Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. D, 55-60
Ofloxacin concentrations in tissues involved in respiratory tract infections Evelio J. Perea
The literature on the penetration of ofloxacin from blood to respiratory tissue and secretions in patients is reviewed. In patients with acute purulent exacerbations of chronic bronchitis ofloxacin has a C^ value in sputum of 2-7 mg/1 after a 400 mg oral dose, 6-1 mg/1 after 600 mg and 6-3 mg/1 after 800 mg. Penetration from blood to sputum varied from 80 to 100%. The concentration of ofloxacin in bronchial aspirate, 1 to 6 h after a single oral dose of 400 mg, varied between 11 and 4-5 mg/1. The ratio between simultaneous mean bronchial aspirate and serum concentrations ranged between 0-53 in the second hour and 0-92 in the fourth hour. Ofloxacin concentrations in bronchoalveolar lavage fluid following an oral dose of 200 mg twice daily for at least four days amounted to 8-3 mg/1 with a corresponding serum concentration of 1-7 mg/1fivehours after the last dose. The distribution ratio between lavage fluid and serum was 4-9. The lung tissue penetration of ofloxacin after a dosage of 200 mg twice daily, reached a mean tissue plasma concentration ratio of 3-5 ±0-4 for healthy tissue and 3-9 ±0-4 for diseased tissue. Ofloxacin reaches high intracellular concentrations in polymorphonudear leucocytes, alveolar macrophages, epithelial cells and fibroblasts. It is likely that these concentrations will have a sustained inhibitory and bactericidal activity against most potential respiratory pathogens including: Haemophihis influenzae, Branhamella catarrhalis, Gram-negative bacilli, Staphylococcus aureus, Legionella pneumophila, Chlamydia spp. and Coxiella bumetti.
Introduction To predict a' therapeutic success in the treatment of an infection it is not only necessary to know the sensitivity of the infective agent, but also the antimicrobial concentration attained at the site of the infection. In general it has been found that the higher the inhibitory quotient (Ellner & Neu, 1981), i.e. the relationship between the concentration of antimicrobial agent at the site of the infection and the minimum inhibitory concentration (MIC) of the causative organism, the greater the chance of successful treatment. The different results obtained with one antimicrobial agent at the same dosage can be explained by different methodologies in the preparation and processing of specimens used, especially in lung tissue because of its high blood content. Tissue penetration can be deduced from the distribution volume. For quinolones the volume of distribution ranges from 100 to 300 1, being approximately 100 1 for 55 0305-7453/90/26D055 + 06 S02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Department of Microbiology, University of Seville Medical School, Seville 41080, Spain
56
£. J. Perea
ofloxacin, thus indicating that tissue concentrations should either be within the same range as the corresponding serum concentrations or higher. However pharmacokinetic parameters do not differentiate non-homogeneous distribution within various tissues (Dalhoff, 1989). In this paper I summarize the data available on ofloxacin penetration into cells, tissues and secretions of the respiratory tract. Penetration into sputum
Table L Ofloxacin penetration from blood to sputum following oral administration of single or multiple doses
Dose (rngT
200 200 400 400 600 800 200 bid
Sputum concentration' (mg/kg)
Patients (no.)
Sampling time*
10 4 5 15 37 36 11
3-6 MP MP MP MP MP
0*-2-5 3-08 5-22
Day 6
1-2-9
2-7 6-1 6-3
References Morel et al. (1986) Yamaguchi et al. (1984) Yamaguchi et al. (1984) Davies et al. (1987) Davies et al. (1987) Davies et al. (1987) Ritzerfeld et al. (1985)
'Single dose unless otbcrwuc indicated. * Hours after dose or time of peak concentration (mean peak, MP). 'Mean peak concentration or minimum and maximum individual concentration.
