The development of Jack Jumper ant venom immunotherapy: our 25 years' experience.

Jack Jumper ant venom allergy is a uniquely Australian medical issue. The stinging ant is a leading cause of insect venom allergy in south-eastern Australia. An effective venom immunotherapy-based treatment was successfully developed by the Tasmanian Jack Jumper Allergy Research group. This paper provides a synopsis of our 25 years' research journey in developing this evidence-based treatment modality.

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 Aliquots were withdrawn at predefined time points and analysed for the concentration of clonidine, changes in pH and colour, and particle content.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.

Towards complete identification of allergens in Jack Jumper (Myrmecia pilosula) ant venom and their clinical relevance: An immunoproteomic approach.

BACKGROUND: The venomous stings of Jack Jumper ant (JJA; species of the Myrmecia pilosula taxonomic group) are a significant public health issue in parts of south-eastern and south-western Australia, causing anaphylaxis in approximately 3% of the population. Three allergenic peptides, Myr p 1, Myr p 2 and Myr p 3, and one histamine-releasing peptide, pilosulin 5, have been fully described, but there are at least 5 additional high molecular weight IgE-binding components that have not been identified. OBJECTIVE: To identify IgE-binding components in JJA venom (JJAV) and to relate the IgE recognition of these components to relevant clinical parameters. METHODS: Identification of IgE-binding components and determination of their sensitizing prevalence was performed using SDS-PAGE immunoblot assay and sera from 90 patients with confirmed allergy to JJAV. Tandem mass spectrometry was used for identification of novel JJAV components fractionated by size exclusion chromatography (SEC) and SDS-PAGE. RESULTS: Using SDS-PAGE immunoblot, 10 IgE-binding bands were identified in JJAV, two of which were recognized by 81% and 47% of the population studied. Mass spectrometry identified 17 novel JJAV proteins, including 2 glycoproteins, and confirmed the presence of 4 known Myr p and pilosulin peptides in JJAV. Most of the newly identified IgE-binding proteins were enzymes, including phospholipase A2 , hyaluronidase, arginine kinase and dipeptidyl peptidase IV. Correlations were found between recognition of certain IgE-binding bands with JJAV-specific IgE titre by ImmunoCAP, intradermal test threshold and treatment-related issues. CONCLUSIONS AND CLINICAL RELEVANCE: This study has for the first time revealed the identity of various proteins with IgE-binding capacity in the venom of JJA and demonstrated their clinical relevance in the diagnosis and treatment of JJAV allergy.

Comparative study of the commonly used protein quantitation assays on different Hymenoptera venoms: A fundamental aspect of Hymenoptera venom proteome analysis.

Determination of protein concentration in Hymenoptera venoms requires an accurate and reproducible assay as the results will be used to support subsequent proteomic techniques employed in their analyses. However, all protein assay techniques have inherent strengths and weaknesses, demanding their assessment before selecting the most suitable platform for sample analysis. In this study, protein profiles of ant, honeybee, and wasp venoms, and bovine serum albumin (BSA) and hyaluronidase standards were qualitatively assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Their amino acid and protein concentration were quantitatively determined via Amino Acid Analysis (AAA). Amino acid concentration was determined via hydrolysis, derivatization, and chromatographic quantification. Protein concentration was estimated using four different protein concentration assays. The ratios of protein concentration in venom samples to protein standards were calculated, and the accuracy of the protein concentration assays was analysed relative to the concentration determined from AAA. SDS-PAGE analysis showed that BSA contained several protein bands, while hyaluronidase contained a mixture of peptide and protein bands. Ant and honeybee venoms contained a higher proportion of peptide bands, while wasp venom contained more protein bands. As determined by AAA, the ratio of protein concentration in Hymenoptera venoms varied between 1.01 and 1.11 to BSA, and between 0.96 and 1.06 to hyaluronidase. Overall, the Bradford assay was found to be the least accurate and the BCA assay was the most accurate in estimating protein concentration in Hymenoptera venoms. There was no significant advantage in using hyaluronidase as a standard or increasing incubation temperature of BCA assay when analysing Hymenoptera venoms. Diluent solutions containing phenol and human serum albumin interfered with Lowry-based assays.

The Human Health Impacts of the Red Imported Fire Ant in the Western Pacific Region Context: A Narrative Review.

