From Acinetobacter to Zika: Finding Balance Between Domestic and Foreign Pathogens

Gram-negative bacterium Acinetobacter baumannii. Image courtesy of Todd Parker/CDC

By Kelly M. Pyrek

In a 2006 lecture, "Emerging and Re-emerging Infectious Diseases: The Perpetual Challenge,' Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), alluded to a statement made by physician and anthropologist T. Aidan Cockburn in 1963 in a book titled The Evolution and Eradication of Infectious Diseases. Cockburn declared, "We can look forward with confidence to a considerable degree of freedom from infectious diseases at a time not too far in the future. Indeed, it seems reasonable to anticipate that within some measurable time … all the major infections will have disappeared."

In the midst of the Zika outbreak and having recently experienced the Ebola pandemic and less recently the MERS, H1N1 influenza and SARS outbreaks, and seeing infectious diseases such as poliovirus re-emerge, Cockburn's declaration from the 1960s seems quaint and overly optimistic in 2016 when the world has witnessed devastating epidemics, and here in the U.S., foreign pathogens such as dengue and monkey-pox have reached our shore. The medical community must also be prepared for an outbreak triggered by a domestic pathogen as well as those of more exotic origin.

"I don’t think that we can afford to focus on any one pathogen to the exclusion of others," cautions Lisa Maragakis, MD, MPH, associate professor of medicine and senior director of infection prevention at the Johns Hopkins Health System. "True preparedness means that we will assess each and all of these known threats and make our preparations according to a risk assessment that considers the number of people affected, the likelihood of infection or transmission, and the severity of harm that the pathogen causes. In the case of Ebola and Zika, the likelihood of infection or transmission is quite low in the U.S. now, but the level of preparedness still needs to be high due to the severe and potentially fatal consequences associated with these diseases. Other pathogens like MRSA are much more common and affect many more patients in the U.S. while having the capability to cause severe disease and even death. All of our preparations for these pathogens increase the awareness of infectious diseases, their modes of transmission and the importance of infection prevention. I view the increased awareness and knowledge that result from our preparations as very positive for infection prevention."

As the NIAID document, "Emerging and Re-emerging Infectious Disease," observes, "Despite remarkable advances in medical research and treatments during the 20th century, infectious diseases remain among the leading causes of death worldwide for three reasons: (1) emergence of new infectious diseases, (2) re-emergence of old infectious diseases, and (3) persistence of intractable infectious diseases. Emerging diseases include outbreaks of previously unknown diseases or known diseases whose incidence in humans has significantly increased in the past two decades. Re-emerging diseases are known diseases that have reappeared after a significant decline in incidence."

The NIAID says that in addition to the continual discovery of new human pathogens, old infectious disease enemies are “re-emerging.” Natural genetic variations, re-combinations, and adaptations allow new strains of known pathogens to appear. As the NIAID states further, "Furthermore, human behavior plays an important role in disease re-emergence. Increased and sometimes imprudent use of antimicrobial drugs and pesticides has led to the development of resistant pathogens, allowing many diseases that were formerly treatable with drugs to make a come-back (e.g., tuberculosis, malaria, hospital-acquired and food-borne infections). Recently, decreased compliance with vaccination policy also has led to re-emergence of diseases such as measles and pertussis, which were previously under control. The use of deadly pathogens such as small-pox or anthrax as agents of bioterrorism is an increasingly acknowledged threat to the civilian population. Moreover, many important infectious diseases have never been adequately controlled on either the national or international level. Infectious diseases that have posed ongoing health problems in developing countries such as food- and water-borne infections, dengue, and West Nile virus, are re-emerging in the United States."

