Clarithromycin versus penicillin in the treatment of streptococcal pharyngitis

Journal of Antimicrobial Chemotherapy (1991) 27, Suppl. A, 67-74 Clarithromycin versus penicillin in the treatment of streptococcal pharyngitis Joseph H. Levenstein* South Africa Academy of Family Practice, Medical House, Pinelands 7405, Capetown, South Africa The safety and efficacy of oral clarithromycin 250 mg every 12 h treatment and of oral penicillin VK (the potassium salt of phenoxymethylpenicillin) 250 mg every 6 h were compared in the treatment of streptococcal pharyngitis caused by Streptococcus pyogenes in an eight centre in-vivo study. A total of 243 patients were enrolled in the study and 125 patients were evaluated for efficacy; evaluable patients included 67 patients in the clarithromycin treatment group and 58 patients in the penicillin VK group. Both antibiotic regimens were effective in the treatment of streptococcal pharyngitis. The clinical rate during the initial post-treatment period (between two and ten days post-treatment) for the penicillin VK treated group was 98% (57/58) and for the clarithromycin treated group was 96% (64/67). The bacteriological rate during the initial post-treatment period for the penicillin VK treated group was 97% (56/58) and for the clarithromycin treated group was 100% (67/67). A total of 17 patients reported adverse events; seven patients were in the clarithromycin treatment group and ten patients in the penicillin VK treatment group. One patient in the penicillin VK group was withdrawn because of the severity of the adverse advent (balanitis). No clinically significant differences were reported between the two treatment groups for haematology, blood chemistry, or urinalysis evaluations. Oral clarithromycin 250 mg 12-hourly treatment was as safe and effective as penicillin VK 250 mg 6-hourly in the treatment of streptococcal pharyngitis. Introduction Clarithromycin, a new generation macrolide antibiotic identical in structure to erythromycin except for the substitution of the hydroxyl group in position six by a CH 3 O group in the erythromycin lactonic ring has proven active in vitro against a variety of Gram-positive organisms (Benson et ai, 1987a, b; Barry, Jones & Thornsberry, 1988). Studies also indicate that clarithromycin exhibits the clinical effectiveness of its predecessor, erythromycin, while providing improved pharmacokinetic profiles, including increased, more consistent serum levels of drug and an improved microbiological profile (Nilsen, 1987). This study compared the safety and efficacy of orally administered clarithromycin and penicillin VK (potassium salt of phenoxymethylpenicillin) in the treatment of outpatients diagnosed as having streptococcal pharyngitis caused by Streptococcus pyogenes. The dosage of penicillin VK used for the study was 250 mg orally ingested Present address: Department of Family and Community Medicine, Ul College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, Illinois 61107-1897, USA. 0305-7453/91/27A067 +08 $02.00/0 67 1991 The British Society for Antimicrobial Chemotherapy

68 J. H. Levenstein every 6h (1000 mg per day), the standard dosage normally used for streptococcal pharyngitis. The oral dosage for clarithromycin was 250 mg every 12 h (500 mg per day). Methods This randomized, double-blind multicentre, outpatient clinical study was conducted by eight investigators in Australia, Chile, South Africa and New Zealand between June 1986 and March 1989. The protocol was approved by local ethics committees and all patients gave informed consent. The study was conducted with male patients between the ages of 13 and 59. Eligibility criteria included: body weight of at least 50 kg; ability to swallow test capsules; presence of sore throat accompanied by at least one other sign of streptococcal pharyngitis (pharyngeal erythema/exudate, cervical lymph node tenderness, or fever), and a positive rapid immunoassay test for group A /J-haemolytic streptococcal (GABHS) antigen. Patients were excluded from the study if they had a history of hypersensitivity to erythromycin or penicillin, a previous course of therapy with clarithromycin or penicillin VK in this study, renal impairment or history of glomerulonephritis, a