(FE) Antimicrobials Flashcards
What are the differences between mammalian cells and bacteria?
- Rigid cell wall present in bacteria
- Ribosomes involves in protein synthesis are different (Bacteria:70S, Eukaryotes: 80S ribosomes)
- Different folate synthesis to make DNA
What are the classes/MOA of antimicrobial agents? (IMPT)
1) Cell wall and cell membrane inhibitors
- Beta-lactams
~ Penicillins
~ Cephalosporins
~ Carbapenems
~ Monobactams
~ Oxapenams (not so much a subgroup)
- Non-beta lactams
~ Glycopeptide
2) Bacterial protein synthesis inhibitors
- 30S Inhibitors (Aminoglycosides, Tetracyclines)
- 50S Inhibitors (Macrolides, Lincosamide, Oxazolidinone)
3) Antimetabolite (Folic acid)
- Sulphonamides
- Trimethoprim
- Cotrimoxazole
4) DNA synthesis inhibitors
- Fluoroquinolones
- Nitrofurantoin
What is the MOA of beta-lactams?
- Inhibits bacterial wall synthesis -> cell death
- Drugs irreversibly bind to penicillin-binding-proteins (PBP) enzymes (aka transpeptidase enzymes)
- Inhibits transpeptidation (cross-linking of adjacent peptidoglycan strands to form rigid cell wall) as enzymes are bound
- Activation of autolytic enzymes that cause lesions in bacterial cell wall
What are the types of penicillins?
Recap: Beta-lactam (cell wall inhibitor)
1) Normal penicillins
- Natural (PENICILLIN V,G)
- Penicillinase-resistant / anti-staphylococcal (CLOXACILLIN, oxacillin, nafcillin)
2) Extended spectrum
- Aminopenicillins (AMOXICILLIN, AMPICILLIN)
- Carboxypenicillin / anti-pseudomonal (Ticarcillin)
- Ureidopenicillins / anti-pseudomonal (Piperacillin)
3) Combination of penicillin/beta-lactamase inhibitors (oxapenams)
- Clavulanic acid (AMOXICILLIN+CLAVULANATE)
- Sulbactam, tazobactam (Ticarcillin+clavulanate, Ampicillin+clavulanate, Piperacillin+clavulanate)
What are the types of cephalosporins?
Recap: Beta-lactam (cell wall inhibitor)
1) 1st gen
- CEFAZOLIN, cephalexin, cefadroxil
2) 2nd gen
- CEFUROXIME, cefoxitin, cephamycin
3) 3rd gen
- CEFTRIAXONE, ceftazidime
4) 4th gen
- Cefepime
5) 5th gen
- CEFTAROLINE
- Can be used against MRSA
What are examples of carbapenems and monobactams?
Recap: Beta-lactam (cell wall inhibitor)
1) Carbapenem
- Imipenem / cilastatin
- MEROPENEM
- Ertapenem
- Doripenem
2) Monobactam
- AZTREONAM (taken when px is hypersensitive to penicillin)
What are oxapenams/beta-lactamase inhibitors and examples?
Recap: Beta-lactam (cell wall inhibitor)
- Sulbactam
- Tazobactam
- CLAVULINIC ACID
Note: Not really a subgroup. Always needs to be paired with another beta-lactam subgroup
What are the side effects of beta-lactams?
Recap: Cell wall inhibitor
- Generally well-tolerated
- Hypersensitivity / allergic reactions (due to products of penicillin degradation)
- Minor rashes, itching, urticaria/hives
- Stevens-Johnson syndrome (systemic disorder of skin and mucous membranes)
~ Starts w flu-like symptoms, then painful rash that spreads and blisters - Toxic epidermal necrolysis (widespread skin detachment and extensive damage to skin and mucous membranes)
- Life-threatening anaphylaxis
What are the types of non-beta lactams?
Glycopeptides
- VANCOMYCIN
What is the MOA of non-beta lactams?
- Usually taken as a last resort
- Binds firmly to the d-Ala-d-Ala terminus of peptidoglycan
- Inhibits transglycosylation (synthesis and elongation of peptidoglycan)
- Weakened peptidoglycan makes cell susceptible to lysis
What are the adverse effects of non-beta lactams?
- Thrombophlebitis, fever and chills
- Red man syndrome
~ Rash above nipple line
~ Due to histamine release when vancomycin infusion is too rapid
~ Treatment: antihistamine or prolong infusion time - Increased nephrotoxicity and ototoxicity when vancomycin + aminoglycoside
~ Need to check vestibular function and hearing acuity of px to assess ototoxicity
~ Send renal panel to assess nephrotoxicity
What is the spectrum of activity of beta-lactams and non-beta lactams?
