Journal of Antimicrobial Chemotherapy () 6, Suppl. E, 87- Comparison of cefpodoxime proxetil with cefaclor in the treatment of sinusitis P. Gehanno", J. Depondt", B. Barry", M. Simonet* and H. Dewever" "Hopital Bichat, 6 rue Henri Huchard, 78 Paris, France; b H6pital Necker, rue de sevres, 7 Paris, France; 'Hdpital Universitaire Saint-Pierre, Bruxelles, Belgium The efficacy and tolerance of cefpodoxime proxetil were compared with those of cefaclor in a multicentre, international, prospective, double-blind, placebocontrolled study in adult outpatients suffering from acute sinusitis. At the end of treatment, cefpodoxime proxetil was more effective than cefaclor, producing complete clinical cure in 8% of cases (/) VJ 68% of cases (77/) in the cefaclor group (P = -). The overall clinical efficacy (cure + improvement) was similar in the two groups with % (6/) satisfactory responses in the cefpodoxime proxetil group and 3% (6/) in the cefaclor group. Bacteriological response was similar with % eradication in the cefpodoxime proxetil group (/ 8) vs % with cefaclor (63/6). Introduction Acute bacterial sinusitis is a common clinical problem complicating approximately one in every common colds (Wald et al., 8). The bacterial species most frequently isolated from infected paranasal sinuses are Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis and Str.pyogenes (Hanobey et al., 7). The signs and symptoms of bacterial infection of the sinus are non-specific and direct puncture with aspiration of the sinus cavities and bacteriological identification are not performed routinely. Treatment is therefore frequently empirical. However, aspiration must be performed in cases of acute or chronic recurring sinusitis. Endoscopic examination of the lateral nasal wall may show purulent secretions emerging from the middle meatus. Increasingly, the combination of nasal endoscopy with computerized axial tomography of the sinuses has proved ideal for the diagnosis of chronic sinusitis. Nasal endoscopy thus represents real progress in the diagnosis of this condition. However, to match this progress in terms of the treatment of sinusitis requires the development of orally administered antibiotics that will prove effective in empirical therapy. Cefpodoxime proxetil, a new oral third generation cephalosporin, has an antibacterial spectrum that includes those pathogens most often responsible for sinusitis. Cefaclor is known as a standard drug among the oral cephalosporins for the treatment of acute sinusitis in adult patients (Wald et al., 8; Ekedahl, 87). It was used as a comparative antibiotic in this international, multicentre, randomized double-blind, placebo controlled study to assess the efficacy and tolerance of cefpodoxime proxetil in adult sinusitis. 87 3O-73/O/6EO87 + $./ The British Society for Antimicrobial Chemotherapy Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on March 6, 6
88 P. Gehamw et al Materials and methods Adult patients with a diagnosis of acute sinusitis suspected from clinical and radiological signs were enrolled in the study, after giving informed consent. A sample of sinus discharge was taken from the inferior meatus via a sterile catheter under local anaesthesia before treatment in all cases. The sinus fluid was cultured by standard laboratory methods. Sensitivity of significant isolates to cefaclor and cefpodoxime was determined by a disc diffusion method. The discs contained 3 /zg of each drug, and the criteria for interpretation of zone diameters were as follows: cefpodoxime, sensitive ^ mm, resistant < mm; cefaclor, sensitive ^ 8 mm, resistant < 8 mm. Patients were randomized to receive either cefpodoxime proxetil mg bd or cefaclor mg tds. In addition to the study drug, all patients received prednisolone orally ( mg tid if < 6 kg body weight or mg tid if > 6 kg) and fenoxazoline (nasal spray, tid for four days) during the trial. Other antibiotic, antipyretic or antiinflammatory drugs were prohibited. The clinical response was considered satisfactory if the infection was completely cleared with disappearance of clinical symptoms (nasal discharge and pain) and disappearance or improvement of radiological signs. The clinical response was considered improved if the clinical symptoms were improved, and unsatisfactory if the clinical features and the sinus X-ray remained unchanged or worsened. A satisfactory bacteriological response implied eradication of the causative pathogen or complete cure of a bacteriologically documented