FInal Flashcards
Principles of Treatment
Early diagnosing & complete treatment, rational use of antimalarial agents, combo therapy & weight based dosing
early diagnosis & complete treatment
○ All patients should have a parasitological diagnosis: Light microscopy or RDTs
Uncomplicated can progress to severe if untreated
Rational use of antimalarial agents
○ Limit unnecessary use
○ Identify other febrile illnesses better
Only those with malaria should get the medicine
Combo therapy
○ Treat with at least 2 effective meds with different MOA = much harder to mutate for both
○ Helps prevent & delay resistance
○ Choose ACT should be based on efficiency and adherence in that region
§ Fixed doses of combo ACT is preferred
§ Solid formulation > liquid
§ Fixed dose combos of all recommended ACT are available except artesunate + SP
Pediatric formulas are not available
Weight based dosing
- Weight based dosing
○ Maximize rapid clinical and parasitological cure
○ Treatment should minimize transmission (and hypnozoites)
○ Need sufficient concentrations to eliminate the infection
Clinical cure = symptoms go away
Clinical cure vs parasitological cure
symptoms go away; parasite is gone
Drug groups
- treat acute attack
- effect radical cure (cure + prevent relapse)
- chemoprophylaxis (kills sporozoites)
Chloroquine
works well against vivax; causes buildup of heme; was developed after quinine and last longer in blood. This caused quinine prices to drop but resistance has developed
Primaquine
Treats hepatic stages of all malaria (prevents recrudesence); hypnozoites of vivax/ovale (prevents relapse) - x14 days
Is the radical cure for vivax
Adverse effects of primaquine
GI, hemolysis with G6PD deficiency; can give low dose to avoid this
Artusenate & derivatives
ACT Therapy; uncomplicated malaria with SP; can cause delayed hemolysis
Artemesenin compound potential danger for:
reinfection as they clear from the blood rapidly and co-drug helps the rest. But window of time where artemesinin is gone and only have co-drug, reinfection means parasite will persist with co-drug = resistance developing
Primaquine MOA
Primaquine
• Inhibits ETC in plasmodium
• Active against hepatic stages of all malaria
• Active against hypnozoite stages of vivax/ovale
• Use for presumptive anti-relapse, prophylaxis for short duration travel & radical cure of vivax/ovale
Adverse effects: GI disturbances, methemoglobinemia, hemolysis in those with G6PD deficiency
G6PD Deficiency
G6PD deficiency: sex linked disorder with some protection to falciparum & vivax but susceptibility to oxidant hemolysis; rarely causes this issue without primaquine so most people don’t know they have it. Screening is not really available. Hemolysis will stop once the drug is stopped
Parenteral
administered anywhere besides oral
How do you treat uncomplicated falciparum?
ACT x 3 days; primiquine to decrease transmission
Artemether + L; Artesunate + A; Artesunate + M; Artesunate + SP; D+P
Risk groups: pregnant, obese, co-infection, non immune travel, uncomplicated hyperparasitemia
Avoid monotherapy; dose by weight; treat symptoms
How do you treat uncomplicated non falciparum?
Primiquine; low dose for those with G6PD deficiency
Not for pregnant women, infants <6 months
Radical cure for vivax/ovale; hemolysis will stop when drug is stopped
How do you treat severe malaria?
IV or IM artesunate for 24 hours; 3 days oral ACT; single primiquine
Parasite count; hematocrit; BGL
1st: prevent death
2nd: prevent disability & recrudescence
How do you treat severe malaria in pregnant women?
Parenteral artusenate full doses; artemether IM if unavailable; Parenteral quinine if unavailable
Those in 2nd or 3rd trimester are more likely to get severe malaria; 50% mortality with treatment
Severe malaria can present after delivery
How do you treat mixed infections?
ACT
Vivax is the most common complication of falciparum
Detect via PCR or microscopy and some RDT
Falsified medication
Little to no active ingredient Sometimes harmful substance Intended to deceive Hard to distinguish Encourage resistance
Substandard medication
Incorrect amounts or stored incorrectly; artemisinin & derivatives have built in instability & are sensitive to heat; humidity and heat problems; sold past expiry date
How do you treat coma?
Maintain airway; R recovery side; exclude other causes; avoid harmful treatments; intubate if necessary
How do you treat hyperprexia?
Treat if fever > 38.5 with antipyretics; no NSAIDs; fanning; cooling blanket; ice packs
How do you treat convulsions?
Maintain airway; admin benzos; check BGL; >2/day is severe malaria
How do you treat hypoglycemia?
