Send Orders for Reprints to reprints@benthamscience.net Combinatorial Chemistry & High Throughput Screening, 2014, 17, 53-67 53 Combination Therapy: The Propitious Rationale for Drug Development Neetu Phougat 1 , Savita Khatri 1 , Anu Singh 1 , Mrridula Dangi 1 , Manish Kumar 1 , Rajesh Dabur 2 and Anil Kumar Chhillar 1* 1 Centre for Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India 2 Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India Abstract: Therapeutic options for many infections are extremely limited and at crisis point. We run the risk of entering a second pre-antibiotic era. There had been no miracle drug for the patients infected by resistant microbial pathogens. Most of the very few new drugs under development have problems with their toxicity, or pharmacokinetics and pharmacodynamics. We are already decades behind in the discovery, characterization and development of new antimicrobials. In that scenario, we could not imagine surviving without newer and effective antimicrobial agents. Bacteria have been the champions of evolution and are still evolving continuously, where they pose serious challenges for humans. Along with the crisis of evolving resistance, the condition is made worst by the meager drug pipeline for new antimicrobials. Despite ongoing efforts only 2 new antibiotics (Telavancin in 2009 and Ceftaroline fosamil in 2010) have been approved since 2009 pipeline status report of Infectious Disease Society of America (IDSA). Recent approval of new combination based antiviral drugs such as Stribild (combination of four drugs for HIV treatment) and Menhibrix (combination vaccine to prevent meningococcal disease and Haemophilus influenzae type b in children) proves that combination therapy is still the most promising approach to combat the ever evolving pathogens. Combination therapy involves the drug repurposing and regrouping of the existing antimicrobial agents to provide a synergistic approach for management of infectious diseases. This review article is an effort to highlight the challenges in new drug development and potential of combination drug therapy to deal with them. Keywords: Antibiotics, combination therapy, drug, resistance, synergy, therapeutics. 1. INTRODUCTION The revolution in the field of medicine has been brought by the discovery of antibiotics which goes back 80 years to the time when penicillin was discovered by Alexander Fleming in 1928. Their introduction is one of the most important factors in improving the human life span [1]. Due to the increased demand, the sale of antibiotics has been increasing day by day [2]. The main obstacle in developing new antibiotics to meet the increased demand is the ever rising resistance and constricted set of drugs from which the new miracle has to be developed. The approval of linezolid in 2000, daptomycin in 2003, tigecycline in 2005 and Telavancin in 2009 (Table 1) represented the novel drug classes since the introduction of nalidixic acid nearly 5 decades ago [3, 4]. Most of the new drugs are formed by upgradation of existing classes of drugs [3]. The increased cases of drug resistance among the pathogen occur due to lack of diversity of antibiotic drug classes. Recognizing the need for new, creative approaches to address the problem of the dwindling antibiotic pipeline, the IDSA launched the “10 × ’20 Initiative” in 2010. This campaign calls for development and regulatory approval of 10 novel, efficacious and safe systemically administered antibiotics by 2020 [4]. IDSA provides clear suggestions for addressing the “synergistic crises” of increasing *Address correspondence to this author at the Centre for Biotechnology, Maharshi Dayanand University, Rohtak, Haryana-124001, India; Tel: +91- 1262-393107; Fax: +91-1262-274133; E-mail: anil.chhillar@gmail.com Table 1. Systemic Antibacterial Drug Approval Since 2000 [4] Antibacterial Year of Approval Novel Mechanism? Linezolid 2000 Yes [5] Cefditoren pivoxil 2001 No [6] Ertapenem 2001 No [7] Gemifloxacin a 2003 No [8] Daptomycin 2003 Yes [9] Telithromycin a 2004 No [10] Tigecycline b 2005 Yes [11] Doripenem 2007 No [12] Telavancin 2009 Yes [13] Ceftaroline fosamil 2010 No [14] a Withdrawn from market due to adverse event profile. b Label warning regarding possible excess mortality. antimicrobial resistance and decreasing availability of new antimicrobial therapies [15]. Ceftolozane/tazobactam, ceftazidime/avibactam, ceftaroline/avibactam and MK- 7655/imipenem drug combinations which are in Phase III clinical trial, offers the potential to enhance β-lactam therapeutic options [4, 16, 17]. Among the resistant pathogens, the methicillin resistant Staphylococcus aureus, penicillin resistant Streptococcus 18 - 0 /14 $58.00+.00 © 2014 Bentham Science Publishers