Background: The red imported fire ant (RIFA) is one of the world's most destructive invasive species. RIFA stings are painful and can lead to allergic reactions, including life-threatening anaphylaxis, yet health impacts remain inadequately defined. Methods: We searched MEDLINE (Ovid) and Google Scholar (grey literature) from inception until 20 September 2023 for articles in English using search terms related to red imported fire ants and allergies, including anaphylaxis. Results: Approximately a third of the population in RIFA-infested areas are stung each year. The most frequent reaction is a sterile 1-2 mm pseudo pustule on the skin. Approximately 20% of stings cause a large local reaction and between about 0.5% and 2% stings cause a systemic allergic reaction which can range from skin symptoms to life-threatening anaphylaxis. Local biodiversity is also significantly disrupted by invading RIFA and may lead to complex adverse effects on human health, from agriculture losses to expanded ranges for pathogen vectors. Conclusions: The potential for red imported fire ants to establish themselves as an invasive species in the Western Pacific presents a substantial and costly health issue. Successful eradication and surveillance programs, to identify and eradicate new incursions, would avoid substantial health impacts and costs.

Ultrarush versus semirush initiation of insect venom immunotherapy: a randomized controlled trial.

BACKGROUND: Venom immunotherapy can be initiated by different schedules, but randomized comparisons have not been performed. OBJECTIVE: We aimed to compare the safety of 2 initiation schedules. METHODS: Patients of any age with prior immediate generalized reactions to jack jumper ant (Myrmecia pilosula) stings were randomized to venom immunotherapy initiation by a semirush schedule over 10 visits (9 weeks) or an ultrarush schedule over 3 visits (2 weeks). In a concurrent treatment efficacy study, the target maintenance dose was randomized to either 50 µg or 100 µg. The primary outcome was the occurrence of 1 or more objective systemic reactions during venom immunotherapy initiation. Analyses were by intention to treat. We also assessed outcomes in patients who declined randomization. RESULTS: Of 213 eligible patients, 93 were randomized to semirush (44 patients) or ultrarush (49 patients) initiation. Objective systemic reactions were more likely during ultrarush initiation (65% vs 29%; P < .001), as were severe reactions (12% vs 0%; P= .029). Times to maximal increases in venom-specific IgG(4) were no different between treatments, whereas the maximal increase in venom-specific IgE occurred earlier with ultrarush treatment. Similar differences between methods were observed in patients who declined randomization. One hundred seventy-eight patients were randomized to maintenance doses of either 50 µg (90 patients) or 100 µg (88 patients). The target maintenance dose had no effect on the primary outcome, but multiple-failure-per-subject analysis found that the 50 µg dose reduced the likelihood of reactions. CONCLUSION: Ultrarush initiation increases the risk of systemic reactions. A lower maintenance dose reduces the risk of repeated reactions, but the effect on treatment efficacy is unknown.

Validation of the Randox colorimetric assays for serum copper and zinc.

BACKGROUND: Serum copper and zinc are measured to assess deficiency and toxicity. Atomic absorption spectrophotometry and mass spectrometry methods are expensive and require highly trained staff. Colorimetric assays are available from Randox which are inexpensive and can be automated. We validated serum copper and zinc colorimetric assays on the Binding Site Optilite analyser including comparison with flame atomic absorption spectrophotometry (FAAS) and inductively coupled plasma-mass spectrometry (ICP-MS). METHODS: Accuracy, imprecision, lower limit of quantitation, and linearity were ascertained. The impact of triglycerides, bilirubin, nickel, and iron on assay performance was also investigated. Comparison of results from colorimetric analysis of patient and external quality assurance samples with those obtained by FAAS and ICP-MS was undertaken. RESULTS: Intra-, and inter-assay imprecision was <9%. Serum copper and zinc assays were linear between 1.8-35.6 and 2.3-45.7 µmol/L, respectively. Agreement was good between colorimetry and FAAS (intercept = -0.7, slope = 1.04) and ICP-MS (intercept = 0.6, slope = 0.99) for serum copper in patients' samples. For serum zinc, agreement was poor between colorimetry and FAAS (intercept = 2.2, slope = 0.87) and ICP-MS (intercept = 1.9, slope = 0.98) in patients' samples. There was a poor concordance in assessment of hypozincaemia between colorimetry and FAAS/ICP-MS. CONCLUSION: The Randox colorimetric assay for serum copper on the Optilite is simple to perform, has a short analysis time, and measured concentrations compare well with FAAS and ICP-MS. Due to poor agreement with FAAS and ICP-MS, colorimetry is not suitable for the measurement of serum zinc.

