1 Department of Paediatrics, University of Alberta, Alberta, Canada; 2 Department of Pharmacy, Stollery Children's Hospital, Capital Health, Edmonton, Alberta, Canada; 3 Department of Internal Medicine, University of Alberta, Alberta, Canada; 4 Department of Laboratory Medicine and Pathology, University of Alberta, Alberta, Canada
Received 11 May 2005; returned 9 June 2005; revised 29 July 2005; accepted 9 August 2005
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Abstract |
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Methods: Solutions were prepared with heparin 5000 U/mL or heparin 10 U/mL and cefazolin 10 mg/mL, ampicillin 10 mg/mL, or piperacillin 40 mg/mL. Solutions of vancomycin 2.5 mg/mL with heparin 5000 U/mL and vancomycin 2 mg/mL with heparin 10 U/mL were also prepared. The ability of each solution to elevate the activated partial thromboplastin time (APTT) of pooled normal plasma and the physical compatibility of the solutions were assessed for 14 days.
Results: The APTT levels never varied by more than 16.4% from baseline. Physical incompatibility never occurred before day 14 in any of the solutions.
Conclusions: Mixing of antibiotics in the concentrations chosen for the study had no clinically significant effect on biological heparin activity, and all solutions were physically compatible for at least 14 days.
Keywords: stability , cefazolin , ampicillin , piperacillin , vancomycin , heparin
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Introduction |
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Materials and methods |
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To study the biological stability of heparin, commercially available ampicillin (500 mg, NovoPharm Limited), cefazolin (1 g, NovoPharm Limited), vancomycin (500 mg, PharmaScience), and piperacillin (3 or 4 g, Mayne Pharma Inc.) were reconstituted with sterile water for injection according to the manufacturers' instructions (except for cefazolin in solutions tested for heparin stability which was reconstituted to 95 mg/mL) and then further diluted with commercially available sodium heparin 10 000 U/mL (mean molecular weight 15 000 Da, Leo Pharma Inc.) and 0.9% sodium chloride (NS) (Baxter, Toronto) to achieve final concentrations of ampicillin 10 mg/mL, cefazolin 10 mg/mL, piperacillin 40 mg/mL, or vancomycin 2.5 mg/mL in heparin 5000 U/mL. These antibiotic concentrations were chosen because they are the concentrations that result when standard administration concentrations of intravenous antibiotic solutions are mixed 1:1 with commercially available or pharmacy-prepared heparin solutions and so would simplify the preparation of solutions for ALT. The combined solutions and control solutions of heparin 5000 U/mL, ampicillin 10 mg/mL, cefazolin 10 mg/mL, piperacillin 40 mg/mL, and vancomycin 2.5 mg/mL were incubated in the dark for a total of 14 days at 4°C (to determine stability while being stored in a refrigerator) and at 37°C (to determine stability at the approximate temperature of an intravascular catheter). The procedure was repeated using heparin 1000 U/mL (mean molecular weight 15 000 Da, Leo Pharma Inc.) diluted with NS and the same concentration of antibiotic (except for vancomycin, where a 2 mg/mL concentration was substituted) to make a final heparin concentration of 10 U/mL. These concentrations of heparin were chosen because 5000 U/mL is a common concentration used in haemodialysis lines and 10 U/mL is the concentration used in central venous lines in the paediatric and adult haematology patients in our centre.
To study physical compatibility, the same solutions used to study the biological stability of heparin and additional solutions that would be considered for ALT (heparin 10 U/mL and heparin 5000 U/mL with either vancomycin 1 mg/mL, vancomycin 0.5 mg/mL, piperacillin 20 mg/mL or piperacillin 10 mg/mL) were prepared by adding 9 mL of a twofold concentration of antibiotic solution to 9 mL of a twofold concentration of heparin solution in NS and stored at 37°C. Solutions were prepared in this manner as immediate precipitation problems had been noted when higher concentrations of vancomycin were added to dilutions of heparin in NS. Control solutions were prepared in the same manner with saline in place of either antibiotic or heparin.
