Bugs Without Borders: The Global Challenge of MDROs

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By Kelly M. Pyrek

In a global economy with expansive travel networks, it is possible now for nations to quickly exchange pathogenic bacteria and viruses. These are bugs without borders, and they are becoming a public health threat that requires vigilance in surveillance, control, prevention and antimicrobial stewardship.

As the Centers for Disease Control and Prevention (CDC) states, "It is not possible to adequately protect the health of our nation without addressing infectious disease problems that occur elsewhere in the world. In an age of expanding air travel and international trade, infectious microbes are transported across borders every day, carried by infected people, animals, and insects, and contained within commercial shipments of contaminated food. 'Old' diseases such as malaria, measles, and foodborne illnesses are endemic in many parts of the globe, and 'new' diseases such as acquired immunodeficiency syndrome (AIDS) -- as well as new forms of old diseases such as multidrug-resistant tuberculosis (TB) -- can emerge in one region and spread throughout the world." The CDC adds, "Left unchecked, today’s emerging diseases can become the endemic diseases of tomorrow. This is what happened with HIV/AIDS, which spread from a remote part of Africa to all other continents and is now entrenched all over the world, necessitating a major international control effort." (CDC, 2002)

In a new essay, David M. Morens and Anthony S. Fauci, of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, reflect on what has been learned about emerging infectious diseases (EIDs) in the two decades since a major report from the U.S. Institute of Medicine (IOM) rekindled interest in this important topic. Twenty years ago, the landmark IOM report, “Emerging Infections: Microbial Threats to Health in the United States,” underscored the important but often underappreciated concept of EIDs. A review of the progress made and setbacks experienced over the past two decades suggests that even though many new diseases have emerged, such as Severe acute respiratory syndrome (SARS) and the 2009 H1N1 influenza pandemic, significant advances have occurred in EID control, prevention and treatment. Among many elements of the increase in the capacity to control EIDs are genomics-associated advances in microbial detection and treatment, improved disease surveillance, and greater awareness of EIDs and the complicated variables that underlie emergence, the authors say.

As Morens and Fauci (2012) note, "As predicted in 1992, previously unrecognized infectious diseases have continued to emerge, including variable Creutzfeldt-Jakob disease/bovine spongiform encephalopathy (vCJD/BSE), severe acute respiratory syndrome (SARS), and 2009 pandemic H1N1 influenza, and others have reemerged, e.g., disease caused by multiple-drug-resistant Staphylococcus aureus (MRSA), multiple-drug-resistant and extensively drug-resistant (MDR and XDR) tuberculosis, cholera and dengue."

The Rise of MDROs
One class of organisms that deserves special focus are multidrug-resistant organisms (MDROs) are defined as microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents. Although certain MDROs describe resistance to only one agent (such as MRSA and VRE), these pathogens are frequently resistant to most available antimicrobial agents .In addition to MRSA and VRE, certain GNB, including those producing extended spectrum beta-lactamases (ESBLs) and others that are resistant to multiple classes of antimicrobial agents, are of particular concern, say Siegel, et al. (2006) the authors of the guideline, " Management of Multidrug-Resistant Organisms In Healthcare Settings." In addition to Escherichia coli and Klebsiella pneumoniae, these include strains of Acinetobacter baumannii resistant to all antimicrobial agents, and organisms such as Burkholderia cepacia that are intrinsically resistant to the broadest-spectrum antimicrobial agents. Strains of S. aureus that have intermediate susceptibility or are resistant to vancomycin (i.e.,vancomycin-intermediate S. aureus [VISA], vancomycin-resistant S. aureus.

The clinical importance of MDROs cannot be overstated, emphasize Siegel, et al. (2006): "In most instances, MDRO infections have clinical manifestations that are similar to infections caused by susceptible pathogens. However, options for treating patients with these infections are often extremely limited. For example, until recently, only vancomycin provided effective therapy for potentially life-threatening MRSA infections and during the 1990s there were virtually no antimicrobial agents to treat infections caused by VRE. Although antimicrobials are now available for treatment of MRSA and VRE infections, resistance to each new agent has already emerged in clinical isolates. Similarly, therapeutic options are limited for ESBL-producing isolates of Gram-negative bacilli, strains of A. baumannii resistant to all antimicrobial agents exceptimipenem and intrinsically resistant Stenotrophomonas sp. These limitations may influence antibiotic usage patterns in ways that suppress normal flora and create a favorable environment for development of colonization when exposed to potential MDR pathogens (i.e., selective advantage). In addition, numerous studies have associated MDROS with increased lengths of stay, costs and mortality -- a significant problem in an era of shrinking institutional budgets and resources, and limited reimbursement.
Regarding the epidemiology of MDROs, experts say that although the prevalence of these pathogens varies temporally, geographically and by healthcare setting, no institution is without the constant threat from these organisms.

