Publications by authors named "David P Nicolau"

544 Publications

Effect of Blood Product Resuscitation on the Pharmacokinetics of Ampicillin-Sulbactam during Orthotopic Liver Transplantation.

Surg Infect (Larchmt) 2021 Nov 24. Epub 2021 Nov 24.

Center for Anti-Infective Research and Development, Hartford Hospital, Harford, Connecticut, USA.

Ampicillin-sulbactam is a piperacillin-tazobactam-sparing alternative antibiotic administered as surgical prophylaxis during orthotopic liver transplant (OLT), but limited data are available describing its pharmacokinetics and impact of blood product resuscitation. The purpose of this study was to determine the intra-operative pharmacokinetics of ampicillin-sulbactam in patients during OLT and evaluate the effects of blood resuscitation on exposure. This was a pharmacokinetic study in 10 OLT patients receiving ampicillin-sulbactam surgical prophylaxis. A 5,000-patient Monte Carlo simulation was conducted to identify optimal ampicillin-sulbactam regimens. Linear regression assessed association between blood product administration and ampicillin exposures. Ampicillin and sulbactam concentrations best fitted two-compartment models. Mean ampicillin pharmacokinetic parameters were central compartment volume (V): 6.9 ± 2.0 L, clearance (CL): 26.6 ± 18.4 L/h, and inter-compartmental rate constants (k and k): 4.8 ± 2.6 and 2.3 ± 1.4 h. Sulbactam pharmacokinetic parameters were V: 8.1 ± 2.7 L, CL: 26.1 ± 7.4 L/h, k and k: 4.9 ± 1.0 and 2.8 ± 1.1 h. Participants received between 500 and 23,642 mL of total blood product. No statistical relations were observed between blood product administration and exposures ( 0.00-0.26). Ampicillin-sulbactam 2/1 g every two hours and 2/1 g bolus followed by 6/3 g continuous infusion provided acceptable probability of target attainment up to minimum inhibitory concentrations (MICs) of 16 and 32 mcg/mL, respectively. High and frequent ampicillin-sulbactam doses are required to maintain 100% T > MIC at relevant MICs during OLT and no impact of blood product resuscitation was observed on ampicillin exposure. These are the first data available to guide ampicillin-sulbactam dosing in patients undergoing OLT.
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http://dx.doi.org/10.1089/sur.2021.218DOI Listing
November 2021

Evaluation of Metallo-β-Lactamase Susceptibility Testing in a Physiologic Medium.

Microbiol Spectr 2021 Nov 24:e0167021. Epub 2021 Nov 24.

Women's Ambulatory Health Services, Hartford Hospitalgrid.277313.3, Hartford, Connecticut, USA.

Research in identifying alternative growth media that better mimic host conditions is gaining ground. Relative to nutrient-rich Mueller-Hinton broth (MHB), data on the influence of physiologic or host-mimicking media on metallo-β-lactamase (MBL) resistance are lacking. The objective was to evaluate meropenem susceptibility against clinical and engineered MBL-harboring strains in a physiologic medium (urine). Antimicrobial susceptibility testing (AST) by broth microdilution was conducted with a wild-type Klebsiella pneumoniae strain and two engineered isogenic variants harboring K. pneumoniae carbapenemase 2 (KPC-2) or New Delhi MBL 1 (NDM-1), as well as two clinical K. pneumoniae isolates (harboring NDM-1 and VIM-1). MICs were determined in conventional cation-adjusted MHB (caMHB) and sterile-filtered urine samples (18 patients). All KPC- and MBL-harboring isolates were meropenem resistant (MICs of ≥16 mg/liter) in caMHB. AST of the KPC isolate in urine resulted in 50% (9/18 urine samples) essential agreement (i.e., within ±1 dilution, relative to the caMHB MIC), highlighting challenges with the use of urine as a medium capable of supporting AST. In the 9 AST-viable urine samples, meropenem MICs were 2- to 9-fold lower than that in caMHB (MIC of 32 mg/liter) among MBL-harboring isolates. Zinc concentrations determined by inductively coupled plasma mass spectrometry averaged 1.25 mg/liter and ranged from 0.12 to 1.14 mg/liter in caMHB and 18 urine samples, respectively. The full extent of MBL-mediated resistance among K. pneumoniae isolates appears to be attenuated in urine. Factors influencing free bioactive zinc levels warrant further investigation. Studies assessing antibiotic susceptibility profiles in nonconventional media are lacking. MBL-mediated resistance has come under scrutiny due to the dependence on extracellular zinc concentrations, which makes the choice of testing medium influential for β-lactam MICs. This study explores human urine as a physiologically relevant matrix with which susceptibility profiles of MBL-harboring isolates can be assessed, relative to conventional broth.
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http://dx.doi.org/10.1128/Spectrum.01670-21DOI Listing
November 2021

Erratum for Crandon et al., "Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model".

Antimicrob Agents Chemother 2021 Nov 17;65(12):e0187821. Epub 2021 Nov 17.

Center for Anti-Infective Research and Development, Hartford Hospitalgrid.277313.3, Hartford, Connecticut.

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http://dx.doi.org/10.1128/AAC.01878-21DOI Listing
November 2021

Clinical exposure-response relationship of cefepime/taniborbactam against Gram-negative organisms in the murine complicated urinary tract infection model.

