LITERATURE CITED. 1. Archer, G. L., R. E. Polk, R. J. Dunn, and R. Lower. 1978. ... Daschner, F. D., V. Frank, A. Kummel, E. Schmidt-Eisenlohr,. V. Schlosser, H.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 1990, p. 1699-1702
Vol. 34, No. 9
0066-4804/90/091699-04$02.00/0 Copyright © 1990, American Society for Microbiology
Concentrations of Teicoplanin in Serum and Atrial Appendages of Patients Undergoing Cardiac Surgery MICHEL G. BERGERON,'* RAPHAEL SAGINUR,2 DENIS DESAULNIERS,3 SYLVIE TROTTIER,1 WILLIAM GOLDSTEIN,4 PAULE FOUCAULT,' AND ClLINE LESSARD' Laboratoire et Service d'Infectiologie, Le Centre Hospitalier de l'Universite' Laval, Ste-Foy, Quebec G] V 4G2,1 Department of Medicine2 and Department of Cardiovascular Surgery, University of Ottawa Heart Institute,4 Ottawa Civic Hospital, Ottawa, Ontario K) Y 4E9, and De'partement de Chirurgie Vasculaire, Institut de Cardiologie, Hopital Laval, Ste-Foy, Quebec G] V 4G5,3 Canada Received 5 January 1990/Accepted 26 June 1990 The concentrations of teicoplanin in sera and heart tissues of 49 patients undergoing coronary bypass were measured. Each patient received a 6- or 12-mg/kg dose of teicoplanin administered in a slow intravenous bolus injection over 3 to 5 min beginning at the time of induction of anesthesia. Mean ± standard error of the mean concentrations in serum were, for the two doses, respectively, 58.1 ± 1.7 and 123.3 ± 7.4 ,g/ml 5 min after administration and 22.2 ± 0.7 and 56.5 ± 2.8 pg/mi at the time of removal of atrial appendages. Mean ± standard error of the mean concentrations in tissue were 70.6 ± 1.7 and 139.8 ± 2.2 ,g/g, respectively, giving mean tissue/serum ratios of 3.7 ± 0.3 and 2.8 ± 0.2, respectively. Teicoplanin penetrates heart tissue readily and reaches levels in the serum far in excess of the MICs for most pathogens that have been found to cause infections following open heart surgery.
The incidence of infection following cardiac surgery caused by multiresistant Staphylococcus aureus, Staphylococcus epidermidis, and group JK diphtheroids is increasing (12, 15, 16). Thus far, vancomycin has been a valid alternative to standard antibiotic prophylaxis; but complications may occur if it is administered by rapid injection, and major side effects have restricted its use. Teicoplanin, a new glycopeptide antibiotic that is chemically related to the vancomycin-ristocetin group, has in vitro activity similar to that of vancomycin and seems to be less toxic (4, 7, 10, 14; A. Kureishi, P. J. Jewesson, C. D. Cole, D. E. Reece, G. L. Phillips, J. A. Smith, and H. W. Chow, Program Abstr. 29th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 597, 1989). Moreover, its pharmacokinetic properties allow for single-daily-dose therapy (5, 6). If used as a prophylactic agent in cardiac surgery, it might be a practical alternative to standard antibiotics, including cefazolin, cefamandole, semisynthetic penicillins given alone or in combination with aminoglycosides, or vancomycin, which is occasionally used when methicillin-resistant staphylococcal contamination is a concern. In the present study, we evaluated the penetration of teicoplanin into the heart tissues of patients undergoing cardiopulmonary bypass surgery. MATERIALS AND METHODS A total of 32 patients (16 from Quebec, Quebec, Canada, and 16 from Ottawa, Ontario, Canada) who were about to undergo cardiopulmonary bypass surgery were studied initially. They all gave written informed consent to take part in the study. They received a 6-mg/kg dose of teicoplanin administered in a slow bolus injection over 3 to 5 min through a peripheral vein beginning at the time of induction of anesthesia. Following this initial study, a second group of 17 patients operated on in Quebec City were studied and were given a 12-mg/kg dose that was administered in a similar fashion. All the assays and analysis of data were done *
Corresponding author.
