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Introduction to Antibiotics

About Bacteria

Infectious diseases are caused by pathogens present in the environment, such as bacteria, fungi and viruses that enter the body through the skin or mucous membranes of the lungs, nasal passages or gastrointestinal tract, and overwhelm the body's immune system. These pathogens establish themselves in various tissues and organs throughout the body and can cause a number of serious and, in some cases, lethal infections.

The market for anti-infective agents consists of three main categories: antibacterials (often referred to as antibiotics), antifungals and antivirals. Antibiotics work by inhibiting an essential function to the pathogen's survival, usually by binding to or interacting with one or more specific targets. Antibiotics are classified by both the type of bacteria against which they are effective, such as gram-positive or gram-negative pathogens, as well as their basic molecular structure, which is known as their antibiotic "class."

Gram-positive bacteria are differentiated from gram-negative bacteria by the structure of the bacterial envelope. Some of the most clinically important gram-positive pathogens include Staphylococcus aureus, also referred to as S. aureus or simply "staph," streptococci and enterococci. Frequently observed infections caused by these pathogens include complicated skin and skin structure infections (cSSSI), hospital-acquired and community-acquired pneumonia, bacteremia (infection of the bloodstream) and osteomyelitis (infection in the bone).

The Market for Antibiotics

There is a growing need for novel antibiotics because bacteria can mutate quickly and often develop resistance to existing antibiotics. Hospital-acquired infections are particularly likely to be resistant to existing antibiotics, but resistance is also growing rapidly in community-acquired infections. As bacteria become more resistant to currently marketed antibiotics, an increasing prevalence of drug-resistant bacterial pathogens can lead to increased mortality rates, prolonged hospitalizations, and increased healthcare costs.

According to IMS Health, in 2006 antibiotics designed to treat serious infections caused by resistant gram-positive bacteria accounted for approximately $945 million in U.S. sales. Use of antibiotics to treat serious gram-positive infections have increased at a compounded annual growth rate of 12% since 2002, while revenues have increased more rapidly due to the introduction of premium- priced antibiotics into the market.

Vancomycin, the first clinically useful glycopeptide, was introduced in 1958 and, according to IMS Health, still accounts for more than 80% of courses of therapy in the U.S. for resistant gram-positive pathogens. Since the 1960s, only two antibiotics from new chemical classes effective against gram-positive pathogens have been approved by the FDA-Cubicin�, a lipodepsipeptide, which is known generically as daptomycin, is marketed by Cubist; and Zyvox�, an oxazolidinone, which is known generically as linezolid, is marketed by Pfizer.

The Emergence of Drug Resistance

In the 1980s and 1990s most large pharmaceutical companies discontinued or sharply reduced their research into antibiotics. As a result, there have been fewer new antibiotics entering the market in the past few years, and the threat of pathogens resistant to the existing antibiotics has continued to increase.

For the past twenty years, vancomycin has been the treatment of choice for patients who have serious gram-positive infections that have failed to respond to most other antibiotics. However, several strains of enterococci, staphylococci and other pathogens have developed resistance to vancomycin. In addition, resistance to linezolid and daptomycin has been reported in both staphylococci and enterococci in recent years. Some pathogens have become resistant to almost all antibiotics.

Examples of antibiotic-resistant gram-positive pathogens include:

  • MRSA (methicillin-resistant Staphylococcus aureus) is an increasingly common bacterial pathogen that causes serious and life-threatening infections. According to the Centers for Disease Control and Prevention, 63% of total S. aureus infections were methicillin-resistant in 2004, as compared with 22% in 1995.

  • CA-MRSA (community-acquired methicillin-resistant Staphylococcus aureus) has substantially changed the prescribing behavior of infectious disease physicians, from penicillin and beta-lactam drugs, among others to antibiotics such as daptomycin and linezolid. While MRSA has historically been found primarily in hospitals and long-term care settings, the incidence of CA-MRSA infections is now rising rapidly.

  • GISA or VISA (glycopeptide- or vancomycin-intermediately susceptible Staphylococcus aureus) have been found in wide geographic areas throughout Japan, North America and Europe. In an April 2004 CDC article, the incidence of VISA around the world was estimated to be between 0.5% and 20%.

  • VRE (vancomycin-resistant enterococci) has led to infections for which only limited commercially available therapy exists. VRE is commonly treated today with daptomycin and linezolid, but bacteria resistant to each of these drugs have recently begun to emerge.

  • VRSA (vancomycin-resistant Staphylococcus aureus) was first isolated in the U.S. in 2002. While VRSA is growing slowly in incidence, any acceleration of its incidence could force to an immediate change in the antibiotics used for first-line therapy of gram-positive infections in hospital settings.

There is a limited number of antibiotics currently available to treat these and other resistant gram-positive pathogens, and therefore a growing need exists for new therapies with novel mechanisms of action.

Shortcomings of Currently Marketed Antibiotics

In addition to the increasing resistance of bacteria to existing antibiotics, currently available antibiotics do not provide adequate or ideal treatment for some serious and life-threatening infections. Shortcomings include:

  • Bacteriostatic Activity. Bacteriostatic antibiotics merely inhibit the growth of pathogens and rely on the immune system to actually kill the bacteria.

  • Narrow Spectrum of Coverage. Many antibiotics are effective against some serious pathogens but not others.

  • Inconvenient Administration. Many of the existing antibiotics used to treat serious infections are difficult or inconvenient to administer.

  • Serious Side Effects Requiring Careful Patient Monitoring. Existing antibiotics may cause serious side effects in some patients, such as severe allergic reaction, decreased blood pressure, suppression of the bone marrow, inflammation, swelling at the site of injection, muscle toxicity, optic and peripheral neuropathies and headaches.

Preferred Attributes of New Antibiotics

Based on market research conducted by Targanta, infectious disease physicians most desire the following attributes in new antibiotics:

  • Greater efficacy: Physicians see the greatest need for antibiotics that improve cure rates and clinical outcomes for patients as compared to currently available treatment options.

  • Fewer side effects: Physicians desire antibiotics that have reduced side effect profiles compared to currently available antibiotics.

  • Fewer treatment issues: Physicians express a preference for treatments that require a minimum of expensive and time-consuming monitoring, as well as those that require fewer dosing adjustments.

  • Better hospital economics: Physicians express a preference for efficacious treatments that require less treatment intensity and shorter duration of therapy, resulting in shorter hospital stays.