Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. E, 41-46
Concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil R. Dumonf, F. Guetaf, J. M. Andrews*, E. Sultanr and B. Lenfanf
Eighteen patients of either sex with pleural effusions underwent aspiration 3, 6 or 12 h after receiving a single oral dose of cefpodoxime proxetil equivalent to 200 mg cefpodoxime. The mean concentrations of cefpodoxime in pleural fluid were, respectively, 0-62, 1-84 and 0-78 mg/1 for these three time intervals, the corresponding ratios between pleural fluid and plasma concentrations being 0-24, 0-67 and 1.07. The findings indicate that there is good penetration of cefpodoxime into pleural fluid. Concentrations between 3 and 12 h after dosing were equal to or above the MIQo for moat of the organisms commonly found in lower respiratory tract infections. Introduction Cefpodoxime proxetil is a prodrug that undergoes rapid hydrolysis by non-specific esterases in the bowel wall to yield the free acid, cefpodoxime—a new cephalosporin. This compound is effective against a wide range of Gram-positive and Gram-negative organisms, though exceptions are Streptococcus faecalis and Pseudomonas aeruginosa (Utsui, Inoue & Mitsuhashi, 1987; Chin & Neu, 1988; Jones & Barry, 1988). The compound is very active against Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, and Branhamella catarrhalis, which are the main pathogenic organisms found in lower respiratory tract infections. After oral administration of 200 mg cefpodoxime (as proxetil) the peak plasma concentration of cefpodoxime is 2-6 mg/1, reached after 2-4 h; the mean elimination half-life is 2-3 h; and between 30% and 50% of the administered dose is eliminated unchanged in the urine (Tremblay el al., 1990). Cefpodoxime is only weakly bound (40%) to plasma proteins (F. Bree, Roussel, data on file). No accumulation occurs after repeated doses up to 200 mg every 12 h for 14 days in healthy subjects (M. T. Bonn & K. K. Forbers, Roussel, data on file). Thus it was of interest to measure the concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of the prodrug, equivalent to 200 mg cefpodoxime. Patients and methods Patients and dosage Male and female patients between 18 and 75 years of age, with serous or serofibrinous pleural effusions, were studied; all gave signed informed consent to undergo pleural fluid aspiration. 0305-7453/90/26E041 +06 $02.00/0
41 © 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
'Department of Pneumology, Regional Hospital Centre, 01000 Bourg en Bresse, France; ^Dudley Road Hospital, Birmingham B18 7QH, UK; 'Institut Roussel Uclaf, 93230 Romainville, France
42
R. Damont et aL
Plasma and pleura! fluid samples
Blood samples (5 ml), obtained just before dosing and at the same time as pleural aspiration, were taken by venepuncture into dry lithium heparin tubes kept on ice and subsequently centrifuged at +4°C. The resultant plasma was stored at -70°C until assay. Samples of pleural fluid (15 ml) were collected into lithium heparin tubes on ice, centrifuged at +4 C C and the supernatant kept at -70°C until duplicate assay. The timing of sampling depended on the group to which each patient had been assigned. Assay of cefpodoxime and albumin Assay of cefpodoxime in plasma and pleural fluid was by a microbiological method (R. Wise & J. M. Andrews, Roussel Uclaf, data on file), the test organism being Providencia rettgeri (323 UC2). This method has a lower limit of sensitivity of 0-02 mg/1 for both plasma and pleural fluid and the coefficient of variation is ^ 10%. The assay of albumin was performed by a standard spectrophotometric method. Pharmacokinetic analysis The pharmacokinetic parameters measured or calculated were the plasma concentrations of cefpodoxime before dosing and plasma and pleural fluid concentrations at 3, 6 or 12 h after, depending on the group, the plasma concentrations of albumin before dosing and plasma and pleural fluid concentrations at 3, 6 or 12 h after, depending on the group, and the ratio of pleural fluid/plasma concentrations of cefpodoxime and albumin for synchronous samples. The three groups of patients were compared with one another by one-way analysis of variance followed by Tukey's test on patient demographic data, prothrombin ratio, serum creatinine, the ratio of pleural fluid/plasma concentrations of cefpodoxime, the plasma concentrations of albumin, the pleural fluid concentrations of albumin and the ratio of pleural fluid/plasma concentrations of albumin. In each group, the relation-
