Abstract
Purpose:
The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration.
Methods:
Ceftazidime—avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate.
Findings:
Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime—avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments.
Implications:
Ceftazidime—avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.
Keywords: avibactam, aztreonam, ceftazidime, compatibility
INTRODUCTION
Antibiotic resistance is a significant threat to public health, accounting for over 2.8 million infections and 35,000 deaths each year in the United States.1,2 A particularly problematic emerging resistance is that mediated by metallo-β-lactamases (MBLs).3,4 These enzymes, such as New Delhi metallo-β-lactamase (NDM), are now appearing in the United States and confer resistance to all currently available β-lactam antibiotics.4,5 In addition, organisms harboring MBLs frequently express other resistance mechanisms, leading to few antibiotics with reliable activity.4 Polymyxins most commonly retain activity against these organisms; however, these agents are known to be highly nephrotoxic and may exhibit suboptimal pharmacokinetic properties in critically ill patients.6,7 Unfortunately, it is unlikely that new agents with reliable in vitro activity against MBL-producing organisms will be available until at least 2021.8,9 Given the lack of safe, reliable, and effective agents for use in the treatment of these infections, it is paramount that we utilize existing antibiotics in innovative ways to optimize patient care.
A strategy that may be effective in the treatment of infections caused by these highly resistant organisms is the combination of ceftazidime—avibactam + aztreonam. Aztreonam is not hydrolyzed by NDM or other MBLs and may retain activity against organisms in which this is the only mechanism of resistance.10 These organisms, however, often co-produce other β-lactamases that do hydrolyze aztreonam, such as extended-spectrum β-lactamases, cephalosporinases (eg, AmpCs), or other carbapenemases (eg, Klebsiella pneumonia carbapenemases).10 Avibactam does not effectively inhibit MBLs; however, it does inhibit other enzymes that hydrolyze aztreonam, such as extended-spectrum β-lactamases, AmpCs, and Klebsiella pneumoniae carbapenemases. This combination has shown synergy in vitro and has shown efficacy in clinical case reports.8,10-13
A recent preclinical study sought to outline the pharmacokinetic and pharmacodynamic drivers of this combination.14 That in vitro study determined that the combination exhibited the greatest bactericidal activity against the tested NDM-producing organisms when both agents were administered simultaneously. Given that the dosing regimens optimal for treating infection with NDM-producing organisms identified in that study required simultaneous administration of these antibiotics, we sought to determine the compatibility of intravenous solutions of ceftazidime—avibactam and aztreonam using simulated and actual Y-site administration.
MATERIALS AND METHODS
Drug Preparation
Commercially available vials of ceftazidime—avibactam* (ceftazidime 2 g + avibactam 0.5 g) and aztreonam† (2-g vials) were used in all experiments. For ease of documentation, the concentrations of ceftazidime—avibactam are expressed as the total weight of both drugs (eg, ceftazidime—avibactam 2.5 g in 50 mL of sodium chloride 0.9% is expressed as 50 mg/mL, instead of ceftazidime 40 mg/mL and avibactam 10 mg/mL). Both products were reconstituted with sodium chloride 0.9% solution available in 100-mL IV bags (lot P379735; Baxter, Deerfield, Illinois), in concordance with the manufacturer's instructions.15,16 Aztreonam was diluted to concentrations of 10 and 20 mg/mL using sodium chloride 0.9% solution, based on commonly utilized doses (eg, 1 or 2 g). Ceftazidime—avibactam was diluted to concentrations of 8, 25, and 50 mg/mL, to encompass a range of clinically relevant dilutions.15,17 For actual Y-site administration experiments, sodium chloride 0.9% solution 100-mL and 250-mL (lot Y311878; Baxter) IV bags were used. Phenytoin ‡ was diluted using sodium chloride 0.9% to a concentration of 25 mg/mL and mixed with aztreonam 20 mg/mL for use as a positive control.
Simulated and Actual Y-Site Mixing
Simulated Y-site mixing was conducted my mixing 5-mL aliquots of each combination in separate clear glass tubes. Each experiment was repeated with alternating order of drug addition to the tube. Samples were stored under fluorescent lighting at room temperature for 12 h, the stability limit for ceftazidime—avibactam in sodium chloride 0.9%.15 Samples were assed for compatibility using 5 methods (visual, Tyndall beam, microscopy, turbidity, and pH) at 0 (immediately after mixing), 1, 2, 4, 8, and 12 h. All experiments were completed in triplicate.
