Antibacterial Agents 1 (PDF)

Antibacterial agents 1 Dr. Suzy FitzGerald 7th February 2024 sfitzgeraldsvhg.ie Learning objectives Agents that inhibit cell wall synthesis (β-lactams, glycopeptides) Agents that disrupt cell membrane (polymixins) Mechanisms of action Pharmacokinetics Side effects Clinical use Bacterial cell wall Pe...

Antibacterial agents 1 Dr. Suzy FitzGerald 7th February 2024 sfitzgeraldsvhg.ie Learning objectives Agents that inhibit cell wall synthesis (β-lactams, glycopeptides) Agents that disrupt cell membrane (polymixins) Mechanisms of action Pharmacokinetics Side effects Clinical use Bacterial cell wall Peptidoglycan structure Inhibitors of bacterial cell wall synthesis Β-lactam antimicrobials Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Vancomycin Teicoplanin Bacitracin Anti-mycobacterial agents Isoniazid Ethambutol difflecture β-lactam antimicrobials Bactericidal kill bacteria bacteriostatic 4-member core β-lactam ring Penicillins have a 5 member side ring Cephalosporins have a 6 member side ring Modifications of side chains can change Antimicrobial activity Resistance to β-lactamase enzymes Pharmacokinetics canchangevolume ofdistribution β-lactam antimicrobials Crosslinking of newly formed peptide to glycan backbone is catalysed by transpeptidase (aka penicillin binding protein, PBP) β-lactam antimicrobials bind to transpeptidase and prevent formation of cross links Inhibition of cell wall synthesis activates autolytic enzymes which trigger cell death Production of β-lactamase by bacteria can inactivate drug and confer resistance strain theaddthis.ms βlactamase Penicillins: classification Natural penicillins penicillin IVform of Penicillin G (benzylpenicillin) Saureusstartedto Penicillin V become resistant ma sina.IE tnsizik Ureidopenicillins Β-lactamase resistant penicillins Flucloxacillin Saureusmaintreatment [Methicillin] 2 in clinicalpractice I 9 [Cloxacillin] [Nafcillin] Aminopenicillins Ampicillin Amoxicillin Carboxypenicillins Temocillin broadspectrum [Ticarcillin] use [Piperacillin] Penicillin and Β-lactamase inhibitor combinations usedfrequently Amoxicillin/clavulanate Ease Piperacillin/tazobactam [Ampicillin/sulbactam] [Ticarcillin/clavulanate] toff frequently island Β-lactamase inhibitor orthosteric Penicillins: pharmacokinetics Routes of administration reasonabs Oral – penicillin V, amoxicillin, flucloxacillinpfees IV – penicillin G, piperacillin, flucloxacillin IM – penicillin G Absorption Amoxicillin > penicillin V Reduced with food, acid pH Protein binding Variable Distribution broaddistribution versatile Most tissues and fluids Cross placenta Cross blood-brain barrier (BBB) if inflamed meningitic won'tcrossifinflammation youdon't brain have Penicillins: metabolism and excretion Predominantly renal excretion Tubular secretion >> glomerular filtration Some hepatic metabolism Nafcillin – 80% hepatic not goofy dysfin Tubular secretion of penicillin inhibited by probenecid Dose reduction required in severe renal impairment (calculate eGFR) kidney g.dksbuiop carin Trapped Penicillins: side effects GI – nausea, vomiting, diarrhoea, C. difficile infection gwi fc.ait cnet.net Skin – rash, phlebitis inflammation hectrophies Haematological – neutropenia, platelet dysfunction from toohighofadose CNS – seizures, encephalopathy notsupercommon Nephrotoxicity – acute interstitial nephritis elevate ASTALT Hepatic effects – hepatitis, cholestasis abnormalitiesinLFT Hypokalaemia Imagine Hypersensitivity type 1 and 4 reactions Penicillins: spectrum of activity Pencillin V/G EEmm.at ofins syphilis Streptococci, Neisseria meningitidis, Treponema pallidum, Clostridia