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Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis in adults
Méd Mal Infect 2001 ; 31 : 425-32 2001 Éditions scientifiques et médicales Elsevier SAS. Tous droits réservés S0399-077X(01)00223-2/FLA
Article original
Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis in adults J.J. Pessey 1∗ , P. Gehanno 2 , H. Dabernat 3 1 Hôpital de Rangueil, Toulouse, France ; 2 hôpital Bichat-Claude Bernard, Paris, France ; 3 hôpital Purpan, Toulouse, France
Summary In a placebo-controlled, double-blind, multicenter study, 308 patients aged from 18 to 88 years with clinical evidence of acute sinusitis lasting less than ten days and defined by the presence of pus in the middle meatus on rhinoscopy and sinus pain were randomly assigned to receive eight days of treatment with pristinamycin 1 g twice daily (n = 160) or cefuroxime axetil 250 mg twice daily (n = 148). Patients were assessed for both clinical and bacteriological responses at the baseline visit (V1), once during treatment V2 (3 to 5 days), at the end of treatment V3 (10 to 12 days) and at the follow-up visit V4 three to four weeks after the end of treatment. A sinus X-ray was taken at baseline and at the final visit. For evaluable patients, the clinical success rate at the end of treatment (V3) was 83.9% (125/149) in patients treated with pristinamycin and 87.2% (123/141) in patients treated with cefuroxime axetil (95% CI: ] − ∞, 10.12%]). At the follow-up visit (V4), clinical success (primary endpoint) was observed in 72.6% (106/146) of patients in the pristinamycin group and 75% (105/140) of those in the cefuroxime axetil group (95% CI: ] − ∞, 10.95%]). The efficacy of pristinamycin in acute sinusitis was equivalent to that of cefuroxime axetil in the two populations (Intention to treat-ITT-, Evaluable Population-EP-) and in both evaluation periods (V3, V4). Eleven patients in the pristinamycin group and 2 in the cefuroxime axetil group discontinued treatment prematurely due to adverse events (p = 0.02). Serious adverse event were reported in three patients in the cefuroxime-axetil group and none in the pristinamycin group. In conclusion, these results confirm the value of pristinamycin as first-line treatment in acute sinusitis in adults. 2001 Éditions scientifiques et médicales Elsevier SAS acute sinusitis / cefuroxime axetil / pristinamycin
Résumé – Pristinamycine versus cefuroxime-axetil dans le traitement de la sinusite aigue de l’adulte. Dans une étude multicentrique, randomisée en double insu, double placebo, 308 patients âgés de 18 à 88 ans présentant une sinusite aiguë définie par la présence d’une rhinorrhée purulente, de pus au niveau du méat moyen et d’une douleur sinusienne, évoluant depuis moins de dix jours ont été traités pendant huit jours soit par pristinamycine (n = 160) à raison de 1 g, 2 fois par jour, soit par céfuroxime-axétil (n = 148) à la dose de 250 mg, deux fois par jour. Les signes et symptômes cliniques ainsi que les données bactériologiques ont été évalués à l’inclusion (C1), trois à cinq jours après le début du traitement (C2), à la fin du traitement à J10-J12 (C3) puis à distance à J30-J40 (C4). La radiographie des sinus était réalisée à l’inclusion et à la visite de contrôle. Dans la population cliniquement évaluable, 290 patients ont été analysés en fin de traitement avec un taux de succès de 83,9 % (125/149) chez les patients traités par pristinamycine et de 87,2 % (123/141) chez les patients traités par céfuroxime-axétil (IC 95 % :] − ∞, 10,12 %]). Le taux de succès clinique (critère principal) a été confirmé pour 286 patients sur 290 suivis à distance du traitement, soit 72,6 % (106/146) dans le groupe pristinamycine et 75 % (105/140) dans le groupe céfuroxime-axétil (IC 95 % :] − ∞, 10,95 %]). L’efficacité de la pristinamycine dans les sinusites aiguës de l’adulte a été équivalente à celle du céfuroxime-axétil dans les deux populations analysées (population en intention de traiter et population cliniquement évaluable) et aux deux temps d’évaluation (C3, C4). Les arrêts prématurés pour événements indésirables ont été plus fréquents (p = 0,02) dans le groupe pristinamycine (11 patients) que dans le groupe céfuroxime-axétil (deux patients). Des événements indésirables
∗ Correspondence and reprints.
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graves étaient rapportés chez trois patients du groupe céfuroxime-axétil et aucun du groupe pristinamycine. Ces résultats cliniques confirment l’intérêt de la pristinamycine en traitement de première intention dans les sinusites aiguës de l’adulte. 2001 Éditions scientifiques et médicales Elsevier SAS céfuroxime-axétil / pristinamycine / sinusite aiguë
Acute sinusitis is a particularly frequent infection in everyday community practice. Antibiotic therapy must be administered at an early stage and must be properly adapted to avoid the risk of serious infectious complications, particularly orbital and meningo-encephalic. The antibiotic spectrum must include H. influenzae, S. pneumoniae and M. catarrhalis [1 – 5]. Epidemiological studies conducted in France in recent years have shown a high incidence of beta-lactamase-producing strains with rates for H. influenzae of 29% in 1993 [6], 32% in 1994–1995 [7] and 34% in 1996–1997 [8] and for M. catarrhalis of 90% [9], at the same time as a reduction in the susceptibility of pneumococci to penicillin G (MIC 0.125 mg/L) with rates of intermediate or resistant pneumococci of 48% in 1997, 42.8% in 1996, 36.3% in 1995 and 32% in 1994 [10, 11]. By virtue of its antibacterial spectrum, pristinamycin is naturally suited to these developments and may be proposed as first-line treatment in acute sinusitis. The objective of this study was to compare the efficacy and safety of pristinamycin with those of cefuroxime axetil, a beta-lactamase stable 2nd generation cephalosporin, in the treatment of acute sinusitis in adults.
PATIENTS, MATERIAL AND METHODS This was a multicentre, randomized, double-blind, doubledummy, comparative, clinical study conducted in two parallel groups by 47 community-based ENT specialists in ten regions of France. The study project received the approval of the Committee for the Protection of Patients Enrolled in Biomedical Research (Ethics Committee) of Toulouse.
Patients Patients eligible for inclusion in the study had to be at least 18 years old and to have been suffering from acute purulent sinusitis lasting less than ten days before the visit. Patients had to have a purulent nasal discharge (confirmed by the presence of pus in the middle meatus on rhinoscopy) associated with sinus pain (spontaneous or induced). Sinus X-rays were taken within 48 hours (and were accepted up to 72 hours) following inclusion and were considered by a Committee of Experts to be indicative of acute sinusitis if they showed a sinus total opacity or an intrasinus air fluid level. Signature of a written consent form was required before definitive inclusion.
Women who might be pregnant or who were breastfeeding, patients with a history of chronic sinusitis, sinonasal polyposis, dental sinusitis, a previous history of hypersensitivity to beta-lactams and/or synergistins, immunodepression (cancer, AIDS, etc.), renal insufficiency, hepatic insufficiency and/or having undergone or due to undergo a surgical procedure or local treatment (drainage, lavage) for the current episode were excluded. Patients having received systemic or nasal antibiotic therapy during the week prior to inclusion and/or systemic corticosteroid therapy within the previous 30 days or nasal therapy within the previous week were not eligible for inclusion.