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
No patient was included in the study who showed severe impairment of liver function (defined as a prothrombin ratio of less than 50% and transaminases above twice the upper limit of normal) or renal failure (with a serum creatinine concentration of more than 180/zmol/l). Patients with a history of hypersensitivity to /?-lactam antibiotics (or who had received such antibiotics within the previous 48 h) were excluded from the study as were those receiving gastric adsorbants, antacid drugs or enzyme-inducing or -inhibiting drugs. Patients who had taken part in any clinical study during the previous two weeks or females who were (or were likely to become) pregnant were also excluded. No other medication was allowed during the study and a record was made of any treatment in progress. Full consideration was given to the ethical aspects of the study; ethics committee approval was obtained and the trial was conducted in accordance with FDA regulations on good clinical practice, in order to ensure quality of trial procedures and data. Each fasting patient received by mouth two 130mg tablets of cefpodoxime proxetil (equivalent to 200 mg cefpodoxime), swallowed with 150 ml water. The time of administration was chosen so that sampling could occur 3 h (group 1); 6 h (group 2) or 12 h (group 3) after administration of the drug.
Concentrations in plasma and pleura)
fluid
43
ships between the pleural fluid concentrations of cefpodoxime and the corresponding pleural fluid concentrations of albumin were tested by correlation analysis. For the pleural fluid/plasma ratio, in order to standardize the variances, the analysis was done on the logarithm of the ratio of the concentrations. The ratio was compared, in each group, with a theoretical value of 1 using Student's /-test. The plasma concentrations of albumin before dosing and at the various pleural fluid sampling times were compared with one another in each group using Student's /-test for paired data. The chosen level of significance was: a = 0-05 (two-tailed).
Eighteen patients (six in each group) were included in the study; although the intended study protocol was violated in the case of two patients, none was excluded from the subsequent analysis of data. The violations were two cases where the prothrombin ratio was less than 50% due to treatment with acenocoumarol. Cefpodoxime proxetil medication was in accord with the study protocol and no adverse events were reported at any time. The five men and 13 women had a mean age of 65-2 years, a mean weight of 59-8 kg and a mean height of 163-9 cm; these data and other demographic and biological aspects are summarized in Table I. No significant differences were found between the three groups for weight, height or serum creatinine; however, there were significant differences regarding age (P = 0-008; Tukey's test: difference between groups 1 and 3) and the prothrombin ratio (P = 005; Tukey's test: difference between groups 1 and 2). The pleural effusions in the patients studied derived from a variety of diseases: five patients with breast carcinoma, one with ovarian, one with thyroid, one with bronchial and one with unspecified carcinoma; two with adenocarcinoma; three with lung disease; three with congestive cardiac failure (in one complicated by myocardial infarction and in another by respiratory failure); and one with pulmonary embolism. As a result, a variety of concomitant medication was required for the management of these underlying conditions. The plasma and pleural fluid samples were obtained at the planned times after dosing; depending on the group, these mean times were 301 h (group 1), 6h (group2)
Table L Patient demographic data, prothrombin ratio and serum creatinine (mean±s.E.M.) Group 1 3h (« = 6)
Group 2 6h (n = 6)
Group 3 12 h
4/2 61-2±2-3
0/6 66-210-9
1/5 68-310-3
Weight (kg) Height (cm) Prothrombin ratio (%)
64-3 ±7-6 169-5 ±2-2 68-8 ±11-6
55-7 ±4-5 160-3 ±2-6 96-012-2
59-516-7 162-013-2 83-513-3
Creatinine (jtmo\fl)
104-5±12-7
950181
78-2140
Males/females Age (years)
NS, Not significant.
