Stability of tobramycin and ceftazidime in icodextrin peritoneal dialysis solution.

PURPOSE: The data describing the compatibility of tobramycin and ceftazidime in icodextrin-based peritoneal dialysis (PD) solution is limited. The objective of this study was to assess the chemical stability of tobramycin and ceftazidime in icodextrin PD solution in polyvinyl chloride containers. METHODS: Commercially available 2-L bags of icodextrin 7.5% PD solution were used for each sample. Nine tobramycin study samples were prepared by adding 80 mg tobramycin HCl to each bag. Nine ceftazidime samples were prepared by adding 1000 mg ceftazidime to each bag. Three bags of tobramycin-icodextrin solution were stored under each of the following conditions: refrigeration (4 degrees C), room temperature (25 degrees C), and body temperature (37 degrees C). Three bags of ceftazidime-icodextrin solution were also stored at each of the respective temperatures. Samples were withdrawn from each bag immediately after preparation and at predetermined intervals (1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 336 hours after preparation). Solutions were visually inspected for precipitation, cloudiness, and discoloration at each sampling interval. All samples were immediately frozen (-80 degrees C) after collection and stored prior to assay. Total concentrations of tobramycin and ceftazidime in dialysate fluid were determined by high-performance liquid chromatography. The last time point when tobramycin or ceftazidime concentration was >90% from baseline was used to denote stability. RESULTS: All solutions were clear in appearance and no color change or precipitation was observed during the study. For tobramycin, under refrigeration, a mean of 94.6%+/-2.3% of the initial concentration remained at 336 hours (14 days); at room temperature, 90.5%+/-4.3% remained at 168 hours (7 days); at body temperature, 90.0%+/-8.1% remained at 24 hours. For ceftazidime, under refrigeration, a mean of 98.0%+/-0.3% of the initial concentration remained at 168 hours (7 days); at room temperature, 91.6%+/-2.0% remained at 48 hours; at body temperature, 93.9%+/-1.1% remained at 8 hours. Stability was not assessed beyond these respective time points. CONCLUSION: Premixed tobramycin-icodextrin PD solution remains stable for 336 hours (14 days) when refrigerated (4 degrees C) and for 168 hours (7 days) at room temperature (25 degrees C). Ceftazidime-icodextrin PD solution is stable for 168 hours and 48 hours, respectively, when stored at 4 degrees C and 25 degrees C. It is recommended that the bags be kept refrigerated whenever possible. Tobramycin-icodextrin solution stored at body temperature was stable up to 24 hours, and ceftazidime-icodextrin solutions up to 8 hours, permitting the practice of pre-warming solutions prior to administration.

Stability of vancomycin in icodextrin peritoneal dialysis solution.

BACKGROUND: Icodextrin is a glucose polymer used as an alternative osmotic agent in peritoneal dialysis (PD) solutions. There are few data regarding the long-term stability of vancomycin in icodextrin PD solution. OBJECTIVE: To determine the chemical stability of vancomycin in icodextrin PD solution in polyvinyl chloride containers over a 7 day period at 4, 24, and 37 degrees C. METHODS: Study samples were prepared by adding 2000 mg vancomycin HCl to commercially available 2.0 L bags of icodextrin 7.5% PD solution. Nine bags were prepared and stored in the following conditions: 3 under refrigeration (5 degrees C), 3 at room temperature (24 degrees C), and 3 at body temperature (37 degrees C). Samples were withdrawn from each bag immediately after preparation and at predetermined intervals over the subsequent 7 days. Solutions were visually inspected for precipitation, cloudiness, or discoloration at each sampling interval. Total concentration of vancomycin in dialysate fluid was determined by high performance liquid chromatography. RESULTS: Under refrigeration, a mean +/- SD of 99.7% +/- 0.5% of the initial vancomycin concentration remained at 168 hours (7 days). At room temperature, 97.5% +/- 3.4% remained at 168 hours. At body temperature, 94.3% +/- 3.9% remained at 24 hours. Stability was not assessed beyond these time points. CONCLUSIONS: Premixed vancomycin-icodextrin PD solutions, whether stored refrigerated or at room temperature, were found to be stable for up to 7 days. However, we recommend that these solutions be kept refrigerated whenever possible. Solutions stored at body temperature were stable for up to 24 hours, permitting the practice of prewarming solutions prior to administration.

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.

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.

Stability of cefepime in icodextrin peritoneal dialysis solution.

