Non-KPC Attributes of Newer ß-lactam/ß-lactamase Inhibitors, Part 1: Enterobacterales and Pseudomonas aeruginosa.

Gram-negative antibiotic resistance continues to grow as a global problem due to the evolution and spread of ß-lactamases. The early ß-lactamase inhibitors (BLIs) are characterized by spectra limited to class A ß-lactamases and ineffective against carbapenemases and most extended spectrum ß-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, avibactam/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 2-part series, we describe the non-KPC attributes of the newer BL/BLIs with a focus on utility against Enterobacterales and Pseudomonas aeruginosa.

Effects of clinically achievable pulmonary antibiotic concentrations on the recovery of bacteria: in vitro comparison of the BioFire FILMARRAY Pneumonia Panel versus conventional culture methods in bronchoalveolar lavage fluid.

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 ~105 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 × 104), no significant growth (NSG) (≥1 × 103, <1 × 104), or no growth (NG) (<1 × 103). The PN Panel accurately identified all isolates, resistance genes, and reported ≥106 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.

Quantitative performance of humanized serum and epithelial lining fluid exposures of tigecycline and levofloxacin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model.

BACKGROUND: Lack of uniformity in infection models complicates preclinical development. The COMBINE protocol has standardized the murine neutropenic pneumonia model. Herein we provide benchmark efficacy data of humanized exposures of tigecycline and levofloxacin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa. METHODS: Following the COMBINE protocol, plasma and ELF human-simulated regimens (HSRs) of tigecycline 100 mg followed by 50 mg q12h and levofloxacin 750 mg once daily were developed and confirmed in the murine neutropenic pneumonia model. Tigecycline HSRs were tested against seven K. pneumoniae isolates. Levofloxacin HSRs were assessed against 10 K. pneumoniae and 9 P. aeruginosa. The change in cfu/lung over 24 h for each treatment was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days. RESULTS: Tigecycline 1.8 and 3 mg/kg q12h achieved humanized exposures of serum and ELF, respectively. Levofloxacin 120 and 90 mg/kg q8h led to fAUC exposures in plasma and ELF similar to in humans. Both tigecycline regimens were ineffective across the MIC range. Levofloxacin regimens achieved multilog kill against susceptible isolates, and no appreciable cfu/lung reductions in isolates with an MIC of ≥32 mg/L. Differences in cfu/lung were evident between the levofloxacin plasma and ELF HSRs against isolates with MICs of 4 and 8 mg/L. CONCLUSIONS: Administering HSRs of tigecycline and levofloxacin based on both serum/plasma and ELF in the COMBINE pneumonia model resulted in cfu/lung values reasonably aligned with MIC. These data serve as translational benchmarks for future investigations with novel compounds.

Establishment of a diverse pheno-genotypic challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa suitable for use in the murine pneumonia model.

BACKGROUND: Preclinical murine infection models lack inter-laboratory uniformity, complicating result comparisons and data reproducibility. The European Innovative Medicines initiative-funded consortium (COMBINE) has developed a standardized murine neutropenic pneumonia protocol to address these concerns. While model methods have been standardized, a major obstacle to consistent results is the lack of available bacteria with defined viability and variability. Herein, we establish a diverse challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa suitable for use in the COMBINE protocol to further minimize experimental inconsistency and improve the interpretability of data generated among differing laboratories. MATERIALS AND METHODS: Sixty-six K. pneumoniae and 65 P. aeruginosa were phenotypically profiled against tigecycline (K. pneumoniae only), levofloxacin, meropenem, cefiderocol and tobramycin. Fifty-nine isolates were introduced into the COMBINE model to assess the sufficiency of the starting bacterial inoculation, resultant baseline bacterial burden, achievement of ≥1 log10cfu/lung growth at 24 h, time to and percentage mortality. Forty-five isolates displaying desirable minimum inhibitory concentration profiles were subjected to replicate in vivo testing to assess target parameters. RESULTS: 83% of K. pneumoniae reached the prerequisite growth at 24 h using a starting bacterial burden ≥7 log10cfu/lung. P. aeruginosa isolates grew well in the model: 90% achieved the growth target with a starting bacterial burden of 6 log10cfu/lung. Mortality was negligible for K. pneumoniae but high for P. aeruginosa. Poor or inconsistent achievement of the 24 h growth target was seen in 11/59 isolates. CONCLUSIONS: With this diverse cache of viable isolates established in the COMBINE pneumonia model, future translational studies can be undertaken to set efficacy benchmarks among laboratories.

Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. METHODS: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen. RESULTS: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ±â€Šstandard deviation parameters were: CL0, 15.21 ±â€Š6.52 L/h; Vc, 10.13 ±â€Š2.26 L; K12, 2.45 ±â€Š1.16 h-1 and K21, 1.76 ±â€Š0.49 h-1 for imipenem, and 6.95 ±â€Š1.34 L/h, 9.81 ±â€Š2.69 L, 2.43 ±â€Š1.13 h-1 and 1.52 ±â€Š0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. CONCLUSIONS: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.

In vitro activity of imipenem/relebactam against Pseudomonas aeruginosa isolated from patients with cystic fibrosis.

Pseudomonas aeruginosa is a common multidrug-resistant pathogen in patients with cystic fibrosis (CF). The in vitro activity of imipenem/relebactam and imipenem was compared with other antipseudomonal antibiotics against 105 isolates from patients with CF from three US hospitals. Imipenem/relebactam, imipenem, meropenem, ceftazidime/avibactam, and ceftolozane/tazobactam susceptibilities were 77%, 55%, 58%, 90%, and 92%, respectively. Relebactam potentiates imipenem against CF P. aeruginosa by fourfold leading imipenem/relebactam to retain susceptibility against most isolates in this cohort.

Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing.

BACKGROUND: Imipenem/funobactam (formerly XNW4107) is a novel ß-lactam/ß-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains. METHODS: Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25-16 mg/L) was assessed as 24 h change in log10cfu/thigh. RESULTS: Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus %fT > MIC were poorly predictive of efficacy; bactericidal activity was observed at %fT > MIC = 0%. Across different threshold plasma funobactam concentrations (CTs), %fT > CT(1 mg/L) had the highest correlation with efficacy. Normalizing the %fT > CT = 1 mg/L index to the respective isolate imipenem/funobactam MIC ([%fT > CT]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (%fT > CT[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT > CT[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii, 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae. CONCLUSIONS: Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (%fT > CT)/MIC appeared to best describe in vivo activity.

Imipenem/cilastatin/relebactam pharmacokinetics in critically ill patients with augmented renal clearance.

BACKGROUND: Imipenem and relebactam are predominantly excreted via glomerular filtration. Augmented renal clearance (ARC) is a common syndrome in critically-ill patients with sepsis, and sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the pharmacokinetics of imipenem/relebactam in critically-ill patients with ARC. METHODS: Infected patients in the ICU with ARC (CLCR ≥ 130 mL/min) received a single dose of imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion. Blood samples were collected over 6 h for concentration determination. Protein binding was assessed by ultrafiltration. An 8 h urine creatinine collection confirmed ARC. Population pharmacokinetic models with and without covariates were fit using the non-parametric adaptive grid algorithm in Pmetrics. A 5000 patient Monte Carlo simulation assessed joint PTA using relebactam fAUC/MIC ≥8 and imipenem ≥40% fT>MIC. RESULTS: Eight patients with ARC completed the study. A base population pharmacokinetic model with two-compartments fitted the data best. The mean ±â€ŠSD parameters were: CL, 17.31 ±â€Š5.76 L/h; Vc, 16.15 ±â€Š7.75 L; k12, 1.62 ±â€Š0.99 h-1; and k21, 3.53 ±â€Š3.31 h-1 for imipenem, and 11.51 ±â€Š4.79 L/h, 16.54 ±â€Š7.43 L, 1.59 ±â€Š1.12 h-1, and 2.83 ±â€Š2.91 h-1 for relebactam. Imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion every 6 h achieved 100% and 93% PTA at MICs of 1 and 2 mg/L, respectively. CONCLUSIONS: Despite enhanced clearance of both imipenem and relebactam, the currently approved dosing regimen for normal renal function was predicted to achieve optimal exposure in critically-ill patients with ARC sufficient to treat most susceptible pathogens.

In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral ß-lactam/ß-lactamase inhibitor combination.