Verification of the Bühlmann fPELA turbo faecal elastase assay on the Binding Site Optilite benchtop analyser.

BACKGROUND: Pancreatic elastase-1 (PE1) can be measured to assess exocrine activity of the pancreas. A semi-automated particle-enhanced, open-channel turbidimetric immunoassay has been introduced by Bühlmann (fPELA turbo, Bühlmann Laboratories AG, Schoenenbuch, Switzerland). Published evaluation data is lacking. We therefore verified performance of the assay on the Binding Site Optilite benchtop analyser and undertook a sample comparison with the DiaSorin PE1 assay on the Liaison. METHODS: Accuracy, imprecision, lower limit of quantitation (LLoQ) and linearity of the Bühlmann fPELA turbo assay on the Binding Site Optilite analyser was ascertained. Comparison with the DiaSorin Liaison PE1 assay was also undertaken. Difference between assays was evaluated using the Wilcoxon signed-rank test and method comparison was undertaken using Spearman's rank correlation (rs), Bland-Altman and Passing-Bablok regression analyses. RESULTS: The fPELA turbo assay was linear between 5 and 2500 µg/g. The LLoQ was 5 µg/g. Intra- and inter-assay imprecision was <6%. There was a good agreement (rs = 0.92) and no significant bias (5.8 µg/g, P = 0.29) present between the Bühlmann fPELA turbo and DiaSorin PE1 assays. CONCLUSION: The Bühlmann fPELA turbo assay performs well on the Binding Site Optilite analyser. Faecal elastase results are commutable between with Bühlmann fPELA turbo and DiaSorin Liaison PE1 assays.

Culture-directed antibiotics in peritoneal dialysis solutions: a systematic review focused on stability and compatibility.

BACKGROUND: This systematic review summarises the stability of less commonly prescribed antibiotics in different peritoneal dialysis solutions that could be used for culture-directed therapy of peritonitis, which would be especially useful in regions with a high prevalence of multidrug antibiotic-resistant strains. METHODS: A literature search of Medline, Scopus, Embase and Google Scholar for articles published from inception to 25 January, 2023 was conducted. Only antibiotic stability studies conducted in vitro and not recently reviewed by So et al. were included. The main outcomes were chemical, physical, antimicrobial and microbial stability. This protocol was registered in PROSPERO (registration number CRD42023393366). RESULTS: We screened 1254 abstracts, and 28 articles were included in the study. In addition to those discussed in a recent systematic review (So et al., Clin Kidney J 15(6):1071-1078, 2022), we identified 18 antimicrobial agents. Of these, 9 have intraperitoneal dosing recommendations in the recent International Society for Peritoneal Dialysis (ISPD) peritonitis guidelines, and 7 of the 9 had stability data applicable to clinical practice. They were cefotaxime, ceftriaxone, daptomycin, ofloxacin, and teicoplanin in glucose-based solutions, tobramycin in Extraneal solution only and fosfomycin in Extraneal, Nutrineal, Physioneal 1.36% and 2.27% glucose solutions. CONCLUSIONS: Physicochemical stability has not been demonstrated for all antibiotics with intraperitoneal dosing recommendations in the ISPD peritonitis guidelines. Further studies are required to determine the stability of antibiotics, especially in icodextrin-based and low-glucose degradation products, pH-neutral solutions.

Global View on Ant Venom Allergy: from Allergenic Components to Clinical Management.

Hymenoptera venom allergy is characterised by systemic anaphylactic reactions that occur in response to stings from members of the Hymenoptera order. Stinging by social Hymenoptera such as ants, honeybees, and vespids is one of the 3 major causes of anaphylaxis; along with food and drug exposure, it accounts for up to 43% of anaphylaxis cases and 20% of anaphylaxis-related fatalities. Despite their recognition as being of considerable public health significance, stinging ant venoms are relatively unexplored in comparison to other animal venoms and may be overlooked as a cause of venom allergy. Indeed, the venoms of stinging ants may be the most common cause of anaphylaxis in ant endemic areas. A better understanding of the natural history of venom allergy caused by stinging ants, their venom components, and the management of ant venom allergy is therefore required. This article provides a global view on allergic reactions to the venoms of stinging ants and the contemporary approach to diagnose and manage ant venom allergy.

