Antibiotics

Learning Outcomes Understand the causes of infections Know about the Classification of Antibacterial agents Understand what Factors guide Antibiotic Choice Know and understand key concepts about the following antibiotics: Penicillins Cephalosporins Macrolides Tetracyclines Aminoglycosides Quinolones Metronidazole

Definitions Antibiotic, antibacterial, antimicrobial, anti- infectives, anti-fungals, anti-virals BNF classification Natural, semi synthetic and synthetic

Importance Host immune system Resistance

Causes of infections 3 types of micro-organisms: Bacteria Fungi Viruses Give an example of a disease caused by each of the above

Identification of Bacterial Organisms Gram staining is a basic microbiologic procedure for detecting and identification of bacteria. The main structural component of cell wall is peptidoglycan. Peptidoglycan and cell wall structural differences form the basis of the different staining properties. With Gram staining: –Gram +ve stain purple –Gram –ve stain pink Why is Gram staining important? Cell shapes(cocci/rods) Aerobic/anaerobic

Gram Positive and Negative organisms What is a Gram stain? Gram positive organisms: –Staphylococcus aureus (cocci) –Streptococcus pneumoniae (diplcocci) –Coagulase negative staphylococcus (cocci) Gram negative organisms: –Escherichia coli (rods) –Klebsiella pneumoniae –Pseudomonas aerguinosa –Salmonella typi (rods) –Neisseria meningitidis (diplococci)

Factors guiding Antibiotic Choice –The presumed site of infection –Positive microbiological culture results –Suspected or known organisms –Resistance patterns of the common microbial flora. –Properties of the antibiotic: e.g. route of administration, pharmacokinetic aspects –Patient’s health status: e.g. immune status (especially neutropenia and immunosuppressive drugs), allergies, renal dysfunction, and hepatic dysfunction

Choosing An Antibiotic Cost Local resistance Environment Patient factors Site

Choosing An Antibiotic BACTERIAL FACTORS -Use only for bacterial infections -Identify bacteria involved, or best guess HOST FACTORS -site, route, allergies, renal function, hepatic function, pregnancy DRUG FACTORS - activity, site,bactericidal/bacteriostatic route, cost

Classification of Antibacterial agents main ways: –Whether they are bacteriostatic or bactericidal –By target site –By chemical structure –Bacterial spectrum targets for antibacterials: –Cell wall synthesis –Protein synthesis –DNA synthesis –Metabolic pathways

Selective Toxicity Kill/harm micro-organism without harming host organism Antibiotics-> high therapeutic index TI = toxic dose/therapeutic dose

Aspects of antibiotics Method of action – bactericidal/bacteriostatic Spectrum of activity -Broad -Narrow

Penicillins Bactericidal agents Contain a β-lactam ring in structure. They inhibit synthesis of the bacterium cell wall by affecting synthesis of peptidoglycan. Peptidoglycan cell wall surrounds certain bacteria and is essential for their survival. This results in dividing cells not being able to maintain the osmotic gradient. Net effect is cell swelling, rupture and death of the bacterium.

Penicillins Spectrum: –Aerobic Gram +ve –Gram –ve cocci –Many anaerobic micro-organisms –Not all penicillins are considered broad spectrum antibiotics

Benzylpenicillin or Penicillin G Very poor oral absorption Given IV or IM (single doses > 1.2g IV route only) High Na + content 1.68mmol/600mg vial, 3.36mmol/3.2g vials. Slow IV injection or infusion over minutes.

Benzylpenicillin Unwanted effects: –Allergic reaction in up to 10% of exposed individuals –Anaphylaxis less common in 0.05% –Immediate anaphylaxis, urticaria, rash after penicillin administration should not receive penicillin. –Minor rash >72 hrs after exposure is probably not a true allergy –Those allergic to one penicillin are allergic to all Elimination: –Renal excretion –Rapid, short half life –Dose reduced in severe renal impairment

Amoxicillin/Ampicillin Broad spectrum Use e.g. community acquired respiratory tract infections- H Influenza and S. Pneumoniae Renal excretion Amoxicillin preferred oral route

Co-amoxiclav Consists of amoxicillin combined with a beta- lactamase inhibitor clavulanic acid Spectrum: –Active against Gram-ve rods resistant to amoxicillin due to beta-lactamases –E.g. resistant strains of E.coli, S. aureus and H. influenzae. –Clavulanic acid has no antibacterial activity

Flucloxacillin Bactericidal antibiotic A beta-lactamase-resistant penicillin Used for penicillin-resistant staphylococci. Can be less effective against bacterium that does not produce beta-lactamase It is less active against Streptococcus pneumoniae and Str. pyogenes than penicillin.

Flucloxacillin IV dose: g every 6 hours Elimination: –Mainly renally excreted as unchanged drug –Small extent of metabolism Unwanted effects: –Hypersensitivity as in penicillin –Hepatitis & cholestatic jaundice were reported several weeks after treatment was stopped. –Risk factor are increasing age and > 2weeks treatment.

Cephalosporins Bactericidal agents Semi-synthetic antibiotics, related to penicillins and contain β-lactam ring. Some are susceptible to β-lactamase activity, so less activity against staphylococcal infections. β-lactamase are enzymes that catalyse the hydrolysis of beta-lactam, resulting in loss of antibacterial activity.

Cephalosporins 1 st, 2 nd 3 rd generation Mostly given IV, IM, except cefalexin(1 st gen.) and cefuroxime(2 nd gen.) They distribute into many tissues. Spectrum: –Second line in many infections –Broad spectrum antibiotics –Generally 3 rd generations have higher activity against Gram –ve bacterium, but less activity against Gram +ve ones.

