Within a few years, penicillinase-producing staphylococci began to emerge. The resistant strains first appeared in hospitals but spread rapidly to the community and eventually became widespread throughout the world. The great pandemic of influenza in 1957 and 1958 was associated with a simultaneous outbreak of penicillin-resistant Staphylococcus aureus phage type 80/81 [3]. Methicillin and vancomycin were not available at the time, and penicillin was ineffective even when given in large doses. I recall vividly my overwhelming sense of helplessness as a previously healthy house officer at the Boston City Hospital and a pregnant woman died of staphylococcal pneumonia accompanied by influenza. We are now faced with a worldwide epidemic of methicillin-resistant Staphylococcus aureus against which only a thin line of defense exists [4]. The prospect of therapeutic impotence looms once again if vancomycin-resistant strains emerge and become widespread.

Streptomycin, the second great antibiotic, was discovered in 1944 [5]. The initial enthusiasm for this drug was so great and medical opinion so dominated by therapeutic empiricism that streptomycin and penicillin were often administered together in a single injection. Unfortunately, streptomycin-resistant bacteria emerged rapidly, even during therapy [6]. The combination product was eventually removed from the market because the potential for vestibular damage from streptomycin was not outweighed by the therapeutic benefit of the combination [7]. Streptomycin soon became almost obsolete and is used today only to treat tuberculosis and some esoteric infections.

The pattern of discovery, exuberant use, and predictable obsolescence has been repeated after the introduction of each new antimicrobial drug. No collective memory appears to exist regarding events of the recent past. The prophetic repeated warnings by so-called Cassandras such as Maxwell Finland [8] were given lip service and soon forgotten. The opportunity to prolong the effective life of each new antimicrobial drug by more appropriate use was squandered by excessive use.

Until recently, a new drug or drug combination has always appeared just in the nick of time. New cephalosporins and ß-lactamase inhibitors were available shortly after ampicillin-resistant gonococci emerged from Thailand and the Philippines and spread rapidly around the world [9]. The plasmid bearing the TEM ß-lactamase gene appears to have originated in Escherichia coli, to have spread across taxonomic boundaries to gonococci and Haemophilus influenzae, and to have been selected by the pressure from excessive use of ampicillin [10].

We have now reached an unacceptable situation. Some hospital strains of invasive gram-negative enteric bacteria and enterococci are not susceptible to any available drug. Multiply resistant tubercle bacilli have appeared and spread rapidly in patients with the acquired immunodeficiency syndrome (AIDS) [11]. Drug-resistant Shigella and Salmonella species are widespread in Asia and in Central and South America [12, 13]. Outbreaks of ß-hemolytic streptococci resistant to the macrolides have been reported in Finland [14]. The holiest of grails has been breached by the multifocal appearance of pneumococci resistant to penicillin in South Africa, Spain, Hungary, and the United States [15].

Resistance to Antimicrobial Drugs Is a Global Problem

The issue of resistance to antimicrobial drugs was discussed in Annals 10 years ago [16] as a follow-up to the report by the World Health Organization Scientific Working Group on Antimicrobial Resistance [17]. The same issues were considered in 1985 by the International Task Force on Antibiotic Use organized by the Fogarty International Center of the National Institutes of Health [18, 19]. They have been brought forcefully to our attention once again in an excellent and comprehensive series of papers in Science [20, 21]. The situation has now reached a crisis stage worldwide and is predicted to worsen with the introduction of the new quinolones, macrolides, and oral cephalosporins.

Antimicrobial Use in Developing Countries

Three quarters of the world's population live in Africa, the Middle East, Latin America, and Asia. They purchase only about 20% of the worldwide supply [22] yet are burdened by the highest rates of resistance to the older antimicrobial drugs [23]. This problem is particularly troubling in young children, who are the most frequent victims of lethal respiratory and gastrointestinal infectious diseases [24, 25]. It is doubtful that persons in these countries will be able to afford the new drugs that could temporarily overcome the problem of resistance. Yet, the mobility of the world population increases the potential for spread of plasmid-mediated, multiply resistant bacteria throughout the world. Even travelers not taking prophylactic antibiotics are at an increased risk for enteric colonization with indigenous, resistant bacteria [26].

