- Email: [email protected]
Pharmacokinetics of intermittent intraperitoneal ceftazidime
Pharmacokinetics of Intermittent Intraperitoneal Ceftazidime Darren W. Grabe, PharmD, George R. Bailie, PharmD, PhD, George Eisele, MD, and Reginald F. Frye, PharmD, PhD ● Ceftazidime is currently recommended as an alternative first-line agent in the treatment of peritonitis and for Pseudomonas peritonitis. The pharmacokinetics of intermittent intraperitoneal (IP) ceftazidime have been poorly characterized. This study was designed to characterize the pharmacokinetic disposition of a single dose of ceftazidime in anuric and non-anuric CAPD patients, over 48 hours. This was a prospective, open label, pharmacokinetic study. The study was conducted in an independent, outpatient dialysis center. Ten volunteer continuous ambulatory peritoneal dialysis (CAPD) patients with and without residual renal function, no peritonitis or antibiotics in the previous 4 weeks, and on CAPD for at least 2 months were recruited. Patients received a single dose of IP ceftazidime (15 mg/kg) in the first daytime exchange over a 6-hour dwell, after an overnight dwell. Serum, urine, and dialysate were collected over a 48-hour period. A high-pressure liquid chromatography (HPLC) assay was used to analyze ceftazidime in these samples. Pharmacokinetic parameters were calculated. Six of the 10 patients were non-anuric with a mean residual renal creatinine clearance of 2.9 ⴞ 1.6 mL/min. The mean ⴞ SD bioavailability was 72% ⴞ 14%, and the volume of distribution was 0.34 ⴞ 0.08 L/kg. The mean serum elimination half-life of 22 ⴞ 5 hours. The peritoneal clearance was 5.74 ⴞ 1.6 mL/min. No difference was detected between anuric and nonanuric patients. Mean plasma and dialysate concentrations at 24 hours were 24 ⴞ 6 g/mL and 18 ⴞ 7 g/mL, respectively, and were 12.0 ⴞ 3.6 µg/mL and 7.4 ⴞ 3.1 µg/mL at 48 hours, respectively. Once-daily IP dosing of ceftazidime achieves serum and dialysate levels greater than the MIC of sensitive organisms over 48 hours. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Ceftazidime; pharmacokinetics; intraperitoneal; peritoneal dialysis; dosing.
P
ERITONITIS remains a cause of significant morbidity and mortality in patients with end-stage renal disease treated with peritoneal dialysis.1-3 This is despite a reduction in the rate of peritonitis since the introduction of peritoneal dialysis in the 1970s.4 For example, the incidence of peritonitis has decreased from about one episode every 6 months to as infrequently as one episode every 5 years.4-7 There are several reasons for the reduction in the frequency of infections. There has been a steady improvement in the technology associated with the delivery of dialysate, including the bags, connection devices, and transfer sets,7-9 particularly since the introduction of double-bag systems. In addition, improved patient education has possibly increased awareness for the necessity for asepsis during exchanges. During the last 15 years, there have been a number of changes in the antibiotic regimens used to treat peritonitis.10 Patients suffering from bacterial peritonitis are now rarely hospitalized, a practice that was widespread a decade ago. The intraperitoneal (IP) route of administration of antibacterials is now more common than the intravenous route.11,12 In addition to this, there has been a general move toward the use of intermittent, as opposed to continuous, IP dosing of antibiotics.13-16 Intermittent treatment implies the use of infrequent dosing, such as once-daily
use of aminoglycosides and cephalosporins, or once-weekly dosing of vancomycin. Intermittent dosing has the advantage in that it requires fewer aseptic manipulations by the patient, which may decrease the risk of accidental contamination of the system. The most recent published guidelines for the treatment of peritoneal dialysis associated peritonitis made numerous dosing recommendations for intermittent IP administration in addition to the more traditional continuous IP administration.10 Although the intermittent regimen has been well studied for vancomycin, and less so for aminoglycosides, there are few adequate studies
From the Division of Pharmacy Practice, Albany College of Pharmacy, Albany, NY; the Department of Medicine, Division of Nephrology, Albany Medical College, Albany, NY; and the Department of Pharmacy Practice, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. Received February 3, 1998; accepted in revised form July 17, 1998. Supported by a grant from Baxter Healthcare Corporation and Glaxo Wellcome. Presented as an abstract at the 1997 annual meeting of the American College of Clinical Pharmacy, Phoenix, AZ, November 1997. Address reprint requests to George R. Bailie, PharmD, PhD, Albany College of Pharmacy, 106 New Scotland Ave, Albany, NY 12208. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3301-0016$3.00/0
American Journal of Kidney Diseases, Vol 33, No 1 (January), 1999: pp 111-117
111
112
of the intermittent dosing strategy for other antibiotics. These new recommendations suggest that ceftazidime, a third-generation cephalosporin, be used as an alternative agent in the empiric treatment of peritonitis. In addition to this, ceftazidime is also recommended for documented infection with Pseudomonas aeruginosa in combination with a second agent. This agent has been selected because it has a broad spectrum of activity along with antipseudomonal properties.17 Doses of 500 mg/L initially then either 500 mg/L in one bag per day or 125 mg/L in every bag as a maintenance dose have been recommended. The pharmacokinetics of IP ceftazidime have been studied previously; however, that investigation failed to fully describe the pharmacokinetic parameters over a 24-hour period, after a prolonged exchange.18 More recently, two additional studies investigated the pharmacokinetics of intermittent IP ceftazidime.19,20 In the one study, the investigators did not describe which of the patients included had residual renal function.19 In addition, a standard dose of ceftazidime was administered to all patients regardless of their weight. Finally, the peritoneal dialysis regimens were not standardized, making it difficult to determine the effects of various dwell times or dialsate dextrose strengths on ceftazidime pharmacokinetics. In the second study, the patients were also given a standard dose of ceftazidime of 1 g, regardless of their actual body weight.20 Data are presented on residual renal function, however no attempt is made on how this affected the pharmacokinetics of ceftazidime. Also, dialysate samples were not collected during the drug-containing dwell, making it impossible to determine time to equilibrium between serum and dialysate. The authors focus attention on serum ceftazidime levels at 24 and 48 hours but fail to mention dialysate concentrations at these time points. These data are crucial to determine adequate MICs in those patients with peritonitis. Therefore, it is difficult to extrapolate those results into clinical practice. With the advent of increased use of alternatives to aminoglycosides, and in the face of the new recommendations, further clarification is required. This study, therefore, was performed to examine the pharmacokinetic disposition of ceftazidime dosed using an intermittent IP regimen
GRABE ET AL
in continuous ambulatory peritoneal dialysis (CAPD). It was hypothesized that an intermittent IP ceftazidime dosing regimen would produce adequate 24-hour serum and dialysate concentrations for the management of bacterial peritonitis. METHODS
Study Population Prospective approval was obtained from the Committee on Research Involving Human Subjects, and informed consent was obtained from those patients selected to participate. Patients with and without residual renal function were included if they were older than 18 years, on a stable regimen of CAPD for at least 2 months without a change in prescription, and with no peritonitis or antibiotics within the previous 4 weeks. Patients were excluded if they were allergic to cephalosporins or had a documented anaphylactic reaction to any beta-lactam antibiotic.