Cephalosporins Unwanted effects: –Hypersensitivity reactions. –10% of penicillin-sensitive patients are also allergic to cephalosporins –2 nd & 3 rd generation higher risk of infection with Clostridium difficile Elimination: –Mainly renal via tubular secretion –Some like 40% ceftriaxone in bile

Macrolides E.g. erythromycin, clarithromycin. Similar antibacterial spectrum to penicillins Mechanism: inhibit bacterial protein synthesis by binding to bacterial ribosome. Bacteriostatic Can be effective against unusual organisms

Macrolides Generally safe drugs Erythromycin can cause gastrointestinal problems which are less common with other agents. Azithromycin has a long half life Macrolides can inhibit cytochrome P450 leading to accumulation of drugs.

Tetracyclines E.g. tetracycline, doxcycline Mechanism inhibit protein synthesis Absorption of tetracyclines is affected by calcium and magnesium ions, food and iron preparations. Broad spectrum antibiotics Bacteriostatic Should be avoided in pregnancy, breast feeding and children under 12 years as they bind to calcium in growing bones and teeth causing discoloration.

Aminoglycosides These include: gentamicin, streptomyocin,, neomycin. They resemble each other in: –Antibacterial activity –Pharmacokinetic properties –toxicity

Aminoglycosides Mechanism: –Bactericidal activity –Inhibit bacterial protein synthesis –They do this by binding to the 30S ribosomal subunit. –They stop the translation of mRNA into the proteins.

Aminoglycosides Spectrum: –Many Gram-ve (Including Pseudomonas) –Some Gram+ve –Inactive against anaerobes –Used in serious Gram –ve infections in combination with agents that disrupt cell wall synthesis (e.g. penicillin) –Synergistic effect with penicillin –Not absorbed orally so only given IM or IV.

Aminoglycosides Elimination: –Renally by glomerular filtration –In renal impairment accumulation occurs rapidly –Result is an increase in toxicity (ototoxicity and nephrotoxicity) –Dose adjustment is essential in renal impairment

Aminoglycosides Unwanted effects: –Serious effects that are dose related. Ototoxicity: –Progressive damage to sensory cells –Result can be irreversible: vertigo, loss of balance, auditory disturbances, deafness. –Effect is increased by ototoxic drugs e.g. loop diuretics.

Aminogylcosides Nephrotoxicity: –Due to damage to kidney tubules which can be reversed by stopping the drug –Risk factors: Pre-existing renal damage Reduced urine output Concomitant use of nephrotoxic drugs (administer far apart if possible) elderly Monitoring of plasma levels is necessary

Quinolones These include ciprofloxacin, levofloxacin. Spectrum of activity may differ between agents. Active against aerobic G – but not active against anaerobes Use: prostate, UTI, respiratory Mechanism: –Bactericidal –Inhibition of replication of bacterial DNA –They block the action of the enzyme DNA gyrase. –DNA gyrase is responsible for forming DNA supercoils for replication and repair.

Quinolones Elimination –Hepatic metabolism –Renal excretion Unwanted effects –CNS effects: dizziness, headache, tremor, convulsions. –Tendon pain and inflammation, damage and rupture, especially in elderly and concomitant use of corticosteroids. –Drug interactions with many agents

Metronidazole Spectrum –Bactericidal activity –Active against anaerobic bacteria & protozoa –Inhibit DNA synthesis and breaks down existing DNA

Metronidazole Used IV, oral and rectal. Elimination: –Metabolised by the liver Unwanted effects; –Nausea and vomiting –Metallic taste –Disulfiram-like reaction when taken with alcohol

Trimethoprim Mechanism Inhibits enzyme – DHFR DHFR = dihydrofolate reductase Folate-> dihydrofolate->tetrahydrofolate-> DHFR-> DNA synthesis Bacteriostatic Spectrum: E Coli+ most urinary pathogens Narrow spectrum (inactive against anaerobes) 1 st line UTI oral

Antibiotic Resistance Innate - Acquired 3 main biochemical mechanisms of acquired resistance a)  bacterial permeability to an antibiotic b)Bacterial enzymes c)Altered target site for antibiotic

Revision Mechanisms Inhibition of cell wall synthesis Inhibition of bacterial protein synthesis Inhibition of bacterial DNA synthesis Inhibition of metabolic pathway (e.g.folate) synthesis

1) Inhibition of cell wall synthesis Beta Lactams – 3 major classes 1)Penicillins 2)Cephalosporins 3)Carbapenems

1) Inhibition of cell wall synthesis No cell wall in mammals/present in bacteria Peptidoglycan Beta lactam ring Bactericidal High therapeutic index Mainly excreted in kidney Safe in pregnancy

2) Inhibition of bacterial protein synthesis Inhibition of ribosomal protein synthesis Formation of amino acids: Gene transcription-> messengerRNA-> ribosomes-> translation-> amino acids->proteins Antibiotics bind to bacterial ribosome Selective toxicity Ususally bacteriostatic but aminoglycosides- cidal Macrolides, aminoglycosides, tetracyclines,

3) Inhibition of bacterial DNA synthesis Bactricidal Selective toxicity – mammals do not contain DNA gyrase Quinolones, metronidazole, Quinolones: Inhibit DNA gyrase, DNA gyrase is responsible for forming DNA supercoils for replication and repair.

4) Inhibition of folate synthesis DNA requires folate Folate-> tetrahydrofolate-> DNA Inibition of enzyme DHFR(DHF->THF_ E.g. trimethoprim DHFR= dihydrofolate reductase DHF = dihydrofolate THF = tetrahydro folate

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