at the Infectious Disease Research Laboratory, Centre Hospitalier de l'Universitd Laval, Quebec City. The group that received the 6-mg/kg dose was composed of 24 males and 8 females, and the group that received the 12-mg/kg dose was composed of 16 males and 1 female. The ages of the two groups of patients were not different (mean + standard error of the mean, 56.1 ± 1.5 years for the 6-mg/kg group and 56.9 ± 2.5 years for the 12-mg/kg group), nor were their weights (72.8 ± 2.0 kg for the 6-mg/kg group and 75.8 ± 3.3 kg for the 12-mg/kg group). Blood samples were collected for the assay of teicoplanin just before administration of teicoplanin; 5 min after the end of injection, at the time of removal of the atrial appendage; at the beginning and at the end of the bypass surgery; and 8, 16, 24, and 48 h after the administration of teicoplanin. Atrial appendages (mean weight, 0.31 ± 0.03 g) were extracted simultaneously with the third blood sample. They were rinsed three times with sterile saline, blotted dry, weighed, homogenized with a Tissue Tearor (Biospec Products, Bartlesville, Okla.) at 4°C with 2 to 4 volumes of 0.1 M sodium phosphate buffer (pH 7.4), and sonicated at 4°C (model W-375; Bionetics Ltd.). Assay of teicoplanin in serum samples was performed by using a microbiological agar well diffusion method with Bacillus subtilis ATCC 6633 as the test microorganism on a low-pH, high-salt medium containing 50 g of Mueller-Hinton II agar (BBL Microbiology Systems, Cockeysville, Md.), 30 g of NaCl, 8 g of CaCl2, and 1 g of citric acid monohydrate per liter of water (Agar Diffusion Bioassay for Teicoplanin Concentrations in Serum in the Presence or Absence of Aminoglycosides, protocol number 7, Merrell-Dow Research Institute, Cincinnati, Ohio). Standard curves of teicoplanin (concentrations, from 0.8 to 96 jig/ml) were prepared in pooled human serum (Flow Laboratories, Inc., Mississauga, Ontario, Canada) and were allowed to remain at room temperature for 2 h to achieve maximum protein binding of the drug (Agar Diffusion Bioassay for Teicoplanin Concentrations in Serum in the Presence or Absence of Aminoglycosides, protocol number 7, Merrell-Dow Re1699
BERGERON ET AL.
1700
ANTIMICROB. AGENTS CHEMOTHER.
1000 -
-.--X
°F U
X-- 12mg/kg
Mean ± SEM concn in:
*
z
0
TABLE 1. Teicoplanin concentrations in sera and atrial appendages after a dose of 6 mg/kg
6mg/kg
Patient no.
100*
10
*
1
0
12
24 36 48 TIME (hours) FIG. 1. Concentration of teicoplanin in serum following an intravenous dose of 6 or 12 mg/kg. Asterisks indicate P < 0.01.