J Antimicrob Chemother 2021 Nov 8. Epub 2021 Nov 8.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Objectives: Complicated urinary tract infections (cUTIs) are frequently encountered in hospitals and ICUs. Increasingly, the causative pathogens harbour enzymatic resistance mechanisms. Taniborbactam is a novel β-lactamase inhibitor with activity against Ambler class A, B, C and D β-lactamases. Herein, we assessed the efficacy of cefepime alone and the combination cefepime/taniborbactam in a neutropenic murine cUTI model.

Methods: Eighteen cefepime-resistant clinical isolates (9 Enterobacterales, 3 Pseudomonas aeruginosa and 6 Stenotrophomonas maltophilia; cefepime MIC = 32 to >512 mg/L) were assessed. Cefepime/taniborbactam MICs ranged from 0.06 to 128 mg/L. Human-simulated plasma regimens (HSRs) of cefepime alone and in combination with taniborbactam were developed in the murine cUTI model. The efficacy of cefepime HSR and cefepime/taniborbactam HSR was determined as the change in log10 cfu/kidney at 48 h compared with 48 h controls.

Results: Mean ± SD initial bacterial burden was 5.66 ± 0.56 log10 cfu/kidney, which increased to 9.05 ± 0.39 log10 cfu/kidney at 48 h. The cefepime HSR was ineffective, as bacterial burden was similar to untreated controls (-0.14 ± 0.40 change in log10 cfu/kidney). In contrast, cefepime/taniborbactam exhibited substantial killing, with log10 cfu/kidney changes of -5.48 ± 1.3, -4.79 ± 0.3 and -5.04 ± 0.7 for ESBL/AmpC-, KPC- and OXA-48-harbouring Enterobacterales, respectively. Cefepime/taniborbactam also exhibited robust killing of P. aeruginosa (-6.5 ± 0.26) and S. maltophilia (-5.66 ± 0.71).

Conclusions: Humanized exposures of cefepime/taniborbactam achieved robust killing of Enterobacterales, P. aeruginosa and S. maltophilia harbouring ESBL, AmpC, KPC and/or OXA-48. These data support the role of cefepime/taniborbactam for cUTI treatment for cefepime/taniborbactam MICs up to 32 mg/L.
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http://dx.doi.org/10.1093/jac/dkab405DOI Listing
November 2021

Development and characterization of a new swine model of invasive pneumococcal pneumonia.

Lab Anim (NY) 2021 11 21;50(11):327-335. Epub 2021 Oct 21.

Division of Animal Experimentation, Pneumology Department, Hospital Clinic, Barcelona, Spain.

Streptococcus pneumoniae is the most common microbial cause of community-acquired pneumonia. Currently, there are no available models of severe pneumococcal pneumonia in mechanically ventilated animals to mimic clinical conditions of critically ill patients. We studied endogenous pulmonary flora in 4 healthy pigs and in an additional 10 pigs in which we intra-bronchially instilled S. pneumoniae serotype 19 A, characterized by its resistance to penicillin, macrolides and tetracyclines. The pigs underwent ventilation for 72 h. All pigs that were not challenged with S. pneumoniae completed the 72-h study, whereas 30% of infected pigs did not. At 24 h, we clinically confirmed pneumonia in the infected pigs; upon necropsy, we sampled lung tissue for microbiological/histological confirmation of pneumococcal pneumonia. In control pigs, Streptococcus suis and Staphylococcus aureus were the most commonly encountered pathogens, and their lung tissue mean ± s.e.m. concentration was 7.94 ± 20 c.f.u./g. In infected pigs, S. pneumoniae was found in the lungs of all pigs (mean ± s.e.m. pulmonary concentration of 1.26 × 10 ± 2 × 10 c.f.u./g). Bacteremia was found in 50% of infected pigs. Pneumococcal pneumonia was confirmed in all infected pigs at 24 h. Pneumonia was associated with thrombocytopenia, an increase in prothrombin time, cardiac output and vasopressor dependency index and a decrease in systemic vascular resistance. Upon necropsy, microbiological/histological pneumococcal pneumonia was confirmed in 8 of 10 pigs. We have therefore developed a novel model of penicillin- and macrolide-resistant pneumococcal pneumonia in mechanically ventilated pigs with bacteremia and severe hemodynamic compromise. The model could prove valuable for appraising the pathogenesis of pneumococcal pneumonia, the effects associated with macrolide resistance and the outcomes related to the use of new diagnostic strategies and antibiotic or complementary therapies.
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http://dx.doi.org/10.1038/s41684-021-00876-yDOI Listing
November 2021

Intrapulmonary Pharmacokinetic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Pneumonia Patients and Healthy Subjects.

J Clin Pharmacol 2021 Oct 14. Epub 2021 Oct 14.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, 06102, USA.

