Systematic Review of Piperacillin-Tazobactam and Vancomycin Y-Site Compatibility: Consideration of Concentration and Solution Variability

Abstract

Simultaneous administration of vancomycin and piperacillin-tazobactam (VPT) poses significant challenges related to physical and chemical compatibility, as well as clinical practice. A systematic review of available literature related to VPT Y-site compatibility was performed. Data was collected from primary and tertiary sources. Seven articles were included in addition to one internal assessment and one review article and information from tertiary drug databases. The literature supports the simultaneous administration via Y-site of piperacillin-tazobactam 33.75 mg/mL in normal saline (NS) and vancomycin 4 to 8 mg/mL in NS. The same drug products at differing concentrations, diluents, storage conditions, or preparations outside of this recommendation should be considered incompatible.

Introduction

Vancomycin and piperacillin-tazobactam (VPT) is a common broad-spectrum antibiotic regimen which has notable limitations such as increased nephrotoxicity and variable Y-site compatibility.^{1 -3} An alternative broad-spectrum regimen that is growing in popularity includes cefepime, metronidazole, and vancomycin. This alternative provides similar microbial coverage, generally Y-site compatible, and less incidence of acute kidney injury.^4-7 Despite the literature related to nephrotoxicity and favorable alternative regimens, VPT remains a common broad-spectrum combination utilized by many health systems. ³ This continued practice prompted a re-evaluation of our health system’s historical approach to VPT compatibility previously established based on the body of literature prior to 2012 and internal data. ⁸

Typical piperacillin-tazobactam regimens include an infusion over 30 minutes every 6 hours in patients with normal renal function. Studies show favorability of extended 4-hour infusion of piperacillin-tazobactam 3 times a day due to improved outcomes, especially in critically ill patients. The use of extended-infusion piperacillin-tazobactam presents scheduling difficulties when administration of vancomycin is also needed for broad spectrum empiric coverage. A typical dosing regimen of piperacillin-tazobactam every 8 hours and vancomycin every 12 hours which may be considered Y-site compatible or require 2 sperate lines if deemed incompatible based on interpretation of the literature and tertiary resources.^1-2 The uncertainty related to compatibility of VPT is multifaceted; variations in concentration of both drugs, compounding diluent, commercial pre-mix products, and storage temperature. The body of literature for compatibility of this drug combination is summarized in several tertiary resources, however there is no literature that summarizes all published literature and provides a clinical practice recommendation. This systematic review aims to summarize the body of literature related to Y-site compatibility of VPT and provide an evidence-based recommendation taking into considerations concentration, diluent, commercial pre-mix, and storage temperature.

Methods

Articles were identified via a PubMed search using a combination of one or more of the following search terms: “piperacillin-tazobactam,” “vancomycin,” “compatibility,” and filtered for English language. A total of 17 articles were identified: seven published articles and one internal assessment were included, these studies focused on the physical and/or chemical stability between VPT when combined. Nine articles were excluded due to the following study focuses: assessed patient related factors after simultaneous administration of the two study drugs; patient population/disease/infection specific; primary comparison of physical stability was not between VPT; and/or not assessing physical compatibility (Table 1). One review article was identified through this search; however, it only offered a simplified compatibility chart for 10 antibiotics and 131 commonly used medications. ⁹ None of the articles included in this assessment are meta-analyses. An additional search was performed utilizing multiple tertiary databases to determine available compatibility information.^6,10-12 Compatibility data listed in package inserts was also assessed.^13,14 Data was collected and analyzed in Microsoft Excel. Data was divided into three main groups for analysis based on compounding diluent: Dextrose 5% in Water (D5W), 0.9% Sodium Chloride (NS), and miscellaneous (undiluted or sterile water for infusion [SWFI]).

Table 1.

Summary of Literature of Compatibility.

