Pyridine levels in ceftazidime - peritoneal dialysis admixtures stored at body temperature.

BACKGROUND: For the treatment of peritoneal dialysis-associated peritonitis (PDAP), ceftazidime is routinely admixed with peritoneal dialysis (PD) solutions before its intraperitoneal administration. One of the major degradation products of ceftazidime is pyridine, a potentially toxic compound. Depending on the type of PD solution, ceftazidime is exposed to an environment with acidic or basic pH, and depending on the type of dosing and individual unit practices related to preparation and storage, ceftazidime can be at body temperature for 4-10 h, resulting in potentially varying rates of degradation to pyridine by-product. No study has investigated whether the amount of generated pyridine exceeds the maximum daily exposure limit of 2 mg when ceftazidime-PD admixtures are kept at body temperature. Therefore, the current study aimed to determine the levels of pyridine generated in PD-ceftazidime admixtures kept at 37°C for various time points. METHODS: Ceftazidime was admixed with 2 L Dianeal (1.5%, 2.5% and 4.25% dextrose) and 2 L Physioneal (1.36%, 2.27% and 3.86% glucose) PD solutions to obtain a concentration of 125 mg/L (continuous dosing model) or 500 mg/L (intermittent dosing model). A total of 36 PD admixtures (3 bags for each type of PD solution and 3 bags for each type of dosing) were prepared and stored at 37°C for 10 h. An aliquot was withdrawn at time 0 (baseline) and after 2, 6, 8 and 10 h of storage. The withdrawn samples were then analysed to determine the concentrations of ceftazidime and pyridine using high-performance liquid chromatography. RESULTS: With the intermittent dosing model (500 mg/L), ceftazidime was found to be stable for only 2 and 6 h when admixed with 3.86% and 2.27% glucose Physioneal PD solutions, respectively. While ceftazidime (500 mg/L) retained more than 90% of its initial concentration in the three types of Dianeal and 1.36% dextrose Physioneal solutions for 10 and 8 h, respectively, the generated amount of pyridine ranged between approximately 290% and 371% more than the daily recommended limit. With the continuous dosing model (125 mg/L), ceftazidime was found to be stable for 6 h in all three types of Physioneal PD solutions, but the total amount of generated pyridine with four daily exchanges (6 h each) was estimated to be 170-360% over the daily recommended limit. Ceftazidime (125 mg/L) was chemically stable when admixed with three types of Dianeal PD solutions and stored at 37°C for 10 h, and the levels of pyridine were estimated to be less than the maximum recommended daily limit. CONCLUSIONS: Until the outcomes of this in vitro study are confirmed by appropriate in vivo studies, continuous dosing of ceftzadime-Dianeal admixtures for the treatment of PDAP may be preferred over continuous dosing of ceftazidime-Physioneal admixtures, and intermittent dosing of ceftazidime-Physioneal and ceftazidime-Dianeal admixtures, as ceftazidime remains stable and the generated levels of pyridine are below the maximum recommended daily exposure.

Stability of ceftolozane and tazobactam in different peritoneal dialysis solutions.

BACKGROUND: Peritonitis is a common and serious complication of peritoneal dialysis (PD). PD-associated peritonitis (PDAP) caused by Pseudomonas is usually resistant to most antibiotics, resulting in high failure rates. Ceftolozane/tazobactam (C/T) has been shown to be effective in treating urinary tract and intra-abdominal infections caused by beta-lactam resistant Pseudomonas and other gram-negative bacteria. Given its favourable adverse effects profile, it has a potential role in the treatment of PDAP caused by Pseudomonas species resistant to other antibiotics. Intraperitoneal administration of antibiotics admixed with PD solutions for the treatment of PDAP is associated with superior outcomes. However, there is a lack of published data on the stability of C/T in PD solutions. Therefore, this study investigated the physical and chemical stability of C/T in commonly used PD solutions at different temperatures. METHODS: A total of 27 PD bags (3 PD bags for each type of PD solution including Dianeal®, Extraneal®, Balance® and Physioneal® PD bags) containing C/T were prepared and stored at 25°C for 6 h, followed by 4°C for 168 h and then 37°C for 12 h. An aliquot from each PD bag was withdrawn, and the concentration of C/T before (0 h) and after predefined time points was determined using a stability-indicating high-performance liquid chromatography assay. Samples were also assessed for pH, colour change and particulate matter immediately after preparation and on each day of analysis. RESULTS: C/T retained more than 97% of their initial concentration when stored at 25°C for 6 h followed by storage at 4°C for 168 h and then at 37°C for 12 h. Particle formation was not detected at any time under the tested storage conditions. The pH and colour remained essentially unchanged throughout the study. CONCLUSIONS: These results provide a platform for clinical studies to determine the safety and therapeutic efficacy of intraperitoneal C/T for the treatment of PDAP caused by resistant Pseudomonas species.

High Pyridine Generation in Ceftazidime-Icodextrin Admixtures Used to Treat Peritoneal Dialysis-associated Peritonitis.

PURPOSE: To investigate the amount of pyridine generated from degradation of ceftazidime in icodextrin peritoneal dialysis (PD) solutions. METHODS: PD solutions that contained 1 and 1.5 g of ceftazidime were stored at 25 °C for 12 hours and then at 37 °C for 14 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentrations of ceftazidime and pyridine. FINDINGS: The amount of pyridine generated was >225% and 400% of its maximum recommended daily exposure in the 1- and 1.5-g ceftazidime-PD admixtures, respectively. IMPLICATIONS: Until these results are confirmed with appropriate in vivo studies, intermittent intraperitoneal dosing of ceftazidime admixed with icodextrin should be used with caution and appropriate clinical monitoring or a suitable alternative antibiotic should be used.

