Teicoplanin pharmacokinetics and bioavailability during peritoneal dialysis

The pharmacokinetics of teicoplanin in serum and dialysate were examined in a crossover study after intravenous and intraperitoneal administration of a 3 mg/kg dose to five anuric patients who were undergoing continuous ambulatory peritoneal dialysis (CAPD). Blood and dialysate samples were obtained for 30 and 15 days, respectively, and were assayed microbiologically. The principal pharmacokinetic parameters after intravenous administration were as follows: total body clearance, 2.76 +/- 1.08 ml/min; elimination half-life, 377 +/- 109 hours; volume of distribution at steady state, 1.04 +/- 0.18 L/kg. Only 9% +/- 6% of the intravenous dose was recovered in the dialysate and the net peritoneal clearance was 0.25 +/- 0.21 ml/min. Bioavailability values, which were assessed by use of three methods after intraperitoneal administration and while dialysate was retained in the peritoneal cavity for 5 hours (dwell time), were 0.77 +/- 0.21, 0.78 +/- 0.05, and 0.76 +/- 0.08. Changes in bioavailability with dwell time were also examined. A dosing guide, which accounts for changes in bioavailability with dwell time, is presented.     

Pharmacokinetics of teicoplanin in patients undergoing continuous ambulatory peritoneal dialysis.

OBJECTIVE: To achieve concentrations of teicoplanin in serum and dialysate within the therapeutic range in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Pharmacokinetic study. SETTING: A tertiary-care hospital. PATIENTS: Eight hospitalized anuric patients undergoing CAPD. INTERVENTIONS: One single dose of 10 mg/kg teicoplanin was administered intravenously, and blood and dialysate were sampled at regular time intervals for 48 hours post drug infusion. Concentrations of teicoplanin were determined by microbiological assay. RESULTS: Teicoplanin serum levels above 10 microg/mL, the level desired to treat systemic infections, were detected for 24 hours after administration. All dialysate concentrations were very low. Teicoplanin presented two phases of elimination: an early first phase and a late second phase. Mean maximum serum concentration was 75.56 microg/mL, mean half-life (t 1/2) of the early elimination was 3.34 hours, mean t 1/2 of the late elimination was 61.68 hours, mean area under the serum-concentration-time curve was 1491.92 mg x hr/L, mean clearance rate was 10.68 mL/ minute, mean apparent volume of distribution was 0.80 L/kg, and mean volume of distribution at steady state was 0.22 L/kg. Mean dialysate excretion was 3.16% and mean peritoneal clearance rate was 0.023 mL/minute. CONCLUSIONS: Based on the time period with the achieved serum levels and on the prolonged t 1/2, it is proposed that teicoplanin might be administered at 10 mg/kg every 24 hours for the therapy of systemic infections in patients undergoing CAPD. However, its intravenous administration should be avoided in the treatment of peritonitis, because the achieved dialysate concentrations were very low.     

Pharmacokinetics of intraperitoneal cefepime in automated peritoneal dialysis.

OBJECTIVE: This study determined the pharmacokinetics of intraperitoneal (IP) cefepime in automated peritoneal dialysis (APD) patients. DESIGN AND METHODS: A prospective pharmacokinetic study was performed in 6 noninfected adult APD patients. All patients were administered a single IP dose of cefepime (15 mg/kg) over a 6-hour dwell. Patients then underwent a fixed APD regimen consisting of the first 6-hour dwell, followed by an 8-hour dialysate-free period and a subsequent series of 3 overnight APD exchanges. Blood and dialysate samples were collected at t = 0, 1, 2, 4, 6 (end of dwell), and 24 hours. Any urine produced during the study period was collected. Cefepime concentrations in serum, dialysate, and urine were determined by liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated assuming a mono-exponential model. RESULTS: One hour after IP administration, serum cefepime levels exceeded the minimum inhibitory concentration (8 microg/mL) for susceptible organisms. The mean serum and dialysate concentrations at 24 hours were 15.8 +/- 3.6 and 6.2 +/- 2.3 microg/mL respectively. Bioavailability was 84.3% +/- 6.2%, volume of distribution 0.34 +/- 0.07 L/kg, and serum half-life 13.8 +/- 3.2 hours. Total, peritoneal, and renal clearances were 16.5 +/- 4.4, 4.3 +/- 0.7, and 3.5 +/- 2.5 mL/minute, respectively. CONCLUSIONS: IP cefepime dosed at 15 mg/kg resulted in adequate serum concentrations in APD patients at 24 hours post dose. Pharmacokinetic predictions suggest that most APD and CAPD patients would achieve adequate serum cefepime concentrations if treated with standard doses of 1000 mg given IP once daily. Patients using APD regimens different from that used in this study, anuric patients, and those with significant residual renal function may require a more individualized approach.     

