Journal of Antimicrobial Chemotherapy (1992) 30, 67-71
Concentrations of cefpodoxime in serum and bronchial mocosal biopsies David R. Baldwin', Richard Wise*, Jennifer M. Andrews* and David Honeyboaroe'
'Department of Thoracic Medicine;lDepartment of Medical Microbiology, Dudley Road Hospital, Birmingham B18 7QH, UK
Introduction
A recent approach to the assessment of antimicrobial agents for use in infections of the respiratory tract has been to measure the drug concentrations in bronchial mucosal biopsies (Martin et a!., 1981, 1984; Baldwin et al., 1990, 1991). The rationale for this approach is that antibiotic concentration at the site of infection may differ markedly from that in serum, and clinical efficacy may correlate with the concentrations of antibiotic at the site of infection. Bronchial mucosal biopsies represent such a site in bronchial infections. There are few orally available ccphalosporins that have been assessed in this way and therefore we report our findings for cefpodoxime proxetil, the orally administered ester of cefpodoxime a /Mactam that has favourable activity against pathogens commonly found in acute exacerbations of chronic bronchitis (Wise et al., 1990). Materials and method
Thirteen patients (ten male) who were undergoing fibreoptic bronchoscopy for diagnostic purposes were administered a single dose of cefpodoxime proxetil equivalent to cefpodoxime base 200 mg between 1 and 6 h before bronchoscopy after fasting for 9 h. The indications for bronchoscopy were focal radiographic abnormality, (six patients), haemoptysis, (three patients), and bronchial neoplasm, (four patients). Subjects had a mean age of 71 years (range 47-85) and mean weight of 65 kg (range 48-90). Exclusion criteria were: active pulmonary infection, hypersensitivity to 0-lactam antibiotics, 67 0305-7453/92/070067+05 $02.00/0
© 1992 The Brituh Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
Cefpodoxime proxetil is a new orally administered cephatosporin which has a favourable spectrum of activity against respiratory pathogens. Concentrations of cefpodoxime in serum and bronchial mucosal biopsy were measured in 13 patients without active respiratory tract infection undergoing fibreoptic bronchoscopy. Samples were taken between 1 and 6 h after a single oral dose of cefpodoxime proxetil equivalent to 200 mg of cefpodoxime base. In twelve patients who completed the study, mean serum concentrations were 1-7 mg/L (S.E.M. (M) and in ten patients mean bronchial biopsy concentrations were 0-9 mg/L (S.EJI. 0-2). The mean penetration was 54% (SXM. 6-1). Cefpodoxime was undetectable in biopsies from two patients. The majority of serum and biopsy concentrations were in excess of the MIQgS for Haemophihis tnfluenzae and Streptococcus pneumoniae. Cefpodoxime proxetil may be worthy of further study in clinical trials in patients with respiratory infections.
68
D. R. Baldwin et aL
Percentage penetration was denned as: Biopsy concentration (mg/kg) x 100 Serum concentration (mg/L) Results The Table shows the serum and bronchial biopsy concentrations of cefpodoxime, percentage penetration and biopsy weights for each subject. The figure shows the cefpodoxime concentrations plotted with respect to time of dose. Using the MIC^s of Wise et al. (1990) concentrations in serum and biopsy samples were greater than the MICJO for Haemophilus influenza*, and Streptococcus pneumoniae (0-12 and 0-06 mg/L respectively) and were mostly above that for Moraxella catarrhalis (0-5 mg/L). The MIC*, for Staphylococcus aureus (4 mg/L) was exceeded in a single serum sample and in no biopsies. The mean percentage penetration was 54%. Cefpodoxime concentrations of > 0-4 mg/L were found up to 4-8 h after dosing. In two subjects with low serum concentrations, bronchial biopsy concentrations were below the limit of detection. One patient was excluded due to probable concomitant use of another antimicrobial agent. Discussion
The sites of bronchial infection are the sputum and bronchial mucosa (Hers & Mulder, 1953). There are well documented methodological problems with the measurement of sputum concentrations including sputum pooling, drug instability and contamination with blood and saliva (Bergogne-Berezin, 1981; Pennington, 1981).
