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AMR - Coggle Diagram
AMR
how does antibiotic resistance develop
suboptimal exposure to antibiotics
incorrect dosage - course of antibiotics not taken correctly/not completed
incorrect treatment - antibiotics given for non-bacterial infection
lack of accurate diagnosis - incorrect antibiotic given for the type of infection (eg. intrinsic resistance, previous resistance mechanism present) or lack of alternatives
use for growth promotion/unnecessary prophylaxis
low dose given to farm animals to promote growth
unlimited use
no guidelines on use of "last resort antibiotics", varies locally, nationally, internationally and according to application eg. human vs. veterinary
antibiotics kill the weak germs but resistant germs remain
drug resistant germs can take over
bacteria can copy and share resistance, then combine it with other resistance, to avoid our best defenses
already tough to treat germs can combine these defence strategies and become completely untreatable
examples of how antibiotic resistance spreads
George gets antibiotics and develops resistant bacteria in his gut
George gets care at a hospital, nursing hope or other inpatient care facility
resistant germs spread directly to other patients or indirectly on unclean hands of healthcare providers
resistant bacteria spread to other patients from surfaces within the healthcare facility
patients go home
pass on to immediate contacts
animals get antibiotics and develop resistant bacteria in their guts
drug resistant bacteria can remain on meat from animals. when not handled or cooked properly the bacteria can spread to humans
fertiliser or water containing animal faces and drug resistant bacteria is used on food crops
drug resistant bacteria in the animal faces can remain on crops and be eaten. these bacteria can remain in the human gut
indiscriminate use
unnecessary use
no prescription required
insufficient dosing selects for resistant clones
spreads between
animal to human
food (vegetables and meat)
patient to patient
community acquired
travel
horizontal gene transfer
spreads antibiotic resistance to other bacterial species via plasmids
rapid diagnostics
- slow antimicrobial susceptibility tests (AST) lead to over/misuse of antibiotics
need for immediate initiation of antibiotic treatment + testing for AMR taking 6-48 hours & cost = broad spectrum antibiotic treatment
eg. gonorrhoea
last line treatment is given on a precautionary basis to almost all patients even though 70-80 percent of cases would be expected to respond to older abandoned first line treatments
cases of multiple drug resistant gonorrhoea are increasing - options for treatment are severely limited
who benefits from ASTs?
patient
correct treatment
less chance of complications
less side effects
less chance of AMR develpment
less chance of needing to be isolated
clincians
higher success rate of treatment
fewer side effects
hospital/trust
fewer healthcare costs
fewer complications
worsening of symptoms
patient isolation due to AMR carriage
specialised care
other patients
less chance of acquiring AMR
society
decrease in risk of acquiring/spreading AMR
decreased economic, mortality and morbidity costs
what is antibiotic resistance
a bacterial isolate is classed as resistant if the minimum inhibitory concentration of the antibiotic is above a set clinical breakpoint
a bacterial isolate is classed as pandrug resistant if it can survive treatment with all available antibiotics
antibiotics act on bacteria
MIC = the lowest concentration of an antibiotic that prevents the visible growth of bacteria. defined using micro dilution, e test or disc diffusion methods
microbroth dilution is gold standard
increasing concentrations of antibiotics
keep diluting until minimum conc. with no growth
technical issues with defining MICs
diffusion of antibiotic through agar
prodrugs require activation (may require special media)
slow growth of organism
area of technical uncertainty
inherent variability (1xlog2 variability is acceptable in MIC readings and n=1)
variation between operators/media - qc can help but not eliminate
interpretation is usually manual so can be done very cheaply
contamination
CLINICAL BREAKPOINT - antibiotic concentration used to define isolates as susceptible, increased dose or resistant
set by European committee on antimicrobial susceptibility testing or clinical and laboratory standards institute in the USA
clinical, pharmacological, microbiological and pharmacodynamic considerations are important in setting breakpoints
different for each organism/antibiotic combination
many exceptions and special conditions
testing carried out by biomedical scientists in diagnostic laboratories
interpretation by bms and clinical microbiologists
treatment decision made by clinician
what information is taken into consideration to define breakpoints?
