Transcript Module4 - UMF IASI 2015

• Primary Tuberculosis
in Children
• TB treatment
1
PATHOGENESIS
• PORTAL OF ENTRY - most frequent: lungs (95%)
- possibly intestine or skin
• HYPERSENSITIVITY TO TUBERCULIN - 2-12 weeks
• PRIMARY COMPLEX
1- parenchimal focus (small round opacity,
3-10mm diam. subpleural in 70% cases);
2- regional lymphadenitis (hilar and paratracheal
lymphnode enlargement);
The primary focus often undergoes caseous necrosis
and encapsulation and heals by fibrosis and
calcification.
TB primary infection
Inhalation of infecting particles
containing 1 to 3 germs (AFB)
MTB multiplication
Evolution of primary infection
1. Progressive reduction of micobacterial
population results in:
– complete elimination of AFB
– persistence of dormant bacili
2. Resorbtion of inflamation areas, sometimes
preceded by caseous necrosis
3. Fibrosis and eventually calcification
RANKE COMPLEX
1. Inoculation
(primary) focus
2. Limfangitis
3
3. Adenopathies
(hilar or
paratracheal)
2
1
adenopathy
primary
complex
PRIMARY
FOCUS
ADENOPATHY
LYMPHANGITIS
RANCKE
TB PRIMARY
COMPLEX
- In 95% of cases, the appearance of cellmediated immunity controls TB primary
infection. The primary complex occurs and
undergoes fibrosis and calcification.
- There are situations of progressive primary
tuberculosis with the emergence of
complicated forms.
COMPLICATIONS OF
PRIMARY COMPLEX (1)
Occur in small age children ,
malnourished,
immunedepressed
- extension of caseous
necrosis and evolution of the
primary focus towards TB
pneumonia;
- the center of the primary
focus liquefies, caseum is
eliminated in a bronchus 
residual cavity
LYMPH NODE
COMPLICATED PRIMARY TB COMPLEX :
caseous pneumonia
COMPLICATIONS OF
PRIMARY COMPLEX (2)
- focus can rupture in pleura  TB pleural
effusion
- enlarged hilar/mediastinal lymph nodes can
compress a bronchus leading to collapse
(atelectasis) of a lung segment/lobe;
- caseum from a soft lymph node can brake
through the bronchial wall and can block a main
bronchus with caseous material  suffocation
 bronchoscopy.
COMPLICATED PRIMARY TB
COMPLEX : focal pneumonitis
COMPLICATIONS OF
PRIMARY COMPLEX (3)
- Via the bronchial tree, caseum (TB) can be
spread everywhere in the lungs.
- Lymph nodes in contact with the posterior part
of the pericardium may rupture 
TB pericarditis.
- Bacilli can escape in the bloodstream 
disseminate disease to liver, spleen, bones,
brain, kidneys, etc.
COMPLICATED TB PRIMARY COMPLEX :
periadenitis
LYMPH
NODE
COMPLICATED PRIMARY TB COMPLEX :
hematogenous dissemination = miliary TB
SCARS AFTER PRIMARY TB :
PARENCHIMAL AND REGIONAL LYMPH NODE CALCIFICATIONS
TB TRANSMISSION IN CHILDREN
- From contagious adults (family, school, etc.)
- Less often by underboiled milk contaminated
with M. bovis
- Very rare by cutaneous inoculation
Between 1990 and 2000:
→ 15 million new cases of TB in children
→ 5 million deaths – mortality > in 0-4 years
than the 5-15 years because of high frequency
disseminated TB in group 0-4 years
→ Children with primary TB are rarely contagious
TREATMENT OF LATENT TB
INFECTION (LTBI)
How to reduce the risk of
TB disease in infected persons
• Primary: isolation and treatment of
active pulmonary TB cases
• Treatment of latent TB infection (LTBI)
(prophylaxis)
• BCG vaccination
Chemoprophylaxis of TB
Used only in high risk groups
• Household members and other close
contacts of a patient with active TB.
• A positive skin test in persons less than 25
years.
