Journal of Antimicrobial Chemotherapy (1992) 29, 701-709
Effect of impaired renal function on the phannacokinetics of coadministered cefoperazone and solbactam
'Pharmacy Service, "Geriatric Research, Education and Clinical Center and 'Medical Department of Veterans Affairs, West Los Angeles Medical Center, Los Angeles, California 90073; 'Department of Medicine, UCLA School of Medicine, Los Angeles, California 90024; and 'Department of Obstetrics and Gynecology, Southwestern School of Medicine, The University of Southwestern Medical Center at Dallas, Dallas, Texas 75235, USA The phannacokinetics of cefoperazone 2 g combined with sulbactam 1 g after a single dose administered intravenously were evaluated in 24 subjects with normal and impaired renal function. Subjects were categorized into four groups based on endogenous creatinine clearance CI^. Patients in groups 1,2 and 3 had C/^s of > 60, 31 to 60, and 10 to 30 mL/min/1-73 m2, respectively. Patients in group 4 required maintenance haemodialysis and were assumed to have Cla < 10 mL/min/1-73 m2. Pharmacokinctic parameters were determined by noncompartmental methods. No significant differences (P > 0-05) in mean peak serum cefoperazone-sulbactam concentrations for group 1 (208-4/29-0 mg/L), group 2 (1990/34-1 mg/L), group 3 (163-2/35-0 mg/L), and group 4 (2340/66-0 mg/L) were noted. Correlations between both total serum (r — 0-58) and renal (r = 0-35) clearance and creatinine clearances were negative for cefoperazone, although both were shown to decline with diminished renal function. Correlations between serum (r = 0-85) and renal (r = 0-72) clearances and creatinine clearance for sulbactam were, on the other hand, both positive and declined in a linear fashion. No significant differences in steady state volumes of distribution were noted for either cefoperazone (P 60 mL/min/1-73 m2); group 2, six subjects with mild to moderate renal failure (Cla between 31 to 60 mL/min/1-73 m2); group 3, six subjects with severe renal failure (C/CT between 10 to 30 mL/min/1-73 m2); and group 4, six subjects requiring maintenance haemodialysis (Cla < 10 mL/min/1-73 m2). The study protocol was approved by the Department of Veterans Affairs West Los Angeles Medical Center, Wadsworth Division Research Committee. Written informed consent was obtained from each individual before enrolment. Each subject underwent a physical examination and screening of basic haematologjcal and biochemical parameters before administration of the drugs and at the end of the study. Endogenous creatinine clearance was measured over a 24-h period before enrolment Subjects were excluded for the following reasons: known hypersensitivity to penicillins and/or cephalosporins, suspicion of infection, concomitant or previous antibiotic therapy within one week of the study, concomitant medications known to interfere with cefoperazone or sulbactam kinetics, evidence of impaired liver function (as determined by abnormal liver enzyme values), pregnancy or lactation. Patients undergoing haemodialysis were assumed to have &Cla < 10 mL/min/1-73 m2. Drug administration Cefoperazone sodium-sulbactam sodium was supplied by Pfizer Pharmaceuticals. A single dose containing 2 g of cefoperazone and 1 g of sulbactam was infused over IS min into a peripheral vein contralateral to the arm used for blood collection. Haemodialysis patients were administered cefoperazone-sulbactam on days between dialysis. Sample collection Seven mL of blood were drawn just before the dose, immediately after completion of the infusion, and 0-25,0-5,1-0,1-5, 2,4, 6, 8,10,12,24 and 48 h after completion of the infusion. Blood samples were allowed to clot at room temperature, centrifuged and the
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acts synergistically in vitro to inhibit many otherwise resistant organisms (Fu & Neu, 1979). The pharmacokinetics of both cefoperazone and sulbactam have been described individually in subjects with varying degrees of renal dysfunction (Balant et al., 1980; Bolton et al., 1981; Blum et al., 1989). Cefoperazone has been reported to be eliminated primarily by non-renal routes, while sulbactam is cleared primarily by the kidneys. Prolonged terminal half-lives and decreased clearances of both cefoperazone and sulbactam have been reported in patients with renal impairment, although to different degrees. The purposes of this investigation were to determine the pharmacokinetic parameters of a fixed combination of cefoperazone and sulbactam in subjects with normal and impaired renal function and whether any dosage adjustments are necessary in patients with renal impairment.
Cefopenuooe-salbactain in patients wtth renal impairment
703
serum stored at — 70°C in plastic cryotubes until assayed. Urine was collected before dosing to empty the bladder completely and during the time intervals 0-2, 2-4, 4-6, 6-8, 8-10 and 10-12 h after cefoperazone-sulbactam administration. Urine volumes were recorded and 3 mL aliquots were stored at — 70cC until assayed Drug assays
Pharmacokinetic analysis Pharmacokinetic parameters of both cefoperazone and sulbactam were determined by noncompartmental methods. The area under the serum concentration versus time curve (AUC) and the area under the serum concentration-time versus time curve (AUMQ were determined by linear-log trapezoidal rules. The terminal elimination rate constants (fi) were estimated by unweighted, linear least-squares regression analysis of the natural log of concentration versus time. The total serum clearance (C/T) was calculated as dose/AUC and the renal clearance (C/r) was calculated as XJAUC, where Xa is the amount of drug excreted unchanged in the urine. The apparent volume of distribution at steady state (KJ was determined according to the following formula: dos^AUMQ/CAUQ 2 . Half-life (7"l/2) was determined according to In 2/fi. Statistical analysis Statistical analysis of the differences between the pharmacokinetic parameters for the groups was performed by an analysis of variance procedure, PROC ANOVA (SAS Institute, 1985) for one-way and balanced multi-way classifications. Included in the ANOVA output are F tests of all effects in the model statement that use residual mean squares as the error term. A Duncan's Multiple Range test (SAS Institute, 1985) was used to rank the means and to test for pairwise differences between means. Results Twenty-four adult subjects (13 males, 11 females) completed the study. The four groups were comparable with respect to age, body weight, height, and body surface area. Mean serum albumin concentrations were similar for all but group 3. Groups 1, 2 and 3 had mean Cla of 71-2, 39-5 and 22-3 mL/min/1-73 m2, respectively. Group 4 consisted of subjects receiving maintenance haemodialysis and were assumed to have a Cla < 10 mL/min/1-73 m1. The demographic characteristics of the groups are summarized in Table I. The mean serum concentration versus time curves for cefoperazone and sulbactam for the four groups are shown in Figures l(a) and l(b), respectively, Mean peak cefoperazone serum concentrations immediately after the infusion of cefoperazone 2 g sulbactam 1 g were 208-4, 199-0, 163-2 and 234-0 mg/L for groups 1, 2, 3 and 4, respectively. All levels declined in an exponential manner over the 48-h collection
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The HPLC assay of cefoperazone has been described previously (Bawdon, Hemsell & Guss, 1982). The methodology was modified slightly in that the eluate was monitored at 229 run instead of 254 nm. Likewise the HPLC assay of sulbactam has been described previously and was used in this study without modification (Bawdon & Madsen, 1986).
704
J.F.ttboetaL 1000
40 Tim. ( h )
Figure 1. Mean terura concentrations after intravenous administration of 2-0 g of cefoperazone and 1-0 g of sulbactam in 24 subjects with normal and varying degrees of renal impairment. Cefoperazone (a) and sulbactam (b) serum concentrations are depicted for group 1 ( • ) , group 2 (x), group 3 (O). and group 4 (A).
period. Mean pharmacokinetic parameters of cefoperazone appear in Table II. Mean peak sulbactam serum concentrations immediately after infusion of the combination were 29-0, 341, 350 and 66-0 mg/L for groups 1, 2, 3 and 4, respectively. All levels declined in an exponential manner over the 48-h collection period. Mean pharmacokinetic parameters of sulbactam appear in Table m . The mean AUCs for both cefoperazone and sulbactam were higher in the groups of subjects with diminished renal function. The half-lives of both cefoperazone and sulbactam increased with diminishing renal function, although more profoundly for sulbactam.
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Cefoperazone-gnlhactam in patients with renal impairment
705
Table L Demographic characteristics of the four groups
Group 1 2
Age (yr)
Weight (*g)
2/4
45-2* ±16-3 56-8* ±18-2 67-7* ±19-0 55-0*
67-6* ±16-9
5/1
3
5/1
4
6/0
±9-7
73* ±207 607* ±9-2 84-7* ±19-8
Mean±SJ). Height Albumin (cm) (g/dL) 66-2* ±3-8 67-2* ±3-5 68-3* ±4-3 68-3" ±2-6
Creatinine clearance (mL/min/1-73 m1)
4-2*
71.2* ±13-9 39-5*
±04 412**
±5-5
±03
22-3' ±6-4
3-6*
±04 4-2*
HD*
±04
••*•'•'Means with the same letters are not significantly different (P > 005). "HD, haemodialysis patients, CrCl flwiimni to be < lOmL/min/1-73 nr2. S.D., Standard deviation.
Table II. Phannacokinetic parameters of cefoperazone Mcan±s.D. Group
1
cp (mg/L)
AUC
163-2* ±39-9 2340* ±1960
3 4
ci,
(mg.h/L) (mL/min/1-73 m^mL/mm/l^:Jm 2 )
208-4*' 408-5* ±135-9 ±801 199-0" 531-2** ±1304 ±600
2
C/T
581-3** ±15O9 786O* ±288-3
94-3' ±39-9 67-6** ±19-5 6O8** ±13-5 49-1* ±200
13-4' ±1-4 13-6* ±4-4 7-7* ±7-3
NA NA
(L)
Vm (h)
Xt (%)
11-6±4-8 11-1±4-3 12-9* ±4-6 154* ±5-8
14* ±02
±3-9
1-9*
±09 2-5*
±08 40*
18-7* 21O*
±64 13-9* ±12-8
±1-9
NA NA
(h)
x.
See text for abbreviations. ••'Means with the same letter are not significantly different (/> > 005). NA, Not available.
