Lec 20 – Antimycobacterial Agents Main Properties of Anti-TB Drugs

TibbsNotes – MGC 1. Bactericidal

o Rapid killing of actively multiplying organisms
Clinical Forms of TB o Agents can be compared by EBA (Early bactericidal activity – EBA fall in
 TB Exposure viable colony forming units of Mycobacterium tuberculosis per mL of
 Latent Tuberculosis Infection (LTBI) sputum per day during the first 2 days of treatment
 TB Disease 2. Sterilizing
o Ability to kill all remaining microorganisms in the patient’s lesion 
Basic Principles in the Treatment of TB preventing reactivation and/or relapse
1. Treatment regimen must contain multiple drugs to which the organisms o A good sterilizing drug will have potential for shortening treatment
are susceptible 3. Ability to prevent or delay emergence of resistance
2. Drug administration must continue for a sufficient period of time (6mos.) to 4. Relatively low toxicity
fully eradicate the tubercle bacilli to achieve lasting cure
3. The goal is to provide the most effective therapy at the shortet period of Anti-TB Drugs
time to prevent the emergence of drug resistance First Line Anti-TB Drugs: Second Line Anti-TB Drugs
Greatest level of efficacy with Low level of efficacy and/or high toxicity
Aims of Chemotherapy acceptable degree of toxicity
1. Provide the most effective therapy 2. Ensure eradication of slow and Injectable Oral
to rapidly reduce bacterial load intermittently ISONIAZID (H) STREPTOMYCIN ETHIONAMIDE
KANAMYCIN CYCLOSERINE/
o Improve clinical manifestation metabolizing/multiplying TB RIFAMPICIN (R) TERIZODONE
o Limit disease progression bacilli or persisters – Prevent PYRAZINAMIDE (Z) AMIKACIN PAS
o Prevent death or late relapse and/or reactivation ETHAMBUTOL (E) CAPREOMYCIN FLUOROQUINOLONES
complication 3. Prevent emergence of the VIOMYCIN RIFABUTIN/ RIFAPENTIN
o Render patient non-infectious resistant organisms THIACETAZONE
o Prevent/stop transmissions 4. Achieve all these with minimum TERIZODONE
adverse effects
It is vital to achieve these aims while preventing the selection of resistant bacilli
in infectious patients
FIRST LINE ANTI-TB DRUGS
ISONIAZID (H)
 Pregnancy Risk Category C
 Prodrug
Pharmacodynamics
 Activated by mycobacterial
catalase-peroxidase (Kat G)
o Activated H exerts lethal
effect by forming
covalent complex with
acyl carrier protein
(AcpM) and beta-keto
acyl carrier protein
synthetase (KasA) which
block mycolic acid
synthesis
 Bactericidal to both
extracellular and
intracellular rapidly growing
tubercle bacili. (MIC: 0.01-
0.2mcg/mL)
Mechanism of Resistance:
Resistant mutants occur in 1 in
106 tubercle bacili due to
mutations in:
1) Kat G
2) Inh A
Therapeutic Uses
1. Treatment of TB disease; given in combination with 2 or more drugs
2. Treatment of latent TB infection (LTBI), 6-9mos.
3. Prophyaxis of close contacts of infectious cases TST negative
 ISONIAZID
 RIFAMPICIN (C)
 PYRAZINAMIDE
 ETHAMBUTOL
Pharmacokinetics
 Absorption: Oral absorption complete in
fasting state, less with food and antacids
 Distribution:
o Diffuses readily to all tissues and body
fluids including CSF
 Does not bind to plasma proteins
 Penetrates well into caseous
material
oTmax: 1-2hr fasting
oCmax: 3-5mcg/mL after a dose of
5mg/kg
 Metabolism: Metabolism in the liver mainly
by acetylation by N-acetyltransferase
(NAT2) is genetically determinded (slow or
rapid) (T½)
o Slow: 3h; Rapid: <1h
o A metabolite, monoacetyl hydrazine, is
associated with hepatotoxicity
o No correlation between acetylation rate
and either efficacy or adverse reactions
 Excretion: Metabolites and unchanged drug
are excreted mainly in urine
Adverse Reactions
 Nervous System: Peripheral
neuropathy due to relative
pyridoxine deficiency; psychosis,
alteration of sensorium, seizures in
dosages >5mg/kg/d
o Give prophylactic PYRIDOXINE
(25-50mg/d) to prevent
peripheral neuropathy in
patients at risk
 Liver: Asymptomatic elevation of
serum ALT (in 10-20% of patients)
o Hepatitis – most frequent toxic
effect
o Age related; higher in alcoholics
and in patients with liver disease
 Allergic Rash
 ANA (+) on long term use (20%), SLE
 Hemolysis in G6PD deficiency
RIFAMPICIN (R)
 Pregnancy Risk Category C
 Semisynthetic derivative of rifamycin B
Pharmacodynamics
 Mechanism of Action: Inhibits DNA dependent
RNA polymerase  Decreased transcription
 Bactericidal against rapidly dividing and slowly
growing bacili (both extracellular and
intracellular)
 MIC <1mcg/mL
 Most potent sterilizing drug available
Drug Interaction
 DME Inhibitor
o Increased PHENYTOIN and
THEOPHYLLINE toxicity