organism
intrinsic resistance
epidemiological cut off values
clinical indication
complicated vs uncomplicated UTI
infection originating from urinary tract or meningitis
screen for resistance mechanisms vs clinical application
dosing regime
oral vs iv
amount, frequency and length of treatment
standard dose vs high dose
pharmacokinetic/pharmacodynamic (PK/PD or exposure-response relationship
location of infection
concentration of antibiotic at location of infection
side effects
sex, age, immunological status of patient
AMR usually refers to organisms that have an acquired resistance to an antibiotic ie. that would normally be susceptible to the normal dosing with a given antibiotic
why is antibiotic resistance a problem
the challenges of AMR
drug
antibiotic classes
combinations
resistance mechanisms
cross resistance
plasmid carriage
organism
gram +ve
gram -ve
slow growing
anaerobic
disease
lower respiratory
blood stream
uti
symptoms
diarrhoea
ulcers
meningitis
route of infection
opportunistic
sexually transmitted
faecal-oral
treatment
iv
oral
combination therapy
phage
faecal transplant
control strategy
vaccine
antibiotic stewardship
access to antibiotics
diverse geographical spread
economic considerations
massive impact both on mortality and economically
resistance develops and is selected for all the time
antibiotic discovery void - the last antibiotic class that has been successfully introduced as treatment was discovered in 1987
no new antibiotics in the pipeline
drug development issues
cost of research vs profit (antibiotics are cheap)
short term treatment (7 day course)
emergence of resistance
new antibiotics will only be used once old ones are useless
the more ana antibiotic is used the faster resistance will develop (the sooner an antibiotic is useless)
the less an antibiotic is used the longer it will be usable (but patent will run out and no profit made initially)
need to find financial incentives
MECHANISMS OF ANTIBIOTIC RESISTANCE
classification of antibiotics based on their mode of action
BROAD SPECTRUM
chloramphenicol
tetracyclines
carbapanems
ciprofloxacin
NARROW SPECTRUM
azithromycin
erythromycin
vancomycin
BACTERIOSTATIC VS BACTERICIDAL
bacteriostatic
inhibit the growth and replication of microbes which allows host immune system to clear infection
in general bacteriostatic antibiotics are protein synthesis inhibitors eg. tetracyclines, choramphenicol
only halts the bacterial growth, does not eliminate the population
removal of a bacteriostatic drug allows the bacteria to reproduce again
bactericidal
kills and reduces the total viable number of microbes
in general cell wall synthesis inhibitors eg. penicillins, carbapenems
preferable
less reliant on host cell defences
advantageous for immunocompromised patients
more rapid action than bacteriostatic antibiotics
general mechansims of antibiotic resistance
what has to happen for an antibiotic to be effective?
antibiotic must penetrate into the cell
sufficient concentration of antibiotic accumulated in cell
antibiotic is able to act on its target
ultimately an antibiotic must be able to reach and act upon its target
ultimately an antibiotic must be able to reach and act upon its target
antibiotic targets
BACTERIAL CELL WALL
beta lactam antibiotics
mode of action of a cell wall synthesis inhibitor
vancomycin
BACTERIAL CELL MEMBRANE
daptomycin
PROTEIN SYNTHESIS
tetracyclines
aminoglycosides
chloramphenicol
DNA AND RNA SYNTHESIS
fluorophinolones
rifamycin
FOLIC ACID (vitamin B9) METABOLISM
trimethoprim
structural analogue of dihydrofolic acid
bind and inhibit dihydrofolate reductase
often given in combination with a sulfonamide (sulfamethoxazole)
sulfonamides
structural analogues of p-aminobenzoic acid
bind and inhibit dihydropteroate synthetaste
folic acid (folate) synthesis pathway
different targets = different resistance mechanisms
types of bacterial resistance
intrinsic natural resistance
bacteria which have a natural resistance to particular antibiotics
do not possess relevant target or metabolic process
efflux
activation of previously silent genes
examples
gram negative bacilli naturally resistant to penicillin
mycobacterium tuberculosis naturally resistant to many anitibiotcs
tetracyclines due to waxy cell wall
clinically not an issue
phenotypic resistance
bacteria when present in a
biofilm
are more resistant to antibiotics than their planktonic counterparts
poor penetration of antibiotic into biofilm
stress response and slow growth of bacteria, antibiotics work on actively dividing cells
linked to the heterogeneity of the population within a biofilm
increased persister cell populaiton
role of specific processes eg. quorum sensing involved within a biofilm community. up regulation of efflux pumps etc.
