Antimicrobial agents

Question 1

Define the following definitions..

a) Antimicrobial agent
b) Antibiotic
c) chemotherapy

Answer 1

A) a chemical that kills or inhibits the growth of organisms
B) chemical produced by a microorganism that kills or inhibits the growth of another microorganism
C) any chemical-based treatment for diseases caused by bacteria, other microorganisms, parasites and tumour cells

Question 2

Name six characteristics of an ideal antimicrobial drug

Answer 2

1. Selectively toxic to the microbe but nontoxic to host cells
2. Relatively soluble; functions even when highly diluted in body fluids
3. Remains potent long enough to act and isn’t broken down or excreted prematurely
4. Doesn’t lead to the development of antimicrobial resistance
5. Compliments or assists the activities of the host’s defences
6. Reasonably priced

Question 3

Define selective toxicity

Answer 3

Drugs specifically targetting microbial processes and not human host cellular processes

Question 4

What are antibiotics? Name two bacteria and two moulds that produce them

Answer 4

Metabolic products of bacteria and fungi that reduce competition for nutrients and space.

Bacteria: Bacillus, streptomyces
Moulds: Penicillium, cephalosporin

Question 5

Which part of penicillin’s chemical structure is the key to its function?

Answer 5

The Beta-lactam ring is key to penicillin’s function

Question 6

Describe the two modes of action for antibacterial drugs and two examples of each. Compare them

Answer 6

1. Bacteriostatic: halts growth of bacteria (gives the immune system a chance to clear the infection). E.g; tetracyclines, sulfonamides
2. Bactericidal: kills the bacteria (no more active bacteria left), a subclass of bacteriocidal drugs are bacteriolytic that also lyses dead bacteria. E.g; penicillin’s, aminoglycosides

Bacteriostatic drugs tend to be slower and require a working immune system for effective elimination of the microorganism, and are therefore not advisable for use in immunosuppressed/compromised conditions and for those suffering from life-threatening acute conditions.

Question 7

How can you classify antibacterial agents? How do they relate?

Answer 7

1. Their molecular structure
2. Their spectrum of activity (broad - killing a wide variety of organisms or narrow)
3. Function or mechanism of action (how it works)

*Antibiotics within a structural class usually show similar modes of action and spectrum of activity

Question 8

Name one narrow and one broad-spectrum antibacterial, when would you use them generally?

Answer 8

Broad-spectrum: isoniazid
Narrow spectrum: tetracyclin

*begin with a broad-spectrum when unsure of what the infection is and introduce narrow-spectrum later

Question 9

Name the five main targets for antibacterials

*and an extra one from the workbook for bonus!

Answer 9

1. Inhibiting cell wall synthesis
2. Inhibiting protein synthesis
3. Inhibiting nucleic acids synthesis (DNA and/or RNA)
4. Disrupting cell membrane function
5. Antimetabolites: inhibiting bacteria’s metabolism (a lot includes inhibition of production of precursors for DNA synthesis)

Drugs blocking pathogens recognition of or attachment to its host

Question 10

How do drugs inhibiting cell wall synthesis work? Which mode of action do they typically display and how? Why are they lox toxicity to humans?

Answer 10

They target the peptidoglycans in the cell wall. They tend to be Bacteriocidal as weakening of the peptidoglycans makes the cell much more permeable, so when exposed to hypotonic environments water easily diffuses into the cell causing the cell to lyse.

Human cells have no cell wall

Question 11

Describe how these drugs target cell wall synthesis…

a) Penicillin and cephalosporin
b) Vancomycin
c) Cycloserine

Answer 11

a) binds and blocks peptidases involved in cross-linking the glycan molecules (in the cell wall)
b) Hinders peptidoglycan elongation
c) Inhibits formation of basic peptidoglycan subunits

Question 12

Compare natural penicillins to semisynthetic penicillins, how might some bacteria attain resistance to penicillin?

Answer 12

Both share a common core structure (beta-lactam ring) but the chemical modification on the side chain of the ring changes.

