| Summary: | <b>Background:</b> The diminishing antimicrobial options for the treatment of XDR and PDR <i>Acinetobacter baumannii</i> is an increasing concern. In this study, we assessed the in vitro synergy of the fosfomycin (FOS) with meropenem (MEM), amikacin (AK), tigecycline (TGC), and colistin (CL) in whole genome sequenced isolates. <b>Methods:</b> Non-replicate whole genome sequenced (illumina next-generation sequencing platform, Clevergene, India), <i>A. baumanii</i> (7 XDR, 1PDR) were subjected to in vitro synergy testing by checkerboard (CB) and time kill assay (TKA) after MIC determination, with glucose-6-phosphate being incorporated in all runs. FOS was used as a cornerstone drug in four combinations and colistin in one. ResFinder, MLST, PlasmidFinder, and CSIPhylogeny tools were used. <b>Results:</b> Mortality occurred in three patients. Diverse MLST were observed, ST-1962 (3 isolates) and one each of ST2062, ST2063, ST1816, ST1806, ST234. FOS MICs ranged from 32 to 128 mg/L, MEM MIC: 16–64 mg/L, TGC MIC: ≤2–≤4 mg/L and AK MIC: >512 mg/L. CL: MIC range, 0.25–≤2 mg/L, PDR MIC > 16 mg/L. Synergy results by CB: FOS-MEM: synergy in ⅞ (90%) isolates. Synergy lowered MEM MICs to susceptibility breakpoints in 6/8 cases. CL-MEM: Excellent synergy (3/3) isolates. FOS-AK: Indifference in ⅞, antagonism ⅛ (AK-susceptible isolate). FOS-TGC: Partial synergy (PS) in 8/8 (TGC MIC dropped to ≤0.25 mg/L in 3/8). In the PDR isolate, synergy was seen in FOS-MEM, CL-MEM, PS in FOS-CL, FOS-TGC, indifference in FOS-AK. TKA: Excellent synergy was observed with FOS-MEM from 4 h, while FOS-AK and FOS-TGC demonstrated synergy at 24 h. Synergy was achieved despite presence of widespread resistance markers against aminoglycosides (<i>AacAad</i>, <i>AadA</i>, <i>AadB</i>, <i>Aph3″Ia</i>, <i>ArmA</i>, <i>Arr</i>, <i>StrA</i>, <i>StrB</i>), beta-lactams (ADC, BlaA1, BlaA2, Zn-dependent_hydrolase, OXA-23, OXA-51, PER-1,TEM-1D, CARB-5, Mbl), sulphonamides (SulII, SulI), phenicols (<i>CatBx</i>, <i>CmlA</i>), macrolides (<i>MphE</i>, <i>MsrE</i>) and tetracycline (<i>TetB</i>) were widespread. Carbapenemase, CARB-5 was present in one isolate. Beta-lactamase genes OXA-23, OXA-51, <i>Bla</i>A2, Zn-dependent_hydrolase, ADC, Mbl and macrolide resistance genes <i>MphE</i>, <i>MsrE</i> were present in all 8 isolates. <b>Conclusions:</b> FOS-MEM and CL-MEM are promising combinations against <i>A. baumannii</i>. Synergy of FOS-MEM in intrinsically resistant <i>A. baumannii</i> shows that this antibiotic combination might be useful in treating such XDR and PDR pathogens.
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