Antimycobacterial agents
Tuberculosis
¨ç first-line essential drug : rifampin, isoniazid, pyrazinamide
¨è first-line supplemental drug : ethambutol, streptomycin
¨é second-line drug : less effective than 1st-line agent
more frequently severe reaction
PAS, ethionamide, cycloserine, kanamycin, amikacin, capreomycin, viomycin,
thiacetazone
¨ê newer antiTbc drug : rifapentine, rifabutin, quinolones(especially, ciprofloxacin,
ofloxacin & sparfloxacin)
1. First-line essential drugs
1) Rifampin
Streptomyces mediterranei¿¡¼ ¾òÀº ¹ÝÇÕ¼º À¯µµÃ¼·Î Ç×°áÇÙÁ¦Áß °¡Àå Áß¿äÇÏ´Ù.
wide spectrum of other organism
: some G(+), G(-) bacteria, legionella, M. kansasii, M. marinum
¨ç pharmacology
ü¾×À» red-orange color·Î º¯È½ÃŰ¹Ç·Î Ä¡·á¿¡ ´ëÇÑ È¯ÀÚÀÇ compliance¸¦
È®ÀÎÇÒ¼ö ÀÖ´Ù.
ÀÏÂ÷ÀûÀ¸·Î´Â bile°ú extrahepatic circulationÀ¸·Î ¹è¼³µÇÁö¸¸ 30-40%´Â kidney·Î ¹è¼³
µÈ´Ù.
¿ë¹ý) 600 mg qd(10mg/kg) -¼ºÀÎ
10-20 mg/kg - ¾ÆÀÌ
¨è action mx
intracellular & extracellular bactericidal activity
DNA-dependent RNA polymerase¸¦ ¾ïÁ¦ÇÔÀ¸·Î½á RNAÇÕ¼ºÀ» block
M. tuberculosis¿Ü¿¡ M. kansasii, M. marinumµµ ¾ïÁ¦(¡Â1¥ìg/mL)
¨é ºÎÀÛ¿ë(Tab 168-3)
mc : GI disturbance
* most serious adverse reaction(hepatitis)°¡ Àß »ý±â´Â °íÀ§Ç豺
: CLD(ƯÈ÷ alcoholism), elderly pt
* other : rash(0.8%), hemolytic anemia(<1%), thrombocytopenia, immunosuppression
* most potent inducer of the hepatic microsomal enzyme
-> ´Ù¸¥ ¾àÀÇ ¹Ý°¨±â¸¦ °¨¼Ò½ÃŲ´Ù.
: DGX, warfarin, prednisone, cyclosporine, methadone, oral contraceptive,
clarithromycin,
HIV protease inhibitors, quinolone µî(Tab 168-2)
¨ê resistance
RNA polymerase gene(rpo B) ¥â subunitÀÇ spontaneous point mutation
2) Isoniazid
¨ç action mx
catalase-peroxidase reaction°ú °°Àº oxygen-dependent pathway¸¦ ÅëÇÏ¿©
mycolic acid cell-wall synthesis¾ïÁ¦
rapidly multiplying organism¿¡ ´ëÇØ¼´Â bactericidal.
resting bacilli¿¡ ´ëÇØ¼´Â bacteriostatic agent. extracellular & intracellular
¨è pharmacology
300 mg qd PO -> Ç÷Áß³óµµ 3-5 ug/mLµµ´Þ
serum, CSF, infected tissue(caseous granulomaÆ÷ÇÔ)¿¡ Ä¡·á³óµµ µµ´Þ
acetylation & hydrolysis¸¦ ÅëÇÏ¿© °£¿¡¼ ´ë»çµÇ¸ç ±× ´ë»ç¹°ÁúÀº ¼Òº¯À¸·Î ¹è¼³µÈ´Ù.
Åë»ó ¿ë·® : ¼ºÀÎ- 5mg/kg ¾ÆÀÌ- 10-20mg/kg µÑ´Ù ÃÖ´ë 300 mg/day
¨é ºÎÀÛ¿ë
2 most important adverse effect
: hepatotoxicity & peripheral neuropathy
i) isoniazid-associated hepatitis : idiosyncratic
³ªÀ̰¡ µé¼ö·Ï ºóµµ°¡ Áõ°¡ÇÑ´Ù.
