ORIGINAL ARTICLE
Efficacy of 5-day cefpodoxime proxetil for recurrent pharyngitis in adults. A comparative study with 10-day penicillin V or amoxycillin-clavulanate
Henri Portierl, Pierre Gehanno’, Philippe Weber3, Henri Dabernat 4, Frangoise Ichou’, Antoine Clerrnonts and Sylvie Fiessinger‘
‘Service des Maladies Infectieuses, Centre Hospitalier RCgional Universitaire, Hepita1 du Bocage, Dijon, ’Service d’ORL, H6pital Bichat: Claude Bernard, Paris, ‘Centre de Diagnostic du Galilbe, Torcy-Marne la Vallee, ‘Centre National de Rbfkrence pour 1’Haeniophilus Influenzae, H6pital Purpan, Toulouse, ‘Laboratoires Diamant, Paris-La DCfenr.e, and 6Roussel UCLAF, Romainville, France
Objective: To compare the clinical and bacteriologic efficacy of a 5-day course of cefpodoxime proxetil (CPD) with that of a 10-day course of penicillin V (PNV) or amoxycillin-clavulanate (AMC) in recurrent pharyngitis in adults. A cost- effectiveness study (reported elsewhere) was carried out at the same time. Methods: This multicenter, randomized, open label trial involved 580 adult patients consulting general practitioners for clinical recurrent pharyngitis (23 episodes within the last 12 months) regardless of the bacterial etiology. Patients were treated for 5 days with CPD, 100 mg twice daily, or for 10 days with PNV, 1x lo6IU three times a day, or for 10 days with AMC, 500 mg (amoxycillin) three times a day. Clinical and bacteriologic outcomes were noted at the end of treatment, and cases of clinical recurrenc:e were recorded during a 6-month follow-up period. \ Results: At the end of treatment, clinical response was satisfactory in 157 of 170 (92.3%) patients on CPD, 147 of 166 (88.5%) patients on PNV, and 168 of 177 (94.9%) patients on AMC. Group A P-hemolytic streptococci (GABHS) were eradicated in 22 of 23 (95.65%) patients on CPD, 16 of 16 (100%) patients on PNV, and 19 of 20 (95%) patients on AMC. The rates of clinical success and GABHS eradication were not significantly different between the groups. Compliance (p INTRODUCTION treatment is dictated by the risk of suppurative com- plications and, above all, by the risk of failing to The diagnosis of acute pharyngitis is generally based on abrogate pharyngitis due to group A P-hemolytic clinical signs and symptoms. In most cases, antibiotic streptococci (GABHS). GABHS pharyngitis represents 11-50% of cases of acute pharyngitis, and the risk of Corresponding author and reprint requests: acute rheumatic fever (ARF) after GABHS pharyngitis Henri Portier, Centre Hospitalier Regional llniversitaire, is 1 to 3% in the absence of antimicrobial chemotherapy Service des Maladies Infectieuses, HBpital du Bocage, [I]. 2 bd de Lattre de Tassigny, 21034 Dijon Cedex, France In France, clinicians are advised to treat all cases Tel: 33 80 29 33 05 Fax: 33 80 29 34 82 of acute pharyngitis, regardless of the age of the patient, Accepted 19 April 1997 and without taking a throat swab for identification of 447 448 Clinical Microbiology and Infection, Volume 3 Number 4, August 1997 group A streptococci [I]. A 3 0-day course of penicillin V (PNV) remains the reference treatment of these acute episodes. This therapeutic strategy differs fi-om that This French nationwide multicenter study, conducted applied in cases of recurrent pharyngitis, where p- from March 1992 to January 1993, involved 580 lactam agents stable to p-lactamases (second- and third- patients recruited by 204 general practitioners. Each generation cephalosporins, anlinopenicillins combined investigator had to include at least a block of three with a p-lactamase inhibitor) are the recommended patients, who were randomly assigned to one of the treatment. three regimens under study. It was thus a prospective, In the literature, the yearly frequency of episodes comparative, randonlized, open trial with three parallel is used as a practical definition of recurrent pharyngitis. groups. Depending on the author, recurrent episodes (from three to five) can be counted over a 2-year or I-year Patients period [2-lo]. Inclusion criteria were as follows: ambulatory patients The pathophysiologic mechanisnis and bacterial over 15 years of age, of either sex, consulting a general epidemiology of these episodes of recurrent pharyngitis practitioner for recurrent pharyngitis. The latter was remain to be documented. Potentially predisposing defined by the presence of clinical signs and symptoms factors include bacterial colonization of hypertrophic of bacterial pharyngitis origin (temperature 238 OC, tonsils (2,6,10-12) and the copathogenicity hypothesis throat pain both spontaneously and on swallowing, [13]. The latter is based on the presence of large possible headache, erythematous or erythemato- numbers of P-lactamase-producing strains in the tonsils exudative