Treatments Treatment was allocated by means of a randomization code. The randomization was balanced in each center by blocks of four patients. Sealed individual envelopes containing the identification of the treatment to be administered to each patient were handed to each investigator. The code number of each patient was noted on each of the envelopes. The treatments had to be assigned by the investigator in ascending order of the numbers on the envelopes. Any failure to adhere to this numbering was considered a protocol violation. Thus, the patients received for a period of eight days: – either pristinamycin (PRI) 1 g twice daily (i.e. 4 tablets of pristinamycin of 500 mg and four placebo capsules of cefuroxime axetil), – or cefuroxime axetil (CA) at a dose of 250 mg twice daily (i.e. four capsules of cefuroxime axetil of 125 mg and four placebo tablets of pristinamycin). Symptomatic treatment with oxymetazoline at a dose of two nasal puffs daily was administered concomitantly for the first three days. No corticosteroid therapy of any kind was permitted.
Study schedule At the baseline visit (V1), in addition to a history taking and a complete clinical examination, the investigator had to confirm the patient’s eligibility (inclusion and exclusion criteria) and obtain their signed written consent. After nebulization of a vasoconstrictor in the nasal fossae, the middle meatus of the infected sinus or sinuses was aspirated using a flexible catheter connected to a tuberculin syringe. The distal end was inserted into the agar of a Portagerm® preservative medium (Bio-Mérieux)
Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis
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and transported to the centralized microbiology laboratory. Culture in an aerobic and anaerobic medium was followed by identification of the strains using the customary method in medical bacteriology with an investigation for micro-organisms belonging to a “pathogenic” or “presumed pathogenic” species. The in vitro susceptibility of all the micro-organisms isolated was determined by measuring the zones of inhibition on disks containing 15 µg of pristinamycin and 10 µg of cefuroxime axetil. Telephone contact (V2) was scheduled to be made three to five days after the beginning of treatment to assess the clinical course, tolerability and treatment compliance. In the event of an unfavorable outcome or the occurrence of adverse events, treatment was discontinued and a visit arranged for a change of treatment. The second consultation was held at least 48 hours after the end of treatment (V3), at which the investigator carried out a further clinical examination and took a bacteriological sample in the event of the persistence of pus in the middle meatus. A clinical cure was defined as the disappearance, firstly, of purulent nasal discharge with the absence of pus in the middle meatus and, secondly, of spontaneous and induced facial pain. A clinical failure was defined as the persistence of purulent nasal discharge and/or the presence of pus in the middle meatus and/or moderate or severe spontaneous and induced pain. The follow-up visit (V4) took place three to four weeks after the end of the study medication. Only patients considered to have been cured at the end of treatment were seen by the investigator. A clinical examination was performed and a sinus X-ray and bacteriological sample (where necessary) taken. The investigator concluded either that the clinical cure still persisted or that there was a clinical relapse, defined by the recurrence of at least one of the signs of sinusitis (purulent nasal discharge and/or pus in the middle meatus and/or spontaneous and/or induced pain in the sinus regions). A radiological cure was defined as the normalization of or a considerable improvement in the radiological pictures. A radiological failure was defined as the persistence of or deterioration from the initial films.
– the Intention to Treat (ITT) population, represented by all the randomized patients having received at least one dose of the study medication. The analysis of safety was conducted on this population; – the Evaluable Population (EP), represented by all the patients eligible by ITT with clinical and radiological evidence of acute sinusitis, having received at least six days of treatment, or at least three days in the event of a premature failure, and not taking any concomitant medication prohibited in the protocol (corticosteroids, etc.).
Evaluation of efficacy
Three hundred and ten (310) patients were included in the study. Two patients were lost to follow-up. A total of 308 were analyzed by ITT, i.e. 160 patients treated with pristinamycin and 148 patients treated with cefuroxime axetil. Analysis of the demographic data (including the male/female ratio) and the previous history of sinusitis revealed no statistically significant difference between the two groups (table I). The majority of patients had an infectious syndrome that had been present for five days at baseline, with a mean rectal temperature of 37.6◦ C (±0.6). All had pus in the middle meatus on inclusion. The frequency of severe spontaneous pain was higher in the pristinamycin
The principal criterion of the assessment of efficacy was purely clinical, based on the course of the clinical signs and symptoms at the follow-up visit (V4) compared with the end of treatment visit (V3). Thus, a clinical success at V4 required a clinical cure of the end of treatment and the persistence of this cure at a later date. There was a clinical failure at V4 if there was no clinical cure at the end of treatment or a clinical relapse at a later date. Three populations were analyzed: – the total population, represented by all the randomized patients;
Evaluation of safety The evaluation of safety was based on the occurrence of adverse events during the study. These were described in terms of their seriousness, severity, duration and relationship (possible or probable) to the study medications.
Statistical methods and procedures Comparison of the efficacy of the two treatment groups involved a one-sided equivalence test at the 5% level based on a calculation of the 95% confidence interval of the difference observed between the two groups. The other intergroup comparisons were performed by means of the usual tests: Student’s test or Wilcoxon’s test (depending on the normality of the variable studied) for quantitative variables, chi2 test or Fisher’s exact test for qualitative variables (depending on the numbers in the classes) and Wilcoxon’s test for ordinal qualitative variables. The number of clinically evaluable patients required (114 per treatment group) was calculated on the basis of the following hypotheses: 85% success rate for the reference product, 15% equivalence level, type one error of 5% and type two error of 10%.
RESULTS Description of the population
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Table I. Demographic characteristics (ITT population). Pristinamycin
Cefuroxime axetil
Total
(n = 160)
(n = 148)
(n = 308)
Age (years) 43.6 ± 15.7
43.2 ± 15.1
43.4 ± 15.4
Range
Mean ± SD
18–82
19–88
18–88
Median
40
42
41
Sex Male
78 (49%)
63 (43%)
141 (46%)
Female
82 (51%)
85 (57%)
167 (54%)
67.7 ± 13.8
66.0 ± 11.4
66.9 ± 12.7
Range
41–110
42–99
41–110
Median
66.5
67
67
88 (45%)
72 (48%)
160 (51.9%)
Weight (kg) Mean ± SD
History of sinusitis
group (20%) than in the cefuroxime axetil group (12.2%). However, the difference was not clinically significant (p = 0.22). The presence of signs and symptoms was comparable in the two treatment groups (table II). The sinus X-ray taken within 72 hours of inclusion confirmed the diagnosis of sinusitis in 95% (152/160) of the patients treated with pristinamycin and 92% (136/148) of the patients treated with cefuroxime axetil. This involved unilateral or bilateral maxillary sinusitis in 84% (242/288) of cases and maxillary and frontal sinusitis in almost 12% (34/288) of cases. The bacteriological sample taken from the middle meatus at baseline enabled 200 “pathogenic” or “presumed pathogenic” micro-organisms to be isolated in 86/160 (53.8%) of patients treated with pristinamycin and in 74/148 (50%) of patients treated with cefuroxime axetil. Principally S. pneumoniae (n = 72), H. influenzae (n = 59) and M. catarrhalis (n = 21) were identified. For the other patients (48%), the samples were either sterile or positive for a micro-organism considered to be nonpathogenic. The distribution of the micro-organisms isolated in terms of their in vitro susceptibility to pristinamycin and cefuroxime is given in table III. Pristinamycin confirmed its activity against S. pneumoniae (94%) and M. catarrhalis (100%), whereas the percentage of strains susceptible to cefuroxime was respectively 69% for S. pneumoniae and 38% for M. catarrhalis. For H. influenzae, 58% of the strains were susceptible to pristinamycin and 42% to cefuroxime by the agar disc sensitivity test. After determination of the minimum inhibitory concentrations (MIC) of pristinamycin against 55 of the 59 strains of H. influenzae isolated at baseline, 36.4%
were inhibited at a MIC 1 mg/L and 49.1% at a MIC = 2 mg/L. The mean treatment duration was 7.7 days (±1.2) in the pristinamycin group and 7.9 days (±0.7) in the cefuroxime axetil group. Treatment was discontinued in 13 patients treated with pristinamycin (11 times for an adverse effect usually of a digestive nature, once for withdrawal of consent, once for no specified reason) and in four patients treated with cefuroxime axetil (two patients with a clinical failure, one patient for a serious adverse event, one patient with a clinical failure and having a serious adverse event).
