ANTIMICROBIAL AGzNTS AND CHZMOTHZRAPY, June 1977, p. 1033-1035 Copyright 0) 1977 American Society for Microbiology
Vol. 11, No. 6 Printed in U.S.A.
Penetration of Cefazolin into Pleural Fluid DONALD R. COLE'* AND JUANITO PUNG Department of Surgery, New York University School of Medicine, New York, N. Y. 10016
Received for publication 10 December 1976
Single doses of cefazolin, 500 mg intramuscularly and 1 g intravenously, were administered to 16 patients having lung pathology who were scheduled for thoracic fluid aspiration. Pleural fluid and serum samples were taken at intervals of 30 to 240 min for determination of cefazolin levels. The levels obtained were variable; however, the levels of cefazolin in pleural fluid generally exceeded the reported minimal inhibitory concentration values for Staphylococcus pneumoniae and Staphylococcus, and group A beta-hemolytic streptococcus. In addition, the pleural fluid levels exceeded the minimal inhibitory concentration for cefazolin against most of the Klebsiella and Haemophilus influenzae strains. These data show that cefazolin, despite its comparative high protein binding, produces levels in the pleural fluid capable of inhibiting the organisms commonly found in respiratory tract infections. Cephalosporins such as cefazolin and cephalothin are used effectively to treat infections of the respiratory tract caused by Streptococcus pneumoniae, Klebsiella species, Staphylococcus aureus, group A beta-hemolytic streptococcus, and Haemophilus influenzae. Cefazolin and cephalothin have a similar broad spectrum of activity; however, cefazolin produces higher and longer-lasting blood levels than does cephalothin. On the other hand, cefazolin is more highly protein bound than cephalothin - 86% compared with 65% - and some investigators have questioned whether this might be a disadvantage to the use of cefazolin in that it might not penetrate the tissue in adequate doses (5). The clinical significance of protein binding, if any, is highly controversial, particularly as in the case of cefazolin, when the antibiotic has been found to be effective in eradicating the causative organisms and producing the desired clinical response in patients with respiratory tract infections (2, 7, 8, 11). However, levels of cefazolin in the pleural fluid have not been reported, and, therefore, the purpose of this study was to determine simultaneous serum and pleural fluid levels of cefazolin following single doses given intravenously or intramuscularly. (Presented at the Sixteenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 111. October 27-29, 1976). l Address reprint requests to: 8 Reimer Road, Scarsdale, NY 10583.
MATERIALS AND METHODS The study group consisted of 16 patients, 11 women and 5 men, aged 43 to 77 years; all had carcinoma with pleural effusion and were scheduled for thoracic fluid aspiration as part of their routine treatment. Informed consent was obtained from all. Single doses of cefazolin were administered, and then serum and pleural fluid samples, each at intervals of 30 min to 4 h, were taken from three patients (two patients participated on two different occasions). Serum and pleural fluid samples were frozen and sent in the frozen condition to Smith Kline & French Laboratories. The concentration of cefazolin was determined microbiologically by disk agar-diffusion technique, with Bacillus subtilis as the test organism. All standards were prepared in pooled human serum for serum and pleural fluid assays. All samples of serum or pleural fluid that required diluting prior to assay were diluted with pooled human serum by using the same lot in which the standards had been prepared. Each of the four to five standards were replicated 12 to 18 times, whereas each sample was replicated 12 times, i.e., 12 to 18 disks per standard concentration with three disks per plate. Although the protein content and pH of the pleural fluid were not known, the samples were evaluated versus a serum curve; therefore, the cefazolin concentration estimates are conservative rather than optimistic, assuming that the serum protein (albumin) content of pleural fluid is less than that of serum, especially with regard to serum albumin.
