Srirupa Das, Associate Director, Medical Affairs, Tushar Fegade, Manager, Clinical Research Abbott Healthcare Private Limited, Mumbai.

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1 Indian Medical Gazette JUNE Comparative A Randomized, Open Label, Prospective, Comparative Evaluating the Efficacy and Safety of Fixed Dose Combination of Cefpodoxime 200 Mg + Clavulanic Acid 125 Mg Vs Cefpodoxime 200 Mg in Acute Bacterial Sinusitis Srirupa Das, Associate Director, Medical Affairs, Tushar Fegade, Manager, Clinical Research Abbott Healthcare Private Limited, Mumbai. Abstract Background: Fixed dose combination of cefpodoximeclavulanic acid and cefpodoxime both are commonly used in the treatment acute bacterial sinusitis. However, comparative clinical studies between the fixed dose combination of cefpodoxime-clavulanic acid versus cefpodoxime alone are not available. Objective: A postmarketing study was conducted to evaluate the efficacy and safety of fixed dose combination of cefpodoxime proxetil plus potassium clavulonate versus cefpodoxime proxetil in treatment of acute bacterial sinusitis. Material and methods: A total of 202 patients were enrolled in an open label, randomized, parallel group, two arms multicentric study. Patients were treated either with fixed dose combination of cefpodoxime 200 mg plus clavulanic acid 125 mg or cefpodoxime 200 mg; both given as one tablet twice daily for ten days. The efficacy was evaluated at baseline, day three, day five and day ten while the safety was assessed at screening and day 10. Statistical analysis: Intention to treat population was used to analyse the safety results while efficacy was evaluated in per protocol population. Chi square test was used to evaluate the efficacy parameters on six point Likert scale, global evaluation of efficacy and safety by investigators and patients. Results: Cure rate was higher in study group (58.43%) compared to control group (46.81%), however, the difference was not significant. No significant difference was seen in improvement and failure rate in both the groups (p=0.288). On day 3, rhinorrhea was either cured or much improved in significantly higher number of patients receiving study drug compared to control group (p=0.038). Global assessment of efficacy by patients significantly higher number of patients had excellent efficacy in the study group compared to control group (p=0.035) while no significant difference was seen in global efficacy assessment done by investigators. No patient reported serious adverse event in either groups. Conclusion: Rhinorrhea in acute bacterial sinusitis is relieved earlier by the combination of cefpodoxime plus potassium clavulonate compared to cefpodoxime alone. Efficacy of the combination is perceived as excellent by significantly more number of patients compared to cefpodoxime alone. Both the study drugs are well tolerated by patients. Keywords acute sinusitis, cefpodoxime, potassium clavulonate Introduction Community acquired respiratory tract infections like sinusitis are one of the most common reasons for the visiting physicians. The most important bacteria responsible for causing acute sinusitis are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. It is difficult to establish the causative microorganism Address for correspondence: Mr. Tushar Fegade. Manager, Clinical Research, Medical Services Division, Abbott Healthcare Private Limited, Mumbai. tushar.fegade@abbott.com

