Bacterial peritonitis is a common complication of peritoneal

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1 Peritoneal Dialysis International, Vol. 27, pp Printed in Canada. All rights reserved /07 $ Copyright 2007 International Society for Peritoneal Dialysis VANCOMYCIN DISPOSITION FOLLOWING INTRAPERITONEAL ADMINISTRATION IN CHILDREN RECEIVING PERITONEAL DIALYSIS Douglas L. Blowey, 1,2 Bradley A. Warady, 1 Susan Abdel Rahman, 2 Reginald F. Frye, 3 and Harold J. Manley 4 Department of Pediatric Nephrology 1 and Department of Clinical Pharmacology, 2 Children s Mercy Hospitals & Clinics, University of Missouri at Kansas City, Missouri; Department of Pharmacy Practice, 3 University of Florida, Gainesville, Florida; Albany College of Pharmacy, 4 Albany, New York, USA Correspondence to: D.L. Blowey, 2410 Gillham Road, Kansas City, Missouri USA. dblowey@cmh.edu Received 22 December 2005; accepted 15 May Background: Little information is available on the disposition of vancomycin during chronic peritoneal dialysis (PD) in children. The primary objective of this study was to investigate the disposition of vancomycin following intraperitoneal (IP) administration in children receiving shortdwell [e.g., automated PD (APD)] and long-dwell [e.g., continuous ambulatory PD (CAPD)] PD. Methods: A 6-hour exchange containing vancomycin 500 mg/l, using an exchange volume of 1100 ml/m 2 body surface area (BSA), was followed by 4-, 6-, and 8-hour antibiotic-free exchanges. The 8-hour exchange was followed by three to four 90-minute antibiotic-free exchanges. Serial blood and dialysis effluent samples were obtained and analyzed for vancomycin concentration by high-pressure liquid chromatography. Pharmacokinetic parameters were computed using noncompartmental methods. Results: The bioavailability of vancomycin during a 6-hour IP exchange was 70% ± 5%, resulting in a delivered dose of 12.0 ± 1.8 mg/kg, and a 6-hour serum vancomycin concentration of 23.3 ± 7.2 µg/ml. µµ Total body vancomycin clearance measured ± 4.52 ml/minute/1.73 m 2 BSA, while clearance attributable to PD measured 2.78 ± 1.08 ml/min/1.73 m 2 BSA and accounted for 29% ± 11% of total vancomycin clearance. Dialysis clearance during long-dwell (CAPD) and short-dwell (APD) regimens was similar, measuring 2.46 ± 1.04 and 3.09 ± 1.28 ml/min/1.73 m 2 BSA, accounting for 25% ± 13% and 32% ± 12% of total body clearance respectively. Conclusions: Intraperitoneal absorption and dialysis clearance of vancomycin in children receiving PD are similar to those reported in adult dialysis patients. In contrast, total body clearance of vancomycin appears to be increased and the elimination half-life decreased in children, due to increased elimination by non-renal nondialysis routes. For intermittent IP vancomycin therapy in children with peritonitis, an IP load containing vancomycin 1000 mg/l (or 30 mg/kg), followed a single full-fill (1100 ml/m 2 BSA) daily exchange, containing vancomycin 250 mg/l (or 7.5 mg/kg), from day 2 until the end of treatment will maintain a vancomycin dialysate concentration of >4 µg/ml. µµ Perit Dial Int 2007; 27: KEY WORDS: Vancomycin; pharmacokinetics; pediatric. Bacterial peritonitis is a common complication of peritoneal dialysis (PD) in children and mandates prompt and effective antibiotic therapy. Although restricted in its use due to concern of antibiotic resistance, intraperitoneal (IP) vancomycin is recommended as a component of empirical therapy in children with evidence of peritonitis and any of the following findings: fever, severe abdominal pain, history of methicillin-resistant Staphylococcus aureus infection, recent or current evidence of an exit-site/tunnel or nasal/exit-site colonization with Staphylococcus aureus, and patient age less than 2 years (1). During treatment of peritonitis, vancomycin is delivered as a loading dose, followed by administration of vancomycin in every exchange (continuous therapy) or as intermittent doses (intermittent therapy). During intermittent therapy, the appearance of vancomycin in the dialysis effluent depends on the transfer of vancomycin from blood to dialysis fluid and is impacted by the time (e.g., dwell time) allowed for exchange. Despite the recommendation for vancomycin therapy, there is little information on vancomycin disposition in children receiving PD (2,3). The current pediatric dosing guidelines for the use of intermittent and continuous vancomycin in the treatment of peritonitis (1) are extrapolated from adult pharmacokinetic studies (4 10). The use of 79

