A 2012-2014 Global Antimicrobial Surveillance of Iclaprim Against Clinical Strains Causing Hospital-Associated Bacterial Pneumonia (HABP) and Skin and Skin Structure Infections (SSSI)

Background: ICL, a new generation diaminopyrimidine compound, is a dihydrofolate reductase inhibitor antibiotic in Phase 3 clinical development. An in vitro retrospective surveillance study on the antimicrobial spectrum and activity of iclaprim was performed against clinical isolates causing HABP and SSSI. Methods: 1636 clinical Gram-positive isolates causing HABP (601) and SSSI (577) were collected from the US, Europe, Latin America, and Asia Pacific during 2012-2014. Reference broth microdilution tests were conducted according to the Clinical and Laboratory Standards Institute (CLSI M07-A10, 2015) methods. Quality control (QC) ranges and interpretive criteria for comparator compounds were as published in (CLSI M100-S25, 2015). QC ranges for iclaprim were those approved by CLSI and published in M100-S25. Results: The MIC distributions of iclaprim, trimethoprim, trimethoprim-sulfamethoxazole and comparator antimicrobials for all S. aureus, including methicillin-resistant (MRSA) and -susceptible (MSSA) strains, beta-hemolytic streptococci, and S. pneumoniae are shown in the Table.

		Antimicrobials (MIC50/90; mg/L)
Pathogen	n	ICL	VAN	LIN	DAP	TMP	TMP/SMX
S.aureus	1,178	0.06/0.12	1/1	1/1	0.25/0.5	1/2	0.06/0.12
MRSA	582	0.06/0.12	1/1	1/1	0.25/0.5	1/8	0.06/0.25
MSSA	596	0.06/0.12	1/1	1/1	0.25/0.5	1/2	0.06/0.06
Beta-hemolytic streptococci	199	0.06/0.25	0.25/0.5	1/1	0.12/0.25	1/2	0.12/0.25
S. pneumoniae	259	0.06/0.2	0.25/0.5	1/1	0.12/0.25	2/64	0.25/8
Total	1636

Globally, ICL MIC50/90s for S. aureus including MRSA were l6-fold lower than those for TMP and similar to TMP/SMX. ICL MIC 50/90s for beta-hemolytic streptococci were 8-fold lower than for TMP and 2-fold lower than for TMP/SMX. ICL 50/90 were 32-fold lower than TMP and 4-fold lower than TMP/SMX for S. pneumoniae. ICL MIC 50/90 were 0.06/0.12, 0.06/0.25, and 0.06/2 for US S. aureus, beta-hemolytic Streptococcus, and S. pneumoniae, respectively; corresponding values for European isolates were 0.6/0.12, 0.12/0.25, and 0.6/4, respectively.

Conclusion: ICL was potently active against all S. aureus, beta-hemolytic streptococcus, and S. pneumoniae clinical SSSI and HABP isolates globally from 2012-2014. ICL could be an important new therapeutic option for the treatment of SSSI and HABP, especially cases caused by multidrug resistant Gram-positive bacteria. Pivotal clinical trials are warranted to evaluate ICL for the indications of SSSI and HABP.