tonsils and pharynx, anterior cervical adeno- of patients with recurrent pharyngitis. Among the pathy; no coryza, conjunctivitis, cough or laryngitis) p-lactam agents used to treat episodes of pharyngitis, and by the frequency of episodes (the current episode PNV and aminopenicillins are sensitive to many 0- having to be at least the third in the last 12 months). lactamases, and this may possibly explain cases of treat- Non-inclusion criteria were as follows: age less ment failure and recurrence. than 15 years; pregnancy or breast-feeding; sinusitis; Cefpodoxime proxetil (CPD), a cefpodoxime pro- history of allergy to p-lactam agents; cancer, hemato- drug, is a p-lactam agent and an oral third-generation logic disorder or acquired immunodepression; anti- cephalosporin. In France, as far as the treatment of biotic treatment in the previous 72 h; treatment with pharyngitis is concerned, CPD should be reserved allopurinol; recurrent infectious lung, urinary tract for the treatment of recurrent episodes. Several com- or gynecologic disease; unlikely compliance with 6 parative trials of CPD in the treatment of streptococcal months of follow-up. pharyngitis have shown that this antibiotic is a safe All the patients (or the parents of patients less than and effective alternative for the eradication of group A 18 years old) gave their informed consent to the study streptococci 114-161. In addition, a 5-day course of and the protocol was approved by a medical ethical cefpodoxime in this setting is as effective in clinical and committee. bacteriologic term (eradication of group A strepto- cocci) as a 10-day course of PNV [15,17-201, with a Treatment regimens clear benefit as regards compliance. The patients were randomized to one of the following These observations led us to perform a clinical oral treatment arms: CPD, one tablet (100 mg) twice study on adult patients with recurrent pharyngitis to daily for 5 days; PNV, one tablet (1 x lo6 IU; 600 mg) compare a 5-day course of CPD with a 10-day course three times a day for 10 days; AMC, one tablet (500 mg of PNV or amoxycillin-clavulanate (AMC). The aims amoxycillin + 125 mg clavulanate) three times a day for of this study were: 10 days. The tablets had to be taken with meals in the morning and evening (CPD), or morning, midday and evening (PNV and AMC). Treatment allocation was 1. to compare the clinical efficacy at the end of treat- managed via a central computer system. Concomitant ment; administration of antiseptics, analgesics, antipyretics 2. to compare the bacteriologic efficacy in the sub- and anti-inflammatory drugs (including steroids) was group of documented GABHS pharyngitis; authorized. In contrast, other antibiotics, even in the 3. to compare the clinical efficacy on the recurrence form of mouthwashes, were forbidden. rate during the 6-month follow-up period. Clinical follow-up Results of the cost-effectiveness study conducted At the enrollment visit (DI), after checking ofinclusion in parallel have been published elsewhere [21]. and non-inclusion criteria, the patients' demographic Portier et al: Short-course treatment of recurrent pharyngitis 449 data and personal histories were recorded, together infection had deteriorated or if the patient’s condition with details of the current episode of pharyngitis. had not improved. It was unevaluable if the study drug General and local signs (temperature, loss of appetite, had been taken for less than 5 days (or less than 48 h in throat pain, headache, color of the pharynx, adeno- case of failure) or if inclusion/non-inclusion criteria pathy) were noted, together with the allocated treat- were not respected. The time (in days) required for ment, other prescribed drugs and sick leave. The the patients to feel better or cured was noted by the patient was seen by the same investigator at an end-of- investigator on a daily record card filled in by the treatment visit (D7-D8 in the CPD group; D12-Dl3 patient. in the PNV and AMC groups) to assess changes in At the end of the follow-up period, treatment was local and general signs, together with compliance, judged successful if no further episode of pharyngitis tolerability and how the patient felt. All the patients had occurred by D180. Recurrence was defined as the treated successfully were seen 6 months later. During onset of a new episode of pharyngitis after the end-of- the follow-up period (from D9 or D14 to D180), the treatment visit. Efficacy was unevaluable in the follow- patient was contacted by telephone every 2 months to ing cases: no follow-up visit or no contact within 6 record any new episodes of pharyngitis or intercurrent months after the beginning of treatment; unsatisfactory infections. When recurrences were diagnosed in the or unevaluable clinical