0.3% (35¼¼¡é)
1.2% (49¼¼¡é)
2.3% (50¼¼¡è)
daily alcohol consumption, concomittent rifampin Åõ¿©, slow isoniazid acetylation¿¡
ÀÇÇØ °£µ¶¼º À§ÇèÀÌ Áõ°¡ÇÑ´Ù.
mortality rate´Â ÃÖ°í 6-12%±îÁö º¸°íÇϰí ÀÖÀ¸³ª ½ÉÇÑ È¯ÀÚµéÀ» ´ë»óÀ¸·Î ÇÑ º¸°íÀ̰í
½ÇÁ¦·Î´Â ³·´Ù.
* ATS recommendations
AST or ALT¸¦ baselineÀ¸·Î ÃøÁ¤Çصΰí 35¼¼ À̻󿡼 ¸Å´Þ ÃøÁ¤ÇÑ´Ù.
¹«Áõ»óÀÇ AST or ALT 150-200 IU(3-5¹è UNL)ÀÏ ¶§ ¾à Áß´Ü.
ii) peripheral neuritis(2-20%)
pyridoxine(vit B6) metabolismÀ» ¹æÇØÇϱ⠶§¹®À̸ç
prophylactic pyridoxine 10-50 mgÅõ¿©·Î ºóµµ¸¦ 0.2%±îÁö °¨¼Ò½Ãų¼ö ÀÖ´Ù.
¨ê resistance
105-106 organism´ç 1°³
catalase-peroxidase gene(kat G) ȤÀº inh A·Î ¾Ë·ÁÁø two-gene locus¿¡¼ÀÇ amino
acid changes.
3) Pyrazinamide
nicotinic acidÀ¯µµÃ¼
important bactericidal drug
¨ç pharmacology
15-30 mg/kg PO 1-2½Ã°£ÈÄ Ç÷Áß³óµµ´Â 20-60 ug/mLµµ´Þ
CSF levelµµ excellent(serumÀÇ 50-100%)
¹Ý°¨±â 9-11½Ã°£
°£¿¡¼ ´ë»ç. ´ë»ç¹°Áú - pyrazinoic acid, 5-hydroxypyrazinamide, 5-hydoxypyrazinoic
acid
¨è action mx
narrow spectrum of antibacterial activity(only M. tuberculosis)
slowly metabolizing organism¿¡ ´ëÇØ bactericidal(pH<6ÀÇ acidȯ°æ or granuloma)
tubercle bacillus¿¡ ÀÇÇØ active formÀÎ pyrazinoic acid·Î ÀüȯµÈ´Ù.
M. tuberculosis 20 ug/mL¿¡¼ inhibition
¨é ºÎÀÛ¿ë
i) hepatotoxicity : isoniazid & rifampin µ¿¹ÝÄ¡·áº¸´Ù ³ôÁö ¾Ê´Ù.
ii) ÀӽŽà »ç¿ë
±¹Á¦ °áÇÙÇùȸ¿¡¼± ÀӽŽà »ç¿ë°¡´ÉÇÏ´Ù ÇÏ¿´À¸³ª ¹Ì±¹¿¡¼± teratogenicity data°¡
ºÒÃæºÐÇÏ¿© ÃßõµÇÁö ¾ÊÀ½.
iii) hyperuricemia´Â ÈçÇϳª rifampinÀ¸·Î ÀÎÇÏ¿© ºóµµ°¡ °¨¼ÒÇϰí ÀÖ´Ù.
clinical gout´Â µå¹°´Ù.
polyarthralgia´Â ²Ï ÈçÇѵ¥ À̶§ hyperuricemia¿Í´Â °ü°è°¡ ¾ø´Ù.
¨ê resistance
Pyrazinamidase activity¼Ò½Ç°ú °ü·ÃµÇ´Âµ¥ À̶§ ´õ ÀÌ»ó pyrazinoic acid·Î ÀüȯµÇÁö
¾Ê´Â´Ù.
90%À̻󿡼 pnc A gene mutationÀÌ °üÂûµÈ´Ù. M. bovisÀÇ ¸ðµç ±ÕÁ¾Àº pyrazinamide
resistantÇѵ¥ À̶§ pnc A gene point mutationÀÌ ÀÖ´Ù.
