4. Antibiotics And Antimicrobials Flashcards
4 antimicrobials (classification)
- Antibacterial – antibiotics
- Antifungal
- Antiviral
- Antiprotozoal
4 Classification of antibacterial agents
– bactericidal or bacteriostatic
– spectrum – ‘broad’ v. ‘narrow’
– target site (mechanism of action)
– chemical structure (antibacterial class)
Define – bactericidal bacteriostatic
- Bacterialcidial = kill bacteria compeltely
* Bacteriostatic = stop bacteria replicating
Define spectrums of antibiotics
– spectrum – ‘broad’ v. ‘narrow’
• Treat a broad spectrum of organisms e.g. treat both gram positive and negatitive
• Treat narrow range
6 ideal features of antimicrobial agents
- Selectively toxic
- Few adverse effects
- Reach site of infection
- Oral/IV formulation
○ Oral drugs are easier to deliver
• Long half-life (infrequent dosing)
○ How long drug lasts in body and how often to take drugs
• No interference with other drugs
Selecting the best antibiotic
1 empirical therapy → give best broad spectrum antibiotic as you have not yet identified causative organisms
- Isolate and identify causative organism
- Determine its sensitivity to antibiotics
4 • treat with appropriate narrow antibiotic
4 antibacterial mechanisms of action
Interfere with Cell wall synthesis
Interfere with Cell membrane function
Interfere with Protein synthesis – impact bacteria that produce proteins (toxins)
Interfere with Nucleic acid synthesis
Examples of antibacterials that
Interfere with Cell wall synthesis
• β-lactams
- bind to enzymes that form cross links between peptidoglycan so prevent cell wall synthesis , gram positive bacteria burst due to high internal osmotic pressure
• Glycopeptides
Examples of antibacterials that
Interfere with Cell membrane function
- Polymixins (e.g. colistin)
* Daptomycin
Examples of antibacterials that
Interfere with Protein synthesis
- Tetracyclines 30s
- Aminoglycosides 30s
• Macrolides 50s
Antibiotics binds to 30s or 50s ribosomal - subunit causing interference in protein synthesis as mrna is misread or not read
Examples of antibiotics that
Interfere with Nucleic acid synthesis
• Quinolones
Bind to dna and enzymes in gram negative causing breaks in dna
* Trimethoprim * Rifampicin
Inhibit bacterial cell dna synthesis = death as it inhibits dna gyrase and topoisomerase iv enzymes needed for replication
4 mechanisms of resistance (that bacteria develop)
- Drug inactivating enzymes (inactivate antibioticis)
- Altered target
- Altered uptake
- Biofilm mode of growth
3 types of mechanisms of resistance (that bacteria develop)
Intrinisic
Acquired
Adaptive
Intrinsic resistance
- no target or restricted access for drug
Bacteria are just naturally resistance
Acquired resistance
Mutates or accquires new genetic material
= most problematic
Adaptative resistance
Organism responds to a stress and adapts to its new growth enviroment
Examples of • Drug inactivating enzymes (inactivate antibioticis)
- e.g. β-lactamases, = beta lactamase breaks up beta lactamase ring of penicillin
- aminoglycoside enzymes
Mechanisms of resistance
-Altered target
• target has lowered affinity for antibacterial e.g. resistance to methicillin, macrolides & trimethoprim
Mechanisms of resistance
• Altered uptake
- ↓permeability, so antibiotic can’t easily go into bacteria
- or ↑efflux, to pump antibiotics out
Mechanisms of resistance
• Biofilm mode of growth
• Bacteria form biofilm, big tent thing to protect them
4 Genetic mechanisms of resistance
Transformation
Transposition
Conjugation
Mutation
Transformation
Genetic mechanisms of resistance
• direct uptake of DNA containing resistance genes
Transposition
Genetic mechanisms of resistance
• movement of resistance genes from plasmids to genome
Conjugation
Genetic mechanisms of resistance
• plasmids containing resistance genes are transferred from other organisms
Mutation
Genetic mechanisms of resistance
• base changes or deletions lead to altered targets of antibiotic action
3 ways of measuring antibiotic activity
• Disc sensitivity testing
Antibiotic sensitivity by Etest
Automated antibiotic sensitivity testing
• Disc sensitivity testing:
○ Sensitive
○ Intermediate = few bacteria grow
○ Resistant = nothing happens around zone bacteria still grow
Look at zones of inhibition to find most effective antibiotic
• Know which antibiotic is the most important
Antibiotic sensitivity by Etest