Author	Drug 1: piperacillin/tazobactam (mg/mL)	Solution 1	Drug 2: vancomycin (mg/mL)	Solution 2	Compatibility	Notes
Wade et al 1	18	NS	2	NS	C
	18	NS	5	NS	C
	18	NS	10	NS	C
	33.75	NS	2	NS	C
	33.75	NS	5	NS	C
	33.75	NS	10	NS	C
Leung et al 17	33.75	NS	4	NS	C
O’Donnell et al 18	33.75	NS	4	NS	C
	33.75	NS	5	NS	C
	33.75	NS	6	NS	C
	33.75	NS	7	NS	C
	33.75	NS	8	NS	C
	33.75	NS	9	NS	NT
	33.75	NS	10	NS	I*	Unstable precipitate formed
	33.75	NS	12	NS	I
Wade et al 1	45	NS	2	NS	C
	45	NS	5	NS	C
	45	NS	10	NS	I
Leung et al 17	45	NS	4	NS	C
O’Donnell et al 18	45	NS	4	NS	C
Waters 8	45	NS	5	NS	C
O’Donnell et al 18	45	NS	5	NS	C
	45	NS	6	NS	C
	45	NS	7	NS	C
	45	NS	8	NS	C
	45	NS	9	NS	NT
	45	NS	10	NS	I*	Unstable precipitate formed
	45	NS	12	NS	I
	50	NS	4	NS	C
	50	NS	5	NS	C
	50	NS	6	NS	C
	50	NS	7	NS	C
	50	NS	8	NS	C
	50	NS	9	NS	NT
	50	NS	10	NS	I*	Unstable precipitate formed
	50	NS	12	NS	I
	60	NS	4	NS	C
	60	NS	5	NS	C
	60	NS	6	NS	C
	60	NS	7	NS	C
	60	NS	8	NS	C
	60	NS	9	NS	NT
	60	NS	10	NS	I*	Unstable precipitate formed
	60	NS	12	NS	I
	67.5	NS	4	NS	C
Waters 8	67.5	NS	5	NS	C
O’Donnell et al 18	67.5	NS	5	NS	C
	67.5	NS	6	NS	C
	67.5	NS	7	NS	C
	67.5	NS	8	NS	C
	67.5	NS	9	NS	NT
	67.5	NS	10	NS	I*	Unstable precipitate formed
	67.5	NS	12	NS	I
Wade et al 1	90	NS	2	NS	C
	90	NS	5	NS	C
	90	NS	10	NS	I
O’Donnell et al 18	80	NS	4	NS	C
	80	NS	5	NS	C
	80	NS	6	NS	C
	80	NS	7	NS	C
	80	NS	8	NS	I
	80	NS	9	NS	NT
	80	NS	10	NS	I*	Unstable precipitate formed
	80	NS	12	NS	I
	90	NS	4	NS	C
	90	NS	5	NS	C
	90	NS	6	NS	C
	90	NS	7	NS	C
	90	NS	8	NS	I
	90	NS	9	NS	NT
	90	NS	10	NS	I*	Unstable precipitate formed
	90	NS	12	NS	I
Waters 8	100	NS	5	NS	C
Wade et al 1	112.5	NS	2	NS	C
	112.5	NS	5	NS	C
	112.5	NS	10	NS	I
Trissel’s 1998 15	1.125	D5W	2	D5W	C
	1.125	D5W	20	D5W	C
	11.25	D5W	2	D5W	C
	11.25	D5W	20	D5W	I
Wade et al 1	18	D5W	4	D5W	C
	18	D5W	8	D5W	I
Meyer et al 19	28	D5W	5	D5W	C
	28	D5W	10	D5W	I
	28	D5W	15	D5W	I
Wade et al 1	33.75	D5W	4	D5W	C
	33.75	D5W	8	D5W	I
	45	D5W	4	D5W	C
	45	D5W	8	D5W	I
Trissel’s 1994 16	45	D5W	10	D5W	I
Trissel’s 1998 15	56.25	D5W	20	D5W	I
	57.375	D5W	2	D5W	C
Kufel et al 2017 2	67.5	D5W	5	D5W	I	Commercial Pre-mix Useda,b
Trissel’s 1998 15	67.5	D5W	20	D5W	I
Wade et al 1	90	D5W	4	D5W	I
	90	D5W	8	D5W	I
	112.5	D5W	4	D5W	I
	112.5	D5W	8	D5W	I
O’Donnell et al 18	67.5	NS	5	NS	C*	Frozen Zosyn a
	67.5	NS	6	NS	C*	Frozen Zosyn a
	67.5	NS	9	NS	C*	Frozen Zosyn a
	67.5	NS	5	NS	C*	Frozen Vancomycin c and Zosyn a
Nichols et al 20	112.5	SWFI	10	D5W	I	Pediatric Data
Trissel’s 1998 15	225	undiluted	2	D5W	C
Raverdy et al 21	225	undiluted	10	D5W	I
Trissel’s 1998 15	225	undiluted	20	D5W	I

C = Compatible; C* = No visual evidence of incompatibility; D5W = Dextrose 5% in Water; I = Incompatible; I* = Unstable precipitate formed; U = Uncertain/insufficient data; NT = Not tested; NS = 0.9% Sodium Chloride.

