Antibiotics

Question 1

Beta-lactam antibiotics

Question 2

**Penicillins **- pharmocokinetics

Answer 2

• Many IV and oral agents
• Peak concentration in 1-2 hours
• Distribution into body water - about 0.2L/kg
• Little metabolism
• Mainly urinary excretion

Question 3

**Penicillin V/G **- indications

Answer 3

• Beta-haemolytic streptococci
• pneumococci
• meningococci
• gonococci
• anerobes, gram-positive anaerobic cocci (GPAC) and clostridia
• Resistance !
  
  • ​pneumococci
  • gonococci

Question 4

**Flucloxacillin **- indications

Answer 4

• S.aureus
  
  • ​NB MRSA

Question 5

**Ampicillin/amoxicillin + clavulanate **- indications

Answer 5

• otitis media
• COAP
• CAP
• UTI
• skin and soft tissue infection
• surgical prophylaxis
• intra-abdominal surgery

Question 6

**Piperacillin/tazobactam **- indications

Answer 6

• Hospital IV therapy - 2nd line

Question 7

Carbapenem antibiotics

Answer 7

• E.g. Meropenem
• Very broad-spectrum
• Injectable only
• Used as 2nd/3rd line therapy in hospital
• Typical Beta-lactam pharmacokinetics
• Not active against:
  
  • MRSA
  • Stenotrophomas maltophilia
  • Some enterococci
• Resistance remains rare

Question 8

First generation cephalosporins

Answer 8

• e.g. cefalexin
• Active against gram positive cocci
  
  • Streptococci and Staphylococci
• Active against gram negatives - cover UTIs
  
  • E.Coli
  • Klebsiella
  • Proteus species
• Mainly oral
• Mainly used in GP land

Question 9

Second generation cephalosporin

Answer 9

• e.g. cefuroxime
• Effective as per first generation (Gram positive cocci and Gram negatives for UTI) + Gram negatives causing CAP and infective exacerbation of COPD:
  
  • H.influenzae
  • M.catarrhalis
• ​Mainly given IV

Question 10

Third generation cephalosporins

Answer 10

• e.g. cefotaxime, ceftriaxone, ceftazidime
• Poor activity against Gram positive cocci (especially ceftazidime)
• Good against Gram negatives found in hospitals:
  
  • Citrobacter, Serratia species –> ceftriaxone/cefotaxime
  • Pseudomonas aeruginosa –> ceftazadime
• ​Mainly given IV
• Good CSF penetration
• Only used sparingly in hospitals

Question 11

Fourth generation cephalosporins

Answer 11

• e.g. cefpirome
• Similar spectrum to *ceftazidime + *good activity against some Gram positive cocci

Question 12

Bacteria resistant to cephalosporins

Answer 12

• MRSA
• Enterococci
• Listeria
• Legionella
• C.difficile
• Camyobacter
• ESBL producing E.Coli/Kleibsiella

Question 13

Cephalosporins - Indications

Answer 13

• Acute meningitis (cefotaxime/ceftriaxone)
• Surgical prophylaxis (abdominal, orthopaedic, head and neck, obstetrical)
• UTI/acute pyelonephritis
• Chest infection
• Community acquired sepsis of unknown site (ceftriaxone)
• Hospital acquired sepsis of unkown site (ceftazidime + 2nd agent)
• Skin/soft tissue infections
• Intra-abdominal infections + metronidazole

Question 14

Beta-lactamase inhibitors

Answer 14

• e.g. co-amoxiclav (amoxicillin + clavulanic acid)
• Clavulanic acid is an inhibitor of Betalactamase activity
• S.aureus - penicillinase —> inhibited
• E.coli, H.influenzae, Gonococcus, Salmonella - TEM 1/2 beta-lactamases –> inhibited
• *Bacteriodes - *? –> inhibited
• *Enterobacter - *AmpC beta-lactamase –> not inhibited

Question 15

Fluoroquinolones

Answer 15

• Mainly used in hospitals for Gram negative infections/LRTIs
• Act by inhibiting DNA gyease
• Resistance increaasingly common:
  
  • Efflux pumps to decrease intracellular concentration
  • Target site mutations
  • Proteins that bind to DNA gyrase
• Pharmacokinetics:
  
  • Good oral bioavailability so PO = IV
  • Wide tissue distribution (2-3L/kg) - good for bone/soft tissue infections
  • Excretion by:
    
    • Metabolism - ciprofloxacin, moxifloxacin
    • Renal clearance - ciprofloxacin, moxifloxacin, levofloxacin**​
• ​​Side effects (unusual):
  
  • Rashes/phototoxicity
  • Tendinitis and rupture
  • GI upset
  • QTC prolongation (moxifloxacin)
  • Hepatoxicity

Question 16

Ciprofloxacin - spectrum

Answer 16

• Effective against:
  
  • Aerobic Gram negative bacteria:
    
    • Coliforms
    • Pseudomonas
  • Neisseria gonorrhoeae ‘Gonococci’
  • H.influenzae
  • Atypical chest pathogens:
    
    • Legionella
    • Mycoplasma
    • Chlamydia
• ​Borderline activity against *S.aureus *and Streptococci
• Not active against anaerobes
• Some activity against M.tuberculosis

Question 17

Moxifloxacin - spectrum

Answer 17

• As for *ciprofloxacin *but much better activity versus *Staphylococci *and Streptococci
• Poor activity against P.aeruginosa
• Better activity against anaerobes

Question 18

Fluoroquinolones - Indications

Answer 18

• Community acquired chest infections (moxifloxacin/levofloxacin)
• UTI/acute pyelonephritis (ciprofloxacin/levofloxacin)
  
