The Department of Veterans Affairs’ (VA) infectious disease research program is all encompassing, involving fundamental investigations of what makes a bacterium, virus, fungus, or parasite into a disease-causing pathogen; of how infectious diseases are passed from person to person; and of the effectiveness of preventive strategies, vaccines, and drugs. In recent years, the infectious disease research community has turned much of its attention to multidrug-resistant organisms (MDROs), a group of pathogens that has led to an increase in microbial infections over the last few decades.

For a number of reasons, our arsenal of antimicrobial drugs, so effective for decades in treating infectious microorganisms, has not evolved – but in the meantime, the organisms they were designed to kill have adapted. The U.S. Centers for Disease Control and Prevention (CDC) estimates that at least 2 million people are infected by MDROs annually, and that at least 23,000 die each year as a result of these infections. An additional 15,000 die every year from Clostridium difficile (C. diff), a pathogen associated with long-term antibiotic use in health care settings.

MDROs are a significant concern for the VA medical community, whose patient population is statistically older and more vulnerable to infection than other Americans due to battle injuries, comorbid diseases, and other factors. Many MDROs are implicated in health care-acquired infections (HAIs), which occur when pathogens colonize and linger in health care settings. One of the most virulent MDROs, methicillin-resistant Staphylococcus aureus, or MRSA, can survive for more than nine months on inadequately disinfected surfaces. About three-fourths of all HAIs are from organisms that resist first-line antibiotics. A 2012 study conducted by the Alliance for Aging Research found that 99,000 Americans died of HAIs annually, and that MRSA infections killed more than emphysema, HIV/AIDS, Parkinson’s disease, and homicide combined.

For a number of reasons, our arsenal of antimicrobial drugs, so effective for decades in treating infectious microorganisms, has not evolved – but in the meantime, the organisms they were designed to kill have adapted.

The VA’s attack on MDROs is two pronged. Its MDRO Prevention Initiative, a collection of procedural guidance for professionals throughout the Veterans Health Administration (VHA), has greatly reduced infection rates for organisms such as MRSA and C. diff throughout its health care facilities. Updates and improvements to the program continue, along with a robust research program into effective infection control techniques and protocols.

In the absence of effective antimicrobial treatments, VA investigators are also probing the weaknesses of these MDROs in basic research that may lead to effective vaccines or drug treatments. Researchers are focusing particular attention on a group of organisms known as the ESKAPE pathogens, highly resistant pathogens responsible for the majority of HAIs:

• Enterococcus faecium (E. faecium)
• Staphylococcus aureus (S. aureus)

These two organisms are unusual for Gram-positive bacteria, which respond to Gram staining due to their lack of a rugged outer cell membrane. Gram-positive bacteria have historically been vulnerable to penicillin-derived antibiotics such as methicillin, but E. faecium and S. aureus have evolved a resistance to these and other drugs.

• Klebsiella pneumoniae
• Acinetobacter baumannii
• Pseudomonas aeruginosa
• Enterobacter species

These four Gram-negative bacteria have a built-in defense against many classes of antibiotics. Broad-spectrum “last-line” antibiotics, such as carbapenems or cephalosporins, that used to be effective against these organisms are losing their edge, and in many cases, are contributing to their evolution into “superbugs.”

VA researchers, however, are discovering new vulnerabilities and possible modes of attack against these organisms, often at the molecular level.

 

Taking Cues from Cancer Research

The increasing resistance of infectious organisms to known antibiotics has led investigators to explore other ways of penetrating and killing pathogens. In some cases, promising treatments have been suggested by findings in cancer research.