Transcript Slide 1

A. Characteristics
I. Slowly growing organism; making them
relatively resistant to antibiotics
II. Mycobacterial cells can also be dormant
and thus completely resistant to many drugs
III. Lipid rich mycobacterial cell wall is
impermeable to many agents
IV. Substantial proportion of mycobacterial
organism are intracellular, residing with
macrophages and inaccessible to drugs
V. Notorious for their ability to develop
resistance to any single drug
B. Agents
 Drugs used in
Tuberculosis
 Drugs used in Atypical
mycobacteria
 Drugs used in Leprosy
Drugs used in
Tuberculosis
First line Anti TB
Drugs
1)Isoniazid
2)Rifampin
3)Pyrazinamide
4)Ethambutol
5)Streptomycin
Isoniazid
 The most active drug for the treatment of TB
 (1952), a small (MW 137) simple molecule freely soluble
in water
 Bactericidal; active-intracellular and extracellular
organisms
 Less effective in atypical mycobacteria
 MOA: inhibits synthesis of mycolic acid
 Availability: 50, 100, 300mg tab; 100-200mg/5ml susp.
 Resistance - due to mutations:
a. inhA
b. katG
c. ahpC
d. kasA
- if used as a single drug, 10-20% prevalence
 Kinetics: readily absorbed in the GIT; serum conc. 35ug/ml in 1-2 hrs.; acetylation by liver N-acetyltransferase
(rapid acetylators vs. slow acetylators); urine
 Dynamics:
dose: 5mgkd (child) or 300mgd (adult) daily
15mgkd or 900mg in twice weekly dosing
+ rifampin 600mg
- add Pyridoxine 25-50mgd if (+) neuropathy
- as a single agent in cases of:
a. recent converters
b. immunocompromised individuals
c. close contacts
d. abnormal CXR but activity has been R/O
300mgd or 900mg twice weekly x 6 mos.
 Adverse effects:
a. allergic reactions – fever, rashes, drug-induced SLE
b. hepatitis – major toxic effect; age-dependent; 10-20%
asymptomatic; if with clinical hepatitis, D/C INH;
acetylhydrazide
c. peripheral neuropathy – seen in 10-20% being given
>5mgkd
d. misc. reactions – hematologic abnormality, GI
discomfort
 Drug interaction: phenytoin, AlOH
Rifampin
 A large (MW 823) complex semisynthetic derivative of
Rifamycin ( Streptomyces mediterranei)
 Active against gm (+), gm(-) cocci, some enteric bacteria,
chlamydia
 Cross resistance with Rifabutin
 Bactericidal; penetrates intracellularly
 MOA: binds with the β-subunit of bacterial DNA dependent
RNA polymerase → inhibit RNA synthesis
 Resistance: mutations in rpoβ
 Kinetics: well absorbed; highly protein-bound (↑ in CSF in
meningeal inflammation); excreted in bile, feces, urine;
undergoes enterohepatic recirculation
 Clinical uses:
a. mycobacterial infection
600mgd (10mgkd) + INH, Ethambutol x 6 mos.
atypical mycobacteria 600mgd or 2x weekly
x 6 mos.
leprosy 600mgd or 2x weekly x 6 mos.
+ sulfone
b. other indications:
meningococcal carriage 600mgd x 2 days
H. influenzae typeB contact – 20mgkd x 4 days
staph. - + another agent
pneumococci (meningitis) - + ceftriaxone or vancomycin
 Adverse effect:
a. orange color urine, sweat, tears, contact lens
b. cholestatic jaundice
c. flu-like syndrome – if given < 2x weekly
d. hepatitis – occ.
 Drug interaction: microsomal enzyme inducer
(methadone, anticoagulant, protease inhibitor, some
anticonvulsant, ketoconazole, contraceptive, cyclosporine,
chloramphenicol)
Ethambutol
 Synthetic, water-soluble, heat stable compound
 MOA: inhibitor of mycobacterial arabinosyl
transferase (involved in the polymeration of arabinoglycan, an essential component of mycobacterial
cell wall barrier) by embCAB operon
 Resistance: mutations within the embB structural
gene or overexpression of emb gene products
 Kinetics: well wbsorbed; CSF conc. –variable (469% in inflammed meninges); excreted 20% feces,
50% urine (reduced dose by half if with renal failure)
 Dose: 15-25 mgkd + INH + Rifampin
50mgkg twice weekly dosing
 Adverse effect:
retrobulbar neuritis – most common; loss of
visual acuity and red-green color blindness);
dose-related (25mgkd)
hyperuricemia
 C/I: very young children because visual acuity
assessment is difficult
Pyrazinamide
 A relative of nicotinamide, stable, inexpensive
 Inhibits intracellular organism
 MOA: inhibits mycobacterial fatty acid synthase I involved in mycolic
acid synthesis
 Resistance: mutations in pncA
 Kinetics: well absorbed; distributed widely, in inflammed meninges; t1/2
8-11 hrs.