• Minimum inhibitory concetration MIC as mg/L
○ Minimum concentration of that antibiotic that inhibits bacterial growth
* Strip with different concentrations of antibiotics * Minimum inhibitory concentration is where zone of bacteria stops
Automated antibiotic sensitivity testing
• Much faster
• Minimum inhibitory concetration MIC as mg/L
○ Minimum concentration of that antibiotic that inhibits bacterial growth
Considerations for antibiotic therapy
- when to use antibiotic depends on Severity /cause of infection
- Consider patient’s medical history, other drugs and allergy to antibiotics (e.g. allergy to penicillin)
- Taking samples (eg swab, blood, urine sample, tissue or bone sample) before start of antibiotic therapy
- Broad spectrum antibiotics should be used if there is an urgency and the causative organism has not been identified
- Route of administration
- Dose of antibiotics
- Combination therapy = 2 antibiotics at a time
- Longevity of therapy
- Prophylaxis = problem with heart valves, heart valves can be very prone to infection
Examples of beta lactams
More info on 4’1 slides
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
Penicillin
• mainly active against streptococci
3 types of penicillins
Penicillin
Amoxicillin
Flucloxacillin
Amoxicillin
- also some activity against Gram-negatives
* Broad spectrum
Flucloxacillin
• active against staphylococci & streptococci
Penicillins: β-lactamase inhibitor combinations
- amoxicillin/clavulanate (all of above +anaerobes + Gram negative bacteria)
- piperacillin/tazobactam (as above + Gram negative, including Pseudomonas species
Cephalosporins
Broad-spectrum but no anaerobe activity – don’t act on anaerobic bacteria (e.g. clostridium)
- Cetriaxone has good activity in the CSF
- Concern over association with C. difficile major side effect of this drug is c.difficile infection
- Ceftazidime + avibactam and ceftolozane + tazobactam used for multidrug resistant Gram negative infections
Carbapenems
→ safe if allergic to penicillin
• Imipenem • meropenem • ertapenem – very broad spectrum (incl anaerobes) – active against most (not all) Gram negatives – generally safe in penicillin allergy
• imipenem + relebactam
– serious Gram negative infections (including anaerobes)
• meropenem + vaborbactam – complicated Gram negative UTI
3 types of glycopeptides
—> interfere with cell wall synthesis
Vancomycin
Teicoplanin
Dalbavancin and telavancin
Vancomycin
– active against most Gram positive (not Gram negative)
– some enterococci resistant (VRE)
– resistance in staphs rare
– not absorbed (oral for C. difficile only as it acts locally), normally given intravenously for other infections
– therapeutic drug monitoring (TDM) required (narrow therapeutic window)
Tetracyclines
Impact bacteria protein synthesis
Tetracycline & doxycycline
– similar spectrum, both oral only
– broad-spectrum but specific use in penicillin allergy, usually for Gram positive
– active in atypical pathogens in pneumonia
– active against chlamydia & some protozoa
– should not be given to children <12 years = as it affects mineralising tissue
Aminoglycosides
- impact bacteria protein synthesis
Most common agent is gentamicin = can be quite toxic
- Profound activity against Gram negative
- Good activity in the blood/urine
- Potentially nephrotoxic/ototoxic
- Therapeutic drug monitoring (TDM) required
- Generally reserved for severe Gram negative sepsis
Macrolides
- impact bacteria protein synthesis
e.g. erythromycin (& clarithromycin)
• Well distributed including intracellular penetration
• Alternative to penicillin for mild Gram positive infections
• Also active against atypical respiratory pathogens
Antifungals
• Azoles (active against yeasts +/- molds
– inhibit cell-membrane synthesis
– fluconazole used to treat Candida
• Itra/vori/posaconazole also active against Aspergillus
• Polyenes (nystatin and amphotericin) – inhibit cell membrane function
– nystatin for topical treatment of Candida
– amphotericin for IV treatment of systemic fungal infections (e.g. Aspergillus)
Fungal infections = very severe in immunocompromised patients
Metronidazole – antibacterial and antiprotozoal agents
• Active against anaerobic bacteria
• Also active against protozoa:
– Amoebae (dysentery & systemic)
– Giardia (diarrhoea)
– Trichomonas (vaginitis)
Antivirals
• Aciclovir