Table ITI. Pharmacokinetic parameters of sulbactam Mean±s.D.
c
AUC
C/T
CI,
Group
p (mg/L)
(mg.h/L) (mL/min/1-73 mJ)(mL/min/l-73 mi2)
1
29O* ±114 34-1* ±140 350* ±8-2 66O* ±41-6
406* ±224 894* ±24-2 1884' ±870 4420* ±195-5
2 3 4
592-8* ±345-9 198-9* ±45-9 116-7* ±700 44-7* ±16-3
v
n (L)
07*
1724* ±324 103-7** ±32-6 66-1* ±611
305* ±14-5 24-8*
±02
±84
±08
±80
4-1*' 37-6* ±2-9 ±24-7
NA NA
27-6* ±8-8
±3-9
See text for abbreviations. '•'•'Means with the same letter are not significantly different (P > OOS). NA, Not available.
28-5*
1-6*
84'
55-3* ±19-8 514'
±7-9 NA NA
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Sex (m/0
706
J. P. Rbo et aL
90 Creotlnln*clearance (mL/mln/l-73 m l )
FIgarc 2. Correlation between total terum clearance of cefoperazone (a) and sulbactam (b) with endogenous creatinine clearance in 24 subjects. The relationship between cefoperazone clearance and creatinine clearance is described by the regression equation (C/T = 0-73 C/o+41-87; r - 058). The relationship between sulbactam clearance and creatinine clearance is described by the regression equation (Clj - 9-82 C/_-111-38; r = 0-85).
Impaired renal function was associated with significantly lower mean clearances of cefoperazone (67-6, 60-8 and 49-1 mL/min/1-73 m2 for groups 2, 3 and 4, respectively versus 94-3 ml/min/1-73 m2 for group 1; P = 0-0061) and sulbactam (198-9, 116-7, 44-7 ml/min/1-73 m2 for groups 2, 3 and 4, respectively versus 592-8 mL/min/1-73 m2 for group 1; P = 0-0004). The relationship between C/T and Cla was defined for cefoperazone as C/T = 0-73 Cla+41-8; r = O-58 and for sulbactam as C/T = 9-82 C^,-111-38; r = 0-85, as shown in Figures 2(a) and (b), respectively. The relationship between Cl, and Cla was denned for cefoperazone as C/r = 0-13 C/CT+6-36; r = 0-35 and for sulbactam as C/r = 2-60 C/,,+6-54; r = 0-72, as shown in Figures 3(a) and (b), respectively. Urinary recovery of both cefoperazone (13-9-21-0% of the administered dose) (Table II) and sulbactam (37-6-55-3% of the administered dose) (Table ITI) after 24 h
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Cefoperagone-tntbartain in patienni with renal impairment
70
Ftgare 3. Correlation between renal clearance of cefopeiazone (a) and sulbectam (b) and endogenous creatinine clearance in IS subjects. The relationship between cefoperazone renal cVflH"*T and crcatmine clearance is described by the regression equation (Cl, - 0-13 C4.+6-36; r - 0-35). The reUtionship between sulbactam renal clearance and creatinine clearance is described by the regression equation (CL « 2-60 C/ o +6-54;r-0-72).
decreased with diminishing renal function but the differences between groups did not reach statistical significance (P > 0-05). Discussion The purpose of this study was to compare the pharmacokinetics of a fixed combination of cefoperazone and sulbactam in patients with normal and varying degrees of impaired renal function. The results demonstrate that the pharmacokinetic parameters of cefoperazone and sulbactam are differentially affected by impairment of renal
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30 50 Crtotlntn* cUaronc* (mL/mln/l-73 tn 1 )
707
708
J. P. Rbo et aL
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function. Total body clearance of sulbactam showed a higher correlation with creatinine clearance (r = 0-85) than did cefoperazone (r = 0-58). This finding is consistent with other reports describing the pharmacokinetics of cefoperazone and sulbactam in patients with renal impairment (Balant et al., 1980; Bolton et al., 1981; Blum et al., 1989). The Vm values of both drugs (11-6-15-4 L and 24-8-30-5 L for cefoperazone and sulbactam respectively; Tables II and III) were not significantly altered by diminished renal function and approximated those of extracellular fluid. Consequently, differences in the half-lives of both drugs may be attributable to the changes in total clearance. The 2-8-fold increase in cefoperazone Tm in group 4 compared with group 1 most likely reflects a 50% decline in total clearance. Similarly, the 12-fold increase in sulbactam Tm may be attributable to the 87% decline in total clearance. The effect of these pharmacokinetic differences on the response to infection is unclear but a number of other variables must be taken into account. These include intrinsic activity of the antibiotic, the serum concentration-time profile in vivo, the protein binding of the antibiotic, the postantibiotic effect, and postantibiotic leucocyte enhancement (Drusano, 1988). However, with the drug combination under investigation the synergy between cefoperazone and sulbactam is dependent in part on maintaining a balanced ratio at the site of infection. Broth microdilution tests and antimicrobial interaction studies have shown that cefoperazone and sulbactam in a fixed (2:1) ratio maximizes cefoperazone activity (Jones et al., 1987). The recommended MIC breakpoints for the combination (2:1 ratio) are < 16/8 mg/L, susceptible; 32/16 mg/L, moderately susceptible; and ^ 64/32 mg/L, resistant (Jones et al., 1987). In the presence of sulbactam at concentrations