Abstract
ABSTRACT
Objective
The primary objective of this study was to evaluate the physical compatibility of ceftazidime-avibactam with selected intravenous antimicrobials during simulated Y-site administration.
Methods
Ceftazidime-avibactam (25 mg/mL) was mixed with select intravenous antimicrobials (tigecycline, metronidazole, meropenem, imipenem and cilastatin, fosfomycin, aztreonam and vancomycin) at an equal volume and evaluated using simulated Y-sites. Each admixture was evaluated immediately (0 hour) and after 1, 2, and 4 hours at room temperature (approximately 22°C) for visual characteristics, Tyndall beam, turbidity, pH, spectroscopic absorption of 550 nm and particle counts. If an admixture failed any one of these six assessments, it was considered incompatible.
Results
No evidence of incompatibility was observed between the combinations of ceftazidime-avibactam and the seven intravenous antimicrobials in simulated Y-site experiments.
Conclusion
Ceftazidime-avibactam was physically compatible with the selected intravenous antimicrobials (tigecycline, metronidazole, meropenem, imipenem and cilastatin, fosfomycin, aztreonam and vancomycin) in simulated Y-site administration.
Keywords: DRUG STABILITY; Drug Monitoring; Drug Stability; Administration, Intravenous; Drug Administration Routes; Drug Stability
WHAT IS ALREADY KNOWN ON THIS TOPIC
Independent catheters of critically ill patients are limited and managing co-administration of drugs is a challenge.
Physical compatibility of selected intravenous antimicrobials is tested within 4 hours using Y-site administration.
WHAT THIS STUDY ADDS
Ceftazidime-avibactam was compatible with tigecycline, metronidazole, meropenem, imipenem and cilastatin, fosfomycin, aztreonam and vancomycin.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study provides valuable compatibility data for ceftazidime-avibactam with certain intravenous antibacterials using simulated Y-sites, providing safe and rational references for clinical practice.
Introduction
Carbapenem-resistant Enterobacteriaceae (CRE) are a significant threat to public health, with high infection and mortality levels worldwide.1 2 Resistance to the antibiotic carbapenem is determined to a great extent by the expression of beta-lactamases during treatment.2 Ceftazidime-avibactam (CAZ-AVI) is a novel agent composed of a combination of a third-generation cephalosporin and a beta-lactamase inhibitor that was approved by the US Food and Drug Administration (FDA) in 2015.3 Compared with other treatments, CAZ-AVI exhibits powerful activity against beta-lactamase.4 Clinical studies have demonstrated that CAZ-AVI shows superior clinical success rates and a lower risk for adverse reactions compared with other therapeutic drugs.5 6 However, some studies have reported the emergence of resistance to CAZ-AVI.7 8
Because of the limited treatment options, the combination of antimicrobial agents is one efficient approach to overcome resistance and enhance efficacy. Recent findings have shown that the combinations of CAZ-AVI with tigecycline, metronidazole, meropenem, imipenem, fosfomycin, aztreonam or vancomycin may be effective in the treatment of CRE.9,13 These combinations may exhibit synergistic antibacterial effects by simultaneously inducing different antibacterial mechanisms. Moreover, studies reported that these combinations help in decreasing bacterial resistance to optimise the pharmacokinetics/pharmacodynamics and reducing the minimum inhibitory concentration of CAZ-AVI.10,12
CRE infection usually occurs in critically ill patients who often require simultaneous administration of medications with long infusion times or continuous administrations. In a hollow-fibre in vitro infection model (HFIM), Lodise et al., found that a 2 hour infusion or continuous infusion of CAZ-AVI with aztreonam was better than a 30 min infusion in killing bacterial.14 Extended or continuous infusion of these antibiotics optimises their therapeutic effects. However, catheters for intravenous therapy in critically ill patients are limited and managing co-administration is a challenge.15 Co-administration can be accomplished by passing multiple drugs through the Y-site access, which can reduce treatment time, decrease the risk of treatment delay and improve patient compliance.16 However, the extended or continuous infusion time of these antibiotics compels the need for compatibility data to determine which drugs can be co-administered via Y-site. This study evaluated the physical compatibility of CAZ-AVI with seven selected intravenous antibiotics during simulated Y-site administration. These findings will provide evidence for future clinical applications and may enable simplification of the administration of extended or continuous infusion.
