“Antimicrobial resistance: No action today, no cure tomorrow.”

Statement by the Director-General
WHO World Day – 7 April 2011

Overview

In 2011, the World Health Organization (WHO) reported that 63,000 patients die each year in US hospitals and 25,000 patients lose their lives annually in the European Union due to antibiotic-resistant infections. The annual estimated economic burden is US $2.1 billion in the European Union, US $34 billion in the United States, and US $2.453 billion globally. 

Antimicrobial drug resistance (AMR or AMDR) is a multidimensional and systemic failure of the health, education, societal behavior, and medical policies and practices. 

Four major challenges should be recognized and addressed by the world medical community. 

1. AMDR is extending beyond national boundaries, presenting a significant threat to health and increasing the costs of medical care. 
    
2. Collaboration among healthcare, pharmaceutical, agricultural, and consumer communities is a prerequisite to ward off this evolving pandemic. 
    
3. Adequate funding for proactive surveillance and development of new antimicrobial drugs and vaccines should be made available. 
    
4. Antibiotic drug stewardship, including education of stakeholders, implementation of hygiene practices, and responsible dispensing and use, are essential strategic elements of all preventive practices.

Antimicrobial Drug Resistance (AMDR)

a Continuing Medical Education Activity

Needs Statement:

It is imperative that all healthcare providers are cognizant of and learn the stewardship of the dwindling inventory of effective antimicrobial drugs given the rising global spread of antibiotic drugs resistance and incidence of hospital- and community-acquired infections.

Learning Objectives:

At the end of this activity, participants should be able to:

• Understand the global threats of antimicrobial drug resistance (AMDR), including epidemiology and multidrug resistance 
• Explore the mechanisms responsible for the spread of AMDR
• Recognize and apply the principles of antibiotic drug stewardship, encompassing medical policies and practices to control the spread of AMDR
• Promote effective and safe healthcare delivery, prevent morbidity, save unnecessary costs, and above all, save lives

Release date: January 3, 2012
Expiration date: January 2014

Joint Sponsorship Statement:
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedEDirect, Inc. and the Center for the Study of International Medical Policies and Practices (CSIMPP), School of Public Policy, George Mason University, in collaboration with the World Medical Association (WMA) and the International Society for Microbial Resistance (ISMR). MedEDirect, Inc. is accredited by the ACCME to provide continuing medical education for physicians. 

Authors and Activity Planners: 

Arnauld Nicogossian, MD, FACPM, FACP
Distinguished Research Professor
Director
Center for the Study of International Medical Policies and Practices
George Mason University
Fairfax, VA
USA

Thomas Zimmerman, PhD
Executive Director, International Society for Microbial Resistance
Founding Dean, Palm Beach Medical College
Fairfax, VA
USA 

Edward Septimus, MD, FACP, FIDSA, FSHEA
Clinical Professor of Internal Medicine
Texas A&M University
Houston, TX
USA 

Otmar Kloiber, MD
Secretary General
World Medical Association
Ferney-Voltaire
France 

Advisors  

William Jacobs, PhD
Senior Scientist
International Society for Microbial Resistance
Fairfax, VA
USA

Allan Morrison, MD, FACP, FIDSA, FSHEA
Professor of Medicine, George Washington University
Epidemiologist, INOVA Health Systems and Fairfax Hospital
Fairfax, VA
USA

Disclosure of Conflicts of Interest:

All individuals participating in the development and implementation of activities sponsored by MedEDirect are expected to disclose any real or perceived conflicts of interest related to the content of the activity.

• Arnauld Nicogossian – has nothing to disclose
• Thomas Zimmerman – has nothing to disclose
• Edward Septimus – reports that he serves on a paid speakers’ bureau as a planner, presenter or reviewer for Sage Pharmaceuticals, Inc, Merck & Co., Inc, and Cubist Pharmaceuticals, Inc.
• Otmar Kloiber – has nothing to disclose
• William Jacobs – has nothing to disclose
• Allan Morrison – reports that he servers on a paid speakers’ bureau as a planner, presenter or reviewer for Cubist Pharmaceuticals, Inc., Care Fusion, Sage Pharmaceuticals Inc., Merck & Co., Inc, Pfizer, Inc., and Ortho-McNeil

Accreditation Statement:

This activity is planned and implemented in accordance with the Essentials and Policies of the Accreditation Council for Continuing Medical Education (ACCME) by MedEDirect, Inc. MedEDirect, Inc. is accredited by the ACCME to provide continuing medical education for physicians. MedEDirect, Inc. designates this activity for 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Target Audience:

This educational activity is intended for all physicians and healthcare professionals, especially those involved with the prevention, detection, and management of infectious diseases.

Estimated Time for Completion:

This activity should take approximately 2.0 hours to complete.

Method of Participation:

The participant should examine the objectives and read and study the report.

If online: Answer the multiple-choice post-test and complete both the registration form and activity evaluation form. Click “finished,” and if you have answered at least 70% of the questions correctly, you will receive certificate of completion for your records.

If by mail: Fill out the registration form, complete the post-test and activity evaluation, and mail to:

Attention: AMDR Course
George Mason University
School of Public Policy
Center for the Study of International Medical Policy
3351 Fairfax Drive
Arlington, VA 22201
USA

Limitations

Caution should be exercised when translating the information presented in this syllabus to a specific geographical or regional practice and/or prevailing socioeconomic situation.

Copyright

Materials presented in this self-assessment are for educational purposes only. They should not be copied for further distribution and are intended for personal use only. Some of the materials contained or cited in this self-assessment may be subject to copyright and should not be used without prior approval by individual authors and/or publishers.

SECTION ONE: The global threat of AMDR

Specific Learning Objective: Understand the global threats of AMDR, including epidemiology and multidrug resistance.

Defining the Problem 

Bacteria have evolved diverse protective mechanisms to cope with and survive in the ever-changing environment (Russell 1997). In the course of evolution, bacteria have had ample time to recognize harmful substances, developing and sharing defense mechanisms to ensure their own survival. As a result, antibiotics, naturally produced by bacteria, existed long before humans discovered their properties and used them on an unprecedented scale. Humans coexist with many microorganisms, of which only a small subset presents a threat to health.

The 2008 global antibiotic market was estimated at US $24 billion and is projected to reach US $40.3 billion by 2015 (PRWeb 2011). Antibiotic drugs, including antivirals, antihelminthes, and antifungal preparations, are sold for both therapeutic and industrial (agricultural) uses. The rate of antibiotic prescriptions is on the rise in Greece, Croatia, Denmark, and Ireland for both outpatient and inpatient services. A modest downward trend (1998-2005) was reported for Belgium, the Czech Republic, France, Slovakia, Slovenia, Sweden, and the United Kingdom (Monnet and Kristinsson 2008; Meropol et al. 2009), whereas in the United States and Japan, the overall rate for antibiotic use remains high (Higashi and Furuhara 2009). Some experts are concerned that we are entering a critical “postantibiotic era” with a decreasing pipeline of new and effective antibiotics and rising trends in mortality from AMDR (Alanis 2005).

The importance of the AMDR threat has been recently highlighted by the WHO (World Health Organization “Combat antibiotic resistance” 2011) as follows. 

• Infections caused by resistant microorganisms often fail to respond to conventional treatment, often leading to prolonged illness and greater mortality risk
• About 440,000 new cases of multidrug-resistant tuberculosis (MDR-TB) emerge annually, causing at least 150,000 deaths
• Resistance to earlier generations of antimalarial preparations such as chloroquine and sulfadoxine-pyrimethamine is widespread in most malaria-endemic countries
• Inappropriate and irrational use of antimicrobial drugs does provide a fertile environment for resistant microorganisms to emerge, spread, and persist 

The economic burden of AMDR is estimated to exceed US $38 billion (Tucker 2010). Nearly 7 out of every 1000 hospitalized patients (in economically developing countries) are either infected with or carriers of microorganisms resistant to common antibiotic drugs. In US hospitals, 96,000 patients contract nosocomial infection(s) annually, making such infections one of the 10 leading causes of death, claiming between 16,000 and 19,000 lives each year. The 2000 EU hospital estimates (Kaier et al. 2008) of AMDR infection incidence found that: 

• Thirty percent to 40% of cases are linked to cross-infection by the hands of healthcare workers (HCW)
• Twenty percent to 25% of cases are due to selective antimicrobial pressure
• Twenty percent to 25% of patients suffer from new pathogen introduction

SECTION TWO: Understanding AMDR

Learning Objective: Explore the mechanisms responsible for the spread of AMDR.

According to the US Centers for Disease Control and Prevention (CDC), the number of antibiotic-resistant pathogens is on the rise, creating a major public health problem. AMDR is the ability of a specific microorganism to withstand a drug or a biocide preparation that interferes with its growth and functions (Meyers 1987; Russell 1999). Resistance is a complex phenomenon involving the microorganism, the drug, the environment, and the patient. It is important to note that resistance and virulence are not related; a resistant pathogen may be no more virulent than its antibiotic-sensitive parent strain (Holmberg et al. 1987; Berkowtiz 1995). The emergence of methicillin-resistant Staphylococcus aureus (MRSA), both hospital and community strains, as well as metallo-beta-lactamase–resistant Gram-negative pathogens, are two recent examples of how microbial resistance emerges and spreads through the global community (Liu et al. 2011; Walsh and Toleman 2011). Central to the emergence and proliferation of antimicrobial resistance in developed countries is the inappropriate use of antibiotics and patient contact with AMDR pathogens, whereas in emerging and developing countries, poor hygiene and crowded living conditions are important additional drivers (Walsh and Toleman 2011). Global mobility and socioeconomic problems such as overcrowding, sanitation, war, health disparities, poor public health literacy, and poor public health systems are intertwined with the spread of resistant infections.  

In the United States, spending on antibiotic prescriptions increased 22% from 1980 to 1996, with a steep increase in resistance rates during the same period (Howard 2004). Studies in European countries also demonstrate a relationship between antimicrobial use and antimicrobial resistance rates (Livermore and Pearson 2007; Naber 2009). Infections caused by AMDR pathogens are associated with increased healthcare resource utilization. MRSA infections increase hospital length of stay (LOS), resource utilization, and cost, and are still associated with higher mortality (Cosgrove 2006). A similar pattern is noted for recently emergent Gram-negative antimicrobial-resistant strains (Walsh and Toleman 2011). Extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae are associated with increased hospital LOS and costs, whereas bloodstream infections caused by ESBL-producing Enterobacteriaceae are associated with increased rates of mortality. Multidrug-resistant (MDR) Pseudomonas aeruginosa (resistant to 4 or more antibiotic drugs) is also associated with increased mortality and increased hospital LOS (Giske et al 2008). Overall, these resistance trends have prompted governments and professional associations to draft strong guidelines around the use of antimicrobial therapies (US Government Accountability Office 2011; World Health Organization 2011).

1.Etiology and Epidemiology

Microorganisms naturally produce antibiotics as a defense mechanism against other microbes, and antibiotic-resistance genes originally evolved as a mechanism for microbes to withstand chemical attacks from other microorganisms (Cohen and Tartasky 1997). Resistance genes can appear through spontaneous mutation of existing genes or through transmission of plasmids (small pieces of mobile genetic material) between bacterial species. The incorporation of resistance genes allows antibiotic resistance to become a stable feature of a bacterial strain, resulting in loss of clinical efficacy for that antibiotic or class of antibiotics. Patients receiving antibiotic therapy can become an important source of resistant pathogens in hospitals and the community (Weinstein 1991; Long et al. 2009; Naber 2009; Schentag 1995; Hota et al. 2009; Choi et al. 2008; Riley 1988; Small et al. 1993). 

