DIAGNMICROBIOLINFECTDIS 1992;15:91S-95S
9J.S
Roxithromycin versus AmoxiciUinClavulanic Acid in the Treatment of Respiratory Tract Infections Daniel Lousbergh, Guido Jochems, Ludwig Everaert, and Marc Puttemans
A multicenter, double-blind, double-dummy trial was conducted in 96 general practice patients with upper and lower respiratory tract infection to compare the efficacy and tolerance of raxithromycin (150 mg b.i.d.) and amoxicillin--clavulanic acid (500 mg/125 mg t.i.d.). Good clinical response was obtained in 96% and 95% of cases, respectively, but only 4% of
patients receiving roxithromycin volunteered adverse events possibly or probably related to their test treatment, as opposed to 17% of those receiving amoxicillin-clavulanic acid. The results indicate that both drugs are equally effective in the treatment of respiratory tract infection, but that roxithromycin is better tolerated.
INTRODUCTION
After repeated dosing for 10 days, no accumulation of roxithromycin is observed. Other pharmacokine~ic parameters are discussed at length in the reviews by Puri and Lassman (1987) and Young et al. (1989). Roxithromycin readily penetrates into bronchial secretions reaching sputum concentrations comparable with those in plasma (Young et al., 1989). Intracellular penetration and accumulation in alveolar macrophages and polymorphonuclear cells provide activity against Legionella and Chlamydia infection (Chastre et al., 1984). The efficacy and safety of roxithromycin in respiratory tract infectien has been demonstrated in several clinical studies (Bertrand et al., 1985; Grassi et al., 1985; Marsac et al., 1985; Hubrechts et al., 1985; Steiner et al., 1985). Amoxicillin-clavulanic acid is a combination of a penicillin resistant to gastric inactivation and a 13lactamase inhibitor that widens the antimicrobial spectrum (Smith and Le Frock, 1985). It is well absorbed following oral administration and reaches clinically effective concentrations (0.5 p,g/ml) in sputum and saliva. Peak plasma concentratio7, of 5 ~g/ml are reached 1-2 hr after single dosing with 250 mg amoxicillin (Spyker et al., 1977). Amoxicillin--clavulanic acid (500 mg/125 mg t.i.d.) is often used by general practitioners as first-line therapy in respiratory tract infections where the pathogen is unknown. We, therefore, chose it as the reference treat-
Macrolides are a class of antibiotic frequently used to treat respiratory tract infection (RTI) because they inhibit a wide range of respiratory pathogens and reach high concentrations in respiratory tissues and secretions. Roxithromycin is an acid-resistant ether-oxime derivative of erythromycin with an antibiotic spectrum comparable with that of the parent compound (Barlam and Neu, 1984), and improved pharmacokinetics, for example, good gastrointestinal absorption and an extended half-life (Nilsen, 1987; Puri and Lassman, 1987; Young et al., 1989). Single-dose pharmacokinetic studies in healthy volunteers with 150 mg give peak plasma levels (Cm,x) of ~6 ~g/ral, compared with ~ Cmaxof 2 ~g/ml following a single dose of erythromycin 500 mg, with a Tmaxof 1.7 hr for both antibiotics. The half-lives of roxithromydn and erythromycin are ~13 and ~1.7 hr, respectively. From the Kortes3em(D.L.);Turnhout, (G.J.);and Roussel Laboratories (L.E., M.P.), Brussels, Belgium. Additionalcopiesof this supplement are availablefrom Roussel UCLAF,DomaineTh~rapeutiqueAntibioth~rapie,35 Boulevarddes Invalides, 75007Paris, France. Received8 October 1991; revisedand accepted 15 Novemb(.~'1991. © 1992ElsevierSdence Publishing Co., Inc. 655 Avenueof the Americas, New York, NY 10010 0732-8893192/$5.00
92S
ment for evaluating the efficacy and tolerance of roxithmmycin when employed for the same purpose.