• A positive skin test in the immunesuppressed,
persons with leukemia, and Hodgkin's
Disease
• HIV + patients with a positive TST test
Candidates for Treatment of LTBI (1)
Positive skin test result over 5 mm
•
HIV-positive persons
•
Recent contacts of a TB case
•
Persons with fibrotic changes on chest
radiograph consistent with old TB
•
Patients with organ transplants and other
immunesuppressed patients
Candidates for Treatment of LTBI (2)
Positive skin test result over 10 mm
•
Recent arrivals from high-prevalence
countries
•
Injection drug users
•
Residents and employees of high-risk
congregate settings
•
Mycobacteriology laboratory personnel
•
Persons with clinical conditions that make
them high-risk
•
Children < 4 years of age, or children and
adolescents exposed to adults in high-risk
categories
Treatment of LTBI with Isoniazid (INH)
ISONIAZID 5 mg/kg/day (max. 300 mg)
• 6-month regimen considered optimal
• 9 to 12 -months regimen in immune-
depressed
LTBI Treatment with Rifampin
• Rifampin (RMP) is recommended for people who:
– cannot tolerate INH
– have been exposed to INH-resistant TB
• RMP should be given daily for 4 months
• RMP should not be used with certain combinations
of anti-retroviral (ARV) therapy
• In some cases, rifabutin may be substituted when
RMP cannot be used
24
PREGNANCY AND BREAST-FEEDING
• INH daily
• Pyridoxine supplementation
• Breast-feeding not contraindicated
Monitoring Patients
Before treatment for LTBI is started,
clinicians should:
•
Rule out possibility of TB disease
•
Determine history of treatment for LTBI or
disease
•
Determine contraindications to treatment
•
Obtain information about current and
previous drug therapy
•
Recommend HIV testing if risk factors are
present
Monitoring Patients (2)
Establish rapport with patient and emphasize:
•
Benefits of treatment
•
Importance of adherence to treatment
•
Possible adverse side effects of medication
•
Establishment of optimal follow-up plan
Monitoring Patients (3)
Baseline laboratory testing
•
Not routinely indicated
•
Baseline hepatic measurements for:
- Patients whose initial evaluation suggests a
liver disorder
- Patients with HIV infection
- Pregnant women and those in immediate
postpartum period
- Patients with history of chronic liver disorder
Monitoring Patients (4)
At least monthly, evaluate for
•
Adherence to prescribed regimen
•
Signs and symptoms of active TB disease
•
Signs and symptoms of hepatitis
TREATMENT OF TB DISEASE
BASIC PRINCIPLES OF THE TB TREATMENT (1)
1. Provide safest, effective therapy in shortest time.
2. Directly observed therapy (DOT).
3. Use multiple drugs to which organisms are susceptible.
4. Never add a single drug to a failing regimen.
5. Ensure adherence to therapy.
6. Treatment regimens have 2 phases:
- Initial phase: 4 or 3 drugs daily; in areas where less
than 4% of cases are resistant to isoniazid, 3 drugs
(H, R and Z) may be adequate for the initial
regimen
- Continuation phase: 2 drugs, 3 days per week.
BASIC PRINCIPLES OF THE TB TREATMENT (2)
7. TB drugs are administered only once a-day, in the morning (before
breakfast).
8. Treatment side effects will be monitored.
9. Protection of rifampicin (rifampicine should not be used for the
treatment of other diseases, in order to avoid selection of resistant
germs).
10. All cases of tuberculosis will be registered.
11. TB treatment is free of charges.
12. In special situations treatment lasts longer than 6 months:
- 9 months, if pyrazinamide or rifampicine are not used;
- 12 months, in AIDS patients and in some extrapulmonary TB;
- 18-24 months, in multidrug-resistant TB.
