Zosyn^® (piperacillin/tazobactam) reformulation: Expanded compatibility and coadministration with lactated Ringer’s solutions and selected aminoglycosides

Figures & data

Figure 1 Hydrolysis of piperacillin followed by formation of a piperacillin dimer with low solubility.

Table 1 Combination matrix for reformulated Tazocin^® plus gentamicin (reconstituted and diluted in D₂O) at clinically relevant bracketed ranges of concentrations

Tazocin sample	Concentration [Pip] and [Tazo]			Gentamicin
	mg/mL in the “bag”a	mg/mL in the Y-site sampleb	mg/mL in the “bag”a	mg/mL in the Y-site sampleb
Reformulated Tazocin High case	40.0 and 5.0	20.0 and 2.5	3.32 High case	1.66
Reformulated Tazocin High case	40.0 and 5.0	20.0 and 2.5	0.7 Low case	0.35
Reformulated Tazocin Low case	13.33 and 1.67	6.67 and 0.84	3.32 High case	1.66
Reformulated Tazocin Low case	13.33 and 1.67	6.67 and 0.84	0.7 Low case	0.35

a Notes: The concentrations listed represent the calculated theoretical high and low concentrations that a hospital pharmacist would prepare in separate intravenous infusion bags for reformulated Tazocin and gentamicin;

b When infused through a Y-site tube, each drug solution will be infused at the same rate. Thus, the resulting admixture solution infused intravenously to the patient will have a final concentration that is half of the concentrations listed above in each individual bag. Therefore, to simulate this practice, the final admixtures will be prepared at concentrations that are half what is listed in the table (eg, For “High Tazocin” – “High Gentamicin” Y-site infusion simulation the sample will be prepared at approximately 20 mg/ml of piperacillin, 2.5 mg/ml of tazobactam, and 1.66 mg/ml of gentamicin in D₂O.).

Table 2 Summary of drug potency results for admixtures of reformulated Zosyn^® in various diluents and stored at room temperature for up to 24 hours

Diluent	Time Point (Hours)	Theoretical values (mg/mL)		Observed values (mg/mL)
		[PIP]	[TAZO]	[PIP]	% Initial PIP	[TAZO]	% Initial TAZO	pH
Saline	0	80.0	10.0	79.91	100.0	10.05	100.0	6.21
Saline	24	80.0	10.0	79.14	99.0	9.90	98.5	6.04
WFI	0	80.0	10.0	77.28	100.0	9.72	100.0	6.48
WFI	24	80.0	10.0	79.26	102.6	9.94	102.2	6.24
D5W	0	80.0	10.0	79.17	100.0	9.95	100.0	6.43
D5W	24	80.0	10.0	77.96	98.5	9.75	98.0	6.23
Compound sodium lactate intravenous infusion BP (Hartmann’s solution)	0	16.0	2.0	15.32	100.0	1.93	100.0	6.10
Compound sodium lactate intravenous infusion BP (Hartmann’s solution)	24	16.0	2.0	14.68	95.8	1.84	95.3	5.92
Saline	0	13.33	1.67	13.79	100.0	1.71	100.0	6.30
Saline	24	13.33	1.67	13.92	100.9	1.72	100.6	6.03
WFI	0	40.0	5.0	38.16	100.0	4.75	100.0	6.53
WFI	24	40.0	5.0	38.83	101.8	4.80	101.1	6.33
D5W	0	13.33	1.67	13.16	100.0	1.63	100.0	6.59
D5W	24	13.33	1.67	13.69	104.0	1.69	103.7	6.31
Compound sodium lactate intravenous infusion BP (Hartmann’s solution)	0	8.0	1.0	8.32	100.0	1.03	100.0	6.09
Compound sodium lactate intravenous infusion BP (Hartmann’s solution)	24	8.0	1.0	8.25	99.2	1.02	99.0	5.90

Abbreviations: PIP, Piperacillin; Saline, 0.9% NaCl solution; TAZO, Tazobactam; WFI, water for injection; D5W, 5% dextrose solution.

Table 3 Summary of drug potency results for simulated Y-site coadministration of reformulated Zosyn^® with amikacin in compound sodium lactate intravenous infusion BP (Hartmann’s solution) at room temperature

