Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Pharmacology

Human-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are Imperative

Christian M. Gill, Tomefa E. Asempa, David P. Nicolau
Christian M. Gill
aCenter for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomefa E. Asempa
aCenter for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David P. Nicolau
aCenter for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
bDivision of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/AAC.00594-20
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Animal infection models are invaluable in optimizing antimicrobial dosage in humans. Utilization of human-simulated regimens (HSRs) in animal models helps to evaluate antimicrobial efficacy at clinically achievable drug concentrations. To that end, pharmacokinetic studies in infected animals and confirmation of the HSR pharmacokinetic profile are essential in evaluating observed versus expected drug concentrations. We present and compare two murine meropenem-vaborbactam HSR profiles, their potential impact on bacterial killing, and clinical translatability.

TEXT

Translation of antimicrobial pharmacokinetic and pharmacodynamic (PK/PD) profiles from animal models to humans has become an invaluable tool in optimizing antimicrobial dosing strategies and predicting clinical outcomes (1–3). Murine models of human-simulated antimicrobial exposures have been utilized for >2 decades and have included agents with time-dependent bacterial killing (4, 5), agents with concentration-dependent protein binding (6, 7), and profiles humanized to exposure at the infection site (i.e., epithelial-lining fluid) (8, 9). Administration of human-simulated regimens (HSRs) in animal models ensures that antimicrobial efficacy is evaluated at clinically relevant exposures.

Recently, investigators have employed HSR to increase the translational value of their in vivo experiments; however, it is imperative that the pharmacokinetic profiles mimic human exposure in terms of biologically active free drug across the MIC distribution. With β-lactam–β-lactamase inhibitor or potentiator combinations, this is even more critical because the efficacy of the β-lactam is dependent on the humanized profile of both compounds over the dosing interval (8, 10–13). Here, we offer some considerations with regard to study design that may influence how readers interpret observations derived from murine infection models using human-simulated antimicrobial exposures.

Pharmacokinetic evaluations of human-simulated exposures in animal models may vary depending on the agent and dosing regimen, but several principles are fundamental. A significant criticism is the performance of pharmacokinetic analyses in uninfected animals and subsequent utilization in infection models (14, 15). Authors have described this as a limitation when, in fact, it renders the data suboptimal and uninterpretable from a translation standpoint. Indeed, numerous reports have demonstrated that the pharmacokinetics of antimicrobials can differ markedly in infected versus uninfected mice, as in humans (16–20). Free-drug exposures at infection sites and the volume of distribution can be altered during infection; thus, pharmacokinetic studies in uninfected mice may not reflect the true drug exposure during infection models and subsequently result in altered PK/PD relationship profiles (20, 21). Specific infection sites (e.g., epithelial lining fluid penetration in pneumonia models) also contribute to pharmacokinetic alterations between infected and uninfected animals (16). Comparative pharmacokinetic parameters and profiles should still be described in scenarios where no differences in antimicrobial exposure are observed by investigators (22, 23).

