Antibiotics Flashcards
What are the 4 mechanisms of drug resistance?
Drug inactivators
Decreased accumulation
Altered binding site
Alternative pathways
How does drug inactivation work?
Bacteria expresses B lactamase - can break down B lactam ring of B lactam type antibiotics (penicillin type drugs)
(B lactam —> penicilloic acid)
How is resistance passed on?
Selection (chromosomal mutation) occurs when antibiotics overprescribed, kill other colonies but resistant one multiplies
Transference - bacteria carry extra DNA within plasmid, can transfer DNA within or outside of strain - multiple resistance within and between strains
Strategies to reduce resistance?
New antibiotics
Correct antibiotic after sensitivity testing
Reduced use as growth promoters
No use in viral infections
Increase compliance
Decrease prescriptions - especially young children (otalgia)
What is gram positive and negative?
Positive - cell wall retains the purple stain
(anthracis, listeria, clostridium, staph, strep, (coccuses))
Negative - doesn’t retain purple (pink)
(enterobacter, gonorrhoea, E coli, salmonella, shigella, H. pylori, meningitidis, haemophilus influenzae)
What factors should be considered when choosing an appropriate antibiotic?
Spectrum - start with broad if don’t know but narrow down if do because broad cause resistance more quickly
Orally active? Bactericidal/static (if bacteria full of toxins, static may be better) Mechanism Adverse effects (penicillin allergy) Resistance Pharmacokinetics
Presumptive treatment (sepsis - if meninges inflammed - some don’t reach there, others only reach there) (simple chest infection - community or hospital?)
Combination therapy Site of action Duration of therapy Chemoprophylaxis Special situation (pregnancy, renal) - e.g. grey baby syndrome with chloramphenicol (now just used for conjunctivitis usually)
Name key antibiotics in each group
1) Nucleic acid
2) Cell wall
3) Protein synthesis
1) Sulfamethoxazole, ciprofloxacin, metronidazole, trimethorpim
2) Flucloxacillin, amoxicillin, (cephalosporins), vancomycin
3) Tetracycline, clarithromycin, chloramphenicol (so toxic used outside body now)
What are types of nucleic acid inhibitors?
Sulphonamides
Trimethoprim
Quinolones
Nitroimidazoles
How do nucleic acid inhibitors work?
Sulphonamides: block dihydropteroate synthase (eventually prevents synthesis of purines and pyrimidines)
Trimethopim: blocks dihydrofolate reductase (has 100x higher affinity for bacterial version)
Quinolones: inhibits DNA gyrase (topoisomerase II) which packages the DNA (coils it for packaging) - so it remains unwound and is easier to shear and break - ATP needed to fix so causes cell exhaustion
Nitroimidazoles: cause strand breaks within the DNA itself - runs out of energy, also can’t replicate DNA for a while
(metronidazole likes low environments of oxygen, gets metabolised by bacteria (to active ingredient) itself so v specific, metabolised enzyme causes the strand breaks
What are sulphonamides?
Sulfadiazine, sulfamethoxazole
Bacteriostatic, orally active
Action prevented by pus (neutrophils provide PABA)
Widespread resistance to hospital acquired infections
Nausea and vomiting
Hypersensitivity reactions (sulphur drug)
Bone marrow suppression (think DMARD - methotrexate inhibits dihydrofolate reductase
Replaced by antimicrobials with less resistance and less toxicity
What is co-trimoxazole?
Sulfamethoxazole and trimethoprim
Using two drugs in linear system:
- Partly because of resistance - (think of alternative pathways) but resistance occurs more when using mono therapy (i.e. nucleic acid only or cell wall only)
- Because not all drugs are 100% effective so increase in effectiveness
- Could use less of each one to reduce side effect profile
Stephen-Johnson syndrome - 1 million per year
Bone marrow suppression
What are the uses of co-trimoxazole?
Used in TB and prophylaxis of TB
- TB associated with HIV
- used if prone to bacterial infections, especially if poor immune system
Otitis media Pneumonia Strepococcus pneumonia and haemophilius influenzae Toxoplasmosis Nocardiasis
What are the uses of trimethoprim?