search Institute). Each unknown serum sample was tested undiluted or, when necessary, was diluted in pooled human serum (Flow Laboratories) in triplicate. Concentrations of teicoplanin in atrial appendages were determined in triplicate by a microbiological agar well diffusion assay with B. subtilis ATCC 6633 as the test microorganism on Mueller-Hinton medium (Difco Laboratories, Detroit, Mich.). A pool of homogenates of atrial appendages containing no antibiotics was used to prepare the standard curve for tissue specimens. Concentrations varied from 1.5 to 96 ,ug/ml, and the lower limit of detection was 4.5 ,ug/g of tissue. Plates for both serum and tissue assays were incubated overnight at 37°C, and zone sizes were measured by using a caliper (Ultra-cal II; Fowler Inc.). The regression coefficient had a mean + standard deviation of 0.9980 + 0.001. The intraassay variations were 1.9% for the high concentrations of teicoplanin and 2.8% for the low concentrations. The interassay variations were 3.0 and 4.2% for the high and low concentrations, respectively. Recovery of antibiotic after the addition of a known amount of teicoplanin in drug-free homogenates of atrial appendages was >90%. The ratio of concentration of drug in atrial appendage/concentration in serum was calculated. Analysis of variance was used for statistical analysis. Hematological evaluation and liver and renal function tests were done in all patients. Patients were monitored daily for any side effects until they were discharged. RESULTS A total of 373 serum samples and 49 atrial appendage specimens were analyzed. No antibiotic could be detected in any of the serum samples taken before the administration of teicoplanin. Five minutes after a dose of 6 or 12 mg/kg, the mean + standard error of the mean concentrations in serum were 58.1 + 1.7 and 123.3 + 7.4 ,ug/ml, respectively (Fig. 1). At the time of removal of atrial appendages, a mean of 55 min after the doses were administered, mean concentrations of drug in serum were 22.2 ± 0.7 and 56.5 ± 2.8 jig/ml, respectively, for the 6- and 12-mg/kg doses. Serum samples taken at the beginning (a mean of 90 min) and the end (a mean of 148 min) of bypass surgery revealed mean concentrations of 10.9 ± 0.5 and 9.5 ± 0.2 ,ug/ml after a dose of 6 mg/kg and 44.6 _ 1.5 and 23.4 ± 0.6 ,ug/ml after a dose of 12 mg/kg, respectively. Teicoplanin could still be detected in serum 8, 16, 24, and 48 h after administration of both dosages; and levels at those times were 4.8 ± 0.1 and 9.6 + 0.2, 3.7 ± 0.1 and 6.6 ± 0.1, 2.8 ± 0.1 and 5.5 ± 0.1, and 1.5
6 13 18 5 27 14 15 10 1 4 8 11 12 16 17 24 28 3 7
b
Serum (,ug/ml)
M
30 30 35 37 44 48 49 50 50 55 55 55 56 57 58 62 65 65 66 69 70 75 75 81 82 85 94 99 110
34.8 ± 0.7 51.2 ± 1.2 31.5 ± 1.5 21.0 ± 0.3 14.6 ± 0.4 29.0 ± 1.4 23.9 ± 0.7 24.1 ± 1.0 21.0 ± 0.5 21.5 ± 0.4 26.5 ± 1.4 35.0 ± 0.8 25.4 ± 1.3 12.8 ± 0.6 36.6 ± 0.8 22.4 ± 1.0 26.9 ± 1.8 22.3 ± 0.5 30.0 ± 1.0 23.0 ± 0.9 NAb 9.4 ± 0.5 21.2 ± 0.8 19.7 ± 0.7 13.6 ± 0.6 16.1 ± 0.9 14.8 ± 0.3 2.9 ± 0.1 15.8 ± 0.4 13.2 ± 0.9 13.7 ± 0.3 14.9 ± 0.8
58 ± 4
22.2 ± 0.7
M
Mean
.
20 20 25
F M M M M M M F F F F F
2
Time (min) after dosage
M M M M M M M M M M F M M M M F M M
9 30 21 23 20 19 22 26 29 32 25 31
a
Sexa
Atrial appendage
('ig/)
72.5 63.0 57.7 74.1 90.6 84.3 63.5 76.5 56.4 46.6 68.7 86.4 74.1 66.5 128.2 98.5 100.6 64.5 85.0
64.8 87.5 44.2 86.6 82.4 79.1 80.7 82.0 29.4 35.7 69.2 33.8 68.2
± 5.4 ± 1.6 ± 0.9 ± 2.5 ± 2.6 ± 1.3 ± 1.7 + 1.6 ± 1.3 ± 0.7 ± 1.7 ± 2.4 ± 2.4 ± 1.1 ± 2.8 ± 5.2 ± 4.2 ± 1.7 ± 2.0 ± 0.6 ± 3.8 ± 1.3 ± 3.4 ± 2.4 ± 0.0 ± 2.0 ± 1.9 ± 2.5 ± 0.4 ± 1.6 ± 0.9 ± 2.0
70.6 ± 1.7
Ratio of concn in atrial ap-
pendage/ concn in serum
2.1 1.2 1.8
3.5 6.2 2.9 2.7 3.2 2.7 2.2 2.6 2.5 2.9 5.2 3.5 4.4 3.7 2.9 2.8
2.8 NA 4.7 4.1 4.2 5.8 5.0 5.5 10.1 2.3
5.2 2.5 4.6
3.7 ± 0.3
M, Male; F, female. NA, Not available.