as low as 2 mg/L cefoperazoneresistant enteric bacilli (MIC > 64 mg/L) became susceptible (Jones et al., 1987). Furthermore, when 16 mg/L of cefoperazone was combined with 2, 4 and 8 mg/L of sulbactam, the number of Bacteroides fragilis isolates which were susceptible to cefoperazone increased from 33% (cefoperazone alone) to 85-7, 95-2 and 96-8%, respectively (Barry, Jones & Packer, 1986). In this study, cefoperazone concentrations remained at or above the MIC susceptibility breakpoint for cefoperazone (16 mg/L) for 5-5, 8, 9 and 10-5 h post-infusion in groups 1, 2, 3 and 4, respectively. Sulbactam concentrations remained at or above the concentrations shown to produce maximum synergy (8 mg/L) for 2-5, 3, 7 and 14 h post-infusion and minimum synergy (2 mg/L) for 3-0, 7-5, 18 and 36 h post-infusion in groups 1, 2, 3 and 4, respectively. It is apparent therefore that when a fixed (2:1) combination of cefoperazone and sulbactam is administered sulbactam will reach threshold concentrations more rapidly than cefoperazone in groups 1 and 2, while remaining above threshold concentrations in groups 3 and 4. The fixed 2:1 ratio is more likely to be maintained pharmacokinetically in patients with severe renal impairment than in those with mild impairment. This is primarily due to the greater renal clearance of sulbactam. In order to reach the sulbactam concentration which provides maximum synergy, it may be necessary to increase the sulbactam dose to a fixed 1:1 ratio (e.g. cefoperazone 2 g: sulbactam 2 g) in patients with only mild renal insufficiency or to increase the dosing frequency. In patients with more severe renal impairment, administration of cefoperazone-sulbactam in a 2:1 ratio appears to provide a balanced pharmacokinetic profile. In conclusion, sulbactam clearance is affected by renal dysfunction to a greater degree than cefoperazone clearance. On the basis of the data presented, it would appear
Cefoperazone-solbactain in patients with renal impairment
709
that the efficacy of the combination is dependent on achieving adequate sulbactam concentrations. In patients with normal renal function the dosing frequency may need to be increased, whilst in patients with profound renal impairment no adjustment is necessary. Acknowledgements
References Balant, L., Daycr, P., Rudhardt, M., AUaz, A. F. & Fabre, J. (1980). Cefopcrazone: pharmacokinetics in humans with normal and impaired renal function and pharmacokinetics in rats. Clinical Therapeutics 3, Special Issue, 50-9. Barry, A. L., Jones, R. N. & Packer, R. R. (1986). In-vitro susceptibility of the Bacteroides fragilis group to cefoperazone, ampicillin, ticarciliin and amoxycillin combined with /J-lactamase inhibitors. Journal of Antimicrobial Chemotherapy 17, 125-7. Bawdon, R. E., Hemsell, D. L. & Guss, S. P. (1982). Comparison of cefoperazone and cefoxitin concentrations in serum and pelvic tissue of abdominal hysterectomy patients. Antimicrobial Agents and Chemotherapy 2, 999-1003. Bawdon, R. E. & Madsen, P. O. (1986). High-pressure liquid chromatographic assay of sulbactam in plasma, urine, and tissue. Antimicrobial Agents and Chemotherapy 30, 231-3. Blum, R. A., Kohli, R. K., Harison, N. J. & Schentag, J. J. (1989). Pharmacokinetics of ampicillin (2-0 grams) and sulbactam (10 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis. Antimicrobial Agents and Chemotherapy 33, 1470-6. Bolton, W. K., Scheld, W. M., Spyker, D. A. & Sande, M. A. (1981). Pharmacokinetics of cefoperazone in normal volunteers and subjects with renal insufficiency. Antimicrobial Agents and Chemotherapy 19, 821-5. Drusano, G. L. (1988). Role of pharmacokinetics in the outcome of infections. Antimicrobial Agents and Chemotherapy 32, 289-97. Fu, K. P. & Neu, H. C. (1979). Comparative inhibition of /J-lactamases by novel /Mactam compounds. Antimicrobial Agents and Chemotherapy 15, 171-6. Gibaldi, M. (1991). Compartmental and noncompartmental pharmacokinetics. In Biopharmaceutics and Clinical Pharmacokinetics, 4th edn, pp. 14-23. Lea and Febiger, Philadelphia, PA. Jones, R. N., Barry, A. L., Packer, R. R., Gregory, W. W. & Thornsbcrry, C. (1987). In vitro antimicrobial spectrum, occurrence of synergy, and recommendations for dilution susceptibility testing concentrations of the cefoperazone-sulbactam combination. Journal of Clinical Microbiology 25, 1725-9. Neu, H. C , Fu, K. P., Aswapokee, N., Aswapokee, P. & Kung, K. (1979). Comparative activity and /Mactamase stability of cefoperazone, a piperazine cephalosporin. Antimicrobial Agents and Chemotherapy 16, 150-7. SAS Institute Inc. (1985). The ANOVA procedure. In SAS/STAT Guide for Personal Computers, 6th edn, pp. 57-82. SAS Institute Inc., Cary, NC. (Received 8 October 1991; revised version accepted 6 February 1992)
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This study was supported by a grant from Pfizer Pharmaceuticals, Roerig Division, New York. We express our deep appreciation for the assistance provided by the staff of the Special Diagnostic and Treatment Unit, Wadsworth Hospital, Department of Veterans Affairs West Los Angeles Medical Center.
