Purpose: In order to understand the prevalence of Streptococcus pneumoniae and Haemophilus influenzae globally and provide the basis for rational use of antimicrobials in clinical settings, in vitro activity of tigecycline and comparative agents was evaluated against 3929 S. pneumoniae and 4043 H. influenzae isolates obtained from 150 centers globally between 2015 and 2017 as a part of the Tigecycline Evaluation and Surveillance Trial (TEST). Methods: Broth microdilution methods were performed to determine the minimum inhibitory concentration (MIC) of the isolates according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI). The CLSI breakpoint was used to determine antimicrobial susceptibilities, except for that of tigecycline, for which the US Food and Drug Administration (FDA) breakpoints were used. Results: More than 99% of S. pneumoniae isolates were susceptible to vancomycin (100%), linezolid (100%), tigecycline (99.9%), and levofloxacin (99.1%). Macrolides (erythromycin, azithromycin, and clarithromycin, 67.1-69.4% susceptibility globally) and penicillin (61.7% in globally) were the drugs with more resisitance to S. pneumoniae. Penicillin-intermediate and -resistant isolates were found in 24.8% and 13.6% of S. pneumoniae isolates. H. influenzae was highly susceptible (>98.7%) to all antibiotics tested except for ampicillin, for which susceptibility was 76.1%. The number of drugs with the lowest susceptibility calculated in Asia were far more than other regions, with 61.5% (8 in 13 drugs) in S. pneumoniae and 70.0% (7 in 10 drugs) in H. influenzae, respectively. Conclusions: Vancomycin, linezolid, tigecycline, and levofloxacin can be used as the first choice in the empirical therapy of infection disease caused by S. pneumoniae. But macrolides and penicillin should be used prudently in treatment of the infection caused by S. pneumoniae, as well as ampicillin treat the infection caused by H. influenzae. Asia was the region with the most severe resistance in S. pneumoniae and H. influenzae.