Special Report
Multiple-Antibiotic-Resistant Pathogenic Bacteria -- A Report on the Rockefeller University Workshop
N Engl J Med 1994; 330:1247-1251April 28, 1994
- Article
Last year, a small group of scientists, physicians, and public health experts gathered at Rockefeller University for a one-day workshop to discuss the accelerating spread of bacterial pathogens resistant to antimicrobial agents and whether multiresistant bacteria pose a threat to public health in the United States. This report is based on the conclusions of that workshop.
After a half-century of virtually complete control over microbial disease in the developed countries, the 1990s have brought a worldwide resurgence of bacterial and viral diseases1. An important factor in this phenomenon is the acquisition of antibiotic-resistance genes by virtually all major bacterial pathogens. Disturbances of ecosystems, the tremendous increase in the size of populations at high risk because of immunocompromise, the increased frequency of invasive medical interventions, and the prolonged survival of many patients with chronic debilitating disease have amplified the problem to one of global dimensions. Recently, bacterial strains resistant to all available antibacterial agents were identified among clinical isolates of some bacterial species. The dissemination of such multidrug-resistant bacteria has become more rapid during the past decade, thanks to the tremendously increased mobility of human populations.
The selection of resistant bacteria began on a global scale in the early 1940s, with the introduction of the first penicillins into clinical use. It increased over the next 50 years as a large number of antibiotics with distinct mechanisms of action were introduced. The strategy of pharmaceutical chemistry has been to widen the antibacterial spectrum of each new antibiotic agent, and thus the introduction of enormous quantities of these potent drugs into the environment during therapy2 and in animal feed3 has challenged the entire prokaryotic world on our planet4.
The Dimensions of the Problem
Nosocomial Pathogens
During the past decade gram-positive bacteria have gradually emerged as the most frequent causes of nosocomial disease. These pathogens are especially difficult to treat because of their high frequency of drug-resistance traits. Methicillin-resistant strains now make up 60 to 90 percent of all isolates of coagulase-negative staphylococci, the most frequent cause of infections related to intravascular catheters and prosthetic devices5,6. In large teaching hospitals, the proportion of methicillin-resistant Staphylococcus aureus among nosocomial staphylococcal isolates increased from 8 percent in 1986 to 40 percent in 19927. S. aureus is the most frequent cause of skin and wound infections and bacteremia, and the second most frequent cause of lower respiratory infections in nosocomial disease7. Strains of methicillin-resistant S. aureus, formerly confined to large teaching hospitals, had spread by the early 1990s into smaller hospital units (where the incidence of resistance is about 20 percent of isolates) and into nursing homes7. The majority of methicillin-resistant S. aureus isolates are also resistant to most other antibiotics, necessitating the use of the glycopeptide antibiotic vancomycin2.
In the United States enterococci have become the third most common organism causing hospital-acquired infections (after S. aureus and Escherichia coli) such as those of wounds and the urinary tract, septicemia, and endocarditis7,8. Vancomycin-resistant Enterococcus faecium (first reported from the United Kingdom and France in 1987) had been detected in several hospitals in the United States by 1989. By 1993, 14 percent of enterococcal isolates from patients in intensive care units were resistant to vancomycin (a 20-fold increase since 1987); 88 percent of the strains were also resistant to β-lactam antibiotics, aminoglycosides, fluoroquinolones, tetracycline, chloramphenicol, and teicoplanin. Of the 10,961 hospital-associated isolates of enterococci that were also tested for vancomycin susceptibility, close to 1900 were from primary bloodstream infections, and 323 of the patients (36.3 percent) died. Mortality among patients who have bloodstream infections with vancomycin-susceptible isolates was reported as 16.4 percent7.
Untreatable Pseudomonas aeruginosa or P. cepacia infections have become a tragically frequent occurrence in patients with cystic fibrosis. Acinetobacter, a common free-living microorganism and inhabitant of the human skin that is resistant to all available antibacterial agents except sulbactam, has caused fatal disease in patients in an intensive care unit9. Novel, plasmid-borne, extended-spectrum β-lactamases capable of inactivating antibiotics (such as ceftazidime or imipenem) specifically developed against β-lactamase-producing gram-negative bacteria have been detected in nosocomial isolates of klebsiella and in P. aeruginosa10.
Each year there are more than 40 million hospitalizations in the United States, and about 2 million patients acquire nosocomial infections, 50 to 60 percent of which involve antibiotic-resistant bacteria. In some intensive care units, patients have a 25 to 70 percent risk of acquiring a nosocomial infection, most often one caused by resistant microorganisms. The number of deaths related to nosocomial disease is estimated at 60,000 to 70,000 per year11,12.
Antibiotic-resistant pathogens contribute to the skyrocketing costs of inpatient care13. Some large U.S. hospitals spend 10 to 15 percent of their total pharmacy budget on a single drug, vancomycin, to treat infections caused by methicillin-resistant staphylococci and the still-susceptible strains of enterococci. Nosocomial disease adds an estimated minimum of $4.5 billion to the cost of health care in the United States each year14,15.
