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TRNG I HC DC H NIB MN DC LCNHOM 1 T 4 LP N1K67KHNG SINH NHM MACROLID

NI DUNG

I. TNG QUAN V NHM KHNG SINH MACROLID 1. NGUN GC, LCH S HNH THNH V PHT TRINThin nhinGm cc macrolid c chit xut t mi trng nui cy streptomyces nh erythromycin, spiramycin, tylosin..2. Bn tng hpGm cc macrolid c to thnh bng cch bin i mt vi chi tit trong cu trc ca macrolid thin nhin khc phc nhng nhc im ca khng sinh m nh: Roxithromycin, clarithromycin, azithromycin

ErythromycinSpriramycin

Azithromycin ClarithromycinClarithromycin

I. TNG QUAN V NHM KHNG SINH MACROLID 1. NGUN GC, LCH S HNH THNH V PHT TRINLch s

I. TNG QUAN V NHM KHNG SINH MACROLID2. CU TOOGENINOSe

Vng lacton t 12-17 nguyn t carbonNhm th trn vng lacton: -OH , alkyl, aldehyd or cetonThng 2 hoc 3 ng, t nht l 1 ng gm:ng desoxyoseng osamin

I. TNG QUAN V NHM KHNG SINH MACROLID3. Phn loi macrolid v cc i dinTheo ngun gcTheo cu trcPhn loiT nhinBn tng hp14 nguyn t C17 nguyn t C15 nguyn t C16 nguyn t C12 nguyn t C

Genin12 C14 C 15 C16 C17 CKhng sinh thin nhinMethymycinPicromycinErythromycinOleandomycinLankacidinLeucomycin Spiramycin Josamycin MidecamycinLankacidinKhng sinh bn tng hpRoxithromycin Clarithromycin Dirithromycin FlurithromycinAzithromycinRokitamycin Miocamycin

Bng: Phn loi macrolid v cc i din

II. C IM DC L NHM KHNG SINH MACROLID1. C CH TC DNG

II. C IM DC L NHM KHNG SINH MACROLID2. PH KHNG KHUNCc macrolid ni chung c:

Ph tc dng trung bnh Ch yu tc dng ln vi khun gram dng (ging vi penicilin t nhin => s dng macrolid trong d phng thp tim do nhim Lin cu m d ng vi penicilin), Ch tc dng ln mt s t vi khun gram m tng t nh penicilin.

II. C IM DC L NHM KHNG SINH MACROLIDVi khun gram (+)Vi khun Gram mVi khun ni boXon khunCc cu khun Gram dngCc trc khun Gram dng a khCc cu khun Gram m:Cc trc khun Gram m:Cc Mycoplasma:Cc ChlamydiaTreponema pallidum Borrelia burgdoferi Lin cu (Streptococcus)T cu (Staphylococcus)Bacillus anthracis Lu cu (Neisseria gonorrhoeae) Haemophilus influenzae Mycoplasma pneumoniae Chlamydia pneumoniae Streptococcus pyogenesStaphylococcus aureusListeria monocytogenes Moraxella catarrhalis Legionnella pneumophilia Ureaplasma urealyticum Chlamydia psittaci Streptococcus pneumoniae Corynebacterium diphteriaem Campylobacter feus Chlamydia trachomatis

Erythromycin:- Vi khun c hi: Mycobacterium kansasii (bnh nhim khun c hi bnh nhn suy gim min dch)- Hu nh khng c trn vi khun a kh Gram mSpiramycin:- Ph td tng t Erythromycin nhng rng hn v hiu lc cng mnh hn- C td c vi Toxoplasma gondii, Branhamella catarhalis v Streptococcus nhy cm vi methicilinClarithromycin:- Tc ng trn Staphylococcus, Streptococcus, H.pylori v cc vi khun c hi mnh hn Erythromycin => ngoi ch nh ging Erythromycin cn dng dit H.pylori v iu tr nhim vi khun c hi bnh nhn AIDSRoxithromycin- Tc dng ln H.influenzae, Ureaplasma urealyticum, Vibrio cholaerae, Enterococcus faecalis v Staphylococcus, Streptococcus khng Erythromycin.Azithromycin- Tc dng mnh trn H.influenzae, M.catarhalis, Neisseria, vi khun ni bo, vi khun c hi bnh nhn nhim HIV/AIDS Ph tc dng ca mt s macrolid in hnh: (ngoi phn chung )

II. C IM DC L NHM KHNG SINH MACROLIDMacrolid (macrolide) l nhng khng sinh c tc dng km khun bng cch gn vo cu t ribosome 50S t c ch qu trnh tng hp protein vi khun. Do tnh trng lm dng khng sinh, s khng macrolid ngy cng tr nn ph bin

3. C CH KHNG

II. C IM DC L NHM KHNG SINH MACROLID1. Thay i cu trc ch tc dngT thay i cu trc ribosom 50s =>kt qu lm gim i lc gn kt vi cc macrolid. V khng sinh macrolid khng th gn vo cu t ribosom 50S, nn qu trnh tng hp protein ca vi khun khng b c ch. Do , vi khun khng b nh hng v tip tc tng hp cc chui polypeptid.

