Microbiology Chapter 12
The aminoglycoside drugs
Composed of one or more amino sugars and an aminocyclitol ring Products of actinomyces Streptomyces Micromonospora Broad antimicrobial spectrum
Polymyxins
Derived from Bacillus polymyxa Toxic to the kidney
True/False: An antibiotic that acts on the bacterial ribosome will have no effect on a human cell.
False
True/False: Cephalosporins have all the characteristics of an ideal antimicrobial drug.
False (There is no ideal drug)
True/False: Once antimicrobial susceptibility is established, choosing the right antibiotic is an easy process.
False (other factors must be considered)
True/False: An antibiotic with a therapeutic index of 4 is less toxic than one with a therapeutic index of 40.
False (you want the higher, the closer they are the more toxic)
Sulfonamides or sulfa drugs
First modern antimicrobial drugs Synthetic: do not originate from bacteria or fungi Sulfisoxazole Silver sulfadiazine Trimethoprim sulfamethoxazole
Antibacterial Drugs Targeting DNA or RNA
Fluoroquinolones
State the main goal of antimicrobial treatment. .
Goal of antimicrobial chemotherapy: Administer a drug to an infected person that destroys the infective agent without harming the host's cells The perfect drug does not exist!
Fluoroquinolones
High potency Broad spectrum Readily absorbed from the intestine Side effects: Seizures and other brain disturbances
Identifying the Agent
Identification of the infectious agent from body specimens should be attempted as soon as possible. - Before any antimicrobial drug is given - Direct examination of body fluids, sputum or stool
The MIC and Therapeutic Index
If treatment fails, the failure is due to: - The inability of the drug to diffuse into that body compartment (the brain, joints, skin) - Resistant microbes in the infection that didn't make it into the sample collected for testing - An infection caused by more than one pathogen (mixed), some of which are resistant to the drug Patient history must be considered: - Preexisting medical conditions that will influence the activity of the drug or the response of the patient - History of allergy to a certain class of drugs - Underlying liver or kidney disease - Infants, elderly and pregnant women require special precautions
Mechanisms of Drug Action Metabolic targets of chemotherapeutic agents:
Inhibition of cell wall synthesis Inhibition of nucleic acid (DNA and RNA) structure and function Inhibition of protein synthesis Interference with cell membrane structure or function Inhibition of folic acid synthesis
List and describe the five mechanisms of antibiotic resistance.
1) New enzymes are synthesized Inactivate the drug Only occurs when new genes are acquired 2)Permeability or uptake of the drug into a bacterium is decreased Usually occurs via mutation 3)Drug is 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 alternative pathway is used Occurs due to mutation of original enzyme or enzymes
Specific Mechanisms of Drug Resistance
1) New enzymes are synthesized Inactivate the drug Only occurs when new genes are acquired 2)Permeability or uptake of the drug into a bacterium is decreased Usually occurs via mutation 3)Drug is 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 alternative pathway is used Occurs due to mutation of original enzyme or enzymes
Three factors must be known before starting antimicrobial therapy
1)The identity of the microorganism causing the infection 2)The degree of the microorganism's susceptibility (sensitivity) to various drugs 3)The overall medical condition of the patient
Antibiotics and Biofilms
1,000 times less sensitive to the same antimicrobials. Different phenotypes are expressed by biofilm bacteria
Treatment of biofilms
Interrupting quorum sensing pathways Adding DNase to antibiotics Pretreatment
Tetracyclines:
Natural parent compound and synthetic derivatives Broad spectrum effects Side effects: Gastrointestinal disruption Deposition in hard tissues
Drugs in Animal Feeds
Nearly 80% of all antibiotics in the US are given to livestock. -Allegedly decreases infections and improves animal health and size -Enteric bacteria share resistance plasmids that are constantly selected and amplified by exposure to drugs -These pathogens "jump" to humans and cause drug-resistant infections
Chemistry and antibiotics
New drugs are created by chemically altering the structure of naturally occurring antibiotics to create semisynthetic drugs
Glycylcyclines:
Newer derivatives of tetracyclines Block 30s ribosomal subunit Effective against bacteria that have become resistant to tetracyclines
Antibacterial Drugs Targeting Protein Synthesis
The aminoglycoside drugs Tetracyclines Glycylcyclines
Antibacterial Drugs Targeting the Cell Wall:
Penicillins Cephalosporins
Drugs with excellent selective toxicity
Penicillins: block the synthesis of the cell wall found only in bacteria
Resistance (R) factors:
Plasmids that are transferred through conjugation, transformation, or transduction
Antibacterial Drugs Targeting Cell Membranes
Polymyxins
Penicillin - Toxicity to Organs
Skin abnormalities
Synthetic drugs
