Microbiology Chapter 12: Antimicrobial Treatment PDF

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Chapter 12: An Antimicr timicr timicrobial obial T Trea rea reatment tment 12.1 Principles of Antimicrobial Therapy

The Origins of Antimicrobial Drugs Anitmicrobial agents are described with regard to their origin, range of effectiveness, and whether they are naturally produced or chemically synthesized. ● Antibiotics originally come from bacteria and fungi. ○ Many derived from bacteria Streptomyces and Bacillus and fungi Penicillium and Cephalosporium

● Naturally occurring antibiotics: directly from either bacteria or fungi ● Semisynthetic antibiotics: natural microbial product joind with various preselected molecules ● Synthetic antibiotics: created in the lab that mimics the action of natural

compounds

Starting Treatment Before starting it is best to know: 1. The identity of the microorganism causing the infection 2. The degree of the microorganism’s susceptibility (also called sensitivity) to various drugs 3. The overall medical condition of the patient

Identifying the Agent Direct examination of body fluids, sputum, or stoll is a rapid initial method for detecting and even identifying bacteria or fungi. ● Further testing may be needed: culturing the microbe or variety of nonculture methods

Testing for the Drug Susceptibility It is important to determine what antimicrobial treatment will work against these microbes that usually show resistance: ● Staphylococcus species ● Neisseria gonorrhoeae ● Streptococcus pneumoniae ● Enterococcus faecalis ● Aerobic Gram-negative enteric bacilli Selecting the correct antimicrobial agent begins by testing the in vitro activity of several drugs against the infectious agent. ● Involve exposing a pure culture of the bacterium to several drugs and determining whether they stop the growth of the microbe. The Kirby-Bauer technique is an agar diffusion test that provides data on antimicrobial susceptibility. ● A plate of medium is spread w/ the test bacterium, and small discs containing antimicrobial are dispensed onto the bacterial lawn. ● After incubation, the zone of inhibition surrounding the discs is measured and compared. ● This profile of antimicrobial sensitivity is called an antibiogram. ● An alternative test is the Etest

More sensitive and quantitative results can be obtained with tube dilution tests. ● First, the antimicrobial is diluted in tubes of broth, then each tube is inoculated with pure culture, then incubated and examined for growth (tubidity). ● The smallest concentration, which is the highest dilution, of durg that inhibits growth is called the minimum inhibitory concentration (MIC). ○ Useful in determining the smallest effective dosage of a drug and compares them

The MIC and Therapeutic Index The results of antimicrobial sensitivity tests guid the physician’s choice of a suitable drug. In a controlled situation, when treatment fails, the failure is due to: 1. The inability of the drug to diffuse into that body compartment (brain, joints, skin) 2. Resistant microbes in the infection that did not make it into the sample collected

for testing 3. An infection caused by mroe than one pathogen, some of which are resistant to the drug It is best to choose the one that has the fewest effects on microbes other than the one being targeted. This descreases the potential for a variety of adverse reactions. It is best to choose the one with high selective toxicity for the infectious agent and low human toxicity. The therapeautic index (TI) is defined as the ratio of the dose of the drug that is toxic to humans to its minimum effective (therapeutic) dose. ● The smaller the ratio, the worse it is

12.2 Interaction Between Drug and Microbe Drugs can either disrupt cell processes or damage structures or inhibit their synthesis. ● They should be selectively toxic, kill microbial cells without damaging host tissues

Mechanism of Drug Action The first step is to identify the structural and metabolic needs of the living microbe. Once determined, methods of removing, disrupting, or interfering with these can be figured out. Metabolism of a cell is marked by the production of a new cell wall components, DNA, RNA, proteins, and cell membrane. Antimicrobial drugs are divided based on which metabolic target they affect: 1. Inhibition of cell wall synthesis 2. Inhibition of nucleic acid (RNA and DNA) strucutre and function 3. Inhibition of protein synthesis, particularly ribosomes 4. Interference with cell membrane structure or function 5. Inhibition of folic acid synthesis

12.3 Survey of Major Antimicrobial Drug Groups Broad spectrum: drugs effective against more than one group of bacteria

Narrow spectrum: drugs that target a specific group

Antibacterial Drugs Targeting the Cell Wall Penicillin and Its Relatives The penicillin group of antibiotics is a large group of compounds that mostly end in -cillin. All consist of three parts: a thiazoldine ring, a beta-lactam ring, and a variable side chain that determines its microbicidal activity. All relatively mild and well tolerated due to mode of action on cell walls. Three subcategories: ● Natural ○ Penicillin G & V ● Semisynthetic ○ Ampicillin ○ Amoxicillin ● Synthetic ○ Methicillin ○ Nafcillin ○ Cloxacillin

The Cephalosporin Group of Drugs The cephalosporins are a group of antibiotics that were isolated in the 1940s from the mold Acremonium. ● Similar to penicillin, they have a beta-lactam structure and a similar mode of action ● Usually end in -cef, -ceph, or -kef ● Broad spectrum ● Resistant to most penicillinases