Actual Y-site mixing utilized SafeDAY IV Administration sets with universal spike, backcheck value, 2 SafeDAY valves, and SpinLock connector (lot 0061612755; B. Braun Medical Inc, Bethlehem, Pennsylvania). IV solutions were set to run over 2 h, consistent with the recommendations in the package insert and preclinical in vitro data.14-16 At least 10 mL of solution was collected from the end of the Y-site tubing at 0 (immediately after start of infusion), 1, and 2 h. Aliquots were tested using the same 5 methods and time points as used in the simulated Y-site testing. All experiments were completed in triplicate.
Visual Compatibility Assessment
Following preparation and mixing, each individual and combination aliquot was visually inspected using light and dark background at the aforementioned time points. Visual incompatibility was defined as any turbidity, visible particulate formation, or color change.17,18
Tyndall Beam Assessment
Immediately following visual inspection, each sample was subjected to a high-intensity mono-directional light source (Tyndall beam) at a 90° angle in front of white-and-black backgrounds. Any sample that prevented the light source from passing through the mixture and appearing on the background was considered incompatible.17,18
Microscopy Assessment
Microscopic analyses were conducted using an AmScope 120 microscope (United Scope LLC, Irvine, California) at magnifications of ×10 and ×16. A 20-μL drop of each sample was compared to a drop of the negative control (sodium chloride 0.9% [lot P379735; Baxter] in water) for the assessment of precipitation and/or crystallization.17,19 Any combination with observed evidence of precipitation or crystallization was considered incompatible.
Turbidity Assessment
Turbidity was measured at each time point using an Oakton T100 turbidity meter (Oakton Instruments, Vernon Hills, Illinois). The means of measurements across replicates were calculated for use in comparisons. Any combination that exhibited a mean increase in nephelometric Turbidity units of >50% compared to the single drug in sodium chloride 0.9% and that had a raw value of ≥0.5 was considered incompatible.18,20
pH Assessment
The pH of each sample was measured using an Agilent 3200P pH meter (Agilent Technologies, Santa Clara, California). The mean of the observed pH values across replicates was calculated for use in the analysis. Any combination with a change in pH of >1 unit compared to the time-0 pH was considered incompatible.17,18
RESULTS
Visual Compatibility Findings
No particulate formation, color changes, or turbidity was noted with any of the combinations at any of the tested time points (simulated or actual). Altering the order of mixing (ie, adding ceftazidime—avibactam to aztreonam vs adding aztreonam to ceftazidime—avibactam) did not affect these results in the simulated Y-site experiments. There was no evidence of visual incompatibility in the samples collected at 0, 1, or 2 h during the actual Y-site experiments. In both the actual and simulated Y-site compatibility experiments, phenytoin + aztreonam led to the formation of a white precipitate.
Tyndall Beam Findings
All combinations passed Tyndall beam tests in both sets of experiments. Results from simulated Y-site administration were not affected by order of mixing. The combination of phenytoin + aztreonam blocked the passage of light through the tube, indicating incompatibility, in both sets of experiments.
Microscopy Findings
No crystallization or precipitate was observed with the ceftazidime—avibactam + aztreonam combinations in either set of experiments. Ceftazidime—avibactam + aztreonam combinations appeared similar to the negative control (sodium chloride 0.9% in water). With the positive control (phenytoin + aztreonam), numerous crystals were identified via microscopy in both sets of experiments.
Turbidity Findings
None of the combinations of ceftazidime—avibactam + aztreonam resulted in a mean turbidity of >0.5 nephelometric Turbidity units at any time point across either the simulated Y-site experiments (see Supplemental Table I in the online version at https://doi.org/10.1016/j.clinthera.2020.06.005) or the actual Y-site experiments (Table I). There were no appreciable differences in turbidity measurements across triplicate experiments in either the simulated or the actual Y-site experiments. With the combination of phenytoin + aztreonam, the mean turbidity measurements were >700 at all time points in both the simulated and the actual Y-site compatibility studies. These values were well above the measurements observed with each drug individually (all, <0.40).
Table I.