Single-dose pefloxacin pharmacokinetics and metabolism in patients undergoing continuous ambulatory peritoneal dialysis (CAPD)

Seven adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of pefloxacin, a novel quinolone antibiotic, orally and intravenously on two separate occasions to characterize the pharmacokinetics and metabolism of the drug. Concentrations of both pefloxacin and its active metabolite N-desmethyl-pefloxacin (norfloxacin) were measured in serum and dialysate by HPLC. Half-life, total body clearance and peritoneal clearance were determined. The overall elimination half-life was 19.9h. Relative to the IV dose the bioavailability following oral administration of pefloxacin was 76%. The mean serum and dialysate concentrations were similar up to 24 h after the oral or IV dose. After a 6-h dwell time the dialysate concentration of pefloxacin was 2.24 mg/L which is above the MIC90 for most bacteria responsible for peritonitis in CAPD patients. The peritoneal clearance of pefloxacin averaged 2.5 mL/min. Serum concentrations of the metabolite norfloxacin were less than 0.5 mg/L during the 24 h study period. We conclude that pefloxacin might be equally effective in the treatment of peritonitis of CAPD after oral or IV administration. Since the peritoneal clearance contributes insignificantly to the elimination of pefloxacin during CAPD, the proposed maintenance regimen of an oral or IV 400 mg dose/day seems to be a reasonable therapy for infections in CAPD patients.     

Pharmacokinetics of aztreonam administered i.p. in continuous ambulatory peritoneal dialysis (CAPD) patients

The pharmacokinetics of Aztreonam (AZT) administered i.p. in six stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD) for end-stage renal disease (ESRD) were studied. One gram of AZT was added into a 2 L bag of dialysate (Medital-Bieffe) just prior to infusion into the peritoneal cavity. The dwell time was 8 h. The serum maximum concentration of AZT was 42.5 +/- 12.4 mg/L (mean +/- SD), achieved in 4.6 +/- 1.0 h. The elimination half-life was 2.4 +/- 0.8 h, almost equal to that found in normal subjects (1.7-2 h). The pharmacokinetic parameters of elimination, as elimination rate constant and clearance of AZT from peritoneal cavity were found 0.305 +/- 0.101 h-1 and 10.05 +/- 3.7 mL/min, respectively, while the bioavailability via the peritoneal membrane was 90.8 +/- 3.05% of administered dose. It is concluded that AZT is eliminated from dialysate at a high rate after i.p. administration and its dialysate and serum levels exceed the MIC for the majority of sensitive organisms including Pseudomonas species. Aztreonam appears to be a potentially useful antibiotic for CAPD peritonitis.     

Single- and multiple-dose kinetics of ofloxacin in patients on continuous ambulatory peritoneal dialysis (CAPD)

To evaluate the pharmacokinetics of ofloxacin, a novel quinolone antibiotic, in patients with end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD), we investigated 6 patients in a single-dose study and 9 patients in a multiple-dose study, all without peritonitis. In the single-dose study, patients received 200 mg ofloxacin orally. Serum concentrations (Cmax) peaked at 3.1 +/- 0.3 mg/L (mean +/- SEM), 1.6 +/- 0.5 h after p.o. administration of the drug. Elimination half-life (t1/2) was 26.8 +/- 2.5 h. Peritoneal clearance accounted for 10% of the total body clearance. After 5-h dwell time, ofloxacin concentrations in the dialysate were 1.5 +/- 0.2 mg/L, which is above the MIC90 for most bacteria responsible for peritonitis in patients on CAPD. In the multiple dose study, 200 mg ofloxacin were administered twice, with a time interval of 12 h, followed by 200 mg for 9 days every morning. Mean trough serum levels were 2.6 +/- 1.0 mg/L, mean peak concentrations were 4.1 +/- 1.7 mg/L. Mean ofloxacin concentrations in the peritoneal effluent were 1.9 +/- 0.9 mg/L. It is concluded that an oral loading dose of 400 mg on the first day and a maintenance dose of 200 mg ofloxacin/day does not lead to significant accumulation, even though the elimination by the peritoneal route is only small. The proposed dosing regimen could be an adequate therapy of peritonitis and exit-site infections in patients on CAPD since levels reached in the dialysate effluent are bactericidal. The clinical usefulness in the treatment of peritonitis has to be proven in further studies.     

