(February 2006) Soon after Alexander Fleming discovered in 1928 the infection-fighting properties of penicillin, scientists proclaimed it a “miracle drug” and a revolutionary medical advancement. Penicillin—the earliest antibiotic—became widely available during World War II as the first successful treatment for infected wounds, the biggest wartime killer.1

Today, penicillin—used to treat a range of bacterial infections including meningitis, pneumonia, and gonorrhea—is virtually useless in many of these cases. The reason? Inappropriate or incomplete use of penicillin and other antibiotics has caused microbes to develop resistance to these drugs.

The problem is not confined to penicillin: The World Health Organization (WHO) estimates that 50 percent of all medicines are inappropriately prescribed, dispensed, or sold, and that 50 percent of all patients fail to take their medicine properly.2 As a result, antimicrobial resistance (AMR) has become a major public health problem worldwide. Penicillin-resistant gonorrhea strains now appear in 60 percent of those infected with that bacteria, and in 98 percent of all strains found in Southeast Asia.3 Tuberculosis, malaria, meningitis, and other major diseases have also developed at least partial resistance to drugs that once effectively treated them.

Surmounting the problem of AMR requires a multipronged approach that addresses the behaviors of consumers and providers as well as the environments in which drugs are prescribed, bought, sold, licensed, and regulated. A number of efforts are underway, but the microbes are smart and quick, and we are running out of time.

The Emergence of Drug-Resistant Microbes

AMR is a natural biological phenomenon exacerbated by the misuse of drugs. The use of an antimicrobial drug for any infection, in any dose, and over any period of time forces microbes to either adapt or die; those that adapt carry genes for drug resistance that are passed on.

But when antimicrobials are used inappropriately—for too short a time, at too low a dose, or at inadequate potency—or for the wrong disease, the likelihood that the microbes will develop resistance to those antimicrobials is enhanced.4 For instance, just a few years after penicillin became available, scientists began to notice the emergence of a penicillin-resistant strain of staphylococcus aureus, a common bacterium that is part of the normal human bacterial flora but that under certain circumstances can cause pneumonia or toxic shock syndrome. When WHO began monitoring AMR in the early 1980s, resistance to penicillin was consistently 5 percent.5 Now, in some regions, over one-half the cases of streptococcal pneumonia are resistant to penicillin.

The most deadly infectious diseases in the world today are also the ones for which AMR resistance has emerged. AMR has rendered care for and treatment of such serious illnesses as diarrheal diseases, respiratory tract infections, sexually transmitted infections, meningitis, pneumonia, and hospital-acquired infections more difficult and expensive than ever imagined.

Drug resistance is not limited to antibiotics. Chloroquine, once the drug of choice for malaria, is no longer effective in 81 of 92 countries where that disease is a problem.6 Multiple drug-resistant tuberculosis (MDR-TB) has appeared throughout the world (from Eastern Europe to sub-Saharan Africa to Asia) in those co-infected with HIV, among health care workers, and in the general population.7 Resistance has also begun to appear to some antiretrovirals.8

Root Causes of AMR

While AMR developed as a result of inappropriate antimicrobial use in more developed countries, it has now spread worldwide, exacerbated by weak regulatory environments for medicines in less developed countries. Human behavior at the individual and societal levels is the root cause of AMR:

  • Direct marketing by pharmaceutical companies influences consumer demand for certain drugs, and providers’ perceptions of patient expectations create pressure to prescribe even in the absence of appropriate indications of disease.
  • Consumer self-medication leads to inappropriate use when a consumer takes a drug unnecessarily, at an inadequate dose, or with inadequate amounts of the active ingredient. Or consumers may not take the prescribed dosage—stopping when their symptoms are better, but before the recommended course of a drug is complete.
  • The Internet has increased access to information as well as advertising about drugs—advertising that is difficult to regulate.
  • Hospital-acquired infections are an important cause of AMR worldwide. It is estimated that as many as 60 percent of hospital-acquired infections are caused by drug-resistant microbes. The most common types are surgical wound infections, respiratory infections, and urinary tract infections. These infections are caused by poor infection-control practices and procedures, unclean and nonsterile environmental surfaces, and/or ill employees.9

Environment is Different in Developing Countries

But the same individual behaviors in a developing country environment are especially worrisome. In developing countries, drug licensing and regulation may be more lax, and low-quality drugs (poorly formulated or manufactured, counterfeited, or expired) are more widely available without a prescription.


Penicillin Sensitivity in Neisseria gonorrhoeae in Six Countries, 2002

Source: The WHO Western Pacific Gonococcal Antimicrobial Surveillance Programme, Communicable Diseases Intelligence 26 (2002): 541-545.


The variation in quality of medicines—especially in low- and middle-income countries—further exacerbates AMR. While most countries have a regulatory authority for medicines and formal requirements for registering them, one-third of WHO member states have either no regulatory authority or only limited capacity to regulate the medicine market.

In recent assessments carried out by WHO, 50 percent to 90 percent of antimalarial drug samples failed quality-control tests, and more than one-half of antiretrovirals assessed did not meet international standards.10 Counterfeit drugs constitute a $32 billion industry worldwide and account for an estimated 25 percent of all antibiotics sold in developing countries.11

And in most developing countries, antimicrobials can be easily obtained in pharmacies or from street vendors without a prescription. Such wide availability of low-quality drugs in low-resource settings means that consumers can take drugs in a variety of inappropriate ways.