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
administration of antimicrobial agents in the previous two weeks, significant hepatic or renal impairment (serum transaminase greater than twice the upper limit of normal, crcatininc > 140 umol/L) and women of child bearing potential. All subjects gave informed written consent and the study was approved by the hospital Ethics Committee. Bronchoscopy was performed after premedication with atropine 0-6 mg im, nebulized 4% lignocaine 160 mg and midazolam 2-7 mg iv. After careful inspection of the airways and before any diagnostic samples were taken, three to four bronchial biopsies were taken from macroscopically normal subcarinae (mucosa free from erythema, nodularity, abnormal friability or oedema). A blood sample was taken simultaneously. Biopsies were immediately transferred into a humidity chamber and transported to the laboratory for assay. Any bloodstained biopsies were discarded and the remaining samples were weighed and a measured volume of cold phosphate buffer (pH 7-0) added. The samples were homogenized by ultrasonication on ice for 2 min at 50% duty cycle (W225 sonicator, Heat Systems Ultrasonics Ltd, UK). Serum samples were assayed using a microbiological method in which the indicator strain (Morganella morganii) was incorporated into No. 2 agar (Oxoid, Basingstoke, UK). For biopsy specimens the indicator organism was Proteus rettgeri 12186 inoculated onto pre-poured plates of agar No. 1 (Oxoid, Basingstoke, UK). Assay plates were incubated at 37°C for 18 h. Standards for biopsy samples were prepared in phosphate buffer pH 7-0 and standards for serum samples were prepared in 100% human serum. Antibiotic-free homogenized bronchial biopsies had no inhibitory effect on the assay organism. The between-assay c.v. was 6-7% for both assays and the lower limit of sensitivity was 0-12 mg/L for serum and 0-02 mg/kg for biopsy samples.
Cefpodoxime in auuiu and bronchial
69
0-12 mg/L MIC*) f o r Spntumonlot
r
0
1
2
3
4
5
Tltt»(h) Flgare. Concentrations of cefpodoxime in serum (A) and bronchial mucosa ( • ) after oral administration.
All /Mactams studied to date show a similar penetration into the bronchial mucosa of between 35 and 55% (Marlin et al., 1981, 1984; Honeybourne et al., 1988; Baldwin et al., 1990, 1991). Review of the available data shows that there are no significant differences between the mean values for different /Mactams. This observation may be explained by the relatively poor permeability characteristics of /Mactams which makes them unable to penetrate cell membranes (Johnson et al., 1980). They are, however, more likely to penetrate into the extracellular fluid because pulmonary capillary
Table. Concentrations of cefpodoxime in serum and bronchial mucosa after oral administration of cefpodoxime proxetil Time
(h) 10 1-0 M 1-4 1-5 1-6 1-9 2-2 2-4 30 3-7 4-8 Mean 21 S.E.M. 0-3
Concentration serum (mg/L)
Bronchial biopsy (mg/kg)
1-6 11 11 0-1 51 1-7
0-5 0-5 09 ND 2-2 0-9 0O9 1-4 ND 09 10 05 O9 02
0-11
31 06 2-7 21 06 1-7 04
ND, No detectable antibiotic.