Pathogens are coming at us from all sides. In its 2008 report, "NIAID: Planning for the 21st Century, the agency noted, "Over the past sever-al decades there has been a global effort to identify and characterize more than 270 infectious agents, which include bacteria, viruses, fungi, parasites, and prions; to define the underlying pathways by which these agents infect humans and cause disease; and to develop preventive measures and treatments for many of the world’s most dangerous pathogens. New challenges are constantly arising, however, including the emergence of new infectious diseases, such as SARS, the re-emergence of bacterial strains no longer responsive to our current treatments (such as methicillin-resistant Staphylococcus aureus and multi- and extensively-drug resistant TB), and the persistence of respiratory, sexually transmit-ted, and enteric pathogens that can cause serious epidemic and endemic global health problems."
Pathogens are mutating, and we haven't completely eradicated older threats. As the 2008 NIAID report explains, "In addition to the continual discovery of new human pathogens and the evolution and emergence of new infectious diseases, natural genetic variations allow novel strains of known pathogens to appear. For example, there is increasing concern that an avian influenza virus, if it became easily transmissible among people, would be unrecognized by the human immune system and lead to a pandemic. Many important infectious diseases have never been adequately controlled. Some that have posed ongoing health problems in developing countries have emerged recently in the United States, including food- and waterborne (e.g., Shigella) and vector-borne (e.g., West Nile virus) infections. In addition, resurgence of some previously treatable diseases, such as TB and malaria, has occurred in part because improper use of pesticides and antimicrobial drugs has led to the evolution of highly resistant strains of the pathogens."

The NIAID has prioritized pathogens into three categories -- A, B and C. Category A pathogens are those organisms/biological agents that pose the highest risk to national security and public health because they can be easily disseminated or transmitted from person to person; result in high mortality rates and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness. These pathogens include Bacillus anthracis (anthrax), Clostridium botulinum toxin (botulism), Yersinia pestis (plague), Variola major (smallpox) and other related pox viruses, Francisella tularensis (tularemia), and viral hemorrhagic fevers. Others include Arenaviruses such as Lassa; Hantaviruses such as Rift Valley Fever, Crimean Congo Hemorrhagic Fever; Flaviviruses such as dengue; Filoviruses such as Ebola and Marburg.

Category B pathogens are moderately easy to disseminate, result in moderate morbidity rates and low mortality rates, and require specific enhancements for diagnostic capacity and enhanced disease surveillance. They include Coxiella burnetii (Q fever); Brucella species (brucellosis), Burkholderia mallei (glanders); Chlamydia psittaci (Psittacosis); Ricin toxin (Ricinus communis); Staphylococcus enterotoxin B (SEB); Typhus fever (Rickettsia prowazekii); food- and waterborne pathogens such as diarrheagenic E.coli, pathogenic Vibrios, Shigella species, Salmonella, Listeria monocytogenes, Campylobacter jejuni, hepatitis A, Giardia lamblia, Toxoplasma gondii; as well as mosquito-borne encephalitis viruses such as  West Nile virus (WNV), California encephalitis, Eastern equine encephalitis (EEE), Western equine encephalitis (WEE) and St. Louis encephalitis virus (SLEV).

Category C pathogens could be engineered for mass dissemination in the future because of availability, ease of production and dissemination, and the potential for high morbidity and mortality rates and major health impact. They include Nipah and Hendra viruses, Yellow fever virus, tuberculosis, including drug-resistant TB, influenza virus, rabies virus, prions, Chikungunya virus, Severe acute respiratory syndrome associated coronavirus (SARS-CoV), MERS-CoV, and other highly pathogenic human coronaviruses.

In the last several years, NIAID added to its list additional pathogens including Aspergillus, Bordetella pertussis, Clostridium difficile, Enterococcus faecium and faecalis, Enterovirus 68, Enterovirus 71, hepatitis C, hepatitis E, Leptospirosis, Lyme borreliosis, mumps virus, poliovirus, Rubeola, Streptococcus Group A, Staphylococcus aureus and Zika virus. 

While many of the pathogenic threats making global headlines these days are the more exotic species migrating toward the west, there are a number of bug on the NIAID priority list that are more home-gown, if you will. Gram-positive pathogens are a major cause of healthcare-associated and community-acquired bacterial infections. Staphylococci, enterococci, streptococci, and Clostridium difficile are the most important species of clinical interest, according to some experts. While it may be less "glamorous" than flashier pathogens making headlines, methicillin-resistant Staphylococcus aureus (MRSA) seems to be the poster child for difficult-to- treat multi-resistant pathogen capable of global-scale diffusion, with significant morbidity, mortality, and healthcare-associated costs. Marinelli  and Genilloud (2013) note that "MRSA, in particular, is the most relevant Gram-positive multi-resistant pathogen in terms of diffusion and overall clinical impact, being a leading cause for healthcare-associated infections worldwide, as well as an emerging cause of community-acquired infections that are often associated with novel MRSA strains. Resistance to anti-MRSA and anti-VRE drugs remains uncommon or exceptional among the respective species."
A number of years ago, the Infectious Diseases Society of America (IDSA) issued a list of pathogens -- known as the ESKAPE pathogens from the acronym created by the list of bugs in this order: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter bau-mannii, Pseudomonas aeruginosa and Enterobacter spp.). Experts say these pathogens are capable of "escaping" the biocidal action of antibiotics and mutually representing new paradigms in pathogenesis, transmission and resistance. According to the latest data from the Centers for Disease Control and Prevention (CDC), the six ESKAPE bacteria are responsible for two-thirds of all healthcare-associated infections (HAIs).

