Carbenicillin therapy in patients with normal and impaired renal function Optimum therapy with carbenicillin entails the use of high serum concentrations and the risk of significant dose-related toxicity. We report a study of the serum clearance method of dose adjustment of carbenicillin in patients with normal and impaired renal function. This method was found to provide serum concentrations considered to be satisfactory in every instance, by either constant-rate or intermittent infusion, and should enable greater precision in the use of the antibiotic. Implications of these findings aimed at providing dosage schedules for patients with renal failure are discussed.
Derrick L. Latos, M.D., Charles S. Bryan, M.D., and William J. Stone, M.D.
Nashville, Tenn. Medical Service, Veterans Administration Hospital, and Department of Medicine, Vanderbilt University School of Medicine
In the 5 years since its introduction, carbenicillin has come to be widely used in serious infections caused by certain gram-negative bacilli, especially Pseudomonas aeruginosa and indole-positive species of Proteus. Limitations to carbenicillin therapy include the requirement for relatively high serum concentrations and the potential for significant doserelated toxicity. A need to reduce the dosage of carbenicillin in patients with renal failure is widely acknowledged. lo • 15 In recent constant-rate infusion studies with penicillin G6 we found that the dose needed to achieve a desired serum concentration could be predicted with considerable accuracy for patients with different degrees of renal impairment. This method of dosage calculation is based on the expected linear relationship be-
tween the serum clearance (total plasma clearance) of the antibiotic and the endogenous creatinine clearance (C cr )' We now report the application of this method to carbenicillin. Methods
Patients and drug administration. Our subjects were 23 adult males, 27 to 68 years old, being followed in the renal clinic of the Veterans Administration Hospital, Nashville, Tenn. Control subjects were 4 healthy male physicians and 5 patients with various chronic diseases (with no known liver or renal disease) hospitalized on a continuing-care ward. Conditions for study have been described previously.6 Disodium carbenicillin (Geopen) in vials of I, 2, and 5 gm, * was dissolved in isotonic sodium chloride prior to administration. Load-
Received for publication Feb. 13. 1975. Accepted for publication March I. 1975.
692
'Kindly supplied by Dc. Robel1 G. Meny of J. P. Roerig.
Carbenicillin and renal function
Volume 17 Number 6
693
•
150r
C E "E
i IOO~
•
./
• ./
• •
LU
..J
-
•
U
Z ..J
:=! ~
z
LU al
a::
0.50)(Student's t test). The mean serum Ph of carbenicillin in 6 patients during 10 hemodialyses was 4.3 hr (± 1.5 SD) compared to 14.6 hr (± 6.9 SD) off hemodialysis as determined in 5 of the same patients (6 studies). TV2 following bolus doses was calculated only from the terminal stage (f3 phase). A mean reduction of 71 % in carbenicillin Ph was observed during hemodialysis. The mean dialyzer extraction ratio was 0.20 (± 0.03 SD). Differences were observed in the serum concentration-time curve depending on whether a steady-state had been approximated by prolonged constant-rate infusion or whether measurements were based on a single bolus infusion (Fig. 4). Rapid changes in serum carbenicillin concentration were seen in the first hour of hemodialysis following bolus infusions but not after a prior steady-state had been achieved by continuous infusion. Complications. One patient complained of mild, transient lightheadedness after a loading dose of 3.3 gm of carbenicillin for intermittent therapy at a desired mean serum concentration of 200 ILg/ml. The peak level of carbenicillin following this infusion was 325 ILg/ml. No other complications of carbenicillin administration were recognized. Discussion
It is generally accepted that a pathogenic microorganism is "sensitive" to carbenicillin if the minimum inhibitory concentration (MIC) is 100 ILg/ml or less. 13 Dosage recommendations in common usage assume a desired mean serum concentration of at least 100 ILg/ml for therapy against most strains of Pseudomonas aeruginosa. Even against "more sensitive" microorganisms such as Serratia species and
697
Table 11. Intermittent carbenicillin therapy Patient
22 lit I
29 30 4 lit
C ss attained*
I {mllmini I
(LU! Iml)
130 16 0 148 16 0 22
50 50 50 100 100 100 200
I (J,Lglml)(+ SD) 44.0 52.3 45.2 63.1 80.6 120.3 209.2
± ± ± ± ± ± ±
0.6 1.2 0.6 2.7 3.3 7.9 8.6
See Table I for abbreviations.
