antimicrobials and antifungals Flashcards
what different types of pathogens do you know?
pathogen is a micro-organism that causes disease
may be bacterial, virus, fungi, protazoa
what is the difference between gram positive and negative bacteria?
depends on structure of cell wall
gram staining includes applying stain to bacteria and washing it off. Gram positive bacterial retains the stain and appears purple, gram negative does not hold the stain and appears pink
gram negative - thin peptidoglycan wall, outer and inner membrane , lipopolysaccharides
gram positive - thick peptidoglycan wall
describe the structure of a bacteria..
cell wall
cell membrane
naked DNA , no nucleus
plasmids
30s and 50s ribosomes (40s and 60s in eukaryotes)
no mitochondria
describe the structure of a virus
genetic material - positive/ negative RNA, DNA
proteins
contained in protein shell = capside
sometimes enveloped
can you classify different bacteria
gram staining + rods/ cones
causes of atypical pneumonias..
mycoplasm
legionella
mycobacterium
can you classify viruses
DNA/ RNA, enveloped and non-enveloped
DNA enveloped = herpes, hep B
DNA non-enveloped = adenovirus
RNA enveloped = Measles, mumps , rubella
RNA non-env = polio, hep A
describe the general structure of fungi
eukaryotic cells
membranes differ from ours - contain ergosterol (not cholesterol)
have cell walls made of chitin
2 main groups - yeast (candida) and moulds (Asperigillus)
what is the size of bacteria, virus and eukaryotes
virus less than 0.3um
bacteria 2um
erykaryotes - 10-100um
what fungal infections do you know
candida albicans - thrush of mouth, vagina. can also cause disseminated disease in immunocompromised
asperigillus - lung infection in immunocompromised
cryptococcus - fungal menigitis assoicated with HIV
how can the antibiotics be classified?
By target
Cell wall
* B lactams
* glycopeptides
Protein synthesis
* 30S - aminoglycosides , tetracyclines
* 50S - macrolides, clindamycin, linezolid, chloramphenicol
Nucleic acid synthesis
* folate synthesis - trimethroprim, sulphonamides
* DNA gyrase - quinolones
* RNA polymerase - rifampicin
what is the difference between bacteriostatic and bacteriocidal.
can you give examples
some Abx work by killing bacterial = bacteriocidal e.g. B lactam and glycopeptides and aminoglycocides
others inhibit growth - macrolides, sulphonamides
what is meant by minimum inhibitory concentration and minimum bacteriocidal concentration?
MIC = lowest Abx conc to inhibit bacterial growth
MBC = lowest conc to kill bacteria in vitro
what pharmacokinetic parameters are important when assessing Abx efficiency
peak serum level
Trough serum level
Area under serum conc time curve
some Abx work via conc dependant killing - in this case the peak serum / MIC ratio shuld be high and the 24h AUC / MIC ratio should be high
(MIC = minimum inhibitory conc)
some Abx work via time dependant killing e.g. efficacy is determined by time above MIC. for these the time above MIC i.e percentage time spent above MIC during dose period, should be high.
give an example of Abx which are dose dependant and time dependant killing..
time dependant = b lactams
conc dependant e..g aminoglycosides
what is the general structure of a penicillin
B lactam ring + Thiazolidine ring + acyl chain
acyl chain varies between different penicillins
previous Q asked to draw this
which bacteria are penicillin used for?
gram positive - inhibit thick peptidoglycan wall
e.g. cellulitis, respiratory tract infection (streptococcus, pseudomonas)
how do penicillins work
bacteriocidal Abx
inhibition of cell wall synthesis
through inhibiting transpeptidase enzyme - normally responsible for cross linking peptidoglycan wall and hence allowing strength to develop
without this strength, weak wall and bacteria cell bursts due to osmotic damage.
what are the pharmacodynamics of the penicillins?
GI - diarrhoea and cholestatic jaundice
immune - anaphylaxis and hypersensitivity.
CNS - some can be pro convulsant (benzylpenicillin)
what are the pharmacokinetics of penicillins?
A: oral, IV. some only can be given IV e.g. benzylpenicillin and amoxicillin only oral
some can penetrate BBB when it is inflammed e..g benzylpenicillin
20% metabolised
mostly excreted unchanged by kidneys
hence renal adjustments necessary
short half life
tell me about penicillin resistance..
bacteria can develop resistance in a number of ways
B lactamases can be priduced by bacteria which breaks down B lactam ring, preventing penicillins acting.
altering transpeptidase target
how can the penicillins be classified?
classified depending on their spectrum of uses….
narrow spec = flucloxacillin. NOT inhibited by B lactamases. good for staphylococcus
Broad spec = benzylpenicillin. howeever destroyed by B lactams and poor GI absorption. can cover gram positive and negative cocci
extended spec = amoxicillin. destroyed by B lactamases. good GI absorption. same as broad spec PLUS increased gram neg cover - bacilli too.
anti-pseudomonal = piperacillin, destroyed by B lactamases, poor GI absorption. broad spec PLUS pseudomonas
how can B lactamase resistance be over come?
combining penicillin with B lactamase inhibtor
e.g. co-amoxiclav = amoxicillin + clauvanic acid
e.g. Tazocin = piperacillin + tazobactam
what are the cephalosporins
bacteriocidal, B lactam antibiotics
B lactam ring like penicillin but no thiazolidine ring instead dihydrothiazine ring
mostly good for gram positive infections….