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Several pharmacokinetic studies were carried out in patients with chronic bronchitis who suffered from recurring acute purulent exacerbations. In these patients the site of infection can be considered as the bronchial mucosa. The drug concentration in the mucosa can be measured in biopsy material and may be relevant but there are few data available. The sputum model has been chosen instead because of the availability of the material. - Davies et al. (1987) carried out a large study on penetration of ofloxacin into sputum in nearly 100 patients with acute purulent exacerbations of chronic respiratory diseases after a single 400, 600 or 800 mg dose of ofloxacin. Both blood and sputum samples were taken simultaneously at different time intervals after dosage and concentrationtime curves were constructed. Maximal concentrations (C^ in serum and sputum were 3-7 and 2-7 mg/1respectivelyafter 400 mg ofloxacin, 71 and 6-1 mg after 600 mg and 88 and 6-3 after 800mg. Penetration from blood to sputum as judged from the ratio of values of Catx and area under the curve (AUC) of sputum and serum ranged from 78% to 103% (Davies et al., 1987). In a series of studies performed with a more limited number of patients with single or multiple doses of ofloxacin similar or higher sputum levels were obtained (Table I). (Yamaguchi et al., 1984; Ritzerfeld, Zimmerman & Ulmer, 1985; Morel et al., 1986). The importance of the penetration of an antimicrobial from blood to sputum is relevant to the clinical and microbiological results of treating patients with this agent (Davies et al., 1987). It is clear from the clinical results with ofloxacin and other quinolones that higher sputum concentrations of ofloxacin (such as those attained 8rter
Ofloxadn penetration in respiratory tract
57
800 mg dosage) are more efective in the bronchial eradication of organisms such as pneumococci, whose susceptibility is no more than moderate (Maesen et al., 1987). Nevertheless, in general, good clinical results were obtained with doses of 200, 300, and 400 mg daily (Grassi, Grassi & Mangiarotti, 1987; Saito, Katsu & Soejiwa, 1987). Ofloxadn penetration into bronchial secretions
Long tissue penetration Only two studies have been carried out to determine the lung tissue penetration of ofloxadn. In one study after a single oral 600 mg dose of ofloxadn, concentrations were measured in lung tissue and plasma in 11 patients undergoing thoracotomy. After correction for blood admixture, the mean lung tissue concentration 2 h after administration of ofloxadn was 17-7 ±4-2 mg/1. The tissue/plasma ratio was 2:1 (Wijnands et al., 1988). In the second study of ofloxadn penetration into lung tissue, a 200 mg dose was administered orally every 12 h for 48 h preceding the surgical operation and a fifth dose was given 1 h before surgery. During the surgical procedure serum samples and spedmens of healthy and diseased lung tissue were taken at a time of 2-5 ±0-5 h after the last dose of ofloxadn. During surgery the mean plasma concentration was 1-9 ±0-2 mg/1 and the pulmonary tissue concentrations corresponding to these plasma
Table EL Ofloxadn bronchial secretion concentrations after a single oral dose of 400 mg (Symonds et al., 1987)
Time intervals (min) 60-120 121-180 181-240 241-300 301-360
Mean concentration (mg/1)
Bronchial secretion serum ratio
1-6 1-7 1-8 2-2 2-5
0-53 0-73 0-92 0-48 0-98
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Symonds et al. (1987) studied the penetration of ofloxadn into bronchial secretions aspirated at bronchoscopy; they evaluated 16 patients 1-6 h after the administration of a single oral dose of ofloxadn 400 mg. Considerable individual variations in serum and bronchial aspirate concentrations were recorded. Bronchial aspirate concentrations varied from 11 to 4-5 mg/1 and exceeded 1-5 mg/1 in 14 of the 16 patients between 1 and 6 h (Table II). The ratio between simultaneous mean bronchial aspirate and serum concentrations ranged between 0-53 in the second hour and 0-98 in the fourth hour (Symonds et al., 1987). Similar values were obtained by Loos, Schwabe & Vogel (1987). Ofloxadn concentrations in bronchoalveolar lavage fluid, following an oral dose of 200 mg twice daily for at least four days, amounted to 8-3 mg/1 with a corresponding serum concentration of 1-7 mg/1 at 5 h after the last dose (Loos et al., 1987) This corresponds well with the results of ofloxadn lung tissue levels. However, no information is given on calculation of the dilution factor in the specimens of lavage fluid.