II. C IM DC L NHM KHNG SINH MACROLID2.Bm y ngc thuc ra ngoi

* mt s vi khun khc nh t cu vng, tn ti 1 h thng bm y ngc thuc khc, c iu ha bi plasmid v qui nh thng tin di truyn bi gen msr (A). Mc d c s hin din ca bm y ngc, cc khng sinh macrolid vn c th i vo vi khun. tuy nhin, mt khi khng sinh i vo bn trong, cc bm s bt u bm ngc cc phn t thuc khng sinh ra ngoi trc khi chng c c hi gn vi cu t ribosom 50S* Cc bm ny nm ngang vi mng t bo vi khun v y khng sinh macrolid ra ngoi ngay khi khng sinh va xm nhp

3. To Enzym bin i khng sinhII. C IM DC L NHM KHNG SINH MACROLID

4. Tc dng khng mong munTC DNG KHNG MONG MUN

Ri lon tiu ha (nn, tiu chy,..)Vim gan mtD ng ngoi dac vi thnh gic c hi phcLon nhp tim (him gp)II. C IM DC L NHM KHNG SINH MACROLID

5. Tng tc thucTng tc quan trng nht ca khng sinh macrolid vi cc thuc khc l do macrolid c kh nng c ch chuyn ha trong gan ca cc thuc khc. Tc dng c ch cytocrom P450 thy r sau khi ung.

* Thuc c ch HMGcoA reductase (statin) :cc statin phi hp vi khng sinh macrolid =>hi chng tiu c vn cp .

* Thuc chn knh calcium- macrolid =>huyt p h n mc nguy him.

* Cisaprid phi hp vi macrolid =>khongcch Q T trn T ko di, xon nh, rung tht.II. C IM DC L NHM KHNG SINH MACROLID

IV. SO SNH CC I DIN QUAN TRNG TRONG NHM

ErythromycinClarithromycin: Azithromycin:

c tnh dc lErythromycinClarithromyciAzithromycinHp thu- Thuc hp thu qua ng ung v ng trc trng- Ch c tc dng khi dng base: + B mt hot tnh bi acid dch v + ng + Khng tan trong nc=> Thng dng dng mui hay dng ester (stearat, ethylsuccinat...), bo ch di dng vin bao tan trong rut- Dng mui gluceptat v lactobionat d tan trong nc nn c th dng tim bp v tim tnh mch- Hp thu nhanh nhng khng hon ton qua ng tiu ha- Thc n v mi trng acid ca d dy khng nh hng ti s hp thu- Hp thu nhanh qua ng tiu ha- Thc n lm gim kh nng hp thu=> ung sau n 1-2hPhn b- Phn b rng khp cc m v dch c th vo c dch g tai gia, tinh dch, tuyn tin lit, nhau thai v sa m- t nng cao gan, mt v lch nhng hu ht khng vo dch no ty- Phn b rng ri vo cc m v dch c th- Nng thuc trong t bo cao hn huyt tng- Phn b rng khp c th- Thuc t nng cao trong t bo hn huyt tng (t 10-100 ln)=> iu tr nhim vi khun ni bo tt

Chuyn haChuyn ha qua gan

- Tc dng km hn Erythromycin trn vi khun Gram (+): Staphylococcus, Streptococcus- Tc dng tt hn Erythromycin + Vi khun Gram (-) : Haemophilus influenza, Neisseria + Vi khun c hi bnh nhn HIV/AIDS + c bit l vi khun ni bo

c tnh dc lErythromycinClarithromycinAzithromycinThi trCh yu qua phnCh yu qua nc tiu=> C li cho nhim khun tit niuCh yu qua phn% thuc lin kt protein huyt tng70 - 90 %80%>99%SKD ng ung30 - 60%50%40%Tmax1 - 2h2 -3h2-3hT1/21.6h3 - 7h68h (2- 4ngy)Ph tc dng- Ch yu tc dng ln vi khun gram (+) tng t penicilin: StreptococcusStaphylococcusBacillus anthracisListeria monocytegenesCorynebacterium diphteriae- Tc dng trn 1 s rt t vi khun gram (-) tng t penicilin- Tc dng tt trn + vi khun ni bo: Mycoplasma, Clamydia, Rickettsia, Brucella, Legionella + xon khun: Treponema pallidum, Borrelia burgdorferi + Vi khun c hi: Mycobacterium kansassiTc dng mnh hn Erythromycin trn- Vi khun Gram (+): Staphylococcus, Streptococcus- Vi khun c hi (Mycobacterium avium) - Xon khun Helicobacter pylori - Tc dng km hn Erythromycin trn vi khun Gram (+): Staphylococcus, Streptococcus- Tc dng tt hn Erythromycin + Vi khun Gram (-) : Haemophilus influenza, Neisseria + Vi khun c hi bnh nhn HIV/AIDS + c bit l vi khun ni bo

