Journal of Antimicrobial Chemotherapy (1991) 27, 335-341
Bronchial penetration of ofloxacin after single and multiple oral dosage P. G. Davey", E. Precious0 and J. Winter* 'Department of Clinical Pharmacology, Ninewells Hospital; b Chest Unit, Kings Cross Hospital, Dundee, DD1 9SY, UK
Introduction Ofloxacin is a new 4-quinolone antibacterial agent which has good in-vitro activity against a wide range of respiratory pathogens, including pneumococci, Haemophilus influenzae, legionellae and Mycoplasma spp. (Gruneberg et al., 1988) Clinical interpretation of these in-vitro data requires information about the concentration of ofloxacin that is achieved in serum and at the site of infection. Measurement of the concentration of antimicrobial drugs in bronchial mucosa has become a common element in the assessment of drugs for respiratory infection (Thadepalli, 1984). However, previous studies have tended to be based on single doses given to patients undergoing diagnostic bronchoscopy who do not have acute infections. In the present study we have also included patients receiving multiple oral doses of ofloxacin for treatment of acute exacerbations of chronic bronchitis. Methods Antimicrobial agents Patients received ofloxacin 200 mg orally either as a single dose on the day of bronchoscopy or as multiple doses of 200 mg twice daily for seven days as therapy for acute exacerbations of chronic bronchitis. 335 0305-7453/91/030335 + 07 $02.00/0 © 1991 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
Simultaneous bronchial biopsy and serum samples were obtained from 14 patients after a single oral dose of 200 mg ofloxacin and from ten patients during the course of multiple dose oral treatment, (200 mg ofloxacin bd) for acute exacerbations of chronic bronchitis. Duplicate bronchial samples from different parts of the lung were obtained from five patients. Concentrations in bronchial mucosa were equal to or higher than serum concentrations. There were no statistically significant differences in concentrations after single or multiple doses but there appeared to be a trend towards higher concentrations after' multiple doses. After a single dose bronchial and serum concentrations ranged from 1-3 to 15-5 mg/kg and from 01 to 50 mg/1, respectively, between 1 and 6 h after dosing. After multiple dosing of patients with acute exacerbations of chronic bronchitis bronchial and serum concentrations ranged from 1-7 to 210 mg/kg and 10 to 61 mg/1, respectively between 1 and 12 h. The percentage difference in ofloxacin concentrations in five duplicate bronchial samples from different parts of the lung was —4%, (95% confidence intervals + 22% to -30%). Thus, the model of bronchial sampling after single dosing of patients before diagnostic bronchoscopy gave results that were similar to those obtained after multiple dosing of patients with acute exacerbations of chronic bronchitis. After multiple dosing ofloxacin concentrations were > 1 mg/1 or > 1 mg/kg in serum and bronchial mucosa throughout the dosing interval, which is above the MIC for most respiratory pathogens.
