Concentration of teicoplanin in the serum of adults with end stage chronic renal failure undergoing treatment for infection

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1 Journal of Antmcrobal Chemotherapy (1996) 37, Concentraton of tecoplann n the serum of adults wth end stage chronc renal falure undergong treatment for nfecton A. MercateUo'*, K. Jaber*, D. Hfflare-Buys*, B. Coronet 1, J. Berland' and E. Despaux' "Department of Nephrology, Hoptal Ed. Herrot, 69437Lyon Cedex 3; b Department of Haemodalyss, Hoptal Ste Marguerte, 139 Marselle; 'Pharmacology Department, Hoptal Sant-Elo, Montpeller; ''Bacterologcal Servce, Hoptal Sant-Elo, Montpeller, France We examned the adequacy of the followng schedule for the admnstraton of v tecoplann to patents wth chronc renal falure: three doses of 6 mg/kg at 12 h ntervals, a fourth dose 24 h later and then subsequent doses every 72 h. Eght nfected patents undergong dalyss were nvestgated, wth serum antbotc concentratons measured ten mnutes before and one hour after admnstraton. Mean trough concentratons were 6.9 ± 3.1 mg/l on day two, 9.8 ± 4.4 mg/l (day three), 9.2 ± 4.8 mg/l (day sx), 1.9 ± 5.5 mg/l (day nne), 12.1 ± 6.1 mg/l (day 12) and 14.8 ± 8. mg/l (day 15). The proposed schedule acheved adequate trough serum tecoplann concentratons by 48 h n sx out of eght patents examned. The dosage regmen was well tolerated. Introducton Patents wth chronc renal falure (CRF) frequently have nfectons caused by Gram-postve bactera (Luzar el al., 199), and tecoplann s therefore useful n ths populaton. The majorty (84%) of the antbotc s excreted unchanged n the urne, and so renal falure affects ts excreton. Tecoplann s not removed by dalyss (Bonat et al., 1987, 1988). Several sngle dose pharmacoknetc studes of tecoplann have been conducted n patents wth varyng degrees of renal falure (Trana et al., 1986; Bonat et al., 1987, 1988; Domart et al., 1987; Falcoz et al., 1987; Derbyshre et al., 1989). However, only two multdose pharmacoknetc studes of ths antbotc have been carred out n nfected patents wth renal falure. In the study by Doman et al. (1987), the patents had moderate acute renal falure (creatnne clearance approxmately 3 ml/mn), whereas n the other study all the patents had end stage CRF (Hoffler et al., 1991). The purpose of ths multcentre study was to determne whether the schedule proposed for the admnstraton of tecoplann n nfected patents wth CRF acheved trough serum antbotc concentratons between 8 and 2 mg/l. Downloaded from at Pennsylvana State Unversty on May 8, 216 Tel: ; Fax: /96/ $12./ 1996 The Brtsh Socety for Antmcrobal Chemotherapy

