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Antimicrobial Chemotherapy – the treatment for disease causing bacteria

that will target a specific area of the bacterium and inhibit it’s growth or kill off the invading pathogen.

Paul Ehrlich was a German scientist that lived from 1854 – 1915. He coined the term “chemotherapy”. His endeavor to kill off any type of parasite that invaded the human body lead him on a mission to discover some type chemical that could and would carry out this process. He found that Arsenic would kill of Trypanosome parasites. He found another Arsenic product called Salvarsan would kill off Treponema pallidum, the agent that caused Syphilis. Alexander Fleming was a British bacteriologist that lived from 1881 – 1955. He accidentally discovered Penicillin. Fleming coined the term “antibiotics”. He used this term to describe an antimicrobial agent that living organisms could produce naturally. Gerhard Domagk was a German chemist who lived from 1895 – 1964. In 1932 he discovered Sulfanilamide. This was the first practical antimicrobial used against bacteria. Molds like Penicillin and Cephalosporin yield antibiotics. Bacteria like Bacillus yield antibiotics. Filamentous bacteria like Streptomyces yield antibiotics. 50%+ of all antibiotics come from species of Streptomyces. By changing the side chains of antibiotics, semisynthetics are produced. This type drug is longer lasting, very effective and easy to administer. An antimicrobial that is completely laboratory synthesized is called a



An effective antimicrobial agent must exhibit “selective toxicity”. The agent must be more toxic to the invading microbe than to the host. Antibiotics/Antimicrobials are used against bacteria because they work well against them. Mainly because there are many differences between the structure and metabolism of the disease causing microbe and it’s host. Drugs that target Helminths, Protozoans or Fungi are fewer. This is because these organisms are eukaryotes, thus they share common features with their hosts. Drugs that target viruses are very limited. Even though there are many differences in their structures, viruses live inside their host cells, using their ribosome, enzymes and cytoplasmic pool components for metabolism and replication. Effective antiviral drugs are usually toxic to the infected host. Clinical Considerations When Prescribing Antimicrobials a. The side effects in relation to toxicity to host cells. b. Is the organism sensitive to that particular drug? c. How long will the agent remain in active form, called Biotransformations. d. The drugs chemical properties. Can sufficient concentrations reach the infection site. Other Clinical Considerations! a. b. c. d. e. Is Is Is Is Is the drug readily available? it inexpensive? the drug chemical stable for storage and transportation. it easily administered? it nontoxic and nonallergenic?


Spectrum of Action The “spectrum of action” is the different types of bacteria that this drug has an effect on. If only a few bacterial types are affected by this drug, it is called a

Narrow Spectrum Drug.

If this medication is effective against a lot of bacterial types, then it is a

Broad Spectrum Drug.

Broad spectrum drugs are not always desirable. They can easily knock out a person’s normal intestinal flora if over used. This will bring about a superinfection. This superinfection can cause Pseudomembranous colitis. Two drugs that can treat this condition are Vancomycin and Flagyl. These medications must be administered orally. SUSCEPTIBILITY TESTING Using disk that are impregnated with an agent and placing these on a Mueller-Hinton agar plate that has been covered with a broth of bacterium, will give you results of the disk-diffusion. This is called the Mueller-Hinton Susceptibility Testing Method. Once the Mueller-Hinton agar is covered with an inoculum, the disks are placed on the surface of the agar. The antibiotic within the disk will diffuse into the agar. If a clear zone surrounds the disk, this is the area called the

“Zone of Inhibition”.

It is according to the diameter of the zone, if that drug will inhibit the growth of the organism or if that drug can kill the organism. MINIMUM INHIBITORY CONCENTRATION TEST (MIC) This is the lowest concentration of the drug that will inhibit the growth and the replicating of the invading pathogen.


This test is performed as a Broth Dilution Test. A standard amount of bacteria is placed within a series of tubes that have been diluted with a specific antibiotic or antimicrobial. These tubes are incubated overnight at 37oC. No cloudiness means no bacterial growth, whereas if the broths are cloudy, there is the presence of bacterial growth. Moving from right to left, you check the smaller dilutions of the broth for cloudiness. The first tube after the last cloudy tube is the MIC value. MINIMUM BACTERICIDAL CONCENTRATION TEST (MBC) This test is also called the “Minimum Lethal Concentration”. This is the concentration of an antibiotic/antimicrobial that can kill an organism in a suspension in a specific amount of time. To determine the MBC, plate out the first three tubes after the last cloudy one on agar plates that contain no antimicrobial agent. This will show if the bacteria are only inhibited by the MIC value or killed by it. After incubating these three plates over night at 37oC, observe the plates for growth at a 24 hour time period. The MBC value is the first plate that shows no grown on the agar surface. The MIC is adequate for establishing the right concentration of an antimicrobial agent that should be administered to a patient to control that patient’s infection. The MBC is essential in cases of endocarditis and in treating patients with lower immune defense responses, such as those who are receiving chemotherapy for cancer.


