Last week, the FDA approved Dalvance, Chicago-based Durata Therapeutic’s new antibacterial drug for the treatment of methicillin-resistant staphylococcus aureus (MRSA) infections.
Why is Dalvance newsworthy? MRSA is an infectionthatis difficult to treat because it is resistant to all the usual medications: the cephalosporins and penicillins (methicillin, dicloxacillin, oxacillin, etc.)
What is MRSA? MRSA skin infections may begin as uncomfortable sores or boils on the skin’s surface that if left untreated may progress to deep, painful abscesses requiring surgical draining. MRSA infections that enter the bloodstream or joint tissue can be life-threatening.
Who is most susceptible to MRSA? MRSA is a serious threat to the hospitalized, potentially infecting surgical wounds or gaining entry into a patient’s bloodstream through an invasive device such as a catheter. MRSA outbreaks are also reported in prisons, shelters, military barracks, and nursing homes because of crowded and confined living conditions. Approximately 2% of the population carries MRSA on their skin and although most do not exhibit signs of infection, they can pass it on to individuals with open wounds or weakened immune systems.
How does Dalvance work? It works by inhibiting bacterial cell wall synthesis. The cell wall is a layer of sugars and amino acids (peptidoglycans) that surround bacterial cell membranes, providing bacteria with structural support and protection, as well as acting as a filtering mechanism. Dalvance is a synthetic “lipoglycopeptide”—a chemical entity similar enough to the peptidoglycans incorporated into the cell wall, but different enough so that once incorporated, cell wall synthesis stops. Without a functional cell wall, bacteria die. Human cells do not have cell walls, therefore they are not affected.
FDA QIDP STATUS GRANTED
Dalvance is the first drug to be approved under the FDA’s new Generating Antibiotic Incentives Now (GAIN) program, established as part of the FDA Safety and Innovations Act of 2012. Under GAIN, antimicrobials in development may be granted Qualified Infectious Disease Product (QIDP) status. QIDP status enabled Dalvance to get priority review, as well as an additional five years of data exclusivity now that it is approved.
In the past decade, drug-resistant and multi-drug resistant bacteria strains have become one of the greatest public health challenges of the twenty-first century. Antibiotic resistance occurs when a few bacteria in a given population develop a genetic mutation that makes them able to survive, even in the presence of a particular antibiotic. For example, suppose an antibiotic works by inhibiting an enzyme required for bacterial replication. If one bacterium mutates so the enzyme now has a slightly different shape and is therefore no longer inhibited by the antibiotic, it will continue to reproduce while all the other bacteria die off. Over time, this resistant type becomes the dominant strain, spreading from person to person, unchecked by antibiotics. This type of resistance is caused in large part by overuse of antibiotics—the more a bacterial population is exposed to antibiotics, the greater the chance that resistance will develop.
Each year in the U.S., at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 die as a direct result of these infections (source: CDC). Many more die from other conditions that are complicated by an antibiotic-resistant infection. In addition to MRSA, other drug-resistant microorganisms of urgent concern include Clostridium difficile (life-threatening diarrhea), Enterobacteriaceae (bloodstream infections), Neisseria gonorrheoeae (severe reproductive complications), Pseudomonas aeruginosa (pneumonia, bloodstream, urinary tract, and surgical site infections), and Mycobacterium tuberculosis (tuberculosis). Hopefully, the GAIN program will lead to the discovery and development of a wide range of novel antimicrobials to fight these emerging threats.
BACTERIA VS. VIRUSES
Most of us have been told by our family doctor that a prescription for antibiotics will do no good against a viral infection such as the flu or the common cold. During flu season, instead of taking a few rounds of pills and starting to feel better, we have to suffer through a week or so of sore throat and exhaustion, aided only by chicken soup and extra rest before getting back to normal. Why is this?
Bacteria are independent, single-celled organisms with their own cell membrane, cell wall, and DNA/protein-making machinery. Bacteria do not need another living organism to survive. Most antibiotics work by targeting structures such as cell walls that are unique to bacteria so the bacteria cells are killed, but human cells are not harmed.
In contrast, viruses are not independently living organisms. Most consist of only some genetic material (DNA or RNA) encapsulated in a few proteins and sometimes a membrane. They are not able to fully replicate their genetic material or make the proteins they need for survival without the aid of another living cell–its host. This means it is more difficult to make a drug targeting just the virus without also harming its host—us.
Fungi have been an important source of antimicrobials. Penicillin was discovered in 1928 when microbiologist Alexander Fleming observed that infection of his bacterial cultures with the Penicillium fungi inhibited bacterial growth. Penicillin was hailed as a wonder drug, but as early as the 1950s—just a few years after widespread use began—problems with bacterial resistance emerged. Despite the many lives penicillin has saved, it is also the most common drug allergy, illustrating why it is important to have a wide range of potential antibiotics on hand.
IN THE PIPELINE
Massachusetts-based Cubist Pharmaceutical’s new antibiotic, Sivextro—also being developed for MRSA skin infections—has received the QIDP designation. Sivextra was unanimously recommended by an FDA advisory panel last March; a final approval decision is expected by June 20th. Sivextra works by inhibiting the bacterial ribosome – the enzyme that makes all bacterial proteins. Without new protein production, the bacterium is unable to carry out functions essential for life, and dies. Cubist Pharmaceuticals has another product in Phase III development for C. difficile-associated diarrhea.