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Effect of impaired renal function on the phannacokinetics of coadministered cefoperazone and solbactam
'Pharmacy Service, "Geriatric Research, Education and Clinical Center and 'Medical Department of Veterans Affairs, West Los Angeles Medical Center, Los Angeles, California 90073; 'Department of Medicine, UCLA School of Medicine, Los Angeles, California 90024; and 'Department of Obstetrics and Gynecology, Southwestern School of Medicine, The University of Southwestern Medical Center at Dallas, Dallas, Texas 75235, USA The phannacokinetics of cefoperazone 2 g combined with sulbactam 1 g after a single dose administered intravenously were evaluated in 24 subjects with normal and impaired renal function. Subjects were categorized into four groups based on endogenous creatinine clearance CI^. Patients in groups 1,2 and 3 had C/^s of > 60, 31 to 60, and 10 to 30 mL/min/1-73 m2, respectively. Patients in group 4 required maintenance haemodialysis and were assumed to have Cla < 10 mL/min/1-73 m2. Pharmacokinctic parameters were determined by noncompartmental methods. No significant differences (P > 0-05) in mean peak serum cefoperazone-sulbactam concentrations for group 1 (208-4/29-0 mg/L), group 2 (1990/34-1 mg/L), group 3 (163-2/35-0 mg/L), and group 4 (2340/66-0 mg/L) were noted. Correlations between both total serum (r — 0-58) and renal (r = 0-35) clearance and creatinine clearances were negative for cefoperazone, although both were shown to decline with diminished renal function. Correlations between serum (r = 0-85) and renal (r = 0-72) clearances and creatinine clearance for sulbactam were, on the other hand, both positive and declined in a linear fashion. No significant differences in steady state volumes of distribution were noted for either cefoperazone (P 60 mL/min/1-73 m2); group 2, six subjects with mild to moderate renal failure (Cla between 31 to 60 mL/min/1-73 m2); group 3, six subjects with severe renal failure (C/CT between 10 to 30 mL/min/1-73 m2); and group 4, six subjects requiring maintenance haemodialysis (Cla < 10 mL/min/1-73 m2). The study protocol was approved by the Department of Veterans Affairs West Los Angeles Medical Center, Wadsworth Division Research Committee. Written informed consent was obtained from each individual before enrolment. Each subject underwent a physical examination and screening of basic haematologjcal and biochemical parameters before administration of the drugs and at the end of the study. Endogenous creatinine clearance was measured over a 24-h period before enrolment Subjects were excluded for the following reasons: known hypersensitivity to penicillins and/or cephalosporins, suspicion of infection, concomitant or previous antibiotic therapy within one week of the study, concomitant medications known to interfere with cefoperazone or sulbactam kinetics, evidence of impaired liver function (as determined by abnormal liver enzyme values), pregnancy or lactation. Patients undergoing haemodialysis were assumed to have &Cla < 10 mL/min/1-73 m2. Drug administration Cefoperazone sodium-sulbactam sodium was supplied by Pfizer Pharmaceuticals. A single dose containing 2 g of cefoperazone and 1 g of sulbactam was infused over IS min into a peripheral vein contralateral to the arm used for blood collection. Haemodialysis patients were administered cefoperazone-sulbactam on days between dialysis. Sample collection Seven mL of blood were drawn just before the dose, immediately after completion of the infusion, and 0-25,0-5,1-0,1-5, 2,4, 6, 8,10,12,24 and 48 h after completion of the infusion. Blood samples were allowed to clot at room temperature, centrifuged and the
Downloaded from http://jac.oxfordjournals.org/ at University of Chicago on November 10, 2014
acts synergistically in vitro to inhibit many otherwise resistant organisms (Fu & Neu, 1979). The pharmacokinetics of both cefoperazone and sulbactam have been described individually in subjects with varying degrees of renal dysfunction (Balant et al., 1980; Bolton et al., 1981; Blum et al., 1989). Cefoperazone has been reported to be eliminated primarily by non-renal routes, while sulbactam is cleared primarily by the kidneys. Prolonged terminal half-lives and decreased clearances of both cefoperazone and sulbactam have been reported in patients with renal impairment, although to different degrees. The purposes of this investigation were to determine the pharmacokinetic parameters of a fixed combination of cefoperazone and sulbactam in subjects with normal and impaired renal function and whether any dosage adjustments are necessary in patients with renal impairment.