Cefiderocol is a siderophore cephalosporin for the treatment of infections caused by Gram-negative bacteria including carbapenem-resistant strains. The aim of this study was to develop an intrapulmonary pharmacokinetic model of cefiderocol and assess pharmacokinetic profile in lungs. An intrapulmonary pharmacokinetic model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 pneumonia patients requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 nosocomial pneumonia patients. Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for pneumonia patients compared to healthy subjects. Lung penetration ratio of cefiderocol in pneumonia patients was calculated to be 34%, which was 1.4 fold of that in healthy subjects. The estimated %fT was 100% in most of nosocomial pneumonia patients, and no pharmacokinetic/pharmacodynamic relationship with %fT was found for microbiological or clinical outcome. The PTA for 100% fT was ≥ 99.5% against MICs ≤ 2 μg/mL and ≥ 87.0% against MICs ≤ 4 μg/mL regardless of renal function. The median of simulated ELF trough concentrations at steady-state was higher than 4 μg/mL regardless of renal function. These results reveal the adequacy of cefiderocol exposure in plasma and ELF at the recommended dosing regimens adjusted based on renal function in critically ill pneumonia patients. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1986DOI Listing
October 2021

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

J Antimicrob Chemother 2021 Sep 20. Epub 2021 Sep 20.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

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 ± 0.20 log10 cfu/thigh. In the 24 h controls, bacterial growth was 1.64 ± 0.66 log10 cfu/thigh. In isolates with levofloxacin MICs ≤1, 2 and ≥4 mg/L, changes in bacterial density following levofloxacin HSR were -1.66 ± 0.89, 0.13 ± 0.97 and 1.54 ± 0.43 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.
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http://dx.doi.org/10.1093/jac/dkab344DOI Listing
September 2021

Ceftolozane/tazobactam for refractory P. aeruginosa endocarditis: A case report and pharmacokinetic analysis.

J Infect Chemother 2022 Jan 15;28(1):87-90. Epub 2021 Sep 15.

Antibiotic Management Program, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States; XDR Pathogens Laboratory, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

We describe a case of a 48 years old male with left sided endocarditis and septic emboli secondary to a Pseudomonas aeruginosa strain that developed resistance to other β-lactam antibiotics during therapy resulting in prolonged bacteremia. Blood cultures sterilized within 1 day of initiating ceftolozane/tazobactam 3 g every 8 hours in combination with ciprofloxacin. Steady state free ceftolozane plasma Cmax and Cmin concentrations were calculated to be 122.2μg/mL and 24.3μg/mL, respectively. The multidrug-resistant strain harbored chromosomal β-lactamases OXA-486 and PDC-3, mutations in ampD and dacB predicted to lead to ampC over-expression, and mutations in OprD predicted to decrease outer membrane permeability. Following completion of a 42 day course and aortic valve replacement, the patient was deemed clinically cured without recurrence of infection at follow up 2 years later. To our knowledge, this is the first reported case to measure ceftolozane concentrations during the treatment of endocarditis which supports dose optimization approaches of severe endovascular disease due to multidrug resistant pathogens.
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http://dx.doi.org/10.1016/j.jiac.2021.08.013DOI Listing
January 2022

Pharmacokinetics, Tissue Distribution, and Efficacy of VIO-001 (Meropenem/Piperacillin/Tazobactam) for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia in Immunocompetent Rabbits with Chronic Indwelling Vascular Catheters.

Antimicrob Agents Chemother 2021 10 30;65(11):e0116821. Epub 2021 Aug 30.

Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA.

Methicillin-resistant Staphylococcus aureus (MRSA) infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous and murine models demonstrated the synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (MPT) (VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for the treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve a time above 4× MIC () of a duration of 3 to 3.30 h required a 1-h infusion with every-4-h (Q4h) dosing. Study groups in efficacy experiments consisted of MPT combinations of 100/150/100 mg/kg of body weight (MPT100), 200/300/200 mg/kg (MPT200), and 400/600/400 mg/kg (MPT400); vancomycin (VAN) at 15 mg/kg; and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1 × 10 organisms) was administered via the SISCV on day 1 and locked for 24 h. The 8-day therapy started at 24 h postinoculation. There was a significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups, with full clearance on day 4, versus UCs ( < 0.05). Consistent with the clearance of SISVC-related infection, full eradication of MRSA was achieved in lungs, heart, liver, spleen, and kidneys at the end of the study versus UC ( < 0.01). These results strongly correlated with time-kill data, where MPT in the range of 4/6/4 μg/ml to 32/48/32 μg/ml demonstrated a significant 6-log decrease in the bacterial burden versus UC ( < 0.01). In summary, VIO-001 demonstrated a favorable PK/pharmacodynamic (PD) profile and activity against SISCV MRSA infection, bacteremia, and disseminated infection. This rabbit model provides a new system for understanding new antimicrobial agents against MRSA SISVC-related infection, and these data provide a basis for future clinical investigation.
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http://dx.doi.org/10.1128/AAC.01168-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522724PMC
October 2021

Elevated MICs of Susceptible Antipseudomonal Cephalosporins in Non-Carbapenemase-Producing, Carbapenem-Resistant Pseudomonas aeruginosa: Implications for Dose Optimization.

Antimicrob Agents Chemother 2021 10 16;65(11):e0120421. Epub 2021 Aug 16.

Center for Anti-Infective Research & Development, Hartford Hospitalgrid.277313.3, Hartford, Connecticut, USA.