(71 = 6)
ANOVA P = 0-008 (group 1 vs group 3) NS NS P = 0-051 (group 1 vs group 3) NS
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
Results
R. Dmnont et aL
44
Table II. Plasma and pleural fluid concentrations of cefpodoxime, ratio of pleural fluid/plasma concentrations and sampling times
Plasma concentration (mg/1) mean±s.E.M.
range
Group 2 6h (n = 6)
Group 3 12 h (n =» 6)
2-73 ±0-34
2-72 ±0-32
0-77 ±0-14
1-49-3-80
1-49-3-52
0-35-1-21
l-84±0-33 1-02-302
O-78±O-10 0-41-1-09
0-67 ±008 0-50-0-95
107 ±008 0-74-1-34
6O±0O
12O±0O
Pleural fluid concentration (mg/1) mean±s.E.M.. 0-62±0-19 range 002-1-28 Pleura] fluid/plasma ratio 0-24±0-07 range 001-043 Sampling time (hours after dosing — mean±s.E.M.) plasma and pleural fluid 301 ±001
and 12 h (group 3). Where applicable, blood and pleural fluid samples were obtained synchronously. Cefpodoxime concentrations in plasma and pleural fluid
The means (±S.E.M.) for each group for the concentrations of cefpodoxime in plasma and pleural fluid, the corresponding pleural fluid/plasma ratios and the time intervals between dosing and sampling are presented in Table II. After dosing, the mean concentrations of cefpodoxime in pleural fluid were, according to group, 0-62 mg/1 (3 h); 1-84 mg/1 (6h); and 0-78 mg/1 (12 h) and the corresponding mean plasma concentrations were, respectively, 2-73, 2-72 and 0-77 mg/1. The mean pleural fluid/plasma ratios were: group 1: 0-24; group 2: 0-67; and group 3: 107. Analysis of variance showed a globally significant difference between the three groups and the mean for group 1 differed significantly from that for groups 2 and 3 (P = 0-003). Table III. Plasma and pleural fluid concentrations of albumin, ratio of pleural/ plasma concentrations of albumin (mean±s.E.M.)
Group 1 3h (n-6) Plasma albumin (g/1)
42-4 ±2-5
Pleura] fluid albumin (g/1) 22-8±4-9 Pleural fluid/plasma ratios albumin 0-49 ±0-11 NS, Not significant.
Group 2 6h
Group 3 12 h
38-7 ±2-7
37-2 ±21
NS
26-3 ±10
26-5 ±20
NS
0-70 ±005
0-72 ±0O6
NS
ANOVA
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
Group 1 3h (n = 6)
Concentrations in plasma and pleura]
fluid
45
Albumin concentrations in plasma and pleural fluid
Discussion The mean plasma concentration of cefpodoxime (2-73 ± 0-34 mg/1) at 3h after dosing was similar to that observed in healthy volunteers under similar conditions: 2-40 ±016 mg/1 (D. Tremblay et ai, Roussel Uclaf, data on file). However, the values found later after dosing were higher: 2-72 mg/1 compared with 1 -23 mg/1 after 6 h; and 0-77 mg/1 compared with 0-19 mg/1 after 12 h. These differences might be due to a slower rate of elimination in the patient population studied. The maximum concentration of cefpodoxime in pleural fluid was seen in group 2 (6 h after dosing); this observation suggests that the penetration of cefpodoxime into pleural fluid is relatively slow. The ratio between concentrations of cefpodoxime in pleural fluid and plasma increased during the 12 h study period after dosing—the values being 0-24, 0-67 and 107 for the three time intervals. Although the two latter values do not differ
3h group 1
6h group 2 Ttme(h)
12 h group3
Figure 1. Mean (±sx.v.) concentration of cefpodoxime in plasma (Q) and pleural fluid (H), 3, 6 and 12 h after a single oral dose of cefpodoxime proxetil 260 mg. MIC* for S.pneumoniae and H. influenza* ( ), K. pntumoniae and B . calarrhalis (•••).
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
Similarly, data and statistical evaluations for concentrations of albumin in plasma and pleural fluid and the corresponding pleural fluid/plasma ratios are given in Table III. The mean concentrations of albumin were, for groups 1, 2 and 3 respectively, 42-4, 38-7 and 37-2 g/1. Analysis of variance did not show a significant difference between the three groups. For albumin in the pleural fluid, the mean concentrations were 22-8, 26-3 and 26-5 g/1 for groups 1, 2 and 3 respectively. No significant differences between the three groups for these parameters were found. The mean pleural fluid/plasma ratios for albumin were: group 1: 0-49, group 2: 0-70 and group 3: 0-72. No statistical difference was found for these parameters between the three groups. Finally, an analysis within each group showed that there was no significant correlation between the pleural fluid concentrations of cefpodoxime and albumin.
