Core Microbiology - Antibacterial Agents (1) Flashcards
Antibiotics
Chemical products of microbes that inhibit or kill other organisms
Antimicrobial agents
- Antibiotics
- Synthetic compounds with similar effect
- Semi-Synthetic (modified from antibiotics)
(Antibacterial, anti fungal, antiviral)
Bacteristatic
Inhibit bacterial growth (inhibit protein synthesis)
Bactericidal
Kill bacteria (cell wall-active agents)
Minimum Inhibitory Concentration (MIC)
Minimum concentration of antibiotic at which visible growth is inhibited
Synergism
Activity of two antimicrobials given together is greater than the sum of their activity if given separately
Antagonism
One agent diminishes activity of another
Indifference
Activity unaffected by addition of another agent
Which drugs is synergism confined to in treatment of streptococcal endocarditis?
B-lactam and aminoglycoside
Selective toxicity
Target not present/significantly different in human host
Antibiotic targets
- Cell wall
- Protein synthesis
- DNA synthesis
- RNA synthesis
- Plasma membrane
Why is bacterial cell wall an ideal potential for selective toxicity?
No cell wall in animal cells
Peptidoglycan in bacterial cell wall is gram…
Can be both gram-positive and gram-negative
What are the glucose-derivatives that make up peptidoglycan’s polymer?
N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG)
- Tetrapeptides cross-linked by Gly5
- Terminal D-Ala lost on cross-linking
Cell wall synthesis inhibitors
- B-lactams
- Glycopeptides
(Cycloserine and Fosfomycin)
Structure of B-lactam antibiotics
All contain B-lactam ring, structural analogue of D-alanyl-D-alanine
How do B-lactam antibiotics work?
Interfere with function of ‘penicillin binding proteins’ - transpeptidase enzymes that are involved in peptidoglycan cross-linking
What was the first true antibiotic in clinical practice?
Benzylpenicillin (B-lactam antibiotic)
4 types of B-lactam antibiotics
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
Examples of penicillins
- Benzypenicillin (PEN)
- Amoxicillin (most commonly used)
- Flucloxacillin
Penicillins are …. spectrum
Narrow
Examples of Cephalosporins
- Cefuroxime (CXM) (most commonly used)
- Ceftazidime
Cephalosporins are … spectrum
Broad
Cephalosporins target gram
-ve, better than penicillins
Examples of Carbapenems
- Meropenem (MER)
- Imipenem
Carbapenems are … spectrum
Extremely broad
Carbapenems target gram
negative, resistant
Examples of Monobactams
Aztreonam (AZT)
Monobactams target gram
negative only
Examples of Glycopeptides
- Vancomycin (most commonly used)
- Teicoplanin
How do Glycopeptides work?
- Large molecules, bind directly to terminal D-alanyl D-alanine on NAM pentapeptides - inhibits binding of transpeptidases - inhibits cross-linking
Glycopeptides target gram
positive activity (inability to penetrate gram negative outer membrane porins)
Protein synthesis in bacteria
- Translation RNA > protein on ribosome
- ribonucleoprotein complexes (2/3 RNA 1/3 protein) catalyse peptide bond formation and synthesis polypeptides
Stages of protein synthesis in bacteria
- Initiation
- Elongation
- Termination
- Ribosome recycling
Subunits that make up ribosome
50S (large) and 30S (small) > 70S imitation complex
In subunits S=?
Svedberg units, relative sedimentation rate
Protein synthesis inhibitors
- Aminoglycosides
- Macrolides, Lincosamides, Streptogramins (MLS)
- Tetracyclines
- Oxazolidinones
- Mupirocin
- Fusidic acid (hardly used)
Examples of aminoglycosides
- Gentamicin (most commonly used)
- Amikacin
Which protein synthesis inhibitors bind to 30S?
- Aminogylcosides
- Tetracyclines
Which protein synthesis inhibitors bind to 50S?
