antibiotics Article Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model Maxwell J. Lasko 1, Tomefa E. Asempa 1 and David P. Nicolau 1,2,* 1 Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA; [email protected] (M.J.L.); [email protected] (T.E.A.) 2 Division of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA * Correspondence: [email protected]; Tel.: +1-860-972-3941; Fax: +1-860-545-3992 Abstract: 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 in- fection model. Enterobacterales isolates expressing no known clinically-relevant enzymatic resistance (n = 7) or harboring an ESBL (n = 2) were evaluated. The ceftibuten minimum inhibitory concentra- tions (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 f T > MICs. A sigmoidal Emax model was fitted to f T > MIC vs. change in log10 CFU/thigh to determine the requirements for net stasis and 1-log10 CFU/thigh bacterial burden reduction. Citation: Lasko, M.J.; Asempa, T.E.; The growth of the 0 h and 24 h control groups was 5.97 ± 0.37 and 8.51 ± 0.84 log CFU/thigh, Nicolau, D.P. Pharmacodynamics of 10 respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log CFU/thigh bacterial burden reduction Ceftibuten: An Assessment of an Oral 10 Cephalosporin against at 24 h across the isolates. Stasis and 1-log10 CFU/thigh reduction were achieved with a f T > MIC of Enterobacterales in a Neutropenic 39% and 67%, respectively. The f T > MIC targets identified can be used to guide ceftibuten dosage Murine Thigh Model. Antibiotics 2021, selection to optimize the likelihood of clinical efficacy. 10, 201. https://doi.org/10.3390/ antibiotics10020201 Keywords: pharmacokinetics; pharmacodynamics; Gram-negative; beta-lactamase Academic Editors: Nicholas Dixon and Anthony William Coleman Received: 6 January 2021 1. Introduction Accepted: 16 February 2021 Gram-negative Enterobacterales that harbor extended spectrum β-lactamases (ESBLs) Published: 19 February 2021 and carbapenemases continue to be a burden on healthcare [1–3]. ESBLs, in particular, are frequent causes of infection in both hospitalized and community-dwelling patients [1,3]. Publisher’s Note: MDPI stays neutral Few oral therapeutic options exist, resulting in the use of intravenous broad-spectrum with regard to jurisdictional claims in antibiotics (i.e., carbapenems) with the potential for further resistance development [4,5]. published maps and institutional affil- iations. Moreover, infections caused by ESBL-harboring Enterobacterales are associated with an approximately two-fold increase in the cost of hospitalization and the length of stay compared with β-lactamase naïve infections [6]. The clear need for carbapenem-sparing antibiotics that can effectively treat ESBL- harboring Enterobacterales has spurred numerous oral drug development efforts over the Copyright: © 2021 by the authors. past several years [7]. Additionally, the availability of an effective oral agent targeting these Licensee MDPI, Basel, Switzerland. challenging organisms would provide a significant therapeutic breakthrough for patients This article is an open access article treated outside the institutional setting. Thus, repurposing older and infrequently utilized distributed under the terms and oral β-lactam agents, such as ceftibuten, cefixime, and cefpodoxime, to be paired with conditions of the Creative Commons β Attribution (CC BY) license (https:// investigational -lactamase inhibitors (BLIs), has become an attractive option. creativecommons.org/licenses/by/ Ceftibuten has been explored as a β-lactam (BL) backbone because of its excellent 4.0/). bioavailability (75–90%) and high fractional excretion in urine [8,9]. In addition, ceftibuten Antibiotics 2021, 10, 201. https://doi.org/10.3390/antibiotics10020201 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, x FOR PEER REVIEW 2 of 10 utilized oral β-lactam agents, such as ceftibuten, cefixime, and cefpodoxime, to be paired with investigational β-lactamase inhibitors (BLIs), has become an attractive option. Ceftibuten has been explored as a β-lactam (BL) backbone because of its excellent bioavailability (75–90%) and high fractional excretion in urine [8,9]. In addition, ceftibuten Antibiotics 2021, 10, 201 demonstrates improved in vitro stability against ESBLs compared with other2 of oral 10 third- generation cephalosporins [8,9]. Ceftibuten’s pharmacodynamic driver is free drug time above MIC (fT > MIC). The fT > MIC requirements that best correlate with cephalosporin demonstratesefficacy vary improvedfrom 40–50%,in vitro as reportedstability against by the ESBLsEuropean compared Committee with other on Antimicrobial oral third- Sus- generationceptibility cephalosporinsTesting (EUCAST) [8,9]. scientific Ceftibuten’s committee pharmacodynamic [10], to as driverhigh as is 50–70% free drug [11,12]. time How- aboveever, a MIC formal (f T > ceftibuten MIC). The fpharmacodynamicT > MIC requirements assessment that best correlate against with clinically-relevant cephalosporin Enter- efficacyobacterales vary has from never 40–50%, been as performed. reported by Previously the European published Committee studies on Antimicrobial have focused on the Susceptibilityactivity of ceftibuten Testing (EUCAST) in combination scientific with committee BLIs, with [10 ],a tofocus as high on understanding as 50–70% [11,12 BLI]. expo- However, a formal ceftibuten pharmacodynamic assessment against clinically-relevant sure requirements for efficacy [13,14]. Thus, ceftibuten-specific pharmacodynamic profil- Enterobacterales has never been performed. Previously published studies have focused oning the is activityneeded of in ceftibuten order to inbetter combination understand with BLIs,the scope with a and focus potential on understanding utility of BLI a range of exposureexposures requirements prior to their for combination efficacy [13,14 with]. Thus, a novel ceftibuten-specific BLI. Herein, pharmacodynamicwe describe a pharmaco- profilingdynamic isassessment needed in of order ceftibuten to better in understand a neutropenic the murine scope and thigh potential infection utility model. of a range of exposures prior to their combination with a novel BLI. Herein, we describe a pharmacodynamic2. Results assessment of ceftibuten in a neutropenic murine thigh infection model. 2.2.1. Results Murine Pharmacokinetic Studies 2.1. MurineCeftibuten Pharmacokinetic single doses Studies were well characterized using a uniform one-compartment modelCeftibuten with first-order single doses absorption were well and characterized elimination using (Figure a uniform 1). Furthermore, one-compartment the pharma- modelcokinetics with of first-order ceftibuten absorption were relative and eliminationly linear (area (Figure under1). Furthermore, the curve (AUC) the pharma- R2 0.98) over cokineticsthe single of doses ceftibuten administered were relatively using linear non-compartmental (area under the curve analysis (AUC) R(Table2 0.98) 1). over The the elimina- singletion half-life doses administered ranged from using 1.0 to non-compartmental 1.8 h. The mean (± analysis standard (Table deviation1). The elimination (SD)) pharmacoki- half-life ranged from 1.0 to 1.8 h. The mean (± standard deviation (SD)) pharmacokinetic netic parameters, namely, volume of distribution (Vd), 0.342 ± 0.09 (L/kg); absorption con- parameters, namely, volume of distribution (Vd), 0.342 ± 0.09 (L/kg); absorption constant stant (Ka), 5.45 ± 2.46 (1/h); and elimination constant (Ke), 0.60 ± 0.17 (1/h), were used to (Ka), 5.45 ± 2.46 (1/h); and elimination constant (Ke), 0.60 ± 0.17 (1/h), were used to simulate ceftibutenceftibuten regimens regimens and and obtain obtain concentration–time concentration–time profiles. profiles. Comparisons Comparisons of the of the %fT %> fMICT > MIC values values achieved achieved with with ceftibuten ceftibuten at atMICs MICs ranging ranging between between 0.030.03 andand 4 4 mg/L, mg/L, as as well as wellthe area as the under area underthe concentration–time the concentration–time curve curve from from 0 to 024 to h 24 for h forthe thefree, free, unbound unbound fraction of fraction of the drug (f AUC ), in mice receiving the selected regimens are presented the drug (fAUC0–24), in mice0–24 receiving the selected regimens are presented in Table 2. in Table2. Figure 1.1.Ceftibuten Ceftibuten free free plasma plasma concentration–time concentration–time profiles profiles in a neutropenic in a neutropenic mouse thigh mouse infection thigh infec- modeltion model following following the administration the administration of single of subcutaneous single subcutaneous doses (0.5–45 doses mg/kg). (0.5–45 mg/kg). Antibiotics 2021, 10, 201 3 of 10 Table 1. Comparison of single dose ceftibuten regimens in mice using non-compartmental analysis. 2 Single Dose Regimen λ1/2 (h) fCmax fAUC0–8 R