* Mean serum carbenicillin concentration attained during infusion calculated by planimetric methods. Values given are means of 5 determinations. tThis patient was studied twice. At the time of the second infusion his C" had improved.
Enterobacter cloacae and aerogenes strains, concentrations of 25 ILg/ml may be necessary to inhibit growth of the great majority of isolates. In comparison with serum levels usually attained with conventional doses of other penicillin congeners, these concentrations are quite high. Carbenicillin therapy is made practical by the drug's unusually low renal clearance and high steady-state serum level per unit dose. 23 Dose-related toxicity is a serious limitation to carbenicillin therapy. Such toxicity is especially likely to occur in patients with renal failure, in whom extremely high serum concentrations have been reported. 3. 24 Carbenicillin neurotoxicity is life-threatening, may be difficult to recognize, has usually been associated with renal failure, and has been accompanied by high serum concentrations when these have been measured. 3, 14, 19,22. 24 In neurotoxic states, serum levels of 250,* 320,15 800,22 1,860,24 and 2,000 3 ILg/ml have been documented. The relative neurotoxicity of carbenicillin compared to other penicillin congeners is not known. The very high sodium load imposed by carbenicillin administration (4.7 mEq of sodium per gram of drug) may cause fluid overload and pulmonary edema. 14 Hypokalemic alkalosis, presumably due to obligatory electrolyte loss during carbenicillin excretion (nonreabsorbable anion), has been described. 16. 20 Two distinctive hematologic • Personal communication. Peter J. Wise, M.D., BeechamMassengill Pharmaceuticals.
698
Latos, Bryan, and Stone
Clinical Pharmacology and Therapeutics
120 110 \ \ 100 ~
E
90
0>
80
.......
.3 z 0
~ 0:::
60 50 40
U Z
"30
U
20
Z
10
0
...J
...J
U
\
0
\
\
~
70
IZ
I.J..I
\
IBOLUS INFUSIONI
\
\
\
mean slope .. - -0.51 ±0.29 --0.099 ± 0.04
\ \
~\
\\
\1\
\
0
2
3
4
5
6
Z I.J..I ID
0:::
«
u
:::E :::>
6°L 50
I.J..I
40
0:::
Cl)
!CONTINUOUS INFUSIONI mean slope = -0.06 ±0.01
30 20 10 0
2
0
HOURS
3
ON
4
5
6
DIALYSIS
Fig. 4. Effects of hemodialysis on serum carbenicillin concentration. Differences between bolus infusion and constant-rate infusion may be a result of multicompartmental drug distribution. Serum concentrations at the beginning of dialysis represent either peak (bolus infusion) or steadystate (prior constant-rate infusion) concentrations.
syndromes-a bleeding diathesis attributed to platelet dysfunction and a reversible granulocytopenia-have also been recognized and are possibly dose-related. 4 • 21 The relatively high cost of carbenicillin is still another reason for not using unnecessarily high doses. For these reasons, we sought to improve the precision with which carbenicillin can be used in patients with normal and impaired renal function. Using the serum clearance method (described in Equation 2 and Fig. I), we achieved serum concentrations that were considered to be satisfactory in all instances for desired concentrations of 50, 100, and 200 ILg/ml. The serum clearance method allows considerable therapeutic flexibility, since the physician can choose a desired serum concentration based on such considerations as the MIC
of the infecting microorganism and the site of infection.17 Dosage recommendations for desired serum concentrations of 50 ILg/ml and 100 ILg/ml based on the mean CCarb at different levels of renal function are shown in Table Ill. A close approximation of the daily dose is obtained by Equation 3. In critical or doubtful Daily dose (mg) = (15
+
Ccr ) (desired serum level)
(3)
situations it may be justifiable to exceed the listed mean doses. Based on the upper limit of the observed Ccarb values at different levels of Ccn a judicious overdose could be obtained by multiplying Equation 3 by 1.2. Conversely, in the case of severe liver disease and a Ccr less than 10 ml/min, the dose should be reduced by one-third (derived from the method of Det-
Carbenicillin and renal function
Volume 17 Number 6
699
Table Ill. Suggested dosage schedule for continuous or intermittent carbenicillin therapy (desired mean serum concentration of 50 or lOO ILg/ml)* Carbenicillin doset Continuous §
lntermittentll Loading dose (gm)
Gm 124 hr
cat mllmin o
~O JLglml
100 JLglml
-----
10
20 40 60 80 100 120 140 160 180 Hemodialysis:
50 JLglml ------
0.8 1.3 1.8 2.8 3.8 4.7 5.7 6.6 7.6 8.6 9.6
