Exam 3 Antimicrobials 10/19 Flashcards
Principles of Antimicrobial Therapy
Administer a drug to an infected person that destroys the infective agent without harming the host’s cells
Antimicrobial drugs are produced naturally or synthetically
Origins of Antimicrobial Drugs
Antibiotics are common metabolic products of aerobic bacteria and fungi
Bacteria in genera Streptomyces and Bacillus
Molds in genera Penicillium and Cephalosporium
By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space
Interactions Between Drug and Microbe
Antimicrobial drugs should be selectively toxic – drugs should kill or inhibit microbial cells without simultaneously damaging host tissues
As the characteristics of the infectious agent become more similar to the vertebrate host cell, complete selective toxicity becomes more difficult to achieve and more side effects are seen
Mechanisms of Drug Action
*KNOW WELL FOR EXAM
- Cell wall inhibitors
Block synthesis and repair
Penicillins
Cephalosporins
Vancomycin
Bacitracin
Monobactams/carbapenems
Fosfomycin
Cycloserine
Isoniazid<– know this one for exam
- Cell membrane
Cause loss of selective permeability
Polymyxins
- DNA/RNA
Inhibit replication and transcription
Inhibit gyrase (unwinding enzyme)
Quinolones (ciprofloxacin)
Inhibit RNA polymerase
Rifampin
- Protein synthesis inhibitors acting
on ribosomes
Site of action
50S subunit
- Chloramphenicol
- Erythromycin
- Clindamycin
- Streptogramin (Synercid
Site of action
30S subunit
- Aminoglycosides
- Gentamicin
- Streptomycin
- Tetracyclines
Both 30S
and 50S
- Blocks initiation of protein
- Synthesis
- Linezolid (Zyvox)
- Metabolic pathways and products
Block pathways and inhibit
Metabolism
Sulfonamides (sulfa drugs)
Trimethoprim
The Spectrum of an Antimicrobic Drug
Spectrum – range of activity of a drug
Narrow-spectrum – effective on a small range of microbes
Target a specific cell component that is found only in certain microbes
Broad-spectrum – greatest range of activity
Target cell components common to most pathogens (ribosomes)
Antimicrobial Drugs That Affect the Bacterial Cell Wall
Most bacterial cell walls contain peptidoglycan
Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse
Active on young, growing cells
Penicillins that do not penetrate the outer membrane and are less effective against gram-negative bacteria
Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria
Antimicrobial Drugs That Disrupt Cell Membrane Function
A cell with a damaged membrane dies from disruption in metabolism or lysis
These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes
Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria
Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage
Drugs That Affect Nucleic Acid Synthesis
May block synthesis of nucleotides, inhibit replication, or stop transcription
Chloroquine binds and cross-links the double helix; quinolones inhibit DNA helicases
Antiviral drugs that are analogs of purines and pyrimidines insert in viral nucleic acid, preventing replication
Drugs That Block Protein Synthesis
Ribosomes of eukaryotes differ in size and structure from prokaryotes; antimicrobics usually have a selective action against prokaryotes; can also damage the eukaryotic mitochondria
Aminoglycosides (streptomycin, gentamycin) insert on sites on the 30S subunit and cause misreading of mRNA
Tetracyclines block attachment of tRNA on the A acceptor site and stop further synthesis
Drugs that Affect Metabolic Pathways
Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis
Drugs that Affect Metabolic Pathways
Competitive inhibition – drug competes with normal substrate for enzyme’s active site
Synergistic effect – the effects of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics
Survey of Major Antimicrobial Drug Groups
Antibacterial drugs
Antibiotics
Synthetic drugs
Antifungal drugs
Antiprotozoan drugs
Antiviral drugs
About 260 different antimicrobial drugs are classified into 20 drug families
Antibacterial Drugs that Act on the Cell Wall
Beta-lactam antimicrobials - all contain a highly reactive 3 carbon, 1 nitrogen ring
Primary mode of action is to interfere with cell wall synthesis
Greater than ½ of all antimicrobic drugs are beta-lactams
Penicillins and cephalosporins most prominent beta-lactams
Penicillin and Its Relatives
Large diverse group of compounds
Could be synthesized in the laboratory
More economical to obtain natural penicillin through microbial fermentation and modify it to semi-synthetic forms
All consist of 3 parts:
- Thiazolidine ring
- Beta-lactam ring
- Variable side chain dictating microbial activity
Subgroups and Uses of Penicillins
Penicillins G and V most important natural forms
Penicillin is the drug of choice for gram-positive cocci (streptococci) and some gram-negative bacteria (meningococci and syphilis spirochete)
Semisynthetic penicillins – ampicillin, carbenicillin, and amoxicillin have broader spectra – Gram-negative infections
Penicillinase-resistant – methicillin, nafcillin, cloxacillin
