Can piperacillin and tazobactam (Zosyn) be infused with Lactated Ringers?

Comment by InpharmD Researcher

The manufacturer of Zosyn states Lactated Ringer's Solution is compatible only with reformulated Zosyn containing EDTA and is compatible with co-administration via a Y-site. Trissel's IV compatibility database notes the older formulation without the added components (most generic products) is incompatible with Lactated Ringer's. Thus, the newer formulation is the only form of the drug mixed with this diluent. A study that tested the physical compatibility of Lactated Ringer's found compatibility with ceftriaxone, amphotericin B, and piperacillin-tazobactam after 4 hours at room temperature, but Sandoz, the manufacturer of the piperacillin-tazobactam used in the study, states that the product is incompatible with Lactated Ringer's Solution in its package insert.

Background

Wyeth, the manufacturer of Zosyn, states Lactated Ringer's Solution is compatible only with reformulated Zosyn containing EDTA and is compatible with co-administration via a Y-site. Many generic formulations (e.g., Apotex) do not contain EDTA. [1, 2]

Trissel's IV compatibility database notes the older formulation without the added components (most generic products) is incompatible with Lactated Ringer's. Ensure that the newer formulation is the only form of the drug mixed with Lactated Ringer's. [3]

A 2019 study that tested the physical compatibility of Lactated Ringer's with 94 medications found incompatibilities with ciprofloxacin, cyclosporine, diazepam, ketamine, lorazepam, nitroglycerin, phenytoin, and propofol after 4 hours at room temperature. This study surprisingly found compatibility with ceftriaxone, amphotericin B, and piperacillin-tazobactam, which all previously were thought to be incompatible with LR (See Tables 1 and 2). [4] The study utilized a formulation of piperacillin-tazobactam manufactured by Sandoz. However, Sandoz's piperacillin-tazobactam package insert specifically states the product is incompatible with Lactated Ringer's Solution. [5]

Relevant Prescribing Information

Zosyn [1]
Compatibile Solutions
Lactated Ringer's Solution (compatible only with reformulated ZOSYN containing EDTA and is compatible for co-administration via a Y-site)

Apotex Generic PIPERACILLIN AND TAZOBACTAM injection, powder, for solution [2]
LACTATED RINGER'S SOLUTION IS NOT COMPATIBLE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION, USP

Sandoz Generic PIPERACILLIN AND TAZOBACTAM injection, powder, for solution [5]
LACTATED RINGER'S SOLUTION IS NOT COMPATIBLE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION, USP

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Can Zosyn be infused with Lactated Ringers?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

Compatibility of Lactated Ringer's Injection with 94 Selected Intravenous Drugs During Simulated Y-Site Administration
Design	Drug excipient compatibility study N = 94
Objective	To test the compatibility of intravenous (IV) lactated Ringer’s injection (LR) with 94 injectable drugs during simulated Y-site administration
Study Groups	Injectable medications (n= 94)
Methods	Injectable drugs were evaluated for compatibility with Lactated Ringers (LR; Baxter). Each sample was prepared as a 1:1 admixture in glass tubes at room temperature. Two observers independently performed visual evaluation immediately upon mixing and then 15 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after admixture. Visual compatibility was defined as the absence of any color change or visible particle matter, gas bubble, substantial haze, or precipitate by a naked eye. Another observer performed a particle counting test on 1 of the 2 duplicates of each admixture that did not immediately show incompatibility and then after 4 hours by a light obscuration particle count test.
Duration	Monitoring: up to 4 hours after admixture
Outcome Measures	Degree of compatibility
Results		Injectable medications (n= 94)
	Compatible	86 (91.5%)
	Incompatible Precipitate Formation: No Precipitate Formation:	8 (8.5%) 7 1
	A full list of the medications can be seen in Table 2.
Study Author Conclusions	Lactated Ringer’s injection was physically compatible for 4 hours with 86 tested drugs during simulated Y-site administration. Eight drugs, ciprofloxacin, cyclosporine, diazepam, ketamine, lorazepam, nitroglycerin, phenytoin, and propofol, were found to be incompatible and should not be administered with LR.
InpharmD Researcher Critique	Due to the modern particle counting test utilized in this study, compatibility with LR was surprisingly found with ceftriaxone, amphotericin B, and piperacillin-tazobactam as well; all previously thought to be incompatible with LR. Reasons for these compatibilities seen may be due to differences in contact time, compounding methods, concentrations, diluents, manufacturers, and excipients. Therefore, this study reinforces the importance of conducting compatibility testing as testing methods periodically advance. Similarly, cyclosporine and nitroglycerin are typically listed as compatible with LR, whereas this study found the admixtures to be incompatible. These findings may be due to the dilution factors and concentrations used or the light obscuration particle count test techniques used by these and previous authors. Additionally, this study only measured physical compatibility at room temperature for up to 4 hours. Chromatography was not performed to assess medication stability during this time.

References:

Vallée M, Barthélémy I, Friciu M, et al. Compatibility of lactated ringer’s injection with 94 selected intravenous drugs during simulated y-site administration. Hosp Pharm. Published online November 18, 2019:001857871988891.

