N. P. B o y e , P. G a u s t a d
Double-Blind Comparative Study of Ofloxacin (Hoe 280) and Trimethoprim-Sulfamethoxazole in the Treatment of Patients with Acute Exacerbations of Chronic Bronchitis and Chronic Obstructive Lung Disease Summary: In a double-blind study of 137 patients with exacerbation of chronic bronchitis and chronic obstructive lung disease, the efficacy and safety of ofloxacin was compared with that of trimethoprim-sulfamethoxazole (TMP/SMX). Both groups improved. The frequency of severe adverse reactions was highest in the TMP/SMX group, and 14.9% of the patients discontinued the treatment. In the ofloxacin group 6% had to stop the treatment. The failure rate was significantly lower in the ofloxacin-treated patients, 3.2% versus 13.8% in the TMP/SMX group. Ofloxacin was found to be an effective drug with few adverse reactions. Zusammenfassung: Doppelblindstudie zum Vergleich von Ofloxacin (Hoe 280) und TrimethoprimSulfamethoxazol bei Patienten mit akuter Exazerbation einer chronischen Bronchitis bei chronisch obstruktiver Lungenerkrankung. Im Rahmen einer Doppelblindstudie wurden Ofloxacin und Trimethoprim-Sulfamethoxazol (TMP/SMX) beziiglich ihrer Wirksamkeit und Sicherheit bei 137 Patienten mit Exazerbation einer chronischen Bronchitis bei chronisch obstruktiver Lungenerkrankung verglichen. Schwere Arzneimittelnebenwirkungen waren in der TMP/SMX-Gruppe h/iufiger und ffihrten in 14,9% der F/ille zur vorzeitigen Beendigung der Therapie, in der Ofloxacingruppe nur in 6% der F/ille. Bei Patienten, die mit Ofloxacin behandelt wurden, war die Versagerquote signifikant geringer als bei Behandlung mit TMP/SMX (3,2 im Vergleich zu 13,8%). Ofloxacin erwies sich als wirksames Arzneimittel und verursachte nur wenige unerwfinschte Nebenwirkungen. Introduction The objective of this study was to compare ofloxacin with trimethoprim-sulfamethoxazole (TMP/SMX) with regard to efficacy and safety in patients with acute exacerbations of chronic bronchitis and chronic obstructive lung disease (COLD). This was studied in both hospitalised and outpatients. Exacerbations of chronic bronchitis and COLD are common, with environmental pollutants, cigarette smoke, and viral and bacterial infections among the known causes [1]. However, it is usually very difficult to know when bacterial infections are the cause or the complication of an exacerbation. The problems with good and representative sputum analysis are well known. S 388
Furthermore, at present we do not have any test that can be used as a "gold standard" for diagnosing bacterial infection in COLD. In COLD, neither the role of bacterial infections nor the efficacy of antimicrobial therapy is clear. Nicotra and coworkers [2] found no difference between tetracyclines and placebo in a relatively small study. Anthonisen and coworkers [3] found in a study with 362 exacerbations of COLD that the success rate with antibiotics was 68% and with placebo 55%. The rate of failure with deterioration was 19% with placebo and 10% with antibiotics. They concluded that treatment with antibiotics was associated with significant benefits, especially with regard to the reduction of failure rates. The rate of positive bacteriological cultures found in different studies varies greatly, from very low percentages to about 90% [2, 4, 5]. Antibiotic therapy is often combined with medication for bronchial obstruction, such as corticosteroids, beta 2 stimulants and theophyllines. Thus far the antibiotics used most frequently to treat exacerbations of COLD have been doxycyline, ampicillin and TMP/SMX. Their effectiveness has been nearly the same in several studies. The introduction of the quinolones has been an important advance in the therapy of COLD [1]. Ofloxacin has been shown to penetrate well into lung tissue, with high concentrations found in lung tissue and bronchial secretions [6]. It causes relatively few adverse reactions [7].