Turbidity with combination of ceftazidime—avibactam (CZA) and aztreonam (ATM) via actual Y-site administration. Data are given as mean (SD) nephelometric turbidity units.
| Drug Combination/Infusion Time | 0 h | 1 h | 2 h | 4 h | 8 h | 12 h |
|---|---|---|---|---|---|---|
| ATM 20 mg/mL | ||||||
| +CZA 50 mg/mL | ||||||
| 0 h | 0.31 (0.04) | 0.32 (0.05) | 0.32 (0.04) | 0.41 (0.05) | 0.31 (0.03) | 0.30 (0.02) |
| 1 h | 0.33 (0.09) | 0.34 (0.09) | 0.41 (0.05) | 0.38 (0.07) | 0.18 (0.02) | 0.26 (0.01) |
| 2 h | 0.42 (0.06) | 0.47 (0.02) | 0.39 (0.04) | 0.44 (0.04) | 0.24 (0.01) | 0.36 (0.03) |
| +CZA 25 mg/mL | ||||||
| 0 h | 0.35 (0.06) | 0.36 (0.06) | 0.31 (0.06) | 0.32 (0.06) | 0.33 (0.03) | 0.43 (0.02) |
| 1 h | 0.44 (0.02) | 0.45 (0.04) | 0.41 (0.01) | 0.38 (0.03) | 0.40 (0.05) | 0.44 (0.04) |
| 2 h | 0.33 (0.11) | 0.31 (0.04) | 0.35 (0.10) | 0.33 (0.09) | 0.37 (0.06) | 0.44 (0.02) |
| +CZA 8 mg/mL | ||||||
| 0 h | 0.33 (0.03) | 0.36 (0.06) | 0.39 (0.07) | 0.36 (0.06) | 0.36 (0.01) | 0.40 (0.04) |
| 1 h | 0.35 (0.04) | 0.32 (0.04) | 0.41 (0.07) | 0.38 (0.05) | 0.40 (0.06) | 0.43 (0.03) |
| 2 h | 0.45 (0.02) | 0.44 (0.02) | 0.42 (0.07) | 0.37 (0.04) | 0.41 (0.06) | 0.39 (0.06) |
| ATM 10 mg/mL | ||||||
| +CZA 50 mg/mL | ||||||
| 0 h | 0.36 (0.04) | 0.32 (0.02) | 0.41 (0.04) | 0.42 (0.05) | 0.39 (0.06) | 0.41 (0.02) |
| 1 h | 0.41 (0.06) | 0.41 (0.09) | 0.40 (0.07) | 0.42 (0.01) | 0.38 (0.05) | 0.43 (0.03) |
| 2 h | 0.33 (0.02) | 0.34 (0.04) | 0.41 (0.05) | 0.34 (0.04) | 0.37 (0.06) | 0.42 (0.04) |
| +CZA 25 mg/mL | ||||||
| 0 h | 0.22 (0.04) | 0.24 (0.06) | 0.28 (0.07) | 0.32 (0.01) | 0.37 (0.06) | 0.43 (0.03) |
| 1 h | 0.29 (0.05) | 0.29 (0.04) | 0.33 (0.09) | 0.37 (0.05) | 0.31 (0.07) | 0.44 (0.03) |
| 2 h | 0.29 (0.06) | 0.32 (0.04) | 0.34 (0.03) | 0.37 (0.06) | 0.38 (0.04) | 0.38 (0.05) |
| +CZA 8 mg/mL | ||||||
| 0 h | 0.32 (0.07) | 0.34 (0.06) | 0.40 (0.09) | 0.32 (0.07) | 0.36 (0.05) | 0.41 (0.06) |
| 1 h | 0.33 (0.04) | 0.36 (0.05) | 0.38 (0.04) | 0.31 (0.04) | 0.38 (0.05) | 0.44 (0.04) |
| 2 h | 0.31 (0.04) | 0.34 (0.03) | 0.34 (0.05) | 0.33 (0.05) | 0.32 (0.05) | 0.44 (0.03) |
pH Findings
Results from the pH assessments showed no evidence of incompatibility in either the simulated Y-site experiments (see Supplemental Table II in the online version at https://doi.org/10.1016/j.clinthera.2020.06.005) or the actual Y-site experiments (Table II). Measured pH exhibited limited changes during the 12-h testing period with all of the ceftazidime—avibactam + aztreonam combinations across both sets of experiments. Observed pH values in simulated Y-site administration were similar to the results from the actual Y-site administration of the same combinations. The pH values of the samples taken during actual Y-site infusions at hours 1 and 2 of infusion were similar to those of the initial sample (time 0).