^aZosyn injection in Galaxy plastic container, Baxter Healthcare Corporation.

^bPiperacillin-tazobactam injection in Galaxy plastic container, Pfizer.

^cVancomycin infection in Galaxy plastic container, Baxter healthcare Corporation.

Results

The package insert of vancomycin states a general potential incompatibility with beta-lactam antibiotics, however, incompatibility with vancomycin is not stated in the piperacillin/tazobactam package insert. ⁶ Elsevier’s 2022 Intravenous Medications and Pediatric Injectable Drugs: The Teddy Bear Book did not have any information related to compatibility of these medications, while Trissel’s 2 Clinical Pharmaceutics Database, and King Guide to Parenteral Admixtures provided detailed summaries of compatibility literature.^6,10-12 A summary of all information regarding Y-site compatibility is listed in Table 1 and displays the data in groups based on diluent and concentration in ascending order from smallest to largest.

All studies included in this review assessed compatibility with at least 3 forms of inspection. Most commonly, the studies utilized visual inspection on a white and black background, magnified visualization with a microscope or magnifying glass, and a form of electronic particle measurement [Marvlen particle size analyzer, nephelometric evaluation, Spectronic 20, absorbance analyses, Turbidity, or HPLC] (Table 2).^1-2,8,17-21 Study drugs were considered compatible if no visible haze, color change, perception, fibers, or particulate matter was seen or incompatible if any haze, color change, perception, fibers, or particulate matter was seen over a minimum of 4 hours.^1-2,15-21 O’Donnell et al did consider combinations compatible if agitation of the combination dissolved the precipitate, however this review considered those combinations to be incompatible (Table 1). ¹⁸

Table 2.

Summary of Compatibility Testing Methods Used in Included Studies.

Study	Visual inspection with normal hospital lighting †	Visual inspection with high intensity lighting	Magnified visualization	Electronic particle measurement ‡	pH assessment
Meyers et al 19	X	X	X ψ, ¥		X
Kufel et al 2	X	X	X §	X	X
O’Donnell et al 18	X		X ¥	X
Wade et al 1	X	X	X ψ	X	X
Leung et al 17	X		X ¥	X
Nichols et al 20	X	X	X §	X	X
Raverdy et al 21	X			X
Waters 8	X		X £	X

^†Visual inspection against light and dark backgrounds

^‡Marvlen particle size analyzer, nephelometric evaluation, Spectronic 20, absorbance analyses, Turbidity, or HPLC

^ψ10× magnification

^¥20× magnification

^§magnifying glass

^£100× magnification

Based on the comprehensive review of the relevant available literature, when the compounding diluent is D5W, piperacillin-tazobactam less than 67.5 mg/mL and vancomycin 4 mg/mL are compatible; piperacillin-tazobactam less than 45 mg/mL and vancomycin 5 mg/mL are compatible; and piperacillin-tazobactam is incompatible with vancomycin greater than 8 mg/mL. When the compounding diluent is NS, piperacillin-tazobactam 18 to 112.5 mg/mL is compatible with vancomycin less than 8 mg/mL and piperacillin-tazobactam 18 to less than 80 mg/mL is compatible with vancomycin 8 mg/mL or less. Vancomycin greater than 10 mg/mL is incompatible with piperacillin-tazobactam.

Kufel et al and O’Donnell et al were the only studies included in this review that utilized at least 1 commercial pre-mix. Kufel et al found incompatibility between pre-mix piperacillin-tazobactam 67.5 mg/mL in D5W and pre-mix vancomycin 5 mg/mL in D5W. ³ , ¹⁸ Compatibility of commercial premix was only assessed via gross visual inspection by O’Donnell et al for frozen, premix Zosyn 67.5 mg/mL in NS and compounded vancomycin 5, 8, and 9 mg/mL in NS or frozen, premix vancomycin 5 mg/mL in NS. ¹⁸ This assessment of compatibility of premix VPT determined there was no visual evidence of incompatibility.