336
P. G. Davey et al.
Study design The study had an open label design. Patients who were treated for acute exacerbations of chronic bronchitis were included only if they had received no other antibacterial treatment within the preceding seven days. There were no other restrictions on concomitant therapy. Selection of study subjects
Single dose protocol Patients who were undergoing diagnostic bronchoscopy received a single oral dose of 200 mg ofloxacin on the morning of bronchoscopy. Serum and bronchial tissue samples were obtained simultaneously during fibreoptic bronchoscopy. Multiple dose protocol Patients were enrolled under this protocol if they had acute exacerbations of chronic bronchitis ( > 5 ml of purulent sputum per day) and required bronchoscopy, for investigation of haemoptysis or radiological signs suggestive of underlying malignancy (hilar enlargement, new parenchymal shadowing). Patients were prescribed 200 mg of ofloxacin twice daily. Serum and bronchial samples were obtained simultaneously during fibre-optic bronchoscopy between the second and fourth day of treatment. Half the patients received a dose of ofloxacin on the morning of bronchoscopy; the remainder had not received a dose since the evening before (approximately 12 h before bronchoscopy). Patients were treated for a total of seven days and a clinical assessment of efficacy and tolerance was made on the last day of treatment. Sample handling Blood samples were taken into glass containers which contained no anticoagulant. Bronchial samples were placed in pre-weighed microcentrifuge tubes. Both samples were delivered to the laboratory within two hours of sampling. Blood samples were centrifuged for 15 min at 1000# and the serum was separated. The microcentrifuge tubes containing bronchial samples were re-weighed and the weight of tissue recorded. Bronchial samples were then suspended in 250 y& phosphate buffered saline. Serum and bronchial samples were stored for up to one month at — 70°C before assay. Immediately before assay the bronchial samples were sonicated with a Dawes probe (Dawe Instruments Ltd; Soniprobe type 21130A and Soniprobe Converter type 1130/ 1A) for one minute in an ice bath. Serum samples and sonicate were each mixed with an equal volume (250 j/1) of 016 N hydrochloric acid before assay.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
All patients had a history of chronic bronchitis (production of purulent sputum for at least three months of the year for at least three years). The following exclusion criteria were used: < 18 years; pregnancy or breast feeding; antibacterial therapy within the last seven days or concurrently; clinical evidence of significant renal or hepatic damage; evidence of active pulmonary tuberculosis; history of hypersensitivity to nalidixic acid or to other quinolones; history of epilepsy.
Bronchial penetration of ofloxarin
337
Ofloxacin stability under handling conditions Preliminary experiments were conducted to assess the effect of sonication and storage on ofloxacin concentrations. Ofloxacin was dissolved in PBS and hydrochloric acid and sonicated. Samples were removed for assay at 30 sec intervals for 4 min. No significant loss of fluorescence occurred up to 3-5 min but at 4 min fluorescence was reduced to 64% of control. Samples were therefore sonicated for 1 min which always resulted in an homogeneous suspension. Samples of ofloxacin were stored in serum and buffer for up to three months at — 70°C with no significant ( < 5%) loss of fluorescence.
The reverse phase HPLC method withfluorescencedetection was based on a method supplied by Hoechst AG. A Waters Microbondapak C18 column was used and the mobile phase was 01 M citric acid (Analar) and methanol (HPLC grade) mixed in the proportions 70/30. Particulate material was removed and the mobile phase was degassed by negative pressure filtration through Whatman Membrane cellulose nitrate filters (pore size 0-45 /XM, 47 mm diameter). The mobile phase was pumped at 2 ml/min. Serum and bronchial samples were assayed with a 100 /il injection loop which made the sensitivity of the assay up to 0-06 mg/1. Ofloxacin was detected with a Waters 420-AC fluorescence detector with a G4T5 lamp, 313 nM excitation filter and 495 nM emission filter. The concentration of ofloxacin in bronchial mucosa was calculated as follows: „ . concentration in sonicate (mg/1) x volume of sonicate (1) concentration (mg/kg) = . ' ,. . sample weight (kg)t Quality control Quality control (QC) samples were stored in serum and buffer at — 70°C; one QC sample was assayed with each patient specimen. Between assay variation was between 3% and 7%. Duplicate specimens were obtained from different parts of the lung from five patients to check on sampling variation. These samples were sent to the laboratory with a coded label and assayed blind. Ethical considerations The protocol was approved by the Dundee Acute Hospitals Ethics Committee. All patients gave informed consent. Results In total, 26 patients were enrolled, 12 on the multiple dose protocol and 14 on the single dose protocol. Two of the 12 patients on the multiple dose protocol were excluded from the analysis of bronchial penetration, one because at bronchoscopy the trachea was partially occluded by tumour so that bronchial specimens could not be obtained, and the other because of failure to take ofloxacin before the bronchoscopy.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
HPLC method
338
P. G. Davey et aL
6
7
8
9
10
II
12
13
14
Time after dose (h)
Figure 1. Serum concentrations of ofloxacin: D, single dose; A, multiple dose.
