Iclaprim,a Novel Diaminopyrimidine for the Treatment of Resistant Gram-Positive Infections

Abstract

Spanish

French

Objective

To review the pharmacology, microbiology, in vitro susceptibility, pharmacokinetics, clinical trial data, safety, and tolerability of iclaprim, a novel dihydrofolate reductase (DHFR) inhibitor.

Data Sources

A MEDLINE search was conducted from 1966 through December 2008. Additional sources included abstracts from meetings of the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America from 2001 to 2008 and information available from the manufacturer's Web site.

Study Selection And Data Extraction

In vitro and clinical studies, in addition to Phase 1, 2, and 3 clinical trials, were included.

Data Synthesis

Iclaprim, a novel diaminopyrimidine and DHFR antagonist, has a mechanism of action similar to that of trimethoprim. It has in vitro activity mainly against gram-positive organisms, including resistant Staphylococcus aureus. In Phase 2 and 3 clinical trials, oral and intravenous administration of iclaprim was effective and well tolerated for the treatment of complicated skin and skin structure infections (cSSSI). Trials are currently ongoing for the treatment of ventilator-associated and healthcare-associated pneumonia.

Conclusions

Iclaprim is a promising antimicrobial agent for the treatment of gram-positive organisms, including resistant S. aureus and trimethoprim-, macrolide-, fluoroquinolone-, and glycopeptide-resistant strains. Additionally, in vitro activity similar to that of trimethoprim has been observed against gram-negative and atypical organisms.

Keywords

AR-100 dihydrofolate reductase gram-positive iclaprim

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References

Arpida Ltd. Press releases. www.arpida.ch/index.php?MenuID=30&UserID=1&ContentID=20 (accessed 2008 Jan 28).

Hawser

Lociuro

Islam

. Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol 2006;71:941–8.

Peppard

Johnston

Urmanski

. Pharmacologic options for CNS infections caused by resistant gram-positive organisms. Expert Rev Anti Infect Ther 2008;6:83–99.

Huovinen

. Resistance to trimethoprim-sulfamethoxazole. Clin Infect Dis 2001;32:1608–14.

Adrian

DuPlessis

Klugman

Amyes

. New trimethoprim-resistant dihydrofolate reductase cassette, dfrXV, inserted in a class 1 integran. Antimicrob Agents Chemother 1998;42:2221–4.

Schneider

Hawser

Islam

. Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. Bioorg Med Chem Lett 2003;13:4217–21.

Kohlhoff

Sharma

. Iclaprim. Expert Opin Investig Drugs 2007;16:1441–8.

Peppard

Schuenke

. Iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor for the potential treatment of antibiotic-resistant staphylococcal infections. Curr Opin Investig Drugs 2008;9:210–25.

Hartman

Kompis

Jaeger

Mukhija

Islam

. AR-100, a novel diaminopyrimidine, can overcome TMP-resistance in staphylococci and streptococci (F-2020). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

10.

Bajaksouzian

Windau

Appelbaum

Jacobs

. AR-100, a novel diaminopyrimidine compound: activity against staphylococci and enterococci (F-2024). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

11.

Gemmell

Middlemas

. AR-100, a novel diaminopyrimidine: activity against various clinical isolates of gram-positive and gram-negative bacteria (F-2022). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemomerapy, San Diego, CA, 2002.

12.

Good

Windau

Bajaksouzian

Jacobs

Appelbaum

. AR-100, a novel diaminopyrimidine compound: activity against streptococci (F-2023). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

13.

Hawser

Weiss

Fischer

Gillessen

Kompis

Islam

. AR-100, a novel diaminopyrimidine compound: activity against selected gram-positive and gram-negative bacterial pathogens and synergy with other antibiotics (F-2019). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

14.

Hawser

Weiss

Fischer

. AR-100, a novel diaminopyrimidine compound: bactericidal activity and post-antibiotic effect on gram-positive pathogens (F-2029). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

15.

Jones

Fritsche

Hawser

Islam

Sader

. In vitro activity of iclaprim, a novel diaminopyrimidine, tested against b-haemolytic streptococci from the U.S. and Europe: results from the international study of iclaprim susceptibility (ISIS) (E-911). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

16.

Sader

Fritsche

Islam

Hawser

Jones

. Antimicrobial activity of iclaprim tested against recent S. aureus clinical isolates: results from the international study of iclaprim susceptibility (ISIS) (E-902). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

17.

Sader

Jones

Rhomberg

Islam

Hawser

Fritsche

. Comparative evaluation of iclaprim potency and bactericidal activity tested against enterococci: results from the international study of iclaprim susceptibility (ISIS) (E-910). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

18.

Mason

Lamberth

Hawser

. In vitro activity of iclaprim against community-acquired and nosocomial clinical isolates of Staphylococcus aureus (E-904). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

19.

Zhanel

Palatnick

Hisanaga

. Activity of iclaprim against penicillin, erythromycin, trimethoprim/sulfamethoxazole or ciprofloxacin resistant Streptococcus pneumoniae from Canada (E-2002). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

20.

