Global Health and TB

what is morbidity rate

diseased state, disability, or poor health due to any cause - incidence, prevalence, cumulative incidence of risk of developing a new medical condition

what is mortality rate

number of deaths in a particular population, scaled to the size of that population, per unit time

what Disability Adjusted Life Year (DALY)

measure of the time lived with disability and the time lost due to premature mortality

Quality Adjusted Life Years (QALY)

combines expected survival with expected quality of life into a single number - measure of the value that individuals place on expected years of survival

which infections are the “big four”

HIV, hepatitis C, malaria, and tuberculosis

examples of high threat pathogens

Ebola, several other hemorrhagic fevers, Zika, Nipah, middle east respiratory syndrome, coronavirus, and severe acute respiratory syndrome (SARS)

what is malaria

mosquito-borne parasite that infects the red blood cells of humans caused by four plasmodium parasites

which plasmodium parasites cause malaria

P. falciparum, P. vivax, P. ovale, and P. malariae

symptoms of malaria

flu-like symptoms, fever, chills, sweats, headaches, N/V, body aches, and malaise

severe cases of malaria can cause deadly complications such as:

organ failure, hemoglobinuria (hemoglobin in urine), acute respiratory distress syndrome, hyperparasitemia (more than 5% of red blood cells are infected)

treatment for children and adults with uncomplicated P. falciparum (except for pregnant women in first trimester)

artemether + lumefantrine

artesunate + amodiaquine

artesunate + mefloquine

dihydroartemisinin + piperaquine

artesunate + sulfadoxine-pyrimethamine (SP)

treatment duration for children and adults with uncomplicated P. falciparum (except for pregnant women in first trimester)

3 days

how is artemether in combo with lumefantrine administered

IM, PO

which version of artemisinin is more lipohylic

artemether in combo with lumefantrine

substrate of artemether in combo with lumefantrine

CYP3A4

how is artesunate available

IV, PO

ADRs of artesunate

hypersensitivity (1 in 3000), mild GI, rare QT, rare hepatotoxicity

T/F: caution use of artesunate in patients with renal or hepatic failure

true

family of ebola virus

Filoviridae

genus of ebola virus

Ebolavirus

what is one of the most pathogenic viruses known to science

Ebola

how is ebola transmitted

infected body fluids, through damaged skin, mucosa (eyes, nose, mouth), and parenterally through contact with blood, stool, saliva, sweat, urine, vomit, breast milk, tears, semen

clinical features of the early febrile phase of ebola (0-3 days from symptom onset)

fever, malaise, fatigue, body aches

clinical features of the GI phase of ebola (3-10 days from symptom onset)

primary: epigastric pain, nausea, vomiting, diarrhea

Associated: persistent fever, asthenia, HA, conjunctival injection, chest pain, abdominal pain, arthralgia, myalgia, hiccups, delirium

clinical features of shock or recovery phase of ebola (7-12 days from symptom onset)

shock: diminished consciousness or coma, rapid thready pulse, oliguria, anuria, tachypnea

recovery: resolution of GI symptoms, increased oral intake, increased energy

clinical features of the late complication phase of ebola (>/= 10 days from symptom onset)

GI hemorrhage, secondary infections, meningo-encephalitis, persistent neurocognitive abnormalities

T/F: there is possible transmission after clinical recovery of ebola through sexual contact (semen)

true

what is the M. tuberculosis complex

includes the tubercle bacillus (M. tuberculosis), M. bovis, M.africanum, M. microti, M. canetti, M. caprae, M.pinnipedii, and M.orygis

what is the major constituent of the cell envelope in M. tuberulosis

mycolic acid, a beta-hydroxy fatty acid (this structure defines the genus)

which infection has a slow growth rate?

