J. Laviltaureix, J. M. Brogard, M. Pinget, F. Ledoux
Dosage Adjustments of Cefazolin According to the Pharmacokinetics of this New Cephalosporin Summary: Serum and urine levels of cefazolin were studied: 1. following a single 500 mg intra-muscular dose of the drug in normal subjects (n = 10), in patients with renal impairment (n = 12) and in patients undergoing maintenance bemodialysis (n = 10); 2. following a single 500 nag intra-venous dose of the drug in normal subjects (n = 10). In normal subjects, serum half-lives averaged 1.75 hour after intravenous injection (Ke = 0.395) and 2.22 hours after intra-muscular injection (Ke = 0.312); urinary recovery of cefazolin over a six hours period amounted to 61% after intra-venous injection and to 47.5 % after intra-muscular injection. The renal clearance of the drug approximated 40 ml/mn. A linear correlation (Ke = 0.022 ÷ 0.0028 CrC1) was established between the overall elimination rate-constants and the creafinine clearances in the subjects under investigation. The various pharmacokinetic constants thus obtained can be used to calculate the maintenance doses, loading doses and dosage intervals adjusted according to creatinine clearances. These data actually yield dosage regimes adapted to each individual case according to the degree of renal function.
Zusammenfassung: Anpassung der Dosierung von CefazoIin an seine Pharmakokinetik. Die Serum- und Urinkonzentrationen yon Cefazolin wurden untersucht: 1. nach einmaliger, intranauskul'~irer Injektion yon 500mg des Antibiotikums bei gesunden Menschen (n = 10), bei Pafienten nait gest~Srter Nierenfunktion (n = 12) und bei fortgesetzt dialysierten Patienten (n = 10); 2. nach einmaliger, intraven/fser Injektion yon 500 mg des Antibiotikums bei gesunden Menschen (n = 10). Bei gesunden Menschen war die Seruna-Halbwertzeit im Mittel 1,75 Stunden nach intraven~Sser Injektion (ke = 0.395) und 2,22 Stunden nach intranauskuliirer Injektion (ke = 0,312); die Urinausscheidung von Cefazolin betrug nach sechs Stunden 61°/0 nach intraven~Sser und 47,5 % nach intramuskul~rer Injektion. Die Nierenclearance des Cefazolin betrug etwa 40 ml/min. Eine iineare Beziehung konnte zwischen den Ausscheidungskoeffizienten (ke) und den Kreatininclearancewerten (CrCI) der Versuchsperson (ke = 0,022 q- 0,0028 CrC1) aufgestellt werden. Durch die so berechneten pharmakokinetischen Daten k6nnen die Erhaltungsdosis, die Ladungsdosis sowie die Dosis-Zeitabst~inde gem~iB den Kreatininclearancewerten festgesetzt werden. Mit Hilfe dieser Daten k~Snnen fiir jeden individuellen Fall je nach der Nierenfunktion Dosis-Tabellen aufgesteltt werden.
Introduction
avoided. One should be particularly careful to prevent accumulation in patients with impaired renal function. The pharmacokinetie data established in this study can serve as guidelines to adjust the dosage of this new antibiotic to the degree of renal impairment and thus rule out possible toxicity.
Cefazolin is a new beta-lactam antibiotic. Its antibacterial spectrums is similar to that of cephalothin, cephaloridine, cephacetrile and cephalexin, although this derivative proved to be more active against some gram-negative pathogens, particularly Escherichia Coli and KlebsMla pneumoniae (7, 11, 19). I n contrast, its pharmacological properties differ from those of other cephalosporin antibiotics: cefazolin undergoes no appreciable degree of metabolic breakdown (8, 9, 14, 16) and is cleared through the kidney at a slower rate (2, 9, 12, 16). This unique characteristic accounts for the following traits: - - a low renal clearance - - relatively high serum peak concentrations - - a slow blood concentration decay - - a prolonged half life time.