Time point (Hours)	Theoretical values (mg/mL)			Observed potency (mg/mL) and % Remaining of three Antibiotics
	[Pip]	[Tazo]	[Amik]	[Pip]	% Initial Pip	[Tazo]	% Initial Tazo	[Amik]	% Initial Amik	pH
0	8.0	1.0	3.75	8.03	100.0	1.00	100.0	3.75	100.0	5.39
1	8.0	1.0	3.75	8.02	99.9	1.00	100.0	3.75	100.0	5.36
2	8.0	1.0	3.75	8.04	100.1	1.00	100.0	3.74	100.0	5.36
4	8.0	1.0	3.75	8.02	99.9	1.00	100.0	3.77	100.5	5.35
0	8.0	1.0	0.875	8.18	100.0	1.02	100.0	0.88	100.0	5.65
1	8.0	1.0	0.875	8.06	98.5	1.00	98.0	0.88	100.0	5.64
2	8.0	1.0	0.875	8.13	99.4	1.01	99.0	0.89	101.1	5.66
4	8.0	1.0	0.875	8.18	100.0	1.02	100.0	0.89	101.1	5.65
0	4.0	0.5	3.75	4.19	100.0	0.52	100.0	3.76	100.0	5.31
1	4.0	0.5	3.75	4.19	100.0	0.52	100.0	3.76	100.0	5.30
2	4.0	0.5	3.75	4.22	100.7	0.52	100.0	3.77	100.2	5.30
4	4.0	0.5	3.75	4.15	99.0	0.51	98.1	3.75	99.7	5.29
0	4.0	0.5	0.875	4.35	100.0	0.53	100.0	0.88	100.0	5.60
1	4.0	0.5	0.875	4.35	100.0	0.54	101.9	0.88	100.0	5.59
2	4.0	0.5	0.875	4.36	100.2	0.54	101.9	0.89	101.1	5.60
4	4.0	0.5	0.875	4.28	98.4	0.53	100.0	0.89	101.1	5.59

Note: The same intravenous diluent was used to reconstitute the lyophilized drug and to prepare the intravenous infusion at the proper concentration for administration to the patient. In this case it was compound sodium lactate intravenous infusion BP (Hartmann’s solution).

Abbreviations: Amik, amikacin; Pip, piperacillin; Tazo, Tazobactam.

Table 4 Degradation products of reformulated Zosyn^® drug components in the presence of amikacin up to 4 hours at room temperature in compound sodium lactate intravenous infusion BP (Hartmann’s solution)

Time point (Hours)	Theoretical potency (mg/mL)		% of degradation productsa of Zosyn^® drug components
			RRT 0.104	RRT 0.516	RRT 0.564	RRT 0.591	RRT 0.635
	[Pip]/[Tazo]	[Amik]
0	8.0/1.0	3.75	0.056	0.59	–	0.078	–
1	8.0/1.0	3.75	0.067	0.72	–	0.078	–
2	8.0/1.0	3.75	0.067	0.89	–	0.078	–
4	8.0/1.0	3.75	0.078	1.13	–	0.067	–
0	8.0/1.0	0.875	0.067	0.56	–	0.078	–
1	8.0/1.0	0.875	0.067	0.58	–	0.078	–
2	8.0/1.0	0.875	0.067	0.62	–	0.078	–
4	8.0/1.0	0.875	0.067	0.70	–	0.078	–
0	4.0/0.5	3.75	0.067	0.56	0.10	0.089	0.20
1	4.0/0.5	3.75	0.067	0.76	–	0.089	0.17
2	4.0/0.5	3.75	0.067	0.89	–	0.089	0.24
4	4.0/0.5	3.75	0.089	1.18	–	0.067	0.10
0	4.0/0.5	0.875	0.067	0.56	–	0.089	0.10
1	4.0/0.5	0.875	0.067	0.60	–	0.089	0.10
2	4.0/0.5	0.875	0.067	0.62	–	0.089	0.11
4	4.0/0.5	0.875	0.067	0.69	–	0.089	0.08

Abbreviations: RRT, Relative retention times of the HPLC chromatograms corresponding to the known degradation products of Zosyn^® and amikacin in simulated y-site mixtures.

Notes: ^aThe observed % value of the degradation products are far below the approved specifications for the products.

Table 5 Simulated Y-site coadministration of reformulated Zosyn^® with amikacin in different admixture diluents (Potency of antibiotics at 4 hours)

Admixture diluent	Initial composition		% Antibiotic remaining of the initial
	Zosyn^® (PIP mg/mL/ Tazo mg/mL)	Amikacin (mg/mL)	% Amikacin	% Tazobactam	% Piperacillin
0.9% NaCl	80/10	7.5	95.7	98.6	98.7
0.9% NaCl	80/10	1.75	105.7	99.0	99.3
0.9% NaCl	13/1.7	7.5	99.8	98.5	98.8
0.9% NaCl	13/1.7	1.75	111.0	99.5	99.4
5% Dextrose	80/10	7.5	94.0	104.9	105.3
5% Dextrose	80/10	1.75	90.0	99.7	99.9
5% Dextrose	13/1.7	7.5	97.6	99.4	99.4
5% Dextrose	13/1.7	1.75	94.4	98.9	99.1
WFI/ 0.9% NaCl	80/10	7.5	99.2	98.6	98.9
WFI/ 0.9% NaCl	80/10	1.75	97.5	101.1	99.3
WFI/ 0.9% NaCl	13/1.7	7.5	100.3	96.2	97.8
WFI/ 0.9% NaCl	13/1.7	1.75	100.3	98.3	98.5
Lactated Ringers	16/2	7.5	93.3	99.0	98.3
Lactated Ringers	16/2	1.75	92.6	99.8	99.4
Lactated Ringers	8/1	7.5	99.7	98.6	99.0
Lactated Ringers	8/1	1.75	97.3	99.6	99.6

Abbreviations: WFI, water for injection; PIP, piperacillin; Tazo, Tazobactam.

