Antibiotic Resistance

Table of Contents

Historical Perspective
Resistance Mechanisms
Where are Antibiotics Used
Factors of Misuse of Antibiotics in Human Medicine
Where Do We See Resistance
Surveillance for Antibiotic Resistance
Specific Organisms and Antibiotic Resistance

Staphylococcus aureus

Streptococcus

Enterococci

Tuberculosis

Salmonella

Shigella

Other Bad News
Prevention and Control Strategies
Student Questions

Readings

Historical Perspective

In 1928 Alexander Fleming discovered penicillin. This discovery came about by accident and could be attributed to his lack of housekeeping. He put several petri dishes with bacteria on them in a sink and went away for several days. When he returned he noticed that a mold growing on one of the petri dishes inhibited the bacteria from growing. This mold was identified as penicillium (where penicillin gets its name). It wasn't until 1942 however that penicillin was available for widespread use. The first antibiotic in use was sulfonamide. Discovered by Gerhard Domajk in the 1930s, this antibiotic was mostly used as a topical agent for wound infections and lacked efficacy in this setting.

In 1942, the first wide spread use of penicillin took place among burn victims. Its success in reducing mortality from wound infections was remarkable for the time and was used during WWII as well. By 1945 however, penicillin resistance among isolates of Staphylococcus aureus was already being seen. A study from hospitals in London, showed that 14% of S. aureus were resistant to penicillin. By 1949 approximately 59% of the S. aureus strains were resistant to penicillin. We can see that in less than a decade the first significant antibiotic breakthrough has been rendered ineffective against a very dangerous and important bacterium.

Development of other antimicrobials came soon after penicillin. Streptomycin was discovered in 1943, tetracycline in 1948 and the first cephalosporins were introduced in 1964. Since then there have been numerous developments in the area of antibiotics including antituberculosis medication, intravenous medication for serious wound and abdominal infections, and newer medication for the treatment of sexually transmitted disease. Despite these advances the bacterial organisms are still one or more steps ahead of us.

Resistance Mechanisms

Definition of resistance: where organisms acquire the ability to grow on high levels of drug to which they were originally susceptible.

Emerging disease definition: drug resistant infections whose incidents in humans has increased within the past two decades.

Mechanisms of resistance:

1. Plasmid mediated - plasmids are small circular pieces of DNA, which are independent from the main chromosome. Resistance genes can be transferred from one plasmid to another within a bacterium or from one bacteria to another bacteria. Bacteria can exchange genetic information by a) transformation - a process where "naked" DNA is taken up by the bacteria, b) transduction - a process where a bacterial virus (bacteriophage) on one strain pick up DNA from the host and infects a second strain, and c) conjugation - a process where there is cell to cell mediated gene transfer.
   
   Plasmid mediated resistance usually causes high level resistance, can be transferred to a wide range of hosts and is very important clinically.
   
   
2. Chromosomal mutation - this causes moderate resistance there is a change in the existing structure. Transfer can occur between daughter cells. This type of resistance is seen in Neisseria gonorrhea (where penicillin binding proteins are modified) and with quinolone resistance.
   
   
3. Intrinsic resistance - certain bacteria that are inherently resistant to one or more antibiotic.

Where are Antibiotics Used

To better understand the factors relating to antibiotic resistance development, we need to know where and how antibiotics are used:

1. Human medicine - Antibiotics are used primarily in two different settings: as preventive medication and as treatment of a disease. Antibiotics are one of the most common medications prescribed in the United States (US). Approximately one out of seven prescriptions in the US is for an antibiotic. In 1994, there were over 100 million physician visits where antibiotics were prescribed for 4 common outpatient conditions (sinusitis, bronchitis, otitis, and pharyngitis). Another study found that 50-70% of visits for colds, URI, and bronchitis resulted in an antibiotic script. A New England Journal of Medicine article found that 30% of hospitalized patients are receiving antimicrobial medication. The true usage of antibiotics in developing countries is almost impossible to measure since many of these medications are available without a prescription and the reason they are being taken is not usually determined. Data has shown that antibiotic resistance can raise inpatient expenses over 2 1/2 times in just direct patient care costs (additional hospital days, longer antibiotic use, etc.)
   