The present study evaluated the potency of ceftazidime and cefepime among carbapenem-resistant Pseudomonas aeruginosa isolates collected as part of a global surveillance program and assessed the pharmacodynamic implications using previously published population pharmacokinetics. When susceptible, MICs resulted at the high end of distribution for both ceftazidime and cefepime, thus 6 g/day was required to achieve optimal pharmacodynamic profiles. These findings should be considered in the clinic and for the application of CLSI susceptibility breakpoints.
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http://dx.doi.org/10.1128/AAC.01204-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522773PMC
October 2021

Intrapulmonary pharmacokinetic profile of cefiderocol in mechanically ventilated patients with pneumonia.

J Antimicrob Chemother 2021 Oct;76(11):2902-2905

Shionogi & Co., Ltd, Osaka, Japan.

Objectives: Lung penetration of cefiderocol, a novel siderophore cephalosporin approved for treatment of nosocomial pneumonia, has previously been evaluated in healthy subjects. This study assessed the intrapulmonary pharmacokinetic profile of cefiderocol at steady state in hospitalized, mechanically ventilated pneumonia patients.

Methods: Patients received cefiderocol 2 g (or ≤1.5 g if renally impaired), administered IV q8h as a 3 h infusion, or 2 g q6h if patients had augmented renal function (estimated CLCR > 120 mL/min). After multiple doses, each patient underwent a single bronchoalveolar lavage (BAL) procedure either at the end of the infusion or at 2 h after the end of infusion. Plasma samples were collected at 1, 3, 5 and 7 h after the start of infusion. After correcting for BAL dilution, cefiderocol concentrations in epithelial lining fluid (ELF) for each patient and the ELF/unbound plasma concentration ratio (RC, E/P) were calculated. Safety was assessed up to 7 days after the last cefiderocol dose.

Results: Seven patients received cefiderocol. Geometric mean ELF concentration of cefiderocol was 7.63 mg/L at the end of infusion and 10.40 mg/L at 2 h after the end of infusion. RC, E/P was 0.212 at the end of infusion and 0.547 at 2 h after the end of infusion, suggesting delayed lung distribution. There were no adverse drug reactions.

Conclusions: The results suggest that cefiderocol penetrates the ELF in critically ill pneumonia patients with concentrations that are sufficient to treat Gram-negative bacteria with an MIC of ≤4 mg/L.
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http://dx.doi.org/10.1093/jac/dkab280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521398PMC
October 2021

Phenotypic/Genotypic Profile of OXA-10-Like-Harboring, Carbapenem-Resistant Pseudomonas aeruginosa: Using Validated Pharmacokinetic/Pharmacodynamic Models To Further Evaluate Enzyme Functionality and Clinical Implications.

Antimicrob Agents Chemother 2021 09 26;65(10):e0127421. Epub 2021 Jul 26.

Center for Anti-Infective Research and Development, Hartford Hospitalgrid.277313.3, Hartford, Connecticut, USA.

MICs and pharmacodynamics of ceftazidime and cefepime human-simulated regimens (HSR) against modified carbapenem inactivation method (mCIM)-positive Pseudomonas aeruginosa isolates harboring different OXA-10-like subtypes were described. The murine thigh model assessed ceftazidime (2 g every 8 h [q8h] HSR) and cefepime (2 g and 1 g q8h HSR). Phenotypes were similar despite possessing OXA-10-like subtypes with differing spectra. Ceftazidime produced ≥1-log killing in all isolates. Cefepime activity was dose dependent and MIC driven. This approach may be useful in assessing the implications of β-lactamase variants.
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http://dx.doi.org/10.1128/AAC.01274-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448098PMC
September 2021

The ERACE-PA Global Surveillance Program: Ceftolozane/tazobactam and Ceftazidime/avibactam in vitro Activity against a Global Collection of Carbapenem-resistant Pseudomonas aeruginosa.

Eur J Clin Microbiol Infect Dis 2021 Dec 22;40(12):2533-2541. Epub 2021 Jul 22.

Center for Anti-Infective Research & Development Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA.

The cephalosporin-β-lactamase-inhibitor-combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have revolutionized treatment of carbapenem-resistant Pseudomonas aeruginosa (CR-PA). A contemporary assessment of their in vitro potency against a global CR-PA collection and an assessment of carbapenemase diversity are warranted. Isolates determined as CR-PA by the submitting site were collected from 2019-2021 (17 centers in 12 countries) during the ERACE-PA Global Surveillance Program. Broth microdilution MICs were assessed per CLSI standards for ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime, and cefepime. Phenotypic carbapenemase testing was conducted (modified carbapenem inactivation method (mCIM)). mCIM positive isolates underwent genotypic carbapenemase testing using the CarbaR, the CarbaR NxG, or whole genome sequencing. The MIC was reported as well as percent susceptible (CLSI and EUCAST interpretation). Of the 807 isolates, 265 (33%) tested carbapenemase-positive phenotypically. Of these, 228 (86%) were genotypically positive for a carbapenemase with the most common being VIM followed by GES. In the entire cohort of CR-PA, ceftolozane/tazobactam and ceftazidime/avibactam had MIC values of 2/ > 64 and 4/64 mg/L, respectively. Ceftazidime/avibactam was the most active agent with 72% susceptibility per CLSI compared with 63% for ceftolozane/tazobactam. For comparison, 46% of CR-PA were susceptible to ceftazidime and cefepime. Against carbapenemase-negative isolates, 88 and 91% of isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against carbapenem-resistant P. aeruginosa, particularly in the absence of carbapenemases. The contemporary ERACE-PA Global Program cohort with 33% carbapenemase positivity including diverse enzymology will be useful to assess therapeutic options in these clinically challenging organisms with limited therapies.
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http://dx.doi.org/10.1007/s10096-021-04308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590662PMC
December 2021

Duration of antibiotic therapy for Enterobacterales and Pseudomonas aeruginosa: a review of recent evidence.

