Lecture 22 - Antimicrobial Resistance (Global Challenges) Flashcards
What are the main causes of resistance?
poor compliance
inadequate treatment and diagnosis
poor health care infrastructure
lack of education and knowledge
global location causes severe logistical issues
How many deaths annually does tuberculosis cause?
1.5 million
> 40 million deaths in the next 20 years
How is tuberculosis spread?
from inhaling droplets from a cough or sneeze by an infected person
What is there a strong epidemiological co-existance between?
HIV and TB as patients who are immunocompromised easily catch TB
What is the structure of the TB cell wall?
very complicated
have long fatty acids called mycolic acids
What is very unique with TB?
persistance - after you become ill with TB bacteria can lie dormant in the body
you can be infected with TB but never full develop the disease
Why is treatment of TB difficult?
the disease causes many complex systems
mycobacterium tuberculosis has a very complex cell wall
reactivation of dormant or persistent bacteria
Bacterial persistence of TB?
after treatment a small % may remain in a dormant state in macrophage
these can become reactivated many years later
patients can show no symptoms - carriers
What is the % of risk of reactivation to secondary TB?
2-23% lifetime risk
What is risk of reactivation increased by?
10% if immunosuppressed
What are the 2 phases of treatment?
initial phase and the continuation phase
What is the initial phase of TB treatment?
4 drugs given together daily
isoniazid
rifampicin
pryazanimide
ethambutol
(first 3 as rifater)
How long is the initial phase?
2 months
can be extended until sensitivity testing is complete
What is the initial phase for?
to reduce the bacterial population as rapidly as possible
prevents resistance
What is pyrazinamide used for?
helps to reduce the chance of reactivation
PZA is only active during the initial phase
Why is PZA only active during the initial phase?
due to host immune response lowering pH in macrophages
What is the continuation phase of TB treatment?
rifampicin and isoniazide used together as Rifinah
How long is the continuation phase?
4 months
What does the continuation phase do?
helps destroy remaining bacteria left from initial phase
When is the treatment of TB extended?
for meningitis or resistant TB
What is directly observed treatment?
necessary for patients who cannot comply with their regime
ensures the best chance of fighting the infection
What needs to be changed in DOT?
regime and doses
How often is supervision given in DOT?
3 times per week
Why is treatment of TB so critical?
because of the complex nature of TB all drugs need to be taken and the treatment must be completed
How is the treatment of TB designed?
it is old and designed due to the complex pathology of the mycobacteria
What are bacteriostatic drugs?
inhibit growing bacteria
What are bactericidal drugs?
kill bacteria outright
What is the distinction of drugs relative to?
the environment
When is PZA bactericidal?
against TB at low pH but bacteriostatic against growing bacteria
What do the first line TB drugs have?
superior efficacy with acceptable toxicity
What do second line TB drugs have?
less efficacy and/or worse side effects
What is isoniazide?
(1952)
isonicotinic acid hydrazide
How does isoniazide work?
targets the ketoenoyl-reductase enzyme InhA in cell wall mycolic acid biosynthesis
What is isoniazide activated to?
a binding complex with InhA
How does rifampicin work?
prevents protein synthesis binding to DNA-dependent RNA polymerase b-subunit
Spectrum of rifampicin?
broad spectrum bactericidal activity
What does rifampicin help sterilise?
persistors and active mycobacteria
What is pyrazinamide bactericidal against?
persisting slow growing mycobacteria
Mode of action of pyrazinamide?
unclear but it is a prodrug
What is pyrazinamide converted to?
the acid form pyrizinoic acid
What does pyrazinamide require?
low pH macrophage environment (intracellular)
How does resistance of TB occur?
rapidly when single drug is used so combination therapy is the standard
What is the mechanism of resistance?
via efflux or mutation at the target enzyme or the enzyme which activates the prodrug to the active form
MDR-TB?
INH and RIF with/out 2nd line drugs
XDR-TB?
INH, RIF at least one second line injectable aminoglycoside and any fluoroquinolone
What is XDR-TB?
extremely drug resistant TB
What do future TB drugs need to be?
more efficacious, reduce bacterial population faster, combat MDRTB and be less prone to inducing resistance
destroy persistant bacteria and prevent cross resistance
reduce duration of therapy and increase compliance, need to be cheap
suitable for infants
What to TB drugs need to be compatible with?
rifampicin
this increases the rate of metabolism of antiviral drugs
Estimated annual deaths of malaria?
1-2 million
Malaria infections annually?
500 million
What increases the pool of infection of malaria?
global warming and ease of international travel
What is the malaria vector?
female anopheles mosquito
What species transmit malaria?
plasmodium vivax, falciparum malariae, ovale
What are the most prevalent species of plasmodium?
vivax and flaciparum (95% of infection)
What do tissue schizontocides do?
inhibit the growth of the pre-erythrocytic stages of the parasite in the liver
sometimes called casual prophylactics
Examples of tissue schizontocides?
sulfafioxine, pyrimethamine, dapsone, proguanil
Type I tissue schizontocides?
anti-folates
inhibits dihydrofolate production
sulfadioxine
dapsone
Type II tissue schizontodices?
anti-folates
inhibit dihydrofolate reductase
pyrimethamine
proguanil
What are hypnozoitocides?
only used to eradicate the dormant liver stage of vivax infections
disrupts the REDOX process in the pentose-phosphate pathway
Example of a hyponozoitocide?
primaquine (UK)
What are blood schizontocides?
act rapidly and only on the erythrocytic stage of the infection
some used prophylactically but mainly for treating established malarial infection
What do blood schizontocides prevent?
hemozoin formation leading to cell death by binding to heme in the parasite
Examples of blood schizontocides?
chloroquine
quinine
How have new antimalarials been found?
through nature or by making analogues of natural products
What are examples of new antimalarials?
mefloquine
artemisinin
What is malarial resistance caused by?
mutation as active site or pro-drug activation in the chromosome
preventing cellular uptake of the drug
What is resistance of malaria mainly due to?
plasmodium falciparum
What varies with destination?
chemoprophylaxis guidelines and the treatment of infection due to resistance