M. tuberculosis complex ~20-24 hours

how is tuberculosis transmitted?

person-to-person, inhalation of droplet nuclei (airborne particles 1 to 5 microns in diameter)

what procedures result in droplet nuclei associated risk for transmission of TB

endotracheal intubation, bronchoscopy, sputum induction, chest physical therapy, administration of aerosolized drugs, irrigation of TB abscess, autopsy

risk factors in America for TB

substance abuse, nutritional status (underweight, vitamin D, iron status), systemic diseases, immunocompromised, household contacts, birth in TB-endemic area, community settings (homelessness, crowding), socioeconomic status, minority groups, increasing age, male gender

TB pathogen characteristics

acid-fast bacilli, may stain blue or not at all with traditional methods, unique cell wall, and slow-growing

what does MTB do in the body?

blocks fusion of lysosome and phagosome which prevents bacterial hydrolysis

T/F: onset of active TB can occur many years following a period of latent infection

true

screening for TB

PPD/TST for latent disease, Interferon-gamma release assay (IGRA)

what does a PPD/TST test of < 5 mm indicate?

AIDS patient with known close contact to active TB patient

what does a PPD/TST test of > 5 mm indicate?

positive in HIV+ patients, close contact of active contagious disease, abnormal chest radiograph, immunosuppressed patients (chemo, transplant, steroids, TNF-a inhibitors)

what does a PPD/TST test of > 10 mm indicate?

clinical conditions that risk reactivation (diabetes, dialysis, malignancies, IVDU, etc.), children less than 4, foreign born from country with high prevalence, residents/employees in high risk settings

what does a PPD/TST test of > 15 mm indicate?

healthy individuals four or older with low likelihood of TB

CDC recommended screening for children < 5 years old

IGRA is acceptable but TST is preferred

CDC recommended screening for TB if difficulty testing or BCG

IGRA preferred, but TST is acceptable

when can there be false negatives for TB

immunosuppression, evidence of natural waning of immunity, anergy testing with mumps or candida not recommended, measles suppressed tuberculin activity (postpone TST 4-6 weeks after MMR)

when can there be false positives for TB

non--tuberculous mycobacteria, BCG vaccination (childhood BCG vaccination is not a major cause of positive results in adulthood, prior BCG vaccination may be associated with boosting), TST reactivity caused by BCG sensitization can be distinguished from latent TB infection by IGRA

treatment for latent TB disease

isoniazid 300 mg PO daily x 9 months (900 mg PO BIW with DOT 9 months)

what needs to be supplemented in patients taking isoniazid for TB

pyridoxine

alternative latent TB treatments

rifampin 600 mg PO QD x 4 months (NYSDOH preferred regimen)

isoniazid 300 mg PO daily for three months + rifampin 600 mg PO daily for three months.

if patient has been exposed to a resistant TB virus, what should the treatment be?

one or two drugs that the patient is not resistant too: FQ + ethambutol x 12 months

clinical presentation of TB

usually asymptomatic - acute progresses to pulmonary (90% become latent)

symptoms of TB

anorexia, fatigue, weight loss, chills, fever, night sweats, productive cough (hemoptysis in advanced disease), CXR may show patchy or nodular infiltrates

diagnosis of TB

positive CXR findings lend strong suspicion, positive sputum smear (5,000-10,000 organisms/mL), MTB PCR determines species of isolated mycobacterium

how long does it take to get sputum smear results back for TB?

1-3 days

how long does it take for sputum cultures results to be back for TB?

1-3 weeks

what is the treatment duration for TB

intensive phase (two months) followed by a continuation phase (four to seven months)

first line drugs for TB

rifampin (rifabutin), isoniazid, pyrazinamide, ethambutol

how should TB drugs be taken?

on an empty stomach if tolerated, doing with food is acceptable if GI upset, preferable to divide doses or change to second-line agents