Analysis of efficacy Among the patients analyzed by ITT, 22/308 patients (7.1%) were excluded from the population evaluable for the analysis of clinical efficacy at V4 (principal criterion). The number of patients excluded was larger in the pristinamycin group than in the cefuroxime axetil group 14/160 (8.8%) versus 8/148 (5.4%). All these excluded cases were reviewed by the Committee of Experts before the code was broken (table IV). In the ITT population, clinical success at the end of treatment was obtained in 83.7% and 87.2% of patients treated with pristinamycin and cefuroxime axetil, respectively. These results are similar to those of the clinically evaluable population (83.9% and 87.2% in the pristinamycin and the cefuroxime axetil group, respectively). Analysis of the principal criterion of this study, in contrast to the published studies, involved the clinical efficacy at the follow-up visit (D30-D40) in the clinically evaluable population. The success rate was 72.6% (106/146) in the pristinamycin group and 75% (105/140) in the cefuroxime axetil group. The upper limit of the confidence interval (95% CI) was 10.95%, so that the hypothesis of equivalence at the 15% level was accepted (table V). Among the 75 patients with a clinical failure, 42 were failures at the end of treatment (24 in the pristinamycin group and 18 in the cefuroxime axetil group) and 33 patients, having been cured at the end of treatment, suffered a clinical relapse at the follow-up visit three to four weeks after the end of treatment (16 in the pristinamycin group and 17 in the cefuroxime axetil group). These failures were classified in categories (table VI): 44/75 patients had a clinical failure characterized by the persistence of pus (purulent nasal discharge and/or pus in the middle meatus) after eight days of treatment or by the recurrence of signs and symptoms after a clinical resolution at the end of treatment. Among the micro-organisms most commonly found at the end of treatment and during the follow-up period in the 17 clinical and bacteriological failures, S. pneumoniae and/or H. influenzae (monomicrobial or polymicrobial
429
Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis
Table II. Signs and symptoms present on inclusion (ITT population). Pristinamycin
Cefuroxime axetil
Total
(n = 160)
(n = 148)
(n = 308)
Duration (days) 5.6 ± 2.6
5.1 ± 2.2
5.4 ± 2.4
Range
Mean ± SD
1–18
2–11
1–18
Median
5
4.5
5
Temperature
(* 4)
(* 2)
(* 6)
Mean ± SD
37.6 ± 0.6
37.6 ± 0.6
37.6 ± 0.6
Range
36.5–39
36.5–39.8
36.5–39.8
Median
37.5
37.7
375
Purulent nasal discharge
156 (97.5%)
143 (96.6%)
299 (97.1%)
Spontaneous pain in sinus regions
156 (97.5%)
146 (98.7%)
302 (98.1%)
Slight
23 (14.4%)
26 (17.6%)
49 (15.9%)
Moderate
101 (63.1%)
102 (68.9%)
203 (65.9%)
Severe
32 (20.0%)
18 (12.2%)
50 (16.2%)
Induced pain in sinus regions
156 (97.5%)
146 (98.6%)
302 (98.1%)
Slight
29 (18.1%)
31 (20.9%)
60 (19.5%)
Moderate
100 (62.5%)
96 (64.9%)
196 (63.6%)
Severe
27 (16.9%)
19 (12.8%)
46 (14.9%)
Pus middle meatus
160 (100%)
148 (100%)
308 (100%)
* number of missing data.
Table III. In vitro susceptibility of the 200 bacterial strains isolated on inclusion (ITT population). Pristinamycin
Haemophilus influenzae
Cefuroxime axetil
n
S
%S
n
S
57
33
58%
55
23
%S 42%
Streptococcus pneumoniae
69
65
94%
71
49
69%
Moraxella catarrhalis
21
21
100%
21
8
38%
Streptococcus spp.
12
12
100%
12
11
92%
Staphylococcus aureus
14
14
100%
14
10
71%
Gram-negative bacilli
7
1
14%
15
5
33%
Coagulase (−) Staphylococcus
1
1
–
1
1
–
Other
1
1
–
1
1
–
Total
182
148
190
108
81.3%
56.8%
n = number of strains tested; S = susceptible; % = % of susceptible strains.
pus) was identified six times in the pristinamycin group and five times in the cefuroxime axetil group. The distribution of these micro-organisms is shown in table VII.
The susceptibility of the micro-organisms found in the follow-up bacteriological sample (V3) in the case of failure was as follows: all the pneumococci were susceptible
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Table IV. Synopsis of exclusions from the principal analysis.
Excluded from the analysis by ITT Patients evaluable for the analysis by ITT Patients not evaluable for the principal analysis (V4)
Pristinamycin
Cefuroxime axetil
Total
(n = 161)
(n = 149)
(n = 310)
1
(0.6%)
1
(0.7%)
2
(0.6%)
160
(99.4%)
148
(99.3%)
308
(99.4%)
14/160
(8.8%)
8/148
(5.4%)
22/308
(7.1%)
Normal x-ray at V1
5
6
11
Appearance of first symptom > 10 days
1
0
1
and/or study
6
2
8
Prohibited medications
2
0
2
Premature discontinuation of treatment
Patients evaluable for the principal
146/160
(91.2%)
140/148
(94.6%)
286/308
(92.9%)
analysis (V4)
Table V. Analysis of clinical efficacy. ITT population
Evaluable population
End of treatment
Clinical efficacy
Follow-up
End of treatment
Follow-up
PRI
CA
PRI
CA
PRI
CA
PRI
CA
134/160
129/148
112/160
111/148
125/149
123/141
106/146
105/140
83.7%
87.2%
70.0%
75.0%
83.9%
87.2%
72.6%
75.0%
(% success)
] − ∞, 10.01%]
] − ∞, 13.35%]
] − ∞, 10.12%]
] − ∞, 10.95%]
PRI: pristinamycin; CA: cefuroxime axetil.
Table VI. Description of clinical failures and number of patients (evaluable population for the principal criterion V4). Persistence of signs:
Pristinamycin
Cefuroxime axetil
Total
• clinical only
20
24
44
• clinical + bacteriological
10
5
15
• clinical + radiological
8
6
14
• clinical + bacteriological + radiological
2
0
2
40
35
75
Total
Table VII. Distribution of pathogens in failures involving H. influenzae and S. pneumoniae. Single pathogen
Multiple pathogens
Pristinamycin
Cefuroxime axetil
Pristinamycin
Cefuroxime axetil
H. influenzae
1
0
–
–
S. pneumoniae
2
2
–
–
H. influenzae + S. pneumoniae
–
–
2
1
H. influenzae + others
–
–
1
2
S. pneumoniae + others
–
–
0
3
Total
3
2
3
3
Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis
to pristinamycin and 2/3 of the pneumococci were resistant to cefuroxime. Two H. influenzae were susceptible to pristinamycin and two were of intermediate susceptibility to pristinamycin. The three H. influenzae in the cefuroxime axetil group were susceptible to cefuroxime.
