Overview: The rapid rise of microbial resistance to carbapenem (CR) and colistin (CoR) in Gram-negative bacteria (GNB) is extremely alarming and presents an unprecedented crisis in healthcare. As we inexorably inch towards the post-antibiotic era, one has to make rational use of the available antibiotics like fosfomycin, colistin, tigecycline, and carbapenems. Combination therapy in such situations provides an effective alternative in the management of extremely drug-resistant (XDR) and pan drug-resistant (PDR) bacterial infections. Understanding the interactions between these antibiotics is essential to warrant successful treatment regimens. Objectives: This study evaluated the in-vitro synergy of various combinations of fosfomycin (FOS) with meropenem (MEM), colistin (CL), tigecycline (TGC), and amikacin (AK) against XDR and PDR GNB using the checkerboard and time-kill assays. Colistin plus meropenem was assessed in few representative bacterial isolates. Methods: Non replicate XDR and PDR strains of K. pneumoniae (n=18), A. baumannii complex (n=10), and P. aeruginosa (n=6) were studied. The phenotypic and genotypic characterizations of the strains were done by BD Phoenix automated system and Xpert Carba-R respectively. Minimal inhibitory concentrations (MICs) were determined by agar dilution (AD) for fosfomycin and broth microdilution (BMD) method for all other antibiotics including fosfomycin. All isolates were exposed to combinations of two antibiotics in a checkerboard assay. Fractional inhibitory concentration index (FICI) was used for interpreting the interactions between the combined antibiotics. Time-kill assay (TKA) was performed for six representative isolates to assess different combinations. Whole Genome Sequencing (WGS) was carried out for the representative K. pneumoniae isolates (n=11). Results: Fosfomycin resistance was identified in 62% and 23.5% of all isolates as per EUCAST and CLSI respectively. Of the isolates, 97% and 100% were resistant to tigecycline and meropenem respectively while 82% were susceptible to colistin. Amikacin was sensitive in 83%, 28%, and 10% of P. aeruginosa, K. pneumoniae, and A. baumannii respectively. Fifteen K. pneumoniae isolates harboured OXA-48-like, mostly OXA232, two were NDM-type, and one was NDM5+OXA232. Three sequence types were identified by WGS: the majority were ST-231, followed by ST-395, and ST147. Multiple resistance genes to β-lactams, aminoglycosides, and fosfomycin were detected by WGS. Carbapenemases were not detected in any of A. baumannii isolates whereas three P. aeruginosa isolates carried IMP1, one was VIM-type, and not detected in two isolates. FOS-MEM was the most successful synergistic combination for all isolates. FOS-AK was extremely active against K. pneumoniae whereas CL-MEM was highly active in A. baumannii and P. aeruginosa with MEM MIC of ≤32 mg/L, and least in K. pneumoniae. Antagonism was observed mostly against V FOS-TGC in 100% and 44% of K. pneumoniae, and A. baumannii respectively, and against FOS-AK in all amikacin-susceptible isolates. FOS-CL demonstrated indifferent interactions in all PDR isolates. Conclusions: Fosfomycin alone has excellent bactericidal activity against all XDR and PDR isolates. FOS+MEM and FOS+AK combinations hold therapeutic potentials for K. pneumoniae while FOS+MEM and CL+MEM are promising combinations for A. baumannii and P. aeruginosa. FOS+CL and FOS+TGC were least effective in all K. pneumoniae and A. baumannii.