A copy of the full analysis can be downloaded by clicking on the link at the bottom of this blog entry.

Infectious diseases are the second leading cause of death worldwide. Since their discovery in the 1940s, antibiotics have been the primary treatment for infectious diseases. However, over time, many diseases have become resistant to the antibiotics that have been used to treat them, causing tens of billions of dollars in added treatment costs and millions of deaths globally.

This analysis analyzes the factors (game) involved in (i) the supply and use of antibiotics to treat disease, and (ii) the eventual resistance of many of these diseases to the use of antibiotics.

Brief Description of the Game

Antibiotics have often been referred to as “wonder drugs” for the fact that their use has saved so many lives. From Infectious Diseases Society of America (IDSA), “Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates ... A Public Health Crisis Brews”:

Antibiotics have saved millions of lives and eased the suffering of patients of all ages for more than 60 years. These “wonder drugs” deserve much of the credit for the dramatic increase in life expectancy in the United States and around the world in the 20th century. They prevent amputations and blindness, advance our ability to perform surgery, enable new cancer treatments to be used, and protect the lives of our military men and women. A famous infectious disease expert once noted that the discovery of penicillin in the early 1940s gave more curative power to a lone provider than the collective talent of all the physicians in New York City at that time. Unfortunately, it is inevitable that, over time, bacteria develop resistance to existing antibiotics, making infections more difficult to treat.

Despite the effectiveness of antibiotics in curing infectious diseases, these diseases continue to take many lives. As Brad Spellberg et al, “The Epidemic of Antibiotic-Resistant Infections: A Call to Action for the Medical Community from the Infectious Diseases Society of America” describe it:

Indeed, we are further away than ever from “closing the book on infectious diseases,” which, despite the availability of antibiotics, remain the second-leading cause of death worldwide and the third-leading cause of death in the United States.

The main reason for the continued loss of life to infectious diseases is their increasing resistance to the use of antibiotic treatments. From the World Health Organization (WHO), “Antimicrobial Resistance: Fact Sheet,”

Antimicrobial resistance is present in all parts of the world. New resistance mechanisms emerge and spread globally.

And from Spellberg et al:

The global spread of microbial resistance is a predominant reason why infectious diseases have not been conquered.

Microbial resistance to antibiotics is a natural phenomenon. However the rate at which microbes have become and continue to become resistant to antibiotics has been greatly intensified as a result of the increasingly abundant use of antibiotics globally in the raising of plants, animals, and fish, and in the treatment of diseases in people. From Henry J. Kaiser Family Foundation, “Global Drug Distribution Programs One Factor in Hastening Drug Resistance, Report Says”:

Drug resistance is a natural occurrence, but careless practices in drug supply and use are hastening it unnecessarily.

The WHO adds that microbial resistance to antibiotics leads to greater costs of treatment and continued loss of life.

Infections caused by resistant microorganisms often fail to respond to the standard treatment, resulting in prolonged illness, higher health care expenditures, and a greater risk of death.

Spelberg et al note the tremendous costs associated with microbial resistance to antibiotics. They indicate that the solution to the problem is the perpetual development of new antibiotics to treat resistant strains. Unfortunately, such development of new antibiotics has not been forthcoming.

… [T]he dramatic costs posed to society by antimicrobial resistance [is] estimated to be in the tens of billions of dollars annually.

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The only viable, long-term solution to the problem of microbial resistance is to have in place in perpetuity a continuing, steady development of new antibiotics and other strategies … to respond to new drug-resistant threats.

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At the very moment when increasing antimicrobial resistance has created a critical need to strengthen society’s response, especially through the development of new antibiotics with novel mechanisms of action, pharmaceutical companies have been abandoning the development of anti-infectives.

Before moving on to a discussion of the pathways of microbial resistance to antibiotics, let me first provide some useful definitions.

First, from Wikipedia:

Antibiotics or antibacterials are a type of antimicrobial used in the treatment and prevention of bacterial infection. They may either kill or inhibit the growth of bacteria. Several antibiotics are also effective against fungi and protozoans, and some are toxic to humans and animals, even when given in therapeutic dosage. Antibiotics are not effective against viruses such as the common cold or influenza, and may be harmful when taken inappropriately.

