33.2 Treatment of Bacterial Infection Flashcards
What are the physical methods by which bacterial infections can be treated?
- Surgical drainage (e.g. of abscesses)
- Debridement (e.g. in necrotizing fasciitis).
What is debridement?
- Debridement is a procedure for treating a wound in the skin. It involves thoroughly cleaning the wound and removing all hyperkeratotic (thickened skin or callus), infected, and nonviable (necrotic or dead) tissue, foreign debris, and residual material from dressings.
- It may be used in e.g. necrotizing fasciitis
How are antibiotics able to be selectively toxic?
kill bacteria w/out damaging host (exploit various structural/ metabolic differences)
What is the action of beta lactams?
*Bacteria have peptidoglycan walls essential for integrity of their structure. W/out cell lysis occurs due to ↑ osmotic pressure
*Beta lactams inhibit transpeptidases (enzymes that crosslink strands of peptidoglycan - inhibition of cell wall synthesis), bind to PBP in cell membrane. Murein hydrolases (autolytic enzymes) activated
*They are bactericidal.
What antibiotics are beta lactams?
Penicillin, Amoxicillin, Benzylpenicillin, Flucloxacillin.
What is the action of Isoniazids?
Blocks long-chain mycolic acids, selective for mycobacteria.
Are isoniazids bactericidal or bacteriostatic?
They are bactericidal for growing organisms, otherwise they are bacteriostatic.
What is the action of Macrolides?
Inhibit translation (inhibiting protein synthesis) by binding 50S ribosomal subunit
Give an example of a macrolide
Erythromycin
What is the action of aminoglycosides?
Inhibit translation by binding 30S ribosomal subunit
What antibiotics are aminoglycosides?
Gentamicin, Tetracycline, Streptomycin.
What is the action of Chloramphenicol?
Inhibition of peptidyl transferase.
What is the action of rifamycins?
Inhibits bacterial transcription?
Give an example of a rifamycin.
Rifampicin.
What is the action of 2,4-diaminopyridines?
Inhibits folate metabolism (which is an essential cofactor for DNA) and hence DNA synthesis.
Give an example of a 2,4-diaminopyridines.
Trimethoprim.
What is the action of quinolones?
Inhibits DNA synthesis by binding DNA gyrase (a topoisomerase)
Give an example of a quinolone.
Ciprofloxacin
Why are sulphonamides now rarely used as antibiotics?
Sulphonamides (antifolates) are now rarely used due to resistance.
How do the properties of antibiotic derivatives differ from the original antibiotic?
The derivatives can have a different spectra of activity, bioavailability, and adverse effects.
What are some reasons why antibiotics may be used in combination?
- Empiric therapy when pathogen is unknown
- Synergistic action (cell wall/protein synthesis)
- Combining ‐cidal with ‐static in general
- Reduce emergence of resistance
How does the choice of antibiotic change before and after a pathogen is identified?
- Before the identity of the pathogen is known, many antibiotics are used. They are likely to be broad-spectrum antibiotics.
- After the pathogen is identified, just one specific antibiotic is used, to prevent the development of resistance.
What type of antibiotic is given when the agent is unknown? Give an example
Empiric therapy = broad spectrum
Amoxicilin in conjugation with clauvic acid (reduces beta lactamase activity)
Doxycyline (tetracycline given against gram negative rods)
Aminoglycosides (not streptomycin)
What is the minimum inhibitory concentration?
The minimum concentration of an antibiotic that must be maintained throughout treatment, in order to ensure that the drug is effective.
What are the consequences of the indiscriminate use of antibiotics?
- Drug resistance
- Elimination of normal microbiota
*Antibiotic-associated infections (e.g. C.difficile).
What can elimination of normal microbiota/ flora lead to?
Colonisation by resistant pathogenic bacteria.
What is synergism in antibiotic use?
When multiple applied antibiotics work together to produce an effect more potent than if each antibiotic were applied singly.
Give examples of synergistic antibiotic combinations.
*Trimethoprim and sulfamethoxazole.
*Beta lactam and clavulanic acid
What is antagonism in antibiotic use?
When one antibiotic inhibits the use of another, so that they should not be used in combination.
Give an example of antibiotic antagonism
Pencilin and tetracylines in the treatment of pneumococcal meningitis
What are the different routes of administration for antibiotics?
*Oral
*Topical
*Intravenous.
What pharmacokinetics need to be considered when prescribing atibiotics?
*Drug absorption
*Route of elimination
Why may topical or local dose be more appropriate than oral delivery?
oral antibiotics cull large amounts of gut microbiome = decrease in commensal bacteria which prevent the growth of opportunistic pathogens leading to antiobiotic associated C.difficle infections and other complications
Give an example of an antibiotic that would be used to treat a UTI and why.
