L71: Drugs Used in the Treatment of Pulmonary Infections Flashcards
URT infection
- pharyngitis/sore throat
- tonsillitis
- sinusitis (inflammation of mucous membrane of sinuses)
- otitis media (inflammation of mucous membrane of middle ear)
- cold/flu
LRT infection
- Acute bronchitis (RSV, parainfluenza virus, adenovirus)
- Acute bronchiolitis (terminal bronchioles, RSV, parainfluenza virus)
- Pneumonia (bacterial infections)
***Drugs used in pneumonia
Beta-lactams:
- Penicillin +/- betalactamase inhibitor (cell wall synthesis)
- Cephalosporin (cell wall synthesis)
Protein synthesis inhibitors:
- Macrolide (50s inhibitor, increasing resistance)
- Tetracycline (30s inhibitor)
Nucleic acid synthesis inhibitors:
5. Fluoroquinolone (DNA gyrase + topoisomerase IV, gram -ve)
Members of beta-lactam antibiotics
- Penicillin (narrow/extended spectrum)
- Cephalosporin (1st -5th gen)
- Carbapenem
- Monobactam
Mechanism of beta-lactam antibiotics
BacterioCIDAL
Mimics structure of D-Ala-D-Ala link
—> covalently bind to and inhibit transpeptidase/penicillin binding protein (PBP)
—> inhibit pentapeptide cross linking between NAM subunits
—> bacterial cell wall weakens
—> autolysin activated to destroy existing cell wall / osmotic lysis
Gram +ve vs Gram -ve bacteria in relation to drug actions
Gram -ve: LPS —> drugs need Porin channel to be actively transported into bacteria
Gram +ve: drugs go in by simple diffusion
Mechanisms of resistance to beta-lactam
Gram +ve:
- Beta-lactamase
- Altered PBP / transpeptidase
Gram -ve:
- Loss of porin channels
- Efflux pump
- Beta-lactamase
- Altered PBP / transpeptidase
Classification of penicillins
- Narrow spectrum, Beta-lactamase sensitive
- Narrow spectrum, Beta-lactamase resistance
- Extended spectrum aminopenicillin
- Extended spectrum antipseudomonal penicillin
Narrow spectrum, Beta-lactamase sensitive
Penicillin G Bad: - Narrow spectrum - Beta-lactamase SENSITIVE - acid labile - short duration - poor penetration into CNS - allergy
Adverse effects
- Diarrhea
- Seizure
- Low toxicity
Narrow spectrum, Beta-lactamase resistance
Antistaphylococcal penicillin
- Methicillin (too nephrotoxic)
- Flucloxacillin
Good
- Beta-lactamase RESISTANT: for beta-lactamase resistant staphylococcal infection
- acid stable
Bad
- Narrow spectrum
- poor penetration into cell membrane (due to bulky side chain)
- less effective than other penicillin
Extended spectrum aminopenicillin
- Ampicillin
- Amoxicillin
Good:
- Broader spectrum
- Gram +ve
- Gram -ve cocci and bacilli
- acid stable
- good oral bioavailability
Bad:
- Beta-lactamase SENSITIVE
- NOT active against Pseudomonas
Antipseudomonal penicillin
Carboxypenicillin: carbenicillin, ticarcillin
Ureidopenicillin: piperacillin
Good:
- effective against gram -ve bacilli
- effective against pseudomonas aeruginosa
Bad:
- Beta-lactamase SENSITIVE
- acid labile
Beta-lactamase inhibitor
- Clavulanate
- Sulbactam
- Tazobactam
Irreversible inhibitor of beta-lactamase
Combined with Broad-spectrum beta-lactam:
- Augmentin: amoxicillin + clavulanate
- Tazocin: piperacillin + tazobactam
- Unasyn: ampicillin + sulbactam
Cephalosporin
BacteriCIDAL
MOA:
- covalently bind to PBP —> inhibit cell wall synthesis
Broad spectrum:
- Gram +ve
- Gram -ve
- anaerobes
- Beta-lactamase RESISTANT
- non-toxic
- hospital overuse
Classification of cephalosporin
1st gen: greatest activity vs Gram +ve
- cefalexin
2nd gen: expanded activity vs Gram -ve
- cefuroxime
—> Nowadays use 3rd gen onwards
3rd gen: mainly vs Gram -ve
- cefotaxime, ceftriaxone
4th gen: wide spectrum, beta-lactamase resistant
- cefepime
5th gen: wide spectrum, MRSA-active
- ceftaroline
Pharmacokinetics of cephalosporin
- IV/IM due to poor oral absorption (except cefalexin, cefuroxime)
- well-distributed in body fluids
- inadequate CSF penetration except 3rd gen
- long half life: once daily
- renal excretion (except ceftriaxone: biliary excretion)
Adverse effects and disadvantages
- GI irritation (diarrhoea, nausea)
- allergy (rare)
- nephrotoxicity (infrequent)
- very expensive (esp. parenteral preparations)
***Protein synthesis inhibitor
BacterioSTATIC
Broad spectrum:
- Tetracycline (30s)
- Chloramphenicol
Moderate spectrum:
- Macrolide (50s)
- Ketolides
Narrow spectrum:
- Linezolid (50s)
- Lincosamides (Clindamycin)
- Streptogramins
Mechanisms of action of macrolide
- Irreversible binding to 50S subunit
- Inhibit translocation of polypeptide chain from A to P site by peptidyltransferase
- block movement of peptidyl tRNA from A to P site
- incoming tRNA cannot bind to A site
- stop protein synthesis
Spectrum of macrolides
Gram +ve: clarithromycin > erythromycin > azithromycin
Gram -ve: azithromycin > clarithromycin > erythromycin
