15. Antibiotics and Antifungals Flashcards
Define ‘chemotherapy’
elimination of invading cells/microorganisms/organisms
Define ‘chemotherapeutic targets’
mechanisms are associated with invading species
Define ‘effective chemotherapeutic agents’
- toxic to invading species/abnormal cells
- relatively non-toxic to host/normal cells
Define ‘selective toxicity’
- exploitable differences between invading species and host based on evolutionary distance
- have implications for toxicity
Why do dentists need to know about selective toxicity?
- chemotherapeutic agents form a major group of drugs in DPF - dentists use a lot
- forms part of clinical due care and responsible prescribing
Invading cells/microorganisms can include …
- neoplastic cells (bacteria, viruses or fungi)
- parasites (protozoa, helminths)
Antibiotics are prescribed for 2 reasons in dentistry. Give them
- 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
Antibacterial drugs are …
bacteriostatic, cidal or bacteriolytic agents
4 ways antibacterial drugs act
- 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
What do beta-lactam antibiotics do?
- e.g penicillins, cephalosporins
- prevent cross-linking peptides from binding to tetra-peptide side chains
- stop peptidoglycan cell wall strength - catalysed by transpeptidase
What do macrolide antibiotics do?
- inhibit ribosomal function
- bacterial ribisomes are different to mammalian (50S and 30S subunits here, compared to mammalian 60S and 40S)
What do fluoroquinolones do?
- inhibit DNA replication or nucleic acid synthesis
- inhibit topoisomerase II (bacterial specific DNA gyrase) prevents normal DNA supercoil process
How else other than what fluororquinolones do can bacterial nucleic acid synthesis be targeted?
- inhibit synthesis of nucleotides
- alter base pairing properties of DNA template
- inhibit either DNA or RNA polymerase
- directly inhibit DNA itself
What do antifolates do? 2 examples
- e.g sulfonamides, trimethoprim
- targeted inhibition of bacterial specific folate synthetic pathway
How does herpes virus present in humans?
- 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
What is Aciclovir?
- 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
Metabolic activation of Aciclovir
- 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
Antiviral action of Aciclovir
- aciclovir-TP is a DNA chain terminator
- inhibitor of viral DNA polymerase
- host significantly less suceptible
- minimal toxicity to host cells
Give some common superficial fungal infections
- candidiasis
- dermatomycoses
Give a systemic rare fungal infection
systemic candidiasis
What has happened to fungal infections recently?
- increase in last 20-30 years
- due to widespread use of antibiotics and increase of immunocompromised patients (cancer treatment, AIDS, transplant medicine etc)
What is a dental indicator for antifungal drug use?
- oral lesions caused by candida albicans
Fungal cell membranes contain …
What’s the main one in mammalian membranes?
- sterol called ergosterol
- we have cholesterol
List antifungal agents
- azoles
- polyenes
- mitotic inhibitors
Which antifungal agents are ergosterol inhibitors and which are intracellular inhibitors?
- azoles and polyenes are ergosterol
- mitotic are both
What do azoles do?
- affect membrane lipid synthesis
- imidazoles or triazoles
- block 14-alpha demethylase cytochrome P450-mediated step in biosynthesis of ergosterol
What do polyenes do?
- 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
What do mitotic inhibitors do?
- interfere with fungal cytoskeleton
- griseofulvin for example
Azoles affect ergosterol. How?
- 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
Azoles are effective against …
- dermatomycoses
- candidiasis
- some systemic infections
Examples of imidazoles
- ketoconazole
- miconazole
- clotrimazole
Example of a triazole
fluconazole
What does ketoconazole do as an azole?
- given orally
- causes inhibition of reactions catalysed by cytochrome P450 involved in both steroid biosynthesis and drug metabolism
2 reasons ketoconazole may not be the best drug
- have to monitor liver function, can cause hepatotoxicity
- largely superceded by safer alternatives except for certain very severe infections
How does miconazole act as an azole?
- used topically, orally (for oral/intestinal infections) or intravenously
- less toxic than ketoconazole but can inhibit drug metabolism
Ketoconazole and miconazole are …
imidazoles
Fluconazole is a …
triazole
How does fluconazole work as an azole?
- given orally
- well distributed and achieves high concs in CSF
- relatively non-toxic
Fluconazole is effective when?
in fungal meningitis
Advantage of imidazole over triazole
- 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
When are polyenes used? Why?
-in GI infections
- poorly absorbed and only orally for this
- can be given IV as detergent or lipid complex
Do polyenes have side effects?
- a variety as effects on membranes
What does griseofulvin do?
- 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