Multiple epidemiologic studies confirm that infections potentially caused by AMDR pathogens should be suspected: 

1. When the prevalence of resistant pathogen strains within a population is high
2. Following contact with individuals infected or colonized with resistant pathogens
3. During and/or following a course of antibiotic treatment 

Additional factors that contribute to the emergence of AMDR pathogens (Cohen and Tartasky 1997; Smith and Coast 2002; Gulbinovic et al. 2001) include failures to: 

• Perform drug susceptibility testing
• Select appropriate antibiotics
• Complete the treatment course   

The spread of AMDR in community settings is also the result of the dissemination of resistant microorganisms (from hospitals or outpatient settings), transfer of resistant genes, or both (Pallecchi et al. 2007). In the United States, more than 58% of community-acquired infections were found to be caused by strains traceable to a hospital or long-term care facility (Charlebois et al. 2004). Interestingly, recent evidence demonstrates that MRSA strains known to have their origin in community settings have become prominent pathogen strains in hospital settings (D’Agata et al. 2009). The latter emphasizes the high mobility of AMDR pathogens associated with the flow patterns of individuals. 

Beyond resistance genes, several host factors can increase the risk for an individual to develop an infection caused by an AMDR organism, including (Fridkin et al. 2005; H. L. Chang et al. 2009; O’Fallon et al. 2009): 

1. Patient age
2. Compromised immune system
3. Prior antibiotic use
4. Recent hospitalization
5. Poor hand hygiene
6. Bronchopulmonary disorders that interfere with clearance of pathogens from the airway
7. Intensive interventions such as hemodialysis or complex surgical procedures
8. Nutritional deficiency
9. Crowded living conditions
10. Increased gastric pH (increased alkalinity facilitating microorganisms survival) 

Some of these host factors can be improved through public and healthcare policy initiatives that improve overall health and well-being, whereas others are intrinsic features of the patients themselves.

AMDR can “travel” with passengers. Increasing travel for business and pleasure facilitates this intra- and intercontinental transmission mechanism. For example, there has been a remarkable increase in the prevalence of penicillin-resistant Streptococcus pneumoniae (PRSP) isolates in Kuwait during the last 20 years (Mokaddas et al. 2007). It is conceivable that Kuwait, with a large expatriate population of workers, may serve as a focal point for further dissemination of resistant clones globally. Policies promoting concentration of human beings in dense living conditions are likely to exacerbate resistance and are socially and politically difficult to change (Livermore 2003).

Finally, the use of antibiotics in agriculture, such as in animal feed supplementation, has contributed to the development of resistance (Tenover and McGowan 1996; Lei et al. 2010). The use of nontherapeutic levels of antibiotics in swine production can select for antibiotic resistance in commensal and pathogenic bacteria in swine (Rosengren et al. 2008).  Retail pork products, as well as surface water and groundwater contaminated with swine waste, have been shown to be sources of human exposure to antibiotic-resistant bacteria (Chapin et al. 2005; Akwar et al. 2008). High-level MDR Enterococcus, coagulase-negative staphylococci, and Viridans streptococci strains were detected in the air of a concentrated swine-feeding operation (Chapin et al. 2005). These findings suggest that the inhalation of air from these facilities could serve as a pathway for the transfer of MDR bacterial pathogens from swine to humans.

2. Incidence and Prevalence of Microbial Resistance

In 2008, the US National Institute of Allergy and Infectious Diseases published a list of pathogens resistant to antibiotics and antivirals: 

• Staphylococci, Enterococcus faecium, Escherichia coli
• Klebsiella pneumoniae, tuberculosis
• Several influenza strains
• Food-borne pathogens such as Salmonella, Shigella, and Campylobacter jejuni
• Sexually transmitted organisms such as Neisseria gonorrhea, HIV/AIDS, Candida albicans, and other fungal infections
• Parasites such as Plasmodium falciparum
• P aeruginosa and A baumanii (in returning wounded US servicemen from the Middle East and Afghanistan; probably acquired in Europe-based health-care facilities)
• C difficile

3. Major AMDR Pathogens

A baumanii is an aerobic encapsulated, nonfermenting gram-negative bacterium resistant to most antibiotics. It can be found in the soil and water. There are more than 29 species of Acinetobacter and A baumanii is responsible for more than 80% of infections. Recently A baumanii became a nosocomial infection and the organism has been reported to survive for months on high-touch surfaces such as patients’ beds, clothing, room doorknobs, call buttons, and bathrooms. It has also been implicated in nosocomial outbreaks of septicemia, ventilator-acquired pneumonia, and urinary tract and wound infections. About 20% to 40% of cases are attributed to cross infections by the hands of HCWs (Weber et al. 2010). A baumannii is an opportunistic infection. There have been many reports of A baumannii infections among American soldiers wounded in Iraq, earning it the nickname "Iraqibacter." Multidrug-resistant Acinetobacter is not a new phenomenon; it has always been inherently resistant to multiple antibiotics. The illness can cause severe pneumonia and infections of the urinary tract, bloodstream, and other body organs (Aquirre-Avalos et al. 2010).

C difficile (C diff) is a major cause of hospital-acquired infectious diarrhea and is associated with increased healthcare costs, prolonged hospitalizations, and higher patient morbidity. Both C diff toxins A and B play a role in the pathogenesis of the infection (Ananthankrishnan 2011). C diff and associated antibiotic therapy have been implicated in the development of enterocolitis, which can be fulminant and result in death. It is an anaerobic spore-forming bacillus and produces a pseudomembranous colitis. Previous antimicrobial use, especially clindamycin or ciprofloxacin, is a risk factor for development of C diff–associated diarrhea (CDAD) by disrupting normal bowel flora and promoting C diff overgrowth (Centers for Disease Control and Prevention 2008). Historically, CDAD has been associated with hospitalized elderly patients or long-term care facility (LTCF) residents. Since 2000, a strain of C diff has been identified as a North American pulsed-field type 1 (NAP1). This strain produces an extra toxin (binary toxin), and is the cause of increased morbidity and mortality among hospitalized patients (Centers for Disease Control and Prevention 2008). In the United States, C diff infections among hospitalized children is also on the rise (Nylund et al. 2011). Patients with vancomycin-resistant C diff infections, especially with diarrhea, have been found to have significant levels of environmental contamination (Sethi et al. 2009). Rifampin-resistant C diff has been found in a US hospital with 37% of recovered isolates and 82% of clone isolates resistant (Curry et al. 2009). Relapse following treatment with metronidazole or vancomycin occurs in 20% of first-time cases, increasing to 40% to 60% in subsequent recurrences (Kelly and LaMont 2008). MDR C diff strains have also been identified in hospital and chronic care facility settings. Guidelines for handling outbreaks of C diff in a healthcare setting include: 

• Visitors and HCWs should be instructed to wash their hands with soap (or antimicrobial soap) and water after being in contact with or caring for patients with C diff infection (CDI)
• For contact with all body substances, gloves are recommended
• Disposable thermometers are preferable to electronic thermometers. In areas of increased CDI transmission, chlorine-containing cleaning agents or other sporocidal agents (such as paracetic acid) should be used to disinfect surfaces (Oie et al. 2011)
• Antimicrobial usage should be monitored, and stewardship efforts should especially focus on antimicrobial drugs associated with a high risk for CDI, especially clindamycin, cephalosporins, and fluoroquinolones
• Treatment of asymptomatic carriers is not recommended 

Use of probiotics to treat C diff carriers and CDI patients remains controversial (Hsu et al. 2010).

E coli is a diverse group of bacteria and only a few strains cause disease by making a toxin called Shiga toxin. The toxin-producing bacteria are known as “Shiga toxin-producing” E coli or STEC. The most commonly identified STEC in North America is E coli O157:H7. Other serogroups can also produce infections.

Fewer than half of all pediatric urinary tract infections are susceptible to commonly prescribed antibiotics (Gaspari et al. 2006). The prevalence of E coli resistant to amoxicillin with ESBLs responsible for the community-acquired urinary tract infections (CA-UTIs) in Phnom-Penh, Cambodia, was reported to be in excess of 82.3% (Ruppé et al. 2009). CA-UTIs were also resistant to cotrimoxazole (75.3%), ciprofloxacin (67.7%), gentamicin (42.5%), and third-generation cephalosporins (37.7%). MDR strains resistant to fluoroquinolones and aminoglycosides have emerged recently (DuPont et al. 2009).

In the United States, resistance is also on the rise. A large study of children treated for UTIs found that long-term use of antibiotics appeared to reduce the risk of relapse, but the benefit was small and must be weighed against the development of resistance (Williams and Craig 2011). More than 48% of self-serve beverage and soft drink dispensing fountains have been found to be contaminated by coliform bacteria, including E coli (White et al. 2010). NDM-1, a gene responsible for AMDR, has been isolated from the E coli residing in drinking fountains and soil water in India. This gene can spread to other bacteria and confer resistance to the last-resort antibiotics called carbapenems. NADM-1 has been already found in France and in some UK hospitals, as well as among patients undergoing treatment in India and those suffering from “traveler’s diarrhea” (Diene et al. 2011; Walsh et al. 2011).

In May 2011, STEC O104:H4 was reported among several travelers returning to the United States from Germany. The Germany-based Robert Koch Institute reported several hundred cases of hemolytic uremic syndrome and deaths due to the STEC O104:H4, presumed to originate from the ingestion of raw vegetables (Robert Koch Institute 2011; Centers for Disease Control and Prevention 2011).

HIV/AIDS, commonly referred to as the “silent epidemic,” has reached pandemic proportions. In 2009, 33.3 million people were estimated to be living with HIV/AIDS (World Health Organization and UNAIDS 2010). Sub-Saharan Africa remains the most affected region. More than two-thirds (68%) of all HIV-positive patients live in this region, making up more than three-quarters (76%) of all related deaths. HIV/AIDS alone or in combination with other STIs contributes to the emergence of AMDR (Savona 2010) and are more likely to seek treatments and use antibiotic preparations.

Table 1. Global Burden of HIV/AIDS in 2009 (in millions)

*Proportion of adults aged 15 to 49 years who are living with HIV/AIDS.

(Source: UNAIDS. www.unaids.org. November 2010)

Southern Africa accounts for 35% of all people living with HIV, with almost one-third (32%) of all new HIV infections and AIDS deaths. In contrast with other regions, the majority of people living with HIV in sub-Saharan Africa (61%) are women. Infections with HIV in Ugandan infants despite nevirapine prophylaxis correlated with the length of the treatment regimen (Church et al. 2008). In Cameroon, more than 90% of patients with HIV resistance had strains that were also resistant to nevirapine-efavirenz and lamivudine-emtricitabine (Kouanfack et al. 2009). The association of HIV/AIDS and extensive drug resistance results in high mortality (Gandhi et al. 2006). 

In North America, the prevalence of transmitted resistance to antiretroviral drugs has been estimated to be between 1% and 11% among newly infected patients (Little et al. 2002). Overall prevalence of HIV strains resistant to 1 or more drugs is on the rise (Scott et al. 2004), especially in smaller clinical centers.

In Europe, 1 in 10 antiretroviral-naive patients carried viruses with more than 1 drug-resistance mutation. Newly infected patients harbored resistant variants more often than did chronically infected patients (13.5% vs 8.7%, respectively). Non–subtype B viruses (30%) carried resistance mutations less frequently than did subtype B viruses (4.8% vs 12.9%, respectively). Baseline resistance increased over time in newly diagnosed cases of non–subtype B infection—from 2.0% in 1996–1998 to 8.2% in 2000–2001 (Wensing et al. 2005). 

