Publications by authors named "Maxwell J Lasko"

10 Publications

  • Page 1 of 1

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

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

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

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

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

Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine-β-Lactamase-Producing and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection Model.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

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

WCK 4282 (cefepime 2 g-tazobactam 2 g) maximizes systemic exposure of tazobactam and restores cefepime activity against various extended-spectrum β-lactamase (ESBL)- and cephalosporinase-producing strains We describe clinical WCK 4282 exposure efficacies against various serine β-lactamase-producing and isolates in a murine pneumonia model. Clinical cefepime-resistant isolates (17 and 2 ) were utilized. Isolates expressed ESBLs, cephalosporinases, and/or serine carbapenemases (KPC and OXA-48-like). WCK 4282 MICs were 4 to 32 μg/ml. For experiments, lungs of neutropenic mice were inoculated using standard inoculum (10 log CFU/ml). Serine carbapenemase-producing isolates were also assessed using a low inoculum (1:5 dilution). Treatment mice received a human-simulated regimen (HSR) of cefepime, meropenem (control for serine carbapenemase expression with low inoculum experiments), or WCK 4282 human-simulated regimens. Efficacy was assessed as change in log CFU/lungs at 24 h compared with 0-h controls. At standard inoculum, the mean 0-h bacterial burden was 6.65 ± 0.23 log CFU/lungs, and it increased at 24 h by 2.48  0.60 log CFU/lungs among untreated controls. Initial bacterial burdens of lower inocula ranged from 5.81 ± 0.12 to 6.39 ± 0.13 log CFU/lungs. At standard and/or low inocula, cefepime and meropenem provided minimal activity. WCK 4282 produced a >1 log reduction against 9/9 ESBL-/cephalosporinase-producing strains. WCK 4282 provided variable activity among mice infected with standard or lower inocula of OXA-48-like-producers. WCK 4282 exposures provided 0.53 ± 1.07 log CFU/lungs growth against KPC producers at a standard inoculum versus bacteriostasis (-0.15 ± 0.54 change in log CFU/lungs) at a low inoculum. WCK 4282 produced potent activity against ESBL- and cephalosporinase-producing and isolates and potential activity against OXA-48-like-producing isolates in a neutropenic pneumonia model.
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http://dx.doi.org/10.1128/AAC.02193-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097431PMC
March 2021

Impact of Intraoperative Cell Salvage on Concentrations of Antibiotics Used for Surgical Prophylaxis.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

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

Intraoperative cell salvage (IOCS) is used to administer autologous blood lost during surgery. We studied antibiotic disposition through an IOCS system for vancomycin, piperacillin, ampicillin, and cefazolin. Only 2% ± 1% of antibiotic inoculated in whole blood was recovered in the IOCS reinfusion bag, whereas 97% ± 17% was found in the waste. These observations were confirmed for ampicillin in two patients undergoing liver transplantation. Studies measuring the impact of IOCS on perioperative antibiotic concentrations are warranted.
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http://dx.doi.org/10.1128/AAC.01725-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674051PMC
November 2020

EDTA-modified carbapenem inactivation method (eCIM) for detecting IMP Metallo-β-lactamase-producing Pseudomonas aeruginosa: an assessment of increasing EDTA concentrations.

BMC Microbiol 2020 07 20;20(1):220. Epub 2020 Jul 20.

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

Background: Prompt identification of carbapenemase-harboring organisms is valuable in informing therapeutic and infection-control measures. The modified carbapenem inactivation method (mCIM) and EDTA-modified carbapenem inactivation method (eCIM) are inexpensive and easy to interpret phenotypic tests endorsed by the Clinical and Laboratory Standards Institute (CLSI) for the detection of carbapenemase-harboring Enterobacterales. Only mCIM is endorsed by CLSI for detecting carbapenemase-harboring Pseudomonas aeruginosa. eCIM's ability to delineate serine and metallo-β-lactamases (MBL) could be advantageous in areas prevalent with carbapenemase-harboring P. aeruginosa. A recent assessment of mCIM/eCIM on MBL-harboring P. aeruginosa demonstrated high eCIM sensitivity for NDMs and VIMs but not for IMP-producers. Therefore, this study aimed to determine whether increasing EDTA concentrations would enhance eCIM sensitivity for a collection of IMP-harboring P. aeruginosa isolates. Twenty-six IMP-harboring P. aeruginosa isolates were utilized. For test validation, additional P. aeruginosa isolates harboring NDM (n = 3), VIM (n = 3), KPC (n = 8), wild-type (n = 1), and Enterobacterales isolates harboring IMP (n = 6) and NDM (n = 1) were assessed. The mCIM test was conducted as outlined by CLSI. Simultaneously, the eCIM test was performed with the standard 5 mM EDTA concentration and doubling EDTA concentrations: 10 mM, 20 mM, and 40 mM.

