Antibiotics - don't do these.. use "fever" below, which has ABx in Flashcards
MOA of macrolide? (2)
> Bind to 50s ribosome sub-unit and inhibit protein synthesis (block translocation)
BACTERIOSTATIC
Which bacteria are macrolides active against? (7)
Gram +ve e.g. staph, strep
Some gram -ve including: > H flu (not erythro) > N meningitidis > Legionella > Mycoplasma > N gonorrhoea
What clinical uses do macrolides have? (4)
> Skin infections
Respiratory infections including pneumonia, legionella, mycoplasma, H flu, chlamydia
STDs (chlamydia, gonorrhoea)
Any strep / staph infections
Common side effects of macrolides? (5)
> N&V
Diarrhoea (erythro ++)
Prolonged QT interval -> arrythmias
Liver dysfunction -> cholestatic jaundice
Increased risk of statin-induced myopathy
Cautions with macrolides? (2)
> Patients with risk of QT prolongation e.g. electrolyte disturbances, other medications that prolong QT
Patients with MG (may aggravate)
Patients taking warfarin, theophylline, statins (CYP metabolised drugs)
Which macrolide causes diarrhoea most commonly and why?
> Erythromycin
> Due to pro-motility effect
When would a macrolide be used in a non-infection setting, why, and which one?
> Erythromycin
Pro-motility
Gastroparesis
Which antibiotics must caution be taken with warfarin and why? What other drugs should be monitored?
> Macrolides
Quinolones
INHIBITION of hepatic CYP450 enzymes
Theophylline, statins
> Also Rifampicin but thats the other way, it INDUCES hepatic CYP450 enzymes
What is the dosing regime and routes available for azithromycin?
> OD
> PO only
What is the dosing regime and routes available for erythromycin?
> QDS or BD
> PO or IV
What is the dosing regime and routes available for clarithromycin?
> BD (modified release = OD)
> PO or IV
What are the names of the macrolides, and their routes?
> Erythromycin PO/IV
Clarithromycin PO/IV
Azithromycin IV
What are the names of the aminoglycosides? (5)
> Gentamicin > Tobramycin > Amikacin > Streptomycin > Neomycin
What is the MOA of aminoglycosides?
> Enter bacterial cells via oxygen-dependent transport system
Bind to 30s sub-unit of ribosome to inhibit protein synthesis
Spectrum of aminoglycosides? (1+5+3)
> Aerobes only as they require oxygen-dependent transport system
> Gram -ve aerobic rods
e.g. E coli, pseudomonas, klebsiella, proteus, enterobacter
> Gram +ve aerobes e.g. staph, strep, mycobacteria
Routes of administration of aminoglycosides? (3 main points)
> Poor oral absorption (highly polar), low lipid diffusion and poor penetration across body membranes so PO not available
> IV or IM injection
> Tobramycin = inhaler/neb
Clinical uses of aminoglycosides?
Gentamicin is the aminoglycoside of choice in the UK usually. It’s used in serious infections.
Usually given in combination therapy.
> Endocarditis (gent) > Bacteraemia / sepsis > TB (streptomycin) > S aureus food poisoning > CF (tobra)
What other antibiotics are aminoglycosides usually administered with and why?
Penicillin or a macrolide because they increase the activity of the aminoglycoside and reduce its toxicity
How are aminoglycosides excreted?
Renal (urine)
Adverse effects of aminoglycosides?
There are many:
> Nephrotoxicity can lead to renal failure
Ototoxicity due to damage of VIIIth cranial nerve causing irreversible deafness and vestibular damage
NMJ breakdown
Headache, fever, dizziness
Why are the aminoglycosides considered more dangerous than many other ABx?
Narrow therapeutic window and serious side effects
Contraindications for aminoglycoside use?
> Myasthenia gravis
Cautions for aminoglycosides?
> Elderly: vulnerable to nephrotoxicity and ototoxicity
> Regular monitoring of serum levels (high peak = lower dose, high trough = longer interval)
Oral absorption, lipid diffusion and membrane penetration of aminoglycosides?
> Poor oral absorption
Low lipid diffusion
Poor penetration
Therefore no PO formulations available
Tetracyclines drug names? (4)
> Doxycycline
Tetracycline
Oxytetracycline
Minocycline
Tetracyclines MOA?
