PHCY220: "Bugs and Drugs" Pharmacology of Antibiotics I PDF 2023 Lecture Notes

PHCY220: “Bugs and Drugs”: Pharmacology of Antibiotics I Dr Ailsa McGregor, 2023  Patient CD4: microbes and Infection CD2: socioeconomic factors Bug Empiric Ther...

PHCY220: “Bugs and Drugs”: Pharmacology of Antibiotics I Dr Ailsa McGregor, 2023  Patient CD4: microbes and Infection CD2: socioeconomic factors Bug Empiric Therapy Drugs? CD5: principles of antimicrobial selection What this lecture will cover 1. How we can classify antibiotics 2. The pharmacodynamics of some classes of antibiotics: ASSESSABLE TASKS! By the end, you should be able to Explain the mechanism of action Briefly describe the PK Discuss the main unwanted effects Give an example of clinical use Golan, Principles of Pharmacology How can we classify antibiotic drugs? 1. By their spectrum of activity 2 layers 3 layers Taking up a gram stain Narrow spectrum: Limited to specific microbe families EITHER gram - OR gram + Some antibiotics can’t activity limited either one or the other penetrate this more complex cell wall Broad spectrum: Extensive Less active against Gram - than Gram + Affects Gram + AND Gram - Hitting both gram bacteria  Gram positive Gram negative Gut GI infections, UTI Skin Cellulitis, wound Water, soil and blood infections various Gut Diarrhoea, colitis More adverse Gut @ the gut. Stomach ulcers Respiratory tract Otitis media, pneumonia, meningitis Mucosal surfaces Meningitis, gonorrhoea  A general rule Antibiotics that interfere with cell wall 2. By their effect on bacteria synthesis or inhibit crucial enzymes generally kill bacteria Those inhibiting protein synthesis tend to be bacteriostatic Bacteriostatic agents Inhibit bacterial growth and replication Host immune system completes elimination Care! - immunocompromised patients Bactericidal agents Kill bacteria Need to be present at adequate concentration Some more effective when cells are dividing Depends on safe [drug] plasma that can be achieved  3. Mechanism of action Characteristics of bacteria that are selective drug targets (Lecture CD4) Class I (not a good target) An area to generate energy. Host and organism similar Bacteria can use alternate energy sources Class II (better bet) X ✓ ✓ Unique pathways or differing sensitivities Synthesis of essential growth factors E.g. folate synthesis Sarah's content Class III (good target) Assembly of macromolecules DNA, RNA, proteins Peptidoglycans (lecture CD9) Rang and Dale A note on unwanted effects of antibiotics in addition of therapeutic effect cause side effects. Type A Dose-dependent, predictable based on pharmacology (and route*) Most common are: for orally administered. 1. Gastrointestinal toxicity* affect ‘good’ bacteria as well as ‘bad’  to microbiota/flora (e.g. c. diff. opportunistic for this bacteria. nausea, pain, vomiting, diarrhoea symptoms 2. Nephrotoxicity kidney toxiication. With antibiotics metabolised/excreted by kidney Superinfections can develop when the antibiotic intended for the preexisting infection kills the protective microbiota Gut (c. diff) Lungs (pseudomonas) Vagina (candida: fungal infection) Type B Idiosyncratic reactions Can’t be predicted by pharmacology Rare! Don’t occur in most patients at any dose Can affect any organ system, but usually Skin (e.g. rashes, eruptions, itching) Liver (hepatotoxicity) Blood cells (haematological toxicity e.g. anaemia)  Class II reaction target (better bet) Antibiotics that interfere with folate synthesis  Note: Sarah's content/ Reminder: Folate biosynthesis pre-cursor Folate required for DNA/RNA synthesis (bacteria and mammalian cells) Enzyme ✓ Humans get folate from diet Bacteria can’t use preformed folate enzyme and synthesise their own (de novo)  Folate biosynthesis is a metabolic pathway in bacteria but not humans → good target bacterial target.  Mechanism and PK Example: Trimethoprim Inhibits key enzyme in folate synthesis stops but doesn't kill the bacteria. BacterioSTATIC (Gram +/-) Sulfonamides (compete with PABA) Pharmacokinetics Oral bioavailability [High] in lung, kidney, CSF……. useful to mange blocks the cascade. Eliminated by kidney (t1/2 =24h) Synergism with sulphonamides E.g. trimethoprim and sulphamethoxazole (co-trimoxazole) double hit of the folate pathway.  Clinical Use Unwanted effects NEVER used in pregnancy Folate used to prevent narrow tubes in pregnancy. Nausea, vomiting Alone Urinary tract infections (UTIs) Folate deficiency Long term use → megaloblastic anaemia big cells caused by B9 deficiency. As co-trimoxazole Bronchitis* Rashes UTIs Ear infections Traveller's diarrhoea * If patient can’t have a penicillin  Class III reaction targets Antibiotics that interfere with bacterial DNA, RNA and protein synthesis Reminder: Bacterial DNA replication Occurs by binary fission Single circular chromosome Multiple steps: all make good targets Best is Topoisomerase Separates intertwined DNA strands to allow replication 2 main types in bacteria DNA gyrase and Topoisomerase IV BioRender  Mechanism and PK Class: Quinolones "Oxacins" Examples: ciprofloxacin, norfloxacin, moxifloxacin (levofloxacin section 29) Inhibits DNA gyrase (Gram –ve) Inhibits topoisomerase IV (Gram +ve) BacteriCIDAL (broad spectrum, G- > G+) Pharmacokinetics Oral absorption Accumulates in kidney, prostate, lung……. Don’t cross BBB (except ofloxacin) not ideal for CNS treatment Excreted predominantly by the kidney…….  