Treatment Protocol The study was conducted in a clinical area of the dialysis unit. Patients arrived in the morning and drained the overnight dwell. They remained in the center for the duration of the first exchange, and returned at pre-ordained times for sampling procedures. Patients with residual renal function urinated immediately before the study. Spent dialysate from the preceding exchange was drained immediately before the instillation of IP ceftazidime. Both the prestudy urine and dialysate were collected, their volumes measured, and 20 mL retained for assay purposes. Ceftazidime (Eli Lilly and Co, Indianapolis, IN) at 15 mg/kg (actual body weight) was added to a 2-L bag of 1.5% dextrose dialysate (Dianeal; Baxter Health Corp, Deerfield, IL). Baseline ceftazidime dialysate concentration was not measured prior to administration. The dialysate/study drug admixture was instilled over 10 to 15 minutes into the peritoneal cavity. Thereafter, each patient was instructed to roll sideways back and forth while lying down, to facilitate mixing of dialysate with any residual contents in the peritoneal cavity. A dialysate sample was collected immediately after mixing. This process was performed according to previously published techniques.16 The dwell was a standard duration of 6 hours. The subsequent exchanges were standardized. The durations of the second, third and fourth dwells were 4, 6, and 8 hours, respectively. The second and third exchanges of the day contained 2.5% dextrose whereas the overnight exchange contained 1.5% dextrose. The same regimen continued during the second 48 hours. At the end of the first (antibiotic-containing) dwell, the dialysate was drained and retained. To ensure a complete drain, effluent was collected until flow had ceased from the peritoneal catheter and patients were seated during the drain. No attempts were made to determine residual volume in the peritoneal cavity. Thereafter, fresh dialysate was instilled. At the end of each of the dwells, the dialysate was drained and retained and fresh, antibiotic-free dialysate administered. The total volume of each dialysate was measured and recorded. A sample (10 mL) of each spent dialysate was
INTRAPERITONEAL CEFTAZIDIME
retained for drug assay. At the end of the eighth exchange (48 hours), each patient reverted back to his or her previous prescription. Time zero was defined as the time immediately after adequate mixing at the end of the instillation of dialysate into the peritoneal cavity. An indwelling peripheral venous catheter was placed in each patient. Blood samples were collected through this port at 0, 0.5, 1, 2, 3, 6, 24, and 48 hours. Blood was permitted to clot in the collection tube and the serum separated. Urine samples (from nonanuric patients) were collected over two 24-hour periods and pooled over the 48-hour period. It is unknown whether ceftazidime is stable under these conditions. Patients voided for the last time just before the end of the study. The urine volume was measured and 10-mL aliquots retained for drug assay and creatinine concentration. The serum creatinine concentration was measured at times 0, 3, 6, 24 and 48 hours as an internal marker and used to determine residual renal function. Serum, dialysate, and urine samples were stored at ⫺70°C until assayed. It is known that ceftazidime is stable in PD fluid.21
113
4. The serum elimination rate constant (kel ) was obtained by linear regression analysis from the serum concentrations between 6 hours and 48 hours. 5. The serum elimination t1⁄2 was calculated as: 0.693/kel 6. The serum area-under-the-curve (AUC) from 0 to 48 hours was calculated using the trapezoidal rule. The serum AUC from 48 hours to infinity (⬁) was calculated by dividing the last concentration time point at 48 hours by the elimination rate constant. 7. The total body clearance was calculated as: Cltotal (L/h) ⫽
F ⫻ Dose AUC0⫺inf
8. Renal clearance in nonanuric patients (Clr), was calculated as: Clr (L/h) ⫽
mg of drug in urine from 0-48 h serum AUC6-48
9. Peritoneal clearance (Clp) was calculated as:
Sample Analysis The serum, dialysate, and urine concentrations of ceftazidime were determined by a modification of the HPLC method of Chan.22 Briefly, samples were prepared by protein precipitation with perchloric acid. An aliquot of the supernatant (20 µL) was injected onto the HPLC system and separation of the analytes was achieved with a Microsorb MV 100 mm ⫻ 4.6 mm ID 3 µm C18 analytical column (Rainin, Woburn, MA). The mobile phase consisted of methanol and potassium phosphate buffer (100 mM, pH 3.8) in a blend of (155:845) for plasma analysis and (180:820) for dialysate and urine analyses; the flow rate was 1.0 mL/min. Column effluent was monitored with a UV detector (Model 486, Waters Corporation, Milford, MA) set at 254 nm. Linear calibration curves were obtained for ceftazidime over the concentration range of 5 to 200 mg/L in each matrix. The within-day and between-day coefficients of variation at low, medium, and high concentrations were all less than 5%.
Pharmacokinetic Calculations A monoexponential model was used, because it was assumed that there was no marked distribution phase after IP administration. 1. The bioavailability (F) was calculated by subtracting the amount of ceftazidime still remaining in the bag at the end of the 6-hour dwell period from the dose of the drug that was instilled into the dialysate prior to administration. 2. The rate constant for the removal of ceftazidime from the dialysate to serum (kabs) was obtained by linear regression analysis of the dialysate concentrations from time 0 to the end of the dwell (6 hours). 3. The half-life (t1/2) of ceftazidime absorption from the peritoneal cavity was calculated as: 0.693/kabs
Clp (L/h) ⫽
mg in dialysate from 6-48 h serum AUC6-48
10. The systemic volume of distribution (Vd) was calculated as: Vd (L/kg) ⫽
[(F) ⫻ (Dose)/SC] ABW
where ABW is the actual body weight and SC is the serum ceftazidime concentration at the end of the antibiotic-containing dwell. 11. Creatinine clearance (CrCl) was calculated by the following formula: CrCl ⫽
(Urine Cr mg/dL) ⫻ (Urine volume mL over 48 hrs) Serum Cr AUC0-48
Statistical Analysis Continuous variables were expressed as means and standard deviations. The differences between the mean pharmacokinetic parameters and between values obtained from anuric and nonanuric patients were analyzed using the Student’s t-test (unpaired).