2 BLOWEY et al. JANUARY 2007 VOL. 27, NO. 1 PDI adult pharmacokinetic data for drug dosing in children ignores potential developmental differences in vancomycin pharmacokinetics and peritoneal physiology, as well as the impact of pediatric-specific dialysis regimens on the delivery of safe and effective therapy. The primary objective of this study was to investigate the disposition of vancomycin in children with end-stage kidney disease receiving short-dwell [e.g., automated peritoneal dialysis (APD)] and long-dwell [e.g., continuous ambulatory peritoneal dialysis (CAPD)] PD regimens using an IP loading dose of vancomycin. METHODS SUBJECTS Children receiving chronic PD were selected for study if they were 1 18 years of age and had received PD for more than 1 month. Those patients allergic to vancomycin or ceftazidime, having a hematocrit <30%, receiving a beta-lactam or aminoglycoside antibiotic within the preceding 2 weeks, and/or those with an episode of peritonitis within the prior month were excluded. Written informed consent was obtained from parents and assent from the child. The trial was approved by the local Institutional Review Board. STUDY DESIGN A standardized peritoneal equilibrium test (PET) was performed within 3 months prior to the pharmacokinetic study (11). On the day of the pharmacokinetic study, each child received an IP infusion of dialysis fluid (2.5% dextrose) containing vancomycin 500 mg/l and ceftazidime 250 mg/l. The infused volume was 1100 ml/m 2 body surface area (BSA) and was administered by way of the PD catheter over 5 10 minutes using a Y-type administration set. The antibiotic-containing dialysis fluid was left in the peritoneal cavity for 6 hours; samples of dialysis effluent and blood were collected immediately after the infusion and at 0.5, 1, 2, 3, 4, and 6 hours. Peritoneal dialysis effluent samples were obtained by draining 20 ml of fluid through the Y-set into a small sterile bag. The drain bag was clamped and a 25-gauge needle attached to a 6-mL syringe was inserted into the flushball device on the Y-set, and 5 ml of PD effluent was withdrawn. The drain was unclamped and the fluid was reinfused. The 6-hour sample was obtained directly from the drain bag at completion of the drain. At the end of 6 hours, the PD fluid containing antibiotic was drained and fresh antibiotic-free dialysis fluid (2.5% dextrose) was infused into the peritoneal cavity at a volume of ml/m 2 BSA. Subsequent exchanges with antibioticfree fresh dialysis solution were conducted over 4, 6, and 8 hours, and samples of the drained dialysis effluent were collected at the conclusion of each dwell period. These dwell times represent those typically observed during CAPD and hereafter are characterized as CAPD. Following the 8-hour exchange, each child underwent a series (n = 3 4) of 90-minute antibiotic-free exchanges using a volume of 1100 ml/m 2 BSA, representing typical APD exchanges and hereafter are characterized as APD. Samples of dialysis effluent and blood were collected at times 0, 45, and 90 minutes of each exchange. Dialysis effluent samples were obtained as previously described. Data from the 90-minute sample were used for pharmacokinetic analysis of the APD regimen. In children with residual kidney function, all urine produced during the study was collected and a sample of the pooled collection was analyzed for vancomycin and ceftazidime concentration. Blood samples (2 ml) were collected into non-heparinized blood-collection tubes and allowed to clot. Serum was separated by centrifugation and stored at 20 C in cryogenic storage tubes until analysis. Dialysis fluid and urine samples were transferred directly into cryogenic storage tubes and stored at 20 C until analysis. Dialysis, blood, and urine samples were analyzed for vancomycin and ceftazidime. ANALYSIS Vancomycin: The concentration of vancomycin in serum and dialysis fluid was determined by high-pressure liquid chromatography (HPLC) (4). The limit of quantification for this method is 2.0 mg/l and the intraday and interday coefficients of variation were 10% or less in each sample matrix. Ceftazidime: The concentration of ceftazidime in serum and dialysis fluid was determined by HPLC. There appeared to be degradation of ceftazidime in the stored samples, making the ceftazidime data unsuitable for analysis. Pharmacokinetics: Pharmacokinetic analysis was performed using the pharmacokinetic software Kinetica (version 4.1.1; InnaPhase, now Thermo Electron, Waltham, Massachusetts, USA). Pharmacokinetic parameters were determined using noncompartmental methods as follows: 1. Delivered Dose (Bioavailability, or F): The amount of vancomycin absorbed from the peritoneal cavity was calculated by subtracting the amount of vancomycin remaining in the dialysis effluent at the end of the 6-hour exchange from the amount introduced into the peritoneum.

