Invent-farma.es

Controlled multicenter study on chronic suppurative otitismedia treated with topical applications of ciprofloxacin0.2% solution in single-dose containers or combination ofpolymyxin B, neomycin, and hydrocortisone suspension NURIA MIRÓ, MD, and THE SPANISH ENT STUDY GROUP,* Badalona, Spain
Otic drops of either ciprofloxacin 0.2% solution (CIP)
still raises questions concerning the antibiotic choice, or a combination of polymyxin B, neomycin, and
adequate route of administration and regimen, and hydrocortisone suspension (PNH) were administered
adverse reactions to drugs. Because Pseudomonas aerug- for 6 to 12 days to patients (14-71 years old) with
inosa, Staphylococcus aureus, gram-negative bacilli, and chronic suppurative otitis media in a randomized,
anaerobic organisms, alone or in combination, are the nonblinded, multicenter clinical trial. Two hundred
predominant source of infection,1,2 it is important to rely thirty-two enrolled patients were analyzed for effica-
on medications with a broad spectrum of activity because cy on a “per protocol” basis. The most frequently
identification and susceptibility tests cannot always be identified causal agents were Staphylococcus
performed on a routine basis in daily practice.
aureus (28% of the patients), Pseudomonas aerugi-
Management of CSOM with ototopical agents is nosa (19%), and Staphylococcus sp (9%). Clinical
common practice among otolaryngologists. Several success was observed in 91% and 87% of the CIP-
combinations of topical otic preparations are available and PNH-treated patients, respectively. At 1-month
to treat external and middle ear infections. They remain follow-up, 4% of CIP and 6% of PNH patients showed
the cornerstone of treatment, despite the fact that some a relapse of otorrhea. Bacteriologic eradication was
of them are recognized as ototoxic drugs, and convinc- seen in 89% and 85% of patients in the CIP and PNH
ing evidence of sensorineural hearing loss in animals groups, respectively. At 1-month follow-up, reinfec-
has been found.3 The major components of these drops tion or recurrence of infection appeared in 3 patients
include polymyxin B, neomycin, gentamicin, or chlo- in the PNH group and in 1 patient in the CIP group.
ramphenicol, to which a corticosteroid is frequently Both treatments were well tolerated. The most fre-
added. In Spain an otic suspension of polymyxin B, quently reported adverse events were pruritus, sting-
neomycin, and hydrocortisone (Otosporin) is available ing, and earache. Audiometric tests did not show
and broadly used, and was subsequently selected as the changes attributable to study drugs in any but 1
reference treatment in our clinical trial. This combina- patient in the PNH group. This clinical trial shows that
tion is also available in most of the European countries topical 0.2% ciprofloxacin solution in single-dose
and also in the United States, where it is the most fre- containers is effective and well tolerated in patients
quently used ototopical treatment by otolaryngologists.4 with chronic suppurative otitis media. (Otolaryngol
Ciprofloxacin, a synthetic fluoroquinolone adminis- tered by oral route, is associated with high bacteriologicand clinical response rates,5-7 because of both its satis-factory penetration in the middle ear and its broad spec- In chronic suppurative otitis media (CSOM), antibacter-
trum of antibacterial activity. In noncontrolled clinical ial therapy for persistent or recurrent episodes of otorrhea experiences, ototopical ciprofloxacin at concentrations aslow as 0.2% has provided higher percentages of clinicaland bacteriologic cures, which are not optimized through From the Servicio de Otorrinolaringología, Hospital Universitario simultaneous administration of oral ciprofloxacin.8,9 No evidence of ototoxicity after topical application of Sponsored by Laboratorios Vita, SA, and Química Farmacéutica ciprofloxacin has been previously seen in animal3,10,11 or clinical5-9,12-14 studies. Ciprofloxacin could not be A complete list of investigators can be found at the end of the article.