Dissociation between clearances of small and middle molecules in incremental peritoneal dialysis.

OBJECTIVE: To evaluate the peritoneal clearance of middle molecules in comparison with the peritoneal clearance of small molecules in incremental peritoneal dialysis (PD). STUDY DESIGN: Peritoneal clearances of creatinine and beta2-microgloblulin (B2M) were compared in 57 continuous ambulatory PD patients on full dose of 4 exchanges, and 54 incremental PD patients with 2 or 3 exchanges over 24 hours. Clearances were also compared when there were changes in the PD regimen, such as in the number of exchanges and the duration of the dwell time. SETTING: Tertiary-care university hospital. RESULTS: Peritoneal creatinine clearance increased almost linearly with the increase in the number of exchanges. In contrast, peritoneal clearance of B2M was 9.1 +/- 3.6 L/week, 8.8 +/- 4.4 L/week, and 7.9 +/- 2.5 L/week with 2,3, and 4 exchanges, respectively, per day, amounts that were not different from each other. Peritoneal clearance of B2M did not change when there was an increase in the number of dialysate exchanges from 2 to 3 and from 3 to 4 over a period of 24 hours; whereas the peritoneal clearance of creatinine increased. Peritoneal clearance of B2M almost doubled, from 5.4 +/- 2.7 L/week with 2 exchanges over 12 hours per day, to 9.5 +/- 4.4 L/week with the same 2 exchanges over 24 hours. The creatinine clearance did not change. CONCLUSION: In contrast to peritoneal clearance of small molecules, such as creatinine, which was dependent on the number of dialysate exchanges, peritoneal clearance of middle molecules, such as B2M, depended mainly on the total dwell hours of PD and not on the number of exchanges of peritoneal dialysate in incremental PD. This might be another advantage of incremental PD, since peritoneal clearance of middle molecules in incremental PD over 24 hours can be comparable to that in full dose PD.     

Pharmacokinetics of oral ciprofloxacin in continuous cycling peritoneal dialysis.

BACKGROUND: In order to avoid aminoglycosides, the International Society for Peritoneal Dialysis recommends cefazolin and ceftazidime for empirical treatment of peritonitis. Ciprofloxacin covers relevant gram-negative pathogens without the resistance associated with ceftazidime. However, ciprofloxacin pharmacokinetic data in patients on continuous cycling peritoneal dialysis (CCPD) are lacking. OBJECTIVES: (1) To determine the pharmacokinetics of oral ciprofloxacin in CCPD patients, (2) to compare serum and dialysate ciprofloxacin concentrations with minimum inhibitory concentrations (MIC) of the gram-negative bacteria associated with peritonitis, and (3) to establish oral ciprofloxacin dosing guidelines for the empirical treatment of peritonitis in patients receiving CCPD. METHODS: Eligible CCPD patients received 2 doses of ciprofloxacin: 750 mg orally every 12 hours. Serial blood and end-of-dwell dialysate samples were collected during the first 12-hour interval; an end-of-dwell dialysate sample from the overnight dwell and a final blood sample were collected at the end of the second 12-hour interval. Ciprofloxacin concentrations were determined using a liquid chromatographic (HPLC)-fluorescence method. Pharmacokinetic calculations were completed assuming a one-compartment model. RESULTS: Eight patients completed the study. The pharmacokinetic parameters determined for ciprofloxacin were (mean +/- SEM) serum half-life 10.1 +/- 1.2 hours, maximum serum concentration 2.7 +/- 0.5 mg/L, time to maximum serum concentration 1.6 +/- 0.1 hours after the first dose, and peritoneal clearance 1.2% +/- 0.1% of the mean calculated total body clearance. While all patients achieved serum area under the concentration-time curve:MIC > 125 for Escherichia coli and Klebsiella species after the first dose, only 2 patients achieved this goal for Pseudomonas aeruginosa. End-of-dwell dialysate concentrations were above the MIC for E. coli, Klebsiella spp, and P. aeruginosa after the second dose. CONCLUSION: Ciprofloxacin 750 mg orally every 12 hours in CCPD patients may be useful for empirical gram-negative coverage of CCPD peritonitis and for treatment of documented peritonitis caused by sensitive E. coli or Klebsiella species. While ceftazidime may be required for documented pseudomonal peritonitis, the oral ciprofloxacin regimen achieved adequate serum concentrations to treat systemic gram-negative infections caused by sensitive E. coli or Klebsiella species.     

