Battling the Superbugs

Sometimes, the laws of evolution play against us. Just as the turning of centuries and generations have made we mere humans a stronger, healthier race, so to have the years been kind to our nemeses.

The organisms that lurk in today’s healthcare environments are more virulent than ever before. This is no secret, and as the recent years — and accompanying illnesses and deaths — have taught us, bacteria and other organisms are getting smarter, sneakier and more resistant. They are beating us at our own game.

Today’s prevalence of multidrug-resistant organisms (MDROs), for example, continues to span and infection control practitioners (ICPs), epidemiologists, and every other healthcare professional need to be at the top of their game to squelch the spread of such threats in their respective institutions.

In American hospitals alone, healthcare associated infections (HAIs) account for an estimated 1.7 million infections and 99,000 associated deaths each year, according to the Centers for Disease Control and Prevention (CDC). Of these infections:¹ 

• 32 percent are due to urinary tract infections (UTIs) 
• 22 percent are due to surgical site infections (SSIs) 
• 15 percent are due to pneumonia 
• 14 percent are due to bloodstream infections (BSIs) 

Many of these infections are caused by today’s MDROs. The epidemiologically important pathogens, according to national guidelines on MDROs, are those infectious agents that have one or more of the following characteristics:² 

A propensity for transmission within healthcare facilities based on published reports and the occurrence of temporal or geographic clusters of greater than two patients.

Such organisms include methicillin-resistant Staphylococcus aureus (MRSA), methicillinsusceptible Staphylococcus aureus (MSSA), extended-spectrum beta-lactamase-producing gram negative bacilli (ESBL), penicillin-resistant Streptococcus pneumoniae (PRSP), multi-drug-resistant Streptococcus pneumoniae (MDRSP) vancomycin intermediate resistant Staphylococcus aureus (VISA) vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA), and Clostridium difficile (C. diff.).

Noted resistance is also occurring in Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli (E. coli), Burkholderia cepacia, Ralstonia picketii, Stenotrophomonas maltophilia, norovirus, respiratory syncytial virus (RSV), influenza, rotavirus, Enterobacter spp; Serratia spp., and group A streptococcus.

Andrew F. Shorr, MD, MPH, associate director of pulmonary and critical care medicine at Washington Hospital Center in Washington, D.C., and author of numerous research articles including one titled, “Epidemiology of staphylococcal resistance” (Clin Infect Dis. 2007 Sep 15;45 Suppl 3: S171-6.), points to the important and obvious gram-positive and gram-negative divide. He says on the gram-positive side, the biggest concern is that of MRSA and now of community-acquired MRSA (CA-MRSA). On the gram-negative side, “We’re certainly worried, continually, about pseudomonas and resistance among pseudomonas, but Acinetobacter has become more of an issue as have the ESBL-producing Klebsiella.

“VRE is going to be more of an issue sporadically,” he adds, noting that in some places, VRE can be a big problem. “In my hospital it is not. I think that will be in the background as well, depending upon where you practice.”

Overall, Shorr says that those healthcare professionals battling these insidious bugs are constantly trying to get a good reach around them. “I think people right now are trying to grapple with and understand (them) in terms of prevention and things,” he says.

Once an MDRO is introduced into a healthcare setting, it is extremely easy for it to run amuck.

Transmission and persistence of a resistant strain is determined by the availability of vulnerable patients, selective pressure exerted by antimicrobial use, increased potential for transmission from larger numbers of colonized or infected patients (colonization pressure); and the impact of implementation and adherence to prevention efforts.² Additional opportunities for transmission of MDROs beyond the acute care setting are that of patients receiving care at multiple healthcare facilities. The authors of the MDRO guidelines note that many patients can move between acute care, ambulatory, chronic care, and other healthcare environments.² System-wide surveillance at LDS Hospital in Salt Lake City, for example, monitored patients identified as being infected or colonized with MRSA or VRE. The researchers found that those patients subsequently received inpatient or outpatient care at as many as 62 different healthcare facilities in that system during a five year span.⁴

The patients most vulnerable to colonization and infection include those with severe disease, especially those with compromised host defenses from underlying medical conditions; those who have had recent surgery; or those with indwelling medical devices.² ICU patients tend to have more risk factors and have the highest infection rates, however, increasing numbers of infections with MDROs also have been reported in non-ICU areas of hospitals.² Back to the claim of organisms beating us at our own game, antibiotic resistance is occurring at alarming rates and resistance trends are frightening.

For example, of all enterococci isolates, those that were vancomycin-resistant in 1990 rested at less than 1 percent. By 2003, that number jumped to 28.5 percent. MRSA has more than doubled. In the early 1990s, 20 percent of S. aureus isolates were methicillin-resistant, but now that number has climbed to 59 percent. Moreover, studies have estimated that nearly a quarter of all residents at the average long-term care facility may be colonized with MRSA, and nearly 50 percent of all infections in an ICU are MRSA-related.⁵

Antibiotic resistance has fast become a topic of grave concern, and the news just keeps getting worse. For example, carbapenems, a relatively young family of antibiotics that works on a wide variety of bacteria, often held for those most critically ill, is even at risk. The BlaKPC gene, which is a resistance gene that allows bacteria to beat this important class of antibiotics, is now spreading geographically. Researchers at Washington University School of Medicine in St. Louis have found this gene — which historically has been found in bacteria taken from East Coast patients — in patients hospitalized at a Midwestern hospital. Researchers found the gene in four patients with BSIs.