Invasive salmonella
Respiratory tract
Prostaitis (UTI)
Shigellosis
What are quinolones?
Ciprofloxacin, norfloxacin
-ve > +ve - widely used in some gram -ve organisms
V.broad spectrum - useful in hospital e.g. simple chest infection - don’t get side effects seen with some drugs
Effective against organisms resistant to penicillins and some cephalosporins
Orally active, poorly absorbed by BBB (not used meningitis, avoid in sepsis - good for presumptive treatments but be careful what you try)
Inhibition of P450 enzymes (interaction with theophylline and warfarin - they build up) - ciprofloxacin interactions
What are first line uses of quinolones?
Pyelonephritis (UTI)
Bacillary dysentry
Severe gastroenteritis - normally even bactericidal gastroenteritis is self limiting - travellers diarrhoea
Pseudomonas (opportunistic often in CF or HIV)
What are nitroimidazoles?
Metronidazole, tinidazole
Bactericidal - causes strand breaks in DNA following metabolism by the bacteria
Broad spectrum
Orally active
Important in serious anaerobic infections e.g. sepsis
Anaerobes metabolise the imidazole to its active form
Effective against H. pylori
Interacts with ethanol, warfarin metabolism Bitter taste (goes into breast milk)
What are first line uses of nitroimidazoles?
Pelvic infections Anaerobic sepsis Infected wounds C. difficile colitis Post surgery
How do cell wall synthesis inhibitors work?
Block elongation and division, makes cell wall less rigid
Peptidoglycan on outside of wall - can provide antigenicity (Cag-A, pic-B) and provide sticky surface for getting into blood vessels/sticking in gut
Has to build using variety of enzymes - one is blocked by penicillin-like antibiotics
Peptidoglycan made of polymer chains cross linked by pentapeptide bridges - B lactam antibiotics inhibit enzymes that cross link PG and render wall weak - lose structural integrity of cell, can’t control what enters/leaves - tries to fix but runs out of energy and dies / ‘pops’
How does methicillin work?
Inhibits transpeptidase (penicillin binding protein, PBP) Stops cross-linking of peptidoglycan
Normally transpeptidase incorporates the building blocks into the cell wall - with methicillin (penicillin-like, B lactam type drug) - worked on by transpeptidase and gets incorporated –> causes bacterial lysis
Lots of resistance due to altered binding site - may be changes to transpeptidases that stops it binding, but still binds to its own correct precursors
What is clavulanic acid?
Not an antibiotic alone but used in combination with amoxicillin / lactamase sensitive antibiotics
Inhibits beta lactamase - amoxicillin not resistant to B lactamase and gets broken down
(alternatives = flucloxacillin, quinolone, some cephalosporins)
If still want to use amoxicillin - use claculanic acid to inhibit the enzyme and amoxicillin is still incorporated into wall causing loss of cell wall –> Co-amoxyclav
Side effects: cholestatic jaundice / acute hepatitis, rarely fatal
How does B lactamase (penicillinase) resistance occur?
B lactamase hydrolyses the lactam ring reducing activity (penicilloic acid)
- Secreted by gram positive (Staph aureus) - secreted easier to test
- Gram negative - often located between outer and inner cell membranes (harder to test for)
Often encoded on plasmid and resistance is by transference (so be careful when start to see B lactamase resistance in a bacteria)
Some lactam antibiotics can induce lactamase enzyme expression so don’t see it when you first test but later on induced by previous exposure to the antibiotics
What are penicillins?
Benzylpenicillin +»>- Flucloxacillin (methacillin) +»>-
Amoxicillin +»- Azlocicillin +>- Piperacillin +>-
Bactericidal, orally available, range of bioactivity
Low adverse effects
Hypersensitivity (1-10% of exposed, 0.05% anaphylaxis) - more likely anaphylaxis/rash if atopic allergy so shouldn’t be given B lactams (e.g. try quinolones, ciprofloxacin)
Encephalopathy
Excreted in kidney (make sure no renal insufficiency, Na penicillin, K penicillin, often given IV)
Resistance
What are first line uses of penicillins?
