Abstract Purpose Sulbactam/durlobactam is a combination antibiotic designed to target Acinetobacter baumannii, including carbapenem-resistant and multidrug-resistant strains. The objective of this study was to determine the physical compatibility of sulbactam/durlobactam solution during simulated Y-site administration with 95 intravenous (IV) drugs. Methods Vials of sulbactam/durlobactam solution were diluted in 0.9% sodium chloride injection to a volume of 100 mL (the final concentration of both drugs was 15 mg/mL). All other IV drugs were reconstituted according to the manufacturer’s recommendations and diluted with 0.9% sodium chloride injection to the upper range of concentrations used clinically or tested undiluted as intended for administration. Y-site conditions were simulated by mixing 5 mL of sulbactam/durlobactam with 5 mL of the tested drug solutions in a 1:1 ratio. Solutions were inspected for physical characteristics (clarity, color, and Tyndall effect), turbidity, and pH changes before admixture, immediately post admixture, and over 4 hours. Incompatibility was defined as any observed precipitation, significant color change, positive Tyndall test, or turbidity change of ≥0.5 nephelometric turbidity unit during the observation period. Results Sulbactam/durlobactam was physically compatible with 38 out of 42 antimicrobials tested (90.5%) and compatible overall with 86 of 95 drugs tested (90.5%). Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, ciprofloxacin, daptomycin, levofloxacin, phenytoin sodium, vecuronium, and propofol. Conclusion The Y-site compatibility of sulbactam/durlobactam with 95 IV drugs was described. These compatibility data will assist pharmacists and nurses to safely coordinate administration of IV medications with sulbactam/durlobactam.
Sulbactam-durlobactam is approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. Patients with serious Acinetobacter infections may require support with continuous renal replacement therapy (CRRT), which presents challenges for optimal dosing of antibiotics. Sulbactam-durlobactam dosing regimens were derived for this population using an ex vivo CRRT model and Monte Carlo simulation (MCS). Transmembrane clearance (CLTM) was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets and with effluent rates of 1, 2, and 3 L/h. Pre-filter, post-filter blood, and effluent samples were collected over 60 min to calculate sieving (SC) and saturation (SA) coefficients for CVVH and CVVHD, respectively. An established population pharmacokinetic model was integrated with the CLTM; then, a 1,000 patient MCS was conducted to determine exposures of potential dosing regimens. Adsorption and degradation in the ex vivo CRRT model were negligible. The overall mean ± standard deviation SC/SA was 1.14 ± 0.12 and 0.93 ± 0.08 for sulbactam and durlobactam, respectively. In multivariable regression analyses, effluent rate was the primary driver of CLTM for both drugs. For effluent rates <3 L/h, sulbactam-durlobactam 1 g-1g q8h as 3 h infusion achieved a high probability of pharmacodynamic target attainment while retaining area under the curve exposures consistent with the standard dose in non-CRRT patients. For effluent rates ≥3 to 5 L/h, the optimal regimen was 1 g-1g q6h 3 h infusion. Sulbactam-durlobactam regimens that provide optimum drug exposures for efficacy and safety were identified for CRRT based on the prescribed effluent rate.
Abstract Background Cefiderocol is the first antibiotic with effluent flow rate–based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations. Methods A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022–2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography–tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration (f T > MIC) and total daily area under the concentration time curve (AUCdaily) were calculated. Results Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k12 and k21) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours−1, and 2.2 ± 2.2 hours−1, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% fT > MIC up to MIC 8 mg/L with an AUCdaily (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients. Conclusions The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUCdaily was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.