 Clinical use:
a. 25mgkd + INH + Rifampin x 6 mos. or
50-70mgkg 2x-3x weekly dosing
b. multi-drug resistant cases
PZA + Ciprofloxacin or Ofloxacin
-prevention of active disease in close
contacts and recent converters
 Adverse effects:
a. hepatotoxicity (1-5%)
b. nausea, vomiting
c. drug fever
d. hyperuricemia (gouty arthritis)
Streptomycin
 Resistant to some non-tuberculous species
 Extracellular tubercle bacilli; inflammed
meninges
 MOA: interfere with protein synthesis (30s
subunit)
 Resistance: point mutation in rpsL gene or
rrs that alters the ribosomal binding site
 Clinical use:
a. severe, life threatening forms of TB
b. drug resistance
 Dose: 15mgkd IM or IV x several weeks ffed.
by 1-1.5gm. 2-3x weekly x 6 mos.
 Adverse reaction: ototoxicity, nephrotoxicity
Alternative
or
Second Line Drugs
•Uses: a. resistance
b. failure of clinical response to conventional tx.
c. toxic effects
Ethionamide
 Related to INH; poorly soluble in water; liver
 MOA: blocks mycolic acid synthesis
 Dose: 1 gm/d – to achieve serum concentration of 20
ug/ml; CSF conc.; causes gastric irritation and
neurologic symptom
 Adverse effect: hepatotoxic; neurotoxicity
 Dose: 250 mg OD → 500-750 mg OD
 Resistance: when used as single agent
Capreomycin
 MOA: peptide protein synthesis inhibitor from
Streptomyces capreolus
 Used for multidrug resistant cases (streptomycin,
amikacin)
 Dose: 1 gm/d IM
 Resistance: rrs mutation
 Adverse effect: nephrotoxic, ototoxic
- reduced if 1 gm is given 2-3x weekly after initial
response is observed
Cycloserine
 MOA: inhibitor of cell wall synthesis
 Dose: 0.5-1gm/d in 2 divided doses
 Renal excretion (dose is reduced if creatinine clearance
is <50ml/min
 Adverse effect:
a. peripheral neuropathy (seen in 1st
2 weeks of therapy)
b. CNS dysfunction – depression, psychotic
reactions (pyridoxine 150mg/d is given
to ameliorate neurologic toxicity)
Aminosalicylic Acid (PAS)
 MOA: folate synthesis antagonist
 Structure – similar to PABA and sulfonamides
 Widely distributed in tissues and body fluids except in
CSF; excreted in urine
 Adverse effect:
a. anorexia, nausea, lbm, epigastric pain
b. peptic ulceration, hgge
c. hypersensitivity reaction – fever, jt. pains,
skin rashes, hepatosplenomegaly,
hepatitis, adenopathy, granulocytopenia
→seen 3-8 weeks of PAS
Kanamycin and Amikacin
 MOA: inhibits 30s ribosomal subunit
 For streptomycin resistant cases, multidrug resistant TB,
atypical mycobacterium
 Dose: 15 mgkd IV, IM + 1,2 or 3 other drugs x
2 mos. then 1-1.5 gm 2-3x weekly x 4 mos.
Ciprofloxacin and Levofloxacin
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MOA: inhibits gyrase mediated DNA-supercoiling
M. tuberculosis: levofloxacin > ciprofloxacin
Atypical mycobacterium: levofloxacin < ciprofloxacin
Dose: ciprofloxacin – 750 mg po BID/
levofloxacin – 500 mg po OD
+
2 or more active drugs
 Prophylaxis: fluoroquinolone + PZA
(multidrug resistant cases)
 Resistance: mutations in gyrase A subunit
Rifabutin
 Derived from rifamycin, related to rifampin
 Uses: a. M. tb, M. avium intracellulare,
M. foruitum
b. disseminated atypical disease in AIDS
pts. with CD4 count of <50/ml.
c. prophylaxis: TB x 6 mos. alone or with
PZA x 2 mos.