46
R. Dnmont et aL
References Chin, N. X. & Neu, H. C. (1988). In vitro activity of an oral iminomethoxy aminothiazolyl cephalosporin, R-3746. Antimicrobial Agents and Chemotherapy 32, 671-77. Jones, R. N. & Barry, A. L. (1988). Antimicrobial activity and disk diffusion susceptibility testing of U-76,253 A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807). Antimicrobial Agents and Chemotherapy 32, 443-9. Tremblay, D., Dupront, C , Ho, C , Coussediere, D. & Lenfant, B. (1990). Phannacokinetics of cefpodoxime in young and elderly volunteers after single doses. Journal of Antimicrobial Chemotherapy TJL, Suppl. E, 21-8. Utsui, Y., Inoue, M. & Mitsuhashi, S. (1987). In vitro and in vivo antibacterial activities of CS-807 a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 1085-92.
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
significantly, these findings suggest that the rate of elimination of cefpodoxime from pleural fluid may be slower than from the plasma, at least until 12 h after dosing. The concentrations of cefpodoxime in pleural fluid between 3 and 12 h after administration of cefpodoxime proxetil were above or equal to the MIC*, (Utsui et al., 1987; Chin & Neu, 1988; Jones & Barry, 1988) for most of the organisms found in lower respiratory tract infections: S. pneumoniae, H. influenzae, K. pneumoniae, B. catarrhalis (Figure 1). The lack of correlation between the concentrations of cefpodoxime and albumin in pleural fluid is consistent with the compound's weak protein binding. These results indicate that, after administration of cefpodoxime proxetil, active cefpodoxime penetrates pleural fluid. This good penetration suggests it may be an effective oral agent for use in lower respiration infections.
Concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil R. Dumonf, F. Guetaf, J. M. Andrews*, E. Sultanr and B. Lenfanf
Eighteen patients of either sex with pleural effusions underwent aspiration 3, 6 or 12 h after receiving a single oral dose of cefpodoxime proxetil equivalent to 200 mg cefpodoxime. The mean concentrations of cefpodoxime in pleural fluid were, respectively, 0-62, 1-84 and 0-78 mg/1 for these three time intervals, the corresponding ratios between pleural fluid and plasma concentrations being 0-24, 0-67 and 1.07. The findings indicate that there is good penetration of cefpodoxime into pleural fluid. Concentrations between 3 and 12 h after dosing were equal to or above the MIQo for moat of the organisms commonly found in lower respiratory tract infections. Introduction Cefpodoxime proxetil is a prodrug that undergoes rapid hydrolysis by non-specific esterases in the bowel wall to yield the free acid, cefpodoxime—a new cephalosporin. This compound is effective against a wide range of Gram-positive and Gram-negative organisms, though exceptions are Streptococcus faecalis and Pseudomonas aeruginosa (Utsui, Inoue & Mitsuhashi, 1987; Chin & Neu, 1988; Jones & Barry, 1988). The compound is very active against Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, and Branhamella catarrhalis, which are the main pathogenic organisms found in lower respiratory tract infections. After oral administration of 200 mg cefpodoxime (as proxetil) the peak plasma concentration of cefpodoxime is 2-6 mg/1, reached after 2-4 h; the mean elimination half-life is 2-3 h; and between 30% and 50% of the administered dose is eliminated unchanged in the urine (Tremblay el al., 1990). Cefpodoxime is only weakly bound (40%) to plasma proteins (F. Bree, Roussel, data on file). No accumulation occurs after repeated doses up to 200 mg every 12 h for 14 days in healthy subjects (M. T. Bonn & K. K. Forbers, Roussel, data on file). Thus it was of interest to measure the concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of the prodrug, equivalent to 200 mg cefpodoxime. Patients and methods Patients and dosage Male and female patients between 18 and 75 years of age, with serous or serofibrinous pleural effusions, were studied; all gave signed informed consent to undergo pleural fluid aspiration. 0305-7453/90/26E041 +06 $02.00/0
41 © 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