1.5
2.5 3.5 5.5 7.4 9.4 11.4 13.2 15.2 17.2 19.2
Maintenance dose (gm)
I 100 JL~ I",!_ '-- 50 JLg Iml I
0.7 0.7 0.8 0.9 1.1 1.0 1.1 1.2
1.4 1.5 1.7
1.3
1.4
1.5
1.8 2.1 1.9 2.1 2.4 2.7 3.0 3.3
JOOJLglml
0.3 q8h 0.4 q8h 0.5 q6h 0.7 q6h 0.9 q6h 0.8 q4h 1.0 q4h 1.1 q4h J.3 q4h 1.5 q4h 1.6 q4h
0.5 0.8 0.9 1.4 1.8 1.6 1.9 2.2 2.5 2.9 3.2
q8h q8h q6h q6h q6h q4h q4h q4h q4h q4h q4h
An additional 0.75 gm (50 JLg/ml desired level) or 1.5 gm (100 JLg/ml desired level) should be given at the termination of each 6-hr hemodialysis to replace expected losses.~
* For each level of renal function the maintenance dose was calculated by Equation 2. with the corresponding values for C,a'b obtained from the regression line shown in Fig. I. Loading dose was determined from the values of K derived from Fig. 2 and the method of Dettli.'-9 In critical or doubtful situations an overestimate of the listed mean doses may be judicious. Based on the upper limit of the observed C'",b values at different levels of C". a suitable overestimate could be obtained by multiplying the listed doses by 1.2. In the presence of severe liver disease and C" less than 10 ml/min. the dose should be reduced by one·third. t Dose was rounded off to closest 0.1 gm. For other desired serum concentrations. the required dosage is directly proportional to the values shown.
:;:C cr is expressed as endogenous creatinine clearance. not corrected for body surface area. *The loading dose for 50 Ilg/ml is 0.5 gm and for 100 Ilg/ml. 1.0 gm. IIThese intervals were chosen to compensate for the "peaks and troughs" of intermittent drug therapy and to facilitate administration by following a practical schedule. Suggested intervals are: 4 hr (q4h) for C" > 60 ml/min. 6 hr (q6h) for C" between II and 60 ml/min. and 8 hr (q8h) for C" of 10 mllmin or less including anephric patients. ~This estimation is based on a dialysance of carbenicillin of 40
tli and associates 7 - 9 and the data of Hoffman, Cestero, and BulIock I5 ). It is worth emphasizing that no method of dose calculation replaces the desirability in many circumstances of measuring serum antibiotic levels 17 or of determining peak serum bactericidal activity against the patient's infecting microorganism. 5 The need to improve precision with which drugs are used in patients with renal failure continues to gain attention. Dettli and associates described a useful method of dosage adjustment for drugs that obey first-order elimination kinetics and are partly excreted by the kidneys. This method is based on the use of serum Ph measurements to derive the overall rate constant of elimination (K). 7-9 We suggest that their method and the serum clearance
mllmin and a dialyzer blood fiow approximating 200 ml/min.
method are complementary, that pharmacokinetic studies aimed at formulating dosage regimens should be based on either constant-rate infusions or on series of intermittent infusions rather than single bolus infusions, and that such studies should include measurements of both serum TV2 and of serum clearance. The wide variation in previously reported carbenicillin Th values for patients with renal failure 2 , 10. 15 may be explained by our observation that the decay of the serum level was biphasic following a bolus dose but monophasic after equilibrium had been attained by constantrate infusion (see Fig. 4). Total body distribution of a drug may be incomplete after a single bolus infusion. 11 For this reason, Th values determined from the decay curve fOllowing
700
Clinical Pharmacology alld Therapeutics
Latos, Bryan, and Stone
constant-rate infusion, or from the final decay curve after a series of intermittent infusions, should be more dependable. The use of constant-rate infusion or of a series of intermittent infusions enables the determination of both serum clearance (which from intermittent infusions can be based on the mean serum concentration, as determined in the present study) and of dependable T~ values. These separate determinations allow evaluation of the consistency of the data obtained, and provide the clinical option for use of either the serum clearance method or the method of Dettli, with their different advantages. The authors wish to thank Dr. Robert M. Huddle for his assistance in some of the early studies, Miss Jane M. Nichols for her technical expertise in the carbenicillin assay, and Mrs. Juanita Watson and Mrs. Betty Holt for their secretarial skill.
