumonia, acute bronchitis or acute on chronic bronchitis) and upper respiratory tract infections (tonsillitis/pharyngitis or sinusitis). All the trials were controlled, randomized, multicentre and international and seven were double-blind, double-dummy designed. Over a period of 18 months from July 1988 to December 1989, 2448 patients were included. Among them, 2429 (99%) were evaluated for tolerance, 2101 (86%) for tolerance and clinical efficacy and 1018 (42%) for tolerance and clinical and bacteriological efficacy. The clinical response was judged satisfactory in 1205/1263 (95-4%) patients treated with cefpodoxime proxetil and in 788/838 (94%) patients treated with comparative antibiotics. The bacteriological response was judged satisfactory for 662/699 (95%) pathogens for cefpodoxime proxetil treatment versus 427/463 (92, 2%) for comparators. Cefpodoxime proxetil has been given to 7351 patients in the course of its international development with no severe side-effect being observed. Common reactions have been noted with a similar frequency to that seen with the other /Mactams. No pseudomembranous colitis has been observed during clinical trials. On this basis, cefpodoxime proxetil appears to be efficacious and well tolerated and could be an antibiotic of first choice in the treatment of lower and upper respiratory tract infections in adults and adolescents.
Introduction
The development of parenteral third-generation cephalosporins represented a major scientific advance in antibiotic therapy. These drugs are characterized by considerably greater activity against Gram-negative bacilli (10-100-fold that of first- and secondgeneration cephalosporins) and increased resistance to /Mactamases. They have an important role in the treatment of severe infections by virtue of their high degree of efficacy and their good tolerance. The development of the oral third-generation cephalosporins is a further important advance. It has proved difficult to combine the remarkable antibacterial activity of third-generation compounds with a good intestinal uptake but the creation of prodrugs by the addition of an ester increasing the lipophilicity of the compound, has facilitated their intestinal absorption. The third-generation oral derivatives thus provide the clinician with a major advance because they constitute an effective, well tolerated, empirical broad-spectrum treatment of several types of infections in outpatients, and because they may be used as an early replacement of, or even an alternative to, parenteral antibiotics. 93 03O5-7453/9O/26EO93 + 09 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 6, 2015
Roussel-Uclaf Institute, 93230 Romainville, France
94
CSafran
Determination of the dose Various studies have shown that the bactericidal action of the cephalosporins is time-dependent (Drugeon et al., 1988) and this mode of action has been confirmed for cefpodoxime (Dabernat, Avril & Boussougant, 1990). It therefore appeared essential to establish the optimal dose for phase 2 trials by performing human pharmacokinetic studies which would ensure that plasma concentrations between doses remained above the MICs of the principal target pathogens. This objective was in theory attained with doses of 100 and 200 mg (expressed as mg cefpodoxime) administered every 10-12 h to fasting healthy volunteers, as indicated in Figure 1 and Table I, particularly as cefpodoxime had been shown to possess a postantibiotic effect against Gram-positive cocci preventing in-vivo bacterial multiplication at least 2h after the antibiotic concentrations have fallen below the MIC (Siebor et al., 1990). In order to define the optimum dosage, a phase 2 clinical trial comparing 200 and 400 mg of cefpodoxime proxetil (expressed as mg cefpodoxime) administered in two daily doses for five to ten days was undertaken (Sieling et al., 1989). In this comparative double-blind study 200 patients hospitalized for communityacquired infectious pneumonia confirmed by parenchymatous changes on chest X-ray were recruited. Bacterial pneumonia was adopted for study as it has a highly stereotyped clinical and X-ray picture in 85% of cases (Tilghman & Finland, 1973) and thus
Downloaded from http://jac.oxfordjournals.org/ at Simon Fraser University on June 6, 2015
Cefpodoxime pTOxetil (RU 51807) is one of the first oral third-generation cephalosporins to have been developed clinically. The compound is a semisynthetic cephalosporin characterized by: (1) an O-methyloxime function conferring on it a very high degree of stability to hydrolysis by /J-lactamases while maintaining good antistaphylococcal activity; (2) a methoxymethyl radical in position 3 of the thiazide nucleus enhancing gastro-intestinal absorption; (3) an esterification of the carboxyl function in position 4 of the thiazide nucleus by a complex hydroxylated residue (isopropyloxycarbonyloxyethyl) which enables the antibiotic to be absorbed by the enterocytes where the host's non-specific esterases release active cefpodoxime, which then enters the blood and tissues. Cefpodoxime proxetil is thus the inactive prodrug of cefpodoxime. Cefpodoxime is, bactericidal, highly stable to hydrolysis by /Mactamases and has a suitable antibacterial spectrum for the treatment of infections of the upper and lower respiratory tract with MIC*, (Jones & Barry, 1987; Fass & Helsel, 1988; Chin & Neu, 1988; Wise et al., 1990) from 0-01-006 mg/1 for Streptococci^ pneumoniae, 006-