Penetration
(%) 340 42-9 82-5
— 43-5
5O6 81-8 44-3 34-4 45-7
780 53-7
6-1
Biopsy weight (n»g)
81 6-6 3-3 9-5 6-2 71 120 7-6 7-6 5-7 111 94 7-8 07
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
01
70
D. R. Baldwin et aL
References Baldwin, D. R., Andrews, J. M., Ashby, J. P., Wise, R. & Honeybouroe, D. (1990). Concentrations of cefixime in bronchial mucosa and sputum after three oral multiple dose regimens. Thorax 45, 401-2. Baldwin, D. R., Maxwell, S. R. J., Honeybournc, D., Andrews, J. M., Ashby, J. P. & Wise, R. (1991). The penetration of cefpirome into the potential sites of pulmonary infection. Journal of Antimicrobial Chemotherapy 28, 79-86. Bergogne-Berezin, E. (1981). Penetration of antibiotics into the respiratory tree. Journal of Antimicrobial Chemotherapy 8, 171-4. Efiros, R. M., Mason, G. R., Silverman, P., Reid, E. &. Hukkanen, J. (1986). Movement of ions and small solutes across endothelium and epithelium of perfused rabbit lungs. Journal of Applied Physiology 60, 100-7. Hers, J. F. P. & Mulder, J. (1953). The mucosal epithelium of the respiratory tract in mucopurutent bronchitis caused by Haemophilus inftuemae. Journal of Pathology and Bacteriology 66, 103-8. Honeybourne, D., Andrews, J. M., Ashby, J. P., Lodwick, R. & Wise, R. (1988). Evaluation of the penetration of ciprofloxacm and amoxycillin into the bronchial mucosa. Thorax 43, 715-9. Ingold, A. (1975). Sputum and serum levels of amoxycillin in chronic bronchial infections. British Journal of Diseases of the Chest 69, 211—6. Johnson, J. D., Hand, W. L., Francis, J. B., King-Thompson, N. & Corwin, R. W. (1980). Antibiotic uptake by alveolar macrophages. Journal of Laboratory and Clinical Medicine 95, 429-39. Maesen, F. P. V., Beeuwkes, H., Davies, B. I., Bujtendiit, H. J., Brombacher, P. J. & Wessman, J. (1976). Bacampicillin in acute exacerbations of chronic bronchitis—a dose range study. Journal of Antimicrobial Chemotherapy 2, 279-85. Martin, G. E., Burgess., K. R., Burgoyne, J., FunneU, G. R. & Guinness, M. D. G. (1984). Penetration of piperacillin into bronchial mucosa and sputum. Thorax 36, 774-80. Martin, G. E., Nicholls, A. J., Funnel!, G. R. & Bradbury, R. (1984). Penetration of cefador into bronchia] mucosa. Thorax 39, 813-7. Pennington, J. E. (1981). Penetration of antibiotics into respiratory secretions. Reviews of Infectious Diseases 3, 67-73. Stewart, S. M., Anderson, I. M. E., Jones, G. R. & Calder, M. A. (1974). Amoxycillin levels in sputum, serum, and saliva. Thorax 29, 110-4.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
endothelium is relatively permeable (Wiebel, 1969; Effros et al., 1986). The extracellular water content of bronchial biopsies is approximately 40% of the total weight (Baldwin et al., 1991). This corresponds to the percentage penetration found for the /J-lactams and suggests that their distribution is mainly into the interstitial fluid of the biopsy. This is also consistent with the low penetration of /Mactams into sputum since an additional barrier must be traversed'—that of the bronchial epithelium. In the present study and other single-dose studies the percentage penetration was unrelated to the time of last dose (Table) indicating the rapid establishment of equilibrium between the bronchial tissues. In the presence of infection or inflammation the permeability of barriers may be greater. Penetration into sputum is greater during infections (Stewart et al., 1974; Ingold, 1975; Maesen et al., 1976)'but it is not clear whether this is due to destruction of epithelium, leading to release of antibiotic into sputum from the interstitial fluid, or due to an increase in permeability of the epithelial membrane and leakage of antimicrobial through intercellular junctions. After oral administration of cefpodoxime proxetil we found the concentrations of cefpodoxime in serum and bronchial mucosa to be above the MIC^ for H. influenzae and S. pneumoniae, cefpodoxime proxetil may be worthy of further study in appropriate clinical trials in patients with respiratory infections.