Cefopenuooe-salbactain in patients wtth renal impairment
703
serum stored at — 70°C in plastic cryotubes until assayed. Urine was collected before dosing to empty the bladder completely and during the time intervals 0-2, 2-4, 4-6, 6-8, 8-10 and 10-12 h after cefoperazone-sulbactam administration. Urine volumes were recorded and 3 mL aliquots were stored at — 70cC until assayed Drug assays
Pharmacokinetic analysis Pharmacokinetic parameters of both cefoperazone and sulbactam were determined by noncompartmental methods. The area under the serum concentration versus time curve (AUC) and the area under the serum concentration-time versus time curve (AUMQ were determined by linear-log trapezoidal rules. The terminal elimination rate constants (fi) were estimated by unweighted, linear least-squares regression analysis of the natural log of concentration versus time. The total serum clearance (C/T) was calculated as dose/AUC and the renal clearance (C/r) was calculated as XJAUC, where Xa is the amount of drug excreted unchanged in the urine. The apparent volume of distribution at steady state (KJ was determined according to the following formula: dos^AUMQ/CAUQ 2 . Half-life (7"l/2) was determined according to In 2/fi. Statistical analysis Statistical analysis of the differences between the pharmacokinetic parameters for the groups was performed by an analysis of variance procedure, PROC ANOVA (SAS Institute, 1985) for one-way and balanced multi-way classifications. Included in the ANOVA output are F tests of all effects in the model statement that use residual mean squares as the error term. A Duncan's Multiple Range test (SAS Institute, 1985) was used to rank the means and to test for pairwise differences between means. Results Twenty-four adult subjects (13 males, 11 females) completed the study. The four groups were comparable with respect to age, body weight, height, and body surface area. Mean serum albumin concentrations were similar for all but group 3. Groups 1, 2 and 3 had mean Cla of 71-2, 39-5 and 22-3 mL/min/1-73 m2, respectively. Group 4 consisted of subjects receiving maintenance haemodialysis and were assumed to have a Cla < 10 mL/min/1-73 m1. The demographic characteristics of the groups are summarized in Table I. The mean serum concentration versus time curves for cefoperazone and sulbactam for the four groups are shown in Figures l(a) and l(b), respectively, Mean peak cefoperazone serum concentrations immediately after the infusion of cefoperazone 2 g sulbactam 1 g were 208-4, 199-0, 163-2 and 234-0 mg/L for groups 1, 2, 3 and 4, respectively. All levels declined in an exponential manner over the 48-h collection
Downloaded from http://jac.oxfordjournals.org/ at University of Chicago on November 10, 2014
The HPLC assay of cefoperazone has been described previously (Bawdon, Hemsell & Guss, 1982). The methodology was modified slightly in that the eluate was monitored at 229 run instead of 254 nm. Likewise the HPLC assay of sulbactam has been described previously and was used in this study without modification (Bawdon & Madsen, 1986).
704
J.F.ttboetaL 1000
40 Tim. ( h )
Figure 1. Mean terura concentrations after intravenous administration of 2-0 g of cefoperazone and 1-0 g of sulbactam in 24 subjects with normal and varying degrees of renal impairment. Cefoperazone (a) and sulbactam (b) serum concentrations are depicted for group 1 ( • ) , group 2 (x), group 3 (O). and group 4 (A).
period. Mean pharmacokinetic parameters of cefoperazone appear in Table II. Mean peak sulbactam serum concentrations immediately after infusion of the combination were 29-0, 341, 350 and 66-0 mg/L for groups 1, 2, 3 and 4, respectively. All levels declined in an exponential manner over the 48-h collection period. Mean pharmacokinetic parameters of sulbactam appear in Table m . The mean AUCs for both cefoperazone and sulbactam were higher in the groups of subjects with diminished renal function. The half-lives of both cefoperazone and sulbactam increased with diminishing renal function, although more profoundly for sulbactam.
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0-1
Cefoperazone-gnlhactam in patients with renal impairment
705
Table L Demographic characteristics of the four groups
Group 1 2
Age (yr)
Weight (*g)
2/4
45-2* ±16-3 56-8* ±18-2 67-7* ±19-0 55-0*
67-6* ±16-9
5/1
3
5/1
4
6/0
±9-7
73* ±207 607* ±9-2 84-7* ±19-8
Mean±SJ). Height Albumin (cm) (g/dL) 66-2* ±3-8 67-2* ±3-5 68-3* ±4-3 68-3" ±2-6
Creatinine clearance (mL/min/1-73 m1)
4-2*
71.2* ±13-9 39-5*
±04 412**
±5-5
±03
22-3' ±6-4
3-6*
±04 4-2*
HD*
±04
••*•'•'Means with the same letters are not significantly different (P > 005). "HD, haemodialysis patients, CrCl flwiimni to be < lOmL/min/1-73 nr2. S.D., Standard deviation.
Table II. Phannacokinetic parameters of cefoperazone Mcan±s.D. Group
1
cp (mg/L)
AUC
163-2* ±39-9 2340* ±1960
3 4
ci,
(mg.h/L) (mL/min/1-73 m^mL/mm/l^:Jm 2 )
208-4*' 408-5* ±135-9 ±801 199-0" 531-2** ±1304 ±600
2
C/T
581-3** ±15O9 786O* ±288-3
94-3' ±39-9 67-6** ±19-5 6O8** ±13-5 49-1* ±200
13-4' ±1-4 13-6* ±4-4 7-7* ±7-3
NA NA
(L)
Vm (h)
Xt (%)
11-6±4-8 11-1±4-3 12-9* ±4-6 154* ±5-8
14* ±02
±3-9
1-9*
±09 2-5*
±08 40*
18-7* 21O*
±64 13-9* ±12-8
±1-9
NA NA
(h)
x.
See text for abbreviations. ••'Means with the same letter are not significantly different (/> > 005). NA, Not available.