> Protein sythesis inhibitor
> Binds to 30s ribosome subunit - prevents amino acids being added during protein synthesis
Tetracyclines spectrum of activity?
> Broad spectrum
> Gram +ve aerobes (staphs & streps)
> Gram -ve rods
Tetracyclines clinical application? (2 main ones in caps, and several others)
First line for:
> CAP (LOCALLY) > Chlamydia infections > Rickettsia infections > Brucella > Borrelia
Also used in:
> ACNE
Respiratory mycoplasma
Cautions associated with tetracyclines administration?
> May increase muscle weakness associated MG
May worsen SLE
Forms chelates with Mg/Ca/Al - so not taken with antacids or dairy, and not suitable for children, breastfeeding or pregnant females
Contraindications associated with tetracycline administration?
> Not for 1. children under 12 2. pregnancy 3. breast-feeding women, as concentrates within tissues undergoing calcification causing STAINING and occasional DENTAL HYPOPLASIA, and can cause GROWTH STUNTING
Adverse effects associated with tetracyclines?
> Phototoxicity reactions
> Irritation of gastric mucosa so take with food (but not dairy)
Why are tetracyclines less commonly used clinically than they were several years ago?
> Development of resistance to tetracyclines among many bacteria
Excretion of tetracyclines is via which route?
> Excreted unchanged in bile (so via liver)
Are tetracyclines safe for patients with renal impairment?
> Doxycycline & minocycline are safe for patients with renal impairment
Are tetracyclines safe for patients with hepatic impairment?
> Tetracyclines shouldn’t be used, or should be used with caution in patients with hepatic impairment
Metronidazole MOA?
> Direct DNA damage via reactive oxygen species formation
> Bactericidal
Metronidazole spectrum of activity?
> Anaerobes e.g. clostridium, h. pylori, bacteroides fragilis
> Protozoa e.g. giardia, amoebae
Clinical application of metronidazole?
> Activity against anaerobes e.g. abdominal infections / abscesses, brain/liver abscesses, oral infections, aspiration pneumonia, C diff, bacterial vaginosis
> Protozoal infections e.g. giardiasis, amoebiasis
> GI surgery prophylaxis
> Also polymicrobial infections (as one is possibly going to be anaerobic!)
Does metronidazole have good oral bioavailability?
Yes, metronidazole has 100% oral bioavailability
How is metronidazole metabolised?
Metronidazole is metabolised by the liver, which means it is excreted in faeces, and needs to be used in caution in those with hepatic impairment
What is “oral bioavailability”?
It is the concentration of drug available after oral administration, when compared to intravenous infusion.
E.g. if 100mg of drug X is administered orally and 10mg is within the blood, but 100mg of drug X is administered IV and 100mg is available in the blood, the oral bioavailability is 10/100 = 10%.
Adverse effects of metronidaole? (4)
> Metallic taste
Rashes
“Disulfiram effect” (reaction when taken with alcohol)
GI effects e.g. N&V
Safety of metronidazole in pregnancy?
Mutagenic especially in 1st trimester, but manufacturer suggests only avoiding high dose regimens
Metronidazole routes available?
IV, PO and rectal
Which antibiotic classes shouldn’t be taken with dairy or antacids?
> Tetracyclines
> Quinolones
Examples of quinolones? (4)
> Ciprofloxacin
Ofloxacin
Levofloxacin
Gatifloxacin
MOA of quinolones?
> DNA/RNA synthesis inhibitor by inhbiition of DNA gyrase (topoisomerase II), preventing supercoiling
Bactericidal (eventually degrades DNA after preventing supercoiling if concentration high enough)
Spectrum of quinolones?
> Gram +ve and gram-ve
> Particularly active against gram -ve e.g. salmonella, neiserria, pseudomonas, shigella, campylobacter
> Some efficacy against anaerobes (not first line)
Clinical uses of quinolones?
> Wide usage
> Respiratory tract infections > Bone & joint infections > UTIs (not first line though) > GI infections > Gonorrhoea
Oral bioavailability of quinolones?
> Good oral bioavailability so can treat severe infections orally (70-90% for cipro)
Excretion route of quinolones?