D. Lousbergh et al.
Patients
A bacteriologic sample (throat swab or sputum collection) was collected at inclusion and at the end of treatment. Isolates were identified by standard techniques, and susceptibility to roxithromycin and amoxicillin was determined by the disk diffusion method. Isolates were described as susceptible or resistant. Treatment was discontinued in patients who did not improve during therapy (these patients were classified as treatment failures if they received a minimum of 4 days of treatment) and if severe adverse events occurred that were probably or possibly related to the study medication. Treatment could also be interrupted if the investigator decided to abandon treatment of patients infected by organisms resistant to roxithromycin or amoxiciUin-clavulanate in vitro. Adverse events were recorded, including any abnormal laboratory results during the trial. The preand posttreatment laboratory tests comprised white cell count and differential, SGOT, SGPT, lactate dehydrogenase (LDH), ~-glutamyl transaminase, alkaline phosphatase, and total bilirubin. At end of the study, the clinician assessed the clinical response as "satisfactory," "unsatisfactory," or "nonevaluable." Bacteriologic response was similarly assessed.
Patients over 18 years of age with clinical signs of upper or lower respiratory tract infection were included in this study. Patients excluded from the trial were pregnant or lactating women, those with a histo W of hypersensitivity to macrolides or ~-lactams, or those known to have severe hepatic or renal insufficiency. Also excluded were patients with other clinicMly s i ~ f i c a n t abnormal findings (including abnormal laboratory results) that might affect the interpretation of the results, and patients unable to comply with the protocol. Patients receiving cyclosporine or ergot derivatives or any drug affecting the absorption of the study drugs were not included. There was a 3-day washout for any other antibiotics (unless the microorganism responsible for the infection was shown to be resistant to the particular antibiotic) and a 2-week washout for any other investigational drug.
The results of the pre- and posttreatment visits were required for efficacy to be evaluable. Treatment had to have been taken for a minimum of 4 days. Patients who received antibiotics other than the test drugs were nonevaluable. The following criteria were required to evaluate bacteriologic efficacy: (a) bacteriologic results had to be available from visit 1, (b) causative or possibly causative pathogens had to be identified in the specimen, (c) the isolate had to be susceptible to both test antibiotics, and (d) bacteriologic results had to be available from the end of the study unless clinical cure made specimen collection impossible. The clinical protocol was approved by the medical Ethics Committee of the Free University of Brussels. Patients gave informed consent.
Assessments
Statistical Analysis
A full clinical examination was performed at the beginning (visit 1) and end of the study (visit 2). Clinical assessment included weight, height, body temperature, respiratory ~ate, radial pulse, and blood pressure. Any symptoms or abnormalities involving the throat, mouth, chest and lungs, lymph nodes, nose, ears, skin, and the cardiovascular system were recorded. The investigator assessed the overall clinical condition as "fair," "serious," or "critical."
All statistical tests were carried out two-tailed with a significance level of 5%. Statistical calculations were performed using the SPSS/PC + program, version 3.0, run on an IBM-compatible PC. Discrete variables were compared by means of the chi-squared test or the Fisher exact test. The chi-squared test was applied with Yates' correction for 2 x 2 tables, and the t-test and Mann-Whitney U test for continuous variables.
MATERIALS AND METHODS
Test Drugs The antimicrobial agents used in this study were 150mg roxithromycin tablets (Roussel Uclaf, Romainville, France) and amoxicillin (500 mg)-clavulanic acid (125 rag) tablets (Beecham, Brussels, Belgium) and their matching placebos. All medications were blister packed. Study Design This was a multicenter double-blind, comparative study. Participating general practitioners had to recruit and treat a minimum of six patients. Patients were assigned at random to one of the treatment groups. A double-dummy technique was used. Patients were examined before and after the 10-day treatment period.
Evaluable Cases
93S
Roxithromycin versus Amoxicillin in RTI
TABLE 1 Patient Characteristics at Entry (Mean
% of cases
-,- S D ) [ ] URTI [ ] LRTI URTI and LRTI
Treatment Regimen Demographic Data° Patients included Age (yrs) Sex Male Female Weight (kg) Height (cm) Interval before treatment
Roxithromydn
AmoxicillinClavulanic Acid
50 42.2 +_ 16.4
46 40.2 -4- 15.7
29 2! 71.4 --- 12.7 169.4 +- 10.1 4.1 -4-- 3.4
21 25 68.0 -+ 11.8 168.3 -+ 8.5 4.1 -+ 3.8
(days) Efficacy evaluable
48
45
"p > 0.05 for each parameter.