efficacy at the end-of-treatment practitioner’s office, general and local signs were visit; prescription of another antibiotic during the recorded, along with any drug prescriptions. follow-up period for an intercurrent infection. Bacteriologic follow-up Evaluation of efficacy by means of Kaplan-Meier plots On Dl , the investigator took two sw,ibs in random All the patients in whom clinical efficacy was judged order, one for diagnosis of group A streptococcal satisfactory at the end-of-treatment visit were included infection by means of a rapid agglutination method in this analysis. The number of days without recurrence (Abbott Test Pack, Abbott, USA), and the other for was defined as the difference between the first day of culture. These two samples allowed an evaluation of the treatment and either the date of recurrence, the date of sensitivity of the rapid diagnosis test in routine practice, loss to follow-up without clinical recurrence, or the even though this test is not available in France at date of the first dose of antibiotics for an inter- the present time. The samples for culture were obtained current infection. Kaplan-Meier survival curves were with Culturette swabs (Becton-Diclrinson, USA), constructed from these data for each treatment group. which were immediately placed in special transport medium for respiratory tract pathogens (Stuart Trans- Evaluation of bacteriologic efficacy port Medium, UNIPATH, UK) and sent by mail the This analysis only took into account group A strepto- same day to a central laboratory (Laboratoire du Centre cocci, the only organism clearly identified as patho- de Diagnostic du GalilCe, Torcy Marne-la-VallCe, genic in pharyngitis. Patients eligible for this analysis France). Only those samples received at the laboratory were those evaluable for clinical efficacy, by protocol, within 3 days after sampling were taken into account at the end of treatment, who had group A streptococci to describe the potential pathogens. Description of cultured from their first sample. Samples received the potential pathogens was applied to the following within 7 days by the central laboratory (initial sample selection of bacteria yielded by culture: all group A, C and end-of-treatment sample) were taken into account, and G P-heniolytic streptococci (irrespective of their in order to describe the maximum number of strepto- quantity); Haemophilus injluenzae and Staphylococcus coccal pharyngitis cases. Bacteriologic efficacy at the aweus cultured from samples not containing strepto- end of treatment was judged satisfactory if group A cocci; Enterobacteriaceae and non-fermenting Gram- streptococci were eradicated, and otherwise as unsatis- negative bacilli cultured from samples containing none factory. of the above pathogens. Strains of the two last groups of bacteria were taken into account only when present Evaluation of tolerance in culture in significant amounts. Culture of a further Tolerance was assessed froin the data collected at the throat swab was performed at the end of treatment end of treatment on the basis of the number of patients under the same conditions as at the enrollment visit. who experienced one or more adverse events in each treatment group. Assessment of clinical efficacy At the end of treatment, clinical efficacy was judged Evaluation of compliance satisfactory if the infection was clinically cured or Compliance, judged by the number of tablets taken improved. Efficacy was judged unsatisfactory if the (recorded by the investigator), was considered good if 450 Clinical Microbiology and Infection, Volume 3 Number 4, August 1997 at least 80% of the treatment course had been taken 1992 and June 1992, five were excluded from the (eight tablets of CPD or 24 tablets of PNV or AMC). analyses (four lost to follow-up, one took no treat- ment); 575 patients were thus evaluable for analysis of Statistical analysis clinical tolerance. The evaluation of clinical efficacy The number of subjects necessary to show a difference at the end of treatment involved 513 patients, as 62 of 10% between CPD and one of the other study drugs patients were excluded because of major deviations was 395 per treatment group, assuming a clinical success from the protocol. Among these 513 patients, 469 rate of 95% at the end of treatment, with a first-order were evaluable for long-term outcome, while 44 were risk of 2.5% and a second-order risk of 2.5% (instead unevaluable; the outcome of treatment had been a of 5%, as there were three treatment groups). clinical failure in 41 of them, and three had received The relapse rate at 6 months with the reference another antibiotic at the end of treatment, based on the treatment was unknown. The power of comparisons results of throat culture. In total, 389 patients