Historical Perspective
Resistance Mechanisms
Where are antibiotics used
Where Do We See Resistance
Specific Organisms and Antibiotic Resistance

Staphylococcus aureus

Streptococcus

Enterococci

Tuberculosis

Salmonella

Shigella
Other Bad News
Prevention and Control Strategies

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 1930’s, 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 the 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.

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-process where "naked" DNA is taken up by the bacteria, b) transduction-process where a bacterial virus (bacteriophage) on one strain pick up DNA from the host and infects a 2^nd strain, and c) conjugation-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

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.
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 1950’s. 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 Diseases- 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 1980’s, 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.

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 on 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 immunecompromised individuals.

Click on image to enlarge

Click on image to enlarge

Staphylococcus aureus

This is the organism that developed such rapid resistance after penicillin introduction in the 1940’s. 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). 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 1^st isolate of vancomycin-intermediate resistance was seen in a child. If S. aureus develops high level resistance to vancomycin, that leaves us without any effective therapy for this infection.

Streptococcus

S. pneumonia is the leading cause of potentially life threatening community acquired disease. It is associated with a global mortality rate of 3-5 million per year.

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.

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.

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.

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 Charlie Nolan’s lecture on global tuberculosis.