Preserving the Power of Antibiotics

‘His breath was in short irregular bursts. His face was bathed in sweat and he moaned in pain. His skin was colored a dusky slate grey. His upper arm was swollen and was exuding pus. Death was in the air. Four days ago he had suffered a sword wound in the left upper arm during a skirmish with the enemy. Now the end was near.’
For most of mankind’s existence on the planet, the above scenario was a true representation of everyday reality. Wounds were mostly fatal. Wounds piercing the skull, the chest cage, or the abdomen inevitably resulted in death.

 

Microbial agents of diseases
For a long time, mankind did not know the cause of these illnesses. Microorganisms were discovered during the renaissance in Europe. Soon, we began to know more about these ‘germs’. The invention of the microscope allowed us to ‘see’ them for the first time. However, we still did not have effective treatment against them. The first agents to be effective against microbes were metals like arsenic and mercury, which were very toxic themselves. The sulfa dyes showed promising activity and eventually led to the development of sulfonamides. Penicillin was discovered by Sir Alexander Fleming in the late 1920s, and at the time of the Second World War, we had only two effective antibiotics—penicillin and sulfonamides.

What are antibiotics?
Antibiotics are substances produced by microorganisms, which inhibit the growth of other microorganisms. Humanity learned to synthesize many antibiotics and different groups of these drugs were discovered in the decades following World War II. The original penicillin is destroyed by stomach acid and had to be given by injection. Newer penicillins were produced that could resist the action of stomach acid. Antibiotics are agents that act against bacteria. They can act at different sites within the bacterial cell-cell wall, cell membrane, the nucleus, and protein producing ribosomes, among others.

Antibiotic misuse
During the Second World War, antibiotics were produced in miniscule amounts, and prices were high. With large scale production, prices dropped, and these agents began to be used widely. They began to be overused and misused. Antibiotics were used for conditions that are mainly caused by viruses. Common cold and upper respiratory tract infections are a common example. For a long time, this was justified as preventing secondary infection by bacteria. Antibiotics are also used in agriculture and animal husbandry. They can reduce infection in the crowded conditions in which animals are housed, and smaller amounts can also serve as growth promoters. Antibiotics used in animals can lead to human exposure through farm workers, animal waste products, and through meat preparations. Though the situation is changing in many developing countries, antibiotics are often available without a prescription. Many patients do not complete the prescribed course of antibiotics. They may stop these medicines once they start feeling better, or they may purchase only a two- or three-day supply. Many families may have leftover antibiotics in their medicine cabinets. These may be shared with other family members or with neighbors. This is dangerous in two ways. One is, the disease condition may not be caused by bacteria and the drug may not be effective, and the second is, the course of treatment is incomplete.

Types of antibiotics
Antibiotics are divided in two main ways—bacteriostatic and bactericidal. Bacteriostatic medicines only prevent the multiplication of bacteria and depend on the body’s immune system to take care of the bacteria that remain. Bactericidal medicines kill the bacteria. The action of an antibiotic in the body may be different from its activity in the laboratory. Sometimes, medicines not effective in the lab may be effective in the body, because the drug is being helped and supported by the body’s immune system. The other way of dividing antibiotics is based on the spectrum or the type of bacteria against which the drug is effective. Narrow spectrum antibiotics act against a limited range of bacteria, while broad spectrum acts against a variety of bacteria. To reduce the risk of resistance, the current recommendation is to use narrow spectrum drugs. I will not go into the different chemical groups of antibiotics.

Some current data
We use a lot of antibiotics. Current estimate is that, around 300 million antibiotics are prescribed annually. About 25-40% of all hospitalized patients receive an antibiotic. At least 30% of the use may be unnecessary or suboptimal, and 5% of patients develop a side effect related to antibiotics. Among outpatients, about one billion USD is spent on unnecessary antibiotic use in upper respiratory infections. About 50-80% of antibiotic use among outpatients may be inappropriate. Data from Nepal showed that salmonella was resistant to ciprofloxacin in 80% of cases. Resistance is also growing among other microbes. About 80% of all antibiotics were used in the community. During the first decade of this century, global antibiotic use increased from 50 to 70 billion standard units. India (13 billion standard units), China (10 billion), and the United States (7 billion) were among the major consumers.