Confirmatory concentration-time profiles are essential in providing readers with the opportunity to evaluate whether the developed HSR profile is similar to simulated exposures derived from single-dose pharmacokinetic analysis (24). The following data illustrate the importance of confirmatory pharmacokinetic analysis. Before conducting the meropenem-vaborbactam murine study, we reproduced the pharmacokinetic profile of the meropenem-vaborbactam murine HSR (originally developed in uninfected mice) of Sabet et al. (14) in the neutropenic thigh infection model, in addition to simulating relevant human exposures (25). All murine studies were IACUC approved. Notably, this regimen (PK1, Sabet et al. regimen [14] [Fig. 1]) consists of 4 intraperitoneal doses of meropenem 300 mg/kg and vaborbactam 50 mg/kg coadministered every 2 h (q2h) over 8 h. We subsequently developed a meropenem-vaborbactam HSR (65/10.8 mg/kg at 0 and 1.25 h, 55/6 mg/kg at 3.5 h, and 50/4 mg/kg at 6 h) administered via subcutaneous injection in a neutropenic thigh infection model (CD-1 female mice; average weight, 20 to 22 g) to yield exposures similar to those achieved in humans after administration of meropenem-vaborbactam 2/2 g q8h as a 3-h infusion (26) (PK2, this study regimen [Fig. 2]) to compare drug exposure between the two dosing regimens. Human profiles were simulated for comparison using the human pharmacokinetic parameters from published data using Phoenix (version 8.1; Certara, Princeton, NJ) (25, 26). In PK1 and PK2, the murine thigh infection model was prepared as previously described (4), except that 150 mg/kg of cyclophosphamide was administered on days −4 and −1 (14). In PK2 only, animals were pretreated with uranyl nitrate as previously described (4, 5). Groups of six mice were sacrificed by CO2 asphyxiation at prespecified time points (n = 7 and 5 for PK1 and PK2, respectively) of the 8-h dosing interval. Confirmatory plasma sampling time points were selected to compare murine drug concentrations with simulated murine concentrations. These time points captured peak and trough concentrations on the murine-simulated profile, as well as murine-simulated concentrations that were expected to be similar to human drug concentrations. Plasma sampling was collected via cardiac puncture as previously described (4), and free-drug concentrations were estimated (14). Murine-simulated regimens were calculated using Phoenix. For PK1, the simulation was constructed using the meropenem-vaborbactam 300/50-mg/kg q2h regimen and matching the simulated output to the free-drug area under the concentration-time curve (fAUC) and percentage of the dosing interval during which free drug concentrations are above the MIC of 8 mg/liter (%fT>MIC 8 mg/liter) to what was reported for both meropenem and vaborbactam to estimate how the proposed profile may look over the 8-h interval (14). Of note, the simulated exposures were based on pharmacokinetics from uninfected mice. The PK2 simulation was based on parameters of previous meropenem pharmacokinetic experiments in infected animals and in the presence of uranyl nitrate (4). Our experience with the PK2 meropenem regimen from previous publications allowed for a robust assessment with five sampling time points (4, 27). Based on equivalent human exposures (i.e., overlapping profiles) of meropenem and vaborbactam, the goal of PK2 was to attain similar meropenem and vaborbactam exposures in the mouse model. The murine-simulated meropenem concentration-time profile therefore served as a target vaborbactam profile. Drug concentration determination was performed using a validated high-performance liquid chromatography assay on murine plasma. The murine plasma assay was linear over the range 0.25 to 50 μg/ml (R2 ≥ 0.998). The coefficients of variation of the quality control samples for meropenem and vaborbactam were ≤6.1%. Interday coefficients of variation were ≤4.1% for meropenem and ≤4.0% for vaborbactam. The accuracy for interday and intraday quality control samples for both compounds was ≥95%.

FIG 1
  • Open in new tab
  • Download powerpoint
FIG 1

Observed meropenem and vaborbactam murine concentration-time profile compared with human simulation PK1. Observed concentrations of free meropenem and vaborbactam in the neutropenic murine thigh infection model after meropenem-vaborbactam 300/50 mg/kg administered intraperitoneally q2h. Plasma sampling occurred at 0.75, 1, 2.25, 3, 5, 5.5, and 7.75 h. Solid lines, human simulations derived from healthy volunteers for meropenem and vaborbactam. Dashed lines, estimated simulated murine exposure based on indices reported by Sabet et al. (14) from uninfected mice. Circles (red) and triangles (green), observed murine meropenem and vaborbactam concentrations (means ± SD), respectively.

FIG 2
  • Open in new tab
  • Download powerpoint
FIG 2

Observed meropenem and vaborbactam murine concentration-time profile compared with human simulation PK2. Observed concentrations of free meropenem and vaborbactam in the neutropenic murine thigh infection model receiving meropenem-vaborbactam 65/10.8 mg/kg at 0 and 1.25 h, 55/6 mg/kg at 3.5 h, and 50/4 mg/kg at 6 h. Plasma sampling occurred at 1, 1.5, 2, 4.75, and 8 h. Solid lines, simulated human meropenem (red) and vaborbactam (green) concentrations derived from infected patients in the phase 3 meropenem-vaborbactam trials. Dashed line (red), murine-simulated exposure of meropenem and vaborbactam. Circles (red) and triangles (green), observed murine meropenem and vaborbactam concentrations (means ± SD), respectively.