Materials and Methods Study design: In this study ofloxacin was compared with TMP/SMX with regard to tolerance, clinical efficacy and bacterial elimination. The study was designed as a comparative double-blind study. Patients received either 200 mg of ofloxacin b.i.d, or two tablets of TMP/SMX b.i.d. (with placebos a total of eight tablets/day) for a total of ten days. Clinical, bacteriological, laboratory and lung function tests along with registration of adverse reactions were performed prior to the start of treatment, on day 4 during the treatment period, two to four days after treatment had ended, and at a follow-up visit two weeks after the end of treatment. Inclusion criteria: Adult patients with exacerbations of chronic bronchitis or COLD with increased cough, dypsnea and increase in sputum volume and purulence were included. Patients who had used antibiotics (other than ofloxacin and TMP/SMX) for less than three days prior to the study without effect could be included. With regard to exclusion criteria, the patients had to be N. P. Boye, M. D., Dept. of Lung Diseases; P. Gaustad, M. D., Dept. of Microbiology,UllevaalUniversityHospital, Kirkevn.166, N-0407 Oslo 4, Norway.
Infection 19 (1991) Suppl. 7 © MMV MedizinVeflag GmbH Mtinchen, Mtinchen 1991
N. P. Boye and P. Gaustad: Ofloxacin vs. TMP/SMX in COLD
Table 3: Organisms isolated in patients evaluable for bacteriological efficacy.
otherwise healthy and could not be using other antibiotics. Results T h e study included 137 patients, most of whom had received antibiotic therapy for C O L D several times previously. Most patients were hospitalized because of the exacerbation. Ofloxacin was allocated to 68 patients and T M P / S M X to 69 patients. Two patients in each group were excluded because they did not meet the inclusion criteria.
Patients Evaluable for Tolerance
Pneumococci
1/elimination = 1
reinfection = 1 3/elimination = 2 reinfection = 1 13
5/elimination = 4 reinfection= 1 6
Other gram-negative bacteria Total
Patients
A total of 133 patients (97.1%), 66 from the ofloxacin group and 67 from the TMP/SMX group, were evaluable for tolerance. Both groups were comparable with regard to age, sex, smoking habits, other medications and the duration of the infections (Table 1) (Figure 1). The evaluation was done at the follow-up visit two weeks after the treatment. The additional adverse events possibly caused by drug reactions were compared with the different symptoms before the treatment and are shown in Table 2. Several patients complained of more than one adverse reaction. In the ofloxacin group three patients had five severe reactions and in the T M P / S M X group eight patients had ten severe reactions. The greatest difference was found in the number of gastrointestinal adverse reactions, with one attributed to ofloxacin and six to TMP/SMX.
i/reinfection = 1
Haemophilus influenzae 9/elimination = 8
Ofloxacin
TMP/SMX
no
4O
20
N~
]
Beta-2agonist
]
Prednisolone per os
[]
Theophylline
[]
Inhaledcorticosteroids
Figure 1: Concurrent medication in the ofloxacin- and TMP/SMX-treated patients. FEV 1
Patients Evaluable for Clinical Efficacy Patients who had received treatment for four 3ays or m o r e were evaluated for clinical efficacy. One hundred twenty-one patients (88.3%) were evT~ able, 63 from the ofloxacin group and 58 from the T M P / S M X group. O f the
Table 1: Patients evaluable for tolerance.
ii iiiiiii
Ni;iiiiiiiiii!i.!ii !!i!i;!i !ii!!!i!ii!iiiiii!!iiii1iiiiii!iiiiiiiiiiiiii! ii
Mean age (range) Sex M/F Duration of present infection (mean no. of days) Smokers / non-smokers No. with previous antibiotic treatmenP
ili
55 (18-80) 33 / 33
59 (22-80) 28 / 39
6 47 / 18
7 50 / 17
26
26
Doxyc3,cline most frequent.