2 226 Indian Medical Gazette JUNE 2015 responsible for acute bacterial sinusitis. Examination of infected fluid by sinus puncture is a painful method and not routinely done in clinical practice. Hence empirical treatment is usually selected based on the suspected bacterial aetiology. While selecting an antibiotic different parameters are considered including most likely pathogen, local pattern of antibiotic resistance, and pharmacological properties of the antibiotic 1. The increasing prevalence of antibiotic resistance is one of the major challenges worldwide 2. Increasing bacterial resistance has led to concerns about the current options for the empirical antibiotic use 1. Cefpodoxime proxetil is a third generation cephalosporin. It has activity against both gram positive and gram negative microorganisms 3. Cefpodoxime has shown good in vitro activity against respiratory pathogens like Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis 1. Cefpodoxime is most widely used in the treatment of respiratory tract infections 4. In clinical trials cefpodoxime proxetil is as effective as amoxicillin in the treatment of acute bacterial maxillary sinusitis 5. It is more effective than cefaclor in producing complete clinical cure in acute sinusitis 6. Cefpodoxime is useful in infections caused by bacteria resistant to penicillins and cephalosporins. However, resistance has been reported against cefpodoxime through beta-lactamase production 7. Clavulanic acid is a beta lactamase inhibitor which enhances activity of penicillin and cephalosporins against many resistant strains of bacteria 3. Clavulanic acid is an effective irreversible inhibitor of beta-lactamases of the Richmond types II, III, IV, and V 8. Potassium clavulanate is a beta lactamase inhibitor combined with cefpodoxime proxetil to overcome the betalactamase mediated bacterial resistance. Fixed dose combination (FDC) of cefpodoxime proxetil with potassium clavulanate is available and marketed in India. Objective The objective of this post-marketing (PMS) phase IV study was to evaluate the efficacy and safety of fixed dose combination of cefpodoxime proxetil 200 mg plus potassium clavulanate 125 mg vs cefpodoxime proxetil 200 mg in treatment of patients with acute bacterial sinusitis. Material and methods In this randomized, open label, comparative, parallel group, two arms, multicentric study adult patients (>18 years of age) of both sex suffering from acute bacterial sinusitis as evidenced by the symptoms of fever, headache, cough, nasal congestion, facial pain or tenderness or radiographic evidence were enrolled. Patients with chronic sinusitis (symptoms for > 4 weeks or >2 other episodes of acute sinusitis within previous 12 months), patients with a known allergy to any of ingredients of investigational product and/or comparator product, those requiring tranquilizers, having history of sinus surgery, cholestatic jaundice or hepatic dysfunction, epilepsy or seizures, requiring systemic antimicrobial agents therapy within 48 hrs of study entry were excluded from the study. Pregnant, lactating women and immunocompromized patients were also not included in the study. After satisfying inclusion and exclusion criteria and obtaining their written informed consent the patients were enrolled in the trial. The study was conducted in compliance with the ICMR guidelines for research on humans, declaration of Helsinki and Schedule-Y of drugs & cosmetics act (Jan 2005). The patients were allocated treatment to either of the two arms (study group or control group) as per predetermined randomization schedule. The patients in study group received fixed dose combination of cefpodoxime 200 mg plus clavulanic acid 125 mg, one tablet twice daily while the patients in control group received only cefpodoxime 200 mg, one tablet twice daily. The duration of treatment in both groups was ten days. Evaluation criteria: The primary end point of the study was clinical success rate at the End-of-Therapy (EOT) based on resolution of signs and symptoms observed on study entry. Clinical success was defined as cure plus improvement. Cure was defined as resolution of signs and symptoms to the level that existed prior to the occurrence of the acute illness with no worsening in the radiographic appearance of the sinuses and without requirement of antibiotics (other than the study drug) given for treatment of sinusitis while the improvement was defined as partial but incomplete resolution of the signs and symptoms of acute sinusitis and no requirement for additional antibiotic use. Failure was defined as persistence of one or more signs or symptoms of ABS or appearance of new signs or symptoms and/or a need for additional antimicrobials or change in antimicrobial therapy.

3 Indian Medical Gazette JUNE Clinical response of signs and symptoms was graded on four point scale (0-cured, 1- improved, 2-same and 3- worse). Signs and symptoms of acute bacterial sinusitis at each follow-up visit (Day 3, Day 5 and Day 10) were graded on 6 point Likert scale ( 1-cured, 2- much improved, 3-slightly improved, 4-same, 5-slightly worse and 6-much worse ). Efficacy was also measured by clinical success rates based on the global assessment of the clinical presentation of the subject made by the investigator as well as patient at the end of treatment on five point scale (excellent, very good, good, satisfactory and poor). Secondary end points included percentage of patients with resolution of sinusitis signs and symptoms at the EOT visit and incidence of treatment-emergent adverse events and changes in physical findings including vital signs from baseline through the end of therapy visit. The enrolled patients were followed up for assessing signs and symptoms i.e. efficacy parameters of acute bacterial sinusitis at baseline, day three, day five and day ten (End of therapy visit). The safety parameters were assessed at screening and day ten. Global assessment for efficacy and tolerability by investigator and patient was also assessed at day ten. Statistical analysis The safety evaluation was done in the Intention-to-treat (ITT) population. The ITT population included all patients who have taken at least one dose of study medication while efficacy was assessed in per protocol population i.e. those patients who completed the study. Paired t-test was performed to analyze the statistical significance between two groups for vital signs and other baseline parameters. Chi square test was used to evaluate the efficacy parameters on six point Likert scale and global evaluation of efficacy and safety by investigators and patients. A p value <0.05 was considered statistically significant. Results A total of 202 patients (100-study group; 102-control) from 8 centres were enrolled in the study out of which 183 patients completed the study. The reasons for noncompletion of 19 patients were loss to follow up (study group: 8, control: 6), request for withdrawal from study (study group and control 1each) and poor response (study group: 2, control: 1). Baseline characteristics: At baseline all the parameters were similar in both groups (p>0.05) (Table 1). There was no significant difference in vital parameters (pulse rate, systolic and diastolic blood pressure and temperature) and symptoms in both groups (Table 2) (t test p>0.05). Table 1 Baseline characteristics N Male 57 (57%) 56 (54.9%) Female 43 (43%) 46 (45.15%) Mean age (yrs) 31.9 (±12.1) 33.4 (±12.1) Mean weight (kg) 59.8 (±10.7) 59.3 (±11.7) Mean height (cm) (±8.9) (±9.7) Table 2 Baseline symptoms (n=100) (n=102) Subjective fever 2.94 (±3.24) 2.54 (±3.10) Nasal congestion 4.93 (±2.80) 5.00 (± 2.71) Headache 5.36 (±2.52) 5.12 (±2.77) Sinus pain 3.78 (±3.07) 3.64 (±2.95) Rhinorrhea 4.42 (±2.92) 4.14 (±2.88) Cough 3.60 (±3.07) 3.47 (±3.21) Maxillary toothache 0.85 (±2.26) 0.75 (±2.13) Energy level 1.95 (±2.52) 2.45 (±2.73) Difficulty sleeping 1.83 (±2.98) 2.37 (±3.30) Loss of appetite 1.41 (±2.63) 1.33 (±2.74) Efficacy Clinical response rate at the end of therapy i.e. at day ten is shown in the Fig. 1. Cure rate was numerically higher in study group compared to control group, however the difference was not significant. Similarly no significant difference was seen in improvement and failure rate in both the groups (chi square test p=0.288). On day 3, rhinorrhea was either cured or much