As  Siegel, et al. (2006) explain: "During the last several decades, the prevalence of MDROs in U.S. hospitals and medical centers has increased steadily. MRSA was first isolated in the United States in 1968. By the early 1990s, MRSA accounted for 20 percent to 25 percent of Staphylococcus aureus isolates from hospitalized patients. In 1999, MRSA accounted for >50 percent of S. aureus isolates from patients in ICUs in the National Nosocomial Infection Surveillance (NNIS) system; in 2003, 59.5 percent of S. aureus isolates in NNIS ICUs were MRSA (93). A similar rise in prevalence has occurred with VRE. From 1990 to 1997, the prevalence of VRE in enterococcal isolates from hospitalized patients increased from <1 percent to approximately 15 percent."

No discussion of MDROs is complete without addressing the so-called ESKAPE pathogens -- Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species --  those organisms that "are responsible for a substantial percentage of nosocomial infections in the modern hospital and represent the vast majority of isolates whose resistance to antimicrobial agents presents serious therapeutic dilemmas for physicians," according to Rice (2010) who adds, "The most recent data available from the National Healthcare Safety Network indicate that the ESKAPE pathogens are involved in slightly more than 40 percent of infections in patients in intensive care units. Resistance rates are substantial in these pathogens, ranging from resistance that virtually completely excludes an antibiotic from empirical therapeutic consideration (e.g., E. faecium with resistance to ampicillin or vancomycin) to resistance that indicates the potential to alter choices of both empirical and definitive antimicrobial therapy (e.g., A. baumannii or P. aeruginosa with resistance to carbapenems)."

In his commentary on the ESKAPE pathogens Louis B. Rice, MD, of Louis Stokes Cleveland VA Medical Center, and the Department of Medicine, Case Western Reserve University School of Medicine, observes, "The difficulty in identifying novel antimicrobial agents with reliable activity against these pathogens argues for an augmentation of research in the basic and population science of resistance, as well as careful studies to identify optimal strategies for infection control and antimicrobial use."

Rice (2010) outlines the resistance mechanisms of several important pathogens, including Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa:

- Klebsiella pneumoniae:  "The study of resistance in K. pneumoniae has focused for years on the description of different extended-spectrum ß-lactamases (ESBLs). The first of these resulted from amino acid substitutions in the common class A plasmid-mediated enzymes TEM-1 and SHV-1.9 These conferred resistance to the extended-spectrum cephalosporins, but isolates generally remained susceptible to combinations of ß-lactams and ß-lactamase inhibitors. Unfortunately, most ESBL-producing K. pneumoniae isolates produced multiple enzymes, overwhelming the ß-lactamase inhibitors and largely negating their utility in the clinical setting. Carbapenems were generally considered to be the treatment of choice for infections due to ESBL-producing isolates. During the past decade, there has been an emergence of ESBLs that further restrict antimicrobial options. Some K. pneumoniae strains now express carbapenem-hydrolyzing ß-lactamases (in the United States, most commonly expression of the K. pneumoniae carbapenemase [KPC] class; elsewhere, most commonly expression of metallo-enzymes)."

- Acinetobacter baumannii: "A. baumannii was considered a relatively minor pathogen until outbreaks of infection with multidrug-resistant strains occurred in different parts of the world. Accordingly, there was very little known about the precise mechanisms of resistance in A. baumannii prior to the past decade. Like P. aeruginosa, A. baumannii is known to have slow porins, giving them an intrinsic advantage against most antimicrobial agents.A. baumannii also has at least two different resistance-nodulation cell division multidrug-resistance efflux pumps that confer levels of resistance to a variety of antimicrobial agents. Resistance to ß-lactam antibiotics is the result of the production of one or more ß-lactamases, including a chromosomal cephalosporinase and a variety of acquired enzymes. Resistance to carbapenems in A. baumannii is often attributed to production of enzymes of the OXA class, although significant in vitro hydrolysis of carbapenems by these enzymes is often difficult to demonstrate."

- Pseudomonas aeruginosa: "P. aeruginosa has long been the 'holy grail' target for antimicrobial development. The importance of P. aeruginosa in causing deaths of patients with febrile neutropenia16 and its intrinsic resistance to many early antimicrobial agents led to concerted efforts to find new antibiotics with activity against this species. By any measure, these efforts were highly successful, with the discovery of the antipseudomonal penicillins, the extended-spectrum cephalosporins with antipseudomonal activity, the monobactam aztreonam, the carbapenems, and fluoroquinolones with antipseudomonal activity. P. aeruginosa proved equal to the challenge, with increasing numbers of multidrug-resistant strains being reported. Ciprofloxacin has lost much of its utility against P. aeruginosa in many hospitals because of the expression of a variety of multidrug efflux pumps and the subsequent topoisomerase mutations that result in high-level resistance."

Ripped From the Headlines
Plagues and the pathogens that cause them have been mankind's earliest companions. Having survived the more recent pandemics of SARs in 2003 and H1N1 influenza in 2009, the world still wakes up to news headlines that attest to pathogens' continued prowess.