3 PDI JANUARY 2007 VOL. 27, NO. 1 VANCOMYCIN PK IN PD 2. Area Under the Vancomycin Concentration Time Curve (AUC): The AUC was computed using the loglinear method. AUC total is the sum of AUC from time zero until the last measured concentration (C last ) and AUC from the last measured concentration to infinity, as determined by C last /terminal elimination rate (λz). 3. Terminal Elimination Rate (λz): The terminal elimination rate constant was calculated as the slope of the best regression line on the logarithmic transformed data points from the end of the IP infusion (hour 6) to the last measured concentration (C last ). 4. Serum Terminal Elimination Half-Life (t½): Serum terminal elimination half-life was calculated as 0.693/λz. 5. Clearance (Cl): Total body clearance (Cl T ) was calculated as delivered dose (mg)/auc total. Renal clearance (Cl R ) was calculated as drug in the urine (mg)/ (AUC 0 Clast ). Dialysis clearance (Cl PD ) was calculated as drug in the dialysis fluid (mg)/(auc onset end dialysis ). Clearance calculations were normalized to a BSA of 1.73 m Volume of Distribution (Vd): Volume of distribution was calculated as dose/auc λz. STATISTICAL ANALYSIS Descriptive data are presented as mean ± SD unless otherwise noted. Comparisons of pharmacokinetic parameters during CAPD and APD regimens were completed using a two-tailed paired t-test. Bivariate correlation was assessed using Pearson s correlation coefficient. A p value less than 0.05 was considered significant. RESULTS Seven of the 8 enrolled children completed the study. One child withdrew from the study due to inability to obtain vascular access. Overall, the children were 12.7 ± 4.1 years old and had received PD for 29.6 ± 30 months. Only 1 child had a history of peritonitis. Demographic information on the 7 children completing the study, including their peritoneal membrane transport capacity, is provided in Table 1. Vancomycin was well absorbed from the noninfected peritoneum, having a bioavailability of 70% ± 5% at the end of a 6-hour exchange. The actual delivered dose of vancomycin was 12.0 ± 1.8 mg/kg and the resulting 6-hour serum vancomycin concentration measured 23.3 ± 7.2 µg/ml. The serum and dialysis effluent vancomycin concentrations measured during the study are graphically depicted in Figure 1. The elimination rate constant (λz) and elimination t½ of vancomycin in the patients were ± 0.004/hour and 25.0 ± 4.6 hours respectively. Volume of distribution (Vd) measured 0.48 ± 0.24 L/kg. Total body vancomycin clearance (Cl T ), which includes vancomycin clearance by renal, dialysis, and other routes, measured ± 4.52 ml/min/1.73 m 2 BSA. Clearance attributable to PD (Cl PD ) measured 2.78 ± 1.08 ml/min/1.73 m 2 BSA and accounted for 29% ± 11% of total vancomycin clearance. Dialysis clearances during CAPD (Cl CAPD ) and APD (Cl APD ) regimens were similar, measuring 2.46 ± 1.04 and 3.09 ± 1.28 ml/min/1.73 m 2 BSA (p = 0.10), and accounted for 25% ± 13% and 32% ± 12% of Cl T respectively. Renal clearance in the 3 children with residual renal function measured 0.63, 0.64, and 8.38 ml/min/1.73 m 2 BSA. Clearance not attributable to dialysis or renal routes accounted for the greatest portion of Cl T, measuring 6.57 ± 3.42 ml/min/1.73 m 2 BSA or 63% ± 18% of total vancomycin clearance. Individual pharmacokinetic parameters are summarized in Table 2. The transfer of vancomycin from blood to dialysis fluid was assessed by measuring the vancomycin dialysate/ plasma (D/P) ratio during the APD regimen at 45 and 90 minutes, and during the CAPD regimen at 6 and 8 hours. Backward extrapolation was used