58
E. J. Perea Table m . Quinolones concentrations in lung tissue (Forst et al., 1987; Dalhoflf, 1989)
Dose Ciprofloxacin Enoxacin Pefloxacin Ofioxacin
200 iv 2x500 p o 4 d 2x400 po 2d 400 iv 2x200 p o 2 d 600 po
Serum (mg/1)
Lung (mg/kg)
10 10
3-2 1-7 12
1-85 7-28 1-95
8-7
13-8
6-7 17-7
Ratio
3-2 1-7 6-5 1-9 3-4 21
Ofloxadn penetration into cells of the respiratory tract Atypical p n e u m o n i a is a frequent syndrome caused by intracellular pathogens such as: Coxiella bumetii, Legionella spp. and Chlamydia spp. The intracellular penetration and activity of antimicrobial agents can be a n important factor in the treatment of infections caused by these pathogens. Ofioxacin penetrates into h u m a n polymorphonuclear leucocytes ( P M N s ) reaching high intracellular concentrations (intracellular/extracellular ratios of 8-3 and 7 at extracellular concentrations of 2 and 5 mg/1 at 20 min). Ofioxacin has a rapid and
Table IV. Lung tissue concentrations of different antibiotics (Perea et al., 1986)
No. of patients
11 11 12 11 12
Dose iv (nig)
750 1000 1000
100 1000
Antibiotic cefuroxime cefoxitin cefoperazone tobramycdn ceftazidime
Tissue concentration/serum concentration ratio at the stated time after dosage 60 min 120 min l-22±0O8 l-26±O13 0-34±0-03 O46±0O4 0-88±0-12 0-50±0-ll no levels were detected in lung tissue 0-27±0-14 0-2910-11
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
levels were 6-7 ± 1 mg/1 for the healthy tissue and 7-3 ± 1 mg/1 for the diseased tissue ( C o u r a u d et al., 1987). The ratios of the mean tissue to plasma concentrations were 3-5 ± 0 - 4 for healthy tissue and 3 - 9 ± 0 4 for diseased tissue. These results indicate good diffusion of ofioxacin into healthy and atelectatic p u l m o n a r y tissue after single or multiple oral doses. Ofioxacin reaches higher concentrations in lung tissue than other quinolones at a similar dose administered orally or intravenously (Dalhoff, 1989) (Table III). These drugs are concentrated in lung tissue from two- t o six-fold irrespective of the n u m b e r of doses and route of administration. T h r o u g h o u t the study periods of 1-12 h, quinolone concentrations in lung tissue are consistently higher than the corresponding serum concentrations. C o m p a r e d with other antimicrobials such as the cephalosporins, which in general reach pulmonary tissue concentrations lower than the simultaneous serum levels (Table IV), and the aminoglycosides which penetrate poorly and slowly, the quinolones penetrate much better (Ayarra, et al., 1982; Perea et al., 1983, 1986).
OBoxadn penetration in respiratory tract
59
Table V. Ofloxacin intracellular penetration in PMNs, epithelial cells and fibroblasts (Pascual et al., 1989, 1990) Cells PMN HEp-2 MCCOY MDCK VeRo
Cellular/extracellular C/P 6-7±l-2 21 ±0-2 3-9±ll 21±0-9 3-411-2
active penetration mechanism and remains active intracellularly (Pascual, Garcia & Perea, 1989). This compound also shows a high penetration into tissue culture epithelial cells and fibroblasts (Pascual, Garcia & Perea, 1990) (Table V). As with other quinolones, ofloxacin penetrates well into alveolar macrophages, (Easmon & Crane, 1985; Carlier et al., 1987) (Table VI). All four cell types are important components of the respiratory tract tissues and they will also host most of the respiratory pathogens. The high intracellular ofloxacin concentrations establish a favourable pharmacokinetic situation that should ensure the success in the treatment of respiratory tract infections with this antimicrobial agent. Conclusion Ofloxacin has excellent activity against most of the classical respiratory pathogens such as Haemophilus influenzae, Branhamella catarrhalis and Legionella spp. Also Escherichia coli and most strains of Klebsiella and Enterobacter spp. are sensitive. Ofloxacin inhibits most strains of Streptococcus pneumoniae and Pseudomonas aeruginosa at 1 mg/1. Against Mycoplasma pneumoniae ofloxacin shows intermediate activity. The excellent penetration of ofloxacin into sputum, bronchial secretions and lung tissue should allow for the effective therapy of such pathogens in respiratory tract infections. Also the marked intracellular penetration should ensure that ofloxacin is effective in the treatment of atypical pneumonia caused by intracellular pathogens such as Legionella, Chlamydia and Coxiella spp. Table VI. Intracellular penetration of different quinolones (Carlier et al., 1987)
Drug Ciprofloxadn Ofloxacin Pefloxacin Fleroxacin
Ratio intra/extracellular Alveolar macrophages PMNs 81111 7-110-3 6-911-7 —
4-610-1 2110-1 4-010-1 2-010-1
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
The extracellular concentration was 5 mg/1; incubation 20 min.