It is estimated that 76% of viremic patients are resistant to 1 or more antiviral drugs, with the odds of resistance increasing in the presence of a history of antiretroviral drug use, advanced HIV disease, higher plasma HIV viral load, and lowest CD4 cell counts (Richman et al. 2004). Between 1987 and 2003, 10.3% of seroconverting patients carried a drug-resistant primary human immunodeficiency type 1 (HIV-1) variant (Masquelier et al. 2005). Of those, 9.1% showed resistance mutations to only 1 class of antiretroviral drugs, 0.5% to 2 classes, and 0.7% to 3 classes of antiretroviral therapy.

Influenza A viruses—including the 2 subtypes 2009 (H1N1) and A (H3N2)—and influenza B viruses are currently circulating worldwide. The pandemic H1N1 is becoming the predominant strain in both hemispheres with an increased activity in the Southeast Asia (Nicogossian et al. 2010). 

It is estimated that worldwide, influenza viruses are responsible for infecting 1 billion individuals annually, resulting in 300,000 to 500,000 deaths. The economic burden in the US alone is a staggering US $1 to 3 billion, annually attributed to related absenteeism, secondary respiratory bacterial infections, hospitalizations, and use of scarce and costly medical resources. 

Primary protective measures consist of a combination of vaccinations, environmental and physical hygiene practices, and, in appropriate settings, the use of antiviral drugs to either prevent or shorten the course of the infection. Recently, however, resistance to antiviral drugs was reported (Glickman et al. 2010; Memoli et al. 2010; Bright et al. 2006; Gooskens et al. 2009). 

In the United States, the CDC has issued interim recommendations and updates for the prevention of the development of resistance to antiviral medications (Centers for Disease Control and Prevention 2009; Centers for Disease Control and Prevention 2010). Recently, influenza has been implicated as a contributing factor in the development of AMDR and fatal MRSA pneumonia (Creel et al. 2009; Pedal and Nolte 2010)

In tropical regions, malaria coexists with tuberculosis and HIV/AIDS infections. The dual infection of HIV and malaria contributes to the spread of both diseases in sub-Saharan African (Abu-Raddad et al. 2006) and could result in nosocomial infections and AMDR. A decade ago, the US National Intelligence Council reported that first-line drug treatment for malaria was no longer effective in 80 of the 92 countries where the disease is a major health problem (Gordon and Gannon 2000). The resistance to chloroquine is so widespread that it is currently not recommended as a therapeutic intervention (Adjuik et al. 2004). 

Malaria is a threat to half of the world's population and the cause of death of more than 1 million people annually. Malaria is caused by 4 different protozoan intracellular parasite species transmitted primarily by the bite of the female Anopheles mosquito.   ·Plasmodium falciparum ·Plasmodium vivax ·Plasmodium ovale ·Plasmodium malariæ   An increase in human infections with Plasmodium knowlesi is being observed in Southeast Asia, probably due to human activities and encroachment into the primate habitat (Lee et al. 2011). Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and some Caribbean islands. Malaria infections coexist with HIV/AIDS and tuberculosis in several equatorial countries in the African continent and contribute to the excess burden of morbidity and mortality in the area.   According to the WHO, resistance of P falciparum to choloroquine, the cheapest and the most prescribed antimalarial drug, is spreading throughout the endemic countries. Resistance to the combination of sulfadoxine-pyrimethamine that is present in South America and in Southeast Asia is now emerging in East Africa (World Health Organization 2011).  

Resistance develops most rapidly with subtherapeutic concentrations of antimalarial drugs. Emergence of resistance to antimalarial drugs is associated with: 

• Greater exposure
• Use of single, shorter-action conventional drugs first
• Use of primary antimalarial drugs for nonmalarial indications in high-risk areas (eg, chloroquine for rheumatoid arthritis in a malarial endemic area)
• Poor compliance with therapy and other preventive measures, such as bed netting at night
• Failure of monitoring for resistance to prevent spread
• Lack of clear policy and protocols for use of newer antimalarial drugs

 The WHO recommends considering treating malaria with combination therapy using azithromycin, an antibiotic with weak antimalarial properties. No significant benefit for this practice was identified using the Cochrane Database (van Eijk and Terlouw 2011). Isolated cases of resistance to artemisinin were recently reported and a research into antimalarial vaccines is in progress (Breman 2009; Pongtavornpinyo et al. 2008).

Approximately 32% (89.4 million persons) and 0.8% (2.3 million persons) of the US population are colonized with S aureus and MRSA respectively (Kuehnert et al. 2006). The number of healthcare-associated staphylococcal infections due to MRSA is on the rise—from 2% of S aureus infections in US intensive care units (ICUs) in 1974 to 22% in 1995 and 64% in 2004 (Klevens et al. 2006). The rate of MRSA has been found to be as high as 59.2% in hospital wards (Naber 2009). There are an estimated 292,000 hospitalizations due to S aureus infections annually in US hospitals (Kuehnert et al. 2005). Of these, approximately 126,000 hospitalizations are related to MRSA. Nosocomial MRSA infections with reduced susceptibility to vancomycin are found to be more virulent than other strains and are a major contributor to in-hospital morbidity and mortality (The Medical Letter 2009; Peleg et al. 2009; Xiong et al. 2009). 

In 2007, rates of MRSA bacteremia ranged from 0.8% in Denmark to 52.4% in Malta (Naber 2009). In Belgium, the MRSA bacteremia–associated mortality among critically ill patients was 23.4% compared with 1.3% for methicillin-susceptible S aureus (MSSA) strains (Blot et al. 2002). The estimated risk of mortality associated with MRSA bacteremia compared with MSSA bacteremia is 1.93 (Cosgrove et al. 2003) with a relative risk of 2.12 (Whitby et al. 2001). 

In Europe, S aureus, including MRSA, are the leading isolates in skin and soft tissue infections (SSTI), with a range of 10% to 51% (Kollef et al. 2008). A study of 9 European country hospitals revealed that 28% of patients with bacteremia received less than optimal therapy, resulting in higher morbidity and mortality rates (Ammerlaan et al. 2009). A study of MRSA and MSSA from 450 European hospitals in 26 different countries showed that strains of MRSA tend to cluster in individual healthcare facilities and also within regional borders. This suggests the spread of MRSA through multiple admissions to different care facilities by infected patients (Grundmann et al. 2010). Spatial mapping and geographic information could help identify the patterns of spread and help in the control of the MRSA transmission (Lowy 2010). 

Figure 1. Prevalence (%) of MRSA Among EU Patients Presenting With Bacteremia

Adapted from: Naber CK. Staphylococcus aureus bacteremia: epidemiology, pathophysiology and management strategies. Clin Infect Dis. 2009;48(suppl 4):231-237.

It is estimated that more than 20% of all HCWs are carriers of MRSA (Chan et al. 2009). Of these, 88% are nasal carriers with the remainder being throat carriers. Colonization with MRSA can persist for to 2 years or longer (Robicsek et al. 2009). Aerosols containing MRSA are commonly found in many residential homes (Gandara et al. 2006).

MRSA is a significant cause of infections outside of the hospital, too (Johnson et al. 2009). Community-acquired MRSA (CA-MRSA) strains have increased dramatically during the last 2 decades (Klevens et al. 2007). It is estimated that 13.7% of invasive MRSA infections are community acquired (Klevens et al. 2007). Between 6% and 21.7 % of end-stage renal disease patients are colonized with MRSA (Wang et al. 2009; Johnson et al. 2009), and the prevalence of CA-MRSA colonization increases with the number of years that a patient is on dialysis (Lin et al. 2009). Available evidence suggests that CA-MRSA pneumonia continues to be associated with seasonal influenza virus, including the 2009 A (H1N1) pandemic (Murray et al. 2010). The Infectious Diseases Society of America (IDSA) recently issued guidelines for prevention and treatment of MRSA (Liu et al. 2011).

Risk factors for CA-MRSA include:

• Group living and activities that increase the frequency of personal physical contact
• Poor personal hygiene practices and inadequate hand washing.
• Scarce resources or inappropriate hygiene practices among group living (such as dormitories, military barracks, prisons, and locker rooms) and activity settings (such as physical impact sports)
• Insufficient local surveillance system and laboratory diagnostic capacity
• Inappropriate use of antibiotics

Beyond the conventional designation of nosocomial and community strains, novel MRSA strains have now been identified worldwide in domesticated animals (particularly swine), which are also capable of transmitting infections to humans (Smith and Pearson 2011). A MRSA mecA (LGA251) was recently isolated in United Kingdom and Denmark laboratories that require special diagnostic testing for detection (García-Álvarez et al. 2011).

This organism causes more than 800,000 deaths among children younger than 5 years (Saha et al. 2009). Although availability of effective pneumococcal vaccines reduces the prevalence of invasive disease in vaccinated children and those they contact in the home (Hicks et al. 2007; Hicks et al. 2011), recent evidence suggests an upward trend in invasive infections by serotypes that are not covered by available vaccines (Rosen et al. 2011). From 2001 to 2004, 824 consecutive S pneumoniae isolates from all Kuwait teaching hospitals and primary-care centers showed 63% resistance to penicillin (55% were of intermediate resistance and 8% were of full resistance) (Mokaddas et al. 2007). S pneumoniae isolates collected during 2000 to 2004 in the United States showed 29.3%, 21.2%, 0.9%, and 0.02% of isolates to be resistant to erythromycin, penicillin, levofloxacin, and telithromycin, respectively. The proportion of isolates exhibiting multidrug resistance remained stable at ~30% during the 4-year study period (Jenkins et al. 2008). The antimicrobial susceptibility of S pneumoniae isolates from hospitalized children in Bangladesh revealed complete resistance to chloramphenicol and cotrimoxazole in 6% and 32% of patients, respectively (Saha et al. 2009).

MDR-TB and extensively-drug resistant (XDR-TB) tuberculosis is a critical problem globally (LoBue 2009). It is estimated that the global proportion of resistance among all tuberculosis cases is 4.8%. China, India, and the Russian Federation combined have the highest number of MDR-TB cases: China and India account for approximately 50% of the global burden and the Russian Federation accounts for an additional 7% (Wright and Zignol 2008). The population-weighted mean of MDR-TB among all TB cases is 5.3%, but ranges from 0% in some western European countries to more than 35% in some countries of the former Soviet Union (Wright and Zignol 2008). The highest proportions of TB cases are resistant to isoniazid and streptomycin, followed by rifampicin and ethambutol (Wright and Zignol 2008). Isolated resistance to fluoroquinolones has also been documented (Long et al. 2009). Increased incidence of pulmonary cavities is associated with MDR-TB (Aguiar et al. 2009). Drug-resistant TB disproportionately affects young adults (Palacios 2009); previous failed treatment, recent relapse, and homelessness are all associated with MDR- and XDR-TB.

Enterococci have been identified as the third most frequent cause of nosocomial bacteremia (Boucher et al. 2009). E faecium is now the major contributor to AMDR in surgical wounds and urinary tract infections. Penicillin, ampicillin, piperacillin, imipenem, and vancomycin are among the few antibiotics that show consistent inhibitory, but not bactericidal, activity against Enterococcus faecalis (Huycke et al. 1998). The spread of antibiotic resistance among enterococci, with some microorganisms becoming resistant to all standard therapies, highlights both the vulnerability of available antibiotics as well as the looming prospect of a "postantibiotic era" with no effective drugs to fight the infections (Huycke et al. 1998). Vancomycin resistance is independently associated with increased mortality among patients with enterococcal bloodstream infection (Diaz-Granados et al. 2005).

