---
title: "Piperine enhances amoxicillin activity and alters pharmacokinetics against resistant E. coli in br"
id: "pubmed-42734861"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42734861"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42734861/"
doi: "10.1007/s11259-026-11500-0"
published_at: "2026-09-14T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Piperine enhances amoxicillin activity and alters pharmacokinetics against resistant E. coli in br
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42734861
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42734861/)
- **DOI:** [10.1007/s11259-026-11500-0](https://doi.org/10.1007%2Fs11259-026-11500-0)
- **Published At:** 2026-09-14T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- This study evaluated combining **piperine** (an efflux pump inhibitor) with **amoxicillin** in broiler chickens experimentally infected with antibiotic- and metal-tolerant E. coli O125. - In vitro, amoxicillin and piperine minimum inhibitory concentrations (MICs) were 32 µg/mL and 5 µg/mL, respectively, with a synergistic fractional inhibitory concentration (FIC) index of 0.2518. - Acute and subacute toxicity testing followed OECD and ARRIVE guidance; dietary piperine at 100 mg/kg was well tolerated and improved antioxidant markers. - Two hundred twenty-five day-old chicks were allocated to five groups: negative control, positive control (infected untreated), and three infected groups treated orally for five days with amoxicillin, piperine, or the combination. - Outcomes included quantitative E. coli counts, expression of efflux-associated genes, tissue heavy metal concentrations, serum and tissue drug levels measured by validated HPLC, pharmacokinetic compartmental analysis, and residue depletion assessment. - Co-administration of piperine with amoxicillin reduced mean E. coli counts to 2.2 log10 CFU/g and downregulated efflux genes by approximately 0.4–0.5-fold change versus comparator(s). - Pharmacokinetics: amoxicillin followed a two-compartment model; piperine fit a one-compartment model. Piperine significantly increased amoxicillin Cmax and AUC and decreased clearance, enhancing systemic exposure and prolonging tissue persistence. - Residue and regulatory implication: when combined with piperine, amoxicillin required an extended withdrawal period of 5 days post-treatment to meet amoxicillin maximum residue limits (MRLs), compared with 3 days for amoxicillin alone. - Low concentrations of zinc, copper, and cadmium were detected in tissues. - The authors conclude that piperine augments amoxicillin efficacy via resistance-modulating (efflux inhibition) and pharmacokinetic interactions; safety and withdrawal implications were noted.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. rehamhosny87@yahoo.com. * 2 Reference Laboratory for Veterinary Quality Control on Poultry Production, (Gamasa Branch), Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. * 3 Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. * 4 Department of Chemistry, Pharmacology and Pyrogen Unit, Toxicology and Feed Deficiency, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. * PMID: **42734861** * DOI: [ 10.1007/s11259-026-11500-0 ](https://doi.org/10.1007/s11259-026-11500-0) Item in Clipboard # Effect of combined piperine and amoxicillin as an efflux pump inhibitor for metal-tolerant and antibiotic - resistant E. coli in broilers Reham A Hosny et al. Vet Res Commun. 2026. Show details Display options Display options Format Abstract PubMed PMID Vet Res Commun Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Vet+Res+Commun%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Vet+Res+Commun%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) . 2026 Sep 14;50(6):566. doi: 10.1007/s11259-026-11500-0. ### Authors [Reham A Hosny](https://pubmed.ncbi.nlm.nih.gov/?term=Hosny+RA&cauthor_id=42734861)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42734861/#short-view-affiliation-1 "Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. rehamhosny87@yahoo.com."), [Amera F Ebrahem](https://pubmed.ncbi.nlm.nih.gov/?term=Ebrahem+AF&cauthor_id=42734861)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42734861/#short-view-affiliation-2 "Reference Laboratory for Veterinary Quality Control on Poultry Production, \(Gamasa Branch\), Animal Health Research Institute, Agricultural Research Center, Giza, Egypt."), [Mai F Abdelaty](https://pubmed.ncbi.nlm.nih.gov/?term=Abdelaty+MF&cauthor_id=42734861)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42734861/#short-view-affiliation-3 "Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt."), [Amany Adel](https://pubmed.ncbi.nlm.nih.gov/?term=Adel+A&cauthor_id=42734861)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42734861/#short-view-affiliation-3 "Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt."), [Zeinab A El-Badiea](https://pubmed.ncbi.nlm.nih.gov/?term=El-Badiea+ZA&cauthor_id=42734861)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42734861/#short-view-affiliation-3 "Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt."), [Mai A Fadel](https://pubmed.ncbi.nlm.nih.gov/?term=Fadel+MA&cauthor_id=42734861)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42734861/#short-view-affiliation-4 "Department of Chemistry, Pharmacology and Pyrogen Unit, Toxicology and Feed Deficiency, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt.") ### Affiliations * 1 Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. rehamhosny87@yahoo.com. * 2 Reference Laboratory for Veterinary Quality Control on Poultry Production, (Gamasa Branch), Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. * 3 Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. * 4 Department of Chemistry, Pharmacology and Pyrogen Unit, Toxicology and Feed Deficiency, Animal Health Research Institute, Agricultural Research Center, Giza, Egypt. * PMID: **42734861** * DOI: [ 10.1007/s11259-026-11500-0 ](https://doi.org/10.1007/s11259-026-11500-0) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract This study investigated the effects of combining piperine, an efflux pump inhibitor, with amoxicillin in