Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. E, 79-85
Five day treatment of pharyngotonsillitis with cefpodoxime proxetil H. Portier", P. Chavanef, J. B. Gouyon* and F. Gnetaf
A ten day course of oral penicillin is still recommended for pharyngotonsillitis with the aim of eradicating Streptococcus pyogenes and preventing rheumatic fever. However there is some evidence that penicillin V therapy is less satisfactory than in former years. Several explanations have been suggested, including inadequate pharmacokinetic properties, poor patient compliance, penicillin tolerance, re-infection and carrier state, and indirect pathogenicity. In this context we evaluated the efficacy of third generation cephalosporins. We have shown that a short course of five days treatment with cefpodoxime is as effective as the ten days of conventional treatment with penicillin in terms of both clinical and bacteriological efficacy. Moreover the possibility of reducing the duration of therapy and the twice daily administration of these new cephalosporins results in better patient compliance with treatment.
Introduction
The duration of oral therapy usually recommended for pharyngotonsillitis is ten days with the aim of eradicating Streptococcus pyogenes and preventing rheumatic fever (Shulman et al., 1984; Anonymous, 1987). Attempts to reduce the penicillin V course to seven or five days have been followed by a marked decrease in the Str. pyogenes eradication rate (Schwartz et al., 1981; Gerber et al., 1987; Stromberg, Schwan & Cars, 1988a). However, a ten day course of oral penicillin is no longer as effective as in the past. Bacteriological failure rates between 18% and 26% are now reported, in some cases correlated with clinical recurrences (Gastanaduy et al., 1980; Kaplan et al., 1981; Schwartz et al., 1981; Roos, Holm & Ekedahl, 1985; Milatovic & Knauer, 1989). Several factors may explain why penicillin therapy is less satisfactory today than in former years and these include: inadequate pharmacological properties, poor patient compliance, penicillin inactivation by /Mactamases produced by the oral flora, Str. pyogenes tolerance to penicillin and the carrier state (Quie, Pierce & Wannamaker, 1966; Rosenstein et al., 1968; Kim & Kaplan, 1985; Roos et al., 1985; Sauzeau et al., 1987). The aim of this paper is to report investigations of cefpodoxime use, to evaluate the efficacy of third generation cephalosporins in pharyngotonsillitis and to assess the possibility of reducing the duration of therapy. The third generation cephalosporins are more stable to pMactamase inactivation, and achieve therapeutic levels in tonsillar tissue that might be expected to be effective 79 0305-7453/90/26E079 + 07 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Monash University on November 26, 2014
'Service des Maladies Infectieuses, andbService de Pe'diatrie, Hopital du Bocage, 21034-Dijon Cedex; 'Institut Roussel UCLAF, 102 Route de Noisy, 93230 Romainville-France
80
H. Porter et aL
against the main causative pathogens of pharyngotonsillitis. This paper reports two open randomized studies that this study group conducted.
Materials and methods
Downloaded from http://jac.oxfordjournals.org/ at Monash University on November 26, 2014
The first pilot study (approved by the local ethics committee) compared, for efficacy and safety, a new oral third generation cephalosporin, cefpodoxime proxetil, with cefuroxime axetil. From February to June 1989, nine general practitioners from France recruited 66 patients over 15 years of age with pharyngotonsillitis presumed to be of bacterial origin. Criteria for entry to the study were temperature > 38°C, sore throat and headache, dysphagia, redness and swelling of oropharynx and/or tonsils, in the absence of coryza, conjunctivitis, anterior stomatitis, cough or laryngitis. Written consent of patients (or parental consent) was obtained before entry to the study. Patients were randomly assigned to one of the following treatments: cefpodoxime proxetil 100 mg bd (group A), or cefuroxime axetil 250 mg bd (group B), both drugs being given for five days. Other antibiotic therapy, local treatment and anti-inflammatory agents were not allowed. Three examinations were carried out for each patient: pretreatment day (day 0), end of treatment between days 5 and 7 and follow-up between days 20 and 50. Throat swabs (one from the tonsils and one from the posterior pharynx) were rapidly taken to the medical laboratory in the Difco culture swab transport system. Sensitivity to the study antibiotics was determined by a disc diffusion method. Focusing on the bacteriological aetiology of pharyngotonsillitis, only the following isolates were considered as pathogens: Str. pyogenes, group C and group G /3-haemolytic streptococci, Haemophilus influenzae, Staphylococcus aurens and anaerobes (the last two only if isolated in pure culture). All patients who received any trial medication were evaluated for clinical safety. Patients were evaluable for bacteriological efficacy only if the isolated pathogen was sensitive to both cefpodoxime and cefuroxime and if the treatment was administered strictly for five days (except in the event of treatment failure). Patients whose pre-treatment culture yielded no pathogens were evaluated only for clinical efficacy. The bacteriological response was considered satisfactory if the causative pathogen was eradicated even if a new pathogen was present, provided there was no clinical evidence of a new infection (colonization). The bacteriological response was considered unsatisfactory if the causative pathogen persisted or was eradicated but a new organism was found with clinical evidence of a new infection. Only those patients with a satisfactory clinical response at the end of treatment were considered as eligible for the follow-up evaluation. The objective of the second study was to evaluate in a larger number of patients whether the shorter duration of antibiotic therapy with cefpodoxime proxetil was as effective as penicillin V administered for ten days. Between July and December 1989, 39 general practitioners from France and South Africa recruited 162 patients over ten years of age suffering from pharyngotonsillitis due to Str. pyogenes detected by a rapid diagnostic method (Strep-A-test, Hybritec). Patients were included in the study only if the infection was confirmed by bacterial culture. The written consent of the patients (or parental consent) was obtained before entry to the study. Patients were randomly assigned to receive cefpodoxime proxetil 100 mg bd for five days or penicillin V 0-6 g tid for ten days. Methodology and evaluability criteria were the same in both studies.