   
2. Animal medicine - As in human medicine, antibiotics are used for prevention of disease and treatment of illness. The selective pressure of antibiotic use is even stronger in animals since domestic animals outnumber humans 5 to 1. Other figures quoted are that 6 billion animals are raised annually for human consumption and most of these animals receive antibiotics during their lifetime. Farm animals receive 30 times more antibiotics than humans. Levy points out in his book that 50% of all antibiotics produced were administered to farm animals. Milk can contain small concentrations of 80 different antibiotics.
   
   
3. Animal Husbandry - In the US, antibiotics have been used as growth promoters in the animal husbandry business since the 1950s. At that time it was shown that antibiotics in animal feed increased the weight for many different animals including chickens and cattle. This practice has been banned in several European countries due to the antibiotic resistance issue. However, no such ban exists in the United States. On the contrary, the animal husbandry business has now started to use quinolones as well. Several studies have shown that there is a strong correlation between antibiotic use and resistance occurrence. There is less information as to how much this practice in animal husbandry contributes to the overall antibiotic resistance problems in humans.
   
   
4. Treatment of Crop Disease - Antibiotics are used both for treatment of bacterial and fungal infections of crops, as well as prevention of these diseases.

To emphasize how much antibiotics exist in today's society we can look at the trend in production of antibiotics. In the United States in 1949, 13,000 pounds of penicillin and streptomycin were produced monthly. In 1954, 400,000-5000,000 pounds of broad-spectrum antibiotics were made and in the 1980s, 40 million pounds of antibacterials were produced annually. It is thought that 5-7 million pounds of antibiotics are used subtherapeutically annually in the US alone.

Factors of Misuse of Antibiotics in Human Medicine

There are several factors that contribute to the misuse of medication around the world:

1. Over prescribing of antibiotics by physicians and other allied health professionals: as mentioned earlier, a large majority of antibiotics are written for common outpatient concerns many of which are caused by viruses, not bacteria.
   
   
2. Over usage and incomplete course of antibiotics by patients: many patients request antibiotics for the common outpatient conditions from their physicians. When appropriate antibiotics are given, patients may only take part of the course of antibiotic and not finish the remainder, possibly leaving a bacteria partially treated. Resistance can increase in these settings.
   
   
3. Over the counter availability of antibiotics: this is a big concern internationally where many antibiotics are available without prescriptions. Many pharmacists in these countries act as the caregiver and give out antibiotics based on patients' complaints without adequate diagnosis or testing.
   
   
4. High cost and lack of adequate medications: many antibiotics are very expensive for several lesser-developed countries. This may contribute to only partial use of an antibiotic. For example, if only one drug is available for TB, it may be used as single therapy, which leads to significant resistant rates.

Where Do We See Resistance

• Bacteria - We will discuss several specific problems with certain bacteria in today's lecture.
  
  
• Parasites - The most relevant resistance pattern in parasitology is in drug resistant malaria. We will not discuss this in detail today since you will be getting a lecture on vector-borne diseases. However, malaria is one of the most common parasitic diseases in the world and accounts for at least 1 million deaths annually. The increasing resistance patterns worldwide are making treatment and prevention difficult. Newer research is being done to look into the development of an effective malaria vaccine. In the meantime, increasing resistance to the newer medications such as mefloquine, will mean increasing morbidity and mortality from this disease.
  
  
• Viruses - We will not discuss this today, but it will be discussed by Dr. Holmes in the lecture on HIV/AIDS and STD's.
  
  
• Fungi - Again, we will not discuss this in today's lecture. There is antifungal resistance, particularly Candida, in the immunocompromised individuals.