Safety The safety of treatment was evaluated in the 308 patient included who had taken at least one day’s treatment. The global incidence of adverse events (AE) was 28% (45/160) in the pristinamycin group and 19% (28/148) in the cefuroxime axetil group (NS). Treatment was discontinued because of the occurrence of AE in 11 patients in the pristinamycin group and two patients in the cefuroxime axetil group (p = 0.02). Severe adverse effects were reported with the same frequency in both groups: 15.7% for pristinamycin and 17.1% for cefuroxime axetil (NS). Four serious AE (dental condition requiring surgical treatment, bronchitis, dyspnoea and obstructive maxillary sinusitis requiring emergency surgical drainage) were reported during the study in three patients in the cefuroxime axetil group, these AEs being related either to a concurrent disease or the condition originally justifying inclusion. No serious AEs were reported in the pristinamycin group
DISCUSSION In the 308 patients included, the diagnosis of acute sinusitis was clearly documented clinically (100% of patients having pus in the middle meatus at baseline), radiologically (93.5% of patients – 288/308 – having an abnormal sinus X-ray at baseline) and bacteriologically (isolation of at least one pathogenic or presumed pathogenic microorganism at baseline in 52% of patients – 160/308). S. pneumoniae was isolated more often (36%) than H. influenzae (29.5%). This incidence was similar to that reported in the American studies [3, 4], in contrast to publications in France and Europe where S. pneumoniae is found less often (15%) than H. influenzae (35%) [1, 2, 5, 20, 21]. This study demonstrated the consistent in vitro activity of pristinamycin against all strains of macrolide-resistant S. pneumoniae (31/71 strains, 43.7%), whether susceptible or resistant to beta-lactams. Of the 21 strains of M. catarrhalis identified, none was resistant to pristinamycin. After measuring the diameters of inhibition of the strains of H. influenzae isolated on inclusion, percentage resistances of 22.4% to penicillin, 17.6% to pristinamycin, 8.6% to erythromycin and 9.1% to cefuroxime were observed. However, after determination of the minimum inhibitory concentrations of pristinamycin against these strains of H. influenzae by the agar dilution method (HTM agar), 14.5% were resistant to pristinamycin (MIC > 2 mg/L).
431
The clinical response involved a large population of evaluable patients at the end of treatment (290 patients) and at a later date (286 patients), which is remarkable considering that only patients with both unequivocal clinical and radiological evidence of acute sinusitis and having also not received any local or systemic corticosteroid therapy during the study were included. Despite these very strict inclusion criteria, only 22 patients (18 patients at the end of treatment and four at the follow-up visit) had to be excluded from the population evaluable for the analysis of efficacy. In terms of the comparison of clinical efficacy of the two antibiotics, this study showed that pristinamycin is equivalent to cefuroxime axetil. The success rate at the end of treatment in the ITT population was 83.7% (134/160) in the pristinamycin group and 87.2% (112/148) in the cefuroxime axetil group. These results were also confirmed in the evaluable population (table V). The clinical success rates observed in the two populations at the follow-up visit were lower than those in the literature [22] (table V). These lower cure rates are undoubtedly related to the prohibition of any corticosteroid therapy during the study (exclusion criterion), in contrast to the reports in the literature [22], and the later date (30 to 40 days) of the clinical evaluation, which identified 33 cases of clinical relapse at V4. However, it should be noted that these rates were comparable in the two groups. Clincial trials in antibiotic therapy are not usually studies of superiority but of equivalence. European recommendations advocating the choice of a delta equivalent to 10% in studies involving non-serious infections were not published until 1997 [23]. At the time the protocol for this study was designed, the choice of delta was unrestricted and was usually set at 10 or 15%. It should however be noted that the confidence interval observed for the principal criterion of efficacy shows that the upper limit of the confidence interval is 10.95%, which can be seen to be close to the limit that would have been determined if an equivalence study with a delta equivalent to 10% had been proposed. The analysis involving the clinical and radiological response at the follow-up visit showed similar efficacy rates in the two treatment groups, but again considerably lower than those reported in the literature. For the pristinamycin-treated group of patients, the success rate was 63% in the evaluable population and 45% in the ITT population versus 69% in the evaluable population and 51.4% in the ITT population for cefuroxime axetil. This might be explained by the fact that the clinical and radiological criterion is evaluated at the end of treatment (ten to 15 days) in the majority of published studies (82 to 87%) – [4, 5, 23] and not at a later date, as in this study. The presumed or definite eradication rate at the end of treatment visit was 87.8% (79/90) in the pristinamycin group and 93.5% (72/77) in the cefuroxime axetil group.
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At the follow-up visit, this eradication rate was 73.3% and 85.7%, respectively. Analysis of the clinical response at the end of treatment in the subgroup of 35 patients treated with pristinamycin in whom 33 strains of H. influenzae had been isolated at baseline showed that when the MIC of pristinamycin for these isolated strains showed that when the MIC was less than or equal to 1 mg/L (strain supposedly susceptible to pristinamycin), the clinical success rate was 91.7% (11/12), when the MIC was 2 mg/L (intermediate strain) the clinical response was 88% (14/16), while with a MIC greater than 2 mg/L (resistant strain) it was only of the order of 60% (3/5). These preliminary results obtained in a small population nevertheless show that a good level of clinical efficacy may be expected with pristinamycin in sinusitis due to Haemophilus which, in this study, had a MIC 2 mg/L in 85% of cases. The safety of treatment was generally satisfactory in both treatment groups with a larger number of drop-outs observed in the pristinamycin group and more frequent serious adverse effects in the cefuroxime axetil.
CONCLUSION In this randomized, double-blind, double-dummy study involving 308 patients with radiological evidence of acute sinusitis, the efficacy of outpatient treatment with pristinamycin 1 g twice daily for eight days was equivalent (at the 15% level) to that of treatment with cefuroxime axetil 250 mg twice daily for eight days. Consequently, pristinamycin may be proposed as firstline treatment in acute sinusitis in adults.
REFERENCES 1 Ylikoski J, Savolaien S, Jousimies-Somer HR. The bacteriology of acute maxillary sinusitis. ORL 1989; 51: 175-81. 2 Simonet M, Gehanno P, Ichou F, Veron M. Etude bactériologique de la sinusite aiguë de l’adulte. Méd Mal Infect 1990; 20(2): 91-6. 3 Gwaltney JM, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis: A fifteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992; 90: 457-62. 4 Camacho AE, Cobo R, Otte J, Spector SL, Lerner CJ, Garrison NA, Miniti A, Mydlow PK, Giguere GC, Collins JJ. Clinical comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of patients with acute bacterial maxillary sinusitis. Am J Med 1992; 93: 271-6.