Table 6 Reformulated Tazocin^® : Simulated Y-site compatibility by NMR for Ratiopharm^® German gentamicin drug product

Product Name	Gentamicin - Ratiopharm^® 40 SF (40 mg/1 ml ampoule gentamicin, Ratiopharm^® Company, Germany)
Components	Gentamicin sulfate Acetylcysteine Na2EDTA NAOH or H2SO4 for pH adjustment WFI
Combination matrix in simulated y-site	High Tazo: High Genta (20 mg/mL Pip: 1.6 mg/mL Genta)a		High Tazo: Low Genta (20 mg/mL Pip: 0.35 mg/mL Genta)a		Low Tazo: High Genta (6.67 mg/mL Pip: 1.6 mg/mL Genta)b		Low Tazo: Low Genta (6.67 mg/mL Pip: 0.35 mg/mL Genta)b
Prepared in D2O solution
Sample number	L39609-28-1		L39609-28-2		L39609-28-3		L39609-28-4
Time (min)	Relative peak area δH:2.85 (-NCH3)c	% Initiald	Relative peak area δH:2.85 (-NCH3)c	% Initiald	Relative peak area δH:2.85 (-NCH3)c	% Initiald	Relative peak area δH:2.85 (-NCH3)c	% Initiald
0	1.7558	100	0.3942	100	1.8981	100	0.4194	100
10	1.7533	99.9	0.3881	98.5	1.8948	99.8	0.4170	99.4
20	1.7518	99.8	0.3846	97.6	1.8953	99.9	0.4183	99.7
30	1.7512	99.7	0.3847	97.6	1.8971	99.9	0.4131	98.5
40	1.7450	99.3	0.3792	96.2	1.8977	100.0	0.4135	98.6
50	1.7496	99.6	0.3784	96.0	1.8897	99.6	0.4116	98.1
60	1.7453	99.4	0.3806	96.5	1.8929	99.7	0.4102	97.8

a Notes: also contains 2.5 mg/ml of tazobactam;

b also contains 0.84 mg/ml of tazobactam;

c observed peak area for δ_H: 2.85 (-NCH₃) of gentamicin is relative to internal standard of hydroquinone methyl ether;

d % of initial concentration of gentamicin remaining. Abbreviations: Tazo: Tazocin^® ; Pip, piperacillin.

Abbreviations: Tazo: Tazocin^®; Pip, piperacillin.

Table 7 Summary of subvisible particulate counts by HIAC for simulated Y-site coadministration of reformulated Zosyn^® and amikacin

Sample description	Reconstitution solvent	Solution concentration	Aminoglycoside concentration	Admixture diluent	Particulate counts by HIAC
					10 μm t = 0 hrs	10 μm t = 4 hrs	25 μm t = 0 hrs	25 μm t = 4 hrs
Particulate Count Specifications as per USP <788>a					NMT 6000	NMT 6000	NMT 600	NMT 600
Low Zosyn	WFI	40 mg/mL piperacillin plus 5 mg/mL tazobactam	Amikacin (7.5 mg/ml)	Saline	2595	1585	45	45
					2920	1320	60	40
					1875	3640	25	30
Low Zosyn	WFI	40 mg/mL piperacillin plus 5 mg/mL tazobactam	Amikacin (1.75 mg/ml)	Saline	4505	1265	70	0
					4265	1465	35	20
					4555	1450	80	25
High Zosyn	WFI	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Amikacin (7.5 mg/ml)	Saline	4430	750	100	15
					4270	2290	50	10
					2235	3320	45	40
High Zosyn	WFI	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Amikacin (1.75 mg/ml)	Saline	3780	1160	50	35
					4840	455	105	0
					3965	1255	25	35
Low Zosyn	Saline	13.33 mg/mL piperacillin plus 1.67 mg/mL tazobactam	Amikacin (7.5 mg/ml)	Saline	845	1730	15	35
					1210	815	15	65
					1600	1250	20	45
Low Zosyn	Saline	13.33 mg/mL piperacillin plus 1.67 mg/mL tazobactam	Amikacin (1.75 mg/ml)	Saline	555	2150	0	120
					1670	1890	15	75
					1940	1485	10	115
High Zosyn	Saline	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Amikacin (7.5 mg/ml)	Saline	1015	5690	15	125
					3145	1295	0	30
					2320	5360	50	160
High Zosyn	Saline	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Amikacin (1.75 mg/ml)	Saline	3960	1665	25	40
					1765	3225	20	75
					2150	1635	15	100
Low Zosyn	Lactated Ringer’s	8 mg/mL piper-acillin plus 1 mg/ mL tazobactam	Amikacin (7.5 mg/ml)	Lactated Ringer’s	1180	185	5	0
					915	285	0	0
					640	580	5	0
Low Zosyn	Lactated Ringer’s	8 mg/mL piper-acillin plus 1 mg/ mL tazobactam	Amikacin (1.75 mg/ml)	Lactated Ringer’s	505	285	15	0
					490	365	5	5
					815	170	0	10
High Zosyn	Lactated Ringer’s	16 mg/mL piperacillin plus 2 mg/mL tazobactam	Amikacin (7.5 mg/ml)	Lactated Ringer’s	645	415	0	20
					635	380	15	0
					1245	275	20	0
High Zosyn	Lactated Ringer’s	16 mg/mL piperacillin plus 2 mg/mL tazobactam	Amikacin (1.75 mg/ml)	Lactated Ringer’s	600	275	15	5
					495	505	10	10
					385	415	5	10

