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Flashcards in Antibacterial Deck (66):
1

Gram positive

Simple cell wall with 50% peptidoglycan which is bound directly to cytoplasmic membrane

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Gram negative

Outer membrane made of lipid bilayer, over peptidoglycan membrane, greater diffusion barrier.

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Antibiotic definition

Natural substances which is made by a micro-organism and prevents/kills the growth of another

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Bactericidal

Kills organisms, decrease population size

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Bacteriostatic

Inhibits growth, lesser decrease in population size but no increase.

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Selective Toxicity

Prevent action on non-pathogenic human microbiome and adverse side effects

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Benefits of combination therapy

Less resistance, increase efficacy and synergism, broader spectrum.

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Drugs which target protein synthesis

Mupirocin (pre-ribosomal stage inhibition). Oxazolidinones, Tetracyclines, Aminoglycosides, Chloramphenicol, Macrolides (Ribosomal inhibitors) and Fusidic Acid

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Selective Toxicity of protein synthesis targeting antibacterials

Ribosomal size is different between mammals and bacteria. Enzyme which Mupirocin acts on is different and lower affinity for mammal one, Uptake of tetracyclines and fusidic acid is not as good in mammalian cells. Can get ADR from interaction with mitochondrial synthesis

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Mupirocin mode of action

Competitive inhibitor for isoleucyl tRNA synthetase, enzyme which links tRNA amino acids together. No raw materials to create polypeptide chain at ribosomes. Bacteriostatic

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Clinical Use of Mupirocin

Only topical as rapidly hydrolysed when ingested. Only against Gram positive. Staphylococcal or streptococcal skin infections, stop nasal carriage of MRSA in hospital patients & staff.

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Oxazolidinones

Bind to 50S subunit and prevent correct positioning of aminoacyl-tRNA and blocks entry of subsequent molecules. Bacteriostatic

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Examples of Oxazolidinoes

Linezolid or Tedizolid (more recent, less ADR and mylosuppression, more ABx activity). All are fully synthetic

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Clinical use of Oxazolidinones

Gram positive only, unable to get high intracellular cones of gram negative. Skin and soft tissue infections and Hospital acquired pneumonia. IV ORAL

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ADR of oxazolidinoes

Reversible thrombocytopenia and anaemia from myelosuppression. Mild LFT abnormalities

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Tetracycline action

Bind to 30S subunit via hydrogen bonds. Prevents associated of aminoacyl- tRNA with the ribosome. Lipophilic tetracyclines more active than hydrophilic.

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Clinical use of tetracyclines

broad spec, Oral, IV or topical.Chlamydia, mycoplasma pneumonia, cholera, Lyme disease,
Rocky Mountain spotted fever

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Examples of tetracyclines

New = tigecyclin IV only. Doxycycline, tetracycline

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ADR of tetracyclines

Due to ability to chelate metal ions CI in young children and late-pregnant woman and deposits in bone and teeth. Photosensitivity.

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Aminoglycosides action

Bactericidal. Bind to 30S or both subunits mRNA misreading causes abnormal proteins to be synthesised. Hydrophobic regions burrow into membrane, destabilising it and contents leak/lyse.

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Clinical use of aminoglycosides

IM or IV. Montherapy in severe sepsis (particular causative agents), plague, enterococcal endocarditis. Combo therapy for gram positive TB or anaerobic infections

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Examples of aminoglycosides

Polycationic with 2 sugars enclosing 3rd ring structure. streptomycin, gentamicin, neomycin.

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ADR of aminoglycosides

Not great selective toxicity. Ototoxicity, Nephrotoxicity, Neuromuscular blockade.

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Chloramphenicol Action

Binds to 50S subunit and inhibits the enzyme responsible for amino acid chain elongation - peptidyl transferase.

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Chlorampenicol clinical aspects

BROAD-SPEC bu toxicity restricts use. Oral, IV or topical. Typhoid and paratyphoid due to Salmonella infections

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ADR of chlorampenicol

Myelosuppression and Gray Syndrome (in the very young - life threatening)

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Macrolides Action

Blocks the exit of the polypeptide chain from the ribosome by binding to 23S rRNA on 50S subunit. Leads to premature dissociation of the chain from peptidyl transferase and incomplete proteins formed

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Macrolide examples

Lactone ring with 2 sugars and one amino sugar attach. e.g. Azithromycin or erythromycin

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Macrolide clinical use

Chlamydia, pneumonia, syphilis, Corynebacterium diphtheria, Legionnaires' disease

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Fusidic acid action

Binds to elongation factor G in post-translocation state, can't dissociate from chain, no further protein synthesis can occur. EFG is responsible for the translocation movement of mRNA and tRNA along chain.

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Clinical aspects of fusidic acid

natural, only gram positive action, topical IV and oral. rare ADR. Staphylococcal infections or in combo therapy to stop resistance of EFG mutations

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Peptidoglycan synthesis

movement from cytoplasm to membrane then to outside of membrane to be incorporated. Outside membrane: Transglycosylation (disaccharide incorporated) and Transpeptidation (cross link 3rd-4th amino acids of chains) via d-alanine energy

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Enzyme for peptidoglycan synthesis

PENICILLIN BINDING PROTEIN. 2-domains, bi-functional, membrane associated. beta-lactams bind to enzyme. glycopeptides bind to substrate

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beta-lactam examples

Parents compound = penicillin, all have lactam ring structure. Penicillin, cephalosporins, carbapenems and monobactams. Benzylpenicillin, broad spec = amoxicillin, penicillinase resistant = flucloxacillin

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Mode of action of beta-lactams

Competitively inhibit PBP, bind via serine residues in active site during TRANSPEPTIDATION reaction as structure analogous to d-alanine d-alanine dipeptide. Null-reaction can occur, no cross-linking, little rigidity in cell wall, cell bursts. Enzymes degrading old cell wall still act to weaken wall further.