Reprint requests: Nuria Miró, MD, Servicio de Otorrinolaringología, detected in plasma after otic applications, suggesting the Hospital Universitario Germans Trias i Pujol, Ctra Canyet, s/n, absence of systemic absorption.13 Therefore the avail- ability of a topical antibiotic preparation with an appro- Copyright 2000 by the American Academy of Otolaryngology– priate antimicrobial spectrum and without the risk of Head and Neck Surgery Foundation, Inc.
ototoxicity would be a valuable addition to the therapeutic 23/77/107888
management of middle ear infections. Furthermore, the Otolaryngology–
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availability of a sterile and preservative-free formula sup- dose vs multiple-dose containers), and galenic form (solution plied in single-dose containers for application to the mid- vs suspension), a double-blind design had to be discarded. The dle ear also represents an achievement according to the limited capacity of the external auditory canal precluded the The objective of this clinical trial was to compare the Patients were examined by the investigators on 3 occa- efficacy and safety of a newly developed sterile and sions: on the day of enrollment (baseline, or visit 1), 2 to 7 preservative-free formula of ciprofloxacin 0.2% solu- days after the end of treatment (visit 2), and 1 month later tion supplied in single-dose containers versus a combi- (visit 3). At visit 1, a thorough ENT examination was done, a nation of polymyxin B, neomycin, and hydrocortisone sample of the ear discharge was taken, and an audiometric suspension (Otosporin), both of which were applied assessment was performed. All patients received aural toilet by microscopic examination and were instructed about theapplication of study treatments. They were advised to apply METHODS AND MATERIAL
the medication in a supine position with the target ear facing This prospective, randomized, open, comparative, multi- the ceiling. One single-dose container (0.5 mL) of CIP or 3 center clinical trial was designed according to the European drops (0.15 mL) of PNH were to be introduced into the exter- Guidelines on evaluation of antibacterial medicinal prod- nal meatus at each application. The tragus was to be massaged ucts.16 ENT physicians from 16 centers in Spain conducted repeatedly, and the same position was maintained for 5 min- the study. Ethics committees from each center as well as the utes. This procedure was to be repeated twice a day for CIP Spanish Health Authorities reviewed and approved the study treatment and 4 times a day for PNH treatment. At visit 2, the protocol. Participants received detailed information on the efficacy of treatments was assessed based on the presence or study, including a patient information sheet, and their written absence of otorrhea. A sample of ear discharge (if present) consent was obtained before enrollment.
was taken for microbiologic culture. Only patients who were To be included in the study, patients of either sex, 14 to 71 cured were appointed to visit 3, where ENT examination and years old and capable of following the investigator’s instruc- audiometric tests were repeated. If ear discharge was present, tions, had to have CSOM defined as serous, mucous, muco- purulent, or purulent otorrhea; a history of persistent tympanic Bacteriologic tests were carried out at each participating perforation or the presence of a tympanostomy tube along with center. Specimens of discharge obtained by the investigators the current episode lasting for at least 6 weeks; and bacteriolog- were inoculated into appropriate agar media (eg, blood, ic confirmation of ear infection. Patients presenting with mucop- MacConkey) and identified after incubation with standard urulent or purulent discharge were enrolled, irrespective of the microbiologic techniques. Sensitivity to ciprofloxacin, poly- culture results. Subjects with persistent ear infection despite top- myxin B, and neomycin was tested using the disk method.
ical or systemic antibacterial therapy could be enrolled after a Audiometric assessment was done by the investigators at 72-hour washout period. The exclusion criteria were as follows: each participating center and consisted of pure-tone audiometry acute otitis externa, fungal otitis, otorrhea associated with the for air- and bone-conduction hearing. Frequencies between 250 presence of cholesteatoma, presence of severe otalgia or fever and 8000 Hz (air hearing) and between 250 and 4000 Hz (bone greater than 38°C, infection requiring systemic therapy, par- conduction) were measured and recorded on the audiogram.
ticipation in another clinical trial in the previous 30 days, The primary variable of efficacy was clinical response at visit contraindication to the study drugs, pregnancy or suspected 2 and was defined as follows: cure, absence of otorrhea or pres- pregnancy and absence of contraceptive measures.
ence of serous/mucous otorrhea with negative microbiologic Patients were randomly allocated to study treatments: culture; and failure, presence of purulent or mucopurulent otor- ciprofloxacin sterile and preservative-free 0.2% solution, sup- rhea irrespective of culture results or presence of serous/mucous plied in 0.5-mL single-dose containers (Laboratorios Vita, otorrhea with positive culture. Dropouts due to lack of efficacy SA, and Química Farmacéutica Bayer, SA), 0.5 mL twice after at least 3 days of treatment or due to adverse events were daily for 10 days (valid interval 6-12 days); or polymyxin B also classified as therapeutic failures. Dropouts resulting from sulfate, neomycin, and hydrocortisone suspension, supplied in any other cause were classified as not evaluable.