Pharmacokinetic parameters of the simulated human regimens and evaluated murine regimens for PK1 and PK2 are described in Table 1. For comparison, pharmacokinetic data from healthy volunteers (25) and a population pharmacokinetic model (derived from phase 3 clinical trials) (26) were simulated. Figure 1 (PK1) depicts our reproduced meropenem-vaborbactam murine profile (14). Notably, we observed an initial meropenem concentration similar to the previously reported peak concentration (210 versus 260 mg/liter) (14). Compared with the simulated murine meropenem profiles, elevated meropenem concentrations were observed, particularly at the end of the murine dosing interval, with observed meropenem concentrations of 393 ± 104 and 36 ± 22 mg/liter at 5 and 7.75 h (trough), respectively, compared with murine-simulated exposures of 14 and 1 mg/liter, respectively. To avoid exposures that are inconsistent with those of humans during the pharmacodynamic investigations, confirmation of the proposed pharmacokinetic profile should be evaluated before initiation of these studies. Furthermore, the presence of infection may explain this supratherapeutic exposure, highlighting potential pharmacokinetic differences in infected versus uninfected animals. The observed elevated concentrations may explain the unexpected meropenem efficacy (bacterial stasis) reported by Sabet et al. (14, 28) against a range of KPC-harboring Enterobacterales, including isolates with meropenem MICs of >64 mg/liter. Similarly, using the same meropenem-vaborbactam regimen, unexpected differences in bacterial density reduction were observed between meropenem-vaborbactam and meropenem alone against Pseudomonas aeruginosa despite the same MIC (29). Confirmatory pharmacokinetic studies of the HSR are ultimately required to determine whether pharmacokinetic discrepancies, like those described above, are products of aberrant drug exposures (e.g., due to drug accumulation, murine drug-drug interactions when combination therapy is administered). In comparison, the confirmatory pharmacokinetic studies for PK2, as depicted in Fig. 2 and Table 1, show a meropenem-vaborbactam HSR that results in observed murine concentrations and pharmacokinetic indices comparable to those of the human profile. For example, at the 4.75- and 8-h time points, the observed murine meropenem concentration was 20 ± 18 and 4 ± 4 mg/liter, respectively, compared to target murine-simulated exposures of 11 and 4 mg/liter, respectively.

View this table:
  • View inline
  • View popup
  • Download powerpoint
TABLE 1

Estimated meropenem-vaborbactam murine pharmacodynamic parameters compared with humans for the two murine regimens

As described in Table 1, Sabet and colleagues (14, 28, 30) compared murine %fT>MIC for meropenem and free area under the curve from 0 to 24 h (fAUC0–24) for vaborbactam with human data, utilizing PK/PD relationships that best correlate with efficacy for each agent. Unfortunately, key pharmacokinetic parameters and indices were not reported, making interpretation of the results challenging. The comparison of the murine and human exposures was solely based on the percentage of the dosing interval during which meropenem exceeds a single MIC of 8 mg/liter (i.e., %fT>8 mg/liter) (14). The murine exposure may in fact be similar to the human profile at other MICs, but given the discordant meropenem exposures (i.e., 4-fold difference) in the murine model compared with that in humans (meropenem fAUC0–24, 1,572 versus 402 mg · h/liter, respectively) (14), the %fT above other MICs should be presented. Additionally, Table 1 (PK2) provides an example displaying the %fT>MIC for a murine meropenem regimen compared with the human profile. By providing the %fT>MIC data over a range of clinically relevant MICs, readers can assess how well the murine exposure compares with the human PK/PD relationships against all included isolates at different meropenem-vaborbactam MICs. This includes isolates with MICs around the CLSI (i.e., 4 mg/liter) and EUCAST (i.e., 8 mg/liter) breakpoints (31, 32).

In summary, consideration of the points above for future studies utilizing humanized drug exposures in mice will allow for valid inferences with respect to breakpoint determination or activity against multidrug-resistant isolates when clinical data are difficult to obtain. No model will perfectly simulate human exposure in mice; however, these considerations are imperative for translation of findings from mice to humans.

ACKNOWLEDGMENTS

We thank Kamilia Abdelraouf for review of the manuscript and critical conversations. We also thank Christina Sutherland for expertise in the development and conduction of the meropenem and vaborbactam high-performance liquid chromatography assay.

We recognize Alissa Padget, Charlie Cote, Deborah Santini, Janice Cunningham, Elias Mullane, Courtney Bouchard, Jennifer Tabor-Rennie, Rebecca Stewart, Nicole DeRosa, Kimelyn Greenwood, Lauren McLellan, Elizabeth Cyr, Elizabeth Martin, Olesya Slipchuk, Maxwell Lasko, Iris Chen, Sergio Reyes, and Wendylee Rodriguez from the Center for Anti-Infective Research and Development for vital assistance in this study.