Outcome measures
Solutions were tested for biological heparin stability by measuring the activated partial thromboplastin time (APTT) of the solution diluted in pooled normal plasma (Precision Biologic, Dartmouth, Nova Scotia, Canada) at 0, 24, 48 and 72 h, and then at 14 days. The APTT assays were performed on a STA Compact coagulation analyser (Diagnostica Stago, Asnieres, France). To assess physical compatibility, a single blinded observer visualized 18 mL of each solution under normal room lighting in a sterile clear colourless glass vial against both a black and a white background daily for 10 days and then again on day 14. Physical incompatibility was defined as the presence of any visible precipitation or cloudiness.
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Results |
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At 4°C with heparin 5000 U/mL, there was a gradual increase in the APTT with time in all solutions except for the heparin/piperacillin solution, where there was an initial increase at 48 h, but then a levelling off at 72 h (Figure 1). The largest increase in APTT was 16.4% in the heparin/cefazolin solution at 14 days (versus 14.1% in the heparin control). At 37°C with 5000 U/mL heparin, APTT values fell and then rose again, with the largest deviation from baseline being a decrease of 12.4% in the heparin/vancomycin solution at 24 h (although APTT was then above baseline at 72 h and at 14 days in this solution). With heparin 10 U/mL, at both temperatures APTT levels tended to fall and then rise. The largest deviation from baseline at 4°C was a decrease of 7.2% in the heparin/ampicillin solution at 48 h. The largest deviation from baseline at 37°C was a decrease of 12.7% in the heparin/piperacillin solution at 48 h.
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Physical compatibility
Physical incompatibility was not detected up to day 14. However, a yellow colour was noted in many of the ampicillin, piperacillin and cefazolin heparin solutions prior to colour change in the control solutions, with the earliest colour change being in the ampicillin 10 mg/mL and piperacillin 40 mg/mL in heparin 5000 U/mL solutions on day 3.
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Discussion |
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Because of the high incidence of Gram-positive infections in intravascular catheter-related bacteraemia, vancomycin is the most commonly used antibiotic for ALT. This study demonstrated that vancomycin concentrations ranging from 0.5 to 2.5 mg/mL in heparin 10 U/mL or 5000 U/mL were physically compatible when mixed 1:1 with heparin at a twofold concentration. Previous studies have not reported precipitation when higher concentrations of vancomycin were used with high concentrations of heparin (vancomycin 3 mg/mL in heparin 10 000 U/mL5 and vancomycin 10 mg/mL in heparin 5000 U/mL6). However, one study reported precipitation when a high concentration of vancomycin (10 mg/mL) was mixed 1:1 with a low concentration of heparin (100 U/mL).7 In ALT studies, vancomycin 13 mg/mL in heparin 1002500 U/mL, vancomycin 0.5 mg/mL and 2 mg/mL in heparin 100 U/mL, and vancomycin 2.5 mg/mL in heparin 2500 U/mL have been used8 but the absence of precipitation and the methods used to determine physical compatibility were not consistently reported.
The duration of chemical stability of antimicrobials in ALT is an important consideration in determining how often ALT solutions need to be changed. At 25°C in NS and stored in glass, ampicillin 10 mg/mL is stable for 24 h, cefazolin 10 mg/mL for 48 h, piperacillin 40 mg/mL for 48 h, and vancomycin 5 mg/mL for 17 days9 but there is limited data on the stability of antibiotics at 37°C. There was minimal loss (9% decrease in absorbance values as measured spectrophotometrically) of cefazolin when combined at 10 mg/mL with heparin 5000 U/mL in glass for 72 h at 37°C, but significant loss (27.4% reduction in absorbance values) in a polyurethane catheter.6 Future stability studies of ALT solutions should be carried out at body temperature in polyurethane rather than in glass vials.
There is a need for further randomized, controlled trials to demonstrate if ALT is effective for intravascular catheter-related bacteraemia.8 It appears that solutions containing vancomycin 2 mg/mL, cefazolin 10 mg/mL, ampicillin 10 mg/mL, or piperacillin 40 mg/mL in heparin 5000 U/mL or heparin 10 U/mL would be appropriate ALT solutions to study.
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Acknowledgements |
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References |
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