history of hepatic disease or liver enzyme elevation, a history of cardiac valvular disease, rash symptomatic of scarlet fever or a history of numerous allergies and/or asthma. Patients were instructed not to take any other antimicrobial agents during the study and all were assessed before the beginning of treatment. Patients were also assessed after five to seven days of antibiotic treatment; between two and ten days after treatment, and between 15 and 56 days after the treatment was finished. The majority of post-treatment evaluations occurred between two and ten days after treatment and 19 to 25 days after treatment. On day 1, patients were evaluated on their eligibility for inclusion in this study, and the following procedures were performed: recording of medical history, physical examination, eye examination, recording of vital signs and clinical assessment. Clinical assessment included recording the presence of sore throat, pharyngeal erythema/exudate, headache, abdominal pain, cervical lymph node tenderness, and fever (present if Ss 37-8 C). Upon study admission, the posterior pharynx and both tonsils, or tonsillar fossae, of the patient were firmly rubbed with two dacron swabs held together. One swab was immediately tested for the presence of GABHS antigen by a rapid immunoassay and the second throat swab was cultured for 5. pyogenes. Blood and urine samples were obtained on day 1 for haematology, chemistry, and urinalysis evaluations. Patients whose rapid immunoassay confirmed the presence of GABHS antigen were randomly assigned to treatment with either 250 mg of clarithromycin every 12 h or 250 mg of penicillin VK every 6 h. Treatment periods were between eight and ten days for patients with clarithromycin and between ten and 14 days for patients treated with penicillin VK. Subjects receiving penicillin VK were given 125 mg tablets placed inside capsules, while clarithromycin was supplied as 125 mg capsules. Each patient was given 40 unit-dose bottles, labelled in numerical sequence. Placebo capsules were added to the clarithromycin regimen and were taken as the second and last dose for each 24 h period to allow all study patients to ingest a capsule every 6 h. The clarithromycin, penicillin and placebo capsules were identical in appearance. After five to seven days of antibiotic treatment patients returned to the study centre for a repeat of the tests done on day 1 with the exclusion of the eye examination. Patient compliance with the dosage regimen was checked. Most patients were also

Treatment of streptococcal pharyngitis 69 given the same tests and dosage compliance check between two and ten days post-treatment. Patients who had received at least 30 doses of study capsules returned to the clinic after 15 to 56 days for post-treatment follow-up tests, including physical examination, clinical assessment, recording of vital signs, blood haematology and chemistry evaluations and urinalysis, and a throat swab for S. pyogenes culture. Patients were instructed to contact the investigator if any adverse event occurred. The severity of the event was rated either mild, where the event was usually transient and easily tolerated by the patient without need for special treatment, moderate, when the adverse event caused discomfort and interruption of usual activities and required symptomatic treatment, or severe, causing considerable interference with the patient's usual activities and might have been incapacitating and/or life threatening. The relationship of the adverse event to the study drug was rated as probable, possible, unlikely, undetermined or unknown, or no relationship. Patients were withdrawn from the study if therapy was ineffective, the patient requested withdrawal from the study, no susceptible S. pyogenes pathogen was isolated in the pretreatment bacterial culture, or for patient non-compliance. Efficacy of the two treatment regimens was assessed both clinically and bacteriologically. The patient's clinical response to therapy was recorded as clinical if the pretreatment signs and symptoms of pharyngitis were resolved, clinical improvement if symptoms improved but were not totally resolved, clinical failure if symptoms did not improve or worsened, or indeterminate