Beta-lactam

AntibioticsYE

ShaojianCase

1A

75

yrs

old

man

can’t

take

care

ofhimself

after

a

stroke

and

suffered

lunginfection

later.

His

condition

did

notimprove

after

penicillin

treatment,

drugssensitivity

test

shown

the

bacterial

of

his

infection

was to

manyantibiotics.Bacteria

cell

wall

is

unique

in

constructionContains

peptidoglycan(肽聚糖,黏肽)Antimicrobials

that

interfere

withthesynthesis

of

cell

wall

do

not

interfere

witheukaryotic

cellDue

to

the

lack

of

cell

wall

in

animal

cellsanddifferences

in

cell

wall

in

plant

cellsThese

drugs

have

very

high

therapeuticindexLow

toxicity

with

high

effectivenessβ

–lactams:

Have

shared

chemicalstructure

calledβ-lactam

ringClassificationPenicillinsCephalosporinsOther

β-Lactam

drugsCephamycins（頭霉素類）Carbapenems（碳青霉烯類）Oxacephalosporins

（氧頭孢烯類）β-Lactamase

inhibitors（

β-內(nèi)酰胺酶抑制劑）Monolactums（單環(huán)β-內(nèi)酰胺類）Mechanism

ofInactivation

of

drug

by

β-lactamaseTrap

mechanismModification

of

PBPsImpaired

penetration

of

drug

toAbsence

of

autolysinsPBPsPenicillinase

(

Lactamase)Figure

20.8ESBLs:

Extended-Spectyum

β-Lactamase超廣譜β-內(nèi)酰胺酶§1

PenicillinsHistoryBasic

structure:

6-APAClassificationNatural

penicillinsSemisynthesized

penicillinsThe antibiotic,

penicillin,

was

discovered

in

1929

by

SirAlexander

Fleming.

Fleming

was

searching

for

potentialantibacterial

compounds.

He

noticedthat

a

patch

ofthemold

Penicillium

notatum

had

grown

on

a

plate

containingthe

bacterium

Staphylococcus

and

that

around

the

moldthere

was

a

zone

where

no

Staphylococcus

could

grow.After

more

research,

he

was

able

to

show

that

culture

brothof

the

mold

prevented

growth

of

the

Staphylococcus

evenwhen

diluted

up

to

800

times.

He

named

the

activesubstance

penicillin

but

was

unable

to

isolate

it.In

the

center

ofthe

plate

is

a

colony

ofPenicillium

notatum,

a

mold

thatproducespenicillin.

After

appearance

of

the

moldcolony,

the

plate

was

overlaid

with

abacterial

culture

of

Micrococcusluteuswhich

forms

a

yellow

"lawn"

of

growth.

Azone

of

inhibition

of

bacterial

growthsurrounds

the

fungal

colony

wherepenicillin

has

diffused

into

the

medium.Several

years

later,

in

1939,Ernst

Chain

and

HowardFloreydeveloped

a

way

to

isolatepenicillin

and

used

it

to

treatbacterial

infections

during

theSecond

World

War.The

newdrug

came

into

clinical

usage

in1946

and

made

a

huge

impacton

public

health.

For

thesediscoveries

Fleming,

Chain

andFlorey

were

awarded

the

Nobelprize

in

1945.

Their

discoveryand

development

revolutionizedmodern

medicine

and

paved

theway

for

the

development

ofmany

more

natural

antibiotics.PharmacokineticsPenicillin

G

(PG)Absorption:

inj.

T1/2=0.5h~1hDistribution:

weak

acidExcretion:

probenecid(丙磺舒)inhibit90%

tubularsecretion10%

glomerularfiltrationBenzathine

benzyl

penicillinProcaine

benzyl

penicillinPenicillin

GAntimicrobial

activityGram-positive

cocciStreptococci(溶血性鏈球菌),pstaphylococci(金葡菌)Gram-positive

rodsococci(球菌),B.anthracis(炭疽),diphtheriae(白喉),clostridium(梭狀芽孢)tetani(破傷風)Gram-negative

cocciMeningococci(腦膜炎),

diplococcus

gonorrhoeae(

)SpirocheteTreponema(

)pallidum

leptospirrosis(鉤端螺旋體)Clinical

useschoice

for

the

following

infectionsInfection

caused

by

streptococci,p ococci,

meningococci

etcInfection

caused

by

gram-positive

rodsInfection

caused

by

spirochetes(螺旋體)Case

2A26

yrsoldfarmerHe

had

a

hand

injury

and

infected.