Check BGL; correct hypoglycemia; maintain with glucose infusion
How do you treat severe anemia?
Transfuse (<5 = high setting; <7 = low setting)
How do you treat acute pulmonary edema?
ARDS = prop to 45 angle; give O2 & diuretic; hypoxemia = stop IV; intubate; + pressure
How do you treat acute kidney injury?
Exclude causes; check fluids; hemofiltration, hemodialysis & peritoneal dialysis
How do you treat bleeding/coagulopathy?
Transfuse; vitamin K inj
How do you treat metabolic acidosis?
Exclude/treat hypoglycemia, hypovolemia or septicemia; add hemofiltration or hemodialysis; body INC lactic acid due to DEC Hb
How do you treat shock?
Suspect septicemia; blood culture; parenteral broad abx; correct hemodynamic disturbances
How do you treat vomiting?
Parenteral antimalarial treatment until oral is tolerated; then 3 day ACT; antiemetics are sedative and can confound severe malaria
List the special risk groups who may need chemo prevention
pregnant women, infants, seasonal children, non immune travelers
Describe IPTP
In endemic areas give IPT + SP in 1st or 2nd pregnancy; dose 1 month apart
Describe IPTI
<12 months in moderate-high transmission, give IPT + SP at 2nd/3rd DTP/MMR
Describe Seasonal chemo treatment
SMC + monthly amodiaquine + SP for children <6 months each season
Describe non immune traveler treatment
Start chemoprophylaxis before entering endemic area
How does chemoprevention work?
prevent malarial illness by maintaining therapeutic levels throughout the period of greatest risk
What are the 3 types of chemoprevention?
Causal prophylaxis: inhibit liver stage development (pre-erythrocytic); stop after leaving endemic area
Suppressive prophylaxis: kill asexual blood stages; taken at least 4 weeks after leaving the area
Disruptive prophylaxis: experimental; monoclonal antibodies disrupt malaria binding to host
What does the Mululaza plant do?
African shrub that reduces the level of parasites; chimpanzees chew on leaves when not feeling well
What does clove/nutmeg/basil/onion do?
reduce body’s repair of free radicals (which normally allow infected cells to be exposed longer)
What does the cinchona tree produce?
Adean (from the Andes) tree bark; Jesuit’s Bark; secondary compound is quinine which interferes with Hb digestion & parasite is poisoned by toxic residue; can’t prevent but can treat
Cinchona is difficult to cultivate; doesn’t produce quinine for 5 years and cant harvest bark for 15 years
Describe British India’s issues
Segregation like in Africa; built dams across riverways making miles of irrigation canals; irrigation canals disrupted drainage = rain bogs; 2x more swollen spleens than in non-irrigated villages
What happened in the US Mississippi River valley?
Malaria from African slaves spread into the boggy swamp areas between the Appalachian and Rockies making a great mosquito habitat; 80% settlers in Pike County IL die and many Norwegian settlers; destroyed effort to build a canal between the great lakes & Mississippi river.
What happened during the Coosa river dam project?
○ In Alabama; damned the Coosa river increasing the 25 cases from the year before to 600 hundred; schools close down & county officials beg for funding to enact Gorgas’ methods; many damns in the south were created for hydropower industry but the local power company denied any connection between the dam and malaria; residents file 700 lawsuits
○ Gorgas was a witness for the power company and said many people agreed they cant fly more than 200 meters from birthplace; says the mosquitoes came from the locals’ land even though the quadrimaculotus species specializes in clear water not dirty puddles
Lawsuits were thrown out and they had the greatest outbreak in the history of Alabama
Why did malaria vanish from the US?
○ Railroads were built = people can move away from rivers
○ Farmers reclaim wetlands by burying tiles & pumping water out
○ Agriculture adjustment act mechanizes southern farms
○ Black sharecroppers relocate to cities = less reservoirs for mosquitoes
○ Government antimalarial regulations for future dams
Better housing and roads = DEC mosquito habitat and INC protection
Why did malaria vanish from Britain?
4 crop rotation system from Holland
More plentiful cow & hog flesh diverted anopheles; local maculopennis preferred calves
What’s the story on quinine?
