Anti-Bacterial Agents II 2024 UCD Dublin, PDF

Anti-Bacterial Agents II Dr. Sinéad McNicholas Consultant Microbiologist St. Vincent’s University Hospital February 2024 Protein Synthesis Inhibitors Objectives of lecture Outline of antibiotics that inhibit protein synthesis – – – – different mechanisms of antibiotics clinical uses pharmacokinetics...

Anti-Bacterial Agents II Dr. Sinéad McNicholas Consultant Microbiologist St. Vincent’s University Hospital February 2024 Protein Synthesis Inhibitors Objectives of lecture Outline of antibiotics that inhibit protein synthesis – – – – different mechanisms of antibiotics clinical uses pharmacokinetics side effects Classification of antimicrobials Protein Synthesis Is the process by which cells make proteins Occurs in ribosomes In mammals ribosomes are located in a cytoplasmic membrane structure known as the endoplasmic reticulum In bacteria, ribosomes are located in the cytoplasm Mammals = 60s + 40s subunits Bacteria = 50s + 30s subunits This difference provides the basis for selective action by antibiotics Protein synthesis is the process by which cells make proteins DNA → RNA → Protein It occurs in two stages (in the cytoplasm of bacterial cells): Transcription produces a messenger RNA (mRNA) strand from a DNA template DNA → RNA Translation produces an amino acid chain from a strand of mRNA RNA → Protein Initiation, elongation and termination After a polypeptide chain is synthesized, it may undergo additional processing to form the finished protein Transcription. Translation Requirements for translation: mRNA tRNA Amino acids (Methionine) Start codon Stop codon Translation is the process in which the genetic code of the mRNA is read to make a protein The small and large subunits of the ribosome bind to the mRNA The ribosomes read the sequence of codons in mRNA and molecules of tRNA bring amino acids to the ribosome in the correct sequence At the end of the mRNA coding is a stop codon which will end the elongation stage – the stop codon doesn’t call for a tRNA, but instead a type of protein called a release factor which will cause the entire comples (mRNA, ribosome, tRNA and polypeptide) to break apart, releasing all of the components Translation. Translation. Antimicrobials Inhibiting Protein Synthesis 30s Ribosomal Subunit 50s Ribosomal subunit Aminoglycosides Tetracyclines Glycylcyclines Chloramphenicol Macrolides Lincosamides Fusidic acid Streptogramins Oxazolidinones Antibiotic vs antimicrobial Antibiotic Substance produced by a micro-organism Treat bacterial infections synonymous Antimicrobial broaderterm Substance of natural, synthetic or semisynthetic origin Treat bacterial, viral, fungal and parasitic infections Bacteriostatic vs bactericidal Bacteriost Bacteriostatic inhibits the growth inhibits the growth of bacteria of bacteria Bactericidal Bactericidal kills killsbacteria bacteria MIC (minimum inhibitory concentration) smallestamount thatwillbe toxigaleria Lowest concentration of the antimicrobial which results in inhibition of detectable growth of the organism if Pharmacokinetics Vs pharmacodynamics Pharmacokinetics (what the body does to the drug) How a drug is processed by the body – ADME Absorption, distribution, metabolism and excretion Pharmacodynamics (what the drug does to the body) Study of a drug’s molecular, biochemical and physiological effects or actions Aminoglycosides Group with complex chemical structure (3 hexagonal rings) Similar to each other in anti-microbial activity, pharmacokinetics and toxicity gentamicin – 9th most commonly prescribed antibiotic in last PPS amikacin tobramycin neomycin netilmicin Streptomycin (1944) Streptomyces griseus Aminoglycosides Neomycin (1949, S. fradiae) Kanamycin (1957, S. kanamyceticus) Gentamicin (1963, Micromonospora purpurea) Netilmicin (1967, derived from sisomicin) Tobramycin (1967, S. tenebrarius) Amikacin (1972, derived from kanamycin) Plazomicin – novel, synthetic antimicrobial designed to overcome common aminoglycoside resistance mechanisms thereby maintaining potency against multidrug-resistant (MDR) pathogens (FDA approved in 2018) Mechanism of action Bactericidal Binds to 30s subunit (the A site on the 16s Ribosomal RNA) Blocks initiation complex causing misreading of mRNA, blocking translocation and inhibiting protein synthesis or leading to abnormal proteins Mechanism of action aerobic Penetration through cell membrane depends on oxygen-dependent active transport, hence minimal action against anaerobes Activity enhanced by inhibitors of cell wall synthesis Some aminoglycosides can also impact protein synthesis by blocking elongation or by directly inhibiting initiation All are rapidly bactericidal Concentration dependent bactericidal killing Peak need not be prolonged Significant post-antibiotic effect Aminoglycosides enter most body fluids well approximating extracellular fluid (excluding pulmonary tissue, fatty tissue, abscess) Aminoglycoside peak serum concentration to bacterial MIC ratio (Peak/MIC) to a value ≥ 10:1 notes ÉÉÉ extended post animitect Pharmacokinetics of aminoglycosides Absorption: Not absorbed in the GIT Administration : IV (rarely IM) Volume of distribution approaches total body volume - broad distribution into tissues (placenta, joint, pleura) Minimal entry to CSF, eye Very low in bronchial secretions Excretion: Excreted almost entirely by glomerular filtration (small amount in bile also), accumulates rapidly in renal failure