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Amoxicillin–Clavulanate-Induced Liver Injury

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Abstract

Background and Aims

Amoxicillin–clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs.

Methods

Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials.

Results

One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P < 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P < 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to <2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI.

Conclusion

AC-DILI causes a moderately severe, mixed hepatocellular–cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.

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Acknowledgments

We thank Thomas Phillips from the Duke Clinical Research Institute for help with statistical analysis.

Grant Support

The DILIN Network is structured as a U01 cooperative agreement with Funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of The NIH, National Cancer Institute.

Author Contributions

Andrew S. deLemos was involved in study concept and design; analysis and interpretation of data; drafting of manuscript; critical revision of the manuscript for intellectual content; statistical analysis. Marwan Ghabril contributed to study concept and design; analysis and interpretation of data; drafting of manuscript; critical revision of the manuscript for intellectual content. Don C. Rockey was associated with study concept and design; analysis and interpretation of data; critical revision of the manuscript for intellectual content. Jiezhun Gu was involved in data collection and statistical analysis; critical revision of the manuscript for important intellectual content. Huiman X. Barnhart was involved in data collection and statistical analysis. Robert J. Fontana contributed to data collection; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. David E. Kleiner was associated with data collection; analysis and interpretation of data; critical revision of the manuscript for important intellectual content. Herbert L. Bonkovsky contributed to study concept and design; analysis and interpretation of data; drafting of manuscript; critical revision of the manuscript for intellectual content; statistical analysis.

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Authors and Affiliations

  1. Department of Medicine, Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 600, Charlotte, NC, 28204, USA

    Andrew S. deLemos

  2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Marwan Ghabril

  3. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Don C. Rockey

  4. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA

    Jiezhun Gu & Huiman X. Barnhart

  5. Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Robert J. Fontana

  6. Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA

    David E. Kleiner

  7. Department of Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, USA

    Herbert L. Bonkovsky

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  1. Andrew S. deLemos
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Drug-Induced Liver Injury Network (DILIN)

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Correspondence to Andrew S. deLemos.

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deLemos, A.S., Ghabril, M., Rockey, D.C. et al. Amoxicillin–Clavulanate-Induced Liver Injury. Dig Dis Sci 61, 2406–2416 (2016). https://doi.org/10.1007/s10620-016-4121-6

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  • DOI: https://doi.org/10.1007/s10620-016-4121-6

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