RESULTS AND DISCUSSION A total of 18 samples of serum and pleural fluid were obtained. Table 1 shows the serum and pleural fluid levels of cefazolin at each
1033
1034
COLE AND PUNG
NTimicRoB. AGENTS CHEMOTHER.
sampling time,. the mean inhibitory concentrations (MIC) of cefazolin, and the standard errors. The serum and pleural fluid levels of cefazolin were variable, but this was not unex-
pected in single sampling. In spite of the variability, the levels of cefazolin in pleural fluid in all patients regardless of dose, route of administration, or sampling time interval, generally
TABLE 1. Cefazolin levels in pleural fluid and serum Cefazolin levels (,ug/ml) Cefazolin dose in subject no.:
Sampling time (min)
Serum
Mean
Standard error
Pleural fluid
Mean
Standard error
1 g intravenously 30
1 2 3 4 5 6
60
7a
120
48.9 68.0 112.0 51.6 57.0 111.2
76.30
18.68
36.0
73.15
13.46
95.3
9
60
11 12
14
16
240
a
341.24 31.8 42.5
6.7
15.08
5.11
12.45
5.75
9.40
4.11
14.63
9.99
52.83
20.31
10.0 16.2 82.67
2.9
19.03
6.5
30.7
17 18
23.18
29.65
89.0 112.0 47 .0
36.63
18.2 65.65
0.5 g intramuscularly 10
13.9 83.0 13.0 28.2 17.8 9.1
42.70
7.68
35.17
3.67
23.4 91.8 43.3
Inadvertently, four samples were taken at 60 min and only two were taken at 120 min.
TABLE 2. In vitro activity of cefazolin against organisms frequently involved in respiratory infections
Organism S. pneurnoniae
S. pyogenes (group A beta-hemolytic streptococcus) S. aureus (includes penicillin-susceptible and -resistant isolates)
Klebsiella
H. influenzae
No. of iwlates
MIC (J&g/ml) Median -90% inhibition
Isolates in-
hibited (
Source
20
6.3 a Minimal bactericidal concentration values in broth dilution assay. b Broth dilution assay. c Broth dilution assay. d Agar dilution assay. e Agar dilution assay.
94 100
9d la
9d la
Job gc
9d la
VOL. 1 l, 1977
PENETRATION OF CEFAZOLIN INTO PLEURAL FLUID
exceeded the reported MICs of all organisms commonly associated with respiratory tract infections, with the exception of a small number of isolates of Klebsiella and H. influenzae. The MICs of those in Table 2 were reported by various investigators by a different methodology; however, there is general agreement among investigators (1, 3, 9, 10). Cephalothin also penetrates the pleural fluid in therapeutic levels (4, 6). Unfortunately, it is not possible to make direct comparisons between these data and ours, since cephalothin was administered in a dosage of 12 g/day, and the serum and pleural fluid samples were taken after 24 or 48 h of dosing. The cephalothin levels reported are of interest, however, in that they show great variability, as did the cefazolin levels. The level of cephalothin in the pleural fluid of one patient, after 2 days of a 12-g/day dosing schedule, was 5.4 ,ug/ml; the pleural fluid level of cephalothin in tie other patient 2 h after dose 11 was 40.8 ,g/ml, and it was 70.6 ug/ml 1 h after dose 24. As was mentioned, cefazolin has been used successfully to treat respiratory tract infections. In our previous study, cefazolin produced satisfactory clinical and bacteriological responses in 22 out of 23 patients having infections such as pneumonia or bronchitis associated with malignant disease; beta-hemolytic streptococcus and S. pneumoniae were the most frequently isolated organisms (2). Turck et al. reported that 64 of his 68 patients with pneumonia due to S. pneumoniae improved on cefazolin (11). Madhavan et al. obtained good results in all 24 patients having pneumonia caused by S. pneumoniae, Staphylococcus, or H. influenzae (7). Similarly, Mogabgab obtained good results in 54 patients having pneumonococcal pneumonia or pneumonococcal bronchitis; all had severe pulmonary or other diseases (8). It would seem, therefore, that any clinical significance of its protein-binding prop-
1035
erties is highly questionable, since cefazolin penetrates the pleural fluid in therapeutic levels and produces the desired clinical and bacteriological responses in pneumonia, bronchitis, and other pulmonary tract infections caused by
cephalosporin-susceptible organisms. ACKNOWLEDGMENTS We would like to thank Smith Kline & French Laboratories for providing supplies of Ancef and a grant to support the study. We also want to thank Donald H. Pitkin of their Research and Development Department for analyzing the serum and pleural fluid specimens. LITERATURE CITED 1. Bergeron, M. G., J. L. Brusch, M. Barza, and L. Weinstein. 1973. Bactericidal activity and pharmacology of
