40. Bacterial Antibiotic Resistance Flashcards
In the US, … million antibiotic-resistant infections occur each year and more than … die
- more than 2.8
- 35,000
It is estimated that by 2050, antimicrobial resistance will kill … yearly globally - this is more than … and … combined
- 10 million
- cancer and diabetes
Define ‘anti-microbial’
a compound that kills or slows the growth of micro-organisms e.g bacteria, fungi, viruses, parasites
Define ‘antimicrobial-resistance’
- the ability of micro-organisms to withstand the effects of an antimicrobial compound to which they were formerly susceptible
Define ‘antibiotic’
- a compound that can kill or slow the growth of bacteria specifically
- can be natural or synthetic
Years when antibiotics were first made
- penicillin discovered in 1928 by Fleming
- paper noted it’s ‘clinical potential’ in 1929
- development of it 19-39 to 1940
- production of penicillin 1941
Why is antimicrobial resistance being monitored?
- serious and growing problem worldwide
- looming crisis and major threat to public health
- major clinical, public health and economic implications
How have the WHO addressed antimicrobial resistance?
- declared it one of the top 10 global public health threats facing humanity
- a paper published in the Lancet in 2022
- estimated 4.95 million associated deaths in 2019m including 1.27 million attributable to bacterial AMR
- 6 leading pathogens for deaths associated are E.Coli, then Staph, aureus, K. pneumoniae, Strep, pneumoniae, A. baumannii and Pseudomonas aeruginosa
Antimicrobial resistance is linked to more deaths that what 2 conditions?
- HIV
- malaria
Factors which contribute to the emergence and spread of AMR
- excessive and prolonged use of antibiotics
- over-the-counter availability of antibiotics
- prolonged survival and treatment of patients with chronic diseases
- antibioitcs in animal feeds
- international travel and migration of pops - inc. medical tourism
- international distribution of fresh produce
List 4 ways to combat AMR
- preventing infections
- surveillance of AMR
- monitor use of antimicrobials
- development of new antimicrobials
How to prevent infection in order to combat AMR?
- promote infection control protocols
- immunisation
- safe food prep
How to surveillance antimicrobial resistance in order to combat AMR?
- public health systems
- epidemiological data
How to monitor use of antimicrobials in order to combat AMR?
- monitor prescribing
- prescribing adults
- monitor food and agricultural industries
How to develop new antimicrobials in order to combat AMR?
- incentives to drug development countries
What is the origin of antibiotic resistance?
- ideally with complete course of antibiotics, all pathogens destroyed but a few persister cells might survive
- if some resistant cells in infecting pop, they survive and grow without competition
- if person feels better and stops the antibiotics, mutant cells have opportunity to express AMR, survive and grow along with persister cells without comp
List 4 mechanisms of resistance
- intrinsic
- acquired
- cross
- multi
What is intrinsic AMR?
- innate property of bacterium in all strains
- characteristic of organisms
- entire species is resistant
- e.g resistance of gram-neg to many beta lactams and vancomycin (too large to cross cell membranes)
What is acquired AMR resistance?
- drug resistance is selected by antibiotic use
- doesn’t affect entire species and will only be seen in some strains
- can be by chromosomal mutation or horizontal gene transfer
- for example penicillin resistance in Staph. aureus
What is cross resistance AMR?
- resistance to one antibiotic leads to antibiotic resistance to another
- often when antibiotics are in same class
What is multi-resistance AMR?
- resistance to several antibiotics via independent mechanisms
Staphylococcus aureus has acquired resistance to …
- penicillin
- erythromycin
- methicillin
- cephalosporins
- vancomycin
- linezolid
Types of horizontal gene transfer
- transformation
- transduction
- conjugation
How does mutation lead to acquired resistance?
- chromosomal mutation resulting in genetically-altered bacterial population
- alteration of DNA within cell
- evolutionary advantage
Explain spontaneous mutation leading to AMR
- antibiotic doesn’t kill the spontaneously mutated AMR pathogen
- it’s then selected so vertical transmission of AMR in future
How does transformation pass on acquired AMR?
- DNA taken up into bacterial cell from environment
- DNA taken up encodes new genes and may include genes to confer antibiotic resistance
How does transduction pass on AMR?
- DNA transmitted via viruses
- certain viruses able to infect bacteria
- DNA picked up by viruses and passed from one bacterial cell to another
Key difference in transformation and transduction
- in transformation, lysis of donor cell releases DNA to be taken up by bacterial cell
- in transduction, virus injection and chromosome disruption so donor DNA-containing viruses attach to bacterial cell
Conjugation to transfer AMR
- occurs via pili
- donor cell containing conjugative plasmid and recipient cell that doesn’t
- only donor cells have pili
- cells drawn together for transfer of DNA - in plasmid form (small DNA rings)
- resistance genes often on plasmids, plasmids able to be transmitted between bacteria
Bacteria use 3 main mechanisms to become resistant to antibiotics. List them
- modification of antibiotic/inactivating antibiotic
- modification of target
- sequestering antibiotic from target/preventing drug from reaching target
A bacteria’s mechanism of AMR is modification of antibiotic. List 5 ways it could do this
- antibiotic hydrolysis
- antibiotic modification
- membrane modification
- target modification
- metabolic pathway alteration
How does antibiotic hydrolysis work?