"There can be new challenges however, most hospitals on a daily basis are focusing on tracking and more importantly implementing activities to reduce healthcare associated infections, such as those from devices (catheter associated urinary tract infection  CA-UTI, catheter associated blood stream infections CA- BSI), surgical site infections (SSIs)  and C. difficile (CDI)," says Belinda Ostrowsky, MD, associate professor of medicine and director of epidemiology, stewardship and infection prevention for Montefiore Health System. "Hospital infection preventionists do surveillance for these infections, but also are responsible for tracking and reporting a series other infectious conditions.  They interact with front-line clinicians who may recognize an unusual diagnosis or presentation. This is important for identifying a possible cluster or outbreak."

Maragakis believes threats are ever-changing. "In some ways, the pathogens of concern are always changing in U.S. hospitals because new pathogens and patterns of antibiotic resistance emerge, and world travel means that pathogens can spread from region to region quite quick-ly," she says. "Of course, we still have the pathogens like methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, which have long been associated with hospitals, but now we increasingly see multidrug-resistant gram-negative bacilli that are of great concern due to a lack of effective treatment options. We also see pathogens, such as Ebola virus disease, Middle East respiratory syndrome and Zika virus, which each present a different set of challenges."

Ostrowsky emphasizes that hospitals must strike a balance in their focus on problematic pathogens, whether they are MRSA or Zika virus. "It’s important that we balance attention that we spend on both of these issues," she says. "For example, each year we spend great effort on Seasonal Influenza. This old pathogen often challenges us in new ways, including issues relating to vaccination or shortages. Sometimes a new threat requires us to shift focus to another pathogen. One of the biggest challenges is that infections can be unpredictable. We must have plans that allow us to be flexible and prepare for the worst, even if we don't have to enact these strategies."

Brian Labus, PhD, MPH, a visiting research assistant professor in the School of Community Health Sciences at the University of Nevada Las Vegas, points to nationwide decreases in central line-associated bloodstream infections, surgical site infections, Clostridium difficile and MRSA, and says, " I think this in large part to a renewed emphasis in preventing healthcare-acquired infections. New pathogens are always emerging, but this doesn't mean that we need to shift our approach to infection prevention each time one does. We are seeing antibiotic-resistant strains of some organisms becoming more prevalent (even if the infections are less common), but our prevention and control practices don't necessarily need to change because the organism is now harder to treat. Chasing the infectious disease flavor of the month is not going to result in a better prepared hospital and will likely shift resources away from dealing with less-glamorous, but more common, diseases."

Labus continues, "Exotic threats are just that, exotic. We had one person die from Ebola in the United States yet that is where our focus, and our funding, shifted. About 100,000 people die from healthcare-acquired infections every year, yet the support to prevent them isn't "sexy" and doesn't demand action from lawmakers. Hospitals are caught in the middle, being forced to still deal with the "garden-variety" pathogens while putting in programs to deal with these exotic threats, even if they don't always make sense. Zika and dengue don't spread from person to person, so there is no reason for a hospital to worry about putting infection prevention programs in place for the diseases de-spite calls from lawmakers or the public."

Jessica Ridgway, MD, MS, assistant professor in the Section of Infectious Diseases and Global Health and associate hospital epidemiologist with the University of Chicago Medicine, reminds clinicians to maintain perspective on the issue. "It’s important to prepare for exotic threats like Ebola, but the fact remains that many more people in the U.S die from common pathogens like influenza," Ridgway says. "I think it’s wise for hospitals to have plans in place to identify and stabilize patients with highly contagious disease like Ebola, but I don’t believe it’s a good use of resources for every hospital to build a biocontainment unit to care for Ebola patients. Once patients are stabilized, they should be transferred to select hospitals with the facilities and training to care for patients with highly contagious diseases in a safe manner, such as Emory or the University of Nebraska."