Kidneys primarily
What instructions would you give in regards to taking quinolones?
> Not with dairy or antacids as chelates with Ca/Al/Mg/Zn/Fe which can interfere with absorption
What drugs would you monitor the effects of in a patient newly started on ciprofloxacin?
Theophylline, warfarin etc
CYP450 inhibition = higher concentrations in blood = possible toxicity
Adverse effects of quinolones? (
> Reduces seizure threshold so careful with epilepsy (even worse with NSAIDs)
Tendon damage (may occur within 48h of treatment)
Can prolong QT interval
Confusion/drowsiness/dizziness (driving)
N&V/diarrhoea/headache
Which drug class has synergistic effects on reducing seizure threshold when used concurrently with ciprofloxacin?
> NSAIDs
Cautions of quinolones?
> Epilepsy history (seizure threshold lowers)
Concurrent NSAIDS (makes seizure A/E worse)
Myasthenia gravis (risk of exacerbation)
Patients with risk of QT prolongation e.g. bradycardia, long QT syndrome
History of tendon disorders related to quinolone use
> Children / adolescents (arthropathy in weight-bearing joints in young animals)
Trimethoprim MOA?
> Antimetabolite
> Inhibits bacterial conversion of folate to active folate by inhibition of dihydrofolate reductase
> Bacteriocidal
Trimethoprim spectrum of activity?
> Enterococci (a gram +ve diplococci species, 90% are E. faecalis)
> Some gram -ves
Trimethoprim clinical use?
> First line treatment of UTIs
> UTI prophylaxis (low dose at night)
> Pneumocystis pneumonitis?
Trimethoprim is first line treatment for what, and why is it so effective?
> UTIs
> Because it is in high concentrations in the urinary tract as it is excreted from there unchanged (therefore still active!)
What would you give and how, for prophylaxis of UTIs?
> Trimethoprim, low dose at night
Cautions/contra-indications to trimethoprim use?
> Contraindicated in first trimester of pregnancy
(though patient likely to refuse at any stage in pregnancy!)
> Contra-indicated in blood dyscrasias
> Caution in those with pre-disposition to folate deficiency
Alternative for UTI treatment if trimethoprim allergic?
> Cefalexin or nitrofurantoin
Which drug would you want to be sure the patient wasn’t taking if you were going to prescribe trimethoprim, and why?
> Methotrexate (anti-cancer)
> Also lowers folate so can cause serious depression of haematopoiesis
What is co-trimoxazole?
Trimethoprim and sulfamethoxazole
MOA of co-trimoxazole?
Inhibits folate processing at 2 sequential steps:
> Inhibits dihydrofolate synthetase
> Inhibits dihydrofolate reductase
Cautions/adverse effect of co-trimoxazole?
Associated with rare but serious side effects such as Stevens-Johnson syndrome & bone marrow depression
Clinical use of co-trimoxazole?
Pneumocystis jiroveci pneumonia, toxoplasmosis
e.g. in patients with AIDS / immunocompression
Absorption of trimethoprim?
Rapid and complete oral absoprtion from GIT
Glycopeptide drug examples and their dosing regimen?
> Vancomycin (BD)
> Teicoplanin (OD)
MOA of glycopeptides
> Cell wall synthesis inhibitors: bind to cell wall causing blockage of polymerisation of glycopeptide
> Causes secondary damage to cytoplasmic membrane (as well as cell wall synthesis inhibition)
> BACTERICIDAL (because of the cell membrane damage)
Spectrum of glycopeptides?
> Gram +ve organisms (including B lactamase producing gram +ves)
> Multi-resistant organisms e.g. MRSA
Note that some MRSA now resistant to vancomycin!
Clinical use of glycopeptides?
> MRSA
> Oral used for C diff if metronidazole doesn’t work or is contraindicated
> Endocarditis (also for prophylaxis before prosthesis insertion)
> Serious gram +ve infections
How is the oral absorption for vancomycin?
> Poor
> This means that IV is the usual route, except in C diff when oral is suitable (as C diff exists in gut, not within the cells)
Excretion of vancomycin?
> Renal excretion - dose needs to be adjusted in renal impairment
Are the glycopeptides concentration-dependent or time-dependent?
