Comparative Efficacy and Safety Evaluation of Cefaclor VS Amoxycillin + Clavulanate in Children with Acute Otitis Media (AOM)

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1 Special Article Comparative Efficacy and Safety Evaluation of Cefaclor VS Amoxycillin + Clavulanate in Children with Acute Otitis Media (AOM) Mukesh Aggarwal, Ramanuj Sinha 1, M. Vasudeva Murali 2, Prita Trihan 1 and P.K. Singhal 3 Pediatric Department, B.Y. Nair Hospital, Mumbai, 1 National Medical College, Kolkata, 2 Gandhi Medical College and Hospital, Secunderabad, Andhra Pradesh, 3 Apollo Hospital, New Delhi, India. Abstract. Acute Otitis Media (AOM) is the most frequent respiratory tract infection of infancy and childhood that is treated with antimicrobial agents. The most common causative pathogens include Streptococcus pneumoniae, Hemophilus influenzae and Moxarella catarrhalis, and therefore antibacterial management should target against these isolates. Cefaclor, a congener of cephalexin monohydrate, is a semisynthetic cephalosporin antibiotic. It is an orally active cephalosporin which has demonstrated activity against a wide range of organisms in vitro. Present study is designed as a multicentric prospective trial to study and compare the efficacy and safety of cefaclor versus amoxicillin+clav in children with acute otitis media. One hundred and sixty seven patients were evaluated for efficacy endpoints in the cefaclor arm comprised of 104 males and 63 females with a mean age of 5.74±2.80 years and 185 patients in the amoxy-clav group comprised of 118 males and 67 females with a mean age of 4.93±2.92 years. Both cefaclor and amoxy-clav caused a significant improvement in all the signs and symptoms after a 10-day treatment period. However, between-the-group comparisons showed that the reduction in most of the symptoms was significantly more in cefaclor arm as compared to amoxicillin-clav arm. The clinical success (clinical cure + improvement) at the end of therapy was significantly more in cefaclor arm: 98% with cefaclor versus 85% with amoxicillin+clav, p<0.05 (Table 3). Failure cases were prescribed other antibiotics according to the culture sensitivity reports, as rescue medication. Bacterial eradication rates were largely consistent with clinical responses. Bacteriological eradication was seen in 95% of patients in cefaclor group and 78% of patients in amoxicillin+clav group. In conclusion, cefaclor is a well tolerated and effective antibacterial option for acute otitis media in children and it is superior to the combination of amoxicillin+clav in efficacy and tolerability in acute AOM. Moreover, its expanded spectrum of activity, ability to achieve adequate concentrations in tissues, suitability for twicedaily dosing, and proven tolerability suggest that it is a good alternative to agents traditionally used in acute otitis media. [Indian J Pediatr 2005; 72 (3) : ] ashok.moharana@ranbaxy.com Key words: Acute Otitis Media (AOM); Cephalosporins; Antibacterial therapy Acute Otitis media (AOM) is the most frequent respiratory tract infection of infancy and childhood that is treated with antimicrobial agents. 1,2 Complications of untreated AOM include mastoiditis, meningitis, lateral sinus thrombosis and chronic suppurative otitis media. 3 Earlier, the complications of untreated AOM were infrequent in developed countries because of the efficacy of orally administered antibiotics. However, with the emergence of multidrug resistance among all the major bacterial pathogens, serious complications can occur. The most common causative pathogens include Streptococcus pneumoniae, Haemophilus influenzae and Moxarella catarrhalis, and therefore antibacterial management should target against these isolates. 4 Increased incidence of beta-lactamase-producing strains of H.influenzae and M.catarrhalis in acute otitis media reinforces the fact that beta-lactamase stable drugs such as Correspondence and Reprint requests : Dr. Mukesh Aggarwal, Head of Unit, Pediatric Department, B.Y. Nair Hospital, Mumbai, India. second and third generation oral cephalosporins and amoxicillin/clavulanate have become alternative therapies, particularly for patients with recurrent otitis media. 5 Resistance to penicillins is also of increasing concern particularly among strains of S. pneumoniae and AOM patients are more likely to be penicillin-resistant than isolates from any other source. Persistent and recurrent AOM more frequently involves pathogens with increased resistance to antimicrobials. 