I!.
12.
13. 14.
15.
16.
References I. Bennett, J. V., Brodie, J. L., Benner, E. J.,
2.
3. 4.
5.
6. 7. 8.
9.
10.
and Kirby, W. M. M.: Simplified, accurate method for antibiotic assay of clinical specimens, Appl. Microbiol. 14: 170-177, 1966. Beroniade, V.: Carbenicillin half-life time in patients with acute and chronic renal failure: Effects of hemodialysis, Proc. Eur. Dial. Transplant Assoc. 7:207-211, 1970. Blum, P., and Matsen, J. M.: Obvious seizures from carbenicillin, Minn. Med. 54:697699, 1971. Brown, C. H., Natelson, E. A., Bradshaw, M. W., Williams, T. W., and Alfrey, C. P.: The hemostatic defect produced by carbenicillin, N. Engl. J. Med. 291:265-270, 1974. Bryan, C. S., Marney, S. R., Alford, R. H., and Bryant, R. E.: Gram-negative bacillary endocarditis: Interpretation of the serum bactericidal test, Am. J. Med. 58:209-215, 1975. Bryan, C. S., and Stone, W. 1.: "Comparably massive" penicillin G therapy in renal failure, Ann. Intern. Med. 82:189-195, 1975. Dettli, L. C.: Drug dosage in patients with renal disease, CUN. PHARMACOL. THER. 16:274280, 1974. Dettli, L., Spring, P., and Habersang, R.: Drug dosage in patients with impaired renal function, Postgrad. Med. J., vol. 46, October, 1970, Supplement, pp. 32-35. Dettli, L., Spring, P., and Ryter, S.: Multiple dose kinetics and drug dosage in patients with kidney disease,Acta Pharmacol. Toxicol. 29 (Suppl. 3): 211-224, 1971. Eastwood, J. B., and Curtis, 1. R.: Carbenicil-
17. 18.
19.
20.
21. 22.
23.
24.
!in administration in patients with severe renal failure, Br. Med. 1. 1:486-487, 1968. Gibaldi, M., and Weintraub, H.: Some considerations as to the determination and significance of biologic half-life, J. Pharm. Sci. 60:624-626, 1971. Hampers, C. L., Schupak, E., Lowrie, E. G., and Lazarus, J. M.: Long-term hemodialysis: The management of the patient with chronic renal failure, New York, 1973, Grune and Stratton, Inc., p. 6. Hewitt, W. L., and Winters, R. E.: The current status of parenteral carbenicillin, 1. Infect. Dis. 127:S 120-S 132, 1973. Hoffman, T. A., and Bullock, W. E.: Carbenicillin therapy of Pseudomonas and other gramnegative bacillary infections, Ann. Intern. Med. 73:165-171, 1970. Hoffman, T. A., Cestero, R., and Bullock, W. E.: Pharmacodynamics of carbenicillin in hepatic and renal failure, Ann. Intern. Med. 73: 173-178, 1970. Klastersky, J., Vanderkelen, B., Daneau, D., and Mathieu, M.: Carbenicillin and hypokalemia (letter), Ann. Intern. Med. 78:774-775, 1973. Kunin, C. M.: Blood level measurements and antimicrobial agents, CUN. PHARMACOL. THER. 16:251-256, 1974. Kunin, C. M., and Finland, M.: Demethylchlortetracycline: A new tetracycline antibiotic that yields greater and more sustained antibacterial activity, N. Engl. J. Med. 259:999-1005, 1958. Kurtzman, N. A., Rogers, P. W., and Harter, H. R.: Neurotoxic reaction to penicillin and carbenicillin, J. A. M. A. 214:1320-1321, 1970. Lipner, H. 1., Ruzany, F., Dasgupta, M., Lief, P. D., and Bank, N.: Behavior of carbenicillin as a non-reabsorbable anion, Abstract, Sixth Annual Meeting, American Society of Nephrology, 1973. Reyes, M. P., Palutke, M., and Lerner, A. M.: Granulocytopenia associated with carbenicillin, Am. J. Med. 54:413-418, 1973. Robinson, O. P. W.: Human pharmacology of carbenicillin, a semisynthetic penicillin active against Pseudomonas aeruginosa, Antimicrob. Agents Chemother., pp. 614-618, 1967. Standiford, H. C., Jordon, M. c., Kirby, W. M. M.: Clinical pharmacology of carbenicillin compared with other penicillins, J. Infect. Dis. 122:S9-S12, 1970. Whelton, A., Carter, G. G., Garth, M. A., Darwish, M. 0., and Walker, W. G.: Carbenicillin-induced acidosis and seizures, J. A. M. A. 218:1942-1943, 1971.