Roxithromycin AmoxNllill ~us clavulanicacid % of cases
I'1 Mild [ ] Serous [ ] No information
o
Roxithromycm Amoxyciltinplus clavulanicacid
FIGURE 1 Types of infection in trial patients. Distribution of upper (URTI) and lower respiratory tract infection (LRTI) in the two treatment groups: roxithromycin and amoxicillin-clavulanic add.
RESULTS
Patients Between 30 April 1989 and 30 July 1990, 96 patients were enrolled by a total of 15 general practitioners. Patient demographic data are given in Table 1. The two antibiotic groups did not differ significantly with respect to sex, age, weight, and the interval between symptom onset and the start of the treatment (p>0.05).
Clinical Characteristics at Visit 1 The initial clinical diagnosis was "lower respiratory tract infection" in 18 cases, "upper respiratory tract infection" in 66 cases, and "upper and lower respiratory tract infection" combined in 12 cases. Randomization with respect to diagnosis and overall condition is shown in Figure 1. Of the 96 patients entered in the study, three were excluded because of protocol violation (concomitant treatment with ergot derivatives, impaired hepatic function at entry), or unnecessary breaking of the randomization code by the investigator. The remaining 93 patients fulfilled the entry criteria and were analyzed in detail. Infection was acute in 83% of cases, and chronic or recurrent in the remainder. Symptoms had been present 1-20 days (mean, 4.1 days). General clinical condition was assessed as "fair" in 61 patients and "serious" in 33, and not recorded in the remaining two patients. The distribution of lower and upper respiratory symptoms together with other abno.~mal clinical findings did not differ significantly between trea'ment groups.
% ot cases
[] success BI Failure
0
Roxithromycin Amoxyc~llinplus c:avulanicadd
FIGURE 2 Clinical response rates. Overall severity of infection at presentation in the two treatment groups: roxithromycin and amoxicillin--clavulanicacid.
TABLE 2
Bacteriologic Results Showing Isola'es and Their Response to Treatment Treatment Regimen AmoxiciUinRoxithromycin Clavulanic acid
Microorganism Streptocaccus pyogenes Streptoco,'cu5 ,group B Streptococcus pneumaniae Haemophilus influenzae Stephylococcus aureus Escherichia coil A. calcoaceticus
Total
Success Failure Success Failure 2
2
3
1
1
0
0
0
1
0
5
0
3 2 1 0
0 0 0 0
2 1 0 1
0 0 0 0
10
2
12
1
91S
D. Lousbergh et al.
TABLE 3 Treatment Side Effects per Antibiotic Group Treatment Regimen Roxithmmydn Epigastric pain Diuresis Diarrhea Mycosis Tiredness Nausea and vomiting
2 1 0 0 0 0
AmoxiciilinClavulanic Acid 1b 0 4~ 2",b 1 2
'One with mycosisand diarrhea. bOne with epigastricpain and mycosis.
Clinical Results The two groups did not differ significantly in respect to vital signs and white blood cell counts. The overall clinical response was assessed as "satisfactory" in 44 (96%) of 48 patients in the roxithromycin group and in 42 (95%) of 45 patients in the amoxicillinclavulanic acid group (Figure 2).
Bacteriologic Results In total, 10 patients (12 isolates) were evaluable for bacteriologic efficacy in the roxithromycin, and 13 patients (13 isolates) in the amoxicillin--clavulanic acid group; eradication was achieved in seven of 10 and 12 of 13 patients, respectively (Table 2).