Table II.
pH with combination of ceftazidime—avibactam (CZA) and aztreonam (ATM) via actual Y-site administration. Data are given as mean (SD) pH.
| Drug Combination/Infusion Time |
0 h | 1 h | 2 h | 4 h | 8 h | 12 h |
|---|---|---|---|---|---|---|
| ATM 20 mg/mL | ||||||
| +CZA 50 mg/mL | ||||||
| 0 h | 6.333 (0.156) | 6.433 (0.018) | 6.457 (0.028) | 6.497 (0.013) | 6.503 (0.016) | 6.449 (0.017) |
| 1 h | 6.306 (0.046) | 6.333 (0.026) | 6.347 (0.043) | 6.361 (0.021) | 6.500 (0.020) | 6.456 (0.027) |
| 2 h | 6.285 (0.028) | 6.284 (0.015) | 6.391 (0.045) | 6.351 (0.032) | 6.498 (0.012) | 6.445 (0.025) |
| +CZA 25 mg/mL | ||||||
| 0 h | 6.020 (0.034) | 6.015 (0.008) | 6.080 (0.030) | 6.161 (0.032) | 6.298 (0.012) | 6.205 (0.011) |
| 1 h | 6.003 (0.003) | 6.008 (0.007) | 6.015 (0.007) | 6.191 (0.016) | 6.284 (0.010) | 6.280 (0.023) |
| 2 h | 6.015 (0.003) | 6.028 (0.007) | 6.023 (0.012) | 6.103 (0.048) | 6.301 (0.007) | 6.301 (0.012) |
| +CZA 8 mg/mL | ||||||
| 0 h | 5.470 (0.019) | 5.482 (0.010) | 5.479 (0.021) | 5.508 (0.020) | 5.651 (0.017) | 5.482 (0.023) |
| 1 h | 5.440 (0.007) | 5.441 (0.009) | 5.466 (0.008) | 5.468 (0.038) | 5.685 (0.009) | 5.504 (0.008) |
| 2 h | 5.472 (0.010) | 5.484 (0.011) | 5.462 (0.035) | 5.500 (0.012) | 5.594 (0.032) | 5.502 (0.014) |
| ATM 10 mg/mL | ||||||
| +CZA 50 mg/mL | ||||||
| 0 h | 6.075 (0.080) | 6.093 (0.009) | 6.047 (0.038) | 6.063 (0.057) | 6.232 (0.030) | 6.214 (0.036) |
| 1 h | 6.083 (0.026) | 6.086 (0.013) | 6.075 (0.033) | 6.107 (0.018) | 6.271 (0.022) | 6.245 (0.038) |
| 2 h | 6.071 (0.020) | 6.088 (0.013) | 6.056 (0.024) | 6.104 (0.049) | 6.288 (0.034) | 6.295 (0.013) |
| +CZA 25 mg/mL | ||||||
| 0 h | 5.661 (0.103) | 5.694 (0.011) | 5.699 (0.022) | 5.687 (0.017) | 5.945 (0.014) | 5.852 (0.008) |
| 1 h | 5.504 (0.220) | 5.506 (0.138) | 5.569 (0.063) | 5.622 (0.035) | 5.949 (0.039) | 5.878 (0.018) |
| 2 h | 5.498 (0.057) | 5.565 (0.15) | 5.511 (0.081) | 5.489 (0.030) | 5.987 (0.010) | 5.880 (0.011) |
| +CZA 8 mg/mL | ||||||
| 0 h | 5.111 (0.099) | 5.091 (0.040) | 5.108 (0.033) | 5.116 (0.011) | 5.263 (0.012) | 5.117 (0.014) |
| 1 h | 5.104 (0.089) | 5.087 (0.028) | 5.077 (0.032) | 5.086 (0.028) | 5.295 (0.011) | 5.125 (0.010) |
| 2 h | 5.032 (0.019) | 5.040 (0.012) | 5.071 (0.018) | 5.108 (0.014) | 5.286 (0.012) | 5.124 (0.008) |
DISCUSSION
This is the first study of the physical compatibility of intravenous ceftazidime—avibactam and aztreonam. Across all simulated and actual Y-site experiments, each performed in triplicate, no evidence of incompatibility was observed with combinations of ceftazidime—avibactam + aztreonam, diluted in sodium chloride 0.9% in water, at clinically relevant concentrations through 12 h. Most importantly, there was minimal variability across all replicate experiments, highlighting the validity of the findings.