Surveillance for Antibiotic Resistance

Definition of surveillance: The continued watchfulness of incidence of disease through systematic collection, consolidation and evaluation of morbidity and mortality reports and other data with regular, timely dissemination of results to those who need to know for purposes of intervention to prevent injury and/or disease.

There are several surveillance systems now available to track and monitor antibiotic resistance:

National Nosocomial Infection Surveillance - This is a hospital based surveillance that monitors inpatient infections and has some data on antibiotic usage and resistance.

European Antimicrobial Resistance Surveillance System (EARSS) - Began in 1998 to gather information and specimens from European countries and consolidate the information to a central laboratory. They can standardize resistance testing technique and then disseminate that information back to the specific countries.

Alexander Project - Ongoing, multicenter surveillance study of antimicrobial susceptibility of community-acquired lower respiratory tract pathogens, sent to central laboratory (UK, USA, Mexico, Brazil, Saudi Arabia, South Africa).

CDC and WHO - Both have sentinel sites for monitoring antibiotic resistance. WHO is especially concerned with drug resistant tuberculosis.

Swedish Strategic Program for Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA)

Italian Surveillance Group for Antimicrobial Resistance (ISGAR)

Organization of Danish Integrated Antimicrobial Resistance Monitoring and Research Program (DANMAP)

There are several issues to consider for antibiotic resistance surveillance:

What method of surveillance is better, active vs. passive?
How important is timeliness of information to this surveillance system?
How do you assure accuracy and standardization of the resistance information?
What is the best way to disseminate information about the resistance patterns and to whom do you give that information?
How do you monitor resistance in an outpatient setting where many times patients get prescribed antibiotics without benefit of cultures?
How do you study resistance rates from consumption of antibiotics?
How do you differentiate where resistance comes from in a community?
Human usage vs. animal usage?

As you can see we have many more questions than answers.

Specific Organisms and Antibiotic Resistance

We will now talk about some specific bacteria and problems with resistance.

[US Map - Emergence of Antimicrobial Resistant Organisms]

[World Map - Emergence of Antimicrobial Resistant Organisms]

Staphylococcus aureus

This is the organism that developed such rapid resistance after penicillin introduction in the 1940s. It remains today a highly resistant organism particularly in the hospital setting. The most resistant strain of S. aureus is methicillin resistant S. aureus (MRSA). This usually implies that the organism is resistant to all penicillins and cephalosporins and usually tetracyclines and erythromycins will also be ineffective. The drug we use to treat these infections with is intravenous Vancomycin. MRSA rates increased in the US from 2.4% (1975) to 29% (1991). [Drug Resistant Staphylococcus aureus Infections Acquired in Hospitals] Ciprofloxacin resistance increased from 5%-80% in one year. One study in VA patients showed that all MRSA strains were also resistant to Ciprofloxacin. Most MRSA strains are found in hospital infection however there has now been MRSA found in a community acquired setting as well.

The most worrisome trend in resistance for this organism is that Vancomycin resistance has been transferred from enterococci to staphylococci in the laboratory. In 1997 the first isolate of Vancomycin-intermediate resistance was seen in a child. There have now been several cases of Vancomycin resistant S. aureus. If S. aureus develops high level resistance to Vancomycin, there is limited treatment options available. In the past 2 years two drugs (SynercidTM and linezolid) have now been approved for treatment of Vancomycin resistant S. aureus. It is anyone's guess how long it will take before this organism is resistant to the newest antibiotics.

Streptococcus

S. pneumonia is the leading cause of potentially life threatening community acquired disease especially pneumonia in the world. It is associated with a global mortality rate of 3-5 million per year worldwide and approximately 40,000 deaths per year in the U.S. The incidence of penicillin resistance has increase 4 fold since 1994 in the United States alone. Resistant clones of this organism have traveled around the world in a short period of time. [Resistance to Various Drugs Among Isolates of Streptococcus pneumoniae, United States, 1992]

A CDC study showed antibiotic use and day care centers were risk factors in a Kentucky outbreak of drug resistant streptococcus. Of the 85 isolates, 28% were resistant to penicillin. Resistant rates are also being seen to erythromycin and other antibiotics. There still remains a large selection of antibiotics to treat this disease in more developed countries. However, in countries with limited resources, the inability to use the least expensive medication is very important.

