1. TREATMENT OF TB Dr. Seham Hafez Marwa Shaaban Rawy Pharm D
Presented by:
Marwa Shaaban Rawy
Pharm D
Supervised by:
Dr. Seham Hafez

2. History of Selman Waksman, Nobel Laureate, 1952.
Evidence of tubercular decay found in the skulls and spines of Egyptian mummies, tell us that TB has been plaguing humans for at least 4,000 years       
    
Robert Koch, Nobel Laureate, 1905.
discovered Mycobacterium tuberculosis
Selman Waksman, Nobel
Laureate, 1952.
discovered streptomycin

3. GENERAL APPROACHES TO TREATMENT
Monotherapy can be used only for infected patients who do not have active TB [latent TB infection (LTBI)]
Once active disease is present, a minimum of two drugs and typically three or four drugs must be used simultaneously.
For most patients, the shortest duration of treatment is 6 months, and 2 to 3 years may be necessary for advanced cases of multidrug resistant TB (MDR-TB).

4. NONPHARMACOLOGIC THERAPY
Aim:
(1) Prevent the spread of TB (respiratory isolation)
(2) Return the patient to a state of normal weight and well-being
Surgery may be needed to remove destroyed lung tissue, tuberculomas (space-occupying infected lesions) and certain extrapulmonary lesions.
Directly Observed Therapy (DOT)
The practice of a health care provider or other responsible person observing as the patient ingests and swallows the TB medications.
preferred core management strategy for all patients with TB.
Patient compliance is often low when multidrug schedules last for 6 mo. or longer
Doses missed during an intermittent TB regimen decrease the efficacy of the
regimen and increase the relapse rate
Purpose:
ensure adherence to TB therapy
reduce the risk of developing drug resistance
reduces the risk to the community.
observe the patient for any apparent toxicities.
DOT have been shown to decrease drug resistance as well as relapse and mortality rates and to improve cure rates.

5. Pharmacologic Therapy
considered 1st-line because of their efficacy & acceptable degree of toxicity.
considered 2nd-line drugs, either because they are no more effective than the first-line agents and their toxicities are often more serious or because they are particularly active against atypical strains of mycobacteria.

6. Pharmacologic Therapy Treating Active Disease
Each case of active TB disease must be reported to the public health departments.
Combination chemotherapy.
It is critical to avoid monotherapy, and it is critical to avoid adding a single drug to a failing regimen.
Isoniazid and rifampin should be used together whenever possible, as they are the best drugs for preventing drug resistance.
Pyrazinamide has a special role in the first 2 months of treatment.
2nd-line drugs are used to suppress the emergence of drug resistance in conjunction with the first-line drugs or for preexisting drug-resistant TB.
Recent research is placing emphasis on the potential role of quinolones such as levofloxacin and moxifloxacin in the treatment of TB. It is possible that future regimens may consider these agents part of the first-line drugs.
Drug susceptibility testing should be done on the initial isolate for all patients with active TB. These data should guide the selection of drugs over the course of treatment

7. Pharmacologic Therapy
Treating Active Disease
The standard TB treatment regimen is:
Initial phase Continuation phase
For a total of 6 months
of treatment
A total of 9 months of isoniazid and rifampin treatment is recommended for patients at greater risk of failure and relapse, including:
-Those with cavitation on initial chest radiograph
-Those with positive cultures at the completion of the initial 2-month phase of treatment.
- Patients treated initially without pyrazinamide.
When INH and RIF cannot be used, treatment durations become 2 years or more.
Isoniazid
Rifampin
Pyrazinamide,
Ethambutol
for 2 months
Isoniazid
Rifampin
for 4 months

8. Drugs Used in the Treatment of T.B First-Line Agents
Daily Dosing
(Maxi-mal Dose)
Primary Side
Effects
Comments 
Isoniazid
(INH)
5 mg/kg
(300 mg)
Children: 10–15 mg/kg
Increased aminotransferases
(transient and asymptomatic)
Clinical hepatitis
Peripheral neuropathy by
interfering with pyridoxine (V B6) metabolism
lupus-like syndrome
Hypersensitivity
most potent of the antitubercular drugs.
potent inhibitor of several CYP450
isoenzymes but has minimal effects on CYP3A.
INH inhibits hepatic metabolism of phenytoin ,carbamazepine, diazepam, increasing plasma concentrations & toxicity of these drugs which may need dose adjustment.
Carbamazepine also may induce INH hepatitis by inducing its metabolism to toxic metabolites.
Patients at risk of
Peripheral neuropathy DM
alcoholism
HIV infection
malnutrition
renal failure
Pregnancy
Children
Peripheral neuropathy preventable with
supplemental pyridoxine 25 mg/day
should be given with INH.