He

askedadoctor

toinject

penicillin

which

hetakenwith

and

refuse

to

take

skin

test

because

hejust

got

penicillin

injection

not

long

ago,

andmake

a

promise

that

the

doctor

is

notresponsible

if

something

wrong

happened.

5min

after

theinjection,

hesweatprofusely,pale

complexion,

tic

of

limbs

andthen

loseconscious.

Thisguy

diedafter.Adverse

reactionsAllergic

reactionsCommon:

urticaria(蕁麻疹),fever,angioneurotic

edema,

hemolytic

anemiaSevere:

anaphylactic(過敏性)shockReason:

degraded

products

of

penicillinPrevention:

allergic

history,

skin

test,

EpinephrineHerxheimer

reactionSemi-synthesized

penicillinsAcid-resistant

penicillinsPenicillinase-resistant

penicillinsExtended-spectrum

penicillinsExtended-spectrum

penicillins

againstP.aeruginosa(銅綠假單胞菌)Penicillins

against

gram-negative

bacteriaAcid-resistant

penicillinsDrugs:

penicillin

V,phenethicillin(非奈西林）CharacterOrally

effective,

not

resist

β-LactamaseLower

potency

than

penicillinGClinical

uses:

moderate

infectionsAdverse

reactions:

allergic

reactionPenicillinase-resistant

penicillinsDrugs:methicillin(甲氧西林）oxacillin（苯唑西林）,cloxacillin（氯唑西林）,dicloxacillin（雙氯西林）flucloxacillin(氟氯西林)Character:

acid-resistant/penicillin-resistant

/lower

activity

than

penicillin

GClinicaluseInfection

caused

by

penicillin-resistantstaphylococciExtended-spectrum

penicillinsAmpicillin(氨芐西林),amoxycillin(羥氨芐西林),pivampicillinOral

effective,

susceptible

to

β-LactamaseBroad

spectrum:

G-

/ G+

<penicillinNo

effect

on

P.aeruginosa(綠膿桿菌)Clinical

uses:

infection

caused

bygram-negative

rodsAmpicillinNot

comple y

absorbed

,F

lowEffective

on

G-To

G+:

<penicillinClinical

use:

G-

infectionAmoxycillinAbsorbed

well

,

FhighG

–infectionMeningitisUpper

respiratory

infectionUrinary

tract

infectionH.p

infectionExtended-spectrum

Penicillins

againstP.aeruginosaCarbenicillin(羧芐西林),sulbencillin,

ticarcillin,furbencillin,

piperacillin(哌拉西林),mezlocillinCharacter:Wide

spectrum

and

more

activity

on

P.aeruginosaNotacid

andβ-lactamase

resistantUsually

incombinationwith

aminoglycosidesCarbenicillinHigh

activity

onG-

andP.aeruginosaConcentration

in

CSF

is

lowMainly

used

to

treat

P.aeruginosa

infection

inburnpatientsPiperacillinEffective

on

anaerobesConcentration

in

CSF

ishighPenicillins

against

gram-negative

bacteriaMecillinam（美西林）,temocillin（替莫西林）

,pivmecillinam（匹美西林）Narrow-spectrum:

mainlyon

G-

rodsβ-Lactamase

resistantNo

effect

on

P.aeruginosaTreatment

of

infections

caused

by

G-

rods口服青霉素是否需皮試?青霉素“燒焦”一個少女慘不忍睹，感冒少女半夜自燃上午，在青島某工廠打工的18歲姑娘王雪燕感冒了。為了不影響工作，她沒有請假，一直堅持到下班。晚上回到宿舍后，感覺頭昏腦漲，她沒有吃晚飯就躺下了。到了晚上9點多，她高燒起來，額頭滾燙。室友 走過來，摸了摸王雪燕的額頭，吃驚地說：“怎么燒成這樣了，要不要陪你去醫(yī)院?”為了供弟弟妹妹上學，王雪燕一向很節(jié)儉，想著到醫(yī)院看一下少說也得五六十元，她便來到門口的藥店，打算買些藥。藥店里的人問了問 情況，建議她買兩種藥：青霉素V鉀片和撲熱

