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Antimicrobial Drug Resistance (AMDR)

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     1. Etiology and Epidemiology



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.



Facts:

  • About 70% of bacteria that cause infections in hospitals are resistant to at least one of the common antibiotics
  • Some organisms are resistant to all approved antibiotics and must be treated with experimental and potentially toxic drugs
  • Antibiotics are given to patients more often than called for in set guidelines
  • Premature discontinuation or early interruption of antibiotic therapy help the spread of resistant strains (an example is MDR-TB)
  • Combination therapy with 2 antibiotics prevents the emergence of resistant strains in contrast with sequential antibiotic therapy
  • Early initiation of antibiotics is among the most important factors for preventing the emergence of resistant strains

A notable patient risk factor for development of certain AMDR infections is the individual’s colonization status. Patient colonization can occur through contact with other infected or colonized individuals or from contact with contaminated surfaces and objects (Tenover and McGowan 1996; Lei et al. 2010). Major colonization sites are skin folds, especially groin and antecubital areas, which are extensively used for indwelling lines. Proper skin cleaning, physical hygiene, and regular culturing is required to detect and handle the multidrug-resistant organism (MDRO) colonization (Barraclough et al. 2009). In a 2009 prospective surveillance study of patient and environmental colonization with MRSA, 50% of hospitalized subjects had nasal colonization with MRSA, while the remainder had either a history of MRSA or an ongoing infection (S. Chang et al. 2009). Skin and environmental contamination with MRSA was equivalent between the 2 groups, indicating that colonized patients can be transmitters of resistant organisms. Environmental contamination has been implicated in the transmission of vancomycin-resistant Enterococcus, Clostridium difficile, and Acinetobacter baumannii (especially among injured US soldiers returning from the Middle East war theater) (Weintrob et al. 2010). In some regions, more than 61% of patients carry at least 2 resistant organisms, whereas 14% are colonized by 3 or more (O'Fallon et al. 2009).

The emergence of AMDR pathogens is accelerated by the misuse of antimicrobial drugs. France, Australia, the United States, Canada, Italy, and the United Kingdom have high rates of oral antimicrobial drug prescriptions, with a corresponding high rate of infections caused by AMDR pathogens (Baird 1997; Livermore and Pearson 2007; Naber 2009). Additional factors include: over-the-counter dispensing of antimicrobial drugs without professional controls; the use of low-potency drugs attributable to poor manufacture or counterfeiting; the availability of drugs from roadside stalls and hawkers who have little or no knowledge of dosage regimens; and, finally, through purchases over the Internet (Smith and Coast 2002, Mainous et al. 2009). A 2009 report draws attention to the availability of antibiotics “over the counter” in some countries, despite regulations requiring a physician prescription (Llor and Cots 2009).

 



Patient attitudes and expectations play an important role in the use of antimicrobial drugs (Holmberg et al. 1987; Levy 1993). Demand for and use of antibiotic drugs is second only to that of analgesics (Standing Medical Advisory Committee Sub-group on Antimicrobial Resistance 1998). Worldwide, 20% of prescribed antibiotics are used in hospitals, whereas 80% are used in the community. In the primary care (community) setting, patients receiving antibiotic drugs for respiratory or urinary tract infections can develop resistance to the antibiotic prescribed. This resistance can persist up to 12 months after treatment, thereby increasing carriage of resistant organisms in community settings (Costelloe et al. 2010). 

Believing that an antibiotic will provide a quicker recovery, patients and families expect and frequently demand a prescription from their physician (Mangione-Smith et al. 2001). There is a limited awareness by patients and their families that inappropriate use of antibiotics increases patients’ risk for developing a resistant infection. Some physicians, in order to preserve a comfortable relationship with their patients, may not wish to challenge these expectations and may prescribe an antimicrobial drug without identifying the pathogen or its susceptibility to the drug (Laxminarayan 2001; Powers 2009). 

The global market of counterfeit drugs also contributes to the rise and spread of AMDR (Targett 1991; Schlagenhauf-Lawlor 2008). Specifically, if the counterfeit drug has subpotent levels of the active ingredient, resistance may be significant (Shakoor et al. 1997) . A WHO survey of 20 countries found that 78% of counterfeit drug sales occurred in developing countries (Wondemagegnehu 1999). As much as of half of the antimalarial medications in Southeast Asia may be counterfeit (Dondorp et al. 2004), with antibiotics being from 8 to 10 times and antiparasite drugs 2 to 3 times more frequently adulterated than other medications (Kelesidis et al. 2007; ten Ham 2003). 

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).

The rate of the rise of AMDR is suspected to be related to antibiotic drug:

  1. Misuse (inappropriate use)
  2. Overuse (exceeding the standards of practice)
  3. Over-the-counter availability (nonprescription dispensing)
  4. Low-potency preparations (counterfeit or adulterated generic drugs)
  5. Excessive and unregulated agricultural use
  6. Patient expectations and attitudes 

Counterfeit drugs

  • Market value will reach USD 75 billion in 2010
  • Will account for 78% of the total consumption in developing countries
  • Will constitute half of all the antimalarial drugs sold in Southeast Asia
  • Antiparasite and antibiotic drugs are 2 to 10 times more frequently adulterated than other drugs

 



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.




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Table of Contents

ACTIVITY OVERVIEW
INTRODUCTION
SECTION ONE: The global threat of AMDR
SECTION TWO: Understanding AMDR
    1. Etiology and Epidemiology
    2. Incidence and Prevalence of Microbial Resistance
    3. Major AMDR Pathogens
       a. Acinetobacter baumanii
       b. Clostridium difficile
       c. Escherichia coli
       d. HIV/AIDS and Sexually Transmitted Infection
       e. Influenza virus
       f. Malaria (Plasmodium)
       g. Methicillin-resistant Staphylococcus aureus (MRSA)
       h. Streptococcus pneumoniae
       i. Tuberculosis and MDR-TB
       j. Vancomycin-Resistant Enterococcus (VRE)
SECTION THREE: Control and Prevention of AMDR
    1. Implications of Microbial Resistance
    2. Infections and Chronic Diseases
    3. Policies and Best Practices
       a. Antimicrobial Drug Stewardship
       b. Surveillance
       c. Environmental Decontamination
       d. Infection Control
       e. Patient Education
    4. Antibiotic Development Pipeline
SECTION FOUR: Conclusions
REFERENCES
APPENDICES
GLOSSARY
Test Questions
Program Evaluation
Self Assessment


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