Flucloxacillin Staph. aureus Amoxicillin fodkfningi.gs Streptococci, enterococci, E. coli, Listeria gastroenteritis Amoxicillin/clavulanate (coamoxiclav) – broad spectrum Gram negative bacilli, streptococci, enterococci, Staph. aureus, anaerobes Piperacillin/tazobactam (piptazobactam) – broad spectrum Gram negative bacilli, Pseudomonas aeruginosa, streptococci, enterococci, uimpnmised Staph. aureus, anaerobes friiii.TT Penicillins - clinical uses Penicillin V/G Streptococcal infections (pharyngitis, skin, soft tissue, pneumonia, bone, joint, endocarditis), meningococcal meningitis, syphilis, diphtheria Flucloxacillin Staph. aureus infections (skin, soft tissue, bone, joint, endocarditis) Amoxicillin intraabdomactions Enterococcal infections (UTI, endocarditis), E. coli infections (UTI, intraabdominal infections), Listeria infections Amoxicillin/clavulanate (coamoxiclav) – broad spectrum Intra-abdominal infections, anaerobic infections, pneumonia Piperacillin/tazobactam (piptazobactam) – broad spectrum Intra-abdominal infections, anaerobic infections, hospital-acquired pneumonia, neutropenic sepsis Cephalosporins: classification First generation Cephalexin Cefazolin Second generation Cefuroxime Cefaclor Third generation Cefotaxime Cetriaxone Ceftazidime structure change cnet.it Fourth generation Cefepime Fifth generation Ceftaroline goodMRSAcover Cephalosporins: pharmacokinetics Routes of administration Oral – cephalexin, cefaclor, [cefuroxime] IV – cefuroxime, cefotaxime, ceftazidime, ceftriaxone IM – ceftriaxone Absorption Cephalexin > cefaclor >> cefuroxime don'tgiveone 4 Protein binding Variable Distribution Most tissues and fluids Cross placenta 1st and 2nd generation do not cross BBB Cephalosporins: metabolism and excretion Predominantly renal excretion Some hepatic metabolism LET's keepaneyeon Dose reduction required in severe renal impairment (calculate eGFR) Cephalosporins: side effects GI – nausea, vomiting, diarrhoea, C. difficile infection Skin – rash, phlebitis Haematological – neutropenia, platelet dysfunction CNS – seizures, encephalopathy Nephrotoxicity – acute interstitial nephritis Hepatic effects – cholestasis Hypersensitivity type 1 and 4 reactions Estimated 10% cross reactivity with penicillins – likely ~1-2% sf probably history Cephalosporins: spectrum of activity 1st generation Streptococci, Staph. aureus , some Gram negative bacilli 2nd generation Streptococci, Staph. aureus , Gram negative bacilli, Haemophilus influenzae 3rd generation (cefotaxime, cetriaxone) Streptococci, Staph. aureus (less than 1st or 2nd), Neisseria meningitidis, Gram negative bacilli 3rd generation (ceftazidime) As above, plus Pseudomonas aeruginosa - much less Staph.aureus cover 4th generation Similar to 3rd 5th generation Enhanced Gram positive cover, including MRSA and enterococci. No anti-pseudomonal cover Cephalosporins - clinical uses 1st generation Streptococcal and Staph. aureus infections (pharyngitis, skin, soft tissue), uncomplicated UTI (some GNB) 2nd generation beforeincision Intra-abdominal infections, surgical prophylaxis, UTI, respiratory tract infection 3rd generation – broad spectrum Meningitis (N. meninigitidis, S, pneumoniae), pneumonia, pyelonephritis Lyme disease, gonorrhoea Neutropenic sepsis, pseudomonal infections (ceftazidime only) Monobactams Aztreonam Active only against aerobic Gram negative bacilli, including P. aeruginosa Resistant to many β-lactamases IV only Renal excretion – reduce dose in severe renal impairment Side effects Rash counts Pancytopenia lowblood Suprainfections, including C. difficile Convulsions Clinical uses – pyelonephritis, Gram negative respiratory