Trimethoprim as it is renally excreted and reaches high concentrations in the urine.
Which class of antibiotics do people commonly have hypersensitivity to?
Penicilin
How does penicillin hypersensitivity occur?
IgE mediated reaction = bronchospasm (H1) and anaphyaltic shock
Results in mast cell degranulation and mass release of histamine
Why should doctors recommend another method of contraception to individuals take in rifampicin?
Rifampicin increases the activity of cytochrome P450 enzymes which the contraceptive pill are metabolised is metabolised by, so the effectiveness of the pill may wear off when taking this antibiotic
What is the effect of selection pressure on antibiotic resistance?
Antibiotics → selection pressure → resistant-bacteria survive (selective advantage) + reproduce → frequency of resistive genome in population ↑
What are the genetic mechanisms of antibiotic resistance?
1) Decreased uptake (cephalosporin resistance via porin modification)
2) Membrane pumps (Tetracycline resistance efflux pump)
3) Drug inactivation (Penicillin resistance via beta-lactamase)
4) Target modification (Fluoroquinolone resistance via topoisomerase mutations)
5) Target amplification (Trimethoprim resistance via increases DHFR expression)
Give an example of target-site insensitivity
Changes to ribosome in erythromycin resistance.
Give examples of enzymatic inactivation.
*Beta lactamases → degrade beta-lactam ring (intact essential for activity)
*phosphotransferases → phosphorylate aminoglycosides inactivating them.
Give an example of decreased drug uptake.
Development of cell wall impermeability by mutant porins in gram-negative bacteria.
* could be due to decreased expression/ diameter/ increased selectivity.
Give an example of increased drug export.
Lmrs = multidrug efflux pump expressed by resistant strains of Staphylococcus aureus.
What are the strategies for reducing antibiotic resistance?
*Improve prescribing practice
*Public health education → ensure full course
*Reduce antibiotic use in farming
*Sanitation + hygiene → reduce spread of resistant bacteria
What are the strategies for combating antibiotic resistance?
*Target mechanisms of resistance (e.g. beta lactamase inhibitors - clavulanic acid + beta lactams)
*Develop + improve uptake of vaccines
How can a bacterium gain antibiotic resistance?
*Vertical gene transfer
*Exchange of genetic mobile elements.
- plasmids largest contributor to AMR.
*Horizontal gene transfer
How does vertical gene transfer allow bacteria to gain resistance?
*Vertical gene transfer → in all organisms
- Chromosome mediated - mutations in genes coding for drug targets/ uptake/ export
- Frequency of spontaneous mutation < plasmid acquisition ∴ lower clinical significance
How does exchange of mobile genetic elements allow bacteria to gain resistance?
*Plasmid-mediated - extrachromosomal dsDNA molecules encoding resistance genes (e.g. inactivating enzymes, export pumps)
- Often confer multidrug resistance.
*Transposon-mediated → DNA segments that can be transferred between plasmids/ chromosomes. Can be readily incorporated into host genome independent of normal mechanisms
- Typically 3 genes:
1.Transposase - catalyses excision + reintegration of transposon
2.Repressor - regulates the synthesis of the transposase
3.Drug resistance gene
How does horizontal gene transfer allow bacteria to gain resistance?
Horizontal gene transfer → only in bacteria. Allow novel advantageous properties to be passed between bacteria
*Conjugation - between 2 bacterial cells in direct contact
*Transduction - injection of foreign DNA into host bacterium by bacteriophage
*Transformation - uptake of naked genetic material through cell membrane(s)
What are transposons? How can it bring about antibiotic resistance?
A DNA sequence that can change its position in the genome (from chromosme to plasmid etc) which results in the addition or reversion of a mutation and genome
What is high level resistance?
Resistance that cannot be overcome by increasing the dose of antibiotic e.g resistance mediated by beta lactamases as all the drug is destroyed
What is low level resistance?
Resistance that can be overcome by increasing the drug dose - altered drug target can still bind some drug
What is the mechanism of resistance to aminoglycosides?
*Enzymatic inactivation:
Phosphorylation (phosotransferase), acetylation and adenylation
Altered target site:
Mutations on chromosome coding for target protein on 30S subunit
Decreased permeability to the drug
Where are most sources of antiobiotic resistant strains? Why?
-Medical settings: there is widespread antibiotic usage in hospitals which become resistant to multiple antibiotics due to accquisition from plasmisds
-Veterinary and agriculture settings: use lots of prophylactic (preventitive) antiobiotic usage in beef and pork industries
Both settings apply a SELECTION PRESSURE