were involving recurrence rates based on survival curves was included in the assessment of clinical efficacy during thus calculated retrospectively, and was 90% for the follow-up, as 124 patients were unevaluable (44 patients cornparison of CPD with AMC, and 80% for the excluded from the Kaplan-Meier analysis, 70 patients comparison of CPD with PNV who had received an antibiotic for an intercurrent Comparisons of frequencies were made using the infection during the follow-up period, and 10 patients chi-squared test or Fisher’s exact test. In cases of an whose final visit had not taken place at M6 or M7). overall difference between the three groups, the CPD Among the 575 patients evaluable for tolerance group was compared with each of the other two (205 men and 370 women; median age 33.7k12.6 groups. The comparison of changes in qualitative years; mean body weight 64.1 k 13 kg), the demo- parameters was based on the Mantel-Haenszel adjusted graphic characteristics, medical history and presenting chi-squared test. Means were compared using one- signs and symptoms were comparable in the three way analysis of variance; in case of a significant overall groups (Table 1). The analysis of the same parameters difference, the groups were compared two-by-two in the population eligible for the analysis of clinical using Dunnet’s T test. Recurrences after successful efficacy also failed to show significant differences treatment were analyzed by the Kaplan-Meier method. between the three groups. The three treatments were compared by means of the log-rank test, and then two-by-two when the Clinical efficacy by protocol at the end of treatment difference was significant. In addition, a Cox model was In the 513 patients evaluable for this analysis, the rate used to identify variables with independent influence of satisfactory clinical responses was not significantly on the recurrence rate. The variables entered in the different between the three groups (Table 2). Among model were those recorded at enrollment and found to the patients in whom the clinical response was satis- have significant influence in a univariate analysis. factory, the mean time required for a subjective im- provement was significantly shorter on CPD (2.5 F 0.8 days) thanonPNV (3.3k1.3days) andAMC (3.321.3 days) (global comparison, p<0.001). Similarly, the time Description of the population required for a subjective cure was significantly shorter Among the 580 patients randomized between March on CPD (4k1.3 days) than on PNV(5.4F1.9 days) and Table 1 Clinical and demographic characteristics of patients evaluable for tolerance CPD PNV AMC iw=188) (?I = 187) (?I =200) P Demographic characteristics Age (years, m f SD) 33.37k12.29 34.03f 12.81 33.64F12.75 NS Weight (kg, m +SD) 65.07f13.66 63.71 2 12.34 63.63k12.48 NS Sex (M/F) 72/116 62/ 125 71/129 NS Medical history Nuniber of episodes in last 12 months (nifSD) 4.2651.22 4.2521.30 4.21 f1.18 NS Tonsillectomy (yes/no) 16/172 20/ 167 261174 NS Date of last pharyngitis (days, miSD) 70.07k43.89 71.58147.26 73.86547.38 NS Timc from clinical onset (days, NI k SD) 2.052331 1.89 k2.47 1.90f2.26 NS CPD=cefpodoxinie proxetil; PNV=penicillin V; AMC=amoxycillin + clavulanic acid; NS=not significant; m=niean. Portier et al: Short-course treatment of recurrent pharyngitis 451 Table 2 AnalyTiT of clinical efficacy by protocol at the end no significant difference was found as regards the mean of treatment time to recurrence (Table 3). CPI) PNV AMC Clinical re.;ponsr (rr=17iI) (rr=166) (n=177) Clinical efficacy: Kaplan-Meier plots Figure 1 shows the ‘non-recurrence’ curves in the Satisfactory (94) * 157 (92.35) 147 (88.55) 168 (94.92) Unsatisfactory (‘X) 13 (7.65) 10 (1 1.45) 9 (5.08) three treatment groups. The three curves were globally different. Two-by-two comparisons (log-rank test) con- CPD=cefpodoxinie proxetil; PNV=prnicillin V; firmed the absence of a significant difference between AMC=anioxycillin + clavulanic acid; *p=O.O9. the PNV and AMC curves. In contrast, the CPL) curve differed significantly from the PNV curve (p=O.Ol) and AMC (5.6 k 2.2 days) (global comparison, p<0.001). the AMC curve (p<0.01). This difference was also found in the Kaplan-Meier The influence of treatment on the onset of recur- plots of subjective amelioration and cure among the rences was studied by means of a Cox model, which patients who were evaluable at the end of treatment. confirmed that recurrences during follow-up were linked to the study drug, even after adjustment for Clinical efficacy by protocol at the end of follow-up baseline variables (type of treatment, sex, salaried job, The recultc obtxned in the 389 evaluable patients age in two arbitrary classes (<40 years and 240 years), (Table 3) show that the rate of non-iecurrence was tonsillectoniy, temperature at inclusion >38 “C, and significantly higher in the CPD group than in the PNV number of episodes of pharyngitis in the previous 12 group (p=0.01) and AMC group (p<0 01). In contract, months, also divided into two classes relative to the Table 3 Clinical efficacy at follow-up (month 6 or nionth 7): comparison of the recurrence rate according to treatment (per protocol analysis) CPD I’NV AMC (If = 130) (11 = 122) (r1=137) I’ Success no. (‘2%) 108 (83.08) 85 (69.67) 94 (68 61) 1- 7.: -1 ....,il ...... 