biofilms confer decreased susceptibility to antibiotics
acquired resistance
bacteria develop resistance to particular antibiotics ie. become resistant
two main mechanisms
mutating existing genes (usually chromosomal (vertical evolution))
change (SNP or Indel)
negative
deletion of repressor function
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positive
increased gene function
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examples
SNPs in two component regulators
phoPQ
and
pmrAB
gives increased resistance to colistin
usually deletions in Nictroreductases
nfsA
and
nfsB
gives increased resistance to nitrofurantoin
mutations to existing antibiotic resistance genes to broaden spectrum
bla
SHV-11 penicillin resistance goes to
bla
SHV-12 (penicillin and cephalosporin resistance (ESBL))
acquisition of novel genes eg. by horizontal gene transfer
this can be through the acquisition of mobile genetic elements
transposons
integrons
phages
vesicles
plasmids
essential in microbial ecology for transportation of genes with different roles through microbial populations
four main processes
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example
acquisition of
mcr
genes given rise to increased resistance to colistin
acquisition of beta-lactamase genes (including carbapenemase encoding genes)
clinically a huge problem
prevention of access to target
changes in membrane composition to reduce antibiotic binding affinity and/or translocation
colistin resistance (LPS modification)
sequestration of antibiotics to prevent binding to target
passage of antibiotic for efflux
efflux examples
AcrAB
Mex pumps
multiple antibiotics
efflux
binding of antibiotic to efflux pump regulator may activate expression of other genes involved in antibiotic tolerance
binding of antibiotic to efflux pump regulator which activates efflux pump gene expression
efflux pumps
transport proteins involved in extrusion of toxic substrates from within cells into the external enviornment
found in both gram-positive and gram-negative bacteria as well as eukaryotic organisms
found on plasmids but mainly found on the chromosome
may be specific for one substrate or transport a range of dissimilar compounds (MDR phenotype)
present in bacterial strains which were isolated before the widespread use of antibiotics (suggest other function - such as maintenance of cell shape, nutrient acquisition and virulence)
types of efflux pump
ATP-binding cassette family (ABC)
antibiotic: macrolides
resistance-nodulation-division family (RND)
antibiotic: beta-lactams
small multi drug resistance (SMR)
antibiotic: fluoroquinolones
major-facilitator superfamily (MFS)
antibiotic: fluoroquinolones, tetracyclines
multidrug and toxic compound extrusion (MATE)
antibiotic: glycylcyclines
why is a change in efflux pump regulation often the first line on the pathway towards generation of high level resistance
potential breakdown of antibiotics to inactive components
beta lactamases
potential modification of antibiotics to less harmful products
acetylation of aminoglycosides
deletion of porins leading to reduced influx (does this affect efflux?)