infection. Results Two hundred and sixty-seven patients were enrolled in this study from 3 centres in Europe. Patients included were predominantly female (8/8 = 6-%). No significant difference was observed between the two treatment groups in terms of demographic characteristics (Table I). No significant difference was observed between the two treatment groups in terms of clinical signs and radiological findings on admission. The mean duration of treatment was - days in both groups. Of the 67 patients enrolled in this study, 8 patients were evaluable for tolerance; and 36 patients were evaluable for clinical efficacy. Nine cases (four in the cefpodoxime proxetil group and five in the cefaclor group) could not be included in the analysis of tolerance; despite consent being obtained for entering the trial, they did not take any of the study medications. Twenty-two patients were excluded from the analysis of clinical efficacy ( because of organisms resistant to cefaclor and/or cefpodoxime at pretreatment culture; and for other reasons such as protocol violation or diagnostic error). Of the 36 patients evaluable for clinical efficacy, 7 were evaluable for bacteriological efficacy. At the end of treatment, cefpodoxime proxetil produced a satisfactory clinical response in 8% of cases (/), while 68% of cases (77/) in the cefaclor group (P = -) showed a satisfactory response. The overall clinical efficacy (satisfactory plus improved) was similar in the two groups with % (/) satisfactory or improved responses after cefpodoxime proxetil and 3% (6/) after cefaclor. Two hundred and five pathogens were identified from sinus aspirates in of 6 (%) patients at inclusion. The distribution of these pathogens is detailed in Table II. The bacteriological response was similar with a satisfactory response in % in the Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on March 6, 6
Treatment of sinusitis 8 Table L Demographic characteristics for all patients treated Characteristics Cefpodoxime proxctil ing bd Cefaclor mg tid All patients Number of patients Age (years) mean Sex M F Race white black oriental Weight (kg) mean* Height (cm) mean' Standard deviation. 33-3 (3-) -77 3 (3-8%) 8 (6-%) 7 (-%) 6 (-%) (-%) 63-(-7) - 68- (8-) 8-8 () -88 7 (37-6%) 78 (6-%) 7(3-6%) 6 (-8%) (-6%) 63-6 (-) - 67- (7-7) 8-8 -7 (-) -88 (38-8%) 8 (6-%) (-6%) (-7%) (-8%) 63-(-3) - 67-6 (8) 8- cefpodoxime proxetil group (/8) and % satisfactory response with cefaclor (63/6). It is interesting to note that all cases of staphylococcal sinusitis were cured in the cefpodoxime proxetil group. Eleven patients were excluded from clinical and bacteriological analysis because of a resistant pathogen. Of these, one patient had a Pseudomonas aeruginosa infection with an organism which was resistant to both cefpodoxime and cefaclor and ten patients had infections with other pathogens apparently resistant on disc sensitivity testing only to cefaclor. Considered as a proportion of the total number of bacteria isolated and considered responsible for the infection, the number of pathogens resistant to cefaclor was significantly greater than the number of pathogens resistant to cefpodoxime (P < -, MacNemar test). The resistant pathogens on pretreatment culture are detailed in Table III. Nineteen adverse events, judged by the investigator as probably or possibly drugrelated (nine in the cefpodoxime proxetil group, ten in the cefaclor group) were observed in seventeen patients (nine in the cefpodoxime proxetil group, eight in the cefaclor group) and discontinuation of therapy occurred in seven cases (three in the cefpodoxime proxetil group, four in the cefaclor group). No unexpected adverse events were observed. No difference between groups in respect of haematological and biochemical changes were observed. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on March 6, 6 Discussion In this series, H. influenzae was responsible for 3% of cases, a proportion similar to that in previous reports. H. influenzae is currently the main causative pathogen found in sinusitis. The frequency of reporting of this organism has increased in recent years (Scheld el al., 86; Jousimes-Somer, Savolatinen & Yukoski, 88). Str.pneumoniae