Comes from the cinchona tree & is used to treat malaria. It is the earliest medication for malaria but it does have side effects: cinchonism - tinnitus/deafness, headache, nausea, bleeding, renal failure. Is known as Blackwater fever because it caused diarrhea, vomiting, black urine and death
What’s the story on quinicrine
persists in blood for a week; not as effective as quinine against vivax; causes jaundice and psychotic reactions; soldiers hated it
○ Soldiers started to get sick and it was thought that they weren’t taking it correctly; many infected with malaria
Resistance spreads thanks to heavy use
What’s the story on chloroquine?
lasts longer in blood, lower side effects, more effective, easy to make; widely available and encouraged to take as soon as fever comes = INC drug pressure on malaria
○ Quinine prices drop when chloroquine hit the market and interest in quinine decreases
Resistance developed as well in SEA; resistant falciparum developed the ability to live better than non resistant malaria in 2 mosquitoes = becomes the dominant strain
What’s the story on artemisinin compounds?
○ Created after everything above; artemisia is one of the first plants tested; boiled in tea (incorrectly) then learned to prepare with lukewarm tea and chinese kept it a secret. Caseload drops from 2 million to 90k
○ Novartis launched an artemisinin derivative (artemether + lumefantrine called Riamet)
Still took years to get support for this drug and by the time it was supported, resistance had already developed due to unethical and criminal sales & recommending insufficient doses
How could bacteria be used against malaria?
B. thuringiensis israelensis designed to only infect mosquito larvae; more environmentally friendly than fish
How can a fungus be used against malaria?
entomopathogenic fungi that will invade and multiply inside the mosquito and kill it like beauveria bassiana and metarhizium anisopliae on gambiae
Red flag indicators:
Rain, sunshine, humidity levels can all predict times when malaria is going to peak or drop
Can keep track of the rise or drop of malaria cases if we monitor these factors
Examples of diffuse solutions
Improving economy + poverty Roads Electricity Safe water Strengthen healthcare systems Education/awareness Avoid mosquito habitats
Examples of focused solutions
Vaccines
New Meds
Spraying/vector control
Genetic modification
Anti-parasitic immunity:
antibody response & cell mediated response.
Targets parasite to try to prevent the infection
Anti-toxic immunity
suppresses toxic response and reduces symptoms.
Doesn’t reduce parasite load, just makes you feel less sick
What type of targets could a vaccine have?
- Parasite stage: direct anti sporozoite
- Hepatozoite: direct anti hepatozoite
- Asexual erythrocytic: anti host erythrocyte, antibodies blocking invasion, anti receptor ligand
- Gametocytes: anti gametocyte, anti host erythrocyte, antibodies blocking fertilization, antibodies blocking egress (leaving) from mosquito gut
Must target the sporozoite if you want to prevent infection
What are some challenges to vaccines?
Malaria can easily mutate Protozoa are more complicated than bacteria = complex vaccine High cost to develop Multiple doses needed Different vaccine for different strain Partial immunity for short duration Side effects
DDT :
use started in WWII; it was long lasting, odorless, did not dissolve, did not seem to affect people, easy to make, easy to spray; DDT war on insects propaganda. Rockefeller Foundation
Resistance accumulated & several side effects from over-using
Insect treated nets ITN
extremely effective when used correctly; long lasting ITN or LLITNs; SSA population still doesn’t have complete access and 20% of anyone with ITNs don’t use them correctly; complaints of itching and headaches from the insecticide; unable to afford them; used for fishing (bad for fish ecology); used to create privacy; embarrassed to show poverty and bringing a torn net in for a new one; difficulty hanging the net; too hot to sleep under; some people believe other things cause malaria too; no protection for daytime feeding; resistance to insecticide
Indoor residual spraying IRS
works well but has to be maintained and continuously sprayed; health considerations and potential for resistance
Chemoprevention
intermittent preventive treatment in pregnancy IPTp has increased; half of eligible pregnant women are taking 1 dose, less are taking 2 and much less are taking 3 or more. IN children, it has been limited due to concerns about what age is ok; some countries do seasonal malaria chemoprevention SMC like Niger, Mali, Guinea
Better treatment
some increase in Children Under 5 with falciparum treated with an ACT
Diffuse solutions:
improving poverty & economy, leveling roads, providing electricity, safe water, strengthen healthcare systems, increase awareness and education, minimize and avoid mosquito habitats
Mosquito life cycle
Eggs hatch in water and transition into larvae
4 aquatic larval stages
Aquatic pupae stage
Adult (imago) emerges
Mosquito mating cycle
- Mated adult females hibernate in sheltered sites
- Females become active in late spring/early summer and take a blood meal
- Females lay eggs in standing water; eggs hatch within 2-3 days
- Adults appear 7-10 days later; adults mate; female takes blood meal
- Females lay eggs on standing water; eggs hatch within 2-3 days
a. Last generation of adults appear in fall; adults mate; males die and females enter hibernation
b. Steps 4 and 5 can be repeated = amplification stage
What do mosquitoes feed on?
nectar and other sugar sources; females need protein from blood to develop their eggs
What do mosquitoes use to home in on prey
Olfactory cues: sensors on antennae to search for CO2 (which rises in plumes because it is warm); sensed from hundreds of feet away
Visual cues: two types of eyes
Large compound eyes for motion detecting
2 photosensitive simple eyes (ocelli) to home in on light and bright colors (which can be used to trap mosquitoes with colorful contrasts)
Thermal cues: sensors on antennae and mouth helps fish for veins; detect heat from warm blooded bodies
What is the first thing mosquitoes do when they take a blood meal?