Cefpodoxtme tn tenan «"d lmm»hl«l nnn-g^m
71
Wise, R., Andrews, J. M., Ashby, J. P. & Thombcr, D. (1990). The in-vitro activity of cefpodoxime: a comparison with other oral cephalosporins. Journal of Antimicrobial Chemotherapy 25, 541-50. Wiebd, E. R. (1969). The ultraitmcture of the alveolar—capillary membrane or barrier. In 77K Pulmonary Circulation and Interstitial Space. (Fuhman, A. P. & Hecht, H. H., Eds), pp. 9-27. University of Chicago Press, Chicago, IL. (Received 30 October 1991; revised version accepted 24 February 1992)
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
Concentrations of cefpodoxime in serum and bronchial mocosal biopsies David R. Baldwin', Richard Wise*, Jennifer M. Andrews* and David Honeyboaroe'
'Department of Thoracic Medicine;lDepartment of Medical Microbiology, Dudley Road Hospital, Birmingham B18 7QH, UK
Introduction
A recent approach to the assessment of antimicrobial agents for use in infections of the respiratory tract has been to measure the drug concentrations in bronchial mucosal biopsies (Martin et a!., 1981, 1984; Baldwin et al., 1990, 1991). The rationale for this approach is that antibiotic concentration at the site of infection may differ markedly from that in serum, and clinical efficacy may correlate with the concentrations of antibiotic at the site of infection. Bronchial mucosal biopsies represent such a site in bronchial infections. There are few orally available ccphalosporins that have been assessed in this way and therefore we report our findings for cefpodoxime proxetil, the orally administered ester of cefpodoxime a /Mactam that has favourable activity against pathogens commonly found in acute exacerbations of chronic bronchitis (Wise et al., 1990). Materials and method
Thirteen patients (ten male) who were undergoing fibreoptic bronchoscopy for diagnostic purposes were administered a single dose of cefpodoxime proxetil equivalent to cefpodoxime base 200 mg between 1 and 6 h before bronchoscopy after fasting for 9 h. The indications for bronchoscopy were focal radiographic abnormality, (six patients), haemoptysis, (three patients), and bronchial neoplasm, (four patients). Subjects had a mean age of 71 years (range 47-85) and mean weight of 65 kg (range 48-90). Exclusion criteria were: active pulmonary infection, hypersensitivity to 0-lactam antibiotics, 67 0305-7453/92/070067+05 $02.00/0
© 1992 The Brituh Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
Cefpodoxime proxetil is a new orally administered cephatosporin which has a favourable spectrum of activity against respiratory pathogens. Concentrations of cefpodoxime in serum and bronchial mucosal biopsy were measured in 13 patients without active respiratory tract infection undergoing fibreoptic bronchoscopy. Samples were taken between 1 and 6 h after a single oral dose of cefpodoxime proxetil equivalent to 200 mg of cefpodoxime base. In twelve patients who completed the study, mean serum concentrations were 1-7 mg/L (S.E.M. (M) and in ten patients mean bronchial biopsy concentrations were 0-9 mg/L (S.EJI. 0-2). The mean penetration was 54% (SXM. 6-1). Cefpodoxime was undetectable in biopsies from two patients. The majority of serum and biopsy concentrations were in excess of the MIQgS for Haemophihis tnfluenzae and Streptococcus pneumoniae. Cefpodoxime proxetil may be worthy of further study in clinical trials in patients with respiratory infections.
68
D. R. Baldwin et aL
Percentage penetration was denned as: Biopsy concentration (mg/kg) x 100 Serum concentration (mg/L) Results The Table shows the serum and bronchial biopsy concentrations of cefpodoxime, percentage penetration and biopsy weights for each subject. The figure shows the cefpodoxime concentrations plotted with respect to time of dose. Using the MIC^s of Wise et al. (1990) concentrations in serum and biopsy samples were greater than the MICJO for Haemophilus influenza*, and Streptococcus pneumoniae (0-12 and 0-06 mg/L respectively) and were mostly above that for Moraxella catarrhalis (0-5 mg/L). The MIC*, for Staphylococcus aureus (4 mg/L) was exceeded in a single serum sample and in no biopsies. The mean percentage penetration was 54%. Cefpodoxime concentrations of > 0-4 mg/L were found up to 4-8 h after dosing. In two subjects with low serum concentrations, bronchial biopsy concentrations were below the limit of detection. One patient was excluded due to probable concomitant use of another antimicrobial agent. Discussion
The sites of bronchial infection are the sputum and bronchial mucosa (Hers & Mulder, 1953). There are well documented methodological problems with the measurement of sputum concentrations including sputum pooling, drug instability and contamination with blood and saliva (Bergogne-Berezin, 1981; Pennington, 1981).
