Low Dose Sultamicillin in Acute Sinusitis Original Articles Sultamicillina a Basse Dosi Per Il Trattamento Della Sinusite Acuta

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Le Infezioni in Medicina, n. 1, 45-48, 2002 Lavori originali Low dose sultamicillin in acute sinusitis Original articles Sultamicillina a basse dosi per il trattamento della sinusite acuta

Bülent Topuz, Orhan Katırcıog˘ lu, ˙Ismet Bayramog˘ lu, Fazıl Nejdet Ardıç, Hüseyin Erbudak Department of Otolaryngology, School of Medicine, Pamukkale University, Denizli, Turkey

■ INTRODUCTION tion and leukocyte count. Most of the patients complained of prolonged common cold, de- The combination of ampicillin with sulbactam spite having symptomatic therapy. At the be- (prodrug sultamicillin) expands the spectrum ginning, they had watery discharge, changing of the former to include beta-lactamase produc- to purulent in the following week. ing microorganisms, such as Haemophilus in- Signs and symptoms of the infection (purulent fluenzae and Moraxella catarrhalis [1, 2]. The postnasal or nasal discharge; nasal inflamma- plasma levels of ampicillin and sulbactam, tion; frontal/maxillary tenderness or pain; when given as sultamicillin, are two to three headache) were assessed and graded (0: ab- times higher than with an equivalent dose of ei- sent, 1: mild, 2: moderate, 3: severe) before, ther drug alone [3]. during (five days after the first dose of study The clinical efficacy and safety of the generally drugs), and at the end of therapy (10 days after recommended daily dose of sultamicillin, 50 the first dose of study drugs), and 20 days after mg/kg administered in the treatment of chil- the last dose (follow-up). A physician indicated dren, and 1500 mg in the treatment of adults, chemotherapy, and another physician who have been established by numerous studies [4, was blind randomly prescribed study drugs. 5, 6, 7, 8]. In Turkey, the recommended daily The first physician carried out control evalua- dose of sultamicillin is 25 mg/kg in the treat- tions. ment of children, and 750 mg in the treatment Exclusion criteria for the study were: of adults. We have found some studies, report- 1) treatment with another antimicrobial agent ing the efficacy of low dose administration [4, 9, within one week prior to enrolment, or receiv- 10, 11], but none of them were comparative. ing prophylactic antimicrobial agent; The aim of this clinical study was to evaluate 2) symptoms no longer than a week that may be the efficacy and safety of orally administered attributed to a common cold; sultamicillin (Pfizer), marketed in low doses in 3) known hypersensitivity to any beta-lactam Turkey, and compare it with orally adminis- antibiotic; tered amoxicillin (ABFAR, a Turkish company) 4) infections requiring treatment with another in the treatment of acute sinusitis antimicrobial agent; 5) terminal illness, immune deficiency or other disease that precluding evaluation of the study ■ METHODS drug therapy; 6) pregnancy. Patients: One hundred and twenty-five patients Each patient or patient’s parent gave informed (58 male and 67 female), between the ages of 16- consent. 63 (mean 36.2), suffering from acute sinusitis, took part in the trial. All patients were outpa- Treatment and evaluation: At the beginning, tients and self-referrals. The diagnosis of infec- the patients were randomized to receive daily, tion was based on medical history, physical ex- oral dose of sultamicillin and amoxicillin, amination, conventional radiographic evalua- 2x375mg and 3x500mg respectively. At the end,