This project was internally funded by the Center for Anti-Infective Research and Development.

FOOTNOTES

    • Received 27 March 2020.
    • Returned for modification 28 April 2020.
    • Accepted 13 May 2020.
    • Accepted manuscript posted online 18 May 2020.
  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

REFERENCES

  1. 1.↵
    1. Bulitta JB,
    2. Hope WW,
    3. Eakin AE,
    4. Guina T,
    5. Tam VH,
    6. Louie A,
    7. Drusano GL,
    8. Hoover JL
    . 2019. Generating robust and informative nonclinical in vitro and in vivo bacterial infection model efficacy data to support translation to humans. Antimicrob Agents Chemother 63:e02307-18. doi:10.1128/AAC.02307-18.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Andes D,
    2. Craig WA
    . 2002. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 19:261–268. doi:10.1016/S0924-8579(02)00022-5.
    OpenUrlCrossRefPubMedWeb of Science
  3. 3.↵
    1. Ambrose PG,
    2. Bhavnani SM,
    3. Rubino CM,
    4. Louie A,
    5. Gumbo T,
    6. Forrest A,
    7. Drusano GL
    . 2007. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis 44:79–86. doi:10.1086/510079.
    OpenUrlCrossRefPubMedWeb of Science
  4. 4.↵
    1. Monogue ML,
    2. Tsuji M,
    3. Yamano Y,
    4. Echols R,
    5. Nicolau DP
    . 2017. Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of Gram-negative bacteria in a murine thigh infection model. Antimicrob Agents Chemother 61:e01022-17. doi:10.1128/AAC.01022-17.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Nicolau DP,
    2. Onyeji CO,
    3. Zhong M,
    4. Tessier PR,
    5. Banevicius MA,
    6. Nightingale CH
    . 2000. Pharmacodynamic assessment of cefprozil-against Streptococcus pneumoniae: implications for breakpoint determinations. Antimicrob Agents Chemother 44:1291–1295. doi:10.1128/AAC.44.5.1291-1295.2000.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Thabit AK,
    2. Monogue ML,
    3. Nicolau DP
    . 2016. Eravacycline pharmacokinetics and challenges in defining humanized exposure in vivo. Antimicrob Agents Chemother 60:5072–5075. doi:10.1128/AAC.00240-16.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Monogue ML,
    2. Thabit AK,
    3. Hamada Y,
    4. Nicolau DP
    . 2016. Antibacterial efficacy of eravacycline in vivo against Gram-positive and Gram-negative organisms. Antimicrob Agents Chemother 60:5001–5005. doi:10.1128/AAC.00366-16.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Asempa TE,
    2. Motos A,
    3. Abdelraouf K,
    4. Bissantz C,
    5. Zampaloni C,
    6. Nicolau DP
    . 2019. Efficacy of human-simulated epithelial lining fluid exposure of meropenem-nacubactam combination against class A serine β-lactamase-producing Enterobacteriaceae in the neutropenic murine lung infection model. Antimicrob Agents Chemother 63:e02382-18. doi:10.1128/AAC.02382-18.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Kidd JM,
    2. Abdelraouf K,
    3. Nicolau DP
    . 2019. Comparative efficacy of human-simulated epithelial lining fluid exposures of tedizolid, linezolid and vancomycin in neutropenic and immunocompetent murine models of staphylococcal pneumonia. J Antimicrob Chemother 74:970–977. doi:10.1093/jac/dky513.
    OpenUrlCrossRef
  10. 10.↵
    1. Monogue ML,
    2. Giovagnoli S,
    3. Bissantz C,
    4. Zampaloni C,
    5. Nicolau DP
    . 2018. In vivo efficacy of meropenem with a novel non-β-lactam–β-lactamase inhibitor, nacubactam, against Gram-negative organisms exhibiting various resistance mechanisms in a murine complicated urinary tract infection model. Antimicrob Agents Chemother 62:e02596-17. doi:10.1128/AAC.02596-17.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. MacVane SH,
    2. Crandon JL,
    3. Nichols WW,
    4. Nicolau DP
    . 2014. In vivo efficacy of humanized exposures of ceftazidime-avibactam in comparison with ceftazidime against contemporary Enterobacteriaceae isolates. Antimicrob Agents Chemother 58:6913–6919. doi:10.1128/AAC.03267-14.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Abdelraouf K,
    2. Stainton SM,