o Increased hepatotoxicity with
RIFAMPIN and ALCOHOL
 Co-administration with Vit. C
appears to inactivate ISONIAZID
suspension markedly
Surveillance: Pre-treatment Liver
Function (for >35yr. old)
 Repeat if symptoms of fatigue,
anorexia, nausea, vomiting,
weakness (>3days) and at 2, 4, and
6 months (for >50yr. old)
 In infants and children, biochemical
monitoring is not necessary,
monthly clinical observation is
enough
Mechanism of
Resistance
 Rifampicin resistance
occur in 1 in 107 to 1 in
108 due to mutation in
rpo gene-reducing its
affinity for the drug
Pharmacokinetics
 Absorption  Metabolism: Deacetylated in the PYRAZINAMIDE (C)
o Complete oral absorption in liver then conjugated to glucuronide  Pregnancy Risk Category C
fasting state, less with food and o R and its deacetylated
 Inactive at neutral pH; pH 5.5; MIC: 20cg/mL
antacids, first pass metabolism metabolites undergo
 Prodrug: converted to pyrazinoic acid by mycobacterial pyrazinamidase,
o Bioavailability is dependent on the enterohepatic recirculation
disrupting mycobacterial cell membrane metabolism and transport functions
formulation: Rx must be filled  Excretion: 30% of dose is excreted in
according to specified INN and the urine and 60-65% in the feces Pharmacodynamics Mechanism of Resistance
brand name  Combinations:  Bactericidal to  Resistant mutants occur due to impaired
 Distribution: oR should not be formulated as a intracellular organisms uptake of Z or mutations in pncA that impair its
o Tmax: w/in 2h in fasting state fixed dose combination (FDC) only at slightly acidic pH conversion to active form
o Cmax: 7-10mcg/mL (600mg dose) suspension with H and Z because (5.5)
o T½: 2-5h R becomes unstable Pharmacokinetics Therapeutic Uses:
o Bound to plasma proteins and oAn oral suspension may be  Readily absorbed orally  Given in the first 2 mos. of the intensive
distributes into: prepared using R powder from a  Tmax: 1-2h phase (DOTs) in conjunction with H, E, and
 Body tissues capsule, mixed with sweetened  Cmax: 30-50mcg/mL at R, as “sterilizing” agents
 Phagocytic cells and fluids water on fruit juice 25mg/kg dose Adverse Reactions
including CSF oFDC formulation must undergo  T½: 9-10hrs in healthy  Hepatotoxicity
 Tears, saliva, sweat, and stools strict bioavailability studies since persons  Hyperuricemia with or without symptoms;
 red orange discoloration it greatly varies with the  Widely distributed in body arthralgia/overt gout in adults
o Penetrates cavities and caseous formulation tissues inc. CSF (inflamed  GIT disturbance – nausea, vomiting,
masses meninges) anorexia
Adverse Reactions Surveillance (in  Hydrolyzed in liver to  Flushing: cutaneous hypersensitivity
 Discoloration of body fluids adults) pyrazinoic acid and Surveillance (adults):
o Permanent discoloration of soft contact lens  Pre-treatment liver hydroxylated to 5-hydroxy  Pre-treatment liver function
 Light Chain Proteinuria function pyrazinoic acid (the major  Monthly SGPT, uric acid
 Rashes, nephritis  Repeat if excretory product)
 Cholestatic jaundice/hepatitis symptoms of
 Flu-like syndrome – fever, chills, myalgias, anemia, & weakness, fatigue,
thrombocytopenia malaise, anorexia,
oAssociated with intermittent rather than daily therapy nausea, and
vomiting
Interactions: DME Inducer
Decrease effects of:
 Anticoagulants  Chloramphenicol  Theophylline
 Corticosteroids  Clarithromycin  Ketoconazole, Fluconazole,
 Oral Contraceptives  PI, NNRTI Propanolol
 Methadone  Quinidine, Tocainide  Cyclosporin
 Oral Hypoglycemics  Anticonvulsants  Ca2+-Channel Bloackers
ETHAMBUTOL (E) Directly Observed Therapy Short Course (DOTS)
 Pregnancy Risk Category B Components of DOTS
Pharmacodynamics Mechanism of Resistance  Political statement to sustain TB control activities
 Inhibition of arabinosyl  Resistance to E develops slowly; it is due to  Case detection by sputum smear microscopy
transferase involved in mutations in emb B gene that encodes  Standardized treatment regimen of 6-8mos., with directly observed
polymerization of arabinosyl transferase treatment (DOT) for at least the initial 2mos.
arabinoglycan Pharmacokinetics  A regular, uninterrupted supply of all essential anti-TB drugs
 Bacteriostatic at usual  Good oral absorption, not affected by food but  A standardized recording and reporting system that allows assessment of
doses (15mg/kg/d) delayed by aluminum hydroxide and alcohol treatment results for each patient and of the TB control program
 Bactericidal at higher  Distributed to most tissues, crosses BBB only Intensive or Bactericidal Phase Continuation Phase or Sterilizing Phase