'Department of Pneumology, Regional Hospital Centre, 01000 Bourg en Bresse, France; ^Dudley Road Hospital, Birmingham B18 7QH, UK; 'Institut Roussel Uclaf, 93230 Romainville, France
42
R. Damont et aL
Plasma and pleura! fluid samples
Blood samples (5 ml), obtained just before dosing and at the same time as pleural aspiration, were taken by venepuncture into dry lithium heparin tubes kept on ice and subsequently centrifuged at +4°C. The resultant plasma was stored at -70°C until assay. Samples of pleural fluid (15 ml) were collected into lithium heparin tubes on ice, centrifuged at +4 C C and the supernatant kept at -70°C until duplicate assay. The timing of sampling depended on the group to which each patient had been assigned. Assay of cefpodoxime and albumin Assay of cefpodoxime in plasma and pleural fluid was by a microbiological method (R. Wise & J. M. Andrews, Roussel Uclaf, data on file), the test organism being Providencia rettgeri (323 UC2). This method has a lower limit of sensitivity of 0-02 mg/1 for both plasma and pleural fluid and the coefficient of variation is ^ 10%. The assay of albumin was performed by a standard spectrophotometric method. Pharmacokinetic analysis The pharmacokinetic parameters measured or calculated were the plasma concentrations of cefpodoxime before dosing and plasma and pleural fluid concentrations at 3, 6 or 12 h after, depending on the group, the plasma concentrations of albumin before dosing and plasma and pleural fluid concentrations at 3, 6 or 12 h after, depending on the group, and the ratio of pleural fluid/plasma concentrations of cefpodoxime and albumin for synchronous samples. The three groups of patients were compared with one another by one-way analysis of variance followed by Tukey's test on patient demographic data, prothrombin ratio, serum creatinine, the ratio of pleural fluid/plasma concentrations of cefpodoxime, the plasma concentrations of albumin, the pleural fluid concentrations of albumin and the ratio of pleural fluid/plasma concentrations of albumin. In each group, the relation-
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
No patient was included in the study who showed severe impairment of liver function (defined as a prothrombin ratio of less than 50% and transaminases above twice the upper limit of normal) or renal failure (with a serum creatinine concentration of more than 180/zmol/l). Patients with a history of hypersensitivity to /?-lactam antibiotics (or who had received such antibiotics within the previous 48 h) were excluded from the study as were those receiving gastric adsorbants, antacid drugs or enzyme-inducing or -inhibiting drugs. Patients who had taken part in any clinical study during the previous two weeks or females who were (or were likely to become) pregnant were also excluded. No other medication was allowed during the study and a record was made of any treatment in progress. Full consideration was given to the ethical aspects of the study; ethics committee approval was obtained and the trial was conducted in accordance with FDA regulations on good clinical practice, in order to ensure quality of trial procedures and data. Each fasting patient received by mouth two 130mg tablets of cefpodoxime proxetil (equivalent to 200 mg cefpodoxime), swallowed with 150 ml water. The time of administration was chosen so that sampling could occur 3 h (group 1); 6 h (group 2) or 12 h (group 3) after administration of the drug.
Concentrations in plasma and pleura)
fluid
43
ships between the pleural fluid concentrations of cefpodoxime and the corresponding pleural fluid concentrations of albumin were tested by correlation analysis. For the pleural fluid/plasma ratio, in order to standardize the variances, the analysis was done on the logarithm of the ratio of the concentrations. The ratio was compared, in each group, with a theoretical value of 1 using Student's /-test. The plasma concentrations of albumin before dosing and at the various pleural fluid sampling times were compared with one another in each group using Student's /-test for paired data. The chosen level of significance was: a = 0-05 (two-tailed).