where the clinical response could not be assigned because of therapy non-compliance or other reasons. The patient's bacteriological response was assessed as, failure, or indeterminate. If patients' pretreatment S. pyogenes was not cultured from any post-treatment throat swab culture, the response was recorded as. Failure was indicated when a positive throat culture for S. pyogenes was obtained during post-treatment assessments. An indeterminable bacteriological response was defined when the diagnosis could not be confirmed microbiologically, the patient did not complete the minimum course of therapy, other antibiotics were administered during therapy, or the required cultures were not obtained. Any subject prematurely discharged from treatment because this was ineffective had a culture taken with 48 h post-treatment and was evaluated by the above definitions. Concurrent medication use during the study was recorded for all patients. Statistical methods Statistical analyses were obtained from Statistical Analysis System Version 5.18 (SAS, 1985) Fisher's Exact test and other chi-squared tests were obtained from PROC FREQ and analysis of variance from PROC GLM. Each treatment group comparison was two-sided with a 005 confidence level of significance. In total, 243 patients were enrolled in the study, with 128 patients receiving clarithromycin and 115 patients receiving penicillin VK. Twenty-eight patients in both the clarithromycin (22%) and penicillin VK (24%) were prematurely discontinued from the study. Most were discontinued because no 5. pyogenes was cultured before treat- Results

70 J. H. Levenstein Table I. Patients excluded from all efficacy analysis Treatment group Reasons for patient exclusion: No S. pyogenes isolated before treatment No pretreatment susceptibility results No post-treatment culture: between 4 and 6 days post-treatment Between 19 and 25 days post-treatment Less than minimum therapy No susceptible pathogen isolated pretreatment Total Clarithromycin (250 mg, 12-hourly) 41 8 5 3 2 2 61 Penicillin VK (250 mg, 6-hourly) 41 8 5 2 4 1 61 Total ment, accounting for 19 withdrawals from the clarithromycin group (15%) and 21 from the penicillin VK group (18%). Other reasons for early withdrawal included patient non-compliance (three patients from the clarithromycin group, and one from the penicillin VK group) and treatment ineffective (two patients from the clarithromycin group), adverse event (one patient from the penicillin VK group), and four patients in each group were discontinued primarily because of lack of follow up information or concomitant bilharzia. Of the total 243 patients, 118 subjects were excluded from the efficacy statistics. Patients were excluded from the efficacy analysis primarily because of lack of isolation of the S. pyogenes pathogen in the pretreatment bacterial culture, resulting in 41 exclusions from both the clarithromycin group (32%) and the penicillin VK group (36%). Table I illustrates all reasons for patient exclusion from efficacy studies. Concurrent medication use during the study was reported by 33% (80/243) of the patients. Medications used included analgesics, antipyretics, non-steroidal anti-inflammatory/anti-rheumatics, antidepressants and antitussives without expectorants. One evaluable penicillin VK patient received concurrent systemic antibiotics for treatment of another illness between the patient's initial post-treatment (between two and ten days post-treatment) evaluation and final post-treatment (between 15 and 56 days posttreatment) evaluation. This patient's post-treatment cultures were excluded from bacterial response analyses. The remaining 125 evaluable patients ranged in age from 13 to 59 years old and included 67 patients in the clarithromycin group (three females and 64 males) and 57 82 16 10 5 6 3 122 Table II. Clinical response during initial post-treatment assessment (between two and ten days post-treatment) Treatment group Garithromycin Penicillin VK Cure 64/67 (96%) 57/58 (98%) Improved 3/67 (4%) 1/58 (2%) Indeterminate Failure The 90% confidence interval for the difference between clinical rates was ( 7-8, 2-3) and the confidence interval expressed as a ratio (per cent of reference) was (92-1, 102-3).