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the remaining 25 patients received sultami- The clinical success (improvement+cure) rate cillin. Demographic data, severity grade of pa- was (17+11)/42 (66.6%) and (28+21)/66 (74.2%) tients, by treatment, are shown in table 1. for amoxicillin and sultamicillin respectively, at In both treatment groups patients were treated the first control, as shown in table 2. All im- for ten days. The first control was made 5 days proved patients were cured at the second con- after the first dose of study drugs. A patient trol. The side effects were seen in two patients was considered clinically cured when all pre- (3.0%) in the sultamicillin group and in five treatment signs and symptoms of infection (11.9%) in the amoxicillin group. All side effects were eliminated. Clinical improvement was de- were in the gastrointestinal system. Treatment fined as partial disappearance of pretreatment was discontinued in no patient for adverse signs and symptoms. In either result study drug reaction. Relapses were observed in four drugs were reconstituted for 5 additional days. patients (6.0%) in the sultamicillin group and Failure was defined as no change or worsening three (7.1%) in the amoxicillin group. of signs and symptoms; and the study drug was Responses to both treatments were similar and changed. Relapse was defined as improvement there were no significant differences between or cure with subsequent reappearance of signs the treatment groups with respect to resolution and symptoms at the follow-up assessment. A of symptoms, side effects and relapse (p>0.05). patient who was either cured or improved was considered a clinical success. No other con- comitant medications were allowed, except for ■ DISCUSSION a few patients who received acetaminophen. Independent-Samples T test was used to com- Pharmacokinetic studies have established that pare demographic information such as age. The ampicillin peak plasma concentrations chi-square test was employed to compare the achieved after oral administration of sultami- sex distribution of patients and the rates of ad- cillin are approximately three times those ob- verse events according to treatment. The tained with equimolar dose of oral ampicillin Wilcoxon two-sample test was used to compare [3]. Although the elimination half-lives of the distribution of clinical efficacy and ampicillin and sulbactam are each approxi- signs/symptoms between two treatment mately 1 hour, the high serum concentrations groups. The level of significance was set at 0.05. achieved, coupled with their synergistic bacte- ricidal activity, permit twice-daily dosing [3]. However, although the proposed daily dose of ■ RESULTS sultamicillin is 50 mg/kg in the treatment of children and 1500 mg in the treatment of adults One hundred and eight patients, 46 male and 62 [4, 5, 6, 7], in Turkey it has been marketed in female, between the ages of 16-56 (mean 32.8), low (25 mg/kg for children, 750 mg for adults) came to their control visits regularly. There and twice-daily dose form for more than 10 were 66 patients in the sultamicillin group, 42 years. in amoxicillin group. The age, weight and sex of There are some studies reporting similar clini- patients were comparable in treatment groups. cal and bacteriological cure rates in the treat-

Table 1 - Demographic data by treatment (age, gender, severity grade of sinusitis).

Treatment Mean age Male/female Mild n (%) Moderate n (%) Severe n (%) Sultamicillin 37.1 37/38 17 (22.6) 51 (68.0) 7 (9.3) Amoxicillin 35.4 21/29 9 (18.0) 37 (74.0) 4 (8.0)

Table 2 - Numbers and percentages of cures, improvements and failures by treatment and disease severity (I: Improvement, C: Cure, F: Failure). The percentages show success rates.

Treatment Mild n (%) Moderate n (%) Severe n (%) Sultamicillin I/C/F 5/9/3 (82.3) 13/24/14 (72.5) 3/1/3 (57.1) Amoxicillin I/C/F 2/5/2 (77.7) 7/21/9 (75.6) 2/0/2 (50.0)

46 2002 ment of mild to moderate community-acquired, vent relapses. Though not significant, sultami- acute ear-nose-throat infections, using a low cillin was found to be more effective than and twice-daily dosage of sultamicillin [4, 9, 10, amoxicillin. The beta lactamase-producing or- 13]. In such studies, overall clinical and bacteri- ganisms may be an explanation of that result. It ological cure rates were high (94-99%). How- is well known that there are some beta lacta- ever, none of them was comparative. The only mase-producing organisms in acute sinusitis comparative study that we found was held in [12,15]. Turkey. In that study, only 24 acute maxillary The side-effects of low-dose sultamicillin were sinusitis patients were involved; and success considerably lower than the generally accepted rate was 83.3% for sultamicillin and 66.6 % for dose, 4-8% [9, 10, 13] and 7-65% [5, 7, 8] re- amoxicillin (P>0.05) [14]. Our cure rates were spectively. The low incidence of side effects not as high as in preceding studies. We con- with low dosage of sultamicillin is confirmed in sider that comparative studies are more reli- the present study. This finding requires further able. investigation. The treatment cost of sultami- In this study, although some patients were cillin was higher than that of amoxicillin. cured by five-day treatment, the duration of the treatment should be at least ten days in order to Key words: amoxicillin, sultamicillin, acute sinu- obtain a cure for improved patients and pre- sitis.