These findings have important implications for clinical practice. With infections with NDM-producing Gram-negative organisms on the rise, and few available agents with reliable activity against these organisms, the use of combination ceftazidime—avibactam + aztreonam in clinical practice has dramatically increased.8,10,12,21 More importantly, recent in vitro findings have suggested that the concurrent administration of ceftazidime—avibactam is necessary for optimizing the bactericidal activity of this combination against NDM-producing Escherichia coli and K pneumoniae.14 In a model of hollow fiber infection studied by Lodise et al,14 bactericidal activity was increased with simultaneous administration compared to that with initial administration of ceftazidime—avibactam followed by aztreonam. Additionally, the investigators demonstrated that prolonged infusion (eg, 2-h infusion or continuous infusion) was associated with greater bactericidal activity than was simultaneous 30-min infusion, which mimicked the growth control. Those findings suggest that simultaneous, prolonged administration of these agents optimizes their effects, highlighting the importance of the findings from the current study. Future studies evaluating the stability of these agents when prepared in the same IV bag may provide further benefit, allowing for simplification of the administration process for prolonged or continuous infusion.
This study was not without limitations. Each of these agents may be diluted in dextrose 5% in water, per the package inserts; however, dilutions in this medium were not evaluated in the present study.15,16 Additionally, a premade frozen aztreonam product and a generic aztreonam formulation are commercially available, although they were not evaluated as a part of the present study. All of the experiments were performed in triplicate, but duplicate assays of each replicate test solution were not performed. We do not believe that this omission detracted from the robustness of the findings, as we conducted a comprehensive compatibility study. We examined 6 combinations of clinically relevant concentrations of ceftazidime—avibactam + aztreonam at 6 different timepoints out to hour 12, the limit of ceftazidime—avibactam stability, which resulted in a total of 216 simulated Y-site experiments (12 compatibility experiments, in triplicate, at each of the 6 time points) and 108 actual Y-site experiments (6 compatibility experiments at 3 infusion time points, each in triplicate, at 6 time points). Most importantly, there was minimal variability across all replicate experiments, which minimized the need for duplicate assays. Finally, the results from these experiments are reflective of the lots and products used, and therefore may not apply to other formulations (ie, generic formulations) and/or lot numbers.
CONCLUSION
Combinations of ceftazidime—avibactam + aztreonam, both diluted in sodium chloride 0.9% in water, showed no evidence of physical incompatibility using either simulated or actual Y-site administration.
Supplementary Material
ACKNOWLEDGMENTS
This work was funded by NIH/National Institute Allergy and Infectious Diseases Antibacterial Resistance Leadership Group grant UM1AI104681.
Dr. O'Donnell contributed to the study design, interpretation of the results, and manuscript preparation. Dr. Xu contributed generation and reporting of the data. Dr. Lodise contributed to the study design, interpretation of the results, and manuscript preparation.
Footnotes
DISCLOSURES
Dr. Lodise has received consultant's fees from Allergan and Merck. Dr. O'Donnell has received research funding from Merck. The authors have indicated that they have no conflicts of interest with regard to the content of this article.
Trademark: Avycaz ® (lot P52J; Allergan, Irvine, California).
Trademark: Azactam ® (lot AGA7108; Fresenius Kabi, Lake Zurich, Illinois).
Lot 048349 (West-Ward Pharmaceuticals, Eatontown, New Jersey).
REFERENCES
- 1.Centers for Disease Control and Prevention. Antibiotic resistant threats in the United States. Available at: https//www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf; 2019. Accessed July 11, 2020.