Antituberculosis Drugs
First-Line Drugs
Second-Line Drugs
• Isoniazid
• Cycloserine
• Rifampin
• p-Aminosalicylic acid
• Pyrazinamide
• Ethambutol
• Ethionamide
• Streptomycin
• Amikacin or
kanamycin*
And recently
• Capreomycin
• Rifabutin*
• Levofloxacin*
• Rifapentine
• Moxifloxacin*
• Gatifloxacin*
Drug Abbreviations
Ethambutol
Isoniazid
Pyrazinamide
Rifampin
Rifapentine
Streptomycin
EMB (E)
INH (H)
PZM (Z)
RMP (R)
RPT
SM (S)
Common Adverse Reactions to
Drug Treatment (1)
Caused by
Any drug
Adverse Reaction
Signs and Symptoms
Allergy
Skin rash
Ethambutol
Eye damage
Isoniazid,
Hepatitis
Pyrazinamide,
or
Rifampin
Blurred or changed vision
Changed color vision
Abdominal pain
Abnormal liver function test
results
Fatigue
Lack of appetite
Nausea
Vomiting
Yellowish skin or eyes
Dark urine
Common Adverse Reactions to
Drug Treatment (2)
Caused by
Isoniazid
Adverse Reaction
Peripheral
neuropathy
Pyrazinamide Gastrointestinal
intolerance
Streptomycin
Signs and Symptoms
Tingling sensation in hands and
feet
Upset stomach, vomiting, lack
of appetite
Arthralgia
Joint aches
Arthritis
Ear damage
Gout (rare)
Balance problems
Hearing loss
Ringing in the ears
Kidney damage
Abnormal kidney function test
results
Common Adverse Reactions to
Drug Treatment (3)
Caused by
Rifamycins
Adverse Reaction
Signs and Symptoms
Thrombocytopenia Easy bruising
• Rifabutin
Slow blood clotting
• Rifapentine Gastrointestinal
intolerance
Upset stomach
• Rifampin
Drug interactions
Interferes with certain
medications, such as birth
control pills, birth control
implants, and methadone
treatment
ISONIAZID (INH; H)
• Considered the drug of choice for the chemotherapy of
TB. discovered in 1945 a hydrazide of isonicotinic acid
– bactericidal for growing bacilli.
• Primary action seems to inhibit the biosynthesis of
mycolic acids which are part of cell wall structure.
• Dose - daily: 10 mg/kg/day, max.600mg/day;
under 50 kg body weight: max.450mg/day
- 3 days/week: 10 mg/kg/day, max.600 mg/day
Pharmacokinetics
• Absorption: INH is rapidly absorbed either
oral or parenteral route. Peak [plasma] of 3-5
micrograms/milliliter after oral administration.
• Distribution:
– Diffuses readily into all bodily fluids; does
not bind to plasma proteins
– In the CSF the conc. is about 20% of
plasma,
– T 1/2 =1-3 hrs.
Resistance to INH
• Organism eventually develops resistance.
• The mechanism of resistance is related to the
failure of the drug to penetrate the bacterial
wall or be taken up by the micro-organism (by
active transport system),
• Remember treatment is up to 2 years.
Excretion (1)
• 75-95% of a dose excreted in urine in 24 hr.
- Mostly as a metabolite.
- The main excretory product – acetylisoniazid,
is a result of enzymatic acetylation
• Very important in terms of metabolism,
Isoniazid is under genetic control.
There are 2 groups of people: fast and slow
acetylators
Excretion (2)
• Those that have slow acetyl transferase activity
are slow acetylators and may produce more of the
toxic intermediate.
• This is an inherited trait ==> autosomal dominant
• Average t 1/2 is less than 90 minutes. In the slow
acetylators, t 1/2 will be about 3 hours.
• Ethnicity: Eskimo, Native American Indians, and
Asians are fast aceytlators.
Adverse Effects
• Induced hepatitis due to the buildup of toxic
metabolic products of acetylisoniazid -->
acetylhydrazine. This is more frequent in slow
acetylators.
• Hepatic reactions to Isoniazid are also age
dependent: 250x increase in the incidence of hepatitis
over age.
• Peripheral neuropathy – higher kisk in diabetes,
alcholism. Malnutrition. For prevention, co-administer
pyridoxine (Vit.B6)
Drug Interaction
• Competition between Isoniazid and Phenytoin
(anticonvulsant). They both compete for drug
metabolism enzymes.
• Phenytoin interferes with metabolism of
isoniazid by reduction in excretion or
enhancement of effect of isoniazid
RIFAMPIN (RMP; R)
• Bactericidal
• Mechanism of action
Rifampin inhibits DNA dependent RNA polymerase of
the bacilli.
• Dose - daily: 10 mg/kg/day, max. 600mg/day;
under 50 kg body weight: max. 450 mg/day
- 3 days/week: 10 mg/kg/day, max. 600 mg/day
Pharmacokinetics (1)
Absorption
• peak levels reached 2-4 hrs. after oral dose
• rapidly eliminated in the bile and reabsorbed
(enterohepatic circulation) It can be delayed
with use of aminosalicylic acid.
• the metabolites maintain full effect
• half life is 6 hours.
Pharmacokinetics (2)
Distribution:
• Throughout the total body water
• Present in effective concentrations in many
organs and body fluids including CSF,
• With Rifampin you must warn patients: the
drug has an orange red color in body
excretions; this color will be imparted to all
body fluids.
