Antibiotic exposure is the main factor promoting antibiotic resistance in both populations and individuals, although crowding and other risk factors also contribute selective pressure for resistance and encourage its spread (Table 3) (8,12,71,72). We have categorized resistant pathogens as foodborne, hospital-acquired, or community-acquired. While appropriate measures to curb development of resistance have different
Three Types of Resistant Pathogens and the Implications for Control Measures
Factors associated with increased likelihood of resistance:
Audience for education:
Resistant pathogen acquired from food ingestion
Resistant pathogen Resistant pathogen acquired in hospital acquired in the community
Vancomycin resistant Enterococcus
Drug-resistant Streptococcus pneumoniae
Antibiotics in feed, Parenteral antibiotics, Recent (previous 3
therapeutic antibiotics, animal hygiene, structural confines on farms
Veterinarians, regulatory agencies, farmers prolonged antibiotics, empirical antibiotic therapy, surgical prophylaxis, poor staff infection control practices
Hospital personnel mo) antibiotic use, community with high resistance rates, day care, schools, military
Community medical practitioners, public
Decreased antibiotics in animal feed, irradiation of food
Formulary controls, good infection control precautions (hand-washing), cohorting, laboratory surveillance for resistance
Appropriate antibiotic use by clinicians, public education, improved diagnostic techniques, vaccines nuances for each pathogen category, they all rely on improvement in the appropriate use of antimicrobial agents.
Factors that Promote Resistance in Foodborne Pathogens
Foodborne pathogens are those that cause illness when a person ingests contaminated meat or other food product. Animals are regularly exposed to antibiotics, as half of the antibiotics used around the world are used in animals (73). Every time an animal is exposed to an antimicrobial agent, the animal's bacterial flora have the opportunity to develop resistance. Thus food animals harbor resistant pathogens and pass these pathogens to consumers; examples include Salmonella, Campylobacter, Enterococcus, and Escherichia coli strains (42,74).
A primary source of animal exposure to antibiotics occurs from animal feed: because of their growth promotion effects, antibiotics are routinely added to animal feed around the world (62,74,75). Millions of tons of antibiotic are used in animal feed yearly and these antibiotics provide a constant low level of antibiotic exposure and promote development of resistance (62). Animals are also exposed to antibiotics for treatment and prophylaxis of infection (74,76). Restrictions on veterinary antibiotic use are variable; in many areas, veterinary use is unregulated and antibiotics are sold by animal supply stores without requiring a prescription. Antibiotic use is not the only factor in the development and spread of resistance; specific animal husbandry practices are also important. When animals are crowded together or farming hygiene is poor, the opportunity for spread of resistant microorganisms is increased.
The key measures to control resistance and its transmission in foodborne pathogens are discontinuation of the use of antibiotics for additives for growth promotion and the removal of contaminating pathogens with means such as irradiation. In the United States, the use of antibiotics for growth promotion is still widespread, but in some countries, antibiotics that are used for human therapy are prohibited for use as growth promoters in animals (76,77). The United States Food and Drug Administration (FDA) has recently begun to actively encourage judicious use of antibiotics for veterinary therapeutic purposes and to undertake antimicrobial regulatory activities (44,44a). Adequate regulatory intervention will be critical to reduce not only the threat of resistance due to therapeutic drug use but also the threat caused by feed additives. Other strategies to control resistance in foodborne pathogens include educating animal farmers about antibiotic practices, vaccinating animals, and enhancing practices for animal hygiene (74,76). Increased surveillance to measure antimicrobial consumption by food animals and development of resistance may heighten awareness and provide the necessary data to enable the implementation of interventions (44,44a,74).
Measures such as pasteurization, irradiation, careful food preparation, and effective cooking can work to limit transmission of resistant bacteria between animals and humans (73,78,79). Encouraging general use of these measures to reduce transmission of foodborne pathogens is a central goal of both state level and nationwide public health campaigns; their consistent implementation can decrease the spread of all food-borne pathogens, both susceptible and resistant.
Factors in Development of Hospital-Acquired Pathogens
In the dense microcosm of the hospital, antibiotics are frequently used and bacteria may be readily passed from one patient to the next (46,80-82). Antibiotic resistance develops in response to the heavy use of antimicrobial agents in hospitals, and resistance to many drugs has been closely correlated with previous use of that drug. One particular concern is patients who have had exposure to vancomycin and thus are more apt to develop infections with vancomycin-resistant Enterococcus (VRE) (42). Once the selective pressure of antibiotic exposure causes susceptible hospital-acquired pathogens to become resistant, these pathogens cause secondary infections when spread further in the hospital. Spread occurs because patients in hospitals are in close proximity to each other, and there are many opportunities for the exchange of infecting organisms. Exchange can be by means of respiratory droplets, the hands of healthcare personnel and visitors, and equipment that has been insufficiently cleaned (83,84).
The key measures for control of resistance in hospital-acquired pathogens are reduction in antimicrobial use, formulary restrictions, and good hand-washing practices. Hospital-acquired resistance must be controlled both by preventing the development of resistance in individual patients with previously susceptible infections and also by controlling the spread of nosocomial pathogens that have already acquired antimicrobial resistance traits (46).