5 Cefaclor, a congener of cephalexin monohydrate, is a semisynthetic cephalosporin antibiotic. It is an orally active cephalosporin which has demonstrated activity against a wide range of organisms in vitro. It is well absorbed when given orally on an empty stomach. Although metabolism may play a role in the disposition of cefaclor, elimination is primarily renal. Cefaclor s spectrum of activity is better than the commonly used first-generation cephalosporins, including a wide range of gram-negative and gram-positive bacteria; in particular, Escherichia coli, Klebsiella spp. Proteus mirabilis, Indian Journal of Pediatrics, Volume 72 March,

2 Mukesh Aggarwal et al Salmonella spp. and Haemophilus influenzae are more susceptible to clinically achievable concentrations of cefaclor than cephalexin. Cefaclor has been demonstrated to be effective against beta-lactamase-producing H. influenzae resistant to ampicillin. Efficacy of cefaclor has been demonstrated in urinary tract, upper and lower respiratory tract, and skin and soft tissue infections in adults and children as well as in pediatric otitis media. Adverse reactions, mostly gastrointestinal, are generally mild and occur in few patients. 6 Combination of amoxycillin and clavulanate (a beta-lactamase inhibitor) have been used in various respiratory tract infections including Otitis media. On this background present study is designed as a multicentric prospective trial to study and compare the efficacy and safety of cefaclor versus amoxicillin+clav in children with acute otitis media. MATERIALS AND METHODS Study Design Under a prospective, open, comparative and multicentric study patients were treated as out-door patients or hospitalized during the treatment period and this was at the discretion of the investigator. All participating patients or their legal guardians provided consent prior to enrollment. And the Institutional Review Board or Independent Ethics Committee of each site approved the study protocol. Patients In the study only the patients aged 6 months to 12 years with clinical symptoms and tympanic membrane signs of AOM, otoscopic evidence of acute inflammation (dullness, cloudiness, erythema or bulging, perforation) plus tympanometric-confirmed middle ear effusion in at least 1 ear were enrolled. Both fresh and recurrent cases (without complications like mastoiditis) were included. Eligible patients were not on any other antibiotic therapy when enrolled in the study. The study excluded the patients with appearance and history more suggestive of chronic otitis media with effusion, ventilation tube, perforated tympanic membrane, and chronic suppurative otitis media; serious chronic disease (for example, cystic fibrosis, valvular heart disease); previous complications (septic complications, hearing impairment); children with complicated AOM (eg. mastoiditis), facial abnormalities, that would confound evaluation of the therapeutic response; known severe renal disease; patients hypersensitive/contraindicated to study drug. Study procedure Either cefaclor 20 mg/kg 40-mg/kg per day in 3 divided doses for 10 days (cefaclor arm) or Amoxycillin + clavulanate 45mg/kg every 12hrly or 40mg/kg every 8hrly for 10 days (amoxycillin arm) was administered to those patients fulfilling the inclusion criteria of the study. No topical aural antibacterial within 2 days before the study or any systemic antibacterial within 2 days before the study or during the study were allowed. Before initiating the antibiotic therapy, the ear canal was cleansed with an antibiotic and tympanocentesis was performed in order to obtain middle ear fluid for isolation of bacterial pathogens as well as determination of antibiotic susceptibilities. From the first day upto the end of therapy (on 10 th day) the patients were evaluated. Wherever possible, tympanocentesis was repeated if there was no clinical improvement after 72 hour of treatment or as clinically indicated. Patients requiring antacids containing aluminium and magnesium salts were administered 8 hours before or after cefaclor/amoxy-clav administration. If the symptoms were not controlled or worsened, additional medications could be given depending at the discretion of the investigator and this rescue medication was recorded in the CRF. Patients were considered to be compliant with the study medication if at least 80% of study medications were taken according to the prescribed regimen (as judged