First line in rare diseases as orally available/active - works in range of areas (internally/surface/absorbed), good bioavailability
Pseudomonas Meningitis UTI gonorrhoea Bronchitis Pneumonia (anthrax, diphtheria, gas gangrene, leptospirosis, Lyme disease)
What are cephalosporins?
Cefalexin po, +ve»>-
Cefuroxime po, -ve»_space; +ve, crosses BBB
Cefotaxime ive, -ve»_space; +ve crosses BBB
Broad-spectrum, but individually slight more specific
Bactericidal
Both oral and parenteral types
Used in surgical prophylaxis (also metronidazole)
‘Blind’ meningitis therapy - meningitis only when inflammed
Renal excretion, reduced dose in impairment
What are uses of cephalosporins?
UTI Peritonitis Biliary tract Meningitis Pneumonia Septicaemia
What can cefotaxime cause and why?
Potent broad spectrum antibiotic so can cause opportunistic infections e.g. Candida and C. Difficile
Candida albicans and candida parapsilosis = fungal infections (antibiotics leave a niche)
Live on skin commencally = not infected because commencal
Back of throat thrush infection
Amphotericin - statin - easily treated
C diff - causes diarrhoea, caused by cephalosporins and amoxicillin
Very difficult to treat
METRONIDAZOLE
What are carbapenems?
Imipenem iv, +ve = -ve
(Add cilastatin - inhibits kidney metabolism)
Meropenem +ve = -ve
Not metabolised in kidney
Beta lactamase resistant
Broadest spectrum - Active against many aerobic and anaerobic gram pos/neg organisms
Side effects similar to penicillins
Neurotoxicity at high doses in renal failure as excreted by kidney
What are used of carbapenems?
Pseudomonas
Gynaecological
Foot infections soft tissue (diabetes)
Community acquired pneumonia (might need something stronger eg quinolone for hospital acquired infection because of increased risk of resistance )
Abdominal infections
What are monobactams?
Aztreonam iv
-ve
Beta lactamase resistant
Only active on aerobic gram negative organisms
Side effects similar to penicillins - all the same warning signs
No cross hypersensitivity, can be used in penicillin sensitive patients
Kidney excretion and short half life
Liver and marrow toxicity
What are uses of monobactams?
H influenzae
Pseudomonas
Gonorrhoea
Meningitis
How do protein synthesis inhibitors work?
Tetracyclines block tRNA binding (stops process of amino acids being brought in)
Chloramphenicol blocks TRANSPEPTIDATION (when growing protein is moved in ribosome) by inhibiting peptidyl transferse
Aminoglycosides cause incorrect reading of mRNA (incorrect amino acid brought in so protein cannot function)
Macrolides & streptogramins block TRANSLOCATION (bring protein back to start position)
How does resistance occur in tetracyclines?
- tetracycline eflux
- ribosome protection
- tetracycline modification
- via transference
How does resistance occur in aminoglycosides/chloramphenicol?
Reduced membrane permeability
Increased acetylation
Ribosomal mutation
Transference and selection
What are tetracyclines?
- Tetracycline
- Doxycycline
- Gram +ve & -ve
Bacteriostatic
Broad spectrum
Widespread resistance therefore use limited (because they are so broad spectrum)
Side effects of tetracyclines?
Tend to live in skin - being treated for acne - have to cover/use sunblock
- 3,4,5,6 months of treatment
- because lives in skin - reacts with sun, photosensitive response, burn much more quickly
Erythema and photosensitisation
Tooth discolouration - causes more calcium to be stored in the teeth
First line uses of tetracyclines?
Chlamydia
Plague - squirrels in US
Brucellosis - zoonotic disease (undulant fevers, sweating wet hay like smell, migratory arthralagia and myalgia)
Community acquired pneumonia
Cholera
What are aminoglycosides?