Eighteen patients (six in each group) were included in the study; although the intended study protocol was violated in the case of two patients, none was excluded from the subsequent analysis of data. The violations were two cases where the prothrombin ratio was less than 50% due to treatment with acenocoumarol. Cefpodoxime proxetil medication was in accord with the study protocol and no adverse events were reported at any time. The five men and 13 women had a mean age of 65-2 years, a mean weight of 59-8 kg and a mean height of 163-9 cm; these data and other demographic and biological aspects are summarized in Table I. No significant differences were found between the three groups for weight, height or serum creatinine; however, there were significant differences regarding age (P = 0-008; Tukey's test: difference between groups 1 and 3) and the prothrombin ratio (P = 005; Tukey's test: difference between groups 1 and 2). The pleural effusions in the patients studied derived from a variety of diseases: five patients with breast carcinoma, one with ovarian, one with thyroid, one with bronchial and one with unspecified carcinoma; two with adenocarcinoma; three with lung disease; three with congestive cardiac failure (in one complicated by myocardial infarction and in another by respiratory failure); and one with pulmonary embolism. As a result, a variety of concomitant medication was required for the management of these underlying conditions. The plasma and pleural fluid samples were obtained at the planned times after dosing; depending on the group, these mean times were 301 h (group 1), 6h (group2)
Table L Patient demographic data, prothrombin ratio and serum creatinine (mean±s.E.M.) Group 1 3h (« = 6)
Group 2 6h (n = 6)
Group 3 12 h
4/2 61-2±2-3
0/6 66-210-9
1/5 68-310-3
Weight (kg) Height (cm) Prothrombin ratio (%)
64-3 ±7-6 169-5 ±2-2 68-8 ±11-6
55-7 ±4-5 160-3 ±2-6 96-012-2
59-516-7 162-013-2 83-513-3
Creatinine (jtmo\fl)
104-5±12-7
950181
78-2140
Males/females Age (years)
NS, Not significant.
(71 = 6)
ANOVA P = 0-008 (group 1 vs group 3) NS NS P = 0-051 (group 1 vs group 3) NS
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
Results
R. Dmnont et aL
44
Table II. Plasma and pleural fluid concentrations of cefpodoxime, ratio of pleural fluid/plasma concentrations and sampling times
Plasma concentration (mg/1) mean±s.E.M.
range
Group 2 6h (n = 6)
Group 3 12 h (n =» 6)
2-73 ±0-34
2-72 ±0-32
0-77 ±0-14
1-49-3-80
1-49-3-52
0-35-1-21
l-84±0-33 1-02-302
O-78±O-10 0-41-1-09
0-67 ±008 0-50-0-95
107 ±008 0-74-1-34
6O±0O
12O±0O
Pleural fluid concentration (mg/1) mean±s.E.M.. 0-62±0-19 range 002-1-28 Pleura] fluid/plasma ratio 0-24±0-07 range 001-043 Sampling time (hours after dosing — mean±s.E.M.) plasma and pleural fluid 301 ±001
and 12 h (group 3). Where applicable, blood and pleural fluid samples were obtained synchronously. Cefpodoxime concentrations in plasma and pleural fluid
The means (±S.E.M.) for each group for the concentrations of cefpodoxime in plasma and pleural fluid, the corresponding pleural fluid/plasma ratios and the time intervals between dosing and sampling are presented in Table II. After dosing, the mean concentrations of cefpodoxime in pleural fluid were, according to group, 0-62 mg/1 (3 h); 1-84 mg/1 (6h); and 0-78 mg/1 (12 h) and the corresponding mean plasma concentrations were, respectively, 2-73, 2-72 and 0-77 mg/1. The mean pleural fluid/plasma ratios were: group 1: 0-24; group 2: 0-67; and group 3: 107. Analysis of variance showed a globally significant difference between the three groups and the mean for group 1 differed significantly from that for groups 2 and 3 (P = 0-003). Table III. Plasma and pleural fluid concentrations of albumin, ratio of pleural/ plasma concentrations of albumin (mean±s.E.M.)
Group 1 3h (n-6) Plasma albumin (g/1)
42-4 ±2-5
Pleura] fluid albumin (g/1) 22-8±4-9 Pleural fluid/plasma ratios albumin 0-49 ±0-11 NS, Not significant.
