A year ago, almost to the day, the Center for Disease Control and Prevention ran this banner headline on its Morbidity and Mortality Weekly Report: "Staphylococcus aureus resistant to vancomycin."
Vancomycin is regarded as the only antibiotic by far that can defeat Staph aureus infection in hospitals. S. aureus is a common bacterial species found especially on mucous membrane and skin hair follicles. The bug's enterotoxin causes food poisoning as well as toxic shock, which are the chief reservoir of S. aureus' weapon of mass infection.
This month, the Oxford University Press ran three consecutive articles, totaling 23 pages, in a special peer-reviewed supplement to its Journal of Antimicrobial Chemotherapy. They are titled:
"Clinical impact of vancomycin-resistant enterococci." Its author is Robin Patel at the Mayo Clinic in Rochester, Minn.
"Therapeutic and preventative options for the management of vancomycin-resistant enterococcal infections," authored by Carol Kauffman at the University of Michigan Medical School in Ann Arbor.
And "Ramoplanin: a novel antimicrobial agent with the potential to prevent vancomycin-resistant enterococcal infection in high-risk patients," authored by Marissa Montecalvo at New York Medical College in Valhalla.
Ramoplanin, a putative antibiotic successor to oral vancomycin, is under development by Genome Therapeutics Corp. in Waltham, Mass. Its chairman and CEO is Steven Rauscher.
VRE, or vancomycin-resistant enterococci, Rauscher told BioWorld Today, "spreads in a hospital environment, namely, the gastrointestinal [GI] tract, which is the key reservoir of the patients themselves. The way VRE takes hold in an institution is that it first colonizes the GI tract, then later on becomes an infectious agent. That is also the means by which VRE spreads throughout a hospital. The bacteria grow up and colonize the patient's GI tract, then contaminate the hospital environment, and gets spread from patient to patient. In humans, VRE most commonly result in intestinal colonization, which does not result in symptoms," Rauscher explained.
"But it may persist for a long time and serves as a reservoir for transmission of VRE to other patients - and hospital health care hands."
Hand To Hand, Patient To Patient
"VRE is capable of surviving at least one week on fabric seat cushions, then transfer to staff hands," he said. "The pathogen has been isolated from virtually everything in the hospital, including call bells, stethoscopes, electronic thermometers, blood pressure cuffs, bed rails, toilet seats, doors, floors, linens.
"In terms of trying to control this antibacterial agent and its spread in a hospital environment, Ramoplanin acts specifically on the GI tract," Rauscher said. "It has potential as an important agent to prevent these adverse effects from occurring. Ramoplanin has a different mechanism of action than vancomycin. It inhibits bacterial cell wall synthesis. It does interfere with this paptidoglycan synthesis, but it's different and it does not complex with the same sequence that vancomycin connects with."
Ramoplanin was discovered by Vicuron Pharmaceuticals Inc. in King of Prussia, Pa.
"So far we have not observed any acquired drug resistance," Rauscher continued, "nor have we seen or observed any cross-resistance with currently used antibiotics. I think the overarching theme here," he said, "is our belief - and the belief of many infectious-disease clinicians we are working with - that the gastrointestinal tract plays a very important role in nosocomial [in-hospital] infections. That applies in particular for Gram-positive pathogenic organisms. Multidrug resistance of these microbes to antibiotics are preventing the treatment and controlling the spread of these infections in the hospital. This will require the clinician to pay close attention to the GI tract of these hospitalized patients.
"Vancomycin's drug-resistance resistance bubble burst," Rauscher went on, "starting in the 1990s when we began to see an increase in resistance in enterococcal species of vancomycin. Actually, that resistance is genetic. There are several packages of genes associated with resistance development. It's not easy for enterococci to develop resistance to vancomycin, and that rate of resistance continued to grow through the 1990s. One of the most important and difficult to overcome is target-site alteration by the organism. When the bacteria's binding site is altered, vancomycin no longer recognizes its regular binding site on the bacterium so it can't kill the pathogenic organism.
"Peptidoglycans form the bacterial cell wall. Ultimately, they manifest a target-site alteration on the peptidoglycan molecule, which comprises the major constituent of that bacterial cell wall. It's one of the terminal steps where the peptidoglycan is cross-linked, and vancomycin ordinarily prevents that cross-linking by binding to the amino-acid terminus that kills the bacteria. Because these genes encode for that target-site alteration, vancomycin can't bind to it and prevent the cell wall from forming. The bacterial cell wall kills the pathogen. It's the same pathway as vancomycin but vancomycin inhibits peptidoglycan synthesis downstream from that of Ramoplanin."
Vancomycin Not Only Drug-Resistant Antibiotic
"The main clinical impact," he continued, "is that some 30 percent of enteroccocal infections that occur in U.S. hospitals will occur to an organism that is now resistant to vancomycin. The same organism will be resistant to other commonly used antibiotics. As a result, the therapeutic options available to the clinician are significantly limited. And the morbidity and mortality due to the VRE infection is higher than if it were caused by a sensitive strain of enterococcus.
"What we're seeking to do with all the controlled clinical trials of Ramoplanin," Rauscher explained, "is to demonstrate the product's ability to help manage these nosocomial infections by killing these multidrug-resistant Gram-positive organisms in the GI patient.
"Our company is sponsoring and funding controlled clinical trials of Ramoplanin," Rauscher noted. "Currently, it is in a Phase III trial for the prevention of bloodstream infections caused by VRE. It is also in a Phase II trial for the treatment of nosocomial diarrhea caused by Clostridium difficile, a bacterial species found in feces of humans and animals. "