Some natural compounds cannot be obtained without the destruction of a habitat or organismal population Drugs created in the laboratory mimic the action of these natural compounds
Identify sources of the most commonly used antimicrobial drugs
Streptomyces and Bacillus in bacteria. From molds Penicillum and Cephalosporium
Antibacterial Drugs Targeting Folic Acid Synthesis
Sulfonamides or sulfa drugs
Antimalarial drugs: Quinine
principal treatment for hundreds of years Replaced by chloroquine and primaquine: less toxicity
Antibiogram:
profile of antimicrobial sensitivity
Resistance through horizontal transfer
-Resistance (R) factor -Transposable drug resistance sequences (transposons)
The ______ ______ test shows antimicrobial susceptibility using large agar plates, a bacterial lawn, and antibiotic-infused discs
(Kirby Bauer test)
Antibiotics
- Antibiotics are common metabolic products of bacteria and fungi. - Inhibiting the growth of other microorganisms in the same habitat reduces competition for nutrients - Selective advantage has allowed the genes for antibiotics production to be preserved in evolution
Selective toxicity
- Central concept in antibiotic treatment - Antimicrobial drugs should kill or inhibit microbial cells without simultaneously damaging host tissues -The best drugs in current use block the actions or synthesis of molecules in microorganisms but not vertebrate cells
Drugs most toxic to human cells
- Drugs that act upon a structure common to both the infective agent and the host cell - As the characteristics of the infectious agent become more similar to that of the host, selective toxicity becomes more difficult
Sharing of resistance genes accounts for the rapid proliferation of drug-resistant species.
- Gene transfers are extremely frequent in nature - Genes from unrelated bacteria, viruses, and other organisms live in the body's normal biota and environment
Metabolic targets of chemotherapeutic agents
- Inhibition of cell wall synthesis - Inhibition of nucleic acid (DNA and RNA) structure and function - Inhibition of protein synthesis - Interference with cell membrane structure or function - Inhibition of folic acid synthesis
Tube dilution tests
- Minimum inhibitory concentration: the smallest concentration (highest dilution) of drug that visibly inhibits growth Useful in determining the smallest effective dosage of a drug Provides a comparative index against other antimicrobials - In clinical laboratories, these tests are performed by automated machinery
Discuss two possible ways that microbes acquire antimicrobial resistance.
- Resistance through spontaneous mutation - Resistance through horizontal transfer - Sharing of resistance genes accounts for the rapid proliferation of drug-resistant species.
The Human Role in Antimicrobial Resistance
-75% of antimicrobial prescriptions are for pharyngeal, sinus, lung, and upper respiratory infections, the majority of which are likely viral -The "shotgun" approach to antimicrobial therapy -Tons of excess antimicrobial drugs produced in the US are exported to other countries.
Natural Selection and Drug Resistance
-Any large population of cells is likely to contain a few individual cells that are naturally drug resistant. -If the drug is not present in the population, the number of these resistant forms will remain low -If the population is exposed to the drug, sensitive individuals will be killed and the resistant forms will remain - As the population exposed to the antibiotic proliferates: Offspring of resistant microbes will inherit drug resistant genes The replacement population will have a preponderance of drug resistant forms Eventually the population will become completely resistant The more "fit" microbe has survived
Three major modes of action of Antiviral Chemotherapeutic Agents
-Barring penetration of the virus into the host cell -Blocking the transcription and translation of viral molecules -Preventing maturation of viral particles
Tetracyclines - Toxicity to Organs
-Bind to the enamel of teeth, causing a permanent gray to brown discoloration -Cause liver damage in pregnant women -Cross the placenta and are deposited in fetal bones and teeth Diarrhea: -Most common complaint associated with oral antimicrobial therapy -Can progress to severe intestinal irritation or colitis -Some drugs directly irritate the intestinal lining -Also caused by disruption of the intestinal microbiota
Categories of major side effects of drugs
-Direct damage to tissues through toxicity -Allergic reactions -Disruption in the balance of normal microbial biota
Allergic responses to drugs
-Drug acts as an antigen that stimulates the allergic response -Can be provoked by the intact drug molecule or substances that develop from the body's metabolic alteration of the drug Penicillin causes the most allergic reactions
Drugs most often adversely affect
-Liver (HEPATOXIC) -Kidneys (NEPHROTOXIC) -Gastrointestinal tract -Cardiovascular system and blood forming tissue (HEMOTOXIC) -Nervous system -Respiratory tract -Skin, bones, teeth
Strategies to Limit Drug Resistance
-Long-term strategies to control drug resistance: -Restriction of the use of first-line antibiotics -Enhanced surveillance mechanisms: PulseNet, WHONET Track food-borne pathogens and pathogenic microbial populations Provides up-to-date views of the changes in resistance genes