multiple-dose containers (Otosporin; Gayoso Wellcome, SA), The secondary variables of efficacy were clinical response at 3 drops (0.15 mL) 4 times daily for 10 days (valid interval 6- visit 3 and bacteriologic outcome at visits 2 and 3. Clinical 12 days). No other treatment for CSOM was permitted. Com- response at visit 3 was defined as sustained cure (absence of pliance with the study medications was checked by counting otorrhea or presence of serous/mucous otorrhea with negative the number of CIP single-dose containers or the volume of culture) or relapse (reappearance of purulent or mucopurulent PNH left in the multiple-dose containers returned to the inves- otorrhea irrespective of culture results or serous/mucous otor- tigators on visit 2. Because of different dosing schedules (0.5 rhea with positive culture). Bacteriologic outcome at visit 2 was mL twice daily vs 0.15 mL 4 times daily), packaging (single- defined according to the following definitions: eradication, the Otolaryngology–
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causative organism of the infection was eliminated in the post- Table 1. Study populations
treatment culture, and no new organism was identified; pre- Study population
sumed eradication, culture could not be done because of theabsence of ear discharge; persistence, at the end of treatment the culture was positive, with isolation of the same pathogen respon- sible for the infection; superinfection, a new pathogen was iden- tified as being responsible for the infection; and indeterminate,baseline cultures were negative or not done, or no cultures were *Patients having received at least 1 dose of either study treatment.
† obtained at the end of therapy despite positive cultures at base- Patients with clinically/bacteriologically proven CSOM and evaluated at visit 2 after a minimum of 3 days of treatment, or less than 3 days in the case of treat- line. At visit 3, bacteriologic outcome was defined as eradication ment withdrawal due to adverse events.
or presumed eradication (absence of the organism in the repeat- ‡Patients fully compliant with protocol specifications or treatment failure after ed culture 1 month after treatment or culture could not be done because of the absence of otorrhea), recurrence (reappearance ofthe pathogen eradicated or presumably eradicated at the end oftreatment), reinfection (isolation of a new pathogen different 90% confidence interval (2 sided) for the observed difference from the organism eradicated or presumed eradicated at the end in clinical cure rates between the two treatments was calculated of treatment), or indeterminate (absence of the organism in by means of the odds ratio–adjusted Mantel-Haenzsel test. As repeated cultures or no cultures performed).
a secondary statistical analysis, the same approach was per- Safety assessment was performed by recording all adverse formed on the “evaluable patients” population and the “ran- events observed and reported by participants during the study domized patients” population. A descriptive statistical analysis period. The study coordinator (N.M.) blindly reviewed all pre- was carried out on the pretreatment and posttreatment data.
treatment and posttreatment audiograms to identify any oto- Qualitative variables were expressed by the number and per- toxicity evidence arising from the treatments. Furthermore, to centages of patients in each category. Continuous variables for evaluate the potential systemic absorption of topically applied each group of patients were analyzed in terms of mean, stan- ciprofloxacin, researchers in one center (H. General de Vic), dard deviation, and median, minimum, and maximum values.
in agreement with the informed consent form, drew a 10-mLblood sample from the patients 1 to 2 hours after the first dos- ing. Plasma samples were kept frozen at –20°C and sent to Study Population
Bayer AG (a pharmacokinetic laboratory in Wuppertal, Between February 1996 and May 1997, 328 patients Germany), where plasma levels of ciprofloxacin were assayed from 16 sites were enrolled in the study, and 322 of by means of a validated high-performance liquid chromatog- them were randomly allocated to study treatments (6 raphy method. The lower limit of detection was set at 10 µg/L.
patients were not randomized because of protocol vio- At each patient visit, the investigators entered the data using lations). Four randomized patients did not receive any a personal computer (IBM ThinkPad) supplied with a validated dosing (3 in the CIP group and 1 in the PNH group), so software program (RDES SL), including an electronic the safety analysis was based on the 318 patients who study–specific case report form, interactive instructions for use, received at least 1 dose of the study treatment. Of the as well as checks for selection criteria compliance, treatment 322 randomized patients, 29 were not evaluable for effi- schedules, inconsistencies, and out-of-range and absent values.