Adverse Effects (1)
• Gastro-intestinal reactions:
- anorexia, nausea ,vomiting, mild
abdominal pain,
- hepatic reactions in children,
pregnant women and alcoholics, can
result in minor elevations in serum
transaminase
- jaundice is a serious adverse effect
and needs stopping treatment
Adverse Effects (2)
•
•
•
•
Allergic reactions: rash, pruritus
Fever (flu-like syndrome)
Skin Eruptions
Rifampin does induce microsomal drug
metabolizing enzymes. This will decrease the
half-life of some other drugs. (ie. phenytoin,
digitoxin, fenobarbital, oral contraceptives, antidiabetic oral medication → patients with TB and
diabetis need insulin during their treatment with
rifampin)
WARNING!
• Rifampin and Isoniazid are the most effective drugs for
the treatment of TB.
• But these 2 drugs should never be given alone! They
are always used in combination because resistance occurs
to one drug alone very rapidly.
• They are used in combination with each other initially
as well as other drugs. Bacilli must become resistant to
two drugs in order to remain viable. Statistically, the
chances are very small of the bacilli becoming resistant to
both.
PYRAZINAMIDE
• highly bactericidal drug, very effective in killing
intracellular TB bacilli. It is supplied as tablets of
500 mg.
• Dose - daily: 25-30 mg/kg/day, maximum
2g/day, in a single dose; under 50 kg body
weight, maximum 1,5g/day;
• - 3 days/week: 40mg/kg/day, maximum
3g/day.
51
Adverse Effects
• Hepatitis (rising of liver transaminases), rash,
abdominal distress and hyperuricemia (with or without
arthralgia)
• The facial flushing or erythematous rash with pruritus
appearing in the first days of treatment are usually
self-limiting.
• Patients with diabetes should be carefully monitored
since blood glucose concentrations may become
labile.
• Arthralgia, particularly of the shoulders, commonly
occurs and is responsive to simple analgesics. Both
hyperuricemia and arthralgia may be reduced by
intermittent administraton of pyrazinamide.
52
ETHAMBUTOL
• Ethambutol is a bacteriostatic drug, given
orally, and is used mainly to prevent
selection of resistant strains of acid-fast
bacilli to the main first-line TB drugs.
• Dose- daily: 15-25 mg/kg/day, in capsules
of 250 mg or tablets of 400 mg. 15
mg/kg/day after the 8-th week of treatment
(to avoid dose-related side effects)
• 3 days/week: 30mg/kg/day, maximum 1,5
g/day.
53
Side effects
• Retrobulbar neuritis is usually dose-related.
Patients complain of blurred vision, red-green
blindness (early symptoms) and, later, central
scotomata. Visual acuity monitoring is strongly
advised before administering ethambutol, and
later if the patient reports visual symptoms.
• Due to difficulties of monitoring visual acuity in
children, the drug should be used with caution
and only after the age of 6 years.
54
STREPTOMYCIN
• The first drug used clinically for treatment of TB
1947-1952; was the only drug available at that
time.
• is an aminoglycoside antibiotic
• acts by protein synthesis inhibitor and decreases
the fidelity mRNA and garbles the message,
leads to nonsense proteins.
• Streptomycin only binds to the 30s subunit.
Adverse Effects
• Affects cranial nerve 8: auditory and
vestibular functions can be damaged.
• With its small molecule, streptomycin
can pass the placental bareer and affect
the fetus. It is forbidden for pregnant
women and small children.
• Streptomycin is also nephrotoxic.
2nd Line Drugs: Not as effective and
have more toxicity
para- Aminosalicylic Acid
• a structural analog of PABA (paminobenzoic acid) is bacteriostatic
inhibits de novo folate synthesis
• half life = 1 hour after 4 g. dose
• you can give this drug up to 12 grams per
day. 80% of the drug is excreted in the
urine and 50% of that is as an acetylated
metabolite which is insoluble. You must
make sure the patient's urine is normal or
alkaline.
Adverse effects
• GI irritation due to the amount of drug given
(high doses) nausea, vomiting, bleeding, occurs
in 30-40% of the patients. be careful with those
who have peptic ulcers
• Hypersensitivity reactions, rash, fever, some
hepatotoxicity
• All will disappear when the drug is stopped
• This drug has poor patient acceptability and
compliance.
Capreomycin, Viomycin, Kanamycin
(aminoglycosides)
Adverse effects (1)
1. These drugs are nephrotoxic - will cause
proteinuria, hematuria, nitrogen
metabolism, and electrolyte disturbances.