息痛片。買了藥回到宿舍，王雪燕按照說明書，服下了兩片青霉素V鉀片和1片撲熱息痛片。本以為病情很快就能減輕， 兩個小時過去了，沒有任何好轉(zhuǎn)。王雪燕心想：“可能是感冒來得太猛了，要加大藥量才好得快。”于是，她又吃了兩片青霉素V鉀片和1片撲熱息痛片。就是這6片藥，讓她經(jīng)歷了一場此生從未有過的極度恐懼。當時王雪燕并沒有太在意，她認為這是發(fā)燒后的自然反應(yīng)。但隨后的發(fā)展出乎 意料：身上的紅疙瘩越起越多，越來越大，然后紅疙瘩變成了小水皰，小水皰又變成了大水皰，嘴巴里也長滿了皰?！昂冒W呀!好熱呀!”王雪燕的額頭上掛滿了豆大的汗珠，痛苦 地叫了出來。天快亮的時候，讓人毛骨悚然的一幕發(fā)生了：王雪燕身上的水皰破了，皮膚開始潰爛，全身就像被火燒的一樣，慢慢變成了紫黑色。接著，皮膚開始一片一片地往下掉，露出了皮下組織。這種情景，一下子將同宿舍的姐妹嚇呆了。趕緊喊來幾名男同事，大家七手八腳地將王雪燕送到了附近的一家醫(yī)院。此時，王雪燕面部和身上的皮膚幾乎全部被“燒光”，整個身體呈黑褐色，小腿上也密密麻麻地布滿被“燒”起

的水皰……命懸一線，元兇竟是青霉素幾名

對王雪燕進行緊急會診，逐一排除了麻疹和一些傳染性皮膚病的可能。表面看起來是被火燒傷的，可又不是，折騰了半天，們沒能找到病因。王雪燕的病情越來越嚴重，多次 。院方?jīng)Q定將王雪燕轉(zhuǎn)到大醫(yī)院進行救治，可聯(lián)系了青島市的10多家醫(yī)院，都表示沒聽 這種病。不過，青島市立醫(yī)院的 接到值班醫(yī)生報告后非常重視，同意將王雪燕轉(zhuǎn)到該院檢查就診。20分鐘后，王雪燕被送進了青島市立醫(yī)院 室。此時，

病情進一步加重，除了整個身體像焦炭一樣，眼結(jié)膜也開始充血，被物粘住不能睜開，呼吸微弱，危在旦夕。病情如此嚴重的患者，市立醫(yī)院的醫(yī)生們也不常見。到底是什么原因讓王雪燕變成這樣?醫(yī)生們十分著急。而對于王雪燕來說， 也許僅僅是一步之遙。因此，對癥搶救成了當務(wù)之急!迅速啟動應(yīng)急方案，組織血液科、皮膚科、內(nèi)科、院ICU

等科室的會診結(jié)果又一次讓，對王雪燕的病情進行緊急會診。們瞠目結(jié)舌：王雪燕從里“燒”到外，除了皮膚被燒焦之外，腸道黏膜潰爛，口腔黏膜起斑，肺部嚴重發(fā)炎，并伴有40.2℃的高燒。同時，醫(yī)生通過化驗發(fā)現(xiàn)，王雪燕尿中帶血，消化道和腎臟等部位也有多處受損。因為病情危重，王雪燕被緊急轉(zhuǎn)往ICU

。同時，ICU

正在向 了解王雪燕的病史和一些生活

。 說：“王雪燕身體挺好的，平時沒有什么病呀!只是昨天感冒，她吃了感冒藥?！薄笆裁此?”曲像發(fā)現(xiàn)了 ?！扒嗝顾豓鉀片和撲熱息痛片。”的一句話，讓曲

茅塞頓開，王雪燕此時的種種癥狀跟青霉素過敏引起的剝脫性皮炎非常相似：全身皮膚泛

發(fā)持續(xù)性紅斑，灼熱、干燥、腫脹或輕度滲液，大片脫落。原來，那小小的青霉素V鉀片竟是“致命

”!死里逃生，萬般 本不必此時的王雪燕已經(jīng)奄奄一息，隨時可能，必須馬上采取治療措施。焦急萬分的們從不同的角度、領(lǐng)域提出建議，探討各種治療方案。仔細研究后， 救治小組制訂了一套特殊的雙重救治方案：既然是從體內(nèi)“冒火”，就先給她“滅火”，然后再對體外傷情進行對癥處理。醫(yī)生們先往王雪燕體內(nèi)注射激素類消炎藥，以將“火勢”全面控制;同時用 將身體浸泡，泡軟后又用 藥膏對王雪燕進行全身敷藥。3月8日晚上8點多鐘，王雪燕慢慢蘇醒。她全身的滲出物開始減少，腫塊出現(xiàn)了消退的跡象。治療初見成效，們松了口氣?！?

