W7 Antibiotics- drug classes and mechanisms Flashcards
Microorganisms – brief recap:
Examples of prokaryotic, eukaryotic cells and acellular microorganisms
Bacteria
Fungi (yeasts/moulds)
Parasites (protozoa)
Viruses
Prions
What are the differences between prokaryotic and human/eukaryotic cells?
- Without a nucleus (different DNA arrangements)
- Without membrane-bound organelles
- Simple organisation and smaller
- Different components (cell walls, glycocalyx, sex pili, fimbriae, flagella
- Different compositions of ribosomes (70s vs 80s)
What is Antimicrobial chemotherapy?
Drugs to treat infectious diseases, having selective toxicity against the pathogens involved, while damaging the host as little as possible
Terminology:
Antibiotics/antibacterial drugs bacterial infections
Antiviral drugs = virus infections
Antifungal drugs= fungal infections Antiprotozoal drugs = protozoan infections (parasites)
Each group has different classes of drugs (different mechanisms of actions/targets)
Prescribed only for patients with evidence of (or a reasonable suspicion of) BACTERIAL infection (along with all the other ANTIMICROBIAL STEWARDSHIP principles
What is Selective toxicity?
- Ability of drug to kill or inhibit pathogen while damaging host as little as possible
What is therapeutic index?
How can you calculate it?
What does a high index indicate?
Selective toxicity
TI= toxic dose/ therapeutic dose
The larger the index, the safer/better the agent
What is a toxic dose?
Drug level that is toxic for the host
What is a therapeutic dose?
Drug level to treat/resolve an infection
Effect on bacteria of antibiotics:
What are the properties of Broad-spectrum drugs?
- Target and inhibit many kinds of
bacteria (e.g. Gram +ve & Gram -ve) - Serious bacterial infections by an
unidentified organism - Infection with multiple bacteria
Spectrum of activity
What are the properties of Narrow-spectrum drugs?
- effective only against a limited
variety of bacteria - When the microorganism is identified
- Minimise the disruption of normal
flora
What is meant by Bacteriostatic?
What is meant by Bacteriocidal?
- Prevent bacterial growth (no killing)
- Reversible effect
- Bacterial clearance depends on the immune system
*Kill the target bacteria
*Irreversible effect
*Appropriate in poor immunity
Often, the distinction of the effect depends upon drug concentration and bacterial species
How can you measure the effectiveness of antimicrobial drugs? (2)
- Minimal inhibitory concentration (MIC)
- lowest concentration of drug that
prevents the visible growth of the pathogen (bacteriostatic)
* It varies against different bacterial species (spectrum of activity)
* Indicator for assessing bacterial drug resistance - Minimum bactericidal concentration (MBC) - lowest concentration of drug
that kills the pathogen
Both expressed as concentrations (usually, mg/mL or μg/mL)
From calculating MBC and MIC, when is a drug considered
bacteriostatic?
bacteriocidal
Bacteriostatic
* When MBC is significantly higher than the MIC
* MBC/MIC ratio is > 4
Bactericidal
* When is MBC ≈ MIC or
* MBC/MIC ratio is < 4
Antimicrobial Activity Can Be Measured by which Specific Tests? (3)
- Dilution Susceptibility Tests
- Disk Diffusion Tests (Kirby-Bauer Method)
- The Etest®
- When the isolated bacteria from biological samples can be cultivated in laboratory settings
- Some bacterial species, cannot be cultivated in the laboratory
What are Dilution Susceptibility Tests?
- Used to determine MIC and MBC values.
- Inoculating media with different concentrations of a drug and a fixed number of bacteria.
- Broth or agar with the lowest concentration showing no growth is MIC.
- Liquid media from tubes that showed no
growth are then cultured into agar plates - The lowest antibiotic concentration from the tubes that fails to support the microbe’s growth is the MBC.
What are Disk Diffusion Tests? (Kirby-Bauer test)
=Used to determine susceptibility or resistance
- Disks impregnated with different antibiotics are placed on agar plates inoculated with a microbe.
- Antibiotic diffuses from disk into agar, establishing concentration gradient.
-Higher concentrations near the disk.
- Innoculated agar plate
- Addition of antibiotic discs
- Measurement of zone of inhibition
- Measurement of the clear zones diameter
(no growth) around disks compared to a
standardized chart, determining
susceptibility or resistance - Diameter correlates with MIC (empirically)
Wider clear zone indicates that a microbe
is more susceptible to that antibiotic.