doses (>25mg/kg/d) when inflamed, accumulates in lung tissue, age st
 1 2 mos.  Months 3-6
 Active for growing has no impact on distribution  Larger burden of TB  Fewer organisms
bacilli and has no effect  Tmax: within 2hrs  More replication  Slower growth phase
on non-replicating  Cmax: 4mcg/mL (after 15mg/kg/dose)  Bactericidal drugs needed  Sterilizing drugs needed
bacilli  T½: 10-15h at normal renal function; prolonged  At least 4 drugs needed  2 drugs needed
 MIC: 1-5mcg/mL renal faiure Preventive Chemotherapy for Tuberculosis
 Eliminated unchanged in the urine Clinical Form Current Treatment Guidelines
Therapeutic Uses Adverse Reactions TB Exposure 3H+ then repeat TST; if
1. To prevent emergence of  Retrobulbar neuritis: Impairment of  Neonate Rx essential  TST(+), CXR(-), asymptomatic,
microbial resistance to other visual acuity and red and green color  Children <5 years of age – Rx continue 6h more – see LTBI
anti-TB drugs (15mg/kg/d) vision (dose-related and duration indicated (Evaluate, rule out TB disease)
2. Intermittent therapy and for related)  TST(-), asymptomatic source case
drug-resistant TB (>25mg/kg/d) o Not given to children <6yo. treated and/or removed, discontinue
3. Treatment of NTTB  GIT symptoms H, give BCG after 2 weeks (for <5
Surveillance – Monthly evaluation of  Hyperuricemia due to decrease urate years old)
red and green color vision & visual excretion  Older children & adults  Patient at high risk of progression
acuity with dose of >15mg/kg  Hypersensitivity – Dermatitis, Risk 2-4% 1st year (no Rx) if and no evidence of active infections
arthralgia, fever repeat TST(-) should be treated for LTBI. For
others, repeat TST at 3mos.; no Rx if
Prevention and Control of TB repeat is (-)
1. Prompt detection of cases and provision of short course chemotherapy LTBI
(DOTS)  TST(+) organisms likely to be H  9H
o Case detection rate: 70% susceptible *3H/rifapentine (given once weekly)
o Cure Rate: at least 80%  TST(+) suspected H resistant  4R
2. Contact investigation and follow-up organism (H) resistant
3. Preventive therapy for LTBI, especially high risk persons  H/R resistant  Moxifloxacin  EMB once daily for 12
4. Immunization mos.
5. Improvement of socio-economic condition – long term solution
Recommended Treatment Regimens to TB Disease Fixed Dose Formulation
TB TB Patients TB Treatment Regimens Drug Formulation
Diagnostic Initial Phase Continuation ISONIAZID + ETHABUTOL Oral:
Category (Daily or 3x Phase - 150mg + 400mg tablet
weekly) (Daily or 3x - 200mg + 500mg tablet
weekly)
ISONIAZID + RIFAMPICIN Oral:
I  New smear positive patients 2 HRZE 4 HR
- 30mg + 60mg tablet (pediatric)
 New smear negative PTB with
extensive parenchymal - 60mg + 60mg tablet (pediatric)
(For intermittent use three times weekly)
involvement
 Severe concomitant HIV disease or - 75mg + 150mg tablet
severe forms of EPTB - 150mg + 150mg tablet
(For intermittent use three times weekly)
II Previously treated sputum smear 2 HRZES/ 5 HRE
positive PTB 1 HRZE - 100mg + 150mg tablet
 Relapse - 150mg + 300mg tablet
 Treatment after interruption - 200mg + 225mg tablet
 Treatment failure - 300mg + 450mg tablet
III New smear negative PTB with 2 HRZE 4 HR - 400mg + 450mg tablet
minimal parenchymal lesions on CXR - 600mg + 400mg tablet
IV Chroic and MDR-TB cases Specially designed ISONIAZID + RIFAMPICIN (B) Oral:
(still sputum-positive after supervised standardized or + PYRAZINAMIDE - 30mg + 60mg + 150mg tablet (pediatric)
re-treatment) individualized regimens are (For intermittent use three times weekly)
suggested for this category. - 75mg + 150mg + 400mg tablet
Immediate referral to PMTM - 150mg + 150mg + 500mg tablet
- 300mg + 450mg + 500mg tablet
WHO 2004 ISONIAZID + RIFAMPICIN (B) Oral:
Fixed Dose Combination Tablets (FDC) + PYRAZINAMIDE + - 60mg + 120mg + 300mg + 225mg tablet
Not combipacks but 2, 3, or 4 drugs in a single tablet
ETHAMBUTOL - 75mg + 150mg + 400mg + 275mg tablet
 Advantages
- 200mg + 450mg + 500mg + 400mg tablet
o Simplicity of treatment
(Restricted for 60 days use only)
o Monotherapy is avoided  less drug resistance
o Improved patient compliance ISONIAZID + THIACETAZONE Oral: 300mg + 150mg tablet
 Number of tablets to ingest is fewer
 Patient cannot be selective in the choice of drugs to ingest
 Disadvantages
o Prescription errors may result in excess dosage or sub-inhibitory concentrations
of all drugs
o Does not guarantee patient’s adherence
o Problem of bioavailability of RIFAMPIN in some formulations

