AA end lectures Flashcards
What are the aims for targeted therapy
limit side effects from infection and antibiotic
reduce development of antibiotic resistance
what is empirical therapy
Using antibiotics through statistical guessing
e.g. purulent tonsilitis - streptococcus pyogenes
how does age affect antibiotic use
Advanced age
- gastric acidity reduced
- Renal function deteriorating
o Toxicities of antibiotics increase retained longer = hepatic and renal problems/ failure
- Allergic reaction increase
Children
- Underdeveloped liver function
- Renal function diminished = reduced antibiotic clearance
o Tetracycline = teeth staining
o Quinolones alter cartilage development
o Sulfonamides displace bilirubin = neurotoxic
Pregnancy
- Not safe – can pass across placenta and affect neonate
o Doxycycline, tetracycline
o Sulfonamide
o Aminoglycosides
- Penicillin, cephalosporins and clindamycin – safe
How does renal and liver function affect antimicrobial
Renal function
- Metabolised or excreted by kidneys
- Half life increases with impaired kidney function
Liver function
- Half life increase with impaired liver = toxicity
How does site of infection affect antimicrobial
Site accessibility may be affected by lipid solubility
- Metronidazole and rifampicin are lipid soluble drugs
o Better penetrate BBB
Abscesses
- Antibiotics cannot penetrate
- Purulent material may present – binds and inactivates aminoglycosides
- Low O2 concentration and low pH
o Aminoglycosides requires O2 for transport
o Reduce activity of erythromycin
Medicinal devices and biofilms
What are biofilms
- Matrix provides physical barrier to diffusion of molecules
- Deeper layers of biofilm are anaerobic and also organism have low metabolic activity there
o Quinolones and aminoglycosides work poorly
What are some reasons for topical therapy
- Targeted
o Can achieve high concentration at the site - Less collateral damage
- Enables the use of agents too toxic for systemic use
- Avoids first pass metabolism
What are factors affecting effectiveness of topical antimicrobials
Some areas requiring treatment are inaccessible
Biological fluids may prevent agents from reaching site
Patient compliance
Topical agents may be more difficult to apply
Formulation may affect acceptability
What are antiseptics
Agents used for destruction or inhibition of microbes in or on living tissues
What medications can you use to treat MRSA
Clindamycin – 300-450mg tds
o 30% are resistant
Doxycycline 100mg bd
o 100% susceptibility
Trimethoprim/ sulfamethoxazole
o 95% susceptible
Rifampicin and fusidic acid
Quinolones – ciprofloxacin
Vancomycin
o 25 mg/kg loading dose to 15-20 mg/kg bd
Linezolid
o Oxazolidinone
Inhibits protein synthesis
Daptomycin
What is melioidosis
Caused by Burkholderia pseudomallei
Transmission:
- Cutaneous, inhalation, aspiration and occasionally ingestion
- Can appear asymptomatic
Clinical presentations
- Most infections are subclinical
- Most common clinical manifestation is pneumonia then skin infections
- Bacteraemia and septic shock
What are antimicrobials that melioidosis are resistant to
Antimicrobial resistance
- Resistant penicillin, ampicillin, first and second generation cephalosporins, gentamicin, tobramycin and streptomycin
Exclusion from the cell melioidosis
Exclusion from the cell
o Reduced outer membrane permeability
o LPS contributes to intrinsic high-level polymyxin B resistance
o Lipid A modification by 4-amino-4-deoxy-L-arabinose
o LPS O-antigen and outer core components are important in resistance to cationic antimicrobial peptides
Efflux from the cell melioidosis
- Efflux from the cell
o AmrAB-OprB
Aminoglycoside and macrolide resistance
o BpeAB-OprB
Macrolides, fluoroquinolones, tetracyclines
o BpeEF-OprC
Trimethoprim resistance
Chloramphenicol, fluoroquinolones and tetracyclines
Enzymatic inactivation melioidosis
- Enzymatic inactivation
o Cleavage of B-lactam antibiotics by PenA
Altered target site melioidosis
- Altered target sites
o Target deletion
o Ceftazidime resistance mechanism
Acquired antimicrobial resistance melioidosis
- Mutations or horizontal gene transfer mediated by phages, plasmids or transposon elements
- Ceftazidime
o Loss of gene required for synthesis of a penicillin binding protein 3
o Point mutation on PenA resulting in amino acid changes = increased ceftazimide hydrolysis
o Upregulation of penA via SNP in promoter region - Clavulanic acid
o Mutations in P167S
What are probiotic therapy
Live micro-organism that when administered in adequate amounts, confer health benefit on the host
Ideal characteristics of probiotic organisms
- Non-pathogenic
- Easily cultivated
- Adherent
- Able to form a stable population at site
What are uses of probiotics