Methods
Sample preparation
CAZ-AVI and the seven intravenous drugs were diluted in 0.9% Sodium chloride (NaCl/NS). Drugs were prepared in NS at the commonly used doses in our hospital (table 1). To simulate Y-site administration, the same volume (5 mL) of each drug was mixed (at a 1:1 volume ratio) in colourless, borosilicate glass culture tubes.17 Each admixture was evaluated immediately (0 hour) and after 1, 2 and 4 hours using six evaluations: visual characteristics, Tyndall beam, turbidity, pH, spectroscopic absorption of 550 nm and particle counts. If an admixture failed any of the six assays, the combination was considered incompatible. All tests were conducted at room temperature (approximately 22°C). CAZ-AVI alone served as a negative control. Positive control solutions included 2.5 mg/mL calcium chloride with 0.0025 mL/mL composite potassium in NS, 10 µm latex particle reference material and 25 µm particle count reference material. Each combination of drugs was prepared and tested in triplicate. Table 1 displays the details of the antibiotic agents and controls used in this study.
Table 1. Details of the drugs in the study.
| Drug | Manufacturer | Specification | Lot | Diluent | Concentration (mg/ml) |
|---|---|---|---|---|---|
| Tigecycline | Yangtze River Pharmaceutical | 50 mg | 23 051 021 | NS | 0.5, 1 |
| Metronidazole and sodium chloride injection | Anhui Shuanghe Pharmaceutical | 100 mL | 23 112 602M | NS | 5 |
| Meropenem | Shenzhen Huayao Nanfang Pharmaceutical | 0.5 g | 62 240 103 | NS | 5 |
| Imipenem and cilastatin | Zhuhai United Pharmaceutical | 0.5 g | 231 220 704 | NS | 5 |
| Fosfomycin sodium | Northeast Pharmaceutical Group Shenyang First Pharmaceutical | 2.0 g | 3 230 521 | NS | 40 |
| Aztreonam | Shenzhen Huayao Nanfang Pharmaceutical | 0.5 g | 21 230 607 | NS | 20 |
| Vancomycin | Zhejiang Medicine | 0.5 g | 117 230 603 | NS | 5 |
| Ceftazidime and avibactam | Pfizer Pharmaceutical | 2.5 g | 23K03017 | NS | 25 |
| Calcium chloride | Sichuan Meida Kangjiale Pharmaceutical | 0.5 g/10 mL | 23 060 226 | NS | – |
| Composite potassium hydrogen phosphate | Tianjin Jinyao Pharmaceutical | 2 mL | 2 310 201 | NS | – |
| NS | Fengyuan Pharmaceutical | 100 mL | 12240416R2 | – | – |
| 10 µm latex particles reference material | Haianhongmeng reference material technology | 100 mL | 20 221 003 | – | – |
| 25 µm particle count reference material | Haianhongmeng reference material technology | 100 mL | L693 | – | – |
NS: 0.9% NaCl.
NS, normal saline.
Visual and Tyndall beam assessments
The samples were visually inspected by the naked eye against a black and white background, as described in a previous study and the United States Pharmacopoeia (USP).18 19 The Tyndall beam was assessed by irradiating the solution with a red laser pen (650 nm, 5 mW laser pen for colourless or nearly colourless solutions, and 50 mW for coloured solutions) at a 90° angle. Any sample that appeared to have a haze, gas, colour changes or a light-path was considered incompatible.19 20
Turbidity measurement
European Pharmacopoeia (Ph. Eur.) recommends that turbidity be analysed using a turbidimeter.21 Incompatibility was defined as a turbidity variation exceeding 0.5 nephelometric turbidity unit (NTU).17
pH and A550 nm measurement
We measured pH changes using a pH metre (Qiwei Instrument Co., Ltd, Hangzhou, China). The haze reaction was determined by measuring A550 nm using an ultraviolet visible spectrophotometer according to the Ph. Eur.21 The sample was considered incompatible if the pH change exceeded 10% or the A550 nm change exceeded 0.0100 compared with 0 hour.20
Particle count measurement
Chapter 788 of the USP recommends that injectable solutions be analysed using a light obscuration particle count test by a particle counter.22 The sample was considered incompatible if particles more than 10 µm exceeded 25 particles/ml or particles over 25 µm exceeded 3 particles/ml.22 23
Statistical analysis
All measurements were performed in triplicate. We calculated the averages of turbidity, pH, A550nm and particle count measurements. The data were recorded as average±standard deviations (AVG±SD).