Why do countries that can afford so little have so great a problem with resistance to antimicrobial drugs? The situation appears to be due to a combination of a heavy burden of bacterial infectious diseases; huge populations without even the rudiments of primary health care; inappropriate use of the available antimicrobial drugs; and rapid spread through crowding, poor sanitation, and sexual contact. Self-prescribing is common in most developing countries, and the effect is compounded by a bewildering array of proprietary drugs containing irrational mixtures of vitamins, stimulants, and steroids and by the availability of drugs without prescription for purchase in local pharmacies or open-air markets [27-43]. Physicians, when available, need to see as many patients as possible in the shortest period of time with minimal, if any, laboratory or radiologic support. They often feel compelled to prescribe antimicrobial drugs to meet patient expectations. The pharmacies work on small mark-ups. The amount of an antimicrobial purchased is often inadequate to treat serious infections [42]. Tetracyclines continue to be prescribed for children, and ineffective and potentially toxic agents are purchased for the treatment of diarrhea [31].

In some countries, the political systems are so corrupt, the local business community so venal, and the physicians so disillusioned that the situation seems hopeless. For example, in Panama there are 3800 drug products, of which 50% are vitamins, tonics, and fixed-ratio combination products [44]; Brazil has 117 different brand names for ampicillin or amoxicillin [45]; and Indonesia markets 13 500 drug formulations [46]. The Philippine government has attempted to rationalize drug use by passage of the Generics Act of 1988. More than 70% of physicians surveyed opposed the act because they believed that the Bureau of Food and Drugs was not capable of ensuring the quality of the generic drugs [47].

This setting, in which much of the world's population obtains its medical care, is well documented by Silverman, Lydecker, and Lee in Bad Medicine, The Prescription Drug Industry in the Third World [48]. They have followed these events for many years and have some good news in an otherwise bad scene. They reported that "in their promotion of drug products in developing countries, the major offenders were originally the big multinational companies based in the United States, Europe, and, more recently, Japan. By the end of the 1980s, however, the situation has changed remarkably. More and more, it was the multinationals which had discovered that they could tell the truth and still make money. Instead it was the local or domestic firms—many with enormous political power, that were lying to, defrauding and endangering the lives of their fellow citizens".

Much of the credit for this change in attitude on the part of many of the multinational firms is due to strong pressure from consumer groups such as Health Action International, the International Organization of Consumer Unions, the Medical Lobby for Appropriate Prescribing, and OXFAM [49, 50].

The Multinational Pharmaceutical Industry Responds to the Challenge

The research-based pharmaceutical industry is composed of powerful, highly competitive firms that produce virtually all of the useful drugs and vaccines. They invest huge sums for research and clinical trials. It would be impossible for them to raise the capital for these ventures without the potential for profit. The industry takes considerable pride in its achievements and justifiably fears the loss of patent and marketing rights. It is no easy task to market drugs in countries where they must compete with local firms that do no research and have unique access to powerful officials.

The industry has responded to the issues raised by consumer advocates through the International Federation of Pharmaceutical Manufacturer's Associations, which has offices in Geneva, Switzerland, and maintains close ties with the World Health Organization (WHO) and related agencies [51]. Its Code of Pharmaceutical Marketing Practices was adopted by the 51 members in 1981. (A copy can be obtained by writing to 67 rue de St. Jean, P.O. Box 392, 1211 Geneva 11, Switzerland.) The main sanction is adverse publicity. The code is a good first step but can be enforced only through a complaints procedure.

Role of the World Health Organization

The WHO has been active in promoting the rational use of drugs in developing countries and in monitoring the problems associated with the emergence of resistant microorganisms [52]. It has developed a useful list of essential drugs and provides educational materials for the development of national drug policies [53]. Working with United Nations International Children's Emergency Fund (UNICEF), it has initiated a scheme for distribution of kits containing essential drugs and supplies for use in local dispensaries in several countries in sub-Saharan Africa. This program has been criticized, however, because of fairly rigid control by the donors (mostly Scandinavian countries) and the UNICEF supply operation. It has not been possible to assess the quantity of drugs lost through pilferage, the degree of responsibility with which the drugs are used, and the appropriateness of the kits in light of local conditions [54].