These pecularities of the serum concentration decay may also account for the high biliary elimination of this antibiotic, exceeding that of other cephalosporins (1, 10, 15). It has yet to be determined whether the high degree of protein binding of cefazolin (74 0/0) will jeopardize its in vivo antibacterial activity (14). Cefazolin may elicit renal tubular damage in rabbits. However, in that case, nephrotoxie doses of cefazolin are 2.5 times higher than those of cephaloridine (20). On account of these experimental data and of a relatively slow renal excretion, it is essential that excessive and prolonged cefazolin accumulation in the body be
Material and Methods
Patient selection Cefazolin serum concentrations were monitored in 42 patients. Patients were divided into four groups. In selecting patients, consideration was given to each individual's renal function and to the mode of administration (intravenous or intra-muscular) of the drug. Group I - - patients 1--10:10 normal subjects (blood urea < 3 8 m g % ; endogenous creatinine clearance > 90mUmn) were given a single 500 nag intra-muscular dose of cefazolin. Group II - - patients I--X: i0 normal subjects (blood urea < 38mgO/0; creatinine clearance > 85ml/mn) were given a single 500 mg intra-venous injection of cefazolin, performed within less than one minute. Group III - - patients 11--12:10 subjects with varying degrees of renal impairment (blood urea in the 60--148 mg %
Received: 3June 1974 S. V. P. Resumd a la fin du manuscript. Prof. J. Lavillaureix, Prof. J. M. Brogard, Dr. M. Pinget, Dr. F. Ledoux, Departement de M6d6cine Interne, Clinique M6dicale B, Centre Hospitalo-Universitaire de Strasbourg, F-67005 Strasbourg, France.
Infection 3 (1975) Nr. 2
105
1. LavilIaureix, J. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the P h a r m a c o k i n e t i c s . . . Table 1: Adjustment of cefazolin intra-muscular dosages according to creatinine clearance values. The reference maintenance dose is 500 mg in a normal subject with a creatinine clearance value of 100 mg/min. Loading doses are calculated for intervals of 6 hrs, 8 hrs and 12 hrs.
Creatinine clearance (ml/min)
Maintenance dose (nag)
100 90 80 70 60 50 40 30 20 10 0
500 454 407 361 315 268 222 175 130 83 36
Loading dose (rag) in = i~ = in = 6 hours 8 hours 12 hours 598 563 527 495 463 431 402 372 348 320 291
549 511 472 438 403 369 338 306 280 252 223
514 472 429 390 351 3t3 277 243 214 184 155
Table 2: Adjustment of dosage intervals (iA) according to creatinine clearance values. The maintenance dose is 500 mg in all patients; there are three series of adjusted intervals according to in = 6 hrs, 8 hrs and 12 hrs. The corresponding loading dose is determinated for each serie. Creatinine clearance (ml/min)
in = 6 hours in =: 8 hours in = 12 hours Loading Dose Loading Dose Loading Dose = 598 mg = 549 mg = 514 mg
nation rate-constant (Km), the renal elimination rate-constant (Kr) were calculated from: - - the regression line generated by plotting the logarithmic values (common logarithms) of serum concentrations (C) against time (t), the regression line generated by plotting Ke values as a t r a c t i o n of creatinine clearences (CrCI). These lines were computed by the method of least squares and analysis was made with reference to a single open compartment body model. Serum half-lives T 1/2 were calculated using Ke values from the formula T i/2 = logn2/K e (3, 4, 5). The absorption coefficient Ka, determined when the drug was administered intra-muscularly was computed by the method of residual values. The half absorption time, Ta 1/2, was equal to logn2/K ~. Cefazolin plasmatic areas (F) were calculated from the Simpson's trapezoidal rule (3) C~ + C2 F' (mcg.bJmI) ~ ~ t Cefazotin renal clearance (Clr) was calculated from the equation (3) f x 10 ~ Clr (ml/mn) -- F x 60 where "f" is the urine excretion (expressed in rag) of cefazolin during the corresponding period (6 hours). The apparent distribution space A V D was determined following the intravenous administration of a 500 mg dose of cefazolin (5). A V D (liters) = d/Co (d is the injected dose in mg). If is then possible (6, 18) to predict the plasma clearance of cefazolin (C1p]) as CtpI (mt/mn) = AVD. Ke. 10 z 60 Results
Urine excretion 100 90 80 70 60 50 40 30 20 10 0
6,0 6,6 7,4 8,3 9,5 11,2 13,6 17,1 23,2 36,2 82,4
8,0 8,8 9,8 11,I 12,7 14,9 18,0 22,8 31,0 48,3 109,9
12,0 13,2 14,7 16,6 19,0 22,4 27,0 34,2 46,5 72,5 164,7
range and creatinine clearance in the 7 0 - 1 8 m l / m n range) were given a single 500 m g intra-muscular dose of cefazolin. Group IV ~ patients 23--32: 10 patients with chronic nephritis surviving thanks to bi-weekly hemodialysis (creatinine clearance in the 5--0 m l / m n range). These patients were given a single 500 mg intra-muscular dose of cefazolin administered on the day following hemodialysis.
