Summary Cell Wall Inhibitors Protein Synthesis Inhibitors Quinolones Folate Antagonists Antimycobacterials Key Points - ## Cell Wall Inhibitors Protein Synthesi
Summary Cell Wall Inhibitors Protein Synthesis Inhibitors Quinolones Folate Antagonists Antimycobacterials Key Points - Cell Wall Inhibitors Protein Synthesis Inhibitors Quinolones Folate Antagonists Antimycobacterials - WEEK 6 — CELL WALL INHIBITORS - Beta-Lactams — Core Recap - MOA : Mimic D-Ala-D-Ala → bind PBPs (transpeptidases) irreversibly → no peptidoglycan crosslinking → osmotic lysis → bactericidal, time-dependent - Beta-lactam ring is essential for activity — beta-lactamases cleave this ring = resistance - Penicillins Drug Spectrum Key Clinical Use --- --- --- Benzylpenicillin (Pen G) Narrow Gram+ Strep, meningitis, syphilis, endocarditis Phenoxymethylpenicillin (Pen V) Narrow Gram+ Oral; strep throat; asplenia prophylaxis Flucloxacillin MSSA only Staph skin, bone, endocarditis Amoxicillin Gram+, some Gram- RTI, UTI, H. - pylori , Listeria Co-amoxiclav Broad + anaerobes Bites, abscesses, mixed infections Piperacillin-tazobactam Broad + Pseudomonas Severe hospital infections, febrile neutropenia - - Flucloxacillin = penicillinase-resistant → used specifically for S. - aureus (MSSA) - Flucloxacillin side effect : cholestatic hepatitis (especially prolonged use, elderly) - Cephalosporins — Generation Rules Generation Example Key Coverage --- --- --- 1st Cefalexin, Cefazolin Gram+ (surgical prophylaxis) 2nd Cefuroxime Gram+ + better Gram- 3rd Ceftriaxone, Ceftazidime Gram- (meningitis); Ceftazidime = Pseudomonas 4th Cefepime Pseudomonas + Gram+ 5th Ceftaroline MRSA activity Detailed Notes --- WEEK 6 — CELL WALL INHIBITORS Beta-Lactams — Core Recap - MOA : Mimic D-Ala-D-Ala → bind PBPs (transpeptidases) irreversibly → no peptidoglycan crosslinking → osmotic lysis → bactericidal, time-dependent - Beta-lactam ring is essential for activity — beta-lactamases cleave this ring = resistance Penicillins Drug Spectrum Key Clinical Use --- --- --- Benzylpenicillin (Pen G) Narrow Gram+ Strep, meningitis, syphilis, endocarditis Phenoxymethylpenicillin (Pen V) Narrow Gram+ Oral; strep throat; asplenia prophylaxis Flucloxacillin MSSA only Staph skin, bone, endocarditis Amoxicillin Gram+, some Gram- RTI, UTI, H. pylori , Listeria Co-amoxiclav Broad + anaerobes Bites, abscesses, mixed infections Piperacillin-tazobactam Broad + Pseudomonas Severe hospital infections, febrile neutropenia - Flucloxacillin = penicillinase-resistant → used specifically for S. aureus (MSSA) - Flucloxacillin side effect : cholestatic hepatitis (especially prolonged use, elderly) Cephalosporins — Generation Rules Generation Example Key Coverage --- --- --- 1st Cefalexin, Cefazolin Gram+ (surgical prophylaxis) 2nd Cefuroxime Gram+ + better Gram- 3rd Ceftriaxone, Ceftazidime Gram- (meningitis); Ceftazidime = Pseudomonas 4th Cefepime Pseudomonas + Gram+ 5th Ceftaroline MRSA activity - Higher generation = better Gram-negative, less Gram-positive (except 5th gen) - Ceftriaxone : once daily, biliary excretion, meningitis, gonorrhoea, CAP - Ceftazidime-avibactam : covers carbapenemase-producers (KPC, OXA-48) Carbapenems Drug Key Feature --- --- Meropenem Broadest; CNS safe; Pseudomonas Imipenem-cilastatin Cilastatin prevents renal inactivation; seizure risk Ertapenem Once daily; NO Pseudomonas/Acinetobacter Doripenem Similar to meropenem - Resistant to most beta-lactamases except carbapenemases (KPC, NDM, OXA-48) - Ertapenem trap : looks like a carbapenem but misses Pseudomonas — don't use empirically for suspected MDR Monobactams - Aztreonam : Gram-negative only, no anaerobes, no Gram+ - Safe in penicillin allergy (minimal cross-reactivity) - Used in CF, febrile neutropenia (penicillin-allergic) Beta-Lactamase Inhibitors Combination Inhibitor Extra Coverage Gained --- --- --- Co-amoxiclav Clavulanate Beta-lactamase producing organisms Tazocin Tazobactam As above + Pseudomonas Ceftazidime-avibactam Avibactam KPC, OXA-48 carbapenemases Meropenem-vaborbactam Vaborbactam KPC carbapenemases --- Glycopeptides Vancomycin - MOA : Binds D-Ala-D-Ala terminus → physically blocks transglycosylation + transpeptidation - Gram-positive only (too large for Gram-negative outer membrane) - Bactericidal against staph; bacteriostatic against enterococci - Routes: IV systemic; oral = C. diff only (not absorbed) - TDM : AUC/MIC 400–600 or trough 10–20 mg/L - Red Man Syndrome : histamine release → flushing, rash, hypotension → NOT allergy → slow infusion, antihistamine - Toxicity : nephrotoxicity (↑ risk with aminoglycosides), ototoxicity Teicoplanin - Same MOA as vancomycin - Longer half-life → once daily (after loading) - Less nephrotoxic; IM or IV VRE Resistance Mechanisms Gene Resistance --- --- VanA Vancomycin + teicoplanin resistant (D-Ala-D- Lac ) VanB Vancomycin only resistant; teicoplanin susceptible VanC Low-level, intrinsic in E. gallinarum --- Other Cell Wall Agents Fosfomycin - Inhibits MurA (first step in peptidoglycan synthesis) - Oral or IV - Uncomplicated UTI (single oral dose), MDR Gram-negatives (IV — combination) - Well tolerated; mainly GI side effects Daptomycin (Cell Membrane) - MOA : Ca²⁺-dependent insertion → membrane depolarisation → bactericidal - Gram-positive only - NOT for pneumonia (inactivated by surfactant) - Side effect: myopathy → monitor CK, hold statins --- WEEK 6 — PROTEIN SYNTHESIS INHIBITORS Aminoglycosides - MOA : Bind 30S irreversibly → misreading of mRNA → aberrant proteins → bactericidal - Require oxygen for cell entry → INACTIVE against anaerobes - Concentration-dependent + long PAE → once daily dosing - Hartford nomogram for dosing in renal impairment Drug Key Use --- --- Gentamicin Gram-negative sepsis, endocarditis synergy Amikacin MDR Gram-negatives (resistant to other aminoglycosides) Tobramycin Pseudomonas in CF (inhaled) Streptomycin TB, brucellosis Toxicity — CRITICAL - Nephrotoxicity : proximal tubule damage; reversible; ↑ risk with dehydration, NSAIDs, vancomycin - Ototoxicity : - Cochlear (hearing loss — irreversible , high-frequency first) - Vestibular (vertigo, ataxia, nystagmus) - Neuromuscular blockade : rare; avoid in myasthenia gravis - Monitor: pre-dose trough (must be undetectable with OD), peak Cmax/MIC ≥ 10 --- Tetracyclines - MOA : Bind 30S reversibly → block aminoacyl-tRNA entry → bacteriostatic - Chelate divalent cations (Ca²⁺, Mg²⁺, Fe²⁺) → reduced absorption with dairy, antacids, iron Drug Key Feature --- --- Doxycycline Most used; once daily; excellent oral bioavailability Minocycline Good tissue penetration; acne; some MRSA Tigecycline IV only; broad including MRSA, ESBL, anaerobes; NOT Pseudomonas Uses : atypicals ( Mycoplasma, Chlamydia, Rickettsia, Coxiella ), Lyme disease, acne, malaria prophylaxis, MRSA soft tissue, STIs, brucellosis, cholera Contraindications : pregnancy, children <8 years (teeth discolouration, bone growth inhibition), renal failure (except doxycycline) Side effects : photosensitivity, oesophageal ulceration (take upright with water), GI upset, pseudotumour cerebri --- Macrolides - MOA : Bind 23S rRNA of 50S → inhibit translocation → bacteriostatic ; excellent intracellular penetration Drug Key Feature --- --- Azithromycin t½ 68h → 3–5 day course; Chlamydia 1g stat; atypicals Clarithromycin H. pylori triple therapy; MAC in HIV Erythromycin Oldest; pro-motility (motilin agonist); pertussis; most GI side effects Uses : CAP (atypicals), Chlamydia , pertussis, H. pylori , MAC prophylaxis in HIV, gastroparesis (erythromycin) Side effects : GI upset, QT prolongation (avoid with other QT drugs), hepatotoxicity, CYP3A4 inhibition → ↑ statin/warfarin/cyclosporin levels Resistance : MLSb — methylation of 23S rRNA (ermB gene); efflux (mefA) --- Chloramphenicol - MOA : Binds 50S → inhibits peptidyl transferase → bacteriostatic ; broad spectrum - Good CNS penetration - Uses : meningitis (when beta-lactams can't be used), typhoid, eye drops (conjunctivitis) - Toxicity : - Dose-dependent : reversible bone marrow suppression - Idiosyncratic : aplastic anaemia (rare, irreversible, fatal) - Grey baby syndrome : neonates lack glucuron