BlaKPC was originally identified less than a decade ago during an East Coast outbreak of the bacterium Klebsiella pneumoniae. The gene is encoded on a DNA structure known as a plasmid that can be easily copied and passed around not just among bacteria of the same species, but from one bacterial species to another as well. Subsequent studies found mortality rates climbing as high as 50 percent when bacteria with the resistance gene infected patients.³ 

BlaKPC spreads easily among bacteria, and scientists are now finding that the method most hospitals use to check for such resistance genes do not detect all BlaKPC-positive strains. “It’s relatively easy for us to find this gene, but most hospitals don’t have access to the same high-tech methods that we have at a major medical center,” senior author David Warren, MD, assistant professor of medicine, notes in a press release. “To help slow the spread of this gene, we need to look at whether we can develop a more effective way to detect it using widely available equipment and procedures.”

The inability to detect the gene may be a result of the resistance gene being inactive in the bacteria, the researchers add in their study which was presented in September at the Interscience Conference on Antimicrobial Agents and Chemotherapy. The gene does not convey its carbapenem-fighting abilities until “the bacteria make a copy of its protein, and the bacterium may need some stimulus from the environment to start making those copies.”

The samples that were found are of bacteria with an active copy of the gene. However, the researchers have yet to conclude whether the gene is spreading in active or inactive form.

Prevention and the Duty of the ICP

The top three administered control measures historically implemented for the control of MDROs in a healthcare setting are:

No. 1 — contact precautions and glove use 
No. 2 — surveillance cultures of patients 
No. 3 — education of staff, patients or visitors 

“Expanded precautions” is a commonly used term in this sense as with some of these organisms, traditional precautions may not be enough. Accumulating the data needed to fight MDROs also can be challenging. Active surveillance measures often prove quite helpful, and adds quality to the daily positive lab reports routinely routed to an ICP's office. Any additional information gathered will help to provide better outcomes for patients.

“The positive lab results give you the information about who is actually infected,” Shorr asserts. “Surveillance gives you some epidemiology and allows you to do cohorting and prevention a little bit better.” However, “I think at this point, the only places where we’ve actually shown that surveillance prospectively really might help us change things is with gram positives; with MRSA. It’s not so clear with gram negatives yet, although we might get there.”

Shorr says that ICPs must work hard to team with their clinicians to provide them with information and data that they can use to make better decisions. “For example, at my hospital, our infection control practitioner is a key part of our ICU quality performance group,” he shares. “She provides us with information — reliable information — about rates of BSIs and hospital acquired pneumonias that we can then investigate and explore and come up with plans to improve outcomes.

“As a concrete example, I was just going through a series of charts that they had pulled for central line infections that they attributed to the ICU. In looking at those, the vast majority of the line infections, which were very few, fortunately, were lines that were placed by people outside of the ICU. So yeah, it’s a line infection that became apparent in the ICU so we’re going to buy the hit, but if I want to improve outcomes, I need to focus my attention some place other than the ICU.

“That kind of information is key.” He continues, “I’ve seen the whole range of infection control practitioners where all they do is make up numbers and give them to doctors and walk away, to infection control practitioners like where I am now where they provide me with reliable data that I can explore and kind of sift through.

“The whole issue is understanding that these pathogens are out there and understanding that our treatment choices for them need to be different from what we are doing — and understanding the epidemiology. If you work in an ICU or a hospital where there is no ESBL problem, that’s important to know because it should drive differently what your protocols are for treatment choices than if you were in a hospital where there is a big ESBL problem. So having that kind of microbiology and epidemiology data so you know not only what the bugs are, but what bugs are causing what condition, clinically helps you decide how to use your antibiotics more appropriately.

“I think they (ICPs) need to realize that their counting and their data collection has implications beyond just the reports they are filing. They can actually come up with some really helpful information that will improve outcomes.” 

References 

1. CDC. Estimates of Healthcare-Associated Infections. May 2007. www.cdc.gov/ncidod/dhqp/hai.html  

2. Siegel, Jane D. Management of Multidrug- Resistant Organisms In Healthcare Settings, 2006. www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf  

3. Marschall J, et. al. Presence of the KPC carbapenemase gene in Enterobacteriaceae bacteremia, correlation with carbapenem susceptibility, and impact on clinical outcomes. Interscience Conference on Antimicrobial Agents and Chemotherapy, Sept. 19, 2007, session 196, paper C2-1935.