± 0.1 and 3.4 ± 0.1 ,ug/ml for the 6- and 12-mg/kg doses, respectively. Tables 1 and 2 summarize the data for the concentration of teicoplanin in atrial appendages and in serum samples taken from the 32 patients who received the 6-mg/kg dose and the 17 patients who were given the 12-mg/kg dose. For all patients, samples were taken at a mean time of 55 min after the dosage was administered (10 to 110 min), and teicoplanin was detectable in all of the atrial appendage specimens at mean ± standard error of the mean concentrations of 70.6 + 1.7 ,ug/g after administration of the 6-mg/kg dose and 139.8 + 2.2 ,ug/g after administration of the 12-mg/kg dose. Simultaneous levels in serum were 22.2 ± 0.7 ,ug/ml for the 6-mg/kg group and 56.5 ± 2.8 ,ug/ml for the 12-mg/kg group, giving mean concentration in tissue/concentration in serum ratios of 3.7 ± 0.3 and 2.8 ± 0.2, respectively (P < 0.05). The teicoplanin concentration in the sera of patient 30 (6-mg/kg dose group) and patient 4 (12-mg/kg dose group) could not be determined, most likely because of interference from a nonantibiotic medication which might have interfered with our assay. In Table 3 data on the penetration of several antibiotics in heart tissue are compared. Teicoplanin accumulated within
TEICOPLANIN IN CARDIAC SURGERY
VOL. 34, 1990
TABLE 2. Teicoplanin concentrations in sera and atrial appendages after a dose of 12 mg/kg Mean
+
Ratio of
SEM concn in:
in atrial apconcn
Patient no.
5 8 16 7 15 1 6 12 17 13 4 10 3 9 11 2 14
Sexa F M M M M M M M M M M M M M M M M
Mean
Time (min) after dosage
Serum (,ug/ml)
153.1 ± 4.8 52.3 ± 3.5 51.8 ± 1.5 77.6 ± 0.9 49.0 ± 1.7 40.8 ± 1.4 44.9 ± 1.2 56.5 ± 1.7 58.6 ± 0.9 56.1 ± 1.5 NAb 43.8 ± 1.2 36.1 ± 1.5 49.0 ± 2.1 53.6 ± 1.8 36.0 ± 2.4 45.3 ± 2.6
10 36 36 41 42 45 45 45 45 47 50 50 55 55 55 91 97
49.7 ± 5.1
pendage
concngi/
penage/
serum
161.5 156.0 113.6 143.0 156.1 142.1 102.7 151.3 133.5 154.3 153.3 117.9 144.8 136.4 137.0 164.0 108.8
± 3.5 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
5.4 2.4 5.6 6.2 6.3 6.0 4.5 3.0 8.1 8.5 2.2 4.2 6.0 5.7 4.8 2.6
56.5 ± 2.8 139.8 ± 2.2
1.1 3.0 2.2 1.8 3.2 3.5 2.3 2.7 2.3 2.8 NA 2.7 4.0 2.8 2.6 4.6 2.4
2.8 ± 0.2
a F, Female; M, male. b NA, Not available.
TABLE 3. Comparative concentrations of antibiotics in heart tissue Antibiotic
Dosea
Concn (,ug/g) in heart tissue (mean concn in heart/concn in
Referenceb
serum ratio)
Cefamandolec
2 g i.v. 1 g i.v.
