Originalia D. Hrffler, R Koeppe, M. Corcilius, A. Przyklink
Cefpodoxime Proxetil in Patients with Endstage Renal Failure on Hemodialysis Summary: The blood levels of cefpodoxime of 16 hemodialysis patients were monitored after a single oral of Cefpodoxime proxetil with a Cefpodixime-equivalent of 200 mg dose. Eight patients were on dialysis during the period of observation, while the other eight patients were observed during a non-dialysis period. During hemodialysis the cefpodoxime levels were determined before and after the capillary dialyzer. It became apparent that hemodialysis patients have considerably higher and longer-lasting concentrations than patients with normal kidney function. The area under the curve is about seven times greater. Cefpodoxime is thus apparently eliminated to a great extent renally. The concentration levels before capillary dialyzer are noticeably higher than those after capillary dialyzer, so that it can be assumed that cefpodoxime is being dialyzed: the area under the curve of the eight patients observed during hemodialysis was about 50% tess than that of the patients observed while not on hemodialysis. Based on the pharmacokinetic data gathered, simulations of the course of concentration were made which took into consideration the clinical circumstances (normal period of dosage administration and dialysis). According to these simulations one can recommend a loading dose of 200 mg and thereafter a dose of 100 mg 12 h later followed by 100 mg every 24 h. This will result in an average concentration of 2 mg/1 and never falling below 1.5 mg/1. With this schedule all bacteria considered to be sensitive can be reached. Cefpodoxime proxetil thereby ensures a simple and effective therapy of bacterial infections in hemodialysis patients.
Introduction Patients on hemodialysis frequently require an antibacterial therapy for numerous reasons: Firstly, they often suffer from staphylococcal infections since bacteria can reach the blood due to repeated vascular punctures as well as through intraveneous catheters. Furthermore, a larger number of dialysis patients suffer from a renal disease which often leads to a sepsis caused by Escherichia coli. Thirdly, hemodialysis patients have a defective immune system; most of them are old and frequently develop pneumonia. In such cases an effective broad spectrum antibacterial therapy is necessary. Oral therapy is preferable to an intravenous therapy since it is tess strenuous for the patient and the doctor, and the patient usually need not be hospitalized. We examined the pharmacokinetics of the oral cephalosporin cefpodoxime proxetil which has broad spectrum ac-
Zusammenfassung: CefpodoximproxetiI bei Patienten mit terminaIer Niereninsuffizienz unter Hiirnodialyse. Nach oraler Gabe von Cefpodoximproxetil (Cefpodoxin~iquivalent = 200 rag) win'den die Plasmaspiegel von Cefpodoxim bei 16 Hgmodialyse-Patienten verfolgt. Acht Patienten wurden wahrend des Untersuchungszeitraumes dialysiert; bei der zweiten Gruppe fiel die Untersuchung in das dialysefreie Intervall. W~ihrend der H~imodialyse wurden die Cefpodoximproxetil-Konzentrationen vor und hinter der Capillarniere bestimmt. Es zeigte sich, dab H~modialyse-Patienten h/3here und insbesondere wesentlich l~tnger anhaltende Spiegel aufweisen als Normalpersonen. Die F15che unter der Plasmaspiegelknrve (AUC) liegt etwa um den Faktor 7 NSher. Offenbar wird Cefpodoximproxetil in hohem MaBe renal eliminiert. Die Spiegel vor der Capillarniere liegen deutlich h6her als die hinter der Capillarniere, so dag geschlossen werden kann, dab Cefpodoximproxetit dialysiert wird: Die AUC der acht Patienten unter HS_modialyse lag urn zirka 50% unter der der Patienten auBerhalb der Wfimodialyse. Aufgrund der gewonnenen pharmakokinetischen Daten wurden Simulationen der Plasmaspiegel vorgenommen, die klinische Gegebenheiten (tibliche Applikations- und Dialysezeiten) berticksichtigen. Aufgrund dieser Simulationen wird empfohlen, nach einer Initialdosis von 200 mg 12 h sp~iter 100 nag und dann alle 24 h 100 mgals Erhaltungsdosis zu geben. Es werden so Spiegel erreicht, die minimal um 1,5 rag/1 und im Mittel tun 2 rag/1 liegen. Hiermit diJrften alle als sensibel bezeichneten Keime erfaBt werden. Cefpodoximproxetil erlaubt somit eine einfache und effektive Therapie yon bakteriellen Infektionen bei HSxnodialysePatienten.