Table ITI. Pharmacokinetic parameters of sulbactam Mean±s.D.
c
AUC
C/T
CI,
Group
p (mg/L)
(mg.h/L) (mL/min/1-73 mJ)(mL/min/l-73 mi2)
1
29O* ±114 34-1* ±140 350* ±8-2 66O* ±41-6
406* ±224 894* ±24-2 1884' ±870 4420* ±195-5
2 3 4
592-8* ±345-9 198-9* ±45-9 116-7* ±700 44-7* ±16-3
v
n (L)
07*
1724* ±324 103-7** ±32-6 66-1* ±611
305* ±14-5 24-8*
±02
±84
±08
±80
4-1*' 37-6* ±2-9 ±24-7
NA NA
27-6* ±8-8
±3-9
See text for abbreviations. '•'•'Means with the same letter are not significantly different (P > OOS). NA, Not available.
28-5*
1-6*
84'
55-3* ±19-8 514'
±7-9 NA NA
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Sex (m/0
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J. P. Rbo et aL
90 Creotlnln*clearance (mL/mln/l-73 m l )
FIgarc 2. Correlation between total terum clearance of cefoperazone (a) and sulbactam (b) with endogenous creatinine clearance in 24 subjects. The relationship between cefoperazone clearance and creatinine clearance is described by the regression equation (C/T = 0-73 C/o+41-87; r - 058). The relationship between sulbactam clearance and creatinine clearance is described by the regression equation (Clj - 9-82 C/_-111-38; r = 0-85).
Impaired renal function was associated with significantly lower mean clearances of cefoperazone (67-6, 60-8 and 49-1 mL/min/1-73 m2 for groups 2, 3 and 4, respectively versus 94-3 ml/min/1-73 m2 for group 1; P = 0-0061) and sulbactam (198-9, 116-7, 44-7 ml/min/1-73 m2 for groups 2, 3 and 4, respectively versus 592-8 mL/min/1-73 m2 for group 1; P = 0-0004). The relationship between C/T and Cla was defined for cefoperazone as C/T = 0-73 Cla+41-8; r = O-58 and for sulbactam as C/T = 9-82 C^,-111-38; r = 0-85, as shown in Figures 2(a) and (b), respectively. The relationship between Cl, and Cla was denned for cefoperazone as C/r = 0-13 C/CT+6-36; r = 0-35 and for sulbactam as C/r = 2-60 C/,,+6-54; r = 0-72, as shown in Figures 3(a) and (b), respectively. Urinary recovery of both cefoperazone (13-9-21-0% of the administered dose) (Table II) and sulbactam (37-6-55-3% of the administered dose) (Table ITI) after 24 h
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Cefoperagone-tntbartain in patienni with renal impairment
70
Ftgare 3. Correlation between renal clearance of cefopeiazone (a) and sulbectam (b) and endogenous creatinine clearance in IS subjects. The relationship between cefoperazone renal cVflH"*T and crcatmine clearance is described by the regression equation (Cl, - 0-13 C4.+6-36; r - 0-35). The reUtionship between sulbactam renal clearance and creatinine clearance is described by the regression equation (CL « 2-60 C/ o +6-54;r-0-72).
decreased with diminishing renal function but the differences between groups did not reach statistical significance (P > 0-05). Discussion The purpose of this study was to compare the pharmacokinetics of a fixed combination of cefoperazone and sulbactam in patients with normal and varying degrees of impaired renal function. The results demonstrate that the pharmacokinetic parameters of cefoperazone and sulbactam are differentially affected by impairment of renal
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30 50 Crtotlntn* cUaronc* (mL/mln/l-73 tn 1 )
707
708
J. P. Rbo et aL
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function. Total body clearance of sulbactam showed a higher correlation with creatinine clearance (r = 0-85) than did cefoperazone (r = 0-58). This finding is consistent with other reports describing the pharmacokinetics of cefoperazone and sulbactam in patients with renal impairment (Balant et al., 1980; Bolton et al., 1981; Blum et al., 1989). The Vm values of both drugs (11-6-15-4 L and 24-8-30-5 L for cefoperazone and sulbactam respectively; Tables II and III) were not significantly altered by diminished renal function and approximated those of extracellular fluid. Consequently, differences in the half-lives of both drugs may be attributable to the changes in total clearance. The 2-8-fold increase in cefoperazone Tm in group 4 compared with group 1 most likely reflects a 50% decline in total clearance. Similarly, the 12-fold increase in sulbactam Tm may be attributable to the 87% decline in total clearance. The effect of these pharmacokinetic differences on the response to infection is unclear but a number of other variables must be taken into account. These include intrinsic activity of the antibiotic, the serum concentration-time profile in vivo, the protein binding of the antibiotic, the postantibiotic effect, and postantibiotic leucocyte enhancement (Drusano, 1988). However, with the drug combination under investigation the synergy between cefoperazone and sulbactam is dependent in part on maintaining a balanced ratio at the site of infection. Broth microdilution tests and antimicrobial interaction studies have shown that cefoperazone and sulbactam in a fixed (2:1) ratio maximizes cefoperazone activity (Jones et al., 1987). The recommended MIC breakpoints for the combination (2:1 ratio) are < 16/8 mg/L, susceptible; 32/16 mg/L, moderately susceptible; and ^ 64/32 mg/L, resistant (Jones et al., 1987). In the presence of sulbactam at concentrations as