Adverse Events All 96 patients enrolled in the trial received study medication and were, therefore, included in the analysis of tolerance. Eleven patients, three in the roxithromycin group and eight in the amoxicillin-
clavulanic acid group experienced adverse events during the study. Of these cases, 10 showed a possible or probable relation to the test treatment: two in the roxithromycin group (4%) and eight in the amoxicillin-clavulanic acid group (17%) (Table 3). The adverse event caused treatment to be discontinued in five patients: two in the roxithromycin and three in the amoxicillin-clavulanic acid group. Pre- and posttreatment laboratory data showed no statistical difference between treatment groups in the total white cell count and differential. Although there was an average increase in SGOT, SGPT, and LDH on roxithromycin and a decrease on amoxicillin-clavulanic acid, this was not considered to be clinically significant in any patient. The treatment groups did not differ significantly with respect to ch~.~es in serum alkaline phosphatase or bilirubin.
Discussion This study compared roxithromycin and amoxicillin-c!avulanate therapy in 96 patients with respiratory tract infection: 66 and 18 with upper and lower respiratory infection, respectively, and 12 with mixed infection. The clinica! response to both antibiotics was satisfactory: 96% and 95% on roxithromycin and amoxicillin-clavulanatre, respectively, as was bacteriologic efficacy, eradication being achieved in seven of 10 and 12 of 13 cases, respectively. Only two patients (4%) in the roxithromycin group experienced adverse events versus eight patients (17%) in the amoxicillin-clavulanate acid groups. Adverse events with roxithromycin are uncommon and usually benign, and were reported by only 4% of all participants in clinical trials (Young et al. 1989). Our study confirms both the recognized side-effect profile of both test medications, and the findings of the study by Hubrechts et al. (1985) comparing roxithromycin and amoxicillin in the treatment of respiratory tract infection.
REFERENCES Barlam T, Neu HC (1984) In vitro comparison of the activity of RU 28965, a new macrolide, with that of erythromycm against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 25:529-531. Bertrand A, Caubarrere I, Chapman A, Clavier J, Constans P, Delaval P, Dellamonice P, Deville JR, Remy G, Freissinaud P, Godard P, Grosbuis S, Lacut JY, Lavandrier M, Lemercier JP, Leng JJ, Leophonte P, Liozon F, Letellier P, Morere P, Oury M, Richard F, Sauvaget J, Roegel E (1985) Multicentre comparative study of the efficacy and safety of roxithromycin and erythromycin ethylsuccinate in the treatment of lower respiratory tract infections. Br J Clin Pract 42(Supp155):98-99. Chastre J, Brun P, Fourtiilan JB, Soler P, Basset G, Manuel C, Trouillet JL, Gibert C (1984) Pulmonaly disposition of roxithromycin (RU 28965): a new ma~olide antibiotic. Antimicrob Agents Chemother 31:1312-1316.
Grasssi C, Bartucci F, Sassella D (1985) Efficacyand safety of roxithromycin in respiratory tract infections. Br ] Clin Pract 42(Suppl 55):104-106. Hubrechts ]M, Kupperberg A, Smets P, Dramaix M, Valante F, Vanhoof R (1985) Multicentre comparative study of oral roxithromycin and amoxiciilin in the treatment of respiratory tract infections. Br l Clin Pract 42(Suppl 55):102-103. Marsac J, Akoun G, Balmes P, Butaeye P, Charpin ], Corroler J, Courty G, Depierre A, Dournovo P, Druart R, Dumont R, Emonot A, Fabre C, Freour P, Guibout P, Janbon C, Kermarec ], Lamy P, Macquet V, Patte D, Pauchant M, Robillard M, Thibault P, Voisin C, Wallaert C (1985) Multicentre comparative study of the efficacy and safety of roxithromycin and doxycycline in the treatment of lower respiratory tract infection. Br J Clin Pract 42($upp155):100--101.