9. INH hepatotoxicity
Most patients with mild, subclinical hepatic damage do not progress to overt hepatitis and recover completely even while continuing INH. In contrast, continuation of INH in patients with symptoms of hepatitis increased the risk of mortality compared with immediate cessation.
The risk of death from TB, however, is estimated to be 11 times higher than the risk of death from INH hepatotoxicity.
Monitor: baseline and regular monitoring of LFTs
High-risk patients :
those who consume alcohol daily
persons >35 years of age
those taking other hepatotoxic drugs
those with pre-existing liver disease
black and Hispanic women
all postpartum women.
INH should be discontinued if the AST level exceeds 3 -5 times the ULN

10. Drugs Used in the Treatment of T.B First-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments 
Rifampin
(RIf)
10 mg/kg (600 mg)
Children: 10–20 mg/kg
(600 mg)
Pruritis, rash
Hepatotoxicity
more likely to
produce cholestasis, as manifested by  ALP & hyper-bilirubinemia without hepatocellular injury
GI effects (nausea,anorexi, abdominal pain)
flu-like Syndrome
Thrombocytopenia
Orange-red discoloration of body secretions (sweat, saliva, tears, urine).
many drug interactions.
potent inducer of CYP450 isoenzymes, especially CYP3A4.
metabolism of warfarin, corticosteroids, antiretroviral agents, azole antifungals, quinidine, oral contraceptives (use an alternative method of birth control),cyclosporine, tacrolimus, theophylline, phenytoin, diazepam, propranolol, metoprolol, sulfonylureas, verapamil,nifedipine, diltiazem, enalapril, and simvastatin.
(monitor conc &  dose If required)
It is important to note that rifampin has the exact
opposite effect on hepatic metabolism than INH.
Rifampin is a stronger inducer than INH is an
inhibitor as documented by the fact that
INH-rifampin combination therapy induces
the metabolism of diazepam, phenytoin, and
other agents metabolized by CYP450 system.

11. Drugs Used in the Treatment of T.B First-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments 
Rifabutin
5 mg/kg (300 mg)
Neutropenia
Uveitis
GI symptoms
polyarthralgia
Hepatotoxicity
rash
derivative of rifampin
the preferred drug for use in T.B patients infected with (HIV) who are concomitantly treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors, because it is a less potent inducer of CYP450 enzymes.
Orange-red discoloration of body secretions.
Pseudojaundice (skin discoloration with normal bilirubin)
Drug interactions are less problematic than rifampin.
The rifamycins differ in their
ability to induce CYP450
isoenzymes,in which:
Rifampin is the most potent,
Rifapentine is intermediate,
Rifabutin is the least potent
enzyme inducer.

12. Drugs Used in the Treatment of T.B First-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments 
Rifapentine
10 mg/kg
(600 mg)
Once weekly
in continuation
phase.
Similar to rifampin
Has activity comparable to that of rifampin but has a longer half-life than rifampin and rifabutin, which permits weekly dosing. 
Pyrazinamide
(PZA)
Based on IBW:
40–55 kg:
1000 mg
56–75 kg:
1500 mg
76–90 kg:
2000 mg
Hepatotoxicity
nausea
anorexia
polyarthralgias
rash
hyperuricemia
dermatitis
Baseline LFTs and uric acid measurment; repeat if abnormal or patient at risk or symptomatic.

13. Drugs Used in the Treatment of T.B First-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments 
Ethambutol
(EMB)
Adults
Based on
IBW
40–55 kg:
800 mg
56–75 kg:
1200 mg
76–90 kg:
1600 mg
Optic neuritis with blurred vision, red green color blindness.
(dose and duration related)
skin rash
drug fever
Baseline visual acuity and color vision; test monthly
50% excreted unchanged in urine
 Need dose adjustment in renal impairment.

14. Drugs Used in the Treatment of T.B Second-Line Agents
Daily Dosing
Primary Side Effects
Comments 
Cycloserine
10–15
mg/kg
per day,
usually
500–750
mg/day in
two doses
CNS
toxicity
Monthly assessments of neuropsychiatric status
May exacerbate seizure disorders or mental illness.
Monitor serum conc.
(peak 20–35 mg/L desirable)
Need dose adjustment in renal
impairment.
although this is the dose recommended generally, most clinicians with experience using cycloserine indicate that it is unusual for patients to be able to tolerate this amount.
Serum concentration measurements are often useful in determining the optimal dose for a given patient.

15. Drugs Used in the Treatment of T.B Second-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments 
Ethionamide
15–20 mg/kg
per day,
usually
500–750
mg/day
in a single
daily dose or
two divided
doses
GI effects
hepatotoxicity
neurotoxicity
endocrine effects
(alopecia, impotence,
gynecomastia,
hypothyroidism)
Difficulty in diabetes management
Must be given with meals and
antacids.
Monitoring:
-Aminotransferases
-TSH at baseline
and monthly
Intervals.

16. Drugs Used in the Treatment of T.B Second-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments 
Streptomycin 
Amikacin/
Kanamycin 
Capreomycin
-15 mg/kg/d (1 g)
-10 mg/kg in persons
older than 50 years of
age (750 mg).
Usual dose: 750–1000
mg administered I.M
or I.V, given as a single
dose 5–7 days/week,
and reduced to 2-3 times
per week after the first 2–4
months or after culture
Conversion.
Ototoxicity
neurotoxicity
Nephrotoxicity
Ototoxicity,
(< Streptomycin)
Monitoring:
-Baseline
audiogram,
vestibular testing,
and SCr.
-Monthly
assessments of
renal function
and auditory
Symptoms.

17. Drugs Used in the Treatment of T.B Second-Line Agents (Cont’d)
Daily Dosing
Primary Side Effects
Comments
 Para –
aminosalicylic
acid (PAS)
8–12
g/day in
two or three
doses
GI intolerance
Hepatotoxicity
Malabsorption
Syndrome
Hypothyroidism
Monitoring:
LFTs and TSH
Levofloxacin
 Moxifloxacin
 Gatifloxacin
500–1000 mg/d
400 mg daily
Nausea
Diarrhea
Headache
Dizziness
Do not give with divalent and/or trivalent cations (e.g., aluminum, magnesium, iron)

18. Pharmacologic Therapy Special Populations
Treating Active Disease:
TB in children:
May be treated with regimens similar to those used in adults , although some physicians extend treatment to 9 months.
Pediatric doses of isoniazid and rifampin on a milligram per kilogram basis are higher than those used in adults.
TB in pregnant women:
untreated TB represents a far greater risk to a pregnant woman and her fetus than does the treatment
administration of antituberculosis drugs is not an indication for termination of pregnancy.
Receive the usual treatment of isoniazid,rifampin, and ethambutol for 9 months. (not teratogenic)
Pyrazinamide is not recommended for use during pregnancy because of insufficient safety data.
Pyridoxine should be provided.(25 mg/day)
Other drugs should be avoided

19. Pharmacologic Therapy Special Populations (Cont’d)
Human Immunodeficiency Virus:
Patients with AIDS may be managed with chemotherapeutic regimens similar to those used in immunocompetent individuals, although treatment is often extended to 9 month.
The precise duration remains a matter of debate.
Highly intermittent regimens (twice or once weekly) are not recommended for HIV-positive TB patients.
Prognosis has been particularly poor for HIV-infected patients infected with MDR-TB.
Some patients with AIDS malabsorb their oral medications,
and drug interactions are common.

20. Pharmacologic Therapy Special Populations (Cont’d)
Renal Failure:
Isoniazid and rifampin (hepatically cleared) do not require dose modification in renal failure.
Renally cleared TB drugs include:
EBM, cycloserine, ethionamide, aminoglycosides (e.g., amikacin, kanamycin, andstreptomycin), capreomycin, levofloxacin.
Dosing intervals need to be extended for these drugs.
Serum concentration monitoring must be performed
for cycloserine to avoid dose-related toxicities in renal failure patients.

21. Pharmacologic Therapy Special Populations (Cont’d)
Hepatic Failure:
Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity.
Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid and these drugs may cause hepatotoxicity esp. in patients with liver impairment.
These patients require close monitoring, and TDM may be the most accurate way to dose them.