Antibiotic resistance
A major problem today is antibiotic resistance. The antibiotic no longer works against the bacteria. Antibiotic resistance can only be slowed, and not prevented. Each time we use an antibiotic we exert selective pressure on the bacteria. Let us assume there is a colony of a thousand bacteria; 990 of these are sensitive to and killed by the antibiotic, while 10 are resistant to its action. The 10 bacteria that are resistant now have greater opportunities to thrive, as there is less competition for space, nutrients, and other resources. These resistant bacteria eventually dominate. This is a type of artificial selection where we select resistant bacteria and create conditions for them to thrive.

Consequences of resistance
Antibiotic resistance makes infections more difficult to treat. The time and cost of treatment also increase. At least one million deaths worldwide can be attributed to antibiotic resistance today, with the number projected to rise to 10 million by 2050. The additional cost would be around 80 trillion USD by 2050. Because common antibiotics do not work, other more expensive antibiotics may have to be used. Another problem is that not many new antibiotics are being developed. So, our weapons to fight bacteria and other microbes are growing smaller day by day. The less common antibiotics have more side effects. Hospitals are a dangerous place with regard to antibiotic resistance. A number of antibiotics are being used exerting significant selective pressure on the bacteria. The problem is particularly pressing in the intensive care unit of hospitals.

Reserve drugs
‘Reserve’ antibiotics are to be used only in case of resistant infections. One good example is vancomycin. For pharmaceutical companies, it does not make much economic sense to develop antibiotics that will not be used much and will be in storage till the appropriate conditions emerge. Humans do that with arms and weapons, where we have very expensive nuclear weapons waiting for the day they may be used. Billions of dollars are spent on deterrence. Probably, this tells something about our priorities as a race. Reserve drugs are more expensive and more toxic than other antibiotics.

How do we reduce the risk of antibiotic resistance?
As I mentioned, antibiotic resistance can take us back to the pre-antibiotic era. The entire modern medical system can collapse. Antibiotics should be used only for bacterial infections, and patients should complete the entire course of antibiotics. Antibiotics should be dispensed only with a prescription, and pharmacists should counsel their patients regarding how to use the antibiotics properly. Many countries are regulating the use of antibiotics in animal husbandry and agriculture. Antibiotic-free animal products command a premium in many countries. In hospitals and health facilities, the use of antibiotics is regulated by two committees, the infection control and the drug and therapeutics committees.

There have been restrictions imposed on the antibiotics that health workers can prescribe. The newer reserve antibiotics can be prescribed only after approval from an infectious disease specialist. Public education is an important part of preserving the power of antibiotics. Educating health professionals is also important. Antibiotics that do not stay long in the environment, and which are broken down by light, is another innovation. Antibiotics are to be prescribed for bacteriologically proven infections. Body specimens (sputum, urine, and blood, among others) are obtained and bacteria are grown. The sensitivity pattern of the bacteria to different antibiotics is then tested. With modern technologies, results from culture and sensitivity are available within 24 hours. The high cost of culture and sensitivity testing and their non-availability in developing nations could be a problem. Initiatives have also been taken to secure funding for the development of new antibiotics.

What are the major side effects of antibiotics?
Many antibiotics like gentamicin are toxic to the kidney. The kidney removes most medicines from the body. Most medicines are broken down in the liver and many may be toxic to the organ. The human body harbors a lot of bacteria. Bacteria are ubiquitous on the skin and in the alimentary system. On using antibiotics, these ‘commensal’ organisms are destroyed. The empty vacated space is now colonized by disease-causing bacteria. This is termed as super- or supra-infection. Patients may develop an allergic reaction to some drugs. This is especially true of penicillins, where drug allergy is a dangerous side effect. However if the patient is not allergic, penicillin is one of the safest antibiotics around. It may not however, be very effective. Penicillin has been around for nearly 90 years, and bacteria have become resistant. Most antibiotics are not safe in pregnancy and could have side effects on the fetus. They may also be excreted in breast milk and be passed on to the breast-feeding infant.

Many of the present problems were foreseen by Sir Fleming, who in his Nobel lecture in 1945 stated, “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself and, by exposing his microbes to non-lethal quantities of the drug, educate them to resist penicillin.”

Acknowledgement: I would like to thank Dr. Jha, Associate Professor of Pharmacology at KIST Medical College for allowing me to use some data from her presentation on antimicrobial resistance.

