Exam 3 Antimicrobials 10/19

Question 1

Principles of Antimicrobial Therapy

Answer 1

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

Question 2

Origins of Antimicrobial Drugs

Answer 2

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

Question 3

Interactions Between Drug and Microbe

Answer 3

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

Question 4

Mechanisms of Drug Action

*KNOW WELL FOR EXAM

Answer 4

1. Cell wall inhibitors

Block synthesis and repair
Penicillins
Cephalosporins
Vancomycin
Bacitracin
Monobactams/carbapenems
Fosfomycin
Cycloserine
Isoniazid<– know this one for exam

2. Cell membrane

Cause loss of selective permeability
Polymyxins

3. DNA/RNA

Inhibit replication and transcription
Inhibit gyrase (unwinding enzyme)
Quinolones (ciprofloxacin)
Inhibit RNA polymerase
Rifampin

4. 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)

5. Metabolic pathways and products

Block pathways and inhibit
Metabolism
Sulfonamides (sulfa drugs)
Trimethoprim

Question 5

The Spectrum of an Antimicrobic Drug

Answer 5

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)

Question 6

Antimicrobial Drugs That Affect the Bacterial Cell Wall

Answer 6

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

Question 7

Antimicrobial Drugs That Disrupt Cell Membrane Function

Answer 7

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

Question 8

Drugs That Affect Nucleic Acid Synthesis

Answer 8

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

Question 9

Drugs That Block Protein Synthesis

Answer 9

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

Question 10

Drugs that Affect Metabolic Pathways

Answer 10

Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA and RNA synthesis

Question 11

Drugs that Affect Metabolic Pathways

Answer 11

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

Question 12

Survey of Major Antimicrobial Drug Groups

Answer 12

Antibacterial drugs
Antibiotics
Synthetic drugs
Antifungal drugs
Antiprotozoan drugs
Antiviral drugs

About 260 different antimicrobial drugs are classified into 20 drug families

Question 13

Antibacterial Drugs that Act on the Cell Wall

Answer 13

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

Question 14

Penicillin and Its Relatives

Answer 14

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

Question 15

Subgroups and Uses of Penicillins

Answer 15

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

Question 16

Cephalosporins

Answer 16

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

Question 17

Cephalosporins: 4 generations

Answer 17

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

Question 18

Additional Beta-lactam Drugs

Answer 18

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

Question 19

Non Beta-lactam Cell Wall Inhibitors

Answer 19

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

Question 20

Antibiotics That Damage Bacterial Cell Membranes

Answer 20

Polymixins, narrow-spectrum peptide antibiotics with a unique fatty acid component

Treat drug resistant Pseudomonas aeruginosa and severe UTI

Question 21

Drugs that Act on DNA or RNA

Answer 21

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

Question 22

Drugs That Interfere with Protein Synthesis

Answer 22

Aminoglycosides – composed of one or more amino sugars and an aminocyclitol (6C) ring; binds ribosomal subunit

Question 23

Drugs That Interfere with Protein Synthesis

Answer 23

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

Question 24

Tetracycline Antibiotics

Answer 24

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

Question 25

Chloramphenicol

Answer 25

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

Question 26

Macrolides and Related Antibiotics

Answer 26

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

Question 27

Drugs That Block Metabolic Pathways

Answer 27

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

Question 28

Newly Developed Classes of Antimicrobials

Answer 28

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)