Results
Visual and Tyndall beam findings
All samples were clear, with no visible particulate formation, gas evolution, colour changes or light path at any of the tested time points. The positive control (calcium chloride with composite potassium hydrogen phosphate) was a white precipitate and displayed a Tyndall beam. The testing results are shown in table 2 (online supplemental material).
Table 2. Findings of visual inspection and Tyndall beam in solutions.
| Drug | Colour/Clarity (White background) | Tyndall beam (Black background) | ||||||
|---|---|---|---|---|---|---|---|---|
| 0 hour | 1 hour | 2 hour | 4 hour | 0 hour | 1 hour | 2 hour | 4 hour | |
| Tigecycline (1 mg/mL)A1 | Yellow/Clear | Yellow/Clear | Yellow/Clear | Yellow/Clear | N | N | N | N |
| Tigecycline (0.5 mg/mL)A2 | Yellow/Clear | Yellow/Clear | Yellow/Clear | Yellow/Clear | N | N | N | N |
| Metronidazole and sodium chloride injectionB | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| MeropenemC | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| Imipenem and cilastatinD | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| Fosfomycin sodiumE | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| AztreonamF | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| VancomycinG | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| CAZ-AVI H | Colourless/Clear | Colourless/Clear | Colourless/Clear | Colourless/Clear | N | N | N | N |
| Calcium chloride with composite potassium hydrogen phosphateI | White/Turbid | White/Precipitate | White/Precipitate | White/Precipitate | P | P | P | P |
| 10 µm latex particles reference materialJ | Colourless/Clear | P | ||||||
| 25 µm particle count reference materialK | Colourless/Clear | P | ||||||
A1-G: the combinations of CAZ-AVI with selected drugs separately; H: negative control, 25 mg/ml CAZ-AVI in NS; I: positive control, calcium chloride with composite potassium in NS; J: 57 positive control, 10 μm latex particles reference material; K: positive control, 25 μm particle count reference material; N: Tyndall negative; P: Tyndall positive.
Turbidity changes
Results from the turbidity measurement were summarised in table 3 (online supplemental material). Positive control (calcium chloride with composite potassium hydrogen phosphate) displayed a turbidity change with 75.840 NTU at 1 hour. None of the samples resulted in a mean turbidity of over 0.5 NTU within 4 hours.
Table 3. Results of turbidity changes in solutions.
| Drug | Turbidity/NTU AVG±SD (change) |
|||
|---|---|---|---|---|
| 0 hour | 1 hour | 2 hour | 4 hour | |
| Tigecycline(1 mg/mL)A1 | 0.103±0.003 | 0.113±0.004 (0.010) | 0.124±0.005 (0.021) | 0.116±0.002 (0.013) |
| Tigecycline(0.5 mg/mL)A2 | 0.082±0.008 | 0.097±0.015 (0.015) | 0.108±0.001 (0.026) | 0.104±0.004 (0.022) |
| Metronidazole and sodium chloride injectionB | 0.132±0.002 | 0.115±0.007 (−0.017) | 0.101±0.004 (−0.031) | 0.092±0.003 (−0.040) |
| MeropenemC | 0.104±0.008 | 0.09±0.003 (−0.014) | 0.096±0.003 (−0.008) | 0.092±0.003 (−0.012) |
| Imipenem and cilastatinD | 0.174±0.005 | 0.168±0.002 (−0.006) | 0.169±0.001 (−0.005) | 0.151±0.002 (−0.023) |
| Fosfomycin sodiumE | 0.199±0.006 | 0.185±0.006 (−0.014) | 0.162±0.006 (−0.037) | 0.152±0.003 (−0.047) |
| AztreonamF | 0.650±0.002 | 0.670±0.016 (0.020) | 0.676±0.003 (0.026) | 0.635±0.003 (−0.015) |
| VancomycinG | 0.186±0.002 | 0.181±0.003 (−0.005) | 0.201±0.004 (0.015) | 0.197±0.004 (0.011) |
| CAZ-AVI H | 0.074±0.009 | 0.079±0.003 (0.005) | 0.079±0.008 (0.005) | 0.078±0.007 (0.004) |
| Calcium chloride with composite potassium hydrogen phosphateI | 26.390±0.181 | 102.23±5.261 (75.840) | – | – |
A1-G: the combinations of CAZ-AVI with selected drugs separately; H: negative control, 25 mg/ml CAZ-AVI in NS; I: positive control, calcium chloride with composite potassium in NS; J: positive control, 10 μm latex particles reference material; K: positive control, 25 μm particle count reference material; N: Tyndall negative; P: Tyndall positive.
