15. Antibiotics and Antifungals

Question 1

Define ‘chemotherapy’

Answer 1

elimination of invading cells/microorganisms/organisms

Question 2

Define ‘chemotherapeutic targets’

Answer 2

mechanisms are associated with invading species

Question 3

Define ‘effective chemotherapeutic agents’

Answer 3

• toxic to invading species/abnormal cells
• relatively non-toxic to host/normal cells

Question 4

Define ‘selective toxicity’

Answer 4

• exploitable differences between invading species and host based on evolutionary distance
• have implications for toxicity

Question 5

Why do dentists need to know about selective toxicity?

Answer 5

• chemotherapeutic agents form a major group of drugs in DPF - dentists use a lot
• forms part of clinical due care and responsible prescribing

Question 6

Invading cells/microorganisms can include …

Answer 6

• neoplastic cells (bacteria, viruses or fungi)
• parasites (protozoa, helminths)

Question 7

Antibiotics are prescribed for 2 reasons in dentistry. Give them

Answer 7

• treatment of bacterial infection - e.g severe acute ulcerative gingivitis, severe infections of dental surgery
• general phophylaxis - to prevent infection following surgery in susceptible individuals like diabetics, patients on steroids, transplant patients

Question 8

Antibacterial drugs are …

Answer 8

bacteriostatic, cidal or bacteriolytic agents

Question 9

4 ways antibacterial drugs act

Answer 9

• inhibition of cell wall synthesis e.g beta-lactam antibiotics/penicillin
• inhibiiton of protein synthesis e.g macrolides (erythromycin), tetracycline
• inhibition of bacterial nucleic acids e.g quinolones
• inhibit bacterial DNA synthesis/degrades DNA e.g metronidazole

Question 10

What do beta-lactam antibiotics do?

Answer 10

• e.g penicillins, cephalosporins
• prevent cross-linking peptides from binding to tetra-peptide side chains
• stop peptidoglycan cell wall strength - catalysed by transpeptidase

Question 11

What do macrolide antibiotics do?

Answer 11

• inhibit ribosomal function
• bacterial ribisomes are different to mammalian (50S and 30S subunits here, compared to mammalian 60S and 40S)

Question 12

What do fluoroquinolones do?

Answer 12

• inhibit DNA replication or nucleic acid synthesis
• inhibit topoisomerase II (bacterial specific DNA gyrase) prevents normal DNA supercoil process

Question 13

How else other than what fluororquinolones do can bacterial nucleic acid synthesis be targeted?

Answer 13

• inhibit synthesis of nucleotides
• alter base pairing properties of DNA template
• inhibit either DNA or RNA polymerase
• directly inhibit DNA itself

Question 14

What do antifolates do? 2 examples

Answer 14

• e.g sulfonamides, trimethoprim
• targeted inhibition of bacterial specific folate synthetic pathway

Question 15

How does herpes virus present in humans?

Answer 15

• simplex - cold sores
• varicella zoster - chicken pox
• eepstein barr (EBV) - glandular fever
• flu-like symptoms, blister/ulcer stage
• infecst sensory ganglia where becomes latent, external stimulation of latent infection

Question 16

What is Aciclovir?

Answer 16

• a synthetic guanosine analogue
• high specificity to simplex - varicella -zoster less suscpetible, cytomegalovirus/CMV small and repoducible and EBV slightly sensitive
• high therapeutic index
• requires intracellular phosphorylation - active

Question 17

Metabolic activation of Aciclovir

Answer 17

• utilises simplex virus specific thymidine kinase - monophosphorylate aciclovir
• high concs of activated form in infected cells (50-100 x conc)
• fewer side effects
• conversion to di- and triphosphate forms via host cell kinases
• antiviral action via triphosphate form

Question 18

Antiviral action of Aciclovir

Answer 18

• aciclovir-TP is a DNA chain terminator
• inhibitor of viral DNA polymerase
• host significantly less suceptible
• minimal toxicity to host cells

Question 19

Give some common superficial fungal infections

Answer 19

• candidiasis
• dermatomycoses

Question 20

Give a systemic rare fungal infection

Answer 20

systemic candidiasis

Question 21

What has happened to fungal infections recently?

Answer 21

• increase in last 20-30 years
• due to widespread use of antibiotics and increase of immunocompromised patients (cancer treatment, AIDS, transplant medicine etc)

Question 22

What is a dental indicator for antifungal drug use?

Answer 22

• oral lesions caused by candida albicans

Question 23

Fungal cell membranes contain …
What’s the main one in mammalian membranes?

Answer 23

• sterol called ergosterol
• we have cholesterol

Question 24

List antifungal agents

Answer 24

• azoles
• polyenes
• mitotic inhibitors

Question 25

Which antifungal agents are ergosterol inhibitors and which are intracellular inhibitors?

Answer 25

• azoles and polyenes are ergosterol
• mitotic are both

Question 26

What do azoles do?

Answer 26

• affect membrane lipid synthesis
• imidazoles or triazoles
• block 14-alpha demethylase cytochrome P450-mediated step in biosynthesis of ergosterol

Question 27

What do polyenes do?

Answer 27

• form pores in membrane
• nystatin or amphotericin (B) for example
• binds to sterols in membrane and forms ion channel
• higher affinity for binding to ergosterol compared with cholesterol

Question 28

What do mitotic inhibitors do?

Answer 28

• interfere with fungal cytoskeleton
• griseofulvin for example

Question 29

Azoles affect ergosterol. How?

Answer 29

• block 14-alpha demethylase cytochrome P450-mediated step in biosynthesis of ergosterol
• ergosterol decreases in fungal membrane
• effects on membrane-associated functions in fungus and increased cell wall permeability and inhibition of replication

Question 30

Azoles are effective against …

Answer 30

• dermatomycoses
• candidiasis
• some systemic infections

Question 31

Examples of imidazoles

Answer 31

• ketoconazole
• miconazole
• clotrimazole

Question 32

Example of a triazole

Answer 32

fluconazole

Question 33

What does ketoconazole do as an azole?

Answer 33

• given orally
• causes inhibition of reactions catalysed by cytochrome P450 involved in both steroid biosynthesis and drug metabolism

Question 34

2 reasons ketoconazole may not be the best drug

Answer 34

• have to monitor liver function, can cause hepatotoxicity
• largely superceded by safer alternatives except for certain very severe infections

Question 35

How does miconazole act as an azole?

Answer 35

• used topically, orally (for oral/intestinal infections) or intravenously
• less toxic than ketoconazole but can inhibit drug metabolism

Question 36

Ketoconazole and miconazole are …

Answer 36

imidazoles

Question 37

Fluconazole is a …

Answer 37

triazole

Question 38

How does fluconazole work as an azole?

Answer 38

• given orally
• well distributed and achieves high concs in CSF
• relatively non-toxic

Question 39

Fluconazole is effective when?

Answer 39

in fungal meningitis

Question 40

Advantage of imidazole over triazole

Answer 40

• doesn’t undergo metabolism
• has a long half life (22 hrs for fluconazole)
• fluconazole has less inhibition of P450 but can inhibit metabolism of some drugs

Question 41

When are polyenes used? Why?

Answer 41

-in GI infections
- poorly absorbed and only orally for this
- can be given IV as detergent or lipid complex

Question 42

Do polyenes have side effects?

Answer 42

• a variety as effects on membranes

Question 43

What does griseofulvin do?

Answer 43

• inhibits cell division by interfering with spindle formation
• used orally in treatment of dermatomycoses (hair and nails)
• appears to be taken up selectively by cells which synthesise keratin
• can be up to 18 months of taking until all infected tissue is shed