The　global　rise　of　antibiotic　resistance　has　renewed　interest　in　phage　therapy,　as　an　alternative　to　antibiotics　to　eliminate　multidrug-resistant　(MDR)　bacterial　pathogens.　However,　optimizing　the　broad-spectrum　efficacy　of　phage　therapy　remains　a　challenge.　In　this　study,　we　addressed　this　issue　by　employing　strategies　to　improve　antimicrobial　efficacy　of　phage　therapy　against　MDR　Klebsiella　pneumoniae　strains,　which　are　notorious　for　their　resistance　to　conventional　antibiotics.　This　includes　the　selection　of　broad　host　range　phages,　optimization　of　phage　formulation,　and　combinations　with　last-resort　antibiotics.　Our　findings　unveil　that　having　a　broad　host　range　was　a　dominant　trait　of　isolated　phages,　and　increasing　phage　numbers　in　combination　with　antibiotics　significantly　enhanced　the　suppression　of　bacterial　growth.　The　decreased　incidence　of　bacterial　infection　was　explained　by　a　reduction　in　pathogen　density　and　emergence　of　bacterial　resistance.　Furthermore,　phage-antibiotic　synergy　(PAS)　demonstrated　considerable　broad-spectrum　antibacterial　potential　against　different　clades　of　clinical　MDR　K.　pneumoniae　pathogens.　The　improved　treatment　outcomes　of　optimized　PAS　were　also　evident　in　a　murine　model,　where　mice　receiving　optimized　PAS　therapy　demonstrated　a　reduced　bacterial　burden　in　mouse　tissues.　Taken　together,　these　findings　offer　an　important　development　in　optimizing　PAS　therapy　and　its　efficacy　in　the　elimination　of　MDR　K.　pneumoniae　pathogens.　IMPORTANCE　The　worldwide　spread　of　antimicrobial　resistance　(AMR)　has　posed　a　great　challenge　to　global　public　health.　Phage　therapy　has　become　a　promising　alternative　against　difficult-to-treat　pathogens.　One　important　goal　of　this　study　was　to　optimize　the　therapeutic　efficiency　of　phage-antibiotic　combinations,　known　as　phage-antibiotic　synergy　(PAS).　Through　comprehensive　analysis　of　the　phenotypic　and　genotypic　characteristics　of　a　large　number　of　CRKp-specific　phages,　we　developed　a　systematic　model　for　phage　cocktail　combinations.　Crucially,　our　finding　demonstrated　that　PAS　treatments　not　only　enhance　the　bactericidal　effects　of　colistin　and　tigecycline　against　multidrug-resistant　(MDR)　K.　pneumoniae　strains　in　in　vitro　and　in　vivo　context　but　also　provide　a　robust　response　when　antibiotics　fail.　Overall,　the　optimized　PAS　therapy　demonstrates　considerable　potential　in　combating　diverse　K.　pneumoniae　pathogens,　highlighting　its　relevance　as　a　strategy　to　mitigate　antibiotic　resistance　threats　effectively.　Copyright　©　2024　zhao　et　al.　This　is　an　open-access　article　distributed　under　the　terms　of　the　Creative　Commons　Attribution　4.0　International　license.