Derrick L. Latos, M.D., Charles S. Bryan, M.D., and William J. Stone, M.D.
Nashville, Tenn. Medical Service, Veterans Administration Hospital, and Department of Medicine, Vanderbilt University School of Medicine
In the 5 years since its introduction, carbenicillin has come to be widely used in serious infections caused by certain gram-negative bacilli, especially Pseudomonas aeruginosa and indole-positive species of Proteus. Limitations to carbenicillin therapy include the requirement for relatively high serum concentrations and the potential for significant doserelated toxicity. A need to reduce the dosage of carbenicillin in patients with renal failure is widely acknowledged. lo • 15 In recent constant-rate infusion studies with penicillin G6 we found that the dose needed to achieve a desired serum concentration could be predicted with considerable accuracy for patients with different degrees of renal impairment. This method of dosage calculation is based on the expected linear relationship be-
tween the serum clearance (total plasma clearance) of the antibiotic and the endogenous creatinine clearance (C cr )' We now report the application of this method to carbenicillin. Methods
Patients and drug administration. Our subjects were 23 adult males, 27 to 68 years old, being followed in the renal clinic of the Veterans Administration Hospital, Nashville, Tenn. Control subjects were 4 healthy male physicians and 5 patients with various chronic diseases (with no known liver or renal disease) hospitalized on a continuing-care ward. Conditions for study have been described previously.6 Disodium carbenicillin (Geopen) in vials of I, 2, and 5 gm, * was dissolved in isotonic sodium chloride prior to administration. Load-
Received for publication Feb. 13. 1975. Accepted for publication March I. 1975.
692
'Kindly supplied by Dc. Robel1 G. Meny of J. P. Roerig.
Carbenicillin and renal function
Volume 17 Number 6
693
•
150r
C E "E
i IOO~
•
./
• ./
• •
LU
..J
-
•
U
Z ..J
:=! ~
z
LU al
a::
0.50)(Student's t test). The mean serum Ph of carbenicillin in 6 patients during 10 hemodialyses was 4.3 hr (± 1.5 SD) compared to 14.6 hr (± 6.9 SD) off hemodialysis as determined in 5 of the same patients (6 studies). TV2 following bolus doses was calculated only from the terminal stage (f3 phase). A mean reduction of 71 % in carbenicillin Ph was observed during hemodialysis. The mean dialyzer extraction ratio was 0.20 (± 0.03 SD). Differences were observed in the serum concentration-time curve depending on whether a steady-state had been approximated by prolonged constant-rate infusion or whether measurements were based on a single bolus infusion (Fig. 4). Rapid changes in serum carbenicillin concentration were seen in the first hour of hemodialysis following bolus infusions but not after a prior steady-state had been achieved by continuous infusion. Complications. One patient complained of mild, transient lightheadedness after a loading dose of 3.3 gm of carbenicillin for intermittent therapy at a desired mean serum concentration of 200 ILg/ml. The peak level of carbenicillin following this infusion was 325 ILg/ml. No other complications of carbenicillin administration were recognized. Discussion
It is generally accepted that a pathogenic microorganism is "sensitive" to carbenicillin if the minimum inhibitory concentration (MIC) is 100 ILg/ml or less. 13 Dosage recommendations in common usage assume a desired mean serum concentration of at least 100 ILg/ml for therapy against most strains of Pseudomonas aeruginosa. Even against "more sensitive" microorganisms such as Serratia species and
697
Table 11. Intermittent carbenicillin therapy Patient
22 lit I
29 30 4 lit
C ss attained*
I {mllmini I
(LU! Iml)
130 16 0 148 16 0 22
50 50 50 100 100 100 200
I (J,Lglml)(+ SD) 44.0 52.3 45.2 63.1 80.6 120.3 209.2
± ± ± ± ± ± ±
0.6 1.2 0.6 2.7 3.3 7.9 8.6
See Table I for abbreviations.
* Mean serum carbenicillin concentration attained during infusion calculated by planimetric methods. Values given are means of 5 determinations. tThis patient was studied twice. At the time of the second infusion his C" had improved.