Treatment of streptococcal pharyngitis 71 patients (three females and 55 males) in the penicillin VK group. There were no statistically or clinically significant differences between the clarithromycin and penicillin VK treatment groups with respect to sex, age, race and weight distribution in both the original 243 study patients and in the 125 patients used in the efficacy evaluation. The favourable clinical response rates assessed during the initial post-treatment period for both clarithromycin and penicillin VK are shown in Table II. The clinical success rate ( or improved) assessed during the initial post-treatment period was 100% for both clarithromycin and penicillin VK. Table III describes the favourable patient bacteriological rate during the initial post-treatment period (between two and ten days post-treatment). In both the clarithromycin and penicillin VK treatment groups, one of the evaluable patients who returned for final post-treatment assessment (between 15 and 56 days post-treatment) showed a recurrence of 5. pyogenes. Table IV lists the final bacteriological rates for both clarithromycin and penicillin VK. Evaluation of the clinical symptoms response during the initial post-treatment assessment (between two and ten days post-treatment) indicated that for most of the symptoms, including sore throat, pharyngeal erythema/exudate, abdominal pain, cervical lymph node tenderness, headache, and fever, both clarithromycin and penicillin VK proved almost 100% effective. Table V summarizes clinical symptoms and responses for the initial post-treatment assessment period. During the final post-treatment period (between 15 and 56 days post-treatment) clinical symptom response remained unchanged for both treatment groups for abdominal pain, cervical lymph node tenderness and fever symptoms. One patient from each treatment group reported sore throat pain, two patients treated with clarithromycin and one patient treated with penicillin VK were assessed as having pharyngeal Table III. Bacteriological response during initial posttreatment assessment (between two and ten days post-treatment) Treatment group Cure Failure Clarithromycin 67/67 (100%) Penicillin VK 56/58 (97%) 2/58 (3%) The 90% confidence interval for the difference between rates was (-0-7, 6-7) and the confidence interval expressed as a ratio (per cent of reference) was (99-3, 106-9). Table IV. Bacteriological response during final posttreatment assessment (between 15 and 56 days post-treatment) Treatment group Cure Failure Clarithromycin 59/60 (98%) 1/60 (2%) Penicillin VK 52/53 (98%) 1/53 (2%) The 90% confidence interval for the difference between clinical rates was ( 7-8, 2-3) and the confidence interval expressed as a ratio (per cent of reference) was (92-1, 102-3).

72 J. H. Levenstein Table V. Clinical symptoms and initial post-treatment responses (approximately between two and ten days post-treatment) Symptoms and assessments Clarithromycin Penicillin VK Sore throat plus improvement Pharyngeal erythema/exudate plus improvement Cervical lymph node tenderness plus improvement Headache plus improvement Fever Abdominal pain 93% (62/67) 100% (67/67) 97% (65/67) 100% (67/67) 100% (43/43) 98% (53/54) 98% (53/54) 100% (33/33) 100% (6/6) 95% (54/57) 100% (56/57) 96% (55/57) 100% (56/57) 98% (42/43) 98% (42/43) 98% (42/43) 98% (42/43) 100% (30/30) 100% (11/11) 'One penicillin VK patient was excluded from data because initial clinical assessment was less than two days post-treatment. erythema and exudate, and the penicillin VK treatment group had 100% of headache symptoms. The safety evaluation for both drugs included all 243 patients who received at least one dose of either clarithromycin or penicillin VK. Seventeen patients reported at least one adverse event, including seven (6%) of the 128 clarithromycin patients and ten (9%) of the 115 penicillin VK patients. Altogether, 25 adverse events were recorded, with 17 reported from the penicillin VK group and eight from the clarithromycin group. Table VI describes all reported adverse events. None of the events reported in the clarithromycin group was considered to be severe. However, two events reported in the penicillin VK group (depression arid balanitis) were put in that category. It was considered that 12 of 17 events (71%) reported in the penicillin VK group and seven Table VI. Patients with adverse events (% of patients treated)" Body system Clarithromycin (/i=128) Penicillin VK (n= 115) Digestive Haemic and lymphatic Metabolic and nutritional Nervous system Skin and appendages Urogenital Total 3 (2%) 1 (1%) 2 (2%) 1 d%) 7 (6%) 1 (1%) 4 (4%) 4 (4%) 1 d%) 2 (2%) io (9%y Patients with more than one event within the same body system are counted only once for that body system. Two patients reported more than one adverse event.

