Monte Carlo Simulation Methodologies for ß-Lactam/ß-Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments.

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for ß-lactam/ß-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the ß-lactam (BL) and ß-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL-BLIC.

Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model.

OBJECTIVES: WCK 5222 combines cefepime with zidebactam, a ß-lactam enhancer that binds PBP2 and inhibits class A and C ß-lactamases. The efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model. METHODS: Nineteen MDR isolates of P. aeruginosa (cefepime MICs ≥64 mg/L) were studied. MICs of zidebactam and WCK 5222 ranged from 4 to 512 mg/L and from 4 to 32 mg/L, respectively. Dosing regimens of cefepime and zidebactam alone and in combination that achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g of cefepime/1 g of zidebactam every 8 h (1 h infusion) were utilized; controls were vehicle-dosed. Lungs were intranasally inoculated with 107-108 cfu/mL bacterial suspensions. Mice were dosed subcutaneously 2 h after inoculation for 24 h, then lungs were harvested. RESULTS: In vitro MIC was predictive of in vivo response to WCK 5222 treatment. Mean±SD changes in bacterial density at 24 h compared with 0 h controls (6.72±0.50 log10 cfu/lungs) for 13 isolates with WCK 5222 MICs ≤16 mg/L were 1.17±1.00, -0.99±1.45 and -2.21±0.79 log10 cfu/lungs for cefepime, zidebactam and WCK 5222, respectively. Against these isolates, zidebactam yielded >1 log10 cfu/lungs reductions in 8/13, while activity was enhanced with WCK 5222, producing >2 log10 cfu/lungs reductions in 10/13 and >1 log10 cfu/lungs reductions in 12/13. Among isolates with WCK 5222 MICs of 32 mg/L, five out of six showed a bacteriostatic response. CONCLUSIONS: Human-simulated bronchopulmonary exposure of WCK 5222 is effective against MDR P. aeruginosa at MIC ≤16 mg/L in a murine pneumonia model. These data support the clinical development of WCK 5222 for pseudomonal lung infections.

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model.

Cefiderocol is a siderophore-cephalosporin conjugate with greater in vitro potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models. Female CD-1 mice rendered neutropenic received 2 weeks of iron dextran at 100 mg/kg of body weight/day intraperitoneally (iron-overloaded model) or no injections (standard model). Mice were inoculated (107 CFU/ml) with Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa with previously determined cefiderocol MICs from 0.25 to 64 mg/liter. Human-simulated regimens of cefiderocol or meropenem (2 g every 8 h [q8h], 3-h infusion) were administered for 24 h (31 strains) or 72 h (15 strains; cefiderocol only). Procedures were simultaneously performed in standard and iron-overloaded models. Mean bacterial burdens (log10 CFU/thigh) at baseline were 5.75 ± 0.47 versus 5.81 ± 0.51 in standard versus iron-overloaded models, respectively. At 24 h, mean burdens in standard versus iron-overloaded models decreased by -0.8 ± 1.9 versus -1.2 ± 2.0 (P = 0.25) in meropenem-treated mice and by -1.5 ± 1.4 versus -1.6 ± 1.5 (P = 0.54) in cefiderocol-treated mice. At 72 h, mean burdens in cefiderocol-treated mice decreased by -2.5 ± 1.5 versus -2.5 ± 1.4. No overall differences in efficacy between the models were observed for meropenem or cefiderocol. Human-simulated exposure of cefiderocol is equally efficacious in iron-overloaded and normal hosts. The potential clinical use of cefiderocol to treat Gram-negative infections in patients with iron overload is supported.

Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates.

Siderophore-antibiotic conjugates have increased in vitro activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. In vivo models of infection with iron overload and deficiency are needed to perform this assessment. The standard neutropenic murine thigh infection model was supplemented with iron-altering treatments: iron dextran at 100 mg/kg of body weight daily for 14 days to load iron or deferoxamine at 100 mg/kg daily plus a low-iron diet for up to 30 days to deplete iron. Human-simulated regimens of cefiderocol and meropenem were administered in both models to assess any impact of iron alteration on plasma pharmacokinetics. Median iron in overloaded mice was significantly higher than that of controls in plasma (1,657 versus 336 µg/dl; P < 0.001), liver (2,133 versus 11 µg/g; P < 0.001), and spleen (473 versus 144 µg/g; P < 0.001). At 30 days, depleted mice had significantly lower iron than controls in liver (2.4 versus 6.5 µg/g; P < 0.001) and spleen (72 versus 133 µg/g; P = 0.029) but not plasma (351 versus 324 µg/dl; P = 0.95). Cefiderocol and meropenem plasma concentrations were similar in iron overloaded and control mice but varied in iron-depleted mice. The iron-overloaded murine thigh infection model was established, and human-simulated regimens of cefiderocol and meropenem were validated therein. While deferoxamine successfully reduced liver and splenic iron, this depleting treatment altered the pharmacokinetics of both antimicrobials.

Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model.

Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of ß-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.

In vitro activity of ampicillin and ceftriaxone against ampicillin-susceptible Enterococcus faecium.

OBJECTIVES: To assess activity of the combination of ceftriaxone and ampicillin against clinical isolates of ampicillin-susceptible Enterococcus faecium. METHODS: Ampicillin-susceptible E. faecium (n = 29) and Enterococcus faecalis (n = 10) collected from locations in the USA and France were used for this analysis. Susceptibility testing was performed by gradient diffusion strip (GDS) and broth microdilution (BMD). Synergy with the combination of ceftriaxone and ampicillin was assessed in all isolates using GDS crossing and double disc diffusion methods. Selected isolates (nine E. faecium and three E. faecalis) were assessed for synergy in time-kill studies using ampicillin alone and in combination with ceftriaxone. RESULTS: In isolates of E. faecium, the median (range) ampicillin MIC by BMD was 0.5 (0.25-4) mg/L and by GDS it was 2 (1-8) mg/L. In E. faecalis, the median (range) ampicillin MIC by BMD was 0.5 (0.5-1) mg/L and by GDS it was 2 (0.75-3) mg/L. A total of 24/29 (82.8%) isolates of E. faecium displayed synergy by GDS and 22/29 (75.9%) by double disc diffusion. Seven of 10 (70%) isolates of E. faecalis displayed synergy by GDS and 4/10 (40%) by double disc diffusion. Time-kill studies found synergy in 3/9 (33.3%) E. faecium and 3/3 (100%) E. faecalis. CONCLUSIONS: In contrast to the demonstrated synergy in time-kill models of ceftriaxone and ampicillin for E. faecalis, this combination does not appear to provide uniform synergy in E. faecium. Antagonism was not observed. Clinical correlation is necessary and caution should be used when considering ampicillin and ceftriaxone for the treatment of infections caused by ampicillin-susceptible E. faecium.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

BACKGROUND: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. PATIENTS AND METHODS: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. RESULTS: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log10 CFU/mL reduction) activity against each of the study isolates. CONCLUSION: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.

Comparative efficacy of human-simulated epithelial lining fluid exposures of tedizolid, linezolid and vancomycin in neutropenic and immunocompetent murine models of staphylococcal pneumonia.

OBJECTIVES: Few antibiotics are approved to treat Staphylococcus aureus pneumonia. Tedizolid is an oxazolidinone with potent in vitro activity against S. aureus and is currently under investigation for hospital-acquired and ventilator-associated bacterial pneumonia. Limited data exist on the comparative efficacy of tedizolid versus current first-line treatments vancomycin and linezolid in the compromised host. Our objective was to compare the efficacy of human-simulated epithelial lining fluid (ELF) exposures of tedizolid, linezolid and vancomycin against S. aureus in neutropenic and immunocompetent murine pneumonia models. METHODS: Eight S. aureus isolates (four MRSA and four MSSA) were studied. Neutropenic and immunocompetent mice were inoculated intranasally with bacterial suspensions of 107 and 109 cfu/mL, respectively, then treated for up to 72 h with model-specific regimens of tedizolid, linezolid and vancomycin simulating human ELF exposures after clinical doses. Mice were sacrificed at 24, 48 or 72 h and changes in log10 cfu/lungs were compared with 0 h controls. RESULTS: Mean bacterial burdens at 0 h were 5.81 and 8.17 log10 cfu/lungs for neutropenic and immunocompetent mice, respectively, and increased at 24 h in the absence of antibiotic treatment to 7.97 and 9.00 log10 cfu/lungs, respectively. In neutropenic and immunocompetent mice, tedizolid was associated with bacterial density changes of -2.69 ± 0.62 and -3.57 ± 0.88 log10 cfu/lungs at 72 h, respectively. In both models, tedizolid treatment produced greater bacterial reductions than vancomycin and was not statistically significantly different from linezolid. CONCLUSIONS: Human-simulated ELF exposures of tedizolid demonstrated sustained efficacy in compromised and competent models of pneumonia. Validation of these findings in patients is warranted.

Optimizing Antibiotic Administration for Pneumonia.

Pneumonia, including community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, and ventilator-acquired bacterial pneumonia, carries unacceptably high morbidity and mortality. Despite advances in antimicrobial therapy, emergence of multidrug resistance and high rates of treatment failure have made optimization of antibiotic efficacy a priority. This review focuses on pharmacokinetic and pharmacodynamic approaches to antibacterial optimization within the lung environment and in the setting of critical illness. Strategies for including these approaches in drug development programs as well as clinical practice are described and reviewed.

Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model.

The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is ≤4 µg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of ≤4 µg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 µg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0-24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0-24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0-24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0-24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 µg/ml and 0/3 E. faecium isolates with MICs of ≥4 µg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint.