60
E.J. Perea References
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Ayarra, J., Garcia Iglcsias, M. C, Loscertales, J. & Perea, E. J. (1982). Lung tissue concentration of cefoperazone. In Current Chemotherapy and Immunotherapy (Peritti, P. & Grassi, G. G., Eds), pp. 627-8. American Society for Microbiology, Washington, DC. Carlier, M. B., Scomeaux, B., Jenebergh, A. & Tulkens, P. M. (1987). Uptake and subcellular distribution of 4-quinolones in phagocytes. Proceedings of the 27th Interscience Conference on Antimicrobial Agents Chemotherapy, Washington, 1987. Abstract, 622. Couraud, L., Fourtillan, J. B., Saux, M. G, Bryskier, A. & du Laurier, M. V. (1987). Diffusion of ofloxacin into human lung tissue. Drugs 33, Suppl. 1, 37-8. Dalhoff, A. (1989). A review of quinolone tissue pharmacokinetics. In Quinolones (Fernandes, P. B., Ed.), pp. 277-312. J. R. Prous Science, Barcelona. Davies, B. I., Maesen, F. P. V., Geraedts, W. H. & Baur, C. (1987). Penetration of ofloxacin from blood to sputum. Drugs 34, Suppl. 1, 26-32. Easmon, C. S. F. & Crane, J. P. (1985). Uptake of ciprofloxacin by macrophages. Journal of Clinical Pathology 38, 442-4. EUner, P. D. & Neu, H. C. (1981). The inhibitory quotient: a method for interpreting minimum inhibitory concentration data. Journal of the American Medical Association 246, 1575-8. Forst, H., Ruskdeschel, G., Unerts, K., Martin, E., Ehret, W. & Sunder-Plassman, L. (1987). Lung tissue concentrations of ciprofloxacin in patients. In Progress in Antimicrobial and Anticancer Chemotherapy (Berkarda, B. & Kuemmerle, H. P., Eds), pp. 1977-9. Ecomed Verlag, Landsberg. Grassi, C , Grassi, G. G. & Mangiarotti, P. (1987). Clinical efficacy of ofloxacin in lower respiratory tract infections. Drugs 34, Suppl. 1, 80-2. Loos, V., Schwabe, H. K. & Vogel, F. (1987). Ofloxacin concentrations in human plasma, bronchial secretions, bronchoalveolar lavage and alveolar macrophages. Program and Abstracts of the 15th International Congress of Chemotherapy, Istanbul, 1987. Abstract 78. Maesen, F. P. V., Davies, B. I., Geraedts, W. H. & Baur, C. (1987). The use of quinolones in respiratory tract infections. Drugs 34, Suppl. 1, 74-9. Morel, C , Malbruny, B., Vcrgnaud, M., Bernard, Y. & Monrocq, N. (1986). Diffusion de l'ofloxacine administree a une dose unique par voie orale dans le mucus bronchique chez rhomme. Pathologic Biologie 34, 353-6. Pascual, A., Garcia, I. & Perea, E. J. (1989). Fluorometric measurement of ofloxacin uptake by human polymorphonuclear leukocytes. Antimicrobial Agents and Chemotherapy 33, 653-6. Pascual, A., Garcia, I. & Perea, E. J. (1990). Uptake and intracellular activity of an optically active ofloxacin isomer in human neutrophils and tissue culture cells. Antimicrobial Agents and Chemotherapy 34, 277-80. Perea, E. J., Garcia Iglesias, M. C , Ayarra, J. & Loscertales, J. (1983). Comparative concentrations of cefoxitin in human lungs and sera. Antimicrobial Agents and Chemotherapy 23, 323-4. Perea, E. J., Loscertales, J., Corcia, S., Ayarra, J. & Garcia-Iglesias, M. (1986). Management of post-operatory respiratory infections following general surgery. Research and Clinical Forums 8, 57-69. Ritzerfeld, W., Zimmermann, I. & Ubner, W. (1985). In vivo studies with ofloxacin. In Ofloxacin: Broad Spectrum Antibacterial Agent (Ishigami, Ed.), pp. 21-2. Proceedings of the 14th International Congress of Chemotherapy, Kyoto. University of Tokyo Press, Tokyo. Saito, A., Katsu, M. & Soejiwa, R. (1987). Ofloxacin in respiratory tract infection: a review of the results of clinical trials in Japan. Drugs 43, Suppl. 1, 83-9. Syrnonds, J., Bone, M., Turner, A. & Javaid, A. (1987). Penetration of ofloxacin into bronchial secretions. Drugs 34, Suppl. 1, 33-6. Wijnands, W. J. A., Vree, T. B., Baars, A. M., Hafkenscheid, C. M., Kholer, B. E. M. & Herwaarden, C. L. A. (1988). The penetration of ofloxacin into hing tissue. Journal of Antimicrobial Chemotherapy 22, Suppl. C, 85-9. Yamaguchi, K., Nakazato, H., Koga, H., Watanabe, K. & Tomita, H. (1984). Laboratory studies and clinical evaluation of DL8280 in patients with respiratory infections. Chemotherapy (Tokyo) 32, Suppl. 1, 487-508.