Curr Opin Infect Dis 2021 Dec;34(6):693-700

Center for Antiinfective Research and Development.

Purpose Of Review: Emergence of multidrug-resistant organisms, impact on intestinal microbiome, side effects and hospital costs are some of the factors that have encouraged multiple studies over the past two decades to evaluate different duration of antibiotic therapy with the goal of shorter but effective regimens. Here, we reviewed the most recent relevant data on the duration of therapy focused on two of the most common Gram-negative organisms in clinical practice, Pseudomonas aeruginosa and Enterobacterales.

Recent Findings: Recent studies including meta-analysis confirm that short antibiotic courses for both Enterobacterales and P. aeruginosa infections have comparable clinical outcomes to longer courses of therapy. Despite the advocacy for short-course therapy in contemporary guidelines, recent evidence in the USA has revealed a high prevalence of inappropriate antibiotic usage due to excessive duration of therapy.

Summary: Although the decision process regarding the optimal duration of antibiotic therapy is multifactorial, the vast majority of infections other than endocardial or bone and joint, can be treated with short-course antibiotic therapy (i.e., ≤7 days). The combination of biomarkers, clinical response to therapy, and microbiologic clearance help determine the optimal duration in patients with infections caused by P. aeruginosa and Enterobacterales.
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http://dx.doi.org/10.1097/QCO.0000000000000756DOI Listing
December 2021

Cefiderocol Pharmacokinetics in a Patient Receiving Continuous Venovenous Hemodiafiltration.

Open Forum Infect Dis 2021 Jul 25;8(7):ofab252. Epub 2021 May 25.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.

Antimicrobial dosing in patients receiving continuous renal replacement therapy is a continued clinical challenge. We describe a case of a patient receiving cefiderocol 2 g intravenously every 8 hours as a 3-hour infusion for a multidrug-resistant pneumonia and bacteremia while undergoing continuous venovenous hemodiafiltration. The clinical course and cefiderocol pharmacokinetics are described.
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http://dx.doi.org/10.1093/ofid/ofab252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266675PMC
July 2021

Efficacy assessment of lysin CF-296 in addition to daptomycin or vancomycin against Staphylococcus aureus in the murine thigh infection model.

J Antimicrob Chemother 2021 09;76(10):2622-2628

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Objectives: CF-296 is a lysin in pre-clinical development for the treatment of MSSA and MRSA infections, used in addition to standard-of-care (SOC) antibiotics. We evaluated the efficacy of CF-296 alone and in addition to daptomycin or vancomycin against Staphylococcus aureus in the neutropenic mouse thigh infection model.

Methods: Eight isolates (one MSSA and seven MRSA) were studied. Mice were administered five CF-296 monotherapy doses ranging from 0.5 to 50 mg/kg intravenously. To assess adjunctive therapy, mice received sub-therapeutic daptomycin alone, sub-therapeutic vancomycin alone, or the five CF-296 doses in addition to either daptomycin or vancomycin.

Results: Relative to starting inoculum (5.80 ± 0.31 log10 cfu/thigh), bacterial density in vehicle controls increased by +2.49 ± 0.98 across all eight strains. Relative to 24 h controls, a dose-response in bacterial killing (range -0.22 ± 0.87 to -2.01 ± 1.71 log10 cfu/thigh) was observed with increasing CF-296 monotherapy against the eight isolates. Daptomycin and vancomycin resulted in -1.36 ± 0.77 and -1.37 ± 1.01 log10 cfu/thigh bacteria reduction, respectively, relative to 24 h controls. Escalating CF-296 exposures (0.5-50 mg/kg) in addition to daptomycin resulted in an enhanced dose-response, ranging from bacterial killing of -0.69 to -2.13 log10 cfu/thigh, relative to daptomycin alone. Similarly, in addition to vancomycin, escalating CF-296 exposures resulted in bacterial reduction ranging from -1.37 to -2.29 log10 cfu/thigh, relative to vancomycin alone.

Conclusions: Relative to SOC antibiotics (daptomycin or vancomycin), addition of CF-296 resulted in robust and enhanced antibacterial dose-response, achieving ≥1 log10 cfu/thigh decrease across most doses, highlighting a potential role for CF-296 adjunctive therapy against MSSA and MRSA isolates.
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http://dx.doi.org/10.1093/jac/dkab206DOI Listing
September 2021

Discrepancy in sustained efficacy and resistance emergence under human-simulated exposure of cefiderocol against Stenotrophomonas maltophilia between in vitro chemostat and in vivo murine infection models.

J Antimicrob Chemother 2021 09;76(10):2615-2621

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Objectives: The present study evaluated the sustained kill and the potential for resistance development of Stenotrophomonas maltophilia exposed to a human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models.