And then from http://dictionary.reference.com/:

microbe: a microorganism, especially a pathogenic bacterium.

pathogen: any disease-producing agent, especially a virus, bacterium, or other microorganism.

bacteria: ubiquitous one-celled organisms, spherical, spiral, or rod-shaped and appearing singly or in chains, comprising the Schizomycota, a phylum of the kingdom Monera (in some classification systems the plant class Schizomycetes), various species of which are involved in fermentation, putrefaction, infectious diseases, or nitrogen fixation.

disease: a disordered or incorrectly functioning organ, part, structure, or system of the body resulting from the effect of genetic or developmental errors, infection, poisons, nutritional deficiency or imbalance, toxicity, or unfavorable environmental factors; illness; sickness; ailment.

infectious disease: a disease resulting from the presence and activity of a pathogenic microbial agent.

Pathways of Microbial Resistance to Antibiotics

This section describes the various pathways through which microbes have developed and continue to develop resistance to antibiotics. Once we define and describe the pathways, we can establish who the players are who are involved in the Microbial Resistance Game. The number arrows in Figure 1 illustrate the pathways.

Figure 1

Through Plant Farming

1: Herbicide (and Pesticide) Manufacturers supply herbicides (and pesticides) to Plant Farmers.

8: Plant Farmers buy herbicides (and pesticides) from Herbicide (and Pesticide) Manufacturers and use them on their lands and plants to kill weeds. When Plant Farmers cover their lands and crops with herbicides, bacteria in the (farming) environment become exposed to those herbicides.

This environmental exposure eventually causes the bacteria to become resistant to antibiotics. Sustainable Pulse describes how this happens in “New Study Shows Roundup Herbicide Causes Antibiotic Resistance in Bacteria:”

“We found that exposure to some very common herbicides can cause bacteria to change their response to antibiotics. They often become antibiotic resistant, but we also saw increased susceptibility or no effect. In most cases, we saw increased resistance even to important clinical antibiotics,” Professor Heinemann says.

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The effects found are relevant wherever people or animals are exposed to herbicides at the range of concentrations achieved where they are applied. This may include, for example, farm animals and pollinators in rural areas and potential children and pets in urban areas. The effects were detectable only at herbicide concentrations that were above currently allowed residue levels on food.

Through Animal Farming

2, 5: Brand Name Antibiotics Developers and Manufacturers are pharmaceutical companies that develop and sell antibiotics. Generic Antibiotics Manufacturers are pharmaceutical companies that develop generic versions of antibiotics that have been developed and sold by Brand Name Antibiotics Developers and Manufacturers. These two sets of Antibiotics Manufacturers sell antibiotics to Animal Farmers.

9, 10: Animal Farmers buy brand name and generic antibiotics from Antibiotics Manufacturers and use them on their animals, putting them in the food to promote growth, and injecting them into sick animals to treat disease.

In “Science of Resistance: Antibiotics in Agriculture,” the Alliance for the Prudent Use of Antibiotics lists several pathways of microbial resistance to antibiotics associated with the use of antibiotics in plant farming:

Several lines of evidence may link antimicrobial use in food animal production to resistant infections in humans. These include: (i) direct studies tracing resistant infections in humans to specific meat and poultry operations; (ii) temporal evidence (i.e. the emergence of resistance in animal-associated bacteria prior to its emergence in human pathogens); (iii) circumstantial evidence linking human disease to trends in resistance among common bacterial pathogens such as Salmonella, Campylobacter and E. coli; (iv) studies suggesting that farmers and family members may be more likely than the general public to harbor antimicrobial-resistant intestinal bacteria; and (v) studies of the transfer of resistance in commensal bacteria.

Through Fish Farming

3, 6: Antibiotics Manufacturers sell antibiotics to Fish Farmers.

11, 12: Fish Farmers buy brand name and generic antibiotics from Antibiotics Manufacturers and use them “to forestall bacterial infections resulting from sanitary shortcomings in fish rearing.”

From FC Cabello, “Heavy use of prophylactic antibiotics in aquaculture: a growing problem for human and animal health and for the environment”:

The accelerated growth of finfish aquaculture has resulted in a series of developments detrimental to the environment and human health. The latter is illustrated by the widespread and unrestricted use of prophylactic antibiotics in this industry, especially in developing countries, to forestall bacterial infections resulting from sanitary shortcomings in fish rearing. The use of a wide variety of antibiotics in large amounts, including non-biodegradable antibiotics useful in human medicine, ensures that they remain in the aquatic environment, exerting their selective pressure for long periods of time. This process has resulted in the emergence of antibiotic-resistant bacteria in aquaculture environments, in the increase of antibiotic resistance in fish pathogens, in the transfer of these resistance determinants to bacteria of land animals and to human pathogens, and in alterations of the bacterial flora both in sediments and in the water column. The use of large amounts of antibiotics that have to be mixed with fish food also creates problems for industrial health and increases the opportunities for the presence of residual antibiotics in fish meat and fish products.