by the investigator by asking questions to the patient and/or their parents/guardian. Otherwise patient was considered to be normal. Evaluation Visits After keen observation of the patient the physician recorded for adherence to therapy, any adverse drug reactions and the clinical response on the following days: Visit 0: Day 0 (inclusion w.r.t. eligibility criteria) Visit 1: Day 1, start of study medications Visit 2: Day 10, end of therapy. In order to assess the tympanic membrane for severity of erythema, opacification, loss of light reflex, fullness or bulging, drainage, perforation, mobility and middle ear effusion autopsy was performed at each visit. Tympanometry was interpreted to confirm the presence (abnormal) or absence (normal) of middle ear effusion. At each visit symptoms of otalgia, irritability, anorexia, lethargy, decreased hearing, vertigo and fever were assessed. For any complications patients were also monitored. Efficacy Assessment Primary outcome measures were listed as follows 1. At the end of the therapy clinical resolution of tympanic membrane (otoscopic) signs and symptoms of AOM determined. 2. No. of cases in which change of antibiotics was needed 3. Physician Global Evaluation of patient condition (using a 5-point scale) 1=Excellent, 2=Very Good, 3 = Good, 4= Fair, 5 =Poor 4. Clinical Outcome was defined as follows: Clinical Cure: Defined as absence of fever, otalgia, 234 Indian Journal of Pediatrics, Volume 72 March, 2005

3 Comparative Efficacy and Safety Evaluation of Cefaclor vs Amoxycillin + Clavulanate irritability and otoscopic signs of AOM for patients who did not require additional antibiotics, regardless of the presence of residual middle ear effusion. Improved: If clinical signs and symptoms including otoscopic findings diminished but did not completely resolve i.e persistence of otitis media with effusion. Relapse/Recurrence: Reappearance of signs and symptoms during treatment. Failure: Unsatisfactory remission of tympanic membrane signs or symptoms of AOM requiring additional antimicrobial therapy. 5. Bacteriological Outcome was defined as follows : Cure: Pathogen eradicated from post treatment cultures. Presumed Cure: No subsequent culture but no signs or symptoms of acute infection with or without persistence of middle ear effusion. Cure with Reinfection: New pathogen isolated following cure, requiring continued or alternate therapy. Failure: No clearance of initial pathogen following > 3 days of treatment. Recurrence: eradication and then reisolation of initial pathogen). Safety Assessment After the close observation of the patients the severity of clinically adverse events was categorized by the investigators as mild, moderate or severe. It is also classified the relationship of adverse events to the study drugs as either certainly, probably, or possibly drug related; not drug related; or with an unknown relationship to the study drug. Global assessment of overall tolerability was also recorded on a 5-point scale (1=excellent, 2 =very good, 3=good, 4=fair, 5=poor). Statistical Analysis Symptom assessment was done with actual patient numbers. Age is presented as mean + SD. Rest of the data is presented as percentages. Comparison of signs and symptoms of disease before and after therapy and comparisons between the two groups was done by Paired t-test. The limit of significance was set at p value < RESULTS Patient Characteristics One hundred and sixty seven patients were evaluated for efficacy endpoints in the cefaclor arm comprised of 104 males and 63 females with a mean age of 5.74±2.80 years and 185 patients in the amoxy-clav group comprised of 118 males and 67 females with a mean age of 4.93±2.92 years (Table 1). These excluded those sixteen patients in the cefaclor group and twenty one patients in the amoxy+ clavulanate group who were dropped from the study mostly because of lost to follow up. All children had one or more pretreatment symptoms of AOM; the most frequent were earache, irritability, lethargy), infection and exudation. In most children the severity of symptoms was classified as moderate. All children had one or more abnormal otoscopy findings; the most frequent were bulging tympanic membrane, erythema and loss of light reflex. Many children also had signs of systemic infection: cough, vomiting and diarrhea and fever. TABLE 1. Demographic Profile and Baseline Characteristics of Patients Evaluated for Efficacy end Points and Safety Profile. Amoxy+ Clav