  • ​! resistance
• Intra-abdominal infections (with metronidazole)
• Bone/joint infections
• Oral therapy for P.aeruginosa (ciprofloxacin)

Question 19

Aminoglycosides

Answer 19

• e.g. *Gentamycin * (most common), tobramycin, amikacin
• Act by inhibition of protein synthesis at ribosome
• Resistance by enzymes (aminoglycosides monitoring enzymes) - rare
• Pharmacokinetics
  
  • Poor oral absorption - IV/IM only
  • Modest tissue distribution
  • Concentrates in kidneys and ears –> toxicity
  • Renal excretion only not metabolises –> accumulation in renal failure
  • Reduced use due to toxicity - requires therapeutic drug monitoring and dosa adjustment
• Side effects:
  
  • Nephrotoxicity (reversible)
  • Ototoxicity (irreversible)

Question 20

Aminoglycosides - spectrum

Answer 20

• Broad Gram negative activity - coliforms, P.aeruginosa
• No anaerobic activity

Question 21

Aminoglycosides - indications

Answer 21

• All in combination therapies for:
  
  • intra-abdominal infection
  • infective endocarditis
  • neutropaenic sepsis
  • neonatal sepsis (penicillin + flucloxacillin)
  • *P.aeuginosa *infection (cystic fibrosis)
  • *S.aureus *infection

Question 22

Glycopeptides

Answer 22

• IV hospital use only
• Wide use to treat multi-resistant Gram positive infection especially MRSA
• Acts by inhibiting cross-linking of bacterial cell wall
• Resistance rare except in enterococci
  
  • ​Altered target site - enterococci, staphylococci
  • Altered permeability - staphylococci
• ​Pharmacokinetics
  
  • IV use only
  • Renal excretion, not metabolised
• Side effects
  
  • Nephrotoxicity (10%) increased by use of other nephrotoxic agents e.g. gentamycin, furosemide
  • Ototoxicity very rarely
  • Red man syndrome (vancomycin)
  • Thrombocytopenia (teicoplanin large doses)
• Requires therapeutic drug monitoring

Question 23

Glycopeptides - spectrum

Answer 23

• Active against nearly all Gram positive bacteria - especially multi-resistant strains
• Not active against Gram negative bacteria

Question 24

Glycopeptides - indications

Answer 24

• *MRSA *infection
• *Clostridium difficile *associated diarrhoea (CDAD) as a second line treatment
• Multi-resistant Gram positive infections:
  
  • Coagulase negative staphylococci
  • Corynebacteria
  • Enterococci
• ​Prosthetic infection (line, joint etc.)
• Penicillin allergy

Question 25

Macrolides

Answer 25

* IV and PO agents widely used in hospital and community to treat LRTIs and in penicillin allergy * Mode of action by inhibition of protein synthesis at ribosome * Resistance common due to target side modification * Pharmacokinetics: * Reasonable bioavailability * Good oral absorption * Good tissue penetration * Renal and biliary excretion * Side effects: * Nausea and GI upset (especially erythromycin) - due to pharmacological effect on stomach motility

Question 26

Macrolides - spectrum

Answer 26

* Active against Gram positive oranganisms i.e. *S.aureus *(not *MRSA*) and *Streptococci* * Resistance 10-20% * Active against atypical respiratory pathogens: * *Legionella* * *Mycoplasma* * *Chlamydia* * *​*No activity against Gram negatives except for *campylobacter*

Question 27

Macrolides - Indications

Answer 27

* Skin/soft tissue infections if allergic to *penicillin* * Community acquired pneumonia * *Campylobacter *infections

Question 28

Tetracyclines

Answer 28

* Used in primary care to treat acne * Used in hospitals to treat MRSA * Acts by inhibitng protein synthesis at the ribosome * Resistance common due to: * Efflux pumps * Target site modification * Contraindicated in children as concentrates in bone/teeth where it binds to calcium * Only oral availability

Question 29

Metronidazole

Answer 29

* Available IV/PO * Widely used to treat anaerobic infections * Resistance very rare * Acts by disrupting DNA * Pharmacokinetics: * Well absorbed PO and PR * Wide tissue distribution * Side effects: * Safety concerns in early pregnancy * Disulphiram-like reaction with alcohol * Rare peripheral neuropathy on long-term therapy

Question 30

Trimethoprin

Answer 30

* Available PO only * Used to treat uncomplicated UTI * Used in combination with *sulphamethoxazole (co-trimoxazole) *to treat *p**neumocystis* pneumonia (PCP) - PO/IV * Acts by inhibiting dihydrofolate resuctase to impair folate metabolism * Resistance due to: * Overproduction of enzyme * Target site modification * 20% of *E.coli* resistant * Renal excretion

Question 31

Linezolid

Answer 31

* Only oxazolidinase available for clinical use * Active against a wide range of Gram positive bacteria including multi-resistant strains *(MRSA, VRE)* * Used as a second line agent in serious Gram positive infection * Pharmacokinetics: * Good bioavailability * Moderate/good tissue distribution * Non-enzymatic degradation * Breakdown products renally excreted * Side effects: * Thrombocytopenia * Neuropathy with long term use

Question 32

Daptomycin

Answer 32

* Only lipopeptide antibiotic available * Active against a wide range of Gram positive bacteria including multi-resistant strains *(MRSA, VRE)* * Used as a second line therapy against serious Gram positive infection * Not suitable for use in lung infections * Pharmacokinetics: * Poor oral absorption - IV only * Renal excretion * Poor lung penetration * Side effects: * Muscle toxicity