Through Prescription and Use by Healthcare Providers

4, 7: Antibiotics Manufacturers sell antibiotics to Healthcare Providers.

Antibiotics Manufacturers speed the rate at which microbes become resistant to bacteria by proving antibiotics in the form of monotherapies, as opposed to combination therapies. Rachel Nugent, Emma Back, and Alexandra Beith, describe this in further detail in “The Race Against Drug Resistance:”

The way drugs are formulated has a huge effect on the ability of microbes to develop resistance. We now know to avoid the use of monotherapies for diseases like TB, malaria, and HIV, and perhaps others, and instead to combine drugs that act on microbes simultaneously in different ways. Sadly though, monotherapies are still found on the market and, as noted previously, the use of artemisinin monotherapy appears to be helping the malaria parasite develop tolerance to artemisinin in Southeast Asia. Fixed-dose combination therapies—where different drugs are combined in a single pill—are the most reliable, provided the half-lives of the drugs can be aligned, as a patient is guaranteed to get an efficacious dose of all drugs. In addition, the patient is not tempted to take just one pill or to share pills with others, as can more easily happen if drugs are simply packaged together (for example, in blister packs). However, fixed-dose combination drugs are more challenging to develop and therefore more costly.

Antibiotic resistance is also hastened when patients take antibiotics that contain too little of the active ingredient, for example by taking low-quality or counterfeit drugs. Again, from Nugent, Back, and Beith:

When people take too little, incorrectly prescribed, counterfeit, or poor-quality medicine, the possibility of resistance increases.

13: Healthcare Providers buy and/or prescribe brand name and generic antibiotics from Antibiotics Manufacturers for use in People to treat disease.

Healthcare Providers speed the rate at which microbes develop a resistance to antibiotics by prescribing the use of antibiotics for patients who do not have bacterial infections. Most notable is the prescription of antibiotics to treat viral infections, such as the flu. Nugent, Back, and Beith describe various circumstances under which Healthcare Providers misuse antibiotics:

The lack of cheap, accessible, and reliable diagnostics, or failure to use those that are available, means diagnosis and prescribing are more often than not determined by a patient’s symptoms. The use of symptomatic diagnosis is most problematic for malaria and some bacterial infections since the symptoms can be so similar. This can lead to misdiagnosis and the use of inappropriate medicines.

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Perverse incentives for health-care professionals have become a normal part of health-care practice in both rich and poor countries. Providers commonly feel (real or perceived) pressure from their patients to treat with drugs. Under such circumstances, the provider’s incentive is to satisfy the customer and prescribe a drug, whether it’s necessary or not... Another factor that drives behavior during the patient-provider interaction is a patient’s expressed desire for a specific drug, often as a result of industry advertising...

Where prescribers are also drug dispensers, incentives can become terribly perverse.

Through Use by People

14: People ingest antibiotics through their food, and they use antibiotics to treat their illnesses. As indicated above, even the proper use of antibiotics by People to treat their diseases will eventually lead to resistance. However, improper use of antibiotics by People can speed the rate of resistance. Nugent, Back, and Beith describe various circumstances under which People improperly use antibiotics:

Patient drug choices are affected by a number of factors, including stigma, cultural preferences and beliefs, gender norms, and the cost of accessing medicines. Stigma can be a direct barrier to drug adherence… Other reasons patients do not follow proper treatment include adverse side-effects of drugs, complex treatment protocols, or simply feeling better after taking a partial treatment. In many parts of the world, cultural preferences and beliefs, such as in the higher effectiveness of multicolored capsules over plain ones or injectables over pills, affect individual drug-taking behavior. All contribute to behaviors that favor resistance development.

Programmatic challenges that interrupt treatment—such as supply inconsistencies and patient care and transport costs—also play a critical role in driving resistance. Where services are costly or far away, patients will often select the drugs themselves and purchase them from an unlicensed dispenser. Self-medication can lead to use of the wrong drug or less than the required full course of a drug.

Go tot Part 2: Players and Incentives in the Microbial Resistance Game