SECTION THREE: Control and Prevention of AMDR 

Specific learning objective: Recognize the principles of antibiotic drug stewardship, including medical and health policies and practices to control the spread of AMDR.

2. Infections and Chronic Diseases

The belief that many chronic diseases are infectious in origin goes back to the mid-19th century, when cancer was studied as a possible infectious disease (Institute of Medicine 2002). In the last 15 years, several chronic disorders have been linked to a virus or microorganism, such as peptic ulcer disease with Helicobacter pylori, human papilloma viruses and cervical cancer, Whipple's disease with Tropheryma whippeli, Lyme arthritis and neuroborreliosis with Borrelia burgdorferi, hepatitis viruses with liver cancer, colon cancer with Streptococcus bovis, and HIV with Kaposi sarcoma (see Appendix C). It has been suggested that the incidence of infection-related cancers is underestimated (de Martel and Franceschi 2009; Yeung et al. 2011). Thus, microorganisms that develop resistance to antibiotic or antiviral drugs might contribute to the burden of increasing incidence of chronic and debilitating diseases.

3. Policies and Best Practices

It is essential that governments, professional organizations, and individual practitioners seriously contemplate policies to contain the advance of resistant pathogens (Garrett 2001; Small and Fujiwara 2001; Podolsky 2005). Historical examples of successful approaches to the eradication or control of infectious diseases include improved basic hygiene, vaccination, and environmental practices combined with sustained effective educational and outreach campaigns. Today, strategies to lower microbial resistance are also linked to guiding the appropriate use of antibiotics and minimizing environmental contamination with AMDR pathogens (Dellit et al. 2007; Guidos 2011; Rybak et al. 2009; Schlaes et al. 1997; Siegel et al. 2006). Strategies can target either the prevention of the emergence of new resistance, or interruption of the transmission of existing resistance. Pursuing both approaches usually provides the best results. 

At the core of the major strategies nationally, regionally, and globally are (Smith and Coast 2002): 

• Surveillance programs to monitor pathogen prevalence and susceptibility to antibiotics
• Tracking of antimicrobial drug consumption
• Incentives to encourage research and development of new antimicrobial preparations
• Application of appropriate alternative treatments
• Adoption of policies promoting antibiotic drug stewardship 

Successful implementation of public health policies is driven through the combined influences of formal legislation, practice regulations, professional standards and guidelines, and informal procedures and customs. Data from evidence-based literature serve as a starting point for developing healthcare policy, further molded by social (cultural or religious) beliefs, applicable models for delivering healthcare, and political perspectives.

a. Antimicrobial Drug Stewardship

The physician’s role and responsibility for the management of antimicrobial drug resources is substantial (Arnold and Straus 2005). The goal of any clinical intervention with an antimicrobial agent is concisely expressed by Tenover as “the prudent use of the appropriate drug at the appropriate dose and for the appropriate duration” (Tenover 2006). Thus, the primary objective is the “eradication of the infection while minimizing side effects” (Paskovaty et al. 2005). 

The Canadian Medical Association’s Committee on Antibiotic Resistance suggests that antimicrobial stewardship may be the key to controlling antimicrobial resistance (Conly 2002). Similar calls to action around stewardship initiatives have been made by the CDC and WHO. Within these programs emphasis is placed on establishing the need for and the choice of antimicrobial drugs, starting with knowledge of the local pathogen prevalence involved in a particular infection (Fishman 2006). 

According to a survey of hospital practitioners, barriers to establishing an antimicrobial stewardship program include (Pope et al. 2009):

From a resource perspective, critical barriers to achieving optimal infection management include; lack of timely laboratory diagnostic information and the availability of community or regional AMDR sensitivity information. In developing nations, access to effective agents may be limited. Community, regional, and global surveillance networks are also lacking. 

The CDC Get Smart (launched in 2002) and WHO campaigns to prevent antimicrobial resistance provide evidence-based principles for judicious use of antimicrobial preparations and tools for implementation. The program emphasizes effective antimicrobial treatment of infections through:

• Use of narrow-spectrum agents
• Avoidance of excessive durations of therapy
• Restricting use of broad-spectrum or more potent antimicrobial preparations to treatment of serious infections when the pathogen is not known or when other effective agents are unavailable 

Strategies for influencing antimicrobial prescribing patterns within healthcare facilities include education; formulary restriction; prior-approval programs, including preapproved indications; automatic stop orders; academic interventions to counteract pharmaceutical influences on prescribing patterns; antimicrobial cycling; computer-assisted management programs; and active efforts to remove redundant antimicrobial combinations. In a recent follow-up report from one region of Canada, implementation of a multipronged education strategy was associated with a significant reduction in antibiotic use and associated costs (Weiss et al. 2011). 

A systematic review of controlled studies identified several successful practices. These include social marketing (eg, consumer education), practice guidelines, authorization systems, formulary restriction, and mandatory consultation, as well as peer review and feedback. It further suggested that online systems that provide clinical information, structured order entry, and decision support are promising strategies. These changes are best accomplished through an organizational, multidisciplinary, antimicrobial management program. These programs should also include the periodic feedback reviews of the effectiveness of the therapy and monitoring for possible development of AMDR (Behta et al. 2008).

Antimicrobial guidelines and treatment algorithms for infectious diseases may further aid rational use of antimicrobial preparations. When reliable data are available, local AMDR trends for infectious diseases should be considered when deciding upon inclusion of each antimicrobial (World Health Organization 2005; Liu et al. 2011).

c. Environmental Decontamination

The role of environmental reservoirs, such as surfaces and medical equipment, in the transmission of MDROs has been the subject of several reports. Monitoring for adherence to recommended environmental cleaning practices is an important determinant for success in controlling transmission of MDROs and other pathogens in the environment. The interior design of healthcare facilities is receiving increased attention in the prevention of transmission of AMDR microorganisms, especially MRSA. High-touch surfaces covered with copper alloys are being tested as potential countermeasures for AMDR, along with control of interior temperatures and humidity (Michels et al. 2009). 

Increased pollution of effluent potable water (Lateef 2004; Naddeo et al. 2009) and antibiotic uses in agriculture also contribute to AMDR spread. Extensive use of antibiotics in the food chain can contribute to the development of AMDR.

d. Infection Control 

Prevention and control of infections caused by MDRO pathogens require knowledge of known critical infection pathways (Livermore 2003), elucidated by surveillance and coupled with application of appropriate contact and environmental controls, as well as antimicrobial stewardship principles for appropriate antibiotic use. 

Since 1996, the CDC has recommended the use of standard and contact precautions for MDROs. Hand hygiene is an important component of this. There is a demonstrated temporal relationship between improved adherence to recommended hand hygiene practices and control of MDROs. In a recent article, Goldman emphasized that infections such as MRSA are transmitted primarily by the contaminated hands of healthcare providers who have touched a colonized patient or something in the patient's environment (Goldmann 2006). It is estimated that 30% to 40% of endemic institutional antibiotic resistance is caused by ineffective or absent hand washing (Jarvis 1994). 

In the absence of ASC data, a patient’s MDRO colonization status is frequently unknown. Therefore, standard precautions must be used in order to prevent transmission from potentially colonized patients. In situations where an MDRO outbreak has been detected, or for patients at high risk for MDRO colonization, more aggressive contact precautions should be implemented (Smith et al. 2008). Even in facilities that use contact precautions for patients with an identified MDRO, standard precautions play an important role in infection control (Cooper et al. 2004). Patients may remain colonized with MDROs for prolonged periods. Shedding of these organisms may be intermittent and surveillance cultures may fail to detect their presence. The duration of contact precautions following successful treatment of MDRO pathogen infections for patients who remain colonized at one or more body sites remains an unresolved issue.

e. Patient Education

Information on preventive measures can be successfully introduced into school and adult health educational curriculum (World Health Organization 2005). Specifically, the fundamentals of AMDR can be included into biology classes and become part of regular occupational health information awareness programs. Educating prospective parents is an effective mode of communicating and teaching AMDR facts. Properly managed media campaigns targeting patient behavior can contribute to reducing the rate of inappropriate antibiotic use (Gonzales et al. 2008; Hemo et al. 2009)

4. Antibiotic Development Pipeline

Investment in drug research and production has reached a staggering US $1.2 billion over a 10- to 15-year period (Knowles 2010). The IDSA has as one of its policy foci the drying up of the pipeline of new antibiotics (Spellberg et al. 2004; Boucher et al. 2009). Pharmaceutical companies have found the antibiotics market to be more difficult than and not as profitable as that for drugs to treat chronic illness and lifestyle issues. Approximately 2 million people acquire bacterial infections in the United States and 90,000 die as a result. The IDSA notes that about 70% of those infections are resistant to at least 1 drug. 

The FDA review and approval of new antibiotics has declined 56% during the last 20 years according to a 2004 IDSA assessment. In 2000, 1 in every 10,000 compounds that entered drug discovery was estimated to make it to market, with an average cost for development in excess of US $800 million. Given the high risks associated with new drug development, new financial incentives are needed to encourage the exploration for new therapeutic agents. Government and professional organizations can develop policies and allocated resources to maintain an adequate pipeline of antibiotics and vaccines targeting AMDR. The rate of the arrival to the US market of different antimicrobial drugs is shown in Figure 2. Some of the newer antibiotics, such as tigecycline, have been found to be no better than treatment with standard antimicrobial agents, carry a higher risk of clinical failure and patient mortality, and should not be used as a monotherapy regimen (Yahav et al. 2011; Tasina et al. 2011). 

Please refer to Appendices A and B at the end of the Syllabus to view the classification of the antibiotic drugs and the top 8 most prescribed drugs, currently at risk of becoming ineffective due to AMDR. 

Figure 2. Decadal Release of New Antibacterial Drugs (1910-2010)

SECTION FOUR: Conclusions 

Antimicrobial resistance recognizes no national boundaries. Unless antibiotic resistance is detected and contained, the world could be faced with diseases that once more will become untreatable (Centers for Disease Control and Prevention 2010). Development of resistant microorganisms is a concern whenever antimicrobial agents are used. Careless use of antibiotics, lack of adherence to prescribed treatment regimens, poor environmental hygiene, antibiotic use in agriculture, and contamination of the food supply chain further exacerbate the situation and accelerate the spread of resistance to antibiotics. The increase in high-risk populations, including immunocompromised patients, those undergoing invasive medical interventions, those with implanted medical devices, and patients with chronic debilitating diseases, has increased the problem. Food-producing animals are frequently given antibiotic drugs for therapeutic, disease prevention, or production reasons. However, these drugs can cause microbes to become resistant to drugs used to treat human illness, ultimately making some human sicknesses harder to treat. 

The global increase in resistance to antimicrobial drugs, including the emergence of bacterial strains resistant to all available antibacterial agents, has created a public health problem of crisis proportions with significant economic and human implications. Increasing antimicrobial resistance presents a major threat to public health by reducing the effectiveness of antimicrobial agents; leading to increased morbidity, mortality, and healthcare expenditure. Salmonella spp and other food-borne pathogens resistant to antimicrobial drugs continue to spread globally (Teuber 1999; Smith and Coast 2002). In 1995, the cost of containing an outbreak of infection caused by MRSA in a district general hospital in the United Kingdom was estimated to exceed US $560,000, while the annual healthcare cost associated with the treatment of resistant infections in the United States was estimated at more than US $4 billion in 2002, an amount recently revised to more than US $7 billion (Smith and Coast 2002). Antimicrobial resistance is a cause of professional, governmental, and public concern and has been classified as a national security risk in the United States (Smith and Coast 2002). 