Group Total Patients Male Female Male Female Mean Age (Years) 5.74± ± 2.92 Overall Clinical Response Both cefaclor and amoxy-clav caused a significant improvement in all the signs and symptoms after a 10-day treatment period (Table 2). However, between-the-group comparisons showed that the reduction in most of the symptoms was significantly more in cefaclor arm as compared to amoxicillin-clav arm (Table 2). The percentage decrease in signs and symptoms at the end of therapy in the two treatment groups is shown in Fig 1. The clinical success (clinical cure + improvement) at the end of therapy was significantly more in cefaclor arm: 98% with cefaclor versus 85% with amoxicillin+clav, p<0.05 (Table 3). Failure cases were prescribed other antibiotics according to the culture sensitivity reports, as rescue medication. Bacteriological Outcome Pretreatment pathogens were isolated from 233 (70%) patients. The most common pathogens isolated were S. pneumoniae, H. influenzae and M. catarrhalis. Bacterial eradication rates were largely consistent with clinical responses. Bacteriological eradication was seen in 95% of patients in cefaclor group and 78% of patients in amoxicillin+clav group (Table 3). Global Assessment 94% physicians rated treatment with cefaclor as excellent to good versus 80% with amoxicillin+clav (Fig. 2) Adverse Effect Profile Table 4 summarizes the drug-related adverse events. Gastrointestinal side effects were the only adverse events reported, and were significantly more in amoxy-clav group compared to cefaclor. Most of the adverse effects were mild and self-limiting in nature. None of the patients withdrew from the study due to these adverse events. At the end of the study overall tolerability of study medications was assessed by the physicians. 95% rated the tolerability of cefaclor as excellent to good versus 72% Indian Journal of Pediatrics, Volume 72 March,

4 Mukesh Aggarwal et al TABLE 2. Comparison of Change in Symptom Scores in the Two Groups Amoxy + Clav Group % Change p-value* % Change p-value* Symptoms Earache/Otalgia % p< % a p<0.001 Irritability % p< % b p<0.001 Lethargy % p< % a p<0.001 Infection % p< % b p<0.001 Exudation -85.6% p< % a p<0.001 Tympanic Membrane Signs Bulging (Otoscopy) % p< % a p<0.001 Erythema % p< % b p<0.001 Loss Of Light Reflex % p< % c p<0.001 Systemic Infection Presence of Cough, Vomiting & Diarrhea % p< % b p<0.001 Fever -90% p< % a p<0.001 *p value is compared to baseline value. a p < 0.001, comparison between two drugs b p < 0.05, comparison between two drugs c p < 0.01, comparison between two drugs TABLE 3. Clinical and Bacteriological Outcomes in the Two Groups Amoxy+Clav. Group Clinical outcome Cure 96.6% 80% Improvement 2.4% 5% Failure 1% 15% Bacteriological outcome Cure/ Presumed Cure 95% 78% Failure/ Presumed failure 5% 16% Recurrence 0% 6% of amoxy-clav. Similarly, 93% of the patients rated tolerability of cefaclor as excellent to good versus 68% in amoxy-clav group. (Figs. 3 and 4) DISCUSSION A common medical problem like acute otitis media is also very familiar to pediatricians who attend children with this condition on a regular basis and to children s caretakers, whose normal routine is so often disrupted as a result. Adequate treatment on time is desirable in order to relieve the child s immediate discomfort. Likelihood of long-term sequelae, such as hearing loss or permanent middle ear damage should be lessened with the help of an effective antibacterial treatment in AOM. 7 Factors influencing the successful management of acute otitis media, include the knowledge of the etiological organisms, primarily S. pneumoniae, H. influenzae and M. catarrhalis and their particular susceptibilities to antimicrobial agents. 8 Due to the increasing isolates with β-lactamase-producing capability, use of amoxicillin and ampicillin has decreased in favor of drugs with greater β-lactamase stability. Thus, the oral cephalosporins cefaclor and oral third generation TABLE 4. Number of Patients with Most Frequently Reported Adverse Events in Each Group Adverse event Cefaclor group Amoxy + Clav group Diarrhea 3 20* Nausea 1 9* Vomiting 1 9* Bloating 1 3 P < 0.05, comparison between two groups cephalosporins, as well as amoxicillin/clavulanate and cotrimoxazole are now frequently prescribed. 4,5 Cefaclor is an oral cepahalosporin with good antibacterial activity against these common pathogens involved in acute otitis media. Its efficacy has been seen to be similar to cefuroxime axetil and azithromycin. 