Infectious Diseases - Antibiotics: Mechanisms of Action Flashcards
Which antibiotic classes (and which antibiotics) are inhibitors of cell wall synthesis?
Beta-Lactams
- penicillins
- cephalosporins
- carbapenems
- monobactams
Glycopeptides
- Vancomycin
- Teicoplanin
Others:
- cycloserine
- bacitracin
Which antibiotic classes are inhibitors of protein synthesis via the 30s ribosomal subunit?
Aminoglycosides
Tetracyclines
Tigecycline
Which antibiotic classes are inhibitors of protein synthesis of the 50s ribosomal subunit?
Chloramphenicol Lincosamides Macrolides Fusidic acid Streptogramin
Which antibiotic classes are inhibitors of nucleic acid synthesis?
Block folic acid synthesis:
- trimethoprim
- sulfonamides
Block DNA gyrase:
- fluoroquinolones
RNA polymerase inhibition
- rifamycins
How do they work: Penicillins
Penicillins are a beta-lactam and inhibit cell wall synthesis
How do they work: Vancomycin
Vancomycin is a glycopeptide and inhibits cell wall synthesis
How do they work: Cycloserine
Inhibits cell wall synthesis
How do they work: Aminoglycosides
Inhibit protein synthesis by 30s ribosomal subunit
How do they work: Cephalosporins
Cephalosporins are a beta lactam and inhibit cell wall synthesis
How do they work: Teicoplanin
Teicoplanin is a glycopeptide and inhibits cell wall synthesis
How do they work: tetracyclines?
Inhibit protein synthesis via 30s ribosomal subunit
How do they work: Carbapenems
Carbapenems are a beta lactam and inhibit cell wall synthesis
How do they work: Bacitracin
Inhibit cell wall synthesis
How do they work: Chloramphenicol
Inhibit protein synthesis via the 50s ribosomal subunit
How do they work: monobactams
Monobactams are a beta lactam and inhibit cell wall synthesis
How do they work: Macrolides
Inhibit protein syntheis via 50s ribosomal subunit
How do they work: Trimethoprim
Inhibit nucleic acid synthesis by blocking FOLIC ACID synthesis
How do they work: Fluoroquinolones
Inhibit nucleic acid synthesis by blocking DNA gyrase
How do they work: Clindamycin
Inhibit protein syntheis via 50s ribosomal subunit
How do they work: sulfonamides
Inhibit nucleic acid synthesis by blocking FOLIC ACID synthesis
How do they work: fusidic acid
Inhibit protein syntheis via 50s ribosomal subunit
How do they work: rifamycins
Inhibit nucleic acid syntheis by blocking RNA polymerase
How do they work: colistin
Inhibit cell membrane FUNCTION
How do they work: polyene antifungal drugs
Inhibit cell membrane FUNCTION
Which antibiotics work by inhibiting cell membrane FUNCTION?
Colistin
Polyene antifungal drugs
How do beta lactams work?
Gram positives have a PBP on their outer surface. Penicillins bind to PBPs to interfere with cell wall peptidoglycin synthesis
Why do enterococcus have a natural resistance to penicillins?
Enterococcus has a different PBP (although amoxycillin can be used because it has a different binding site)
What are the narrow spectrum penicillins?
Penicillin V (phoxymethylpenicillin) Penicillin G (benzylpenicillin) Procaine penicillin
What do narrow spectrum penicillins target?
Gram positives: strep pneumo and viridans, and enterococcus FAECALIS
Gram negative:
N meningitidis
Syphilis
Gonorrhoea
Ben pen covers H influenzae
Which are the anti-staph penicillins?
Flucloxacillin
Dicloxacillin
What does broad spectrum penicillin cover?
All gram positives INCLUDING enterococcus EXCEPT FAECIUM
NOT MRSA
Pseudomonas and gram negatives covered.
What are the first generation cephalosporins?
IV: cephazolin
Oral: Cephalexin, cefadroxil
What are the 2nd gen cephalosporins?
IV: cefuroxime
Oral: cefaclor, cefuroxime
What are the 3rd gen cephalosporins?
IV: cefotaxime, cefriaxone
Oral: cefixime
What are the 4th gen cephalosporins?
IV cefepime
What are the 5th gen cephalosporins?
IV ceftaroline
What do cephalosporins cover?
1st gen is gram positives
2nd gen is gram positives plus respiratory gram negatives, and also against bacteroides
3rd gen has both gram negative and gram positive cover.
They also have some cover for H influenza and Klebsiella
And have better activity against shigella and salmonella
4th gen have both gram positives and gram negative INCLUDING PSEUDOMONAS
5th gen covers MRSA with enhanced activity against strep and enterococcus
What do cephalosporins do badly?