T/F: daily dosing is preferred for TB agents

true - intermittent dosing works if used with directly observed therapy (DOT)

active MTB treatment regimen 1

Isoniazid, rifampin, pyroxinamide, ethambutol daily x 8 weeks

which drugs are typically used for continuous TB treatment

isoniazid and rifampin for 4 more months

when should continuous isoniazid/rifampin treatment be extended to 7 months if:

intensive phase didn’t include pyrazinamide, patient has both cavitary pulmonary TB and positive AFB culture after intensive phase (ONE OR THE OTHER)

when can continuous isoniazid/rifampin treatment for TB be shortened to 2 month if:

HIV negative patient with negative sputum cultures, radiographic/symptomatic improvement, absence of alternative diagnosis (ALL REQUIRED)

what drugs can have increased serum concentrations if taken with isoniazid

phenytoin and theophylline

risks of isoniazid?

hepatitis and peripheral neuropathy (highest risk in poor nutritional status, alcoholism, diabetes, or uremia)

what supplement can reduce risk of isoniazid-induced peripheral neuropathy

25-50 mg daily to reduce risk

Interactions with isoniazid

food may decrease absorption and peak concentration, potent inhibitor of 2C19 and can inhibit 3A4, weak inhibitor of 2A6, 2C9, and 2D6, inhibits plasma MAO, avoid high histamine foods which may cause low blood pressure, avoid green tear with MAOIs

how long should dietary changes continue for after stoppng isoniazid

2 weeks

who is at risk for isoniazid induced neuropathy

pregnant women, breastfeeding infants, HIV infected patients, diabetes, alcoholics, malnourished patients, chronic renal failure, advanced age

if patients develop peripheral neuropathy from isoniazid what should be the pyridoxine dose

100 mg/day

signs and symptoms of hepatotoxicity

unexplained anorexia, N/V, dark urine, clay colored stool, icterus, rash, pruritus, persistent fatigue, weakness or fever lasting 3 or more days, abdominal discomfort, easy bruising or bleeding, arthralgias also can occur

MOA of rifampin

inhibits bacterial DNA-dependent RNA polymerase

when is rifampin useful

for treatment of intracellular pathogens

how can absorption be improved when taking rifampin

taking oral dose on an empty stomach

ADRs of rifampin

orang red discoloration of secretions, N/V/D, HA, fever, flu-like symptoms start 1-2 hours after and resolve 6-8 hours later, rash, itching, flushing, hepatitis is infrequent unless combined with other hepatotoxins

DDIs for rifampin

inducer of several enzymes and transporter systems (3A4, 2B6, 2C9, 2C19), weak inducer of 1A2, modest inducer of 2D6, inducer of P-gp

MOA of pyrazinamide

mechanism is unknown - considered bacteriostatic

which drug accelerates sterilizing effect of isoniazid and rifampin

pyrazinamide

ADRs of pyrazinamide

hepatotoxicity, hyperuricemia, N/V, dermatologic and hematologic more rare

how should pyrazinamide be taken in regards to food

can be taken with or without

DDI with pyrazinamide

drugs that alter uric acid levels (thiazides, diuretics, aspirin, NSAIDS), drugs that also cause hepatotoxicity

MOA of ethambutol

mechanism not well understood - bacteriostatic activity by virtue of inhibition of arabinosyl transferase (enzyme turns arabinose into arabinan and then arabinogalactan, a mycobacterial cell wall constituent)

ADRs of ethambutol

visual changes, hematologic, GI, HA, dizziness, confusion

T/F: ethambutol dose is not significantly altered by food, but is reduced by aluminum hydroxide

true

when are ADRs more likely with ethambutol

with increased length of use or increased doses

what test is recommended at baseline before using ethambutol

Snellen test

what are the second line antimycobacterial agents

levo, moxi, streptomycin, capreomycin, Amikacin/Kanamycin, P-Aminosalicylic acid, cycloserine, ethionamide

baseline lab monitoring:

SCr, visual acuity and color perception, hepatitis

routine monitoring:

liver function tests not recommended unless patient is experiencing symptoms, monthly visual acuity and color vision for patients receiving EMB at doses > 15-25 mg/kg or if continuing for > 2 months