Globalization increases the vulnerability of all nations to imported diseases, and today infectious diseases travel faster and farther than ever before. During the 1990s, a resistant Pneumococcus spp first identified in Spain rapidly spread to Argentina, Brazil, Chile, Taiwan, Columbia, Malaysia, Mexico, the Philippines, Republic of Korea, South Africa, Thailand, United States, and Uruguay. No country acting on its own can adequately protect the health of its population against AMDR. International collective action is essential, yet responsibility for health remains predominantly a national responsibility. Consequently, there is a potentially significant disparity between the problems and solutions associated with AMDR, healthcare institutions, and the systems available to deal with them (Centers for Disease Control and Prevention 2010). Morbidity and mortality increases with delayed diagnosis and initiation of effective treatment (World Health Organization 2005). Physicians in developing countries may have to use older antimicrobial drugs that are becoming increasingly ineffective, resulting in higher rates of treatment failure (Howard et al. 2003). Most developing countries lack drug susceptibility testing, a key element that guides delivery of effective antimicrobial therapy. Countries of market economy should consider political and policy solutions such as redefining AMDR as a complex humanitarian crisis and provide appropriate tools and knowledge management to developing countries to handle this emerging global security threat.

Vaccines are needed to prevent infection, and transmission of resistant organisms (Interagency Task Force on Antimicrobial Resistance 2001). Further, vaccines are needed to prevent common bacterial infections, thus reducing antibacterial use. The development of novel vaccines occurs over a continuum, beginning with basic research, extensive clinical research, and trials and moving to product education, marketing, and distribution. An understanding at the molecular level of the mechanisms of resistance, policy, and political support for extensive evaluation of intervention strategies, as well as capital investment and product development capability, are required to successfully bring new vaccines into mass availability.

In 2009, the United States and the European Union signed a collaborative agreement to address the global AMDR health crisis. Although microbial resistance is a serious concern in countries of market economy, it is potentially devastating in developing countries. The global cost of AMDR morbidity and mortality now outstrips the total antibiotic market. All healthcare providers should have access to tools such as patient testing for AMDR, timely training to enhance knowledge, modification of attitudes, and improvement in the standards of clinical practices. Proactive polices to fight AMDR should be implemented by all national Ministries of Health. 

In conclusion, preventing transmission of infections should be priority in all healthcare settings and should include as a minimum: 

• Hand washing or alcohol-based rinses by staff between patients and before undertaking invasive procedures such as injections
• Use of barrier precautions, eg, wearing gloves and gowns for procedures that might result in transmission of pathogens
• Adequate sterilization and disinfection of all supplies and equipment
• Use of sterile techniques, together with protocols, for medical and nursing procedures capable of bridging skin or mucosal membrane integrity such as: bladder catheterization, administration of injections, insertion of intravenous cannulas, use of respirators, sterilization of equipment, and other surgical interventions
• Maintenance of appropriate disinfection and sanitary control of the hospital environment, including:
  • Adequate ventilation
  • Cleaning of wards, operating theater, laundry, and other objects used by patients
  • Provision of adequate water supply and sanitation
  • Safe food handling
  • Safe disposal of infectious equipment, eg, dirty needles, body fluids, and other suspected contaminated materials
Isolation of infected patients from noninfected patients, eg, separation of suspected and proven sputum-positive TB cases (particularly from HIV-positive patients)
• Visiting policies, such as preventing visitors with infections from visiting patients who may be immunocompromised (for example, patients with AIDS or leukemia or premature babies)
• Training of healthcare staff in appropriate sterile techniques and infection control procedures

 Additional AMDR Resources (Pagani et al. 2009; Centers for Disease Control and Prevention 2010): 

1. The Centers for Disease Control and Prevention — http://www.cdc.gov/drugresistance/healthcare/default.htm
2. National Healthcare Safety Network (NHSN) — www.cdc.gov/nhsn/dataStat.htm
3. The World Health Organization — http://www.who.int/drugresistance/surveillance/en; http://www.who.int/drugresistance/en;
   http://www.who.int/mediacentre/factsheets/fs194/en
4. Cochrane Library — http://www2.cochrane.org/reviews/en/ab003539.html
5. Ovid Medlines^® — http://www.ovid.com/site/catalog/DataBase
6. European Center for Disease Prevention and Control — http://www.ecdc.eu.int

References

SECTION ONE: Introduction

Alanis, A. J. 2005. Resistance to antibiotics: are we in the post-antibiotic era? Archives of Medical Research 36:697–705.

Awad, A. I., D. E. Ball, and I. B. Eltayeb. 2007. Improving rational drug use in Africa: the example of Sudan. Eastern Mediterranean Health Journal 13:1202–11.

Berild, D., T. G. Abrahamsen, S. Andresen, et al. 2008. A controlled intervention study to improve antibiotic use in a Russian pediatric hospital. International Journal of Antimicrobial Agents 31:478–83.

Higashi, T., and S. Furuhara. 2009. Antibiotic prescriptions for upper respiratory tract infection in Japan. Internal Medicine 48:1369–75.

Isturiz, R. E., and C. Carbon. 2000. Antibiotic use in developing countries. Infection Control and Hospital Epidemiology 21:394–7.

Kaier, K., C. Wilson, M. Chalkley, et al. 2008. Health and economic impacts of antibiotic resistance in European hospitals—outlook on the BURDEN project. Infection 36):492–4.

Khor, M. 2005. TWN Info Service on Health Issues No. 9: Irrational drug use causing rise of antimicrobial resistance. Third World Network. http://www.twnside.org.sg/title2/health.info/twninfohealth009.htm.

Meropol, S. B., Z. Chen, and J. P. Metlay. 2009. Reduced antibiotic prescribing for acute respiratory infection in adults and children. British Journal of General Practice 59:e321–8.

Monnet D. L., and K. G. Kristinsson. 2008. Turning the tide of antimicrobial resistance: Europe shows the way. Eurosurveillance 13:19039.

Pharmaceutical Security Institute. 2011. Counterfeit Situation. http://www.psi-inc.org/counterfeitSituation.cfm.

PRWeb. 2011. Global antibiotics market to reach US$40.3 billion by 2015, according to new report by Global Industry Analysts, Inc., news release, October 25. http://www.prweb.com/releases/antibiotics/anti_infectives/prweb4688824.htm.

Russell, A. D. 1997. Plasmids and bacterial resistance to biocides. Journal of Applied Microbiology 83:155–65.

Tucker, M. E. 2010. Cost of antibiotic resistance hits private payers. Hospitalist News (March 1). http://www.ehospitalistnews.com/specialty-focus/infectious-diseases/single-article-page/
cost-of-antibiotic-resistance-hits-private-payers/6031fbf760.html.

Tünger, O., G. Dinç, B. Ozbakkaloglu, U. C. Atman, and U. Algün. 2000. Evaluation of rational antibiotic use. International Journal of Antimicrobial Agents 15:131–5.

Weinstein, R. A. 2001. Controlling antimicrobial resistance in hospitals: infection control and use of antibiotics. Emerging Infectious Diseases 7:188–92.

Woodward, R. S., G. Medoff, M. D. Smith, and J. L. Gray. 1987. Antibiotic cost savings from formulary restrictions and physician monitoring in a medical-school-affiliated hospital. American Journal of Medicine 83:817–23.

World Health Organization. 2011. Combat antibiotic resistance. http://whd2011.euro.who.int.

World Health Organization. 2011. World Health Day 2011. Combat drug resistance: no action today means no cure tomorrow. Statement by WHO Director-General, Dr Margaret Chan, http://www.who.int/mediacentre/news/statements/2011/whd_20110407/en./index.html.

World Health Organization. 2010. Medicines: rational use of medicines. http://www.who.int/mediacentre/factsheets/fs338/en/index.html.

World Medical Association. 2011. WMA Statement on Resistance to Antimicrobial Drugs. http://www.wma.net/en/30publications/10policies/a19/index.html.

SECTION TWO. Understanding AMDR: The Knowledge Base

Abu-Raddad, L. J., P. Patnaik, and J. G. Kublin. 2006. Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa. Science 314:1603–6.

Adjuik, M., A. Babiker, P. Garner, P. Olliaro, W. Taylor, N. White, and the International Artemisinin Study Group. 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363:9–17.

Aguiar, F., M. A. Vieira, A. Staviack, et al. 2009. Prevalence of anti-tuberculosis drug resistance in an hiv/aids reference hospital in Rio de Janeiro, Brazil. International Journal of Tuberculosis and Lung Diseases 13:54–61.

Akwar, H. T., C. Poppe, J. Wilson, et al. 2008. Associations of antimicrobial uses with antimicrobial resistance of fecal Escherichia coli from pigs on 47 farrow-to-finish farms in Ontario and British Columbia. Canadian Journal of Veterinary Research 72:202–10.

Ammerlaan, H., H. Seifert, S. Harbarth, et al. 2009. Adequacy of antimicrobial treatment and outcome of Staphylococcus aureus bacteremia in 9 Western European countries. Clinical Infectious Diseases 49:1006–8.

Ananthakrishnan, A .N. 2011. Clostridium difficile infection: epidemiology, risk factors and management. National Reviews of Gastroenterology and Hepatology 8:17–26.

Aquirre-Avalos, G., J. C. Mijangos-Méndez, and G. Amaya-Tapia. 2010. Acinetobacter baumannii bacteremia. Revista Medica del Instituto Mexicano del Seguro Social 48:625–34.

Baird, J. W. 1997. Antibiotic prescribing, controls, and antimicrobial resistance: an Australian experience. Alliance for the Prudent Use of Antibiotic Newsletter 15:1–2,6.

Barraclough, K. A., C. M. Hawley, E. G. Playford, and D. W. Johnson. 2009. Prevention of access-related infection in dialysis. Expert Review of Anti-Infective Therapy. 7:1185–200.

Berkowtiz, F. E. 1995. Antibiotic resistance in bacteria. Southern Medical Journal 88:797–804.

Blot, S. I., K. H. Vandewoude, E. A. Hoste, and F. A. Colardyn. 2002. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Archives of Internal Medicine 162: 2229–35.

Boucher, H. W., G. H. Talbot, J. S. Bradley, et al. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clinical Infectious Diseases 48:1–12.

Breman, J. G. 2009. Eradicating malaria. Science Progress 92(Pt 1):1–38.

Bright, R. A., D. K. Shay, B. Shu, N. J. Cox, and A. J. Klimov. 2006. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. Journal of the American Medical Association 295:891–4.

Centers for Disease Control and Prevention. 2008. Surveillance for community-associated Clostridium difficile --- Connecticut, 2006. Morbidity and Mortality Weekly Report 57:340–3.

Centers for Disease Control and Prevention. 2009. Update: influenza activity --- United States, August 30--October 31, 2009. Morbidity and Mortality Weekly Report 58:1236–41.

Centers for Disease Control and Prevention. 2010. Influenza antiviral drug resistance: questions and answers. http://www.cdc.gov/flu/about/qa/antiviralresistance.htm.

Centers for Disease Control and Prevention. 2011. Investigation announcement: outbreak of Shiga toxin-producing E. coli O104 (STEC O104:H4) infections associated with travel to Germany. http://www.cdc.gov/ecoli/2011/ecoliO104.

Chan, K. S., M. L. Ling, L. Y. Hsu, and A. L. Tan. 2009. Methicillin-resistant Staphylococcus aureus throat colonization among healthcare workers during an outbreak in Singapore General Hospital. Infection Control and Hospital Epidemiology 30:95–6.

