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Objectives: To determine antibiotic susceptibility of isolates of Streptococcus pneumoniae (n = 573) and Haemophilus influenzae (n = 345) collected in 2014-16 from Bulgaria, Romania, Serbia and Croatia., Methods: MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints., Results: Among S. pneumoniae, susceptibility was generally lowest in Romania and Serbia and highest in Bulgaria. Rates of susceptibility to penicillin (CLSI oral or EUCAST) were 22.3% and 21.8% in Romania and Serbia respectively, 57% in Croatia and 86.6% in Bulgaria. Similarly, macrolide susceptibility using CLSI/EUCAST breakpoints was low in Romania and Serbia (∼28% and 34.5%, respectively), higher in Croatia (55.9%) and highest in Bulgaria (∼75%). Only fluoroquinolones were active against all isolates in all four countries. Susceptibility was higher and variability across countries less pronounced for H. influenzae. Susceptibility by CLSI criteria to amoxicillin/clavulanic acid, azithromycin, cefuroxime, ceftriaxone and fluoroquinolones was ≥98% in all countries. Ampicillin susceptibility ranged from 85.3% in Romania to 100% in Bulgaria. Much greater variability was seen across breakpoints. Susceptibility to azithromycin and cefuroxime using CLSI criteria was ≥98% in all four countries, but was 0%-1% by EUCAST criteria., Conclusions: The variability in antimicrobial susceptibility using different breakpoints makes it difficult for clinicians to interpret antimicrobial resistance data, and efforts should be made to harmonize breakpoints. The variability found across the four neighbouring countries demonstrates the need to monitor and publish national and local resistance patterns. These findings provide information critical for the selection of appropriate antimicrobial agents for the treatment of S. pneumoniae and H. influenzae.