In normal subjects the amount of cefazolin recovered from the urines collected over the six hours following the injection (Figure 1) was 47.5 '~/0 of the intra-muscular dose and 61 °/0 of the intravenous dose.
Urinary excretion Administered dose
0- 6 h I.V.
I.M.
500 mg
305 + 24 mg 238
+ 33 mg
Experimental procedure and bioassay determinations Following i n t r a v e n o u s and intra-muscular administration of 500 mg of cefazolin, blood samples were taken at well defined intervals. Sera remained frozen a t 18 ° C until assayed. Cefazolin levels were also determined in urines collected in their totality over the six hours following antibiotic administration. Concentration determinations were carried out by a cylinder plate method on agar with Bacillus subtilis A T C C 6633 as test organism.
Calculation o/pharmacokinetic data T h e theoretical initial serum concentration (Co-mcg/ml), the overall elimination rate-constant (Ke), the extrarenal elimi-
106
Infection 3 (1975) Nr. 2
~i::~7~.~,
N lOO% i
~?i:i?i;'~g~.':i?~:!.
}ol
'(il re ~ i.......
47,5%!
II
Figure 1: Urinary excretion of cefazolin during the 6 hours period following the administration of a 500 mg intra-muscular or intra-venous dose of the drug
]. Lavillaureix, ]. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the P h a r m a c o ~ n e t i c s . . . Cefazolin
Cefazolin !~51~ rng
500 mg
70
L~ C
1Go,o
.®
50 0
46:o
E
,?.
60
c
I.V.
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~
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3o, o
E
.E
50
~
4o
~
30
20,0 10,0
bg CIV - 4,1H - 0,395 t ']r~0,9%
5,0 4,0 3,0
~"-..._
p < 0,001
2, 0 .~
~...
1,0
I:2
E
!
8 20
O5
Log C1. = 3, 696 - 0, 312 t
!
E
0,2
'~
0,3 ~-
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tVtr~0,996 n = 10
10
8
~4
0,1 i
I
II
,
,
,
,
,
l
,
,
,
0
1
2
3
4
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8
9
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'i
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i
,
,
l
,
,
i
1
2
3
4
5
6
7
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9 I0 11 12
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Figure 2: Left: comparative serum concentrations (mean) of cefazolin after administration of a 500 mg intra-muscular (n = 10 normal subjects) and intra-venous (n = 10 normal subjetcs) single dose of the drug Right: determination of the overall elimination rate constants (Ke) and the serum half-lives after comparative administration of a 500 mg intra-muscular (n = 10 n o r m a l subjects) and intm-venous (n = 10 n o r m a l subjects) single dose of cefazolin
Serum concentrations N o r m a l subjects: After administration of a 500 mg intra-muscular dose (patients 1--10) of cefazolin, serum concentrations (Figure 2) were already amounting to 23.4 ± 3.3 mcg/ml* at 30 minutes but blood peak concentrations were not reached until 1 hour (26.6 + 2.9 mcg/ml). Afterwards, the decay curve has an exponential shape (2 hrs : 22.5 ± 2.0 mcg/ml, 3 hrs : 17.2 _+ 1.4 mcg/ml; 4 hrs : 11.4 ± 10. m c g l / m l ; 6 hrs : 6.6 ± 0.8 mcg/ml; 8 hrs : 3.1 ± 0.3 mcg/ml). After a 500 mg intra-venous dose of cefazolin (patients I X), serum levels (Figure 2) were 72.5 ± 7.6 mcg/ml at 15 minutes, 54.4 + 5.8 mcg/mt at 30 minutes, 36.3 _+ 2.8 mcg/ml at 1 hour, 26.0 _+ 2.1 mcg/ml at 2 hours, 20.4 ± 1.7 meg/ ml at 3 hours, 13.2 ± 1.0 mcg/ml at 4 hours, 6.4 ± 0.8 mcg/ m l at 6 hours, 2.7 ± 0.8 mcg/ml at 8 hours and 1.25 _+ 0.6 mcg/mt at 10 hours. Decay was total 12 hours. Patients with impaired renal function: In patients with impaired renaI function in whom no hemodialysis was performed (patients 11--22) (Figure 3), serum peak concentration were also achieved at one hour after a 500 mg intra-muscular dose of cefazolin. These values were slightly in excess of the m a x i m u m concentrations observed in normal subjects. Serum concentration decay was markedly slowed down especially in patients with a creatinine clearance of less than 50 ml/mn. In patients with chronic nephritis undergoing maintenance hemodiMysis (patients 23--32), serum concentrations at 1 hour were very high (m = 73.2 ± 10.2 mcg/ml). Serum level decay was extremely slow: 64.6 + 8.7 mcg/ml at 2 hours, 62.0 ± 7.9 mcg/ml at 4 hours, 54.9 ± 6.0 mcg/ml at 6 hours, * Concentrations are expressed as average values _+ S. E. M. Standard E r r o r of the Mean)
50.6 _+ 5.4 mcg/ml at 8 hours, 43.1 ± 4.1 mcg/ml at 12 hours, 34.2 4" 3.2 mcg/ml at 24 hours, 22.0 ___ 1.9 mcg/ml at 48 hours.