Narrower clear zone indicates drug
resistance - Cannot distinguish bacteriostatic and bactericidal effects
- Cannot compare efficacies between drugs
What is The Etest?
- Bacterial is inoculated on agar,
then Etest® strips are placed on
the surface. - Etest® strips contain a gradient of
an antibiotic. - Intersection of elliptical zone of inhibition with strip indicates MIC
Mechanism of action: different classes of antibiotics
What are the different mechanisms of action?
- Inhibition of cell wall synthesis (bactericidal)
- Inhibition of protein synthesis
- Acting as antimetabolites
- Inhibition of nucleic acids synthesis
- Alternative mechanisms
What are examples of inhibitors of cell wall synthesis?
- B-lactams
- Penicillins
- Cephalosporins
- Monobactams
- Carbapanems
- Glycopeptides
- Vancomycin
(RECAP – PMP101)
What are the Differences of cell wall in Gram+ and Gram?
- Cell wall confers protection, gives the cell shape and prevents the cell from burIf damaged or inhibited, bacteria burst by osmosis
- Sting by osmosis
Gram-Positive Cell Walls
* Thick peptidoglycan (including teichoic acids
Gram-Negative Cell Walls
Thin peptidoglycan
* Outer membrane (LPS, porins)
Peptidoglycan formation: What 2 subunits are they formed from?
- N-acetylglucosamine (NAG)
- N-acetylmuramic acid (NAM)
Bacterial transpeptidase (or penicillin-binding proteins) form peptide cross-link bridges between tetrapeptide of NAMs of peptidoglycan strands
What are β-Lactam mechanisms of action?
- Block NEW cell wall formation
- Bacterial lysis
- β-Lactams bind to and block transpeptidases (PBP)
- β-Lactams block the transpeptidation of peptidoglycan strands
- Prevent the synthesis of complete cell walls, leading to lysis of bacteria
-Only effective against bacteria reproducing - Activates enzymes to break down peptidoglycan
1) Inhibitors of Cell Wall Synthesis: β-Lactam antibiotics
Important Structure they have?
MoA?
- Containing a β-lactam ring — core structure
- Essential for bioactivity
Same mechanism of action:
- Blocking the formation of peptide bridges between peptidoglycan chains
- Bactericidal effect and high therapeutic index
- Some resistant bacteria produce β -lactamase (penicillinase, more common
in Gram-negative bacteria) which hydrolyses and inactivate the ring
What are the subclasses of β-lactam antibiotics?
Penicillins
Cephalosporins
Carbapenems
Monobactams
(They all have a β-lactam ring)
Same mechanism of action, but distinct related features
What are the Natural Penicillins? (2)
– the first antibiotics
Penicillin G (Benzylpenicillin)
Penicillin V (Phenoxymethylpenicillin)
Bacterial β-lactamases cut the β-lactam ring to inactivate antibiotics of this class
Development of semisynthetic penicillins to overcome this limitation
Semisynthetic Penicillins
What are the 3 major groups?
- Antistaphylococcal penicillins
- Aminopenicillins (Broad-spectrum penicillins)
- Antipseudomonal penicillins (Extended broad-spectrum)
-cillin: a suffix for penicillin antibiotics
Semisynthetic penicillins 1/3
Antistaphylococcal penicillins - Penicillinase-resistant penicillins
Example?
Features?
Used for?
Flucloxacillin – acid-stable (oral and iv)
* Bulkier side chains – Resistant to β-lactamase of Staphylococci
( Retain a narrow-spectrum activity (not active against Gram-
Skin/wounds infections
Ear infections
Osteomyelitis
Pneumonia
Semisynthetic penicillins 2/3
Aminopenicillins/Broad-spectrum penicillins:
Examples?
Features?
Ampicillin (oral)
Amoxicillin (oral)
Active against Gram-negative (e.g. E. coli, Salmonella spp)
o Hydrophilicity allows passage through porins of outer membrane in Gram-negative only) combined with beta-lactamase/penicillinase inhibitors (e.g. clavulanic acid)
o inactivating bacteria producing β-lactamases
o do not have anti-bacterial activity
Amoxicillin combinations:
- Augmentin (Co-amoxiclav) = Amoxicillin+Clavulanic acid
- Co-fluampicil = Amoxicillin + Flucloxacillin
Semisynthetic penicillins 3/3
Antipseudomonal penicillins – extended broad-spectrum
Examples?