The judicious use of antibiotics in the hospital setting can slow the development of resistant pathogens. Formulary restrictions have been one way to successfully decrease inappropriate hospital use of antibiotics (7,46). Another way to facilitate treatment with the most appropriate and narrowest spectrum antimicrobial drug is by the use of rapid, sensitive, and specific diagnostic tests. In addition, clinicians should base empiric treatment of hospitalized patients with probable nosocomial infections on hospital surveillance antibiograms. Because hospitals will have complete information for nosocomial pathogens, the hospital antibiogram is particularly well suited for use in deciding empiric treatment for nosocomial infections. Control of the transmission of hospital-acquired resistant pathogens requires consistent use of infection control practices such as hand-washing, gowning, gloving, and use of isolation rooms (82,84).
Infection control guidelines such as those created jointly by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America address the problems of antibiotic choice, infection control practices, and surveillance systems in the hospital setting (46). In areas and countries where antibiotic availability and hospital resources are limited, changes in hospital practices will be more difficult to implement than in areas where resources are relatively abundant.
Hospital-based health care professionals should be educated about the appropriate uses of antibiotics, infection control practices, resistance testing, and surveillance data. However, educational interventions can be a challenging way to induce behavior change. Constraints on time and persistent acceptance of long-held beliefs are difficult obstacles for any educational program to overcome (85).
Factors in Development of Resistance in Community-Acquired Pathogens
Exposure to antibiotics also promotes antimicrobial resistance among pathogens acquired in the community. One example is drug-resistant Streptococcus pneumoniae (DRSP) (9). S. pneumoniae is a frequent cause of outpatient respiratory infections including otitis media, pneumonia, and sinusitis. The strongest risk for developing an infection with DRSP is the prior use of antibiotics, in particular during the 3 previous months (86,87). Other risk factors for DRSP infection relate either directly or indirectly to antibiotic exposure. These risk factors have included young age, white race, higher income, suburban residence, and day care attendance (86,88-91). Day care attendance has been an important risk factor, probably because the environment presents a combination of frequent antibiotic usage with crowding and close contact of a large number of small children who share respiratory and other secretions (92-95).
Control of Resistance in Community-Acquired Pathogens
The key measure for controlling antibiotic resistance in community-acquired pathogens is avoiding the use of antibiotics for probable viral conditions (43,96). However, other measures—education, vaccinations, surveillance, and the development of new antimicrobial agents—supplement judicious antibiotic use, and are actively being pursued by public health advocates, pharmaceutical companies, and researchers.
Although time-consuming and labor-intensive, education can result in decreased antibiotic use (5,8,97) and subsequently decreased community-acquired resistance (5,8). To decrease overprescribing, education of health care professionals should emphasize judicious antibiotic use and the issues of resistance in their community. Educating the public about the need for prudent use of antimicrobial agents will raise awareness of resistance issues and enable patients and their families to cooperate with their healthcare providers and seek care appropriately.
Vaccination can prevent disease caused by community-acquired pathogens and, in some cases, may play a role in decreasing resistant pathogens. The current conjugate 7-valent pneumococcal vaccine formulation covers more than 75% of resistant pneumo-cocci and reduces carriage. Routine use of this conjugate pneumococcal vaccine to prevent pediatric disease may prove to be a valuable tool in controlling pneumococcal resistance (41).
Surveillance has an important role in describing the resistance problem and suggesting new management possibilities (5,8,96). However, because of the variation in populations and the importance and difficulty of compiling surveillance data that is population-based and relevant to a particular locale, it may be inappropriate to use surveillance information to directly guide outpatient management (71). For community-acquired infections, appropriate culture and susceptibility information is not often available for the most common outpatient illnesses such as otitis media. For this reason, on a local level in an outpatient setting, the application of hospital-based antibiograms is uncertain. The difficulty of creating a truly representative surveillance system for resistance in community-acquired pathogens combined with the financial cost of surveillance on a scale large enough to represent common outpatient infections present an enormous challenge to the development of useful outpatient population-based surveillance.
Emerging resistance continues to drive the need for development of new antibiotics. Several new classes of antibiotics, including the oxazolidinones, streptogramins, fluo-roquinolones, and others, hold promise for treating resistant infections such as methi-cillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (98).
Fundamentally, however, to decrease resistance, the selective pressure of antibiotic use must decrease. In 1992, some 110 million prescriptions for oral antimicrobial drugs were written in the United States, three-quarters of which were for upper respiratory tract infections (99). Most of these prescriptions were for viral infections and therefore unnecessary (99-101). Because upper respiratory tract infections represent such a large amount of unnecessary antibiotic use and because antibiotic use in the recent past is associated with carriage of resistant pneumococci (87) and invasive disease (86,87), efforts to decrease antimicrobial resistance have focused on judicious use of antimicrobial agents for outpatient upper respiratory tract infections (43,87,102).
In some areas and countries, judicious antibiotic use may be hindered both by limitations of antimicrobial agent availability and also by the ability to buy antibiotics without a prescription. Although freely available over the counter in some parts of the world, antimicrobial agents are costly, and some evidence indicates that in most cases people will consult with a healthcare provider before purchasing them. In one study on the outskirts of Mexico City, 72% of antibiotic courses sold had been recommended by a physician despite the widespread availability of drugs without a prescription (103).
In 1998, the CDC with the American Academy of Pediatrics published the "Principles of Judicious Use of Antimicrobial Agents for Pediatric Upper Respiratory Tract Infections" to address the issues of treatment of upper respiratory infections in the era of antimicrobial resistance (43). These principles identify specific conditions for which antibiotics should be used and where they should be avoided; they may be helpful to practitioners by providing an up-to-date review of the literature and expert discussion of the issues. However, guidelines cannot substitute for critical thinking on the part of the practitioner, and physicians are the key contact for successful antibiotic control programs.
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