SUMMARY

Objectives: to study the effectiveness of low dose and symptoms; and study drug was changed. The sultamicillin in the treatment of acute sinusitis. second control was made between 10-12th days, Methods: a total of 108 patients, between 16-56 and the third was four weeks later. years of age (mean 32.8), suffering from acute si- Results: The clinical success (improvement + nusitis took part in the trial. Patients received cure) rate was (17+11)/42 (66.6%) and orally 2x375 mg sultamicillin, and compared with (28+21)/66 (74.2%) for amoxicillin and sultami- patients receiving 3x500 mg amoxicillin. The first cillin respectively, at first control. All improved control was made between the 5th and 7th days. A patients were cured at the second control. No si- patient was considered clinically cured when all gnificant side-effects were noted in either amoxi- pretreatment signs and symptoms of infection cillin or sultamicillin treated patients. All side ef- were eliminated. Clinical improvement was defi- fects were gastrointestinal, 11.9% and 3.0% in ned as the partial disappearance of pretreatment the same order. signs and symptoms. In either result, study drugs Conclusions: Low dose sultamicillin was compa- were reconstituted for additional 5 days. Failure rable to amoxicillin; sultamicillin has fewer side was defined as no change or worsening of signs effects than amoxicillin (p>0.05).

RIASSUNTO

Obiettivi: studiare l’efficacia terapeutica della della scomparsa di tutti i segni e sintomi sultamicillina a basso dosaggio nel tratta- dell’infezione precedenti l’inizio del trattamento della sinusite acuta. mento. Miglioramento clinico è stato definito Metodi: 108 pazienti di età compresa tra 16 e come parziale scomparsa dei segni clinici. 56 anni (media 32.8) affetti da sinusite acuta Nel caso di mancata guarigione o migliora- sono stati arruolati nel presente studio. I pa- mento il trattamento con i farmaci in studio è zienti suddivisi in due gruppi sono stati sot- stato proseguito per ulteriori 5 giorni. Il falli- toposti a trattamento orale con sultamicillina mento è stato definito come nessuna varia- (2x375 mg) o con amoxicillina (3x500 mg). Il zione o peggioramento dei segni e sintomi. Il primo controllo clinico è stato effettuato tra il secondo controllo clinico è stato effettuato tra 5° e il 7° giorno dall’inizio della terapia. La il 10° e il 12° giorno; il terzo controllo dopo 4 guarigione clinica è stata definita sulla base settimane.

47 2002 Risultati: al primo controllo è stato osservato collaterali (prevalentemente gastrointesti- successo clinico (miglioramento +guarigione) nali) nei due gruppi di trattamento (11.9% in (17+11)/42 (66.6%) ed in (28 + 21)/66 per amoxicillina, 3% per sultamicillina) (74.2%) pazienti rispettivamente trattati con (P>0.05). amoxicillina e sultamicillina; al secondo con- Conclusioni: i risultati terapeutici ottenuti con trollo tutti i pazienti migliorati sono risultati sultamicillina a basse dosi sono stati parago- guariti. Si è osservata una differenza statisti- nabili a quelli dell’amoxicillina. La sultami- camente significativa nell’incidenza di effetti cillina ha mostrato minori effetti collaterali.

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