Drug Resistance occurs when Drug Resistant Bacilli outgrow

the Drug Susceptible Bacilli DRUGS o STREPTOMYCIN
Types: MDR-TB – presence of at least 1% of o AMIKACIN & KANAMYCIN
 Primary – No Hx of previous mycobacterium strains in a bacterial  ETHIONAMIDE
treatment: initially infected with population or culture that are  CAPREOMYCIN
resistant organisms resistant to both H and R  CYCLOSERINE/TERIZODONE
 Secondary (acquired) – Drug XDR-TB – MDR + resistance to FQ and  PAS
resistance develops during 1 injectable drug  THIACETAZONE
treatment  Virtually untreatable Indications
Risk Factors for Drug Resistance  Used when resistance to 1st-line antituberculosis drugs is suspected or
 Prior therapy confirmed
 Non-adherence  Used when severe adverse effects to 1st-line drugs develop
 Under dosing  Used in case of failure of clinical response to 1 st-line drugs
 Country of origin has high prevalence of drug-resistant TB (Latin America,  Used when expert guidance is available to deal with the toxic effects
Asia, Africa) Principles for Treatment of MDR-TB
Genetic Resistance 1. Use 1st-line agents showing susceptibility (PYRAZINAMIDE, ETHAMBUTOL,
 Due to spontaneous  The probability of development of RIFABUTIN)
mutations in the simultaneous resistance to at least 2 drugs is 2. Include an injectable agent (STREPTOMYCIN, KANAMYCIN, AMIKACIN,
bacterial chromosomes multiplicative; several orders of magnitude CAPREOMYCIN)
 natural mutants greater than the infecting organisms  3. One fluoroquinolone (OFLOXACIN, LEVOFLOXACIN, MOXIFLOXACIN
 Determined by the size prevent emergence of DR bacilli – thereby 4. 2nd-line oral bacteriostatic anti-TB agents (CYCLOSERINE, PAS,
of the population – The averts treatment failure ETHIONAMIDE, TERIZIDONE)
bigger the population,  Untreated patient with advanced PTB (cavitary) 5. Group 5 agents (unclear efficacy) CLOFAZIMINE, LINEZOLID, AMOXICILLIN,
the greater the chance has a bacillary load of 109 bacilli CLAVULANATE, THIAZETAZONE, CLARITHROMYCIN, IMIPENEM
that one of its members  If given monotherapy: 6. Treat for 2 years after culture conversion
harbors a mutation o Drug susceptible bacilli get killed by the
 In a population of M. antibiotic while mutant bacilli resistant to
tuberculosis with the antibiotic grow unopposed and
multiple generations of dominate the population
bacilli, the ratio of drug-  Selection Pressure: Selective survival
resistant to susceptible advantage that resistant TB bacilli have in the
bacilli: presence of drugs to which they are resistant
o H 1:106  Giving combination therapy would prevent the
o R 1:108 emergence of drug resistant bacilli therapy
o Z 1:106 averts treatment failure