Some bacteria may pick up a beta-lactamase gene which encodes beta-lactamase/penicillinase, an enzyme that will break down the lactam rings in penicillin

Question 13

Name the two major subgroups of Semi-synthetic penicillins and an example of each

Answer 13

1. Penicillinase resistant penicillins: methicillin
2. Penicillins + beta-lactamase inhibitors: co-amoxiclav (combines amoxicillin (the penicillin antibiotic) with clavulanic acid (an inhibitor of the beta-lactamase)

Question 14

What does it mean when there is “co” in a drug name?

Answer 14

The drug is a combination of two or more active components

Question 15

What is the name of the mould that produces cephalosporin? Contrast the molecular structures and spectrum range of penicillin and cephalosporin

Answer 15

Produced by acremonium cephalosporium. Both have a beta-lactam ring, but penicillin is attached to a 5C ring, cephalosporin has a 6C ring and it is a broader spectrum drug

Question 16

What kind of spectrum of activity do drugs inhibiting protein synthesis have and what is their mechanism of action? Which mode of action do they tend to have?
Name four examples and what differentiates them?

What is one con of these kinds of drugs?

Answer 16

Broad-spectrum, they target prokaryotic ribosomes (not eukaryotic, human ones). Many bind to either the 30S or 50S subunits of the intracellular ribosomes causing disruption of the bacteria’s normal metabolism leading to the death of the organism or inhibition of its growth and multiplication. They tend to be bacteriostatic

1. Aminoglycosides; streptomycin, neomycin, etc
2. Tetracyclines
3. Macrolides; erythromycin
4. Chloramphenicol
   * all target different components of a ribosome’s structure/function

Can have toxicity problems

Question 17

What was streptomycin formerly used to treat?

Answer 17

The plague

Question 18

What are the two major categories of drug targets for inhibitors of nucleic acid synthesis?

Answer 18

1. The beta subunit of bacterial RNA polymerase

2. DNA gyrase/ topoisomerase; targets the replication of DNA by interfering with the separation of dsDNA

Question 19

How does rifamycin work? What kind of spectrum of activity does it have, and where has it been effective?

Answer 19

It targets the beta subunit of bacterial RNA polymerase, inhibiting RNA synthesis. Has a narrow spectrum, targetting mycobacteria/gram positives and is anti-tuberculosis

Question 20

How do quinalones and fluoroquinolones work (including their mode of action)? What is their spectrum of activity and where are they most commonly used?

Answer 20

They target DNA gyrase/ topoisomerase and tend to be bacteriocidal. They’re broad spectrum and can be effective in urinary tract and respiratory infections

Question 21

Name one example of a drug that disrupts the cell membrane function and describe its mechanism and mode of action.

What is one con of using this drug and how is this overcome?

Answer 21

Polymyxin B (targets gram negatives)

Tends to be bactericidal as it mimics the overall structure of the phospholipid bilayer by having a polar head group and hydrophobic tail so it can get into and disrupt the bacterial PM. This results in the leakage of solutes essential for the cell’s survival

Since both eukaryotic and prokaryotic cells have a PM, the action of this class of antibiotics is often poorly selective and can be toxic (i.e neurotoxic), so it is often used topically on the sites of infection

Question 22

How is polymyxin B commonly used?

Answer 22

Commonly combined with another agent, for e.g; bacitracin and/or neomycin

Question 23

What are the two major metabolic pathways targetted by antimetabolites and why? Which pathway is the more commonly targeted?

Answer 23

1. Folic acid synthesis - main targeting pathway. Folic acid is required for the synthesis of purines and nucleic acids
2. Mycolic acid synthesis or incorporation; inhibits synthesis of mycobacterium cell wall

Question 24

Name two examples of drugs targetting folic acid synthesis, what is their mode of action and why do they not all cells?

Answer 24

Sulphonamides and trimethoprim, bacteriostatic

Don’t affect human cells or certain bacteria that can use preformed folic acid.