Treatment of tonsillitis
81
Results
Initial investigation (cefpodoxime proxetil vs cefuroxime axetil)
Second investigation (cefpodoxime proxetil vs phenoxymethylpenicillin) One hundred and sixty-two patients were included in this study; the mean demographic characteristics of these patients are detailed in Table I. Str. pyogenes was isolated from the throat swab taken on day 0 in 131 patients of 162. At the end of treatment, among
Table I. Demographic and background characteristics Characteristics Number of patients Age (years) mean (S.D.)
range
Cefpodoxime lOOmgbd
Penicillin 0-6 g tid
Total
84
78
30O (12-4) (11-82)
27-1 (9-8) (11-61)
28-6(11-3) (11-82)
49 35
(58-3%) (41-7%)
44 34
(56-4%) (43-6%)
93 69
(57-4%) (42-6%)
56 28
(66-7%) (33-3%)
51 27
(65-4%) (34-6%)
107 55
(660%) (340%)
162
Sex male female Race white black Weight (kg) mean (S.D.) range Height (cm) mean (S.D.)
range
660 (12-9) (37-100) 168 7 (9-4) (148-191)
62-9 (12-0) (35-94) 167-3 (9-5) (130-187)
64-5 (12-5) (35-100) 1680 (9-5) (130-191)
Downloaded from http://jac.oxfordjournals.org/ at Monash University on November 26, 2014
Sixty-six patients were included. The mean age was 28-8 ±11-2 years (range 15-64) in the cefpodoxime proxetil group and 31 -6 ± 16-3 years (range 15-79) in the cefuroxime axetil group. The causative agent was detected in the pre-treatment culture in 40 cases (60-6%). The pathogens isolated comprised 32 Streptococcus spp. (80%), including 21 Str. pyogenes (52-5%), seven group C (17-5%) and four group G (10%) /?-haemolytic streptococci; eight H. influenzae (20%) were also isolated. All the organisms were susceptible to both antibiotics except for one H. influenzae apparently resistant to cefpodoxime and one group C /J-haemolytic streptococcus apparently resistant to both antibiotics (by disc-sensitivity testing). At the end of treatment, 62 patients were clinically evaluable; the response was satisfactory in 100% in both groups. Bacteriological efficacy was evaluable in 18 patients of group A (cefpodoxime)—Str. pyogenes were eradicated in 10/11 cases, streptococci of Lancefield groups C and G in 3/5 and H. influenzae in 1/2—and in 19 patients of group B (cefuroxime axetil)—Str. pyogenes was eradicated in 8/10 cases, streptococci of groups C and G in 5/5 and H. influenzae in 4/4. At the follow-up visit at which 61 patients were assessed, two bacteriologically undocumented clinical relapses were observed in trial group A as against three in trial group B, one of which was due to Str. pyogenes. Clinical tolerance was good with no side-effects reported in trial group A and two in group B: one case of moderate oral candidosis and one of epigastric pain resulting in discontinuation of therapy on day 2.