Used to treat?
Piperacillin, Ticarcillin
- But only available in combination with the beta-lactamase inhibitors
e.g. Zosyn- Pipericillin + Tazobactam
Timentin- Ticarcillinn + Clavulanic acid
Coverage: Extended broad-spectrum
-wider range against Gram- (e.g. Pseudomonas aeruginosa) and anaerobes
-not active against MRSA (resistant to several widely used antibiotics)
- Uses: treat sepsis, hospital-acquired pneumonia and complicated infections like UTIs
Adverse effects of Penicillins:
Penicillin hypersensitivity:
- Penicillin hypersensitivity – 0.4% to 10 %
Patients must be questioned about penicillin allergies before treatment starts!! - Mild: Rash - Hives (raised, itchy, red or white swellings). It disappears within hours.
Breathing and swallowing difficulties - Severe: anaphylaxis (0.05%) & death
- Cross-reactivity across all Penicillins. Avoid other β-lactams
~5-15% cross-reactivity with other β-lactams (e.g. cephalosporins and carbapenems) - Amoxicillin and ampicillin can give Maculopapular rashes (non-allergic)
Smaller pink (non-itchy) spots in the chest, abdomen (can last 1-6 days)
Increased risk with viral infections - In both cases, the drug must be discontinued.
Penicillin adverse effects:
What effects are common for penicillin oral antibiotics?
What are the contraindications?
GI distress
Diarrhoea and nausea
- disturbing gut flora, rarely leading to pseudomembranous colitis
- Clostridium difficile infections may occur
- Consider probiotics (a few hours later)
CNS toxicity
Flucloxacillin is rarely associated woth hepatic disorders
- Penicillin resistance
-Mainly due to the production of β-lactamases to cleave the β-lactam ring
-Mutations changing the transpeptidase conformational structure
Which enzymes inactivate the activity of penicillins?
a) β-lactamases
b) Transpeptidases
c) Nucleases
d) Lysozymes
e) Kinases
=A
Which of the following antibiotic is less likely to disrupt the normal flora when administered orally?
Narrow spectrum antibiotic
Which of the following penicillins have the broadest spectrum of antibacterial activity?
a) Penicillin G
b) Amoxicillin
c) Flucloxacillin
d) Piperacillin + Tazobactam
=D
What are Cephalosporins (2nd β-lactam subgroup)?
Used for treatment of?
Cell wall inhibitors
- Originally isolated from the fungus Cephalosporium
- Structurally and functionally similar to penicillins
- 5 cephalosporin generations (different coverage)
- Earlier-generation drugs have better Gram+ coverage than later
generations (more effective against
Gram-) - 1st -2nd generations (mainly oral), while the 3rd/4th (mainly IV)
- Same mechanism as all the β-lactams and Bactericidal
Cef- suffix (eg Cefotaxime)
Used for the treatment of sepsis, pneumonia, meningitis, biliary-tract infections, peritonitis, and urinary-tract
infections
What are the adverse effects of Cephalosporins?
C/I?
- Overall, low toxicity and they are generally safe
- Oral cephalosporins may disturb the gut flora and give rise to diarrhoea
- Antibiotic-associated colitis (2nd/3rd generation – e.g. cefradine)
- Patients allergic to penicillins may also be allergic to cephalosporins of the1st and 2nd generations (10% of cases). Reduced risk for the other generations (2-3%)
- Disulfiram-like reactions with alcohol
- Nephrotoxicity (kidney damage) rare
- Drug resistance mechanism similar to penicillins (cross-resistance)
Contraindications: patients with hypersensitivity (or suspected) reactions to cephalosporins, penicillins and other β-lactams
Carbapenem- drug class
What dosage form are they used in?
What are some examples?
Broad/narrow spectrum?
SE?
C/I?
- β-lactams –same mechanism of penicillins (β-lactam ring)
- Only in IV form and used to treat complex infections of resistant bacteria
Imipenem, ertapenem, meropenem.
-broad spectrum activity (Gram+, Gram-, anaerobes), expect for meropenem
(only against Gram-). No MRSA or Enterococcus activity.
SE: ( similar to those of penicillins)
* Neurotoxicity (seizures, confusion) with high dose (imipenem, ertapenem)
* Skin reactions-rash
C/I= pt with severe penicillin allergy
Monobactams:
Example?