What hospitals can do, is ensure they are running and adequately resourcing their infection prevention departments so that they can respond to the usual pathogens but also rise without too much difficulty to meet the needs of occasional pathogens that require more where-withal. To do so, institutions first must determine if they are following a horizontal (practice-driven) or a vertical (pathogen-driven) approach to infection prevention and control, and create the appropriate policies and procedures, and then resource the program adequately and appropriately, with an eye toward routine matters and outbreak preparedness.

"I believe that horizontal and vertical approaches to infection prevention are needed to address these pathogens," Maragakis says. "The horizontal approaches are extremely important as the foundational, cross-cutting interventions to prevent all infections. It is hard to exceed the impact of a robust hand hygiene program, for instance, because high levels of hand hygiene protect so many patients, family members, visitors and staff members from a variety of pathogens. Vertical approaches, however, are also important to identify and intervene to prevent trans-mission of specific pathogens. These approaches tend to be more costly, and it is sometimes difficult to know which vertical approaches are the most effective or how to appropriately target them to the highest-risk settings and pathogens (e.g., surveillance cultures)." 

"C. difficile and drug resistant pathogens (e.g. CRE) are becoming more of a concern," Ridgway says. "Both horizontal and vertical approaches to infection prevention are important. Healthcare associated infections are caused by a wide variety of pathogens, and so we can’t ignore basic horizontal measures (such as hand hygiene and environmental cleaning) that protect against the majority of pathogens. That being said, a vertical approach is also important to target specific pathogens. For example, C. difficile spores are not killed by routine cleaning methods, and so a vertical approach may be useful to identify patients with C. difficile so that appropriate infection prevention measures can be taken to prevent spread (e.g. cleaning with bleach, soap and water handwashing)."

"After 9/11 and the anthrax attacks of 2001, we shifted our focus to a very pathogen-specific approach to preventing disease in the com-munity and preparing our hospitals for outbreaks," Labus says. "It didn't take long to realize that this vertical approach was limiting and that there was no reason that we couldn't use this window of opportunity to take an all-hazards planning and response approach. While we need the vertical approach to deal with problem (as in the case of an outbreak), the horizontal approach should provide the greatest benefit in pre-venting infections overall. Outbreak planning should not focus on known pathogens, but should always consider newly emerging diseases. By doing so, we will have a system that can respond to all types of infectious disease threats, not just the ones we anticipate."

"Not to be dire or alarmist, but there will most certainly be another nationwide pathogenic threat at some point," says Maragakis. "History shows us that epidemics and pandemics occur with fair regularity. Pathogens continue to evolve and emerge, and factors like the global economy and travel bring more people into contact more rapidly with each other than ever before in history. Early recognition and the three Cs of communication, cooperation and collaboration will be key to our global response to such pandemic threats. Our preparedness activities for known pathogens will also serve us well when facing new infectious threats."

U.S, hospitals vary when it comes to overall preparedness for a pandemic. A 2015 survey conducted by the Association for Professionals in Infection Control and Epidemiology (APIC) found that 9 in 10 infection control leaders (92 percent) believe their facilities are better prepared today than a year ago to receive a patient with a highly lethal infectious disease such as Ebola, but more than half (55 percent) say their facilities have not provided additional resources to support their infection prevention and control programs as a result of the Ebola crisis.

The survey polled APIC members to determine their ongoing needs a year after the first Ebola patient was admitted to a U.S. hospital. Respondents included 981 U.S.-based infection preventionists working in acute-care hospitals. Half of respondents (53 percent) reported that there is fewer than one or just one full-time infection preventionist at their organization. Of these, 45 percent work in facilities with more than 100 beds. As a result of the Ebola crisis, 10 percent of respondents received additional personnel from their facilities, and one-third (37 percent) received support for staff training programs on infection control protocols.

“We were encouraged to learn that our members feel their facilities are more prepared to handle patients with highly lethal infectious dis-eases, and to know that some infection prevention and control departments have obtained additional staff and resources,” said Susan Dolan, RN, MS, CIC, president-elect of APIC and hospital epidemiologist at Children’s Hospital Colorado. “But with the ongoing threat of emerging infectious diseases and antibiotic-resistant organisms, we remain concerned that many facilities are lagging behind in providing adequate support to protect patients and healthcare workers. We urge healthcare leaders to assess the needs of their infection prevention programs and dedicate the necessary staff, training, and technology resources to this critical area.”