Resistance through spontaneous mutation
-Minimal chance that the mutation will be advantageous -Smaller chance that the mutation will confer drug resistance -Large microbial populations and constant rate of mutation ensures that such mutations do occur
Helping Nature Along
-Probiotics: Preparations of live microorganisms fed to animals and humans to improve intestinal biota Replace microbes lost during antimicrobial therapy Augment the biota already there Example: probiotic yogurt Safe, effective, useful in treating food allergies -Prebiotics: Nutrients that encourage the growth of beneficial microbes in the intestine Example: fructans encourage the growth of Bifidobacterium in the large intestine and discourage the growth of pathogens
Kirby-Bauer technique
-The surface of a plate of special medium is spread with test bacterium - Small discs containing pre-measured amounts of antibiotics are dispensed onto the bacterial lawn - A zone of inhibition formed during incubation is measured and compared with a standard for each drug
Drug resistance
Adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory Due to the genetic versatility and adaptability of microbial populations
Penicillins:
Can be obtained naturally or synthesized in the laboratory Consist of three parts: Thiazolidine ring Beta lactam ring Variable side chain
List and describe one antibiotic from each of the following categories: Drugs that target cell wall synthesis: Drugs that target protein synthesis Drugs that target DNA or RNA: Drugs that target folic acid synthesis:
Drugs that target cell wall synthesis: penicillins, cephalosporins Drugs that target protein synthesis: tetracyclines, glycyclines Drugs that target DNA or RNA: fluorroquinolones Drugs that target folic acid synthesis: sulfonamides
Drugs that target the cell wall Drugs that target protein synthesis Drugs that target folic acid synthesis Drugs that target DNA or RNA Drugs that target cell membranes
Drugs that target the cell wall : Penicillins, Cephalosporins Drugs that target protein synthesis: The aminoglycoside drugs Tetracyclines, Glycylcyclines Drugs that target folic acid synthesis: Sulfonamides or sulfa drugs Drugs that target DNA or RNA : Fluoroquinolones Drugs that target cell membranes : Polymyxins
Transposable drug resistance sequences (transposons):
Duplicated and inserted from one plasmid to another or from the plasmid to the chromosome
Broad spectrum drugs
Effective against more than one group of bacteria Example: tetracyclines
Intrinsic vs. acquired resistance
Intrinsic: bacteria must be resistant to any antibiotic that they themselves produce Acquired: bacterial resistance to a drug to which they were previously sensitive
Suppression and Alteration of the Microbiota
Introduction of a broad-spectrum antimicrobial: -Treats infection -Destroys normal biota, even those far removed from the original infection Superinfection: -Beneficial resident species are destroyed through antibiotic therapy -Microbes once small in number begin to overgrow and cause disease
Summarize two methods for testing antimicrobial susceptibility.
Kirby-Bauer technique & Tube dilution tests
Antihelminthic drug therapy:
Mebendazole and albendazole Pyrantel Praziquantel
Chemotherapy for other protozoan infections
Metronidazole: amoebicide
Narrow spectrum drugs
Only target a specific group Examples: polymyxin and penicillins
New Approaches to Antimicrobial Therapy
Past approach: Finding new targets in the bacterial cell Customizing drugs that aim for these new targets Novel approach: Disabling host molecules that the invaders use to enhance their position Low-tech solutions: Using bacteriophages in Eastern European countries Incorporating phage into wound dressings Phage are extremely specific and only infect one species of bacteria, leaving normal microbiota alone
The Hospital Factor
The hospital environment continually exposes pathogens to a variety of drugs. -Hospitals house susceptible patients with weakened defenses -Workforce may not strictly adhere to universal precautions -This has lead to penicillin resistance in nearly 100% of all Staphylococcus aureus strains in 30 years
Global Transport
The majority of infectious diseases are showing drug resistance in all areas of the world. Global travel and globalization of food products allows rapid export of drug resistance
Define therapeutic index, and identify whether a high or low index is preferable in a drug.
Therapeutic index (TI): The ratio of the dose of the drug that is toxic to humans to its minimum effective (therapeutic) dose The closer these two figures are to each other (the smaller the ratio), the greater potential for toxic drug reactions TI of 1.1 is a riskier choice than a TI of 10 When drugs have similar MICs, the drug with the highest TI has the widest margin of safety
True/False: An antibiotic that acts on the bacterial cell wall will have no effect on a human cell.
True
True/False: Antifungal and antihelminthic drugs can be toxic to human cells.
True (Because they are eukaryotic)