Then

Hartman

Locher

. AR-100, a novel diaminopyrimidine compound: in vitro activity against pneumococci (F-2021). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

21.

Jacobs

Windau

Bajaksouzian

Appelbaum

. AR-100, a novel diaminopyrimidine compound: activity against Haemophilus species and Moraxella catarrhalis (F-2026). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

22.

Milatovic

Verhoef

Fluit

. In vitro activity of iclaprim (AR-100) against gram-positive and gram-negative bacteria (E-2006). In: Abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2003.

23.

Windau

Bajaksouzian

Appelbaum

Jacobs

. AR-100, a novel diaminopyrimidine compound: activity against Enterobacteriaceae (F-2025). In: Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002.

24.

Biedenbach

Sader

Fritsche

Hawser

Lociuro

Jones

. In vitro activity of iclaprim and comparison agents tested against Neisseria gonorrhoeae including growth stimulating effects (E-908). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

25.

Donati

Pignanelli

Shurdhi

Hawser

Lociuro

Cevenini

. In vitro activity of iclaprim and comparators against Chlamydia trachomatis (E-903). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

26.

Hammerschlag

Kohlhoff

Roblin

Reznik

Hawser

Islam

. In vitro activity of iclaprim, a novel diaminopyrimidine compound, against Chlamydia trachomatis and C. pneumoniae (E-2001). In: Abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2003.

27.

Morrissey

Hawser

Islam

Williams

Leakey

Shackcloth

. Activity of iclaprim and comparators against atypical bacterial respiratory pathogens (E-2003). In: Abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2003.

28.

Jones

Hawser

Islam

Torres

Draghi

Sahm

. Iclaprim (ICL): defined quality control (QC) limits for MIC and disk diffusion (DD) susceptibility testing according to CLSI M23-A2 procedures (D-243). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

29.

Engelhardt

Yusof

Bylund

. Comparative evaluation of iclaprim (ICL) MIC testing with Etest and CLSI reference methods (D-244). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

30.

Brandt

John

Henderson

Harris

Islam

. Absorption, pharmacokinetics, metabolism, and excretion of iclaprim in healthy humans (A-805). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

31.

Brandt

Matthews

Hall

Islam

. Interactions of iclaprim with human cytochrome P450 enzymes (A-807). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, 2007.

32.

Brandt

Neuenhofer

Thomsen

Hadvary

Islam

. Pharmacokinetics and bioavailability of iclaprim oral and intravenous formulations in humans (A-806). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

33.

Brandt

Warrington

McBurney

Islam

. Tolerability and pharmacokinetics of single and repeat ascending doses of iclaprim in healthy adults (A-804). In: Abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.

34.

Andrews

Honeyboume

Ashby

. Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men. J Antimicrob Chemother 2007;60:677–80.

35.

Zhanel

Goolia

Rusen

. Pharmacodynamic activity of iclaprim vs. resistant Streptococcus pneumoniae using an in vitro model. In: 14th European Congress of Clinical Microbiology and Infectious Diseases, Prague, Czech Republic, 2004.

36.

Krievens

Leighton

Brandt

. Efficacy and safety of intravenous iclaprim in complicated skin and skin structure infections: results of a phase 2 study (L-1579). In: Proceedings of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2005.

37.

Stevens

Leighton

Dankner

Islam

Hadvary

. Efficacy of iclaprim in complicated skin and skin structure infections: preliminary results of ASSIST-1 (1079). In: Abstracts of the 45th Annual Meeting of Infectious Diseases Society of America, San Diego, CA, 2007.

38.

Hadvary

de la Motte

Klinger

Islam

. Pharmacokinetics of iclaprim in subjects with varying degrees of hepatic or renal insufficiency or obesity (448). In: Abstracts of the 45th Annual Meeting of Infectious Diseases Society of America, San Diego, CA, 2007.

39.

Leighton

Dankner

Stevens

Islam

Hadvary

. Safety of iclaprim in complicated skin and skin structure infections: ASSIST-1 results (1104). In: Abstracts of the 45th Annual Meeting of Infectious Disease Society of America, San Diego, CA, 2007.

40.

Hadvary

Leighton

Wargenau

Thomsen

Islam

. Evaluation of the effect of iclaprim on the QT interval in healthy volunteers (432). In: Abstracts of the 45th Annual Meeting of Infectious Diseases Society of America, San Diego, CA, 2007.

41.

Hadvary

Dankner

Leighton

Stevens

Islam

. Effect of iclaprim on the QT interval based on results of ASSIST-1 (1083). In: Abstracts of the 45th Annual Meeting of Infectious Diseases Society of America, San Diego, CA, 2007.

42.

FDA briefing document for anti-infective drugs advisory committee meeting. Iclaprim for the treatment of complicated skin structure infections. November 20, 2008. www.fda.gov/ohrms/dockets/ac/briefing/2008-4394b3-01-FDA.pdf (accessed 2009 Apr 23)