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
administration of antimicrobial agents in the previous two weeks, significant hepatic or renal impairment (serum transaminase greater than twice the upper limit of normal, crcatininc > 140 umol/L) and women of child bearing potential. All subjects gave informed written consent and the study was approved by the hospital Ethics Committee. Bronchoscopy was performed after premedication with atropine 0-6 mg im, nebulized 4% lignocaine 160 mg and midazolam 2-7 mg iv. After careful inspection of the airways and before any diagnostic samples were taken, three to four bronchial biopsies were taken from macroscopically normal subcarinae (mucosa free from erythema, nodularity, abnormal friability or oedema). A blood sample was taken simultaneously. Biopsies were immediately transferred into a humidity chamber and transported to the laboratory for assay. Any bloodstained biopsies were discarded and the remaining samples were weighed and a measured volume of cold phosphate buffer (pH 7-0) added. The samples were homogenized by ultrasonication on ice for 2 min at 50% duty cycle (W225 sonicator, Heat Systems Ultrasonics Ltd, UK). Serum samples were assayed using a microbiological method in which the indicator strain (Morganella morganii) was incorporated into No. 2 agar (Oxoid, Basingstoke, UK). For biopsy specimens the indicator organism was Proteus rettgeri 12186 inoculated onto pre-poured plates of agar No. 1 (Oxoid, Basingstoke, UK). Assay plates were incubated at 37°C for 18 h. Standards for biopsy samples were prepared in phosphate buffer pH 7-0 and standards for serum samples were prepared in 100% human serum. Antibiotic-free homogenized bronchial biopsies had no inhibitory effect on the assay organism. The between-assay c.v. was 6-7% for both assays and the lower limit of sensitivity was 0-12 mg/L for serum and 0-02 mg/kg for biopsy samples.
Cefpodoxime in auuiu and bronchial
69
0-12 mg/L MIC*) f o r Spntumonlot
r
0
1
2
3
4
5
Tltt»(h) Flgare. Concentrations of cefpodoxime in serum (A) and bronchial mucosa ( • ) after oral administration.
All /Mactams studied to date show a similar penetration into the bronchial mucosa of between 35 and 55% (Marlin et al., 1981, 1984; Honeybourne et al., 1988; Baldwin et al., 1990, 1991). Review of the available data shows that there are no significant differences between the mean values for different /Mactams. This observation may be explained by the relatively poor permeability characteristics of /Mactams which makes them unable to penetrate cell membranes (Johnson et al., 1980). They are, however, more likely to penetrate into the extracellular fluid because pulmonary capillary
Table. Concentrations of cefpodoxime in serum and bronchial mucosa after oral administration of cefpodoxime proxetil Time
(h) 10 1-0 M 1-4 1-5 1-6 1-9 2-2 2-4 30 3-7 4-8 Mean 21 S.E.M. 0-3
Concentration serum (mg/L)
Bronchial biopsy (mg/kg)
1-6 11 11 0-1 51 1-7
0-5 0-5 09 ND 2-2 0-9 0O9 1-4 ND 09 10 05 O9 02
0-11
31 06 2-7 21 06 1-7 04
ND, No detectable antibiotic.