 Resistance: rpo mutation
 Less potent inducer – for HIV infected patients receiving other
meds
 Dose: 300 mg/d
if with protease inhibitor – 150 mg/d
if with efavirenz – 450 mg/d
Rifapentine
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Analog of rifampin; against M. tb, M. avium
MOA: bacterial RNA polymerase inhibitor
Potent inducer of cytochrome p450
Toxicity:
Dose: 600 mg once or 2x weekly
Clofazimine
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Last resort for multidrug resistant TB
Effective against leprosy
MOA: unknown ( involved in DNA binding)
Adverse effect: skin discoloration, GIT intolerance
Dose: 200 mg po as single or divided doses
(t1/2 2 mos.- slowly released)
Atypical Mycobacteria
 Not communicable from person to person
 Disease produced are less severe than TB
 MAC – disseminated disease in late stages of AIDS;
incurable
- 1st line tx: azithromycin 500 mg OD or clarithromycin
500 mg BID + ethambutol 15 mgkd or Clofazimine or
Ciprofloxacin 750mg BID or Amikacin
- 2nd line tx: Rifabutin 300 mg OD; Rifampicin;
Ethionamide; Cycloserine; Imipenem
- prophylaxis in AIDS pts.: Rifabutin 300 mg OD
Mycobacterium marinarum
- skin infections
- 1st line tx: Rifampicin + Ethambutol
- 2nd line tx: TMP-SMX; Clarithromycin;
Amikacin; Kanamycin; Minocycline;
Doxycycline
 Mycobacterium scrofulaceum
- cervical lymphadenitis
- tx: surgical excision
 Mycobacterium fortuitum
- chronic lung disease and skin/soft tissue
infection
- 1st line tx: Amikacin + Doxycycline
- 2nd line tx: Cefoxitin; Rifampicin; TMP-SMX;
Ciprofloxacin; Ofloxacin; Imipenem;
Clarithromycin
Mycobacterium kansasii
- similar to TB but milder
- 1st line tx: INH + Rifampicin + Ethambutol
- 2nd line tx: Ethionamide; Cycloserine;
Clarithromycin; Amikacin; Streptomycin
Leprosy
Caused by M. leprae
Tropical, warm temperate regions
Skin and nerve predilection
Depends upon cell-mediated immunity
Dx: biopsy; slit skin smears
Mode of transmission: nasal secretions
Clinical types of Leprosy:
1. Tuberculoid leprosy – skin macules with
clear centers and well defined margins;
anesthetic; no Virchow cells; (+) lepromin
test
2. Borderline tuberculoid
3. Borderline disease
4. Borderline lepromatous
5. Lepromatous – impaired cell immunity;
atrophy of skin, muscles; amputations;
spontaneous ulcerations
Leprosy
Dapsone (diaminodiphenylsulfone)
 MOA: inhibits folate synthesis
 Uses: a. leprosy
b. prevent and treat P. carinii in AIDS
 Mgt: dapsone + rifampin + clofazimine
(100mg OD) (600mg monthly) (100mg/d po)
 Adverse effect: hemolysis, GIT intolerance,
erythema nodosum leprosum
(steroids/thalidomide)
Jarisch-Herxheimer reaction:
- exacerbation of lepromatous leprosy
- is induced 5-6 wks. after initiation of
treatment
- fever, malaise, exfoliative dermatitis,
jaundice with hepatic necrosis,
lymphadenopathy, methemoglobinemia,
anemia
Leprosy (cont.)
Rifampicin – 600mg OD or once a month
Clofazimine (Lamprene)
MOA: inhibit the template function of DNA
by binding to it
-prevents the development of erythema
nodosum leprosum
- oral; 100mg OD
- SE: discoloration of the skin, eosinophilic
enteritis
Miscellaneous agents for leprosy
Thalidomide – treatment of erythema
nodosum leprosum
-dose: 100 – 300mg/day; teratogenic
Ethionamide – a substitute for clofazimine
-dose: 250 -375mg/day
Management of Leprosy
 Tuberculoid, borderline tuberculoid and
indeterminate disease:
Dapsone 100 mg daily +
Rifampicin 600 mg daily/monthly
X 6 mos.
 Lepromatous, borderline lepromatous,
borderline disease:
Dapsone 100 mg daily +
Rifampicin 60 mg daily/monthly +/Clofazimine 100 mg daily X 1–5 yrs.
 Leprosy-Classic Facial Appearance: Patient
with chronic M Leprae infection that has led to
collapse of nasal structure and subsequent
development of classic "Leonine Facies.“
Skin discoloration is due to medication used to
treat this infection. Patient has lost digits of hand
secondary to leprosy as well.
Thank you
Ma. Victoria M. Villarica, M.D.