cefazolin. Antimicrob. Agents Chemother. 4:396-401. 2. Cole, D. R. 1973. Pulmonary and genitourinary infections in hospitalized patients with malignant disease: response to cefazolin. Presented as a Scientific Exhibit at the Meeting of the Southern Medical Association, November 11-14, 1973, San Antonio, Texas. 3. Emerson, B. B., 1975. Hemophilus influenza type B susceptibility to 17 antibiotics. J. Pediatr. 6:617-620. 4. Gump, D. W., and R. L. Lipson. 1968. The penetration of cephalothin into synovial and other body fluids. Curr. Ther. Res. Clin. Exp. 10:583-591. 5. Kirby, W. M. M., and C. Regamey. 1973. Pharmacokinetics of cefazolin compared with four other cephalosporins. J. Infect Dis. 128(Suppl.):S341-S346. 6. Klein, J. 0. 1964. Cephalothin: activity in vitro absorption and excretion in normal subjects and clinical observations in 40 patients. Am. J. Med. Sci. 52: 640-656. 7. Madhavan, T., E. L. Quinn, E. Freimer, E. J. Fisher, F. Cox, K. Burch, and D. Pohlod. 1973. Clinical studies of cefazolin and comparison with other cephalosporins. Antimicrob. Agents Chemother. 4:525-531. 8. Mogabgab, W. J. 1973. Treatment of acute infections in hospitalized patients with cefazolin. Clin. Med. 80:27-30. 9. Motley, M., and S. Shadomy. 1974. In vitro studies with cefazolin. Antimicrob. Agents Chemother. 6:856-861. 10. Ries, K., M. E. Levison, and D. Kaye. 1973. Clinical and in vitro evaluation of cefazolin, a new cephalosporin antibiotic. Antimicrob. Agents Chemother. 3:168-174. 11. Turck, M. 1973. Cefazolin in the treatment of bacterial pneumonia. J. Infect. Dis. 128(Suppl.):S382-S385.
Vol. 11, No. 6 Printed in U.S.A.
Penetration of Cefazolin into Pleural Fluid DONALD R. COLE'* AND JUANITO PUNG Department of Surgery, New York University School of Medicine, New York, N. Y. 10016
Received for publication 10 December 1976
Single doses of cefazolin, 500 mg intramuscularly and 1 g intravenously, were administered to 16 patients having lung pathology who were scheduled for thoracic fluid aspiration. Pleural fluid and serum samples were taken at intervals of 30 to 240 min for determination of cefazolin levels. The levels obtained were variable; however, the levels of cefazolin in pleural fluid generally exceeded the reported minimal inhibitory concentration values for Staphylococcus pneumoniae and Staphylococcus, and group A beta-hemolytic streptococcus. In addition, the pleural fluid levels exceeded the minimal inhibitory concentration for cefazolin against most of the Klebsiella and Haemophilus influenzae strains. These data show that cefazolin, despite its comparative high protein binding, produces levels in the pleural fluid capable of inhibiting the organisms commonly found in respiratory tract infections. Cephalosporins such as cefazolin and cephalothin are used effectively to treat infections of the respiratory tract caused by Streptococcus pneumoniae, Klebsiella species, Staphylococcus aureus, group A beta-hemolytic streptococcus, and Haemophilus influenzae. Cefazolin and cephalothin have a similar broad spectrum of activity; however, cefazolin produces higher and longer-lasting blood levels than does cephalothin. On the other hand, cefazolin is more highly protein bound than cephalothin - 86% compared with 65% - and some investigators have questioned whether this might be a disadvantage to the use of cefazolin in that it might not penetrate the tissue in adequate doses (5). The clinical significance of protein binding, if any, is highly controversial, particularly as in the case of cefazolin, when the antibiotic has been found to be effective in eradicating the causative organisms and producing the desired clinical response in patients with respiratory tract infections (2, 7, 8, 11). However, levels of cefazolin in the pleural fluid have not been reported, and, therefore, the purpose of this study was to determine simultaneous serum and pleural fluid levels of cefazolin following single doses given intravenously or intramuscularly. (Presented at the Sixteenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 111. October 27-29, 1976). l Address reprint requests to: 8 Reimer Road, Scarsdale, NY 10583.