c tnh dc lErythromycinClarithromycinAzithromycinCh nhiu tr cc bnh nhim khun do vi khun nhy cm ba gm:- Cc nhim khun h hp, da, m mm, tit niu - sinh dc- D phng thp khp cp (thay th cho penicilin)- Ch nh ging Erythromycin- Ngoi ra: + Dit H. pylori: dng phi hp trong iu tr vim lot d dy-t trng + iu tr nhim khun c hi bnh nhn AIDS- Ch nh tng t Erythromycin- C th iu tr nhim khun ng tiu ha- Liu duy nht 1g: dit Chlamydia, h cam mmTDKMM-Thng gp: Tiu chy, nn ma, ri lon tiu ho, au bng, v nhc u=> Dng thuc sau khi n-Phn ng d ng mc khc nhau t my ay, pht ban, nga n phn v v hi chng Steven Johnson.-C th gp vim i trng mng gi, c th t nh n e da tnh mng.-Thnh gic: Mt kh nng nghe (nu dng liu cao) c th hi phc, ch yu ph n ln tui.-Gan: chc nng gan bt thng, tng enzyme gan, vim gan mt c hoc khng c km theo vng da. Phn ng ri lon chc nng gan c th trm trng v c th hoi t gy t vong.CC -Vim gan, ri lon porphyrin -Mn cm vi thuc

MI LIN QUAN GIA PK/PD VI NG DNG LM SNG CA MT S I DIN NHM

Tai sao phai ng dung PK/PD vo thc hnh lm sng ???Hiu chnh liu theo nguyn tc PK v PD tr thanh c s la chn khng sinh truyn thng ca cc nh lm sngHin tng khng khng sinh v s lan truyn cc tc nhn khng thuc rt a dang

Phi c cc chin thut m bo s dng hiu qu cc khng sinh ang c.

Ti u ha liu khng sinh s dung Lm gim vic s dng khng sinh khng hp l hoc lm dng khng sinhMUC ICH

C max

AUC : Area Under the Curve Cmax : Maximum Conc. Observed Tmax : needed time to rise the Cmax T1/2 : half-life, needed time to observe 50% plasm. level decreasing Vd: Distribution Volume Cl : ClearanceMinimum Activity Concentration T maxT 1/2TherapeuticIntervalThng s PK/PD

Cpeak/MIC Cmax/MIC: c tnh bi nng nh hoc ti a chiacho MIC. %T>MICT l thi gian T>MIC: l t l thi gian phi nhim ca vikhun vi khng sinh c nng trn MIC

+AUC/MIC L ch s c xc nh bi din tch di ng cong nng theo thi gian so vi MIC ca vi khun gy bnhBa thng s PK/PD

C ch tc dng Gn vo tiu phn 50s ca ribosom vi khun, cn tr to chui a peptid (ngn cn chuyn v ca ARNt) ca vi khun

Macrolid -L cc khng sinh dit khun t ph thuc vo nng , ph thucvo thi gian v c tc dng hu khng sinh trung bnh, thng s d on tt nhthiu qu iu tr l AUC/MIC

Log(cfu/ml)

AUC/MICT(h)PAEMICPAEPAE co y nghia khi thi gian lam chm s phat trin cua VSV sau khi dung khang sinh trn 3 gi

U IMChng minh tc dng T NG NG SINH HOC gia cc khng sinh. Ti u ha tc dng dit khun v hiu qu iu tr ca tng khng sinh

HN CH

V DMIC ca azithromycin v clarithromycin trong iu tri ph cu c gen erm (B) l 256 g/ml. Vi nhng chng m ha bi gen mef(A), MIC ca azithromycin dao ng t 1 n 32 g/ml. -Tuy nhin, ch s PK/PD ti u nh gi hiu qu iu tr khc nhau gia cc khng sinh trong h ny l khc nhau. -Vi azithromycin, mt khng sinh c thi gian bn thi di, t s fAUC/MIC cn t trn 25. Ti u ha vic s dng erythromycin v clarithromycin da vo PK/PD c th t c bng cch ko di thi gian tip xc vi thuc.- Da vo thng s PK/PD, azithromycin bo ch n liu dng vi cu hm lng 2mg dng ng ung c ng dng trong iu tr cho bnh nhn CAP

AUC cho bit ton b lng KS t c trong huyt thanh

MIC: Cn bao nhiu KS c ch c VK trong ng nghim

AUC/MICCmax256 mg/mlT>MICNng (mg/ml)

Thi gian (h)

Azithromycin

256 mg/mlThc t dng 250 mg6vin

mg/ml

T (h)

256 mg/ml

Dung vin 500 mg (1 ln/ngy/3ngay)

Thay i ch liu s dung

mg/mlT (h)

Ti u ha liu dng v thi gian s dng liu php khng sinh theo nguyn tc PK/PD l mt chin thut gim khng khng sinh

Liu dng da vo PK/PD l mt liu php c th ha vi tng ngi bnh v trn tng loi vi khun gy bnh, cn c vo chc nng thn, tc nhn gy nhim khun v tnh hnh khng tai c s iu tr s gip cho vic s dung khng sinh an ton hn v t hiu qu cao hn.Kt Lun

Thanks you !!