SECOND LINE ANTI-TB  Aminoglycocides AMINOGLYCOSIDES – STREPTOMYCIN

 Pregnancy Risk Category: D  Chemically related to H; blocks mycolic acid synthesis
Pharmacodynamics Mechanism of Resistance  Remains active when H resistance is due to Kat G gene mutations; ineffective
 Inhibits protein synthesis by binding  Resistant mutants occur in 1 in 10 8 if resistance is caused by inhA mutation
to 30s ribosomal subunit tubercle bacilli  Adverse Effects: GIT irritation, Obnoxious taste
 Bactericidal to actively multiplying  Resistance is due to mutations in
extracellular bacilli in alkaline S12 protein encoded by rpsl and 16s CAPREOMYCIN
medium and in caseous lining of the rRNA, encoded by ms gene, which
 Peptidepeptide protein synthesis inhibitor
walls of pulmonary cavitations alters the ribosomal binding site
 Important injectable agent for drug-resistant TB (if resistant to
Pharmacokinetics Therapeutic Uses
STREMTOMYCN or AMIKACIN)
 Poor penetration into cells;  Serious form of TB such as disseminated TB,
 Nephtrotoxicity; Ototoxic
MIC: 1-10mcg/mL TB meningitis
 Not absorbed from the GIT  MDR-TB known to be susceptible to it
 Distributed to most tissues; Adverse Reactions CYCLOSERINE/TERIZODONE
crosses inflammed  Ototoxicity: vestibular dysfunction (8%)  Inhibitor of cell wall synthesis
meninges tinnitus and high frequency hearing loss  Has no cross-resistance with other drugs; useful in 2nd-line regimen to
 Tmax – 1h after IM  Nephrotoxicity (Rare) prevent resistance to companion drug
injection  Paresthesia, dizziness, nausea  Most serious side effects: peripheral neuropathy, CNS dysfunction
 Cmax – 40mcg/mL after IM  Peripheral neuropathy including depression & psychosis
injection of 15 mg/kg dose  Allergy: fever, skin rashes; anaphylaxis;
 PYRIDOXINE 150mg/d should be given concomitantly
 T½ - 3h exfoliative dermititis
 Excretion: Excreted Surveillance
unchanged thru the  Monthly audiogram PAS
kidneys by glomerular  Serum creatinine, BUN at the onset (in older  Folic acid synthesis inhibitor
filtration patients)  Useful in patients with extended spectrum of resistance
 GIT symptoms including peptic ulcers and GIT hemorrhage
AMINOGLYCOSIDES – AMIKACIN & KANAMYCIN
 No cross-resistance with streptomycin and they can be used in the presence THIACETAZONE
of STREPTOMYCIN resistance  Inhibitor of cell wall synthesis
 Prevalence of AMIKACIN resistant strains is low (<5%) and most MDR strains  Associated with high incidence of severe toxic epidermal necrolysis
remain susceptible particularly in HIV infected patients
 Must not be used alone  Adverse Effects: GIT and neurosurgical
 2nd-line drug for MDR-TB including STREPTOMYCIN resistant and used with 2
or 3 drugs to which isolate is susceptible

NEW/REPURPOSED ANTI-TB  BEDAQUILINE

ETHIONAMIDE  DELAMANID
DRUGS  LINEZOLID  Undergoing phase III studies
 FLUOROQUINOLONES (C) Pharmacodynamics
 RIFAMYCINS  Blocks the synthesis of mycolic acid;
 In MDR-TB:
poisons the bacterial cell by oCulture conversion after
releasing nitric oxide when 2mos. of treatment with
BEDAQUILINE metabolized
 A diarylquinolone DELAMID + background
 Currently undergoing Phase III testing in pulmonary MDR-TB  Active against replicating and regimen was 45.4% vs 29.6%
 First new drug from a new class of drug to be approved for treatment of TB (US FDA non-replicating bacteria  has placebo + background
accelerated approval – part of combination therapy in adults [ 18yrs.] with pulmonary MDR- potential in shortening treatment regimen
TB)
Pharmacodynamics Pharmacokinetics for active disease and in the oMost frequent are nausea,
 Inhibits mycobacterial ATP synthase  Metabolism: metabolized by management of LTBI arthralgia, headache
 Strong mycobacterial and sterilizing CYP3A4; blood levels may be Pharmacokinetics
properties (laboratory tests and clinical reduced or increased by co-  Has no effect on the activity of CYP450; not affected by CYP450
trials) administration of CYP3A4 *Use only when effective treatment regimen cannot be provided
 Highly potent against drug susceptible inducers or inhibitors
and drug resistant strains of Adverse Effects
Mycobacterium tuberculosis  Prolongation of QT interval
LINEZOLID
 Phase II studies of 440 patients with
 An oxalidone
 Most frequent are nausea,
Pharmacodynamics Adverse Effects (Treatment limiting)
DR-TB: arthralgia, headache
o BEDAQUILINE + 5-drug background  Inhibits protein synthesis by binding  Bone marrow suppression
 Used with caution when co-
to 70s ribosomes  Irreversible peripheral and optic
regimen given for 6mos. achieved administered with CLOFAZIMINE
79% culture conversion vs. 58% who and FLUOROQUINOLONES  Broad spectrum of activity against neuritis
received placebo + background anaerobic and Gram (+) aerobic Drug of last resort for infections
 Should not be used with
regimen bacteria and mycobacteria caused by MDR-TB that are also
RIFAMPICIN and RIFAPENTINE
o Median time to conversion in  Used in combination regimen for resistant to several 1st and 2nd line
MDR-TB agents
BEDAQUILINE group was 12 wks. Vs. *Reserved for use when an
18wks in placebo arm effective treatment regimen
 Has potential for shortening treatment cannot be provided