BACKGROUND: Icodextrin is a glucose polymer used as an alternative osmotic agent in peritoneal dialysis (PD) solutions. Cefepime may be a suitable antibiotic for the treatment of PD-related peritonitis. The stability of cefepime in icodextrin PD solution has not been examined. OBJECTIVE: To determine the chemical stability of cefepime in icodextrin PD solution over a 7-day period. METHODS: Samples were prepared by adding cefepime HCl 1000 mg to commercially available 2.0-L bags of icodextrin 7.5% PD solution. Nine bags were prepared and stored in the following conditions: 3 under refrigeration (4 degrees C), 3 at room temperature (20 degrees C), and 3 at body temperature (37 degrees C). Study samples were drawn from each bag immediately after preparation and at predetermined intervals over the subsequent 7 days. Solutions were visually inspected for precipitation, cloudiness, or discoloration at each sampling interval. Total concentration of cefepime in dialysate fluid was determined by liquid chromatography-tandem mass spectrometry. RESULTS: Under refrigeration, a mean +/- SD of 95.7 +/-4.2% of the initial cefepime concentration remained at 168 hours (7 days). At room temperature, 92.0 +/- 17.9% remained at 48 hours. At body temperature, 92.2 +/- 4.7% remained at 4 hours. Beyond these respective time points, <90% of the initial cefepime concentrations remained. CONCLUSIONS: Pre-mixed cefepime-icodextrin PD solutions stored at room temperature were stable for up to 48 hours. However, it is recommended that these be kept refrigerated whenever possible. When refrigerated, cefepime-icodextrin solutions were found to be stable for up to 7 days. Solutions stored at body temperature were stable up to 4 hours, permitting the practice of pre-warming solutions prior to administration.

Factors associated with long-term antibody production induced by hepatitis B vaccine in patients undergoing hemodialysis: a retrospective cohort study.

STUDY OBJECTIVE: To assess the influence of various clinical factors on antibody production induced by hepatitis B vaccine in patients receiving hemodialysis up to 24 months after vaccination. DESIGN: Retrospective cohort study. SETTING: Outpatient dialysis center. PATIENTS: Adult patients undergoing hemodialysis who received a three-dose series of intramuscular hepatitis B vaccine 40 microg at time 0, 1, and 6 months, according to protocol. MEASUREMENTS AND MAIN RESULTS: Antibody to hepatitis B surface antigen (anti-HBs) titers were monitored quarterly, and booster doses were given according to protocol. Patients with anti-HBs of at least 10 mIU/ml were considered seropositive. Clinical variables--age, diabetes mellitus status, serum albumin level, and equilibrated Kt/V (eKt/V; Kt/V is a measure of urea clearance during dialysis, used to quantify the delivered dose of hemodialysis)--were compared between seropositive and seronegative patients 12 months (cohort 1) and 24 months (cohort 2) after vaccination. In cohort 1 (66 patients), 24 (36.4%) were seropositive at 12 months. In cohort 2 (40 patients), 15 (37.5%) were seropositive at 24 months. Comparison of seropositive and seronegative patients revealed no statistically significant differences in mean age, sex, serum albumin level, or eKt/V. However, at 24 months, patients with diabetes were 2.5 times more likely to demonstrate seropositivity than those without diabetes (60% vs 24%, respectively, p=0.02). CONCLUSION: Long-term seroprevalence induced by hepatitis B vaccine was low in our patients 12 and 24 months after vaccination. These results were comparable to previously reported long-term results. Larger, prospective studies would be needed to confirm the finding that patients with diabetes had superior hepatitis B vaccine-induced antibody production at 24 months.

Influence of peritoneal dialysate flow rate on the pharmacokinetics of cefazolin.

OBJECTIVE: To determine the impact of dialysate flow rate (DFR) on cefazolin pharmacokinetics (PK) in peritoneal dialysis (PD) patients. METHODS: A meta-analysis of published reports, identified by MEDLINE search (1966-2002) and other sources, containing information on cefazolin PK data in PD patients was conducted. Data were analyzed based upon low DFR (< or = 5.50 mL/minute) or high DFR (> 5.50 mL/minute). Data available were from North American (NA) (n = 45) and Singaporean (n = 10) patients. Complete data sets were available for 33 patients (CDS patients). Data were analyzed with respect to data origin and data set completeness: all patients (ALL), NA, and CDS. Analysis of log-transformed cefazolin PK data was performed to determine coefficient of determination (r2) between DFR and cefazolin elimination rate constant (kel), clearance total (ClT), and clearance peritoneal (ClPD). Clearance total data were extrapolated to DFR observed in continuous flow PD. RESULTS: Published literature provided data on 55 PD patients (12 high DFR, 43 low DFR). Regardless of data origin (ALL, NA, or CDS), a prominent coefficient of determination (p < 0.0001) existed between DFR and all cefazolin PK data except ClPD. The p value for DFR correlation to ClPD was 0.953, 0.011, and 0.036 for ALL, NA, and CDS patients, respectively. Cefazolin ClT and ClPD increased at higher DFRs. CONCLUSION: These findings demonstrate that an increased DFR leads to an increased rate of cefazolin clearance in NA PD patients. The impact of Asian descent on cefazolin ClPD warrants further investigation. Clinicians dosing cefazolin in PD patients using a higher DFR than that used to determine cefazolin PK should use increased doses or prescribe lower/comparable DFRs. Data are not yet available for patients prescribed very high DFRs (e.g., continuous flow PD); extrapolation of our results demonstrates significant influences on clearance and risk for underdosing.