- Gentamicin
- Streptomycin
- Neomycin
Gram -ve > gram +ve
Spectrum and bacterial resistance varies with individual drug
- Poor penetration of BBB (so not for meningitis)
- Not orally active
Resistance a problem: bacteria makes drug degrading enzymes
Serious side effects: ototoxicity, (deafness), nephrotoxicity (netilmicin less toxic)
Renal assessment and drug monitoring required
What are first line uses of aminoglycosides?
MRSA
- if MRSA and other multi-drug resistant infections
- have to go to things that are very old - not used a drug for 40 years, the bacteria that were resistant have moved on
- tend to be out-competed by other bacteria because of their resistances etc.
- some of the drugs that haven’t been used for years become useful again
Gram -ve septicaemia
Endocarditis: Streptococci or Staph
- Drug injectors right heart others more commonly on the left
- Heart valve involvement
- No blood flow, no humoral immune response
- Therefore antibiotics to clear infection
What are macrolides?
- Erythromycin +ve»_space;> -ve
- po
- Clarithromycin +ve > -ve
- po
- iv
- Azithromycin +ve > -ve
- po
- iv
Bacteriostatic
Similar range of action and efficacy to penicillins
(alternative to penicillin sensitive individuals- monobactam aztreonam can be used for penicillin allergy - Clarithromycin can be used instead_
Can cause diarrhoea (bad bacteria take over) and jaundice (affects liver)
- Because of that may have CYP450 interactions
Warfarin and some antihistamines - blocker - antihistamines that cause drowsiness - may get more drowsiness as not metabolised - so be careful with clarithromycin
Proton pump inhibitors - omeprazole and clarithromycin interaction can be problem - both of which - drug concentrations increase because they both inhibit the same CYP450 enzyme
First line uses of macrolides?
- Respiratory infection
- Otitis media
- Pertussis
- Legionnaire’s disease
- Bronchitis
- H. pylori
What is cloramphenicol?
- Bacteriostatic
- Orally active
- Gram +ve > Gram -ve
- Very toxic: bone marrow suppression, effects on newborns ‘grey baby syndrome’
- builds up in fetus
- tends to only be used externally e.g. eye drops
- can be used internally as well but less often as so toxic
- Acts in the same way as erythromycin but wider spectrum
First line uses chloramphenicol?
- conjunctivitis
- meningitis
- haemophilus influenza
- reserved for serious infections because of all of side effects
What are glycopeptides?
- Vancomycin
- Teicoplanin
- Gram +ve»_space;> Gram -ve (restricted spectrum)
- Bactericidal except against Streptococci
Resistance is developing
Teicoplanin similar to vancomycin only longer acting
- so strong - usually used for 3 days - relatively short time but higher dosage - contrast to amoxicillin - 7-14 days
Synergises with amino glycosides (works better than individually/alone)
Adverse effects of glycopeptides?
- Ototoxicity
- Allergic ‘red man syndrome’
Uses of glycopeptides?
- Reserved for serious Gram +ve infections by IV administration
- Give po in resistant C. difficult (treat C. diff with metronidazole but if can’t get rid of it need things like vancomycin, teicoplanin)
Which antibiotics are high risk for developing C. diff?
CEPHALOSPORINS (quite often have C diff inside of us but kept in control by other bacteria)
- also clindamycin, co-amoxiclav, ciprofloxacin and other quinolones
- More people take AMOXICILIN so more likely to get it in association with amoxicillin - even though the risk is lower (MEDIUM) - more people to take it so more likely to see it
- Classic side effect seen with amoxicillin but not the only one!
- Metronidazole (LOW) used for C. diff treatment anyway
- and vancomycin/teicoplanin (vanomycin also LOW)
- Soton uses tetracycline in house, instead of amoxicillin for a simple chest infection because of C. diff risk - but only 15% of hospitals do this, 85% would first treat chest infection with amoxicillin and run risk of C. diff
- Soton lots of problems with C. diff rampant strains - difficult to treat with metronidazole and vancomycin
1) B lactam antibiotics inhibit which enzyme?
2) Name mechanisms of resistance?
3) Which drugs make up co-amoxyclav?
1) transpeptidase (penicillin binding protein)
2) - alternative pathway
- decreased accumulation
- altered binding site
3) amoxicillin, clauvanic acid