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Discussion It is difficult to specify the duration of antibacterial treatment that is needed since there is no absolute clinical criterion for a cure apart from the absence of recurrence on discontinuation of therapy or the lack of post-streptococcal complications in the cases of Str. pyogenes pharyngotonsillitis. Thus the only available criterion to assess efficacy is bacterial eradication based on the throat cultures at the end of treatment and during the follow-up. The American Heart Association Council recommends that a full ten-day course of oral penicillin should be given to prevent rheumatic fever (Shulman et al., 1984). Attempts to reduce this duration with penicillin V have resulted in a marked decrease in the Str. pyogenes eradication rate: 73% with afive-daycourse (Stromberg et al.. 1988a), 69% after seven days (Schwartz et al., 1981). Nevertheless, during the last ten years, the failure rate with the conventional treatment duration of ten days has increased, reaching 18% (Schwartz et al., 1981) and 26% (Kaplan et al., 1981). Thus there is some evidence that penicillin V therapy for streptococcal pharyngotonsillitis is less satisfactory than in former years, even when given for ten days. Several explanations have been proposed: a wide interpatient variation in the absorption rate resulting in low or undetectable salivary or tonsillar concentrations (Kaplan et al., 1974; Roos et al., 1985); poor patient compliance, proved by Bergman & Werner (1963) and correlated with bacteriological failure in the study of Green, Stephen & Charney (1969), remains
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the 125 patients evaluable for clinical efficacy, all 65 patients in the cefpodoxime proxetil group had a satisfartory response as compared with 58/60 (96-7%) in the penicillin V group (P = 0-22). Of the 113 patients evaluable for bacteriological efficacy, Str.pyogenes was eradicated in 59/61 (96-7%) and 49/52 (94-2%), in the cefpodoxime group and the penicillin V group respectively (P = 0-42). At the follow-up visit, 58/60 (96-7%) and 52/53 (981%) had a satisfactory clinical response in the cefpodoxime group and the penicillin V group, respectively {P - 0-55). Str.pyogenes was eradicated in 51/54 (94-4%) and in 43/48 (89-6%), respectively (P = 0-29). Patient compliance was assessed in both groups by inspecting containers for the number of tablets returned to the monitor as well as careful questioning about antibiotic intake. Good compliance was observed more frequently in the cefpodoxime group with 81/83 cases (97-6%) than in the penicillin V group 66/77 (85-7%) cases (P < 0-01). The two cases of bad compliance in the cefpodoxime group were excluded from the efficacy analysis. Among the 11 cases of bad compliance in the penicillin group, six were also excluded from the efficacy analysis, three had a treatment duration of nine, seven and nine days respectively, and two others missed six and four tablets respectively during the second half of their treatment. Among the bacteriological failures, the pre- and post-treatment strains had been preserved in four cases and could be serotyped. In all cases, the Str. pyogenes isolated at the end of treatment and/or on follow-up was indistinguishable from that isolated on dayO. The clinical tolerance was considered good with three side-effects in the cefpodoxime group (two cases of diarrhoea and one case of urticaria) and one in the penicillin V group (urticaria).
Treatment of tonsfflitis
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controversial (Roos et al., 1985). Similarly the roles of penicillin tolerance, of reinfection and of the carrier state for Str.pyogenes are still unclear (Gastanaduy et al., 1980; Roos et al., 1985; Stromberg et al., 1988ft; Milatovic & Knauer, 1989). In recent years many workers have incriminated penicillin inactivation by /Mactamases produced by the oral flora and particularly by Branhamella catarrhalis, H. influenzae, H.parainfluenzae, Staph.aweus, or Bacteroides spp. (Brook, Yocum & Shah, 1980; Roos, Grahn & Holm, 1986; Milatovic & Knauer, 1989; Eliasson et al., 1990). Of course these factors may all contribute to the therapeutic failure. Oral first generation cephalosporins are as effective as penicillin (Gerber et al., 1986; Stromberg et al., 1988*) or even better (Stillerman, 1986; Milatovic and Knauer, 1989) when given for a ten day course. Such results may be explained by the more appropriate pharmacological properties of these compounds, their stability vis-a-vis penicillinase-producing strains and perhaps their broader spectrum including Staph. aureus. It was