Ofloxacin concentrations in tissues involved in respiratory tract infections Evelio J. Perea
The literature on the penetration of ofloxacin from blood to respiratory tissue and secretions in patients is reviewed. In patients with acute purulent exacerbations of chronic bronchitis ofloxacin has a C^ value in sputum of 2-7 mg/1 after a 400 mg oral dose, 6-1 mg/1 after 600 mg and 6-3 mg/1 after 800 mg. Penetration from blood to sputum varied from 80 to 100%. The concentration of ofloxacin in bronchial aspirate, 1 to 6 h after a single oral dose of 400 mg, varied between 11 and 4-5 mg/1. The ratio between simultaneous mean bronchial aspirate and serum concentrations ranged between 0-53 in the second hour and 0-92 in the fourth hour. Ofloxacin concentrations in bronchoalveolar lavage fluid following an oral dose of 200 mg twice daily for at least four days amounted to 8-3 mg/1 with a corresponding serum concentration of 1-7 mg/1fivehours after the last dose. The distribution ratio between lavage fluid and serum was 4-9. The lung tissue penetration of ofloxacin after a dosage of 200 mg twice daily, reached a mean tissue plasma concentration ratio of 3-5 ±0-4 for healthy tissue and 3-9 ±0-4 for diseased tissue. Ofloxacin reaches high intracellular concentrations in polymorphonudear leucocytes, alveolar macrophages, epithelial cells and fibroblasts. It is likely that these concentrations will have a sustained inhibitory and bactericidal activity against most potential respiratory pathogens including: Haemophihis influenzae, Branhamella catarrhalis, Gram-negative bacilli, Staphylococcus aureus, Legionella pneumophila, Chlamydia spp. and Coxiella bumetti.
Introduction To predict a' therapeutic success in the treatment of an infection it is not only necessary to know the sensitivity of the infective agent, but also the antimicrobial concentration attained at the site of the infection. In general it has been found that the higher the inhibitory quotient (Ellner & Neu, 1981), i.e. the relationship between the concentration of antimicrobial agent at the site of the infection and the minimum inhibitory concentration (MIC) of the causative organism, the greater the chance of successful treatment. The different results obtained with one antimicrobial agent at the same dosage can be explained by different methodologies in the preparation and processing of specimens used, especially in lung tissue because of its high blood content. Tissue penetration can be deduced from the distribution volume. For quinolones the volume of distribution ranges from 100 to 300 1, being approximately 100 1 for 55 0305-7453/90/26D055 + 06 S02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Department of Microbiology, University of Seville Medical School, Seville 41080, Spain
56
£. J. Perea
ofloxacin, thus indicating that tissue concentrations should either be within the same range as the corresponding serum concentrations or higher. However pharmacokinetic parameters do not differentiate non-homogeneous distribution within various tissues (Dalhoff, 1989). In this paper I summarize the data available on ofloxacin penetration into cells, tissues and secretions of the respiratory tract. Penetration into sputum
Table L Ofloxacin penetration from blood to sputum following oral administration of single or multiple doses
Dose (rngT
200 200 400 400 600 800 200 bid
Sputum concentration' (mg/kg)
Patients (no.)
Sampling time*
10 4 5 15 37 36 11
3-6 MP MP MP MP MP
0*-2-5 3-08 5-22
Day 6
1-2-9
2-7 6-1 6-3
References Morel et al. (1986) Yamaguchi et al. (1984) Yamaguchi et al. (1984) Davies et al. (1987) Davies et al. (1987) Davies et al. (1987) Ritzerfeld et al. (1985)
'Single dose unless otbcrwuc indicated. * Hours after dose or time of peak concentration (mean peak, MP). 'Mean peak concentration or minimum and maximum individual concentration.