Chlamydia
Mycoplasma
Listeria
When might ceftriaxone be used in IE?
Used synergistically if not tolerating aminoglycosides
Side effects of cephalosporins?
Common: n+v, diarrhoea
Rare: neurotoxicity, renal impairment, blood dyscrasia
Immune: eosinophilia, SJS, TEN, AIN, arthritis
How do Carbapenems work? And what are the three we use?
Act with high affinity for multiple PBPs and stability against most beta lactamases including Class A ESBL and class C beta lactamases (AmpC)
Imipenem
Meropenem
Ertapenem
Of the carbepenems which has the best gram positive cover?
Imipenem
How do glycopeptides work and what are the two we have?
Bind to d-alanyl-D-alynine moieties to inhibit final stage of peptidoglycan synthesis
Teicoplanin
Vancomycin
What do glycopeptides kill?
ONLY gram positives EXCEPT listeria
examples of glycopeptides:
Teicoplanin
Vancomycin
Common side effects after glycopeptides
(teicoplanin / vancomycin)
- Nephrotoxicity (vanc causes interstitial nephritis)
- Immune mediated thrombocytopenia, neutropenia
- ototoxicity
- multi organ hypersensitivity
- red man syndrome
Of the carbapenems which has the best gram negative cover?
Meropenem
Of the carbapenems which is NOT good against pseudomonas?
Ertapenem
Mechanism of aztreonam?
Inhibits Cell wall synthesis by binding to PBP3 of gram NEGATIVE
Side effects of Aztreonam?
GIT Taste C diff Hepatitis Neutropenia Thrombocytopenia
mech: Inhibits Cell wall synthesis by binding to PBP3 of gram NEGATIVE
Name the aminoglycosides
IV: amikacin, gentamicin, streptomycin, tobramycin
Oral: neomycin
How do aminoglycosides work?
(amikacin, gentamicin, streptomycin, tobramycin)
Bind IRREVERSIBLE to 30s ribosomal subunit
Is rapidly bactericidal due to sudden release of toxic proteins
What DONT carbapenems cover?
Stenotrophomonas multophila Burkholderia MRSA Enterococcus Pseudomonas containing new KPC mutation
What precautions for aminoglycosides?
(amikacin, gentamicin, streptomycin, tobramycin) Neuromuscular disease (ie myasthenia gravis)
Hypocalcaemia
Mutation in mitochondrial DNA A1555g (increases risk of ototoxicity)
What precautions for carbapenems?
- avoid treating with valproate (lowers valproate level)
- imipenem and ertapenem are contraindicated in meningitis due to seizures
What to aminoglycosides cover?
(amikacin, gentamicin, streptomycin, tobramycin)
All gram negative except:
Aeromonas Moraxella H influenza Pasturella Salmonella and shigella Stenotrophomonas
What is Red Man Syndrome
Histamine release mediated reaction to glycopeptides like vancomycin
Mechanism of Fosfomycin?
When is it used?
Irreversible blockage of MurA enzyme (enzyme in peptidoglycan synthesis) which disrupts Cell wall synthesis
It also decreases bacterial adherence to uroepithelial cells
It’s action is INSIDE renal tubule cells so it doesn’t work if poor renal function
Broad spectrum BUT
Only used for simple UTIs
Side effects of aminoglycosides?
(amikacin, gentamicin, streptomycin, tobramycin)
Common: nephrotoxicity and ototoxicity
Other: Bronchospasm Oliguria Peripheral neuropathy Neuromuscular blockade (reverse with IV calcium gluconate)
Tobramycin also gives voice alteration, tinnitus and sore throat
Name the four macrolides and how they work?
Azithromycin
Erythromycin
Clarithromycin
Inhibit ribosomal function of protein subunit 50s
What do macrolides cover?
(Azithromycin, Erythromycin, Clarithromycin)
C jejuni H influenza Moraxella Chlamydia Legionella Actinomycetes Clostridium Mycoplasma
PLUS
Gram positives:
Strep pneumonia
Staph saprolyticus
AND AZITHROMYCIN:
Neisseria
Shigella
Salmonella
Side effects of macrolides?
(Azithromycin, Erythromycin, Clarithromycin)
GIT: increased peristalsis
C diff
Pancreatitis
Cholestatic hepatitis
Prolonged QT
Blood dyscrasia
Psych disturbances
Ototoxicity
What are the two lincosamides and how do they work?