Treatment of streptococcal pharyngitis 73 of eight events (88%) reported in the clarithromycin group to be probably or possibly related to the antibiotic administration. No deaths were reported during the study or within 30 days of study discontinuation. One penicillin VK patient was discontinued from the study after he developed severe pruriginous desquamating balanitis which was considered to be possibly related to penicillin VK treatment. Subgroup analysis showed that the majority of the adverse events in the clarithromycin group occurred in patients older than 36 years while the majority of the adverse events in the penicillin VK group occurred in patients between the ages of 21 and 36 years old. One clarithromycin patient exhibited a clinically significant elevation of prothrombin time from 12 sec upon study admission to 19-8 sec after six days of antibiotic treatment. The patient's prothrombin time was normal (10-5 sec) six days post-treatment. Three penicillin VK patients exhibited clinically significant elevation of chemistry values from study admission values. One patient had an elevated SGPT value which was normal (14 U/l) and rose to 136 U/l after four days of antibiotic treatment. No additional SGPT values were obtained for this patient. One patient exhibited an elevated bilirubin which rose from 13 /imol/1 to 74 jzmol/1 after seven days of antibiotic treatment and returned to normal (14/zmol/l) five days post-treatment. One patient exhibited an elevated BUN which increased from 4-2 mmol/1 to 8-7 mmol/1 after ten days of antibiotic treatment and was also elevated (8 mmol/1) ten days post-treatment. No clinically significant changes in vital sign values, urinalysis evaluations, or eye examinations were recorded for either patient group. All abnormalities sited in urinalysis evaluations were attributed to a patient's systemic infection or the presence of a urinary tract infection. Discussion Both oral clarithromycin 250 mg 12-hourly and penicillin VK 250 mg 6-hourly proved effective in treating streptococcal pharyngitis. Clarithromycin and penicillin VK treatment groups achieved favourable initial post-treatment (between two and ten days post-treatment) clinical rates (96% and 98%, respectively) and bacteriological rates (100% and 97%, respectively). Although more patients from the penicillin group reported adverse events than those in the clarithromycin group, the difference was not statistically significant. The main adverse events reported in the clarithromycin group were associated with the digestive system, while the majority of the penicillin group reported adverse events associated with the blood or lymphatic systems, biochemical abnormalities or nutritional system upsets. One penicillin VK patient was discontinued from the study because of severe balanitis and another patient in that group reported severe depression. No clarithromycin patients suffered severe adverse events. Both treatments were generally well tolerated in the patient population and oral clarithromycin 250 mg 12-hourly (500 mg per day) proved to be as safe and effective as the standard treatment, penicillin VK 250 mg 6-hourly (1000 mg per day) for the treatment of pharyngitis caused by S. pyogenes. References Barry, A. L., Jones, R. N. & Thornsberry, C. (1988). In vitro activities of azithromycin (CP 62,993), clarithromycin (A-56268; TE-031), erythromycin, roxithromycin, and clindamycin. Antimicrobial Agents and Chemotherapy 32, 752 4.

74 J. H. Levenstein Benson, C. A., Segreti, J., Beaudette, F. E., Hines, D. W., Goodman, L. J., Kaplan, R. L. el al. (1987a). In vitro activity of A-56268 (TW-031), a new macrolide, compared with that of erythromycin and clindamycin against selected Gram-positive and Gram-negative organisms. Antimicrobial Agents and Chemotherapy 31, 328-30. Benson, C. A., Segreti, J., Kessler, H., Hines, D., Goodman, L., Kaplan, R., et al. (19876). Comparative in vitro activity of A-56268 (TE-031) against Gram-positive and Gram-negative bacteria and Chlamydia trachomatis. European Journal of Clinical Microbiology 6, 173-8. Nilsen, O. (1987). Comparative pharmacokinetics of macrolides. Journal of Antimicrobial Chemotherapy 20, Suppl. B, 81-8. SAS (1985). Statistical Analysis System Users Guide: basic version 5. SAS Institute Inc., Cary, NC.