    3. Nicolau DP
    . 2019. In vivo pharmacodynamic profile of ceftibuten-clavulanate combination against extended-spectrum-β-lactamase-producing Enterobacteriaceae in the murine thigh infection model. Antimicrob Agents Chemother 63:e00145-19. doi:10.1128/AAC.00145-19.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Avery LM,
    2. Abdelraouf K,
    3. Nicolau DP
    . 2018. Assessment of the In vivo efficacy of WCK 5222 (cefepime-zidebactam) against carbapenem-resistant Acinetobacter baumannii in the neutropenic murine lung infection model. Antimicrob Agents Chemother 62:e00948-18. doi:10.1128/AAC.00948-18.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Sabet M,
    2. Tarazi Z,
    3. Nolan T,
    4. Parkinson J,
    5. Rubio-Aparicio D,
    6. Lomovskaya O,
    7. Dudley MN,
    8. Griffith DC
    . 2017. Activity of meropenem-vaborbactam in mouse models of infection due to KPC-producing carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother 62:e01446-17. doi:10.1128/AAC.01446-17.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Chambers HF,
    2. Basuino L,
    3. Diep BA,
    4. Steenbergen J,
    5. Zhang S,
    6. Tattevin P,
    7. Alder J
    . 2009. Relationship between susceptibility to daptomycin in vitro and activity in vivo in a rabbit model of aortic valve endocarditis. Antimicrob Agents Chemother 53:1463–1467. doi:10.1128/AAC.01307-08.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Keel RA,
    2. Crandon JL,
    3. Nicolau DP
    . 2012. Pharmacokinetics and pulmonary disposition of tedizolid and linezolid in a murine pneumonia model under variable conditions. Antimicrob Agents Chemother 56:3420–3422. doi:10.1128/AAC.06121-11.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Crandon JL,
    2. Kim A,
    3. Nicolau DP
    . 2009. Comparison of tigecycline penetration into the epithelial lining fluid of infected and uninfected murine lungs. J Antimicrob Chemother 64:837–839. doi:10.1093/jac/dkp301.
    OpenUrlCrossRefPubMedWeb of Science
  18. 18.↵
    1. Watanabe A,
    2. Matsumoto K,
    3. Igari H,
    4. Uesato M,
    5. Yoshida S,
    6. Nakamura Y,
    7. Morita K,
    8. Shibuya K,
    9. Matsubara H,
    10. Yoshino I,
    11. Kamei K
    . 2010. Comparison between concentrations of amphotericin B in infected lung lesion and in uninfected lung tissue in a patient treated with liposomal amphotericin B (AmBisome). Int J Infect Dis 14:e220–e223. doi:10.1016/j.ijid.2009.07.020.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Oshima K,
    2. Nakamura S,
    3. Iwanaga N,
    4. Takemoto K,
    5. Miyazaki T,
    6. Yanagihara K,
    7. Miyazaki Y,
    8. Mukae H,
    9. Kohno S,
    10. Izumikawa K
    . 2017. Efficacy of high-dose meropenem (six grams per day) in treatment of experimental murine pneumonia induced by meropenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 61:e02056-16. doi:10.1128/AAC.02056-16.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Gonzalez D,
    2. Schmidt S,
    3. Derendorf H
    . 2013. Importance of relating efficacy measures to unbound drug concentrations for anti-infective agents. Clin Microbiol Rev 26:274–288. doi:10.1128/CMR.00092-12.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Xiong J,
    2. Zhu Q,
    3. Yang S,
    4. Zhao Y,
    5. Cui L,
    6. Zhuang F,
    7. Qiu Y,
    8. Cao J
    . 2019. Comparison of pharmacokinetics of tilmicosin in healthy pigs and pigs experimentally infected with Actinobacillus pleuropneumoniae. N Z Vet J 67:257–263. doi:10.1080/00480169.2019.1633434.
    OpenUrlCrossRef
  22. 22.↵
    1. Housman ST,
    2. Crandon JL,
    3. Nichols WW,
    4. Nicolau DP
    . 2014. Efficacies of ceftazidime-avibactam and ceftazidime against Pseudomonas aeruginosa in a murine lung infection model. Antimicrob Agents Chemother 58:1365–1371. doi:10.1128/AAC.02161-13.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Bulik CC,
    2. Okusanya ÓO,
    3. Lakota EA,
    4. Forrest A,
    5. Bhavnani SM,
    6. Hoover JL,
    7. Andes DR,
    8. Ambrose PG