2. First-line supplemental drug
1) Ethambutol
only mycobacteria¿¡¼¸¸ active
susceptible species : M. tuberculosis, M. marinum, M. kansasii, MAI
the least potent against M. tuberculosis
¨ç action mx
bacteriostatic against rapidly growing mycobacteria
cell wall inhibition
¨è pharmacology 15 mg/kg
CSF¿¡ Àß µµ´ÞÇÏÁö ¾ÊÁö¸¸ °í¿ë·®(25mg/kg)À» inflamed meningesȯÀÚ¿¡°Ô Åõ¿©ÇÏ¿´À»
¶§ 50%±îÁö µµ´ÞÇÑ´Ù.
24½Ã°£³» ½ÅÀåÀ¸·Î ¸ðµÎ ¹è¼³µÇ¹Ç·Î renal insufficiency(GFR < 25 ml/min)ȯÀÚ¿¡¼ drug
accumulation & toxicity¸¦ ¿¹¹æÇϱâ À§ÇØ ¿ë·®À» ³·Ãç¾ß ÇÑ´Ù.
¨é ºÎÀÛ¿ë
i) retrobulbar optic neuritis : most serious adverse effect
ocular toxicity sxÀº º¸Åë ¼ö°³¿ùÈÄ¿¡ ¹ß»ýÇϸç dose & duration¿¡ ºñ·ÊÇÑ´Ù.
25 mg/kg -> 5%, 15mg/kg -> 1%
optic neuritis with associated visual loss : reversible ±×·¯³ª 6°³¿ùÀÌ»ó ¼Ò¿äµÊ.
ii) hyperuricemia - asymptomatic
¨ê resistance
emb B gene mutation(70%)
2) Streptomycin
Streptomyces griseus¿¡¼ ºÐ¸®ÇÑ aminoglycoside·Î IM, IV·Î »ç¿ë.
toxicity¿Í CSF level¿¡ ºÒÃæºÐÇÏ°Ô µµ´ÞÇϹǷΠ¹Ì±¹¿¡¼± »ç¿ëÀÌ Á¦ÇÑÀûÀÌ´Ù.
M. tuberculosis, M. kansasii, M. marinumÀÇ untreated strain°ú MAIÁß ÀϺΠ±ÕÁ¾¿¡ ´ëÇØ
active.
¨ç pharmacology
1.0 g IM or IVÈÄ 25-40 ug/mLÀÇ Ç÷Áß³óµµ µµ´Þ.
rapidly dividing extracellular mycobacteria¿¡ ´ëÇØ bactericidal.
macrophage³»ÀÇ acidic environment¿¡¼± ineffective.
³ú¸·À» ÅëÇØ¼± Àß ÀüÆÄ°¡ ¾ÈµÈ´Ù.(meningitisȯÀÚ¿¡¼ CSF levelÀº serumÀÇ 20%)
0.5-1.0 g(10-15 mg/kg) daily or ÁÖ 5ȸ
¼Ò¾Æ´Â 20-40 mg/kg/day(maxium 1.0 g/d)
½ÅÀåÀ¸·Î ´ëºÎºÐ ¹è¼³µÇ¹Ç·Î 50¼¼ ÀÌ»ó & renal impairmentȯÀÚ¿¡¼´Â ¿ë·®À» ÁÙÀ̰í,
Åõ¿©È½¼öµµ ÁÖ 2-3ȸ·Î ÁÙ¿©¾ß ÇÑ´Ù.
¨è action mx
ribosomal fx disruption¿¡ ÀÇÇÑ protein synthesis¹æÇØ
¨é ºÎÀÛ¿ë(10-20%)
ototoxicity & renal toxicity : mc & most serious
i) renal toxicity : nonoliguric renal failure
´Ù¸¥ aminoglycoside(Gentamicin)º¸´Ü ´ú ÈçÇÏ´Ù.
ii) ototoxicity : hearing loss & vestibular dysfunction
- vestibular dysfunctionÀÌ ´õ ÈçÇϰí Áõ»óÀº balance loss, vertigo, tinnitus.
iii) less serious reaction : perioral paresthesia, eosinophilia, rash, drug fever
¨ê resistance
105-106°³´ç 1°³
3. Second-line drugs
drug resistant or first-line supplemental drugÀÌ À¯¿ëÇÏÁö ¾ÊÀ» ¶§ »ç¿ë.
