Anti tuberculosis

1. ANTIMICROBIALS-6
RUTH MBUGUA

2. Antimycobacterial agents
• The main mycobacterium infections are the
tuberculosis and leprosy.
• The treatment of TB assumes the principle of
combination therapy for two main reasons:
To prevent emergence of resistant (tubercle
bacilli which develops resistance very fast when
monotherapy is used).
To reduce the rate of spread by reducing the
bacterial population rapidly.
• For this reason the available tablets contain
multiple drugs in Fixed Dose Combinations (FDC)

3. Drugs for management of Tuberculosis,
Mycobacterium avium Complex and Leprosy
M. tuberculosis
• First line of treatment
• Isoniazid + rifampin*+pyrazinamide + ethambutol or
streptomycin
• Alternative
• Moxifloxacin or gatifloxacin; cycloserine; capreomycin;
kanamycin; amikacin; ethionamide; clofazimine;
aminosalicylic acid
M. kansasii
• First line of treatment
• Isoniazid + rifampin*+ ethambutol
• Alternate
• Trimethoprim-sulfamethoxazole; ethionamide; cycloserine;
clarithromycin; amikacin; streptomycin; moxifloxacin or
gatifloxacin

4. M. avium complex
• First line of treatment
• Clarithromycin or azithromycin + ethambutol with
or without rifabutin
• Alternate
• Rifabutin; rifampin; ethionamide; cycloserine;
moxifloxacin or gatifloxacin
M. leprae
• First line of treatment
• Dapsone + rifampin ± clofazimine
• Alternate
• Minocycline; moxifloxacin or gatifloxacin;
clarithromycin; ethionamide

5. Anti tuberculosis agents
• Tuberculosis has been a killer disease till around
40 years ago when most of the current anti TB
drugs were invented.
• However, the problem has re-emerged again as a
big challenge to health due to multidrug resistant
strains.
• TB kills approximately 2million persons per year.

6. • Anti TB agents are divided into first line and
second line drugs.
• The first or second line criterion is not a universal
principle but depend on local scientific evidence.
• The first line drugs include isoniazid,
rifampin/rifampicin, ethambutol, pyrazinamide
streptomycin .
• While the second line drug include capreomycim,
cycloserine, clarithromycin and ciprofloxacin.

7. Antimicrobials Used in the Treatment
of Tuberculosis.
Drug Typical Adult Dosage
First-line agents
Isoniazid 300 mg/d
Rifampin 600 mg/d
Pyrazinamide 25 mg/kg/d
Ethambutol 15–25 mg/kg/d
Streptomycin 15 mg/kg/d

8. Antimicrobials Used in the Treatment
of Tuberculosis.
SECOND LINE
Amikacin 15 mg/kg/d
Aminosalicylic acid 8–12 g/d
Capreomycin 15 mg/kg/d
Ciprofloxacin 1500 mg/d, divided
Clofazimine 200 mg/d
Cycloserine 500–1000 mg/d, divided
Ethionamide 500–750 mg/d
Levofloxacin 500 mg/d
Rifabutin 300 mg/d2
Rifapentine 600 mg once or twice weekly

9. Tuberculosis treatment
• First initial phase: takes two months and three
drugs are used concomitantly.
• These include Isoniazid, Rifampicin, Pyrazinamide
(plus ethambutol or streptomycin) if resistant
organism suspected. This combination reduces
bacterial population rapidly.
• Continuation phase: takes four months and two
drugs are used. These are isoniazid and
rifampicin.
• Sometimes ethambutol may be used instead of
rifampicin in which case the treatment proceeds
for 6 months instead of 4 months.

10. Isoniazid
Isoniazid remains the primary drug for tuberculosis.
All patients with disease caused by sensitive strains
should receive the drug if they can tolerate it.
Pharmacodynamics:
• Its postulated to inhibit synthesis of mycolic acid,
important constituents of cell wall and peculiar to
mycobacterium.
• Therefore they are bacteriostatic against resting
organism but can also kill dividing bacteria.
• Resistance is due to reduced penetration in the
mycobacterial cell.

11. Pharmacokinetics
• It has good gut absorption and wide distribution.
Metabolism is usually though acetylation.
• It portrays slow and fast acetylation properties.
• Half life in slow in acetylators is three hours and rapid
acetylators is one hour.
• The excreted in urine partly unchanged and partly
acetylated form.
Unwanted effects:
• These are dose- dependent and occur in 5% of
patients.
• Allergy skin eruptions are the commonest side effects.
• Others include; fever, hepatotoxity, hematological
changes, arthritic symptoms and vasculitis.