carbapenems
alteration of target
modification of target
use of alternative protein
target bypass
how resistance mechanisms contribute to antibiotic failure
antibiotic must penetrate into the cell
sufficient concentration of antibiotic accumulated in cell
antibiotic is able to act on its target
target modification, target bypass
efflux, modification/breakdown of antibiotic, antibiotic sequestration
cell impermeability
decrease effective antibiotic concentration at its target site
specific examples
CARBAPENEMS
member of the beta lactam group of antibiotics with a core beta lactam structure with a mode of action which is common
imipenem
meropenem
ertapenem
doripenem
developed due to increased presence of beta lactamases and decline in effectiveness of penicillin
most effective group of antibiotics against MDR pathogens, particularly gram negatives
have a wide range of activity including anaerobes, gram negative and gram positive bacteria
resistance is uncommon, although increasing
seven carbapenems in use, some more widely used
mechanisms of carbapenem resistance
production of carbapenem hydrolysing enzymes (carbapenemase) eg. blaKPC or blaNDM-1 which cleave the beta-lactam ring inactivating the antibiotic
mainly plasmid based but can be on the chromosome
mutation or complete loss of certain porins
increased expression of certain efflux pumps
organism has an ESBL or contains an AmpC beta-lactamase and undergoes porin loss
in certain cases mutations or reduced transcription of PBPs
fitness cost associated with antibiotic resistance
many amr bacteria have a fitness cost in the absence of an antibiotic
what could motivate drug companies (and academia) to invest in antimicrobial research
money!
push incentives
government funding for early stages of research, clinical trials etc
extending patenting for a set time once product on the market
pull incentives/delinkage - separate income generation from sales
lump sum on development of antibiotic
lump sum and pay as you go payment
Netflix model -pay subscription no matter how much it is used
payment for keeping antibiotic in reserve and not selling
heavily dependent on government policy and international collaboration
what can we do about AMR now?
one health response
humans
food and feed
massive reduction in antibiotic use in the uk poultry meat sector due to salmonella vaccination
plants and crops
environment
terrestrial and aquatic animals
interagency coordination group on antimicrobial resistance recommendations
accelerate progress in countries
innovate to secure the future
collaborate for more effective action
invest for a sustainable response
strengthen accountability and global governance
antibiotic stewardship
dramatically lower antibiotic volumes currently used (human and non human)
restrict broad spectrum and critically important antibiotics in people
diagnostics - the right antibiotic at the right time
patient
clinical evaluation
diagnostic stewardship: right test, right patient, right time
rapid diagnostic tests ordered
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ban the use of critically important antibiotics in food animals
do not use antibiotics to spray plants and in aquaculture
do not dump antibiotics into the environment
stop the presence of antibiotic residues in foods and water
infection prevention
NO INFECTION
NO NEED FOR ANTIBIOTICS
REDUCED CHANCE OF ANTIBIOTIC RESISTANCE
basic hygiene
: hand washing, equipment sterilisation etc
vaccination
screening
: early detection of carriage of or infection with resistant bacteria
following detection
: patient isolation, patient disinfection/bathing, cohort nursing, separate and dedicated care team and equipment, room disinfection following discharge
following outbreak detection
: specifically tailored outbreak
example: KPC in Israel
uk 5 year action plan for amr 2019-2024
ultimately designed to ensure progress towards 20y vision on AMR - resistance is effectively contained and controlled
focuses on three key ways of tackling AMR
reducing need for, and unintentional exposure to, antimicrobials
optimising use of antimicrobials
investing in innovation, supply and access
limiting and reversing impacts of amr
taking it seriously - policy
money makes the world go round - use the numbers we now have
economic impact and mortality
worldwide collaborative effort
holistic view - one health
surveillance
development of novel antimicrobials and diagnostics using different funding models
support and make funding available for antibiotic stewardship
personal responsibility
future strategies to combat antibiotic resistance
better diagnostics leading to more rapid identificiation of pathogen resistance profile
development of molecules which prolong existing antibiotics
beta lactamase inhibitiors
efflux pump inhibitors
development of alternative therapies such as phage therapy
development of antibiotics to bypass existing problems eg. pro drugs
better hygiene, use of disinfectants etc.
development of novel antibiotics, preferably a completely different class
antimicrobials
act on all microbes
antimicrobial resistance = a microorganisms ability to resist the action of one or more antimicrobial agents
AMR = a microorganisms is resistant to an antimicrobial that it is normally susceptible to