OBJECTIVES: Oral ß-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable ß-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model. METHODS: Twelve ceftibuten-resistant clinical isolates (six Klebsiella pneumoniae, five Escherichia coli and one Enterobacter cloacae) were utilized. Ceftibuten/ledaborbactam MICs ranged from 0.12 to 2 mg/L (ledaborbactam fixed at 4 mg/L). A ceftibuten murine dosing regimen mimicking ceftibuten 600 mg q12h human exposure was developed and administered alone and in combination with escalating exposures of ledaborbactam. The log10 cfu/thigh change at 24 h relative to 0 h controls was plotted against ledaborbactam fAUC0-24/MIC and the Hill equation was used to determine exposures associated with bacteriostasis. RESULTS: The mean ±â€ŠSD 0 h bacterial burden was 5.96 ±â€Š0.24 log10 cfu/thigh. Robust growth (3.12 ±â€Š0.93 log10 cfu/thigh) was achieved in untreated control mice. Growth of 2.51 ±â€Š1.09 log10 cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure-response relationships were strong (mean ±â€ŠSD R2 = 0.82 ±â€Š0.15). The median ledaborbactam fAUC0-24/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model. CONCLUSIONS: Ledaborbactam fAUC0-24/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against ß-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145).

Minocycline pharmacodynamics against Stenotrophomonas maltophilia in the neutropenic murine infection model: implications for susceptibility breakpoints.

BACKGROUND: Minocycline displays high susceptibility rates against Stenotrophomonas maltophilia at the current breakpoint of 4 mg/L. However, no pharmacodynamic data are available to guide dosing or justify this breakpoint. METHODS: The murine neutropenic thigh infection model was utilized to determine minocycline pharmacodynamics against four S. maltophilia through dose ranging and fractionation studies. The efficacy of a human simulated regimen (HSR) of 100 mg IV q12h was tested against 17 isolates with a range of minocycline MICs. Monte Carlo simulation was employed to assess the PTA for achieving defined pharmacodynamic thresholds in critically ill patients. RESULTS: The pharmacodynamic index best correlated with reductions in cfu was fAUC/MIC (R2 = 0.376). The composite fAUC/MIC required for stasis and 1 log10 reduction was 9.6 and 23.6, respectively. The minocycline 100 mg q12h HSR yielded no bacterial reduction at MICs ≥1 mg/L and mixed efficacy at 0.5 mg/L. Monte Carlo simulation of minocycline 200 mg IV q12h achieved the 1 log10 kill threshold with PTAs of 93% and 51.7% at MICs of 0.5 and 1 mg/L, respectively, but 0.1% at the current breakpoint of 4 mg/L. CONCLUSIONS: Clinically utilized minocycline dosing regimens fail to reach exposures predicted to be efficacious against S. maltophilia in critically ill patients at the current susceptibility breakpoint.

Pharmacokinetics and soft-tissue distribution of tebipenem pivoxil hydrobromide using microdialysis: a study in healthy subjects and patients with diabetic foot infections.

OBJECTIVE: Tebipenem pivoxil hydrobromide is a novel oral carbapenem prodrug of tebipenem, the active moiety. We assessed tebipenem steady-state pharmacokinetics in the skin and soft tissue in healthy subjects and infected patients with diabetes using in vivo microdialysis. METHODS: Six healthy subjects and six patients with an ongoing diabetic foot infection (DFI) received tebipenem pivoxil hydrobromide 600 mg orally every 8 h for three doses. A microdialysis probe was inserted in the thigh of healthy subjects or by the wound margin in patients. Plasma and dialysate samples were obtained immediately prior to the third dose and sampled over 8 h. RESULTS: Tebipenem plasma protein binding (mean ±â€ŠSD) was 50.2% ±â€Š2.4% in healthy subjects and 53.5% ±â€Š5.6% in infected patients. Mean ±â€ŠSD tebipenem pharmacokinetic parameters in plasma for healthy subjects and infected patients were: maximum free concentration (fCmax), 3.74 ±â€Š2.35 and 3.40 ±â€Š2.86 mg/L, respectively; half-life, 0.88 ±â€Š0.11 and 2.02 ±â€Š1.32 h; fAUC0-8, 5.61 ±â€Š1.64 and 10.01 ±â€Š4.81 mg·h/L. Tebipenem tissue AUC0-8 was 5.99 ±â€Š3.07 and 8.60 ±â€Š2.88 mg·h/L for healthy subjects and patients, respectively. The interstitial concentration-time profile largely mirrored the free plasma profile within both populations, resulting in a penetration ratio of 107% in healthy subjects and 90% in infected patients. CONCLUSIONS: Tebipenem demonstrated excellent distribution into skin and soft tissue of healthy subjects and patients with DFI following oral administration of 600 mg of tebipenem pivoxil hydrobromide.

Omadacycline pharmacokinetics and soft-tissue penetration in diabetic patients with wound infections and healthy volunteers using in vivo microdialysis.