RESULTS
Ten patients were recruited for the study. Demographics features at baseline are shown in Table 1. Four patients had no residual renal function. Patients who were nonanuric produced a variable amount of urine, ranging from 325 to 3,100 mL (2,017 ⫾ 823 mL). Table 2 shows the summary of the calculated
114
GRABE ET AL Table 1. Patient Demographics
Patient
Age (yr)
1 2 3 4 5 6 7 8 9 10 Mean SD
39 77 57 49 51 62 42 29 39 37 48.2 14.2
Gender
Time on Dialysis (mo)
Height (inches)
IBW (kg)
ABW (kg)
Dose of Ceftazidime (mg)
Urine Output (mL/48 h)
Male Male Male Female Male Male Male Female Female Female N/A N/A
8 41 10 37 17 4 47 49 3 37 25.3 18.6
72.5 72 70 66 * 65 72 60 64 64 67.3 4.5
79 78 73 59 76 62 78 45 54 54 65.8 12.5
75 77.3 127 109 103 98 113.8 73.6 71 65.4 91.3 21.4
1,125 1,160 1,900 1,600 1,500 1,600 1,700 1,100 1,100 1,000 1,378.5 316
3,100 325 2,750 2,400 0 775 0 0 2,750 0 2,017 823
Abbreviations: IBW, ideal body weight; ABW, actual body weight. *Patient had bilateral above-knee amputation.
pharmacokinetic parameters. Because of difficulties with venous access in some patients, actual sample times did not always correlate with proposed collection times. The mean bioavailability of ceftazidime after a 6-hour dwell was 72% ⫾ 14%. These data are calculated from the theoretical dose administered. No statistical difference was found in elimination half-life, total body clearance, or peritoneal clearance in patients with or without residual renal function (Table 3). Figure 1 shows the serum and dialysate concentration time profile of a representative patient on a semi-logarithmic plot. Mean peak serum concentration was 46.3 ⫾ 9.4 µg/mL at the end of the 6-hour antibiotic-containing dwell. The mean initial dialysate concentration was 689.3 ⫾ 158 µg/mL and declined to a mean of 186.3 ⫾ 88.8 µg/mL by the end of the first exchange.
Figure 2 illustrates the serum and dialysate concentrations over the study period. The mean dialysate concentrations at 24 and 48 hours were 18.3 ⫾ 6.8 µg/mL and 7.4 ⫾ 3.1 µg/mL, respectively. Corresponding mean serum concentrations at 24 and 48 hours were 24.4 ⫾ 5.7 µg/mL and 12.0 ⫾ 3.6 µg/mL, respectively. The mean half-life of absorption of ceftazidime from dialysate to serum was 2.72 ⫾ 0.71 hours. There was a poor correlation between renal ceftazidime clearance and renal creatinine clearance, as shown in Figure 3. DISCUSSION
In the current study, we have shown that if dosed appropriately, ceftazidime administered in one exchange per day for at least a 6-hour dwell
Table 2. Pharmacokinetic Parameters
Patient
kel (hr-1)
t1/2
kabs (hr-1)
F
Cltotal (mL/min)
Clp (mL/min)
Clr (mL/min)
Vd (L/kg)
CrCl (mL/min)
1 2 3 4 5 6 7 8 9 10 Mean SD
0.041 0.023 0.026 0.034 0.041 0.037 0.025 0.033 0.041 0.036 0.033 0.0068
17.1 30.1 26.7 20.4 17.1 18.8 28.2 20.9 17.0 19.4 21.6 4.92
0.276 0.188 0.224 0.240 0.346 0.392 0.257 0.549 0.253 0.216 0.294 0.108
0.79 0.48 0.74 0.66 0.79 0.78 0.74 0.96 0.74 0.49 0.72 0.14
16.9 10.1 14.5 10.8 20.8 17.3 17.4 12.9 15.0 6.1 14.1 4.24
3.79 2.86 2.23 3.13 2.76 2.68 3.37 5.05 5.21 4.36 3.54 0.06
6.79 0.55 4.97 4.96 0 2.76 0 0 5.34 0 4.20 2.20
0.44 0.45 0.28 0.25 0.26 0.34 0.38 0.30 0.41 0.30 0.34 0.075
6.41 0.45 4.54 4.46 0 3.73 0 0 1.74 0 3.56 2.1
INTRAPERITONEAL CEFTAZIDIME
115
Table 3. Pharmacokinetic Parameters (Mean ⴞ SD) of Anuric and Nonanuric Patients Renal Status
kel (hr-1)
t1/2 (hrs)
kabs (hr-1)
F
Cl Total (mL/min)
Clp (mL/min)
Vd (L/kg)
Cl Renal (mL/min)
Nonanuric Anuric P value
0.034 ⫾ 0.008 0.034 ⫾ 0.007 0.98
21.7 ⫾ 5.5 21.4 ⫾ 4.8 0.94
0.26 ⫾ 0.07 0.34 ⫾ 0.15 0.28
0.70 ⫾ 0.1 0.75 ⫾ 0.2 0.64
14.1 ⫾ 3.05 14.1 ⫾ 6.21 0.50
3.32 ⫾ 1.06 3.89 ⫾ 1.02 0.42
0.36 ⫾ 0.09 0.31 ⫾ 0.05 0.31
4.2 ⫾ 2.2 0
should provide adequate serum and dialysate concentrations over 24 hours. No statistical difference was found in elimination half-life, total body clearance, and peritoneal clearance between those with and without residual renal function, however, there were only four anuric patients. Although we were unable to detect a difference between the anuric and nonanuric patients, caution is still warranted when treating those patients with significant residual renal function. It is recommended that dialysis be initiated when glomerular filtration rate reaches 10.5 mL/ min/1.73m2.23 This value is much higher than that seen in our patients and may contribute to significantly more renal ceftazidime clearance. Patients with that degree of residual renal function would have an increase of approximately 50% in renal ceftazidime clearance. That would lead to 24-hour serum and dialysate concentrations of approximately 12 mg/L and 8 mg/L, respectively, which may be considered inadequate for some organisms, particularly Pseudomonas aeruginosa. In addition, there is increas-
ing discussion about initiating dialysis at an earlier stage of chronic renal failure to avoid the associated morbidity with advanced renal insufficiency. Peritoneal dialysis may be the preferred modality for the ‘‘early-start’’ patients. These patients will have significantly more residual renal function, resulting in higher clearance for those drugs eliminated by the kidney. The current recommendations for the use of intermittent antibiotics suggest that patients with residual renal function may require either increased doses or more frequent dosing; these recommendations may still hold true.23 Inadequate patient compliance with 48-hour urine collections may have contributed to similar results seen in the two patient groups. In this study, we showed that one dose of ceftazidime at 15 mg/kg in one exchange per day can provide adequate dialysate concentrations and systemic concentrations for 24 hours, with
Fig 1. Concentration time profile after IP ceftazidime in a representative patient (patient 7).
Fig 2. Mean (SD) serum and dialysate ceftazidime concentrations.
116
Fig 3. Correlation between ceftazidime and creatinine clearances.