Ceftizoxime elimination kinetics in continuous ambulatory peritoneal dialysis

We investigated the kinetics of ceftizoxime, a beta-lactamase stable cephalosporin, in eight subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 500-mg or 1-gm dose was injected IV, or a 500-mg dose was given intraperitoneally in the CAPD fluid during a 6-hr dwell time. The ceftizoxime (500 mg) serum kinetic parameters were as follows: peak concentrations, 21 to 46 mg/l; volume of distribution, 0.27 l/kg; elimination rate constant, 0.0784 hr-1; plasma clearance, 1.66 l/kg hr-1; and t1/2, 10.2 hr. The t1/2 after 1 gm was 12 hr. Dialysate ceftizoxime concentrations rose rapidly between 0.25 and 2 hr and slowly over the next 4 hr, but only 4.04 +/- 1.8 and 7.4 +/- 2.9 mg ceftizoxime/hr was eliminated by the peritoneal route over a 6-hr dwell time after 500 mg or 1 gm IV. This represents only 4% to 5% of the dose. After intraperitoneal instillation, the antibiotic appeared in the serum within 15 min in all four subjects, and the peak serum concentrations ranged from 12 to 19.8 mg/l (mean +/- SD = 16.4 +/- 3.3) between 5 and 6 hr. Approximately 78% of ceftizoxime was absorbed from the peritoneal dialysis fluid during a single 6-hr dwell time. Rate constant for absorption, ka, was 0.3959 hr-1 and absorption t1/2 was 1.75 hr (as calculated by the residual equation). These data suggest that ceftizoxime has bidirectional exchange characteristics through the peritoneal membrane. Instillation of ceftizoxime in CAPD fluid alone may permit rapid absorption to reach therapeutic serum concentrations.     

Trimethoprim-sulfamethoxazole pharmacokinetics during continuous ambulatory peritoneal dialysis (CAPD)

Ten adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of trimethoprim-320 mg (TMP) and sulfamethoxazole 1600 mg (SMX) orally (p.o.), intravenously (i.v.), and intraperitoneally (i.p.) on three separate occasions to characterize the pharmacokinetics of both drugs. Concentrations of both TMP and SMX were measured in serum and dialysate by HPLC to 48 h. Half-life, total body clearance (TBC), and peritoneal clearance (PCl) were determined. The mean half-life of TMP was 28 h, while for SMX it was 12.5 h. Relative to the i.v. dose, the bioavailability following oral administration for TMP was 98% and 87% for SMX. Intraperitoneal bioavailability was 73% for TMP and 65% for SMX after a 4-h dwell. After 24 h, regardless of the route of administration, less than 3% of TMP and less than 6% of SMX appeared in dialysate. We conclude that peritoneal losses contribute insignificantly to TMP/SMX elimination during CAPD.     

The disposition and dynamics of labetalol in patients on dialysis

The disposition of labetalol was assessed in 16 patients on dialysis after intravenous dosing with 0.7 to 1.0 mg/kg during an interdialytic period and just before hemodialysis (n = 8) and during continuous ambulatory peritoneal dialysis (CAPD) (n = 8). The plasma concentration time data exhibited triexponential decay in all patients. The terminal t 1/2 of labetalol was 12.90 +/- 4.68 hours, the total body clearance was 1198.2 +/- 249.4 ml/min, and the AUC was 921.4 +/- 175.2 ng hr/ml during the interdialytic period. No significant changes were observed in these parameters after dosing with labetalol just before dialysis. The hemodialysis clearance of labetalol was 30.67 +/- 5.49 ml/min, and only 0.189 +/- 0.042 mg of labetalol was removed by hemodialysis. The terminal t 1/2 averaged 13.05 +/- 6.32 hours during CAPD. Steady-state volume of distribution, total body clearance (Clp), and CAPD clearance were 10.39 +/- 2.77 L/kg, 1397.2 +/- 372.3 ml/min, and 1.94 +/- 0.65 ml/min, respectively. The fraction of the dose recovered in the CAPD dialysate during the 72-hour study period was 0.14% +/- 0.09%. The decay of the antihypertensive effect of labetalol was gradual and paralleled the decline in the log plasma concentration. There was a significant correlation between labetalol plasma concentration and the fall in supine diastolic and mean blood pressure after the interdialytic dose and during CAPD. Although labetalol is removed by dialysis, dialysis does not significantly enhance Clp.     

Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD.

BACKGROUND: Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. OBJECTIVE: This study aimed to define the potential role of azithromycin in treating CAPD peritonitis. DESIGN: The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. SETTING: The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. PATIENTS: Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). RESULTS: Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. CONCLUSION: Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.     