Table I. Individual patient data for multiple and single doses of ofloxacin
Time since Number of last dose doses h Multiple dose
9
9 9 7 5 4 4
8 8 6 Single dose
100 100 200 215 500 11-75 1200 1200 1200 1300
200 200 3-45 3-45
400 400 400 400
Concentration in serum bronchus (mg/kg) (mg/1)
Bronchial specimen weight (mg)
900
610 510 105 518
7-31 2100 10-22 12-95
2-60 1-47 0-95
800
2-40 1-86 13-40 8-30
1-77
5-49 2-57 2-57 1-73
1110 1303 1316
107
278
710
4-97 4-80 2-70 2-70 3-80 2-90 2-60 2-40
9-84
12-60 11-95 6-60 9-60 8-30 2-30 13-70 8-50 17-00
115
110 200
4-00 4-50 4-50 4-50
410
500 600
1-40 0-10
1-90
600 7-30 9-20 10-20 7-70
510 6-70 1-30 3-40 3-40 15-50 3-40 2-40
410
910 4-40 8-90 6-80 6-80
Percentage penetration
120 412 973 250 308 373 271 223 98 260 198 125 270 341 268 266 196 279 118 170 179 378 243 2400
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
5
Bronchial penetration of ofloxacin
2
3
4
5
6
7
8
9
12
10
13
14
Figure 2. Bronchial concentrations of ofloxacin: O, single dose; O. multiple dose.
Bronchial concentrations were higher than serum concentrations after both single and multiple doses so that the bronchial to serum ratio was greater than 100% for all but one sample pair (Table I). There was considerable scatter of both serum and bronchial concentrations at all time points (Figures 1 and 2). There was no consistent difference between concentrations after single and multiple doses but, if anything, they tended to be higher in both serum and bronchial tissue after multiple dosing. Concentrations in bronchial tissue were consistently higher than 1 mg/kg between 2 and 6 h after single doses and between 1 and 13 h after multiple doses (Table I; Figures 1 and 2). Duplicate samples
Duplicate samples were obtained from five patients (one after multiple and four after single doses). Results showed good agreement between the duplicates; the mean difference between the paired samples was —0-82, and between the duplicates; the mean % deviation from the individual subject mean was 8-9% (Table II). Table II. Ofloxacin concentrations in duplicate bronchial samples
Sample 1 6-6
7-5 14-9 9-3 1-5
Sample 2
Difference S.-S,
Subject mean S, + S2 2
% deviation from subject mean (±)
8-8 8-9 161 90 11
-2-2 -1-4 -1-2 + 0-3 + 0-4
7-7 8-2 15-5 9-2 1-3
14-3 8-5 3-9 2-2 15-4
Mean difference -0-82
Average = ±8-9%
Standard error of mean difference, 0-506 (360); Student's /, 1-619; P, 0-18 (2-tail test).
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
I
339
340
P. G. Davey et al.
Clinical safety and efficacy There were no adverse events associated with single or multiple dosing of ofloxacin, including the two patients who were excluded from the multiple dose kinetic analysis. All ten patients who completed seven days treatment were judged to have improved clinical condition and four had no residual signs of acute exacerbation. Discussion
Acknowledgement
We acknowledge support from Hoechst UK. References Davey, P. G. & Lang, C. (1988). Pharmacokinetics of cefuroxime axetil and a review of the relationship between antibiotic tissue penetration and efficacy. In Issues in the Treatment of Upper Respiratory Tract Infections (Phillips, I., Ed.), pp. 7-13 (Royal Society of Medicine International Congress and Symposium Series, (No 30). Royal Society of Medicine, London.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
Previous studies of penetration of antibacterial drugs into bronchial tissue have only enrolled patients after a single dose and most patients have not had active acute exacerbations of chronic bronchitis at the time of study. There are conflicting experimental data on whether infection increases or decreases penetration of antibacterial drugs into artificial tissue cages or natural body cavities (Davey & Lang 1988; Schentag 1989). In the present study we have shown that a single dose of ofloxacin achieves serum and bronchial tissue concentrations in excess of 1 mg/1 or 1 mg/kg, the MIC^, for most respiratory pathogens (Gruneberg et al., 1988), between 2 and 6 h after dosing. Moreover, serum and bronchial concentrations were equal to or greater than 1 mg/1 or 1 mg/kg between and 1 and 13 h after a dose in patients who had received between four and nine doses of ofloxacin for acute exacerbations of chronic bronchitis. These results suggest that acute exacerbations of chronic bronchitis do not have a major effect on ofloxacin penetration into bronchial mucosa. Obtaining duplicate specimens from different parts of the lung gave useful objective confirmation that the procedure was not subject to major sampling error. However, we found that duplicate sampling significancy prolonged the bronchoscopy