CephalosporinsChemistry:

7-ACAClassification:

four

generations-generation

cephalosporinsSecond-

generation

cephalosporinsThird-generation

cephalosporinsFourth-

generation

cephalosporins-generation

cephalosporins頭孢噻吩——先鋒I頭孢噻啶——先鋒II頭孢來星——先鋒III頭孢氨芐——先鋒IV頭孢唑啉——先鋒V頭孢拉定——先鋒VI頭孢乙——先鋒VII頭孢匹林——先鋒VIII頭孢羥氨芐CefalothinCefaloridineCefaloglycinCefalexinCefazolinCefradineCefacetrileCefapirinCefadroxilCommon

characters:Activity

on

gram-positivebacteria:>second>thirdActivity

on

gram-negativebacteria:

<second<thirdNo

effect

on

P.aeruginosa(綠膿桿菌)and

anaerobes(厭氧菌)Stability

toβ-Lactamase

produced

bygram-negative

rods:<second<thirdStable

toβ-Lactamase

produced

by

gram-positivebacteria>second>thirdRenal

toxicity:Clinical

usesPenicillin-resistant

staphylococcal(金葡菌)infectionMinor

to

moderate

infections

caused

by

sensitive

bacteriaSecond-generation

cephalosporinsDrugsCefamandole（頭孢孟多）,Cefuroxime（頭孢呋辛）Cefaclor（頭孢克洛，

）CommoncharactersMore

active

on

gram-negative

bacteriaLess active

on

gram-positive

bacteria

More

stable

to

β-Lactamaseproduced

bygram-negative

rodsSome

are

effective

on

anaerobes(厭氧菌)No

effect

on

P.aeruginosa(綠膿桿菌)Less

renal

toxicityClinicaluseschoiceGram-negative

bacteria

infections：Anaerobic

infectionsThird-generation

cephalosporinsDrugsCeftriaxone

（頭孢曲松，羅氏芬）Ceftazidime

（頭孢他定）CefoperazoneCefotaxime(頭孢哌酮）(頭孢噻圬）CommoncharactersMu ore

active

on

gram-negative

bacteriaTo

gram-positive

bacteria:

third<second<Stable

to

extended

β-Lactamase

produced

by

gram-negative

bacteriaEffective

on

anaerobes

and

P.aeruginosaNo

renal

toxicityPenetrating

body

fluids

and

tissues

wellClinicalusesa

wide

variety

of

serious

infections

caused

byorganisms

that

are

resistant

to

most

other

drugsFourth-

generation

cephalosporinsCefpirome（頭孢匹羅）,cefepime（頭孢吡圬）,cefclidin（頭孢利定）Character:Enhanced

antimicrobial

activityStableto

ESBLsMore

activity

on

gram-positive

cocciClinicaluses:infections

caused

by

organisms

that

are

resistant

tothird-generation

cephalosporinsComparison

between

1st,

2nd

&

3rd

G1st

G2nd

G3rd

GG+++++++G-++++++綠膿桿菌--+厭氧菌-++對-內(nèi)酰胺酶穩(wěn)定性G+

+++G-

-+++++++++++腎毒性+++-Side

effect

of

cephalosporinsAllergic

effectGastrointestinal

reactionsRenal

toxicityOther:

bleedingDisulfiram-like

effect(雙硫侖反應(yīng)）Case

3Mr.

Zhao

likes

drink

very

much.

Hecatch

cold

recently

and

taken

somedrugs

which

include

cefradine.

Hedrinks

about

100

ml

wine

after

taking

2pills

of

cefradine

and

feel

palpitation,breath

hard

soon

after.Diagnosis:

alcohol

toxication§3Other

β-Lactam

drugsCarbapenems（碳青霉烯類）The

most

important

antimicrobial

agents

in1990’sWide

spectrum

and

high

activity

Resistant to

mostβ-Lactamase(including

ESBLs

and

cephalosporinase)CarbapenemsThienamycin（硫霉素）Imipenem（亞胺培南）Imipenem-cilastatin:tienam（泰能）Meropenem（美羅培南）Panipenem（帕尼培南）Imipenem-cilastatin:tienamImipenem

is

inactivated

by

dehydropeptidases(脫氫肽酶)in

renal

tubules,cilastatin

is

a

renal

deh