Penetration
(%) 340 42-9 82-5
— 43-5
5O6 81-8 44-3 34-4 45-7
780 53-7
6-1
Biopsy weight (n»g)
81 6-6 3-3 9-5 6-2 71 120 7-6 7-6 5-7 111 94 7-8 07
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
01
70
D. R. Baldwin et aL
References Baldwin, D. R., Andrews, J. M., Ashby, J. P., Wise, R. & Honeybouroe, D. (1990). Concentrations of cefixime in bronchial mucosa and sputum after three oral multiple dose regimens. Thorax 45, 401-2. Baldwin, D. R., Maxwell, S. R. J., Honeybournc, D., Andrews, J. M., Ashby, J. P. & Wise, R. (1991). The penetration of cefpirome into the potential sites of pulmonary infection. Journal of Antimicrobial Chemotherapy 28, 79-86. Bergogne-Berezin, E. (1981). Penetration of antibiotics into the respiratory tree. Journal of Antimicrobial Chemotherapy 8, 171-4. Efiros, R. M., Mason, G. R., Silverman, P., Reid, E. &. Hukkanen, J. (1986). Movement of ions and small solutes across endothelium and epithelium of perfused rabbit lungs. Journal of Applied Physiology 60, 100-7. Hers, J. F. P. & Mulder, J. (1953). The mucosal epithelium of the respiratory tract in mucopurutent bronchitis caused by Haemophilus inftuemae. Journal of Pathology and Bacteriology 66, 103-8. Honeybourne, D., Andrews, J. M., Ashby, J. P., Lodwick, R. & Wise, R. (1988). Evaluation of the penetration of ciprofloxacm and amoxycillin into the bronchial mucosa. Thorax 43, 715-9. Ingold, A. (1975). Sputum and serum levels of amoxycillin in chronic bronchial infections. British Journal of Diseases of the Chest 69, 211—6. Johnson, J. D., Hand, W. L., Francis, J. B., King-Thompson, N. & Corwin, R. W. (1980). Antibiotic uptake by alveolar macrophages. Journal of Laboratory and Clinical Medicine 95, 429-39. Maesen, F. P. V., Beeuwkes, H., Davies, B. I., Bujtendiit, H. J., Brombacher, P. J. & Wessman, J. (1976). Bacampicillin in acute exacerbations of chronic bronchitis—a dose range study. Journal of Antimicrobial Chemotherapy 2, 279-85. Martin, G. E., Burgess., K. R., Burgoyne, J., FunneU, G. R. & Guinness, M. D. G. (1984). Penetration of piperacillin into bronchial mucosa and sputum. Thorax 36, 774-80. Martin, G. E., Nicholls, A. J., Funnel!, G. R. & Bradbury, R. (1984). Penetration of cefador into bronchia] mucosa. Thorax 39, 813-7. Pennington, J. E. (1981). Penetration of antibiotics into respiratory secretions. Reviews of Infectious Diseases 3, 67-73. Stewart, S. M., Anderson, I. M. E., Jones, G. R. & Calder, M. A. (1974). Amoxycillin levels in sputum, serum, and saliva. Thorax 29, 110-4.
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
endothelium is relatively permeable (Wiebel, 1969; Effros et al., 1986). The extracellular water content of bronchial biopsies is approximately 40% of the total weight (Baldwin et al., 1991). This corresponds to the percentage penetration found for the /J-lactams and suggests that their distribution is mainly into the interstitial fluid of the biopsy. This is also consistent with the low penetration of /Mactams into sputum since an additional barrier must be traversed'—that of the bronchial epithelium. In the present study and other single-dose studies the percentage penetration was unrelated to the time of last dose (Table) indicating the rapid establishment of equilibrium between the bronchial tissues. In the presence of infection or inflammation the permeability of barriers may be greater. Penetration into sputum is greater during infections (Stewart et al., 1974; Ingold, 1975; Maesen et al., 1976)'but it is not clear whether this is due to destruction of epithelium, leading to release of antibiotic into sputum from the interstitial fluid, or due to an increase in permeability of the epithelial membrane and leakage of antimicrobial through intercellular junctions. After oral administration of cefpodoxime proxetil we found the concentrations of cefpodoxime in serum and bronchial mucosa to be above the MIC^ for H. influenzae and S. pneumoniae, cefpodoxime proxetil may be worthy of further study in appropriate clinical trials in patients with respiratory infections.
Cefpodoxtme tn tenan «"d lmm»hl«l nnn-g^m
71
Wise, R., Andrews, J. M., Ashby, J. P. & Thombcr, D. (1990). The in-vitro activity of cefpodoxime: a comparison with other oral cephalosporins. Journal of Antimicrobial Chemotherapy 25, 541-50. Wiebd, E. R. (1969). The ultraitmcture of the alveolar—capillary membrane or barrier. In 77K Pulmonary Circulation and Interstitial Space. (Fuhman, A. P. & Hecht, H. H., Eds), pp. 9-27. University of Chicago Press, Chicago, IL. (Received 30 October 1991; revised version accepted 24 February 1992)
Downloaded from http://jac.oxfordjournals.org/ at University of Manitoba on June 12, 2015