Time dependent
Adverse effects of glycopeptides?
> “red man syndrome” if infused too rapidly (vanc)
> phlebitis if not diluted sufficiently (vanc)
> Nephrotoxicity (particularly in renal impairment and elderly)
> Ototoxicity (particularly in renal impairment and elderly)
> Neutropenia (1w+)
Which antibiotics require monitoring of serum concentrations and why? How often would you monitor them?
> Glycopeptides (vancomycin particularly)
> Can cause nephrotoxicity and ototoxicity
> Monitor after 3rd or 4th dose in everybody, but even sooner in renal impairment (as renally excreted)
> Also monitor in pregnancy as toxic concentrations can cause fetal harm
Are the glycopeptides safe in pregnancy?
> If benefits outweigh risk, but serum concentrations must be regularly monitored to prevent toxic doses reaching the foetus
What is Rifampicin’s mechanism of action?
> Inhibits DNA-dependent RNA polymerase activity in bacterial cells
Spectrum of activity of Rifampicin?
> Active in mycobacteria (TB)
> Staphylococci including MRSA
> N. meningiditis (nasal carriage)
Clinical uses of rifampicin?
> TB
> Always used in combination with a second antibiotic to avoid conferring resistance
> Eliminating nasal carriage of N. meningitidis*
> Serious staph infections including MRSA, endocarditis
> Leprosy
- (so meningitis prophylaxis basically)
Which drug causes your bodily fluids to go orange? (Bile, urine, tears, contact lenses)
> Rifampicin
What cautions are taken with rifampicin?
> Hepatic monitoring during treatment
> Those on contraceptive pill (alternative should be taken)
> Warn patient that contact lenses / bodily fluids likely to turn orange
> CYP450 enzyme inducer - may need to alter levels of warfarin, theophylline etc
Which antibiotic would require family planning advice to be given in certain situations and why?
> Rifampicin
> Effectiveness of hormonal contraceptives are reduced and so alternative family planning advice should be given
What significant drug interaction(s) are caused by Rifampicin?
> CYP450 induction
> Therefore affects concentrations (lowers them) of warfarin, theophylline, statins etc
What are the 1st generation cephalosporins?
> Cefadrine
Cefadroxil
Cefalexin
What are the 2nd generation cephalosporins?
> Cefaclor
> Cefuroxime
What are the 3rd generation cephalosporins?
> Cefotaxime
Ceftazidime
Ceftriaxone
What is the MOA of the cephalosporins?
> Interferes with cross-linking of the bacterial cell wall
> Only active in rapidly dividing cells (e.g. not effective in abscesses)
Spectrum of cephalosporins
Primary coverage (not absolute limitations but a good general rule of thumb):
> 1st gen: Gram +ves (not MRSA)
> 2nd gen: Anaerobes and some gram -ves
> 3rd gen: Gram -ves
> 4th gen: Pseudomonas
> 5th gen: ?MRSA
Name 3 first generation cephalosporins and their clinical use
> Cefadrine
Cefadroxil
Cefalexin
> Skin and soft tissue infections
Name 2 second generation cephalosporins and their clinical use
> Cefaclor
Cefuroxime
> Infections that should be self limiting that don’t clear up e.g. otitis media, sinusitis, upper respiratory tract, skin and soft tissue
Name 3 third generation cephalosporins and their clinical use
> Cefotaxime
Ceftazidime
Ceftriaxone
> Greatest gram -ve activity; meningitis, pseudomonas
Which cephalosporin can be used in meningitis due to good CSF penetration? What class is it?
> Ceftriaxone
> Third-generation
Which cephalosporin is active against pseudomonas? What class is it?
> Ceftazidime
> Third-generation
Adverse effects of cephalosporins?
> 10% of patients allergic to penicillins will be allergic to cephalosporins due to same beta-lactam ring
> Diarrhoea / GI upset
Excretion of cephalosporins?
> Renal, except ceftriaxone
Which cephalosporin is excreted differently to the others?
> Ceftriaxone, hepatically
Do cephalosporins have good oral absorption?
No
What is the treatment for TB?
RIPE
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
6 months??
Why is benzylpenicillin a treatment for meningitis even though penetration through the healthy blood brain barrier is poor?