cacy at visit 2 (13 in the CIP group and 16 in the PNH Data were transmitted each month by study monitors (Phoenix group), as a consequence of loss to follow-up (10 International Life Sciences Spain) to a central database for final cases), fungal otitis (7 cases), or bacteriologic tests not review, data cleaning, and final statistical analysis.
performed (12 cases). Finally, the evaluable population The study was designed as an equivalence clinical trial to consisted of 293 patients. Sixty-one evaluable patients demonstrate the null hypothesis that CIP is not therapeutically were considered invalid as “per protocol” because of inferior to PNH (unilateral equivalence analysis), assuming a violations concerning either visit schedules (32 cases), maximum difference in clinical cure rates between the treat- treatment compliance (27), duration of therapy (20), ments equal to or lower than 15%. The sample size was esti- randomization error (3), concomitant prohibited therapy mated to be 360 randomized patients (180 per treatment (2), or presence of cholesteatoma (2). Therefore the group). Power curves were obtained for this sample size final population of valid per protocol patients on which according to the formulas of Machin and Campbell.17 This primary efficacy analysis was performed consisted of sample size ensures a power of at least 80% in any case of 232 patients (119 in the CIP group and 113 in the PNH observed cure rates of at least 65% and rates of valid patients group). The study populations are shown in Table 1.
not higher than 30%. The confirmatory statistical analysis was Unless otherwise stated, all the results given below refer performed on the “per protocol” population of patients. The to the per protocol population of patients. Otolaryngology–
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Table 2. Baseline and initial evaluation characteristics
Characteristics
CIP (n = 119)
PNH (n = 113)
Years since first symptoms of CSOM [median (range)] No. of episodes of otorrhea during the previous year* [median (range)] Months since last episode [median (range)] Patients treated during the previous episode [n (%)] Patients with previous ear surgery [n (%)] Days of evolution of current episode [median (range)] *Including the current episode. †No percentage per patient group is given because more than 1 pathogen could be isolated per subject. Other pathogens isolated were Klebsiella sp (5), Serratia sp(4), Pseudomonas sp (2), Escherichia sp (8), Proteus sp (13), other Enterobacteriaceae (16), Haemophilus sp (4), other gram-negative bacilli (8), Streptococcus sp (5),Corynebacterium sp (15), and other pathogens (10).
Table 3. Analysis of clinical responses at visit 2 (primary efficacy variable)
Cure rates [% (+/n)]
Observed difference
90% CI of the
population (n)
in cure rates
difference
Baseline Evaluation
quently observed symptoms were hypoacusia (95%), No difference was seen between the two treatment tinnitus (30%), otalgia (25%), vertigo (14%), and groups as far as baseline and initial evaluation charac- cephalea (14%). Tympanic perforation was present in teristics are concerned (Table 2). Time elapsed since the all cases, and discharge was purulent or mucopurulent first episode of otitis extended from less than 1 year to in 91% of CIP patients and 84% of PNH patients.
58 years, and the total number of episodes during the Cultures were positive in 92% of patients in the CIP previous year ranged from 1 to 20. In most patients, 3 group (111/119) and in 91% of patients in the PNH months had elapsed since the last episode, although the group (103/113); 19 patients with purulent or mucopu- interval was longer than 1 year in some cases.
rulent discharge had negative cultures. Of the 278 About half of the patients had received some treat- micro-organisms isolated from bacteriologic cultures ment during the last episode of otorrhea (dexamethasone, (140 CIP, 138 PNH), 219 were considered as the causal 40 cases; ciprofloxacin, 21 cases; boricated alcohol, 13 pathogen of the infection (116 CIP, 103 PNH). The cases; fluocinolone acetonide, 12 cases; amoxicillin, 8 most prevailing causal pathogens were S aureus (28%), cases). Approximately one third of the patients had pre- P aeruginosa (19%), and Staphylococcus sp (9%).
viously undergone extensive ear surgery.