MATERIALS AND METHODS The study group consisted of 16 patients, 11 women and 5 men, aged 43 to 77 years; all had carcinoma with pleural effusion and were scheduled for thoracic fluid aspiration as part of their routine treatment. Informed consent was obtained from all. Single doses of cefazolin were administered, and then serum and pleural fluid samples, each at intervals of 30 min to 4 h, were taken from three patients (two patients participated on two different occasions). Serum and pleural fluid samples were frozen and sent in the frozen condition to Smith Kline & French Laboratories. The concentration of cefazolin was determined microbiologically by disk agar-diffusion technique, with Bacillus subtilis as the test organism. All standards were prepared in pooled human serum for serum and pleural fluid assays. All samples of serum or pleural fluid that required diluting prior to assay were diluted with pooled human serum by using the same lot in which the standards had been prepared. Each of the four to five standards were replicated 12 to 18 times, whereas each sample was replicated 12 times, i.e., 12 to 18 disks per standard concentration with three disks per plate. Although the protein content and pH of the pleural fluid were not known, the samples were evaluated versus a serum curve; therefore, the cefazolin concentration estimates are conservative rather than optimistic, assuming that the serum protein (albumin) content of pleural fluid is less than that of serum, especially with regard to serum albumin.
RESULTS AND DISCUSSION A total of 18 samples of serum and pleural fluid were obtained. Table 1 shows the serum and pleural fluid levels of cefazolin at each
1033
1034
COLE AND PUNG
NTimicRoB. AGENTS CHEMOTHER.
sampling time,. the mean inhibitory concentrations (MIC) of cefazolin, and the standard errors. The serum and pleural fluid levels of cefazolin were variable, but this was not unex-
pected in single sampling. In spite of the variability, the levels of cefazolin in pleural fluid in all patients regardless of dose, route of administration, or sampling time interval, generally
TABLE 1. Cefazolin levels in pleural fluid and serum Cefazolin levels (,ug/ml) Cefazolin dose in subject no.:
Sampling time (min)
Serum
Mean
Standard error
Pleural fluid
Mean
Standard error
1 g intravenously 30
1 2 3 4 5 6
60
7a
120
48.9 68.0 112.0 51.6 57.0 111.2
76.30
18.68
36.0
73.15
13.46
95.3
9
60
11 12
14
16
240
a
341.24 31.8 42.5
6.7
15.08
5.11
12.45
5.75
9.40
4.11
14.63
9.99
52.83
20.31
10.0 16.2 82.67
2.9
19.03
6.5
30.7
17 18
23.18
29.65
89.0 112.0 47 .0
36.63
18.2 65.65
0.5 g intramuscularly 10
13.9 83.0 13.0 28.2 17.8 9.1
42.70
7.68
35.17
3.67
23.4 91.8 43.3
Inadvertently, four samples were taken at 60 min and only two were taken at 120 min.
TABLE 2. In vitro activity of cefazolin against organisms frequently involved in respiratory infections
Organism S. pneurnoniae
S. pyogenes (group A beta-hemolytic streptococcus) S. aureus (includes penicillin-susceptible and -resistant isolates)
Klebsiella
H. influenzae
No. of iwlates
MIC (J&g/ml) Median -90% inhibition
Isolates in-
hibited (
Source
20
6.3 a Minimal bactericidal concentration values in broth dilution assay. b Broth dilution assay. c Broth dilution assay. d Agar dilution assay. e Agar dilution assay.