Question 25

Name two examples of drugs inhibiting mycolic acid synthesis

Answer 25

Isoniazid (INH) and ethambutol

Question 26

Name the four methods that can be used to determine whether an antibacterial will be effective against a particular strain of bacteria/its microbial sensitivity? Describe the process of two (the major ones talked about)

Answer 26

1. Diffusion method: spread out bacterium on an agar plate and put discs containing diff antibiotics on the plate. The antibiotics will begin to diffuse out and confluent growth of the bacteria will occur. Observe the diameter of the different ‘zones of inhibition’ (areas of no bacterial growth) with diff antibiotics and/or diff concentrations of the same antibiotic to determine how susceptible the bacteria is to the antibiotic
2. Dilution method: sequential dilutions of bacteria with antibiotics and observe how the bacterial growth is affected amongst diff antibiotics

Serum Killing power and automated methods

Question 27

What is the significance of the ‘innovation gap’?

Answer 27

Period of time between the 60s and 2000s where no new antibiotics were developed, this led to the chance of bacteria developing more resistance

Question 28

Define empirical and definitive therapy

Answer 28

Empirical is when you have an idea of the infecting organism and might use a broad-spectrum antibiotic.

Definitive is when the microorganism has been identified (after lab tests) and a narrow-spectrum low toxicity antibiotic is given to complete the treatment

Question 29

Name 6 factors you would need to know about the microorganism to select the most appropriate antibiotic

Answer 29

1. Gram +/-
2. It’s susceptibility to a particular agent
3. The site of infection; how will the drug reach it (topically, orally, does it need to cross BBB, etc)
4. Patient factors; sex, pregnancy, immune system, renal/hepatic nature
5. Safety of the agent
6. Cost of the therapy

Question 30

Why are viruses more difficult targets than bacteria? When are they most vulnerable?

Answer 30

They mutate rapidly. They’re most vulnerable during reproduction, but many use the host cell organelles/enzymes to do this so antiviral compounds are often as toxic to the host as they are to the virus

Question 31

Name the five main categories that antivirals are classified in

Answer 31

1. DNA polymerase inhibitors
2. mRNA synthesis inhibitors
3. Neuraminidase inhibitors; prevents of the release of virus from the cell surface
4. Immunomodulators; can minimize the viral effect
5. Viral penetration and uncoating inhibitors (no longer used as antivirals)

Question 32

What defines a retrovirus and what is the main mechanism of action for antiretroviral drugs? Name one example of a retrovirus

Answer 32

A retrovirus is an RNA virus that gets translated into DNA and into the genome, antiretroviral drugs target this process.
E.g; HIV

Question 33

What are the three main classes of anti-retroviral drugs?

Answer 33

1. Nucleoside reverse transcriptase inhibitors (NRTIs) (inhibiting translation into DNA)
2. Protease inhibitors; proteases are important in the retroviral life cycle
3. Fusion/entry inhibitors (inhibit entry into the cell)
4. Integrase inhibitors (inhibiting viral DNA from being incorporated into the genome)

Question 34

How do infectious diseases occur?

*list four “ways”

Answer 34

1. sporadically
2. epidemics
3. pandemics
4. endemic

Question 35

What kind of antibiotics are penicillin and cephalosporin?

Answer 35

They are all beta-lactam antibiotics; meaning they have a beta-lactam ring and target the penicillin-binding proteins (PBPs; a group of enzymes found anchored in the cell membrane which is involved in the cross-linking of the bacterial cell wall). Beta-lactam antibiotics tend to be bactericidal

Question 36

How can drugs for internal infections be administered? List 5 scenarios where IV administration be preferred

Answer 36

IV, orally or intramuscularly
IV would be preferred if…
1. Oral antibiotics can’t be tolerated (i.e; the person is vomiting)
2. They can’t be absorbed (i.e; malabsorption after intestinal surgery)
3. Impaired intestinal motility (i.e opioid use)
4. No formula available
5. The patient is critically ill (brief delay may be detrimental)

Question 37

Define the following terms

a) therapeutic range

b) therapeutic index

Answer 37

a) range of concentrations of the drug that are effective without being toxic
b) dose of drug the patient can take that’s proportional to the drugs effective dose

Question 38

How might one’s gut flora be affected by the use of antimicrobial treatment?

Answer 38

May allow opportunistic pathogens to cause secondary infections (i.e; long term antibiotics may cause overgrowth of C. Albicans and C. difficile)

Question 39

What is antibiotic stewardship?