to estimate the 6-hour serum vancomycin level as a blood sample was not obtained at this time. The D/P vancomycin ratio increased with time, measuring 0.18 ± 0.10 at 45 minutes, 0.22 ± 0.11 at 90 minutes, 0.40 ± 0.14 at 6 hours, and 0.45 ± 0.20 at 8 hours (p < 0.05). Table 3 provides the individual vancomycin D/P ratios at 90 minutes and 8 hours, PET results, and vancomycin PD clearance values. There was a positive correlation between the D/P ratios and vancomycin Cl PD at 90 minutes (r = 0.76, p < 0.05) and 8 hours (r = 0.86, p < 0.05). Although the number of patients in each PET category is small, there does not appear to be a correlation between peritoneal transport capacity and vancomycin D/P ratios. DISCUSSION In this study of vancomycin pharmacokinetics in children receiving chronic PD, bioavailability (absorption) of IP vancomycin and dialysis clearance were similar to values reported in adult dialysis patients, whereas Cl T was increased and elimination t½ was decreased in children. In adult PD patients, the bioavailability of IP vancomycin following a 4- to 6-hour exchange is 52% 73%, irrespective of whether or not the peritoneum is infected (6,8 10). A similar bioavailability was observed in this pediatric study, with 70% absorption of IP vancomycin 81

4 BLOWEY et al. JANUARY 2007 VOL. 27, NO. 1 PDI TABLE 1 Demographic Data Age Weight BSA PET PD duration Peritonitis Patient (years) Gender (kg) (m 2 ) (D/P urea) (months) episodes (n) 1 14 M High F High-average F Low-average F High-average F Low-average M High-average M High-average 8 0 BSA = body surface area; PET = peritoneal equilibrium test; D/P = dialysate-to-plasma ratio; PD = peritoneal dialysis. Figure 1 Serum (closed squares) and dialysis effluent (open circles) vancomycin (VANC) concentration (mean ± SD) versus-time curve following a 6-hour intraperitoneal (IP) exchange (1100 ml/m 2 ) containing vancomycin 500 mg/l. The dialysate effluent (open circles) concentration during shortdwell peritoneal dialysis (PD) represents the vancomycin concentration at 90 minutes. from an uninfected peritoneum following a 6-hour exchange. This is consistent with a previous report of 65% vancomycin absorption following a 4-hour IP load in 4 children with peritonitis (3). The transfer of drug from blood to dialysis fluid (i.e., dialysis clearance) is governed by the intrinsic properties of the peritoneal membrane, effective peritoneal surface area, drug size and protein binding, and concentration gradient. Of these, drug size [e.g., molecular weight (MW)] and protein binding have the greatest influence on the transfer of drug. The transfer of vancomycin is likely restricted due to its large size (MW = 1449 Da). In the present pediatric study, the ratio between dialysis and plasma vancomycin concentrations (D/P vancomycin) was used to assess the transfer rate of vancomycin, similar to the use of the D/P ratio for urea and creatinine in the PET. The D/P vancomycin ratio at 90 minutes measured 0.22 ± 0.11 and reflects a slower rate of solute transfer compared to D/P ratios of >0.5 and 0.4 at 2-hours for smaller MW solutes such as urea (MW < 500 Da) (11) and gentamicin (MW = 464 Da) (12) 82 TABLE 2 Vancomycin Pharmacokinetic Parameters in Children Receiving Peritoneal Dialysis % Absorbed 6-hour level Vd λz t½ Clearance (ml/minute/1.73 m 2 ) Patient (F) (µg/ml) (L/kg) (L/hour) (hours) Total Renal CAPD APD Mean±SD 0.7± ± ± ± ± ± ± ± ±1.28 F = bioavailability; Vd = volume of distribution; λz = elimination rate constant; t½ = terminal elimination half-life; CAPD = continuous ambulatory peritoneal dialysis; APD = automated PD.