1) Capreomycin
2) Amikacin & kanamycin : bactericidal to extracellular organism
Amikacin - M. tuberculosis¿Í ¸î°¡Áö NTM¿¡ ´ëÇØ È¿°úÀû
(rapidly growing mycobacteria, M. scrofulaceum, M. leprae, MAI)
10-15 mg/kg IM or IV 3-5ȸ/ÁÖ
3) PAS
folate synthesis¸¦ ¹æÇØÇÏ¿© M. tuberculosisÀÇ ¼ºÀåÀ» ¾ïÁ¦ÇÏ´Â calcium or sodium salt
GI toxicity(N/V, diarrhea), low level of antiTbc activity ¶§¹®¿¡ °ÅÀÇ »ç¿ëµÇÁö ¾Ê´Â´Ù.
4) Thincetazone
5) Viomycin
6) Ethionamide
isoniazid & pyrazinamideó·³ isonicotinic acidÀ¯µµÃ¼·Î bacteriostatic
MDR Tbc¿¡ °¡Àå À¯¿ë.
toxicity & frequent side effect ¶§¹®¿¡ »ç¿ëÀÌ Á¦ÇѵȴÙ.
: ½ÉÇÑ GI intolerance, serious neurologic reactiion, reversible heaptitis(5%),
hypersensitivity reaction, hypothyroidism
7) Cycloserine
Streptomyces orchidaceus¿¡¼ »ý¼ºµÇ¸ç Àß Èí¼öµÇ°í ³Î¸® ºÐÆ÷µÈ´Ù(CSFÆ÷ÇÔ)
* serious S/E : psychosis, seizure, peripheral neuropathy, headache, somnolence,
allergic rx
*CIx : epilepsy, active alcohol abuse, severe renal insufficiency, depression or
psychosis Hx(+)
8) Newer antiTbc drug
¨ç Rifabutin
¨è Rifapentine
¨é Quinolones : ofloxacin, ciprofloxacin, sparfloxacin, pefloxacin
¸¹Àº mycobacteria¿¡ ´ëÇØ active.
°æ±¸·Î Àß Èí¼öµÇ°í high serum level¿¡ µµ´ÞÇÏ¿© ü¾×¿¡ Àß ºÐÆ÷µÊ.
fluoroquinolone¿¡ ´ëÇÑ resistance°¡ »¡¸® ¹ß»ý
(DNA gyraseÀÇ A gene mutation = gyr A gene)
MDR ȯÀÚ È¤Àº 1st-line drug¿¡ tolerableÇÏÁö ¸øÇÑ È¯ÀÚ¿¡¼ »ç¿ë
Nontuberculous mycobacteria
M. tuberculosisº¸´Ù ´ú pathogenicÇÏÁö¸¸ nontuberculous mycobacteria´Â AIDS¿Í °°Àº
immunocompromised host¿¡¼ÀÇ disseminated pulmonary, skin, bone & joint, LN, soft
tissue infectionÀ» ÀÏÀ¸Å²´Ù.
* 2 most common cause : MAI, M. kansasii
AIDSÀÇ 40%°¡±îÀÌ MAI¿¡ ÀÇÇÑ disseminated disease°¡ ¹ß»ýÇÑ´Ù.
1. Clarithromycin(Klaricid)
Àß Èí¼öµÇ°í À§ÀåÀå¿¡µµ °ÅÀÇ ¾ø´Ù.
°£¿¡¼ ´ë»çµÇ¸ç ´ë·« 30%°¡ ¼Òº¯À¸·Î ¹è¼³µÈ´Ù.
Ccr ¡Â 30 mL/min¸é °¨·®.
´Ù¸¥ NTM¿¡µµ highly active.
Ç¥ÁØ ¿ë·® : 500 mg bid
more common S/E : N/V, bitter taste, abnormal LFT
teratogenicÇϹǷΠÀӽŽà »ç¿ë±ÝÁö.
mutation :108-109 ´ç 1°³
2. Azithromycin(Zithromax)
clarithromycinº¸´Ü ´ú active
clarithromycin°ú cross-resistance
3. Specific Tx
1) MAI
MAI lung disease : "HER + SM"
clarithromycin 500 mg bid°¡ isoniazid´ëü
rifabutin(300 mg/d)ÀÌ rifampin´ë½Å »ç¿ë
12°³¿ù°£ culture negative°¡ µÉ ¶§±îÁö »ç¿ë
2) M. kansasii
pul. disease : 18-24°³¿ù Ä¡·á
"HER"
rifabutin(150mg) or clarithromycin(500mg) bid·Î rifampin´ëü°¡´É