Pharmacokinetics of intravenous and intraperitoneal cefotaxime in chronic ambulatory peritoneal dialysis

We investigated the kinetics of cefotaxime in eight subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 1 gm iv dose was injected and a 1 gm dose was given intraperitoneally in the CAPD fluid during a 4-hour dwell time. Cefotaxime and desacetylcefotaxime were assayed by HPLC. After intravenous injection the cefotaxime serum kinetic parameters were as follows: plasma t 1/2, 2.31 +/- 0.20 hours; volume of distribution, 0.35 +/- 0.04 L/kg; total plasma clearance, 118.7 +/- 12.3 ml/min; and peritoneal clearance, 6.7 +/- 1.3 ml/min. Dialysate cefotaxime concentrations rose rapidly, but only 5% of the dose was eliminated by the peritoneal route. After intraperitoneal instillation, cefotaxime appeared in the serum rapidly and the peak serum concentrations ranged from 9 to 20 micrograms/ml between 1 and 3 hours. The absorption of cefotaxime from peritoneal space was 58.7% +/- 5.4%. Data suggest that cefotaxime has bidirectional exchange characteristics through the peritoneal membrane. Instillation of cefotaxime in CAPD fluid may permit rapid absorption to achieve therapeutic serum concentrations.     

Acute effects of high-dose furosemide on residual renal function in CAPD patients.

BACKGROUND: High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute kinetics. METHODS: Diuretic response and the effect on peritoneal fluid and solute transport parameters were investigated in 7 stable CAPD patients with residual renal function (median urine volume 350 mL/24 hours, range 140- 1900 mL/24 hours). Comparisons were made during two clearance periods of 24 hours: one without (P1) and one during 2 g furosemide (P2). RESULTS: The median increase in urine volume was 400 mL (range 270 - 910 mL, p < 0.02) and the increase in sodium excretion was 54 mmol (range 25 - 118 mmol, p < 0.02). No change in GFR was found between P1 (2.4 mL/ minute, range 0.6 - 5.7 mL/min) and P2 (2.0 mL/min, range 1.0 - 4.8 mL/min). An increase in fractional clearance was found for volume, sodium, potassium, and osmolality (p < 0.02). No change was found in the fractional clearance of urea and electrolyte-free water. Furosemide excretion in urine was 8.7 mg/24 hours (range 2.1 - 38 mg/24 hours) and in dialysate 4.9 mg/24 hours (range 1.9 - 7.8 mg/ 24 hours). Plasma furosemide concentration was 29.5 mg/L (range 6.2 - 43.9 mg/L). A positive correlation was found between residual GFR and total urine furosemide excretion (r = 0.93, p < 0.005). Efficiency, expressed as the increase in fractional sodium clearance (percent) per milligram of furosemide excreted per 24 hours, was 1.2%/mg (range 0.3% - 11.3%/mg). CONCLUSION: High-dose furosemide is effective in CAPD patients in increasing urine volume and electrolyte excretion without affecting urea and creatinine clearance. In CAPD patients, the individual response to an identical high dose of furosemide is dependent on the magnitude of residual GFR.     

Intermittent intravenous piperacillin pharmacokinetics in automated peritoneal dialysis patients.

BACKGROUND: Use of intermittent antibiotic dosing is increasing in the treatment of peritoneal dialysis (PD)-related peritonitis. We studied the pharmacokinetics of intravenous (i.v.) piperacillin in automated PD patients. PATIENTS AND METHODS: Eight patients (3 males, 5 females) were recruited and received a single i.v. dose of piperacillin (35 mg/kg actual body weight). Blood and dialysate samples were collected at the beginning, middle, and end of dwells 1-3 (on cycler), and end of dwells 4-5 (off cycler) for a 24-hour period. Baseline and 24-hour urine samples (nonanuric patients, n = 7) were collected. Pharmacokinetic parameters were calculated assuming a one-compartment model. Glomerular filtration rate (GFR) and piperacillin clearance (CL) values were normalized to 1.73 m2. RESULTS: The patients were 49.5 +/- 10.1 years of age (mean +/- SD) and had been receiving PD for a median of 3 months (range 2-66 months). Dwell times were 2.25 +/- 0.06 hours on cycler and 7.26 +/- 0.14 hours off cycler. Piperacillin half-life was not statistically different on or off the cycler (on cycler 1.99 +/- 0.39 hr, off cycler 4.39 +/- 5.4 hr; p = 0.12) and remained insignificant, even accounting for an outlier (on cycler 2.01 +/- 0.41 hr, off cycler 2.54 +/- 1.48 hr; p = 0.19). Piperacillin total CL (CL(T)) was 31.29 +/- 6.02 mL/minute. Renal CL (CL(R)) and PD CL (CL(PD)) accounted for 8.8% and 16.8% of CL(T); CL(R) correlated well with GFR (CL(R) = 0.86 GFR + 0.1; p < 0.00003). Mean piperacillin serum and dialysate end-of-dwell concentrations were above minimum inhibitory concentration of susceptible organisms (8 microg/mL) for the three cycler exchanges only. Serum and dialysate concentrations predicted using a one-compartment model suggest that i.v. piperacillin 4000 mg would provide adequate concentrations for susceptible organisms over a 12-hour period. CONCLUSION: The current i.v. piperacillin dosing recommendations of 4000 mg every 12 hours for PD-related peritonitis are appropriate for patients on automated PD. Intermittent intraperitoneal piperacillin is not recommended.     