20 mg/kg i.m.
50 (0.4) 20 (0.37) 26.7 (0.51)
11 2 1
Cloxacillinc
1 g i.v.
17 (0.7)
2
Flucloxacillinc
500 mg i.m.
2.3 (0.2)
8
Fusidic acidc
580 mg i.v.
10.3 (0.3)
2
Vancomycinc
15 mg/kg i.v.
3.1 (0.4)
5
Vancomycind
10 mg/kg i.v.
16.5 (0.2)
Pefloxacind
800 mg i.v.
Pefloxacine
800 mg i.v.
Teicoplaninc
6 mg/kg i.v. 12 mg/kg i.v.
8.5 (1.03) 20.1 (2.8) 70.6 (3.7) 139.8 (2.8)
Garaud et al. 3 3
Foucault et al. Bergeron et al.
a i.V., Intravenous; i.m., intramuscular. b Garaud et al., G. G. Garaud, B. Barbier-Bacham, J. Blanchet, S. Malbezin, L. Slim, and M. Assur, Abstr. Reunion Interdisciplinaire de Chimiotherapie Antiinfectieuse, abstr. no. P6, p. 98, 1989; Foucault et al., P. Foucault, D. Desaulniers, R. Saginur, and M. G. Bergeron, 28th ICAAC, abstr. no. 937, 1988; Bergeron et al., M. G. Bergeron, D. Desaulniers, W. Goldstein, R. Saginur, and P. Foucault, 16th International Congress of Chemotherapy, p. 249, 1989. Atrial appendages. d Heart valve. Cardiac muscle.
1701
heart tissue and reached levels in the heart that were up to severalfold higher than those found in serum or observed with other antibiotics in atrial appendages. Pefloxacin also has good penetration into cardiac muscle, but limited levels were observed in heart valves. All patients tolerated the drug well, and no signs of allergy or other side effects or any biological abnormalities were observed in any of them.
DISCUSSION Results of this study demonstrate that teicoplanin penetrates readily into heart tissue. The antibiotic was detectable in all atrial appendage specimens taken from 10 to 110 min postinjection and was still present in the serum after 24 h at levels higher than the MICs for 90% of the staphylococci, streptococci, and group JK diphtheroids tested (4, 7, 10, 14). Mean concentrations detected in heart tissue reached values which were at least 10 to 20 times higher than the MICs for 90% of the methicillin-susceptible and -resistant S. aureus and S. epidermidis, Streptococcus faecalis, and group JK diphtheroids tested (10). This is in contrast to the concentration of vancomycin in heart tissue, which is about equivalent to the MIC for these microorganisms (5, 10). Moreover, as described previously, maximum levels of cefamandole, cloxacillin, and flucloxacillin in atrial appendages were four to eight times higher than the MICs of these antibiotics for the methicillin-susceptible bacteria (1, 2, 11) but lower than the MICs of these drugs for methicillinresistant bacteria. The extremely long half-life of teicoplanin in serum coupled with high levels of drugs which were constantly maintained in heart tissue throughout the operative time suggest that the levels in tissue, which were always higher than the levels in serum, can be maintained for a long period of time after surgery, probably up to 48 h, as levels in serum were still detectable at that time. Although there was some intervariability in antibiotic levels between patients, they were not as striking as those observed with antibiotics with shorter half-lives, like the ,3-lactams. These variations observed with the 1-lactams can be explained, in part, by the different ages of the patients, their variable physiological statuses, and the cardiopulmonary bypass that patients underwent during antibiotic administration. The diminished renal perfusion and renal function which may occur during cardiac and cardiopulmonary bypass surgery could have modified the pharmacologies of these agents. We cannot eliminate the possibility that an alteration in protein binding caused by a decrease in serum albumin, associated with an increase in free fatty acids which also bind to albumin, could be responsible for some of the variations observed. The ratio of the teicoplanin concentration in tissue/teicoplanin concentration in serum varied between 1:1 and 10:1, which is higher than those we obtained previously with fusidic acid (0.33), cloxacillin (0.73), and cefamandole (0.35) (2) and those reported by Daschner et al. (5) (0.4) and Garaud et al. (G. G. Garaud, G. Barbier-Bacham, J. Blanchet, S. Malbezin, L. Slim, and M. Assur, Abstr. Reunion Interdisciplinaire de Chimiothdrapie Anti-Infectieuse, abstr. no. p6, p. 98, 1989) (0.2) with vancomycin in heart valves. Brion et al. (3) also found a relatively high ratio of the teicoplanin concentration in cardiac muscle/teicoplanin concentration in serum that ranged from 1.70 to 4.00 after one injection of pefloxacin, but the ratio of the concentration in cardiac valve/concentration in serum varied from 0.75 to 1.33. Wilson et al. (15) observed ratios of the
1702
BERGERON ET AL.