There is a pneumococcal vaccine which is now in use for adults. This may be the advancement of the future for prevention of serious disease with S. pneumonia. The currently available vaccine is not for use in children under two years of age. A newer polyvalent vaccine is in development and may be available soon for use in this age group. That would be a huge breakthrough. But remember, the vaccine (if effective) still needs to get to the most affected populations. A challenge we have not conquered yet with the currently available vaccinations!

Enterococci

Enterococcus infections can be a cause of bacteremias, surgical wound infections, and urinary tract infections. Vancomycin resistance increased from 0.8% (1988) to 4% (1991) to 14% (1993).

In 1993, fifteen percent of ICU enterococci isolates were Vancomycin resistant. Enterococci are intrinsically resistant to B-lactams, aminoglycosides and sulfonamides. Treatment has usually included at least 2 drug therapy for serious infections. Transmission of Vancomycin resistance has happened between this organism to S. aureus in vitro, we will likely see this happen in vivo as well.

Tuberculosis

This will be covered in more detail in the global tuberculosis lecture. The new face of TB includes a worldwide increase of multidrug resistance. In New York City, 19% of the TB isolates are multidrug resistant. The late 1980s hospital outbreak of multidrug resistant TB in New York had a mortality rate of 85%, the majority of the patients were co-infected with HIV. The co-infection of TB with HIV is a huge international public health problem and one that is gathering much interest to find solutions to this ever-growing problem. Global resistance to single drug therapy to TB ranges from 0% (areas of low TB) to 54% (areas of higher TB incidence) based on data gathered by the WHO in their report on drug resistant tuberculosis. The cost to treat drug resistant TB compared to drug sensitive is astronomical. One case of MDR-TB, in Seattle-King County, cost $500,000 compared to $2000-$3000 for a drug sensitive case. There has been no new TB drugs developed at this time nor has there been development of a new, more effective vaccine.

Salmonella

Salmonella bacteria are one of the more common causes of bacterial diarrheal illnesses worldwide. Salmonella typhi, the cause of typhoid fever, still remains a significant cause of morbidity and mortality worldwide. [Rising Resistance]

In 1979, 16% of salmonella were multidrug resistant. In 1984, 24% were multidrug resistant and in 1989, 32% were multidrug resistant. Multidrug resistant isolates of S. typhimurium (DT-104) were found in the US and England; these isolates were resistant to ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline. These isolates were also found in domestic animals and poultry (a significant source of salmonella food borne infection) in the United Kingdom. All of these antibiotics are inexpensive in developing countries and are fairly readily available. Resistance to these means there is little to offer in a resource poor country to treat these infections.

Shigella

Shigella species are also a cause of serious bacterial diarrheal disease. A study in Burundi Africa in 1990 showed that Shigella dysenteriae isolates were resistant to all available oral agents in that country. In China, over 50% of Shigella isolates are now quinolone resistant as well.

Other Bad News

Research and development market growth for new antibiotic production dropped from 25% in the 1980s to 6% in the 1990s.

Prevention and Control Strategies

I have put together my top 10 list of prevention and control strategies for minimizing the impact of antibiotic resistance. I will present them in reverse order:

Number 10: Continue research into the mechanisms of drug resistance.

Number 9: Encourage new research into developing new classes on antimicrobials.

Number 8: Educate the public (and policy makers) about the appropriate use of these medications. The public in terms of taking the medication unnecessarily and the policy makers to consider changes in the animal husbandry business.

Number 7: Disseminate information about resistance patterns locally and in other parts of the world in a timely fashion.

Number 6: Improve surveillance for drug resistance by use of rapid laboratory identification.

Number 5: Reduce or ban the use of antimicrobials as growth promoters in the animal husbandry business.

Number 4: Isolate potential serious resistance cases from other patients.