Abstract Background Optimal antibiotic dosing in critically ill patients receiving CRRT is crucial. Drug clearance (CL) can be affected by multiple factors such as CRRT mode, effluent rate (ER) or filter type. We investigated FEP transmembrane CL (CLTM) in an ex vivo CRRT model to inform optimal dosing regimens and validate these regimens by re-simulation in a clinical cohort of CRRT patients. Methods CLTM was determined ex vivo in hemofiltration and hemodialysis modes with M100 and HF1400 filters. Bovine blood spiked with FEP was sampled from pre-, post-filter and effluent fluids at 10, 30, and 60 minutes in duplicate runs at ER of 1, 2 and 3 L/h. CLTM was calculated via sieving (SC) and saturation coefficients (SA). A multiple linear regression was performed to describe CLTM as a function of ER, filter, and mode. Monte Carlo Simulations (MCS; n=1000) using the equation CL= non-renal CL + CLTM and distribution parameters from a published population pharmacokinetic (popPK) model were executed for ascending ER (1-5 L/h). The resulting FEP regimens were selected by probability of target attainment (PTA) for 70%fT > MIC (MIC = 8mg/L CLSI susceptible breakpoint) and mean AUC within the 25th-75th percentile of a non-CRRT cohort. Selected regimens were validated by re-simulating fT > MIC and AUC using popPK defined Bayesian parameters in Pmetrics for R from 10 CRRT patients receiving FEP in clinical practice. Results Mean (SD) ex vivo SC/SA were 1.01 (0.08). ER was the main predictor (p< 0.001) for CLTM (CLTM= 0.139+0.841*ER) with no effect from mode or filter type. MCS of FEP 1g and 2g q8h provided 100% PTA at 8 mg/L with AUCs similar to the non-CRRT comparator for ER of 1-2.4 and 2.5-5 L/h respectively. Mean (SD) popPK parameter estimates of the validation cohort were CL, 3.8 (1.1); Vc, 17.3 (15.3) L; k12, 5.0 (3.1) h-1; and k21, 6.4 (7.6) h-1. Selected regimens tested in the validation cohort demonstrated good performance with the algorithm (Figure 1). Conclusion These are the first data to translate the findings of ex vivo CRRT CLTM in a dosing algorithm based on CRRT ER to achievable exposure in patients receiving FEP. For CRRT ER of 1-2.4 L/h and 2.5-5 L/h FEP 1g and 2g 8h as 0.5h infusions achieve 70% fT > MIC, respectively, while retaining AUC in range with safe exposures in non-CRRT patients. Disclosures Christina Konig, PhD, Gilead Inc.: Honoraria|Pfizer Inc.: Honoraria|Shionogi Inc.: Honoraria David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support Joseph L. Kuti, PharmD, Abbvie: Advisor/Consultant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria|Venatorx: Grant/Research Support
An 8.1-kb DNA fragment from Xanthomonas oryzae pv. oryzae that contains six open reading frames (ORF) was cloned. The ORF encodes proteins similar to flagellar proteins FlhB, FlhA, FlhF, and FliA, plus two proteins of unknown function, ORF234 and ORF319, from Bacillus subtilis and other organisms. These ORF have a similar genomic organization to those of their homologs in other bacteria. The flhF gene product, FlhF, has a GTP-binding motif conserved in its homologs. Unlike its homologs, however,X. oryzae pv. oryzae FlhF carries two transmembrane-like domains. Insertional mutations of the flhF gene with the omega cassette or the kanamycin resistance gene significantly retard but do not abolish the motility of the bacteria. Complementation of the mutants with the wild-type flhF gene restored the motility. The X. oryzae pv. oryzae FlhF interacts with itself; the disease resistance gene product XA21; and a protein homologous to the PilL protein of Pseudomonas aeruginosa, XooPilL, in the yeast two-hybrid system. The biological relevance of these interactions remains to be determined.