MICs of sensitive organisms being 16 µg/mL. Ceftazidime was dosed according to actual body weight to achieve adequate serum concentrations in order to provide an ample body reservoir to supply the peritoneal space with sufficient amount of ceftazidime to treat an episode of peritonitis. Dosing according to ideal body weight would have resulted in much lower concentrations since a number of our patients were significantly above their ideal weights. However, those patients who were closer to their ideal body weights did not achieve inadequate serum and dialysate ceftazidime concentrations. In comparison, Stea et al recommend a standard dose of 1.5 g of ceftazidime regardless of either body weight or residual renal function. In our study, that dose was lower than that administered to 4 of the 10 study volunteers and may have led to significantly lower 24-hour serum and dialysate ceftazidime concentrations. The mean 24-hour serum concentration was higher in our study compared to that in Stea et al (24 mg/L v 17 mg/L) despite a lower mean actual body weight (91 kg v 97 kg). Ceftazidime was rapidly absorbed from the peritoneal cavity into the systemic circulation with 72% of the dose absorbed in 6 hours. The volume of distribution was higher than reported values for healthy individuals but similar to what has been reported previously for end-stage renal disease patients.18-20 Ceftazidime is widely distributed into body tissues and fluids including skeletal
GRABE ET AL
muscle, adipose tissue, and cerebral spinal fluid. In healthy individuals, ceftazidime is primarily excreted unchanged in the urine. However, there is evidence to suggest that as renal function diminishes the clearance of ceftazidime via the biliary route becomes more significant. This may explain the discrepancy between total clearance and the sum of the peritoneal clearance and renal clearance. The patients in this study were not infected, and therefore serum concentrations are expected to be lower than those reached during an active infection and with an inflammed peritoneal membrane. A patient with peritonitis would be expected to absorb a greater amount of ceftazidime, thus achieving higher serum concentrations resulting in dialysate concentrations that are above the MIC for a longer period of time. A change in the dwell time of the antibioticcontaining exchange would also alter the amount of ceftazidime absorbed. For example, a dwell time of 4 hours would result in a decrease in bioavailability to approximately 62%. Conversely, an increase in the dwell time would increase the amount absorbed. Steady-state would be achieved after 5 half-lives, in this case, about 13 hours. Finally, although we did not assess peritoneal function by peritoneal equilibration test (PET) or adequacy of dialysis by Kt/V prospectively, it might be important to evaluate this component of solute transfer for future studies. The hypothesis that patients who have variable solute transport characteristics with markers such as creatinine, urea, and glucose may also have similar characteristics for drug molecules. In addition, adequacy of dialysis may also play a role. In patients with higher Kt/V values, one might expect higher drug clearances in those patients compared to those being underdialyzed. These factors may have also contributed to variability in peritoneal ceftazidime clearance, and these studies are currently underway. Finally, we did not study patients on continuous cycling peritoneal dialysis, another variant of peritoneal dialysis, and these results cannot be applied to those patients, this study is also ongoing. CONCLUSION
In conclusion, patients should be dosed according to actual body weight because this is the most appropriate means to accomplish the desired serum/dialysate concentrations. A dose of 15
INTRAPERITONEAL CEFTAZIDIME
mg/kg appears to be adequate to produce serum and dialysate concentrations above the MIC for greater than 24 hours. Further study is warranted in those individuals on CAPD with significantly more residual renal function. ACKNOWLEDGMENT The authors thank the staff at Albany Regional Kidney Center and Albany Dialysis Center for their assistance in conducting this study.
REFERENCES 1. Fried LF, Bernardini J, Johnston JR, Piraino B: Peritonitis influences mortality in peritoneal dialysis patients. J Am Soc Nephrol 7:2176-2182, 1996 2. Churchill DN, Thorpe KE, Vonesh EF, Keshaviah PR: Lower probability of patient survival with continuous peritoneal dialysis in the United States compared to Canada. J Am Soc Nephrol 8:965-971, 1997 3. Golper TA, Brier ME, Bunke M, Schreiber MJ, Bartlett BK, Hamilton RW, et al: Risk factors for peritonitis in long-term peritoneal dialysis: The Network 9 peritonitis and catheter survival studies. Am J Kidney Dis 28:428-436, 1996 4. Gahrmani N, Gorban-Brennan N, Kliger LS, Finkelstein FO: Infection rates in end-stage renal disease patients treated with CCPD and CAPD using the UltrabagJ system. Adv Perit Dial 11:164-167, 1995 5. Bloembergen WE, Port FK, Mauger EA, Wolfe RA: A comparison of mortality between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 6:177183, 1995 6. Bloembergen WE, Port FK, Mauger EA, Wolfe RA: A comparison of cause of death between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 6:184-191, 1995 7. Bazzato G, Landini S, Fracasso A, Morachiello P, Righetto F, Scanferla F, et al: Why the double-bag system still remains the best technique for peritoneal fluid exchange in continuous ambulatory peritoneal dialysis. Perit Dial Int 13:S152-S155, 1993 (suppl 2) 8. Buoncristiani U: Continuous ambulatory peritoneal connection systems. Perit Dial Int 13:S139-S145, 1993 (suppl 2) 9. Harris DCH, Yuill EJ, Byth K, Chapman JR, Hunt C: Twin-versus single-bag disconnect systems: Infection rates and cost of continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 7:2392-2398, 1996 10. Advisory Committee on Peritonitis Management:
117
Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update. Perit Dial Int 16:557-573, 1996 11. Vas SI: Single daily dose of aminoglycosides in the treatment of CAPD peritonitis. Perit Dial Int 13:S355-S356, 1993 (suppl 2) 12. Bailie GR, Eisele G, Venezia R, Yocum D, Hollister A: Prediction of serum vancomycin concentration following intraperitoneal loading doses in continuous ambulatory peritoneal dialysis patients with peritonitis. Clin Pharmacokinet 22:298-307, 1992 13. Lye WC, Wong PL, van der Straaten JC, Leong SO, Lee EJ: A prospective randomized comparison of single versus multidose gentamicin in the treatment of CAPD peritonitis. Adv Perit Dial 11:179-181, 1995 14. Lai M-N, Kao M-T, Chen C-C, Cheung S-Y, Chung W-K: Intraperitoneal once-daily dose of cefazolin and gentamicin for treating CAPD peritonitis. Perit Dial Int 17:87-89, 1997 15. Vas S, Bargman J, Oreopoulos DG: Treatment in PD patients of peritonitis caused by gram-positive organisms with single daily dose of antibiotics. Perit Dial Int 17:91-94, 1997 16. Low CL, Bailie GR, Evans A, Eisele G, Venezia RA: Pharmacokinetics of once-daily ip gentamicin in CAPD patients. Perit Dial Int 16:379-384, 1996 17. Rains CP, Bryson HM, Peters DH: Ceftazidime: An update of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 49:577-617, 1995 18. Demotes-Mainard F, Vincon G, Ragnaud JM, Morlat P, Bannwarth B, Dangoumau J: Pharmacokinetics of intravenous and intra-peritoneal ceftazidime in chronic ambulatory peritoneal dialysis. J Clin Pharmacol 33:475-479, 1993 19. Stea S, Bachelor T, Cooper M, de Souza P, Koenig K, Bolton WK: Disposition and bioavailability of ceftazidime after intraperitoneal administration in patients receiving continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 7:2399-2402, 1996 20. Plant WD, Martin U, Barron W, Scouse PK, Winney RJ, Prescott LF: Absorption and clearance of ceftazidime during CAPD. Perit Dial Int 15:378-382, 1995 21. Bailie GR, Kane MP: Stability of drug additives to peritoneal dialysate. Perit Dial Int 5:328-335, 1995 22. Chan CY, Chan K, French GL: Rapid high performance liquid chromatographic assay on cephalosporins in biological fluids. J Antimicrob Chemother 18:537-545, 1986 23. NKF-DOQI Peritoneal Dialysis Adequacy Work Group: Clinical practice guidelines for peritoneal dialysis adequacy: Initiation of dialysis. Am J Kid Dis 30:S70-S73, 1997 (suppl 2)
P
ERITONITIS remains a cause of significant morbidity and mortality in patients with end-stage renal disease treated with peritoneal dialysis.1-3 This is despite a reduction in the rate of peritonitis since the introduction of peritoneal dialysis in the 1970s.4 For example, the incidence of peritonitis has decreased from about one episode every 6 months to as infrequently as one episode every 5 years.4-7 There are several reasons for the reduction in the frequency of infections. There has been a steady improvement in the technology associated with the delivery of dialysate, including the bags, connection devices, and transfer sets,7-9 particularly since the introduction of double-bag systems. In addition, improved patient education has possibly increased awareness for the necessity for asepsis during exchanges. During the last 15 years, there have been a number of changes in the antibiotic regimens used to treat peritonitis.10 Patients suffering from bacterial peritonitis are now rarely hospitalized, a practice that was widespread a decade ago. The intraperitoneal (IP) route of administration of antibacterials is now more common than the intravenous route.11,12 In addition to this, there has been a general move toward the use of intermittent, as opposed to continuous, IP dosing of antibiotics.13-16 Intermittent treatment implies the use of infrequent dosing, such as once-daily
use of aminoglycosides and cephalosporins, or once-weekly dosing of vancomycin. Intermittent dosing has the advantage in that it requires fewer aseptic manipulations by the patient, which may decrease the risk of accidental contamination of the system. The most recent published guidelines for the treatment of peritoneal dialysis associated peritonitis made numerous dosing recommendations for intermittent IP administration in addition to the more traditional continuous IP administration.10 Although the intermittent regimen has been well studied for vancomycin, and less so for aminoglycosides, there are few adequate studies
From the Division of Pharmacy Practice, Albany College of Pharmacy, Albany, NY; the Department of Medicine, Division of Nephrology, Albany Medical College, Albany, NY; and the Department of Pharmacy Practice, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. Received February 3, 1998; accepted in revised form July 17, 1998. Supported by a grant from Baxter Healthcare Corporation and Glaxo Wellcome. Presented as an abstract at the 1997 annual meeting of the American College of Clinical Pharmacy, Phoenix, AZ, November 1997. Address reprint requests to George R. Bailie, PharmD, PhD, Albany College of Pharmacy, 106 New Scotland Ave, Albany, NY 12208. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3301-0016$3.00/0
American Journal of Kidney Diseases, Vol 33, No 1 (January), 1999: pp 111-117
111
112
of the intermittent dosing strategy for other antibiotics. These new recommendations suggest that ceftazidime, a third-generation cephalosporin, be used as an alternative agent in the empiric treatment of peritonitis. In addition to this, ceftazidime is also recommended for documented infection with Pseudomonas aeruginosa in combination with a second agent. This agent has been selected because it has a broad spectrum of activity along with antipseudomonal properties.17 Doses of 500 mg/L initially then either 500 mg/L in one bag per day or 125 mg/L in every bag as a maintenance dose have been recommended. The pharmacokinetics of IP ceftazidime have been studied previously; however, that investigation failed to fully describe the pharmacokinetic parameters over a 24-hour period, after a prolonged exchange.18 More recently, two additional studies investigated the pharmacokinetics of intermittent IP ceftazidime.19,20 In the one study, the investigators did not describe which of the patients included had residual renal function.19 In addition, a standard dose of ceftazidime was administered to all patients regardless of their weight. Finally, the peritoneal dialysis regimens were not standardized, making it difficult to determine the effects of various dwell times or dialsate dextrose strengths on ceftazidime pharmacokinetics. In the second study, the patients were also given a standard dose of ceftazidime of 1 g, regardless of their actual body weight.20 Data are presented on residual renal function, however no attempt is made on how this affected the pharmacokinetics of ceftazidime. Also, dialysate samples were not collected during the drug-containing dwell, making it impossible to determine time to equilibrium between serum and dialysate. The authors focus attention on serum ceftazidime levels at 24 and 48 hours but fail to mention dialysate concentrations at these time points. These data are crucial to determine adequate MICs in those patients with peritonitis. Therefore, it is difficult to extrapolate those results into clinical practice. With the advent of increased use of alternatives to aminoglycosides, and in the face of the new recommendations, further clarification is required. This study, therefore, was performed to examine the pharmacokinetic disposition of ceftazidime dosed using an intermittent IP regimen
GRABE ET AL
in continuous ambulatory peritoneal dialysis (CAPD). It was hypothesized that an intermittent IP ceftazidime dosing regimen would produce adequate 24-hour serum and dialysate concentrations for the management of bacterial peritonitis. METHODS
Study Population Prospective approval was obtained from the Committee on Research Involving Human Subjects, and informed consent was obtained from those patients selected to participate. Patients with and without residual renal function were included if they were older than 18 years, on a stable regimen of CAPD for at least 2 months without a change in prescription, and with no peritonitis or antibiotics within the previous 4 weeks. Patients were excluded if they were allergic to cephalosporins or had a documented anaphylactic reaction to any beta-lactam antibiotic.