Susceptibility tests showed that 84% of the causal Enrollment took place after a median otorrhea devel- pathogens were sensitive to ciprofloxacin (84% CIP, opment of 15 days (range 1-365 days). About 90% of 83% PNH) and 78% were sensitive to polymyxin B the patients had a unilateral ear affected. The most fre- Otolaryngology–
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No statistical difference was observed between Table 4. Bacteriologic outcome at visits 2 and 3
evaluable and per protocol patients with respect to base- Bacteriologic
line parameters or pretreatment microbiologic results.
Treatment Compliance and Duration
All the patients were fully compliant with the treat- ment and received at least 80% and no more than 100% of the prescribed doses. The median duration of therapy was 10 days (7-12 days) in both treatment groups.
Clinical and Bacteriologic Efficacy
Clinical results. In the per protocol population, 108
of 119 (91%) patients in the CIP group and 98 of 113 (87%) patients in the PNH group were cured at visit 2 (Table 3). The 90% confidence interval of the observed difference in clinical cure rates between PNH and CIP(–4%) yielded a lower limit of –8.86% and an upper Streptococcus pneumoniae, other Enterobacteriaceae, limit of 4.8%, both of which were below the maximum other pathogens). Superinfection was identified in 7 value of 15% that defined therapeutic equivalence.
patients, 5 in the CIP group (S epidermidis [2], P In the evaluable patients and the randomized patients, mirabilis, Candida sp, other pathogens) and 2 in the the percentages of subjects classified as cured at visit 2 PNH group (Candida sp, Streptococcus sp).
were also slightly higher in the CIP group (90% and 87%, At visit 3, eradication (including presumed eradica- respectively) than in the PNH group (81% and 76%, tion) was maintained at a rate of 78% in both treatment respectively). Lower and upper limits of the 90% confi- groups. In 42 patients no culture was done, and these dence intervals of the observed differences in clinical cure infections were classified as indeterminate. Three rein- rates were also below the maximum value of 15%.
fections, 1 in the CIP group (S aureus) and 2 in the PNH At the third visit, 1 month after the end of treatment, group (P aeruginosa, Pseudomonas sp), and 1 recur- 78% of patients in both the CIP and PNH groups had rence in the PNH group (P aeruginosa) were seen at the sustained cure, 17% of patients (18% in the CIP group, 1-month follow-up visit at the end of treatment.
16% in the PNH group) did not attend the follow-upvisit, and 5% of patients (4% in the CIP group and 6% in the PNH group) showed a relapse of otorrhea.
The safety analysis was carried out in the population Bacteriologic results. With respect to the bacterio-
of randomized patients who received at least 1 dose of logic response at visit 2 (Table 4), the performance of the study treatment (N = 318). Adverse events were microbiologic culture was not always possible, in gen- recorded in 24 (15%) patients in the CIP group and 12 eral as a consequence of the absence of otorrhea (76% (8%) patients in the PNH group. The number of patients in both treatment groups) and to a lesser extent for other with adverse reactions to the drugs (possibly, probably, reasons (eg, culture not done, culture not evaluable).
or very probably associated) dropped to 15 (9%) in the The rate of eradication (including presumed eradica- CIP group and 7 (5%) in the PNH group.
tion) was 79% in the CIP group and 76% in the PNH Among the 25 drug-related adverse events reported group. The bacteriologic outcome was classified as in 22 patients, the most frequent were pruritus (4 CIP, 2 indeterminate in 38 patients (20 in the CIP group and 18 PNH), stinging (3 CIP, 2 PNH), earache (2 CIP, 3 PNH), in the PNH group). Of these, 14 in the CIP group and 12 passage of the medication into the mouth (2 CIP, 1 in the PNH group were clinically cured at visit 2, but the PNH), vertigo (2 CIP), and cephalea (2 CIP). Eight sub- bacteriologic outcome was indeterminate because either jects withdrew from the study because of an adverse baseline cultures were negative or not done or no cul- event that was not considered to be related to the drug tures were obtained at the end of therapy despite posi- in the 4 CIP cases or related to PNH in 2 of 4 cases.
tive cultures at baseline. Excluding these patients, the Pretreatment and posttreatment audiometric tests rate of eradication (including presumed eradication) at were available in 295 patients (157 in the CIP group, visit 2 was 89% in the CIP group and 85% in the PNH 138 in the PNH group). No changes in the audiometric group. Infection persisted in 8 patients, 1 in the CIP assessment were recorded in the CIP group. One patient group (Staphylococcus epidermidis) and 7 in the PNH in the PNH group evolved from a normal audiogram at group (P aeruginosa [2], Proteus mirabilis, S aureus, visit 1 to hearing loss at all frequencies at visit 3.
