Effect of Chlorhexidine Gluconate and Benzydamine Hydrochloride Mouth Spray on Clinical Signs and Quality of Life of Patients with Streptococcal Tonsillopharyngitis: Multicentre, Prospective, Randomised, Double-blinded, Placebo-controlled Study

Cingi C. , Songu, M. , Ural A. , Erdogmus N. , Yildirim M. , Cakli H Cingi C., Songu, M., Ural A., Erdogmus N., Yildirim M., Cakli H., and Bal C. The Journal of Laryngology and Otology February 11, 2011 Prepared by: Dr. Wilmark N. Gular

Streptococcal Pharyngitis There are 11 million cases of pharyngitis in the U.S. in a year. S. pyogenes is the cause of pharyngitis in 15–30% of cases in children and 5–20% in adults. 1 15% of school-age children in developed countries will have strep throat each year, while those in developing countries may have five to ten times that number. 2 1 Choby B. A. Diagnosis and Treatment of Streptococcal pharyngitis. American Family Physician. 2009. 2 Carapetis J. R., Steer A. C., Mulholland E. K., Weber M. Te global burden of group A streptococcal infections. The Lancet Infectious Diseases. 2005

Signs and Symptoms of Strep Throat Abrupt onset of: Fever Malaise Sore throat Pain with swallowing Swollen anterior cervical lymph nodes Erythema and edema of the posterior pharynx and the tonsils, sometimes with an exudate Wessels, M. Pharyngitis and Scarlet Fever. Streptococcus pyogenes. February 10, 2016. Image from: https://nutraceuticalasia.com/2017/05/23/sore-throat-or- strep-throat-how-to-tell-the-difference/

Diagnosis of Streptococcal Tonsillopharyngitis Gold standard is a throat swab culture Rapid antigen detection for group A streptococcus is quicker and results are reliable . 1 1 Cingi C., et al. Effect of Chlorhexidine Gluconate and Benzydamine Hydrochloride Mouth Spray on Clinical Signs and Quality of Life of Patients with Streptococcal Tonsillopharyngitis: Multicentre, Prospective, Randomised, Double- blinded, Placebo-controlled Study. The Journal of Laryngology and Otology. February 11, 2011 Image from: https://accubiotech.en.ecplaza.net/products/rapid-strep-a- test_1360056

How to Manage Streptococcal Tonsillopharyngitis Strep throat warrants antibiotic treatment. Pain medications and steroid may be needed. Lozenges containing flurbiprofen, an analgesic, alleviates symptoms of pharyngitis. 1 An ectoine mouth and throat spray is effective against acute pharyngitis and laryngitis. 2 1 Shephard A. et al. Randomized, Double-blind, Placebo-controlled Studies on Flurbiprofen 8.75 mg Lozenges in Patients with/without Group A or C Streptococcal Throat Infection, with an Assessment of Clinician’s Prediction of ‘Strep throat’ Int. Journal of Clinical Practice. Jan 2015 2 Muller D, et al. Efficacy and Tolerability of an Ectoine Mouth and Throat Spray Compared with those of Saline Lozenges in the Treatment of Acute Pharyngitis and/or Laryngitis: A Prospective, Controlled, Observationall Clinical trial. April 2016.

RELEVANCE Chlorhexidine gluconate is broad spectrum antimicrobial agent used as a topical antiseptic. Benzydamine hydrochloride ,on the other hand, is an anti-inflammatory agent. There is a need to determine the efficacy of the combination of these medications as adjunct to antimicrobial treatment in GAS tonsillopharyngitis. At present, numerous pharmaceutical preparations (containing disinfectants, anti-inflammatory agents and/or topical anaesthetics) have been approved for the local treatment of acute pharyngitis.3 Our study assessed the effect of a mouth spray containing chlorhexidine gluconate and benzydamine hydrochloride.16 Benzydamine hydrochloride is an effective anti-inflammatory agent, while chlorhexidine gluconate is an antimicrobial agent frequently used for topical antiseptic effects. The effectiveness of chlorhexidine against gingivitis and recurrent oral mucosa ulceration has been shown in many studies.17,18 Chlorhexidine is effective against a wide variety of bacteria, including Gram-positives, Gram-negatives, aerobes and anaerobes.19 Chlorhexidine is effective against bacteria commonly found in the oral cavity, and against organisms associated with oral cavity disease.20–22 In addition to its in vitro antibacterial activity, studies have shown that chlorhexidine mouth rinse reduces the number of oral bacteria.23,24

OBJECTIVES To evaluate the effect of chlorhexidine gluconate and benzydamine hydrochloride mouth spray, in conjunction with antibiotic treatment, on the: intensity of clinical signs quality of life of patients with group A streptococcal (GAS) tonsillopharyngitis

METHODOLOGY This study has multicentre, prospective, randomised, double-blinded, placebo- controlled, parallel-group design. It lasted for 3 months (May to October 2009). It was done in the ENT clinics of three university hospitals and one tertiary hospital

METHODOLOGY The study patients had clinical signs of acute tonsillopharyngitis and tested positive for streptococcal A antigen.

METHODOLOGY 171 patients met the inclusion criteria and were randomized to receive one of two treatments: penicillin V plus active drug mouth spray penicillin V plus placebo mouth spray The active drug mouth spray contained chlorhexidine gluconate 0.12 % and benzydamine hydrochloride 0.15 %. Patients used their mouth spray 4x daily and were instructed to avoid taking any other medications for the relief of sore throat.