2 118 A. Mercatello et at. Patents Materals and methods The study patents were adults undergong haemodalyss (three tmes a week for more than two months), wth nfectons caused by bactera suspected or proven to be susceptble to tecoplann. Ethcs approval for the study was obtaned, as was nformed consent n all cases. The study dd not nterfere wth the routne management of the patents, ncludng the admnstraton of other drugs. Tecoplann regmen Tecoplann was admnstered as 6 mg/kg doses by v bolus njecton, gven, f possble, after dalyss. Three loadng doses (12 h apart) were gven, followed by a fourth dose 24 h after the thrd, and repeat doses every 72 h thereafter. Blood samples From the fourth to the seventh doses of tecoplann, blood samples were taken durng the 1 mn precedng and one hour (±5 mn) followng every njecton. Antbotc assay Tecoplann plasma concentratons were assayed by HPLC (Hllare-Buys et al., 1995); the am was to acheve serum trough and peak antbotc concentratons of close to 8-2 and 25-5 mg/l, respectvely, by the thrd dose. The clncal progress of the patents, though noted, dd not affect the evaluaton. Statstcal analyss Multple comparsons were performed wth an analyss of varance for repeated measures, and parwse comparsons were performed wth Fsher's exact test (Statvew II for Macntosh Abacus Concepts, Inc. Berkeley, CA., USA). Results and dscusson Eleven patents were ntally ncluded n the study but three dropped out (two ded of shock secondary to septcaema wthn 72 h, and one because of a mssed dose of tecoplann). The mean ± S.D. age of the patents was 58 ± 13 years (range 42-83). They had been undergong haemodalyss for 4.6 ± 3.4 years (4 months-14 years). The actual doses of tecoplann gven were very close to that requred n the study protocol (mean 5.9 ±.2 mg/kg; percentage rato of the theoretcal doses to the gven doses 99 ± 2%). The percentage rato of the actual ntervals between doses to the theoretcal ntervals was 99 ± 1%. The Fgure shows the varatons n mean antbotc concentratons. The trough concentratons showed sgnfcant dfferences at the varous tmes (ANOVA; P =.1) for day two compared wth all the other tmes, day three vs day 12 and day 15, and day sx vs day 12 and day 15. Although trough concentratons ncreased between day 9 and day 15 (1.9 ± 5.5 mg/l (day 9), 12.1 ± 6.1 mg/l (day 12) and Downloaded from at Pennsylvana State Unversty on May 8, 216

3 Patent number Day Table. Indvdual patent serum concentratons (mg/l) of tecoplann Day Day Day Day ed from at Pennsylvana State Unversty on May 8, Day T P Day 15 T H I' 5' 1 T. (rough; P, peak;, not documented.

4 12 A. Mercatello et al. DO 48 - j 4 \ 32 l» g 16 8 _ 4 \ \ \ \ ) \ Days Fgure. Mean trough ( ) and peak (A) tecoplann serum concentratons ± 8. mg/l (day 15)) these dfferences were not statstcally sgnfcant. There were no sgnfcant dfferences between the concentratons one hour after njecton at the varous tmes (P =.9). The treatment was well tolerated; nether local nor systemc adverse events were noted. Seven of the eght patents were cured of ther nfecton. Durng the study, all the patents receved haemodalyss. The parameters of these sessons dffered from patent to patent and also from sesson to sesson for gven ndvduals. The fluctuatng severtes of the nfectons n ths patent group necesstated modfcatons to the haemodalyss sesson parameters. In four cases Staphylococcus aureus was solated (n three nstances from blood cultures and once from a bronchoalveolar lavage specmen), whch concurs wth the experence wth CRF patents (Luzar et al., 199). In the other four patents, no organsm was found (two cases of respratory dsease, where t s often dffcult to fnd the bacterum responsble for the clncal pcture and two cases of enterocolts where the antbotc was gven as cover). Satsfactory response to treatment occured n 8/11 patents ntally ncluded, and n 7/8 of those retaned n the fnal analyss. Three deaths occurred (two cases of shock n mmunocompromsed patents wth multple myeloma, and one patent had ntra-abdomnal sepss). The desred mean trough plasma concentraton of 8 mg/l was only obtaned at 48 h (9.8 mg/l), although patent dfferences were seen. Thus, at 24 h, 48 h, days 6, 9, 12 and 15, one, sx, four, sx, seven and eght patents respectvely, had trough concentratons >8 mg/l. By 24 h, concentratons lh post njecton were 2-5 mg/l on average. One patent (patent 8) always had the hghest trough and peak concentratons of tecoplann, whle another (patent 6) had the lowest trough concentratons throughout the study. The half lfe of tecoplann n patents wth CRF s approxmatve^ 16-2 h (Rowland, 199) and, therefore, t s not surprsng that the steady state was not reached by day 15. However, n our populaton, though the dfference between the trough tecoplann concentratons determned on day 6 and day 12 s sgnfcant, the dfferences between day 9 and day 12 or day 15 are not statstcally dfferent. Nevertheless, t s logcal to beleve that, wth ths protocol, trough antbotc concentratons wll ncrease; Downloaded from at Pennsylvana State Unversty on May 8, 216