interesting to evaluate the efficacy of more stable compounds of the second and particularly the third generation cephalosporins, whose spectrum of action includes H. influenzae. In order to improve patient compliance, shorter courses of five days have been studied. Our investigation in Str. pyogenes pharyngitis resulted in an eradication rate of 95-8% at the end of treatment and 95-3% at the follow-up with cefpodoxime proxetil, equivalent to that with penicillin V given for ten days in the second prospective study. Although these trials were conducted in an open design and were not double-blind, they confirm the results previously obtained against Str. pyogenes in a double-blind study comparing ten day courses of cefpodoxime proxetil bd with amoxycillin 500 mg tid (Portier et al., 1990). This concept of shorter therapy in streptococcal pharyngitis has already been studied by Hebblethwaite, Brown & Cox (1987) and Cerstelotte et al. (1990) with cefuroxime axetil and cefetamet pivoxil, respectively. The latter compound given for seven days resulted in complete Str. pyogenes eradication in 35 adult patients and there were only two persistent Str. pyogenes at the end of treatment in 37 children. Our studies were conducted in patients aged over 10 or 15 years because, at the time, only tablets of cefpodoxime proxetil were available. Another study in infants and in children, using the oral suspension, is in progress. Various authors have reported that organisms other than Str. pyogenes may be responsible for bacterial pharyngotonsillitis but with a considerable lower incidence: Group C and Group G /?-haemolytic streptococci, H. influenzae, Arcanobacterium (Corynebacterium) haemolyticum, Staph. aureus (as long as it is in pure culture), anaerobes (as long as they are associated with clinical signs of anaerobic infection and that they are in pure culture), or Chlamydia pneumoniae although its role is disputed (Anonymous, 1987; Huovinen et al., 1989; Flaherty et. al., 1989). Since throat swabs are not taken routinely in Europe in out-patients, whether or not these organisms must be included in the spectrum of the empirical antibiotic therapy is controversial. However, cephalosporins of the second and particularly the third generation are effective against the majority of the bacteria mentioned previously. A short course of five days treatment with these compounds is as efficacious as the ten days of conventional treatment and this is an important factor to enhance the cost-benefit ratio. Furthermore, with regard to patient compliance, it must be pointed out that the twicedaily administration of newer cephalosporins may result in better compliance than the conventional tid schedule with penicillin V.
84
H. Portier et aL References
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Anonymous (1987). Bacterial pharyngitis. Lancet i, 1241-2. Bergman, A. & Werner, R. (1963). Failure of children to receive penicillin by mouth. New England Journal of Medicine 268, 1334-8. Brook, I., Yocum, P. & Shah, K. (1980). Surface vs core-tonsillar aerobic and anaerobic flora in recurrent tonsillitis Journal of American Medical Association 244, 1695-8. Cerstelottc, E., Vandenberghe, P., Bradbury, F., Murphy, N., Kasnanen, T., Germano, G. et al. (1990). Cefetamet pivoxil and penicillin V in the treatment of group A beta-haemorytic streptococcal pharyngitis. Ada Therapeutica 16, 163-73. Eliasson, I., Hoist, E., Molstad, S. & Kamme, C. (1990). Emergence and persistence of betalactamase producing bacteria in the upper respiratory tract in children treated with betalactam antibiotics. American Journal of Medicine 88, Suppl.SA, 51S-5S. Flaherty, L., Strauss, L., Lee, B., Schachter, I., Mills, J., Hadley, K. et al. (1989). Etiology of pharyngitis in adults. In Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy Houston, 1989. Abstract 259. American Society for Microbiology, Washington, DC. Gastanaduy, A. S., Kaplan, E. L., Huwe, B. B., McKay, C. & Wannamaker, L. W. (1980). Failure of penicillin to eradicate group A streptococci during an outbreak of pharyngitis. Lancet ii, 498-502. Gerber, M. A., Randolph, M. F., Chanatry, J., Wright, L. L., Anderson, L. R. & Kaplan, E. L. (1986). Once daily therapy for streptococcal pharyngitis with cefadroxil. Journal of Pediatrics 109, 531-7. Gerber, M. A., Randolph, M. F., Chanatry, J., Wright, L. L., De Meo, K. & Kaplan, E. L. (1987). Five vs ten days of penicillin V therapy for streptococcal pharyngitis. American Journal of Diseases of Children 141, 224-7. Green, J. L., Stephen, P. R. & Chamey, E. (1969). Recurrence rate of streptococcal pharyngitis related to oral penicillin. Journal of Pediatrics 