DELAMANID FLUOROQUINOLONES (C)

 Nitro-dihydro-imidazooxazole  Broad spectrum antibiotic drugs (G+ and G-)
 Inhibit strains of M. tubercolosis at concentration less than 2mcg/mL
 Used as second-line drugs for the treatment of MDR-TB
 FATIFLOXACIN and MOXIFLOXACIN have better in-vitro activity against
Mycobacterium tuberculosis than CIPROFLOXACIN
 Regimens containing new FQ have the potantial to shorten treatment of DS
TB from 6mos. to 4 mos.
 Rates of 2-month sputum culture conversion showed better results in phase
2 trials in which GATIFLOXACIN or MOXIFLOXACIN was substituted for E or H
in the control regimen
 Phase 3 trials are in progress to investigate whether treatment of DS TB can
be shortened to 4mos. by substitution of GATIFLOXACIN for E, or
MOXIFLOXACIN for E or H

RIFAMYCINS (RIFAMPICIN, RIFAPENTINE, RIFABUTIN)

 RIFAMPICIN is a key component of TB treatment
 Increased exposure to R leads to improved bactericidal activity in mice and in
humans
 High dose of R for DS TB might shorten treatment to 3mos.
 RIFAPENTINE, a potent analog with longer half-life is being evaluated for
active TB and LTBI
 In LTBI – RIFAPENTINE 900mg + H 900mg given once a week for 3mos. was
not inferior to the standard 9 months with H.

