Abstract Background Pharmacokinetic-pharmacodynamic (PK/PD) target attainment rates for meropenem-vaborbactam (MV) in real-world acutely ill patients are poorly defined. We sought to evaluate target attainment rates for MV in patients with various degrees of renal dysfunction including those requiring continuous renal replacement therapy (CRRT).Figure 1.Observed versus predicted meropenem concentrations from the population (A) and individual (B) model fits Methods Patients treated with MV from December 2017 to July of 2022 were included. MV was dosed according to institutional protocols based on renal function and indication. After informed consent, opportunistic plasma samples were collected. Plasma MEM and VAB were quantified using a validated LC-MS/MS assay. Patients with acute kidney injury, and those requiring CRRT were included. Patients requiring hemodialysis were excluded. Multiple compartmental models and covariate effects [e.g., Cockcroft Gault calculated creatinine clearance (CRCL) per 1.73m2 on clearance (CL) and total body weight (WT) on volume (Vd)] were tested. Analyses were performed using Pmetrics 2.1.1 for R. A free (f) fraction of 98% and 67% were assumed for MEM and VAB, respectively. Targets of 40% fT >MIC and 100% fT >MIC for MEM and fAUC:MIC of 38 for VAB were evaluated vs. the MIC50 and full EUCAST MIC distribution for K. pneumoniae (https://mic.eucast.org/).Figure 2.Observed versus predicted vaborbactam concentrations from the population (A) and individual (B) model fits Results 18 (50% female) patients aged 54±14 years contributed 83 paired MV observations. Baseline CRCL was 114±102 mL/min/1.73m2, and baseline WT was 91±31 kg. Three patients received CRRT. A one-compartment, two-input, two-output, population PK model was fit for purpose (MEM Fig1, VAB Fig2). Non-CRRT MEM CL was higher than VAB CL (median 10.6 vs. 6.8 L/hr). CRRT MEM CL was also higher than VAB CL (median 4.1 vs. 2.7 L/hr). However, MEM Vd was similar to VAB Vd (median 23.9 vs. 21.5 L) (Table1). The simulated PTA vs. the EUCAST MIC50 of 0.75/8 was high for MEM and VAB targets (Table2). The simulated CFR for MEM was >80% with 4g IV every 8 hr at a 40% fT >MIC goal but was reduced at a 100% fT >MIC goal whereas the CFR for VAB approached 80% across renal states (Table2). Conclusion CRRT patients had roughly 40% lower MV CL vs. non-CRRT patients. VAB had lower CL vs. MEM resulting in accumulation. Aggressive (e.g., 100% fT >MIC) MV targets may be challenging to attain vs. contemporary isolates while target attainment vs. susceptible isolates remains high. Disclosures Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria Brandon Smith, MD, PharmD, Melinta Therapeutics: Advisor/Consultant|Shionogi, INC: Advisor/Consultant Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant
Abstract Background M/V demonstrates potent in vitro activity against KPC-producing organisms. It is unclear whether the combination interacts synergistically with other active agents. Methods We tested isolates for responses to M/V alone (1 and 4x MIC; V fixed at 8 µg/mL), and in combination with colistin (COL; 2 µg/mL), fosfomycin (FOS; 100 µg/mL + 25 µg/mL G6P), gentamicin (GEN; 2 µg/mL), and tigecycline (TGC; 2 µg/mL) by time-kill using a starting inoculum of 1 × 108 cFu/mL. 24h was the primary endpoint. Results 16 KPC-Kp isolates were studied (7 KPC-2 and 9 KPC-3); all were M/V-susceptible (MIC range: 0.015 – 4 µg/mL). 