75, 292. Hebblethwaite, E. M., Brown, G. W. & Cox, D. M. (1987). A comparison of the efficacy and safety of cefuroxime axetil and Augmentin in the treatment of upper respiratory tract infections. Drugs under Experimental and Clinical Research 13, 91-4. Huovinen, P., Lahtonen, R., Ziegler, T , Meurman, Hakkarainen, K., Miettinen, A. et al. (1989). Pharyngitis in adults: the presence and coexistence of viruses and bacteria] organisms. Annals of Internal Medicine 110, 612-6. Kaplan, J. M., McCracken, G. H. & Culbertson, M. C. (1974). Penicillin and erythromycin concentrations in tonsils. Relevance to treatment failures in streptococcal pharyngitis. American Journal of Diseases of Children 127, 206-11. Kaplan, E. L., Gatanaduy, A. S. & Huwe, B. B. (1981). The role of the carrier in treatment failure after antibiotic therapy for group A streptococci in the upper respiratory tract. Journal of Laboratory and Clinical Medicine 98, 326-35. Kim, K. S. & Kaplan, E. L. (1985). Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. Journal of Paediatrics 107, 681-4. Milatovic, D. & Knauer, J. (1989). Cefadroxil versus penicillin in the treatment of streptococcal tonsillopharyngitis. European Journal of Clincial Microbiology and Infectious Diseases 8, 282-8. Portier, H., Waldner, A., Clarysse, C , Kurzeja, A. H. & Rostand, A. (1990). Cefpodoxime proxetil vs amoxycillin in the treatment of pharyngitis or tonsillitis in adult outpatients. International Congress of Infectious Diseases, Montreal 1990. Abstract 631. Quie, P., Pierce, H. & Wannamaker, L. (1966). Influence of penicillinase producing staphylococci on the eradication of group A streptococci from the upper respiratory tract by penicillin treatment. Pediatrics 37, 467-75. Roos, K., Holm, S. E. & Ekedahl, C. (1985). Treatment failure in acute streptococcal tonsillitis in children over the age of 10 and in adults. Scandinavian Journal of Infectious Diseases 17, 357-65. Roos, K., Grahn, E. & Holm, J. E. (1986). Evaluation of beta-lactamase activity and microbial interference in treatment failure of acute streptococcal tonsillitis. Scandinavian Journal of Infectious Diseases 18, 313-9.
Treatment of tonsflUtb
85
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Rosenstein, B. J., Markowitz, M., Goldstein, E., Kramer, I., O'Mansky, B., Seidel, H. et al., (1968). Factors involved in treatment failures following oral penicillin therapy of streptococcal pharyngitis. Journal of Pediatrics 73, 513-20. Sauzeau, C , Bingen, E., Lambert-Zechovsky, N. & Mariani-Kurkdjian, P. (1987) Analyse des causes d'echec de l'eradication du streptocoque A dans les angines. Le Pidiatre 23, 247-9. Schwartz, R., Wientzen, R., Pedaeira, F., Feroli, E. T., Mella, G. W. & Guandolo, V. L. (1981). Penicillin V for group A streptococcal pharyngotonsillitis. Journal of the American Medical Association 246, 1790-5. Shuhnan, S. T , Amren, D. P., Bisno, A. L., Dajani, A. S., Durack, D. T., Gerber, M. A. et al. (1984). Prevention of rheumatic fever. Circulation 70, 1118A-22A. Stillerman, M. (1986). Comparison of oral cephalosporins with penicillin therapy for group A streptococca] pharyngitis. Pediatric Infectious Diseases 5, 649-54. Stromberg, A., Schwan, A. & Cars, O. (1988a). Five versus ten days treatment of group A streptococca] pharyngotonsillitis: a randomized controlled clinical trial with phenoxymethylpenicillin and cefadroxil. Scandinavian Journal of Infectious Diseases 20, 37-46. Stromberg, A., Schwan, A. & Cars, O. (19886). Throat carrier rates of beta-hemolytic streptococci among healthy adults and children. Scandinavian Journal of Infectious Diseases 20,411-7.
Five day treatment of pharyngotonsillitis with cefpodoxime proxetil H. Portier", P. Chavanef, J. B. Gouyon* and F. Gnetaf
A ten day course of oral penicillin is still recommended for pharyngotonsillitis with the aim of eradicating Streptococcus pyogenes and preventing rheumatic fever. However there is some evidence that penicillin V therapy is less satisfactory than in former years. Several explanations have been suggested, including inadequate pharmacokinetic properties, poor patient compliance, penicillin tolerance, re-infection and carrier state, and indirect pathogenicity. In this context we evaluated the efficacy of third generation cephalosporins. We have shown that a short course of five days treatment with cefpodoxime is as effective as the ten days of conventional treatment with penicillin in terms of both clinical and bacteriological efficacy. Moreover the possibility of reducing the duration of therapy and the twice daily administration of these new cephalosporins results in better patient compliance with treatment.