Roxithromycin versus Amoxicillin in RTI
Nilsen OG (1987) Comparative pharmacokinetics of macrolides. J Antimicrob Chemother 20(Suppl B):81-88. Puri SK, Lassman lib (1987) Roxithromycin: a pharmacokinetic review of a macrolide. J Antimicrob Chemother 20(Suppl B):89-100. Smith BR, Le Frock JL (1985) Amoxicillin-potassium clavulanate: a novel {$-lactamase inhibitor. Drug Intell Clin Pharm 19:415-420. Spyker DA, Rugloski RJ, Vann RL, O'Brien WM (1977)
955
Pharmacokinetics of amoxicillin: dose dependence after intravenous, oral, and intramuscular administration. Antimicrob Agents Chemother 11:132-141. Steiner G, Huber W, Wutz R, Neumann M, Janistyn W, Hofmann W (1985) Roxithromycin: a safe and efficacious antibiotic in the treatment of lower respiratory tract infections. Br J Clin Pract 42(Suppl 55):96-97. Young R, Gonzaales J, Sakin (1989) Roxithromycin: a review of its antimicrobial activity, pharmaco~.~aetic properties and clinical efficacy. Drugs 37:8-41.
9J.S
Roxithromycin versus AmoxiciUinClavulanic Acid in the Treatment of Respiratory Tract Infections Daniel Lousbergh, Guido Jochems, Ludwig Everaert, and Marc Puttemans
A multicenter, double-blind, double-dummy trial was conducted in 96 general practice patients with upper and lower respiratory tract infection to compare the efficacy and tolerance of raxithromycin (150 mg b.i.d.) and amoxicillin--clavulanic acid (500 mg/125 mg t.i.d.). Good clinical response was obtained in 96% and 95% of cases, respectively, but only 4% of
patients receiving roxithromycin volunteered adverse events possibly or probably related to their test treatment, as opposed to 17% of those receiving amoxicillin-clavulanic acid. The results indicate that both drugs are equally effective in the treatment of respiratory tract infection, but that roxithromycin is better tolerated.
INTRODUCTION
After repeated dosing for 10 days, no accumulation of roxithromycin is observed. Other pharmacokine~ic parameters are discussed at length in the reviews by Puri and Lassman (1987) and Young et al. (1989). Roxithromycin readily penetrates into bronchial secretions reaching sputum concentrations comparable with those in plasma (Young et al., 1989). Intracellular penetration and accumulation in alveolar macrophages and polymorphonuclear cells provide activity against Legionella and Chlamydia infection (Chastre et al., 1984). The efficacy and safety of roxithromycin in respiratory tract infectien has been demonstrated in several clinical studies (Bertrand et al., 1985; Grassi et al., 1985; Marsac et al., 1985; Hubrechts et al., 1985; Steiner et al., 1985). Amoxicillin-clavulanic acid is a combination of a penicillin resistant to gastric inactivation and a 13lactamase inhibitor that widens the antimicrobial spectrum (Smith and Le Frock, 1985). It is well absorbed following oral administration and reaches clinically effective concentrations (0.5 p,g/ml) in sputum and saliva. Peak plasma concentratio7, of 5 ~g/ml are reached 1-2 hr after single dosing with 250 mg amoxicillin (Spyker et al., 1977). Amoxicillin--clavulanic acid (500 mg/125 mg t.i.d.) is often used by general practitioners as first-line therapy in respiratory tract infections where the pathogen is unknown. We, therefore, chose it as the reference treat-
Macrolides are a class of antibiotic frequently used to treat respiratory tract infection (RTI) because they inhibit a wide range of respiratory pathogens and reach high concentrations in respiratory tissues and secretions. Roxithromycin is an acid-resistant ether-oxime derivative of erythromycin with an antibiotic spectrum comparable with that of the parent compound (Barlam and Neu, 1984), and improved pharmacokinetics, for example, good gastrointestinal absorption and an extended half-life (Nilsen, 1987; Puri and Lassman, 1987; Young et al., 1989). Single-dose pharmacokinetic studies in healthy volunteers with 150 mg give peak plasma levels (Cm,x) of ~6 ~g/ral, compared with ~ Cmaxof 2 ~g/ml following a single dose of erythromycin 500 mg, with a Tmaxof 1.7 hr for both antibiotics. The half-lives of roxithromydn and erythromycin are ~13 and ~1.7 hr, respectively. From the Kortes3em(D.L.);Turnhout, (G.J.);and Roussel Laboratories (L.E., M.P.), Brussels, Belgium. Additionalcopiesof this supplement are availablefrom Roussel UCLAF,DomaineTh~rapeutiqueAntibioth~rapie,35 Boulevarddes Invalides, 75007Paris, France. Received8 October 1991; revisedand accepted 15 Novemb(.~'1991. © 1992ElsevierSdence Publishing Co., Inc. 655 Avenueof the Americas, New York, NY 10010 0732-8893192/$5.00
92S
ment for evaluating the efficacy and tolerance of roxithmmycin when employed for the same purpose.