Treatment Protocol The study was conducted in a clinical area of the dialysis unit. Patients arrived in the morning and drained the overnight dwell. They remained in the center for the duration of the first exchange, and returned at pre-ordained times for sampling procedures. Patients with residual renal function urinated immediately before the study. Spent dialysate from the preceding exchange was drained immediately before the instillation of IP ceftazidime. Both the prestudy urine and dialysate were collected, their volumes measured, and 20 mL retained for assay purposes. Ceftazidime (Eli Lilly and Co, Indianapolis, IN) at 15 mg/kg (actual body weight) was added to a 2-L bag of 1.5% dextrose dialysate (Dianeal; Baxter Health Corp, Deerfield, IL). Baseline ceftazidime dialysate concentration was not measured prior to administration. The dialysate/study drug admixture was instilled over 10 to 15 minutes into the peritoneal cavity. Thereafter, each patient was instructed to roll sideways back and forth while lying down, to facilitate mixing of dialysate with any residual contents in the peritoneal cavity. A dialysate sample was collected immediately after mixing. This process was performed according to previously published techniques.16 The dwell was a standard duration of 6 hours. The subsequent exchanges were standardized. The durations of the second, third and fourth dwells were 4, 6, and 8 hours, respectively. The second and third exchanges of the day contained 2.5% dextrose whereas the overnight exchange contained 1.5% dextrose. The same regimen continued during the second 48 hours. At the end of the first (antibiotic-containing) dwell, the dialysate was drained and retained. To ensure a complete drain, effluent was collected until flow had ceased from the peritoneal catheter and patients were seated during the drain. No attempts were made to determine residual volume in the peritoneal cavity. Thereafter, fresh dialysate was instilled. At the end of each of the dwells, the dialysate was drained and retained and fresh, antibiotic-free dialysate administered. The total volume of each dialysate was measured and recorded. A sample (10 mL) of each spent dialysate was
INTRAPERITONEAL CEFTAZIDIME
retained for drug assay. At the end of the eighth exchange (48 hours), each patient reverted back to his or her previous prescription. Time zero was defined as the time immediately after adequate mixing at the end of the instillation of dialysate into the peritoneal cavity. An indwelling peripheral venous catheter was placed in each patient. Blood samples were collected through this port at 0, 0.5, 1, 2, 3, 6, 24, and 48 hours. Blood was permitted to clot in the collection tube and the serum separated. Urine samples (from nonanuric patients) were collected over two 24-hour periods and pooled over the 48-hour period. It is unknown whether ceftazidime is stable under these conditions. Patients voided for the last time just before the end of the study. The urine volume was measured and 10-mL aliquots retained for drug assay and creatinine concentration. The serum creatinine concentration was measured at times 0, 3, 6, 24 and 48 hours as an internal marker and used to determine residual renal function. Serum, dialysate, and urine samples were stored at ⫺70°C until assayed. It is known that ceftazidime is stable in PD fluid.21
113
4. The serum elimination rate constant (kel ) was obtained by linear regression analysis from the serum concentrations between 6 hours and 48 hours. 5. The serum elimination t1⁄2 was calculated as: 0.693/kel 6. The serum area-under-the-curve (AUC) from 0 to 48 hours was calculated using the trapezoidal rule. The serum AUC from 48 hours to infinity (⬁) was calculated by dividing the last concentration time point at 48 hours by the elimination rate constant. 7. The total body clearance was calculated as: Cltotal (L/h) ⫽
F ⫻ Dose AUC0⫺inf
8. Renal clearance in nonanuric patients (Clr), was calculated as: Clr (L/h) ⫽
mg of drug in urine from 0-48 h serum AUC6-48
9. Peritoneal clearance (Clp) was calculated as:
Sample Analysis The serum, dialysate, and urine concentrations of ceftazidime were determined by a modification of the HPLC method of Chan.22 Briefly, samples were prepared by protein precipitation with perchloric acid. An aliquot of the supernatant (20 µL) was injected onto the HPLC system and separation of the analytes was achieved with a Microsorb MV 100 mm ⫻ 4.6 mm ID 3 µm C18 analytical column (Rainin, Woburn, MA). The mobile phase consisted of methanol and potassium phosphate buffer (100 mM, pH 3.8) in a blend of (155:845) for plasma analysis and (180:820) for dialysate and urine analyses; the flow rate was 1.0 mL/min. Column effluent was monitored with a UV detector (Model 486, Waters Corporation, Milford, MA) set at 254 nm. Linear calibration curves were obtained for ceftazidime over the concentration range of 5 to 200 mg/L in each matrix. The within-day and between-day coefficients of variation at low, medium, and high concentrations were all less than 5%.
Pharmacokinetic Calculations A monoexponential model was used, because it was assumed that there was no marked distribution phase after IP administration. 1. The bioavailability (F) was calculated by subtracting the amount of ceftazidime still remaining in the bag at the end of the 6-hour dwell period from the dose of the drug that was instilled into the dialysate prior to administration. 2. The rate constant for the removal of ceftazidime from the dialysate to serum (kabs) was obtained by linear regression analysis of the dialysate concentrations from time 0 to the end of the dwell (6 hours). 3. The half-life (t1/2) of ceftazidime absorption from the peritoneal cavity was calculated as: 0.693/kabs
Clp (L/h) ⫽
mg in dialysate from 6-48 h serum AUC6-48
10. The systemic volume of distribution (Vd) was calculated as: Vd (L/kg) ⫽
[(F) ⫻ (Dose)/SC] ABW
where ABW is the actual body weight and SC is the serum ceftazidime concentration at the end of the antibiotic-containing dwell. 11. Creatinine clearance (CrCl) was calculated by the following formula: CrCl ⫽
(Urine Cr mg/dL) ⫻ (Urine volume mL over 48 hrs) Serum Cr AUC0-48
Statistical Analysis Continuous variables were expressed as means and standard deviations. The differences between the mean pharmacokinetic parameters and between values obtained from anuric and nonanuric patients were analyzed using the Student’s t-test (unpaired).
RESULTS
Ten patients were recruited for the study. Demographics features at baseline are shown in Table 1. Four patients had no residual renal function. Patients who were nonanuric produced a variable amount of urine, ranging from 325 to 3,100 mL (2,017 ⫾ 823 mL). Table 2 shows the summary of the calculated
114
GRABE ET AL Table 1. Patient Demographics
Patient
Age (yr)
1 2 3 4 5 6 7 8 9 10 Mean SD
39 77 57 49 51 62 42 29 39 37 48.2 14.2
Gender
Time on Dialysis (mo)
Height (inches)
IBW (kg)
ABW (kg)
Dose of Ceftazidime (mg)
Urine Output (mL/48 h)
Male Male Male Female Male Male Male Female Female Female N/A N/A
8 41 10 37 17 4 47 49 3 37 25.3 18.6
72.5 72 70 66 * 65 72 60 64 64 67.3 4.5
79 78 73 59 76 62 78 45 54 54 65.8 12.5
75 77.3 127 109 103 98 113.8 73.6 71 65.4 91.3 21.4
1,125 1,160 1,900 1,600 1,500 1,600 1,700 1,100 1,100 1,000 1,378.5 316
3,100 325 2,750 2,400 0 775 0 0 2,750 0 2,017 823
Abbreviations: IBW, ideal body weight; ABW, actual body weight. *Patient had bilateral above-knee amputation.
pharmacokinetic parameters. Because of difficulties with venous access in some patients, actual sample times did not always correlate with proposed collection times. The mean bioavailability of ceftazidime after a 6-hour dwell was 72% ⫾ 14%. These data are calculated from the theoretical dose administered. No statistical difference was found in elimination half-life, total body clearance, or peritoneal clearance in patients with or without residual renal function (Table 3). Figure 1 shows the serum and dialysate concentration time profile of a representative patient on a semi-logarithmic plot. Mean peak serum concentration was 46.3 ⫾ 9.4 µg/mL at the end of the 6-hour antibiotic-containing dwell. The mean initial dialysate concentration was 689.3 ⫾ 158 µg/mL and declined to a mean of 186.3 ⫾ 88.8 µg/mL by the end of the first exchange.