What spectrum?
Aztreonam (IV)
Spectrum limited to aerobic Gram- (including Pseudomonas)
Glycopeptides e.g. Vancomycin
What is the mechanism of action? (3)
What are they effective against?
What is it used to treat? (2)
- Non β-lactam antibiotics – (Vancomycin and teicoplanin)
- Vancomycin is a glycopeptide produced by Streptomyces spp.
Mechanism:
* Inhibit cell wall synthesis - bactericidal effect
* Binds to terminal amino acids linked to NAM of peptidoglycan (the substrate of the transpeptidase)
* Prevents the transpeptidation, without targeting the enzyme (difference with β-lactams)
- Coverage: only effective against Gram+
- Uses – Drug of last resort for the treatment of multi-resistant staphylococcal (MRSA) and enterococcal infections. To treat C. difficile infections
- Vancomycin-resistance strains (VRE) are a serious health threat
Glycopeptides e.g. Vancomycin
Side effects? (4)
What should be monitored?
C/I? (2)
Hydrophilic molecule – Reduced intestinal absorption – Administered by IV
Renally excreted
- Dose-related ototoxicity (ears): high-tone deafness, can progress to total deafness
- Nephrotoxicity (kidney damage)
- “Red man” syndrome (allergic reaction with rash on the face/neck, hands, feet)
- Agranulocytosis/neutropenia. (reduced levels of white blood cells
Recommended to monitor the drug level in serum
* 10-20 mg drug/L (through level) should be maintained to reduce toxicities
C/I= patients with history of deafness and elderly
What are examples of drug classes that inhibit protein synthesis?
Ribosome 30S (2) 50S (4)
30S subunit:
1. Aminoglycosides
2. Tetracyclines
50S:
1. Macrolides
2. Lincosamides
3. Chloramphenicol
4. Oxazolidinones
Protein Synthesis Inhibitor classes:
- Many antibiotics bind to the bacterial ribosome
- Ribosomes: machinery to synthesise proteins
- Inhibition of protein synthesis leads to
cessation of bacterial growth or cell death - Bacterial ribosome 70S differ sufficiently from the eukaryotic ones (80S) to allow selective toxicity
- Bacterial 70S are smaller, consisting of a small (30S) and a large subunit (50S), if compared to the eukaryotic ones 80S (formed by 40S and 60S)
What are the 3 phases of translation in bacteria?
- Initiation: ribosome assemble with the mRNA and the first tRNA
- Elongation: amino acids are brought to the ribosome by tRNAs and linked together to form a chain
- Termination : the finished polypeptide is released and the ribosome is disassembled
Protein Synthesis Inhibitor classes:
What do they target?
examples of these steps? (4)
Target different ribosomal subunits components and steps in protein synthesis
* Translation assembly/initiation
* Aminoacyl-tRNA binding to site A
* mRNA reading
* Translocation step
Examples:
* Macrolides & Lincosamines -Prevent the translocation step
* Oxazolidinones- Interfere with the
translation initiation
*Chloramphenicol- Block the attachment of tRNA to the ribosome site A
* Aminoglycosides- cause mRNA misreading (faulty/premature protein).
Also, they may block the translation initiation
Tetracyclines- Block the attachment of
tRNA to the ribosome site A
Aminoglycosides
What are some examples?
What is the mechanism of action?
Structure - a cyclohexane ring and amino sugars
Streptomycin,gentamycin,neomycin,amikacin, tobramycin
- Mechanism: Disrupt protein elongation in translation - Bactericidal effect
- Target: Irreversible binding to 30S,
-interfere with mRNA reading by tRNAs causing early termination of protein synthesis or aberrant proteins - Additional: Some also block the ribosome assembly, preventing initiation
Coverage - Mainly used for aerobic Gram- (serious infections)
Streptomycin can be used with other drugs for tuberculosis (by IM)
Low/fair activity against few Gram+ (e.g. staphylococci).
Inactive against anaerobes (Cell penetration is O2-dep. transport)
Aminoglycosides:
What are the pharmacokinetics?
What are the adverse effects?
IV infusion or applied locally (neomycin)
* Highly polar drugs – Poor oral bioavailability. Not absorbed from the gut
* Drugs excreted unchanged in the urine by glomerular filtration (dose adjustment in renal insufficiency)
Adverse effects - Used sparingly!! Narrow therapeutic range!
