New Antibiotics for Healthcare-Associated Pneumonia

Elizabeth A. Neuner, Pharm.D.; David J. Ritchie, Pharm.D.; Scott T. Micek, Pharm.D.


Semin Respir Crit Care Med. 2009;30(1):92-101. 

In This Article


Iclaprim, a synthetic diaminopyrimidine, is a selective inhibitor of the enzyme dihydrofolate reductase (DHFR), similar to trimethoprim. A racemic mixture of two equipotent enantiomers, iclaprim prevents the production of tetrahydrofolic acid by interrupting the bacterial biosynthetic pathway.[40] As a specific and selective DHFR inhibitor, iclaprim preferentially prevents the synthesis of bacterial DNA and RNA.[41]

Iclaprim has in vitro activity against S. aureus, including methicillin-resistant strains, and a single VRSA strain.[42,43] Against penicillin-sensitive and penicillin-resistant pneumococci, iclaprim demonstrates more potent activity than trimethoprim.[39,44] Iclaprim is also active against trimethoprim-resistant staphylococci and pneumococci.[44] Iclaprim is active against the respiratory pathogens H. influenzae and Moraxella catarrhalis.[45] Unlike trimethoprim, iclaprim exhibits activity against the intracellular pathogen C. pneumoniae.[46] In addition, iclaprim is active against the atypical pathogen Legionella pneumophila.[47] The activity of iclaprim against Enterobacteriaceae is generally comparable to trimethoprim.[45] Iclaprim is not active against P. aeruginosa isolates and displays variable activity against Acinetobacter spp. and S. maltophilia.[45] Although iclaprim exhibits significant in vitro synergy in combination with sulfonamides, it is currently being developed as monotherapy due to its potent intrinsic activity.[48]

Compared with trimethoprim, iclaprim has a low propensity for the development of resistance in S. aureus.[49] Serial passage experiments suggest an unstable resistance mechanism for iclaprim compared with the DHFR gene mutation for trimethoprim.

Iclaprim displays linear pharmacokinetics. The protein binding of iclaprim is 92 to 94% and the half-life is 2 to 4 hours.[49,50] In a pulmonary distribution study, iclaprim concentrations in the epithelial lining fluid, alveolar macrophages, and bronchial mucosa exceeded the MIC90 for MRSA, S. pneumoniae, and C. pneumoniae for up to 7 hours.[50] These data suggest iclaprim achieves the necessary respiratory concentrations to be efficacious for the treatment of pneumonia. An oral formulation of iclaprim recently completed phase I clinical studies demonstrating a bioavailability of ~40% for both a solution and capsule formulation.[51] To date, there are no published reports analyzing the pharmacodynamics of iclaprim.

Iclaprim's effect on the QTc interval was assessed in a phase II trial for cSSSIs.[52] In this study, the mean maximal prolongation of the QTc was 6.3 millisecond for iclaprim and 1.2 millisecond for linezolid. In the iclaprim arm only one patient showed a QTc interval exceeding 500 millisecond, and two patients experienced an increase > 60 millisecond from baseline. There were no cardiac events attributable to QTc prolongation.

A new drug application (NDA) for iclaprim in the treatment of cSSSIs was submitted to the FDA based on data from two phase III studies (ASSIST-1 and -2) demonstrating iclaprim 0.8 mg/kg every 12 hours was noninferior to linezolid.[53] A phase II trial of iclaprim for the treatment of HAP, VAP, or HCAP suspected or confirmed to be due to gram-positive organisms is currently recruiting. The trial is designed to assess the safety and efficacy of two different dosages of iclaprim compared with vancomycin in a randomized, double-blinded fashion. Early preclinical data suggest iclaprim may have a role in the treatment of HCAP due to gram-positive pathogens, and clinical trials are under way. With an oral formulation of iclaprim in phase II of clinical development, the option of an IV to PO switch would be appealing.