5 Gehanno P, Berche P, the sinusitis study group. Sparfloxacin versus cefuroxime axetil in the treatment of acute purulent sinusitis. J Antimicrob Chemother 1996(Suppl. A): 105-14. 6 Dabernat H, Seguy M, Delmas C. Situation 1993 de la résistance aux antibiotiques chez Haemophilus influenzae en France (bilan du Centre National de Référence pour H. influenzae). Méd Mal Infect 1994; 24: 1244-7. 7 Dabernat H, Delmas C. Activité du Centre National de Référence pour Haemophilus influenzae, bilan 1994–1995. Les débuts de l’après vaccination. Méd Mal Infect 1996; 26: 698-703. 8 Dabernat H, Delmas C. Activité du Centre National de Référence des Haemophilus influenzae, années 1996–1997 le déclin du type b. Méd Mal Infect 1998; 28: 940-6. 9 Pean Y, Goldstein FW, Guerrier ML, le Groupe de Travail Français. Activité des antibiotiques sur Streptococcus pneumoniae, Haemophilus influenzae et Branhamella catarrhalis isolés d’infections respiratoires et ORL en France: résultats d’une enquête multicentrique. Méd Mal Infect 1998; 28: 253-7. 10 Geslin P. Bilan d’activité du Centre National de Référence du Pneumocoque. Année 1994–1995. 11 Geslin P, Fremaux A, Sissia G. Evolution de la résistance des pneumocoques responsables des infections des voies respiratoires en France. Méd Mal Infect 1992; 22: 74-86. 12 Videau D. Etude de l’activité bactéricide de la pristinamycine. Path Biol 1982; 30(6): 529-34. 13 PYOSTACINE 500 (pristinamycin), investigator’s brochure, November 1992. 14 Comite de l’antibiogramme de la societe francaise de microbiologie. Communique 1999. Path Biol 1999; 47(8): 845-72. 15 Denis F, Dabernat H, le groupe d’étude multicentrique. Activités comparées de la pristinamycine et de onze antibiotiques: Etude multicentrique portant sur les bactéries du spectre des streptogramines. Concours Med 1992; 114(27): 2293-8. 16 Fremaux A, Sissia G, Geslin P. Activité antibactérienne in vitro de la pristinamycine sur Streptococcus pneumoniae résistant à la pénicilline. Path Biol 1993; 41: 7. 17 Dabernat H. Evaluation de l’activité in vitro de la pristinamycine sur Haemophilus influenzae. Path Biol 1993; 41: 7. 18 Dabernat H, Seguy M, Delmas C. Situation 1993 de la résistance aux antibiotiques chez Haemophilus influenzae en France. Méd Mal Infect 1994; 24: 1244-7. 19 Reverdy ME, Bes M, Brun Y, Fleurette J. Evolution de la résistance aux antibiotiques et aux antiseptiques de souches hospitalières de Staphylococcus aureus isolées de 1981 à 1991. Path Biol 1993; 41(9): 897-904. 20 Gehanno P, Depondt J, Barry B. Comparison of Cefpodoximeproxetil with Cefaclor in the treatment of sinusitis. J Antimicrob Chemother 1990; 26: 87-91. 21 Gehanno P, Pessey JJ. Inventaire bacteriologique lors des sinusites aiguës et chroniques: Conséquence thérapeutique. Rev Prat 1994: 21-2. 22 Pessey JJ, Gobert P, Panthier G. Efficacité et tolérance du cefpodoxime-proxétil versus céfuroxime-axétil dans le traitement des sinusites aiguës de l’adulte. Méd Mal Infect 1994; 24: 686-92. 23 Note for guidance on evaluation of new antibacterial products, 1997; CPMP/EWP/558/85.
Article original
Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis in adults J.J. Pessey 1∗ , P. Gehanno 2 , H. Dabernat 3 1 Hôpital de Rangueil, Toulouse, France ; 2 hôpital Bichat-Claude Bernard, Paris, France ; 3 hôpital Purpan, Toulouse, France
Summary In a placebo-controlled, double-blind, multicenter study, 308 patients aged from 18 to 88 years with clinical evidence of acute sinusitis lasting less than ten days and defined by the presence of pus in the middle meatus on rhinoscopy and sinus pain were randomly assigned to receive eight days of treatment with pristinamycin 1 g twice daily (n = 160) or cefuroxime axetil 250 mg twice daily (n = 148). Patients were assessed for both clinical and bacteriological responses at the baseline visit (V1), once during treatment V2 (3 to 5 days), at the end of treatment V3 (10 to 12 days) and at the follow-up visit V4 three to four weeks after the end of treatment. A sinus X-ray was taken at baseline and at the final visit. For evaluable patients, the clinical success rate at the end of treatment (V3) was 83.9% (125/149) in patients treated with pristinamycin and 87.2% (123/141) in patients treated with cefuroxime axetil (95% CI: ] − ∞, 10.12%]). At the follow-up visit (V4), clinical success (primary endpoint) was observed in 72.6% (106/146) of patients in the pristinamycin group and 75% (105/140) of those in the cefuroxime axetil group (95% CI: ] − ∞, 10.95%]). The efficacy of pristinamycin in acute sinusitis was equivalent to that of cefuroxime axetil in the two populations (Intention to treat-ITT-, Evaluable Population-EP-) and in both evaluation periods (V3, V4). Eleven patients in the pristinamycin group and 2 in the cefuroxime axetil group discontinued treatment prematurely due to adverse events (p = 0.02). Serious adverse event were reported in three patients in the cefuroxime-axetil group and none in the pristinamycin group. In conclusion, these results confirm the value of pristinamycin as first-line treatment in acute sinusitis in adults. 2001 Éditions scientifiques et médicales Elsevier SAS acute sinusitis / cefuroxime axetil / pristinamycin
Résumé – Pristinamycine versus cefuroxime-axetil dans le traitement de la sinusite aigue de l’adulte. Dans une étude multicentrique, randomisée en double insu, double placebo, 308 patients âgés de 18 à 88 ans présentant une sinusite aiguë définie par la présence d’une rhinorrhée purulente, de pus au niveau du méat moyen et d’une douleur sinusienne, évoluant depuis moins de dix jours ont été traités pendant huit jours soit par pristinamycine (n = 160) à raison de 1 g, 2 fois par jour, soit par céfuroxime-axétil (n = 148) à la dose de 250 mg, deux fois par jour. Les signes et symptômes cliniques ainsi que les données bactériologiques ont été évalués à l’inclusion (C1), trois à cinq jours après le début du traitement (C2), à la fin du traitement à J10-J12 (C3) puis à distance à J30-J40 (C4). La radiographie des sinus était réalisée à l’inclusion et à la visite de contrôle. Dans la population cliniquement évaluable, 290 patients ont été analysés en fin de traitement avec un taux de succès de 83,9 % (125/149) chez les patients traités par pristinamycine et de 87,2 % (123/141) chez les patients traités par céfuroxime-axétil (IC 95 % :] − ∞, 10,12 %]). Le taux de succès clinique (critère principal) a été confirmé pour 286 patients sur 290 suivis à distance du traitement, soit 72,6 % (106/146) dans le groupe pristinamycine et 75 % (105/140) dans le groupe céfuroxime-axétil (IC 95 % :] − ∞, 10,95 %]). L’efficacité de la pristinamycine dans les sinusites aiguës de l’adulte a été équivalente à celle du céfuroxime-axétil dans les deux populations analysées (population en intention de traiter et population cliniquement évaluable) et aux deux temps d’évaluation (C3, C4). Les arrêts prématurés pour événements indésirables ont été plus fréquents (p = 0,02) dans le groupe pristinamycine (11 patients) que dans le groupe céfuroxime-axétil (deux patients). Des événements indésirables
∗ Correspondence and reprints.
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graves étaient rapportés chez trois patients du groupe céfuroxime-axétil et aucun du groupe pristinamycine. Ces résultats cliniques confirment l’intérêt de la pristinamycine en traitement de première intention dans les sinusites aiguës de l’adulte. 2001 Éditions scientifiques et médicales Elsevier SAS céfuroxime-axétil / pristinamycine / sinusite aiguë
Acute sinusitis is a particularly frequent infection in everyday community practice. Antibiotic therapy must be administered at an early stage and must be properly adapted to avoid the risk of serious infectious complications, particularly orbital and meningo-encephalic. The antibiotic spectrum must include H. influenzae, S. pneumoniae and M. catarrhalis [1 – 5]. Epidemiological studies conducted in France in recent years have shown a high incidence of beta-lactamase-producing strains with rates for H. influenzae of 29% in 1993 [6], 32% in 1994–1995 [7] and 34% in 1996–1997 [8] and for M. catarrhalis of 90% [9], at the same time as a reduction in the susceptibility of pneumococci to penicillin G (MIC 0.125 mg/L) with rates of intermediate or resistant pneumococci of 48% in 1997, 42.8% in 1996, 36.3% in 1995 and 32% in 1994 [10, 11]. By virtue of its antibacterial spectrum, pristinamycin is naturally suited to these developments and may be proposed as first-line treatment in acute sinusitis. The objective of this study was to compare the efficacy and safety of pristinamycin with those of cefuroxime axetil, a beta-lactamase stable 2nd generation cephalosporin, in the treatment of acute sinusitis in adults.