Abstract Background Optimal dosing of antibiotics in patients on CRRT is complicated by factors that can influence drug adsorption and clearance including filter type, CRRT mode, effluent rate (ER), and the drug’s properties itself. SUL-DUR is a novel combination antibiotic under development for management of Acinetobacter baumannii infections. We sought to characterize SUL and DUR adsorption and transmembrane clearance (CLTM) in an ex vivo CRRT model. Methods CLTM was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets. One liter of heparinized bovine blood was allowed to circulate in the Prismaflex CRRT system for 10 minutes. SUL and DUR were then added to achieve a plasma concentration of 30 mg/L, the average maximum concentration achieved in humans following SUL-DUR 1g/1g q6h as a 3h infusion. Pre-filter blood, post-filter blood and effluent samples were collected at 0, 10, 30, and 60 minutes to determine SUL and DUR concentrations. Combinations of filters, modes, and replacement fluid were tested in triplicate at effluent rates of 1, 2 and 3 L/h. The sieving coefficient (SC) for CVVH and the saturation coefficient (SA) for CVVHD were calculated to determine CLTM. Adsorption was measured through a closed loop system bypassing effluent elimination. Multiple linear regression was used to determine SUL and DUR CLTM as a function of ER, filter, and mode. Results SUL and DUR adsorption was minimal at 10% for both drugs. Mean ± standard deviation initial SUL and DUR concentrations were 28.6 ± 2.5 and 27.4 ± 1.9 mg/L, respectively. The overall mean SC/SA across different modes, filters, and ERs was 1.0 and 0.9 for SUL and DUR, respectively. Multiple linear regression demonstrated that the ER was the primary driver (p< 0.001) of CLTM for both drugs based on the equations: SUL CLTM (L/h) = -0.0123 + (1 x ER), R2 = 0.998; DUR CLTM (L/h) = 0.0346 + (0.91 x ER), R2 = 0.958. Conclusion SUL and DUR were efficiently cleared by both CVVH and CVVHD through M100 and HF1400 filters. The clearance of both drugs during CRRT was dependent primarily on the ER. When incorporated into established population pharmacokinetic models, these data can be used to estimate CLTM and devise dosing recommendations for SUL-DUR for patients requiring CRRT. Disclosures Xiaoyi Ye, MD, Sanofi Genzyme: Honoraria David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support Joseph L. Kuti, PharmD, bioMeriuex Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Merck & Co, Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria
Abstract Background FDC is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving CRRT including modalities such as continuous venovenous hemodiafiltration (CVVHDF). The objective of this study was to investigate the population pharmacokinetics of FDC among patients receiving CRRT and validate these novel dosing recommendations. Methods A multicenter pharmacokinetic study among critically ill patients receiving CRRT was conducted. Subsequent blood sampling was performed at steady-state, and FDC concentrations were assayed by a validated Liquid Chromatography with tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R. The free time above the minimum inhibitory concentration (fT>MIC) was calculated with a target of ≥75% fT >MIC associated with clinical success. Total daily area under the concentration time curve (AUCdaily) was used as a surrogate for safety and tolerability. Results Fourteen patients on CVVHDF renal support were enrolled from August 2022 until December 2023; Hartford Hospital (n=7), Banner University Medical Center (n=5), and University of Kentucky Medical Center (n=2). Average age was 55 years and majority were male (n=9). Mean body weight was 113.5 kg, and effluent flow rates ranged from 2.1 to 5.1 L/h. FDC concentrations best fitted a two-compartment model. Mean ± SD parameter estimates for clearance, volume of the central compartment, and intercompartment transfer constants (K12 and K21) were 3.5 ± 1.5 L/h, 10.7 ± 8.4 L, 3.9 ± 1.8 h-1, and 2.2 ± 2.2 h-1, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% fT >MIC up to MIC 8 mg/L with an AUCdaily (mean ± SD) of 1444 ± 423 mg*h/ L (Table 1). FDC was well tolerated with no serious adverse events reported among these critically ill patients. Conclusion Based on these data, the current package insert dosing recommendations resulted in pharmacodynamically optimized FDC exposures. The simulated concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUCdaily were within the range observed in patients not receiving CRRT in the Phase 3 clinical trials, suggestive of a safe and therapeutic profile. Disclosures Emir Kobic, BCIDP, Shionogi: Grant/Research Support|Shionogi: Speaker Bureau Melissa L. Thompson Bastin, PharmD, PhD, Baxter Healthcare: Advisor/Consultant|Baxter Healthcare: Board Member|Fresenius: Advisor/Consultant Andrew J. Fratoni, PharmD, InsightRX: Grant/Research Support Xiaoyi Ye, MD, Sanofi: Advisor/Consultant Joseph L. Kuti, PharmD, Abbvie: Advisor/Consultant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria|Venatorx: Grant/Research Support David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support Tomefa E. Asempa, PharmD, FDA/CDER: Grant/Research Support|Paratek: Grant/Research Support|Shionogi: Grant/Research Support|Spero: Grant/Research Support|VenatoRx: Grant/Research Support
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