Organic salts and ionic liquids based on β-lactam antibiotics active pharmaceutical ingredients (OSIL-APIs): ampicillin (Amp), penicillin G hydrolysate (seco-Pen) and amoxicillin hydrolysate (seco-Amx) were prepared in 60-97% yield using ammonia buffer procedure. The prepared OSIL-APIs were tested against sensitive and resistant gram-positive and gram-negative strains. They show good solubility and significant increase of antibiotic activity particularly against resistant species with relative decrease of inhibitory concentration in respect to parent antibiotics (RDICs) up to >1000 for [C₁₆Pyr][Amp] against E. coli TEM CTX M9 and [C₁₆Pyr][seco-Amx] against MRSA ATCC 43300. The gathered data suggest that the adequate ionic pairing is vital to enhance or promote antibiotic activity, with possible alterations in their mechanism of action according to the selected counter-ion. As recently suggested combination of antimicrobials with non-active compounds may provide a promising strategy to address bacterial resistance and in this respect OSIL-APIs can provide ideal platform for drug modification.