OBJECTIVES: 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. METHODS: 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. RESULTS: The mean ± SD omadacycline pharmacokinetic parameters in plasma for infected patients and healthy volunteers were: Cmax, 0.57 ± 0.15 and 1.14 ± 0.26 mg/L; t½, 16.19 ± 5.06 and 25.34 ± 12.92 h; and total omadacycline AUC0-24, 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 AUC0-24 of 1.13 ± 0.37 and 2.78 ± 0.55 mg·h/L, respectively. Omadacycline tissue AUC0-24 was 0.82 ± 0.38 and 1.37 ± 0.48 mg·h/L for patients and volunteers, respectively. CONCLUSIONS: 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.

Levofloxacin pharmacodynamics against Stenotrophomonas maltophilia in a neutropenic murine thigh infection model: implications for susceptibility breakpoint revision.

BACKGROUND: Levofloxacin displays in vitro activity against Stenotrophomonas maltophilia (STM); however, current susceptibility breakpoints are supported by limited data. We employed the murine neutropenic thigh infection model to assess levofloxacin pharmacodynamics against STM. METHODS: Twenty-six clinical STM were studied using the neutropenic murine thigh infection model. Human simulated regimens (HSR) of levofloxacin 750 mg q24h were administered over 24 h. Efficacy was measured as the change in log10 cfu/thigh at 24 h compared with 0 h. Composite cfu data were fitted to an Emax model to determine the fAUC/MIC needed for stasis and 1 log10 reduction at 24 h. Monte Carlo simulation was performed to determine PTA. RESULTS: Levofloxacin MICs ranged from 0.5-8 mg/L. Mean bacterial burden at 0 h was 6.21 ±â€Š0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ±â€Š0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ±â€Š0.89, 0.13 ±â€Š0.97 and 1.54 ±â€Š0.43 log10 cfu/thigh, respectively. The Emax model demonstrated strong agreement between fAUC/MIC and change in bacterial density (R2 = 0.82). The fAUC/MIC exposure needed for stasis and 1 log10 reduction was 39.9 and 54.9, respectively. PTAs for the 1 log10 reduction threshold were 95.8, 72.2, and 26.6% at MICs of 0.5, 1 and 2 mg/L, respectively. CONCLUSIONS: These are the first data to describe fAUC/MIC thresholds predictive of cfu reductions for levofloxacin against STM. Due to poor in vivo efficacy and PTA at MICs ≥2 mg/L, reassessment of the current susceptibility breakpoint is warranted.

Validation of Cefiderocol Package Insert Dosing Recommendation for Patients Receiving Continuous Renal Replacement Therapy: A Prospective Multicenter Pharmacokinetic Study.

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.

A Retrospective Case Series of Concomitant Carbapenem and Valproic Acid Use: Are Best Practice Advisories Working?

Background: A Best Practice Advisory (BPA) warns clinicians of an interaction between carbapenems and valproic acid (VPA) that can cause significant declines in VPA levels leading to serious consequences for patients treated for seizure disorder and unknown implications for alternative indications. Objective: The goal of this study was to assess BPA efficacy in avoiding concomitant VPA/carbapenems, and to characterize use of these agents, clinical implications, and potential alternative therapeutic options. Methods: Retrospective chart review was performed on all patients over the course of 1 year who were concomitantly prescribed a carbapenem and VPA at Hartford Hospital, Hartford, CT. Data collected included: level of care, duration of concomitant therapy, indications, VPA levels during or surrounding overlap, documentation of the interaction, and therapeutic implications. Results: Carbapenems and VPA were administered to 591 and 625 patients, respectively; the BPA fired 126 times in 24 patients, and 15 patients were initiated on these agents concomitantly. Eight (53%) patients received VPA for seizures. The remaining seven (47%) received VPA for alternative indications. Eight of nine VPA levels were sub-therapeutic during carbapenem therapy and polypharmacy was administered in all patients receiving VPA for non-convulsive indications. Conclusion: Co-prescribing of these drugs was rare; however, the BPA was ineffective in 63% of instances. Reductions in VPA efficacy for any indication should be expected with concomitant carbapenem administration. Antibiotics other than carbapenems should be considered when coverage of multidrug resistant Gram-negative pathogens is required in patients whose VPA treatment cannot be interrupted or switched to a therapeutic alternative.

Impact of a Pharmacist-Managed Procalcitonin Program on COVID-19 Respiratory Tract Infection Outcomes and Health Care Resource Utilization.