Elimination rate constant (Ke) In normal subjects, the overall elimination rate constant Ke averaged 0.312 following a 500 mg intra-muscular dose of cefazolin and 0.395 following the intra-venous administration of the same dose. A satisfying correlation (r = 0.944, p < 0.001) can be established between the Ke and CrC1 values of the patients under investigation after the intra-muscular injection of cefazolin (Figure 4). W h e n these two factors are plotted one against the other, they yield a straight line with the formula: Ke = Km + K r = 0.022 + 0.0028 CrC1. W h e n it is calculated theoretically from this equation (4), the Ke value is 0.302 for a creatinine clearance of 100 ml/mn.
Half-lives T 1/2 In normal subjects, T 1/2 values averaged 2.22 hours after a 500 mg intra-muscular dose of cefazolin and 1.75 h o u r after the intra-venous injection of the same dose. In patients with impaired renal function, there was an increase in the duration of T 1/2 which was inversely related to creatinine clearance values. When the half-lives T 1/2 were plotted against the creatinine clearances of all the patients under study given a 500 mg intra-muscular dose of cefazolin, a straight-line relationship was demonstrated (Figure 4), with the formula: Log. T 1/2 = 3.341 - - 0.024 CrC1 (r = 0.932, p 0.001). The T 1/2 value caIculated from this formula was 2.56 hours for a creatinine clearance of 100 mI/mn and 28.24 hours for a creatinine clearance of 0 mt/mn. N o satisfying correlation could be demonstrated between initial theoretical concentrations Co and creatinine clearances.
Infection 3 (1975) Nr. 2
107
J. Lavillaureix, or. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the P h a r m a c o k i n e t i c s . . . Log C
CefazoLin 500 mg I.M.
i00
90 80 70
60 50 40 30 2O
-
15
tzn E
o=
s
.--
]
=
6 5 4
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3 o_
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12
67
4, 6
0,151
13 14
60 57
5,8
0,119
, ,,J,
11, 7
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55 50
4,6
0,p0
5, 8
0,119
43 37
15,4
0,O45
19,3
0,036
36 31
1I, 7
0,059
20
7,4
O. O94
21 22
22 18
63, 0
O, 011
10,7
0,o65
15 16
I 0,90,80,70,60,50,4-
•
17 18
i9
0,30,2--
I
I
I
I
I
0
I
2
3
4
.... I
5
I
6
'
I
I
I
I
I
1
7
8
9
10
11
12 {h0ursl
Time
Figure 3: Linear representation of the serum concentration decay-time curves of Cefazolin in 12 patients with renal failure. The serum half-lives (T 1/2) and the overall elimination rate constants (Ke) have been derived from these lines
Distribution space: A VD
Cefazolin plasmatic clearance
When calculated in the group of normal subjects given a single 500 mg intra-venous injection of cefazolin an average value of 8.64 _+ 1.01 liters i.e. 14.4 + 1.2 o/o of the mean body weight was found. This value closely approximates that of the body extra-cellular fluid compartment.
The plasmatic clearance of cefazolin calculated in normal subjects given a 500 nag intra-venous injection of cefazolin averaged 52.17 + 3.57 ml/mn.
Areas under the curve of cefazotin in plasma The total plasmatic area, "FIv tot" measured in normal subjects given a 500 mg intra-venous injection of cefazolin averaged 151.06_ 9.86 mcg.h/ml. The plasmatic area at 6 hours, "Ft. v. 6 hrs" amounted to 137.76 + 9.62 mcg.h/ml. The total plasmatic area "FIM tot" measured in normal subjects given an intra-muscular injection of the same dose of cefazolin averaged 114.13 + 9.21 mcg.h/ml aud the plasmatic area at 6 hours, "FI. ~.I. 6 h r s ' , amounted to 94.85 _47.78 mcg.h/ml.