D. Lousbergh et al.
Patients
A bacteriologic sample (throat swab or sputum collection) was collected at inclusion and at the end of treatment. Isolates were identified by standard techniques, and susceptibility to roxithromycin and amoxicillin was determined by the disk diffusion method. Isolates were described as susceptible or resistant. Treatment was discontinued in patients who did not improve during therapy (these patients were classified as treatment failures if they received a minimum of 4 days of treatment) and if severe adverse events occurred that were probably or possibly related to the study medication. Treatment could also be interrupted if the investigator decided to abandon treatment of patients infected by organisms resistant to roxithromycin or amoxiciUin-clavulanate in vitro. Adverse events were recorded, including any abnormal laboratory results during the trial. The preand posttreatment laboratory tests comprised white cell count and differential, SGOT, SGPT, lactate dehydrogenase (LDH), ~-glutamyl transaminase, alkaline phosphatase, and total bilirubin. At end of the study, the clinician assessed the clinical response as "satisfactory," "unsatisfactory," or "nonevaluable." Bacteriologic response was similarly assessed.
Patients over 18 years of age with clinical signs of upper or lower respiratory tract infection were included in this study. Patients excluded from the trial were pregnant or lactating women, those with a histo W of hypersensitivity to macrolides or ~-lactams, or those known to have severe hepatic or renal insufficiency. Also excluded were patients with other clinicMly s i ~ f i c a n t abnormal findings (including abnormal laboratory results) that might affect the interpretation of the results, and patients unable to comply with the protocol. Patients receiving cyclosporine or ergot derivatives or any drug affecting the absorption of the study drugs were not included. There was a 3-day washout for any other antibiotics (unless the microorganism responsible for the infection was shown to be resistant to the particular antibiotic) and a 2-week washout for any other investigational drug.
The results of the pre- and posttreatment visits were required for efficacy to be evaluable. Treatment had to have been taken for a minimum of 4 days. Patients who received antibiotics other than the test drugs were nonevaluable. The following criteria were required to evaluate bacteriologic efficacy: (a) bacteriologic results had to be available from visit 1, (b) causative or possibly causative pathogens had to be identified in the specimen, (c) the isolate had to be susceptible to both test antibiotics, and (d) bacteriologic results had to be available from the end of the study unless clinical cure made specimen collection impossible. The clinical protocol was approved by the medical Ethics Committee of the Free University of Brussels. Patients gave informed consent.
Assessments
Statistical Analysis
A full clinical examination was performed at the beginning (visit 1) and end of the study (visit 2). Clinical assessment included weight, height, body temperature, respiratory ~ate, radial pulse, and blood pressure. Any symptoms or abnormalities involving the throat, mouth, chest and lungs, lymph nodes, nose, ears, skin, and the cardiovascular system were recorded. The investigator assessed the overall clinical condition as "fair," "serious," or "critical."
All statistical tests were carried out two-tailed with a significance level of 5%. Statistical calculations were performed using the SPSS/PC + program, version 3.0, run on an IBM-compatible PC. Discrete variables were compared by means of the chi-squared test or the Fisher exact test. The chi-squared test was applied with Yates' correction for 2 x 2 tables, and the t-test and Mann-Whitney U test for continuous variables.
MATERIALS AND METHODS
Test Drugs The antimicrobial agents used in this study were 150mg roxithromycin tablets (Roussel Uclaf, Romainville, France) and amoxicillin (500 mg)-clavulanic acid (125 rag) tablets (Beecham, Brussels, Belgium) and their matching placebos. All medications were blister packed. Study Design This was a multicenter double-blind, comparative study. Participating general practitioners had to recruit and treat a minimum of six patients. Patients were assigned at random to one of the treatment groups. A double-dummy technique was used. Patients were examined before and after the 10-day treatment period.