broilers infected with resistant E. coli O125, evaluating antibacterial efficacy, efflux-associated gene expression, pharmacokinetics, and residue depletion. In vitro, amoxicillin and piperine minimum inhibitory concentrations (MICs) were 32 and 5 µg/mL, respectively, with a synergistic fractional inhibitory concentration (FIC) index of 0.2518. Piperine toxicity and oxidative stress markers were also assessed. Two hundred twenty-five-day-old chicks were divided into five groups: negative and positive controls, and three infected groups treated orally for five days with amoxicillin, piperine, or their combination. E. coli counts, efflux gene expression, and heavy metal concentrations were evaluated at multiple time points. Serum and tissue drug concentrations were quantified using validated HPLC, followed by compartmental pharmacokinetic and residue depletion analyses. Dietary piperine (100 mg/kg) was well-tolerated and improved antioxidant status. Co-administration with amoxicillin reduced mean E. coli counts to 2.2 log10 CFU/g and downregulated efflux genes 0.4-0.5-fold change. Amoxicillin followed two-compartment kinetics, while piperine followed a one-compartment model. Piperine significantly increased amoxicillin maximum plasma concentration (Cmax) and area under the curve (AUC), while decreasing clearance. Furthermore, piperine enhanced amoxicillin systemic exposure and prolonged tissue persistence. From a regulatory standpoint, this combination requires an extended withdrawal period of 5 days post-cessation compared to 3 days for amoxicillin alone, to ensure compliance with amoxicillin maximum residue limits (MRLs). Low concentrations of zinc, copper, and cadmium were detected across tissues. These findings suggest piperine enhances amoxicillin efficacy through resistance-modulating and pharmacokinetic mechanisms. **Keywords:** E. coli; Antimicrobial resistance; Efflux pump; Heavy metal; Piperine; Resistance. © 2026. The Author(s), under exclusive licence to Springer Nature B.V. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Ethics approval: Acute oral toxicity and subacute oral toxicity studies were carried out in in accordance with ARRIVE 2.0 guidelines and current animal welfare recommendations outlined in (Percie du Sert et al. 2020). Acute oral toxicity was evaluated in accordance with the Organization for Economic Co-operation and Development Test Guideline 223 (Edwards et al. 2017). The experimental study was approved by then Regulations of the Institutional Animal Care and Use Committee (ARCIACUC) (Agricultural Research Center) under registration number (ARC AHRI, 6725). Competing interests: The authors declare no competing interests. ## References 1. 1. Aboubakr M, Elbadawy M (2017) Bioequivalence study of two oral amoxicillin formulations (Biocillin® and Atcomox 87%®) in broiler chickens. Int J Basic Clin Pharm 6(5):1042–1047. - [DOI](https://doi.org/10.18203/2319-2003.ijbcp20171654) 2. 1. Alfonso-Carrillo C, Akbari Moghaddam Kakhki R, Garcia-Ruiz AI (2024) Comparison of hydroxychloride versus oxide and sulfate sources of manganese, zinc, and copper in rearing diets on pullet growth, tibia traits, and egg production and eggshell quality in ISA brown hens up to 50 weeks. Animals 14(24):3581. - [DOI](https://doi.org/10.3390/ani14243581) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/39765485/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/11672641/) 3. 1. Algammal AM, El-Sayed ME, Youssef FM, Saad SA, Elhaig MM, Batiha GE, Hozzein WN, Ghobashy MOI (2020) Prevalence, the antibiogram and the frequency of virulence genes of the most predominant bacterial pathogens incriminated in calf pneumonia. AMB Express 10(1):99. - [DOI](https://doi.org/10.1186/s13568-020-01037-z) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/32472209/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/7260340/) 4. 1. Ali A, El-Mawgoud AIA, Dahshan A, EL-Sawah AA, Nasef SA, Ibrahim M (2019) Virulence gene constellations associated with lethality in avian pathogenic E. coli recovered from broiler chickens. Adv Anim Vet Sci 7(12):1076–1082. - [DOI](https://doi.org/10.17582/journal.aavs/2019/7.12.1076.1082) 5. 1. Alves FS, Cruz JN, de Farias Ramos IN, do, Nascimento Brandão DL, Queiroz RN, da Silva GV, Dolabela MF, da Costa ML, Khayat AS et al (2022) Evaluation of antimicrobial activity and cytotoxicity effects of extracts of piper nigrum L. and piperine. Separations.10(1):21. Show all 94 references ## MeSH terms * Alkaloids* / administration & dosage Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alkaloids%2Fadministration+and+dosage%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alkaloids) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Alkaloids* / pharmacokinetics Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alkaloids%2Fpharmacokinetics%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alkaloids) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Alkaloids* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Alkaloids%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Alkaloids) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Amoxicillin* / administration & dosage Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Amoxicillin%2Fadministration+and+dosage%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Amoxicillin) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Amoxicillin* / pharmacokinetics Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Amoxicillin%2Fpharmacokinetics%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Amoxicillin) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Amoxicillin* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Amoxicillin%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Amoxicillin) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Amoxicillin* / therapeutic use Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Amoxicillin%2Ftherapeutic+use%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Amoxicillin) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42734861/) * Anti-Bacterial Agents* / administration & dosage Action
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