4 228 Indian Medical Gazette JUNE % 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% Fig. 1 Clinical response rate (study group n=89; control group n=94) 58.43% 46.81% 37.08% 47.87% 4.49% 5.32% Cure Improvement Failure group group improved in significantly higher number of patients receiving study drug compared to control group (p=0.038). No significant difference was seen in any other symptom improvement on day three and day five (p>0.05) (Tables 3 and 4). On tenth day i.e. at the end of treatment, proportions of patients with resolution of most of the signs and symptoms were higher in study group compared with control group. However, the difference was not significant. There was trend of large number of patients showing improvement in headache with study drugs compared to control group (p=0.057) (Table 5). There was no significant difference in global assessment of efficacy between two groups as assessed by investigator (chi square test p=0.090; Fig. 2) % 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% Fig. 2 Global assessment of efficacy by investigator 33.71% Excellent 22.83% 34.78% 29.21% Very good group 16.85% Good 29.35% 15.73% Satisfactory 7.61% group 5.43% 4.49% Poor Table 3 Improvement in symptoms at day three Subjective fever Nasal congestion Headache Rhinorrhea Cough Cured % Much improved % Slightly improved % Same % Slightly worse % Much worse % P value

5 Indian Medical Gazette JUNE Table 4 Improvement in symptoms at day five Subjective fever Nasal congestion Headache Rhinorrhea Cough Table 5 Resolution of signs and symptoms on day ten Symptom group group Chi square test (p vale) Subjective fever 96.63% 97.87% Nasal congestion 65.17% 54.26% Headache 67.42% 61.70% Sinus pain 86.52% 79.79% Rhinorrhea 69.66% 60.64% Cough 70.79% 58.51% Maxillary toothache 92.13% 92.55% Energy level 67.42% 60.64% Difficulty sleeping 83.15% 84.04% Loss of appetite 82.02% 81.91% Cured % Much improved % Slightly improved % Same % Slightly worse % Much worse % P value Global assessment of efficacy by patients significantly higher number of patients had excellent efficacy in the study group compared to control group (chi square test p=0.035; Fig. 3). Safety assessment: A total of 8. 9% patients (study group 7% and control group 1.9%) reported adverse events (study group n=100; control group n=102). All the adverse events were mild in nature except one adverse event of moderate intensity in both groups (diarrhea in study group; vomiting in control group). No serious adverse events were reported by any of the patients during the study period. No significant difference was seen in the global assessment of tolerability evaluated by both an investigator (chi square test p=0.535) and patient (chi square test p=0.965) (Table 6). Discussion In primary care clinic, antibiotics are prescribed in about 85% to 98% of cases presenting with acute sinusitis 9. Generally antibiotics in acute sinusitis should be prescribed for ten to 14 days, or seven days after the patient is symptom free 10. In this study, cefpodoxime plus potassium clavulanate as well as cefpodoxime were given for ten days.