VACCINES TO PREVENT TB
BCG (BACILLE-CALMETTE-GUERIN)
 Protects against severe forms of TB in children (TB meningitis and miliary TB)
 Variable efficacy in preventing PTB in adults
New vaccines currently under development
To Prevent:
 Pre-exposure (infection)
 Primary progression to disease or reactivation of LTBI (post-exposure) – eg. MYA85A,
an attenuated vaccinia vectored candidate designed as a booster vaccine for infants,
adolescents and adult
To improve responsiveness to chemotherapy (used as immunne-therapeutic agent)
First Line Anti-TB Drugs Toxicity
Drug Mechanism of Action Main Adverse Effects Single Intermitten Drug Mechanism of Action Main Adverse Events* Single Daily Dose
oral** t oral (mg/kg [max]
daily 3k/wk route)
dose dose*** ETHIONAMIDE (ETH) -Bactericidal - GIT upset 15-20 (750mg)
-Inhibition of cell - Hepatotoxicity oral
(mg/kg (mg/kg
wall (mycolic acid) - Hypothyroidism
[max]) [max])
ISONIAZID (H) - Inhibition of cell wall - Peripheral 10-15 20-30 synthesis
(mycolic acid) neuropathy (300mg) (900mg) FLUOROQUINOLONES+ -Bactericidal - Arthralgia 15-20 (800mg) oral
synthesis - Hepatotoxicity* - OFLOXACIN -Inhibition of DNA - Insomnia, headache, 7.5-10 (750mg)
restlessness, confusion oral
- Bactericidal - DME Inhibition - LEVOFLOXACIN gyrase 7.5-10 (400mg)
- GI upset
RIFAMPICIN (R) - Inhibition of RNA - Hepatotoxicity 10-20 10-20 - MOXIFLOXACIN (transcription) oral
synthesis - Arthralgia (older (600mg) (600mg) AMINOGLYCOSIDES -Bactericidal - Auditory & vestibular 20-40 (1g) IM
- Bactericidal/Sterilizing children & adults) - STREPTOMYCIN -Inhibition of toxicity 15-30 (1g) IM/IV
- Hyperuricemia - Nephrotoxicity 15-30 (1g) IM/IV
- KANAMYCIN protein synthesis
PYRAZINAMIDE - Disruption of - Hepatotoxicity 20-40 50 - AMIKACIN
(Z) membrane energy - Arthralgia (older (2g) (2g) POLYPEPTIDE -Bactericidal - Auditory and 15-30 (1g) IM
metabolism children & adults) - CAPREOMYCIN -Inhibition of vestibular toxicity
- Sterilizing - Hyperuricemia protein synthesis - Nephrotoxicity
ETHAMBUTOL - Inhibition of cell wall - Optic neuritis 15-25 30-50 CYCLOSERINE C -Bacteriostatic - Personality changes, 10-20 (1g) oral
(E) (arabinogal actan) - Impaired red-green (1.2g) (2.5g) Derivative -Inhibition of cell psychosis, depression
synthesis color discrimination - TERIZODONE wall - Seizures
- Bacteriostatic at low (usually reversible) (peptidoglycan)
dose synthesis
- Bactericidal at high PARA-AMINOSALICYLIC -Bacteriostatic - GI upset 150mg (12g) oral
dose ACID (PAS)  C -Inhibits folic acid - Hypothyroidism
- Delays emergence od synthesis and iron - Crystalluria
drug resistance metabolism
*Skin rash may occur with any drug, H & E least likely; THIACETAZONE, most likely THIACETAZONE -Bacteriostatic - Gastric irritation 2.5 (max 150mg)
when in combination with RIFAMPICIN, hepatotoxicity increases if h dose exceeds -Inhibition of cell - Bone marrow PO
wall synthesis suppression
10mg/kg/day
- Cutaneous reaction in
DME – drug metabolized enzyme inhibition or induction can lead to serious adverse (mycolic acid)
HIV patients
drug interaction with other drugs LINEZOLID -Bacteriostatic - Bone marrow 1200mg in 2 doses
**total daily dose of each drug should be taken as a single dose; splitting of dose may -Inhibition of suppression
- Irreversible Peripheral
result in sub-therapeutic levels protein synthesis
and optic neuropathy
***thrice weekly treatment is not recommended by WHO RIFABUTIN -Bactericidal - Hepatotoxicity, 5mg/kg (300mg)
 – To be used in consultation with TB specialist myositis,
-Inhibition of RNA
* – Skin rash may occur with any drug thrombocytopenia,
+ – Not for children <18yrs. old for theoretical risk of arthropathy but may be used for MDR-TB RIFAPENTINE synthesis 10mg/kg (600mg)
neutropenia,
 – Split dose initially; if ni GIT adverse events, give once daily hypersensitivity,
 – Dose adjustment in renal insufficienct orange color of body
 – Currently not available in the Philippines market fluids; yellowish-tan
NB – Thiacetazone, formerly listed as an essential anti-TB agent by WHO, is no longer recommended since it skin (pseudo jaundice)
is associated with high incidence of severe toxic epidermal necrolysis, gastrointestinal and neurological
adverse effects, particularly in HIV-infected patients
Second-Line Anti-TB Drugs for Drug Resistance, Drug Intolerance, or DRUGS FOR NON-TUBERCULOUS MYCOBACTERIA
(MOTT, ATYPICAL)
DRUGS USED IN LEPROSY
Aims of Treatment:
 To cure the disease
 To render patient
noncontagious in in order to cut
down transmission
MDT is the regimen of choice for
all cases of leprosy
DAPSONE
 Pregnancy Risk Category C
 MOA: Competitive inhibitor
of dihyropteroate synthesis,
inhibiiting folate synthesis
 Bacteriostatic vs. M. leprae
Therapeutic Indications
 All forms of leprosy