Intraperitoneal cefazolin and ceftazidime effects on human peritoneal mesothelial cell release of cancer antigen-125

BACKGROUND: Intraperitoneal (IP) cefazolin and ceftazidime are recommended as empiric treatment for peritoneal dialysis (PD)-associated peritonitis. Human peritoneal mesothelial cells (HPMCs) may be affected by high IP cefazolin and ceftazidime concentrations. Peritoneal dialysate cancer antigen-125 (CA-125) appearance rate can be used to measure HPMC damage. OBJECTIVE: To determine whether IP cefazolin and ceftazidime increase peritoneal CA-125 appearance rate. METHODS: The study consisted of 2 phases. In phase I, no antibiotic was administered, and in phase II, patients received IP cefazolin and ceftazidime (15 mg/kg rounded to nearest 100 mg). Phase II occurred immediately after phase I. Each phase used a 4-hour dwell time with 2 L of dextrose 2.5% dialysate. Dialysate samples were collected at 0, 0.5, 1, 2, and 4 hours during each phase. Samples were assayed for CA-125, and CA-125 appearance rate was calculated. RESULTS: Thirteen patients were recruited (7 men; aged 44.0 +/-16.0 y). The mean +/- SD (range) CA-125 dialysate concentration after phases I and II were 6.6 +/- 3.7 U/mL (2.3-15.0) and 6.4 +/-3.8 U/mL (1.6-13.8), respectively (p = 0.46). The CA-125 appearance rate after phases I and II were 51.9 +/- 31.3 U/min/1.73 m(2) (13.8-113.0) and 50.5 +/- 32.9 U/min/1.73 m(2) (11.0-104.0), respectively (p = 0.57). The slopes of the regression lines of CA-125 appearance rate were not significantly different between phases I and II. CONCLUSIONS: These findings demonstrate that concurrently administered IP cefazolin and ceftazidime have no effect on HPMC release of CA-125 in non-infected PD patients.     

Multiple-dose-kinetics of ofloxacin after intraperitoneal application in CAPD patients.

Pharmacokinetics of ofloxacin in plasma and peritoneal fluid were studied in 11 patients on continuous ambulatory peritoneal dialysis (CAPD). Seven patients without peritonitis received 20 mg ofloxacin added to 2L dialysate i.p. every 6 h for one day only, while 4 patients with acute peritonitis were treated with this same dosage every 4 h for 3 days, then every 6 h for the next 7 days. Ofloxacin concentrations in plasma and dialysate were determined by HPLC. After i.p. drug application there was a rapid elimination of ofloxacin from dialysate, this being significantly faster in patients with peritonitis as compared to those without. Likewise, the total amount lost from the first bag after a 3 h dwell was higher in the peritonitis group (84.7 +/- 1.5%; mean +/- SEM) than in the non-peritonitis group (75.6 +/- 2.1%). Twenty-four h after start of ofloxacin treatment, the mean peritoneal fluid concentrations at the end of each exchange studied were all above 3 mg/L. In patients with peritonitis, plasma concentrations of ofloxacin rose to 0.94 +/- 0.05 mg/L after 24 h reaching a Cmax of 1.8 +/- 0.2 mg/L after a tmax of 84 +/- 23 h. Intraperitoneal administration of ofloxacin was well tolerated, and no local or systemic adverse events were observed. Peritonitis episodes that were caused by Staphylococcus epidermidis (3) and by E. coli (1) were cured in all patients.     

An amino acid-based peritoneal dialysis fluid buffered with bicarbonate versus glucose/bicarbonate and glucose/lactate solutions: an intraindividual randomized study.