Community-Acquired Pathogens
Although resistance has been recognized as a substantial problem for a number of community-acquired pathogens, including Neisseria gonorrhoeae, salmonella, and shigella, even more ominous is the emergence of multiple-antibiotic resistance among such important community-acquired pathogens as Mycobacterium tuberculosis and Streptococcus pneumoniae. According to estimates by the World Health Organization, about one third of the world's population is infected with mycobacteria; each year disease develops in about 8 million people, and 3 million die of it. After a gradual decline, the incidence of tuberculosis has been rising since 1985 in the United States (an 18 percent increase by 1992, with a 41 percent increase among children). About 27,000 Americans are given a diagnosis of tuberculosis each year, and about 2000 die16.
Although infections due to the usual strains of tuberculosis have high rates of cure, multidrug-resistant strains have emerged in several countries, including the United States, with case fatality rates of 40 to 60 percent in patients with normal immunity and over 80 percent in immunocompromised patients. One particular strain (strain W) that is resistant to the most frequently used antituberculosis agents -- isoniazid, rifampin, streptomycin, and ethambutol -- and frequently also resistant to kanamycin and ethionamide, has recently been identified in 100 cases in New York City. Outbreaks of multidrug-resistant tuberculosis have been reported in 35 states16.
S. pneumoniae causes several serious and potentially life-threatening diseases. There are an estimated 6000 cases of pneumococcal meningitis, 500,000 cases of pneumonia, 55,000 cases of bacteremia, and about 6 million cases of otitis media annually in the United States, causing a total of 40,000 deaths,17 and there are 3 million to 5 million deaths per year globally. The patients at greatest risk for pneumococcal disease are young children and the elderly. Other high-risk groups are patients with splenic dysfunction and patients positive for the human immunodeficiency virus. The introduction of penicillin in the mid-1940s found pneumococci uniformly and highly susceptible to this drug, and penicillin therapy caused a substantial decline in mortality due to pneumococcal diseases worldwide, but penicillin-resistant pneumococci are now global pathogens18. In multidrug-resistant clones (those with resistance to erythromycin, tetracycline, chloramphenicol, penicillin, and trimethoprim-sulfamethoxazole), treatment of even relatively localized pneumococcal infection, such as otitis media, may require hospitalization because of the need to use parenteral vancomycin19. Resistance to third-generation cephalosporins has recently been detected in some pneumococcal isolates in the United States, Spain, and South Africa20,21.
Prospects for the Future
Spread of Resistance Genes and Resistant Clones
After the introduction of penicillin into clinical practice in the early 1940s, the first penicillin-resistant S. aureus isolates appeared within three to four years because of the acquisition by the pathogen of the β-lactamase-carrying plasmid. In contrast, the same event was recorded for E. faecalis only some 40 years later, in 1983. The first penicillin-resistant pneumococcus was detected in a remote village in Papua New Guinea in 1967, and clinical isolates of penicillin-resistant group A streptococci have still not been described, in spite of the extensive use of penicillin therapy and prophylaxis against this bacterium.
Although the time required for the acquisition of genetic determinants of resistance may vary widely, once this critical step is completed the progeny of resistant ancestral cells and their resistance genes tend to spread with great rapidity within the species. S. aureus strains carrying the β-lactamase gene had spread worldwide by the late 1950s; E. faecalis carrying β-lactamase had spread within the United States and had also appeared in South America and Europe by the early 1990s22. Penicillin-resistant pneumococci became global pathogens by the 1990s partly because of the geographic spread of multidrug-resistant clones -- as was demonstrated for the capsular type 23F clone in the United States and a type 6B clone in Iceland23,24.
Among contemporary pathogens, resistance to a specific drug is often part of a larger package of resistance factors located on plasmids or transposons. Therefore, changing the patterns of antibiotic use would not end the selective pressure unless all relevant drugs were withdrawn. With regard to some of the most important resistance mechanisms, there is little evidence to support genetic instability. More than 90 percent of all isolates of S. aureus now carry the β-lactamase gene, both in the United States and in Europe. The stability of multidrug-resistant pneumococcal strains during in vitro cultivation in nonselective mediums has been demonstrated over hundreds of generations25.
Resistance to Antibiotics and Virulence
Because of the disproportionately high incidence of multidrug-resistant bacteria in hospitals (particularly in medical and surgical intensive care units), the argument has been made that resistant pathogens are dangerous only to severely ill patients. It is argued that the genetic load of carrying resistance genes against a large number of antibiotics is incompatible with full virulence. But is this true? Methicillin-resistant and methicillin-susceptible strains of staphylococcus are equally capable of producing toxins,26 and the frequency and spectrum of staphylococcal diseases caused by susceptible and resistant strains appear to be the same27,28.