* Serum concentration must be monitored (reduce toxicity and avoid subtherapeutic dose)
* Ototoxicity: Loss of hearing (cochlear damage; amikacin) and balance (vestibular damage;gentamycin)
* Nephrotoxicity - killing of proximal tubular cells
* Neuromuscular toxicity -blockage of presynaptic ACh release= respiratory suppression
Tetracyclines
What are some examples?
What is the mechanism of action?
What do they target?
What are their uses?
4-cyclohexane core structure
Tetracycline HCl, Minocycline, Doxycycline
Mechanism:
* inhibition of the protein synthesis elongation - Bacteriostatic effect
-Target 30S ribosomal subunit
-by blocking the binding of aminoacyl tRNA on the mRNA-ribosome (to the A site
Tetracyclines- Block the access of tRNA to the ribosome site A
Coverage – Broad spectrum
* Uses - Susceptible infections (chlamydia, rickettsia, mycoplasma), acne and in resp. tract. May be used to treat MRSA infections (with other antibiotics)
Tetracyclines
What are the pharmacokinetics?
What are the adverse effects?
C/I?
Pharmacokinetics – Usually, via the oral route. Topical, IM, IV administration also possible.
-Oral absorption impaired by food (Multivalent cations reduces their absorption in the gut)
- Adverse effects – tetracyclines chelate large cations (Ca2+, Fe2+)
- GI distress, including antibiotic-associated colitis
- Oesophageal irritation
- Photosensitivity, (Sunlight can trigger immune system reactions) which can manifest as a red rash or skin blistering. avoid exposure to sunlight
- Incorporation into teeth and bone = staining of teeth; retardation of bone growth
- Rare risk of hepatotoxicity
- Headache and visual disturbances (due to intracranial hypertension)
Contraindications: in children (<12 years old ) and during pregnancy
-Caution in Myasthenia gravis (it may increase muscle weakness); systemic lupus erythematosus
Macrolides
What are examples?
What is the MoA?
What do they target?
What are they used for?
Erythromycin, Azithromycin,
Clarithromycin
-Prevent the translocation step
* Inhibition of protein elongation –
Bacteriostatic effect (may become bactericidal at high dose)
-Target reversibly 50S ribosomal subunit
-Block the translocation step (ribosome cannot shift along the mRNA)
-Broad spectrum (mostly against Gram+ & some Gram-). Similar to penicillins
Used for patients allergic to penicillin, various respiratory infections (CAP) andskin/cellulitis infections (β-haemolytic streptococci and Staphylococcus aureus), GI infection (H. pylori eradication - Clarithromycin) sexually transmitted infections of Chlamydia and Gonococcus- STIs (Azithromycin)
Macrolides
What are the Pharmacokinetics?
What are the adverse effects? (5)
Contraindications?
Usually oral route. Excellent tissue and cellular penetration
* Oral absorption impaired by food (better without food, if no GI upset)
-ALL hepatic elimination
- GI disturbance (nausea, vomiting, abdominal pain, and diarrhoea)
- Hepatotoxicity and Ototoxicity
- Prolongated QT intervals cardiac arrhythmia (used with antiarrhythmic drugs)
- Dry mouth
- Drug resistance – readily acquired (cross-resistance across all macrolides
Contraindications: patients with predisposition to QT internal prolongation
-in Myasthenia gravis (it may aggravate the conditions);
-Patients taking Rivaroxaban – interaction (increased risk of bleeding)
Lincosamines (Clindamycin)
What is the MoA?
What does it target?
What is it used to treat?
Side effects?
Contraindications?
Clindamycin (IM or IV)
Inhibition of protein elongation- Bacteriostatic effect
* Target 50S ribosomal subunit and interfere with the translocation step
- Contraindications: in neonates (Clindamycin Injection contains benzyl alcohol)
- Cautions: Monitor liver and renal function if treatment exceeds 10 days
Oxazolidinones (Linezolid)
What is the mechanism of action?
What does it target?
What is it used to treat?
Side effects?
Contraindications?