low as 2 mg/L cefoperazoneresistant enteric bacilli (MIC > 64 mg/L) became susceptible (Jones et al., 1987). Furthermore, when 16 mg/L of cefoperazone was combined with 2, 4 and 8 mg/L of sulbactam, the number of Bacteroides fragilis isolates which were susceptible to cefoperazone increased from 33% (cefoperazone alone) to 85-7, 95-2 and 96-8%, respectively (Barry, Jones & Packer, 1986). In this study, cefoperazone concentrations remained at or above the MIC susceptibility breakpoint for cefoperazone (16 mg/L) for 5-5, 8, 9 and 10-5 h post-infusion in groups 1, 2, 3 and 4, respectively. Sulbactam concentrations remained at or above the concentrations shown to produce maximum synergy (8 mg/L) for 2-5, 3, 7 and 14 h post-infusion and minimum synergy (2 mg/L) for 3-0, 7-5, 18 and 36 h post-infusion in groups 1, 2, 3 and 4, respectively. It is apparent therefore that when a fixed (2:1) combination of cefoperazone and sulbactam is administered sulbactam will reach threshold concentrations more rapidly than cefoperazone in groups 1 and 2, while remaining above threshold concentrations in groups 3 and 4. The fixed 2:1 ratio is more likely to be maintained pharmacokinetically in patients with severe renal impairment than in those with mild impairment. This is primarily due to the greater renal clearance of sulbactam. In order to reach the sulbactam concentration which provides maximum synergy, it may be necessary to increase the sulbactam dose to a fixed 1:1 ratio (e.g. cefoperazone 2 g: sulbactam 2 g) in patients with only mild renal insufficiency or to increase the dosing frequency. In patients with more severe renal impairment, administration of cefoperazone-sulbactam in a 2:1 ratio appears to provide a balanced pharmacokinetic profile. In conclusion, sulbactam clearance is affected by renal dysfunction to a greater degree than cefoperazone clearance. On the basis of the data presented, it would appear
Cefoperazone-solbactain in patients with renal impairment
709
that the efficacy of the combination is dependent on achieving adequate sulbactam concentrations. In patients with normal renal function the dosing frequency may need to be increased, whilst in patients with profound renal impairment no adjustment is necessary. Acknowledgements
References Balant, L., Daycr, P., Rudhardt, M., AUaz, A. F. & Fabre, J. (1980). Cefopcrazone: pharmacokinetics in humans with normal and impaired renal function and pharmacokinetics in rats. Clinical Therapeutics 3, Special Issue, 50-9. Barry, A. L., Jones, R. N. & Packer, R. R. (1986). In-vitro susceptibility of the Bacteroides fragilis group to cefoperazone, ampicillin, ticarciliin and amoxycillin combined with /J-lactamase inhibitors. Journal of Antimicrobial Chemotherapy 17, 125-7. Bawdon, R. E., Hemsell, D. L. & Guss, S. P. (1982). Comparison of cefoperazone and cefoxitin concentrations in serum and pelvic tissue of abdominal hysterectomy patients. Antimicrobial Agents and Chemotherapy 2, 999-1003. Bawdon, R. E. & Madsen, P. O. (1986). High-pressure liquid chromatographic assay of sulbactam in plasma, urine, and tissue. Antimicrobial Agents and Chemotherapy 30, 231-3. Blum, R. A., Kohli, R. K., Harison, N. J. & Schentag, J. J. (1989). Pharmacokinetics of ampicillin (2-0 grams) and sulbactam (10 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis. Antimicrobial Agents and Chemotherapy 33, 1470-6. Bolton, W. K., Scheld, W. M., Spyker, D. A. & Sande, M. A. (1981). Pharmacokinetics of cefoperazone in normal volunteers and subjects with renal insufficiency. Antimicrobial Agents and Chemotherapy 19, 821-5. Drusano, G. L. (1988). Role of pharmacokinetics in the outcome of infections. Antimicrobial Agents and Chemotherapy 32, 289-97. Fu, K. P. & Neu, H. C. (1979). Comparative inhibition of /J-lactamases by novel /Mactam compounds. Antimicrobial Agents and Chemotherapy 15, 171-6. Gibaldi, M. (1991). Compartmental and noncompartmental pharmacokinetics. In Biopharmaceutics and Clinical Pharmacokinetics, 4th edn, pp. 14-23. Lea and Febiger, Philadelphia, PA. Jones, R. N., Barry, A. L., Packer, R. R., Gregory, W. W. & Thornsbcrry, C. (1987). In vitro antimicrobial spectrum, occurrence of synergy, and recommendations for dilution susceptibility testing concentrations of the cefoperazone-sulbactam combination. Journal of Clinical Microbiology 25, 1725-9. Neu, H. C , Fu, K. P., Aswapokee, N., Aswapokee, P. & Kung, K. (1979). Comparative activity and /Mactamase stability of cefoperazone, a piperazine cephalosporin. Antimicrobial Agents and Chemotherapy 16, 150-7. SAS Institute Inc. (1985). The ANOVA procedure. In SAS/STAT Guide for Personal Computers, 6th edn, pp. 57-82. SAS Institute Inc., Cary, NC. (Received 8 October 1991; revised version accepted 6 February 1992)
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This study was supported by a grant from Pfizer Pharmaceuticals, Roerig Division, New York. We express our deep appreciation for the assistance provided by the staff of the Special Diagnostic and Treatment Unit, Wadsworth Hospital, Department of Veterans Affairs West Los Angeles Medical Center.
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