Abbreviations: NMT, not more than; WFI, water for injection; Saline, 0.9% sodium chloride.

a Notes: Particulate count specifications in EU and other Pharmacopeia are similar.

Table 8 Summary of subvisible particulate counts by HIAC for simulated Y-site coadministration of reformulated Zosyn^® and gentamicin

Sample description	Reconstitution solvent	Solution concentration	Aminoglycoside concentration	Admixture diluent	Particulate counts by HIAC
					10 μm t = 0 hrs	10 μm t = 4 hrs	25 μm t = 0 hrs	25 μm t = 4 hrs
Particulate Count Specifications as per USP <788>					NMT 6000	NMT 6000	NMT 600	NMT 600
Low Zosyn	WFI	40 mg/mL piperacillin plus 5 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	Saline	545	1750	20	5
					435	715	5	10
					570	1555	15	5
Low Zosyn	WFI	40 mg/mL piperacillin plus 5 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	Saline	550	1435	5	50
					1745	390	5	5
					730	395	10	15
High Zosyn	WFI	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	Saline	1470	110	35	0
					1980	170	10	25
					540	1110	0	60
High Zosyn	WFI	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	Saline	1170	600	30	50
					2770	310	20	5
					1465	210	20	20
Low Zosyn	Saline	13.33 mg/mL piperacillin plus 1.67 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	Saline	765	1465	5	70
					4220	1130	145	30
					2700	1485	35	50
Low Zosyn	Saline	13.33 mg/mL piperacillin plus 1.67 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	Saline	935	4425	25	70
					1500	2465	50	30
					1375	760	25	50
High Zosyn	Saline	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	Saline	3385	4120	140	140
					2275	2560	35	110
					2265	2660	60	120
High Zosyn	Saline	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	Saline	2035	1175	45	45
					5235	1865	215	105
					2790	1800	80	60
Low Zosyn	5% Dextrose	13.33 mg/mL piperacillin plus 1.67 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	5% Dextrose	860	540	25	165
					1175	435	25	75
					695	445	20	95
Low Zosyn	5% Dextrose	13.33 mg/mL piperacillin plus 1.67 mg/mL tazobactam	Gentamicin(0.7 mg/ml)	5% Dextrose	515	190	20	15
					310	165	5	20
					505	305	10	15
High Zosyn	5% Dextrose	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	5% Dextrose	2545	675	65	20
					1905	845	55	20
					1030	985	40	20
High Zosyn	5% Dextrose	80 mg/mL piperacillin plus 10 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	5% Dextrose	1860	690	25	20
					2825	680	15	5
					2240	630	10	25
Low Zosyn	Lactated Ringer’s	8 mg/mL piperacillin plus 1 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	Lactated Ringer’s	1120	170	0	5
					930	85	15	0
					135	165	5	0
Low Zosyn	Lactated Ringer’s	8 mg/mL piperacillin plus 1 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	Lactated Ringer’s	1215	180	10	5
					250	325	5	10
					465	190	15	0
High Zosyn	Lactated Ringer’s	16 mg/mL piperacillin plus 2 mg/mL tazobactam	Gentamicin (3.32 mg/ml)	Lactated Ringer’s	325	270	5	0
					870	155	10	5
					1235	250	0	0
High Zosyn	Lactated Ringer’s	16 mg/mL piperacillin plus 2 mg/mL tazobactam	Gentamicin (0.7 mg/ml)	Lactated Ringer’s	375	330	15	0
					410	205	5	0
					630	270	5	5

Abbreviation: NMT, not more than.