5 09- ...... I..” ...... , :%:”. L1 ‘h). . --:I. I...... ” ..... -_(_ .. :__I...1:. -- - L I- 0 8 ..... ! .1 .a:’ ..I ...... 1 - I.I .- ...... I I I ,I 05 ,I I 0 30 60 90 120 150 180 Days from beginning of treatment Figure 1 Kaplan-Meier plots of non-recurrence in patients with satisfactory clinical results at the end of treatment. ~ cefpdoxinic proxetil (~~156);...... penicillin V (n=147); - - - - arnoxycillin-clavulanate (11=l66). 452 Clinical Microbiology and Infection, Volume 3 Number 4, August 1997 median of episode number (<4 per year and 24 per section, strains were considered significant (i.e. probably Year)). pathogenic or copathogenic) in 185 (48%) samples, The results of the Cox model used to identie 23% of which yielded more than one potential patho- parameters independently linked to recurrences showed gen. The nature and frequency of the isolates are given that these were significantly less frequent after treat- in Table 5. ment with CPD than with PNV and AMC (p<0.002), less frequent in patients over 40 (p Pathogen tI (Yo) GABHS 65 (16.9) DISCUSSION GCBHS 23 (6) GGBHS 8 (2.1) The optimal treatment of acute pharyngitis is a matter Haernophilus injuenzae" 5 (1.3) of debate in several countries. The main preoccupation Staphylococcus uureusa 22 (5.7) Enterobacteriaceaeh 51 (13.2) is to eradicate group A streptococci, in order to prevent Non-fermenting Gram-negative bacilli 13 (3.4) acute rheumatic fever. Other considerations are cost and the impact of antibiotics on the microbial ecology. GABHS=group A P-hemolytic streptococci; GCBHS=group C P-hemolytic streptococci; GGBHS = group G P-hemolytic In France, GABHS rapid screening tests are not avail- streptococci. able for reasons inherent in the public healthcare samples without P-hemolytic streptococci, including one sample system. The recommendation is thus to treat all acute that contained both Huemophilns injuenzue and Staphylococcus (weus. the samples in which none of the above species were isolated, episodes of pharyngitis with antibiotics, regardless of including a sample containing both a member of the Entero- the age of the patient, a 10-day course of PNV remain- bacteriaceae and non-fermenting Gram-negative rods. ing the reference treatment. For French authorities, Portier et al: Short-course treatment of recurrent aharyngitis 453 p-lactam agents combined with P-lactainase inhibitors, courses of CPD in the treatment of streptococcal and p-lactamase-resistant cephalosporins should be pharyngitis. reserved for recurrent pharyngitis. On the other hand, a number of shorter treatment courses have been pro- Acknowledgments posed; however, they have been exclusively assessed in This work was supported in part by a grant from Les patients with acute streptococcal pharyngitis [15-19, Laboratoires Dianiant (Paris-La Dkfense, France) and a 22-25]. grant from the French Ministry of Research and This is the first trial of a 5-day treatment with CPD Technology. at a dose of 100 nig morning and evening for recurrent pharyngitis irrespective of bacterial etiology. In order to conduct a study with nationwide relevance, and to References assess the value of the routine use of thr GABHS rapid 1. Conftrence de Consensus organike par l’AFOK<:OPI test, we chose to select as investigators a large number (Asociation pour la Forniation Continue en I’athologie of general practitioners scattered throughout the French Infectieuse). Le traitenient des angines aigues et la prevention territory, who were asked to recruit three patients each. de leurs coniplicat~ons.Med Ma1 Infect 1991; 21: 277-84. 2. Brook I, Yocum P, Shah K. Surface VF core tonsillar aerobic A 73% sensitivity of the GABHS rapid test was denion- and anaerobic flora in recurrent tonsillitis. JAMA 1980; 244: strated in this setting. This study had an open design, 1696-8. a so that cost-effectiveness study could be conducted in 3. Brook I, Foote PA. Comparison of the niicrobiology of parallel, and the compliance to regimens with different recurrent tonsillitis between children and adults. Laryngo- daily doses and different durations could be assessed. To scope 1986; 96: 1385-8. minimize judgment biases, all the files were blindly 4. Brook I. 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