‘His breath was in short irregular bursts. His face was bathed in sweat and he moaned in pain. His skin was colored a dusky slate grey. His upper arm was swollen and was exuding pus. Death was in the air. Four days ago he had suffered a sword wound in the left upper arm during a skirmish with the enemy. Now the end was near.’
For most of mankind’s existence on the planet, the above scenario was a true representation of everyday reality. Wounds were mostly fatal. Wounds piercing the skull, the chest cage, or the abdomen inevitably resulted in death.

Microbial agents of diseases
For a long time, mankind did not know the cause of these illnesses. Microorganisms were discovered during the renaissance in Europe. Soon, we began to know more about these ‘germs’. The invention of the microscope allowed us to ‘see’ them for the first time. However, we still did not have effective treatment against them. The first agents to be effective against microbes were metals like arsenic and mercury, which were very toxic themselves. The sulfa dyes showed promising activity and eventually led to the development of sulfonamides. Penicillin was discovered by Sir Alexander Fleming in the late 1920s, and at the time of the Second World War, we had only two effective antibiotics—penicillin and sulfonamides.

What are antibiotics?
Antibiotics are substances produced by microorganisms, which inhibit the growth of other microorganisms. Humanity learned to synthesize many antibiotics and different groups of these drugs were discovered in the decades following World War II. The original penicillin is destroyed by stomach acid and had to be given by injection. Newer penicillins were produced that could resist the action of stomach acid. Antibiotics are agents that act against bacteria. They can act at different sites within the bacterial cell-cell wall, cell membrane, the nucleus, and protein producing ribosomes, among others.

Antibiotic misuse
During the Second World War, antibiotics were produced in miniscule amounts, and prices were high. With large scale production, prices dropped, and these agents began to be used widely. They began to be overused and misused. Antibiotics were used for conditions that are mainly caused by viruses. Common cold and upper respiratory tract infections are a common example. For a long time, this was justified as preventing secondary infection by bacteria. Antibiotics are also used in agriculture and animal husbandry. They can reduce infection in the crowded conditions in which animals are housed, and smaller amounts can also serve as growth promoters. Antibiotics used in animals can lead to human exposure through farm workers, animal waste products, and through meat preparations. Though the situation is changing in many developing countries, antibiotics are often available without a prescription. Many patients do not complete the prescribed course of antibiotics. They may stop these medicines once they start feeling better, or they may purchase only a two- or three-day supply. Many families may have leftover antibiotics in their medicine cabinets. These may be shared with other family members or with neighbors. This is dangerous in two ways. One is, the disease condition may not be caused by bacteria and the drug may not be effective, and the second is, the course of treatment is incomplete.

Types of antibiotics
Antibiotics are divided in two main ways—bacteriostatic and bactericidal. Bacteriostatic medicines only prevent the multiplication of bacteria and depend on the body’s immune system to take care of the bacteria that remain. Bactericidal medicines kill the bacteria. The action of an antibiotic in the body may be different from its activity in the laboratory. Sometimes, medicines not effective in the lab may be effective in the body, because the drug is being helped and supported by the body’s immune system. The other way of dividing antibiotics is based on the spectrum or the type of bacteria against which the drug is effective. Narrow spectrum antibiotics act against a limited range of bacteria, while broad spectrum acts against a variety of bacteria. To reduce the risk of resistance, the current recommendation is to use narrow spectrum drugs. I will not go into the different chemical groups of antibiotics.

Some current data
We use a lot of antibiotics. Current estimate is that, around 300 million antibiotics are prescribed annually. About 25-40% of all hospitalized patients receive an antibiotic. At least 30% of the use may be unnecessary or suboptimal, and 5% of patients develop a side effect related to antibiotics. Among outpatients, about one billion USD is spent on unnecessary antibiotic use in upper respiratory infections. About 50-80% of antibiotic use among outpatients may be inappropriate. Data from Nepal showed that salmonella was resistant to ciprofloxacin in 80% of cases. Resistance is also growing among other microbes. About 80% of all antibiotics were used in the community. During the first decade of this century, global antibiotic use increased from 50 to 70 billion standard units. India (13 billion standard units), China (10 billion), and the United States (7 billion) were among the major consumers.

