Definition of Resistance
 

Organisms acquire the ability to grow on high levels of drug to which they were originally susceptible. Some organisms have an innate insusceptibility to a specific antibiotic.

 

Mechanisms of resistance: Genetic factors

1. Chromosomal mutations such as seen with quinolone resistance where there is a mutation on the DNA gyrase or topoisomerase.
    
2. Plasmid mediated where bacteria acquire a resistant gene on transmissible plasmids. Plasmids may code for resistance to several unrelated families of antimicrobial agent and this can occur rapidly. The is extremely important for penicillin resistance and the transfer of beta lactamase.
    
3. Transposons or "jumping genes" are capable of integration into the chromosome of a bacteria or into plasmids. The can be a whole gene or part of a gene.

Mechanisms of resistance: Organisms factors

1. Alteration in the target site thereby lowering the affinity for the antibacterial. An example is penicillin binding proteins.
    
2. Alteration in access to target sites by decreasing the amount of drug reaching the target. This can occur by increasing the impermeability of the cell wall or by pumping the drug out of the cell.
    
3. Production of enzymes which modify or destroy the antimicrobial, an example is beta lactamase.

Where does antimicrobial resistance occur: we see resistance in bacteria, viruses, parasites, and fungus. For the purposes of this talk we will be concentrating on antibacterial resistance.

The notion of antibiotic resistance has only been around for the past 60 years since the initial introduction in the use of penicillin for infections. Penicillin was first used in World War II

In 1944 and by 1946 we were already starting to see resistance to penicillin from the bacteria Staphylococcus aureus.

In 1949 the United States produced about 13,000 pounds of antibiotics. In 1980 we produced 40 million pounds of antibiotics annually and the number has only continued to rise.

We use antibiotics for many things: we use them in human medicine for treatment and prevention; animal medicine for treatment and prevention; animal husbandry for growth promotion; and in agriculture to treat our crops. At present time our biggest selective pressure for the development of antibiotic resistance is the human use and misuse of antibiotics. The use in animal husbandry and veterinary medicine however is also extremely important.

US and Global Microbial Resistant Outbreaks

[Figure:  US Map - Emergence of Antimicrobial Resistant Organisms]

[Figure:  World Map - Emergence of Antimicrobial Resistant Organisms]

These two maps show some of the significant national and international outbreaks of resistant organisms. Since these maps were produced, there have also been cases of Vancomycin intermediate sensitivity Staphylococcus aureus and continued increase of mefloquine resistant Plasmodium falciparum malaria. There is also an increasing quinolone resistance among Neisseria gonorrhea species in Asia and Hawaii.

Human Medicine

How are antibiotics misused in human medicine: the selective pressures

1. Overuse of antimicrobials for non-bacterial infections
    
2. Subtherapeutic use of antibiotics even if an antibiotic is appropriate
    
3. Dissemination of resistance through travel or food including resistant clones. This was seen with the transmission of a multidrug resistant strain of Streptococcus pneumoniae from Spain to Iceland. This particular clone 6 Band, 23F carries resistance for multiple drugs including penicillin, erythromycin and sulfa drugs.
    
4. Misuse of broad spectrum antibiotics when a narrow spectrum is available
    
5. Environmental pressure from use elsewhere such as the availability of antibiotics over the counter in many developing countries and used for all types of ailments without supervision.

A study by Levy et al showed that in the hospital there was approximately 190 million daily doses per year of antibiotics given when only 25-45% of that was considered necessary. They also showed that in the community or outpatient setting there are 145 million courses annually and only 20-50% are considered necessary.

What is the cost in human medicine to this type of overuse and misuse?

Treating resistant bacteria increases cost by at least 2.5 times that of sensitive bacteria. Studies have shown that failure of antibacterial therapy can occur while a patient is in the hospital and that many of these patients fail and have to be changed to another drug.

In 1992, 13,300 patients died from multidrug resistant bacteria in the United States

The majority of outpatient antibiotics are used for four predominately viral conditions: otitis media, pharyngitis, sinusitis, and bronchitis.