Changes in pH and A550 nm
The pH and spectroscopic measurement results are summarised in table 4 (online supplemental material). There was no evidence of incompatibility in any admixture.
Table 4. Results of pH and A550 nm changes of solutions.
| Drug | pH AVG±SD (change) |
A550 nm AVG±SD (change) |
||||||
|---|---|---|---|---|---|---|---|---|
| 0 hour | 1 hour | 2 hour | 4 hour | 0 hour | 1 hour | 2 hour | 4 hour | |
| Tigecycline(1 mg/mL)A1 | 6.62±0.02 | 6.63±0.01 (0.15%) |
6.67±0.04 (0.76%) |
6.67±0.03 (0.76%) |
0.0005±0.0002 | 0±0 (−0.0005) |
0±0 (−0.0005) |
0±0 (−0.0005) |
| Tigecycline(0.5 mg/mL)A2 | 6.67±0.03 | 6.64±0.02 (−0.45%) |
6.69±0.03 (0.30%) |
6.71±0.03 (0.60%) |
0.003±0.0003 | 0.0026±0.0001 (−0.0004) |
0.002±0 (−0.0010) |
0.005±0.0001 (0.0020) |
| Metronidazole and sodium chloride injectionB | 6.77±0.02 | 6.75±0.02 (−0.30%) |
6.82±0.01 (0.74%) |
6.74±0.01 (−0.44%) |
0.0023±0.0001 | 0.0022±0.0001 (−0.0001) |
0.0027±0 (0.0004) |
0.0043±0.0002 (0.0020) |
| MeropenemC | 7.77±0.01 | 7.76±0.01 (−0.13%) |
7.71±0.01 (−0.77%) |
7.69±0.01 (−1.03%) |
0.0066±0.0002 | 0.007±0.0006 (0.0004) |
0.004±0.0013 (−0.0026) |
0.0045±0.0007 (−0.0021) |
| Imipenem and cilastatinD | 7.11±0.03 | 7.13±0.02 (0.28%) |
7.15±0.03 (0.56%) |
7.15±0.03 (0.56%) |
0.0014±0.0001 | 0.0035±0.0001 (0.0021) |
0.0011±0.0003 (−0.0003) |
0.0017±0.0001 (0.0003) |
| Fosfomycin sodiumE | 7.51±0.01 | 7.53±0.01 (0.27%) |
7.54±0.01 (0.40%) |
7.51±0.01 (0) |
0.0003±0.0001 | 0.0065±0.0005 (0.0062) |
0.0038±0.0001 (0.0035) |
0.0019±0.0001 (0.0016) |
| AztreonamF | 6.49±0.01 | 6.49±0.02 (0) |
6.53±0.03 (0.62%) |
6.54±0.03 (0.77%) |
0.0082±0.0001 | 0.007±0.0002 (−0.0012) |
0.0055±0.0001 (−0.0027) |
0.0043±0.0001 (−0.0039) |
| VancomycinG | 6.96±0.01 | 6.93±0.02 (−0.43%) |
6.92±0.01 (−0.57%) |
6.88±0.02 (−1.15%) |
0.0047±0.0001 | 0.0047±0.0002 (0) |
0.0019±0.0001 (−0.0028) |
0.0042±0.0001 (−0.0005) |
| CAZ-AVI H | 6.84±0.02 | 6.91±0.02 (1.02%) |
6.99±0.04 (2.19%) |
6.9±0.02 (0.88%) |
0.003±0.0001 | 0.001±0 (−0.0020) |
0.0024±0.0001 (−0.0006) |
0.0008±0.0001 (−0.0022) |
A1-G: the combinations of CAZ-AVI with selected drugs separately; H: negative control, 25 mg/ml CAZ-AVI in NS.