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Several pharmacokinetic studies were carried out in patients with chronic bronchitis who suffered from recurring acute purulent exacerbations. In these patients the site of infection can be considered as the bronchial mucosa. The drug concentration in the mucosa can be measured in biopsy material and may be relevant but there are few data available. The sputum model has been chosen instead because of the availability of the material. - Davies et al. (1987) carried out a large study on penetration of ofloxacin into sputum in nearly 100 patients with acute purulent exacerbations of chronic respiratory diseases after a single 400, 600 or 800 mg dose of ofloxacin. Both blood and sputum samples were taken simultaneously at different time intervals after dosage and concentrationtime curves were constructed. Maximal concentrations (C^ in serum and sputum were 3-7 and 2-7 mg/1respectivelyafter 400 mg ofloxacin, 71 and 6-1 mg after 600 mg and 88 and 6-3 after 800mg. Penetration from blood to sputum as judged from the ratio of values of Catx and area under the curve (AUC) of sputum and serum ranged from 78% to 103% (Davies et al., 1987). In a series of studies performed with a more limited number of patients with single or multiple doses of ofloxacin similar or higher sputum levels were obtained (Table I). (Yamaguchi et al., 1984; Ritzerfeld, Zimmerman & Ulmer, 1985; Morel et al., 1986). The importance of the penetration of an antimicrobial from blood to sputum is relevant to the clinical and microbiological results of treating patients with this agent (Davies et al., 1987). It is clear from the clinical results with ofloxacin and other quinolones that higher sputum concentrations of ofloxacin (such as those attained 8rter
Ofloxadn penetration in respiratory tract
57
800 mg dosage) are more efective in the bronchial eradication of organisms such as pneumococci, whose susceptibility is no more than moderate (Maesen et al., 1987). Nevertheless, in general, good clinical results were obtained with doses of 200, 300, and 400 mg daily (Grassi, Grassi & Mangiarotti, 1987; Saito, Katsu & Soejiwa, 1987). Ofloxadn penetration into bronchial secretions
Long tissue penetration Only two studies have been carried out to determine the lung tissue penetration of ofloxadn. In one study after a single oral 600 mg dose of ofloxadn, concentrations were measured in lung tissue and plasma in 11 patients undergoing thoracotomy. After correction for blood admixture, the mean lung tissue concentration 2 h after administration of ofloxadn was 17-7 ±4-2 mg/1. The tissue/plasma ratio was 2:1 (Wijnands et al., 1988). In the second study of ofloxadn penetration into lung tissue, a 200 mg dose was administered orally every 12 h for 48 h preceding the surgical operation and a fifth dose was given 1 h before surgery. During the surgical procedure serum samples and spedmens of healthy and diseased lung tissue were taken at a time of 2-5 ±0-5 h after the last dose of ofloxadn. During surgery the mean plasma concentration was 1-9 ±0-2 mg/1 and the pulmonary tissue concentrations corresponding to these plasma
Table EL Ofloxadn bronchial secretion concentrations after a single oral dose of 400 mg (Symonds et al., 1987)
Time intervals (min) 60-120 121-180 181-240 241-300 301-360
Mean concentration (mg/1)
Bronchial secretion serum ratio
1-6 1-7 1-8 2-2 2-5
0-53 0-73 0-92 0-48 0-98
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Symonds et al. (1987) studied the penetration of ofloxadn into bronchial secretions aspirated at bronchoscopy; they evaluated 16 patients 1-6 h after the administration of a single oral dose of ofloxadn 400 mg. Considerable individual variations in serum and bronchial aspirate concentrations were recorded. Bronchial aspirate concentrations varied from 11 to 4-5 mg/1 and exceeded 1-5 mg/1 in 14 of the 16 patients between 1 and 6 h (Table II). The ratio between simultaneous mean bronchial aspirate and serum concentrations ranged between 0-53 in the second hour and 0-98 in the fourth hour (Symonds et al., 1987). Similar values were obtained by Loos, Schwabe & Vogel (1987). Ofloxadn concentrations in bronchoalveolar lavage fluid, following an oral dose of 200 mg twice daily for at least four days, amounted to 8-3 mg/1 with a corresponding serum concentration of 1-7 mg/1 at 5 h after the last dose (Loos et al., 1987) This corresponds well with the results of ofloxadn lung tissue levels. However, no information is given on calculation of the dilution factor in the specimens of lavage fluid.
