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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