Primary problems – allergies and resistant strains of bacteria
Cephalosporins
Account for one-third of all antibiotics administered
Synthetically altered beta-lactam structure
Relatively broad-spectrum, resistant to most penicillinases, and cause fewer allergic reactions
Some are given orally; many must be administered parenterally
Generic names have root – cef, ceph, or kef
Cephalosporins: 4 generations
4 generations exist: each group more effective against gram-negatives than the one before with improved dosing schedule and fewer side effects
First generation – cephalothin, cefazolin – most effective against gram-positive cocci and few gram-negative
Second generation – cefaclor, cefonacid – more effective against gram-negative bacteria
Third generation – cephalexin, ceftriaxone – broad-spectrum activity against enteric bacteria with beta-lactamases
Fourth generation – cefepime – widest range; both gram- negative and gram-positive
Additional Beta-lactam Drugs
Carbapenems
Imipenem – broad-spectrum drug for infections with aerobic and anaerobic pathogens; low dose, administered orally with few side effects
Monobactams
Aztreonam – narrow-spectrum drug for infections by gram-negative aerobic bacilli; may be used by people allergic to penicillin
Non Beta-lactam Cell Wall Inhibitors
Vancomycin – narrow-spectrum, most effective in treatment of Staphylococcal infections in cases of penicillin and methicillin resistance or if patient is allergic to penicillin; toxic and hard to administer; restricted use
Bacitracin – narrow-spectrum produced by a strain of Bacillus subtilis; used topically in ointment
Isoniazid (INH) – works by interfering with mycolic acid synthesis; used to treat infections with Mycobacterium tuberculosis
Antibiotics That Damage Bacterial Cell Membranes
Polymixins, narrow-spectrum peptide antibiotics with a unique fatty acid component
Treat drug resistant Pseudomonas aeruginosa and severe UTI
Drugs that Act on DNA or RNA
Fluoroquinolones – work by binding to DNA gyrase and topoisomerase IV
- Broad spectrum effectiveness
Concerns have arisen regarding the overuse of quinoline drugs - CDC is recommending careful monitoring of their use to prevent ciprofloxacin-resistant bacteria
Drugs That Interfere with Protein Synthesis
Aminoglycosides – composed of one or more amino sugars and an aminocyclitol (6C) ring; binds ribosomal subunit
Drugs That Interfere with Protein Synthesis
Aminoglycosides –
Products of various species of soil actinomycetes in genera Streptomyces and Micromonospora
Broad-spectrum, inhibit protein synthesis, especially useful against aerobic gram-negative rods and certain gram-positive bacteria
Streptomycin – bubonic plague, tularemia, TB
Gentamicin – less toxic, used against gram-negative rods
Newer – tobramycin and amikacin gram-negative bacteria
Tetracycline Antibiotics
Broad-spectrum, block protein synthesis by binding ribosomes
Treatment for STDs, Rocky Mountain spotted fever, Lyme disease, typhus, acne, and protozoa
Generic tetracycline is low in cost but limited by its side effects
Chloramphenicol
Potent broad-spectrum drug with unique nitrobenzene structure
Blocks peptide bond formation and protein synthesis
Entirely synthesized through chemical processes
Very toxic, restricted uses, can cause irreversible damage to bone marrow
Typhoid fever, brain abscesses, rickettsial, and chlamydial infections
Macrolides and Related Antibiotics
Erythromycin – large lactone ring with sugars; attaches to ribosomal 50s subunit
Broad-spectrum, fairly low toxicity
Taken orally for Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diphtheria and as a prophylactic prior to intestinal surgery
For penicillin-resistant – gonococci, syphilis, acne
Newer semi-synthetic macrolides – clarithromycin, azithromycin
Drugs That Block Metabolic Pathways
Most are synthetic; most important are sulfonamides, or sulfa drugs - first antimicrobic drugs
Narrow-spectrum; block the synthesis of folic acid by bacteria
- Sulfisoxazole – shigellosis, UTI, protozoan infections
- Silver sulfadiazine – burns, eye infections
- Trimethoprim – given in combination with sulfamethoxazole – UTI, PCP
Newly Developed Classes of Antimicrobials
Formulated from pre-existing drug classes
Three new drug types:
Fosfomycin trimethamine – a phosphoric acid effective as alternate treatment for UTIs; inhibits cell wall synthesis
Synercid – effective against Staphylococcus and Enterococcus that cause endocarditis and surgical infections; used when bacteria is resistant to other drugs; inhibits protein synthesis
Daptomycin – directed mainly against gram-positive; disrupts membrane function
Ketolides – telitromycin (Ketek), new drug with different ring structure from Erythromycin; used for infection when resistant to macrolides
Oxazolidinones – linezolid (Zyvox); synthetic antimicrobial that blocks the interaction of mRNA and ribosome
Used to treat methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE)