6 230 Indian Medical Gazette JUNE 2015 group Table 6 Global assessment of tolerability Investigator group (n=93) group Patient group (n=93) Good 97.75% 98.92% 97.75% 97.85% Moderate 2.25% 1.08% 2.25% 2.15% Poor % 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% Fig. 3 Global assessment of efficacy by patient 32.58% Excellent 19.35% 36.56% 28.09% Very good group 16.85% Good 29.03% 17.98% Satisfactory 8.60% group 6.45% 4.49% Fixed dose combination of cefpodoxime proxetil 200 mg and potassium clavulanate 125 mg has showed higher clinical cure and improvement in the symptoms of lower respiratory tract infections compared to cefuroxime axetil 500 mg 2. However, there are no clinical studies comparing cefpodoxime plus potassium clavulanate versus cefpodoxime in acute bacterial sinusitis. On most of the efficacy and safety parameters cefpodoxime proxetil plus potassium clavulanate was found to be comparable to cefpodoxime proxetil alone. Though the significant difference was not seen, the cure rate was higher in patients who received cefpodoxime proxetil plus potassium clavulanate compared to control Poor group. Overall there was no significant difference in cure rate, improvement and failure rate in both the groups. Rhinorrhea is a bothersome symptom for the patients. Significantly higher number of patients receiving cefpodoxime proxetil plus potassium clavulanate showed improvement in rhinorrhea on day three compared to cefpodoxime alone (Table 3). Similarly, at the end of therapy visit, number of patients with resolution of nasal congestion, sinus pain, headache, cough and energy level with cefpodoxime proxetil plus potassium clavulanate were higher, compared to cefpodoxime alone (Table 5). However, the difference was not statistically significant. Patient satisfaction is important in any treatment for improved compliance and in turn better outcome. In this study, significantly higher number of patients had expressed the combination to be excellent in efficacy compared to cefpodoxime proxetil monotherapy. Tolerability of both the formulations was good. No patient reported serious adverse event in either groups. Open label study design and subjective evaluation of improvement are the limitations of this study. Larger studies are required to confirm the findings of our observation. Conclusion Rhinorrhea in acute sinusitis is relieved earlier by the combination of cefpodoxime plus potassium clavulonate compared to cefpodoxime alone. Efficacy of the combination is excellent as evaluated by significantly more number of patients compared to cefpodoxime alone. On other parameters of efficacy and safety, the combination is comparable to cefpodoxime monotherapy. Acknowledgement The authors thank all investigators for their contribution,

7 Indian Medical Gazette JUNE Dr. Deepak Langde for statistical analysis and Dr. Anant Patil for assistance in writing the manuscript. References 1. Cohen R. Clinical efficacy of cefpodoxime in respiratory tract infection. Journal of Antimicrobial Chemotherapy. 50; T1: 23-27, Awad N.T. Efficacy and Safety of Fixed Dose Combination of Cefpodoxime Proxetil and Potassium Clavulanate (Cefchamp) in Comparison with Cefuroxime Axetil in Patients with Lower Respiratory Tract Infections. Indian Medical Gazette , April Malathi S., Dubey R.N. and Venkarnarayanan R. Simultaneous RP-HPLC estimation of cefpodoxime proxetil and clavulonic acid in tablets. Indian J. of Pharm. Sci. 71; 1: , Todd W.M. Cefpodoxime proxetil: a comprehensive review. International Journal of Antimicrobial Agents. 4;1: 37-62, March Sydow C.V., Savolainen S., Soderqvist A. Treatment of Acute Maxillary Sinusitis Comparing Cefpodoxime Proxetil with Amoxicillin. Scandinavian Journal of Infectious Diseases. 27; 3: , Gehanno P., Depondt J., Barry B., Simonet M., Dewever H. Comparison of cefpodoxime proxetil with cefaclor in the treatment of sinusitis. J. Antimicrob. Chemother. 26 (suppl E): 87-91, Pennan M. Barry, Jeffrey D. Klausner. The use of cephalosporins for gonorrhea: The impending problem of resistance. Expert OpinPharmacother. 10(4): , March Neu H.C., Fu K.P. Clavulanic Acid, a Novel Inhibitor of f3-lactamases. Antimicrobial Agents and Chemotherapy. 14;5: , Nov Anon J.B., Jacobs M.R., Poole M.D., et al. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg. 130(Suppl 1):S1 45, Leung R.S., Katial R. The Diagnosis and Management of Acute and Chronic Sinusitis. Prim Care Clin Office Pract. 35: 11 24, 2008.