Injects saliva that numbs area and keeps blood from clotting, then sucks blood
2 mosquito eye types
Large compound eyes for motion detecting
2 photosensitive simple eyes (ocelli) to home in on light and bright colors (which can be used to trap mosquitoes with colorful contrasts)
What does mosquito saliva do
Negatively affects:
- Vascular constriction: makes vessels dilate
- Blood clotting: blood flows more easily
- Platelet aggregation: no clotting
- Angiogenesis and immunity: reduces local immunity
- Stimulates inflammation
- contains enzyme to breakdown sugar and antimicrobial to reduce infection in their sugar meals
Open marsh water managment
connect the marsh to a pond or canal and give predators like fish access to larvae; reduces other control methods
Rotational impoundment management
pump water into marsh in late spring and summer to prevent laying eggs on damp soil; marsh is allowed to drain in the fall, winter and early spring; gates in the culverts permit fish, crustaceans and other marsh organisms to enter and exit, and feed on whatever is left
Removal of breeding habitats
Dredging (wash the larvae away), larvivorous fish
Insecticidal use types
larvacide and adulticide
larvacide
- contact posion means bug has to come into contact in high enough concentrations to kill; ex: organophosphates like Raid; some resistance
- insect growth regulators like methoprene which is more targeted and persists longer
- Surface films: larvae will get in more contact with it
- Stomach poisons: bacterial agents
- Biological agents: fungi, nematodes, fish
- Treat mud several meters from puddles
adulticid
- Paris Green (copper acetoarsenite) and petroleum byproducts; discontinued because of high toxicity and pollution
- Treated bed nets
- Indoor residual spraying IRS
predators for mosquito control
gambusia affinis but they have negative impact on fauna; dragonfly adults eat mosquitoes and larvae; some lizards and geckos; predator mosquito toxorhynchites; predator crustaceans
releasing insects with lethal genes
GM to express a repressible lethal gene; offspring with that gene do not survive to adult stage because they are missing the dietary additive in the wild
Sterile insect technique
sterile males compete with native population and unable to produce viable offspring; eradicate native population
○ Challenges: loss of male fitness after sterilization = less attractive to males
Transgenesis
make them refractory to plasmodium infection; self limiting
Need effective germline transformation system
Need suitable promoters
Need effector genes that impair parasite development or act as parasiticidal agents
Paratransgenesis
introduce modified symbiotic bacteria to deliver anti pathogenic gene products and reduce vector competence; not self limiting
Need to choose symbiont related to vector and malaria
Needs to be easily cultivable and amendable
Needs uncompromised fitness of symbiont
Needs suitable method for reintroduction like feeding in nectar
Needs spread of symbiont in vector population
behavioral modification
eliminate part of their sense of smell; develop new repellants; photosensory
monitor mosquito population
track adult mosquito (landing rates, mechanical traps) or larvae (traps or in situ counting)
human factors
herd immunity; migration; parasite reservoir
drug factors
half life; dosing; pharmacokinetics; cross resistance; drug pressure
Parasite factors
fitness, GM; transmission level; cross mating; recombination; migration
vector/environment factors
clonal multiplicity; vector affinity of parasites
Challenges on data collection
- 36.5% of statistics are made up
- Politicization of results: highlighting successes and not failures
- Lack of staff, hardware & software
- Indonesia: 2 encounters are counted as 2 or more cases
- Cases not presenting to clinic are not counted
- Most of malaria reporting is done on clinical diagnosis not lab
○ 80% false + in Angola and 90% false + in Sudan
PMI & WHO use diagnoses from deaths from fevers as they can “retroactively diagnoses malaria with household questionnaires”
challenges/limitations overall
○ Seasonal variations =red flag indicators could help overcome complexity of environment
○ Politicization of results = Oliver Sabot using map of countries that ever had malaria shaded and showing its regression through time (no regional distinctions and historically inaccurate)
○ Lack of software and hardware =expensive and can’t train/retain personnel
○ Paper records and poor collection records
○ Decision makers misunderstand data application-> they distort data to fit their needs and agenda
○ Measurement bias
What is drug resistance
ability of parasite strain to survive/multiply despite administration and absorption of a drug in doses equal to or higher than what’s recommended
What are the factors in generating drug resistance?