Evaluable Cases
93S
Roxithromycin versus Amoxicillin in RTI
TABLE 1 Patient Characteristics at Entry (Mean
% of cases
-,- S D ) [ ] URTI [ ] LRTI URTI and LRTI
Treatment Regimen Demographic Data° Patients included Age (yrs) Sex Male Female Weight (kg) Height (cm) Interval before treatment
Roxithromydn
AmoxicillinClavulanic Acid
50 42.2 +_ 16.4
46 40.2 -4- 15.7
29 2! 71.4 --- 12.7 169.4 +- 10.1 4.1 -4-- 3.4
21 25 68.0 -+ 11.8 168.3 -+ 8.5 4.1 -+ 3.8
(days) Efficacy evaluable
48
45
"p > 0.05 for each parameter.
Roxithromycin AmoxNllill ~us clavulanicacid % of cases
I'1 Mild [ ] Serous [ ] No information
o
Roxithromycm Amoxyciltinplus clavulanicacid
FIGURE 1 Types of infection in trial patients. Distribution of upper (URTI) and lower respiratory tract infection (LRTI) in the two treatment groups: roxithromycin and amoxicillin-clavulanic add.
RESULTS
Patients Between 30 April 1989 and 30 July 1990, 96 patients were enrolled by a total of 15 general practitioners. Patient demographic data are given in Table 1. The two antibiotic groups did not differ significantly with respect to sex, age, weight, and the interval between symptom onset and the start of the treatment (p>0.05).
Clinical Characteristics at Visit 1 The initial clinical diagnosis was "lower respiratory tract infection" in 18 cases, "upper respiratory tract infection" in 66 cases, and "upper and lower respiratory tract infection" combined in 12 cases. Randomization with respect to diagnosis and overall condition is shown in Figure 1. Of the 96 patients entered in the study, three were excluded because of protocol violation (concomitant treatment with ergot derivatives, impaired hepatic function at entry), or unnecessary breaking of the randomization code by the investigator. The remaining 93 patients fulfilled the entry criteria and were analyzed in detail. Infection was acute in 83% of cases, and chronic or recurrent in the remainder. Symptoms had been present 1-20 days (mean, 4.1 days). General clinical condition was assessed as "fair" in 61 patients and "serious" in 33, and not recorded in the remaining two patients. The distribution of lower and upper respiratory symptoms together with other abno.~mal clinical findings did not differ significantly between trea'ment groups.
% ot cases
[] success BI Failure
0
Roxithromycin Amoxyc~llinplus c:avulanicadd
FIGURE 2 Clinical response rates. Overall severity of infection at presentation in the two treatment groups: roxithromycin and amoxicillin--clavulanicacid.
TABLE 2
Bacteriologic Results Showing Isola'es and Their Response to Treatment Treatment Regimen AmoxiciUinRoxithromycin Clavulanic acid
Microorganism Streptocaccus pyogenes Streptoco,'cu5 ,group B Streptococcus pneumaniae Haemophilus influenzae Stephylococcus aureus Escherichia coil A. calcoaceticus
Total
Success Failure Success Failure 2
2
3
1
1
0
0
0
1
0
5
0
3 2 1 0
0 0 0 0
2 1 0 1
0 0 0 0
10
2
12
1
91S
D. Lousbergh et al.
TABLE 3 Treatment Side Effects per Antibiotic Group Treatment Regimen Roxithmmydn Epigastric pain Diuresis Diarrhea Mycosis Tiredness Nausea and vomiting
2 1 0 0 0 0
AmoxiciilinClavulanic Acid 1b 0 4~ 2",b 1 2
'One with mycosisand diarrhea. bOne with epigastricpain and mycosis.
Clinical Results The two groups did not differ significantly in respect to vital signs and white blood cell counts. The overall clinical response was assessed as "satisfactory" in 44 (96%) of 48 patients in the roxithromycin group and in 42 (95%) of 45 patients in the amoxicillinclavulanic acid group (Figure 2).