and concluded that it was difficult to justify as a routine in this type of study. Enrolment of patients to the multiple-dose protocol was extremely slow as it was difficult to find patients who satisfied all of the entry criteria for treatment of an acute exacerbation who also required a diagnostic bronchoscopy. Since the results showed essentially no difference from the single dose study we conclude that a single dose protocol in any patient who is undergoing diagnostic bronchoscopy is a reasonable method for assessment of bronchial penetration of new quinolone antibacterial drugs. This study has shown that ofloxacin is concentrated in bronchial mucosa, like other 4-quinolones (Schentag, 1989). The dosage regimen of 200 mg twice daily achieved serum and bronchial concentrations > 1 mg/1 or 1 mg/kg throughout the dosing interval, which is above the MIC for most respiratory pathogens. The regimen fulfills the criteria proposed by Schentag (1989) for optimum dosage of quinolones.
Bronchial penetration of ofloxacin
341
Griineberg, R. N., Felmingham, D., O'Hare, M. D., Robbins, M. J., Perry, K., Wall, R. A. el at (1988). The comparative in-vitro activity of ofloxacin. Journal of Antimicrobial Chemotherapy 22, Suppl. C, 9-19. Schentag, J. J. (1989). Clinical significance of antibiotic tissue penetration. Clinical Pharmacokinetics 16, Suppl. 1, 25-31. Thadepalli, H. (1984). Lower respiratory tract. In Antimicrobial Therapy (Ristuccia, A. M. & Cunha, B. A., Eds), pp. 439-54. Raven Press, New York. (Received 11 June 1990; revised version accepted 18 October 1990)
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
Bronchial penetration of ofloxacin after single and multiple oral dosage P. G. Davey", E. Precious0 and J. Winter* 'Department of Clinical Pharmacology, Ninewells Hospital; b Chest Unit, Kings Cross Hospital, Dundee, DD1 9SY, UK
Introduction Ofloxacin is a new 4-quinolone antibacterial agent which has good in-vitro activity against a wide range of respiratory pathogens, including pneumococci, Haemophilus influenzae, legionellae and Mycoplasma spp. (Gruneberg et al., 1988) Clinical interpretation of these in-vitro data requires information about the concentration of ofloxacin that is achieved in serum and at the site of infection. Measurement of the concentration of antimicrobial drugs in bronchial mucosa has become a common element in the assessment of drugs for respiratory infection (Thadepalli, 1984). However, previous studies have tended to be based on single doses given to patients undergoing diagnostic bronchoscopy who do not have acute infections. In the present study we have also included patients receiving multiple oral doses of ofloxacin for treatment of acute exacerbations of chronic bronchitis. Methods Antimicrobial agents Patients received ofloxacin 200 mg orally either as a single dose on the day of bronchoscopy or as multiple doses of 200 mg twice daily for seven days as therapy for acute exacerbations of chronic bronchitis. 335 0305-7453/91/030335 + 07 $02.00/0 © 1991 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
Simultaneous bronchial biopsy and serum samples were obtained from 14 patients after a single oral dose of 200 mg ofloxacin and from ten patients during the course of multiple dose oral treatment, (200 mg ofloxacin bd) for acute exacerbations of chronic bronchitis. Duplicate bronchial samples from different parts of the lung were obtained from five patients. Concentrations in bronchial mucosa were equal to or higher than serum concentrations. There were no statistically significant differences in concentrations after single or multiple doses but there appeared to be a trend towards higher concentrations after' multiple doses. After a single dose bronchial and serum concentrations ranged from 1-3 to 15-5 mg/kg and from 01 to 50 mg/1, respectively, between 1 and 6 h after dosing. After multiple dosing of patients with acute exacerbations of chronic bronchitis bronchial and serum concentrations ranged from 1-7 to 210 mg/kg and 10 to 61 mg/1, respectively between 1 and 12 h. The percentage difference in ofloxacin concentrations in five duplicate bronchial samples from different parts of the lung was —4%, (95% confidence intervals + 22% to -30%). Thus, the model of bronchial sampling after single dosing of patients before diagnostic bronchoscopy gave results that were similar to those obtained after multiple dosing of patients with acute exacerbations of chronic bronchitis. After multiple dosing ofloxacin concentrations were > 1 mg/1 or > 1 mg/kg in serum and bronchial mucosa throughout the dosing interval, which is above the MIC for most respiratory pathogens.