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.

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.

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.

Pharmaceutical and preclinical evaluation of Advax adjuvant as a dose-sparing strategy for ant venom immunotherapy.

A major challenge in broader clinical application of Jack Jumper ant venom immunotherapy (JJA VIT) is the scarcity of ant venom which needs to be manually harvested from wild ants. Adjuvants are commonly used for antigen sparing in other vaccines, and thereby could potentially have major benefits to extend JJA supplies if they were to similarly enhance JJA VIT immunogenicity. The purpose of this study was to evaluate the physicochemical and microbiological stability and murine immunogenicity of low-dose JJA VIT formulated with a novel polysaccharide adjuvant referred to as delta inulin or Advax™. Jack Jumper ant venom (JJAV) protein stability was assessed by UPLC-UV, SDS-PAGE, SDS-PAGE immunoblot, and ELISA inhibition. Diffraction light scattering was used to assess particle size distribution of Advax; pH and benzyl alcohol quantification by UPLC-UV were used to assess the physicochemical stability of JJAV diluent, and endotoxin content and preservative efficacy test was used to investigate the microbiological properties of the adjuvanted VIT formulation. To assess the effect of adjuvant on JJA venom immunogenicity, mice were immunised four times with JJAV alone or formulated with Advax adjuvant. JJA VIT formulated with Advax was found to be physicochemically and microbiologically stable for at least 2 days when stored at 4 and 25 °C with a trend for an increase in allergenic potency observed beyond 2 days of storage. Low-dose JJAV formulated with Advax adjuvant induced significantly higher JJAV-specific IgG than a 5-fold higher dose of JJAV alone, consistent with a powerful allergen-sparing effect. The pharmaceutical data provides important guidance on the formulation, storage and use of JJA VIT formulated with Advax adjuvant, with the murine immunogenicity studies providing a strong rationale for a planned clinical trial to test the ability of Advax adjuvant to achieve 4-fold JJAV dose sparing in JJA-allergic human patients.

Stability of milrinone in continuous ambulatory delivery devices.

PURPOSE: The stability of milrinone in continuous ambulatory delivery devices (CADDs) stored at 4, 25, and 35 °C was evaluated. METHOD: Six CADDs (3 devices containing milrinone plus 0.9% sodium chloride injection and 3 devices containing milrinone plus 5% dextrose injection) were prepared. Devices were kept at 4 °C for 168 hours, followed by 24 hours at 25 °C and an additional 24 hours at 35 °C. Samples (n = 3) were withdrawn aseptically at 0, 24, 48, 72, 96, 120, 144, and 168 hours from the CADDs stored at 4 °C and at 0, 6, and 24 hours from the CADDs stored at 25 and 35 °C. The milrinone concentration of each aliquot was analyzed using a stability-indicating high performance liquid chromatographic method within 15-30 minutes of preparation. The samples were also evaluated for changes in pH, changes in color, and particulate content. Six control samples (3 containing 0.9% sodium chloride injection and 3 containing 5% dextrose injection) were prepared and similarly analyzed. RESULTS: Milrinone admixtures retained more than 99% of their initial concentration for 168 hours at 4 °C and for 24 hours when stored at 25 and 35 °C. No evidence of particle formation, color change, or pH change was observed throughout the study period. CONCLUSION: Milrinone 600 µg/mL prepared in either 0.9% sodium chloride injection or 5% dextrose injection in CADDs was stable for 168 hours when stored at 4 °C and for 24 hours when stored at 25 and 35 °C.

Stability of Cefazolin in Polyisoprene Elastomeric Infusion Devices.