For example, a novel type of human coronavirus that is alarming public health authorities can infect cells from humans and bats alike, a fact that could make the animals a continuing source of infection, according to a study published recently in mBio®, the open-access journal of the American Society for Microbiology. The new coronavirus, called hCoV-EMC, had first been identified in two patients, both previously healthy adults who suffered severe respiratory illness. hCoV-EMC is blamed for five deaths and several other cases of severe disease originating in countries in the Middle East. According to the new study, hCoV-EMC uses a different receptor in the human body than the SARS virus, and can infect cells from a wide range of bat species and pigs, indicating there may be little to keep the virus from passing from animals to humans over and over again. First identified in a patient in Saudi Arabia in June, nine laboratory-confirmed cases of hCoV-EMC infection have now been identified, five of whom have died. Although the virus does not apparently pass from person-to-person very readily, the case fatality rate and the fact that the source of the virus has not been identified have caused concern among global public health authorities. Cases of hCoV-EMC infection are marked by severe pneumonia and often by kidney failure.

Another example is a distinctly new type of methicillin-resistant Staphylococcus aureus (MRSA) that is not detected by traditional genetic screening methods that has been discovered in patients in Irish hospitals according to recent research. These findings provide significant insights into how new MRSA strains emerge and highlight the potential for the transmission of infectious agents from animals to humans. MRSA strains are characterized by the presence of a mobile DNA cassette (known as SCCmec) encoding genes that confer resistance to beta-lactam antibiotics including methicillin and recombinase genes that allow the cassette to transfer into methicillin-susceptible S. aureus (MSSA). Scientists at the University of Dublin, the Irish National MRSA Reference Laboratory and the University of Dresden and Alere Technologies in Germany identified the new MRSA strain using high throughput DNA microarray screening. Complete genome sequencing revealed that this strain is distinctly different to previously described MRSA. It carries a new type of SCCmec encoding highly divergent genes that are very different to any described previously in MRSA or in any other organism. Consequently the new strain is not detected as MRSA by routine conventional and real time DNA-based polymerase chain reaction (PCR) assays commonly used to screen patients for MRSA. The MRSA strain was found to belong to the genetic lineage clonal complex 130 (CC130), which has previously only been associated with MSSA from cows and other animals, but not humans, strongly suggesting that the new MRSA originated in animals. During the publication process, the authors became aware that a consortium of researchers lead by the University of Cambridge and the Wellcome Trust Sanger Institute in the United Kingdom had identified bovine MRSA with an almost identical SCCmec element to that in the Irish CC130 human MRSA. These researchers also identified MRSA harboring the novel SCCmec element emerging in bovine and human populations in the United Kingdom and Denmark.

A third example is new insights by researchers that show the global epidemic of Clostridium difficile 027/NAP1/BI in the early to mid-2000s was caused by the spread of two different but highly related strains of the bacterium rather than one as was previously thought. The spread and persistence of both epidemics were driven by the acquisition of resistance to a frontline antibiotic. Unlike many other healthcare-associated bacteria, C. difficile produces highly resistant and infectious spores. These spores can promote the transmission of C. difficile and potentially facilitates its spread over greater geographical distances, even across continents. This study highlights the ease and rapidity with which the hospital bacterium, C. difficile, can spread throughout the world, emphasizing the interconnectedness of the global healthcare system. Between 2002 and 2006, there were highly publicized outbreaks of C. difficile in hospitals across the UK, U.S., Canada and Europe. Researchers used advanced DNA sequencing to determine the evolutionary history of this epidemic and the subsequent pattern of global spread; they found that this outbreak came from two separate epidemic lineages of C. difficile, FQR1 and FQR2, both emerging from North America over a very short period and rapidly spreading between hospitals around the world. The team used the genetic history to map both epidemic strains of C. difficile using a global collection of samples from hospital patients between 1985 and 2010. They demonstrated that the two C. difficile strains acquired resistance to this antibiotic, fluoroquinolone, separately, a key genetic change that may have instigated the epidemics in the early 2000s. The researchers found the first outbreak strain of C. difficile, FQR1 originated in the U.S. and spread across the country. They also saw sporadic cases of this strain of C. difficile in Switzerland and South Korea. They found that the second strain of C. difficile, FQR2, originated in Canada and spread rapidly over a much wider area, spreading throughout North America, Australia and Europe. They showed that the spread of C. difficile into the UK was frequently caused by long-range geographical transmission event and then spread extensively within the UK. They confirmed separate transmission events to Exeter, Ayrshire and Birmingham from North America and a transmission event from continental Europe to Maidstone. These events triggered large-scale C. difficile outbreaks in many hospitals across the UK in the mid-2000s.

A fourth example is a hospital in Canada that has detected the presence of New Delhi Metallo-ß-lactamase-1-Producing Klebsiella pneumoniae (NDM1-Kp). NDM1-Kp is common in other parts of the world such as the Indian subcontinent, but rare in North America except for imported cases from patients previously hospitalized in endemic regions. Between January 2011 and March 2012, seven patients at a tertiary care teaching hospital in Toronto acquired NDM1-Kp from two index patients. Risk factors for acquisition were a history of prior use of certain antibiotics, and transmission likely occurred through direct contact. Four of the seven were roommates with an affected patient, two were on the same ward, and one was admitted to a room immediately following the discharge of an infected patient. The environmental sources of transmission highlight the importance of maintaining meticulous cleaning, hand hygiene, and disinfection standards in prevention and containment.

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