Some of the top 10 resistant microbes include Staphylococcus aureus, Mycobacterium tuberculosis, Streptococcus pneumoniae, Salmonella species, Enterococcus species, Plasmodium falciparum and Neisseria gonorrheae. Many of these bacteria cause serious fatal diseases such as sepsis, active tuberculosis, fulminant malaria, meningitis and others.

[Figure:  Resistance to Various Drugs Among Isolates of Streptococcus pneumoniae, United States, 1992]

Hyde et al did a study on macrolide resistance of invasive S. pneumoniae isolates. They analyzed 15, 481 isolates from invasive S. pneumoniae in the US from 1995-1999. During the time of their study macrolide use increased by 13%. Macrolide resistance during this same time period increased from 10% to 20%. Some concerns this study emphasized is that there is increasing use of the newer macrolides such as azithromycin and clarithromycin as first line agents and that we will start to see increasing resistance with these medications as well.

A study by Seppala et al mapped the areas of macrolide use in Finland and then mapped the percentage of erythromycin resistance. The areas of use and resistance correlated very well in their study and I think gives credibility to the selective pressure argument for antibiotic resistance.

Chen et al using the Canada Bacterial Surveillance data looked at 7550 isolates of Streptococcus pneumoniae in 1988 and then from 1993-1998. From 1988 to 1998 the use of quinolones increased from 0.8 to 5.5 per 100 person years. Quinolone resistance of the streptococcus isolates increased from 0% in 1993 to almost 2% in 1997. Much of the quinolone use and resistance in this study was related to foreign travel and use of quinolones for treatment of diarrhea. Their study also showed that early on most of the quinolone resistance was in the elderly population since quinolones are one of the first line therapies for community acquired pneumonia. However, by the end of the study period these age differences no longer existed implying the increase use of quinolones in all ages of the population.

Whitney et al conducted a study looking at 3475 isolates of invasive Streptococcus pneumoniae from 1995 to 1998. They showed that penicillin resistant isolates increased to 24% by 1998. Also the multidrug resistance rates increased from 9-14% during this same time period.

A prospective study by Vergis et al showed that Vancomycin resistant enterococci (VRE) is an independent predictor of death from enterococcal bacteremia. Thirty seven percent of the isolates were resistant to vancomycin. E. faecium had 22% resistance to one of the new antibiotics streptogramin. This antibiotic had only been available for 2 years in human medicine however had been used in animal feed for 40 years. The mortality rate for Enterococcus bacteremia ranged from 42-73%. One of the concerns about this pattern is the potential ability to transfer vancomycin resistance from enterococci to Staphylococcus aureus. Currently vancomycin is the drug of choice to treat resistant S. aureus, if resistance increases to a large degree we have an almost untreatable condition. There are a couple of newer antibiotics that have been developed such as linezolid but, resistance has already been seen with these as well.

A final study I want to present to emphasize the human medicine selective pressures is a study from Liu et al from Taiwan. They measured the antimicrobial activity in the urine.(AAU) of all patients seen in one of the emergency rooms during a 3 month time period. The AAU could capture antibiotic use within 48 hours of the urine collection. They then did a retrospective chart review to see whether admission to the hospital was delayed for 7 days or more or whether there was a missed diagnosis. They evaluated data on 444 persons. Of these 220 (50%) had evidence of antimicrobial activity in their urine. Patients with AAU and infection were more likely to have a delayed admission (13%) and missed or masked diagnosis (23%). This study emphasizes that antibiotic use was common in the community either prescribed by physicians or by the pharmacist and has more serious consequences for care.

Animal Medicine Use

Over 40% of all antibiotic produced in the United States are used in animals, the majority as growth promoters.

Farm animals receive 30 times more antibiotics than humans. At least 500 human deaths annually can be attributed to microbes in meat and poultry.