PURPOSE: The aim was to investigate the stability of cefazolin in elastomeric infusion devices. METHODS: Elastomeric devices (Infusor LV) that contain cefazolin (3 g/240 mL and 6 g/240 mL) were prepared and stored at 4°C for 72 hours and then at 35°C for 12 hours, followed by 25°C for 12 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentration of cefazolin. Samples were also assessed for changes in pH, solution color, and particle content. FINDINGS: Cefazolin retained acceptable chemical and physical stability over the studied storage period and conditions. IMPLICATIONS: These findings will allow the administration of cefazolin by the Infusor LV elastomeric device in the outpatient and remote settings.

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.

Physical and chemical stability of ceftaroline in an elastomeric infusion device.

BACKGROUND: Severe infections such as endocarditis and osteomyelitis require long-term treatment with parenteral antibiotics and hence prolonged hospitalisation. Continuous infusion of ceftaroline through elastomeric devices can facilitate early hospital discharge by managing parenteral antibiotics in patient's home. Therefore, the purpose of this study was to investigate the stability of ceftaroline in a commonly used elastomeric device. METHOD: A total of 24 elastomeric devices were prepared, and six elastomeric devices containing 6mg/mL of ceftaroline (three in each type of diluents) were stored at one of the following conditions: 4°C for 6 days, 25°C for 24hours, 30°C for 24hours or 35°C for 24hours. An aliquot was withdrawn before storage and at different time points. Chemical stability was measured using a stability indicating high-performance liquid chromatography, and physical stability was assessed as change in pH, colour and particle content. RESULTS: Ceftaroline, when admixed with both diluents, was stable for 144, 24 and 12hours at 4°C, 25°C and 30°C, respectively. At 35°C, ceftaroline admixed with normal saline (NS) and glucose 5% was stable for 12hours and for 6hours, respectively. No evidence of particle formation, colour change or pH change was observed throughout the study period. CONCLUSIONS: Our findings support 12 or 24hours continuous elastomeric infusion of ceftaroline-NS admixture, and bulk preparation of elastomeric pumps containing ceftaroline solution in advance. This would facilitate early hospital discharge of patients eligible for the elastomeric-based home therapy and avoid the need for patient's caregivers travelling to the hospital on a daily basis.

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.

Investigations into the physical and chemical stability of concentrated co-trimoxazole intravenous infusions.

OBJECTIVES: High dose of intravenous sulfamethoxazole and trimethoprim (co-trimoxazole) is often used in immunocompromised patients for the treatment of Pneumocystis jiroveci pneumonia. Current manufacturer's dilution recommendation for intravenous co-trimoxazole (1:25 v/v) requires the administration of 2 L of additional fluid per day causing serious complications including pulmonary oedema. Intravenous administration of concentrated solution of co-trimoxazole may minimise the risk of fluid overload associated side effects. Therefore, the objective of the study was to investigate the physicochemical stability of concentrated intravenous co-trimoxazole solutions. METHODS: Four ampoules of intravenous co-trimoxazole were injected into an infusion bag containing either 480 (1:25 v/v), 380 (1:20 v/v), 280 (1:15 v/v) or 180 (1:10 v/v) mL of glucose 5% solution. Three bags for each dilution (total 12 bags) were prepared and stored at room temperature. An aliquot was withdrawn immediately (at 0 hour) and after 0.5, 1, 2 and 4 hours of storage for high-performance liquid-chromatography (HPLC) analysis, and additional samples were withdrawn every half an hour for microscopic examination. Each sample was analysed for the concentration of trimethoprim and sulfamethoxazole using a stability indicating HPLC method. Samples were assessed for pH, change in colour (visually) and for particle content (microscopically) immediately after preparation and on each time of analysis. RESULTS: Intravenous co-trimoxazole at 1:25, 1:20, 1:15 and 1:10 v/v retained more than 98% of the initial concentration of trimethoprim and sulfamethoxazole for 4 hours. There was no major change in pH at time zero and at various time points. Microscopically, no particles were detected for at least 4 hours and 2 hours when intravenous co-trimoxazole was diluted at 1:25 or 1:20 and 1:15 v/v, respectively. More than 1200 particles/mL were detected after 2.5 hours of storage when intravenous co-trimoxazole was diluted at 1:15 v/v. CONCLUSIONS: Intravenous co-trimoxazole is stable over a period of 4 hours when diluted with 380 mL of glucose 5% solution (1:20 v/v) and for 2 hours when diluted with 280 mL glucose 5% solution (1:15 v/v).