PATIENTS, MATERIAL AND METHODS This was a multicentre, randomized, double-blind, doubledummy, comparative, clinical study conducted in two parallel groups by 47 community-based ENT specialists in ten regions of France. The study project received the approval of the Committee for the Protection of Patients Enrolled in Biomedical Research (Ethics Committee) of Toulouse.
Patients Patients eligible for inclusion in the study had to be at least 18 years old and to have been suffering from acute purulent sinusitis lasting less than ten days before the visit. Patients had to have a purulent nasal discharge (confirmed by the presence of pus in the middle meatus on rhinoscopy) associated with sinus pain (spontaneous or induced). Sinus X-rays were taken within 48 hours (and were accepted up to 72 hours) following inclusion and were considered by a Committee of Experts to be indicative of acute sinusitis if they showed a sinus total opacity or an intrasinus air fluid level. Signature of a written consent form was required before definitive inclusion.
Women who might be pregnant or who were breastfeeding, patients with a history of chronic sinusitis, sinonasal polyposis, dental sinusitis, a previous history of hypersensitivity to beta-lactams and/or synergistins, immunodepression (cancer, AIDS, etc.), renal insufficiency, hepatic insufficiency and/or having undergone or due to undergo a surgical procedure or local treatment (drainage, lavage) for the current episode were excluded. Patients having received systemic or nasal antibiotic therapy during the week prior to inclusion and/or systemic corticosteroid therapy within the previous 30 days or nasal therapy within the previous week were not eligible for inclusion.
Treatments Treatment was allocated by means of a randomization code. The randomization was balanced in each center by blocks of four patients. Sealed individual envelopes containing the identification of the treatment to be administered to each patient were handed to each investigator. The code number of each patient was noted on each of the envelopes. The treatments had to be assigned by the investigator in ascending order of the numbers on the envelopes. Any failure to adhere to this numbering was considered a protocol violation. Thus, the patients received for a period of eight days: – either pristinamycin (PRI) 1 g twice daily (i.e. 4 tablets of pristinamycin of 500 mg and four placebo capsules of cefuroxime axetil), – or cefuroxime axetil (CA) at a dose of 250 mg twice daily (i.e. four capsules of cefuroxime axetil of 125 mg and four placebo tablets of pristinamycin). Symptomatic treatment with oxymetazoline at a dose of two nasal puffs daily was administered concomitantly for the first three days. No corticosteroid therapy of any kind was permitted.
Study schedule At the baseline visit (V1), in addition to a history taking and a complete clinical examination, the investigator had to confirm the patient’s eligibility (inclusion and exclusion criteria) and obtain their signed written consent. After nebulization of a vasoconstrictor in the nasal fossae, the middle meatus of the infected sinus or sinuses was aspirated using a flexible catheter connected to a tuberculin syringe. The distal end was inserted into the agar of a Portagerm® preservative medium (Bio-Mérieux)
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427
and transported to the centralized microbiology laboratory. Culture in an aerobic and anaerobic medium was followed by identification of the strains using the customary method in medical bacteriology with an investigation for micro-organisms belonging to a “pathogenic” or “presumed pathogenic” species. The in vitro susceptibility of all the micro-organisms isolated was determined by measuring the zones of inhibition on disks containing 15 µg of pristinamycin and 10 µg of cefuroxime axetil. Telephone contact (V2) was scheduled to be made three to five days after the beginning of treatment to assess the clinical course, tolerability and treatment compliance. In the event of an unfavorable outcome or the occurrence of adverse events, treatment was discontinued and a visit arranged for a change of treatment. The second consultation was held at least 48 hours after the end of treatment (V3), at which the investigator carried out a further clinical examination and took a bacteriological sample in the event of the persistence of pus in the middle meatus. A clinical cure was defined as the disappearance, firstly, of purulent nasal discharge with the absence of pus in the middle meatus and, secondly, of spontaneous and induced facial pain. A clinical failure was defined as the persistence of purulent nasal discharge and/or the presence of pus in the middle meatus and/or moderate or severe spontaneous and induced pain. The follow-up visit (V4) took place three to four weeks after the end of the study medication. Only patients considered to have been cured at the end of treatment were seen by the investigator. A clinical examination was performed and a sinus X-ray and bacteriological sample (where necessary) taken. The investigator concluded either that the clinical cure still persisted or that there was a clinical relapse, defined by the recurrence of at least one of the signs of sinusitis (purulent nasal discharge and/or pus in the middle meatus and/or spontaneous and/or induced pain in the sinus regions). A radiological cure was defined as the normalization of or a considerable improvement in the radiological pictures. A radiological failure was defined as the persistence of or deterioration from the initial films.
– the Intention to Treat (ITT) population, represented by all the randomized patients having received at least one dose of the study medication. The analysis of safety was conducted on this population; – the Evaluable Population (EP), represented by all the patients eligible by ITT with clinical and radiological evidence of acute sinusitis, having received at least six days of treatment, or at least three days in the event of a premature failure, and not taking any concomitant medication prohibited in the protocol (corticosteroids, etc.).
Evaluation of efficacy
Three hundred and ten (310) patients were included in the study. Two patients were lost to follow-up. A total of 308 were analyzed by ITT, i.e. 160 patients treated with pristinamycin and 148 patients treated with cefuroxime axetil. Analysis of the demographic data (including the male/female ratio) and the previous history of sinusitis revealed no statistically significant difference between the two groups (table I). The majority of patients had an infectious syndrome that had been present for five days at baseline, with a mean rectal temperature of 37.6◦ C (±0.6). All had pus in the middle meatus on inclusion. The frequency of severe spontaneous pain was higher in the pristinamycin
The principal criterion of the assessment of efficacy was purely clinical, based on the course of the clinical signs and symptoms at the follow-up visit (V4) compared with the end of treatment visit (V3). Thus, a clinical success at V4 required a clinical cure of the end of treatment and the persistence of this cure at a later date. There was a clinical failure at V4 if there was no clinical cure at the end of treatment or a clinical relapse at a later date. Three populations were analyzed: – the total population, represented by all the randomized patients;
Evaluation of safety The evaluation of safety was based on the occurrence of adverse events during the study. These were described in terms of their seriousness, severity, duration and relationship (possible or probable) to the study medications.
Statistical methods and procedures Comparison of the efficacy of the two treatment groups involved a one-sided equivalence test at the 5% level based on a calculation of the 95% confidence interval of the difference observed between the two groups. The other intergroup comparisons were performed by means of the usual tests: Student’s test or Wilcoxon’s test (depending on the normality of the variable studied) for quantitative variables, chi2 test or Fisher’s exact test for qualitative variables (depending on the numbers in the classes) and Wilcoxon’s test for ordinal qualitative variables. The number of clinically evaluable patients required (114 per treatment group) was calculated on the basis of the following hypotheses: 85% success rate for the reference product, 15% equivalence level, type one error of 5% and type two error of 10%.
