[Table of Contents]

Volume: 23S7 - November 1997

CONTROLLING ANTIMICROBIAL RESISTANCE
An Integrated Action Plan for Canadians

BACKGROUND

The problem of antimicrobial resistance is not new, yet in only the last 5 to 10 years has it become clear that resistance is increasing rapidly, that it is worldwide, and that it poses a very serious threat to the treatment of infectious diseases.

Strains of methicillin-resistant Staphylococcus aureus (MRSA), a bacterium associated with pneumonia, bronchitis, abscesses, osteomyelitis, furuncles, and skin and wound infections, have been responsible for many outbreaks of infection in hospitals over the last 2 decades. In the early 1980s the prevalence of these organisms was <3%, but 10 years later it had risen to as high as 40% in many hospitals in the United States and Europe^(1,2). More than 90% of strains of S. aureus in the United States are believed to be resistant to penicillin and other ß-lactam antibiotics. Very recently, a strain of methicillin-resistant S. aureus was isolated in Japan that has intermediate susceptibility (minimum inhibitory concentration [MIC] of >= 8µg/mL) to vancomycin - the last effective anti-microbial, in many cases, to combat this pathogen⁽³⁾.

In Canada, the first MRSA strain was reported in Ontario in 1981⁽⁴⁾, and outbreaks have been reported since, in hospitals and long-term care facilities throughout Canada^(5-7). The first national MRSA surveillance study⁽⁸⁾, conducted as part of the Canadian Nosocomial Infection Surveillance Program (CNISP, a collaborative effort between LCDC, Health Canada, and the Canadian Hospital Epidemiology Committee, a subcommittee of the Canadian Infectious Disease Society), found that the number of cases of MRSA reported by 20 participating hospitals (mainly tertiary care) increased from 209 (1.2% of S. aureus isolates) during 1995 to 231 (2.3% of isolates) during the first half of 1996.  In 1995, only 39% of the cases were from Ontario and Quebec, whereas in the first 6 months of 1996, 70% were from these two provinces. Much of the increase was believed to be due to one particular strain, currently identified in Ontario, which has several features that may facilitate its spread throughout health care facilities.Thus, although overall isolation rates of MRSA are substantially lower than those in the United States, they are increasing.

MRSA is a problem not only in hospitals: in a recent US hospital-based study⁽⁹⁾, 170 patients were found to have MRSA infection or colonization over a period of 21 months; 99 (58%) of the patients investigated had community-acquired MRSA, which was associated with one or more factors - hospitalization within the previous year, prior antibiotic therapy, nursing home residence and intravenous drug use. However, in 22% of patients none of these risk factors was present.

Until 1989, vancomycin resistance in enterococci, another cause of hospital-acquired infection, had not been reported in US hospitals; by 1994, nearly 14% of hospital-acquired enterococci reported by intensive care units to the Centers for Disease Control and Prevention (CDC), in Atlanta, were vancomycin resistant⁽¹⁰⁾. The concern is that vancomycin-resistant enterococci (VRE) are no longer confined to intensive care units but may be found in other inpatient areas of the acute care hospital, and even beyond the hospital. In Ontario there had been no strains reported before 1993. In a passive surveillance system established within the CNISP for the reporting of VRE occurrences and outbreaks in Canada⁽¹¹⁾ 408 cases of VRE were identified over a period of 3 years. Of these, 89% were colonized, 8% infected and for 3% the information was not reported. Index cases were found within the following services: medical (42%), intensive care unit (17%), surgical (14%), chronic care (13%), oncology and bone marrow transplantation (5%) and others (9%). The source was identified in 44% of cases. In 55% of these the likely mode of transmission was patient to patient, in 35% a contaminated environment, and in 10% a patient carrier. It is feared that the mechanism of vancomycin resistance in enterococci may transfer to other pathogens, notably S. aureus.

Pneumococcal bacteria are responsible for infectious diseases such as meningitis, pneumonia, bacteremia, sinusitis and otitis media, which is one of the commonest conditions among children that lead to an antibiotic prescription. Penicillin had been an effective treatment since its introduction in the 1940s. Resistance to penicillin in isolates of Streptococcus pneumoniae was noted in New Guinea in 1967, but it was felt that the threat was minimal since the resistant microorganisms were unlikely to spread. By the 1970s, however, penicillin-resistant pneumococcal infections had become common in South Africa, and from there they spread to Europe and then to North America. Increasingly, pneumococcal organisms are showing "MIC shift," that is, their level of resistance, as measured by the minimum concentration of antimicrobial agent in which they can survive and grow (in the laboratory), is moving steadily upward.

Several recent Canadian surveys of pneumococcal isolates from normally sterile and non-sterile body fluids have found that between 7.3% and 11.7% of isolates had reduced susceptibility to penicillin^(12-15). Reduced susceptibility to penicillin was found in 7.8% of strains evaluated between 1992 and 1995 at the Canadian National Reference Centre for Streptococcus; there was a significant increasing trend in the proportion of isolates with full resistance (2 µg/mL of penicillin) but not in the overall change in reduced susceptibility. During the 1996 study in the Sentinel Health Surveillance System, reduced susceptibility was identified in 7.4% of strains. Finally, in cross-Canada studies carried out within the Canadian Bacterial Surveillance Network, 2% to 3% of S.  pneumoniae showed intermediate resistance to penicillin during 1988, whereas in 1996 up to 5% of isolates were found to have high levels of resistance and up to 9% had intermediate levels⁽¹⁶⁾.

Antimicrobial resistance is also becoming a problem in the treatment of fungal infections. The widespread use of the antifungal agent fluconazole has been accompanied by a dramatic increase in fluconazole resistance among Candida species. Treatment of tuberculosis is complicated by the resistance of Mycobacterium tuberculosis to many first-line drugs, and drug-resistant strains of Plasmodium falciparum present serious problems in most areas of the world where malaria is endemic.

The use of antibiotics is widespread in the food production industry, particularly in subtherapeutic doses given to animals for disease prevention and growth promotion. The proportion used to control bacterial diseases in plants and fish is much smaller, however. As in humans, the number of therapeutic options for treating disease in animals is diminishing. Antimicrobial-resistant pathogens in animals are a concern with respect not only to animals but also to human health: food containing drug-resistant organisms may be consumed by humans, who then become infected (e.g., Salmonella is usually present on raw poultry); or the drug-resistant organisms may not cause disease but, rather, share their resistant traits with the bacteria already present in the human intestine. Overall, however, the contribution to antimicrobial resistance in humans from the food and agriculture industry's use of antibiotic drugs has been extremely difficult to gauge.

The most disturbing consequences of antimicrobial resistance in humans, from whatever source, are the threats to the well-being of individuals infected with resistant pathogens. Such infections are likely to be more difficult to treat and may carry an increased risk of death. Prolonged illnesses may lead to loss of income, delays in recovery or rehabilitation, isolation, and the extra costs of expensive drugs. The immediate and future impact of antimicrobial resistance on the continum of health care within a community has yet to be described. Costs to the health care system will increase as hospital stays become longer, drug costs increase, special isolation procedures are put in place with their attendant costs, and laboratory services are required more frequently.

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