Number 3: USE ANTIMICROBIALS APPROPRIATELY

• Use the most specific antibacterial that will inhibit growth.
  
• Use for bacterial infections (not for viral illnesses such as URI, etc.)
• Use for the appropriate length of time to treat and cure the infection.
  
• Avoid giving low level antibiotics.
  
• Educate patients as to the appropriateness of an antibiotic medication.

Number 2: IMPROVE SANITARY CONDITIONS
There is no substitute for clean water, adequate waste disposal and access to preventive health care.

NUMBER ONE PREVENTION:   WASH YOUR HANDS !!!!!!!
This is one of the most cost effective and cost beneficial strategies in reducing the spread of antibiotic resistance and preventing infections from occurring in the first place.

Student Questions

Q: Does the use of prophylactic antibiotics in humans contribute to the overall picture of resistance?

A: We don't know the answer to that question. Short course antibiotic to prevent more serious infections is a standard of care for many medical conditions (i.e., those with serious heart valve disease, pre and post abdominal/chest/orthopedic surgeries). There may be temporary resistance. We don't know what they do to the overall community rates of resistance.

Q: What do you think about empiric use of antibiotics for certain infections, such as E. coli?

A: I think we need to be extremely careful about general empiric use of antibiotics; many infections such as E. coli and Vibrio cholera do not require treatment with antibiotics. This type of practice can and does lead to antibiotic resistance. There are infections where it is absolutely essential to empirically treat with antibiotics (bacterial meningitis for example). The ultimate goal would be to use antibiotics for a bacterial problem and use the most specific and narrow spectrum antibiotic to take care of the infection. The question about empiric use of antibiotics pre and post surgery is one we should perhaps revisit. Do the studies from years ago still hold true? In the age of increasing antibiotic resistance is this practice reasonable and appropriate?

Q: Does the discontinuation of antibiotics in a community or specific setting reduce resistance rates?

A: We don't have a huge amount of good studies in this area. But the few studies, such as gonococcal resistance have shown reduction in penicillin resistance when quinolones were used instead. The question is how long will the sensitivity last if we reintroduce the previous antibiotic. Bacteria have good memory it seems because they do gain the ability to develop resistance rapidly. I think we need to reduce antibiotic use in ALL arenas where these medicines are used (humans, animals, and animal husbandry). That is a significant challenge for the next millennium.

Q: It seems like prevention that works takes a significant investment. Is it there?

A: Not as much as it should be. In the US, less than 5% of the total health care budget is spent on public health/preventive medicine. The majority is spent for secondary and tertiary care. It could and should definitely be higher.

Prevention takes not only an investment of money, it also takes time, training, and ongoing evaluation for efficacy. Public health is not a quick fix, it is a persistent need in a community and in my opinion is grossly underfunded both nationally and definitely internationally.

Ann Marie Kimball, MD, MPH - comment: It is not only a function of financing and money but may be a factor of business. A lot of developing countries take a more preventative approach to healthcare, but they may also be more dependent on outside funding from donor agencies. The mindset of the donors may be one that wants to put money into "things" such as facilities and institutions as a one time cost rather than into ongoing maintenance of a public health/preventive medicine system. Prevention requires ongoing education, evaluation and change. Trade and travel also play a role in dissemination of antibiotic resistance

Readings:

Editorials concerning antimicrobial resistance. BMJ, 1998 Sep; 317: 609-16.

Tenover FC, Hughes JM. "The challenges of emerging infectious diseases: development and spread of multiply-resistant bacterial pathogens." JAMA, 1996 Jan; 275(4): 300-304.

O'Brien TF. "The global epidemic nature of antimicrobial resistance and the need to monitor and manage it locally." Clin Infect Dis, 1997; 24(Suppl I): S2-S8.

Cohn DL, Bustreo F, Raviglione MC. "Drug-resistant tuberculosis: review of the worldwide situation and the WHO/IUATLD global surveillance project." Clin Infect Dis, 1997; 24(Suppl I): S121-S130.