15/11 16/15 0/2 0/2 31/30
13/15 15/7 6/1 2/1 36/24
2-4 days After treatment
14 days
Figure 2: Forced e)
Double-Blind Comparative Study of Ofloxacin (Hoe 280) and Trimethoprim-Sulfamethoxazole in the Treatment of Patients with Acute Exacerbations of Chronic Bronchitis and Chronic Obstructive Lung Disease Summary: In a double-blind study of 137 patients with exacerbation of chronic bronchitis and chronic obstructive lung disease, the efficacy and safety of ofloxacin was compared with that of trimethoprim-sulfamethoxazole (TMP/SMX). Both groups improved. The frequency of severe adverse reactions was highest in the TMP/SMX group, and 14.9% of the patients discontinued the treatment. In the ofloxacin group 6% had to stop the treatment. The failure rate was significantly lower in the ofloxacin-treated patients, 3.2% versus 13.8% in the TMP/SMX group. Ofloxacin was found to be an effective drug with few adverse reactions. Zusammenfassung: Doppelblindstudie zum Vergleich von Ofloxacin (Hoe 280) und TrimethoprimSulfamethoxazol bei Patienten mit akuter Exazerbation einer chronischen Bronchitis bei chronisch obstruktiver Lungenerkrankung. Im Rahmen einer Doppelblindstudie wurden Ofloxacin und Trimethoprim-Sulfamethoxazol (TMP/SMX) beziiglich ihrer Wirksamkeit und Sicherheit bei 137 Patienten mit Exazerbation einer chronischen Bronchitis bei chronisch obstruktiver Lungenerkrankung verglichen. Schwere Arzneimittelnebenwirkungen waren in der TMP/SMX-Gruppe h/iufiger und ffihrten in 14,9% der F/ille zur vorzeitigen Beendigung der Therapie, in der Ofloxacingruppe nur in 6% der F/ille. Bei Patienten, die mit Ofloxacin behandelt wurden, war die Versagerquote signifikant geringer als bei Behandlung mit TMP/SMX (3,2 im Vergleich zu 13,8%). Ofloxacin erwies sich als wirksames Arzneimittel und verursachte nur wenige unerwfinschte Nebenwirkungen. Introduction The objective of this study was to compare ofloxacin with trimethoprim-sulfamethoxazole (TMP/SMX) with regard to efficacy and safety in patients with acute exacerbations of chronic bronchitis and chronic obstructive lung disease (COLD). This was studied in both hospitalised and outpatients. Exacerbations of chronic bronchitis and COLD are common, with environmental pollutants, cigarette smoke, and viral and bacterial infections among the known causes [1]. However, it is usually very difficult to know when bacterial infections are the cause or the complication of an exacerbation. The problems with good and representative sputum analysis are well known. S 388
Furthermore, at present we do not have any test that can be used as a "gold standard" for diagnosing bacterial infection in COLD. In COLD, neither the role of bacterial infections nor the efficacy of antimicrobial therapy is clear. Nicotra and coworkers [2] found no difference between tetracyclines and placebo in a relatively small study. Anthonisen and coworkers [3] found in a study with 362 exacerbations of COLD that the success rate with antibiotics was 68% and with placebo 55%. The rate of failure with deterioration was 19% with placebo and 10% with antibiotics. They concluded that treatment with antibiotics was associated with significant benefits, especially with regard to the reduction of failure rates. The rate of positive bacteriological cultures found in different studies varies greatly, from very low percentages to about 90% [2, 4, 5]. Antibiotic therapy is often combined with medication for bronchial obstruction, such as corticosteroids, beta 2 stimulants and theophyllines. Thus far the antibiotics used most frequently to treat exacerbations of COLD have been doxycyline, ampicillin and TMP/SMX. Their effectiveness has been nearly the same in several studies. The introduction of the quinolones has been an important advance in the therapy of COLD [1]. Ofloxacin has been shown to penetrate well into lung tissue, with high concentrations found in lung tissue and bronchial secretions [6]. It causes relatively few adverse reactions [7].
