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Chapter 9 Outline
Introduction Characteristics of an Ideal Antimicrobial Agent Drug Resistance Some Strategies in the War Against Drug Resistance
Empiric Therapy
Undesirable Effects of Antimicrobial Agents Concluding Remarks
Introduction
Chemotherapy is the use of any chemical (drug) to treat any disease or condition. A chemotherapeutic agent is any drug used to treat any condition or disease. An antimicrobial agent is any chemical (drug) used to treat an infectious disease, either by inhibiting or killing pathogens in vivo. Some antimicrobial agents are antibiotics.
Introduction, cont.
Drugs used to treat bacterial diseases are called antibacterial agents; those used to treat fungal diseases, antifungal agents; those used to treat protozoal diseases, antiprotozoal agents; those used to treat viral diseases, antiviral agents. An antibiotic is a substance produced by a microorganism that kills or inhibits growth of other microorganisms.
Antibiotics that have been chemically modified to kill a wider variety of pathogens or reduce side effects are called semisynthetic antibiotics; examples include semisynthetic penicillins such as ampicillin and carbenicillin.
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The discovery of penicillin by Alexander Fleming. (A) Colonies of Staphylococcus aureus are growing well in this area of the plate. (B) Colonies are poorly developed in this area of the plate because of an antibiotic (penicillin) being produced by a colony of Penicillium notatum (a mould), shown at C.
Antibacterial Agents
Bacteriostatic drugs inhibit growth of bacteria, whereas bactericidal drugs kill bacteria. Sulfonamide drugs inhibit production of folic acid (a vitamin) in those bacteria that require p-aminobenzoic acid to synthesize folic acid; without folic acid bacteria cannot produce certain essential proteins and die. Sulfa drugs are competitive inhibitors; they are bacteriostatic. In most Gram-positive bacteria, penicillin interferes with the synthesis and cross-linking of peptidoglycan, a component of cell walls. By inhibiting cell wall synthesis, penicillin destroys the bacteria.
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Antibiotics that are destructive to both Gram-positive and Gram-negative bacteria are called broad-spectrum antibiotics (examples: ampicillin, chloramphenicol and tetracycline). Multidrug therapy
Sometimes one drug is not sufficient; 2 or more drugs may be used simultaneously, as in the treatment of tuberculosis.
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Macrolides (bacteriostatic at lower doses; bactericidal at higher doses; inhibit protein synthesis)
Fluoroquinolones (bactericidal; inhibit DNA synthesis)
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Antifungal Agents
Most antifungal agents work in one of 3 ways: By binding with cell membrane sterols (e.g., nystatin and amphotericin B) By interfering with sterol synthesis (e.g., clotrimazole and miconazole) By blocking mitosis or nucleic acid synthesis (e.g., griseofulvin and 5-flucytosine) Antifungal agents and antiprotozoal agents tend to be more toxic to the patient because, like the infected human, they are eucaryotic organisms.
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Antiprotozoal Agents
Antiprotozoal agents are usually toxic to the host. Antiprotozoal agents work by: Interfering with DNA and RNA synthesis (e.g., chloroquine, pentamidine, and quinacrine) Interfering with protozoal metabolism (e.g., metronidazole)
Antiviral Agents
Antiviral agents are the newest weapons in antimicrobial methodology. Difficult to develop these agents because viruses are produced within host cells. Some drugs have been developed that are effective in certain viral infections, but not others; they work by inhibiting viral replication within cells. Antiviral agent cocktails (several drugs that are administered simultaneously) are being used to treat HIV infection.
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Drug Resistance
Before a drug enters a bacterial cell it must first bind to proteins on the surface of the cell; these proteins are called drug-binding sites. A chromosomal mutation that affects the structure of a drug-binding site can prevent the drug from binding, resulting in drug resistance.
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Drug Resistance
Many bacteria have become resistant to penicillin because they have acquired the gene for penicillinase production during conjugation.
A plasmid that contains multiple genes for drug resistance is known as a resistance factor (R-factor).
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Drug Resistance
Drug Resistance
-Lactamases
Every penicillin and cephalosporin molecule contains a double-ringed structure (referred to as a house and garage). The garage is known as the -lactam ring.
Some bacteria produce enzymes, -lactamases, that destroy this ring; when the lactam ring is destroyed, the drug no longer works.
2 types of -lactamases - penicillinases and cephalosporinases; some bacteria produce both types. Drug companies have developed special drugs that combine a lactam antibiotic with a -lactamase inhibitor.
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Empiric Therapy
Empiric therapy is when drug therapy is initiated before laboratory results are available (i.e., before the pathogen is identified and/or before susceptibility test results are available). Empiric therapy is sometimes necessary to save a patients life.
Clinicians make an educated guess based on past experience with the type of infectious disease and the most effective drugs.
Clinicians must take a number of factors into consideration before prescribing antimicrobial agents.
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Factors to be Considered
In the hospital formulary? Site of the infection? What other medication(s) is the patient taking? What other medical problems does the patient have? Is the patient leukopenic or immunocompromised? What is the cost of the drug(s)?
Pocket chart for aerobic Gram-negative bacteria. The chart is a quick reference whenever empiric therapy is necessary.
With prolonged use, a broad-spectrum antibiotic may destroy the normal flora, resulting in an overgrowth of bacteria known as a superinfection.
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