12. • Others are hemolytic anemia- in glucose 6
phosphate dehydrogenase deficiency patients.
• CNS effects due to pyridoxine deficiency especially
in malnourished persons.
• Pyridoxal- hydrazone formation occurs especially
in slow acetylators
Drug interactions
• Inhibit metabolism of antiepileptic agents like
ethosuximide, carbamazapine which lead to
increased plasma concentration and potential
toxicity of these drugs.

13. Rifampicin (rifampin)
• This is one of the most active anti TB known. It is
also active against gram positive and negative
bacteria.
Pharmacodynamics
• It acts by inhibiting DNA –dependent RNA
polymerase leading to suppression of initiation of
chain formation in RNA synthesis.
• High inhibit RNA synthesis and is bactericidal
• Resistance is due to one to chromosomal
mutation leading to chemical modification of
microbial DNA dependent RNA polymerase.

14. Pharmacokinetics.
• It is given orally and has a wide distribution.
• It causes orange tinge coloration to saliva, sputum,
tears and sweat.
• In CSF, it reaches 10 to 40% of plasma
concentrations.
• It is excreted in urine and undergoes heterohepatic
recycling.
• Metabolism is in the liver and the metabolite has
antibacterial activity but poorly absorbed from the
gut.
• Half life is 1-5 hours but reduces during treatment
since it induces microsomal enzymes, hence its own
metabolism.

15. Unwanted Effects
• These are often infrequent. However the
commonest are skin eruptions.
• Others include fever, GIT disturbances.
• Liver damage which is fatal with small number of
patients. (Asses for liver function before
treatment).

16. • Drug interactions
• As a potent inducer of hepatic CYPs, rifampin
decreases the t1/2 of many drugs, including HIV
protease and non-nucleoside reverse
transcriptase inhibitors.
• Others include digoxin, quinidine, disopyramide,
mexiletine, tocainide, ketoconazole, propranolol,
metoprolol, clofibrate, verapamil, methadone,
cyclosporine, glucocorticoids, oral anticoagulants,
theophylline, barbiturates, oral contraceptives,
halothane, fluconazole, and the sulfonylureas.

17. • Rifampin for oral administration is available
alone
• Its also available as a fixed- dose combination
with isoniazid (150 mg of isoniazid, 300 mg of
rifampin)
• Also with isoniazid and pyrazinamide (50 mg of
isoniazid
• Or 120 mg of rifampin, and 300 mg
pyrazinamide

18. • Rifabutin is a rifampin derivative and has the
same mechanism of action.
• Because rifabutin is a less potent inducer of CYPs,
it is used in tuberculosis-infected HIV patients
treated concurrently with protease inhibitors.
• Unique side effects of rifabutin include
polymyalgia and anterior uveitis.
• About 25% of rifampin-resistant M. tuberculosis
isolates are rifabutin-sensitive, so it may have a
role in the treatment of multidrug-resistant
tuberculosis.

19. Ethambutol
Pharmacodynamics
• Mechanism of action is through inhibition of arabinosyl
transferases involved in cell wall biosynthesis.
• Resistance to ethambutol develops very slowly but can
result from single amino acid mutations when given alone.
Phamacokinetics:
• Good absorption from GIT and peak plasma within four
hours.
• Taken up by erythrocytes and slowly released.
• Metabolism occurs in the liver with half life of three to
four hours.
• It is excreted in urine.
• It can reach therapeutic concentrated with CFS for
tuberculosis, meningitis.

20. Unwanted Effects
• These are common. Important ones include optic
neuritis –dose –related especially if renal function
decreases.
• Leading to visual disturbances, red green color
blindness followed by decrease in visual activity.
• Monitor color vision in long term treatments.

21. Pyrazinamide
Pharmacodynamics
• It is often inactive in neutral PH.
• It’s tuberculostastic at acidic PH. The target is the
mycobacterial fatty acid synthase I gene involved in
mycolic acid biosynthesis.
• Resistance develops rapidly if pyrazinamide is used
alone.
• It is very effective against intracellular organisms in
macrophages since after phagocytosis, the PH is low.
Pharmacokinetics:
• It has good gut absorption and a wide distribution in
that it crosses the blood brain barrier BBB.
• Its excretion is through kidneys.

22. • Unwanted effects:
• Gout, Git upsets, Malaise, Fever, hepatic
damage may occur in high doses.
• Assess liver functions before treatment.

23. STREPTOMYCIN
Antibacterial activity
• Streptomycin is bactericidal for the tubercle
bacillus.
• The vast majority of strains of M. tuberculosis are
sensitive. M. kansasii is frequently sensitive, but
not other mycobacteria.
• Streptomycin does not eradicate the tubercle
bacillus because the drug does not readily enter
living cells and thus cannot kill intracellular
microbes.

24. • Bacterial resistance
• Primary resistance to streptomycin is found in
only 2–3% of isolates of M. tuberculosis.
• The longer therapy, the greater the incidence
of resistance.