5 PDI JANUARY 2007 VOL. 27, NO. 1 VANCOMYCIN PK IN PD TABLE 3 Individual Vancomycin Dialysate-to-Plasma (D/P) Ratios, Vancomycin Cl PD, and Peritoneal Equilibrium Test (PET) Results Vancomycin D/P ratio Vancomycin Cl PD Patient 90-minute 8-hour (ml/min/1.73 m 2 ) PET High High-average Low-average High-average Low-average High-average High-average Mean±SD 0.22±0.11 a 0.45±0.20 b 2.78±1.08 Cl PD = clearance attributable to peritoneal dialysis [(Cl CAPD + Cl APD )/2]. a Correlation with vancomycin Cl PD : r = 0.76 (p < 0.05). b Correlation with vancomycin Cl PD : r = 0.86 (p < 0.05). respectively. The discrepancy in solute transport among small (e.g., urea) and large (e.g., vancomycin, MW = 1449 Da) solutes explains the apparent lack of correlation between the peritoneal transport capacity, as assessed in the PET, and the vancomycin D/P ratio. As expected, the vancomycin D/P ratio positively correlated with the measured vancomycin dialysis clearance (Cl PD ). The dialysis clearance of vancomycin in the present study did not differ between short-dwell (APD) and longdwell (CAPD) regimens, nor did we find a difference between dialysis clearance of vancomycin in children and that reported in adult PD patients (4,6,8,10) [2.78 ± 1.08 ml/min/1.73 m 2 vs ml/min (adult data not corrected for BSA)]. These findings are consistent with the concept that the main determinant of vancomycin dialysis clearance is intrinsic to the drug; that is, the large MW of vancomycin and other factors, such as developmental differences in peritoneal physiology, inflamed or noninflamed peritoneum, and dialysis regimen, are of secondary importance. This study did reveal an apparent increase in the total body vancomycin clearance and a decrease in the elimination t½ in children receiving PD compared to adult PD patients (4,6,8,10). These findings are consistent with prior reports describing developmental differences in vancomycin pharmacokinetics among neonates, infants, children, and adults (13,14). Prior studies have shown that the Cl T of vancomycin in children without kidney disease is 2 to 3 times higher, and the elimination halflife 2 to 3 times faster than in adults. Consistent with the reported developmental changes in vancomycin pharmacokinetics, the Cl T of vancomycin in this study, in which the children had minimal to no residual kidney function, was about 2 times that reported in adult PD patients (4,10) (11 ml/min/1.73 m 2 vs 5 7 ml/min), and the elimination t½ was about 2 3 times faster than that reported in the majority of adult studies (25 vs hours) (4,6,8,10). Since the volume of distribution for vancomycin in our patients was similar to that reported in adults, it can be suggested that the increased Cl T in children is due to enhanced elimination from a route other than renal or dialysis (gastrointestinal, biliary, degradation, etc.). Although not designed as a pharmacokinetic study, the elimination t½ (not reported, but calculated from the data) observed in a study of intermittent vancomycin therapy in children with peritonitis (2) was approximately 54 hours and is longer than the elimination t½ of 25 ± 4.6 hours observed in our study. However, the method of vancomycin measurement was not mentioned in that report and it is possible that the method of measurement did not discriminate vancomycin from inactive vancomycin crystalline degradation products, leading to falsely elevated vancomycin levels at 60 hours and 7 days and an inaccurate estimate of the elimination rate. Crystalline degradation products do not interfere with vancomycin measurement by HPLC as was used in this study (15). Due to the slow transfer rate of vancomycin from blood to dialysis fluid, therapeutic end-of-dwell dialysis effluent concentrations may not be achieved during intermittent therapy, particularly when using short exchange times, if the serum vancomycin level is not maintained at a level that allows for the adequate transfer of drug from blood to the dialysis compartment. During dialysis with short duration exchanges (e.g., APD), the serum concentration required to obtain therapeutic end-ofdwell dialysis effluent concentration will be higher than that required in long duration exchanges (e.g., CAPD) 83

