|Biotech's response to the MRSA epidemic|
|By Sebastian Thaler|
|Wednesday, 09 March 2011 02:21|
This article begins with an overview of the MRSA epidemic, and continues with a more detailed look at its destructive potential. We then examine different approaches that biotech companies have taken to developing treatments and a diagnostic test for it.
An Evolving Epidemic
Meanwhile, an epidemic of so-called community-acquired MRSA (CA-MRSA) involves a bacterial strain, USA300, that exhibits several characteristics. It is highly acquisitive and promiscuous, acquiring genetic material with ease; it colonizes both fomites and the body, with high recurrence rates of 30-50%; it is associated with necrotizing skin/soft tissue infections; and it is associated with pneumonia, especially severe cases that occur after cases of flu. It is also associated with a variety of wounds, abscesses, cellulitis and necrotizing fasciitis. Additionally, even bacteremia and infective endocarditis are now caused by the community-acquired form of MRSA.
The latest iteration of the infection is multidrug-resistant CA-MRSA, containing the plasmid pUSA03. This variant of MRSA is resistant not only to beta-lactams, fluoroquinolones and macrolides, but also tetracycline, clindamycin and Mupirocin. Even more significantly, Vancomycin, the “gold standard” for the treatment of MRSA, has significant limitations; it exhibits poor tissue penetration and increasing nephrotoxicity, and is only slowly bactericidal. Vancomycin is also encountering increasing resistance from MRSA with worsening outcomes, resulting in a poor response to therapy for prolonged infection, or even complete failure of antibiotic therapy.
Unfortunately, existing alternatives to vancomycin have weaknesses. Resistance has been noted for all approved alternatives, and there are limited bactericidal options. Further, there are few options for the treatment of pneumonia or bacteremia, and all antibiotics have treatment-limiting side effects. In short, resistant S. aureus infections are at epidemic proportions in the US, and clinicians need new, safe treatment options with novel mechanisms of action.
The Advance of MRSA
Kepa from San Francisco, Jay from New Jersey, Carlos from California: These ordinary Americans have had their lives tragically altered by MRSA. Their stories, detailed by Maryn McKenna in her book Superbug: The Fatal Menace of MRSA (Free Press, 2010), sound like horror movie plots.
One day in 2007, Kepa noticed a single pustule on her face. Three courses of antibiotics failed to stem fever, pain and weakness, and more pustules soon formed on her extremities. Confined to bed, a buttock abscess led to a diagnosis of community-acquired MRSA. Luckily, after six months of further treatment, the MRSA resolved. In the hospital in 2005 for a bowel resection after diverticulitis, Jay S. contracted surgical-site MRSA. His abdominal wall was so weakened by the Staph that over the next five years, he suffered 12 hernias, underwent eight surgeries, and to date has experienced eight recurrences of MRSA. In total, he has spent six months in the hospital at a cost of more than $1 million. After three days of fever in 2007, schoolboy Carlos D. went into the hospital, where he suffered hypoxia and hallucinations. Diagnosed with MRSA necrotizing pneumonia, his lungs quickly became unusable. Despite two weeks on advanced life support, he died within four weeks of his first symptoms.
The initial three cases of HA-MRSA were identified in 1961 in the UK. Its first appearance in the US came in 1968, with 18 cases reported at Boston City Hospital. The year 1980 witnessed a massive outbreak at Seattle’s Harborview Medical Center; over the course of 15 months, the facility was the site of 27 cases of MRSA involving 17 deaths and two ward closures. Thirty years later, in May 2010, the Agency for Healthcare Research and Quality noted that “very little progress has been made on eliminating health care-associated infections.”
As noted earlier, this hospital epidemic of MRSA was followed by a community epidemic. The first identification of CA-MRSA was made in Chicago in 1996. Two years later, a report of 25 cases (along with a skeptical editorial) appeared in The Journal of the American Medical Association, and in 1999 the CDC’s Morbidity & Mortality Weekly Report wrote on four cases in the upper Midwest. Over the past decade, cases of MRSA have also been reported on farms, carried by pigs and pig-farm workers.
How did the situation get so bad? Resistance is an inevitable biological process. It is made worse by insufficient hospital infection control and antibiotic overuse in primary care medicine and unregulated and out-of-control use in animal feed. MRSA’s spread is abetted in part by the fact that it is not a reportable disease and there is no national surveillance program to oversee it. People are at increased risk both because of increasing resistance to last-resort antibiotics and the slowing development of new antibiotics. Infection control and antibiotic misuse should be improved, but new compounds will always be needed.
Mimicking the Body’s Innate Immune Natural Defenses
One approach toward solving the growing problem of MRSA and drug-resistant pathogens is being pursued by NovaBay Pharmaceuticals (AMEX: NBY), an Emeryville, CA-based biotechnology company developing topical, nonsystemic anti-infective compounds for the treatment and prevention of antibiotic-resistant infections.
NovaBay is developing a new class of drugs it has named Aganocide® compounds with a new mechanism of action that is different than traditional antibiotics. NovaBay’s lead Aganocide compound, NVC-422 is a first-in-class, broad-spectrum, fast-acting synthetic N-chlorinated antimicrobial molecule specifically designed and developed to mimic the body’s natural innate defense against infection. NVC-422 maintains the potent antimicrobial activity of the naturally occurring N-chlorotaurine but with superior chemical stability making it suitable for a cost-effective manufacturing under GMP requirements. The Aganocide compounds are the result of finely tuned medicinal chemistry at NovaBay Pharmaceuticals.