> When the meninges are inflamed, the BBB is more permeable to penicillins and the drug can reach the CSF
MOA of penicillins?
> Cell wall synthesis inhibitor - interfering with cross-linking of the cell wall
> Not useful in abscesses as only active during production of cell wall e.g. in rapidly dividing cells
> Bactericidal
Excretion of penicillins?
> Urine
What percentage of patients is hypersensitivity to penicillin prevalent in? (according to the BNF)
10%
What percentage of patients is anaphylaxis due to penicillins estimated to be prevalent in?
0.2%
Which individuals are at higher risk of anaphylaxis to penicillins?
> Atopic individuals (asthma, eczema, hay fever)
> History of anaphylaxis, rash, urticaria due to penicillins
> Those who had a history of minor rash, or a rash occurring more than 72 hours after penicillins should not have penicillins withheld for serious infectons!
Adverse effects of penicillins?
> Hypersensitivities are most common e.g. rash, anaphylaxis
> Diarrhoea due to disturbance of bowel flora
> Cholestatic jaundice (Fluclox over 2/52)
> Convulsions/encephalopathy due to cerebral irritation in poor renal function
Which drug has a possible risk of causing cholestatic jaundice?
> Flucloxacillin (particularly if used for > 2/52)
What demographic of patients is at risk of convulsions, and due to which drug class, and why?
> Those with impaired renal function
> Due to penicillins
> Impaired renal function means high concentrations can accumulate and cause cerebral irritation which can cause convulsions
Which is the adverse effect most commonly caused by penicillins?
> Diarrhoea, due to disruption of bowel flora. Can also cause ABx associated colitis.
Which commonly used penicillin is best by a non-oral route, what is the route, and why?
> Benzylpenicillin (Pen G)
> IV
> Pen G is inactivated by gastric acid and so absorption from the gut is low
Spectrum of action of benzylpenicillin?
> Gram -ve cocci & bacilli
Gram +ve cocci
Spirochetes eg. syphilis
BUT NOT BETA LACTAMASE PRODUCERS e.g. most staph aureus, and many of the common gram -ve rods!
Spectrum of action of phenoxymethylpenicillin (Pen V)?
> Gram -ve cocci & bacilli
Gram +ve cocci
Spirochetes eg. syphilis
BUT NOT BETA LACTAMASE PRODUCERS e.g. most staph aureus and many of the common gram -ve rods e.g. E coli, Klebsiella, Proteus
** Note that Pen V and Pen G have basically the same spectrum, Pen V is just PO and Pen G is IV **
Clinical use of Pen G?
> Throat infections > Otitis media > Endocarditis > MENINGOCOCCAL DISEASE > Anthrax
I reckon the main things to remember are that penicillins are given for throaty stuff, endocarditis (as its common caused by gram positives), and a dose of Pen G is given as soon as meningitis is suspected, even before the patient gets to hospital if possible
Clinical use of Pen V?
> Otitis media
Throat infections e.g. tonsils etc
Some skin infections such as cellulitis
Group A strep infections
I think its important to remember perhaps that Pen G is active against Strep B and Pen V against Strep A. Also that all throaty stuff is generally penicillins.
Are penicillins safe in pregnancy / breast feeding etc?
Yes
What bacteria are particularly known to be beta lactamase producers, and therefore are not treated with Pen V or Pen G? What drug is used instead?
> Staphylococci spp.
> Flucloxacillin
Clinical use of flucloxacillin?
> Only used in staph infections as they are penicillin-resistant
> Otitis externa > Impetigo > Cellulitis > Pneumonia (in combo therapy) > Staph endocarditis > Osteomyelitis
So basically if its on the skin, or endocarditis, its likely to be flucloxacillin as the infective organism is probably a staph.
Cautions with flucloxacillin?
> Risk of kernicterus in jaundiced neonates
> Risk of cholestatic jaundice in long term use (> 2/52)
Adverse effects of flucloxacillin?
> Gi upsets
> Cholestatic jaundice
Clinical use of amoxicillin?
> Broad-spectrum penicillin
> Gram +ve and gram -ves but inactivated by beta lactamases so not useful against Staph, E Coli or H flu
> Acute exacerbations of chronic bronchitis
> Otitis media
What is the combination formulation involving amoxicillin, and why?