teicoplanin concentration in sternal bone/concentration in serum that ranged from 0.26 to 1.58, with a mean value of 0.65. The high penetration ratio of teicoplanin into atrial appendages can be explained, at least in part, by its long half-life in serum (14), but we cannot exclude the possibility of the intracellular penetration of teicoplanin. This antibiotic was also found to penetrate polymorphonuclear leukocytes (9, 13). Our observation is compatible with that of Verbist et al. (14), who studied the three-compartment pharmacokinetics of teicoplanin in healthy volunteers and observed a very low ratio between the transfer rate constants out of and into the peripheral compartments, indicating important penetration and binding of teicoplanin to tissues. Overall, teicoplanin has in vitro activity greater than or similar to that of vancomycin against S. aureus, S. epidermidis, and enterococci (4) and activity similar to that of vancomycin against group JK diphtheroids (7) and Listeria monocytogenes (10). As shown here and in other clinical studies, it is well tolerated (14) and does not significantly affect heart rate or blood pressure. All of our 49 patients tolerated the drug very well. Although we did not observe any prophylactic failures in the patients that we studied, the number of subjects evaluated was too small to draw any valid conclusions on the value of teicoplanin as prophylaxis, but based on its low toxicity following rapid administration and its unique capacity to concentrate in the heart, teicoplanin should be evaluated further in the treatment of endocarditis and as a potential prophylactic agent during open heart surgery. A recent study has shown that the incidence of severe infections was no greater in patients who received a prophylactic regimen of teicoplanin (6 mg/kg) as a single dose than in patients who were given the combination of flucloxacillintobramycin over 4 days, but the incidence of minor sternal wound infections was greater in the teicoplanin group (16). Those investigators (15, 16) speculated that low levels of teicoplanin in fat may explain their results. Further studies of prophylaxis with higher doses of teicoplanin (up to 12 mg/kg) are thus needed to confirm those observations. With the increasing rate of valvular infections caused by methicillin-resistant S. aureus and S. epidermidis following cardiac surgery (12, 16), there is an urgent need for alternative drugs that penetrate heart tissue and that are well tolerated, easy to handle, and active against these pathogens. Teicoplanin warrants further investigation.
ANTIMICROB. AGENTS CHEMOTHER.
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12. 13. 14.
ACKNOWLEDGMENTS This study was supported by Merrell-Dow Pharmaceuticals Inc., Cincinnati, Ohio. We thank J. J. Garaud and P. H. Roy for reviewing the manuscript and Paul Cartier, Michel Lemieux, Jean-Paul Despres, Gilles Raymond, Daniel Doyle, and Jacques Metras, surgeons from the Department of Cardiovascular Surgery, H6pital Laval, and Christine Spence, research assistant, Ottawa Civic Hospital. LITERATURE CITED 1. Archer, G. L., R. E. Polk, R. J. Dunn, and R. Lower. 1978. Comparison of cephalothin and cefamandole prophylaxis during
15.