- beta-lactamase break the structure of antibiotics like penicillin
- production of enzymes to degrade/inactivate antibiotic
How does antibiotic modification work?
- chemical groups or modifiers inactivate an antibiotic like streptomycin
- production of enzymes to degrade/inactivate antibiotics
How does membrane modification work?
- cell membrane pumps out antibiotic like tetracycline
- reduced uptake into cell/removal of antibiotic from cell
How does target modification work?
- cell targets such as ribosomes change structure so antibiotics like streptomycin can’t bind
- structural alteration to drug target
How does metabolic pathway alteration work?
- alternate pathway used to bypass an antibiotic-blocked metabolic pathway
- such as for sulfa drugs
- contingency measures to avoid drug toxicity
How does amoxicillin work?
- penicillin family of antibiotics (beta-lactam antibiotics, bacteriocidal)
- inhibits synthesis of bacterial peptidoglycan cell wall
- prevents formation of rigid cross-linked cell wall structure
- weakened cell wall leads to cell rupture
How does amoxicillin actually stop the cell wall of bacteria forming?
- beta-lactam antibiotics block the cross linking of peptidoglycan units
- as they inhibit transpeptidases which enable peptide bond formation
Gram-negative bacteria are intrinsically resistant to … due to …
- early penicillins
- lack of permeability through outer membrane, multidrug efflux pumps, beta-lactamases encoded on chromosome
How do staph aureus have acquired resistance to penicillins?
- plasmid-borne beta-lactamase
- modification of mecA gene encoding PBP2a - reduced binding of beta-lactams (methicillin resistance)
Which mechanism of AMR do these fall into?
- lack of permeability through membrane
- multidrug efflux pumps
- beta-lactamases encoded on chromosome
- plasmid-borne beta-lactamase
- modification of mecA gene encoding PBP2a - reduced binding to beta-lactams
- sequestering from target
- sequestering from target
- modification of antibiotic
- modifcation of antibiotic
- modification of target
Role of Beta-lactamases
- modified penicillin binding proteins
- bind to beta-lactam ring and hydrolyse it
What can inhibit beta-lactamases?
- clavalanic acid
- augmentin (Co-amoxiclav) = amoxicillin + clavulanic acid
How does horizontal gene transfer occur in NDM-1 for AMR?
- carbapenems are potent beta-lactams (last line antibiotics vs penicillin resistant gram-negs)
- NDM-1 can break down the carbapenem ring
- gene encoding NDM-1 is present on a plasmid - can be transferred between bacteria including E.Coli and Klebsiella etc
How has NDM-1 spread from first cases in UK?
- many of first cases in UK from patients visiting India for medical care
- dental care one of the most common reasons for healthcare-related international travel
- by 2015, NDM-1 in over 70 countries
Dentists issue around …% of all antibiotic prescriptions in NHS primary care and … % of the NHS total
- 10.8
- 5%
… million antibiotic prescriptions dispensed by pahrmacists for dental prescription in 2017
2.9
Treatment of odontogenic infections (with AMR in mind)
- usually require dental treatment
- done via removal of the source of infection
- antibiotics should only be prescribed if necessary as adjunct
- odontogenic infections are polymicrobial and in biofilms - more resistant to antibiotics
Why is there increased antimicrobial resistance in biofilms?
- slow penetration of antibiotics and can be complete failure/de-activated before it can diffuse through like beta-lactamase
- resistant phenotype like persisters. some bacteria can differentiate into protected phenotypic state
- altered microenvironment - microscale gradients can antagonise antibiotics like oxygen, pH - in zones of nutrient depletion or waste product accumulation, antibiotic action may be antagonised
AMR mechanisms in oral biofilm
- modification of antibiotic - reaction with ECM
- modification of target - slow growth
- reduced intracellular concentration - exclusion by matrix, up-regulation of efflux pumps
Treatment steps of bacterial dental infection
- local measures
- drain pus if present
- tooth extraction
- access and drain through root canals
- soft tissue pus drain by incision
- debride infected periodontal pockets
- irrigate/debride infected operculum
What guidance is followed for what to prescribe?
- BNF
- SDCEP Drug Prescribing in Dentistry
- FGDP (UK) Antimicrobial Prescribing for GDPs
What antibiotics are prescribed by dentists?
- amoxicillin
- phenoxymethylpenicillin
- metronidazole
Explain antimicrobial stewardship
- appropriate, safe and discriminate use of antimicrobials
- systematic effort to educate and persuade prescribers of antimicrobials to follow evidence-based prescribing in order
- to stem antibiotic overuse and antiobiotic resistance
How to avoid over-prescribing?
- follow uo-to-date prescribing guidance
- prioritise local measures
- ensure suitable length to appointments
- informed consent for treatment - options, risks, benefits
- communication regarding risks of over-prescribing
How can dentists be responsible prescribers?
- justify prescribing
- follow guidance
- communicate with patient regarding prescription
- prescribing audits completed
- prescribing monitored
How to increase public awareness of antimicrobial resistance?
- toolkit to support antimicrobial stewardship
- ongoing training of staff and CPD
- communication with patients
- patient education
- information for patients and posters for dental practice waiting rooms