OBJECTIVE: In order to study acute metabolic changes and peritoneal transport, amino acids as osmotic agent and bicarbonate as buffer were tested as new agents in peritoneal dialysis (PD) solutions. DESIGN: In a prospective, cross-over, randomized, intraindividual study, we investigated the acute metabolic changes following the application of three different PD fluids: (1) a 1% amino acid-based PD solution buffered with bicarbonate (34 mmol/L) (Amino/Bic); (2) a 1.5% glucose anhydrous-containing bicarbonate-buffered solution (34 mmol/L) (Glu/Bic); and (3) a conventional 1.5% glucose anhydrous-based dialysis solution with lactate (35 mmol/L) (Glu/Lac). SETTING: University medical center. PATIENTS: Ten nondiabetic patients stable on continuous ambulatory peritoneal dialysis (time on dialysis, 42.5 +/- 21.5 months) were treated and monitored with the test solutions over a 6-hour dwell.Three different study days followed in a randomized order for each patient (interval of 1-3 weeks). Blood and dialysate samples were taken at 0.25, 0.5, 1, 2, 4, and 6 hours. Immediately after the 1-hr dwell (and after sampling), the patients received a standardized breakfast, thereby simulating usual food intake. RESULTS: Following the application of Amino/Bic a significant increase in plasma amino acids occurred, with peak levels (maximum 250% increase) after either the 1-hr or the 2-hr dwell. Before taking the standard meal (0.5 hr, 1 hr), the mean serum glucose level with Amino/Bic was 8% +/- 13% lower than with Glu/Bic (p = 0.06) and 14% +/- 8% lower than with Glu/Lac (p < 0.01). This difference was still significant after the standard breakfast and also for the whole dwell (average serum glucose 0.5-6 hr: Amino/Bic, 91 +/- 6 mg/dL; Glu/Bic, 100 +/- 8 mg/dL; Glu/Lac, 102 +/- 7 mg/dL; p < 0.01 MANOVA). The serum insulin profiles did not differ between the fluids. A transperitoneal protein- and amino acid-related nitrogen loss of 0.49 +/- 0.18 g and 0.48 +/- 0.12 g per dwell was measured using Glu/Bic and Glu/Lac, while a positive balance of 1.80 +/- 0.43 g was achieved with Amino/Bic. The parameters of acid-base status (pH, HCO3, pCO2) remained nearly unchanged in the blood, irrespective of the solution used, while dialysate values differed markedly. No significant differences with respect to ultrafiltration (Amino/Bic, -68 +/- 199 mL/6 hr; Glu/Bic, -51 +/- 89 mL/6 hr; Glu/ Lac, -2 +/- 134 mL/6 hr) and peritoneal creatinine clearance (Amino/Bic, 4.9 +/- 0.6 mL/min; Glu/Bic, 5.1 +/- 0.6 mL/min; Glu/ Lac, 4.8 +/- 0.5 mL/min) were measured. CONCLUSIONS: Our results demonstrate that ultrafiltration and small solute clearance over a 6-hour dwell with a 1% Amino/Bic solution were comparable to those of 1.5% Glu/Bic and 1.5% Glu/Lac. Reduced serum glucose concentrations were found with Amino/Bic and this fluid compensated the transperitoneal protein-nitrogen loss of about three glucose dwells. Bicarbonate buffering (34 mmol/L) did not change blood acid-base status combined with either glucose or amino acids.     

Moxalactam epimer disposition in patients undergoing continuous ambulatory peritoneal dialysis

The kinetics of the epimers of moxalactam (R-MOX, S-MOX) were investigated in patients without infections who were receiving continuous ambulatory peritoneal dialysis after both intravenous and intraperitoneal injections of moxalactam. R-MOX and S-MOX were well absorbed from the peritoneal cavity, with mean systemic availability of 0.71 +/- 0.18 and 0.79 +/- 0.18, respectively. After intravenous MOX, serum clearance was 10.2 +/- 3.4 (R-MOX) and 10.9 +/- 3.2 (S-MOX) ml/hr/kg. Net time-averaged peritoneal dialysis clearance of both epimers was minimal, about 10% of serum clearance. Serum and dialysate MOX concentrations were above the minimum inhibitory concentrations for susceptible bacteria for 24 hours after a 2.0 or 1.0 gm intravenous or intraperitoneal dose. Gastrointestinal side effects occurred after a 2.0 gm dose (both intravenous and intraperitoneal) but not after a 1.0 gm dose. There were no significant differences in the kinetics of R-MOX and S-MOX. A single 1.0 gm ip dose leads to serum and dialysate MOX concentrations above the minimum inhibitory concentration for susceptible pathogens for 24 hours.     

Can the inflammation markers of patients with high peritoneal permeability on continuous ambulatory peritoneal dialysis be reduced on nocturnal intermittent peritoneal dialysis?