 Dermatitis herpetiformis
 Prophylaxis & treatment of
Pneumocystitis jiroveci
pneumonia
Contraindication
 Hypersensitivity to DAPSONE  Dose-related hemolysis, methemoglobinemia
or any component
Precautions in patients with:
 Severe anemia
 G8PD deficiency  Hemolysis
 Hypersensitivity to
sulfonamides
Preparation: 25, 100mg tablets
RIFAMPICIN
 DAPSONE
 RIFAMPICIN
 CLOFAZIMINE
 MINOCYCLINE
Advantages
 Effective in cases with primary DAPTONE
resistance
 Prevents emergence of drug resistance
 Affords quick symptom relief and
renders MBL contagious
 Reduces total duration of therapy
Pharmacokinetics
 Slowly but completely absorbed (100%) from
oral route and distributed to all body tissues
and fluids
o Tends to be retained in the skin, muscle,
liver, and kidneys
o Skin heavily infected with M. leprae contain
several times as much as normal skin
 T½: 1-2 days
 Metabolized in the liver and excreted into the
bile, reabsorbed in the inestine and finally
excreted in the urine
Adverse Reactions
with cyanosis; peripheral neuropathy;
insomnia, headache, exfoliative dermatitis,
leukopenia, agranulocytosis, cholestatic
jaundice, blurred vision; sulfone syndrome;
ENL after initial DAPSONE therapy in those
with multibacillary disease
 Pregnancy Risk Category C
MOA & Pharmacokinetics Clinical Use:
(See under anti-TB drugs)  To prevent emergence of RIFAMPICIN resistant
 Bactericidal for M. leprae M. leprae, it is usually given in combination
 Strikingly effective in with DAPSONE or another anti-leprosy drug
lepromatous leprosy;  A single monthly dose of 600mg may be
infectivity is reversed beneficial in combination therapy
rapidly  Cost is greatest limiting factor in its clinical use
CLOFAZIMINE
 Pregnancy Risk Category C (*to be avoided)
 A Phenazine dye
Mechanism of Action
 Weakly bactericidal vs. M. leprae by binding preferentially to mycobacterial DNA to
inhibit mycobacterial growth, exerts anti-inflammatory effect
Mechanism of Action Pharmacokinetics
 Weakly bactericidal vs. M. leprae by binding  Absorbed orally
preferentially to mycobacterial DNA to  Accumulates in the tissues for
inhibit mycobacterial growth, exerts anti- prolonged periods making possible
inflammatory effect discontinuous therapy separated by
Therapeutic Indications 4wks
 Combination regimen with DAPSONE &  Highly lipophilic
RIFAMPICIN for multibacillary leprosy  Does not cross BBB
 Erythema Nodosum Leprosum (ENL)  Stored in the RES and skn
 Mycobacterium avium intracllulare  T½: 2mos. metabolized in liver
infection  Excreted in feces
Therapeutic Indications
 Combination regimen with DAPSONE & RIFAMPICIN for multibacillary leprosy
 Erythema Nodosum Leprosum (ENL)
 Mycobacterium avium intracllulare infection
Precautions Adverse Reactions
 Avoid treatment with daily  Gastric irritation and diarrhea in high doses
doses exceeding 100mg  Pink to brownish black discoloration of skin
 Crosses placental barrier and  Conjunctivase and urine and blue black
excreted in breast milk discoloration of lesions
 Use with caution during the  Rash, pruritus, elevate blood sugar, phototoxicity
first trimester of pregnancy  Hepatitis
Preparations: 50mg capsule
 Should be undertaken in consultation in an expert in leprosy
MINOCYCLINE
Pauciballary Leprosy Multibacillary Leprosy
 Pregnancy Risk Factor D
(PB) (MB)
Pharmacokinetics/Pharmacodynamics
RIFAMPIN 600mg once a month 600mg once a month
 Bacteriostatic
(supervised) (supervised)
 Long acting Tetracycline (T½: 16-18h; almost complete absorption and slow
DAPSONE 100mg daily (self- 100mg daily (self-
excretion allow once daily dosing)
administered) administered)
 100mg/d dose produces peak blood levels that exceed MIC against M. leprae
CLOFAZIMINE 300mg once a month
by 10-20 times
(supervised)
 See tetracyclines
50mg daily (self
Adverse Reactions
administered)
 Similar to other tetracyclines:Vestibular symptoms (30-90%), vertigo (33%),
Duration 6mos. 12mos.
ataxia (43%), nausea (50%), vomiting (3%) SLPB Single Dose: R 600mg + OFOXACIN 400mg + MINOCYCLINE 100mg
 women more frequently than men
 Reversible Treatment of Erythema Nodosum Leprosum (ENL)
 Hypersensitivity, pneumonitis (Commonly occurs in patients with multibacillary disease after drug therapy is
initiated)
1. THALIDOMIDE
o Treatment of choice; acts thru inhibition of tumor necrosis factor
o Pregnancy Risk Categoy X
o Contraindicated in women of child bearing age; causes severe life-
threatening birth defects
2. CORTICOSTEROIDS (PREDNISONE) – Alternative in patients in whom
THALIDOMIDE is unacceptable
3. CLOFAZIMINE

Treatment Regimen for Leprosy

DRUGS FOR NON-TUBERCULOUS MYCOBACTERIA Pregnancy Risk Factors:

(NTMB)
Clinical features and treatment options for infections with atypical (non-
tuberculous, environmental) mycobacteria