25. THERAPEUTIC USES
• The use of streptomycin for the treatment of
pulmonary tuberculosis has declined sharply.
• Many clinicians still prefer to give 4 drugs, of which
streptomycin may be one, for the most serious forms
of tuberculosis.
• Adults should be given 15 mg/kg/day in divided
doses given by intramuscular injection every 12 hours,
not to exceed 1 g/day.
• Children should receive 20–40 mg/kg/day in divided
doses every 12–24 hours, not to exceed 1 g/day.
• Therapy usually is discontinued after 2–3 months, or
sooner if cultures become negative.

26. • Untoward effects
• In tuberculosis patients treated with
streptomycin, 8% had adverse reactions;
• Half of which involved the auditory and
vestibular functions of the eighth cranial nerve.
• Other problems included rash and fever.

27. Other drugs
• Quinolones
• The fluoroquinolones are highly active against M.
tuberculosis and are important drugs for
multidrug- resistant tuberculosis.
• Agents such as gatifloxacin and moxifloxacin
are most active and least likely to select for
quinolone resistance.
• Mycobacterial resistance to one fluoroquinolone
imparts cross-resistance for the entire class.

28. AMINOSALICYLIC ACID
• Antibacterial activity
• Aminosalicylic acid is bacteriostatic. Most strains of
M. tuberculosis are sensitive to a concentration of 1
mg/mL.
• Microorganisms other than M. tuberculosis are
unaffected.
Mechanism of action and bacterial resistance
• Aminosalicylic acid is a structural analog of para-
aminobenzoic acid, and has the same mechanism of
action as the sulfonamides.
• Nonetheless, the sulfonamides are ineffective
against M. tuberculosis, and aminosalicylic acid is
inactive against sulfonamide-susceptible bacteria.
• Resistant strains of tubercle bacilli emerge slowly in
patients treated with aminosalicylic acid.

29. Absorption, distribution, and excretion
• Aminosalicylic acid is readily absorbed from the
GI tract.
• The drug is distributed throughout total body
water; it reaches high concentrations in pleural
fluid and caseous tissue, but CSF levels are low.
• It has a t1/2 of 1 hour, and concentrations in
plasma are negligible within 4–5 hours after a
single dose.
• Over 80% of the drug is excreted in the urine.
• The drug should not be used in the setting of
renal insufficiency.

30. • Therapeutic uses
• Aminosalicylic acid is a second-line agent in the
management of tuberculosis.
• It is administered orally in a daily dose of 10–12 g.
• Because of GI irritation, it is administered after
meals and divided into 2–4 equal portions.
• Children should receive 150–300 mg/kg/day in 3–4
divided doses.

31. Untoward effects
• GI problems (e.g., anorexia, nausea, epigastric pain,
and diarrhea)
• Patients with peptic ulcers tolerate the drug poorly.
• Hypersensitivity reactions to aminosalicylic acid
• Fever may develop abruptly or may appear gradually
and be low-grade.
• Generalized malaise, arthralgias, and sore throat may
be present.
• Rashes appear as isolated reactions or accompanied
by fever.
• Hematological abnormalities include leukopenia,
agranulocytosis, eosinophilia, lymphocytosis,
thrombocytopenia, and hemolytic anemia.

32. CYCLOSERINE
• Cycloserine is a broad-spectrum antibiotic that
is used with other drugs in the treatment of
tuberculosis when primary agents have failed.
Cycloserine is D-4-amino-3-isoxazolidone.
• Antibacterial activity
• Cycloserine inhibits M. tuberculosis in
concentrations of 5–20 mg/mL
Mechanism of action
• Cycloserine and D-Ala are structural analogs;
thus, cycloserine inhibits bacterial cell-wall
synthesis.

33. Absorption, distribution, and excretion
• When given orally, 70–90% of cycloserine is
rapidly absorbed.
• Cycloserine is distributed throughout body
fluids and tissues.
• About 50% of a parenteral dose of cycloserine is
excreted unchanged in the urine in the first 12
hours.
• Very little of the antibiotic is metabolized.
• The drug may reach toxic concentrations in
patients with renal insufficiency.

34. • Therapeutic uses
• Cycloserine is used only when retreatment is
necessary or microorganisms are resistant to
otherdrugs.
• It must be given together with other effective
agents. The usual dose for adults is 250–500
mg twice daily.

35. • Untoward effects
• They include: somnolence, headache, tremor,
dysarthria, vertigo, confusion, nervousness,
irritability, psychotic states, paranoid reactions,
catatonic reactions, twitching, ankle clonus,
hyperreflexia, visual disturbances, paresis, and
seizures.
• Large doses or concomitant ingestion of alcohol
increases the risk of seizures.
• Cycloserine is contraindicated in individuals with a
history of epilepsy and should be used with
caution in individuals with a history of depression.