Hepatitis B vaccination: addressing a drug-related problem in hemodialysis outpatients with a collaborative initiative.

UNLABELLED: The CDC recommends that all hemodialysis (HD) patients be vaccinated against hepatitis B virus (HBV). In 1999, only 39 of our 134 (29%) HD patients had received HBV vaccine. Since the vaccine is indicated for all HD patients, this presented a drug-related problem (DRP): indication without treatment. In response, nurses and pharmacists initiated a proactive HBV vaccination program. METHODS: An immunization protocol based on then current CDC recommendations was developed. HBV vaccine (40 mcg i.m.; at 0, 1 and 6 months) was administered to consenting HD patients. Anti-hepatitis B surface antibody (anti-HBs) titers were monitored and booster doses were given per the protocol. RESULTS: By August 2001, all consenting HD patients (n = 110) had received > or = 1 dose of HBV vaccine and 90 (81.8%) had either received a full course (> or = 3 doses) or had received > or = 1 dose and developed a positive anti-HBs titer (> or = 10 mIU/mL). Of these 90 patients, 52 (58%) developed a positive anti-HBs titer, 33 (37%) responded to < or = 3 doses, and 19 (21%) following a booster. The DRP was significantly improved. CONCLUSION: Given CDC guidelines, HBV vaccine should be offered to all HD patients. This initiative demonstrates that with concerted effort all consenting HD patients can receive HBV vaccination, thereby addressing an important DRP.

Combined furosemide and human albumin treatment for diuretic-resistant edema.

OBJECTIVE: To evaluate the clinical usefulness of combined furosemide and human albumin for the treatment of diuretic-resistant edema in patients with nephrotic syndrome and cirrhosis. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-May 2002). Key search terms included furosemide, albumin, human albumin solution, nephrotic syndrome, and cirrhosis. DATA SYNTHESIS: Hypoalbuminemia, edema, and ascites are often manifestations of nephrotic syndrome and cirrhosis of the liver. Many patients with these conditions are resistant to the effects of diuretics. The combination of furosemide and human albumin solution is occasionally used in these patients. An evaluation of published studies focusing on combined furosemide and albumin in the management of nephrotic syndrome and cirrhosis was conducted. CONCLUSIONS: Published studies report conflicting results regarding the efficacy of combined furosemide and albumin. Although it is difficult to generate firm conclusions, it appears the combination may provide clinical benefits for select patients. Given these findings, we believe that the addition of albumin to enhance diuretic efficacy should be reserved for patients with recalcitrant edema or ascites in whom diuretic doses have been maximized and those with severe hypoalbuminemia.

Stability of furosemide in human albumin solution.

OBJECTIVE: To determine the chemical stability of furosemide in human albumin solution over a 28-day period and to assess admixtures for microbiologic contamination. METHODS: Samples were prepared by mixing furosemide injectable solution and 25% human albumin solution in a 1:1 molar ratio. Six bulk containers were prepared and stored in the dark: 3 under refrigeration (approximately 4 degrees C) and 3 at room temperature (approximately 25 degrees C). Study samples were withdrawn from each bulk solution immediately after preparation and at predetermined intervals over the subsequent 28 days. Containers were observed for color change and precipitation against a light and dark background at each sampling interval. Total furosemide concentration was determined using HPLC. Additional vials were prepared and assessed for microbiologic growth at time points corresponding with chemical stability results. RESULTS: A mean of 94.5%+/-1.33% of the initial furosemide concentration remained after 48 hours at room temperature. Under refrigeration, 100.6%+/-1.02% of the initial concentration remained at 14 days. Beyond these respective time points, <90% of the initial furosemide concentration remained. No bacterial or fungal growth was observed. CONCLUSIONS: When combined with 25% human albumin solution and stored under darkness, furosemide is chemically stable and free of microbiologic contamination for 48 hours at room temperature and 14 days under refrigeration.