Mechanism of Action
The working hypothesis for the mechanism of action of NVC-422 is by the inactivation of thiol-containing amino acids resulting in a change of their physiochemical properties. This change of physiochemical properties induces a compulsory three-dimensional change of membrane proteins resulting in protein dysfunction, dysregulation or shedding from bacterial membrane. This cascade leads to the rapid and irreversible death of the pathogens without causing bacterial lysis or resistance. This is a major differentiating feature of the Aganocide compounds from traditional antibiotics. Microbial repair systems are inadequate to compensate for multiple protein inactivation; while human cells have a potent antioxidant defense system thereby sparing them from oxidative stress allowing for a wider therapeutic window. This is an important differentiating feature when targeting pathogens like MRSA.
NovaBay’s lead Aganocide compound NVC-422 has shown efficacy against the recently reported “superbug,” the New Delhi metallo-beta-lactamase (NDM-1). NDM-1 is an enzyme that imparts bacterial resistance to a broad range of beta-lactam antibiotics including the carbapenem family used for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. NVC-422 is also effective against the “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) that cause most hospital infections, and increasingly these pathogens escape the effects of antibiotics.
Clinical Development of NVC-422
Initially, NovaBay will be focusing its Aganocide technology on a number of topical, non-systemic infections. Community-Associated MRSA infections are mostly skin infections that have the potential of reaching the bloodstream causing sepsis. In recently completed Phase 2 human trials in 129 patients suffering from impetigo, a highly contagious staph skin infection, NovaBay’s lead Aganocide compound showed up to 92% clinical efficacy and 95% bacteriological efficacy against MSSA and MRSA. NovaBay’s partner in dermatology is Galderma, S.A. of Switzerland.
NovaBay believes that this first-in-class compound has the potential to deliver the same or better efficacy than antibiotics, without contributing to the growing problem of antibiotic resistance by employing a novel mechanism of action for a number of topical / non-systemic infections. NovaBay is focusing its technology on four distinct therapeutic areas: dermatology, ophthalmology, hospital infection and urology. In dermatology, NovaBay is focused on developing its lead Aganocide NVC-422 for impetigo and acne. NovaBay has the distinct advantage of being partnered with Galderma, the leading dermatology company in the world. In ophthalmology, NovaBay is developing an eye drop for conjunctivitis with Alcon Labs, the world’s leading ophthalmology company. In hospital infection, NovaBay has a 510K-approved solution targeting a six-million-patient market of chronic non-healing wounds such as pressure, venous stasis and diabetic ulcers. In urology, NovaBay aims to reduce the incidence of urinary catheter blockage and encrustation (UCBE) and the corresponding urinary tract infections.
Destroying MRSA From the Inside Out
A third potential line of attack in the battle against MRSA involves harnessing phages, naturally occurring bacteria-eating viruses. Phages destroy bacteria from the inside out; they enter a bacterium through its membrane and deposit DNA inside, where the phages replicate. Baby phages burst out of the bacterium, exploding it like a water balloon, and head after other bacteria. Since each species of a phage attacks one specific type of bacteria, phages work best in a cocktail custom-mixed to combat the particular bacteria causing a patient’s infection.
One biotechnology company interested in this approach is Baltimore-based Intralytix Inc., which is focused on the production and marketing of bacteriophage-based products to control bacterial pathogens in environmental, food processing, and medical settings. The company’s human health products currently under development include SAP-100™, which targets S. aureus, including MRSA, and VRSA (vancomycin-resistant S. aureus). Its possible applications include nasal decolonization to reduce nosocomial infections, and the treatment of wounds infected with strains of S. aureus that cannot be killed by any currently available antibiotics.
A blood culture assay for MRSA
As if developing a sure-fire treatment for MRSA weren’t sufficiently daunting, it is also proving to be a considerable technical challenge to develop a consistently reliable diagnostic test to determine its presence or absence in patients.
Based in Sunnyvale, California, Cepheid (Nasdaq: CPHD) has for several years marketed a rapid genetic test to detect MRSA. The company’s Xpert® MRSA/SA Blood Culture Assay is designed to reduce the timeframe required for diagnosis from 2-3 days down to a little over 1 hour, providing on-demand results and in some cases eliminating the need to presumptively isolate patients.
Cepheid’s MRSA test is built on a system that fully automates and integrates the steps required for PCR-based DNA testing: sample preparation, DNA amplification and detection. The system involves microfluidic cartridges that incorporate a syringe drive, rotary drive and a sonic horn. The sonic horn delivers ultrasonic energy necessary to lyse the raw specimen and release nucleic acids contained within, while the combination of the syringe drive and rotary drive moves liquid between cartridge chambers in order to wash, purify and concentrate these nucleic acids. After the automatic extraction is complete, the nucleic acid concentrate is moved into the cartridge reaction chamber where amplification and detection takes place. Software and a barcode scanner manage data and display results.
In July 2010, Cepheid announced a voluntary recall of this product “after learning of rare, false-negative MRSA results from the testing of blood culture samples,” recommending that further testing be conducted following the rendering of a negative test result. In a company press release dated July 1, the company identified the emergence of novel MRSA strain types as one of the causes of false-negative MRSA results. According to a notice issued by the US Food and Drug Administration, however, “positive results generated on the Cepheid MRSA/SA Blood Culture Assay can still be reported.”
As we have seen, MRSA is a serious and growing problem demanding the utmost attention from the infectious disease community. Should the development of novel drugs and more refined diagnostic tests prove feasible, these could potentially serve as significant advances in the treatment and management of MRSA-related infections.
Disclosure: No Positions