6 BLOWEY et al. JANUARY 2007 VOL. 27, NO. 1 PDI as there is less time for vancomycin to move across the peritoneal membrane. Using the D/P vancomycin ratios observed in this study, a serum level of at least 18 µg/ml would be needed to achieve an end-of-dwell vancomycin dialysis effluent concentration of 4 µg/ml, a concentration that exceeds the minimum inhibitory concentration for most gram-positive organisms, during APD-type regimens. Similarly, a serum vancomycin level of at least 9 µg/ml will result in a dialysis effluent concentration of 4 µg/ml or greater during CAPD. This finding may support the suggestion that the dialysis prescription of patients receiving APD be modified to long-dwell dialysis at the initiation of antibiotic therapy for peritonitis and highlights the importance of maintaining adequate serum levels during intermittent therapy. Although intermittent IP vancomycin has been successfully used to treat peritonitis in children receiving APD (2), a recent review of the International Pediatric Peritonitis Registry (16) found that intermittent empirical therapy was associated with a poor early response compared to continuous therapy (personal communication). With the goal of maintaining a serum vancomycin level that would result in an end-of-dwell dialysis fluid effluent vancomycin concentration of at least 4 µg/ml, we created a pharmacokinetic model, using the pharmacokinetic characteristics and D/P vancomycin values obtained in this study, to explore vancomycin dosing regimens for APD and CAPD in children. The model uses a 6-hour IP vancomycin load followed by three 6-hour antibiotic-free exchanges. After the initial 24 hours, the routine APD or CAPD regimen is resumed. Figure 2(a) shows the predicted serum and dialysis effluent vancomycin levels during an APD regimen using an IP load containing 1000 mg/l (or 30 mg/kg), followed by a single full-fill (1100 ml/m 2 ) daily exchange lasting at least 6 hours and containing 250 mg/l (or 7.5 mg/kg) vancomycin, from day 2 until the end of treatment. If a full fill is not used for the daytime exchange, the exchange should contain 7.5 mg/kg vancomycin, as using 250 mg/l would result in a reduced drug dosage due to a decreased exchange volume. Figure 2(b) shows the predicted serum and dialysis effluent vancomycin levels during a CAPD regimen using the same treatment protocol. In each case, the protocol maintained the dialysate vancomycin concentration at >4 µg/ml. In summary, peritoneal transfer of vancomycin in children receiving dialysis is similar to that observed in adult dialysis patients, and dialysis clearance is not affected by the duration of exchanges (e.g., APD vs CAPD). On the other hand, total body clearance of vancomycin in children appears to be faster than that observed in 84 Figure 2 Serum (dashed line) and dialysis effluent (solid line) vancomycin concentration-versus-time curve modeled for a child receiving automated peritoneal dialysis (A) and for a child receiving continuous ambulatory peritoneal dialysis (B) following a 6-hour intraperitoneal exchange (1100 ml/m 2 ) containing vancomycin 1000 mg/l and then 250 mg/l once daily from day 2 forward. adults. Because of the enhanced vancomycin elimination in children and the slow peritoneal transfer of vancomycin, the current recommendations for intermittent therapy (30 mg/kg IP every 5 7 days) should be reevaluated, particularly in children receiving short-dwell dialysis regimens (APD). Based on the vancomycin pharmacokinetic data presented in this study, it is recommended that children receiving intermittent vancomycin therapy for peritonitis receive a 6-hour IP load containing vancomycin 1000 mg/l (or 30 mg/kg), followed by a single full-fill daily exchange, lasting at least 6 hours and containing vancomycin 250 mg/l (or 7.5 mg/kg), from day 2 until the end of treatment. As the above recommendations are predictions based on a small number of children and there appears to be significant variability in vancomycin pharmacokinetics, particularly when there is residual renal function, we recommend that a serum vancomycin level be obtained on day 3 or day 4 prior to the daytime exchange containing antibiotics (e.g., trough level), targeting a serum vancomycin level of >18 µg/ml in APD and >9 µg/ml in CAPD. A trough level of <18 µg/ml or A B