    . 2017. Pharmacokinetic-pharmacodynamic evaluation of gepotidacin against Gram-positive organisms using data from murine infection models. Antimicrob Agents Chemother 61:e00115-16. doi:10.1128/AAC.00115-16.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Drusano GL,
    2. Louie A
    . 2019. Breakpoint determination when multiple organisms are tested for effect targets. Eur J Pharm Sci 130:196–199. doi:10.1016/j.ejps.2019.01.033.
    OpenUrlCrossRef
  25. 25.↵
    1. Wenzler E,
    2. Gotfried MH,
    3. Loutit JS,
    4. Durso S,
    5. Griffith DC,
    6. Dudley MN,
    7. Rodvold KA
    . 2015. Meropenem-RPX7009 concentrations in plasma, epithelial lining fluid, and alveolar macrophages of healthy adult subjects. Antimicrob Agents Chemother 59:7232–7239. doi:10.1128/AAC.01713-15.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    US Food and Drug Administration. 2017. Center for Drug Evaluation and Research application number 209776Orig1s000: clinical pharmacology and biopharmaceutics review(s) addendum. U.S. Food and Drug Administration, Silver Spring, MD. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000ClinPharmR.pdf.
  27. 27.↵
    1. Kidd JM,
    2. Abdelraouf K,
    3. Nicolau DP
    . 2019. Development of neutropenic murine models of iron overload and depletion to study the efficacy of siderophore-antibiotic conjugates. Antimicrob Agents Chemother 64:1–8. doi:10.1128/AAC.01961-19.
    OpenUrlCrossRef
  28. 28.↵
    1. Griffith DC,
    2. Sabet M,
    3. Tarazi Z,
    4. Lomovskaya O,
    5. Dudley MN
    . 2018. Pharmacokinetics/pharmacodynamics of vaborbactam, a novel beta-lactamase inhibitor, in combination with meropenem. Antimicrob Agents Chemother 63:e01659-18. doi:10.1128/AAC.01659-18.
    OpenUrlCrossRef
  29. 29.↵
    1. Sabet M,
    2. Tarazi Z,
    3. Griffith DC
    . 2018. Activity of meropenem-vaborbactam against Pseudomonas aeruginosa and Acinetobacter baumannii in a neutropenic mouse thigh infection model. Antimicrob Agents Chemother 63:e01665-18. doi:10.1128/AAC.01665-18.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Nicolau DP
    . 2008. Pharmacokinetic and pharmacodynamic properties of meropenem. Clin Infect Dis 47:S32–S40. doi:10.1086/590064.
    OpenUrlCrossRefPubMed
  31. 31.↵
    Clinical and Laboratory Standards Institute. 2019. Performance standards for antimicrobial susceptibility testing—29th ed. CLSI supplement M100. Clinical and Laboratory Standards Institute, Wayne, PA.
  32. 32.↵
    European Committee on Antimicrobial Susceptibility Testing. 2020. Breakpoint tables for interpretation of MICs and zone diameters. https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_10.0_Breakpoint_Tables.pdf.
  33. 33.
    1. Sabet M,
    2. Tarazi Z,
    3. Rubio-Aparicio D,
    4. Nolan TG,
    5. Parkinson J,
    6. Lomovskaya O,
    7. Dudley MN,
    8. Griffith DC
    . 2017. Activity of simulated human dosage regimens of meropenem and vaborbactam against carbapenem-resistant enterobacteriaceae in an in vitro hollow-fiber model. Antimicrob Agents Chemother 62:e01969-17. doi:10.1128/AAC.01969-17.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Download PDF
Citation Tools
Human-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are Imperative
Christian M. Gill, Tomefa E. Asempa, David P. Nicolau
Antimicrobial Agents and Chemotherapy Jul 2020, 64 (8) e00594-20; DOI: 10.1128/AAC.00594-20

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Human-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are Imperative
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Human-Simulated Antimicrobial Regimens in Animal Models: Transparency and Validation Are Imperative
Christian M. Gill, Tomefa E. Asempa, David P. Nicolau
Antimicrobial Agents and Chemotherapy Jul 2020, 64 (8) e00594-20; DOI: 10.1128/AAC.00594-20
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • TEXT
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

β-lactams
human-simulated exposure
murine model
pharmacodynamics
pharmacokinetics

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596