Enterobacter cloacae and aerogenes strains, concentrations of 25 ILg/ml may be necessary to inhibit growth of the great majority of isolates. In comparison with serum levels usually attained with conventional doses of other penicillin congeners, these concentrations are quite high. Carbenicillin therapy is made practical by the drug's unusually low renal clearance and high steady-state serum level per unit dose. 23 Dose-related toxicity is a serious limitation to carbenicillin therapy. Such toxicity is especially likely to occur in patients with renal failure, in whom extremely high serum concentrations have been reported. 3. 24 Carbenicillin neurotoxicity is life-threatening, may be difficult to recognize, has usually been associated with renal failure, and has been accompanied by high serum concentrations when these have been measured. 3, 14, 19,22. 24 In neurotoxic states, serum levels of 250,* 320,15 800,22 1,860,24 and 2,000 3 ILg/ml have been documented. The relative neurotoxicity of carbenicillin compared to other penicillin congeners is not known. The very high sodium load imposed by carbenicillin administration (4.7 mEq of sodium per gram of drug) may cause fluid overload and pulmonary edema. 14 Hypokalemic alkalosis, presumably due to obligatory electrolyte loss during carbenicillin excretion (nonreabsorbable anion), has been described. 16. 20 Two distinctive hematologic • Personal communication. Peter J. Wise, M.D., BeechamMassengill Pharmaceuticals.
698
Latos, Bryan, and Stone
Clinical Pharmacology and Therapeutics
120 110 \ \ 100 ~
E
90
0>
80
.......
.3 z 0
~ 0:::
60 50 40
U Z
"30
U
20
Z
10
0
...J
...J
U
\
0
\
\
~
70
IZ
I.J..I
\
IBOLUS INFUSIONI
\
\
\
mean slope .. - -0.51 ±0.29 --0.099 ± 0.04
\ \
~\
\\
\1\
\
0
2
3
4
5
6
Z I.J..I ID
0:::
«
u
:::E :::>
6°L 50
I.J..I
40
0:::
Cl)
!CONTINUOUS INFUSIONI mean slope = -0.06 ±0.01
30 20 10 0
2
0
HOURS
3
ON
4
5
6
DIALYSIS
Fig. 4. Effects of hemodialysis on serum carbenicillin concentration. Differences between bolus infusion and constant-rate infusion may be a result of multicompartmental drug distribution. Serum concentrations at the beginning of dialysis represent either peak (bolus infusion) or steadystate (prior constant-rate infusion) concentrations.
syndromes-a bleeding diathesis attributed to platelet dysfunction and a reversible granulocytopenia-have also been recognized and are possibly dose-related. 4 • 21 The relatively high cost of carbenicillin is still another reason for not using unnecessarily high doses. For these reasons, we sought to improve the precision with which carbenicillin can be used in patients with normal and impaired renal function. Using the serum clearance method (described in Equation 2 and Fig. I), we achieved serum concentrations that were considered to be satisfactory in all instances for desired concentrations of 50, 100, and 200 ILg/ml. The serum clearance method allows considerable therapeutic flexibility, since the physician can choose a desired serum concentration based on such considerations as the MIC
of the infecting microorganism and the site of infection.17 Dosage recommendations for desired serum concentrations of 50 ILg/ml and 100 ILg/ml based on the mean CCarb at different levels of renal function are shown in Table Ill. A close approximation of the daily dose is obtained by Equation 3. In critical or doubtful Daily dose (mg) = (15
+
Ccr ) (desired serum level)
(3)
situations it may be justifiable to exceed the listed mean doses. Based on the upper limit of the observed Ccarb values at different levels of Ccn a judicious overdose could be obtained by multiplying Equation 3 by 1.2. Conversely, in the case of severe liver disease and a Ccr less than 10 ml/min, the dose should be reduced by one-third (derived from the method of Det-
Carbenicillin and renal function
Volume 17 Number 6
699
Table Ill. Suggested dosage schedule for continuous or intermittent carbenicillin therapy (desired mean serum concentration of 50 or lOO ILg/ml)* Carbenicillin doset Continuous §
lntermittentll Loading dose (gm)
Gm 124 hr
cat mllmin o
~O JLglml
100 JLglml
-----
10
20 40 60 80 100 120 140 160 180 Hemodialysis:
50 JLglml ------
0.8 1.3 1.8 2.8 3.8 4.7 5.7 6.6 7.6 8.6 9.6
1.5
2.5 3.5 5.5 7.4 9.4 11.4 13.2 15.2 17.2 19.2
Maintenance dose (gm)
I 100 JL~ I",!_ '-- 50 JLg Iml I
0.7 0.7 0.8 0.9 1.1 1.0 1.1 1.2