- 2.Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2011—2014. Infect Control Hosp Epidemiol. 2016;37:1288–1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kazmierczak KM, Rabine S, Hackel M, et al. Multiyear, multinational survey of the incidence and global distribution of metallo-beta-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60:1067–1078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sader HS, Castanheira M, Duncan LR, et al. Antimicrobial susceptibility of Enterobacteriaceae and Pseudomonas aeruginosa isolates from United States medical centers stratified by infection type: results from the International Network for Optimal Resistance Monitoring (INFORM) surveillance program, 2015—2016. Diagn Microbiol Infect Dis. 2018;92:69–74. [DOI] [PubMed] [Google Scholar]
- 5.Guh AY, Limbago BM, Kallen AJ. Epidemiology and prevention of carbapenem-resistant Enterobacteriaceae in the United States. Expert Rev Anti Infect Ther. 2014;12(5):565–580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Zavascki AP, Nation RL. Nephrotoxicity of polymyxins: is there any difference between colistimethate and polymyxin B? Antimicrob Agents Chemother. 2017;61. e02319–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Nation RL, Velkov T, Li J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis. 2014;59:88–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Marshall S, Hujer AM, Rojas LJ, et al. Can ceftazidime-avibactam and aztreonam overcome beta-lactam resistance conferred by metallo-beta-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017;61. e02243–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017;8:704–712. [DOI] [PubMed] [Google Scholar]
- 10.Davido B, Fellous L, Lawrence C, et al. Ceftazidime-avibactam and aztreonam, an interesting strategy to overcome beta-lactam resistance conferred by metallo-beta-lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2017;61:e01008–e01017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Monogue ML, Abbo LM, Rosa R, et al. In vitro discordance with in vivo activity: humanized exposures of ceftazidime-avibactam, aztreonam, and tigecycline alone and in combination against New Delhi metallo-beta-lactamase-producing Klebsiella pneumoniae in a murine lung infection model. Antimicrob Agents Chemother. 2017;61. e00486–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Shaw E, Rombauts A, Tubau F, et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. J Antimicrob Chemother. 2017;73:1104–1106. [DOI] [PubMed] [Google Scholar]
- 13.Wenzler E, Deraedt MF, Harrington AT, et al. Synergistic activity of ceftazidime-avibactam and aztreonam against serine and metallo-beta-lactamase-producing Gram-negative pathogens. Diagn Microbiol Infect Dis. 2017;88:352–354. [DOI] [PubMed] [Google Scholar]
- 14.Lodise TP, Smith NM, O'Donnell N, et al. Determining the optimal dosing of a novel combination regimen of ceftazidime/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model. J Antimicrob Chemother. 2020May28: dkaa197. 10.1093/jac/dkaa197. Online ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Avycaz (ceftazidime and avibactam) for injection, for intravenous use [package insert]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206494s002lbl.pdf.Accessed May 22, 2020.
- 16.Kabi Fresenius. Aztreonam [prescribing information]. Available at: http://editor.fresenius-kabi.us/pis/us-ph-aztreonam-for-inj-usp-fk-451086d-10-2014-pi.pdf.Accessed January 3, 2019.
- 17.Meyer K, Santarossa M, Danziger LH, et al. Compatibility of ceftazidime-avibactam, ceftolozane-tazobactam, and piperacillin-tazobactam with vancomycin in dextrose 5% in water. Hosp Pharm. 2017;52:221–228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Asempa TE, Avery LM, Kidd JM, et al. Physical compatibility of plazomicin with select i.v. drugs during simulated y-site administration. Am J Health Syst Pharm. 2018;75:1048–1056. [DOI] [PubMed] [Google Scholar]
- 19.O'Donnell JN, Venkatesan N, Manek M, et al. Visual and absorbance analyses of admixtures containing vancomycin and piperacillin-tazobactam at commonly used concentrations. Am J Health Syst Pharm. 2016;73:241–246. [DOI] [PubMed] [Google Scholar]
- 20.Trissel LA, Bready BB. Turbidimetric assessment of the compatibility of Taxol with selected other drugs during simulated y-site injection. Am J Hosp Pharm. 1992;49:1716–1719. [PubMed] [Google Scholar]
- 21.Mojica MF, Ouellette CP, Leber A, et al. Successful treatment of bloodstream infection due to metallo-beta-lactamase-producing Stenotrophomonas maltophilia in a renal transplant patient. Antimicrob Agents Chemother. 2016;60:5130–5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
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