Clindamycin
Lincomycin
Inhibit protein synthesis by binding 50s subunit
INHIBITS toxin production so really good for GAS and toxic shock (alongside penicillin)
Which aminoglycosides has a synergistic effect with amoxicillin?
Gentamicin
Side effects of lincosamides?
(Clindamycin, Lincomycin)
C diff (HIGH RISK)
Go effects and LFT derangement
Blood dyscrasia
Polyarthralgias
What mutation increases risk of ototoxicity in aminoglycosides?
Mutation in mitochondria DNA A1555g
What extra thing does gentamicin cover compared to other aminoglycosides?
Aeromonas
What do tetracyclines cover?
(doxycycline, tetracycline and minocycline)
All gram positive streps and staph
Gram negative: c jejuni, aeromonas, H influenza, moraxella, pasturella, salmonella, yersinia
Anaerobes: acinetomyces and propiobae
Chlamydia
Mycoplasma pneumonia
What is the only gram negative with natural resistance to tetracyclines?
(doxycycline, tetracycline and minocycline)
Proteus mirabilus
When should you you avoid giving tetracyclines?
(doxycycline, tetracycline and minocycline)
If someone is on oral retinoids (acitretin) they increase risk of benign intracranial Hypertension
What extra thing does amikacin cover than the other aminoglycosides?
Mycobacterium
Nocardia
Side effects of tetracyclines:
(doxycycline, tetracycline and minocycline)
GI symptoms and reflux Photosensitivity Tooth discolouration Stomatitis Hepatitis Benign intracranial Hypertension
In the body where do lincosamides (clindamycin and lincomycin) act best?
Really good pus penetration
Really bad CNS penetration
What is chloramphenicol?
What does it cover?
Binds to 50s subunit
Covers most gram positives and negatives
PLUS
Chlamydia
Mycoplasma
Rickettsia
Side effects of chloramphenicol?
(Binds to 50s subunit)
Bone marrow aplasia
Grey baby syndrome
What is Streptogramin?
When is it used?
A mix of a macrolide (pristinamycin 1A) and Streptogramin A (pristinamycin 2A)
Inhibit ribosome 50s subunit
Used for VRE and vanc resistant staph aureus
Name the three tetracyclines? How do they work?
Doxycycline
Tetracycline
Minocycline
REVERSIBLY bind 30s subunit to prevent peptide chain elongation
Which oxalidinone do we use?
How does it work?
Linezolid
Binds PROXIMALLY on 50s subunit to prevent formation of 70s complex
What is Tigecycline?
Binds to 30s ribosomal subunit with 5 times affinity than tetracyclines
Covers most gram positives PLUS VRE MRSA and LISTERIA
Is linezolid bacteriostatic or cidal?
Bacteriostatic against enterococci and staph
Bacteriocidal against strep
Benefits of Linezolid?
Good CSF penetration
In ICU some evidence it is SUPERIOR to vancomycin
Side effects of daptomycin
(daptomycin = cyclic lipopeptides)
Myopathy and rhabdo Hepatotoxicity Hypotension Eosinophilic pneumonia C diff
What happens in linezolid resistance?
Bacteria develop resistance via 23S ribosome
This usually stops when linezolid is stopped
S/E of linezolid?
REVERSIBLE myelosuppression GIT sx and LFT derangement Serotonin syndrome Eosinophilia C diff Seizures
OTOTOXIC and NEUROTOXIC due to inhibition of mitichondrial protein synthesis
How do polymyxins (Polymyxin B and Colistin) work?
Target membrane phospholipids (LPS and lipoproteins)
Bind to cell membrane and disrupt the structure to make it more permeable
Gram Pos cell walls are too thick to allow it access
How do cyclic lipopeptides (Daptomycin) work?
In th presence of Ca they bind to cell membrane components to cause rapid depolarisation, K efflux and cell death
**Concentration dependent killing
Gram negatives are naturally resistant
Do fluoroquinolones cover gram negatives?
(ciprofloxacin, moxifloxacin and norfloxacin)
Yes!
their best effect is against enterobacter, pseudomonas and haemophilis
BUT REMEMBER moxiflox does NOT cover pseudomonas
AND moxiflox WILL cover gram positive except staph
When should you NOT use daptomycin?
Pneumonia
Daptomycin is inactivated by surfactant
When should fluoroquinolones NOT be given?
(ciprofloxacin, moxifloxacin and norfloxacin)
G6PD deficiency: results in haemolytic anaemia
Myasthenia gravis: can unmask it
Side Effects of fluoroquinolones?
(ciprofloxacin, moxifloxacin and norfloxacin)
Reduce seizure threshold Tendinopathy Interstitial nephritis Tremor and myalgias Peripheral neuropathy LFT derangements QTc prolongation
What is the mechanism for sulfamethoxazole action?