Penicillins: Fairly broad spectrum (most)
- Gram pos + some Gram neg
Cephalosporins: Fairly broad spectrum
- Some Gram pos + neg
Monobactams and carbapenems: Narrow spectrum
- Some Gram neg
Vancomycin: Narrow spectrum (least)
- Some Gram po
What are the drug-drug interactions for beta-lactams and non-beta lactams?
1) Penicillin + Oral contraceptives = Dec oral contraceptive levels
2) Cephalosporins + Warfarin = Reduces vitamin K -> Increases warfarin effects (anticoagulant)
3) Meropenem/carbapenems + Valproate = Disrupt VPA metabolism -> decrease valproate levels (anticonvulsant, mood stabiliser)
4) Vancomycin + Aminoglycosides = Nephrotoxicity + Ototoxicity (IMPT)
How are proteins synthesized within a cell?
- 70S (bacteria) and 80S (eukaryote) ribosomes are different enough that antibiotics can target specifically target one
- Ribosomes have 2 subunits (1 Large, 1 Small)
- Bacterial 70S subunits are 50S and 30S subunits
- Synthesis of mRNA in nucleus -> movement of mRNA into cytoplasm via nuclear pore -> synthesis of protein
What is the MOA of protein synthesis inhibitors?
- Binding to 30S subunit
~ Interferes with binding of tRNA to mRNA-ribosome complex = inhibits initiation of protein synthesis - Binding to 50S subunit
~ Interferes with movement of ribosome = premature termination of protein synthesis = nonfunctional proteins - Both
What are the types of 30S protein synthesis inhibitors?
1) Aminoglycosides
- GENTAMICIN
- STREPTOMYCIN
- Amikacin
2) Tetracyclines
- DOXYCYCLIN
- TETRACYCLIN
What are the types of 50S protein synthesis inhibitors?
1) Macrolides
- ERYTHROMYCIN
- AZITHROMYCIN
- CLARITHROMYCIN
2) Lincosamide
- CLINDAMYCIN
3) Oxazolidinone
- Linezolid
What are the side effects of aminoglycosides? (IMPT)
Recap: 30S Protein synthesis inhibitors
1) Ototoxicity
- Auditory and vestibular damage (hearing loss, poor balance, N&V, vertigo)
- May be irreversible
2) Nephrotoxicity
- Risk factors include concentration, prolonged therapy duration (>10-14 days), older age, use of vancomycin, sepsis, use of gentamicin, amikacin and tobramycin
- Reversible
What are the adverse effects of tetracyclines?
Recap: 30S Protein synthesis inhibitors
1) GI disturbance
2) Liver failure
3) Vertigo
4) Deposition of drug in bones and teeth
5) Phototoxicity
6) Harmful in pregnancy
What are the adverse effects of macrolides?
Recap: 50S Protein synthesis inhibitors
1) GI disturbances
2) Thrombophlebitis
3) Ototoxicity (rare)
4) Hepatotoxicity (rare)
5) QT prolongation (rare)
Note: Clarithromycin and azithromycin are better tolerated than erythromycin
What are the adverse effects of linezolid?
Recap: 50S Protein synthesis inhibitors
1) GI intolerance
2) Myelosuppression (thrombocytopenia, anemia)
- Usually in treatements >2 weeks
- Risk factors: renal failure, on drugs that cause myelosuppresion
- Reversible upon discontinuation
3) Serotonin syndrome (life threatening)
4) Peripheral and optic neuropathy
5) Lactic acidosis
What are the drug-drug interactions for 30S inhibitors?
1) Aminoglycosides + Vancomycin / NSAIDS / Amphotericin B =
- Reduced renal blood flow
- Neuromuscular blockade, hypocalcemia,
- Nephrotoxicity
2) Tetracycline + Phenytoin / Carbamazepine / Phenobarbitone = Shorten doxycycline half-life by 50%
3) Tetracycline + Antacids / Warfarin = Reduced absorption, ^ conc of warfarin but not INR
4) Tetracycline + Calcium / Iron / Aluminum = Reduced absorption of tetracycline
What are the drug-drug interactions for 50S inhibitors?