58
E. J. Perea Table m . Quinolones concentrations in lung tissue (Forst et al., 1987; Dalhoflf, 1989)
Dose Ciprofloxacin Enoxacin Pefloxacin Ofioxacin
200 iv 2x500 p o 4 d 2x400 po 2d 400 iv 2x200 p o 2 d 600 po
Serum (mg/1)
Lung (mg/kg)
10 10
3-2 1-7 12
1-85 7-28 1-95
8-7
13-8
6-7 17-7
Ratio
3-2 1-7 6-5 1-9 3-4 21
Ofloxadn penetration into cells of the respiratory tract Atypical p n e u m o n i a is a frequent syndrome caused by intracellular pathogens such as: Coxiella bumetii, Legionella spp. and Chlamydia spp. The intracellular penetration and activity of antimicrobial agents can be a n important factor in the treatment of infections caused by these pathogens. Ofioxacin penetrates into h u m a n polymorphonuclear leucocytes ( P M N s ) reaching high intracellular concentrations (intracellular/extracellular ratios of 8-3 and 7 at extracellular concentrations of 2 and 5 mg/1 at 20 min). Ofioxacin has a rapid and
Table IV. Lung tissue concentrations of different antibiotics (Perea et al., 1986)
No. of patients
11 11 12 11 12
Dose iv (nig)
750 1000 1000
100 1000
Antibiotic cefuroxime cefoxitin cefoperazone tobramycdn ceftazidime
Tissue concentration/serum concentration ratio at the stated time after dosage 60 min 120 min l-22±0O8 l-26±O13 0-34±0-03 O46±0O4 0-88±0-12 0-50±0-ll no levels were detected in lung tissue 0-27±0-14 0-2910-11
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
levels were 6-7 ± 1 mg/1 for the healthy tissue and 7-3 ± 1 mg/1 for the diseased tissue ( C o u r a u d et al., 1987). The ratios of the mean tissue to plasma concentrations were 3-5 ± 0 - 4 for healthy tissue and 3 - 9 ± 0 4 for diseased tissue. These results indicate good diffusion of ofioxacin into healthy and atelectatic p u l m o n a r y tissue after single or multiple oral doses. Ofioxacin reaches higher concentrations in lung tissue than other quinolones at a similar dose administered orally or intravenously (Dalhoff, 1989) (Table III). These drugs are concentrated in lung tissue from two- t o six-fold irrespective of the n u m b e r of doses and route of administration. T h r o u g h o u t the study periods of 1-12 h, quinolone concentrations in lung tissue are consistently higher than the corresponding serum concentrations. C o m p a r e d with other antimicrobials such as the cephalosporins, which in general reach pulmonary tissue concentrations lower than the simultaneous serum levels (Table IV), and the aminoglycosides which penetrate poorly and slowly, the quinolones penetrate much better (Ayarra, et al., 1982; Perea et al., 1983, 1986).
OBoxadn penetration in respiratory tract
59
Table V. Ofloxacin intracellular penetration in PMNs, epithelial cells and fibroblasts (Pascual et al., 1989, 1990) Cells PMN HEp-2 MCCOY MDCK VeRo
Cellular/extracellular C/P 6-7±l-2 21 ±0-2 3-9±ll 21±0-9 3-411-2
active penetration mechanism and remains active intracellularly (Pascual, Garcia & Perea, 1989). This compound also shows a high penetration into tissue culture epithelial cells and fibroblasts (Pascual, Garcia & Perea, 1990) (Table V). As with other quinolones, ofloxacin penetrates well into alveolar macrophages, (Easmon & Crane, 1985; Carlier et al., 1987) (Table VI). All four cell types are important components of the respiratory tract tissues and they will also host most of the respiratory pathogens. The high intracellular ofloxacin concentrations establish a favourable pharmacokinetic situation that should ensure the success in the treatment of respiratory tract infections with this antimicrobial agent. Conclusion Ofloxacin has excellent activity against most of the classical respiratory pathogens such as Haemophilus influenzae, Branhamella catarrhalis and Legionella spp. Also Escherichia coli and most strains of Klebsiella and Enterobacter spp. are sensitive. Ofloxacin inhibits most strains of Streptococcus pneumoniae and Pseudomonas aeruginosa at 1 mg/1. Against Mycoplasma pneumoniae ofloxacin shows intermediate activity. The excellent penetration of ofloxacin into sputum, bronchial secretions and lung tissue should allow for the effective therapy of such pathogens in respiratory tract infections. Also the marked intracellular penetration should ensure that ofloxacin is effective in the treatment of atypical pneumonia caused by intracellular pathogens such as Legionella, Chlamydia and Coxiella spp. Table VI. Intracellular penetration of different quinolones (Carlier et al., 1987)
Drug Ciprofloxadn Ofloxacin Pefloxacin Fleroxacin
Ratio intra/extracellular Alveolar macrophages PMNs 81111 7-110-3 6-911-7 —
4-610-1 2110-1 4-010-1 2-010-1
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
The extracellular concentration was 5 mg/1; incubation 20 min.