Why do we have to think about renal (dys)function? Patients with chronic kidney disease may have alterations in protein binding volumes of distribution kidney and nonrenal clearance → antibiotic dose adjustments to prevent toxicity for renal clearance  https://bpac.org.nz/2021/docs/quinolone.pdf Unwanted effects Clinical Use Usually mild, reversible Rarely first line Most frequent Reserved for serious infections GI (ciprofloxacin, c. diff. colitis) (stewardship – keep pseudomonas cover) Skin rashes Prostatitis, bone and joint Rare infections (if no alternative) Tendon rupture (elderly + corticosteroids) joint pains Arthropathy (young patients) Gonorrhoea QT prolongation = heart rhythm defects (longer QT interval.) Important interactions for quinolones Partly metabolized in the liver. Pharmacodynamic (direct) Al and Mg containing antacids inhibit absorption Physical effect Pharmacokinetic (influence ADME of other drugs) Ciprofloxacin is a moderate inhibitor of CYP1A2 Increases [plasma] of drugs metabolised by this enzyme Clozapine, olanzapine (antipsychotics → QT prolongation) Common Tizanidine (a2 agonist, muscle relaxant in MS → weakness, bradycardia) rare occurrence Most important in elderly patients and those with hepatic impairment Renal clearance renders as you grow older. Do we need to know all this stuff? For exams and in clinical practice drug names are non-negotiable ☺ Mechanisms Help you select desired (clinical) effect (And predict possible side effects) PK/PD Clinical management: Drug: drug integrations Help make decisions about safe use Reminder: bacterial protein synthesis Ribosomal components differ between bacteria and humans 30s: decodes mRNA 50s: catalyses peptide bond formation  Mechanism and PK Class: Tetracyclines Examples: doxycycline, minocycline Excretion Bind to 30s, inhibit binding of aa-tRNA Dox: unchanged in bile, BacterioSTATIC (Broad spectrum) Hits growth and replication. urine Pharmacokinetics Mino: hepatic metabolism, Oral or i.v (parenterally) so, no dose adjustment for Better taken on an empty stomach these 2 why to have it on an empty stomach Dairy antacids, Fe supplements decrease absorption Ca2+, Mg2+  Unwanted effects GI disturbances orally Photosensitivity Clinical Use Oesophagitis (doxycycline) Declined due to resistance, but staging a comeback Ca2+ chelation Respiratory infections: chronic → deposited in bones and teeth causing discoloration bronchitis, community-acquired pneumonia (CAP) Avoid in children, pregnancy Acne Hepatotoxicity (renal failure, parenteral)  Mechanism and PK Class: Aminoglycosides = mincin common in NZ Examples: gentamicin, tobramycin Irreversible inhibition of 30s subunit Misreading of codons on mRNA→ improper protein expression Kill bacteria BacteriCIDAL (many Gram -, some Gram +) but not as broad as tetracyclines Pharmacokinetics i.v. or i.m administration (not absorbed from GI tract) Cross placenta but not BBB Elimination entirely renal think about renal function in patients?? Renal failure → accumulation measure the concentration of the drug serum >48h therapy, Therapeutic Dose Monitoring (TDM): [serum]  Unwanted effects In general, little allergic potential Clinical Use ear toxicities Ototoxicity 2-45% (cochlea, vestibular) Hospital only these are sensory cells Serious infections Dose-dependent Kidney damage Pneumonia Nephrotoxicity 10-25% (tubule damage) Meningitis Dehydration, pregnancy, hepatic Synergism with penicillins (CD9) dysfunction, NSAIDs, diuretics Neuromuscular blockade (less common)  Mechanism and PK Class: Macrolides "thromycin" Examples: erythromycin, roxithromycin, azithromycin and clarithromycin Reversible binding to 50s ribosomal subunit * Similar spectrum to penicillins BacterioSTATIC (most active against Gram +)* Pharmacokinetics Orally or parenteral t1/2 short (azithromycin longer >12h) Hepatic metabolism do not need dose adjustment CYP1A2, 3A4 inhibitors → affect the bioavailability of other drugs Important drug interactions Erythromycin, clarithromycin inhibit CYP3A4 (and CYP1A2) Increase the [plasma] and effects of: Benzodiazepines (e.g. triazolam)→ excess sleepiness Antipsychotics (e.g. clozapine) → blood, cardiac toxicity Simvastatin → rhabdomyolysis muscle ache and breakdown Warfarin → risk of bleeding If too high  Unwanted effects Clinical Use GI effects (erythromycin > others) Respiratory infections (Pertussis, Legionella) Cardiac toxicity Chlamydia Arrhythmias Mycoplasma infections QT prolongation Skin infections Hepatotoxicity Summary Antibiotic target: 1. Key metabolic pathway 2. Bacterial machinery involved in ‘central dogma’ Most are bacteriostatic Can be bacterioCIDAL (quinolones, aminoglycosides) All have some degree of toxicity (some life-threatening) Be aware of drug interactions that have clinical impact (quinolones, macrolides)  ‘Broad spectrum’ ‘Narrow’ Overview Activity cheat sheet Which drugs for which bugs? A guide only Gram + Gram - Trimethoprim Quinolones Tetracyclines Aminoglycosides Macrolides