● Cause few allergic reactions then penicillins ● Some given orally but some must be given parenterally by injection into a muscle or vein ● There are 5 generation that display different levels of antibacterial activity

Other Beta-Lactam Antibiotics Newer antibiotics like doripenem and imipenem belong to a class called carbapenems. ● Powerful but potentially dangerous and reserved for use in hospitals Bacitracin: narrow-spectrum antibiotic produced by a strain of the bacterium Bacillus subtilis ● Used in Neosporin Isoniazid (INH): bactericidial to Mycobacterium tuberculosis, but only against growing cells Vancomycin: narrow-spectrum antibiotic most effective in treating staphylococcoal infections

Antibacterial Drugs Targeting Protein Synthesis Aminoglycosides: antibiotics composed of one or more amino sugars and a 6-carbon rings ● Products of various species of soil actinomycetes in the genera Steptomyces and Micromonospora ● Broad antimicrobial spectrum because they inhibit the structures involved in protein synthesis ● Useful in treating infections caused by aerobic gram-negative rods and certain gram-positive bacteria ● Streptomycin

Tetracycline Antibiotics Terrmycin and tetracycline, the natural parent compounds and semisynthetic derivatives are known as the tetracyclines. ● Ability to bind to ribosomes and block protein synthesis ● Broad spectrum

Glycylcyclines Glycylcyclines are newer derivatives of tetracyclines. ● Bind to the 30S ribosomal subunit and block the entry of the tRNA

Erythormycin and Telithromycin ● Broad spectrum and fairly low toxicity ● Blocks protein synthesis by attaching to the ribosome

Synercid A combined antibiotic from the streptogramin group of drugs. ● Effective against Staphylococcus and Enterococcus species ● One of the main choices when other drugs are ineffective ● Binds to sites on the 50S ribosome, inhibiting translation

Antibacterial Drugs Targeting Folic Acid Synthesis The very first modern antimicrobial drugs (1930s) were the sulfonamides, or sulfa drugs. ● Synthetic, do not originate from bacteria or fungi

Antibacterial Drugs Targeting DNA or RNA Fluoroquinolones exhibit several ideal traits, including high potency and broad spectrum. ● Inhibit a variety of gram-positive and gram-negative bacterial species ● 4 generations Another product of genus Streptomyces is rifamycin, which is altered chemically into rifampin. ● Used against Mycobacterium ● Inhibits RNA polymerase

Antibacterial Drugs Targeting Cell Membranes Some drugs target membranes, but are not usually the first choice except in a few circumstances. ● Bacillus polymyxa is the source of the polymyxins, narrow spectrum peptide antibiotics w/ a fatty acid component that contributes to their detergent activity.

Agents to Treat Fungal Infections Because the cells of fungi are eukaryotic, they present problems for antimicrobial treatmment. ● Most drugs are designed for bacteria and are ineffective in combating fungal infections ● Fungal and human cells mean drugs toxic to fungal cells can also harm human tissues

Antiprotozoal and Antihelminthic Treatment ● Quinine was the main treatment for malaria for centuries, but it was replaced by synthesized quinolones, chloroquine and primaquine, which are less toxic to humans. ● Flagyl (a metronidazole) is effective in treating mild and severe intestinal infections and hepatic disease.

Antihelminthic Drug Therapy Most effective drugs immobilize, disintegrate, or inhibit the metabolism of all stages of the life cycle. ● Albendazole: a broad spectrum drug that inhibits function of microtubules in roundworms ● Pyrantel paralyzes the muscles of intestinal roundworms ● Praziquantel and Ivermectin are used for tapeworm and fluke infections

Antiviral Agents There are three major modes of action used by antiviral drugs: 1. Barring penetration of the virus into the host cell 2. Blocking the replication, transcription, and translation of viral molecules 3. Preventing the maturation of viral particles

Interferon: a alternative to artificial drugs that is human-based. ● A glycoprotein produced by fibroblasts and leukocytes in response to immune

stimuli

12.4 Antimicrobial Resistance Interactions Between Microbes and Drugs: The Acquisition of Drug Resistance Drug resistance: microorganisms begin to tolerate an amount of drug that would usually be inhibitory ● Due to genetic versatility and adaptability of microbial populations ● Can be intrinsic or acquired

Specific Mechanisms of Drug Resistance 1. New enzymes are synthesized. These inactivate the drug (only occurs when new genes are acquired). 2. Permeability or uptake of drugs into bacterium is decreased (usually occurs via mutation). 3. Drugs are immediately eliminated (usually occurs via acquisition of new genes). 4. Binding sites for drug are decreased in number or affinity (can occur via mutation or acquisition of new genes). 5. An affected metabolic pathway is shut down or an alternative pathway is used (occurs due to mutation of original enzyme or enzymes)....