5 Telcoplanln n renal falure 121 repeat estmatons of tecoplann serum concentratons would therefore be requred wth prolonged admnstraton. Hoffler et al. (1991) gave 8 mg of tecoplann on the frst day then 4 mg every 7 days. Mean serum concentratons were > 5 mg/l 1 h after the frst admnstraton and > 4 mg/l 1 h after the followng ones. In ths study, mean trough antbotc concentratons were < 8 mg/l on day seven (5.7 ± 2.2 mg/l), day 15 (6.8 ± 2.4 mg/l) and day 22 (7.7 ± 2.4 mg/l). Hence, t appears that no publshed protocol s truly satsfactory. The proposed treatment schedule examned n the present study seems to be satsfactory, apart from the antbotc trough concentratons acheved n the frst 48 h whch are somewhat low n relaton to the ntal objectves; the concentratons observed 1 h after admnstraton were acceptable. Acknowledgements We are grateful to Dr J. B. Durrande, Dr C. Atlan and Dr C. Dumas, Maron Merrell Dow Laboratores, for materal support, and to Dr L. Ghrard, Informaton and Communcaton Consultants (Pars) for montorng and data analyss. References Bonat, M., Trana, G. L., Rosna, R. & Bunva, G. (1988). Pharmacoknetcs of a sngle ntravenous dose of tecoplann n subjects wth varous degrees of renal mparment. Journal of Antmcrobal Chemotherapy 21, Suppl. A, Bonat, M., Trana, G. L., Vlla, G., Salvadeo, A., Gentlle, M. G., Felln, G. et al. (1987). Tecoplann pharmacoknetcs n patents wth chronc renal falure. Clncal Pharmacoknetcs 12, Derbyshre, N., Webb, D. B., Roberts, D., Glew, D. & Wllams, J. D. (1989). Pharmacoknetcs of tecoplann n subjects wth varyng degrees of renal functon. Journal of Antmcrobal Chemotherapy 23, Domart, Y., Perre, C, Clar, B., Garaud, J. J., Regner, B. & Glbert, C. (1987). Pharmacoknetcs of tecoplann n crtcally ll patents wth varous degrees of renal mparment. Antmcrobal Agents and Chemotherapy 31, Falcoz, C, Ferry, N., Pozet, N., Cusnaud, G., Zech, P. Y. & Sassard, J. (1987). Pharmacoknetcs of tecoplann n renal falure. Antmcrobal Agents and Chemotherapy 31, Hllare-Buys, D., Peyrere, M., Lobjoe, E., Bres, J., Ossart, M., Despaux, E. (1995). Influence of an artero-venous hemofltraton on tecoplann elmnaton. Brtsh Journal of Clncal Pharmacology 4, Hoffler, D., Koeppe, P., Naumann, E., Lang, E. & Sorgel, F. (1991). Pharmacoknetcs of tecoplann n hemodalyss patents. Infecton 19, Luzar, M. A., Coles, G. A., Faller, B., Slngeneyer, A., Dah Dah, G., Brat, C. et al. (199). Staphylococcus aureus nasal carrage and nfecton n patents on contnuous ambulatory pertoneal dalyss. New England Journal of Medcne 322, Rowland, M. (199). Clncal pharmacoknetc of tecoplann. Clncal Pharmacoknetc 18, Trana, G. L., Gentle, M. G., Feln, G., Rosna, R., Cavenagh, L., Bunva, G. & Bonat, M. (1986). Pharmacoknetcs of tecoplann n patents on contnuous ambulatory pertoneal dalyss. European Journal Clncal Pharmacology 31, Downloaded from at Pennsylvana State Unversty on May 8, 216 (Receved II July 1995; returned 14 August 1995; revsed 21 September 1995; accepted 6 December 1995)