Erythromycin (same as penicillin):
- active vs Gram +ve
- for patient allergic to penicillin
Clarithromycin:
- higher activity vs Intracellular pathogens (Chlamydia)
Azithromycin:
- enhanced activity vs Gram -ve
- less activity vs Gram +ve
Telithromycin (similar to azithromycin):
- effective vs macrolide-resistant strains
Pharmacokinetics of macrolides
- acid stable (except erythromycin —> enteric coating)
- All well absorbed
- well distributed in tissue
- poor penetration into CSF
- concentrated in phagocyte (useful vs intracellular pathogen)
- Time-dependent post-antibiotic effect: long half life of azithromycin
- conversion to active metabolite: all except erythromycin
- clarithromycin excreted in urine
- erythromycin + azithromycin excreted in bile
- erythromycin + telithromycin extensively metabolised
Good and Adverse effects of macrolide
- Large therapeutic index
- Non-toxic
- GI disturbance (stimulation of motilin receptor)
- Arrhythmia (QT prolongation)
- Erythromycin: deafness (high dosage)
- Drug interaction (inhibit CYP3A4 except azithromycin)
- Caution with liver disease
- Taking erythromycin estolate ester preparation for >1-2 weeks can cause cholestatic hepatitis (fever, abdominal pain, jaundice)
Uses of macrolide and Resistance mechanism
Use
- Penicillin substitute
- Mycoplasma, Legionella pneumoniae
- Empirical antibiotic for outpatient pneumonia
Resistance
- Efflux pump (NOT for telithromycin)
- 50S subunit modification by methylases encoded by “erm”
- Esterase to hydrolyse macrolide
Tetracyclines
- BacterioSTATIC
- Broad spectrum
- inhibit protein synthesis (30S)
- used for uncommon infections
- resistance problem
- Doxycycline
- Long duration of action
- Good oral absorption
- 20% reduced taken with milk/food (take on empty stomach)
- Biliary excretion (for renal impaired patients)
Mechanisms of action of tetracyclines
Bind to 30S
—> prevent access of amino acid tRNA to A site on mRNA-ribosome complex
—> block addition of amino acid to existing peptide chain
—> stop protein synthesis
Glycylcyclines
Derived from tetracycline
- IV infusion
- effective vs multi-resistant Gram +ve
- NOT effective vs Proteus + Pseudomonas spp.
- Biliary excretion
- for complicated intra-abdominal infections
Adverse effects of tetracycline
- Local tissue irritation
- GI irritation
- Hepatotoxicity
- Teeth discolouration (avoid giving pregnant and under age of 8)
- Photosensitation
- vestibular problems
Resistance mechanisms to tetracycline
- Impaired influx (Porin channel)
- Increased efflux
- Production of proteins that prevent binding to 30S
- Tetracycline-inactivating enzyme
Quinolone
1st gen: Non-fluorinated
- Nalidixic acid
- urinary antiseptic, no systemic effect
- effective vs Gram -ve causing recurrent UTI
- resistance problem
2nd gen: Fluorinated (Fluoroquinolone)
- Ciprofloxacin
- expanded vs Gram -ve
- some vs Gram +ve
- NOT effective against anaerobes
- for UTI, LRTI
- resistance problem
3rd gen:
- Levofloxacin
- expanded vs Gram -ve
- improved vs Gram +ve
4th gen:
- Moxifloxacin, Gemifloxacin
- maintained vs Gram -ve
- improved vs Gram -ve
- Anaerobic coverage
Fluoroquinolone
BacterioCIDAL
- Broad spectrum (esp Gram -ve)
- Safe
- Effective in LOWER RT infection
- reserved for respiratory and urinary infections caused by resistant bacteria
- Uncommon resistance
Mechanism of action of fluoroquinolone
- Inhibit DNA gyrase (topoisomerase II)
—> quinolone-DNA-gyrase complex
—> induced cleavage of DNA - Inhibit DNA topoisomerase IV
Pharmacokinetics and Adverse effects of fluoroquinolone
Pharmacokinetics:
- high tissue penetration
- renal excretion
Adverse effects
- GI symptoms
- CNS symptoms (dizziness, confusion, insomnia)
- photosensitivity
- Ruptured tendons / Arthropathy (CI in children, pregnant and nursing women)
- interaction with antacids
- CYP450 inhibitor (warfarin, theophylline)
Mechanisms of resistance to Fluoroquinolone
- Efflux pump (upregulation)
- Mutations of DNA gyrase / topoisomerase IV
- Reduced Porin channel (in outer membrane of gram -ve bacteria)
- Drug-modifying enzyme acetyltransferase
Empirical antibiotic selection for CAP
Amoxicillin:
Good: S. pneumoniae
Bad: Atypical agents / beta-lactamase (add clavulanate)
Cephalosporins:
Good: most S. pneumoniae and ALL H. Influenzae
Bad: Atypical agents
Macrolide:
Good: most common pathogen including Atypical agents
Bad: resistance problem
Fluoroquinolone:
Good: H. influenzae, Atypical agents (mycoplasma), less vs S. pneumoniae
Bad: increasing resistance
CDC recommendations in prescribing antibiotics
- Identify causative agent
- Susceptibility testing
- Give empirical —> then specific
- Appropriate dose and duration