P. Gehanno et al Table EL isolated in the prctreatment culture from sinus fluid (all patients) Treatment Cefpodoxime proxetil group Cefaclor Total Haemophilus spp. H. influenzat H. parainfluenzae Haemophilus spp* Streptococcus spp. Str. pneumoniae Str. anaerobes Group A, C. Streptococcus spp.' B. catarrhalis Staphylococcus spp. Staph. aureus Staphylococcus spp.' Corynebacterium spp.* Others Proteus spp. Klebsiella spp. Escherichia coli Serratia marcescens Moraxella spp. Neisseria meningitidis Acinetobacter spp.' Peptostreptococcus spp.' Enterobacter cloacae Ps. aeruginosa Citrobacter spp.* Number of pathogens Number of patients from whom pathogens were isolated Not speciated. 3 3 3 () 6 7/3 3 6 7 3 6 8/ 7(3%) 7 (3-%) 3 6 6 (-7%) (-%) (-%) 3 (-%) 8 ;! /6 was found in 6% of the samples, a percentage which is similar to that which has been reported in European studies (Gehanno et al., 88; Fasquelle et al., 8), but somewhat lower than the proportion found in the USA (Wald et al., 8; Scheld et al., 86). B. catarrhalis is rarely encountered in adult sinusitis (%). In this trial, B. catarrhalis was found in 3% of cases, an isolation rate close to that previously described in Sweden during 87. Staph. aureus was found in % of cases. A similar percentage has been reported in other studies (Gehanno et al., 88). Thus, H. influenzas, Str. pneumoniae, B. catarrhalis and S. aureus together represent the majority of the organisms responsible for acute sinusitis in adul.s. One of the expected advantages of the antibacterial spectrum of cefpodoxime, as compared with cefaclor, is its potential activity against most /?-lactamase-producing bacterial species (Utsui, Inoue & Mitsuhashi, 87; Chin & Neu, 88; Jones & Barry, 88). This was confirmed in the present trial with H. influenzas where six strains Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on March 6, 6
Treatment of sinusitis Table HI. Apparently resistant pathogens (disc diffusion test) isolated before treatment. For method, see text resistant to cefpodoxime resistant to cefaclor Number of patients H. influemae B. catarrhalis Ent. cloacae Citrobacter spp. Morganella morganii Pr. vulgaris Acinetobacter spp. Staph. aureus Ps. aeruginosa Total resistant to cefaclor were all sensitive to cefpodoxime. In this study strains of Staph. aureus were identified. From the findings in this study, as judged by clinical and radiological responses, cefpodoxime proxetil ( mg bd) may be somewhat more effective than cefaclor mg tds for ten days, in the treatment of acute sinusitis in adult out-patients. Noneradication of H. influemae occurred in five cases with cefaclor. All cases of H. influenzae were eradicated with cefpodoxime proxetil. References Chin, N. X. & Neu, H. C. (88). In vitro activity of an oral iminomethoxy aminothiazolyl cephalosporin. Antimicrobial Agents and Chemotherapy 3, 67-7. Ekedahl, F. (87). Akute Sinusitis bei Erwachusenen. Infection, -. Fasquelle, D., Dumas, G., Alami, M. & Burnichon, J. (8). Examen microbiologique des ponctions de sinus lors de sinusites. Etude retrospective de 7 ponctions et revue de la litterature. Medecwe et Maladies Infectieuses, -3. Gehanno, P., Leclercq, M., Thibault, M., Pichon, F. & Duval, J. (88). Bacteriologie des sinusites aigues et des sinusites chroniques en 88. Reunion Interdisciplinaire de la Chimtotherapie Anti-lnfectieuse. Paris, 88. Hanobey, B. H., Sande, M. A., Seale, D. L. & Gwaltney, J. L. (7). Etiology and antimicrobial therapy of acute maxillary sinusitis. Journal of Infectious Diseases 3, 7-. Jones, R. & Barry, A. L. (88). Antimicrobial activity and disk diffusion susceptibility testing of U-76, 3 A (R-376), the active metabolite of the new cephalosporin ester, U-76, (CS- 87). Antimicrobial Agents and Chemotherapy 3, 3-. Jousimes-Somer, H. R., Savolatinen, S. & Yukoski, J. S. (88). Bacteriological findings of acute maxillary sinusitis in young adults. Journal of Clinical Microbiology 6, -. Scheld, W. M., Sydnor, A., Farr, B., Gratz, J. C. & Gwaltney, J. M. (86). Comparison of cyclacillin and amoxycillin for therapy of acute maxillary sinusitis. Antimicrobial Agents and Chemotherapy 3, 3-3. Utsui, Y., Inove, M. & Mitsuhashi, S. (87). In vitro and in vivo antibacterial activities of CS- 87, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 3, 8-. Wald, E. R., Mihnoe, G. J., Bowen, A., Ledesma-Medina, J., Salamon, N. & Bluestone, C. D. (8). Acute maxillary sinusitis in children. New England Journal of Medicine 3, 7-. Wald, E. R., Reilly, J. S., Casselbrant, M., Ledesma-Medina, J., Milmoe, G. J., Bluestone, C. D. et al. (8). Treatment of acute maxillary sinusitis in childhood: a comparative study of amoxycillin and cefaclor. Journal of Pediatrics, 7-3.! Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on March 6, 6