Almost two-thirds of respondents (62 percent) are continuing to train staff on the management of patients with Ebola. But a quarter may not have enough personal protective equipment (PPE) to meet the Centers for Disease Control and Prevention (CDC) guidelines for care of Ebola patients, according to the poll.
It's a work in progress, certain to be tested by an increasing number of emerging and re-emerging infectious diseases, facilitated by modern travel, a global economy, and human behavior favorable to the transmission of pathogens. Experts around the globe have studied the spectrum of emerging pathogens, the epidemiologic reasons for emergence and the interventions to control emergence. As Ewald (1996) observed, "The feasibility of disease control is hampered by the potentially vast number of emerging and reemerging pathogens, the diversity of geographic sources, the potential for rapid global dissemination from these sources, and numerous ecologic and social factors influencing emergence."

As Ridgway notes, "As the world becomes more interconnected, and more people travel internationally, the threat of spreading a novel pandemic virus from one part of the world to another is increasing."

"Over the last several years we have had many emerging infections (e.g., West Nile Virus, SARS, H1N1/Influenza, Legionella, Ebola, Zika)," Ostrowsky
says. "It’s likely that will have other emerging infections due to a series of factors. Some of these include global travel/ importing, over-use of antibiotics, changes in where populations live, exposures to animals, vaccination issues, and increased care for more complex and immunosuppressed populations.  The challenge is predicting the pathogen, its transmission and the unique challenges that will be raised."

Labus sees the situation from a slightly different perspective. "I wouldn't say that the threat is increasing; I would say that it is constantly changing," he says. "As our behavior and environment changes, we are exposed to different pathogens that we not have been in the past. Every time we change the way we interact with the environment and with other people, we provide a new avenue for disease transmission while closing another one down."

Despite varied preparedness levels, experts agree that hard lessons were learned during previous pandemics and outbreaks such as SARS, H1N1 and Ebola.  Shortages of personal protective equipment (PPE) were rampant, and healthcare workers were confused by conflicting guidance on airborne pathogen transmission and the best ways to protect frontline workers and patients.

"So many lessons were learned from each of these outbreaks," Maragakis says. "In general, I would say that each of these events showed us that we are not as prepared as we like to think we are. We have a lot of work to do to build an appropriate infrastructure to respond to high-consequence pathogens. Personal protective equipment (PPE) is one of the main areas of concern I will highlight. We need to ensure that we have the best PPE and processes in place to ensure that health care workers can safely put on their PPE, provide clinical care and remove their PPE without fear of self-contamination or transmission in these highly stressful clinical situations. Like most hospitals, ours has seen clusters and outbreaks of communicable diseases from time to time. We dealt with these events using standard epidemiological outbreak investigation steps and targeted interventions to interrupt pathogen transmission. Importantly, we have been able to ensure that these kinds of events are quite rare through our department’s proactive work with hospital leadership and front-line staff members to implement evidence-based infection prevention measures, emergency preparedness, and early recognition and communication of infectious threats."

"Communication is a key component to any response," Ostrowsky says. "Since information was changing quickly it was sometimes a challenge to refine messages for frontline healthcare workers, those HCWs less involved in the response and for our patients and the community." She adds, "A silver lining of these kinds of experiences is using existing staff and their skill set to address these challenges. During the Ebola response I had the privilege of interacting with staff I might not have worked with in the past. Since then, I have used some of these relationships to help me in my daily activities.  If there are other challenges the plans for response might not be the same, however I know we have the infrastructure and talented people throughout the health system who can assist."  

Labus concurs: "In every outbreak we have found communication to be a challenge. While we have made great progress in implementing the Incident Command System in times of crisis, we don't use it to its full potential. We are still not completely comfortable working with each other across agencies and facilities, and we lack systems that allows us to easily integrate our responses.  With Ebola, a major challenge was a demand for information that wasn't always available. Hospitals were looking for guidance on how to handle soiled linen from the rooms of a patient with Ebola and it took some time for federal officials to create guidance that followed all the applicable laws and regulations."

As with infection prevention programs in general, funding and resourcing for preparedness efforts varies from one healthcare system to an-other, and disparities are common.