94 100
9d la
9d la
Job gc
9d la
VOL. 1 l, 1977
PENETRATION OF CEFAZOLIN INTO PLEURAL FLUID
exceeded the reported MICs of all organisms commonly associated with respiratory tract infections, with the exception of a small number of isolates of Klebsiella and H. influenzae. The MICs of those in Table 2 were reported by various investigators by a different methodology; however, there is general agreement among investigators (1, 3, 9, 10). Cephalothin also penetrates the pleural fluid in therapeutic levels (4, 6). Unfortunately, it is not possible to make direct comparisons between these data and ours, since cephalothin was administered in a dosage of 12 g/day, and the serum and pleural fluid samples were taken after 24 or 48 h of dosing. The cephalothin levels reported are of interest, however, in that they show great variability, as did the cefazolin levels. The level of cephalothin in the pleural fluid of one patient, after 2 days of a 12-g/day dosing schedule, was 5.4 ,ug/ml; the pleural fluid level of cephalothin in tie other patient 2 h after dose 11 was 40.8 ,g/ml, and it was 70.6 ug/ml 1 h after dose 24. As was mentioned, cefazolin has been used successfully to treat respiratory tract infections. In our previous study, cefazolin produced satisfactory clinical and bacteriological responses in 22 out of 23 patients having infections such as pneumonia or bronchitis associated with malignant disease; beta-hemolytic streptococcus and S. pneumoniae were the most frequently isolated organisms (2). Turck et al. reported that 64 of his 68 patients with pneumonia due to S. pneumoniae improved on cefazolin (11). Madhavan et al. obtained good results in all 24 patients having pneumonia caused by S. pneumoniae, Staphylococcus, or H. influenzae (7). Similarly, Mogabgab obtained good results in 54 patients having pneumonococcal pneumonia or pneumonococcal bronchitis; all had severe pulmonary or other diseases (8). It would seem, therefore, that any clinical significance of its protein-binding prop-
1035
erties is highly questionable, since cefazolin penetrates the pleural fluid in therapeutic levels and produces the desired clinical and bacteriological responses in pneumonia, bronchitis, and other pulmonary tract infections caused by
cephalosporin-susceptible organisms. ACKNOWLEDGMENTS We would like to thank Smith Kline & French Laboratories for providing supplies of Ancef and a grant to support the study. We also want to thank Donald H. Pitkin of their Research and Development Department for analyzing the serum and pleural fluid specimens. LITERATURE CITED 1. Bergeron, M. G., J. L. Brusch, M. Barza, and L. Weinstein. 1973. Bactericidal activity and pharmacology of
cefazolin. Antimicrob. Agents Chemother. 4:396-401. 2. Cole, D. R. 1973. Pulmonary and genitourinary infections in hospitalized patients with malignant disease: response to cefazolin. Presented as a Scientific Exhibit at the Meeting of the Southern Medical Association, November 11-14, 1973, San Antonio, Texas. 3. Emerson, B. B., 1975. Hemophilus influenza type B susceptibility to 17 antibiotics. J. Pediatr. 6:617-620. 4. Gump, D. W., and R. L. Lipson. 1968. The penetration of cephalothin into synovial and other body fluids. Curr. Ther. Res. Clin. Exp. 10:583-591. 5. Kirby, W. M. M., and C. Regamey. 1973. Pharmacokinetics of cefazolin compared with four other cephalosporins. J. Infect Dis. 128(Suppl.):S341-S346. 6. Klein, J. 0. 1964. Cephalothin: activity in vitro absorption and excretion in normal subjects and clinical observations in 40 patients. Am. J. Med. Sci. 52: 640-656. 7. Madhavan, T., E. L. Quinn, E. Freimer, E. J. Fisher, F. Cox, K. Burch, and D. Pohlod. 1973. Clinical studies of cefazolin and comparison with other cephalosporins. Antimicrob. Agents Chemother. 4:525-531. 8. Mogabgab, W. J. 1973. Treatment of acute infections in hospitalized patients with cefazolin. Clin. Med. 80:27-30. 9. Motley, M., and S. Shadomy. 1974. In vitro studies with cefazolin. Antimicrob. Agents Chemother. 6:856-861. 10. Ries, K., M. E. Levison, and D. Kaye. 1973. Clinical and in vitro evaluation of cefazolin, a new cephalosporin antibiotic. Antimicrob. Agents Chemother. 3:168-174. 11. Turck, M. 1973. Cefazolin in the treatment of bacterial pneumonia. J. Infect. Dis. 128(Suppl.):S382-S385.