108
Infection 3 (1975) Nr. 2
Cefazolin renal clearance The renal clearance of cefazolin measured over a six-hours period in normal subjects (groups I and II) averaged 38.49 + 3.83 ml/mn following a 500 mg intra-venous dose of cefazolin and 41.58 + 6.25 ml/mn following the intra-muscular injection of the same dose. In patients given intra-venous injections, the ratio of cefazotin plasmatic clearance to cefazolin renal clearance was 1.36.
Absorption coefficient (Ka) and absorption half-life (Ta 1/2) Following the administration of a 500 mg intra-muscular dose of cefazolin the absorption coefficient (Ka) in normal
J. Laviltaureix, J. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the Pharmacokinetics... Ke
Log T 112
o, 350
- ~oo,o
30o
- 5O,O " 40,0 " 30,0 20, 0
O, 250 o= ¢o
lO,o 5,0 4,0
0,200
o:
r
/
o,15o-
17. ,
2,0
o
Dosage Adjustments of Cefazolin According to the Pharmacokinetics of this New Cephalosporin Summary: Serum and urine levels of cefazolin were studied: 1. following a single 500 mg intra-muscular dose of the drug in normal subjects (n = 10), in patients with renal impairment (n = 12) and in patients undergoing maintenance bemodialysis (n = 10); 2. following a single 500 nag intra-venous dose of the drug in normal subjects (n = 10). In normal subjects, serum half-lives averaged 1.75 hour after intravenous injection (Ke = 0.395) and 2.22 hours after intra-muscular injection (Ke = 0.312); urinary recovery of cefazolin over a six hours period amounted to 61% after intra-venous injection and to 47.5 % after intra-muscular injection. The renal clearance of the drug approximated 40 ml/mn. A linear correlation (Ke = 0.022 ÷ 0.0028 CrC1) was established between the overall elimination rate-constants and the creafinine clearances in the subjects under investigation. The various pharmacokinetic constants thus obtained can be used to calculate the maintenance doses, loading doses and dosage intervals adjusted according to creatinine clearances. These data actually yield dosage regimes adapted to each individual case according to the degree of renal function.
Zusammenfassung: Anpassung der Dosierung von CefazoIin an seine Pharmakokinetik. Die Serum- und Urinkonzentrationen yon Cefazolin wurden untersucht: 1. nach einmaliger, intranauskul'~irer Injektion yon 500mg des Antibiotikums bei gesunden Menschen (n = 10), bei Pafienten nait gest~Srter Nierenfunktion (n = 12) und bei fortgesetzt dialysierten Patienten (n = 10); 2. nach einmaliger, intraven/fser Injektion yon 500 mg des Antibiotikums bei gesunden Menschen (n = 10). Bei gesunden Menschen war die Seruna-Halbwertzeit im Mittel 1,75 Stunden nach intraven~Sser Injektion (ke = 0.395) und 2,22 Stunden nach intranauskuliirer Injektion (ke = 0,312); die Urinausscheidung von Cefazolin betrug nach sechs Stunden 61°/0 nach intraven~Sser und 47,5 % nach intramuskul~rer Injektion. Die Nierenclearance des Cefazolin betrug etwa 40 ml/min. Eine iineare Beziehung konnte zwischen den Ausscheidungskoeffizienten (ke) und den Kreatininclearancewerten (CrCI) der Versuchsperson (ke = 0,022 q- 0,0028 CrC1) aufgestellt werden. Durch die so berechneten pharmakokinetischen Daten k6nnen die Erhaltungsdosis, die Ladungsdosis sowie die Dosis-Zeitabst~inde gem~iB den Kreatininclearancewerten festgesetzt werden. Mit Hilfe dieser Daten k~Snnen fiir jeden individuellen Fall je nach der Nierenfunktion Dosis-Tabellen aufgesteltt werden.
Introduction
avoided. One should be particularly careful to prevent accumulation in patients with impaired renal function. The pharmacokinetie data established in this study can serve as guidelines to adjust the dosage of this new antibiotic to the degree of renal impairment and thus rule out possible toxicity.
Cefazolin is a new beta-lactam antibiotic. Its antibacterial spectrums is similar to that of cephalothin, cephaloridine, cephacetrile and cephalexin, although this derivative proved to be more active against some gram-negative pathogens, particularly Escherichia Coli and KlebsMla pneumoniae (7, 11, 19). I n contrast, its pharmacological properties differ from those of other cephalosporin antibiotics: cefazolin undergoes no appreciable degree of metabolic breakdown (8, 9, 14, 16) and is cleared through the kidney at a slower rate (2, 9, 12, 16). This unique characteristic accounts for the following traits: - - a low renal clearance - - relatively high serum peak concentrations - - a slow blood concentration decay - - a prolonged half life time.