Discussion

Drug compatibility is influenced by the concentration of each drug, the diluent, pH of each drug, and completeness of mixing. ⁶ The completeness of mixing can have a significant impact on if a solution is considered compatible, however it is a limiting factor in healthcare. Inconsistencies in mixing results in compatibility differences due to concentration variation across a single solution when mixing is not through. Combinations that are compatible when well mixed may be incompatible if the concentrations vary across regions of the admixture because of partial mixing. ⁷ This compatibility factor is highlighted by the requirement of agitation and additional mixing for some combinations of VPT to eliminate precipitates in the O’Donnell study. ¹⁸ This is a limiting factor in the clinical setting because additional mixing and agitation are not possible when administering two solutions via Y-site. Therefore, a drug combination that is considered compatible requires compatibility without assistance. The compatibility summary of VPT provided by this review indicates another factor that results in limited compatibility; D5W as the compounding diluent. While the literature does indicate some combinations of VPT in D5W are compatible, the ranges of compatibility varies frequently and do not offer a clinically useful standard. Alternatively, the compatibility on VPT in NS is consistent across a large range of VPT concentrations, which offers a clinically useful standard range. Finally, there is limited evidence to support a recommendation related to compatibility of VPT at various concentrations when commercial pre-mix products are used, when compounded with diluents other than D5W or NS, or when drugs are reconstituted but not diluted.

The body of literature supports an overall recommendation that compounded piperacillin-tazobactam 33.75 to 45 mg/mL in NS and vancomycin 4 to 8 mg/mL in NS are compatible. Due to the limited data related to products that are commercially pre-mixed, or a diluent other than D5W and NS, they should be considered incompatible until further data becomes available. The diluent of choice when the intent is to simultaneously administer VPT is NS. In addition to the numerous factors that can impact the compatibility of medications, there are a multitude of factors that can make administering multiple medications simultaneous necessary; intravenous line access, medication administration timing, and patient outcomes.^22-25 These chemical and practical factors support the need for a complete summary of VPT compatibility literature, as well as an evidence-based recommendation for clinical practice.

While all eight of the published articles included in this study provide advancement in the body of literature of VPT compatibility, they do not offer a recommendation for clinical practice. Nunez-Nunez et al was the only review article assessed which made the overall conclusion that VPT are compatible. However, their review admittedly provided a “simplified” and “two-dimensional” recommendations that did not take into consideration variations in concentrations or diluents. ⁹ Currently, the Nunez-Nunes et al review is the only published literature that attempts to provide a clinical practice guideline related to the compatibility of VPT. However, their broad recommendation leaves gaps in relation to a multifaceted VPT compatibility recommendation. The current systematic review offers a complete assessment of the available literature related to VPT compatibility, as well as concise, evidence-based recommendations for clinical practice, thereby closing gaps in current available data surrounding the differing concentrations and diluents.

A limitation of our assessment was having one reviewer performed an in-depth assessment of the literature in this review, while the other reviewers read the literature to verify the assessment and recommendations at a baseline and our interpretation of literate that mentioned agitation required for compatibility. Future studies are needed to assess the compatibility of commercial pre-mix products; the extended shelf life of pre-mix products provide incentives to smaller health systems such as decreased staffing burden, potential cost savings, decreased storage burden (if not requiring refrigeration), and decreased drug waste.

Conclusion

Vancomycin and piperacillin-tazobactam (VPT) combination remains a staple broad-spectrum antibiotic regimen for empiric coverage despite undesirable side effect profiles and practical administration challenges. Aside from the risk of nephrotoxicity when used concomitantly, they have also been shown to have variable compatibility via Y-site, resulting in difficulties during co-administration if extended dosing is used for piperacillin-tazobactam. Several studies have been performed to assess the compatibility of VPT via Y-site; however, they lack standardization across studies to easily indicate a clinical practice recommendation. This systematic review provides a summary of available VPT compatibility data, as well as the first published evidence-based recommendation related to the topic. Overall, the literature supports the simultaneous administration via Y-site of piperacillin-tazobactam 33.75 mg/mL in NS and vancomycin 4 to 8 mg/mL in NS and these same drug products at concentrations, diluents, storage conditions, or preparations outside of this recommendation should be considered incompatible (Table 3).

Table 3.

Summary of Systematic Review Recommendations.

Summary of recommendations
Compounded piperacillin/tazobactam 33.75-45 mg/mL in NS and vancomycin 4-8 mg/mL in NS are compatible
Compatibility data for manufacturer piperacillin/tazobactam and vancomycin pre-mix products is limited and should not be administered simultaneously
Vancomycin and piperacillin/tazobactam when diluted with D5W have very limited compatible and should not be administered simultaneously