tivity against gram-positive and gram-negative bacteria [1--4] in patients hemodialyzed for endstage renal failure. The compound was broadly examined for its toxicologic and pharmacologic properties. No principal differences to other cephalosporins were found. The first clinical results were promising [5]. The drug was administered to eight patients during their time off dialysis and to eight patients during dialysis. We Received: 6 March 1990/Revision accepted: 30 April 1990 Prof. Dr. D. tIrffler, M. Corcilius, A. Przyklink, (technical assistance), Medizinische Klinik I/I, SNdtische Kliniken Darmstadt, Grafenstrage 9, I)-6100 Darmstadt, FR Germany; Prof. Dr. P. Koeppe, Klinikum Steglitz, Freie Universit~t Berlin, Hindenburgdamm 30, D-1000 Berlin 45. This article contains substantial results of the dissertation ofM. Corcitius. Dedicated to Prof. Dr. F. Scheler on the occasion of his 65th birthday.
Infection 18 (1990) No. 3 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1990
157/35
D. H6ffler et al.: Cefpodoxime Proxetil in Hemodialysis Patients
Table 1 Results of the pharmacokinetic evaluations for eight patients with chronic renal failure (upper half) contrasted with evaluations using the same pharmacokinetic methods for ten young and healthy volunteers according to Saathoff, Lode et al. (8); lower half.
f f m m f m m f
68 68 54 62 66 58 63 69
156 143 168 160 173 164 168 160
51.8 45.5 74.0 51.3 72.6 63.7 64.3 52.5
1.51 1.35 1.85 1.52 1.86 1.70 1.73 1.54
64.9 8.6 6.6 25.3 22.2 43.4 14.4 11.8
343 267 409 310 282 368 259 356
3.51 3.93 2.39 3.07 5.63 3.05 3.68 4.39
2183 2890 2313 2103 2610 2612 1522 2750
1419 1958 t528 1437 1805 1733 999 1809
Mean S.D. Minimal Maximal
64 5 54 69
162 9 143 173
59.5 10.7 45.5 74.0
1.63 0.18 1.35 1.86
24.6 20.1 6.6 64,9
324 54 259 409
3.71 0.99 2.39 5.63
2373 441 1522 2890
1586 140.8 306 52.6 999 93.1 1958 226.2
m m m m m m m m m m
27 33 21 25 29 24 30 23 32 27
178 170 190 176 176 168 182 178 178 180
66 61.5 82 65 79 70 76 65 70 76
1.81 1.71 2.08 1.79 1.96 1.80 1.96 1.80 1.85 1.94
12.1 22.7 13.3 11.4 22.9 10.6 9.1 11.4 11.8 10.8
134 154 85 113 150 107 141 111 154 132
2.44 2.39 2.71 2.31 2.54 2.18 1.97 1.10 3.45 2.66
291 321 271 265 337 247 265 516 295 318
169 237 158 171 241 173 135 380 238 244
13~33 13.25 12.60 11.08 15.38 9.82 9.85 9.45 17.89 15.28
13.70 13.63 12.73 11.28 15.77 9.94 10.00 9.48 18.28 15.61
Mean S.D. Minimal Maximal
27 4 21 33
178 6 168 190
71.0 6.8 61.5 82.0
1.87 0.11 1.71 2.08
13.6 5.0 9.1 22.9
128 23 85 154
2.37 0.60 1.10 3.45
312 77 247 516
214.6 71.0 135.3 380.3
12.79 2.81 9.45 17.89
Level of significance
n.s.