Since the mid 1990’s quinolones have been licensed for use in animal feed in poultry in the United States. Numerous studies have tried to look at the impact between antibiotic use in animals and its impact on human disease. While studies exist to show some correlation there has not been a ban on antibiotics as growth promoters in the United States in the animal husbandry business.

Molbak et al looked at an outbreak of multidrug resistant Salmonella enterica typhimurium DT 104. This was a surveillance study in Denmark for salmonella. They evaluated 2 million sam;es from live animals and food of animal origin which is tested annually. In 1998 they was an outbreak of DT104 in humans. There were 27 cases and 5/27 had decreased quinolone sensitivity. They found that eating pork was associated with disease as well as quinolone resistance which was confirmed by isolates form the pork slaughter house. The use of quinolones in veterinary medicine began in 1993.

Smith et al looked at 4953 human stool isolates of Campylobacter jejune from 1992-1998. They showed that quinolone resistance increased from 1.3% in 1992 to 10.2% in 1998. A case-comparison showed that quinolone resistance for the year 1996-1997 was associated with foreign travel and quinolone use before stool collection. Quinolone resistant C. jejune was isolated from 14% of chickens tested in 1997. Subtyping showed an association between the chicken strains and human infection.

White et al did a study by taking 200 samples of ground meat (chicken, turkey, beef and pork) from retail stores in the United States and analyzed them for salmonella bacteria. Twenty percent of all samples contained salmonella which included 45 isolates and 13 serotypes. Eighty four percent of the isolates were resistant to at least one antibiotic and 53% were resistant to 3 antibiotics. Of these 16% were resistant to ceftriaxone. Chicken had the highest number of isolates (35%), turkey (24%), pork (16%) and beef (6%).

How can we improve our control of antibiotic resistance?

Surveillance

Currently there are several surveillance systems in place for antibiotic resistance. These can be identified by being local, national or international. Locally, most hospitals produce antibiograms which identify the resistance patterns for specific diseases in that hospital. This local information is used to guide clinical management, educate prescribers and develop infection control policies.

Nationally surveillance includes the National Nosocomial Infection Surveillance with over 200 hospitals in the United States reporting. The CDC also has initiated 8 sites for active bacterial core surveillance program to look at invasive Streptococcal pneumoniae isolates. This area of surveillance is necessary to guide national policy, update list of essential medications, develop national treatment guidelines and evaluate the effectiveness of interventions.

Internationally, Canada has the Canadian Bacterial Surveillance network which includes private lab and community hospitals in all 10 provinces but participation is voluntary.

SENTRY which is a multinational antibiotic resistance surveillance.

WHONET which is a collaborating center for surveillance of worldwide resistance and collaboration of laboratory isolates. There are also separate surveillance systems for specific diseases such as tuberculosis, gonorrhea and HIV infection. Internationally, the importance is to share information on what resistant strains are circulating, to improve communication and collaboration among countries and to guide policy and drug monitoring.

Prevention and control of antibiotic resistance

Reduce selective pressures:

• Use antibiotics for bacterial disease
   
• Use appropriate dosing and length of time
   
• Change medication if ineffective
   
• Use appropriate medication for a specific site
   
• Stop use of antibiotics in the animal husbandry for growth promotion
   
• Regulate prescribing practices in veterinary medicine
   
• Establish antibiotic prescribing practices and distribution especially in countries that allow over the counter medications without precripton
   
• Educate the public to the dangers of overuse/misuse of antibiotics

• Handwashing is effective and essential for reducing transmission of resistance
   
• Reduce crowding in living situations as well as hospitals
   
• Sterilize equipment or use disposable equipment whenever possible.

• Standardize laboratory testing for resistance
   
• Improve access to higher technology such as pulse field gel electrophoresis
   
• Enhance internet communication and sharing of data in a timely fashion.
   
• Improve vaccination status among the vaccine preventable diseases

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© 2002 University of Washington Department of Health Services Box 357660, Seattle, WA 98195-7660 e-mail: carrieho@u.washington.edu