Group 2 6h
Group 3 12 h
38-7 ±2-7
37-2 ±21
NS
26-3 ±10
26-5 ±20
NS
0-70 ±005
0-72 ±0O6
NS
ANOVA
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
Group 1 3h (n = 6)
Concentrations in plasma and pleura]
fluid
45
Albumin concentrations in plasma and pleural fluid
Discussion The mean plasma concentration of cefpodoxime (2-73 ± 0-34 mg/1) at 3h after dosing was similar to that observed in healthy volunteers under similar conditions: 2-40 ±016 mg/1 (D. Tremblay et ai, Roussel Uclaf, data on file). However, the values found later after dosing were higher: 2-72 mg/1 compared with 1 -23 mg/1 after 6 h; and 0-77 mg/1 compared with 0-19 mg/1 after 12 h. These differences might be due to a slower rate of elimination in the patient population studied. The maximum concentration of cefpodoxime in pleural fluid was seen in group 2 (6 h after dosing); this observation suggests that the penetration of cefpodoxime into pleural fluid is relatively slow. The ratio between concentrations of cefpodoxime in pleural fluid and plasma increased during the 12 h study period after dosing—the values being 0-24, 0-67 and 107 for the three time intervals. Although the two latter values do not differ
3h group 1
6h group 2 Ttme(h)
12 h group3
Figure 1. Mean (±sx.v.) concentration of cefpodoxime in plasma (Q) and pleural fluid (H), 3, 6 and 12 h after a single oral dose of cefpodoxime proxetil 260 mg. MIC* for S.pneumoniae and H. influenza* ( ), K. pntumoniae and B . calarrhalis (•••).
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
Similarly, data and statistical evaluations for concentrations of albumin in plasma and pleural fluid and the corresponding pleural fluid/plasma ratios are given in Table III. The mean concentrations of albumin were, for groups 1, 2 and 3 respectively, 42-4, 38-7 and 37-2 g/1. Analysis of variance did not show a significant difference between the three groups. For albumin in the pleural fluid, the mean concentrations were 22-8, 26-3 and 26-5 g/1 for groups 1, 2 and 3 respectively. No significant differences between the three groups for these parameters were found. The mean pleural fluid/plasma ratios for albumin were: group 1: 0-49, group 2: 0-70 and group 3: 0-72. No statistical difference was found for these parameters between the three groups. Finally, an analysis within each group showed that there was no significant correlation between the pleural fluid concentrations of cefpodoxime and albumin.
46
R. Dnmont et aL
References Chin, N. X. & Neu, H. C. (1988). In vitro activity of an oral iminomethoxy aminothiazolyl cephalosporin, R-3746. Antimicrobial Agents and Chemotherapy 32, 671-77. Jones, R. N. & Barry, A. L. (1988). Antimicrobial activity and disk diffusion susceptibility testing of U-76,253 A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807). Antimicrobial Agents and Chemotherapy 32, 443-9. Tremblay, D., Dupront, C , Ho, C , Coussediere, D. & Lenfant, B. (1990). Phannacokinetics of cefpodoxime in young and elderly volunteers after single doses. Journal of Antimicrobial Chemotherapy TJL, Suppl. E, 21-8. Utsui, Y., Inoue, M. & Mitsuhashi, S. (1987). In vitro and in vivo antibacterial activities of CS-807 a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 1085-92.
Downloaded from http://jac.oxfordjournals.org/ at Michigan State University on March 10, 2015
significantly, these findings suggest that the rate of elimination of cefpodoxime from pleural fluid may be slower than from the plasma, at least until 12 h after dosing. The concentrations of cefpodoxime in pleural fluid between 3 and 12 h after administration of cefpodoxime proxetil were above or equal to the MIC*, (Utsui et al., 1987; Chin & Neu, 1988; Jones & Barry, 1988) for most of the organisms found in lower respiratory tract infections: S. pneumoniae, H. influenzae, K. pneumoniae, B. catarrhalis (Figure 1). The lack of correlation between the concentrations of cefpodoxime and albumin in pleural fluid is consistent with the compound's weak protein binding. These results indicate that, after administration of cefpodoxime proxetil, active cefpodoxime penetrates pleural fluid. This good penetration suggests it may be an effective oral agent for use in lower respiration infections.