Cefpodoxime Proxetil in Patients with Endstage Renal Failure on Hemodialysis Summary: The blood levels of cefpodoxime of 16 hemodialysis patients were monitored after a single oral of Cefpodoxime proxetil with a Cefpodixime-equivalent of 200 mg dose. Eight patients were on dialysis during the period of observation, while the other eight patients were observed during a non-dialysis period. During hemodialysis the cefpodoxime levels were determined before and after the capillary dialyzer. It became apparent that hemodialysis patients have considerably higher and longer-lasting concentrations than patients with normal kidney function. The area under the curve is about seven times greater. Cefpodoxime is thus apparently eliminated to a great extent renally. The concentration levels before capillary dialyzer are noticeably higher than those after capillary dialyzer, so that it can be assumed that cefpodoxime is being dialyzed: the area under the curve of the eight patients observed during hemodialysis was about 50% tess than that of the patients observed while not on hemodialysis. Based on the pharmacokinetic data gathered, simulations of the course of concentration were made which took into consideration the clinical circumstances (normal period of dosage administration and dialysis). According to these simulations one can recommend a loading dose of 200 mg and thereafter a dose of 100 mg 12 h later followed by 100 mg every 24 h. This will result in an average concentration of 2 mg/1 and never falling below 1.5 mg/1. With this schedule all bacteria considered to be sensitive can be reached. Cefpodoxime proxetil thereby ensures a simple and effective therapy of bacterial infections in hemodialysis patients.
Introduction Patients on hemodialysis frequently require an antibacterial therapy for numerous reasons: Firstly, they often suffer from staphylococcal infections since bacteria can reach the blood due to repeated vascular punctures as well as through intraveneous catheters. Furthermore, a larger number of dialysis patients suffer from a renal disease which often leads to a sepsis caused by Escherichia coli. Thirdly, hemodialysis patients have a defective immune system; most of them are old and frequently develop pneumonia. In such cases an effective broad spectrum antibacterial therapy is necessary. Oral therapy is preferable to an intravenous therapy since it is tess strenuous for the patient and the doctor, and the patient usually need not be hospitalized. We examined the pharmacokinetics of the oral cephalosporin cefpodoxime proxetil which has broad spectrum ac-
Zusammenfassung: CefpodoximproxetiI bei Patienten mit terminaIer Niereninsuffizienz unter Hiirnodialyse. Nach oraler Gabe von Cefpodoximproxetil (Cefpodoxin~iquivalent = 200 rag) win'den die Plasmaspiegel von Cefpodoxim bei 16 Hgmodialyse-Patienten verfolgt. Acht Patienten wurden wahrend des Untersuchungszeitraumes dialysiert; bei der zweiten Gruppe fiel die Untersuchung in das dialysefreie Intervall. W~ihrend der H~imodialyse wurden die Cefpodoximproxetil-Konzentrationen vor und hinter der Capillarniere bestimmt. Es zeigte sich, dab H~modialyse-Patienten h/3here und insbesondere wesentlich l~tnger anhaltende Spiegel aufweisen als Normalpersonen. Die F15che unter der Plasmaspiegelknrve (AUC) liegt etwa um den Faktor 7 NSher. Offenbar wird Cefpodoximproxetil in hohem MaBe renal eliminiert. Die Spiegel vor der Capillarniere liegen deutlich h6her als die hinter der Capillarniere, so dag geschlossen werden kann, dab Cefpodoximproxetit dialysiert wird: Die AUC der acht Patienten unter HS_modialyse lag urn zirka 50% unter der der Patienten auBerhalb der Wfimodialyse. Aufgrund der gewonnenen pharmakokinetischen Daten wurden Simulationen der Plasmaspiegel vorgenommen, die klinische Gegebenheiten (tibliche Applikations- und Dialysezeiten) berticksichtigen. Aufgrund dieser Simulationen wird empfohlen, nach einer Initialdosis von 200 mg 12 h sp~iter 100 nag und dann alle 24 h 100 mgals Erhaltungsdosis zu geben. Es werden so Spiegel erreicht, die minimal um 1,5 rag/1 und im Mittel tun 2 rag/1 liegen. Hiermit diJrften alle als sensibel bezeichneten Keime erfaBt werden. Cefpodoximproxetil erlaubt somit eine einfache und effektive Therapie yon bakteriellen Infektionen bei HSxnodialysePatienten.