RESULTS Description of the population
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Table I. Demographic characteristics (ITT population). Pristinamycin
Cefuroxime axetil
Total
(n = 160)
(n = 148)
(n = 308)
Age (years) 43.6 ± 15.7
43.2 ± 15.1
43.4 ± 15.4
Range
Mean ± SD
18–82
19–88
18–88
Median
40
42
41
Sex Male
78 (49%)
63 (43%)
141 (46%)
Female
82 (51%)
85 (57%)
167 (54%)
67.7 ± 13.8
66.0 ± 11.4
66.9 ± 12.7
Range
41–110
42–99
41–110
Median
66.5
67
67
88 (45%)
72 (48%)
160 (51.9%)
Weight (kg) Mean ± SD
History of sinusitis
group (20%) than in the cefuroxime axetil group (12.2%). However, the difference was not clinically significant (p = 0.22). The presence of signs and symptoms was comparable in the two treatment groups (table II). The sinus X-ray taken within 72 hours of inclusion confirmed the diagnosis of sinusitis in 95% (152/160) of the patients treated with pristinamycin and 92% (136/148) of the patients treated with cefuroxime axetil. This involved unilateral or bilateral maxillary sinusitis in 84% (242/288) of cases and maxillary and frontal sinusitis in almost 12% (34/288) of cases. The bacteriological sample taken from the middle meatus at baseline enabled 200 “pathogenic” or “presumed pathogenic” micro-organisms to be isolated in 86/160 (53.8%) of patients treated with pristinamycin and in 74/148 (50%) of patients treated with cefuroxime axetil. Principally S. pneumoniae (n = 72), H. influenzae (n = 59) and M. catarrhalis (n = 21) were identified. For the other patients (48%), the samples were either sterile or positive for a micro-organism considered to be nonpathogenic. The distribution of the micro-organisms isolated in terms of their in vitro susceptibility to pristinamycin and cefuroxime is given in table III. Pristinamycin confirmed its activity against S. pneumoniae (94%) and M. catarrhalis (100%), whereas the percentage of strains susceptible to cefuroxime was respectively 69% for S. pneumoniae and 38% for M. catarrhalis. For H. influenzae, 58% of the strains were susceptible to pristinamycin and 42% to cefuroxime by the agar disc sensitivity test. After determination of the minimum inhibitory concentrations (MIC) of pristinamycin against 55 of the 59 strains of H. influenzae isolated at baseline, 36.4%
were inhibited at a MIC 1 mg/L and 49.1% at a MIC = 2 mg/L. The mean treatment duration was 7.7 days (±1.2) in the pristinamycin group and 7.9 days (±0.7) in the cefuroxime axetil group. Treatment was discontinued in 13 patients treated with pristinamycin (11 times for an adverse effect usually of a digestive nature, once for withdrawal of consent, once for no specified reason) and in four patients treated with cefuroxime axetil (two patients with a clinical failure, one patient for a serious adverse event, one patient with a clinical failure and having a serious adverse event).
Analysis of efficacy Among the patients analyzed by ITT, 22/308 patients (7.1%) were excluded from the population evaluable for the analysis of clinical efficacy at V4 (principal criterion). The number of patients excluded was larger in the pristinamycin group than in the cefuroxime axetil group 14/160 (8.8%) versus 8/148 (5.4%). All these excluded cases were reviewed by the Committee of Experts before the code was broken (table IV). In the ITT population, clinical success at the end of treatment was obtained in 83.7% and 87.2% of patients treated with pristinamycin and cefuroxime axetil, respectively. These results are similar to those of the clinically evaluable population (83.9% and 87.2% in the pristinamycin and the cefuroxime axetil group, respectively). Analysis of the principal criterion of this study, in contrast to the published studies, involved the clinical efficacy at the follow-up visit (D30-D40) in the clinically evaluable population. The success rate was 72.6% (106/146) in the pristinamycin group and 75% (105/140) in the cefuroxime axetil group. The upper limit of the confidence interval (95% CI) was 10.95%, so that the hypothesis of equivalence at the 15% level was accepted (table V). Among the 75 patients with a clinical failure, 42 were failures at the end of treatment (24 in the pristinamycin group and 18 in the cefuroxime axetil group) and 33 patients, having been cured at the end of treatment, suffered a clinical relapse at the follow-up visit three to four weeks after the end of treatment (16 in the pristinamycin group and 17 in the cefuroxime axetil group). These failures were classified in categories (table VI): 44/75 patients had a clinical failure characterized by the persistence of pus (purulent nasal discharge and/or pus in the middle meatus) after eight days of treatment or by the recurrence of signs and symptoms after a clinical resolution at the end of treatment. Among the micro-organisms most commonly found at the end of treatment and during the follow-up period in the 17 clinical and bacteriological failures, S. pneumoniae and/or H. influenzae (monomicrobial or polymicrobial
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Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis
Table II. Signs and symptoms present on inclusion (ITT population). Pristinamycin
Cefuroxime axetil
Total
(n = 160)
(n = 148)
(n = 308)
Duration (days) 5.6 ± 2.6
5.1 ± 2.2
5.4 ± 2.4
Range
Mean ± SD
1–18
2–11
1–18
Median
5
4.5
5
Temperature
(* 4)
(* 2)
(* 6)
Mean ± SD
37.6 ± 0.6
37.6 ± 0.6
37.6 ± 0.6
Range
36.5–39
36.5–39.8
36.5–39.8
Median
37.5
37.7
375
Purulent nasal discharge
156 (97.5%)
143 (96.6%)
299 (97.1%)
Spontaneous pain in sinus regions
156 (97.5%)
146 (98.7%)
302 (98.1%)
Slight
23 (14.4%)
26 (17.6%)
49 (15.9%)
Moderate
101 (63.1%)
102 (68.9%)
203 (65.9%)
Severe
32 (20.0%)
18 (12.2%)
50 (16.2%)
Induced pain in sinus regions
156 (97.5%)
146 (98.6%)
302 (98.1%)
Slight
29 (18.1%)
31 (20.9%)
60 (19.5%)
Moderate
100 (62.5%)
96 (64.9%)
196 (63.6%)
Severe
27 (16.9%)
19 (12.8%)
46 (14.9%)
Pus middle meatus
160 (100%)
148 (100%)
308 (100%)
* number of missing data.
Table III. In vitro susceptibility of the 200 bacterial strains isolated on inclusion (ITT population). Pristinamycin
Haemophilus influenzae
Cefuroxime axetil
n
S
%S
n
S
57
33
58%
55
23
%S 42%
Streptococcus pneumoniae
69
65
94%
71
49
69%
Moraxella catarrhalis
21
21
100%
21
8
38%
Streptococcus spp.
12
12
100%
12
11
92%
Staphylococcus aureus
14
14
100%
14
10
71%
Gram-negative bacilli
7
1
14%
15
5
33%
Coagulase (−) Staphylococcus
1
1
–
1
1
–
Other
1
1
–
1
1
–
Total
182
148
190
108
81.3%
56.8%
n = number of strains tested; S = susceptible; % = % of susceptible strains.
pus) was identified six times in the pristinamycin group and five times in the cefuroxime axetil group. The distribution of these micro-organisms is shown in table VII.
The susceptibility of the micro-organisms found in the follow-up bacteriological sample (V3) in the case of failure was as follows: all the pneumococci were susceptible
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J.J. Pessey et al.
Table IV. Synopsis of exclusions from the principal analysis.
Excluded from the analysis by ITT Patients evaluable for the analysis by ITT Patients not evaluable for the principal analysis (V4)
Pristinamycin
Cefuroxime axetil
Total
(n = 161)
(n = 149)
(n = 310)
1
(0.6%)
1
(0.7%)
2
(0.6%)
160
(99.4%)
148
(99.3%)
308
(99.4%)
14/160
(8.8%)
8/148
(5.4%)
22/308
(7.1%)
Normal x-ray at V1
5
6
11
Appearance of first symptom > 10 days
1
0
1
and/or study
6
2
8
Prohibited medications
2
0
2
Premature discontinuation of treatment
Patients evaluable for the principal
146/160
(91.2%)
140/148
(94.6%)
286/308
(92.9%)
analysis (V4)
Table V. Analysis of clinical efficacy. ITT population
Evaluable population
End of treatment
Clinical efficacy
Follow-up
End of treatment
Follow-up
PRI
CA
PRI
CA
PRI
CA
PRI
CA
134/160
129/148
112/160
111/148
125/149
123/141
106/146
105/140
83.7%
87.2%
70.0%
75.0%
83.9%
87.2%
72.6%
75.0%
(% success)
] − ∞, 10.01%]
] − ∞, 13.35%]
] − ∞, 10.12%]
] − ∞, 10.95%]
PRI: pristinamycin; CA: cefuroxime axetil.