Bacteriologic Results In total, 10 patients (12 isolates) were evaluable for bacteriologic efficacy in the roxithromycin, and 13 patients (13 isolates) in the amoxicillin--clavulanic acid group; eradication was achieved in seven of 10 and 12 of 13 patients, respectively (Table 2).
Adverse Events All 96 patients enrolled in the trial received study medication and were, therefore, included in the analysis of tolerance. Eleven patients, three in the roxithromycin group and eight in the amoxicillin-
clavulanic acid group experienced adverse events during the study. Of these cases, 10 showed a possible or probable relation to the test treatment: two in the roxithromycin group (4%) and eight in the amoxicillin-clavulanic acid group (17%) (Table 3). The adverse event caused treatment to be discontinued in five patients: two in the roxithromycin and three in the amoxicillin-clavulanic acid group. Pre- and posttreatment laboratory data showed no statistical difference between treatment groups in the total white cell count and differential. Although there was an average increase in SGOT, SGPT, and LDH on roxithromycin and a decrease on amoxicillin-clavulanic acid, this was not considered to be clinically significant in any patient. The treatment groups did not differ significantly with respect to ch~.~es in serum alkaline phosphatase or bilirubin.
Discussion This study compared roxithromycin and amoxicillin-c!avulanate therapy in 96 patients with respiratory tract infection: 66 and 18 with upper and lower respiratory infection, respectively, and 12 with mixed infection. The clinica! response to both antibiotics was satisfactory: 96% and 95% on roxithromycin and amoxicillin-clavulanatre, respectively, as was bacteriologic efficacy, eradication being achieved in seven of 10 and 12 of 13 cases, respectively. Only two patients (4%) in the roxithromycin group experienced adverse events versus eight patients (17%) in the amoxicillin-clavulanate acid groups. Adverse events with roxithromycin are uncommon and usually benign, and were reported by only 4% of all participants in clinical trials (Young et al. 1989). Our study confirms both the recognized side-effect profile of both test medications, and the findings of the study by Hubrechts et al. (1985) comparing roxithromycin and amoxicillin in the treatment of respiratory tract infection.
REFERENCES Barlam T, Neu HC (1984) In vitro comparison of the activity of RU 28965, a new macrolide, with that of erythromycm against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 25:529-531. Bertrand A, Caubarrere I, Chapman A, Clavier J, Constans P, Delaval P, Dellamonice P, Deville JR, Remy G, Freissinaud P, Godard P, Grosbuis S, Lacut JY, Lavandrier M, Lemercier JP, Leng JJ, Leophonte P, Liozon F, Letellier P, Morere P, Oury M, Richard F, Sauvaget J, Roegel E (1985) Multicentre comparative study of the efficacy and safety of roxithromycin and erythromycin ethylsuccinate in the treatment of lower respiratory tract infections. Br J Clin Pract 42(Supp155):98-99. Chastre J, Brun P, Fourtiilan JB, Soler P, Basset G, Manuel C, Trouillet JL, Gibert C (1984) Pulmonaly disposition of roxithromycin (RU 28965): a new ma~olide antibiotic. Antimicrob Agents Chemother 31:1312-1316.
Grasssi C, Bartucci F, Sassella D (1985) Efficacyand safety of roxithromycin in respiratory tract infections. Br ] Clin Pract 42(Suppl 55):104-106. Hubrechts ]M, Kupperberg A, Smets P, Dramaix M, Valante F, Vanhoof R (1985) Multicentre comparative study of oral roxithromycin and amoxiciilin in the treatment of respiratory tract infections. Br l Clin Pract 42(Suppl 55):102-103. Marsac J, Akoun G, Balmes P, Butaeye P, Charpin ], Corroler J, Courty G, Depierre A, Dournovo P, Druart R, Dumont R, Emonot A, Fabre C, Freour P, Guibout P, Janbon C, Kermarec ], Lamy P, Macquet V, Patte D, Pauchant M, Robillard M, Thibault P, Voisin C, Wallaert C (1985) Multicentre comparative study of the efficacy and safety of roxithromycin and doxycycline in the treatment of lower respiratory tract infection. Br J Clin Pract 42($upp155):100--101.
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