Methods: A total of seven S. maltophilia isolates with cefiderocol MICs of 0.03-0.5 mg/L were utilized. The sustained bactericidal activity compared with the initial inoculum and the appearance of resistance after the 72 h treatment were evaluated in both an in vitro chemostat model (four strains) and an in vivo murine thigh infection model (six strains) under the human-simulated exposure of cefiderocol (2 g every 8 h as a 3 h infusion).

Results: In the in vitro model, regrowth was observed for three of four tested isolates and resistance emergence (>2-dilution MIC increase) was observed for all of the four test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed for all of the six tested isolates in the in vivo models. The mechanism of all resistant isolates that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters.

Conclusions: The discrepancy in the sustained efficacy and resistance emergence between in vivo and in vitro models appears to be due to the resistance acquisition mechanism caused by mutation in the tonB-exbB-exbD region developing in the enriched media utilized in vitro. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among Stenotrophomonas evaluated under human-simulated exposures.
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http://dx.doi.org/10.1093/jac/dkab221DOI Listing
September 2021

Optimised cefiderocol exposures in a successfully treated critically ill patient with polymicrobial Stenotrophomonas maltophilia bacteraemia and pneumonia receiving continuous venovenous haemodiafiltration.

Int J Antimicrob Agents 2021 Sep 27;58(3):106395. Epub 2021 Jun 27.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijantimicag.2021.106395DOI Listing
September 2021

Comment on: An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa.

J Antimicrob Chemother 2021 Nov;76(12):3326-3327

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

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http://dx.doi.org/10.1093/jac/dkab229DOI Listing
November 2021

A Novel Dosing Strategy of Ceftolozane/Tazobactam in a Patient Receiving Intermittent Hemodialysis.

Open Forum Infect Dis 2021 Jun 12;8(6):ofab238. Epub 2021 May 12.

Department of Pharmacy Services, Yale New Haven Health System, New Haven, Connecticut, USA.

We describe the case of a 54-year-old male receiving intermittent hemodialysis (iHD) who was found to have bacteremia secondary to osteomyelitis of the calcaneus bone. The patient was clinically cured without recurrence using a ceftolozane/tazobactam (CTZ) dosing strategy of 100/50 mg every 8 hours (standard dosing) and 1000/500 mg thrice weekly following iHD. Utilizing a susceptibility breakpoint of ≤4 µg/mL for , the T > MIC for standard dosing and the 1000/500-mg thrice-weekly following iHD regimen were calculated to be 92.7% and 94.1%, respectively. Ceftolozane total body clearance for the standard q 8 h dosing and the 1000/500-mg thrice-weekly following iHD regimen were calculated to be 0.196 L/h and 0.199 L/h, respectively. To our knowledge, this is the first report to illustrate the administration of CTZ at a dose of 1000/500 mg thrice weekly following iHD.
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http://dx.doi.org/10.1093/ofid/ofab238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204874PMC
June 2021

Reply to Rennie, "Zinc Concentration Affects Metallo-Beta-Lactamase Susceptibility Testing of ".

J Clin Microbiol 2021 08 18;59(9):e0121121. Epub 2021 Aug 18.

Center for Anti-Infective Research and Development, Hartford Hospitalgrid.277313.3, Hartford, Connecticut, USA.

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http://dx.doi.org/10.1128/JCM.01211-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373002PMC
August 2021

Comparative in vivo activity of human-simulated plasma and epithelial lining fluid exposures of WCK 5222 (cefepime/zidebactam) against KPC- and OXA-48-like-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model.

J Antimicrob Chemother 2021 08;76(9):2310-2316

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Objectives: This was a comparative assessment of WCK 5222 (cefepime/zidebactam 2/1 g as a 1 h infusion every 8 h) efficacy using human-simulated plasma and ELF exposures against serine-carbapenemase-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model.

Methods: Ten clinical isolates were utilized: eight were serine-carbapenemase-producing (KPC, n = 4; OXA-48-like, n = 4) Enterobacterales with WCK 5222 MICs (1:1) ranging from 1 to 4 mg/L; and two were previously studied MDR isolates serving as quality controls. Lungs of mice were inoculated with 50 μL of 107 cfu/mL. Treatment mice received human-simulated regimens of cefepime, zidebactam or WCK 5222 derived from plasma or epithelial lining fluid (ELF) profiles obtained from healthy subjects. Lung bacterial densities resulting from the humanized exposures in plasma and ELF were compared.

Results: Initial lung bacterial densities ranged from 6.06 to 6.87 log10 cfu/lungs, with a mean bacterial burden increase to 9.06 ± 0.42 after 24 h. Human-simulated plasma and ELF exposures of cefepime and zidebactam monotherapy had no activity. Human-simulated WCK 5222 plasma exposures resulted in a >1 log10 cfu/lungs reduction in bacterial burden for all isolates. Humanized WCK 5222 ELF exposures achieved a >1 log10 cfu/lungs reduction for all isolates. While statistically significant differences in bacterial burden reduction were observed between the plasma and ELF exposures for WCK 5222 in 5/8 isolates, all treatments achieved the translational kill target of a >1 log10 cfu reduction.

