Evaluation of Strategies for Reducing Vancomycin-Piperacillin/Tazobactam Incompatibility

Abstract

Background: Drug incompatibility is defined as a physical-chemical reaction between two or more injectable drugs and that results mainly in precipitation or insolubility. Several strategies for reducing incompatibilities have been implemented empirically in intensive care units. However, these strategies have never been compared directly (and particularly in terms of the particulate load and drug mass flow rate) under standardized conditions. The objective of the present in vitro study was to evaluate the impact of various strategies for preventing incompatibility between simultaneously infused vancomycin and piperacillin/tazobactam.

Methods: An in-line filter, a dilute vancomycin solution (5 mg/mL), and an alternative saline administration line were evaluated separately. The infusion line outlet was connected to a dynamic particle counter. The antibiotic concentration was measured in an HPLC-UV assay.

Result: The use of an in-line filter and an alternative saline administration route did not significantly reduce the particulate load caused by vancomycin-piperacillin/tazobactam incompatibility. Dilution of the vancomycin solution was associated with a significantly lower particulate load and maintenance of the vancomycin mass flow rate.

Discussion: It is important to systematically compare the efficacy of strategies for preventing drug incompatibility. The use of diluted vancomycin solution gave the best results in the case of vancomycin-piperacillin/tazobactam incompatibility.

Keywords: drug incompatibility; in-line filter; infusion; particulate load; piperacillin/tazobactam; vancomycin.

Figure 1

Timeline for the standard infusion of vancomycin and piperacillin/tazobactam.

Figure 2

The standard manifold infusion set (A), the vancomycin solution replaced by SS (B), the piperacillin/tazobactam solution replaced by SS (C), the manifold infusion set with a filter on the vancomycin solution tubing (D), the manifold infusion set with a filter on the tubing downstream of the tap manifold (E), the manifold infusion set with diluted vancomycin (F), the manifold infusion set with two SS administration routes (G), and the manifold infusion set with an SS alternative administration route (H).

Figure 3

Visual observation of the infusion lines. The red arrows indicate the direction of infusion. (A) Formation of the initial white precipitate, following contact between the vancomycin solution and the piperacillin/tazobactam solution. (B) The initial precipitate is only visible at the end of the infusion tubing. (C) The white precipitate dissolves along the tubing during VPT co-perfusion. The red circles (D) correspond to the presence of visible particles, and the green circle (E) corresponds to the absence of visible particles. (F) The absence of visible precipitate during a VPT co-infusion.

Figure 4

The particulate load observed during the infusion of vancomycin and/or piperacillin/tazobactam with a 200 cm manifold + extension set. The standard infusion protocol (A) is shown in red, the vancomycin-only infusion (C) is shown in green, and the piperacillin/tazobactam-only infusion is shown in blue (B). The blue dotted lines correspond to the start and the end of the piperacillin/tazobactam infusion (t = 30 min and t = 2.5 h, respectively). The results are expressed as the mean ± SD (n = 3–6).

Figure 5

The particle distribution over time, showing the impact of in-line filtration and the hydration position on the particulate load in set-up D (A), set-up E (B), set-up G (C), and set-up H (D). The results are expressed as the mean ± SD (n = 5 or 6).

Figure 6

Impact of the choice of infusion set or protocol on the particulate load. Comparisons of the total particulate load (A), the particulate load ≥10 µm (B), and the particulate load ≥25 µm (C) in the various infusion sets and protocols (set-ups A, D, E, F, G, and H). The results are expressed as the median (range) (* p < 0.05 and ** p < 0.01 in a Mann-Whitney test, n = 5–6).

Figure 7

Influence of the vancomycin solution concentration on the specific charge, solution pH and active ingredient MFR. (A) Change in pH during VPT co-infusion with a 20.8 mg/mL or 5.95 mg/mL vancomycin solution. The results are expressed as the mean ± SD, n = 3. (B) The particulate load as a function of the infusion time for set-up A (in red) and set-up F (in green). The results are expressed as the mean ± SD, n = 6. (C–E) Change over time in the experimental/theoretical MFR (%) in the plug-flow model of vancomycin (C), piperacillin (D), and tazobactam (E) at the manifold and in the tubing infusion line in set-up A or set-up F. The results are expressed as the mean ± SD, n = 3.