tract infections (cystic fibrosis), intra-abdominal infections (in combination with other antimicrobials) Carbapenems Ertapenem Meropenem Imipenem-cilastin Doripenem Resistant to most β-lactamases (including extended-spectrum β-lactamases, ESBLs) Extremely broad spectrum cover – Gram negative bacilli, streptococci, Listeria, anaerobes, Pseudomonas aeruginosa (not ertapenem) Uses – RESERVE drug, used only for infections due to bacteria caused by resistant organisms, septic shock IV only, renal excretion, reduce dose in severe renal impairment Rash, hepatic and haematological effects, seizures Glycopeptide antimicrobials Inhibit bacterial cell wall synthesis Interact with the terminal amino acids of the side chain, thereby interfering with the formation of cross links between chains Vancomycin Teicoplanin Oritavancin (single dose) Dalbavancin (weekly dosing) Narrow spectrum of activity Molecule too big to pass through the outer membrane of Gram negative bacteria Gram positive organisms – Staph. aureus (including MRSA), coagulase negative staphylococci, enterococci, streptococci Glycopeptides: pharmacokinetics IV use only as not absorbed orally Exception is the use of oral vancomycin for treatment of C. difficile infection (not absorbed, so drug available at intended site of action in bowel) IV dose based on weight and renal function Vancomycin Penetrates into most tissues Crosses BBB, if inflamed Most excreted unchanged in kidneys Teicoplanin Penetrates into most tissues Does not cross BBB Most excreted unchanged in kidneys Glycopeptides: Therapeutic drug monitoring Vancomycin crosses BBB Regular monitoring of serum trough levels Adequate dosing Avoid toxicity Aim serum trough level 10-20 Teicoplanin can'tcrossBBB Regular monitoring of serum trough levels Adequate dosing Avoid toxicity Aim serum trough level 20-40 Glycopeptides: side effects Anaphylaxis Rash Red man syndrome (vancomycin>teicoplanin) - pruritis, flushing, erythema (upper body > lower) - +/- dyspnoea, hypotension, pain in back/chest - not immunologically mediated, often related to infusion rate Haematological – neutropenia Drug fever Phlebitis Renal toxicity (uncommon) – more likely if used in conjunction with other nephrotoxic agents Ototoxicity (rare) Glycopeptides: clinical uses Gram positive infections in patients allergic to other antimicrobials Infections caused by coagulase negative staphylococci Line infection Endocarditis Prosthetic joint infection MRSA infections Enterococcal infections (except VRE – vancomycin resistant enterococci) Antimicrobials that disrupt cell membrane function Polymixins C cellmembrane onlygram soonly works These Antifungal agents (will be covered in antifungal agents lecture, April) Polyenes Azoles 4850 Polymixins: mechanism of action Interaction with LPS on outer membrane of Gram negative bacteria Derangement of cell membrane with displacement of Ca2+ and Mg2+ Increased permeability of cell membrane, leakage of cell contents and cell death Polymixin B Colistin (polymixin E) Polymixins Topical IV Nebulised CFpatients verytoxic No oral absorption Highly protein bound Side effects Neurotoxicity –dizziness, ataxia, confusion, neuromuscular blockade Nephrotoxicity – acute tubular necrosis Also rash, fever, GI disturbance Polymixins: clinical uses Topical – ear and eye infections caused by Gram negative bacteria IV – treatment of infections caused by multi-resistant Gram negative bacteria (e.g., CPE – carbapenemase producing Enterobacterales, resistant Acinetobacter) Need to monitor serum levels to avoid toxic levels Nebulised – adjunctive treatment of Gram negative infections in cystic fibrosis