4. Evans, R. Scott. System-wide Surveillance for Clinical Encounters by Patients Previously Identified with MRSA and VRE. http://cmbi.bjmu.edu.cn/news/report/2004/medinfo2004/pdffiles/papers/5019Evans.pdf  

5. NH DHHS/ Division of Public Health Services. Recommendations for the Prevention & Control of Multidrug-Resistant Organisms. September 2004. www.dhhs.nh.gov/NR/rdonlyres/eeakkjmj37q3mxe7sr73bsndllkwd3rilwzupbjrjphz5eyc6me2v4lrl4glo67tuyki7cofjbrygmga64bx4tkmzvf/MDROs+9-2004-FINALc.pdf 

Top 3 MDROs to Guard Against:

MRSA: Methicillin-resistant Staphylococcus Aureus (MRSA)

MRSA is a specific strain of the Staphylococcus aureus bacterium that has developed antibiotic resistance, first to penicillin since 1947, and later to methicillin and related anti-staphylococcal drugs (such as flucloxacillin).

Popularly termed a “superbug” it was first discovered in Britain in 1961.¹ Worldwide, an estimated 2 billion people carry some form of S. aureus. Of that 2 billion, up to 53 million are thought to carry MRSA.² In the United States, an estimated 95 million carry S. aureus in their noses; of these 2.5 million are MRSA.³ A 2007 study found that 4.6 percent of patients in US healthcare facilities were infected or colonized with MRSA.⁴

References:

1. http://en.wikipedia.org/wiki/MRSA 

2. MRSA Infections - [keepkidshealthy.com] 

3. Graham P, Lin S, Larson E (2006). “A U.S. population-based survey of Staphylococcus aureus colonization.” Ann Intern Med 144 (5):318-25. PMID 16520472.

4. Association for Professionals in Infection Control & Epidemiology (2007-06-25).

National Prevalence Study of Methicillin- Resistant Staphylococcus aureus (MRSA) in U.S. Healthcare Facilities.

ESBL: Extended-spectrum beta-lactamase-producing gram negative bacilli 

ESBLs are enzymes that can be produced by bacteria making them resistant to antibiotics. ESBLs, which are plasmid mediated beta lactamases, have so far only been described in gram negative bacilli — most often associated with E. coli or Klebsiella pneumoniae, but they have been noted to transfer to Proteus mirabilis, Citrobacter, Serratia and other enteric bacilli. There are more than 170 different ESBLs. ESBLs were first described in the mid-1980s. During the 1990s, they were mostly found in Klebsiella species in the healthcare environment. In recent years, a new class of ESBL (called CTX-M enzymes) has emerged and these have been widely detected among E. coli bacteria. ESBLs are difficult to detect and are capable of efficiently hydrolyzing penicillins, narrow spectrum cephalosporins, many extended-spectrum cephalosporins, the oxyimino group containing cephalosporins (cefotaxime, ceftazidime), and monobactams (aztreonam). The prevalence of these organisms is probably underestimated as a significant proportion of laboratories do not perform tests specifically designed to detect them. Moreover, ESBLs have shown increasing geographical variations, further complicating detection. For a chart listing the amino acid sequences for TEM, SHV and OXA ESBLs, visit: http://www.lahey.org/Studies/. 

References 

1. Farkosh, Mary S. Extended-Spectrum betalactamase Producing Gram Negative Bacilli. http://nosoweb.org/infectious_diseases/esbl.htm 

2. Medscape. Problems Associated with ESBLs. www.medscape.com/viewarticle/409761_4 

3. Asian Intensive Care: problems & solutions. Extended spectrum beta-lactamases. www.aic.cuhk.edu.hk/web8/esbl.htm 

4. Health Protection Agency. Extended-Spectrum Beta-Lactamases (ESBLs). www.hpa.org.uk/ infections/topics_az/esbl/default.htm 

C. Diff.: Clostridium difficile 

Clostridium difficile is a species of bacteria of the genus Clostridium — which are gram-positive, anaerobic spore-forming rods.¹ Clostridium difficile associated disease (CDAD) occurs when the normal gut flora is eradicated by the use of antibiotics and pseudomembranous colitis, a severe infection of the colon, occurs. As of April 3, 2007 the CDC states that 27 states now are confirmed to have the North American Pulsed Field Type 1 (NAP1) strain of C.difficile.² 

One New Jersey multi-hospital survey documented increases in the rates of C. difficile disease (by 2-fold), C. difficile–associated complications (by 7-fold), and C. difficile outbreaks (by 12-fold) between 2000 to 2004 by tracking a virulent strain of C. diff.³ 

References 

1. Wikipedia. Clostridium difficile.en.wikipedia.org/wiki/Clostridium_difficile  

2. CDC. Data & Statistics about Clostridium difficile Infections. www.cdc.gov/ncidod/dhqp/ id_Cdiff_data.html   

3. Tan ET, Robertson CA, Brynildsen S, Bresnitz E, Tan C, McDonald LC. Clostridium difficile– associated disease in New Jersey hospitals, 2000–2004. Emerg Infect Dis [serial on the Internet]. 2007 Mar [date cited]. Available from www.cdc.gov/EID/content/13/3/498.htmReferences