It had to happen sooner or later. But not to worry - overmuch.
On July 5, the Centers for Disease Control and Prevention (CDC) in Atlanta published its regular Morbidity and Mortality Weekly Report - a heads-up on communicable diseases in the U.S. Its banner headline reads: "Staphylococcus aureus resistant to vancomycin - United States, 2002."
"Over the years, calling vancomycin the antibiotic of last resort' was an accurate statement," infectious-disease physician Scott Fridkin told BioWorld Today. "Traditionally, methicillin-resistant Staph aureus was resistant to most antimicrobials, with the exception of vancomycin." Fridkin is a medical epidemiologist in the CDC's Division of Health Care Quality.
(Curiously, vancomycin is itself derived from another pathogenic microorganism, Nocardia orientalis. And methicillin is a weaker version of its parent antibiotic, penicillin.)
"This report," the CDC's weekly bulletin noted, "describes the first documented case of infection caused by vancomycin-resistant S. aureus [VRSA] in a patient in the U.S. In June 2002," it went on, "VRSA was isolated from a swab obtained from a catheter exit site from a Michigan resident, a woman aged 40 years with diabetes, peripheral vascular disease and chronic renal failure. She received dialysis at an outpatient facility.
"Since April 2001," the case history continued, "the patient had been treated for chronic foot ulcerations with multiple courses of antibiotic therapy, including vancomycin. In April 2002, she underwent amputation of a gangrenous toe and subsequently developed methicillin-resistant S. aureus bacteremia caused by an infected arteriovenous hemodialysis graft." In June, she was found to have antibiotic resistance to S. aureus.
This patient is under the care of the Michigan State Department of Community Health in Lansing. "We have no reason to believe there is any threat to the general public," observed its director, James Haveman Jr., "and will aggressively continue this investigation with the assistance of the CDC." Infectious disease experts from CDC were sent to Michigan to work collaboratively with state epidemiologists and laboratory personnel. To date, no other vancomycin-resistant Staph aureus infection has been identified.
"I appreciate the cooperation we have received from this patient," Haveman observed, "and would urge all involved health care workers, the press and the public to recognize this individual's right to confidential health care treatment."
Fridkin updated her current situation: "The clinical team is managing the patient with aggressive local wound debridement. It also has her on other antibiotics that this organism is susceptible to, rather than resistant." He noted. "There have been newer agents approved by FDA for treating Gram-positive infections, including Staph aureus. These drugs are available to her clinicians as of now. They happen to be using an agent approved for many years - trimethoprim-sulfamethoxazole - or Bactrim as it's usually called. I think," Fridkin pointed out, " that these newer FDA-approved agents will give physicians additional options if vancomycin-resistant Staph aureus becomes more common than it is now."
Two Related Cocci Swap Vancomycin Resistance
"We know that there is a DNA in this bacterium that is well described in another organism called enterococcus, which inhabits the intestinal tract," he said. "For enterococci resistance to vancomycin there are several well-described genetic determinants. That same resistance factor has been detected in vancomycin resistance in S. aureus, suggesting that the DNA telling this organism to become resistant to vancomycin was acquired by the enterococci. Both organisms had to cohabit patients' wounds and cause infections at the same time. I think scientists discovered over a decade ago that these pathogens can share DNA. And it was only a matter of time until we witnessed it in nature.
"The environment with which this resistance can occur," Fridkin went on, "is of course promoted by excessive use of vancomycin. And I think reducing excessive or inappropriate use of vancomycin would help decrease the atmosphere in which this type of sharing DNA, and promoting resistance, occurred."
One decisive end-run around these stop-gap drug options would be the construction of vaccines directed against the likes of Staph aureus. "Several companies are developing active and passive immunization products," Fridkin said. "Active meaning you give a vaccine and the body builds immunity. Passive is that you pool the immunoglobulins of patients who have been vaccinated, and give this pooled antibody to susceptible people. Those vaccines are in development," he noted. "I don't believe any are approved for use, but I think in the next five years we will start to see such vaccines become available, and hopefully used for patients at greatest risk of Staph aureus infections, such as hemodialysis or elective surgery patients."
Cubist's Antibiotic, Daptomycin, Poised For NDA
Cubist Pharmaceuticals Inc., of Lexington, Mass., has an antibacterial drug on its drawing board aimed at forfending this fateful history.
"There's a short list of new, alternative antibiotics to vancomycin," observed Cubist's CEO, Scott Rocklage. "One of them is our daptomycin, which is active against the vancomycin gene-based resistance factor - what this Staphylococcus aureus resistant isolate has. I think the key about our daptomycin," Rocklage continued, "is that it works by a unique mechanism, which Gram-positive organisms like Staph aureus have never seen before. It's a brand new mechanism. That's one of the reasons why it's able to be active against these kinds of mutated isolates with these kinds of genetics.
"The second thing that's interesting about daptomycin is that its modus operandi is a 'cidal mechanism - bactericidal is the whole word. That means it actually kills organisms as opposed to inhibiting their growth, which other antibiotics often do. So that's very important when you're fighting drug-resistant organisms. You want to kill them, and prevent further mutations. We're filing the new drug application on daptomycin the fourth quarter of this year, so we'll have an interesting 2003 and see how we manage our way through the regulatory process. Remember," Rocklage concluded, "dead bugs don't mutate."