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No plasma levels of ciprofloxacin were detected with 0.5% or 0.2% ciprofloxacin solutions. As com- among the 14 subjects (9 CIP, 5 PNH) from whom pared with oral treatment (500 mg twice daily), topical blood was drawn 1 to 2 hours after the first dosing.
treatment9 with 0.2% ciprofloxacin solution resulted insignificantly higher percentages of clinical improve- DISCUSSION
ment or cure (95% vs 68%) and microbiologic eradica- Designed as a therapeutic equivalence study, this tion (95% vs 55%); furthermore, combining oral and trial required the primary efficacy variable to be ana- topical therapy did not further enhance the efficacy lyzed on a large number of patients who satisfied all (90% clinical improvement or cure). In a study12 com- protocol requirements (per protocol population) and paring otic applications of ciprofloxacin 0.3% solution were randomly allocated to either study treatment. We and gentamicin 0.3% solution, clinical cure (absence of managed to rely on 232 comparable and fully compliant otorrhea) was found in 95% and 94%, and bacteriologic subjects. On the basis of the observed clinical cure eradication in 96% and 93% of the patients, respectively.
rates, we calculated the power of the study a posteriori.
A recently published meta-analysis of 24 clinical trials According to the formulas of Machin and Campbell,17 involving 1660 patients reviewed the effectiveness of dif- the study had a power greater than 95% to conclude the ferent medical treatments of CSOM.18 Topical treatment therapeutic equivalence between the two treatments.
with antibiotics or antiseptics was more effective than Because it was impossible to carry out the trial under treatment with systemic antibiotics in resolving otorrhea double-blind conditions, we tried to avoid any subjective and in eradicating bacteria. Combining topical and sys- assessment of the investigator by selecting a primary effi- temic antibiotics was no more effective than using topical cacy end point (clinical cure) based on objective obser- antibiotics alone. Regarding topical antibiotic treatments, vations, such as disappearance of otorrhea or presence of quinolones were more effective than nonquinolones.
serous/mucous discharge giving negative cultures.
Topical treatments are highly desirable in children, Both treatments showed a high degree of success considering the high incidence of CSOM in childhood, based on both clinical and bacteriologic responses. mainly as a complication of tympanostomy tube inser- The difference observed between the two treatments tion. No oral antibiotics effective against P aeruginosa in clinical cure rates (–4%) showed a confidence inter- are available for use in children. The potential for oto- val ranging from –8.86% to 4.48%, an interval that is toxicity of aminoglycoside or antibiotic-steroid otic entirely below the maximum value (15%), which was drops has limited their use in children. Ototoxicity has defined as therapeutic equivalence in the study protocol.
been investigated as a possible adverse effect of oto- Similarly, the data obtained in the evaluable patients topical ciprofloxacin therapy in several animal3,10,11 and the randomized patients did not show any inferiority and clinical5-9,12-14 studies. No study has documented of ciprofloxacin and rather pointed toward a higher cure ototoxicity of ciprofloxacin after topical application of rate under ciprofloxacin because the confidence inter- vals showed negative values on both sides.
Two studies13,14 in children aged 1 to 14 years with The clinical cure (91%) and bacteriologic eradication otorrhea due to P aeruginosa indicate that ciprofloxacin, (89%) rates seen in the ciprofloxacin-treated patients are 3 drops of a 0.3% solution applied topically 3 times higher than those observed after oral administration of daily for 14 days, resulted in clinical cure rates of 91% ciprofloxacin.5-7 These 3 studies, carried out in adult and 69%. Bone-conduction audiometry tests performed patients with CSOM treated with oral ciprofloxacin, 500 at baseline and at the end of treatment showed no rele- mg twice daily, showed that, at the end of the treatment, otorrhea had disappeared in 67%,5 59%,6 or 58%7 and The distribution of causal agents, similar within our two that bacterial eradication was seen in 59%, 62%, and treatment groups, showed that Staphylococcus, P aerugi- 70%, respectively. When 750 mg of oral ciprofloxacin6 nosa, and other gram-negative bacilli were the most preva- was given twice daily, success rates of 70% and 74% lent micro-organisms, although a higher incidence of were reached as far as otorrhea disappearance and bac- Pseudomonas over Staphylococcus is usually described.2 teriologic eradication, respectively, were concerned.