Nucleotide and DNA formation require TETRAHYDROFOLATE (TH4)
Bacteria make their own TH4 using PABA (para-amino-benzoid acid)
BUT Bacteria use sulfur in preference to PABA
–> so providing sulfur inhibits TH4 production
Humans dont make TH4 so our cells are unaffected
What is the MoA for trimethoprim?
TH4 becomes TH2 and so it needs to be converted back by bacteria to TH4
Bacteria convert TH2 back to TH4 with DIHYDROFOLATE REDUCTASE
Trimethoprim is a COMPETITIVE inhibitor (mimics the action of) dihydrofolate reductase
What is the MoA of fluoroquinolomes?
What are the three we commonly use?
Ciprofloxacin
Moxifloxacin
Norfloxacin
They inhibit bacterial DNA synthesis by inhibiting DNA gyrase and topoisomerase IV
Which fluoroquinolone will NOT cover pseudomonas?
but WILL cover gram positives except staph
Moxifloxacin
Which are the three rifamycins we use?
How do they work?
Rifabutin
Rifampicin
Rifamaxin
Inhibit nucleic acid synthesis by inhibiting RNA polymerase
** RifaMaxin has very poor absorption, but acts locally in the gut
What do rifamycins target?
Gram positives: ONLY Haemophilus and Pasturella
Gram negatives: ALL except enterococci and listeria
Side effect profiles of the three rifamycins
Rifampicin and Rifabutin: orange secretions, hepatitis and c diff
Rifabutin: neutropenia, thrombocytopenia, anaemia and uveitis
Rifampicin: Pychosis, ataxia and confusion
What are the two nitromidazoles we use and how do they work?
Metronidazole
Tinidozole
Metabolised to active metabolites that interfere with DNA synthesis
S/E of nitromidazoles?
Common: GI sx, CNS effects and paraesthesia, and metallic taste
Uncommon: Furry tongue, glossitis and stomatitis
Rare: SJS, peripheral neuropathy, dark urine and seizures
Fidaxomicin: mech and used in?
Bactericidal, inhibits bacterial RNA synthesis by binding to RNA polymerase
Used in SEVERE c diff
BUT ONLY ACTS IN INTESTINAL LUMEN
Hexamine Hippurate: mech and when to avoid?
Hydrolysed in acidic pH to become ammonia and formaldehyde
** DONT use in diarrhoea or gout as it can PRECIPIYATE URATE CRYSTALS **
Nitrofurantoin: side effects?
GIT sx, vertigo Hepatotoxicity Peripheral neuropathy Lupus like syndrome Eosinophilia Arthralgias
Reversible allergic pneumonitis
Chronic interstitial pulm fibrosis
Mech for sodium fusidate?
When is it used?
Inhibits bacterial protein synthesis by preventing translocation of protein subunits
Used in MRSA
What drug do you avoid with sodium fusidate?
Statins
Causes rhabdo!
What is dapsone?
When is it used?
Antimycobacterial that blocks folic acid synthesis
Used in:
- leprosy
- dermatitis herpetiformis
- 2nd line in PCP
What is ethambutol?
How does it work?
Anti-mycobacterial
Inhibits incorporation of mycolic acid into mycobacterium cell wall
Side effect of ethambutol?
When should it be avoided?
AVOID: gout and optic neuritis
SIDE EFFECTS: Eye: optic neuritis (decreased acuity, colour blindness and scotoma) Gout Renal failure Peripheral neuritis
What is isoniazid?
When should you avoid it?
Side effects?
Antimycobacterial
Inhibits synthesis of mycolic acid
**AVOID in liver disease and epilepsy
Peripheral neuropathy
Peripheral neuritis (**if not given with pyridoxane)
Hepatitis and pancreatitis
Acne
Seizures and encephalopathy and psychosis
Pellagra
Haemolytic anaemia
What drug must you give WITH isoniazid and why?
Pyridoxane
prevents development of peripheral neuritis
What increases your risk of peripheral neuropathy when giving isoniazid?
HIV
Diabetes
Malnutrition
Which are broad spectrum penicillin?
Tazocin
If you add clavulanate to moderate spectrum penicillins (amoxycillin and ampicillin) what do you additionally cover?
More gram negative coverage: E coli Klebsiella Moraxella Shigella yersinia Bacterioides
What do moderate spectrum penicillins target?
Gram positive: streptococcus and clostridium
Gram negative: Neisseria H influenxa Salmonella Proteus mirabilis
Which are the moderate spectrum penicillins?
Amoxycillin
Ampicillin
