Simple SummaryCarbapenems and colistin are reserved as the last-resort treatments of multidrug-resistant (MDR) infections in humans. Consequently, the emergence of carbapenem and colistin-resistant Klebsiella pneumoniae (K. pneumoniae) in poultry, contact workers and hospitalized patients is of grave concern for therapeutic options, and no data are available supporting this assumption on a regional or countrywide scale. We investigated the frequency and typing of extended-spectrum β-lactamase (ESBL) and carbapenemase-producing K. pneumoniae (ESBLK and CPK) in hospitalized patients, chickens from 10 poultry farms and their environment (water, food and litter) and farm workers in Egypt. All isolates from patients (13/90, 14.4%), workers (5/22, 22.7%), chickens (9/100, 9%) and the environment (10/60, 16.7%) harbored a single or multiple β-lactamase genes, blaSHV, blaTEM, blaCTX-M1 and blaOXA-1, often in combination with carbapenemase genes (blaVIM, blaNDM-1 or blaIMP; 45.9%), the mcr-1 gene (18.9%) or both (13.5%). Enterobacterial repetitive intergenic consensus (ERIC)-PCR genotyping highlighted potential inter and intraspecies clonal dissemination in the study area. The increased frequency and genetic relatedness of ESBLK and CPK from chickens and humans pose a public health threat that urges more prudent use of antimicrobials in chicken farms to avoid the propagation and expansion of both ESBLK and CPK from the chicken sources to humans.This study investigated the frequency of carbapenem and colistin resistance in ESBL-producing K. pneumoniae (ESBLK) isolates recovered from chickens and their environment, contact farm workers and hospitalized patients in Egypt. Further, the phenotypic and genotypic relationships between the community and hospital-acquired K. pneumoniae isolates in the same geographical area were investigated. From 272 total samples, 37 (13.6%) K. pneumoniae isolates were identified, of which 20 (54.1%) were hypervirulent. All isolates (100%) were multidrug-resistant (MDR) with multiple antibiotic resistance (MAR) indices ranging from 0.19 to 0.94. Colistin-resistant isolates (18.9%) displayed colistin MIC values >2 μg/mL, all harbored the mcr-1 gene. All isolates from patients (13/90, 14.4%), workers (5/22, 22.7%), chickens (9/100, 9%) and the environment (10/60, 16.7%) harbored a single or multiple β-lactamase genes, blaSHV, blaTEM, blaCTX-M1 and blaOXA-1, often in combination with carbapenemase genes (blaVIM, blaNDM-1 or blaIMP; 45.9%), the mcr-1 gene (18.9%) or both (13.5%). Enterobacterial repetitive intergenic consensus (ERIC)–PCR genotyping revealed 24 distinct ERIC types (ETs) with a discrimination index of 0.961. Six ETs showed clusters of identical isolates from chicken and human sources. The increased frequency and genetic relatedness of ESBLK and carbapenemase-producing K. pneumoniae (CPK) from chickens and humans pose a public health threat that urge more prudent use of antimicrobials in chicken farms to avoid the propagation and expansion of both ESBLK and CPK from the chicken sources to humans.