Year in review – why only one new antibiotic this year?

December 2005

To coincide with the special issue of 2005 in review, this month’s Pharmacology Consult will focus upon the relative lack of newly approved antibiotics in 2005 and in recent years past. Of 13 and 31 new molecular entity (NME) drug approvals by the FDA in 2005 (until October 31) and 2004, respectively, only one of these drugs in each year has been an antibacterial agent. The FDA approved telithromycin (Ketek, Sanofi Aventis) was approved in 2004 and tigecycline (Tygacil, Wyeth) in 2005. Neither of these agents is labeled for use in children. This relative lack of new antibiotics is raising concern, as bacterial resistance to currently available antibiotics is increasing and there is growing need for new antibacterial agents.

Manufacturing on the decline

Bringing a new drug to the commercial market is an expensive proposition for pharmaceutical manufacturers, which invest and spend $400 million to $800 million in research and development per chemical compound to win FDA approval. Unfortunately, antibiotics are becoming less economically attractive to pharmaceutical manufacturers. Reasons for this include: aging of the U.S. population, resulting in priority development for drugs to treat chronic medical conditions, significant competition in the antibiotic product market, and recent trends to restrict use of newly developed antibiotics for first-line therapy and of antibiotics overall. Thus, some major pharmaceutical companies are investing new drug development resources in agents that are likely to be used long term (eg, hyperlipidemia), and some companies have publicly announced intention to lessen or eliminate development of new antimicrobial agents.

Spellberg and colleagues recently reviewed research and development programs and FDA approval of new systemically active antibacterial agents from 1980-2002 for 15 major pharmaceutical companies and 7 major biotechnology companies. A new agent was defined as a new molecular entity, a compound that had not previously been approved by the FDA in any formulation (not including topical antimicrobials, vaccines, or antibodies).

The number of NMEs steadily declined from 1983 to 2002. Compared with the five-year period of 1983 to 1987, the FDA approval of new antibacterial agents declined 56% in the period 1998 to 2002. The FDA approved a total of 225 new drugs (NME, antibacterial and nonantibacterial) from 1998 to 2002. Of these, only 3% were antibacterial drugs. Table I lists new antibacterial drugs approved for use from 2000 to 2005 (as of October 31). Of these 7 agents, only 1 (linezolid, Zyvox, Pharmacia and Upjohn) has FDA-approved pediatric labeling. Additionally, only 2 new antibacterial drugs (linezolid and daptomycin, Cubicin, Cubist Pharmaceuticals) possess novel pharmacology (i.e., new mechanisms of action). Novel mechanisms of action may be more beneficial in treating resistant pathogens and may slow resistance development.

The researchers also reviewed development and FDA approval trends for antiviral agents and found that from 1998 to 2003, FDA approved an equal number (nine) of antiviral (all for HIV infection) and antibacterial agents for use.

The potential for future antibacterial product development was additionally determined by a review of company research programs. Of 315 NMEs under development (as of 2002), 10% are anti-infective compounds, and only 1.6% are antibacterial agents. This trend contrasts with data describing the significant impact of infectious diseases as one of the leading causes of mortality among the United States population.

What’s on the horizon?

Clinicians can choose from a relatively lengthy list of commercially available antibiotics when treating their patients. For pediatric clinicians, however, this list significantly decreases due to lack of FDA-approved pediatric labeling for many antibacterials, lack of data supporting safety and efficacy in the pediatric population, or suitable dosage forms, among other concerns.

Many of the available antibacterial agents share one of two common pharmacologic mechanisms of action – inhibition of protein synthesis (e.g., azithromycin) or disruption of bacterial cell wall integrity (eg, amoxicillin).

Not only does the need for additional antibacterial agents exist, but an even greater need is the development of antibacterials with novel mechanisms of action, to combat increasing resistance trends. Some antibiotics were developed and promoted for their activity towards resistant pathogens. Examples include meropenem (Merrem, AstraZeneca), cefepime (Maxipime, Bristol-Myers Squibb, a 4th generation cephalosporin), linezolid, daptomycin, or tigecycline (Tygacil, Wyeth).

However, resistance has been documented towards some of these agents that have now been available for several years.

Although the list is relatively short, new antibacterial agents are under development by several pharmaceutical companies. Examples include ceftobiprole, a new cephalosporin generation, with activity towards methicillin-resistant Staphylococcus aureus (MRSA) and nonsusceptible Streptococcus pneumoniae (Basilea Pharmaceutica and Cilag AG International), and dalbavancin (Vicuron Pharmaceuticals) or oritavancin (InterMune), both glycopeptide agents (similar to vancomycin), with activity towards MRSA and nonsusceptible S. pneumoniae.

Within the past several years, discussion ensued between regulatory agencies (ie, the FDA), the pharmaceutical industry, academia, and professional medical organizations relating to the promotion of increased research for antibacterial agent development. The pharmaceutical industry has raised concern that requirements for clinical trial design and data submission for drug approval are too restrictive to be economically feasible. These discussions may have resulted in a workable balance of regulatory requirement and economic stimulus for antibacterial product development by several pharmaceutical and biotechnology companies. However, concerns for the most productive balance of regulation, demonstrable drug efficacy, and economic stimulation continue to exist and be debated.

In summary, while new antibiotics were recently added to the commercial market, and several agents, some with novel mechanisms of action, are under development, this list is comparatively quite small. Clinicians should not rely on the idea of a “steady stream” of new antibiotics into our current armamentarium of antibacterial agents, to choose among when resistant pathogens have caused older agents to be not as valuable. The principles of judicious use of all antibiotics, new and old, continue to apply.

For more information:

• Spellberg B. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis. 2004;38:1279-1286.
• Bosso JA. The antimicrobial armamentarium: evaluating current and future treatment options. Pharmacotherapy. 2005;25(Supplement):S55-62.
• Projan SJ. Why is big pharma getting out of antibacterial drug discovery? Current Opin Microbiol. 2003;6:427-430.
• Shlaes DM, Moellering RC. The United States Food and Drug Administration and the end of antibiotics. Clin Infect Dis. 2002;34:420-422.
• Gilbert DN, Edwards JE. Is there hope for the prevention of future antimicrobial shortages? Clin Infect Dis. 2002;35:215-217.
• Projan SJ. Wyeth Research. Personal communication. Nov. 14, 2005.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.