Conclusions: Clinically achievable WCK 5222 plasma and ELF exposures produced in vivo killing of carbapenem-resistant Enterobacterales in the neutropenic murine pneumonia model that is predictive of efficacy in humans.
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http://dx.doi.org/10.1093/jac/dkab183DOI Listing
August 2021

Activity of β-Lactam Antibiotics against Metallo-β-Lactamase-Producing in Animal Infection Models: a Current State of Affairs.

Antimicrob Agents Chemother 2021 05 18;65(6). Epub 2021 May 18.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Metallo-β-lactamases (MBLs) result in resistance to nearly all β-lactam antimicrobial agents, as determined by currently employed susceptibility testing methods. However, recently reported data demonstrate that variable and supraphysiologic zinc concentrations in conventional susceptibility testing media compared with physiologic (bioactive) zinc concentrations may be mediating discordant - MBL resistance. While treatment outcomes in patients appear suggestive of this discordance, these limited data are confounded by comorbidities and combination therapy. To that end, the goal of this review is to evaluate the extent of β-lactam activity against MBL-harboring in published animal infection model studies and provide contemporary considerations to facilitate the optimization of current antimicrobials and development of novel therapeutics.
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http://dx.doi.org/10.1128/AAC.02271-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315912PMC
May 2021

Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model.

Antibiotics (Basel) 2021 Feb 19;10(2). Epub 2021 Feb 19.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.

Efforts to develop and pair novel oral β-lactamase inhibitors with existing β-lactam agents to treat extended spectrum β-lactamase (ESBL) and carbapenemase-producing Enterobacterales are gaining ground. Ceftibuten is an oral third-generation cephalosporin capable of achieving high urine concentrations; however, there are no robust data describing its pharmacodynamic profile. This study characterizes ceftibuten pharmacokinetics and pharmacodynamics in a neutropenic murine thigh infection model. Enterobacterales isolates expressing no known clinically-relevant enzymatic resistance ( = 7) or harboring an ESBL ( = 2) were evaluated. The ceftibuten minimum inhibitory concentrations (MICs) were 0.03-4 mg/L. Nine ceftibuten regimens, including a human-simulated regimen (HSR) equivalent to clinical ceftibuten doses of 300 mg taken orally every 8 h, were utilized to achieve various T > MICs. A sigmoidal E model was fitted to T > MIC vs. change in log CFU/thigh to determine the requirements for net stasis and 1-log CFU/thigh bacterial burden reduction. The growth of the 0 h and 24 h control groups was 5.97 ± 0.37 and 8.51 ± 0.84 log CFU/thigh, respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log CFU/thigh bacterial burden reduction at 24 h across the isolates. Stasis and 1-log CFU/thigh reduction were achieved with a T > MIC of 39% and 67% respectively. The T > MIC targets identified can be used to guide ceftibuten dosage selection to optimize the likelihood of clinical efficacy.
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http://dx.doi.org/10.3390/antibiotics10020201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922365PMC
February 2021

In vitro synergy of ticarcillin/clavulanate in combination with aztreonam and ceftolozane/tazobactam against SPM-1-producing Pseudomonas aeruginosa strains.

Diagn Microbiol Infect Dis 2021 Jun 10;100(2):115343. Epub 2021 Feb 10.

Universidade Federal de São Paulo (UNIFESP), Laboratório Especial de Microbiologia Clínica (LEMC), Division of Infectious Diseases, Department of Internal Medicine, Escola Paulista de Medicina (EPM), São Paulo, Brazil.

Minimal inhibitory concentrations (MICs) of ticarcillin/clavulanic acid (TLc), ceftolozane/tazobactam (C/T), and aztreonam (AT) were determined for 6 SPM-1-producing Pseudomonas aeruginosa (PSA) using Etest® strips and the synergistic effect of such antimicrobials against was evaluated by gradient diffusion strip crossing (GDSC) test. The fraction inhibitory concentration indexes (FICI) were calculated and showed a synergistic (n = 3) and additive (n = 2) effects of TLc + AT against SPM-1 producers, while TLc + C/T combination caused no effect. Average MIC reduction of TLc and AT by GDSC was 3-fold and 2-fold dilutions, respectively. Thus, TLc + AT might be a candidate as a combination therapy to treat SPM-1-producing PSA infections.
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http://dx.doi.org/10.1016/j.diagmicrobio.2021.115343DOI Listing
June 2021

Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance.

Int J Antimicrob Agents 2021 Apr 7;57(4):106299. Epub 2021 Feb 7.

Merck & Co., Inc., Kenilworth, New Jersey, USA. Electronic address:

Objective: To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection.

Methods: ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated.

Results: Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate.

Conclusions: In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS.

Gov Identifier: NCT02387372.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106299DOI Listing
April 2021

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

Pharmacotherapy 2021 02 14;41(2):220-233. Epub 2021 Feb 14.

Center for Anti-infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.

Therapeutic drug monitoring (TDM) opens the door to personalized medicine, yet it is infrequently applied to β-lactam antibiotics, one of the most commonly prescribed drug classes in the hospital setting. As we continue to understand more about β-lactam pharmacodynamics (PD) and wide inter- and intra-patient variability in pharmacokinetics (PK), the utility of TDM has become increasingly apparent. For β-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 β-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 β-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 β-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 β-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 β-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 β-lactam TDM, review supporting evidence, and provide guidance for implementation in specific patient populations.
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http://dx.doi.org/10.1002/phar.2505DOI Listing
February 2021

Contemporary analysis of ETEST for antibiotic susceptibility and minimum inhibitory concentration agreement against Pseudomonas aeruginosa from patients with cystic fibrosis.