The work of the WHO in this field is summarized in Drugs Policy in Developing Countries [55], the product of a group of scholars at the London School of Hygiene and Royal Tropical Institute in Amsterdam. They were commissioned by the donors to the WHO program to conduct a thorough investigation of the problems of drug use in developing countries and of the WHO's efforts in meeting these problems. They conclude their study with the following statement: "In the light of the world economic recession, the exploding world population and the AIDS epidemic, WHO could play a crucial role by helping to redesign the frameworks of primary care practices, essential drugs and family planning. However, the emphasis at present seems to be on technical support, not policy or advocacy".

Efforts of Other Organizations

Several organizations have made important contributions to the problems of drug treatment and distribution in developing countries. The Alliance for Prudent Use of Antibiotics [56] was formed to raise concern about antibiotic resistance. The International Network for Rational Use of Drugs is a cooperative organization of health professionals and researchers in developing countries whose aim is to promote improved quality of care through more clinically effective and economically efficient use of pharmaceuticals [57]. The International Clinical Epidemiology Network, which was created by the Rockefeller Foundation, has developed a program in pharmacoepidemiology in developing countries [58]. Another active group is the Department of International Health Care Research at the Karolinska Institute in Sweden [59], which emphasizes the societal aspects of drug-seeking behavior. The various programs are described in the report of a symposium on Pharmacoepidemiology in Developing Countries, held in April 1990 [58]. The efforts of these groups are limited to demonstration projects, training, and advocacy. The sum of their annual budgets is far less than the amount spent for drugs in one medium-sized community hospital in the United States.

Prospects for the Future

It is expected that the situation in developing countries will worsen unless governments become more stable, major advances occur in standards of living, and preventive as well as adequate medical care are provided. Improvements in the availability and appropriate use of therapeutic drugs in developing countries must continue to be supported by the WHO acting as the world's advocate, by financial support from the more wealthy countries, and by expertise offered by private and public foundations and the business community. Ultimately, the initiative for more rational drug and medical care policies will depend, however, on the resolve of the developing countries to help themselves. Change will occur only when they strengthen their national drug policies, restrict licensing to safe and effective drug products, and enforce regulations aimed at more rational use of the available drugs by physicians and consumers.

Need for Partnership between Advocates and Industry

It is time for a truce between advocacy groups and the multinational pharmaceutical industry. The issue of resistance to antimicrobial drugs requires a joint effort to make drugs more readily available, to improve usage, and to develop new products. Each side perceives itself as having a unique mission, yet these groups share many common goals. It should be to the advantage of the multinational firms to support national policies that require better quality control, proof of safety and efficacy, and assurance of patent protection. Such requirements would enable them to compete more effectively in the generic market and with local repackagers and to market their products in more structured and stable environments. The advocacy groups need to recognize that the multinational firms are the source of all new drugs and vaccines and need to profit from their investments.

The recent agreement by the pharmaceutical industry to pay fees to the FDA for additional staff to expedite the review process for new drug applications may provide a model for this effort. In return for the help from governments to provide stable markets for their products, the industry may find it useful to support independent national foundations whose role it is to educate physicians and the public about the appropriate use of drugs, to improve the availability and distribution of effective drugs, to monitor the emergence of resistant strains, and to foster the careers of young investigators in therapeutics. This proposal may appear too ambitious, but the crisis of resistance to antimicrobial drugs is a supreme threat that must be addressed.

Final Statement

I began this perspective by recalling the beginnings of the modern antimicrobial era only 50 years ago. We are in great danger of losing many of these hard-won gains through our own shortsighted practices. To preserve some of these gains, we need more imaginative, collective action by governments, the pharmaceutical industry, health care providers, and consumers. No one group or country can accomplish this goal alone. Resistant microorganisms do not recognize geographic boundaries. Inappropriate or excessive use of antimicrobial drugs by any person or practitioner can affect the entire ecologic system and cannot be condoned. We must begin to focus our attention on societal issues that determine how these drugs are used and rededicate ourselves to more selective and rational use of antimicrobial drugs in our practices and hospitals. The Infectious Diseases Society of America has begun the process by developing guidelines to improve the use of antimicrobial drugs in hospitals [60] and by entering into a cooperative venture with the FDA and the pharmaceutical industry to establish new guidelines for clinical trials of new anti-infective drugs [61]. As physicians, we need to be selective in the use of antimicrobial drugs; we must never use them for trivial indications and should counsel our colleagues to do the same.