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Burton's Microbiology for the Health Sciences

Chapter 9. Controlling Microbial Growth in Vivo Using Antimicrobial Agents

Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Chapter 9 Outline
• Introduction • Characteristics of an Ideal Antimicrobial Agent • Drug Resistance • Some Strategies in the War Against Drug Resistance

• How Antimicrobial Agents Work
• Antibacterial Agents • Antifungal Agents • Antiprotozoal Agents • Antiviral Agents

• Empiric Therapy
• Undesirable Effects of Antimicrobial Agents • Concluding Remarks

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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.

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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.

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Characteristics of an Ideal Antimicrobial Agent
• The ideal antimicrobial agent should:
– Kill or inhibit the growth of pathogens – Cause no damage to the host – Cause no allergic reaction in the host – Be stable when stored in solid or liquid form – Remain in specific tissues in the body long enough to be effective – Kill the pathogens before they mutate and become resistant to it
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How Antimicrobial Agents Work
• The 5 most common mechanisms of action of antimicrobial agents are: – Inhibition of cell wall synthesis – Damage to cell membranes – Inhibition of nucleic acid synthesis (either DNA or RNA synthesis)

– Inhibition of protein synthesis
– Inhibition of enzyme activity

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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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The effect of sulfonamide drugs.

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Antibacterial Agents, cont.
• Colistin and nalidixic acid destroy only Gram-negative bacteria; they are referred to as narrow-spectrum antibiotics.

• 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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Some Major Categories of Antibacterial Agents
• Penicillins (bactericidal; interfere with cell wall synthesis) • Cephalosporins (bactericidal; interfere with cell wall synthesis) • Tetracyclines (bacteriostatic; inthibit protein synthesis)) • Aminoglycosides (bactericidal; inhibit protein synthesis)

• Macrolides (bacteriostatic at lower doses; bactericidal at higher doses; inhibit protein synthesis)
• Fluoroquinolones (bactericidal; inhibit DNA synthesis)
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Antibacterial Agents, cont.
• Synergism Versus Antagonism – Synergism is when 2 antimicrobial agents are used together to produce a degree of pathogen killing that is greater than that achieved by either drug alone. Synergism is a good thing! – Antagonism is when 2 drugs actually work against each other. The extent of pathogen killing is less than that achieved by either drug alone. Antagonism is a bad thing!

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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)

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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 “Superbugs”
• Superbugs are microbes (mainly bacteria) that have become resistant to one or more antimicrobial agent. Infections caused by superbugs are difficult to treat!

• Bacterial superbugs include:
– methicillin-resistant Staphylococcus aureus (MRSA); vancomycin-resistant Enterococcus spp. (VRE); multidrug-resistant Mycobacterium tuberculosis (MDRTB); multidrug-resistant strains of Acinetobacter, Burkholderia, E. coli, Klebsiella, Pseudomonas, Stenotrophomonas, Salmonella, Shigella. and N. gonorrhoeae; β–lactamaseproducing strains of Streptococcus pneumoniae and Haemophilus influenzae; carbapenemase-producing Klebsiella pneumoniae.
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Drug Resistance

How Bacteria Become Resistant to Drugs
• Some bacteria are naturally resistant because they lack the specific target site for the drug or the drug is unable to cross the organism’s cell wall or cell membrane and thus, cannot reach its site of action. Resistance of this type is known as intrinsic resistance. • If bacteria that were once susceptible to a particular drug become resistant, this is called acquired 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

How Bacteria Become Resistant to Drugs, cont.
• To enter a bacterial cell, a drug must be able to pass through the cell wall and cell membrane; chromosomal mutations may alter the structure of the cell membrane, thus preventing the drug from entering the cell; this results in drug resistance. • Bacteria can develop the ability to produce an enzyme that destroys or inactivates a drug.

– 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

How Bacteria Become Resistant to Drugs, cont.
• Bacteria can also become resistant to drugs by developing the ability to produce multidrug-resistance (MDR) pumps (also known as MDR transporters or efflux pumps). – An MDR pump enables the cell to pump out drugs before they can damage or kill the cell. • Summary: Bacteria can acquire resistance to antimicrobial agents by chromosomal mutation or by the acquisition of new genes by transduction, transformation and, most commonly, by conjugation.

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Drug Resistance
β-Lactamases
• Every penicillin and cephalosporin molecule contains a double-ringed structure (referred to as a “house and garage”). The “garage” is known as the β-lactam ring.

• Some bacteria produce enzymes, β-lactamases, that destroy this ring; when the β–lactam ring is destroyed, the drug no longer works.
– 2 types of β-lactamases - penicillinases and cephalosporinases; some bacteria produce both types. • Drug companies have developed special drugs that combine a β–lactam antibiotic with a β-lactamase inhibitor.
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Sites of β-lactamase Attack on Penicillin and Cephalosporin Molecules.

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Some Strategies in the War Against Drug Resistance
• Education of healthcare professionals and patients • Patients should stop demanding antibiotics every time they are, or their child is, sick • Physicians should not be pressured by patients and should prescribe drugs only when warranted • Clinicians should prescribe a narrow-spectrum drug if lab results indicate that it kills the pathogen • Patients should destroy any excess or out-dated medications • Antibiotics should not be used in a prophylactic manner • Healthcare professionals should practice good infection control • Patients should take drugs in manner prescribed

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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 patient’s 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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Empiric Therapy, cont.
• If pathogen identity is known, use the “pocket chart” of antimicrobial susceptibility test data from past year. • Is the patient allergic to any antimicrobial agents? • What is the age of the patient? • Is the patient pregnant? • Inpatient or outpatient?

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)?

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Pocket chart for aerobic Gram-negative bacteria. The chart is a quick reference whenever empiric therapy is necessary.

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Undesirable Effects of Antimicrobial Agents
• Reasons why antimicrobial agents should not be used indiscriminately:
– Organisms susceptible to the agent will die, but resistant ones will survive; this is known as selecting for resistant organisms. – The patient may become allergic to the agent. – Many agents are toxic to humans and some are very toxic.

– 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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Selecting for drug-resistant organisms:
A. Indigenous microflora of patient before antibiotic therapy. (S = susceptible; R = resistant) B. After antibiotic therapy has been initiated C. Resistant organisms multiply and become the predominant organisms.

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