In the CIP group, 84% of the causal pathogens iso- Although carried out with slightly different designs lated were sensitive to ciprofloxacin, whereas those iso- and treatment response assessments, similar efficacy lated in the PNH group were sensitive to polymyxin B results to those observed in the present clinical trial and/or neomycin in 76% of the cases; this difference have been reported after topical treatment with differ- may explain the slightly better results obtained with ent ciprofloxacin concentrations (0.2%, 0.3%, and ciprofloxacin in our primary efficacy end point and 0.5%).8,9,12-14 In a subset of patients with CSOM,8 cure indicates to what extent the use of ciprofloxacin adjusts rates were seen in 80% and 71% of the patients treated Otolaryngology–
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Both treatments were equally well tolerated, with a (0,3%) versus gentamicina tópica (0,3%) en el tratamiento de la higher incidence of adverse drug events in the CIP otitis media crónica simple no colesteatomatosa en fase supurati-va. Ann Iber-Amer 1995;XXII:521-33.
group (9%) as compared with the PNH group (5%).
13. Force RW, Hart MC, Plummer SA, et al. Topical ciprofloxacin Because most adverse events were of local nature, the for otorrhea after tympanostomy tube placement. Arch Otolaryn- predominant incidence observed with ciprofloxacin 14. Wintermeyer SM, Hart MC, Nahata MC. Efficacy of ototopical might be attributed to the greater volume instilled into ciprofloxacin in pediatric patients with otorrhea. Otolaryngol the ear with each application (0.50 mL CIP vs 0.15 mL PNH). In no case was the treatment with ciprofloxacin 15. Ear preparations (1997:0652). In: European Pharmacopoeia Commission. European Pharmacopoeia. 3rd ed. Strasbourg: interrupted after an adverse drug reaction, and no artic- 16. Committee for Proprietary Medicinal Products. Note for guid- Audiometric assessment did not find any changes in ance on evaluation of new anti-bacterial medicinal products.
CPMP/EWP/558/95. April 1997.
hearing by 1 month after the end of ciprofloxacin treat- 17. Machin D, Campbell MJ. Statistical tables for the design of clin- ment, as previously reported in other studies.12,13,19,20 ical trials. Oxford: Blackwell Scientific Publications; 1987.
Ciprofloxacin was not detected in the plasma samples 18. Acuin J, Smith A, Mackenzie I. Treatment of chronic suppurative otitis media (Cochrane review). In: The Cochrane Library. Issue of the 14 patients who were tested with an analytical sensitivity of 10 µg/L, suggesting that the compound is 19. Ganz H. Bakterielle Otitis externa mit Überschreitung der not absorbed into the systemic circulation13 when Organgrenzen—systemische und lokale Kombinations-behandlung mit Ciprofloxacin. Z Artzl Fortbild 1993;87:413-5.
administered topically in a 0.2% solution to patients 20. De Schepper S, Schmelzer B. Lokale behandeling van otitis media en otitis externa: rol van de quinolones. Acta Otorhino- On the basis of clinical and bacteriologic data, we can conclude that a 0.2% otic solution of ciprofloxacin LIST OF INVESTIGATORS
supplied in single-dose containers is at least as effectiveas an otic suspension combining polymyxin B, neo- From the ENT departments of the following institutions: mycin, and hydrocortisone (Otosporin) in neutralizing • H. Universitario Germans Trias i Pujol, Badalona: Nuria Miró, MD; Enrique Perelló, MD; Francesc Casamitjana. • H. Mutua de Terrasa, Terrasa: Javier Maiz, MD; Jordi We thank S. Juncà for the statistical analysis of study data.
• H. Clínic i Provincial, Barcelona: Francisco Sabater, REFERENCES
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• H. General Universitario, Valencia: Jorge Basterra 7. Legent F, Bordure Ph, Beauvillain B, et al. Controlled prospec- Alegría, MD; Rafael Barona de Guzmán, MD.
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