Chang, H. L., C. H. Tang, Y. M. Hsu, et al. 2009. Nosocomial outbreak of infection with multi-drug resistant Acinetobacter baumannii in a medical center in Taiwan. Infection Control and Hospital Epidemiology 30:34–8.

Chang, S., A. K. Sethi, B. C. Eckstein, U. Stiefel, J. L. Cadnum, and C. J. Donskey. 2009. Skin and environmental contamination with methicillin-resistant Staphylococcus aureus among carriers identified clinically versus through active surveillance. Clinical Infectious Diseases 48:1423–28.

Chapin, A., A. Rule, K. Gibson, T. Buckley, and K. Schwab. 2005. Airborne multidrug-resistant bacteria isolated from a concentrated swine feeding operation. Environmental Health Perspectives 113:137–42.

Charlebois, E. D., F. Perdreau-Remington, B. Kreiswirth, et al. 2004. Origins of community strains of methicillin-resistant Staphylococcus aureus. Clinical Infectious Diseases 39:47–54.

Choi, S., J. E. Lee, S. J. Park, et al. 2008. Emergence of antibiotic resistance during therapy for infections caused by Enterobacteriaceae producing AmpC β-lactamase: implications for antibiotic use. Antimicrobial Agents and Chemotherapy 52:995–1000.

Church, J. D., S. B. Omer, L. A. Guay, et al. 2008. Analysis of nevirapine (NVP) resistance in Ugandan infants who were HIV infected despite receiving single-dose (SD) NVP versus SD NVP Plus Daily NVP up to 6 weeks of age to prevent HIV vertical transmission. The Journal of Infectious Diseases 198:1075–82.

Cohen, F. L., and D. Tartasky. 1997. Microbial resistance to drug therapy: a review. American Journal of Infection Control 25:51–64.

Cosgrove, S. E. 2006. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clinical Infectious Diseases 42(suppl 2):S82–9.

Cosgrove, S. E., G. Sakoulas, E. N. Perencevich, M. J. Schwaber, A. W. Karchmer, and Y. Carmeli. 2003. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clinical Infectious Diseases 36:53–9.

Costelloe, C., C. Metcalfe, A. Lovering, D. Mant, and A.D. Hay. 2010. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 340:c2096.

Creel, A. M., S. H. Durham, K. W. Benner, J. A. Allen, and M. K. Winkler. 2009. Severe invasive community-associated methicillin-resistant Staphylococcus aureus infections in previously healthy children. Pediatric Critical Care 10:405–7.

Curry, S. R., J. W. Marsh, K. A. Shutt, et al. 2009. High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clinical Infectious Diseases 48:425–9.

D'Agata, E. M., G. F. Webb, M. A. Horn, R. C. Moellering Jr, and S. Ruan. 2009. Modeling the invasion of community-acquired methicillin-resistant Staphylococcus aureus into hospitals. Clinical Infectious Diseases 48:274–84.

Diaz-Granados, C. A., S. M. Zimmer, M. Klein, and J. A. Jernigan. 2005. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clinical Infectious Diseases 41:327–33.

Diene, S. M., N. Bruder, D. Raoult, and J. M. Rolain. 2011. Real-time PCR assay allows detection of the New Dehli metallo-β-lactamase (NDM-1)-encoding gene in France. International Journal of Antimicrobial Agents 37:544–6.

Dondorp, A. M., P. N. Newton, M. Mayxay, et al. 2004. Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinationalcross-sectional survey on the prevalence of fake antimalarials. Tropical Medicine and International Health 9:1241–46.

DuPont, H. L., C. D. Ericsson, M. J. Farthing, et al. 2009. Expert review of the evidence base for prevention of travelers’ diarrhea. Journal of Travel Medicine 16:149–60.

Fridkin, S.K., J.C. Hageman, M. Morrison et al. 2005. Methicillin resistant Staphylococcus aureus disease in three communities. New England Journal of Medicine 352:1436–44.

Gandara, A., L. C. Mota, C. Flores, H. R. Perez, C. F. Green, and S. G. Gibbs. 2006. Isolation of Staphylococcus aureus and antibiotic-resistant Staphylococcus aureus from residential indoor bioaerosols. Environmental Health Perspectives 114:1859–64.

Gandhi, N. R., A. Moll, A. W. Sturm, et al. 2006. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368:1575–80.

García-Álvarez, L., M. T. Holden, H. Lindsay, et al. 2011. Meticillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: a descriptive study. Lancet Infectious Diseases 11:595-603.

Gaspari, R. J., E. Dickson, J. Karlowsky, and G. Doern. 2006. Multidrug resistance in pediatric urinary tract infections. Microbial Drug Resistance 12:126–29.

Giske, C. G., D. L. Monnet, O. Cars, Y. Carmeli, and ReAct-Action on Antibiotic Resistance. 2008. Clinical and economic impact of common multidrug-resistant gram-negative bacilli. Antimicrobial Agents and Chemotherapy 52:813–21.

Glikman, D., Z. Zonis, M. Hindiyeh, et al. 2010. Development of oseltamivir resistance during oseltamivir therapy in a child with severe 2009 H1N1 influenza. Pediatric Infectious Disease 29:385–6.

Gooskens, J., M. Jonges, E. C. Claas, A. Meijer, and A. C. Kroes. 2009. Prolonged influenza virus infection during lymphocytopenia and frequent detection of drug-resistant virus. The Journal of Infectious Diseases 199:1435–41.

Gordon, D.F., and J. C. Gannon. 2000. The global infectious disease threat and its implications for the United States. National Intelligence Council. http://www.dni.gov/nic/special_globalinfectious.html.

Grundmann, H., D. M. Aanensen, C. C. van den Wijngaard, B. G. Spratt, D. Harmsen, A. W. Friedrich, and the European Staphylococcal Reference Laboratory Working Group. 2010. Geographic distribution of Staphylococcus aureus causing invasive infections in Europe: a molecular-epidemiological analysis. PLoS Medicine 7:e1000215.

Gulbinovic, J., K. E. Myrbäck, J. Bytautiene, B. Wettermark, J. Struwe, and U. Bergman. 2001. Marked differences in antibiotic use and resistance between university hospitals in Vilnius, Lithuania, and Huddinge, Sweden. Microbial Drug Resistance 7:383–9.

Hicks, L. A., Y-W Chien, T. H. Taylor, M. Haber, and K. P. Klugman. 2011. Outpatient antibiotic prescribing and non-susceptible Streptococcus pneumoniae in the United States, 1996–2003. Clinical Infectious Diseases 53:631–39.

Hicks, L. A., L.H. Harrison, B. Flannery, et al. 2007. Incidence of pneumococcal disease due to non–pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998–2004. Journal of Infectious Diseases 196:1346–54.

Holmberg, S. D., S. L. Solomon, and P. A. Blake. 1987. Health and economic impacts of antimicrobial resistance. Reviews of Infectious Diseases 9:1065–78.

Hota, S., Z. Hirji, K. Stockton, et al. 2009. Outbreak of multidrug-resistant Pseudomonas aeruginosa colonization and infection secondary to imperfect intensive care unit room design. Infection Control and Hospital Epidemiology 30:25–33.

Howard, D. H. 2004. Resistance-induced antibiotic substitution. Health Economics 13:585–95.

Hsu J., C. Abad, M. Dinh, and N. Safdar. 2010. Prevention of endemic healthcare-associated Clostridium difficile infection: reviewing the evidence. American Journal of Gastroenterology 105:2327–39.

Huycke, M. M., D. F. Sahm, and M. S. Gilmore. 1998. Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future. Emerging Infectious Diseases 4:239–49.

Jenkins, S. G., S. D. Brown, and D. J. Farrell. 2008. Trends in antibacterial resistance among Streptococcus pneumoniae isolated in the USA: update from PROTEKT US Years 1-4. Annals of Clinical Microbiology and Antimicrobials 7:1.

Johnson, L. B., J. Jose, F. Yousif, J. Pawlak, and L. D. Saravolatz. 2009. Prevalence of colonization with community-acquired methicillin-resistant Staphylococcus aureus among end-stage renal disease patients and healthcare workers. Infection Control and Hospital Epidemiology 30:4–12.

Kelesidis, T., I. Kelesidis, P. I. Rafailidis, and M. E. Falagas. 2007. Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. Journal of Antimicrobial Chemotherapy 60:214–36.

Kelly, C. P., and J. T. LaMont. 2008. Clostridium difficile—more difficult than ever. The New England Journal of Medicine 359:1932–40.

Klevens, R. M., J. R. Edwards, F. C. Tenover, L. C. McDonald, T. Horan, R. Gaynes, and the National Nosocomial Infections Surveillance System. 2006. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992-2003. Clinical Infectious Diseases 42: 389–91.

Klevens, R. M., M. A. Morrison, J. Nadle, et al. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. Journal of the American Medical Assocation 298:1763–71.

Kollef, M. H., L. M. Napolitano, J. S. Solomkin, et al. 2008. Health care-associated infection (HAI): a critical appraisal of the emerging threat-proceedings of the HAI Summit. Clinical Infectious Diseases 47(suppl 2):S55–99; quiz S100–1.

Kouanfack, C., C. Montavon, C. Laurent, et al. 2009. Low levels of antiretroviral-resistant HIV infection in a routine clinic in Cameroon that uses the World Health Organization (WHO) public health approach to monitor antiretroviral treatment and adequacy with the WHO recommendation for second-line treatment. Clinical Infectious Diseases 48:1318–22.

Kuehnert, M. J., H. A. Hill, B. A. Kupronis, J. I. Tokars, S. L. Solomon, and D. B. Jernigan. 2005. Methicillin-resistant-Staphylococcus aureus hospitalizations, United States. Emerging Infectious Diseases 11:868–72.

Kuehnert, M. J., D. Kruszon-Moran, H. A. Hill, et al. 2006. Prevalence of Staphylococcus aureus nasal colonization in the United States, 2001-2002. The Journal of Infectious Diseases 193:172–9.

Laxminarayan, R. 2001. Fighting antibiotic resistance: can economic incentives play a role? Resources 143:9–12.

Lee, K. S., P. C. Divis, S. K. Zakaria, et al. 2011. Plasmodium knowlesi: reservoir hosts and tracking the emergence in humans and macaques. PLoS Pathogens; 7:e1002015.

Lei, T., W. Tian. L. He, et al. 2010. Antimicrobial resistance in Escherichia coli isolates from food animals, animal food products and companion animals in China. Veterinary Microbiology 146:85–9.

Levy, S. B. 1993. Confronting multidrug resistance: a role for each of us. Journal of the American Medical Association 269:1840–2.

Lin, C. C., J. L. Wang, C. Y. Lin, et al. 2009. Methicillin-resistant Staphylococcus aureus bacteremia in patients with end-stage renal disease in Taiwan: distinguishing between community-associated and healthcare-associated strains. Infection Control and Hospital Epidemiology 30:89–92.

Little, S. J., S. Holte, J. P. Routy, et al. 2002. Antiretroviral-drug resistance among patients recently infected with HIV. The New England Journal of Medicine 347:385–94.

Liu, C., A. Bayer, S. E. Cosgrove, et al. 2011. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clinical Infectious Diseases 52:285–92.

Livermore, D. M. 2003. Bacterial resistance: origins, epidemiology, and impact. Clinical Infectious Diseases 36(suppl 1):S11–23.

Livermore, D. M., and A. Pearson. 2007. Antibiotic resistance: location, location, location. Clinical Microbiology and Infection 13(suppl 2):7–16.