Results: Concentration-dependent improvement was observed among the IMP-harboring P. aeruginosa with eCIM sensitivities at 0, 31, 85, and 100% respectively. Remaining Enterobacterales and P. aeruginosa responded concordantly with their genotype at the standard 5 mM eCIM concentration, with doubling EDTA concentrations providing no greater sensitivity.

Conclusion: Combination of mCIM and an eCIM with a 40 mM EDTA concentration appropriately capture IMP-harboring P. aeruginosa without sacrificing test utility for other carbapenemase-harboring isolates.
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http://dx.doi.org/10.1186/s12866-020-01902-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372831PMC
July 2020

Evaluation of the EDTA-Modified Carbapenem Inactivation Method for Detecting Metallo-β-Lactamase-Producing .

J Clin Microbiol 2020 05 26;58(6). Epub 2020 May 26.

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

The prevalence of carbapenem-resistant is increasing. Identification of carbapenemase-producing will have therapeutic, epidemiological, and infection control implications. This study evaluated the performance of the EDTA-modified carbapenem inactivation method (eCIM) in tandem with the modified carbapenem inactivation method (mCIM) against a large collection of clinical isolates ( = 103) to provide clinicians a phenotypic test that not only identifies carbapenemase production but also distinguishes between metallo-β-lactamase and serine-carbapenemase production in The mCIM test was performed according to Clinical and Laboratory Standards Institute guidelines, while the eCIM was conducted as previously described for Test performance was compared to the genotypic profile as the reference. mCIM testing successfully categorized 91% (112/123) of isolates as carbapenemases or non-carbapenemase producers, with discordant isolates being primarily Guiana extended-spectrum (GES)-type producers. To increase the sensitivity of the mCIM for GES-harboring isolates, a double inoculum, prolonged incubation, or both was evaluated, with each modification improving sensitivity to 100% (12/12). Upon eCIM testing, all Verona integrin-encoded metallo-β-lactamases (VIM;  = 27) and New Delhi metallo-β-lactamases (NDM;  = 13) tested had 100% concordance to their genotypic profiles, whereas all carbapenemase (KPC;  = 8) and GES ( = 12) isolates tested negative, as expected, in the presence of EDTA. The eCIM failed to identify all imipenemase (IMP)-producing ( = 22) and Sao Paulo metallo-β-lactamase (SPM)-producing ( = 14) isolates. KPC-, VIM-, and NDM-producing were well defined by the conventional mCIM and eCIM testing methods; additional modifications appear required to differentiate GES-, IMP-, and SPM-producing isolates.
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http://dx.doi.org/10.1128/JCM.02015-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269398PMC
May 2020

Carbapenem-Resistant Enterobacterales: Considerations for Treatment in the Era of New Antimicrobials and Evolving Enzymology.

Curr Infect Dis Rep 2020 Feb 7;22(3). Epub 2020 Feb 7.

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

Purpose Of Review: Gram-negative resistance is a growing concern globally. Enterobacterales, formerly Enterobacteriaceae, have developed resistance mechanisms to carbapenems that leave very few antimicrobial options in the clinician's armamentarium.

Recent Findings: New antimicrobials like ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and plazomicin have the potential to overcome resistance mechanisms in Enterobacterales including different classes of carbapenemases. Novel β-lactam/β-lactamase inhibitors, plazomicin, and cefiderocol give the clinician options that were once not available. Utilizing these options is of the utmost importance when treating carbapenem-resistant Enterobacterales.
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http://dx.doi.org/10.1007/s11908-020-0716-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223591PMC
February 2020
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