These pecularities of the serum concentration decay may also account for the high biliary elimination of this antibiotic, exceeding that of other cephalosporins (1, 10, 15). It has yet to be determined whether the high degree of protein binding of cefazolin (74 0/0) will jeopardize its in vivo antibacterial activity (14). Cefazolin may elicit renal tubular damage in rabbits. However, in that case, nephrotoxie doses of cefazolin are 2.5 times higher than those of cephaloridine (20). On account of these experimental data and of a relatively slow renal excretion, it is essential that excessive and prolonged cefazolin accumulation in the body be
Material and Methods
Patient selection Cefazolin serum concentrations were monitored in 42 patients. Patients were divided into four groups. In selecting patients, consideration was given to each individual's renal function and to the mode of administration (intravenous or intra-muscular) of the drug. Group I - - patients 1--10:10 normal subjects (blood urea < 3 8 m g % ; endogenous creatinine clearance > 90mUmn) were given a single 500 nag intra-muscular dose of cefazolin. Group II - - patients I--X: i0 normal subjects (blood urea < 38mgO/0; creatinine clearance > 85ml/mn) were given a single 500 mg intra-venous injection of cefazolin, performed within less than one minute. Group III - - patients 11--12:10 subjects with varying degrees of renal impairment (blood urea in the 60--148 mg %
Received: 3June 1974 S. V. P. Resumd a la fin du manuscript. Prof. J. Lavillaureix, Prof. J. M. Brogard, Dr. M. Pinget, Dr. F. Ledoux, Departement de M6d6cine Interne, Clinique M6dicale B, Centre Hospitalo-Universitaire de Strasbourg, F-67005 Strasbourg, France.
Infection 3 (1975) Nr. 2
105
1. LavilIaureix, J. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the P h a r m a c o k i n e t i c s . . . Table 1: Adjustment of cefazolin intra-muscular dosages according to creatinine clearance values. The reference maintenance dose is 500 mg in a normal subject with a creatinine clearance value of 100 mg/min. Loading doses are calculated for intervals of 6 hrs, 8 hrs and 12 hrs.
Creatinine clearance (ml/min)
Maintenance dose (nag)
100 90 80 70 60 50 40 30 20 10 0
500 454 407 361 315 268 222 175 130 83 36
Loading dose (rag) in = i~ = in = 6 hours 8 hours 12 hours 598 563 527 495 463 431 402 372 348 320 291
549 511 472 438 403 369 338 306 280 252 223
514 472 429 390 351 3t3 277 243 214 184 155
Table 2: Adjustment of dosage intervals (iA) according to creatinine clearance values. The maintenance dose is 500 mg in all patients; there are three series of adjusted intervals according to in = 6 hrs, 8 hrs and 12 hrs. The corresponding loading dose is determinated for each serie. Creatinine clearance (ml/min)
in = 6 hours in =: 8 hours in = 12 hours Loading Dose Loading Dose Loading Dose = 598 mg = 549 mg = 514 mg
nation rate-constant (Km), the renal elimination rate-constant (Kr) were calculated from: - - the regression line generated by plotting the logarithmic values (common logarithms) of serum concentrations (C) against time (t), the regression line generated by plotting Ke values as a t r a c t i o n of creatinine clearences (CrCI). These lines were computed by the method of least squares and analysis was made with reference to a single open compartment body model. Serum half-lives T 1/2 were calculated using Ke values from the formula T i/2 = logn2/K e (3, 4, 5). The absorption coefficient Ka, determined when the drug was administered intra-muscularly was computed by the method of residual values. The half absorption time, Ta 1/2, was equal to logn2/K ~. Cefazolin plasmatic areas (F) were calculated from the Simpson's trapezoidal rule (3) C~ + C2 F' (mcg.bJmI) ~ ~ t Cefazotin renal clearance (Clr) was calculated from the equation (3) f x 10 ~ Clr (ml/mn) -- F x 60 where "f" is the urine excretion (expressed in rag) of cefazolin during the corresponding period (6 hours). The apparent distribution space A V D was determined following the intravenous administration of a 500 mg dose of cefazolin (5). A V D (liters) = d/Co (d is the injected dose in mg). If is then possible (6, 18) to predict the plasma clearance of cefazolin (C1p]) as CtpI (mt/mn) = AVD. Ke. 10 z 60 Results
Urine excretion 100 90 80 70 60 50 40 30 20 10 0
6,0 6,6 7,4 8,3 9,5 11,2 13,6 17,1 23,2 36,2 82,4
8,0 8,8 9,8 11,I 12,7 14,9 18,0 22,8 31,0 48,3 109,9
12,0 13,2 14,7 16,6 19,0 22,4 27,0 34,2 46,5 72,5 164,7
range and creatinine clearance in the 7 0 - 1 8 m l / m n range) were given a single 500 m g intra-muscular dose of cefazolin. Group IV ~ patients 23--32: 10 patients with chronic nephritis surviving thanks to bi-weekly hemodialysis (creatinine clearance in the 5--0 m l / m n range). These patients were given a single 500 mg intra-muscular dose of cefazolin administered on the day following hemodialysis.