– when phosphorylated inhibits viral DNA polymerase = inhibit DNA viruses
– Herpes simplex – genital herpes, encephalitis
– Varicella zoster – chicken pox & shingles
• Oseltamivir (‘Tamiflu’)
– inhibits viral neuraminidase = stops virus from leaving the cell
– influenza A & B
• Specialist agents for HIV, HBV, HCV, CMV
Process of antibiotic resistance
→ through natural selection
1. Genetic mechanisms confer drug resistance due to mutations and genetic variation 2. Antibiotics kill non-resistant bacteria 3. Drug resistant bacteria selected and reproduce due to competitive advantage (less competition for food and space etc) 4. Drug resistance gene transmitted through (exposure naïve) population
3 levels of antibiotic resistance
MDR (multi-drug resistant)
XDR (extensively drug resistant)
PDR (pan-drug resistant)
MDR (multi-drug resistant)
Non-susceptibility to at least one agent in three or more antimicrobial categories
XDR (extensively drug resistant)
• Non-susceptibility to at least one agent in all but two or fewer antimicrobial categories
PDR (pan-drug resistant)
- Non-susceptibility to all agents in all antimicrobial categories
- Smallest populations of bacteria
Relationship between antimicrobial use and resistance
As prescribing and use increases so does resistance
3 forms of Evidence that anti-bacterials cause resistance
Laboratory evidence
Ecological studies
Individual level data
Laboratory evidence
- Provides biological plausibility
* Colonies growing on agar plates – see antibiotics working
Ecological studies
- Relates levels of antibacterial use in a population with levels of resistance
- Patterns of resistance and prescribing
Individual level data
• Relates prior antibacterial use in an individual with the subsequent presence of bacterial resistance (detected by culture or molecular means)
Pharmaceutical companies and antiniotics
- Get a lot of money for making medications for chronic conditions
- Not much money to be made in antibiotics
- Hard to make antibiotics from scratch as we don’t have enough understanding
Define antimicrobial stewardship
Commitment to always use antibiotics appropriately and safe
Only when they are needed
Choose right antibiotics and administer them in the right way
Why do GP staff prescribe antibiotics – inappropriately
• Relief of symptoms
○ They think the antibiotics might work, better than just leaving the infection
• Worry about complications/more serious illness ○ Worried that leaving it untreated may lead to something more serious • Patient pressure ○ what the patient wants, we want to be liked by patients
IDSA defintion of antimicrobial
Stewardship
Coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration. Antimicrobial stewards seek to achieve optimal clinical outcomes related to antimicrobial use, minimize toxicity and other adverse events, reduce the costs of health care for infections, and limit the selection for antimicrobial resistant strains
Symptom benefit from antibiotics
—> if antibiotics are given appropriately, duration of infection can be reduced
• The antibitoics do relieve symptoms but patients need to understand if the antibiotics will actually be benefical for them
NNT – number needed to treat
• NNT for an adverse effect is always lower than the NNT for one additional benefit to patient
• If you take na antibiotic and give it to patient= you are more likely to harm them than improve them if the antibiotic is given inappropriately
3 Elements of antimicrobial stewardship programme
• MDT
Surveillance
Interventions
• MDT
Effective collaboration across multidisciplinary team in implementing antimicrobial stewardship
• Surveillance
– Process measures
• Antibacterial use (quantity, type, appropriateness)
• Benchmarking within and between organisations
– Outcome measures • Patient • Emergence of resistant organisms
• Interventions
– Persuasive = people, opinions, advice
– Restrictive = rules and regulations
– Structural = • Computerised records, Rapid lab tests, Expert systems,Quality monitoring
Cellulitis - cause
Infection of deep dermis
Streptococcus pyogenes
Staphylococcus aureus
How does phagocytotic cell recognise pathogen
Prp recognise pamps
Cellutis supportive treatment
Nsaid
Pain relief
Elevation and immobilisation of leg
Saline dressings
Antibiotics for cellulitis
Vancomyosin
flucloxacilin
Doxycilin
Dysuria
Difficulty, pain , discomfort passing urine