The spectacular recent spread of a single multidrug-resistant pneumococcal clone throughout Iceland within three years, causing more than 20 percent of all pneumococcal disease and a comparable proportion of cases of colonization, suggests the coexistence of resistance and virulence19,23. What little information we have about mortality rates is ominous. In South Africa mortality due to pneumococcal meningitis in children is reported to be significantly higher if the causative agent is carrying the penicillin-resistance trait than if the disease is caused by penicillin-susceptible isolates29.
Infection Control
The transmission of resistant pathogens can be effectively curtailed in a hospital by means of intensive infection-control measures, provided these efforts include the control of antibiotic use,30 the application of therapy to a well-defined patient population, and considerable support from the microbiology laboratory. Nevertheless, the problem remains that much in today's world works against the very principles of infection control. The high proportion of families with two working parents and single-parent families results in a large concentration of children in day-care centers, which serve as sites for the transmission and amplification of infectious agents. In Iceland over 80 percent of children are in day-care centers, and that is thought to be one of the chief epidemiologic factors facilitating the rapid spread of multidrug-resistant pneumococci there19.
The increased use of invasive procedures, the AIDS epidemic, the increase in the number of patients with other types of immunocompromise, and the crowding and often inadequate sanitary conditions of homeless shelters and urban ghettos all work to increase the likelihood of the acquisition and patient-to-patient spread of infectious agents. One must add to this list the increasingly global nature of the food supply and the increases in the mobility and mixing of human populations. Over 100 million people currently live outside the countries in which they were born31.
Development of New Antibacterial Agents
Participants at a recent workshop sponsored by the National Institutes of Health conducted an informal telephone survey about the development of new antibiotics among the heads of departments conducting research on antimicrobial agents in large U.S. and Japanese pharmaceutical companies. About half the companies had either reduced or phased out their antibacterial programs five or six years ago, partly because of an erroneous assumption that bacterial diseases were already successfully controlled32. There are relatively few new drugs ready for introduction today, and promising agents in the developmental stage will require several more years of testing for toxicology and clinical efficacy.
Another reason for concern is that new agents will undoubtedly be used selectively against pathogens that are already multidrug-resistant; this practice will virtually ensure that, eventually, resistance to the new drug will appear in the currently multiresistant bacteria. For example, 85 to 90 percent of all ciprofloxacin-resistant strains of staphylococci are also resistant to methicillin.
Threats to Public Health in the United States
Rather than ask whether multidrug-resistant bacteria are a threat to the public health, perhaps we should ask at what stage of epidemiologic investigation public health agencies should be able to take steps to avert a potential crisis. The participants in the workshop believe that the epidemiologic data briefly surveyed here strongly suggest that we have already reached such a stage. The acquisition of resistance to vancomycin either by methicillin-resistant S. aureus or by resistant pneumococci would create highly invasive bacterial clones that could not be controlled by any currently available chemotherapeutic agent. Transfer and expression of the glycopeptide-resistance genes to staphylococci have already been demonstrated in the laboratory,33 and their emergence in clinical strains may be only a matter of time. A similarly serious situation would be caused by the acquisition of a β-lactamase plasmid by group A streptococci.
Conclusions
The emergence and spread of resistant pathogens is an environmental problem analogous to other problems in the human environment that threaten health at the end of the 20th century. The frequent misuse of antibacterial agents in clinical practice, both in the Third World and in the developed nations, and the release of enormous quantities of antibiotic agents in agriculture, fisheries, and animal husbandry continue to provide conditions favorable to the selection of resistant bacteria. There is a need for both more prudent use of antibacterial agents and reevaluation of marketing policies, since the pharmaceutical industry will need to remain profit-making even if the use of antibiotics is better controlled and the development of agents with a more discriminate, narrower spectrum of activity is encouraged. Bringing these problems under control will require international agreements and strengthened alliances among the research, medical, and pharmaceutical communities35.
Source Information
Rockefeller University, New York, NY 10021-6399
The participants in the workshop that formed the basis for this article are listed in the Appendix.
Appendix
The participants in the workshop held at Rockefeller University were as follows: J. Acar, President, European Society of Clinical Microbiology and Infectious Diseases; G.H. Cassell, President, American Society for Microbiology; M.L. Cohen, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, Atlanta; R. Gaynes, Hospital Infections Program, National Center for Infectious Diseases, CDC; D.A. Goldmann, Hospital Infection Control Advisory Committee, Division of Infectious Diseases, Children's Hospital, Boston; S. Handwerger, Laboratory of Microbiology, Rockefeller University Clinical Center; J.J. Hughes, National Center for Infectious Diseases, CDC; W.G. Johanson, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark; J. Lederberg, Rockefeller University; G.L. Mandell, President, Infectious Diseases Society of America; E. McSweegan, Bacteriology and Mycology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.; R. Roberts, Department of Medicine, New York Hospital-Cornell Medical Center, New York; A. Sheldon, Division of Anti-Infective Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Md.; F. Tenover, Nosocomial Pathogens Laboratory Branch, CDC; A. Tomasz, Laboratory of Microbiology, Rockefeller University; and D. Weber, Rockefeller University.
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