Gram-negative antibiotic resistance continues to grow as a global problem due to the evolution and spread of β-lactamases. The early β-lactamase inhibitors (BLIs) are characterized by spectra limited to class A β-lactamases and ineffective against carbapenemases and most extended spectrum β-lactamases. In order to address this therapeutic need, newer BLIs were developed with the goal of treating carbapenemase producing, carbapenem resistant organisms (CRO), specifically targeting the Klebsiella pneumoniae carbapenemase (KPC). These BL/BLI combination drugs, ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam, have proven to be indispensable tools in this effort. However, non-KPC mechanisms of resistance are rising in prevalence and increasingly challenging to treat. It is critical for clinicians to understand the unique spectra of these BL/BLIs with respect to non-KPC CRO. In Part 1of this two-part series, we describe the non-KPC attributes of the newer BL/BLIs with a focus on utility against Enterobacterales and Pseudomonas aeruginosa.

We assessed the plasma and soft-tissue pharmacokinetic exposure of omadacycline in infected patients with diabetic foot infection (DFI) and healthy volunteers using in vivo microdialysis. Eight patients and six healthy volunteers were enrolled and received an omadacycline IV loading dose (200 mg) followed by two oral doses (300 mg) every 24 h. Microdialysis catheters were placed in the soft tissue near the infected diabetic foot wound (patients) or thigh (healthy volunteers). Plasma and dialysate fluid samples were collected, starting immediately prior to the third dose and continued for 24 h post-dose. Protein binding was determined by ultracentrifugation. The mean ± SD omadacycline pharmacokinetic parameters in plasma for infected patients and healthy volunteers were: C_max, 0.57 ± 0.15 and 1.14 ± 0.26 mg/L; t_½, 16.19 ± 5.06 and 25.34 ± 12.92 h; and total omadacycline AUC_0–24, 6.27 ± 1.38 and 14.06 ± 3.40 mg·h/L, respectively. The omadacycline mean plasma free fraction was 0.21 and 0.20 for patients and healthy volunteers, corresponding to free plasma AUC_0–24 of 1.13 ± 0.37 and 2.78 ± 0.55 mg·h/L, respectively. Omadacycline tissue AUC_0–24 was 0.82 ± 0.38 and 1.37 ± 0.48 mg·h/L for patients and volunteers, respectively. The present study describes the plasma and soft-tissue exposure of omadacycline in patients with DFI and healthy volunteers. Integrating these data with the microbiological, pharmacokinetic/pharmacodynamic and clinical efficacy data is foundational to support clinical assessments of omadacycline efficacy specifically for DFI. This, coupled with the once-daily oral administration, suggests omadacycline could be an advantageous translational therapy for the hospital and outpatient setting.

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. 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 (AUC_daily) were calculated. 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 AUC_daily (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients. 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 AUC_daily was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.

Empiric antibiotics may affect bacterial pathogen recovery using conventional culture methods (CCMs), while PCR-based diagnostics are likely less affected. Herein, we conducted an in vitro study of bronchoalveolar lavage fluid (BAL) inoculated with bacteria and clinically relevant antibiotic concentrations to compare the recovery between the BioFire FILMARRAY Pneumonia Panel (Pn Panel) and CCMs. Remnant clinical BAL specimens were inoculated to ~10 ⁵ cfu/mL using 12 clinical isolates. Isolates consisted of one wild-type (WT) and one or more resistant strains of: Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Acinetobacter baumannii , and Staphylococcus aureus . Piperacillin–tazobactam, cefepime, meropenem, levofloxacin, or vancomycin was added to achieve pulmonary epithelial lining fluid peak and trough concentrations. Post-exposure cfu/mL was quantified by CCMs and simultaneously tested by the PN Panel for identification and semi-quantitative genetic copies/mL. CCM results were categorized as significant growth (SG) (≥1 × 10 ⁴ ), no significant growth (NSG) (≥1 × 10 ³ , <1 × 10 ⁴ ), or no growth (NG) (<1 × 10 ³ ). The PN Panel accurately identified all isolates, resistance genes, and reported ≥10 ⁶ genetic copies/mL regardless of antibiotic exposure. The CCM also identified all S. aureus strains exposed to vancomycin. For WT Gram-negative isolates exposed to antibiotics, SG, NSG, and NG were observed in 7/52 (13%), 18/52 (35%), and 27/52 (52%) of CCM experiments, respectively. For resistant Gram-negatives isolates, SG, NSG, and NG were observed in 62/88 (70%), 17/88 (19%), and 9/88 (10%), respectively. These in vitro data demonstrate that the PN Panel is able to identify Gram-negative pathogens in the presence of clinically significant antibiotic concentrations when CCM may not.

The β-lactam/β-lactamase inhibitor (BL/BLI) combination drugs, ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam, have proven especially useful for treating carbapenemase-producing, carbapenem-resistant organisms (CRO), specifically Klebsiella pneumoniae carbapenemases (KPCs). However, non-KPC mechanisms of resistance are rising in prevalence among Gram-negatives and are increasingly challenging to treat. These newer BL/BLIs, including sulbactam/durlobactam, have an array of activity against mechanisms of carbapenem resistance beyond KPC and therefore play an important role in the treatment of non-KPC carbapenem-resistant organisms. This review, the second in a 2-part series, lays out the non-KPC attributes of the newer BL/BLIs with a focus on clinical utility against Burkholderia cepacia complex, Stenotrophomonas maltophilia, Acinetobacter baumannii, and other rare pathogens.