OUTCOME MEASURES The intensity of patients’ clinical signs before treatment and on the 7th day of treatment was assessed. The clinical signs included: sore throat erythema and edema of the posterior pharynx presence of exudate cervical lymphadenopathy headache Investigators assessed the intensity of patients’ clinical signs prior to treatment and on the seventh day of treatment. The assessed clinical signs comprised included sore throat, erythema and oedema of the posterior pharynx, exudate, cervical lymphadenopathy, and headache. These were graded on a four-point scale (with 0 = absent, 1 = mild, 2 = moderate and 3 = severe), and an overall clinical sign score was generated. Investigators were provided with reference guidelines to aid their classification of clinical sign intensity

OUTCOME MEASURES Patients were asked to subjectively assess their health state using a 10 cm visual analogue scale (VAS). Patients also completed the Short Form 36 (SF36) Health Questionnaire, a quality of life scoring system. Patients used a customized questionnaire to assess any side effects of treatment. Patients were asked to subjectively assess their health state using a 10 cm visual analogue scale (VAS) graded from zero (representing ‘the best imaginable health state’) to 10 (‘the worst imaginable health state’).6 Patients completed a VAS before treatment and on the third and seventh days of treatment. This information was used as a quantitative measure of patients’ individual, subjective health outcome. Patients completed the Short Form 36 Health Questionnaire before treatment and on the seventh day of treatment. This questionnaire (comprising a short form with 36 questions) is a well documented, self-administered, simple, standardised quality-of-life scoring system which has been widely used and validated.7,8 The questionnaire contains eight independent scales summarised into two ‘dimensions’: the physical health dimension and the mental health dimension. Each dimension includes three specific and two overlapping scales. The questionnaire also includes a question on self-evaluated change in health during the past year (‘reported health’); this question is scored independently. Scores for the two dimensions, and the total score, are based on mathematical averaging of scale component scores.

CLINICAL SIGNS INTENSITY SCORES At the end of the treatment period, there was a significant difference in clinical sign intensity scores between the intervention and control groups (p < 0.001). The reduction in intensity of clinical signs was significantly greater in the treatment group than in the control group . Prior to treatment, there was no significant difference in patients’ clinical sign intensity scores, comparing the treatment and control groups (p = 0.403). At the end of the treatment period, however, there was a significant difference in clinical sign intensity scores between these two groups (p < 0.001) Clinical sign scores significantly reduced over time in both the treatment and control groups (p < 0.001 for both). However, this reduction was significantly greater in the treatment group than in the control group (p < 0.001; Figure 1)

VISUAL ANALOG SCORES (VAS) A significant difference in VAS was seen between the treatment and controls groups, on both the 3rd and 7th days of treatment. Following treatment initiation, a significant difference in VAS scores was seen between the treatment and controls groups, on both the third and seventh days of treatment (p < 0.001 and p < 0.001, respectively)

SHORT FORM 36 HEALTH QUESTIONNAIRE Analysis of SF36 score on the 7th day of treatment revealed no statistically significant difference between the two groups. A significant improvement in quality-of life scores was seen over time in both groups. Analysis of Short Form 36 Health Questionnaire quality-of-life scores on the seventh day of treatment revealed no statistically significant difference between treatment and control groups (p > 0.05; Table IV, Figure 3). A significant improvement in quality-oflife scores was seen over time in both the treatment and control groups (p < 0.001 for both).

SIDE EFFECTS Mild taste disturbance and mild to moderate oral mucosal numbness were the most frequent side effects reported by 28 of the 72 patients in the treatment group. The chlorhexidine– benzydamine mouth spray was generally very well tolerated, at the dosage administered, and no serious adverse events were observed. Analysis of side effects in the treatment and control groups revealed a statistically significant difference on the third day of treatment (p = 0.004) but no significant difference on the seventh day of treatment (p = 0.937) (Figure 4). Mild taste disturbance and mild to moderate oral mucosal numbness were the most frequent side effects, being reported by 28 of the 72 patients in the treatment group.

RECOMMENDATIONS Chlorhexidine–benzydamine mouth spray represent a safer and cheaper form of analgesia for those who cannot tolerate non-steroidal anti- inflammatory drugs. This has to be explored further. Further research is warranted to fully assess the efficacy of chlorhexidine–benzydamine mouth spray in treating GAS tonsillopharyngitis, using larger sample sizes or alternative control groups.

CONCLUSION Chlorhexidine gluconate and benzydamine hydrochloride mouth spray significantly decreased the intensity of clinical signs in patients with streptococcal pharyngitis when used , in conjunction with standard antibiotic treatment.

REFERENCES Choby B. A. Diagnosis and Treatment of Streptococcal pharyngitis. American Family Physician. 2009. Carapetis J. R., Steer A. C., Mulholland E. K., Weber M. Te global burden of group A streptococcal infections. The Lancet Infectious Diseases. 2005. Wessels, M. Pharyngitis and Scarlet Fever. Streptococcus pyogenes. February 10, 2016. Cingi C., et al. Effect of Chlorhexidine Gluconate and Benzydamine Hydrochloride Mouth Spray on Clinical Signs and Quality of Life of Patients with Streptococcal Tonsillopharyngitis: Multicentre, Prospective, Randomised, Double-blinded, Placebo-controlled Study. The Journal of Laryngology and Otology. February 11, 2011. 1 Shephard A. et al. Randomized, Double-blind, Placebo-controlled Studies on Flurbiprofen 8.75 mg Lozenges in Patients with/without Group A or C Streptococcal Throat Infection, with an Assessment of Clinician’s Prediction of ‘Strep throat’ Int. Journal of Clinical Practice. Jan 2015. 2 Muller D, et al. Efficacy and Tolerability of an Ectoine Mouth and Throat Spray Compared with those of Saline Lozenges in the Treatment of Acute Pharyngitis and/or Laryngitis: A Prospective, Controlled, Observationall Clinical trial. April 2016.

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