336
P. G. Davey et al.
Study design The study had an open label design. Patients who were treated for acute exacerbations of chronic bronchitis were included only if they had received no other antibacterial treatment within the preceding seven days. There were no other restrictions on concomitant therapy. Selection of study subjects
Single dose protocol Patients who were undergoing diagnostic bronchoscopy received a single oral dose of 200 mg ofloxacin on the morning of bronchoscopy. Serum and bronchial tissue samples were obtained simultaneously during fibreoptic bronchoscopy. Multiple dose protocol Patients were enrolled under this protocol if they had acute exacerbations of chronic bronchitis ( > 5 ml of purulent sputum per day) and required bronchoscopy, for investigation of haemoptysis or radiological signs suggestive of underlying malignancy (hilar enlargement, new parenchymal shadowing). Patients were prescribed 200 mg of ofloxacin twice daily. Serum and bronchial samples were obtained simultaneously during fibre-optic bronchoscopy between the second and fourth day of treatment. Half the patients received a dose of ofloxacin on the morning of bronchoscopy; the remainder had not received a dose since the evening before (approximately 12 h before bronchoscopy). Patients were treated for a total of seven days and a clinical assessment of efficacy and tolerance was made on the last day of treatment. Sample handling Blood samples were taken into glass containers which contained no anticoagulant. Bronchial samples were placed in pre-weighed microcentrifuge tubes. Both samples were delivered to the laboratory within two hours of sampling. Blood samples were centrifuged for 15 min at 1000# and the serum was separated. The microcentrifuge tubes containing bronchial samples were re-weighed and the weight of tissue recorded. Bronchial samples were then suspended in 250 y& phosphate buffered saline. Serum and bronchial samples were stored for up to one month at — 70°C before assay. Immediately before assay the bronchial samples were sonicated with a Dawes probe (Dawe Instruments Ltd; Soniprobe type 21130A and Soniprobe Converter type 1130/ 1A) for one minute in an ice bath. Serum samples and sonicate were each mixed with an equal volume (250 j/1) of 016 N hydrochloric acid before assay.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
All patients had a history of chronic bronchitis (production of purulent sputum for at least three months of the year for at least three years). The following exclusion criteria were used: < 18 years; pregnancy or breast feeding; antibacterial therapy within the last seven days or concurrently; clinical evidence of significant renal or hepatic damage; evidence of active pulmonary tuberculosis; history of hypersensitivity to nalidixic acid or to other quinolones; history of epilepsy.
Bronchial penetration of ofloxarin
337
Ofloxacin stability under handling conditions Preliminary experiments were conducted to assess the effect of sonication and storage on ofloxacin concentrations. Ofloxacin was dissolved in PBS and hydrochloric acid and sonicated. Samples were removed for assay at 30 sec intervals for 4 min. No significant loss of fluorescence occurred up to 3-5 min but at 4 min fluorescence was reduced to 64% of control. Samples were therefore sonicated for 1 min which always resulted in an homogeneous suspension. Samples of ofloxacin were stored in serum and buffer for up to three months at — 70°C with no significant ( < 5%) loss of fluorescence.