"We can always be more prepared, so I cannot say that we will ever reach a point that I would endorse as adequately prepared," says Maragakis. "New threats can emerge that require a different approach, and constant work is required to ensure that we have the appropriate level of staffing, equipment, infrastructure, planning and preparedness to confront these threats. Ideally, both the public health infrastructure and health care facilities themselves will continue to advocate for funding and resources to ensure preparedness for the infectious threats we know and the ones we know will come in the future." She adds, "Communication, collaboration and planning are the best preparations for infectious threats. Drills and practice are also important exercises to build knowledge and skill, and to highlight areas of planning that need to be refined and improved. All of this takes time and effort, which require resources. It is hard to dedicate scarce resources to prevention activities, but doing so will pay huge dividends in the long run because it is much more expensive - in terms of money, health, morbidity and mortality - to pay for an infectious disease outbreak than to pay for preparedness." 

"Many of the pathogens that lead to global outbreaks arise in developing countries that may not have the same resources for disease detection, surveillance, and containment that we have in the U.S.," Ridgway says. "It’s important to provide funds and resources to bolster the public health response globally. It’s also important to share resources, including vaccines, when an outbreak arises." She adds, "I don’t believe that the spread of ZIka virus will pose a huge crisis for American hospitals. From what we know about Zika, it should actually not be a major infection control concern for hospitals. It is predominantly spread by mosquitoes. It can also be sexually transmitted or spread by blood transfusions, but is not readily transmitted from person-to-person. In terms of managing the public health response to Zika and dengue, that will largely fall to public health agencies like the CDC, rather than individual hospitals."

"We are better prepared than we were, but are never going to be as prepared (or funded) as we would like to be," Labus emphasizes. "Hospitals will step up and handle the next pathogen-related crisis just as they have always done, as they can't just close the doors and not accept patients. For all the media hype, hospitals did not really have to deal with Ebola. However, by having to respond to the threat of a deadly disease that could put the hospital staff at risk, it opened the door to conversations about employee safety and infection control that were largely just theoretical up until that point. Every time we deal with an infectious disease outbreak, it helps us be better prepared for the next one."

To that end, preparedness requires appropriate education and training of frontline healthcare personnel as well as general awareness by all healthcare stakeholders that ongoing risk management is the 'new normal" for the industry. Identifying weak areas in emergency and out-break management is an ongoing process.  
"The major challenge isn't that there are gaps in our knowledge, it's that we don't know what those gaps are," Labus says. "We don't know what they next outbreak is going to bring, so it is difficult to plan for what will likely be the biggest stumbling block. Issues related to the transport of Ebola-contaminated waste from patient rooms didn't come up until we dealt specifically with that scenario. The (unfounded) safety concerns over the 2009 H1N1 influenza vaccine didn't appear until we started distributing the vaccine. The best way to remedy these things is through tabletops and exercises. By bringing everyone to the table, we can work through many of these issues in advance and come up with solutions to the problems we identify. For example, if an employee union has concerns about a particular approach being in conflict with the collective bargaining agreement, the best time to identify and work through that issue is an advance rather than when there are patients needing care in the emergency room."

References:

Cockburn TA. The Evolution and Eradication of Infectious Diseases. Baltimore, Md.: Johns Hopkins Press. 1963.

Ewald PW. Guarding Against the Most Dangerous Emerging Pathogens: Insights from Evolutionary Biology. Emerging Infectious Disease. Vol. 2, No. 4. October-December 1996. ftp://ftp.cdc.gov/pub/eid/vol2no4/adobe/ewald.pdf

Fauci AS.  2005 Robert H. Ebert Memorial Lecture Emerging and Re-emerging Infectious Diseases: The Perpetual Challenge. January 2006. Accessible at: http://www.milbank.org/uploads/documents/0601fauci/0601fauci.html

Marinelli F and Genilloud O. Antimicrobials: New and Old Molecules in the Fight Against Multi-resistant Bacteria. Springer Science & Business Media, Oct 4, 2013.

National Institute of Allergy and Infectious Diseases (NIAID). Emerging and Re-emerging Infectious Disease. Accessible at: https://www.niaid.nih.gov/about/whoWeAre/profile/fy2004/Documents/research_emerging_re-emerging.pdf

National Institute of Allergy and Infectious Diseases (NIAID). NIAID Emerging Infectious Diseases/Pathogens. Accessible at: https://www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/Pages/CatA.aspx

National Institute of Allergy and Infectious Diseases (NIAID). NIAID: Planning for the 21st Century. 2008. Accessible at: https://www.niaid.nih.gov/about/whoWeAre/Documents/niaidstrategicplan2008.pdf