Answer 39

Healthcare system wide approach to promoting and monitoring appropriate use of antimicrobial drugs to preserve their future effectiveness.

Question 40

List the seven principles of antimicrobial stewardship recommended for secondary care

Answer 40

1. Don’t start antibiotics without clinical evidence of a bacterial infection
2. If there’s evidence or suspicion of a bacterial infection, use the local guidelines to begin antibiotic treatment
3. Document on medicines chart and in person’s medical notes the clinical indication, duration or review date, route and dose
4. Obtain cultures (to go from broad-narrow spectrum treatment and to know when to stop antibiotics if a culture suggests an infection is unlikely)
5. Prescribe single-dose antibiotics for surgical prophylaxis (surgical action taken to prevent disease) (if antibiotics have been shown to be effective)
6. Review the clinical diagnosis and the continuing need for antibiotics within 48 hours from the first antibiotic dose and make a clear plan of action
7. Clearly document the review and the subsequent decision in the person’s medical notes

Question 41

List the five principles of antimicrobial stewardship recommended for primary care

Answer 41

1. Only prescribe an antibiotic if there is likely to be a clear clinical benefit
2. Consider a no or delayed antibiotic strategy for acute self-limiting upper resp tract infections
3. Limit prescribing over the phone (except in exceptional cases)
4. Use simple generic antibiotics if possible (avoid broad-spectrum antibiotics if narrow-spectrum remains effective)
5. Avoid widespread use of topical antibiotics

Question 42

What are the main distinctive diagnostic features of Staph.aureus? *List 3

Answer 42

1. Production of an extracellular enzyme, coagulase; which converts plasma fibrinogen into fibrin with the assistance of an activator found in plasma
2. Production of thermostable nucleases that break down DNA
3. Production of a surface-associated protein known as clumping factor or bound coagulase that reacts with fibrinogen

Question 43

How have strains of S.aureus acquired resistance to methicillin?

Answer 43

Strains have acquired the MecA gene which encodes for a novel penicillin-binding protein PBP-2a, this protein shows a low affinity for methicillin and takes over the functions of PBPs when they are inactivated by the antibiotic

Question 44

Name five different types of infections caused by MRSA, how are infections transmitted?

Answer 44

Transmitted by direct contact

1. Skin
2. Bone and joint
3. Pneumonia
4. Infective endocarditis
5. TSS

Question 45

How do the majority of CA-MRSA infections begin? Who is particularly vulnerable of HA-MRSA?

Answer 45

As skin infections. Those particularly vulnerable to HA-MRSA include those in ICU and who have undergone major surgery

Question 46

What are MRSA strains resistant to? What would you choose to treat an MRSA infection with?

Answer 46

All beta lactam antibiotics and often other agents like aminoglycosides and fluoroquinolones. Glycopeptides are the agents of choice when treating a systemic MRSA infection.

Question 47

What can isolates of MRSA have that makes them susceptible or fully resistance to glycopeptide antibiotics? Name one antibiotic that can be given to treat glycopeptide resistant MRSA

Answer 47

Thickened cell walls = reduced susceptibility

VanA gene = fully resistant

Can give linezolid

Question 48

Name two antibiotics that might be given to treat an MRSA infection if the patient is allergic to penicillin

Answer 48

Erythromycin, vancomycin

Question 49

What does clostridium difficult colitis arise from? What will most patients experience during or shortly after their antibiotic treatment begins?

Answer 49

Alteration in the normal gut flora of the colon leads to C. difficile colonization and release of toxins which leads to mucosal inflammation.

Most patients develop diarrhea and abdominal pain during/after starting antibiotic treatment

Question 50

When should the diagnosis of C. difficile colitis be suspected and how is it diagnosed?

Answer 50

This condition should be suspected in any patient with diarrhea who has received antibiotics within the previous 3 months.

To diagnose, stool samples (types 5-7 on the Bristol stool chart) are sent to the lab to have an EIA test which will detect the presence of an antigen produced in high amounts by C. difficile.

Diagnosis of CDI is likely if the glutamate dehydrogenase immunoassay is positive and toxin is positive.