Llor, C., and J. M. Cots. 2009. The sale of antibiotics without prescription in pharmacies in Catalonia, Spain. Clinical Infectious Diseases 48:1345–9.

LoBue, P. 2009. Extensively drug-resistant tuberculosis. Current Opinion in Infectious Diseases 22:167–73.

Long, R., H. Chong, V. Hoeppner, et al. 2009. Empirical treatment of community-acquired pneumonia and the development of fluoroquinolone-resistant tuberculosis. Clinical Infectious Diseases 48:1354–60.

Lowy, F. D. 2010. Mapping the distribution of invasive Staphylococcus aureus across Europe. PloS Medicine 7:e1000215.

Mainous, A. G., III, C. J. Everett, R. E. Post, V. A. Diaz, and W. J. Hueston. 2009. Availability of antibiotics for purchase without a prescription on the internet. Annals of Family Medicine 7:431–35.

Mangione-Smith, R., E. A. McGlynn, M. N. Elliott, L. McDonald, C. E. Franz, and R. L. Kravitz. 2001. Parent expectations for antibiotics, physician-parent communication, and satisfaction. Archives of Pediatrics & Adolescent Medicine 155:800–6.

Masquelier, B., K. Bhaskaran, D. Pillay, et al. 2005. Prevalence of transmitted HIV-1 drug resistance and the role of resistance algorithims: data from seroconverters in the CASCADE collaboration from 1987 to 2003. Journal of Acquired Immune Deficiency Syndromes 40:505–11.

Memoli, M. J., R. J. Hrabal, A. Hassantoufighi, et al. 2010. Rapid selection of a transmissible multidrug- resistant influenza A/H3N2 virus in an immunocompromised host. The Journal of Infectious Diseases 201:1397–403.

Meyers, B. R. 1987. Bacterial resistance: exploring the facts and myths. Bulletin of the New York Academy of Medicine 63:211–6.

Mokaddas, E. M., V. O. Rotimi, and M. J. Albert. 2007. Increasing prevalence of antimicrobial resistance in Streptococcus pneumoniae in Kuwait: implications for therapy. Microbial Drug Resistance 13:227–34.

Murray, R. J., J. O. Robinson, J. N. White, et al. 2010. Community-acquired pneumonia due to pandemic A(H1N1)2009 influenzavirus and methicillin resistant Staphylococcus aureus co-infection. PLoS One 5:e8705.

Naber, C. K. 2009. Staphylococcus aureus bacteremia: epidemiology, pathophysiology, and management strategies. Clinical Infectious Diseases 48(suppl 4):S231–37.

Nicogossian, A., N. Ebadirad, T. Zimmerman, G. Kreps, and E. J. Septimus. 2010. Influenza immunization: synthesizing and communicating the evidence. World Medical and Health Policy DOI: 10.2202/1948-4682.1090.

Nylund, C. M., A. Goudie, J. M. Garza, G. Fairbrother, and M. B. Cohen. 2011. Clostridium difficile infection in hospitalized children in the United States. Archives of Pediatrics & Adolescent Medicine 165:451–7.

O'Fallon, E., S. Gautam, and E. M. D’Agata. 2009. Colonization with multidrug-rresistant gram-negative bacteria: prolonged duration and frequent cocolonization. Clinical Infectious Diseases 48:1375–81.

Oie, S., A. Obayashi, H. Yamasaki, et al. 2011. Disinfection methods for spores of Bacillus atrophaeus, B. anthracis, Clostridium tetani, C. botulinum and C. difficile. Biological and Pharmaceutical Bulletin 34:1325–9.

Palacios E., R. Dallman, M. Muñoz, et al. 2009. Drug-resistant tuberculosis and pregnancy: treatment outcomes of 38 cases in Lima, Peru. Clinical Infectious Diseases 48:1413–9.

Pallecchi, L., C. Lucchetti, A. Bartoloni, et al. 2007. Population structure and resistance genes in antibiotic-resistant bacteria from a remote community with minimal antibiotic exposure. Antimicrobial Agents and Chemotherapy 51:1179–84.

Pedal, I., and O. Nolte. 2010. Community-associated MRSA and Panton-Valentine leukocidin (PVL): novel trends in epidemiology and forensic implications. Archiv fur Kriminologie 225:119–29.

Peleg, A. Y., D. Monga, S. Pillai, E. Mylonakis, R. C. Moellering Jr, and G. M. Eliopoulos. 2009. Reduced susceptibility to vancomycin influences pathogenicity in Staphylococcus aureus infection. The Journal of Infectious Diseases 199:532–6.

Pongtavornpinyo, W., S. Yeung, I. M. Hastings, A. M. Dondorp, N. P. Day, and N. J. White. 2008. Spread of anti-malarial drug resistance: mathematical model with implications for ACT drug policies. Malaria Journal 7:229.

Powers, J. H. 2009. Risk perception and inappropriate antimicrobial use: yes, it can hurt. Clinical Infectious Diseases 48:1350–53.

Richman, D. D., S. C. Morton, T. Wrin, et al. 2004. The prevalence of antiretroviral drug resistance in the United States. AIDS 18:1393–1401.

Riley, T. V. 1988. Antimicrobial resistance in Branhamella catarrhalis. The Journal of Antimicrobial Chemotherapy 21:147–50.

Robert Koch Institute (RKI). 2011. New epidemiological data support current dietary recommendations of BfR: Joint press release of Federal Institute for Risk Assessment (BfR)/ Robert Koch Institute (RKI). http://www.rki.de/cln_178/nn_217400/EN/Home/PM__072011.html.

Robicsek, A., J. L. Beaumont, and L. R. Peterson. 2009. Duration of colonization with methicillin-resistant Staphylococcus aureus. Clinical Infectious Diseases 48:910–3.

Rosen, J. B., A. R. Thomas, C. A. Lexau, et al. 2011. Geographic variation in invasive pneumococcal disease following pneumococcal conjugate vaccine introduction in the United States. Clinical Infectious Diseases. 53:137–43.

Rosengren, L. B., C. L. Waldner, R. J. Reid-Smith, S. L. Checkley, M. E. McFall, and A. Rajic. 2008. Antimicrobial resistance of fecal Escherichia coli isolated from grow-finish pigs in 20 herds in Alberta and Saskatchewan. Canadian Journal of Veterinary Research 72:160–7.

Ruppé, E., S. Hem, S. Lath, et al. 2009. CTX-M β-lactamases in Escherichia coli from community-acquired urinary tract infections, Cambodia. Emerging Infectious Diseases 15:741–8.

Russell, A. D. 1999. Bacterial resistance to disinfectants: present knowledge and future problems. The Journal of Hospital Infection 43(suppl):S57–68.

Saha, S. K., A. Naheed, S. El Arifeen, et al. 2009. Surveillance for invasive Streptococcus pneumoniae disease among hospitalized children in Bangladesh: antimicrobial susceptibility and serotype distribution. Clinical Infectious Diseases 48(suppl 2):S75–81.

Savona, N. 2010. Older people are at risk of sexually transmitted infections. Sexually Transmitted Infections 87:70.

Schentag, J. J. 1995. Understanding and managing microbial resistance in institutional settings. American Journal of Health-System Pharmacy 52(6 suppl 2):S9–14).

Schlagenhauf-Lawlor, P. Travelers' Malaria. Ontario: BC Decker Inc, 2008.

Scott, P., E. Arnold, B. Evans, et al. 2004. Surveillance of HIV antiretroviral drug resistance in treated individuals in England: 1998-2000. The Journal of Antimicrobial Chemotherapy 53:469–73.

Sethi, A. K, W. N. Al-Nassir, M. M. Nerandzic, and C. J. Donskey. 2009. skin and environmental contamination with vancomycin-rresistant enterococci in patients receiving oral metronidazole or oral vancomycin treatment for Clostridium difficile-associated disease. Infection Control and Hospital Epidemiology 3:13–24.

Shakoor, O., R. B. Taylor, and R. H. Behrens. 1997. Assessment of the incidence of substandard drugs in developing countries. Tropical Medicine and International Health 2:839-45.

Small, P. M., R. W. Shafer, P. C. Hopewell, et al. 1993. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. The New England Journal of Medicine 328:1137–44.

Smith, R. D., and J. Coast. 2002. Antimicrobial resistance: a global response. Bulletin of the World Health Organization 80:126–33.

Smith, T. C., and N. Pearson. 2011. The emergence of Staphylococcus aureus ST398. Vector Borne and Zoonotic Diseases. 11:327–39.

Standing Medical Advisory Committee Sub-group on Antimicrobial Resistance. 1998. The Path of Least Resistance: Main Report. United Kingdom Department of Health. http://www.advisorybodies.doh.gov.uk/pub/docs/doh/smacrep.pdf.

Targett, G. A. T., ed. Malaria: Waiting for the Vaccine. New York: John Wiley and Sons, 1991.

ten Ham, M. 2003. Health risks of counterfeit pharmaceuticals. Drug Safety 26:991–7.

Tenover, F. C., and J. E. McGowan Jr. 1996. Reasons for the emergence of antibiotic resistance. The American Journal of the Medical Sciences 311:9–16.

The Medical Letter. 2009. Drugs for MRSA with reduced susceptibility to vancomycin. The Medical Letter 51:36.

US Government Accountability Office. 2011. Antibiotic Resistance: Data Gaps Will Remain Despite HHS Taking Steps to Improve Monitoring. Report to the Committee on Agriculture, House of Representatives. Washington, DC. GAO-11-406.

van Eijk, A. M., and D. J. Terlouw. 2011. Azithromycin for treating uncomplicated malaria. Cochrane Database of Systematic Reviews February 16:CD0006688.

Walsh T. R., and M.A. Toleman. 2011. The emergence of pan-resistant Gram-negative pathogens merits a rapid global political response. Journal of Antimicrobial Chemotherapy [e-pub ahead of print].

Walsh, T. R., J. Weeks, D. M. Livermore, and M. A. Toleman. 2011. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. The Lancet Infectious Diseases 11:355–62.

Wang, C. Y., V. C. Wu, Y. M. Chen, C. T. Su, K. D. Wu, and P. R. Hsueh. 2009. Nasal carriage of methicillin-resistant Staphylococcus aureus among patients with end-stage renal disease. Infection Control and Hospital Epidemiology 30:93–4.

Weber, D. J., W. A. Rutala, M. B. Miller, K. Huslage, and E. Sickbert-Bennett. 2010. Role of hospital surfaces in the transmission of emerging health care-associated pathogens: norovirus, Clostridium difficile, and Acinetobacter species. American Journal of Infection Control 38(5 suppl 1):S25–33.

Weinstein, R. A. 1991. Epidemiology and control of nosocomial infections in adult intensive care units. The American Journal of Medicine 91(3B):S179–84.

Weintrob, A. C., M. P. Roediger, M. Barber, et al. 2010. Natural history of colonization with gram-negative multidrug-resistant organisms among hospitalized patients. Infection Control and Hospital Epidemiology 31:330–7.

Wensing, A. M., D. A. van de Vijver, G. Angarano, et al. 2005. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. The Journal of Infectious Diseases 192:958–66.

Whitby, M., M. L. McLaws, and G. Berry. 2001. Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis. The Medical Journal of Australia 175:264–7.

White, A. S., R. D. Godard, C. Belling, V. Kasza, and R. L. Beach. 2010. Beverages obtained from fountain machines in the U.S. contain microorganisms, including coliform bacteria. International Journal of Food Microbiology 137:61–6.

Williams, G., and J. C. Craig. 2011. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database of Systematic Reviews March 16:CD001534.         

