Carbapenem resistance has become major concern in healthcare settings globally; therefore, its monitoring is crucial for intervention efforts to halt resistance spread. During May 2019-April 2022, 2170 clinical strains were characterized for antimicrobial susceptibility, resistance genes, replicon and sequence types. Overall, 42.1% isolates were carbapenem-resistant, and significantly associated with Klebsiella pneumoniae (K. pneumoniae) (p = 0.008) and Proteus species (p = 0.043). Carbapenemases were detected in 82.2% of isolates, with bla(NDM-1) (41.1%) associated with the ICU (p < 0.001), cardiology (p = 0.042), pediatric medicine (p = 0.013) and wound samples (p = 0.041); bla(OXA-48) (32.6%) was associated with the ICU (p < 0.001), cardiology (p = 0.008), pediatric medicine (p < 0.001), general surgery (p = 0.001), general medicine (p = 0.005) and nephrology (p = 0.020); bla(KPC-2) (5.5%) was associated with general surgery (p = 0.029); bla(NDM-1)/bla(OXA-48) (11.4%) was associated with general surgery (p < 0.001), and wound (p = 0.002), urine (p = 0.003) and blood (p = 0.012) samples; bla(OXA-48)/bla(VIM) (3.1%) was associated with nephrology (p < 0.001) and urine samples (p < 0.001). Other detected carbapenemases were bla(VIM) (3.0%), bla(IMP) (2.7%), bla(OXA-48)/bla(IMP) (0.1%) and bla(VIM)/bla(IMP) (0.3%). Sequence type (ST)147 (39.7%) represented the most common sequence type identified among K. pneumoniae, along with ST11 (23.0%), ST14 (15.4%), ST258 (10.9%) and ST340 (9.6%) while ST405 comprised 34.5% of Escherichia coli (E. coli) isolates followed by ST131 (21.2%), ST101 (19.7%), ST10 (16.0%) and ST69 (7.4%). Plasmid replicon types IncFII, IncA/C, IncN, IncL/M, IncFIIA and IncFIIK were observed. This is first report describing the carbapenem-resistance burden and emergence of bla(KPC-2)-ST147, bla(NDM-1)-ST340 and bla(NDM-1)-ST14 in K. pneumoniae isolates and bla(NDM-1)-ST69 and bla(NDM-1)/bla(OXA-48)-ST69 in E. coli isolates coharboring extended-spectrum beta-lactamases (ESBLs) from Pakistan.