March 15, 2009 (Vol. 29, No. 6)

Significant Opportunity Exists for Innovative Biopharmaceutical Companies

Hospital acquired infections (HAIs), also called nosocomial infections to better describe the range of places they can occur, have become a major health concern. In the U.S., between 5% and 10% of patients admitted to acute care hospitals acquire infections. This accounts for over two million patients per year, and these infections result in over 90,000 deaths per year.  Over one-quarter of HAIs occur in ICUs, but nursing homes and rehabilitation centers are also impacted.

The cost of HAIs is significant and troubling; in 2005, it was estimated at $4.7 billion per year in the U.S. alone. Given the increased incidence in certain medical conditions and the growth in hospital populations and cost of stays, as well as the expense of treating some advanced cases, Kalorama estimates that nearly $6 billion per year is spent on treatment and extended hospital stays.

Yet, despite the cost and negative impact on patients, pharmaceutical companies have not responded as we would expect. This, in our view, leaves open an opportunity for new treatments from innovative biopharmaceutical companies.

The type of infections vary, with the most common being pneumonias and urinary tract infections, accounting for 60% of hospital acquired infections, but conditions like MRSA continue to increase. It is estimated that MRSA cases have doubled over this decade. Drug-resistant pneumonia, Clostridium difficile, Acinetobacter baumannii, and MRSA are the most prevelant hospital acquired infections.

Pneumonia is a leading cause of death among the elderly and people who are chronically and terminally ill, and are therefore, normally hospitalized in acute care, short-stay, or extended-care hospitals. Nosocomial pneumonia is pneumonia acquired during or after hospitalization for another illness or procedure with onset at least 72 hours after admission. Up to 10% of patients admitted to a hospital for other causes subsequently develop pneumonia.

C. difficile is a bacterium that can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon.    From 1996 through 2003, there were an estimated 264,000 hospital discharges for which Clostridium difficile-associated disease was listed as a diagnosis. 

Acinetobacter baumannii is emerging as a cause of numerous global outbreaks and is displaying ever-increasing rates of resistance. There are reports of multidrug resistant (MDR) A. baumannii from hospitals around the world. More recently, military and nonmilitary personnel returning from operations in Iraq and Afghanistan have harbored infections caused by MDR A. baumannii.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for difficult-to-treat infections in humans. It may also be referred to as multiple-resistant Staphylococcus aureus (as methicillin is no longer on the market). MRSA is, by definition, a strain of Staphylococcus aureus that is resistant to a large group of antibiotics called the beta-lactams, which include the penicillins and the cephalosporins.

MRSA is especially troublesome in nosocomial infections. In hospitals, patients with open wounds, invasive devices, and weakened immune systems are at greater risk for infection than the general public.

Recent reports indicate that there is a nationwide epidemic of MRSA in the United States. A 2007 CDC report on emerging infectious diseases estimated that the number of MRSA infections treated in hospitals doubled nationwide, from approximately 127,000 in 1999 to 278,000 in 2005, while at the same time deaths increased from 11,000 to more than 17,000.  

Prevention Methods

Nosocomial infections will not be stopped by simple preventive measures. The pathogens that cause nosocomial infections exist throughout healthcare facilities. Many of them are extremely hardy and persist for long periods of time. It is simply not possible to disinfect every  area of the facility all the time. Because of this, there will most likely be a strong market for antibiotics to treat nosocomial infections and a market for diagnostics to define the existing infections.

Containment practices are isolation and cleanliness procedures and should be woven into the healthcare facility’s procedures. These work on the basis of isolating infected individuals from the general patient population and by removing pathogens from their routes of transmission.

Therapeutics clearly will be needed near and long term. A significant problem of HAIs, however, is the rapid spread of drug-resistance. This is not only an issue within the hospital setting, it is also an important issue in terms of public health. It should be remembered that not all nosocomial infections present themselves while the patient is actually in the hospital. These infections can show up within 48 hours of discharge. 

Opportunity for Biotech

Despite the need, HAIs do not seem to be a priority for large pharmaceutical companies. In 2007, the FDA approved 74 new therapeutics, of these, two were antibiotics—one a topical ointment for the treatment of impetigo and the other an intravenous drug for the treatment of complicated intra-abdominal and urinary tract infections.

Only about 50 of the more than 2,700 compounds currently in development are being developed as bacterial antibiotics.  Significantly, only 20% of these projects, a total of 10 out of 50 are being undertaken by large pharmaceutical firms. 

Why isn’t Big Pharma responding? It’s a fair question to ask. It could be that there is no potential for a blockbuster drug in this application, as the frequency of resistance makes it a difficult area to commit to long-term product investment. Therefore, as a result of the low priority such products have in traditional pharma, we believe the most logical player is the the biopharmaceutical community.

One option for the therapeutic community is to somehow silence drug-resistance genes. There is the possibility that some molecular method may be devised that will affect the genes of a bacterium preventing its reproduction, but this may be more expensive than other approaches. It will also require determining the relevant genes and empirically ascertaining which may be the most effective in eliminating the bacterial infection. In addition, it may be a possibility to restore drug sensitivity to bacteria in vivo.

If a bacterium is resistant to one class of antibiotic, it will readily develop resistance to all, or almost all, of the antibiotics in that chemical class. This means that the cause of the drug class resistance may be a single gene or it may be a family of closely related genes. If this is the case, and it likely is, it may be possible to silence the responsible gene(s). This could be done via antisense, siRNA, or other nucleic acid-based therapeutics technologies.

Rapid diagnostic tests would then, determine the specific resistance of a bacterial strain. A combination or a sequential administration, of silencing agents and antibiotics could provide the necessary conditions for effective treatment of the infection, and it could breathe new life into the tired and often ineffective antibiotics now on the market.

One problem, however, is that biotechnological therapeutics tend to be expensive. Compared to penicillin, their purchase is akin to the difference between purchasing a Rolls Royce and a Chevrolet. Even among some of the most expensive antibiotics, such as vancomycin, this is the case. How, then, can these new technologies address the problems of drug-resistant nosocomial and other infections?

It is clear that the solution lies in small molecules. For example, the development of recombinant human antibodies to bacterial strains is far too expensive. On the other hand, smaller molecules, such as small nucleic acid-based compounds or combinations of these compounds, may be the answer. Single molecules that address the silencing of a gene may need to be too large to penetrate the bacterial wall.

Combinations of smaller polynucleotides, addressing different and complementary portions of the bacterial genes may be made to enter the bacterial wall and silence the bacterium’s genetic resistance mechanisms or reproductive mechanisms. Such therapeutics may be somewhat more expensive than current antibiotics, but at the same time, their utility may be far greater.

Imagine that several strains of a particular species contain a similar, or possibly identical, reproductive sequence—not an impossibility and, in fact, highly probable.  If this is the case, then a series of neutralizing probes could be used to eliminate the pathogen by cutting off the reproductive mechanisms. 

This presupposes a great deal of genetic knowledge about bacterial pathogens. It also presupposes that there are companies willing to take a chance on developing such unique antimicrobials for nosocomial and community infections. We believe this effort is far more likely to emerge from the innovators in biotechnology than in the pharmaceutical establishment.

Bruce Carlson ([email protected]) is publisher at Kalorama Information.Web: This article was excerpted from a recent Kalorama report on Nosocomial Infections: Market Impact on Diagnostics and Therapeutics: (MRSA, HAP, C. diff. and other Hospital Acquired Infections).

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