Figure 2 illustrates the serum and dialysate concentrations over the study period. The mean dialysate concentrations at 24 and 48 hours were 18.3 ⫾ 6.8 µg/mL and 7.4 ⫾ 3.1 µg/mL, respectively. Corresponding mean serum concentrations at 24 and 48 hours were 24.4 ⫾ 5.7 µg/mL and 12.0 ⫾ 3.6 µg/mL, respectively. The mean half-life of absorption of ceftazidime from dialysate to serum was 2.72 ⫾ 0.71 hours. There was a poor correlation between renal ceftazidime clearance and renal creatinine clearance, as shown in Figure 3. DISCUSSION
In the current study, we have shown that if dosed appropriately, ceftazidime administered in one exchange per day for at least a 6-hour dwell
Table 2. Pharmacokinetic Parameters
Patient
kel (hr-1)
t1/2
kabs (hr-1)
F
Cltotal (mL/min)
Clp (mL/min)
Clr (mL/min)
Vd (L/kg)
CrCl (mL/min)
1 2 3 4 5 6 7 8 9 10 Mean SD
0.041 0.023 0.026 0.034 0.041 0.037 0.025 0.033 0.041 0.036 0.033 0.0068
17.1 30.1 26.7 20.4 17.1 18.8 28.2 20.9 17.0 19.4 21.6 4.92
0.276 0.188 0.224 0.240 0.346 0.392 0.257 0.549 0.253 0.216 0.294 0.108
0.79 0.48 0.74 0.66 0.79 0.78 0.74 0.96 0.74 0.49 0.72 0.14
16.9 10.1 14.5 10.8 20.8 17.3 17.4 12.9 15.0 6.1 14.1 4.24
3.79 2.86 2.23 3.13 2.76 2.68 3.37 5.05 5.21 4.36 3.54 0.06
6.79 0.55 4.97 4.96 0 2.76 0 0 5.34 0 4.20 2.20
0.44 0.45 0.28 0.25 0.26 0.34 0.38 0.30 0.41 0.30 0.34 0.075
6.41 0.45 4.54 4.46 0 3.73 0 0 1.74 0 3.56 2.1
INTRAPERITONEAL CEFTAZIDIME
115
Table 3. Pharmacokinetic Parameters (Mean ⴞ SD) of Anuric and Nonanuric Patients Renal Status
kel (hr-1)
t1/2 (hrs)
kabs (hr-1)
F
Cl Total (mL/min)
Clp (mL/min)
Vd (L/kg)
Cl Renal (mL/min)
Nonanuric Anuric P value
0.034 ⫾ 0.008 0.034 ⫾ 0.007 0.98
21.7 ⫾ 5.5 21.4 ⫾ 4.8 0.94
0.26 ⫾ 0.07 0.34 ⫾ 0.15 0.28
0.70 ⫾ 0.1 0.75 ⫾ 0.2 0.64
14.1 ⫾ 3.05 14.1 ⫾ 6.21 0.50
3.32 ⫾ 1.06 3.89 ⫾ 1.02 0.42
0.36 ⫾ 0.09 0.31 ⫾ 0.05 0.31
4.2 ⫾ 2.2 0
should provide adequate serum and dialysate concentrations over 24 hours. No statistical difference was found in elimination half-life, total body clearance, and peritoneal clearance between those with and without residual renal function, however, there were only four anuric patients. Although we were unable to detect a difference between the anuric and nonanuric patients, caution is still warranted when treating those patients with significant residual renal function. It is recommended that dialysis be initiated when glomerular filtration rate reaches 10.5 mL/ min/1.73m2.23 This value is much higher than that seen in our patients and may contribute to significantly more renal ceftazidime clearance. Patients with that degree of residual renal function would have an increase of approximately 50% in renal ceftazidime clearance. That would lead to 24-hour serum and dialysate concentrations of approximately 12 mg/L and 8 mg/L, respectively, which may be considered inadequate for some organisms, particularly Pseudomonas aeruginosa. In addition, there is increas-
ing discussion about initiating dialysis at an earlier stage of chronic renal failure to avoid the associated morbidity with advanced renal insufficiency. Peritoneal dialysis may be the preferred modality for the ‘‘early-start’’ patients. These patients will have significantly more residual renal function, resulting in higher clearance for those drugs eliminated by the kidney. The current recommendations for the use of intermittent antibiotics suggest that patients with residual renal function may require either increased doses or more frequent dosing; these recommendations may still hold true.23 Inadequate patient compliance with 48-hour urine collections may have contributed to similar results seen in the two patient groups. In this study, we showed that one dose of ceftazidime at 15 mg/kg in one exchange per day can provide adequate dialysate concentrations and systemic concentrations for 24 hours, with
Fig 1. Concentration time profile after IP ceftazidime in a representative patient (patient 7).
Fig 2. Mean (SD) serum and dialysate ceftazidime concentrations.
116
Fig 3. Correlation between ceftazidime and creatinine clearances.