In normal subjects the amount of cefazolin recovered from the urines collected over the six hours following the injection (Figure 1) was 47.5 '~/0 of the intra-muscular dose and 61 °/0 of the intravenous dose.
Urinary excretion Administered dose
0- 6 h I.V.
I.M.
500 mg
305 + 24 mg 238
+ 33 mg
Experimental procedure and bioassay determinations Following i n t r a v e n o u s and intra-muscular administration of 500 mg of cefazolin, blood samples were taken at well defined intervals. Sera remained frozen a t 18 ° C until assayed. Cefazolin levels were also determined in urines collected in their totality over the six hours following antibiotic administration. Concentration determinations were carried out by a cylinder plate method on agar with Bacillus subtilis A T C C 6633 as test organism.
Calculation o/pharmacokinetic data T h e theoretical initial serum concentration (Co-mcg/ml), the overall elimination rate-constant (Ke), the extrarenal elimi-
106
Infection 3 (1975) Nr. 2
~i::~7~.~,
N lOO% i
~?i:i?i;'~g~.':i?~:!.
}ol
'(il re ~ i.......
47,5%!
II
Figure 1: Urinary excretion of cefazolin during the 6 hours period following the administration of a 500 mg intra-muscular or intra-venous dose of the drug
]. Lavillaureix, ]. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the P h a r m a c o ~ n e t i c s . . . Cefazolin
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Figure 2: Left: comparative serum concentrations (mean) of cefazolin after administration of a 500 mg intra-muscular (n = 10 normal subjects) and intra-venous (n = 10 normal subjetcs) single dose of the drug Right: determination of the overall elimination rate constants (Ke) and the serum half-lives after comparative administration of a 500 mg intra-muscular (n = 10 n o r m a l subjects) and intm-venous (n = 10 n o r m a l subjects) single dose of cefazolin
Serum concentrations N o r m a l subjects: After administration of a 500 mg intra-muscular dose (patients 1--10) of cefazolin, serum concentrations (Figure 2) were already amounting to 23.4 ± 3.3 mcg/ml* at 30 minutes but blood peak concentrations were not reached until 1 hour (26.6 + 2.9 mcg/ml). Afterwards, the decay curve has an exponential shape (2 hrs : 22.5 ± 2.0 mcg/ml, 3 hrs : 17.2 _+ 1.4 mcg/ml; 4 hrs : 11.4 ± 10. m c g l / m l ; 6 hrs : 6.6 ± 0.8 mcg/ml; 8 hrs : 3.1 ± 0.3 mcg/ml). After a 500 mg intra-venous dose of cefazolin (patients I X), serum levels (Figure 2) were 72.5 ± 7.6 mcg/ml at 15 minutes, 54.4 + 5.8 mcg/mt at 30 minutes, 36.3 _+ 2.8 mcg/ml at 1 hour, 26.0 _+ 2.1 mcg/ml at 2 hours, 20.4 ± 1.7 meg/ ml at 3 hours, 13.2 ± 1.0 mcg/ml at 4 hours, 6.4 ± 0.8 mcg/ m l at 6 hours, 2.7 ± 0.8 mcg/ml at 8 hours and 1.25 _+ 0.6 mcg/mt at 10 hours. Decay was total 12 hours. Patients with impaired renal function: In patients with impaired renaI function in whom no hemodialysis was performed (patients 11--22) (Figure 3), serum peak concentration were also achieved at one hour after a 500 mg intra-muscular dose of cefazolin. These values were slightly in excess of the m a x i m u m concentrations observed in normal subjects. Serum concentration decay was markedly slowed down especially in patients with a creatinine clearance of less than 50 ml/mn. In patients with chronic nephritis undergoing maintenance hemodiMysis (patients 23--32), serum concentrations at 1 hour were very high (m = 73.2 ± 10.2 mcg/ml). Serum level decay was extremely slow: 64.6 + 8.7 mcg/ml at 2 hours, 62.0 ± 7.9 mcg/ml at 4 hours, 54.9 ± 6.0 mcg/ml at 6 hours, * Concentrations are expressed as average values _+ S. E. M. Standard E r r o r of the Mean)
50.6 _+ 5.4 mcg/ml at 8 hours, 43.1 ± 4.1 mcg/ml at 12 hours, 34.2 4" 3.2 mcg/ml at 24 hours, 22.0 ___ 1.9 mcg/ml at 48 hours.