Antibiotic resistance
A major problem today is antibiotic resistance. The antibiotic no longer works against the bacteria. Antibiotic resistance can only be slowed, and not prevented. Each time we use an antibiotic we exert selective pressure on the bacteria. Let us assume there is a colony of a thousand bacteria; 990 of these are sensitive to and killed by the antibiotic, while 10 are resistant to its action. The 10 bacteria that are resistant now have greater opportunities to thrive, as there is less competition for space, nutrients, and other resources. These resistant bacteria eventually dominate. This is a type of artificial selection where we select resistant bacteria and create conditions for them to thrive.

Consequences of resistance
Antibiotic resistance makes infections more difficult to treat. The time and cost of treatment also increase. At least one million deaths worldwide can be attributed to antibiotic resistance today, with the number projected to rise to 10 million by 2050. The additional cost would be around 80 trillion USD by 2050. Because common antibiotics do not work, other more expensive antibiotics may have to be used. Another problem is that not many new antibiotics are being developed. So, our weapons to fight bacteria and other microbes are growing smaller day by day. The less common antibiotics have more side effects. Hospitals are a dangerous place with regard to antibiotic resistance. A number of antibiotics are being used exerting significant selective pressure on the bacteria. The problem is particularly pressing in the intensive care unit of hospitals.

Reserve drugs
‘Reserve’ antibiotics are to be used only in case of resistant infections. One good example is vancomycin. For pharmaceutical companies, it does not make much economic sense to develop antibiotics that will not be used much and will be in storage till the appropriate conditions emerge. Humans do that with arms and weapons, where we have very expensive nuclear weapons waiting for the day they may be used. Billions of dollars are spent on deterrence. Probably, this tells something about our priorities as a race. Reserve drugs are more expensive and more toxic than other antibiotics.

How do we reduce the risk of antibiotic resistance?
As I mentioned, antibiotic resistance can take us back to the pre-antibiotic era. The entire modern medical system can collapse. Antibiotics should be used only for bacterial infections, and patients should complete the entire course of antibiotics. Antibiotics should be dispensed only with a prescription, and pharmacists should counsel their patients regarding how to use the antibiotics properly. Many countries are regulating the use of antibiotics in animal husbandry and agriculture. Antibiotic-free animal products command a premium in many countries. In hospitals and health facilities, the use of antibiotics is regulated by two committees, the infection control and the drug and therapeutics committees.

There have been restrictions imposed on the antibiotics that health workers can prescribe. The newer reserve antibiotics can be prescribed only after approval from an infectious disease specialist. Public education is an important part of preserving the power of antibiotics. Educating health professionals is also important. Antibiotics that do not stay long in the environment, and which are broken down by light, is another innovation. Antibiotics are to be prescribed for bacteriologically proven infections. Body specimens (sputum, urine, and blood, among others) are obtained and bacteria are grown. The sensitivity pattern of the bacteria to different antibiotics is then tested. With modern technologies, results from culture and sensitivity are available within 24 hours. The high cost of culture and sensitivity testing and their non-availability in developing nations could be a problem. Initiatives have also been taken to secure funding for the development of new antibiotics.

What are the major side effects of antibiotics?
Many antibiotics like gentamicin are toxic to the kidney. The kidney removes most medicines from the body. Most medicines are broken down in the liver and many may be toxic to the organ. The human body harbors a lot of bacteria. Bacteria are ubiquitous on the skin and in the alimentary system. On using antibiotics, these ‘commensal’ organisms are destroyed. The empty vacated space is now colonized by disease-causing bacteria. This is termed as super- or supra-infection. Patients may develop an allergic reaction to some drugs. This is especially true of penicillins, where drug allergy is a dangerous side effect. However if the patient is not allergic, penicillin is one of the safest antibiotics around. It may not however, be very effective. Penicillin has been around for nearly 90 years, and bacteria have become resistant. Most antibiotics are not safe in pregnancy and could have side effects on the fetus. They may also be excreted in breast milk and be passed on to the breast-feeding infant.
Many of the present problems were foreseen by Sir Fleming, who in his Nobel lecture in 1945 stated, “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself and, by exposing his microbes to non-lethal quantities of the drug, educate them to resist penicillin.”

Acknowledgement: I would like to thank Dr. Jha, Associate Professor of Pharmacology at KIST Medical College for allowing me to use some data from her presentation on antimicrobial resistance.