9,10 Cefaclor is effective in vitro against the organism most commonly associated with the otitis media including S. pneumoniae and β-lactamase-positive and negative strains of H. influenzae. This multicenter study reveals that cefaclor is an effective antimicrobial agent for acute AOM and its efficacy is significantly superior to that of the combination of amoxicillin+clav. There was a marked improvement in all the signs and symptoms associated with acute AOM over 10 days of the study. Clinical success was obtained in 98% of patients in cefaclor group versus 85% with amoxicillin+clav. The results of this study are in line with those of earlier multicentre, randomized, comparative clinical trials carried out to assess the efficacy of cefaclor in the treatment of children with acute and uncomplicated otitis media with effusion. Cefaclor produced a statistically higher response rate than amoxycillin (p=0.03) in a double-blind randomized clinical trial in 110 children suffering from acute AOM with effusion. 11 The most common pathogens isolated from patients in the present study were S. pneumoniae, H. influenzae and M. 236 Indian Journal of Pediatrics, Volume 72 March, 2005

5 Comparative Efficacy and Safety Evaluation of Cefaclor vs Amoxycillin + Clavulanate 0.00% % Change % % % Earache / Otalgia Irritability Lethargy Infection Exudation Bulging (Otoscopy) Erythema Loss Of Light Reflex Presence Of Cough, Vomiting & Diarrhea Fever Cefaclor Amoxy+Clav % % % Symptoms Fig. 1. Change in symptoms score in each group 60% 50% 50% cefaclor amoxy+clav % physicians 40% 30% 35% 33% 25% 20% 20% 18% 10% 11% 6% 0% 2% 0% Excellent Very good Good Fair Poor Grading of efficacy Fig 2. Global efficacy assessment by physicians 50.00% 39.90% 50.00% 29.20% 32.30% 33.80% 31.50% 37.70% 34.60% 25.00% 21.50% 16.50% 25.00% 23.80% 20.20% 19.80% 10.20% 11.80% 13.50% 11.90% 3.80% 5.80% 0.80% 0.00% Excellent Assessment Of Overall Tolerability Good Amoxy+Clav Group Poor 0.80% 0.00% Excellent Very Good Good Fair Poor Assessment Of Overall Tolerability Amoxy+Clav Group Fig 3. Analysis of Physicians Overall Tolerability of Drugs Fig. 4. Analysis of Patients Overall Tolerability of Drugs Indian Journal of Pediatrics, Volume 72 March,

6 Mukesh Aggarwal et al catarrhalis. Cefaclor eradicated pathogens in 95% of the patients compared to 78% in amoxy-clav group. The clinical effectiveness of cefaclor may be related to its excellent in vitro activity against a wide range of organisms. Its spectrum of activity is wider than that of cephalexin. Cefaclor was better tolerated by our study population compared to amoxicillin+clav. The side effects observed in both groups were of mild intensity and no patient withdrew from the study due to adverse events. CONCLUSION For acute otitis media in children, cefaclor is a well tolerated and effective antibacterial option. It is superior to the combination of amoxicillin+clav in efficacy and tolerability in acute AOM. Moreover, its expanded spectrum of activity, ability to achieve adequate concentrations in tissues, suitability for twice-daily dosing, and proven tolerability suggest that it is a good alternative to agents traditionally used in acute otitis media. REFERENCES 1. Dagan R. Can the choice of antibiotics for acute AOM be logical? Eur J Clin Microbiol Infect Dis 1998; 17: Parsons DS, Wald ER. Otitis media and sinusitis: similar diseases. Otolaryngol Clin North Am 1996; 29: Poole MD. Otitis media complications and treatment failures: implications of pneumococcal resistance. Pediatr Infect Dis J 1995; 14 : S Rodriguez WJ, Shwartz RH, Thorne MM. Increasing incidence of penicillin and ampicillin-resistant middle ear pathogens. Pediatr Inf Dis J 1995; 14 : Pichichero ME, Pichichero CL. Persistent acute otitis media: causative pathogens. Pedaitr Inf Dis J 1995; 14: Derry JE. Evaluation of cefaclor. Am J Hosp Pharm 1981; 38(1) : Bluestone CD, Klein JO, eds. Otitis Media in Infants and Children. WB Saunders Co., Philadelphia, Glebink GS. The microbiology of otitis media. Pedaitr Inf Dis 1989; 8 : S18-S Rodriguez AF. An open study to compare azithromycin with cefaclor in the treatment of children with acute otitis media. J Antimicrob Chemother 1996; 37 Suppl C : Turik MA, Johns D. Comparison of cefaclor and cefuroxime axetil in the treatment of acute AOM with effusion in children who failed amoxicillin therapy. J Chemother 1998; 10(4) : Indian Journal of Pediatrics, Volume 72 March, 2005