Introduction
The duration of oral therapy usually recommended for pharyngotonsillitis is ten days with the aim of eradicating Streptococcus pyogenes and preventing rheumatic fever (Shulman et al., 1984; Anonymous, 1987). Attempts to reduce the penicillin V course to seven or five days have been followed by a marked decrease in the Str. pyogenes eradication rate (Schwartz et al., 1981; Gerber et al., 1987; Stromberg, Schwan & Cars, 1988a). However, a ten day course of oral penicillin is no longer as effective as in the past. Bacteriological failure rates between 18% and 26% are now reported, in some cases correlated with clinical recurrences (Gastanaduy et al., 1980; Kaplan et al., 1981; Schwartz et al., 1981; Roos, Holm & Ekedahl, 1985; Milatovic & Knauer, 1989). Several factors may explain why penicillin therapy is less satisfactory today than in former years and these include: inadequate pharmacological properties, poor patient compliance, penicillin inactivation by /Mactamases produced by the oral flora, Str. pyogenes tolerance to penicillin and the carrier state (Quie, Pierce & Wannamaker, 1966; Rosenstein et al., 1968; Kim & Kaplan, 1985; Roos et al., 1985; Sauzeau et al., 1987). The aim of this paper is to report investigations of cefpodoxime use, to evaluate the efficacy of third generation cephalosporins in pharyngotonsillitis and to assess the possibility of reducing the duration of therapy. The third generation cephalosporins are more stable to pMactamase inactivation, and achieve therapeutic levels in tonsillar tissue that might be expected to be effective 79 0305-7453/90/26E079 + 07 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Monash University on November 26, 2014
'Service des Maladies Infectieuses, andbService de Pe'diatrie, Hopital du Bocage, 21034-Dijon Cedex; 'Institut Roussel UCLAF, 102 Route de Noisy, 93230 Romainville-France
80
H. Porter et aL
against the main causative pathogens of pharyngotonsillitis. This paper reports two open randomized studies that this study group conducted.
Materials and methods
Downloaded from http://jac.oxfordjournals.org/ at Monash University on November 26, 2014
The first pilot study (approved by the local ethics committee) compared, for efficacy and safety, a new oral third generation cephalosporin, cefpodoxime proxetil, with cefuroxime axetil. From February to June 1989, nine general practitioners from France recruited 66 patients over 15 years of age with pharyngotonsillitis presumed to be of bacterial origin. Criteria for entry to the study were temperature > 38°C, sore throat and headache, dysphagia, redness and swelling of oropharynx and/or tonsils, in the absence of coryza, conjunctivitis, anterior stomatitis, cough or laryngitis. Written consent of patients (or parental consent) was obtained before entry to the study. Patients were randomly assigned to one of the following treatments: cefpodoxime proxetil 100 mg bd (group A), or cefuroxime axetil 250 mg bd (group B), both drugs being given for five days. Other antibiotic therapy, local treatment and anti-inflammatory agents were not allowed. Three examinations were carried out for each patient: pretreatment day (day 0), end of treatment between days 5 and 7 and follow-up between days 20 and 50. Throat swabs (one from the tonsils and one from the posterior pharynx) were rapidly taken to the medical laboratory in the Difco culture swab transport system. Sensitivity to the study antibiotics was determined by a disc diffusion method. Focusing on the bacteriological aetiology of pharyngotonsillitis, only the following isolates were considered as pathogens: Str. pyogenes, group C and group G /3-haemolytic streptococci, Haemophilus influenzae, Staphylococcus aurens and anaerobes (the last two only if isolated in pure culture). All patients who received any trial medication were evaluated for clinical safety. Patients were evaluable for bacteriological efficacy only if the isolated pathogen was sensitive to both cefpodoxime and cefuroxime and if the treatment was administered strictly for five days (except in the event of treatment failure). Patients whose pre-treatment culture yielded no pathogens were evaluated only for clinical efficacy. The bacteriological response was considered satisfactory if the causative pathogen was eradicated even if a new pathogen was present, provided there was no clinical evidence of a new infection (colonization). The bacteriological response was considered unsatisfactory if the causative pathogen persisted or was eradicated but a new organism was found with clinical evidence of a new infection. Only those patients with a satisfactory clinical response at the end of treatment were considered as eligible for the follow-up evaluation. The objective of the second study was to evaluate in a larger number of patients whether the shorter duration of antibiotic therapy with cefpodoxime proxetil was as effective as penicillin V administered for ten days. Between July and December 1989, 39 general practitioners from France and South Africa recruited 162 patients over ten years of age suffering from pharyngotonsillitis due to Str. pyogenes detected by a rapid diagnostic method (Strep-A-test, Hybritec). Patients were included in the study only if the infection was confirmed by bacterial culture. The written consent of the patients (or parental consent) was obtained before entry to the study. Patients were randomly assigned to receive cefpodoxime proxetil 100 mg bd for five days or penicillin V 0-6 g tid for ten days. Methodology and evaluability criteria were the same in both studies.