Patients hospitalized with coronavirus disease 2019 (COVID-19) often receive empiric antibiotic coverage. Procalcitonin (PCT) is a biomarker with Food and Drug Administration-approved guidance cutoffs for antibiotic use in lower respiratory tract infections. Herein we describe the implementation and impact of a pharmacist-managed PCT monitoring program in hospitalized patients with COVID-19. In this quasi-experimental, single-center, retrospective study of a prospective antimicrobial stewardship pharmacist-managed program, inpatients who were severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction positive were reviewed during weekday working hours and evaluated for appropriateness of antibiotic treatment by utilizing the PCT biomarker. As needed, the infectious diseases pharmacist offered feedback around antibiotic discontinuation in patients with PCT values ≤0.25 ng/mL. Adherence to PCT cutoffs, clinical outcomes, and utilization of health care resources were quantified and compared with a time frame immediately preceding the program's implementation. A total of 772 patients hospitalized with COVID-19 were analyzed. The pre-intervention cohort was comprised of 519 patients, and 253 patients were included after program implementation. Antibiotics were prescribed within 72 hours of admission to 232 (44.7%) and 108 (42.7%) patients during the control and intervention phases, respectively. There was no difference in the primary outcome of percentage of patients who received >1 day of antibiotic therapy (23.5% vs 21.7%; P = .849) or in any secondary outcome including hospital length of stay, 30-day readmission rates, or discharge disposition. In a hospital where the majority of COVID-19 patients did not receive empiric antibiotics, the implementation of a pharmacist-managed PCT monitoring program did not significantly decrease antibiotic use or health care resource utilization.

A guide to therapeutic drug monitoring of ß-lactam antibiotics.

Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to ß-lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about ß-lactam pharmacodynamics (PD) and wide inter- and intra-patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For ß-lactams, the time that free concentrations remain above the minimum inhibitory concentration (MIC) as a function of the dosing interval (%fT>MIC) has been shown to best predict antibacterial effect. Many studies have shown that ß-lactam %fT>MIC exposures are often suboptimal across a wide variety of disease states and clinical settings. A limitation to implementing this practice is the general lack of understanding on how to best operationalize this intervention and interpret the results. The instrumentation and expertise needed to quantify ß-lactams for TDM is rarely available locally, but certain laboratories advertise these services and perform them regularly. Familiarity with the modalities and nuances of antimicrobial susceptibility testing is crucial to establishing ß-lactam concentration targets that meet the relevant exposure thresholds. Evaluation of these concentrations is best accomplished using population PK software and Bayesian modeling, for which a multitude of programs are available. While TDM of ß-lactams has shown an ability to increase the rate of target attainment, there is currently limited evidence to suggest that it leads to improved clinical outcomes. Although consensus guidelines for ß-lactam TDM do not exist in the United States, guidance would help to promote this important practice and better standardize the approach across institutions. Herein, we discuss the basis for ß-lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations.

Rivaroxaban vs. warfarin and renal outcomes in non-valvular atrial fibrillation patients with diabetes.

AIMS: Vascular calcification is common in diabetic patients. Warfarin has been associated with renovascular calcification and worsening renal function; rivaroxaban may provide renopreservation by decreasing vascular inflammation. We compared the impact of rivaroxaban and warfarin on renal outcomes in diabetic patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: Using United States IBM MarketScan data from January 2011 to December 2017, we identified adults with both NVAF and diabetes, newly-initiated on rivaroxaban or warfarin with ≥12-month insurance coverage prior to anticoagulation initiation. Patients with Stage 5 chronic kidney disease (CKD) or undergoing haemodialysis at baseline were excluded. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting (IPTW) based on propensity scores (absolute standardized differences <0.1 achieved for all after adjustment). Outcomes included incidence rates of emergency department/hospital admissions for acute kidney injury (AKI) and the composite of the development of Stage 5 CKD or need for haemodialysis. Patients were followed until an event, index anticoagulant discontinuation/switch, insurance disenrollment, or end-of-data availability. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression. We assessed 10 017 rivaroxaban (22.6% received a reduced dose) and 11 665 warfarin users. In comparison to warfarin, rivaroxaban was associated with lower risks of AKI (HR = 0.83, 95% CI = 0.74-0.92) and development of Stage 5 CKD or need for haemodialysis (HR = 0.82, 95% CI = 0.70-0.96). Sensitivity and subgroup analyses had similar effects as the base-case analysis. CONCLUSION: Rivaroxaban appears to be associated with lower risks of undesirable renal outcomes vs. warfarin in diabetic NVAF patients.