16.
insertion of prosthetic heart valves. Antimicrob. Agents Chemother. 13:924-929. Bergeron, M. G., D. Desaulniers, C. Lessard, M. Lemieux, J. P. Despres, J. Metras, G. Raymond, and G. Brochu. 1985. Concentrations of fusidic acid, cloxacillin, and cefamandole in sera and atrial appendages of patients undergoing cardiac surgery. Antimicrob. Agents Chemother. 27:928-932. Brion, N., A. Lessana, F. Mossett, J. J. Lefebre, and G. Montay. 1986. Penetration of pefloxacin in human heart valves. J. Antimicrob. Chemother. 17(Suppl. B):89-92. Cynamon, M. H., and P. A. Granato. 1982. Comparison of the in vitro activities of teichomycin A2 and vancomycin against staphylococci and enterococci. Antimicrob. Agents Chemother. 21:504-505. Daschner, F. D., V. Frank, A. Kummel, E. Schmidt-Eisenlohr, V. Schlosser, H. Spillner, B. Schuster, and M. Schindler. 1987. Pharmacokinetics of vancomycin in serum and tissue of patients undergoing open-heart surgery. J. Antimicrob. Chemother. 19: 359-362. Dowart, Y., C. Pierre, B. Clair, J. J. Garaud, B. Regina, and C. Gilbert. 1987. Pharmacokinetics of teicoplanin in critically ill patients with various degrees of renal impairment. Antimicrob. Agents Chemother. 31:1600-1604. Jadeja, L., V. Fainstein, B. LeBlanc, and G. P. Bodey. 1983. Comparative in vitro activities of teichomycin and other antibiotics against JK diphtheroids. Antimicrob. Agents Chemother. 24:145-146. Kiss, I. J., E. Farago, A. Gomoru, and J. Szamaransky. 1980. Investigation on the flucloxacillin levels in human serum, lung tissue, pericardial fluid and heart tissue. Int. J. Clin. Pharmacol. Ther. Toxicol. 18:405-411. Maderazo, E. G., S. P. Breaux, C. L. Woronick, R. Quintiliani, and C. H. Nightingale. 1988. High teicoplanin uptake by human neutrophils. Chemotherapy 34:248-255. Neu, H. C., and P. Labthavikul. 1983. In vitro activity of teichomycin compared with those of other antibiotics. Antimicrob. Agents Chemother. 24:425-428. Olson, N. H., C. H. Nightingale, and R. Quintiliani. 1980. Penetration characteristics of cefamandole into the right atrial appendage and pericardial fluid in patients undergoing openheart surgery. Ann. Thorac. Surg. 29:104-108. Thompson, R. L., I. Gabezudo, and R. P. Wenzel. 1982. Epidemiology of nosocomial infections caused by methicillin-resistant Staphylococcus aureus. Ann. Intern. Med. 97:309-317. Van der Auwera, P., T. Matsumoto, and M. Husson. 1988. Intraphygocytic penetration of antibiotics. J. Antimicrob. Chemother. 22:185-192. Verbist, L., B. Tjandramaga, B. Hendrickx, A. Van Hecken, P. Van Melle, R. Verbesselt, J. Verhaegen, and P. J. De Schepper. 1984. In vitro activity and human pharmacokinetics of teicoplanin. Antimicrob. Agents Chemother. 26:881-886. Wilson, A. P. R., B. Taylor, T. Treasure, R. N. Gruneberg, K. Patton, D. Felmingham, and M. F. Sturridge. 1988. Antibiotic prophylaxis in cardiac surgery: serum and tissue levels of teicoplanin, flucloxacillin and tobramycin. J. Antimicrob. Chemother. 21:201-212. Wilson, A. P. R., T. Treasure, R. N. Gruneberg, M. F. Sturridge, and D. N. Ross. 1988. Antibiotic prophylaxis in cardiac surgery: a prospective comparison of two dosage regimens of teicoplanin with a combination of flucloxacillin and tobramycin. J. Antimicrob. Chemother. 21:213-223.