Treatment of tonsillitis
81
Results
Initial investigation (cefpodoxime proxetil vs cefuroxime axetil)
Second investigation (cefpodoxime proxetil vs phenoxymethylpenicillin) One hundred and sixty-two patients were included in this study; the mean demographic characteristics of these patients are detailed in Table I. Str. pyogenes was isolated from the throat swab taken on day 0 in 131 patients of 162. At the end of treatment, among
Table I. Demographic and background characteristics Characteristics Number of patients Age (years) mean (S.D.)
range
Cefpodoxime lOOmgbd
Penicillin 0-6 g tid
Total
84
78
30O (12-4) (11-82)
27-1 (9-8) (11-61)
28-6(11-3) (11-82)
49 35
(58-3%) (41-7%)
44 34
(56-4%) (43-6%)
93 69
(57-4%) (42-6%)
56 28
(66-7%) (33-3%)
51 27
(65-4%) (34-6%)
107 55
(660%) (340%)
162
Sex male female Race white black Weight (kg) mean (S.D.) range Height (cm) mean (S.D.)
range
660 (12-9) (37-100) 168 7 (9-4) (148-191)
62-9 (12-0) (35-94) 167-3 (9-5) (130-187)
64-5 (12-5) (35-100) 1680 (9-5) (130-191)
Downloaded from http://jac.oxfordjournals.org/ at Monash University on November 26, 2014
Sixty-six patients were included. The mean age was 28-8 ±11-2 years (range 15-64) in the cefpodoxime proxetil group and 31 -6 ± 16-3 years (range 15-79) in the cefuroxime axetil group. The causative agent was detected in the pre-treatment culture in 40 cases (60-6%). The pathogens isolated comprised 32 Streptococcus spp. (80%), including 21 Str. pyogenes (52-5%), seven group C (17-5%) and four group G (10%) /?-haemolytic streptococci; eight H. influenzae (20%) were also isolated. All the organisms were susceptible to both antibiotics except for one H. influenzae apparently resistant to cefpodoxime and one group C /J-haemolytic streptococcus apparently resistant to both antibiotics (by disc-sensitivity testing). At the end of treatment, 62 patients were clinically evaluable; the response was satisfactory in 100% in both groups. Bacteriological efficacy was evaluable in 18 patients of group A (cefpodoxime)—Str. pyogenes were eradicated in 10/11 cases, streptococci of Lancefield groups C and G in 3/5 and H. influenzae in 1/2—and in 19 patients of group B (cefuroxime axetil)—Str. pyogenes was eradicated in 8/10 cases, streptococci of groups C and G in 5/5 and H. influenzae in 4/4. At the follow-up visit at which 61 patients were assessed, two bacteriologically undocumented clinical relapses were observed in trial group A as against three in trial group B, one of which was due to Str. pyogenes. Clinical tolerance was good with no side-effects reported in trial group A and two in group B: one case of moderate oral candidosis and one of epigastric pain resulting in discontinuation of therapy on day 2.
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Discussion It is difficult to specify the duration of antibacterial treatment that is needed since there is no absolute clinical criterion for a cure apart from the absence of recurrence on discontinuation of therapy or the lack of post-streptococcal complications in the cases of Str. pyogenes pharyngotonsillitis. Thus the only available criterion to assess efficacy is bacterial eradication based on the throat cultures at the end of treatment and during the follow-up. The American Heart Association Council recommends that a full ten-day course of oral penicillin should be given to prevent rheumatic fever (Shulman et al., 1984). Attempts to reduce this duration with penicillin V have resulted in a marked decrease in the Str. pyogenes eradication rate: 73% with afive-daycourse (Stromberg et al.. 1988a), 69% after seven days (Schwartz et al., 1981). Nevertheless, during the last ten years, the failure rate with the conventional treatment duration of ten days has increased, reaching 18% (Schwartz et al., 1981) and 26% (Kaplan et al., 1981). Thus there is some evidence that penicillin V therapy for streptococcal pharyngotonsillitis is less satisfactory than in former years, even when given for ten days. Several explanations have been proposed: a wide interpatient variation in the absorption rate resulting in low or undetectable salivary or tonsillar concentrations (Kaplan et al., 1974; Roos et al., 1985); poor patient compliance, proved by Bergman & Werner (1963) and correlated with bacteriological failure in the study of Green, Stephen & Charney (1969), remains
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the 125 patients evaluable for clinical efficacy, all 65 patients in the cefpodoxime proxetil group had a satisfartory response as compared with 58/60 (96-7%) in the penicillin V group (P = 0-22). Of the 113 patients evaluable for bacteriological efficacy, Str.pyogenes was eradicated in 59/61 (96-7%) and 49/52 (94-2%), in the cefpodoxime group and the penicillin V group respectively (P = 0-42). At the follow-up visit, 58/60 (96-7%) and 52/53 (981%) had a satisfactory clinical response in the cefpodoxime group and the penicillin V group, respectively {P - 0-55). Str.pyogenes was eradicated in 51/54 (94-4%) and in 43/48 (89-6%), respectively (P = 0-29). Patient compliance was assessed in both groups by inspecting containers for the number of tablets returned to the monitor as well as careful questioning about antibiotic intake. Good compliance was observed more frequently in the cefpodoxime group with 81/83 cases (97-6%) than in the penicillin V group 66/77 (85-7%) cases (P < 0-01). The two cases of bad compliance in the cefpodoxime group were excluded from the efficacy analysis. Among the 11 cases of bad compliance in the penicillin group, six were also excluded from the efficacy analysis, three had a treatment duration of nine, seven and nine days respectively, and two others missed six and four tablets respectively during the second half of their treatment. Among the bacteriological failures, the pre- and post-treatment strains had been preserved in four cases and could be serotyped. In all cases, the Str. pyogenes isolated at the end of treatment and/or on follow-up was indistinguishable from that isolated on dayO. The clinical tolerance was considered good with three side-effects in the cefpodoxime group (two cases of diarrhoea and one case of urticaria) and one in the penicillin V group (urticaria).