The reverse phase HPLC method withfluorescencedetection was based on a method supplied by Hoechst AG. A Waters Microbondapak C18 column was used and the mobile phase was 01 M citric acid (Analar) and methanol (HPLC grade) mixed in the proportions 70/30. Particulate material was removed and the mobile phase was degassed by negative pressure filtration through Whatman Membrane cellulose nitrate filters (pore size 0-45 /XM, 47 mm diameter). The mobile phase was pumped at 2 ml/min. Serum and bronchial samples were assayed with a 100 /il injection loop which made the sensitivity of the assay up to 0-06 mg/1. Ofloxacin was detected with a Waters 420-AC fluorescence detector with a G4T5 lamp, 313 nM excitation filter and 495 nM emission filter. The concentration of ofloxacin in bronchial mucosa was calculated as follows: „ . concentration in sonicate (mg/1) x volume of sonicate (1) concentration (mg/kg) = . ' ,. . sample weight (kg)t Quality control Quality control (QC) samples were stored in serum and buffer at — 70°C; one QC sample was assayed with each patient specimen. Between assay variation was between 3% and 7%. Duplicate specimens were obtained from different parts of the lung from five patients to check on sampling variation. These samples were sent to the laboratory with a coded label and assayed blind. Ethical considerations The protocol was approved by the Dundee Acute Hospitals Ethics Committee. All patients gave informed consent. Results In total, 26 patients were enrolled, 12 on the multiple dose protocol and 14 on the single dose protocol. Two of the 12 patients on the multiple dose protocol were excluded from the analysis of bronchial penetration, one because at bronchoscopy the trachea was partially occluded by tumour so that bronchial specimens could not be obtained, and the other because of failure to take ofloxacin before the bronchoscopy.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
HPLC method
338
P. G. Davey et aL
6
7
8
9
10
II
12
13
14
Time after dose (h)
Figure 1. Serum concentrations of ofloxacin: D, single dose; A, multiple dose.
Table I. Individual patient data for multiple and single doses of ofloxacin
Time since Number of last dose doses h Multiple dose
9
9 9 7 5 4 4
8 8 6 Single dose
100 100 200 215 500 11-75 1200 1200 1200 1300
200 200 3-45 3-45
400 400 400 400
Concentration in serum bronchus (mg/kg) (mg/1)
Bronchial specimen weight (mg)
900
610 510 105 518
7-31 2100 10-22 12-95
2-60 1-47 0-95
800
2-40 1-86 13-40 8-30
1-77
5-49 2-57 2-57 1-73
1110 1303 1316
107
278
710
4-97 4-80 2-70 2-70 3-80 2-90 2-60 2-40
9-84
12-60 11-95 6-60 9-60 8-30 2-30 13-70 8-50 17-00
115
110 200
4-00 4-50 4-50 4-50
410
500 600
1-40 0-10
1-90
600 7-30 9-20 10-20 7-70
510 6-70 1-30 3-40 3-40 15-50 3-40 2-40
410
910 4-40 8-90 6-80 6-80
Percentage penetration
120 412 973 250 308 373 271 223 98 260 198 125 270 341 268 266 196 279 118 170 179 378 243 2400
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
5
Bronchial penetration of ofloxacin
2
3
4
5
6
7
8
9
12
10
13
14
Figure 2. Bronchial concentrations of ofloxacin: O, single dose; O. multiple dose.
Bronchial concentrations were higher than serum concentrations after both single and multiple doses so that the bronchial to serum ratio was greater than 100% for all but one sample pair (Table I). There was considerable scatter of both serum and bronchial concentrations at all time points (Figures 1 and 2). There was no consistent difference between concentrations after single and multiple doses but, if anything, they tended to be higher in both serum and bronchial tissue after multiple dosing. Concentrations in bronchial tissue were consistently higher than 1 mg/kg between 2 and 6 h after single doses and between 1 and 13 h after multiple doses (Table I; Figures 1 and 2). Duplicate samples
Duplicate samples were obtained from five patients (one after multiple and four after single doses). Results showed good agreement between the duplicates; the mean difference between the paired samples was —0-82, and between the duplicates; the mean % deviation from the individual subject mean was 8-9% (Table II). Table II. Ofloxacin concentrations in duplicate bronchial samples
Sample 1 6-6
7-5 14-9 9-3 1-5
Sample 2
Difference S.-S,
Subject mean S, + S2 2
% deviation from subject mean (±)
8-8 8-9 161 90 11
-2-2 -1-4 -1-2 + 0-3 + 0-4
7-7 8-2 15-5 9-2 1-3
14-3 8-5 3-9 2-2 15-4
Mean difference -0-82
Average = ±8-9%
Standard error of mean difference, 0-506 (360); Student's /, 1-619; P, 0-18 (2-tail test).