to toxic levels The half-life of aminoglycosides is ~2-3 hours with normal renal function Aminoglycosides are removed by haemodialysis and, to a lesser extent, by peritoneal dialysis Levels should be checked at least 16 hours post dose Resistance Enzymatic modification and inactivation by a number of enzymes Increased efflux Decreased permeability Modification of the 30S ribosomal subunit Spectrum of activity of aminoglycosides Aerobic Gram-ve (some Gram +ve) Used in combination with penicillin for the treatment of Streptococcus, Listeria monocytogenes Acts synergistically with amoxicillin for the treatment of Enterococcus Combination therapy for MDR-TB and NTM Preferred treatment for plague and tularaemia (Y. pestis, F. tularensis) Inhalational tobramycin – Cystic fibrosis and chronic lung disease Spectrum of activity of aminoglycosides E. coli Klebsiella pneumoniae, K. oxytoca Citrobacter freundii, C. koseri Enterobacter cloacae, E. aerogenes Aeromonas spp. Brucella spp. Proteus mirabilis, P. vulgaris Morganella morganii Pseudomonas aeruginosa Salmonella spp. Serratia marcescens Spectrum of activity of aminoglycosides Gentamicin = most commonly used Tobramycin = preferred for Pseudomonas infections Amikacin = widest spectrum, used against gentamicin and tobramycin resistant strains Indications Sepsis Bloodstream infection UTI IE – in combination Intra-abdominal infection PID Side effects of aminoglycosides Nephrotoxicity – Proximal tubular necrosis – Damage to the renal tubules can be reversed when drug discontinued – Beware if patient dehydrated, on other nephrotoxic drugs (vancomycin, cyclosporine, amphotericin B, radiocontrast) or has preexisting renal failure Cochlear toxicity lossof balance – Initial damage is to high frequency hair cells (may not be appreciated by the patient) – 1/500 patients in Europe have mitochondrial mutation that predicts cochlear toxicity – Study showed aspirin (3gm/day) attenuated risk of cochlear injury from gentamicin Side effects of aminoglycosides Vestibular toxicity – May be more common than hearing loss but goes unrecognized as it’s most often bilateral and symmetrical – Vertigo if unilateral damage unstable vision – Imbalance and oscillopsia with head movement if bilateral – If bedbound - no symptoms until attempt to walk – Not related to dose or duration – Suspected genetic predisposition but not yet identified Neuromuscular blockade - Avoid in patients with Myasthenia gravis Tetracyclines Commonly used – Doxycycline amiary – Lymecycline (tetrasyl, acne) – Minocycline (synthetic)(acne) Bacteriostatic – combination of concentration and time dependent killing Mechanism of action inhibition of protein synthesis by competing with tRNA for the A site on the ribosome. Requires active transport into bacterial cells Glycylcycline Tigecycline – semisynthetic derivative of minocycline – Inhibits protein synthesis by binding to the 30s ribosomal subunit and blocking entry of the tRNA molecules – Bateriostatic mostly – Broad spectrum of activity – Licensed for complicated skin and skin structure infections and complicated intra-abdominal infections – Activity against Clostridium difficile MRSA Doxycycline spectrum broad Indications very Commonly used – CAP, RTI, exacerbation COPD, Asthma – STI (C. trachomatis, NGU – Ureaplasma urealyticum) – Ophthalmic infection – Trachoma (C. trachomatis) – Rickettsial infection (rocky mountain spotted fever [R. rickettsia], typhus [R. prowazekii], Q fever and Coxiella burnetti endocarditis) – Other – psittacosis, brucellosis, cholera, louse and tick-borne relapsing fever, Lyme disease (Borrelia burgorferi), leptospirosis, malaria Pharmacokinetics of tetracyclines Administration: PO (IV preparation “available”) Absorption: decreased in the presence of divalent and trivalent cations (calcium, aluminium, antacids, milk or milk products) Distribution: wide distribution, penetrate fairly well into body fluids and tissue Crosses the placenta Penetrate well into breast-milk Low concentrations in saliva cancause Does not adequately penetrate CSF Lower concentrations in bone, skin, SC fat, tendon and tissue compared to muscle issuiedren Become markedly bound to bones, teeth and neoplasms causing yellow fluorescence Pharmacokinetics of tetracyclines Excretion: bile and kidney (unchanged) Doxycycline which is not excreted by kidney can be found in faeces, but minocycline incompletely absorbed from gut In renal impairment, there is increased excretion of doxycycline in the faeces, preventing accumulation of the drug Metabolism: small amount metabolised by the liver Resistance: common Plasmid mediated (e.g., tetM) Increased efflux of the drug from the bacterial cell Ribosomal protection – tetracyclines are unable to prevent the tRNA attaching Spectrum of activity of tetracyclines Very wide – Gram +ve and Gram –ve organisms Atypical organisms – Mycoplasma – Rickettsia – Chlamydia – some spirochaetes and protozoa Clinical uses of tetracycline Respiratory tract infection including atypical infections Skin and soft tissue infection (penicillin allergy) Rickettsial infections (typhus, Q fever) Chlamydial infections (PID, trachoma, psittacosis) Brucellosis Cholera Plague Leptospirosis (1st line) Acne (minocycline) SIADH (Na+) - demeclocycline renders renal tubular cells unresponsive to ADH (SIADH-syndrome of inappropriate anti-diuretic hormone release) Side effects of tetracyclines Nausea and vomiting (common, ≥1/100 to