1.4 1.5 1.7
1.3
1.4
1.5
1.8 2.1 1.9 2.1 2.4 2.7 3.0 3.3
JOOJLglml
0.3 q8h 0.4 q8h 0.5 q6h 0.7 q6h 0.9 q6h 0.8 q4h 1.0 q4h 1.1 q4h J.3 q4h 1.5 q4h 1.6 q4h
0.5 0.8 0.9 1.4 1.8 1.6 1.9 2.2 2.5 2.9 3.2
q8h q8h q6h q6h q6h q4h q4h q4h q4h q4h q4h
An additional 0.75 gm (50 JLg/ml desired level) or 1.5 gm (100 JLg/ml desired level) should be given at the termination of each 6-hr hemodialysis to replace expected losses.~
* For each level of renal function the maintenance dose was calculated by Equation 2. with the corresponding values for C,a'b obtained from the regression line shown in Fig. I. Loading dose was determined from the values of K derived from Fig. 2 and the method of Dettli.'-9 In critical or doubtful situations an overestimate of the listed mean doses may be judicious. Based on the upper limit of the observed C'",b values at different levels of C". a suitable overestimate could be obtained by multiplying the listed doses by 1.2. In the presence of severe liver disease and C" less than 10 ml/min. the dose should be reduced by one·third. t Dose was rounded off to closest 0.1 gm. For other desired serum concentrations. the required dosage is directly proportional to the values shown.
:;:C cr is expressed as endogenous creatinine clearance. not corrected for body surface area. *The loading dose for 50 Ilg/ml is 0.5 gm and for 100 Ilg/ml. 1.0 gm. IIThese intervals were chosen to compensate for the "peaks and troughs" of intermittent drug therapy and to facilitate administration by following a practical schedule. Suggested intervals are: 4 hr (q4h) for C" > 60 ml/min. 6 hr (q6h) for C" between II and 60 ml/min. and 8 hr (q8h) for C" of 10 mllmin or less including anephric patients. ~This estimation is based on a dialysance of carbenicillin of 40
tli and associates 7 - 9 and the data of Hoffman, Cestero, and BulIock I5 ). It is worth emphasizing that no method of dose calculation replaces the desirability in many circumstances of measuring serum antibiotic levels 17 or of determining peak serum bactericidal activity against the patient's infecting microorganism. 5 The need to improve precision with which drugs are used in patients with renal failure continues to gain attention. Dettli and associates described a useful method of dosage adjustment for drugs that obey first-order elimination kinetics and are partly excreted by the kidneys. This method is based on the use of serum Ph measurements to derive the overall rate constant of elimination (K). 7-9 We suggest that their method and the serum clearance
mllmin and a dialyzer blood fiow approximating 200 ml/min.
method are complementary, that pharmacokinetic studies aimed at formulating dosage regimens should be based on either constant-rate infusions or on series of intermittent infusions rather than single bolus infusions, and that such studies should include measurements of both serum TV2 and of serum clearance. The wide variation in previously reported carbenicillin Th values for patients with renal failure 2 , 10. 15 may be explained by our observation that the decay of the serum level was biphasic following a bolus dose but monophasic after equilibrium had been attained by constantrate infusion (see Fig. 4). Total body distribution of a drug may be incomplete after a single bolus infusion. 11 For this reason, Th values determined from the decay curve fOllowing
700
Clinical Pharmacology alld Therapeutics
Latos, Bryan, and Stone
constant-rate infusion, or from the final decay curve after a series of intermittent infusions, should be more dependable. The use of constant-rate infusion or of a series of intermittent infusions enables the determination of both serum clearance (which from intermittent infusions can be based on the mean serum concentration, as determined in the present study) and of dependable T~ values. These separate determinations allow evaluation of the consistency of the data obtained, and provide the clinical option for use of either the serum clearance method or the method of Dettli, with their different advantages. The authors wish to thank Dr. Robert M. Huddle for his assistance in some of the early studies, Miss Jane M. Nichols for her technical expertise in the carbenicillin assay, and Mrs. Juanita Watson and Mrs. Betty Holt for their secretarial skill.
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