Linezolid (available in tablets, suspension, and injection
MoA= inhibition of protein elongation- Bacteriostatic effect
* Target the 50S ribosomal subunit and prevent the assembly of the 70S initiation complex
Active against Gram+ (including MRSA & vancomycin-resistant enterococci). Not active against Gram-infections of the skin/soft tissue and pneumonia
Side effects
* Thrombocytopenia (decreased platelets) or other blood disorders (anaemia, eosinophilia). Full blood
counts should be monitored weekly
* Severe optic neuropathy (visual impairment) may occur rarely (if >28 days). Visual functions should be
monitored and referred to an ophthalmologist
Oxazolidinones- Interfere with the
translation initiation/assembly
Chloramphenicol
What is the Mechanism of action?
What does it target?
What is it used to treat?
Side effects?
Contraindications?
Chloramphenicol (available in eye/ear drops, tablets, and injection
Mechanism: inhibition of protein elongation - Bacteriostatic effect
-Target 50S subunit and prevent the access aminocyl-tRNA to the A site
Coverage- Broad spectrum - Active against Gram+, Gram- and Mycoplasma spp.
* Side effects – dose-related (considered quite toxic for systematic use)
- Aplastic anaemia, risk of Leukaemia
- Blood disorder; bone marrow depression (even when used by ear)
- Hypersensitivity reactions
* Uses- eyes/ears infections or life-threatening infections (because of side effect
Contraindications: patients predisposed to blood Acute porphyrias
What are examples of antimetabolites?
Folic acid synthesis:
Sulfonamides
- Trimethoprim
- Mycolic acid synthesis
-Izoniazid
What are the functions of antimetabolites?
- Antagonize, or block, functioning of bacterial metabolic pathways (different to eukaryotic ones – selective toxicity).
- Compete with metabolites for binding sites.
- Stop the progression of the metabolic pathway
What is the coverage and effect of antimetabolites?
Coverage&effect:
*Bacteriostatic (if removed, the metabolic activity can be restored),
*Broad-spectrum activity
What is the mechanism of sulphonamides?
- Folic acid is essential to produce purines (DNA)
- Folic acid cannot cross the bacterial cell wall
- Bacteria synthesise folic acid, starting from a precursor p-aminobenzoic acid (PABA)
- Sulfonamides act by competing with PABA as a substrate for the enzyme dihydropteroate synthase
- Bacteriostatic effect
Selective toxicity- In Human body,Folic acid (Vitamin B9) obtained in the diet
What is the mechanism of Trimethoprim?
- Dihydrofolate reductase (DHFR) targeted by Trimethoprim
- DHFR is also present in human cells, as folic acid needs to be reduced to be active
- Trimethoprim has 100.000 higher affinity to the bacterial enzyme rather the human DHFR (selective toxicity)
- Bacteriostatic effect
Which ONE of the following classes of antibiotics is NOT a cell wall
inhibitor?
a) Vancomycin
b) Cephalosporins
c) Penicillins
d) Tetracyclines
e) Monopenemens
D= Tetracyclines
What are the two drugs in co-trimoxazole?
What is the MoA?
Sulfonamides and Trimethoprim
Sequential blocking mechanism:
- Both drugs block the folic acid synthesis at two distinct steps of = potential synergistic effect
- Both substrate analogues inhibiting two different enzymes:
-Dihydropteroate synthase by Sulphonamides
-Dihydrofolate reductase (DHFR) by Trimethoprim - Bacteriostatic effect
Sulfonamides + trimethoprim (co-trimoxazole)
When is it used?
What are the SE?
C/I?
Cautions?
Uses combination or Trimethoprim - UTIs, prostatitis and Pneumocystis
jirovecii pneumonia (PCP treatment and prevention) in immunocompromised patients
- Contraindications: blood dyscrasias and in first-trimester of pregnancy
- Cautions: in acute porphyria, elderly, neonates, predisposition to folate deficiency
Side effects
-Risk of folate deficiency (during pregnancy is associated with neural tube defects- contraindicated)
-Hyperkalaemia (high levels of potassium - monitor renal function)
-Hypersensitivity; rash and anaphylaxis
- Contraindications: blood dyscrasias and in first-trimester of pregnancy
- Cautions: in acute porphyria, elderly, neonates, predisposition to folate deficiency
What are examples of drug classes that are inhibitors for nucleic acid synthesis?