44% harbored ompK36 mutations (4 IS5 promoter insertion, 2 134–135 DG duplication, and 1 premature stop codon). Median M/V MICs were higher against isolates with mutant ompK36 (0.25 vs. 0.03; P = 0.002). Mean log-kills by M/V at 1x and 4x were -0.50 and -2.41, respectively; M/V was bactericidal (≥3-log kill) against 6% and 56%, respectively (Figure 1). Mean log-kills at 4× were greater against KPC-2 (-3.79) than KPC-3 (−1.33) isolates (P = 0.09), and among isolates with (−3.31) vs. without (−1.71) ompK36 mutations (P = 0.11). GEN was the most active single agent (bactericidal against 56%, mean log-kill = −3.04). In combo with M/V, rates of synergy (>2-log kill in combo) with COL, FOS, GEN, and TGC were 44%, 19%, 12.5%, and 12.5%, respectively (Figure 2). Corresponding rates of bactericidal activity were 44%, 25%, 69%, and 31%, respectively. Antagonism (> 1-log kill by most active single agent) was identified for each combo against 2 isolates. Mean log-kills by M/V + GEN were greater against isolates with GEN MICs ≤1 (−7.16) vs. ≥2 (−1.66; P = 0.001), reflecting the activity of GEN alone. Mean log-kills by M/V + COL were greater against isolates with IS5 insertions (-6.32) compared with wild type (−2.38) or other mutations (−1.77) in ompK36. Responses to M/V + FOS were not dependent upon FOS MIC, but log-kills were greater against mutant (-2.13) vs. wild-type (0.01) ompK36 (P = 0.03). Conclusion M/V + GEN is rapidly cidal if GEN MICs are ≤1, while M/V + COL resulted in highest rates of synergy against diverse KPC-Kp. Mean log-kills were highest among isolates with IS5 promoter insertions suggesting a potential role for COL combination therapy against KPC-Kp isolates with decreased outer membrane permeability. Disclosures All authors: No reported disclosures.
Abstract We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.
Abstract Background Cefiderocol demonstrates excellent activity against MDR Pseudomonas aeruginosa; however, the activity against isolates from patients previously treated with β-lactam agents is unknown. We aimed to determine the activity of cefiderocol against P. aeruginosa collected before and after treatment with traditional β-lactams and new β-lactam/β-lactamase inhibitors. Methods Cefiderocol MICs were determined in triplicate in iron-depleted cation-adjusted Mueller–Hinton broth and compared with β-lactam MICs tested by standard methods. All isolates underwent WGS analysis to identify mutations associated with resistance. Results One hundred and seventy-eight P. aeruginosa isolates were evaluated; 48% (86/178) were non-susceptible to ceftazidime/avibactam, ceftolozane/tazobactam and/or imipenem/relebactam. The cefiderocol MIC50 and MIC90 were 0.12 and 1 mg/L, respectively. Median cefiderocol MICs did not vary against isolates classified as MDR, XDR, or those non-susceptible to ceftazidime/avibactam, ceftolozane/tazobactam and/or imipenem/relebactam when compared with non-MDR isolates. Against isolates collected from patients previously treated with ceftolozane/tazobactam, cefiderocol MICs were increased 4-fold compared with baseline. Cross-resistance to cefiderocol was identified in 21% (3/14) of patients who developed treatment-emergent resistance to ceftolozane/tazobactam. Overall, 6% (11/178) of isolates demonstrated cefiderocol MICs ≥2 mg/L, which were disproportionately collected from patients previously treated with ceftolozane/tazobactam (73%; 8/11). Isolates with reduced cefiderocol susceptibility harboured mutations in ampC, tonB-dependent receptors, the response regulator pirR and ftsI. Conclusions Cefiderocol demonstrates excellent in vitro activity against P. aeruginosa isolates exposed to other novel β-lactam agents; however, some exceptions were identified. Cross-resistance between cefiderocol and ceftolozane/tazobactam was evident, but not with ceftazidime/avibactam or imipenem/relebactam. Reduced cefiderocol susceptibility was mediated by mutations in ampC and tonB-dependent receptors.
Among consecutive patients with multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia we found those treated with ceftazidime-avibactam were more likely to develop resistance (defined as ≥4-fold increased MIC) than those treated with ceftolozane-tazobactam (40% vs 10%; P = .002). Ceftazidime-avibactam resistance was associated with new mutations in ampC and efflux regulatory pathways.
Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We describe the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered Escherichia coli isolates harboring mutant bla KPC genes associated with ceftazidime-avibactam resistance.
Bloodstream infections caused by MSSA are associated with significant morbidity and mortality. Traditional treatment of MSSA bacteraemia includes an IV antistaphylococcal β-lactam and surgical source control when indicated.To evaluate the time to blood culture clearance as well as in-hospital and 90 day mortality in patients with persistent MSSA bacteraemia treated with combination antistaphylococcal penicillin plus carbapenem therapy.Consecutive patients with persistent MSSA bacteraemia treated with combination therapy were identified by study investigators and reviewed by independent clinicians. The decision to initiate combination therapy was made by the consulting clinician or by the institution's multidisciplinary endocarditis team.Among 10 patients with a median of 5 days of persistent MSSA bacteraemia, treatment with an antistaphylococcal penicillin plus carbapenem led to sterilization of blood cultures in all patients. Blood culture clearance occurred in a median of 1 day and patients received a median of 6 days of combination treatment. Four of seven patients who underwent source control of their primary site of infection cleared their bacteraemia on combination therapy prior to the surgical intervention. All patients survived to hospital discharge and 90 days post-discharge.These data extend prior findings and provide further evidence that suggests the potential benefits of combination therapy among patients with persistent MSSA bacteraemia.
Abstract Background CZA and CT are front-line agents for treatment (tx) of MDR Pseudomonas aeruginosa; however, comparative data are lacking. The purpose of this study was to compare rates of tx-emergent resistance among patients (pts) with bacteremia or pneumonia at a single center. Methods Adult pts treated for >48 hours with CZA or CT were included. Pts with cystic fibrosis or colonization were excluded. Isolates were tested by broth microdilution (BMD) in triplicate and underwent whole-genome sequencing. Results 113 pts were included. Demographics, severity of illness, and durations of tx were similar for pts tx’d with CZA or CT (Table 1). CT-treated pts were less likely to receive prolonged infusions and monotherapy, but more likely to have empyema/endovascular infections. Baseline median (range) MICs were 4 (2–8mg/L) and 2 (0.25–8mg/L) for CZA and CT, respectively. Within 90-days from tx onset, rates of resistance defined as either ≥4-fold MIC increase or MIC >8mg/L were higher among CZA-treated pts (Table 1). Corresponding median MICs of resistant isolates were 16 (16–128mg/L) and 64 (32–512mg/L), respectively. Across 107 baseline isolates, 59 different sequence types (ST) were represented. The most common P. aeruginosa cephalosporinase (PDC) variants were PDC-3, PDC-5, and PDC-8, present in 10%, 21%, and 10% of isolates, respectively. Resistance evolved across varying STs. A subgroup of contemporary pts was well-balanced and supported overall findings (Table 2). From this subgroup, rates of tx-emergent resistance among pts receiving CZA or CT monotherapy were 50% (6/12) and 6% (1/17), respectively (P=0.01). Rates of CT-resistance were lower among pts who received prolonged (5%, 1/19) versus standard (20%, 5/25) infusions. Paired baseline and resistant isolates showing ≥4-fold MIC increase were compared (Table 3). CZA resistance was associated with sequence changes in ampD and/or efflux genes in 5 pts; 2 additional pairs showed mutations in ftsI (PBP3). CT resistance was associated with new ampC mutations in 83% of pairs. Conclusion In this non-matched, descriptive analysis, tx-emergent resistance occurred more commonly among pts treated with CZA compared to CT for MDR P. aeruginosa infections. Future multicenter studies evaluating comparative clinical outcomes are warranted. Disclosures Ghady Haidar, MD, Allovir: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|NIH: Grant/Research Support jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Honoraria|La Jolla (Entasis): Advisor/Consultant|LabSimply: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support
We compared the in vitro susceptibility of multidrug-resistant Pseudomonas aeruginosa isolates collected before and after treatment-emergent resistance to ceftolozane-tazobactam. Median baseline and postexposure ceftolozane-tazobactam MICs were 2 and 64 μg/ml, respectively.