Table VI. Description of clinical failures and number of patients (evaluable population for the principal criterion V4). Persistence of signs:
Pristinamycin
Cefuroxime axetil
Total
• clinical only
20
24
44
• clinical + bacteriological
10
5
15
• clinical + radiological
8
6
14
• clinical + bacteriological + radiological
2
0
2
40
35
75
Total
Table VII. Distribution of pathogens in failures involving H. influenzae and S. pneumoniae. Single pathogen
Multiple pathogens
Pristinamycin
Cefuroxime axetil
Pristinamycin
Cefuroxime axetil
H. influenzae
1
0
–
–
S. pneumoniae
2
2
–
–
H. influenzae + S. pneumoniae
–
–
2
1
H. influenzae + others
–
–
1
2
S. pneumoniae + others
–
–
0
3
Total
3
2
3
3
Pristinamycin versus cefuroxime axetil in the treatment of acute sinusitis
to pristinamycin and 2/3 of the pneumococci were resistant to cefuroxime. Two H. influenzae were susceptible to pristinamycin and two were of intermediate susceptibility to pristinamycin. The three H. influenzae in the cefuroxime axetil group were susceptible to cefuroxime.
Safety The safety of treatment was evaluated in the 308 patient included who had taken at least one day’s treatment. The global incidence of adverse events (AE) was 28% (45/160) in the pristinamycin group and 19% (28/148) in the cefuroxime axetil group (NS). Treatment was discontinued because of the occurrence of AE in 11 patients in the pristinamycin group and two patients in the cefuroxime axetil group (p = 0.02). Severe adverse effects were reported with the same frequency in both groups: 15.7% for pristinamycin and 17.1% for cefuroxime axetil (NS). Four serious AE (dental condition requiring surgical treatment, bronchitis, dyspnoea and obstructive maxillary sinusitis requiring emergency surgical drainage) were reported during the study in three patients in the cefuroxime axetil group, these AEs being related either to a concurrent disease or the condition originally justifying inclusion. No serious AEs were reported in the pristinamycin group
DISCUSSION In the 308 patients included, the diagnosis of acute sinusitis was clearly documented clinically (100% of patients having pus in the middle meatus at baseline), radiologically (93.5% of patients – 288/308 – having an abnormal sinus X-ray at baseline) and bacteriologically (isolation of at least one pathogenic or presumed pathogenic microorganism at baseline in 52% of patients – 160/308). S. pneumoniae was isolated more often (36%) than H. influenzae (29.5%). This incidence was similar to that reported in the American studies [3, 4], in contrast to publications in France and Europe where S. pneumoniae is found less often (15%) than H. influenzae (35%) [1, 2, 5, 20, 21]. This study demonstrated the consistent in vitro activity of pristinamycin against all strains of macrolide-resistant S. pneumoniae (31/71 strains, 43.7%), whether susceptible or resistant to beta-lactams. Of the 21 strains of M. catarrhalis identified, none was resistant to pristinamycin. After measuring the diameters of inhibition of the strains of H. influenzae isolated on inclusion, percentage resistances of 22.4% to penicillin, 17.6% to pristinamycin, 8.6% to erythromycin and 9.1% to cefuroxime were observed. However, after determination of the minimum inhibitory concentrations of pristinamycin against these strains of H. influenzae by the agar dilution method (HTM agar), 14.5% were resistant to pristinamycin (MIC > 2 mg/L).
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The clinical response involved a large population of evaluable patients at the end of treatment (290 patients) and at a later date (286 patients), which is remarkable considering that only patients with both unequivocal clinical and radiological evidence of acute sinusitis and having also not received any local or systemic corticosteroid therapy during the study were included. Despite these very strict inclusion criteria, only 22 patients (18 patients at the end of treatment and four at the follow-up visit) had to be excluded from the population evaluable for the analysis of efficacy. In terms of the comparison of clinical efficacy of the two antibiotics, this study showed that pristinamycin is equivalent to cefuroxime axetil. The success rate at the end of treatment in the ITT population was 83.7% (134/160) in the pristinamycin group and 87.2% (112/148) in the cefuroxime axetil group. These results were also confirmed in the evaluable population (table V). The clinical success rates observed in the two populations at the follow-up visit were lower than those in the literature [22] (table V). These lower cure rates are undoubtedly related to the prohibition of any corticosteroid therapy during the study (exclusion criterion), in contrast to the reports in the literature [22], and the later date (30 to 40 days) of the clinical evaluation, which identified 33 cases of clinical relapse at V4. However, it should be noted that these rates were comparable in the two groups. Clincial trials in antibiotic therapy are not usually studies of superiority but of equivalence. European recommendations advocating the choice of a delta equivalent to 10% in studies involving non-serious infections were not published until 1997 [23]. At the time the protocol for this study was designed, the choice of delta was unrestricted and was usually set at 10 or 15%. It should however be noted that the confidence interval observed for the principal criterion of efficacy shows that the upper limit of the confidence interval is 10.95%, which can be seen to be close to the limit that would have been determined if an equivalence study with a delta equivalent to 10% had been proposed. The analysis involving the clinical and radiological response at the follow-up visit showed similar efficacy rates in the two treatment groups, but again considerably lower than those reported in the literature. For the pristinamycin-treated group of patients, the success rate was 63% in the evaluable population and 45% in the ITT population versus 69% in the evaluable population and 51.4% in the ITT population for cefuroxime axetil. This might be explained by the fact that the clinical and radiological criterion is evaluated at the end of treatment (ten to 15 days) in the majority of published studies (82 to 87%) – [4, 5, 23] and not at a later date, as in this study. The presumed or definite eradication rate at the end of treatment visit was 87.8% (79/90) in the pristinamycin group and 93.5% (72/77) in the cefuroxime axetil group.
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At the follow-up visit, this eradication rate was 73.3% and 85.7%, respectively. Analysis of the clinical response at the end of treatment in the subgroup of 35 patients treated with pristinamycin in whom 33 strains of H. influenzae had been isolated at baseline showed that when the MIC of pristinamycin for these isolated strains showed that when the MIC was less than or equal to 1 mg/L (strain supposedly susceptible to pristinamycin), the clinical success rate was 91.7% (11/12), when the MIC was 2 mg/L (intermediate strain) the clinical response was 88% (14/16), while with a MIC greater than 2 mg/L (resistant strain) it was only of the order of 60% (3/5). These preliminary results obtained in a small population nevertheless show that a good level of clinical efficacy may be expected with pristinamycin in sinusitis due to Haemophilus which, in this study, had a MIC 2 mg/L in 85% of cases. The safety of treatment was generally satisfactory in both treatment groups with a larger number of drop-outs observed in the pristinamycin group and more frequent serious adverse effects in the cefuroxime axetil.
CONCLUSION In this randomized, double-blind, double-dummy study involving 308 patients with radiological evidence of acute sinusitis, the efficacy of outpatient treatment with pristinamycin 1 g twice daily for eight days was equivalent (at the 15% level) to that of treatment with cefuroxime axetil 250 mg twice daily for eight days. Consequently, pristinamycin may be proposed as firstline treatment in acute sinusitis in adults.
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