DRUG ADMINISTRATION ROUTES If a drug is to be effective against the infecting pathogen, then the adequate amount of that agent must reach the infection site. External infections need drugs that are applied Topically. Internal infections can be treated by drugs that are administered orally, intramuscularly (IM), or intravenously (IV). When drugs are taken orally, the concentration of that drug will be lower that if administered by some other route. Giving a drug IM via a needle, will allow the drug to diffuse into blood capillaries within that muscle tissue. Drug concentration is higher is administered IV. Initially the concentration is high, but the drug can be lose concentration by being eliminated through the kidneys and liver. Your doctor should consider how the drug will be distributed to infected tissues by the blood. If you used the drug of choice for a urinary tract infection and it was removed rapidly from the blood by the kidneys, then this drug should not be used to treat a heart condition. The blood-brain barrier is almost impermeable to drugs, so these agents have a hard time getting to infections of the eye, brain and spinal cord. Infections in these areas are very hard to treat. DRUG TOXICITY Drugs can have toxic side effects to the host, even though the drug is selective toxic to the infecting organism. Toxicity sites are usually the nerves, kidneys and liver. The drug Polymyxin and some Aminoglycosides are fatally toxic to the kidneys.


Metronidazole or Flagyl, which is a medication used again Protozoans and anaerobes, will cause a non-toxic side effect called Black Hairy Tongue”. This occurs when hemoglobin breaks down and those products accumulate on the tongue, giving a black coloration. Prescriptions for pregnant women should be done carefully. Even though the drug may not harm the mom to be, it can cross the placenta and affect the fetus. Tetracyclines form complexes with calcium that can become incorporated into bones and developing teeth, which can cause a yellowing of the teeth enamel and malformation of the skull and stunted growth in the long bones. DISRUPTION OF NORMAL FLORA Secondary infections occur when a person’s normal flora is disrupted. If someone uses a broad spectrum drug for an extended period of time, a resistant bacterium or yeast can overgrow, resulting in a superinfection. The yeast infection with Candida albicans can cause Vaginitis within the vagina or Thrust within the mouth. An over growth of Clostridium difficile within the large intestine (colon) will cause a potentially fatal condition termed Pseudomembranous colitis. RESISTANCE TO ANTIMICROBIAL DRUGS An individual bacterial cell may acquire resistance to drugs in two ways. A chromosomal gene that has become mutated. Or by acquiring a resistance gene from a plasmid called an R-factor. Bacterial cells that are resistant to drugs reproduce very slowly and are the minority in the population. If bacterial cells are sensitive to an antimicrobial agent, it will either kill them or inhibit their growth. This causes the resistant cells to grow and replicate. Sometimes they will grow rapidly because they have less competition.


The result is that these resistant bacterial cells will soon replace the sensitive cells as the majority in the population. Mechanisms of Resistance 1. Some bacteria will synthesize an enzyme that can deactivate a drug. Some bacteria produce B-lactamases (penicillinases). This enzyme will break the Carbon-Nitrogen bond of the B-lactam ring of Penicillin or Cephalosporin. 200 different B-lactamases have been discovered. 2. Some resistant Gram Negative bacteria may alter the Porin Protein in the cell walls. This will either prevent the entry of the drug into the cell or greatly slow down the drugs entry into the cell. It also changes the electrical charge of the outer membrane. 3. Resistant cells may alter their surface receptor and the drug cannot bind with it. If binding does occur, it can be less efficient. 4. Some resistant cells have altered their metabolic chemistry. Some cells have become resistant to Sulfonamides by stopping their synthesis of folic acid within their cytoplasm and acquiring it from their external environment. 5. Resistant cells may pump the drug out of the cell before it has a chance to act in it’s required way. Drugs have specific mechanisms of action: a. b. c. d. e. Inhibition of cell wall synthesis Inhibition of protein synthesis Disruption of the plasma membrane Inhibition of Metabolic pathways Inhibition of Nucleic Acid synthesis


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