- Active treatment or as preventative
o To restore, rebalance and support normal flora - Used for gastrointestinal and urogenital tract infections
- Administered by
o Ingesting capsules, drinks or applying pessaries to site
Mechanism of action of probiotics
General mechanism
- Competitive inhibition for sites/ nutrients
- Antagonism through production of inhibitory substances
- Inhibition of toxin produced by pathogens
- Immunodomulation of the host
Lactobacilli
- Production of lactic acid
- Production of antimicrobial substances
- Production of hydrogen peroxide
- Formation of colonisation barrier
What are bacteriocins
- Antimicrobial peptides
- Produced by wide range of organism
Mechanism of action
- Form pores in bacterial cell membrane
- Narrow spectrum activity
What are probiotic yeast
Mechanism of action
- Secretes a protease that
o Digests toxin A and B molecules
o Digests toxin A and B receptors on brush border membrane
Faecal microbiota transplantation
Transplanted into unhealthy recipient
- Recipient has reduced microbial diversity
- Transplanted via nasogastric tube or colonoscopy
Donors must be healthy
- Donor blood and stool are screened
Mechanism of action
- Transplant flora establishes in recipient
o Restore gut flora
- Increases microbial diversity in recipient compared to pre-transplant
Bacteriophage therapy
Mechanism of action
- Phage lyses bacterial cells resulting in bacterial cell death
Stages of bacteriophage
- Phage infects bacteria
- Phage replicates using bacterial cell machinery
- Lyses bacteria and new phage released
- New phage infect other bacteria
advantages and disadvantages of bacteriophage
Advantages:
- Phages are highly specific
- Effective against MDR
- No overgrowth of bacteriophages
- No deleterious effects on host cell
- Relatively cheap
Disadvantages:
- Bioavailability
o Reduced with stomach acid
- Safety concern
o Development of phage antibody by host
o Bacterial toxin present in pahge preparation
o Lysogenic conversion
- Other
o Some MRSA less susceptible to phage
o Bacteria may develop phage resistance
Garlic
Antimicrobial action from allicin
- Breaks down into sulfides = very potent against bacteria and fungi
Mechanism of action
- Allicin interferes with thiol containing enzymes
o Forms disulfide bonds with protonated sulfhydryl groups
o Inactivates protein in key microbial processes
Cranberry
- For urinary tract infections
- Active components are proanthocyanidins
Mechanism of action
- Reduces E.coli expression of fimbriae
- Reduces E.coli adhesion and binding to epithelial cells
Green tea
- Traditional Chinese medicine used to treat a range of general ailments
- Contains catechins
o Phenolic compounds
o Flavonoids
o Anti-oxidant activity
Mechanism of action
- Antiviral
- Weak antibacterial
- Weak antifungal
- Immune-stimulatory
Qinghaosu
- Contains artemisinin
Mechanism of action
- Against plasmodium still investigated
Honey
- Mostly sugar
Mechanism of action
- Antibacterial activity against a range
- Due to
o High osmolarity/ low water availability
o Low pH
o Generation of hydrogen peroxide
o Other minor component
Tea tree oil
- Mostly terpenes
Mechanism of action
- Broad spectrum antimicrobial activity
- Loss of cell membrane polarity and integrity
- Loss of cell homeostasis
- Inhibition of respiration
- Anti-inflammatory activity
Target selection
decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility
Target identification
to identify molecular targets that are required for microbial growth or target a human gene
Target validation
to prove that manipulating the molecular target can provide therapeutic benefit for patients
Genomics
study of genes and their function
Proteomics
study of proteome, the complete set of proteins produced by a species using technologies of large scale protein separation and identification
Lead discovery
identification of small molecule modulators of protein function
High throughput screening
screening of drug target against selection of chemicals
Silico screening
computer simulated screening of chemicals
Drug affinity
ability of drug to bind to its biological target
Selectivity
drug should bind to specific receptor site on the cell
Animal models of disease states
test conditions involving induced disease or injury similar to human conditions
Behavioural studies
tools to investigate behavioural results of drugs
Functional imaging
method of detecting or measuring changes in metabolism, blood flow, regional chemical composition and absorption
Ex-vivo studies
experimentation on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions
Clinical trials
set of procedures in medicinal research and drug development to study the safety and efficacy of new drug