Particle count findings
The particle count findings are shown in table 5 (online supplemental material). After 4 hours, the average particle count of all samples did not exceed 25 particles/ml at concentrations of 10 µm or three particles/ml at concentrations of 25 µm. The number of particles in the positive control exceeded the limits.
Table 5. Results of particle count changes of solutions.
| Drug | ≥10 µm Particles/mL AVG±SD |
≥25 µm Particles/mL AVG±SD |
||||||
|---|---|---|---|---|---|---|---|---|
| 0 hour | 1 hour | 2 hour | 4 hour | 0 hour | 1 hour | 2 hour | 4 hour | |
| Tigecycline(1 mg/mL)A1 | 15±1 | 7.7±1.2 | 7±1 | 3.3±0.6 | 0.7±0.6 | 0±0 | 1±0 | 0.3±0.6 |
| Tigecycline(0.5 mg/mL)A2 | 6.7±0.6 | 12±1 | 9±1 | 6±1 | 0±0 | 0.3±0.6 | 0.7±0.6 | 0.3±0.6 |
| Metronidazole and sodium chloride injectionB | 24.4±2 | 20.9±1.4 | 10.8±1.4 | 8.8±0.9 | 0.8±0.4 | 0.9±0.5 | 0.3±0.1 | 0.3±0.1 |
| MeropenemC | 10±1.1 | 18.8±1 | 16.9±1.2 | 13.5±0.7 | 0.4±0.5 | 0.6±0.3 | 0.5±0.3 | 0.1±0.1 |
| Imipenem and cilastatinD | 23.8±0.8 | 13.4±1 | 10.4±1.9 | 8.1±0.7 | 0.5±0.4 | 0.8±0.3 | 0.3±0.3 | 0±0 |
| Fosfomycin sodiumE | 17.1±1.9 | 9.3±0.3 | 12.6±1.9 | 8.8±0.9 | 0.2±0.1 | 0.1±0.1 | 0.7±0.3 | 0.1±0.1 |
| AztreonamF | 14.5±2 | 9.8±0.4 | 15.8±0.4 | 10.9±1.5 | 0.5±0.5 | 0.1±0.1 | 0.3±0.3 | 0.4±0.4 |
| VancomycinG | 24±0.8 | 19.3±0.4 | 20±2.8 | 13.2±1.1 | 0.3±0.3 | 0.3±0.1 | 0.3±0 | 0.7±0.1 |
| CAZ-AVI H | 10.7±1.5 | 6.7±0.6 | 6±1 | 3.3±0.6 | 0.3±0.6 | 0±0 | 0.3±0.6 | 0±0 |
| 10 µm latex particles reference materialJ | 865.6±8.8 | – | – | – | – | – | – | – |
| 25 µm particle count reference materialK | – | – | – | – | 1098.8±29.5 | – | – | – |
A1-G: the combinations of CAZ-AVI with selected drugs separately; H: negative control, 25 mg/ml CAZ-AVI in NS; J: positive control, 10 μm latex particles reference material; K: positive control, 25 μm particle count reference material.