BACKGROUND: Patients with high peritoneal permeability have the greatest degree of inflammation on continuous ambulatory peritoneal dialysis (CAPD), which may be associated with their higher mortality. Nocturnal intermittent peritoneal dialysis (NIPD; "dry day") may decrease inflammation by reducing the contact between dialysate and peritoneum and/or providing better fluid overload control. Therefore, the aims of this study were to determine and compare serum and dialysate concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) of patients with high or high-average peritoneal transport on CAPD, changed to NIPD, and ultimately to continuous cyclic peritoneal dialysis (CCPD). METHODS: Crossover clinical trial in 11 randomly selected patients. All subjects had been on CAPD and were changed to NIPD, and ultimately to CCPD (6.4 +/- 3.1 months after initiation of study). All patients used glucose-based dialysate. Evaluations of clinical and biochemical parameters, dialysis adequacy, and serum and dialysis inflammation markers were performed at baseline on CAPD, 7 - 14 days after changing to NIPD, 7 - 14 days after switching to CCPD, and after 1 year of follow-up. All patients used only 1.5% glucose dialysate during evaluation days. CRP was determined by nephelometry, and IL-6 and TNF-alpha by ELISA. RESULTS: Seven patients were high transporters and 4 high average. Ultrafiltration increased (p < 0.05) when patients changed from CAPD [0.38 L (-0.3 - 1.1 L)] to NIPD [2.64 L (0.7 - 4.7 L)]; it then decreased on CCPD [0.88 L (0.4 - 1.3 L) and at the end of study [0.65 L (0.3 - 1.0 L)]. This better fluid overload control was accompanied by decreased weight and systolic and diastolic blood pressure when patients changed from CAPD (89 +/- 13 kg, 160 +/- 23 and 97 +/-9 mmHg, respectively) to NIPD (86 +/- 17 kg, 145 +/- 14 and 86 +/- 9 mmHg, respectively), and increased weight and systolic and diastolic blood pressure on CCPD (85 +/- 15 kg, 143 +/-23 and 88 +/- 14 mmHg, respectively) and at the end of follow-up (87 +/- 16 kg, 155 +/- 24 and 89 +/- 12 mmHg, respectively). Median serum CRP decreased (p = 0.03), from 3.8 (1.6 - 8.5) mg/L on CAPD to 1.0 (0.4 - 4.4) mg/L on NIPD, but increased on CCPD [1.8 (1.3 - 21) mg/L] and at the end of the study [3.2 (0.3 - 8.2) mg/L]. Dialysate CRP decreased nonsignificantly, from 0.10 (0 - 0.5) mg/L on CAPD to 0 (0 - 0.03) mg/L on NIPD, to 0.01 (0 - 0.08) mg/L on CCPD, and to 0 (0 - 0) mg/L at final evaluation. Serum TNF-alpha concentration decreased, from 0.14 (0.04 - 0.6) pg/mL on CAPD to 0.01 (0 - 0.08) pg/mL on NIPD, and then increased to 0.06 (0 - 0.4) pg/mL on CCPD and to 0.11 (0 - 0.2) pg/mL at the end of the study; whereas dialysate TNF-alpha decreased, from 0.08 (0.03 - 0.2) pg/mL on CAPD to 0.04 (0 - 0.2) pg/mL on NIPD, and to 0 (0 - 0) pg/mL and 0 (0 - 0.05) pg/mL on CCPD and final evaluation respectively. Serum IL-6 decreased (p = 0.07), from 2.5 (2.0 - 4.2) pg/mL on CAPD to 1.0 (0.7 - 2.0) pg/mL on NIPD, and to 1.0 (0.8 - 2.9) pg/mL on CCPD and 1.0 (0.5 - 9.8) pg/mL at the end of the study; whereas dialysate levels remained similar on CAPD [8.0 (3.7 - 13) pg/mL] and NIPD [7.8 (5.1 - 23) pg/mL], and increased on CCPD [11.2 (9.5 - 19) pg/mL] and at final evaluation [11.2 (8.3 - 15) pg/mL]. CONCLUSIONS: NIPD significantly decreased serum CRP and displayed a trend to decrease TNF-alpha and IL-6 serum concentrations compared with CAPD; whereas CCPD tended to reverse these effects. These results did not appear to be due to decreased local peritoneal inflammation, but they could be associated with better control of fluid overload on NIPD. Thus, NIPD, as Long as the residual renal function allows it, may be useful in reducing the systemic inflammation of patients with high peritoneal membrane permeability.