36. Chemotherapy of tuberculosis
• Patients must be seen frequently to follow the
course of their disease and treatment.
• Contact tracing and prophylactic treatment.
• To prevent the development of resistance to these
agents, treatment must include at least 2 drugs to
which the bacteria are sensitive.
• Drug interactions are a special concern in patients
receiving highly active antiretroviral therapy
(HAART).
• Directly observed therapy(DOTs) is best and
ensures treatment completion rates of ~90%.

37. Drugs used to treat Leprosy.
• For paucibacillary leprosy i.e. leprosy due to few
bacilli the treatment is with dapsone and
rifampicin for six months while
• For multibacillary leprosy i.e. leprosy due to
numerous (lepromatous type) bacilli the
treatment for at least two years with Rifampin,
dapsone, clofazimine.

38. SULFONES
Dapsone
Pharmacodynamics:
• Dapsone is chemically related to sulfonamides and
it acts by inhibiting the enzyme dihydrofolate
reductase hence inhibits folate synthesis.
• Dapsone is bacteriostatic for M. leprae due to
competitive inhibiton of dihydropteroate synthase,
which prevents bacterial utilization of para-
aminobenzoic acid.
• Resistance to this drug has been increasing; hence
it’s combined with others during treatment.

39. Therapeutic uses
• Dapsone is given orally with a daily dose of
100 mg.
• Therapy usually is begun with smaller
amounts, and doses are increased to those
recommended over 1–2 months.
• Therapy should be continued for at least 3
years and may be necessary for life.

40. • M. leprae may develop drug resistance during
therapy, which is termed secondary resistance;
this typically occurs in lepromatous
(multibacillary) patients treated with a single
drug.
• Partial-to-complete primary resistance in
previously untreated patients has been described
in 2.5–40% of patients, depending on
geographical location.

41. Pharmacokinetics
• This drug has good oral absorption.
• It undergoes enterohepatic recycling.
• It has a half life of 24-48 hours and is excreted in
feces.
Unwanted effects:
• Haemolysis of red blood cells;
• Anorexia, nausea and vomiting;
• fever; allergic dermatitis;
• neuropathy;
• leprareaction where there is exacerbation of
lepromatous lesions can occur and a syndrome
resembling infectious mononucleosis which can be
fatal.

42. Rifampin
• Rifampin is rapidly bactericidal for M. leprae
with a minimal inhibitory concentration of <1
mg/mL.
• Infectivity of patients is reversed rapidly by
therapy that includes rifampin.

43. Clofazimine
• Clofazimine (LAMPRENE) binds preferentially to GC-
rich mycobacterial DNA
• It increases mycobacterial phospholipase A2
activity, and inhibits microbial K transport.
• It is weakly bactericidal against M. intracellulare.
• The drug also exerts an anti-inflammatory effect and
prevents the development of erythema nodosum
leprosum.
• Clofazimine is recommended as a component of
multiple- drug therapy for leprosy.
• It also is useful for treatment of chronic skin ulcers
produced by Mycobacterium ulcerans.

44. • Clofazimine is orally absorbed and accumulates in
tissues.
• Human leprosy from which dapsone-resistant bacilli
have been recovered has been treated with
clofazimine with good results.
• However, unlike dapsone-sensitive microorganisms,
in which killing occurs immediately after dapsone is
administered, dapsone-resistant strains do not
exhibit an appreciable effect until 50 days after
initiation of therapy with clofazimine.
• The daily dose of clofazimine is usually 100 mg.
• Patients treated with clofazimine may develop red
discoloration of the skin.

45. • The WHO recommends therapy with multiple drugs
for all patients with leprosy to reduce the
development of resistance and reduce the duration
of therapy.
• For patients with lepromatous disease, the following
regimen is suggested: dapsone, 100 mg/day; plus
clofazimine, 50 mg/day (unsupervised); plus
rifampin, 600 mg, and clofazimine, 300 mg, once a
month under supervision for 1–5 years.
• Some prefer to treat lepromatous leprosy with daily
dapsone (100 mg) and daily rifampin (450–600 mg).
All drugs are given orally.
• The minimal duration of therapy is 2 years, and
treatment should continue until acid- fast bacilli are
not detected in lesions.

46. • Patients with a small population of bacteria
(i.e., with tuberculoid disease) should be
treated with dapsone, 100 mg daily, plus
rifampin, 600 mg once monthly for a minimum
of 6 months.
• The regimen is repeated if relapse occurs.
Single-dose multidrug therapy with rifampin
(600 mg), ofloxacin (400 mg), or minocycline
(100 mg) also may be as effective.