Ann Clin Microbiol Antimicrob 2021 Jan 19;20(1). Epub 2021 Jan 19.

Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, 06102, CT, USA.

Objectives: Cystic fibrosis (CF) acute pulmonary exacerbations are often caused by Pseudomonas aeruginosa, including multi-drug resistant strains. Optimal antibiotic therapy is required to return lung function and should be guided by in vitro susceptibility results. There are sparse data describing ETEST performance for CF isolates using contemporary isolates, methods and interpretation, as well as novel antibiotics, such as ceftazidime-avibactam and ceftolozane-tazobactam.

Methods: Pseudomonas aeruginosa (n = 105) isolated during pulmonary exacerbation from patients with CF were acquired from 3 US hospitals. Minimum inhibitory concentrations (MICs) were assessed by reference broth microdilution (BMD) and ETEST for aztreonam, cefepime, ceftazidime, ceftazidime-avibactam, ceftolozane-tazobactam, ciprofloxacin, levofloxacin, meropenem, piperacillin-tazobactam, and tobramycin. Broth microdilution was conducted in concordance with the Clinical and Laboratory Standards Institute M100. ETEST methodology reflected package insert recommendations. Performance of ETEST strips was evaluated using the Food and Drug Administration (FDA) and Susceptibility Testing Manufacturers Association (STMA) guidance.

Results: Of the 105 P. aeruginosa included, 46% had a mucoid phenotype. ETEST MICs typically read 0-1 dilution higher than BMD for all drugs. Categorical agreement and essential agreement ranged from 64 to 93% and 63 to 86%, respectively. The majority of observed errors were minor. A single very major error occurred with ceftazidime (4.2%). For ceftazidime-vibactam, 2 very major errors were observed and both were within essential agreement. Major errors occurred for aztreonam (3.3%), cefepime (9.4%), ceftazidime-avibactam (5.3%, adjusted 2.1%), ceftolozane-tazobactam (1%), meropenem (3.3%), piperacillin-tazobactam (2.9%), and tobramycin (1.5%).

Conclusions: ETEST methods performed conservatively for most antibiotics against this challenging collection of P. aeruginosa from patients with CF.
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http://dx.doi.org/10.1186/s12941-021-00415-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816365PMC
January 2021

In vivo activity of WCK 4282 (high-dose cefepime/tazobactam) against serine β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa in the neutropenic murine thigh infection model.

J Antimicrob Chemother 2021 03;76(4):993-1000

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Objectives: WCK 4282, high-dose cefepime/tazobactam, possesses potent in vitro activity against Gram-negative organisms including ESBL- and cephalosporinase-harbouring strains. The purpose of this evaluation was to investigate the in vivo activity of human-simulated exposures of WCK 4282 against serine-β-lactamase-harbouring Enterobacterales and Pseudomonas aeruginosa.

Methods: Nineteen clinical isolates were evaluated (ESBL/cephalosporinase producers, n = 8 Escherichia coli, n = 4 P. aeruginosa; KPC producers, n = 3 Klebsiella pneumoniae, n = 1 Klebsiella aerogenes; OXA-48/181 producers, n = 2 K. pneumoniae, n = 1 E. coli). WCK 4282 MICs ranged from 4 to 32 mg/L compared with 16 to >128 mg/L for cefepime. Thigh-infected neutropenic mice received cefepime, WCK 4282 or sham control over 24 h prior to harvest. Cefepime and tazobactam dosing regimens produced plasma profiles of fAUC, fT>MIC and fCmax similar to human exposure after WCK 4282 2/2 g every 8 h (1.5 h infusion).

Results: Bacterial burdens (log10 cfu/thigh) were 5.81 ± 0.36 at 0 h and 9.29 ± 0.88 at 24 h in untreated controls. WCK 4282 produced potent activity against ESBL/cephalosporinase-producing strains with WCK 4282 MIC ≤16 mg/L; mean changes in log10 cfu/thigh from 0 h were -1.70 ± 0.77 and +1.86 ± 2.03 log10 cfu/thigh for WCK 4282 and cefepime human-simulated regimens, respectively. WCK 4282 produced variable activity against serine-carbapenemase-harbouring isolates. For the KPC-harbouring strains, WCK 4282 produced bacteriostasis with a mean -0.1 ± 0.61 log10 cfu/thigh. Against OXA-48/181-harbouring isolates, WCK 4282 produced a range of change in bacterial burden of -1.23 ± 0.33 to +1.04 ± 0.7 log10 cfu/thigh.

Conclusions: Human-simulated exposures of WCK 4282 produced in vivo efficacy against ESBL/cephalosporinase-producing, piperacillin/tazobactam- and ceftolozane/tazobactam-non-susceptible Enterobacterales and P. aeruginosa. These findings support further development of this combination as a carbapenem-sparing agent.
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http://dx.doi.org/10.1093/jac/dkaa551DOI Listing
March 2021
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