60
E.J. Perea References
Downloaded from http://jac.oxfordjournals.org/ at University of Regina on September 7, 2015
Ayarra, J., Garcia Iglcsias, M. C, Loscertales, J. & Perea, E. J. (1982). Lung tissue concentration of cefoperazone. In Current Chemotherapy and Immunotherapy (Peritti, P. & Grassi, G. G., Eds), pp. 627-8. American Society for Microbiology, Washington, DC. Carlier, M. B., Scomeaux, B., Jenebergh, A. & Tulkens, P. M. (1987). Uptake and subcellular distribution of 4-quinolones in phagocytes. Proceedings of the 27th Interscience Conference on Antimicrobial Agents Chemotherapy, Washington, 1987. Abstract, 622. Couraud, L., Fourtillan, J. B., Saux, M. G, Bryskier, A. & du Laurier, M. V. (1987). Diffusion of ofloxacin into human lung tissue. Drugs 33, Suppl. 1, 37-8. Dalhoff, A. (1989). A review of quinolone tissue pharmacokinetics. In Quinolones (Fernandes, P. B., Ed.), pp. 277-312. J. R. Prous Science, Barcelona. Davies, B. I., Maesen, F. P. V., Geraedts, W. H. & Baur, C. (1987). Penetration of ofloxacin from blood to sputum. Drugs 34, Suppl. 1, 26-32. Easmon, C. S. F. & Crane, J. P. (1985). Uptake of ciprofloxacin by macrophages. Journal of Clinical Pathology 38, 442-4. EUner, P. D. & Neu, H. C. (1981). The inhibitory quotient: a method for interpreting minimum inhibitory concentration data. Journal of the American Medical Association 246, 1575-8. Forst, H., Ruskdeschel, G., Unerts, K., Martin, E., Ehret, W. & Sunder-Plassman, L. (1987). Lung tissue concentrations of ciprofloxacin in patients. In Progress in Antimicrobial and Anticancer Chemotherapy (Berkarda, B. & Kuemmerle, H. P., Eds), pp. 1977-9. Ecomed Verlag, Landsberg. Grassi, C , Grassi, G. G. & Mangiarotti, P. (1987). Clinical efficacy of ofloxacin in lower respiratory tract infections. Drugs 34, Suppl. 1, 80-2. Loos, V., Schwabe, H. K. & Vogel, F. (1987). Ofloxacin concentrations in human plasma, bronchial secretions, bronchoalveolar lavage and alveolar macrophages. Program and Abstracts of the 15th International Congress of Chemotherapy, Istanbul, 1987. Abstract 78. Maesen, F. P. V., Davies, B. I., Geraedts, W. H. & Baur, C. (1987). The use of quinolones in respiratory tract infections. Drugs 34, Suppl. 1, 74-9. Morel, C , Malbruny, B., Vcrgnaud, M., Bernard, Y. & Monrocq, N. (1986). Diffusion de l'ofloxacine administree a une dose unique par voie orale dans le mucus bronchique chez rhomme. Pathologic Biologie 34, 353-6. Pascual, A., Garcia, I. & Perea, E. J. (1989). Fluorometric measurement of ofloxacin uptake by human polymorphonuclear leukocytes. Antimicrobial Agents and Chemotherapy 33, 653-6. Pascual, A., Garcia, I. & Perea, E. J. (1990). Uptake and intracellular activity of an optically active ofloxacin isomer in human neutrophils and tissue culture cells. Antimicrobial Agents and Chemotherapy 34, 277-80. Perea, E. J., Garcia Iglesias, M. C , Ayarra, J. & Loscertales, J. (1983). Comparative concentrations of cefoxitin in human lungs and sera. Antimicrobial Agents and Chemotherapy 23, 323-4. Perea, E. J., Loscertales, J., Corcia, S., Ayarra, J. & Garcia-Iglesias, M. (1986). Management of post-operatory respiratory infections following general surgery. Research and Clinical Forums 8, 57-69. Ritzerfeld, W., Zimmermann, I. & Ubner, W. (1985). In vivo studies with ofloxacin. In Ofloxacin: Broad Spectrum Antibacterial Agent (Ishigami, Ed.), pp. 21-2. Proceedings of the 14th International Congress of Chemotherapy, Kyoto. University of Tokyo Press, Tokyo. Saito, A., Katsu, M. & Soejiwa, R. (1987). Ofloxacin in respiratory tract infection: a review of the results of clinical trials in Japan. Drugs 43, Suppl. 1, 83-9. Syrnonds, J., Bone, M., Turner, A. & Javaid, A. (1987). Penetration of ofloxacin into bronchial secretions. Drugs 34, Suppl. 1, 33-6. Wijnands, W. J. A., Vree, T. B., Baars, A. M., Hafkenscheid, C. M., Kholer, B. E. M. & Herwaarden, C. L. A. (1988). The penetration of ofloxacin into hing tissue. Journal of Antimicrobial Chemotherapy 22, Suppl. C, 85-9. Yamaguchi, K., Nakazato, H., Koga, H., Watanabe, K. & Tomita, H. (1984). Laboratory studies and clinical evaluation of DL8280 in patients with respiratory infections. Chemotherapy (Tokyo) 32, Suppl. 1, 487-508.