(DNA Synthesis)
* Fluoroquinolones
-ciprofloxacin, levofloxacin, moxifloxacin
(RNA Synthesis)
* Rifamycins
-rifampin
Inhibitors of nucleic acid synthesis:
- Anti-bacterial drugs that inhibit nucleic acid (DNA/RNA) synthesis function by inhibiting:
-Topoisomerases (by fluoroquinolones)
essential for DNA replication
-RNA polymerase (by rifamycins) catalysing the step of DNA transcription into mRNA
-Drugs not as selectively toxic as other antibiotics
Fluoroquinolones
What is the -ending?
What are some examples?
Coverage? What do they target?
What are they used to treat?
‘floxacin’
Ciprofloxacin, levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin
- Coverage & effect - Broad spectrum Wide range of activity against Gram positive and
negative bacteria (e.g. H. influenzae, Pseudomonas aeruginosa). Bactericidal effect - Uses – Serious RTIs (CAP), skin and soft tissue infections- and UTI (E. coli)
What is the Mechanism of action of Fluoroquinolones?
- Inhibit DNA replication by interfering with the bacterial topoisomerases (2 types)
- DNA gyrase (not present in human)= target in Gram-
- Topoisomerase IV (the human enzyme is inhibited at high dose) =target in Gram+
Nucleic Acid Synthesis Inhibition:
What 2 enzymes are involved in nucleic acid synthesis?
What are their roles?
DNA Gyrase and DNA topoisomerase IV
DNA gyrase unravels (relaxes) supercoiled DNA
*It is required for bacterial DNA replication.Without this step, helicase cannot unwind DNA
DNA topoisomerase IV
* DNA topoisomerase IV removes “DNA knots” generated behind the replication fork
*To keep the two duplicated DNA molecules separated
Fluoroquinolones inhibit DNA gyrase and topoisomerases IV= making DNA inaccessible
–blocking bacterial DNA replication= leading to cell death
Fluoroquinolones
WHat are the SE?
C/I?
Cautions?
- All orally active, and several are available as intravenous injections
Side effects (generally, well tolerated)
* GI distress (antibiotic-induced diarrhoea due to C.difficile overgrowth)
* tendonitis, tendon rupture – 2% cases (discontinue the treatment at the first sign of tendinitis, painful swelling, inflammation)
* Prolongs QT interval (very rare) and cardiac arrhythmia
* Seizures (rare, but taking NSAIDs may also induce them)
* Risk of aortic aneurysm (very rare and conflicting)
* Overuse is leading to rapid development of resistance
* Contraindications: patients with history of tendon damage or taking corticosteroids
* Cautions: Patients with QT prolongation risk factors, in epilepsy, psychiatric disorders, patients with renal impairment, exposure to sunlight.
Rifamycins:
What is the mechanism of Rifampicin?
- Inhibit the initiation of bacterial DNA transcription
- By blocking the activity of the β-subunit of the bacterial RNA polymerase (enzymatic complex)
- Bactericidal effect
Rifamycins
Coverage?
Uses?
SE?
C/I?
- Coverage- Broad spectrum INCLUDING Mycobacterium tuberculosis, but also
against Gram-positive and negative bacteria. - Uses – Used to treat tuberculosis with other antitubercular drugs. Enters the
cerebrospinal fluid treatment of some meningitis (N. meningitidis or H. influenzae - Side effects
GI distress
Minor hepatotoxicity
Discoloration of body fluids (urine and sweat turn orange - harmless)
Many interactions (by inducing cytochrome P450) - Contraindications: patients with acute porphyrias
- rapid development of resistance
Contraindications: patients with acute porphyria
Alternative mechanisms: antibacterials:
e.g. Nitroimidazoles- Metronidazole, Nitrofurantoin
How do they work?
Generating free radicals
Alternative mechanisms (free radicals) - Nitroimidazole
What is the MoA of Metronidazole?
What is the coverage?
What are the uses?
- Mechanism – Generating free radicals in bacteria
-It is activated by reduction in pathways, generating unstable nitroso radical metabolites (ROS)
-ROS leads to DNA fragmentation (DNA strand breakage)
-Bactericidal effect - Coverage – Only anaerobes (including protozoa – other class of microbes)
-Reduction to the free radicals requires low redox potential within cells
-NOT active against aerobic bacteria (high redox potential due to O2) - Uses – Used to treat infections of anaerobic bacteria, Helicobacter pylori eradication
Alternative mechanisms (free radicals) -
Metronidazole:
SE?
Caution?