Discussion
With CRE infections on the rise, drug resistance continues to increase. Thus, the use of a combination of CAZ-AVI with other effective antimicrobial agents in clinical practice has dramatically increased. This study evaluated for the first time the physical compatibility of CAZ-AVI with tigecycline, metronidazole, meropenem, imipenem, fosfomycin, aztreonam or vancomycin using a simulated Y-site. O’Donell et al, previously analysed combinations of CAZ-AVI at 8, 25, or 50 mg/mL with aztreonam at 10 or 20 mg/mL; no evidence of incompatibility was observed in simulated and actual Y-site experiments.24 Lodise et al, observed increased bactericidal activity with co-administration of CAZ-AVI and subsequent administration of aztreonam compared with administration of CAZ-AVI alone. Extended infusion resulted in greater bactericidal activity compared with simultaneous infusion for 30 min.14 Our results were consistent with these findings and furthered the evaluation of more antibiotics for additional recommendations for clinical practice.
Allen et al, reported that the mixing of intravenous fluid in the administration set with the secondary additive from the Y-site occurs approximately in a 1:1 ratio.25 Therefore, when two intravenous drugs are administered through a Y-site, they can be seen as being given approximately in a 1:1 ratio. The simulated Y-site model in our study is based on those used in previous compatibility studies. Investigating physical compatibility requires testing multiple indicators. In this study, we evaluated the physical compatibility of CAZ-AVI with seven intravenous antimicrobials by six assays: visual characteristics, Tyndall beam, turbidity, pH, spectroscopic absorption of 550 nm and particle counts. Visual and Tyndall beam assessment reflects the quality of the infusion.20 Each admixture passed visual and Tyndall inspection within 4 hours. Turbidity was measured to evaluate the clarity and the scattered light intensity caused by particles.20 In all samples, turbidity changes compared with results at the initial time were less than 0.5 NTU. Measuring pH can determine whether acid-base reactions are involved in some incompatibility results.20 In this study, pH values after 4 hours were similar to the values obtained immediately after admixture. Changes in A550 nm can reflect the haze reaction; the results of all solutions in the current study were less than 0.0100. The number of insoluble particles is also an important indicator for the quality of intravenous infusion; all samples in our study passed the particle count test. The dissolution process of CAZ-AVI powder involves gas production. To avoid measurement errors, an ultrasonic machine was used for proper defoaming before particle counting. In future studies addressing compatibility issues, appropriate assays are required to assess the potential efficacy and safety of drug mixtures.
This study has several limitations. First, Y-site administration was simulated by mixing two drugs in a glass bottle without the use of an intravenous tube. This is a common method for simulating Y-site administration, as mixing the drug in a glass vial simulates a suspended static state; however, it does not evaluate possible physico-chemical interactions between the intravenous tube and the drug. Second, we selected metronidazole and sodium chloride injection as a test drug. In order to avoid the influence of different diluents on the testing results, we chose normal saline (NS) as the sole diluent for this study. Other diluents (such as dextrose 5% in water (D5W)) should be evaluated in similar compatibility studies. Third, the definition of incompatibility was determined following previous studies but is somewhat arbitrary. To the best of our knowledge, there are no validated methods to assess NTU or pH changes. Finally, we only tested samples combined at a 1:1 volume ratio; different ratios with different infusion rates through a Y-site connector may lead to different compatibility results. Further work should focus on the abnormal situation of the Y-site administration in clinical practice.
Conclusion
CAZ-AVI at 25 mg/mL was physically compatible with tigecycline (0.5 and 1 mg/mL), metronidazole and sodium chloride injection (5 mg/mL), meropenem (5 mg/mL), imipenem and cilastatin (5 mg/mL), fosfomycin sodium (40 mg/mL), aztreonam (20 mg/mL) and vancomycin (5 mg/mL) in simulated Y-site administration at room temperature.
Supplementary material
Acknowledgements
We would like to express our gratitude to the experts from the Anhui Provincial Key Clinical Specialty Construction Project for their support and guidance.
Footnotes
Funding: This study was supported by funding from the Anhui Provincial Key Clinical Specialty Construction Project.
EAHP statement: EAHP Statement 3: Production and Compounding.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: Not applicable.
Correction notice: The funding statement has been updated since this article was first published.
Data availability statement
Data are available upon reasonable request.
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Supplementary Materials
Data Availability Statement
Data are available upon reasonable request.