Health practices in developing countries also contribute to the spread of AMR. In some cultural settings, antimicrobials given by injection (which causes resistance to spread more rapidly) are considered more efficacious than oral formulations. Prescribing “just to be on the safe side” increases when there is diagnostic uncertainty, lack of prescriber knowledge regarding optimal diagnostic approaches, or lack of opportunity for follow-up—all common conditions in low-resource settings.

In addition, inadequate prescribing may be a problem of poor provider training or the high cost of drugs; many who are poor cannot afford the recommended treatment for their particular illness.12 Inadequate lab facilities contribute to AMR, too, because many labs in developing countries are not equipped to accurately detect drug resistant strains of a microbe.

These factors result in an AMR problem qualitatively different in developing countries. For example, penicillin-resistant gonorrhea is lower in high-income countries and increases in prevalence stepwise across middle- and low-income countries (see figure).

Consequences of AMR

The consequences of failure to contain resistant microbes are grave:

  • Those infected with a resistant strain may have a protracted illness with longer periods of infection, increasing exposure of others to the drug-resistant strain of the disease. For example, while drug-susceptible TB can be cured within six months, drug-resistant TB requires extensive chemotherapy for up to two years.13
  • The costs for prolonged care are increased, and patients are at greater risk of dying due to treatment failure. The mortality from resistant malaria, for example, rises to 15 percent to 20 percent from less than 1 percent when effective drugs are available for a nonresistant strain.14
  • When first-line drugs fail, second- and third-line drugs are often more expensive and more toxic. For example, medications to treat one person for MDR-TB can cost as much as 300 times more than traditional treatment (US$50 versus US$15,000).15 The costs can become so prohibitive that providers can in effect no longer treat some infectious diseases.

Unfortunately, there are few new drugs on the horizon. Only one new class of antibiotics has been developed since 1970.16 Moreover, the length of time it takes to get a new drug to the market is between 10-20 years and costs an average of US$500 million.17 But recent initiatives to increase funding for antimalarials (Medicines for Malaria Venture); anti-TB drugs (Global TB Drug Facility); and antiretrovirals (The Global Fund to Fight AIDS, Tuberculosis, and Malaria) will assist development of necessary drugs to addresses these infectious diseases and the resistant strains that have evolved.

Is Containment Possible?

Ironically, the key to containing AMR is improving access to drugs—the right ones. The global scale of the problem requires all countries to promote rational drug use and secure their drug supply. WHO has spearheaded these efforts, developing a Global Strategy for Containment of Antimicrobial Resistance and an Essential Medicines List.18

WHO’s Global Strategy urges national governments to strengthen health systems and AMR surveillance strategies, improve and enforce licensing and regulatory policies, increase access to appropriate antimicrobials, promote appropriate drug use, and encourage the development of new drugs and vaccines.

The Essential Medicines List is a blueprint of critical drugs required to treat specific complaints. Analysis shows that in countries with essential drug policies, individuals have greater access to the drugs they really need, yet resort to fewer injections and antimicrobial prescriptions when confronted with possible infections.19

Many agencies—private, nonprofit, and intergovernmental—are working toward improvements in drug access and rational drug use. For example, WHO recently requested an immediate halt to the provision of one form of the most effective malaria drug—single-drug artemisinin—because of rapidly rising resistance (the correct usage of the drug is in combination with other antimalarials).20 Averting the menace of AMR and its consequences requires decisionmakers at the highest levels to assign accountability and equity to the health care marketplace. Also required is wiser behavior on the part of individuals when an illness requires prescription medication.


Heidi Worley is a senior policy analyst with the Population Reference Bureau.


References

  1. Ricki Lewis, “The Rise of Antibiotic-Resistant Infections,” FDA Consumer Magazine 29, no. 7 (1995), accessed online at www.fda.gov, on Jan. 25, 2006.
  2.  World Health Organization (WHO), “Medicines Strategy: Countries at the Core 2004-2007,” accessed online at www.who.int, on Jan. 12, 2006.
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  4. WHO, “Antimicrobial Resistance,” accessed online at www.who.int, on Jan. 11, 2006.
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  9. WHO, “Prevention of Hospital-Acquired Infections: A Practical Guide,” accessed online at www.who.int, on Jan. 12, 2006.
  10. WHO, “Medicines Strategy.”
  11. WHO, “Substandard and Counterfeit Medicines,” accessed online at www.who.int, on Jan. 13, 2006.
  12. WHO, “Overcoming Microbial Resistance.”
  13. WHO, “Drug- and Multi-drug Resisistant TB.”
  14. Nicholas J. White, “Antimalarial Drug Resistance,” Journal of Clinical Investigation 113, no. 8 (2004): 1084-92.
  15. WHO, “Progress in DOTS Plus and Management of MDR-TB” ( Geneva : WHO, 2001), accessed online at www.who.int, on Jan. 12, 2006.
  16. Dominique Monnet, “Antibiotic Development and the Changing Role of the Pharmaceutical Industry,” accessed online at www.dhf.uu.se, on Jan. 18, 2006.
  17. Patrick G.P. Charles and M. Lindsay Grayson, “The Dearth of New Antibiotic Development: Why We Should Be Worried and What We Can Do About It,” Medical Journal of Australia 181, No. 10 (2004): 549-53.
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  19. WHO, “Overcoming Microbial Resistance.”
  20. WHO, “WHO Calls for an Immediate Halt to the Provision of Single-Drug Artemisinin Malaria Pills,” accessed online at www.who.int.