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
I
339
340
P. G. Davey et al.
Clinical safety and efficacy There were no adverse events associated with single or multiple dosing of ofloxacin, including the two patients who were excluded from the multiple dose kinetic analysis. All ten patients who completed seven days treatment were judged to have improved clinical condition and four had no residual signs of acute exacerbation. Discussion
Acknowledgement
We acknowledge support from Hoechst UK. References Davey, P. G. & Lang, C. (1988). Pharmacokinetics of cefuroxime axetil and a review of the relationship between antibiotic tissue penetration and efficacy. In Issues in the Treatment of Upper Respiratory Tract Infections (Phillips, I., Ed.), pp. 7-13 (Royal Society of Medicine International Congress and Symposium Series, (No 30). Royal Society of Medicine, London.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
Previous studies of penetration of antibacterial drugs into bronchial tissue have only enrolled patients after a single dose and most patients have not had active acute exacerbations of chronic bronchitis at the time of study. There are conflicting experimental data on whether infection increases or decreases penetration of antibacterial drugs into artificial tissue cages or natural body cavities (Davey & Lang 1988; Schentag 1989). In the present study we have shown that a single dose of ofloxacin achieves serum and bronchial tissue concentrations in excess of 1 mg/1 or 1 mg/kg, the MIC^, for most respiratory pathogens (Gruneberg et al., 1988), between 2 and 6 h after dosing. Moreover, serum and bronchial concentrations were equal to or greater than 1 mg/1 or 1 mg/kg between and 1 and 13 h after a dose in patients who had received between four and nine doses of ofloxacin for acute exacerbations of chronic bronchitis. These results suggest that acute exacerbations of chronic bronchitis do not have a major effect on ofloxacin penetration into bronchial mucosa. Obtaining duplicate specimens from different parts of the lung gave useful objective confirmation that the procedure was not subject to major sampling error. However, we found that duplicate sampling significancy prolonged the bronchoscopy and concluded that it was difficult to justify as a routine in this type of study. Enrolment of patients to the multiple-dose protocol was extremely slow as it was difficult to find patients who satisfied all of the entry criteria for treatment of an acute exacerbation who also required a diagnostic bronchoscopy. Since the results showed essentially no difference from the single dose study we conclude that a single dose protocol in any patient who is undergoing diagnostic bronchoscopy is a reasonable method for assessment of bronchial penetration of new quinolone antibacterial drugs. This study has shown that ofloxacin is concentrated in bronchial mucosa, like other 4-quinolones (Schentag, 1989). The dosage regimen of 200 mg twice daily achieved serum and bronchial concentrations > 1 mg/1 or 1 mg/kg throughout the dosing interval, which is above the MIC for most respiratory pathogens. The regimen fulfills the criteria proposed by Schentag (1989) for optimum dosage of quinolones.
Bronchial penetration of ofloxacin
341
Griineberg, R. N., Felmingham, D., O'Hare, M. D., Robbins, M. J., Perry, K., Wall, R. A. el at (1988). The comparative in-vitro activity of ofloxacin. Journal of Antimicrobial Chemotherapy 22, Suppl. C, 9-19. Schentag, J. J. (1989). Clinical significance of antibiotic tissue penetration. Clinical Pharmacokinetics 16, Suppl. 1, 25-31. Thadepalli, H. (1984). Lower respiratory tract. In Antimicrobial Therapy (Ristuccia, A. M. & Cunha, B. A., Eds), pp. 439-54. Raven Press, New York. (Received 11 June 1990; revised version accepted 18 October 1990)
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 25, 2015