Materials and Methods Study design: In this study ofloxacin was compared with TMP/SMX with regard to tolerance, clinical efficacy and bacterial elimination. The study was designed as a comparative double-blind study. Patients received either 200 mg of ofloxacin b.i.d, or two tablets of TMP/SMX b.i.d. (with placebos a total of eight tablets/day) for a total of ten days. Clinical, bacteriological, laboratory and lung function tests along with registration of adverse reactions were performed prior to the start of treatment, on day 4 during the treatment period, two to four days after treatment had ended, and at a follow-up visit two weeks after the end of treatment. Inclusion criteria: Adult patients with exacerbations of chronic bronchitis or COLD with increased cough, dypsnea and increase in sputum volume and purulence were included. Patients who had used antibiotics (other than ofloxacin and TMP/SMX) for less than three days prior to the study without effect could be included. With regard to exclusion criteria, the patients had to be N. P. Boye, M. D., Dept. of Lung Diseases; P. Gaustad, M. D., Dept. of Microbiology,UllevaalUniversityHospital, Kirkevn.166, N-0407 Oslo 4, Norway.
Infection 19 (1991) Suppl. 7 © MMV MedizinVeflag GmbH Mtinchen, Mtinchen 1991
N. P. Boye and P. Gaustad: Ofloxacin vs. TMP/SMX in COLD
Table 3: Organisms isolated in patients evaluable for bacteriological efficacy.
otherwise healthy and could not be using other antibiotics. Results T h e study included 137 patients, most of whom had received antibiotic therapy for C O L D several times previously. Most patients were hospitalized because of the exacerbation. Ofloxacin was allocated to 68 patients and T M P / S M X to 69 patients. Two patients in each group were excluded because they did not meet the inclusion criteria.
Patients Evaluable for Tolerance
Pneumococci
1/elimination = 1
reinfection = 1 3/elimination = 2 reinfection = 1 13
5/elimination = 4 reinfection= 1 6
Other gram-negative bacteria Total
Patients
A total of 133 patients (97.1%), 66 from the ofloxacin group and 67 from the TMP/SMX group, were evaluable for tolerance. Both groups were comparable with regard to age, sex, smoking habits, other medications and the duration of the infections (Table 1) (Figure 1). The evaluation was done at the follow-up visit two weeks after the treatment. The additional adverse events possibly caused by drug reactions were compared with the different symptoms before the treatment and are shown in Table 2. Several patients complained of more than one adverse reaction. In the ofloxacin group three patients had five severe reactions and in the T M P / S M X group eight patients had ten severe reactions. The greatest difference was found in the number of gastrointestinal adverse reactions, with one attributed to ofloxacin and six to TMP/SMX.
i/reinfection = 1
Haemophilus influenzae 9/elimination = 8
Ofloxacin
TMP/SMX
no
4O
20
N~
]
Beta-2agonist
]
Prednisolone per os
[]
Theophylline
[]
Inhaledcorticosteroids
Figure 1: Concurrent medication in the ofloxacin- and TMP/SMX-treated patients. FEV 1
Patients Evaluable for Clinical Efficacy Patients who had received treatment for four 3ays or m o r e were evaluated for clinical efficacy. One hundred twenty-one patients (88.3%) were evT~ able, 63 from the ofloxacin group and 58 from the T M P / S M X group. O f the
Table 1: Patients evaluable for tolerance.
ii iiiiiii
Ni;iiiiiiiiii!i.!ii !!i!i;!i !ii!!!i!ii!iiiiii!!iiii1iiiiii!iiiiiiiiiiiiii! ii
Mean age (range) Sex M/F Duration of present infection (mean no. of days) Smokers / non-smokers No. with previous antibiotic treatmenP
ili
55 (18-80) 33 / 33
59 (22-80) 28 / 39
6 47 / 18
7 50 / 17
26
26
Doxyc3,cline most frequent.
15/11 16/15 0/2 0/2 31/30
13/15 15/7 6/1 2/1 36/24
2-4 days After treatment
14 days
Figure 2: Forced e)