Medication	Compatibility with Lactated Ringers (LR)	Concentration (mg/mL or as specified)
1. Acetazolamide Sodium	Compatible	100
2. Acetylcysteine	Compatible	200
3. Acyclovir sodium	Compatible	50
4. Albumin, human (Alburex-25)	Compatible	250
5. Amikacin sulfate	Compatible	250
6. Aminophylline	Compatible	25
7. Amiodarone hydrochloride	Uncertain	50
8. Amphotericin B liposomal	Compatible	4
9. Amphotericin B deoxycholate	Compatible	5
10. Ampicillin sodium	Compatible	100
11. Atropine sulfate	Compatible	0.4
12. Azithromycin	Compatible	500
13. Bretylium tosylate	Compatible	50
14. Bupivacaine hydrochloride	Compatible	0.005
15. Caffeine citrate	Compatible	10
16. Calcium gluconate	Compatible	100
17. Calcium chloride	Compatible	100
18. Caspofungin acetate	Uncertain	5
19. Cefazolin sodium	Compatible	100
20. Cefotaxime	Compatible	100
21. Cefoxitin	Compatible	100
22. Ceftazidime	Compatible	100
23. Ceftriaxone sodium	Compatible	100
24. Cefuroxime	Compatible	100
25. Chlorpromazine hydrochloride	Compatible	25
26. Ciprofloxacin	Incompatible	2
27. Clindamycin phosphate	Uncertain	150
28. Cloxacillin sodium	Compatible	100
29. Cyclosporine	Precipitate	50
30. Dexamethasone sodium phosphate	Compatible	4
31. Dexmedetomidine hydrochloride	Compatible	0.1
32. Dextrose 50%	Compatible	500
33. Diazepam	Immediate precipitate	5
34. Digoxin	Compatible	0.25
35. Dimenhydrinate	Compatible	10
36. Diphenhydramine hydrochloride	Compatible	50
37. Dobutamine hydrochloride	Compatible	12.5
38. Dopamine hydrochloride	Compatible	3.2
39. Enalaprilat	Compatible	1.25
40. Epinephrine hydrochloride	Compatible	1
41. Erythromycin lactobionate	Compatible	50
42. Esmolol hydrochloride	Compatible	10
43. Fentanyl citrate	Compatible	0.05
44. Fluconazole	Compatible	2
45. Furosemide	Compatible	10
46. Gentamicin sulfate	Compatible	10
47. Granisetron hydrochloride	Compatible	1
48. Haloperidol lactate	Compatible	5
49. Heparin sodium	Compatible	1000 IU/mL
50. Hydralazine hydrochloride	Compatible	20
51. Hydrocortisone sodium succinate	Compatible	50
52. Hydromorphone hydrochloride	Compatible	10
53. Hydroxyzine hydrochloride	Compatible	50
54. Insulin regular (Humulin R)	Uncertain	100 IU/mL
55. Isoproterenol hydrochloride	Compatible	0.2
56. Ketamine hydrochloride	Incompatible	50
57. Labetalol hydrochloride	Compatible	5
58. Lidocaine hydrochloride	Compatible	1%
59. Linezolid	Compatible	2
60. Lorazepam	Incompatible	4
61. Magnesium sulfate	Compatible	500
62. Mannitol	Compatible	250
63. Meropenem	Compatible	50
64. Methylprednisolone sodium succinate	Uncertain	62.5
65. Metoclopramide hydrochloride	Compatible	5
66. Metronidazole	Compatible	5
67. Midazolam hydrochloride	Compatible	5
68. Milrinone lactate	Compatible	1
69. Morphine sulfate	Compatible	50
70. Multivitamins (Multi-12/K1 pediatric)	Uncertain	n/a
71. Multivitamins Adult (Multi-12)	Uncertain	n/a
72. Naloxone hydrochloride	Compatible	0.4
73. Nicardipine hydrochloride	Compatible	0.2
74. Nitroglycerin	Uncertain	5
75. Norepinephrine bitartrate	Compatible	1
76. Octreotide acetate	Compatible	0.5
77. Oxytocin	Compatible	10 IU/mL
78. Penicillin G sodium	Compatible	500,000 IU/mL
79. Phenytoin sodium	Incompatible	50
80. Piperacillin sodium	Compatible	200
81. Piperacillin sodium /Tazobactam	Compatible	200
82. Potassium chloride	Compatible	2 mEq/mL
83. Potassium phosphate	Compatible	3 mmol/mL
84. Propofol	Precipitate	10
85. Ranitidine hydrochloride	Compatible	25
86. Rocuronium bromide	Compatible	10
87. Salbutamol	Compatible	1
88. Sodium bicarbonate	Compatible	1 mEq/mL
89. Sodium nitroprusside	Compatible	25
90. Tobramycin sulfate	Compatible	40
91. Trimethoprim / Sulfamethoxazole	Compatible	16/80
92. Vancomycin hydrochloride	Compatible	50
93. Verapamil hydrochloride	Uncertain	2.5
94. Voriconazole	Compatible	10

References: