ANTI-TUBERCULAR DRUGS

Presented by –

Dr.Sushrut Varun Satpathy

3 rd year PG

Deptt.of Pharmacology,SMIMS

Moderator –

Dr.Supratim Datta

Assoc.Prof.

Deptt. Of pharmacology

• CHRONIC GRANULOMATOUS DISEASE • MAJOR HEALTH PROBLEM ( DEVELOPING

COUNTRIES)• 1/3RD OF WORLD’S POPULATION INFECTED

WITH MYCO. TUBERCULOSIS • 9.4 MILLION ACTIVE TB CASES GLOBALLY ( 2.3

MILLION CASES – INDIA – HIGHEST CONTRIBUTOR)-WHO-2010

• G.O.I 2012 DECLARED TB – NOTIFIABLE DISEASE

EVERY DAY IN INDIA ,

More than 900 people die of TB

( ~ 2 deaths every 3 minutes )

CONTROL AND TREATMENT OF TB –COVERED UNDER NATIONAL PROGRAMME (RNTCP)

Goal of RNTCP –

Decrease mortality and morbidity due to TB

Cut transmission of infection until TB cases ceases to be major public health problem – detecting and curing sputum smear positive patients

Achieve and maintain a cure rate of atleast 85% among new sputum smear (+) and maintain detection of atleast 70%

Only effective means to achieve the goal of RNTCP is the application of DOTS strategy

Components of DOTS – systematic strategy having 5 components

Political and administrative commitment Good quality diagnosis, primarily by sputum

smear microscopy Uninterrupted supply of good quality drugs Directly observed treatment (DOT) Systematic monitoring and accountability

Diagnosis of tuberculosis

Identification of TB suspects –

m/c symptom –

Persistent cough , usually with expectorationOthers – weight loss , tiredness , fever with

evening rise , night sweats , chest pain , shortness of breath , anorexia and haemoptysis

Sites of extra-pulmonary tuberculosis

A pulmonary TB suspect is defined as :

An individual having a cough of 2 weeks or more

Contacts of smear positive TB pts having cough of any duration

Suspected/confirmed extra-pulmonary TB having cough of any duration

HIV pts having cough of any duration

1specimen (+) out of 2 - smear positive TB

Smear (+) TB is further classified as new or re-treatment cases based on their previous treatment history

Both specimens are smear (-) - prescribed symptomatic treatment and broad spectrum anti-biotics as Co-trimoxazole for 10-14 days

Antibiotics such as FQs ( ciprofloxacin, ofloxacin, levofloxacin etc), rifampicin or streptomycin, which are active against TB , should never be used

According to clinical utility – Anti-TB drugs can be divided into first line and second line

First line drugs –1. ISONIAZID (H)2. RIFAMPIN (R)3. PYRAZINAMIDE

(Z)4. ETHAMBUTOL (E)5. STREPTOMYCIN

(S)

Second line drugs – Ethionamide (Eto) Prothionamide (Pto) Cycloserine (Cs) Terizidone (Trd) Para-Amino salicylic acid (PAS) Rifabutin Thiacetazone (Thz) FLUOROQUINOLONES Ofloxacin (Ofx) Levofloxacin (Lvx) Moxifloxacin (Mfx) Ciprofloxacin (Cfx) INJECTABLE DRUGS – Kanamycin (Km) Amikacin (Am) Capreomycin(Cm)

Alternative grouping of Anti-tubercular drugs

GROUP 1 First line oral anti-TB drugs Isoniazid,Rifampin,Pyrazinamide,Ethambutol

GROUP 2 Injectable anti-TB drugs Streptomycin , Kanamycin, Amikacin,Capreomycin

GROUP 3 Fluoroquinolones Ofloxacin,Levofloxacin,Moxifloxacin,Ciprofloxacin

GROUP 4 Second line oral anti-TB drugs Ethionamide ,Prothionamide,Cycloserine,Terizidone,PAS

GROUP 5 Drugs with unclear efficacy Thiacetazone, Clarithromycin, Clofazimine,Linezolid,Amoxicillin/clavulanate,Imipenem/cilastatin

• Adopted from : treatment of tuberculosis guidelines ; WHO, Fourth edition(2010) and RNTCP, DOTS-plus Guidelines 2010

• Not recommended by WHO for routine use in MDR-TB patients

Group 1 – are the most potent and best tolerated oral drugs used routinely

Group 2 – potent and bactericidal , but injectable drugsGroup 3 – include FQs which are well tolerated

bactericidal oral drugs ; all patients with drug resistant TB should receive one FQ

Group 4 – less effective, bacteriostatic/more toxic oral drugs for resistant TB

Group 5 – drugs with uncertain efficacy; not recommended for MDR-TB; may be used in XDR-TB

Isoniazid (Isonicotinic acid hydrazide, H)Primarily tuberculocidal Fast multiplying are rapidly killed , but

quiescent ones are only inhibitedActs on extracellular as well as on intracellular

TBEqually active in acidic or alkaline pHOne of the cheapest anti-tubercular drugs

Mechanism of Action -

Inhibition of synthesis of mycolic acids Two gene products labelled ‘InhA’ and ‘ KasA’ ,

which function in mycolic acid synthesis are targets of INH action

INH enters sensitive mycobacteria which convert it by a catalase-peroxidase enzyme into a reactive metabolite

then forms adduct with NAD that inhibits InhA and KasA

INH enters bacilli by passive diffusion

Drug is not directly toxic to the bacillus but must be activated to its toxic form within the bacillus by KatG (multifunctionary , catalase –peroxidase)

KatG catalyzes the production from INH of an isoNicotinoyl radical that subsequently interacts with mycobacterial NAD and NADP to produce a dozen adducts

A nicotinoyl-NAD isomer, inhibits the activities of enoyl acyl carrier protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase (KasA)

Inhibition of these enzymes inhibits synthesis of mycolic acid -- bacterial cell death

Another Adduct, a nicotinoyl-NADP isomer , potently inhibits mycobacterial DHFRase ,thereby interfering with nucleic acid synthesis

Other products of KatG activation of INH include superoxide,H2O2 , alkyl hydroperoxides and NO radical may also contribute to INH bactericidal effect

Resistance of INHAbout 1 in 106 tubercle bacilli is inherently

resistant to clinically attained INH concentration If INH given alone , such bacteria will proliferate

selectively and after 2-3 months , an apparently resistant infection appears

M/C mechanism which confers HIGH level resistance – mutation of KatG (single point mutations in heme binding catalytic domain of KatG , serine to asparagine change at position 315)

INH resistance may also involve mutation in InhA and KasA genes

Resistance due to efflux is also possible

Combined with other drugs ,INH has good resistance preventing action . No cross resistance with other anti-tubercular drugs occurs ???? (KD tripathi 7th edition ;767)

Overexpression of of the genes for InhA – confers low level resistance to INH and some cross-resistance to ethionamide

KatG 315 mutants have a high probablity of co-occurrence with ethambutol resistance

Mutation in KatG, ahpC, and inhA have also been associated with rpoB mutations

Absorption , Distribution and Excretion Bioavailability of oral isoniazid is ~ 100% for 300 mg

dose

INH is completely absorbed orally and penetrates all body tissues , tubercular cavities, placenta and meninges

Extensively metabolized in liver

Most important pathway being N-acetylation by NAT2Acetylated pathway is excreted in urineRate of acetylation shows genetic variation

Fast acetylators (30 – 40% of indians) T1/2 of INH 1 Hr Slow acetylators (60 – 70% of indians )T1/2 of INH 3 Hr Acetylator status does not matter if INH is

taken daily,but biweekly regimes are less effective in fast acetylators

INH induced peripheral neuritis > common in slow acetylators

A hepatotoxic minor metabolite is produced by CYP2E1 from acetylhydrazine

Interactions Aluminium hydroxide inhibits INH absorption

INH retards phenytoin , carbamazepine, diazepam, theophylline and warfarin metabolism by inhibiting CYP2C19 and CYP3A4

Since rifampin is an enzyme inducer, its concurrent use counteracts the inhibitory effect of INH

PAS inhibits INH metabolism and prolongs its T1/2

Drug Daily dose Mg/kg maximum

3 times per week doseMg/kg Daily Max

ISONIAZID (H) 5 (4-6) 300 10(8-12) 900 mg

Adverse effects Well tolerated Peripheral neuritis and a variety of neurological

manifestations ( paresthesias , numbness , mental disturbances , mental disturbances , rarely convulsions ) – dose dependent toxic effects

Interference with the production of the active co-enzyme

pyridoxal phosphate from pyridoxine -- increased excretion in urine – pyridoxine given prophylactically (10 mg/dl)

INH neurotoxicity is treated by pyridoxine 100 mg/day Hepatotoxicity ( rare in children ), but more common in

older people and in alcoholics ( chronic alcoholism induces CYP2E1 – generates the hepatotoxic metabolite )

Others – lethargy , rashes , fever , acne and arthralgia

Rifampin (Rifampicin , R) Semisynthetic derivative of Rifamycin B obtained from

streptomyces mediterranei

Bactericidal to M. Tuberculosis and many other gram(+) and gram (-) bacteria like staph.aureus , N.meningitidis, H.influenza, E.coli,Kleibsella , Pseudomonas,Proteus and legionella

Against TB bacilli , it is as efficacious as INH and better than all other drugs

Bactericidal actions covers all subpopulations of TB bacilli , but acts best on slowly or intermittenly dividing ones (spurters)

Both extra and intracellular organisms are affected Good sterilizing and resistance preventing actions

Mechanism of action - Interrupts RNA synthesis by binding to β

subunit of mycobacterial DNA dependent RNA polymerase (encoded by rpoB gene )

RESISTANCE –

Prevalence of rifampin-resistant isolates are 1 in every 107 to 10 8 bacilli

Rifampin resistance is nearly always due to mutation in the rpoB gene reducing its affinity for the drug

( In 86% cases due to mutations at codons 526 and 531 of rpoB gene)

No cross resistance with any other anti-tubercular drug, except rifampin congeners

Rifampin monoresistance occurs at a higher rates when pts with AIDS and multi-cavitary TB are treated with either rifapentine or rifabutine

Pharmacokinetics - Well absorbed orally Bioavailability ~ 70% , food decreases absorption Rifampin is to be taken in empty stomach Widely distributed in the body; penetrates intracellularly , enters tubercular

cavities, caseous masses and placenta It crosses meninges , largely pumped out of CNS

by P– glycoprotein Metabolized in liver – active deacetylated

metabolite – excreted mainly in Bile , some in urine

Rifampin and its deacetylated metabolite undergoes enterohepatic circulation

T1/2 – 2-5 hrs

Interactions Rifampicin is a microsomal enzyme inducer – increases

several CYP450 isoenzymes – CYP3A4 , CYP2D6, CYP1A2 , CYP2C subfamily

Enhances its own metabolism ( area under the plasma concentration-time curve is reduced by ~ 35%) as well as that of many drugs including warfarin , oral contraceptives, corticosteroids, sulfonylureas, corticosteroids, HIV protease inhibitors, NNRTIs , theophylline, metoprolol, fluconazole,ketoconazole, clarithromycin, phenytoin etc

Contraceptives failure have occurred – advisable to switch over to an OCP containing higher dose ( 50 µg ) of estrogen or alternative method of contraception

Adverse effects - Incidence of adverse effects is similar to INH Hepatitis , a major adverse effect, generally

occurs in pts with pre-existing liver disease and is dose related

Jaundice – discontinuation of drug – reversible Minors reactions , not requiring drug withdrawal

and more common with intermittent regimes Cutaneous syndrome : Flu syndrome : Abdominal syndrome : Urine and secretions may become orange-red but

this is harmless

Other uses of rifampin 1. Leprosy 2. Prophylaxis of Meningococcal and

H.influenza meningitis and carrier state3. Second/third choice drug for MRSA,

Diptheroids and legionella infections4. Combination of doxycycline and rifampin is

first line therapy of brucellosis

Pyrazinamide (Z) Chemically similar to INH – Pyrazinamide was

developed parallel to it (1952) Weakly tuberculocidal more active in acidic medium and slowly

replicating bacteria More lethal to intracellular bacilli and at sites

showing inflammatory response Highly effective during the first 2 months of

therapy when inflammatory changes are present

Inclusion enabled duration of treatment to be shortened and risk of relapse to be reduced

M.O.A – not well established Similar to INH – converted inside mycobacterial

into active metabolite pyrazinoic acid by pyrazinamidase encoded by pncA gene

Gets accumulated in acidic medium and probably inhibits mycolic acid synthesis, but by interacting with a different fatty acid synthase

Pyrazinoic acid also appears to disrupt mycobacterial cell membrane and its transport function

Resistance to Z develops rapidly if it is used alone, and is mostly due to mutation in the pncA gene

Absorbed orally Widely distributed , good penetration in CSF Extensively metabolized in liver and excreted in

urine Plasma T1/2 ~ 6 hrs

Adverse effects – 1. Hepatotoxicity 2. Hyperuricaemia 3. Others – abdominal distress non-gouty arthralgia fever

Ethambutol (E) Selectively Tuberculostatic Active against MAC as well as some other

mycobacteria Fast multiplying bacilli – more susceptible Added to triple regime of RHZ – hastens the rate of

sputum conversion and prevents development of resistance

M.O.A – Inhibits arabinosyl transferases (encoded by embAB

genes) involved in arbinogalactan synthesis

interfering mycolic acid incorporation in mycobacterial cell wall

Resistance to E develops slowly Most commonly associated with mutation in

embB gene , About 3/4th of oral dose is absorbed

Distributed widely , but penetrates meninges incompletely and is temporarily stored in RBCs

Excreted in urine by GFR and tubular secretion

Plasma T1/2 ~ 4 hrs

ADVERSE EFFECTS - 1. Dose dependent and reversible visual

disturbances like Optic Neuritis - reduced visual acuity , central scotoma and loss of ability to see Green, less commonly Red - ? Due to its effect on Amacrine and bipolar cells of retina ^

2. Hyperuricemia 3. Peripheral neuritis

Streptomycin First clinically useful anti-TB drug Tuberculocidal but less effective than INH or

rifampin Acts only on extracellular bacilli – poor

penetration Penterates tubercular cavities , but does not

cross to CSF Poor action in acidic medium Not absorbed orally , must be administerd by

IM inj. T1/2 is prolonged in renal failure NOT HEPATOTOXIC Use restricted to max. of 2 months- labelled

as ‘supplemental’ 1st line drug !

Other drugs - Thiacetazone – tuberculostatic drug. Major A/E –

hepatitis , bone marrow suppression and steven johnson syndrome ( not used in HIV pys due to risk of severe hypersensitivity reactions including exfoliative dermatitis)

PAS related to sulfonamides , acts by similar mechanism –bacteriostatic

Ethionamide/prothionamide – tuberculostatic –hepatitis , optic neuritis and hypothyroidism , can also be used in leprosy ^

Cycloserine is a cell wall synthesis inhibiting drug and can cause neuropsychiatric adverse effects

Kanamycin and Amikacin are injectable aminoglycosides – used in treatment of MDR TB

Capreomycin – injectable polypeptide – ototoxicity , nephrotoxicity ,hypokalemia and hypomagnesemia

FQs – Ofloxacin , Moxifloxacin and Levofloxacin - effective against MAC in AIDS patients

Newer macrolides like Azithromycin and Clarithromycin against non-tubercular atypical mycobacteria

Rifabutin more effective than Rifampicin against MAC , longer T1/2 ~ 45 hrs , less potential than rifampicin to induce microsomal enzymes and thus , prefered in pts on anti-HIV drugs ( protease inhibitors or NNRTIs mainly nevirapine )

commonly causes – GI discomfort Anterior Uveitis, Hepatitis,

clostridium associated diarrhoea , diffuse polymyalgia syndrome , yellow skin discoloration

Rifapentine – similar to rifampicin but more lipophillic and longer acting . Not approved for adm. to HIV pts because of higher rate of relapse

Treatment of Tuberculosis - Combination chemotherapy ( short course

chemotherapy) – to prevent the emergence of resistance to any 1drug

For treatment purpose , previously treated patients were divided into three categories . Under RNTCP 2010 guidelines , only two categories are distinguished

Category 1 – new pts who have not been exposed to anti-tubercular agents earlier ( previous category 1 as well as 3 cases)

Category 2 – old cases who have been exposed to anti-tubercular drugs earlier ( treatment defaulters and relapse cases)

First line agents

New patient ( category 1) Initial treatment with 4 drugs (HRZE) including

3 bactericidal drugs reduces the risk of selecting resistant bacilli ^

After intensive phase – few bacilli left – only 2 highly effective cidal drugs in the continuation phase

Extension of intensive phase beyond 2 months is not recommended now . However , In such cases , authorities recommend 9 month treatment instead of 6 month ?? ( KD Tripathi 7th ed. ;2013: 774-775 )

RNTCP guideline - If the sputum smear is positive after 2 months of

treatment , the intensive phase of four drugs (HRZE) are continued for another 1 month

sputum examined after completion of extension of intensive phase

irrespective of the results – 4 months of continuation phase is started

If sputum smear postitve after 5 or more months of treatment – “ failure”- placed on “previously treated” and sputum sent ( C & DST)

While treating TB meningitis( NEW pts) , Streptomycin is used in place of ethambutol during the intensive phase ( H3R3Z3S3 instead of H3R3Z3E3)

Continuation phase of treatment with TBM or spinal TB is for 7 months – total duration is for 9 months

In areas with high level of primary (H) resistance – WHO suggests inclusion of (E) along with (H+R) in continuation phase

Previously treated ( Category 2) For TB pts who have had more than one

month anti-TB treatment previously Higher risk of having drug resistance 5 drugs are prescribed in the intensive phase

and total duration of treatment is 8 months Relapses , Treatment after default ,

Failures and others are treated with this regime

Regimen is 2 S3H3R3Z3E3 /1 H3R3Z3E3 /5 H3R3E3

Intensive phase consists of 2 months of HRZES followed by 1 month of HRZE, all given under direct observation thrice a week on alternate days

Pts subjected for follow up sputum examination at the end of 3 months

If sputum smear (+) at the end of 3 months of treatment , intensive phase drugs (HRZE) are extended for another

Irrespective of sputum results at the end extended intensive phase , 5 months of continuation phase is started

If the sputum remains positive at the end of extended intensive phase, sputum is sent to accredited C & DST

MultiDrug-Resistant (MDR) TB Defined as resistance to both H and R , and may be any

number of other (1st line) drug MDR –TB has a more rapid course with worse outcomes IDENTIFICATION OF MDR – TB SUSPECTS – Following are the criteria to label a patient as MDR-TB

suspect – A new smear (+) pt. remaining smear (+) at end of 5th

month A new smear (-) pt. becoming smear (+) at the end of 5th

monthA pt. treated with regimen for previously treated remaining

(+) at fourth month Smear-positive contacts of an established / confirmed MDR-

TB case

Diagnosis of MDR-TB Diagnosis of MDR-TB should be done through

C & DST from a quality assured lab On being diagnosed as MDR-TB case- Pt.

referred to a designated state level DOTS-plus site

Specialized centers limited in number , atleast one such center is expected to be in each state with ready access to an C & DST

DOTS-plus site- supported by qualified staff available to manage pts. using second line RNTCP MDR-TB regimen

RNTCP MDR-TB treatment regimen - RNTCP is using a standardised treatment

regimen (STR) , comprising of 6 drugs ( kanamycin (Km), levofloxacin(lvx), ethionamide (Eto), pyrazinamide (Z), ethambutol (E) and cycloserine (Cs)

Dosages of drugs are based upon 3 weight bands

Drug 16-25 kg 26-45 kg > 45 kg

Km 500 mg 500 mg 750 mg

LVX 200 mg 500 mg 750 mg

Eto 375 mg 500 mg 750 mg

E 400 mg 800 mg 1000 mg

Z 500 mg 1250 mg 1500 mg

Cs 250 mg 500 mg 750 mg

PAS 5 g 10 g 12 g

Pyridoxine 50 mg 100 mg 100 mg

All drug given in a single daily dosage under DOT by a DOT provider

All pts. will receive drugs under direct supervision on 6 days of the week

On the 7th day (Sunday) , oral drugs will be administered unsupervised and kanamycin will be omitted

If intolerance occurs to drugs , ethionamide , cycloserine and PAS may be split into two dosages and the morning dose adm. under DOT and evening subsequently self-administered

Empty blister packs of self-administered doses will be checked the next morning during DOT

100 mg of pyridoxine is adm. to all pts under RNTCP MDR-TB regimen

If pts gain atleast 5 kgs of weight during treatment and crosses the weight band range , DTS-plus site committee may consider moving the patient to the higher weight band drug dosages ^

DURATION OF TREATMENT - IP – atleast 6 months Extended up to 7/8/9th months in pts who have (+)

culture result taken in 4/5/6th months of treatment correspondingly

Continuation phase is given for 18 months following IP

Follow up schedule - Smear examination should be conducted

monthly during IP and atleast quaterly during the CP

Culture examinations should be done atleast 4, 6,12, 18 and 24 months of treatment

Guidelines fro treatment of MDR + XDR TB1. Use minimum 4 drugs ( 6 drugs in extensive

phase )2. Follow the hierarchy of drugs from class 1

through class 5 as follows :a. Use any first line oral agent that may be

effective b. Use injectable agent to which strain is

susceptible c. Use a later generation FQd. Use second line oral drugs to which the patient

is not exposed previously e. Use drugs with unclear efficacy

Class 1 First line oral drugs H,R,Z,E

Class 2 Injectable agents Streptomycin, Kanamycin, Amikacin, Capreomycin

Class 3 Fluoroquinolones Levofloxacin , Moxifloxacin

Class 4 Oral Bacteriostatic PAS, Cycloserine , Ethionamide

Class 5 Drugs with uncertain efficacy

Linezolide , Clofazimine , Amoxicillin + clavulanate , Clarithromycin ,Imipenem/cilastatin, Thiacetazone , high dose Isoniazid

For example if bacteria is resistant to H and R only, the treatment will be 6 ZE + FQ + One injectable + PAS + Cycloserine in the extensive phase

18E + FQ + PAS + Cycloserine in the continuation phase

Injectable drugs and Z is removed and rest 4 drugs are continued for minimum 18 months in continuation phase

Extensively drug resistant TB MDR-TB cases that are also resistant to FQs as well one

of the injectable 2nd line drugs and may be any number of other drugs

Bacilli are resistant to atleast 4 most effective cidal drugs viz. H,R,FQ and one of Km/Am/Cm

XDR-TB- very difficult to treat - rapid course and high mortality

To prevent further amplification of resistance – standardized MDR regimen ( category 4 treatment) must be immediately stopped

Expert panel may decide on instituting category 5 treatment , including group 5 drugs – uncertain efficacy and expensive

New drugs like PA-824 and TMC-207 is also being evaluated

Tuberculosis in Pregnant Women - H,R,E and Z safe to the foetus and

recommends the standard 6 month (2HRZE + 4 HR)- WHO and British Thoracic Society

S is C/I - ototoxic Z not recommended in US – lack of adequate

teratogenecity data In India – advisable to avoid Z and to treat

pregnant TB pts in India – 2 HRE + 7 HR ( total 9 months)

All pregnant women treated with INH should receive Pyridoxine 10-25 mg/day

Role of Corticosteroids - Tb is a relative C/I for use of glucocorticoids .

However in certain situations , Glucocorticoids may be used under the cover of effective Anti-TB therapy –

1. Tuberculosis of serous membranes like pleura , pericardium , meninges etc. to prevent fibrous tissue formation and its sequelae

2. To treat hypersensitvity reactions to antitubercular drugs

3. Tuberculosis of the eye , larynx , genitourinary tract to prevent fibrosis and scar tissue formation

Prednisolone is a preferred agent except in meningitis ( dexamethasone is preferred)

Steroids C/I in intestinal TB – risk of perforation

Atypical Mycobacterial Infections - Clarithromycin or Azithromycin is

recommended for prophylaxis of Mycobacterium Avium Complex (MAC) in pts with CD4 count < 50 µl

Treatment of MAC requires REC regimen ( Rifabutin + Ethambutol + Clarithromycin/Azithromycin

Due to its long T1/2 , Azithromycin can be used as once weekly dose in place of one daily dose of Clarithromycin for prophylaxis of MAC

Other drugs effective against atypical mycobacteria are quinolones ( ciprofloxacin , levofloxacin , moxifloxacin and gatifloxacin) and Amikacin

Treatment regimen of MAC infection - Intensive phase 1. Clarithromycin 500 mg BD or Azithromycin 500 mg OD2. Ethambutol 1000 mg/day (15 mg/kg) depends on3. Rifabutin 300 mg/day the response ± till CD4 >100 Ciprofloxacin 500 mg BD and

sympt.relief or Levofloxacin 500 mg OD ( 2- 6 months) or Moxifloxacin 400 mg OD Maintenance phase 1. Clarithromycin /azithromycin2. Ethambutol /Rifabutin / 1 FQ doses – same min 12

mths

THANK YOU FOR YOUR PATIENCE !!

HAVE A GREAT DAY !