1) Erythromycin / Clarithromycin + Simvastatin / Carbamazepines / Ciclosporin = Increased drug levels (non-macrolide)
2) Erythromycin / Clarithromycin + Digoxin = 2-4x of digoxinn levels (toxic)
3) Linezolid + SSRI / tyramine-rich food + adrenergic agents = Serotonin syndrome
4) Linezolid + Rifampicin = Decrease linezolid levels
What are the types of anti-folate agents?
1) Sulfamethoxazole
- SMZ
- Sulphadiazine
2) Trimethoprim
- TMP
3) Co-trimoxazole
- TMP + SMZ in 1:5 ratio
MOA of anti-folates?
In DNA synthesis:
1) p-Aminobenzoid acid -> Dihydrofolic acid (through dihydropteroate synthase)
2) Dihydrofolic acid -> Tetrahydrofolic acid (through dihydrofolate reductase)
3) Tetrahydrofolic acid -> Purines -> DNA
Tf:
- Sulfonamides inhibits dihydropteroate synthase
- Trimethoprim inhibits dihydrofolate reductase
Spectrum of activity of anti-folates?
Broad spectrum (Both Gram neg and pos)
Adverse effects of anti-folates?
- N&V, Diarrhoea
- Hypersensitivity/allergic rxns
- Phototoxicity
- Hemolytic rxns in G6PD px (IMPT)
- Nephrotoxicity
- Crytalluria
- Hyperkalemia
- Bone marrow suppression, megaloblastic anemia
- Thrombocytopenia
What are the types of fluoroquinolones?
Recap: DNA Synthesis inhibitors
1) 1st gen
- Nalidixic acid
2) 2nd gen
- CIPROFLOXACIN, Norflaxacin, Ofloxacin
3) 3rd gen
- Levofloxacin
4) Moxifloxacin
What is nitrofurantoin used for and it’s MOA?
- Uncomplicated UTI
- A bacterial enzyme known as nitrofuran reductase reduces the nitrofuran structure to form reactive intermediates
- Which damages bacterial DNA, ribosomal proteins and respiration through oxidative stress
What is the spectrum of activity of DNA synthesis inhibitors?
1) Fluoroquinolones: Broad-spectrum (mycobacteria, Gran neg and Gram pos)
2) Nitrofurantoin: Broad-spectrum
(many Gram pos and Gram neg)
Adverse effects of fluoroquinolones?
1) N&V, diarrhea, dyspepsia
2) Headache, agitation, insomnia, dizziness
3) Rare hallucinations and seizures in elderly
4) Hypersensitivity
5) QT interval prolongation
- Usually in Moxifloxacin
6) Arthropathy (joint inflammation)
- Cartilage damage, arthralgias and joint swelling
7) Tendonitis and tendon rupture
- Black box warning
8) Alteration in blood glucose
Note: Do not give to elderly and athletes with tendon ruptures
Adverse effects of nitrofurantoin?
1) N&V, diarrhea, dyspepsia
2) Hypersensitivity and allergic reactions
3) Occasional and reversible skin rashes, pneumonitis, chills and fever
4) Colours urine brown
5) Pulmonary interstitial fibrosis with chronic use
- Especially in elderly
6) Blood dyscrasias
- Neutropenia
- Hemolysis in infants and G6PD px
Note: Contraindicated in elderly and pregnant women
What is metronidazole used for and its MOA?
- Infx of the reproductive system, gastrointestinal tract, skin, heart, bone, joint, lung, blood, nervous system, and other areas of the body
- Amoebiasis, giardiasis, anaerobic peritoneal infx, bacteremia, H. pylori
- Enzyme nitroreductase reduces the nitro group in metronidazole to cytotoxic metabolites
- Which bind to DNA to cause strand breakage and loss of helical structure
- Thus interferes with nucleic acid synthesis
Adverse effects of DNA synthesis inhibitor Metronidazole?
1) N&V, diarrhea
2) Headache, encephalopathy, aseptic meningitis, optic neuropathy
3) Disulfiram-like reaction with alcohol
- Flushing, headaches, N&V, stomach cramps
4) Peripheral neuropathy
5) Metallic, bitter taste
Spectrum of activity of metronidazole?
Narrow spectrum (Against anaerobe bacteria and protozoa)
- As aerobic microbes do not have the enzyme to activate the drug
Structure of a virus?
- Double or single-stranded DNA or RNA enclosed in a protein coat called a capsid
- Some viruses possess a lipid envelope derived from the infected host cell, and may contain antigenic glycoproteins
- Distinct stages of viral replication that allow different classes of antivirals to act on at each stage