Physicochemical stability of extemporaneously prepared clonidine solutions for use in neonatal abstinence syndrome.

WHAT IS KNOWN AND OBJECTIVE: Extemporaneously prepared clonidine admixture is increasingly used for the management of neonatal abstinence syndrome. However, its stability beyond 15 minutes at room temperature is currently unknown. Therefore, healthcare professionals must prepare clonidine admixtures multiple times a day while the treatment is indicated, resulting in subsequent limitations and problems. The aim of this study was to investigate the physicochemical stability of clonidine in commonly used pharmaceutical diluents at clinically relevant concentrations and temperatures. METHODS: Glass bottles (n = 18) and plastic syringes (n = 18) containing 0.5 and 5 µg/mL of clonidine in either 5% glucose, 10% glucose or 0.9% normal saline were prepared and stored at 4°C for 7 days and at 35°C for 24 hours, respectively. Aliquots were withdrawn at predefined time points and analysed for the concentration of clonidine, changes in pH and colour, and particle content. RESULTS AND DISCUSSION: No evidence of particle formation, or colour or pH change was observed throughout the study period. Clonidine retained more than 98% of its initial concentration when stored in the tested diluents at 4°C for 7 days and at 35°C for 24 hours. WHAT IS NEW AND CONCLUSION: Our findings will allow healthcare professionals to prepare weekly dose of clonidine in glass bottles for storage in a refrigerator. The daily required dose of clonidine can be drawn aseptically from the glass bottle each day and stored in a plastic syringe at room temperature. Clonidine present in a plastic syringe can be administered via the nasogastric route 4-6 times a day. This practice would not only save nursing time and avoid delays in the timely administration of clonidine, but also reduce the risk of potential medication errors as well as preparation-associated costs.

Stability of Meropenem and Piperacillin/Tazobactam with Heparin in Various Peritoneal Dialysis Solutions.

BACKGROUND: Infections caused by ceftazidime-resistant Pseudomonas and extended-spectrum beta-lactamase (ESBL)-producing gram-negative bacteria are increasing worldwide. Meropenem and piperacillin/tazobactam (PIP/TZB) are recommended for the treatment of peritoneal dialysis-associated peritonitis (PDAP) caused by ceftazidime-resistant Pseudomonas and other resistant gram-negative bacteria. Patients may also receive intraperitoneal heparin to prevent occlusion of their catheters. However, the stability of meropenem or PIP/TZB, in combination with heparin, in different types of peritoneal dialysis (PD) solutions used in clinical practice is currently unknown. Therefore, we investigated the stability of meropenem and PIP/TZB, each in combination with heparin, in different PD solutions. METHODS: A total of 15 PD bags (3 bags for each type of PD solution) containing meropenem and heparin and 24 PD bags (3 bags for each type of PD solution) containing PIP/TZB and heparin were prepared and stored at 4°C for 168 hours. The same bags were stored at 25°C for 3 hours followed by 10 hours at 37°C. An aliquot withdrawn before storage and at defined time points was analyzed for the concentration of meropenem, PIP, TZB, and heparin using high-performance liquid chromatography. Samples were also analysed for particle content, pH and color change, and the anticoagulant activity of heparin. RESULTS: Meropenem and heparin retained more than 90% of their initial concentration in 4 out of 5 types of PD solutions when stored at 4°C for 168 hours, followed by storage at 25°C for 3 hours and then at 37°C for 10 hours. Piperacillin/tazobactam and heparin were found to be stable in all 8 types of PD solutions when stored under the same conditions. Heparin retained more than 98% of its initial anticoagulant activity throughout the study period. No evidence of particle formation, color change, or pH change was observed at any time under the storage conditions employed in the study. CONCLUSIONS: This study provides clinically important information on the stability of meropenem and PIP/TZB, each in combination with heparin, in different PD solutions. The use of meropenem-heparin admixed in pH-neutral PD solutions for the treatment of PDAP should be avoided, given the observed suboptimal stability of meropenem.

Physicochemical stability of voriconazole in elastomeric devices.

OBJECTIVES: Voriconazole is the drug of choice for invasive aspergillosis (IA), a leading cause of mortality and morbidity in immunocompromised patients. Prolong intravenous administration of voriconazole is often needed in such patients due to high incidence of oral mucositis and unreliable bioavailability of oral dosage form. Administration of voriconazole through elastomeric pump may facilitate early hospital discharge of clinically stable immunocompromised patients needing prolonged intravenous treatment. Therefore, we investigated the physicochemical stability of voriconazole in one of the commonly used elastomeric pumps at three different temperatures for various time points. METHODS: A total of 18 elastomeric pumps were prepared and 6 containing 2 mg/mL of voriconazole (3 in 0.9% sodium chloride and 3 in 5% glucose) were stored at either 4°C for 96 hours, 25°C for 4 hours or at 35°C for 4 hours. An aliquot withdrawn immediately before storage (time 0) and at various time points was analysed for chemical stability using high-performance liquid chromatography and for physical stability using visual, pH and microscopic analyses. RESULTS: Voriconazole was stable for at least 96 hours, 4 hours and 4 hours at 4°C, 25°C and 35°C, respectively, when admixed with either 0.9% sodium chloride or 5% glucose. No evidence of particle formation, colour change or pH change was observed throughout the study period. CONCLUSIONS: These findings would allow early hospital discharge using elastomeric intravenous administration of voriconazole in patients in whom oral route of administration is not available.