- Rapid and effective absorption (Oral and IV)
- Penetrate well all tissues
Side effects
-GI distress
-Skin reaction (topic use only)
-Taste disturbances (metallic taste), furred tongue
-Peripheral neuropathy (rare)
-Disulfiram-like adverse reactions when alcohol is consumed
- Caution. Avoid exposure to sunlight with topical use.
Avoid intravaginal preparations in young girls. Avoid alcohol (disulfiram-like reaction)
Alternative mechanisms - Nitrofurantoin
What is the mechanism?
Coverage?
Uses?
Mechanism –
* Generating reactive free radicals in bacteria
* Activate pathways in bacteria to generate instable metabolites that interfere with RNA, DNA and other components synthesis.
-Bactericidal effect
- Coverage is active against most Gram+ cocci and some Gram- (E. coli)
- Uses – Used to treat and prevent uncomplicated acute UTIs
Alternative mechanisms - Nitrofurantoin
SE? (4)
C/I?
Caution?
SE
1. Discoloration of body fluids (urine and sweat turn orange/brown - harmless)
2. Pulmonary toxicity (fever, chills, cough, myalgia, and dyspnea)
3. Peripheral neuropathy (rare)
4. blood disorders (rare, hemolytic anemia)
Contraindications: in patients with decreased renal function (if eGFR <45
mL/min), G6PD deficiency; infants less than 3 months old
* Caution in anaemia, diabetes, electrolyte imbalances and folate deficiency
What is TB?
Tuberculosis
* Infection in the lungs (pulmonary), or spread to other organs (extrapulmonary)
* Latent (asymptomatic) and active tuberculosis (symptomatic)
Features of the bacteria- Mycobacterium tuberculosis?
- Gram+ and aerobe (requires oxygen - lungs)
- Complex and unique cell wall
* Virulence factors – allowing the bacteria to survive after the phagocytosis of macrophages. Mycobacteria can
even replicate inside a macrophage and kill it
- Marker for the microbiological diagnosis
-Acid-fast staining (lipid-rich cell wall)
-Auramine fluorescent staining (mycolic acids of the cell wall)
*Therapeutic target
What is the structure of the cell wall of Mycobacteria?
Mycobacterium cell wall – thick, hydrophobic, robust and waxy (variety of lipids)
*Hydrophobic barrier to antibiotics –difficult to treat Mycobacteria
Principles of the therapy for tuberculosis? (4)
- Multidrug-resistant TB (MDR-TB) is a public health threat
Principles of the therapy:
* Prompt and effective treatment of identified cases
* Combination of drugs and long therapy to prevent the emergence of MDR-TB
* Therapy adherence is vital to avoid resistance and be effective
* Rifampicin and erythromycin (less used), are the only antibiotics used to treat
tuberculosis and also other bacterial infections
* The other antitubercular drugs are only used to treat tuberculosis
What is the Treatment for TB in newly diagnosed patients?
- NEWLY DIAGNOSED (6-months therapy)
-initial phase (RIPE):Rifampicin+ Isoniazid + Pyrazinamide + Ethambutol (2 months)
-continuation phase (RI): Rifampicin+ Isoniazid (4 months)
What is the Treatment for TB in retreat patients?
Re-treatment
(7-months therapy)
* initial phase: RIPE + Streptomycin (2 months)
* continuation: RI + Ethambutol (5 months)
- Treatment needs to be supervised (Directly Observed Therapy) in patients at risk of non-compliance
What are some drug-resistant strains of TB?
- Multidrug-resistant TB (MDR-TB), TB resistant to Rifampicin AND Isoniazid
- Extensively drug-resistant TB (XDR-TB), TB resistant to Rifampicin, Isoniazid, AND at least two types of drugs of the second line
Treatment for tuberculosis (TB)
What 4 drugs are used?
What are their moA?
- R- Rifampicin
(RNA polymerase inhibitor)
*I- Isoniazid
(Prodrug) - Inhibitor of mycolic acids
synthesis
*P- Pyrazinamide
(Prodrug) - interferes with fatty acid
synthesis
*E- Ethambutol interferes with synthesis of arabinogalactans
Which of the following is the target of the antibiotic trimethoprim?
a) Cell wall synthesis
b) Protein synthesis
c) Folic acid synthesis
d) RNA polymerase
=C
Which of the following is NOT a first line drug in the treatment of
tuberculosis?)
a) Rifampicin
b) Isoniazid
c) Pyrazinamide
d) Amoxicillin
e) Ethambutol
=D