> Co-amoxiclav
> Amoxicillin + clavulanic acid
> Clavulanic acid is a beta lactamase inhibitor so extends spectrum of action
> Used in infections where beta lactamase producers may be likely e.g. S aureus, H flu, E coli, Klebsiella, Bacteroides
Clinical use of co-amoxiclav?
> Used in infections where beta lactamase producers may be likely e.g. S aureus, H flu, E coli, Klebsiella, Bacteroides
> Respiratory tract infections (particularly nosocomial) - this is the main one to know I think
> Abdominal infections
> Hospital acquired infections
What is tazocin?
> Piperacillin (beta lactam antibiotic) and tazobactam (beta lactamase inhibitor)
> Extends spectrum
What is the use of tazocin?
> Hospital acquired pneumonia
> Complicated abdominal infections
> Infections in neutropenic patients
> “Anti-pseudomonal”
** This is a good drug to know - it’s commonly given in the hospital. Imagine an old lady who has been in for a week or so, and she develops a fever and crackly chest. It sounds like pneumonia but because its hospital acquired, the likely cause is aspiration, meaning a gram negative, or a penicillin resistant bacteria, and so tazocin or co-amoxiclav are commonly given **
Which class of bacteria do not have a cell wall, and how does that directly impact their susceptibility to certain antibiotics?
> Mycoplasma
> Not susceptible to penicillins as they act on the cell wall
Which penicillin is “anti-pseudomonal”? (and therefore heavily utilised in nosocomial respiratory tract infections)?
> Tazocin
How should oral penicillins be taken and why?
> 60 minutes before food on an empty stomach
> Absorption is delayed by food
Why is delayed absorption particularly harmful in penicillins, and how could this occur? (2 reasons)
>
- Delayed can mean incomplete absorption if they reach the lower GIT beyond the absorptive region, and so low levels of penicillins = incomplete therapeutic benefit
>
- Active drug reaching the lower GIT (colon) can affect bowel flora -> ABx associated colitis
> Delayed absorption can be due to food, hence penicillins should be taken on an empty stomach
What drug class are penicillins often prescribed with and why?
> Aminoglycosides e.g. gentamicin
> The penicillins boost the efficacy of the aminoglycosides, and lowers their toxic effects (e.g. gentamicin is often given with a penicillin to lower chance of nephrotoxicity and ototoxicity)
How are penicillins excreted? >
> Renal (urine)
What new class of drug is active against multi-resistant microbes and so is reserved only for these purposes?
> Oxazolidinones
What drugs are within the oxazolidinones class?
> Linezolid
MOA of linezolid?
> Binds to bacterial ribosome 50s subunit preventing formation of functional 70s initiation complex, preventing protein synthesis
> Protein synthesis inhibitor (prevents translation)
Spectrum of action of linezolid?
> Gram positive bacteria, including MRSA and VRE
Clinical uses of linezolid?
> Serious infections only, where other antibiotics have failed e.g. refractory MRSA, VRE
(usually skin/soft tissue infections, and respiratory infections)
Cautions with linezolid?
> Not licensed for Monitor full blood count at least weekly to monitor for signs of haematopoietic suppression
> Monitor optic function as can cause optic neuropathy
> Higher chance of neuropathy and bone marrow suppression in elderly
> Those taking SSRIs, TCAs, MAOIs (serotonin syndrome)
Adverse effects of linezolid?
> Haematopoietic disorders e.g. thrombocytopaenia, anaemia, leucopenia, pancytopenia - MONITOR FBC WEEKLY … elderly are more vulnerable
> Acts as MAOI so avoid tyramine-rich foods and serotonin sparing drugs (serotonin syndrome)
> Optic neuropathy (28 days+ = increased chance)
What are the three main adverse effects associated with linezolid?
> Bone marrow suppression leading to haematopoietic disorders
> Optic neuropathy
> Serotonin syndrome
Which bacteria commonly cause UTIs?
> Coliforms
Proteus spp.
(Coliforms are gram negative rods: Citrobacter, Enterobacter, Hafnia, Klebsiella, Escherichia)