7 PDI JANUARY 2007 VOL. 27, NO. 1 VANCOMYCIN PK IN PD 9 µg/ml, respectively, would require upward adjustment in the IP vancomycin concentration of the once-daily exchange. A trough level >25 µg/ml would suggest the need to decrease the vancomycin concentration of the once-daily exchange or change to every other day dosing. An alternative to intermittent therapy is continuous therapy where vancomycin is present in all exchanges, typically at a concentration of 30 mg/l. The latter does not require assessment of serum vancomycin levels unless a systemic infection is present that requires maintenance of therapeutic systemic vancomycin levels. ACKNOWLEDGMENT This study was supported by a Clinical Scholars Grant at Children s Mercy Hospitals & Clinics, Kansas City, Missouri, USA. REFERENCES 1. Warady BA, Schaefer F, Alexander SR, Firanek C, Mujais S. Care of the Pediatric Patient on Peritoneal Dialysis. Clinical Process for Optimal Outcomes. Deerfield, IL: Baxter Healthcare Corporation; Schaefer F, Klaus G, Muller-Wiefel DE, Mehls O, and The Mid-European Pediatric Peritoneal Dialysis Study Group (MEPPS). Intermittent versus continuous intraperitoneal glycopeptide/ceftazidime treatment in children with peritoneal dialysis-associated peritonitis. J Am Soc Nephrol 1999; 10: Dabbagh S, Carroll K. Absorption of intraperitoneal vancomycin and tobramycin in pediatric patients on chronic cycling peritoneal dialysis (CCPD) with peritonitis [Abstract]. Perit Dial Int 2000; 20(Suppl 1):S Manley HJ, Bailie GR, Frye RF, McGoldrick MD. Intravenous vancomycin pharmacokinetics in automated peritoneal dialysis patients. Perit Dial Int 2001; 21: Neal D, Bailie GR. Clearance from dialysate and equilibration of intraperitoneal vancomycin in continuous ambulatory peritoneal dialysis. Clin Pharmacokinet 1990; 18: Bunke CM, Aronoff GR, Brier ME, Sloan RS, Luft FC. Vancomycin kinetics during continuous ambulatory peritoneal dialysis. Clin Pharmacol Ther 1983; 34: Boyce NW, Wood C, Thomson NM, Kerr P, Atkins RC. Intraperitoneal (IP) vancomycin therapy for CAPD peritonitis a prospective, randomized comparison of intermittent v continuous therapy. Am J Kidney Dis 1988; XII: Pancorbo S, Comty C. Peritoneal transport of vancomycin in 4 patients undergoing continuous ambulatory peritoneal dialysis. Nephron 1982; 31: Rogge MC, Johnson CA, Zimmerman SW, Welling PG. Vancomycin disposition during continuous ambulatory peritoneal dialysis: a pharmacokinetic analysis of peritoneal drug transport. Antimicrob Agents Chemother 1985; 27: Morse GD, Farolino DF, Apicella MA, Walshe JJ. Comparative study of intraperitoneal and intravenous vancomycin pharmacokinetics during continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother 1987; 31: Warady BA, Alexander SR, Hossli S, Vonesh E, Geary D, Watkins S, et al. Peritoneal membrane transport function in children receiving long-term dialysis. J Am Soc Nephrol 1996; 7: Brophy DF, Sowinski KM, Kraus MA, Moe SM, Klaunig JE, Mueller BA. Small and middle molecular weight solute clearance in nocturnal intermittent peritoneal dialysis. Perit Dial Int 1999; 19: Schaad UB, McCracken GH, Nelson JD. Clinical pharmacology and efficacy of vancomycin in pediatric patients. J Pediatr 1980; 96: Rodvold KA, Everett JA, Pryka RD, Kraus DM. Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children. Clin Pharmacokinet 1997; 33: Somerville AL, Wright DH, Rotschafer JC. Implications of vancomycin degradation products on therapeutic drug monitoring in patients with end-stage renal disease. Pharmacotherapy 1999; 19: Feneberg R, Warady BA, Alexander SR, Schaefer F. The international pediatric peritonitis registry: a global Internet-based initiative in pediatric dialysis. Perit Dial Int 2005; 25(Suppl 3):S