tivity against gram-positive and gram-negative bacteria [1--4] in patients hemodialyzed for endstage renal failure. The compound was broadly examined for its toxicologic and pharmacologic properties. No principal differences to other cephalosporins were found. The first clinical results were promising [5]. The drug was administered to eight patients during their time off dialysis and to eight patients during dialysis. We Received: 6 March 1990/Revision accepted: 30 April 1990 Prof. Dr. D. tIrffler, M. Corcilius, A. Przyklink, (technical assistance), Medizinische Klinik I/I, SNdtische Kliniken Darmstadt, Grafenstrage 9, I)-6100 Darmstadt, FR Germany; Prof. Dr. P. Koeppe, Klinikum Steglitz, Freie Universit~t Berlin, Hindenburgdamm 30, D-1000 Berlin 45. This article contains substantial results of the dissertation ofM. Corcitius. Dedicated to Prof. Dr. F. Scheler on the occasion of his 65th birthday.
Infection 18 (1990) No. 3 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1990
157/35
D. H6ffler et al.: Cefpodoxime Proxetil in Hemodialysis Patients
Table 1 Results of the pharmacokinetic evaluations for eight patients with chronic renal failure (upper half) contrasted with evaluations using the same pharmacokinetic methods for ten young and healthy volunteers according to Saathoff, Lode et al. (8); lower half.
f f m m f m m f
68 68 54 62 66 58 63 69
156 143 168 160 173 164 168 160
51.8 45.5 74.0 51.3 72.6 63.7 64.3 52.5
1.51 1.35 1.85 1.52 1.86 1.70 1.73 1.54
64.9 8.6 6.6 25.3 22.2 43.4 14.4 11.8
343 267 409 310 282 368 259 356
3.51 3.93 2.39 3.07 5.63 3.05 3.68 4.39
2183 2890 2313 2103 2610 2612 1522 2750
1419 1958 t528 1437 1805 1733 999 1809
Mean S.D. Minimal Maximal
64 5 54 69
162 9 143 173
59.5 10.7 45.5 74.0
1.63 0.18 1.35 1.86
24.6 20.1 6.6 64,9
324 54 259 409
3.71 0.99 2.39 5.63
2373 441 1522 2890
1586 140.8 306 52.6 999 93.1 1958 226.2
m m m m m m m m m m
27 33 21 25 29 24 30 23 32 27
178 170 190 176 176 168 182 178 178 180
66 61.5 82 65 79 70 76 65 70 76
1.81 1.71 2.08 1.79 1.96 1.80 1.96 1.80 1.85 1.94
12.1 22.7 13.3 11.4 22.9 10.6 9.1 11.4 11.8 10.8
134 154 85 113 150 107 141 111 154 132
2.44 2.39 2.71 2.31 2.54 2.18 1.97 1.10 3.45 2.66
291 321 271 265 337 247 265 516 295 318
169 237 158 171 241 173 135 380 238 244
13~33 13.25 12.60 11.08 15.38 9.82 9.85 9.45 17.89 15.28
13.70 13.63 12.73 11.28 15.77 9.94 10.00 9.48 18.28 15.61
Mean S.D. Minimal Maximal
27 4 21 33
178 6 168 190
71.0 6.8 61.5 82.0
1.87 0.11 1.71 2.08
13.6 5.0 9.1 22.9
128 23 85 154
2.37 0.60 1.10 3.45
312 77 247 516
214.6 71.0 135.3 380.3
12.79 2.81 9.45 17.89
Level of significance
n.s.