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Clinical aspects of beta-lactam use

Broadspec activity. Can have allergy to metabolite of drug Pneumococcal pneumonia, syphilis, gonorrhoea.

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Beta-lactam resistance

Beta-lactamases can hydrolyse ring structure of ABx. A, B and C serine beta-lactamase nucleophilic attack create open ring structure. D = zinc beta-lactamase.

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Prevent resistance of beta-lactams

Clavulanic acid. Is a beta-lactam with no ABx properties. Binds to beta-lactamases instead of active drug and prevents breakdown and inactivity. e.g. co-amoxiclav

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Example of gylcopeptides

Vancomycin

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Mode of action of glycopeptides

Steric hinderance of transglycosylation. H bond to d-alanine d-alanine substrate for PBP. Minor effect on transpeptidation by preventing cross-link.

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Clinical use of glyopeptides

Gram positive only. IV/IM unless for GI C.difficle infection (oral). Use in MRSA esp penicillin allergic patients. C.difficle colitis. In combo with aminoglycosides for enterococcal endocarditis.

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ADR of glycopeptides

Red Man syndrome when given too quickly. Ototoxicity, and nephrotoxicity. reversible thrombocytopenia and neutropenia.

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Polymyxins action

Polymyxin B and polymyxin E. Aggregate with both cytoplasmic membrane and outer membrane, compromise integrity and function.

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Polymyxins clinical use

Mostly gram negative action. Highly neuro and nephro toxic. use in Pseudomonas (CF), gut decontamination, burn infections and drug resistant gram negative pathogens. Aersol (CF patient use), IV, oral, topical, IM

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Daptomycin

Aggregates and depolarises cell membrane, compromising integrity and structure. Action mediated by calcium ions. Only Gram positive action. IV. use on skin and soft tissue infections.. ADR include muscle toxicity which is rare.

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Drugs inhibiting nucleotide biosynthesis and how they are selectively toxic

Trimethoprim and sulphonamides (e.g. prontosil, sulfasalazine). Mixture = co-trimoxazole. Act on tetrahydrofolate synthesis. Mammals get folate from diet, no need for synthesis reaction so no enzymes in mammal cell

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Drugs inhibiting bacterial DNA topoisimerase

Quinilones and fluoroquinilones

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DNA damaging antibacterials

Nitroimidazoles

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Drugs inhibiting RNA synthesis

Rifamycin

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Sulphonamides Action

Competitive inhibition of dihydropteroate synthetase. Analogous structure to normal substrate PABA which gives product of dihydropteroate. ABx gives null product unable to form tetrahydrofolate.

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Sulphonamides ADR

hepatitis, allergic reaction, myelosppression and AKI = interstitial nephritis and crystalluria

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Mode of action of trimethoprim

Competitive inhibitor of dihydrofolate reductase, enzyme which creates tetrafolate from dihydrofolate.

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Use of co-trimoxazole

UTI, RTI, GI infection but use restricted due to resistance potential. Combinations used for treatment/ prophylaxis of Pneumocystis jiroveci pneumonia in HIV.

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Mode of action of quinolines and fluoroquinilones

Inhibit the action of DNA gyrase/topoisomerase2 (negative supercoiling for packing) and DNA topoisomerase IV (decatenation). Enzymes covalently link to DNA via tyrosine residue on enzyme and 5" strand, lead to ATP dependent strand breaking and repair. ABx binds to quinolone binding pocket structure in broken DNA at 5" end, via base-stacking. Trap DNA in broken state prevent resealing. Bactericidal

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Use of quinolones and fluoroquinolones

gram -ve = gyrase primary target. gram +ve = toposiomerase primary target. Bacteriocidal. Gonorrhea, GI infections, anthrax, UTI and RTI.

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Selective toxicity of quinolones

Gyrase not present and topoisomerase II is a A2 dimer, not A2B2 like bacterial cells.

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Examples of quinolones and fluoroquinolones

Nalidixic acid, Ciprofloxacin, Levofloxacin (1-3 gens) Increase gen, increase spec of activity, increase toxicity.

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ADR of quinolones and fluorquinolones

Rarely - tendonitis, GI upset, phytotoxicity, CNS toxicity. CI in the pregancy and adolescents due to arthropathy.

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Selective toxicity of nitroimidazoles

Ingested as prodrug, only enzyme in anaerobic bacteria activate them. Nitro group of drug is reduced by low-redox- potential nitroreductases e.g. Pyruvate: ferredoxin oxidoreductase (PFOR). No anaerobic enzymes in humans

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Mode of action of nitroimidazoles

DNA damage by oxidation, strand break and helix destabilisation

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Use of nitroimidazoles

Obligate anaerobic bacteria and protozoa, facultative anaerobes if in anaerobic condition. RTI, abode infections, meningitis, brain abscess, osteomyelitis, oral and dental infections, C.difficile colitis, H.pyloria gastoduodenal ulcers.

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ADR of nitroimidazole

GI disturbance, CNS effect, reversible neutropenia. With alcohol accumulation of acetaldehyde give hangover feeling, vague animal evidence of teratogenic, carcinogenic and mutagenic.

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Examples of rifamycins

Rifampicin, rifamycin. Natural antibiotic

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Mode of action of rifamycins

Bind to beta-subunit of RNA polymerase of bacteria. Block exit channel of chain. Leads to abortive initiation and RNA strand breaks off. Baceriocidal.

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Use of rifamycins

TB therapy, Leprosy, S.aureus combo therapy with fusidic acid, penicillin resistant S.pneumoniae. little gram negative activity

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ADR of rifamycins

Heptatis, skin reaction, flu-like reaction, urine discolouration in oral dose