Antimicrobials 1 Flashcards
What is an antibiotic?
A natural substance produced by micro-organisms antagonistic to growth or life of others in high dilution
Loosely interchangeable with antimicrobial
What occurred during the 19th century?
Louis Pasteur and Robert Koch
Bacteria as causative agents and recognised need to control them
What did Paul Ehrlich achieve in the 20th century?
Chemotherapy and Magic Bullet (value of dyes)
Therapeutic Index= Toxic concentration/ effective concentration
What did Gerhard Domagk achieve?
Prontosil active against infection
Active component- Sulphanilamide
1st synthetic antibacterial in general clinical use
What did Alexander Fleming achieve?
Killing of staphylococci by fungal exudate
Unable to purify compound penicillin
Predominantly active against Gram positive bacteria
What did Selman Waksman achieve?
Gram-negatives and mycobacterium tuberculosis
Streptomycin
What is pharmacodynamics?
Bactericidal and bacteriostatic activity
Minimum Inhibitory Concentration
Minimum Bactericidal Concentration
How are antibiotics classified?
- Effect on microorganism
- Chemical structure
- Target site
What are the effects on microorganisms?
- Bacteriostatic= prevents the multiplying of bacteria without destroying them
- Bactericidal (particularly preferred in serious infections)= kills bacteria
What are the different mechanisms of action/ target sites?
- Cell wall
- Cell membrane
- Protein synthesis
- Nucleic acid synthesis= tetrahydrofolate synthesis (folic acid), RNA synthesis, DNA synthesis
What are the general components of a bacterium?
- Infolding of plasma membrane
- Capsule
- Cell wall
- DNA coiled into nucleoid
- Flagellum
- Basal body (attaches to flagellum)
- Ribosomes
- Cytoplasm
- Plasma membrane
- Pili
- Cytoplasmic inclusion
Describe cell wall synthesis inhibitors
- Earliest known antibiotics
- Still some of the safest antibiotics
- Selectively toxic to bacteria because there is no cell-wall in mammalian cells
- Removal of cell-wall destroys bacterial maintenance of osmotic pressure
- Usually bactericidal in action
Examples of cell wall synthesis inhibitors
-Beta-lactams
-Glycopeptides=
Vancomycin/ Teicoplanin/ Fosfomycin/ Cycloserine/ Bacitracin
What is the action of Fosfomycin?
inhibitor of the MurA enzyme, UDP- N -acetylglucosamine-enolpyruvyltransferase, that catalyzes the first committed step in peptidoglycan synthesis, the reaction of UDP- N -acetylglucosamine (UDP-GlcNAc) with phosphoenolpyruvate (PEP) to form UDP-GlcNAc-enoylpyruvate plus inorganic phosphate
What is the action of Cycloserine?
alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).[12] The first enzyme is a pyridoxal 5’-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.[12] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules
What are beta lactams?
All posses a beta lactam ring
Differ in the side chain attached to this nucleus
Target site is peptidoglycan which is present only in bacteria
Examples of beta lactams
Penicillins Cephalosporins Monobactams Carbapenems (meropenem) Clavulanic acid
What is the mechanism of action of beta lactams?
Act in the final step of cell wall synthesis by binding to the enzymes (transpeptidases/ penicillin binding proteins) responsible for cross linking of the polysaccharide chains in the cell wall peptidoglycan
Describe the action of cell wall synthesis inhibitors
NAG-NAMA-pentapeptide-phospholipid and amino acids for interpeptide bridge into ell wall- blocked by Glycopeptides
Cell wall to cross-linking of peptidoglycan strands blocked by beta lactams
What does NAG-NAMA stand for?
NAG= N-acetylglucosamine NAMA= N-acetylmuramic acid ala= alanine
Overview of Penicillins
- First antibiotic to be discovered
- Natural and semi synthetic products available
- Narrow spectrum (Penicillin G- Group A strep, meningococci) OR Broad spectrum (carbapenems)
What are the side effects of Penicillins?
- Relatively safe
- Hypersensitivity rash
- Avoid amoxicillin in patients with infectious mononucleosis- ‘glandular fever’- EBV
- Anaphylaxis rare (0.004%) but can be fatal
- Excreted by the kidneys: reduce dose in renal failure
- Diarrhoea- not uncommon
Describe Cefalosporins
- More than 30 agents available
- Grouped into “generations” or “classes”
- Cefalexin, cefuroxime, cefotaxime
- Exhibit broader spectrum cover than Penicillins
- Lack activity against enterococci
What are the clinical uses of Cefalosporins?
- Mostly stable to staphylococcal beta lactamase
- Much less than 10% cross allergy with Penicillins
- So diverse- defy rigid classification
- Oral cefalexin= UTI
- IV cefuroxime/ ceftriaxone/ cefotaxime= sepsis, meningitis
- IV ceftazidime= pseudomonas
- Improved beta lactamase stability- cefalexin
Name beta lactam antibiotic ‘allergy’ responses
Minor rash
Anaphylaxis
Describe minor rash response to beta lactam antibiotic allergy
- Localised, non itchy, >72hr after exposure to penicillin
- Acceptable to use Cefalosporins, monobactams instead provided spectrum of cover appropriate
- Consider penicillin use for severe infection
Describe anaphylaxis response to beta lactam antibiotic allergy
- Treated patient= wheezing, collapse, itchy rapid onset urticarial rash
- Use no beta lactam= should consider alternative classes (Glycopeptides, quinolones, metronidazole)
Describe Glycopeptides
- Inhibit cell wall synthesis by binding to terminal D-ala-D-ala of the peptide chain and prevents incorporation of new sub units to the growing cell wall
- vancomycin, teicoplanin
- For Gram positives not Gram negatives= important in MRSA infection
- Some nephro and ototoxicity= check spectrum levels
- IV for systemic infection (but oral for C. difficile infection- no absorbed)
Describe inhibitors of cell membrane function
Bacterial cell membrane is different from mammalian cell membrane
Bacitracin acts at Gram positive cell membrane
Examples of Protein synthesis inhibitors
- Aminoglycoside (gentamicin)
- Tetracyclines
- Macrolides (erythromycin, clarithromycin)
- Chloramphenicol (rarely used in UK)
- Lincosamides
- Oxazolidones
- Fusidic acid
What is the action of protein synthesis inhibitors?