5 generations , each with improved spectrum of activity. common ones include cefuroxime (2nd gen) and cefotaxime and ceftriaxone (3rd gen). 5th generation ones have MRSA cover.
lipid solubility gives them good BBB penetration for CNS infections.
what abx belong to B lactam group
penicillins e.g. amoxicillin
cephalosporins e.g. ceftriaxone
carbapenems e.g. meropenem
which Abx should be used in caution in those with penicillin allergy?
cephalosporins - cross reactivity
both have B lactam ring
tell me about the carbopenems
bacteriocidal Abx in B lactam group
similar to penicillins and cephalosporins as all have B lactam ring.
broader spectrum, gram positive and negative and anerobic cover.
not susceptible to B lactamases
tell me about the glycopeptides..
glycopeptides are a class of Abx that work via inhibiting cell wall synthesis (non B lactams)
includes vancomycin, teicoplanin
they work by inhibiting the transpeptidase enzyme which is responsible for cross linking bacterial peptidoglycan cell wall. hence bacteria killed by osmotic pressure - bacterocidal.
can be used for both aerobic and anerobic gram positive.
pharmacodymanics
* nephrotoxic
* ototoxic
* histamine release - red man syndrome + hypotension
* allergy - teicoplanin is highest (NAP6)
pharamcokinetics
* no GI absorption - hence acts locally for C diff. can give intrathecally for CNS infection
* excreted unchanged in urine
* needs monitoring to maintain levels between 10-15mg/l
common uses of glycopeptides
- oral vancomycin for C diff
- endocarditis
- MSRA
how does ciprofloxacin work?
quinolone Abx
DNA gyrase inhibition
prevents DNA synthesis
good for gram negative
which Abx penetrate BBB well
3rd gen cephalosporins
rifampicin
ciprofloxacin
how does rifampicin work and when is it used?
TB infection
inhibits DNA dependant RNA polymerase - transcription
bacteriocidal
Mechanism of metronidazole?
breakdown of bacterial DNA
mostly works in anaerobes - mechanism involves free radical production that destroys DNA
which Abx should be avoided with alcohol?
metronidazole - nausea vomitting, headache (hangover)
how do macrolides work?
bacteriostatic
50S inhibition
prevent protein synthesis
give an example of a macrolide
erythromycin
clarithromycin
azithromycin
what precautions should be taken with macrolides?
prolong QTc
risk of rhabdo with statins
cyp450 inhibitor - increases warfarin
prokinetics - diarrhoea, N&V
give examples of aminoglycosides
gentamicin
streptomicin
what bacteria are aminoglycosides most effective against. how do they work?
gram neg
30S inhibition
what precautions should be taken with aminoglycosides?
ototoxic and nephrotoxic
can also cause muscle weakness by inhibiting nACHR presynaptically - bad for myasthenia gravis (prolong NMBA)
needs monitoring - initially dose via height and weight and then by levels
narrow therapeutic index
hence contraindicated in MG
which Abx belong to tetracyclines. how do these work?
doxycycline
30S inhibition
good for intracellular bacteria e.g. chlamydia
what are the side effects of tetracyclines
photosensitivity
shouldnt be given to children - due to teeth and bone development
mechanism of clindamycin
50S inhibition
mechanism of trimethroprim
dihydrofolate reductase inhibitor - prevents folate and nucleic acid synthesis
what is meant by antimicrobial stewardship?
coordinated programme that promotes correct use of antibiotics to reduce risk of resistance devloping and improve patient outcomes.
methods include
- only when clinically indicated
- use local guidelines
- correct dose and duration
- collect samples and target therapy to sensitivity - de-escalate from broad to narrow spec when possible
- stop spread - PPE
what is meant by antimicrobial resistance
microbes are rapidly dividing
within the population mutations will develop and some of these will be beneficial and provide resistance to Abx. these will be selected for and resistance will develop
plasmids can also share resistance genes in the population
mechanisms for mutation include
- enzymes that destroy Abx - b lactamases
- altering bacterial target
- pumping Abx out of the cell
what factors are considered when starting Abx
patient factors
* age e.g. avoid gentamicin in older people
* allergies
* renal function
* pregnancy
infection factors
* culture and sensitivities
* gram staining
* location of infection - BBB needs penetrating
local policies
what antivirals do you know?
viruses replicate within host cells
hence hard to target without killing host.
antivirals work by targeting virally infected cells selctively
they may inhibit protein synthesis, viral release or DNA replication
examples include
aciclovir - inhibits nucleic acid syntheiss as it is a guanine analogue but only activated in virally infected cells.
Tamiflu
neuraminidase inhibitor prevents release of influenza
HIV antivirals act via targetting reverse transcriptase
what antifungal agents do you know?
3 groups
azoles, polyenes, echinocandins
azoles = inhibit ergosterol synthesis - important component of fungal cell wall. e.g. fluconazole
polyenes = bind ergosterol and create a pore within membrane - intracellular contents leak. e..g amphotericin , nystatin
echinocandins - inhibit B1,3 glucan synthase - prevents synthesis of b-1,3 glucan which gives cell wall strength e.g. capsofungin
do you know any other mechanisms of antifungals?
inhibit DNA and RNA synthesis
inhibit mitosis
tell me about amphotericin
polyene antifungal agent
works via binding ergosterol and creating pores that allow leakage of fungal cell contents
given IV
for systemic fungal infections.
what are the side effects of azoles and polyenes
polyenes
- nephrotoxic, electrolyte disturbance
azoles
* hepatic dysfunction
* prolonged QT
* CYP450 inhibitor
when are antifungals given prophylactically
immunocompromised patients
e.g. transplanted patients, HIV
what are the risk factors for developing fungal disease?
immunocompromisation
HIV, diabetes, chemo, transplant , long term steroid
resp compromise - bronchiectasis , CF , prolonged mechanical ventilation