However effect is reversible when drug is
stopped.
Adverse effects (2)
• Ototoxic will result in deafness and some
loss of vestibular function, leads to
cranial nerve 8 damage. The nerve
damage is permanent.
• Capreomycin has replaced viomycin
because of less toxic effects, but all three
drugs have the same effects (also like
streptomycin).
Cycloserine
• can cause CNS disturbances
• Therapeutic States
Cycloserine should be used when retreatment is necessary or when the microorganism is resistant to the other drugs.
• It must be given in combination with other
anti-tuberculosis drugs.
• Mechanism of Action:
An analog of D-alanine synthetase, will block
bacterial cell wall synthesis.
Adverse effects
Most common in the CNS:
• headache, tremor, vertigo, confusion,
nervousness,
• psychotic states with suicidal tendencies ,
paranoid reactions, catatonic and
depressed reactions
Treatment
• Isoniazid, Rifampin, Pirazinamide & Ethambutol
(or Streptomycin in rare situations) are given for 2
months.
• Isoniazid & Rifampin are given for 4 months.
• Prolonged bed rest is not necessary or helpful in
obtaining a speedy recovery. The patient must be
seen at regular and frequent intervals to follow the
course of the disease and treatment. Look for toxic
effects
Classification of Patients in Categories
for Standardized Treatment Regimen
Category
Type of Patient
Regimen
Duration
months
Category I
New Sputum Positive Seriously
ill sputum negative, Seriously ill
extra pulmonary,
2 (HRZE)
or 2 (HRZS)
4 (HR)3
6
Category II
Sputum Positive relapse Sputum 2 (HRZES),
Positive failure
1 (HRZE)
Sputum Positive treatment after 5 (HRE)3
default
Category III Drug-resistant TB (MDR, XDR)
Severe adverse effects
4/6/2017
Individualized
treatment
regimens
8
18-24 and
more
Main drugs and doses (mg/kg/day);
maximum dosage/day in parentheses
DAILY
DAILY
3 TIMES /
WEEK
3 TIMES /
WEEK
CHILDREN
ADULTS
CHILDREN
ADULTS
ISONIAZID
(H)
10-20
(300 mg)
5
(300 mg)
20-40
(750 mg)
10
(750 mg)
RIFAMPICIN
(R)
10-20
(600 mg)
10
(600 mg)
10-20
(600 mg)
10
(600 mg)
PYRAZINAMIDE
(Z)
15-30
(2 g)
30
(2 g)
50
(3 g)
50
(3 g)
ETHAMBUTOL
(E)
15-25
(1,5 g)
15-25
(1,5 g)
30
(1,5 g)
30
(1,5 g)
STREPTOMYCIN
(S)
20
(1 g)
15
(1 g)
30
(1,5 g)
30
(1,5 g)
DRUG
65
Infectiousness
Patients no longer considered infectious if
they meet all of these criteria:
•
•
•
Are on adequate therapy
Have had a significant clinical response to
therapy, and
Have had 3 consecutive negative sputum
smear results
Adherence
•
Nonadherence is a major problem in TB control
•
Use case management and directly observed
therapy (DOT) to ensure patients complete
treatment
Directly Observed Therapy (DOT)
•
Health care worker watches patient swallow each
dose of medication
•
Consider DOT for all patients
•
DOT should be used with all intermittent regimens
•
DOT can lead to reductions in relapse and
acquired drug resistance
•
Use DOT with other measures to promote
adherence
Treatment of TB for HIV-Negative
Persons
• Include four drugs in initial regimen
- Isoniazid (INH)
- Rifampin (RMP)
- Pyrazinamide (PZM)
- Ethambutol (EMB) or streptomycin (SM)
Treatment of TB for HIV-Positive
Persons
•
Management of HIV-related TB is complex
•
Care for HIV-related TB should be provided
by or in consultation with experts in
management
of both HIV and TB
Extrapulmonary TB
•
In most cases, treat with same regimens
used for pulmonary TB
Bone and Joint TB, Miliary TB,
or TB Meningitis in Children
•
Treat for a minimum of 12 months
Multidrug-Resistant TB (MDR TB)
•
Presents difficult treatment problems
•
•
Treatment must be individualized
Clinicians unfamiliar with treatment of MDR TB
should
seek expert consultation
•
Always use DOT to ensure adherence