Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model
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 concentratio...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/2/201 |
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| author | Maxwell J. Lasko Tomefa E. Asempa David P. Nicolau |
| author_facet | Maxwell J. Lasko Tomefa E. Asempa David P. Nicolau |
| author_sort | Maxwell J. Lasko |
| collection | DOAJ |
| description | 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 (<i>n</i> = 7) or harboring an ESBL (<i>n</i> = 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 <i>f</i>T > MICs. A sigmoidal E<sub>max</sub> model was fitted to <i>f</i>T > MIC vs. change in log<sub>10</sub> CFU/thigh to determine the requirements for net stasis and 1-log<sub>10</sub> 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<sub>10</sub> CFU/thigh, respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log<sub>10</sub> CFU/thigh bacterial burden reduction at 24 h across the isolates. Stasis and 1-log<sub>10</sub> CFU/thigh reduction were achieved with a <i>f</i>T > MIC of 39% and 67%<b>,</b> respectively. The <i>f</i>T > MIC targets identified can be used to guide ceftibuten dosage selection to optimize the likelihood of clinical efficacy. |
| first_indexed | 2024-03-09T00:46:02Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T00:46:02Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-cac88e6583034cd598974962b6f90a0e2023-12-11T17:33:13ZengMDPI AGAntibiotics2079-63822021-02-0110220110.3390/antibiotics10020201Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh ModelMaxwell J. Lasko0Tomefa E. Asempa1David P. Nicolau2Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USACenter for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USACenter for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USAEfforts 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 (<i>n</i> = 7) or harboring an ESBL (<i>n</i> = 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 <i>f</i>T > MICs. A sigmoidal E<sub>max</sub> model was fitted to <i>f</i>T > MIC vs. change in log<sub>10</sub> CFU/thigh to determine the requirements for net stasis and 1-log<sub>10</sub> 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<sub>10</sub> CFU/thigh, respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log<sub>10</sub> CFU/thigh bacterial burden reduction at 24 h across the isolates. Stasis and 1-log<sub>10</sub> CFU/thigh reduction were achieved with a <i>f</i>T > MIC of 39% and 67%<b>,</b> respectively. The <i>f</i>T > MIC targets identified can be used to guide ceftibuten dosage selection to optimize the likelihood of clinical efficacy.https://www.mdpi.com/2079-6382/10/2/201pharmacokineticspharmacodynamicsGram-negativebeta-lactamase |
| spellingShingle | Maxwell J. Lasko Tomefa E. Asempa David P. Nicolau Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model Antibiotics pharmacokinetics pharmacodynamics Gram-negative beta-lactamase |
| title | Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model |
| title_full | Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model |
| title_fullStr | Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model |
| title_full_unstemmed | Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model |
| title_short | Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model |
| title_sort | pharmacodynamics of ceftibuten an assessment of an oral cephalosporin against enterobacterales in a neutropenic murine thigh model |
| topic | pharmacokinetics pharmacodynamics Gram-negative beta-lactamase |
| url | https://www.mdpi.com/2079-6382/10/2/201 |
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