Wondemagegnehu, E., and Essential Drugs and Other Medicines. 1999. Counterfeit and Substandard Drugs in Myanmar and Viet Nam: Report of a Sudy Carried out in Cooperation With the Governments of Myanmar and Viet Nam. World Health Organization. http://apps.who.int/medicinedocs/pdf/s2276e/s2276e.pdf.

World Health Organization. 2011. Global Alert and Response (GAR). http://www.who.int/csr/en.

World Health Organization, UNAIDS. 2010. AIDS epidemic. Joint United Nations Programme on HIV/AIDS and World Health Organization. http://data.unaids.org/pub.

Wright, A., and M. Zignol. 2008. Anti-tuberculosis Drug Resistance in the World: Fourth Global Report. World Health Organization. http://whqlibdoc.who.int/hq/2008/WHO_HTM_TB_2008.394_eng.pdf.

Xiong, Y. Q., V. G. Fowler, M. R. Yeaman, F. Perdreau-Remington, B. N. Kreiswirth, and A. S. Bayer. 2009. Phenotypic and genotypic characteristics of persistent methicillin-resistant Staphylococcus aureus bacteremia in vitro and in an experimental endocarditis model. The Journal of Infectious Diseases 199:201–8.

SECTION THREE: Control and Prevention of AMDR Best Practices

Arnold, S. R., and S. E. Straus. 2005. Interventions to improve antibiotic prescribing practices in ambulatory care. Cochrane Database of Systematic Reviews October 19:CD003539.

Behta, M., B. Ross, and R. Chaudhry. 2008. A comprehensive decision support system for the identification, monitoring and management of patients with multi-drug resistant organisms (MDRO). AMIA Annual Symposium Proceedings 6:1218.

Boucher, H. W., G. H. Talbot, J. S. Bradley, et al. 2009. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clinical Infectious Diseases 48:1–12.

Cassell, G. H., and J. Mekalanos. 2001. Development of antimicrobial agents in the era of new and reemerging infectious diseases and increasing antibiotic resistance. Journal of the American Medical Association 285:601–5.

Conly, J. 2002. Antimicrobial resistance in Canada. Canadian Medical Association Journal 167:885­–91.

Cooper, B. S., S. P. Stone, C. C. Kibbler, et al. 2004. Isolation measures in the hospital management of methicillin-resistant Staphylococcus aureus (MRSA): systematic review of the literature. BMJ 329:533.

Dellit, T. H., R. C. Owens, J. C. McGowan Jr, et al. 2007. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clinical Infectious Diseases 44:159–77.

de Martel, C., and S. Franceschi. 2009. Infections and cancer: established associations and new hypotheses. Critical Reviews in Oncology/Hematology 70:183–94.

Fishman, N. 2006. Antimicrobial stewardship. The American Journal of Medicine 119(6 suppl 1):S53–61, discussion S62–70.

Garrett, L. 2001. The return of infectious disease. In Plagues and Politics, ed. A. T. Smith-Price, 183–194. New York: Palgrave Publishers Ltd.

Goldmann, D. 2006. System failure versus personal accountability--the case for clean hands. The New England Journal of Medicine 355:121–3.

Gonzales, R., K. K. Corbett, S. Wong, et al. 2008. “Get Smart Colorado”: impact of a mass media campaign to improve community antibiotic use. Medical Care 60:597–605.

Guidos, R.J. 2011. Combating antimicrobial resistance: policy recommendations to save lives. Clinical Infectious Diseases 52(suppl 5):S397–428.

Harris, S. R., E. J. Feil, M. T.  Holden, et al. 2010. Evolution of MRSA during hospital transmission and intercontinental spread. Science 327:469–74.

Harrison, P.F., and J. Lederberg, eds. 1998. Antimicrobial Resistance: Issues and Options. Workshop Report. Institute of Medicine. Washington, DC: National Academy Press. http://www.iom.edu/Reports/1998/Antimicrobial-Resistance-Issues-and-Options.aspx.

Hemo B., N. H. Shamir-Shtein, B. G. Silverman, et al. 2009. Can nationwide media campaign affect antibiotic use? The American Journal of Managed Care 15:529–34.

Institute of Medicine. 2002. Linking infectious agents and chronic diseases: defining the relationship, enhancing the research, and mitigating the effects. Forum on microbial threats. http://www.iom.edu/Activities/PublicHealth/MicrobialThreats/2002-OCT-21.aspx.

Jarvis, W. R. 1994. Handwashing--the Semmelweis lesson forgotten? Lancet 344:1311–2.

Knowles, S. M. 2010. Intellectual property. Fixing the legal framework for pharmaceutical research. Science 327:1083–4.

Lateef, A. 2004. The microbiology of pharmaceutical effluent and its public health implications. World Journal of Microbiology & Biotechnology 20:167–71.

Liu, C., A. Bayer, S. E. Cosgrove, et al. 2011. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clinical Infectious Diseases 52:285–92.

Livermore, D. M. 2003. Bacterial resistance: origins, epidemiology, and impact. Clinical Infectious Diseases 36(suppl 1):S11–23.

Michels, H. T., J. O. Noyce, and C. W. Keevil. 2009. Effects of temperature and humidity on the efficacy of methicillin-resistant Staphylococcus aureus challenged antimicrobial materials containing silver and copper. Letters in Applied Microbiology 49:191–5.

Monnet D. L., and K. G. Kristinsson. 2008. Turning the tide of antimicrobial resistance: Europe shows the way. Eurosurveillance 13:19039.

Naber, C. K. 2009. Staphylococcus aureus bacteremia: epidemiology, pathophysiology, and management strategies. Clinical Infectious Diseases 48(suppl 4): S231–7.

Naddeo, V., S. Meriç, D. Kassinos, V. Belgiorno, and M. Guida. 2009. Fate of pharmaceuticals in contaminated urban wastewater effluent under ultrasonic irradiation. Water Research 43:4019–27.

Paskovaty, A., J. M. Pflomm, N. Myke, and S. K. Seo. 2005. A multidisciplinary approach to antimicrobial stewardship: evolution into the 21st century. International Journal of Antimicrobial Agents 25:1–10.

Podolsky, S. H. 2005. The changing fate of pneumonia as a public health concern in 20th-century America and beyond. American Journal of Public Health 95:2144–54.

Pope, S. D., T. H. Dellit, R. C. Owens, T. M. Hooton, Infectious Diseases Society of America, and Society for Healthcare Epidemiology of America. 2009. Results of survey on implementation of Infectious Diseases Society of America and Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Infection Control and Hospital Epidemiology 30:97–8.

Philipson, T., and R. A. Posner. Private Choices and Public Health: The AIDS Epidemic in an Economic Perspective. Cambridge: Havard University Press, 1993.

Phillips, M., and P. A. Phillips-Howard. 1996. Economic implications of resistance to antimalarial drugs. Pharmacoeconomics 10:225–38.

Rybak, M., B. Lomaestro, J. C. Rotschafer, et al. 2009. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. American Journal of Health-System Pharmacy 66:82–98.

Schlaes, D. M., D. N. Gerding, J. F. John Jr, et al. 1997. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clinical Infectious Diseases 25:584–99.

Siegel J. D., E. Rhinehart, M. Jackson, L. Chiarello, and the Healthcare Infection Control Practices Advisory Committee. 2006. Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006. Atlanta, GA: Centers for Disease Control and Prevention.

Small, P. M., and P. I. Fujiwara. 2001. Management of tuberculosis in the United States. The New England Journal of Medicine 345:189–200.

Smith, P. W., G. Bennett , S. Bradley, et al. 2008. SHEA/APIC guideline: infection prevention and control in the long-term care facility. Infection Control and Hospital Epidemiology 29:785–814.

Smith, R. D., and J. Coast. 2002. Antimicrobial resistance: a global response. Bulletin of the World Health Organization 80:126–33.

Spellberg, B., J. H. Powers, E. P. Brass, et al. 2004. Trends in antibiotic drug development: implications for the future. Clinical Infectious Diseases 38:1279–86.

Tasina, E., A. B. Haidich, S. Kokkali, and M. Arvanitidou. 2011. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. The Lancet Infectious Diseases July 22 [epub ahead of print].

Tenover, F. C. 2006. Mechanisms of antimicrobial resistance in bacteria. The American Journal of Medicine 119(6 suppl 1):S3–10, discussion S62–70.

US Congress, Office of Technology Assessment. 1995. Impacts of Antibiotic-Resistant Bacteria. U.S. Congress (OTA-H-629). Washington, DC: US Government Printing Office.

Weber S. G., S. S. Huang, S. Oriola,et al. 2007. Legislative mandates for use of active surveillance cultures to screen for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: position statement from the Joint SHEA and APIC Task Force. SHEA/APIC position statement.

Weiss K., R. Blais, A. Fortin, S. Lantin, and M. Gaudet. 2011. Impact of a multipronged education strategy on antibiotic prescribing in Quebec, Canada. Clinical Infectious Diseases In press.

World Health Organization. 2005. Containing Antimicrobial Resistance. WHO Policy and Perspectives on Medicines. http://www.who.int/management/anmicrobialresistance.pdf.

Yahav, D., A. Lador, M. Paul, and L. Leibovici. 2011. Efficacy and safety of tigecycline: a systematic review and meta-analysis. The Journal of Antimicrobial Chemotherapy 66:1963–71.

Yeung, W. C., W. D. Rawlinson, and M. E. Craig. 2011. Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ  342:d35.

SECTION FOUR: Conclusions

Centers for Disease Control and Prevention. 2010. Facts about antibiotic resistance. http://www.cdc.gov/getsmart/antibiotic-use/fast-facts.html.

Howard, D. H., R. D. Scott 2nd, R. Packard, and D. Jones. 2003. The global impact of drug resistance. Clinical Infectious Diseases 36(suppl 1):S4–10.

Interagency Task Force on Antimicrobial Resistance. 2001. A Public Health Action Plan to Combat Antimicrobial Resistance. Part I: Domestic Issues. http://www.cdc.gov/drugresistance/actionplan/aractionplan.pdf.

Pagani, L., I. C. Gyssens, B. Huttner, D. Nathwani, and S. Harbarth. 2009. Navigating the web in search of resources on antimicrobial stewardship in health care institutions. Clinical Infectious Diseases 48:626–32.

Smith, R.D., and J. Coast. 2002. Antimicrobial resistance: a global response. Bulletin of the World Health Organization 80:126–33.

Teuber M. 1999. Spread of antibiotic resistance with food-borne pathogens. Cellular and Molecular Life Sciences 56:755–63.

World Health Organization. 2005. Containing Antimicrobial Resistance. WHO Policy and Perspectives on Medicines. http://www.who.int/management/anmicrobialresistance.pdf.

APPENDICES 

Appendix A: Antibiotics and Anti-infective Agents by Category and Mechanism of Action

Appendix A (cont)

Appendix B

Top 8 Most Prescribed Antibiotics (2008)

Appendix C

Pathogens Suspected in the Genesis of Chronic Disorders^2-5

1. Chronic Disorders and Cancers

2. Neurologic Disorders

21. Sentinel event is an unexpected event in a healthcare setting involving death or serious physical or psychological injury, or the risk thereof, and not related to the patient’s illness (adapted from the Joint Commission for Accreditation of Healthcare Organizations USA).
     
22. Virulence defines the ability of an infective agent to cause disease. The number of microorganisms required to trigger the infection is inversely correlated with the virulence level of the infective agent. Sometimes referred to as “extremely infective pathogen” capable of a rapid course and high morbidity and mortality.