Elimination rate constant (Ke) In normal subjects, the overall elimination rate constant Ke averaged 0.312 following a 500 mg intra-muscular dose of cefazolin and 0.395 following the intra-venous administration of the same dose. A satisfying correlation (r = 0.944, p < 0.001) can be established between the Ke and CrC1 values of the patients under investigation after the intra-muscular injection of cefazolin (Figure 4). W h e n these two factors are plotted one against the other, they yield a straight line with the formula: Ke = Km + K r = 0.022 + 0.0028 CrC1. W h e n it is calculated theoretically from this equation (4), the Ke value is 0.302 for a creatinine clearance of 100 ml/mn.
Half-lives T 1/2 In normal subjects, T 1/2 values averaged 2.22 hours after a 500 mg intra-muscular dose of cefazolin and 1.75 h o u r after the intra-venous injection of the same dose. In patients with impaired renal function, there was an increase in the duration of T 1/2 which was inversely related to creatinine clearance values. When the half-lives T 1/2 were plotted against the creatinine clearances of all the patients under study given a 500 mg intra-muscular dose of cefazolin, a straight-line relationship was demonstrated (Figure 4), with the formula: Log. T 1/2 = 3.341 - - 0.024 CrC1 (r = 0.932, p 0.001). The T 1/2 value caIculated from this formula was 2.56 hours for a creatinine clearance of 100 mI/mn and 28.24 hours for a creatinine clearance of 0 mt/mn. N o satisfying correlation could be demonstrated between initial theoretical concentrations Co and creatinine clearances.
Infection 3 (1975) Nr. 2
107
J. Lavillaureix, or. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the P h a r m a c o k i n e t i c s . . . Log C
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Figure 3: Linear representation of the serum concentration decay-time curves of Cefazolin in 12 patients with renal failure. The serum half-lives (T 1/2) and the overall elimination rate constants (Ke) have been derived from these lines
Distribution space: A VD
Cefazolin plasmatic clearance
When calculated in the group of normal subjects given a single 500 mg intra-venous injection of cefazolin an average value of 8.64 _+ 1.01 liters i.e. 14.4 + 1.2 o/o of the mean body weight was found. This value closely approximates that of the body extra-cellular fluid compartment.
The plasmatic clearance of cefazolin calculated in normal subjects given a 500 nag intra-venous injection of cefazolin averaged 52.17 + 3.57 ml/mn.
Areas under the curve of cefazotin in plasma The total plasmatic area, "FIv tot" measured in normal subjects given a 500 mg intra-venous injection of cefazolin averaged 151.06_ 9.86 mcg.h/ml. The plasmatic area at 6 hours, "Ft. v. 6 hrs" amounted to 137.76 + 9.62 mcg.h/ml. The total plasmatic area "FIM tot" measured in normal subjects given an intra-muscular injection of the same dose of cefazolin averaged 114.13 + 9.21 mcg.h/ml aud the plasmatic area at 6 hours, "FI. ~.I. 6 h r s ' , amounted to 94.85 _47.78 mcg.h/ml.
108
Infection 3 (1975) Nr. 2
Cefazolin renal clearance The renal clearance of cefazolin measured over a six-hours period in normal subjects (groups I and II) averaged 38.49 + 3.83 ml/mn following a 500 mg intra-venous dose of cefazolin and 41.58 + 6.25 ml/mn following the intra-muscular injection of the same dose. In patients given intra-venous injections, the ratio of cefazotin plasmatic clearance to cefazolin renal clearance was 1.36.
Absorption coefficient (Ka) and absorption half-life (Ta 1/2) Following the administration of a 500 mg intra-muscular dose of cefazolin the absorption coefficient (Ka) in normal
J. Laviltaureix, J. M. Brogard, M. Pinget, F. Ledoux: Dosage Adjustments of Cefalozin According to the Pharmacokinetics... Ke
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