MICs of sensitive organisms being 16 µg/mL. Ceftazidime was dosed according to actual body weight to achieve adequate serum concentrations in order to provide an ample body reservoir to supply the peritoneal space with sufficient amount of ceftazidime to treat an episode of peritonitis. Dosing according to ideal body weight would have resulted in much lower concentrations since a number of our patients were significantly above their ideal weights. However, those patients who were closer to their ideal body weights did not achieve inadequate serum and dialysate ceftazidime concentrations. In comparison, Stea et al recommend a standard dose of 1.5 g of ceftazidime regardless of either body weight or residual renal function. In our study, that dose was lower than that administered to 4 of the 10 study volunteers and may have led to significantly lower 24-hour serum and dialysate ceftazidime concentrations. The mean 24-hour serum concentration was higher in our study compared to that in Stea et al (24 mg/L v 17 mg/L) despite a lower mean actual body weight (91 kg v 97 kg). Ceftazidime was rapidly absorbed from the peritoneal cavity into the systemic circulation with 72% of the dose absorbed in 6 hours. The volume of distribution was higher than reported values for healthy individuals but similar to what has been reported previously for end-stage renal disease patients.18-20 Ceftazidime is widely distributed into body tissues and fluids including skeletal
GRABE ET AL
muscle, adipose tissue, and cerebral spinal fluid. In healthy individuals, ceftazidime is primarily excreted unchanged in the urine. However, there is evidence to suggest that as renal function diminishes the clearance of ceftazidime via the biliary route becomes more significant. This may explain the discrepancy between total clearance and the sum of the peritoneal clearance and renal clearance. The patients in this study were not infected, and therefore serum concentrations are expected to be lower than those reached during an active infection and with an inflammed peritoneal membrane. A patient with peritonitis would be expected to absorb a greater amount of ceftazidime, thus achieving higher serum concentrations resulting in dialysate concentrations that are above the MIC for a longer period of time. A change in the dwell time of the antibioticcontaining exchange would also alter the amount of ceftazidime absorbed. For example, a dwell time of 4 hours would result in a decrease in bioavailability to approximately 62%. Conversely, an increase in the dwell time would increase the amount absorbed. Steady-state would be achieved after 5 half-lives, in this case, about 13 hours. Finally, although we did not assess peritoneal function by peritoneal equilibration test (PET) or adequacy of dialysis by Kt/V prospectively, it might be important to evaluate this component of solute transfer for future studies. The hypothesis that patients who have variable solute transport characteristics with markers such as creatinine, urea, and glucose may also have similar characteristics for drug molecules. In addition, adequacy of dialysis may also play a role. In patients with higher Kt/V values, one might expect higher drug clearances in those patients compared to those being underdialyzed. These factors may have also contributed to variability in peritoneal ceftazidime clearance, and these studies are currently underway. Finally, we did not study patients on continuous cycling peritoneal dialysis, another variant of peritoneal dialysis, and these results cannot be applied to those patients, this study is also ongoing. CONCLUSION
In conclusion, patients should be dosed according to actual body weight because this is the most appropriate means to accomplish the desired serum/dialysate concentrations. A dose of 15
INTRAPERITONEAL CEFTAZIDIME
mg/kg appears to be adequate to produce serum and dialysate concentrations above the MIC for greater than 24 hours. Further study is warranted in those individuals on CAPD with significantly more residual renal function. ACKNOWLEDGMENT The authors thank the staff at Albany Regional Kidney Center and Albany Dialysis Center for their assistance in conducting this study.
REFERENCES 1. Fried LF, Bernardini J, Johnston JR, Piraino B: Peritonitis influences mortality in peritoneal dialysis patients. J Am Soc Nephrol 7:2176-2182, 1996 2. Churchill DN, Thorpe KE, Vonesh EF, Keshaviah PR: Lower probability of patient survival with continuous peritoneal dialysis in the United States compared to Canada. J Am Soc Nephrol 8:965-971, 1997 3. Golper TA, Brier ME, Bunke M, Schreiber MJ, Bartlett BK, Hamilton RW, et al: Risk factors for peritonitis in long-term peritoneal dialysis: The Network 9 peritonitis and catheter survival studies. Am J Kidney Dis 28:428-436, 1996 4. Gahrmani N, Gorban-Brennan N, Kliger LS, Finkelstein FO: Infection rates in end-stage renal disease patients treated with CCPD and CAPD using the UltrabagJ system. Adv Perit Dial 11:164-167, 1995 5. Bloembergen WE, Port FK, Mauger EA, Wolfe RA: A comparison of mortality between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 6:177183, 1995 6. Bloembergen WE, Port FK, Mauger EA, Wolfe RA: A comparison of cause of death between patients treated with hemodialysis and peritoneal dialysis. J Am Soc Nephrol 6:184-191, 1995 7. Bazzato G, Landini S, Fracasso A, Morachiello P, Righetto F, Scanferla F, et al: Why the double-bag system still remains the best technique for peritoneal fluid exchange in continuous ambulatory peritoneal dialysis. Perit Dial Int 13:S152-S155, 1993 (suppl 2) 8. Buoncristiani U: Continuous ambulatory peritoneal connection systems. Perit Dial Int 13:S139-S145, 1993 (suppl 2) 9. Harris DCH, Yuill EJ, Byth K, Chapman JR, Hunt C: Twin-versus single-bag disconnect systems: Infection rates and cost of continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 7:2392-2398, 1996 10. Advisory Committee on Peritonitis Management:
117
Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update. Perit Dial Int 16:557-573, 1996 11. Vas SI: Single daily dose of aminoglycosides in the treatment of CAPD peritonitis. Perit Dial Int 13:S355-S356, 1993 (suppl 2) 12. Bailie GR, Eisele G, Venezia R, Yocum D, Hollister A: Prediction of serum vancomycin concentration following intraperitoneal loading doses in continuous ambulatory peritoneal dialysis patients with peritonitis. Clin Pharmacokinet 22:298-307, 1992 13. Lye WC, Wong PL, van der Straaten JC, Leong SO, Lee EJ: A prospective randomized comparison of single versus multidose gentamicin in the treatment of CAPD peritonitis. Adv Perit Dial 11:179-181, 1995 14. Lai M-N, Kao M-T, Chen C-C, Cheung S-Y, Chung W-K: Intraperitoneal once-daily dose of cefazolin and gentamicin for treating CAPD peritonitis. Perit Dial Int 17:87-89, 1997 15. Vas S, Bargman J, Oreopoulos DG: Treatment in PD patients of peritonitis caused by gram-positive organisms with single daily dose of antibiotics. Perit Dial Int 17:91-94, 1997 16. Low CL, Bailie GR, Evans A, Eisele G, Venezia RA: Pharmacokinetics of once-daily ip gentamicin in CAPD patients. Perit Dial Int 16:379-384, 1996 17. Rains CP, Bryson HM, Peters DH: Ceftazidime: An update of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 49:577-617, 1995 18. Demotes-Mainard F, Vincon G, Ragnaud JM, Morlat P, Bannwarth B, Dangoumau J: Pharmacokinetics of intravenous and intra-peritoneal ceftazidime in chronic ambulatory peritoneal dialysis. J Clin Pharmacol 33:475-479, 1993 19. Stea S, Bachelor T, Cooper M, de Souza P, Koenig K, Bolton WK: Disposition and bioavailability of ceftazidime after intraperitoneal administration in patients receiving continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 7:2399-2402, 1996 20. Plant WD, Martin U, Barron W, Scouse PK, Winney RJ, Prescott LF: Absorption and clearance of ceftazidime during CAPD. Perit Dial Int 15:378-382, 1995 21. Bailie GR, Kane MP: Stability of drug additives to peritoneal dialysate. Perit Dial Int 5:328-335, 1995 22. Chan CY, Chan K, French GL: Rapid high performance liquid chromatographic assay on cephalosporins in biological fluids. J Antimicrob Chemother 18:537-545, 1986 23. NKF-DOQI Peritoneal Dialysis Adequacy Work Group: Clinical practice guidelines for peritoneal dialysis adequacy: Initiation of dialysis. Am J Kid Dis 30:S70-S73, 1997 (suppl 2)