- Macrolides, Lincosamides, Streptogramins (MLS)
- Oxazolidinones (maybe 70S)
Adverse effects of Aminoglycosides
- Reversible renal impairment on accumulation, can be irreversible (rare)
- Need therapeutic drug monitoring
MLS inhibit
Protein elongation, block exit tunnel by which newly synthesised peptic leaves ribosome
Tetracyclines inhibit
RNA translation (interfere with rRNA and tRNA binding)
MLS examples
Macrolides - Erythromycin, Clarithromycin (most commonly used)
Lincosamides - Clindomycin
Tetracycline examples
- Tetracycline
- Doxytetracycline (most commonly used)
Oxazolidinones inhibit
Initiation of protein synthesis (inhibiting assembly of imitation complex)
Adverse effect of Linezolid
Bone marrow depression
Examples of Oxazolidinones
Linezolid
DNA synthesis inhibitors
- Trimethoprim (most commonly used) and sulfonamides
- Quinolones and Fluoroquinolones
Tritemthoprim targets
Dihydrofolate reductase
Sulfonamides target
Dihydropteroate synthetase
Trimethoprim and sulfonamide inhibit
Folate synthesis (purine synthesis precursor)
Co-trimoxazole
Trimethoprim-Sulfomethoxazole combined, bad side effects
Quinolone and Fluoroquinolones examples
- Nalidix acid
- Ciprofoloxacin (most commonly used)
- Levofloxacin
Quinolone and Fluoroquinolones inhibit
DNA gyrate and/or topoisomerase IV (remodel DNA during DNA replication - supercoiling/strand separation)
RNA synthesis inhibitors
Rifampicin - RNA polymerase inhibitor (prevents synthesis of mRNA)
Plasma membrane agents
- Daptomycin
- Colistin
Daptomycin works by
It is a cyclic lipopeptide tail (frying pan shaped), inserts lipophilic tail into cell membrane > depolarisation and ion loss > destruction of cell membrane
Daptomycin effects gram
positive only
Colistin is a
Last resource for gram negative
Adverse effects of all
- Nausea
- Vomiting
- Headache
- Rash
- Allergies
- Infusion reaction
- Antibiotic resistance
- Fungal infection - superficial/invasive candidasis
- C.diff
B-lactams intolerance
Nausea, diarrhoea and headache
B-lactams minor allergy
Non-severe skin rash
B-lactams minor allergy use … instead
Cephalosporins or carbapenems
B-lactams severe allergy
Anaphylaxis, urticaria (hives), angio-oedema, bronchospasm, severe skin reaction (Stevens-Johnson syndrome)
What drug can you use in a patient with any type of B-lactam allergy?
Aztreonam
C.diff infection
- Commonest cause of antibiotic-associated diarrhoea
- Produces toxins A and B, caused by abolition of colonal resistance
- Enterotoxin and spore production > clinical features and transmissibility
- Hypervirulent strain 027 (more severe)
Which antibiotics commonly precipitate C.diff?
- Co-amoxiclav (amoxicillin-clavulanate)
- Cephalosporins
- Ciprofloxacin
- Clindamycin
Which antibiotics precipitate C.diff, but less commonly?
- Benzylpenicillin
- Aminoglycosides
- Glycopepties
- Piperacillin-tazobactam (broad spec)
- Any
What is Flucloxacillin used for?
Staphylococcus aureus (not MRSA)
What is Benzypencillin used for?
Streptococcus pyogenes
What is Cephalosporins used for?
Gram negative bacilli (avoid in elderly)
What is Metronidazole used for?
Anaerobes
What is Vancomycin used for?
Gram positive (MRSA)
What is Meropenem used for?
Most clinically-relevant bacteria
What has good availability in CSF?
B-lactams in inflammation
What has poor availability in CSF?
Amino glycosides and vancomycin
What has good availability in urine?
Trimethoprim and B-lactams
What has poor availability in urine?
MLS antibiotics
Reasons for combining antibiotics
- Increase efficacy (synergy)
- Broad spectrum (polymicrobial infection/empiric treatment of sepsis)
- Decrease resistance (antituberculous chemo)