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controversial (Roos et al., 1985). Similarly the roles of penicillin tolerance, of reinfection and of the carrier state for Str.pyogenes are still unclear (Gastanaduy et al., 1980; Roos et al., 1985; Stromberg et al., 1988ft; Milatovic & Knauer, 1989). In recent years many workers have incriminated penicillin inactivation by /Mactamases produced by the oral flora and particularly by Branhamella catarrhalis, H. influenzae, H.parainfluenzae, Staph.aweus, or Bacteroides spp. (Brook, Yocum & Shah, 1980; Roos, Grahn & Holm, 1986; Milatovic & Knauer, 1989; Eliasson et al., 1990). Of course these factors may all contribute to the therapeutic failure. Oral first generation cephalosporins are as effective as penicillin (Gerber et al., 1986; Stromberg et al., 1988*) or even better (Stillerman, 1986; Milatovic and Knauer, 1989) when given for a ten day course. Such results may be explained by the more appropriate pharmacological properties of these compounds, their stability vis-a-vis penicillinase-producing strains and perhaps their broader spectrum including Staph. aureus. It was interesting to evaluate the efficacy of more stable compounds of the second and particularly the third generation cephalosporins, whose spectrum of action includes H. influenzae. In order to improve patient compliance, shorter courses of five days have been studied. Our investigation in Str. pyogenes pharyngitis resulted in an eradication rate of 95-8% at the end of treatment and 95-3% at the follow-up with cefpodoxime proxetil, equivalent to that with penicillin V given for ten days in the second prospective study. Although these trials were conducted in an open design and were not double-blind, they confirm the results previously obtained against Str. pyogenes in a double-blind study comparing ten day courses of cefpodoxime proxetil bd with amoxycillin 500 mg tid (Portier et al., 1990). This concept of shorter therapy in streptococcal pharyngitis has already been studied by Hebblethwaite, Brown & Cox (1987) and Cerstelotte et al. (1990) with cefuroxime axetil and cefetamet pivoxil, respectively. The latter compound given for seven days resulted in complete Str. pyogenes eradication in 35 adult patients and there were only two persistent Str. pyogenes at the end of treatment in 37 children. Our studies were conducted in patients aged over 10 or 15 years because, at the time, only tablets of cefpodoxime proxetil were available. Another study in infants and in children, using the oral suspension, is in progress. Various authors have reported that organisms other than Str. pyogenes may be responsible for bacterial pharyngotonsillitis but with a considerable lower incidence: Group C and Group G /?-haemolytic streptococci, H. influenzae, Arcanobacterium (Corynebacterium) haemolyticum, Staph. aureus (as long as it is in pure culture), anaerobes (as long as they are associated with clinical signs of anaerobic infection and that they are in pure culture), or Chlamydia pneumoniae although its role is disputed (Anonymous, 1987; Huovinen et al., 1989; Flaherty et. al., 1989). Since throat swabs are not taken routinely in Europe in out-patients, whether or not these organisms must be included in the spectrum of the empirical antibiotic therapy is controversial. However, cephalosporins of the second and particularly the third generation are effective against the majority of the bacteria mentioned previously. A short course of five days treatment with these compounds is as efficacious as the ten days of conventional treatment and this is an important factor to enhance the cost-benefit ratio. Furthermore, with regard to patient compliance, it must be pointed out that the twicedaily administration of newer cephalosporins may result in better compliance than the conventional tid schedule with penicillin V.
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