Drug must gain access to the parasite or infected RBC for the duration of time necessary for its normal action (bowel movement before it’s able to work does not mean resistance)
Must demonstrate parasitemia in patient who has received an observed dose or antimalarial drug
Must demonstrate that adequate blood concentrations occurred (analyze that blood has therapeutic levels of the medicine)
Can cause treatment failure but not all treatment failure is from resistance
Incorrect dosing, non compliance, drug interactions, poor absorption, misdiagnosis
What is the most important factor in drug resistance
overall drug pressure
Detecting resistance in vivo
treatment of group of symptomatic and parasitemic individuals with known drug doses & monitoring or parasitological/clinical response
○ Sequester patients 7-14 days after treatment to avoid reinfections
Advantage: gives best info on efficacy (does this treatment work); clinical response emphasis; can detect hematological recover after illness
Disadvantage: not standardized techniques = hard to compare studies; diminished drug therapeutic efficacy can be masked by high acquired immunity; other external factors
Detecting resistance in lab
fingerprick blood exposed to known quantities of drug and observe under microscopy for inhibition of maturation into schizonts
Advantage: more control on external variables like acquired immunity; multiple tests can be done
Disadvantage: correlation of clinical response is not clear; prodrugs like proguanil that require host conversion to active metabolite cannot be tested; non-falciparum strains cannot be evaluated in vitro; more expensive
Detecting resistance in animal models
in vivo in a non human
Advantage: similar to in vivo; no host immunity
Disadvantage: similar to in vivo; parasites that can survive non humans can only be tested
Detecting resistance in molecular techniques
PCR to indicate presence of mutations encoding resistance to antimalarial drugs
Advantage: frequency of mutation occurrence from patients could indicate frequency of resistance in population; only need small amounts of genetic material, not live parasites; independent from host and environmental factors
Disadvantage: expensive; expertise needed; known gene mutations for resistance are limited; confirmation of association between mutation & resistance is difficult (may involve multiple genes)
Detecting resistance in case reports & passive detection
use reports of treatment failure
Advantage: low investment time and money; ongoing basis; good red flag source
Disadvantage: rates of resistance cannot be calculated
Passive detection: treated patients are told to come back if symptoms return or persist and only those who return are considered treatment failures = biased results
Preventing resistance
Reduce overall drug pressure, improve how we use drugs, combination therapy
Reducing overall drug pressure
Most important factor in drug resistance; reduce how many bugs are exposed to the drug
Better diagnoses, encourage restrictive drug use, promote better prescribing practices, prophylaxis programs only where compliance is high, the drug is effective & in high risk regions
Founder effect: characteristics of a small founding population can greatly determine the rest
Improving how we use drugs
DOT directly observed therapy
Single dose regimens (SP, mefloquine)
- Weight benefits and risks of single dose DOT against the costs (have long half lives = take longer for body to clear an adverse reaction)
Close follow up and prompt retreatment PRN
Reliable microscopy in detecting low levels
Combination therapy
Combine malaria drug with artemisinin derivative
Artemesinin compounds reduce parasite levels & likelihood that gametocytes with resistant genes will pass on
Could possibly be combined with vaccines designed to inhibit transmission in the future
Promotes mismatched half lives between these combination of drugs = can be re-infected while sub therapeutic drug levels are still present
- Take combo pill on day 1 = equal amounts of drug 1 and drug 2
- Day 2 = 2 high drug 1 amounts and lower drug 2 amounts
- Day 3 = 3 high drug 1 and very low drug 2
Resistance 0 1 2 3
1st graph: successful treatment
RI: delayed recrudescence; same initial response as the first but there were a few bugs left that were more resistant and immune system was not able to mop them up
Level 2 resistance AKA early recrudescence: parasite levels (two types of graphs)
Level 3: virtually no response with drug
EC: artemisinin compound discovery
Project 523= China found it from one of the 10 plants but kept it a secret
Was initially incorrectly extracted
WHO only approved it for use when US started producing it (Novartis)
EC: quinine escaped africa
Peru banned export of cinchona seeds (the only way to get it was Andes cinchona bark until late 19th century)
Manuel Incra spent 5 yrs gathering seeds, British trader Charles Ledger smuggled them out of the country “ledgeria”
Cinchona was very difficult to cultivate and the Dutch spent 30 yrs w/Kina bureau trying to make it widely available