Physical compatibility of plazomicin with select i.v. drugs during simulated Y-site administration.

PURPOSE: The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported. METHODS: Plazomicin injection solution (500 mg/10 mL) was diluted in 0.9% sodium chloride or 5% dextrose for injection to a final volume of 50 mL (final plazomicin concentration, 24 mg/mL), consistent with a 15-mg/kg dose administered to an 80-kg patient (i.e., 1,200 mg). All other i.v. drugs were reconstituted according to manufacturers' recommendations and diluted with 0.9% sodium chloride or 5% dextrose for injection to the upper range of concentrations used clinically. Y-site conditions were simulated by mixing 5 mL of plazomicin solution with 5 mL of tested drug solutions in a 1:1 ratio. Solutions were assessed for visual (via color and Tyndall beam testing), turbidity (using a laboratory-grade turbidimeter), and pH changes over a 60-minute observation period. Incompatibility was defined a priori as precipitation, color change, a positive Tyndall test, or a turbidity change of ≥0.5 nephelometric turbidity units at any time during the 60-minute observation period. RESULTS: Plazomicin was physically compatible with 79 of the 92 drugs tested. Determinations of physical incompatibility with plazomicin were made for 13 drugs: albumin, amiodarone, amphotericin B deoxycholate, anidulafungin, calcium chloride, daptomycin, esomeprazole, heparin, levofloxacin, methylprednisolone, micafungin, phenytoin, and propofol, CONCLUSION: Plazomicin at a concentration of 24 mg/mL was physically compatible with 85% of the drugs tested, including 31 of 36 antimicrobial agents.

Novel pharmacotherapy for the treatment of hospital-acquired and ventilator-associated pneumonia caused by resistant gram-negative bacteria.

INTRODUCTION: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are among the most prevalent infections in hospitalized patients, particularly those in the intensive care unit. Importantly, the frequency of multidrug resistant (MDR) Gram-negative (GN) bacteria as the bacteriologic cause of HABP/VABP is increasing. These include MDR Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem resistant Enterobacteriaceae (CRE). Few antibiotics are currently available when such MDR Gram-negatives are encountered and older agents such as polymyxin B, colistin (polymyxin E), and tigecycline have typically performed poorly in HABP/VABP. AREAS COVERED: In this review, the authors summarize novel antibiotics which have reached phase 3 clinical trials including patients with HABP/VABP. For each agent, the spectrum of activity, pertinent pharmacological characteristics, clinical trial data, and potential utility in the treatment of MDR-GN HABP/VABP is discussed. EXPERT OPINION: Novel antibiotics currently available, and those soon to be, will expand opportunities to treat HABP/VABP caused by MDR-GN organisms and minimize the use of more toxic, less effective drugs. However, with sparse clinical data available, defining the appropriate role for each of the new agents is challenging. In order to maximize the utility of these antibiotics, combination therapy and the role of therapeutic drug monitoring should be investigated.

Physical Compatibility of Meropenem and Vaborbactam With Select Intravenous Drugs During Simulated Y-site Administration.

PURPOSE: Meropenem/vaborbactam is a novel intravenous antibiotic combining the carbapenem, meropenem, with a novel ß-lactamase inhibitor, vaborbactam. Meropenem/vaborbactam is administered as a 3-hour infusion given every 8 hours, thereby potentially restricting an intravenous line for 9 h/d. Intravenous medications may be given concurrently via Y-site when compatibility data are available. Herein, physical compatibility was determined for the identification which medications can be coadministered with meropenem/vaborbactam via Y-site. METHODS: Y-site administration was simulated in vitro by admixing 5 mL of meropenem 8 mg/mL and vaborbactam 8 mg/mL with an equal volume of 88 other diluted intravenous medications, including 34 antimicrobials. All other medications were diluted with 0.9% sodium chloride to the upper range of concentrations considered standard for intravenous infusion. Visual inspection, turbidity measurement, and pH measurement were performed prior to admixture, directly after admixture, and at time points up to 3 hours after admixture. FINDINGS: Of the 88 medications tested, meropenem/vaborbactam was compatible with 73 (83%), including many antibiotics such as aminoglycosides (amikacin, gentamicin, and tobramycin), colistin, fosfomycin, linezolid, tedizolid, tigecycline, and vancomycin. Physical incompatibility was observed with albumin, amiodarone, anidulafungin, calcium chloride, caspofungin, ceftaroline, ciprofloxacin, daptomycin, diphenhydramine, dobutamine, isavuconazole, midazolam, nicardipine, ondansetron, and phenytoin. IMPLICATIONS: The majority of intravenous medications tested were found to be physically compatible with meropenem/vaborbactam. These data will help pharmacists and nurses to improve line access in patients receiving meropenem/vaborbactam.