Aminoglycosides inhibit binding of 30S subunit to mRNA- do not bind 40S mammalian ribosomes so bactericidal
-Tetracyclines inhibit binding of tRNA- do not penetrate mammalian cells- bacteriostatic
Describe Aminoglycosides
- Low therapeutic Index
- Very good vs Gram negative (E coli, pseudomonas aeruginosa and mycobacteria)
- Anti-staphylococci activity
- Not active against anaerobes
- Not absorbed orally
- Ototoxic and nephrotoxic
- Monitor serum levels during therapy
Describe tetracyclines
- Bacteriostatic
- Broad spectrum
- Intracellular bacteria (chlamydia)
- May cause diarrhoea, nausea
- Teeth discolouration, avoid in children, pregnant and lactating women
Describe Macrolides
-Erythromycin, clarithromycin, azithromycin
-Usually bacteriostatic, bactericidal in high concentrations
-Mainly narrow spectrum (mainly Gram positives- Aureus, Group A streptococci)
-Suitable for penicillin allergic patients
-Intracellular bacteria (legionella sp, chlamydia)
Erythromycin cheap
What are the side effects of Macrolides?
- Gastrointestinal upset common- less with newer agents
- Thrombophlebitis when given intravenously
- Newer macrolides have broader spectrum- clarithromycin and azithromycin
Describe Lincosamides
- clindamycin
- Gram positives- Group A strep, anaerobes
- Bacteriostatic, oral/IV
- Cheap/ diarrhoea/ colitis
Describe Streptogramins
- Pristinamycin, ‘Synercid’
- Gram positives
- Bacteriostatic, oral/IV gram positives
- Costly, GI upset
Describe Oxazolidones
- Linezolid
- Bacteriostatic, gram positives only
- VRE/ MRSA, may cause pancytopenia, neuritis and neuropathy, oral/IV, costly
What are the actions of inhibitors of nucleic acid synthesis?
-Inhibit synthesis of tetrahydrofolic acid (THFA)
-Inhibit synthesis of RNA
Inhibit synthesis of DNA
Describe THFA inhibitors
-Sulphonamides- structural analogues of PABA (para-aminobenzoic acid)
-Trimothoprim- ‘folate’ antagonist- binds dihydrofolate reductase- selectively toxic to bacteria
(humans do not make folic acid)
What is the mechanism of THFA inhibitors?
PABA to DHFA via synthase (inhibited by sulphonamides)
DHFA to THFA via reductase (inhibited by Trimethoprim)
THFA to Purines to DNA
What are the reasons for combining Trimethoprim and sulphonamides (cotrimoxazole)?
- There is in vivo synergy between the two drugs- the combined effect is greater than the expected sum of their activities- used in pneumocystis pneumonia
- Individually the drugs are bacteriostatic- combination bactericidal
- Use of 2 drugs delay the mergence of resistance
What is the con of cotrimoxazole?
Side effects greater- clinical evidence of greater efficacy weak
UK- trimethoprim used alone for UTA
Describe inhibitors of RNA synthesis
- Rifampicin
- Inhibits RNA polymerase enzyme
- Used as part of combination treatment for mycobacterium tuberculosis and M. leprae
- Also for severe S. Aureus infections
- Always in combination as resistance develops easily on monotherapy
- Significant drug interaction (hepatic enzyme inducer), colour secretions- inactivates oral contraceptive pill
Describe the action of Rifampicin
- Binds to DNA-dependent RNA polymerase
- Forms stable complex with beta-subunit (encoded by rpoB gene mutates readily)
- Inhibits initiation- not elongation
- Usually bactericidal
Describe inhibitors of DNA synthesis
- Quinolones
- Useful- mainly: multi R GNB; UTI; typhoid
- Synthetic, well absorbed. IV/ PO
- Act by inhibiting DNA gyrase (Gram negatives) and topoisomerase IV (Gram positives)
- Enzymes act together to ensure that DNA molecule has proper conformation for efficient replication and packaging within cell
- Bactericidal
Describe fluoroquinolones (Ciprofloxacin)
- Broad spectrum
- Low MICs
- Rapidly bactericidal
- Resistance can be slow to develop
What are the side effects of Quinolones?
- Neurotoxicity, confusion, fits
- Cartilage defects. Not used in pregnant women and children
- Photosensitivity
- Association with C. difficile infection
- 1st choice for meningococcal contacts prophylaxis
What are the qualities of an ‘ideal’ antibiotic?
- Desirable pharmacokinetic and pharmacodynamic properties
- High therapeutic index= good safety margin
- Low toxicity
- Bactericidal
- Cheap
- Does not accumulate/ increase resistance
- No interaction with other drugs
- Does not cause diarrhoea or C. difficile infection
What are the main routes of administration?
- Parenteral (intravenous/ intra muscular)
- Intraperitoneal
- Oral
- Rectal
- Topical often discouraged
What are the important issues when choosing an antibiotic?
- Infection present? Is it bacterial?
- Source control- drain abscess, remove foreign body
- Ideally obtain cultures before commencing antibiotics
- Complete laboratory request details properly
- Empiric (best guess) therapy may be started if required
- Cost, route, dose, monitoring, frequency and duration
- Document indication and review/ stop date
