beta lactam antibiotics lu iv

8/9/2019 Beta Lactam Antibiotics Lu IV

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Chemical substancesChemical substances

Selectively toxic to bacteriaSelectively toxic to bacteria

Source: natural and syntheticsSource: natural and synthetics

Beta lactam ringBeta lactam ring

BetaBeta--lactamslactams

1.1. PenicillinsPenicillins

2.2. CephalosporinsCephalosporins

3.3. CarbapenemsCarbapenems

4.4. MonobactamsMonobactams

NonNon-- Beta lactamsBeta lactams

1.1. AminoglycosidesAminoglycosides

2.2. MacrolidesMacrolides

3.3. LincosamidesLincosamides

4.4. TetracyclinesTetracyclines

5.5. ChloramphenicolChloramphenicol

6.6. SulfonamidesSulfonamides--TrimethoprimTrimethoprim

7.7. QuinolonesQuinolones

8.8. NitrofuransNitrofurans


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Beta lactam antibiotics- inhibits cell wall synthesis

CellCell wallwall

Penicillin binding proteinPenicillin binding protein


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C NH CH CH C

O

O C N CH

CH3

CH3

COOH

S

Site of penicillinase action.Breakage of the lactam ring.

STRUCTURE OF PENICILLIN

PENICILLINPENICILLINPENICILLINPENICILLINPENICILLINPENICILLINPENICILLINPENICILLIN

Fleming, Florey, Chain and Heatleywon the Nobel prize for discovery ofpenicillin


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..

S S p p e e c c t t r r u u m m o o f f AAc c t t i i v v i i t t y y R R o o u u t t e e o o f f U U s s e e

N N a a t t u u r r a a l l P P e e n n i i c c i i l l l l i i n n s s P P e e n n i i c c i i l l l l i i n n G G ,, K K o o r r N N a a B B e e n n z z a a t t h h i i n n e e P P e e n n i i c c i i l l l l i i n n P P e e n n i i c c i i l l l l i i n n V V K K

AAccttiivvee aaggaaiinnsstt mmoosstt ssttrreeppttooccooccccii,, ppnneeuummooccooccccii,, mmeenniinnggooccooccccii,, oorraall aannaaeerroobbeess,, ssppiirroocchheetteess,, lliisstteerriiaa,, CCoorryynneebbaacctteerriiuumm sspppp..

IIVV IIMM PPOO

P P e e n n i i c c i i l l l l i i n n a a s s e e - - r r e e s s i i s s t t a a n n t t p p e e n n i i c c i i l l l l i i n n

M M e e t t h h i i c c i i l l l l i i n n O O x x a a c c i i l l l l i i n n C C l l o o x x a a c c i i l l l l i i n n

AAccttiivvee aaggaaiinnsstt ssttaapphhyyllooccooccccii aanndd ssttrreeppttooccooccccii;; iinnaaccttiivvee aaggaaiinnsstt eenntteerrooccooccccii,, aannaaeerroobbiicc bbaacctteerriiaa aanndd GG((--))

IIMM,, IIVV PPOO

AAm m i i n n o o p p e e n n i i c c i i l l l l i i n n s s AAm m p p i i c c i i l l l l i i n n AAm m o o x x i i c c i i l l l l i i n n

SSiimmiillaarr ttoo NNaattuurraall ppeenniicciilllliinnss bbuutt hhaass aaccttiivviittyy aaggaaiinnsstt ssoommee GG((--)) bbaacctteerriiaa IIVV

PPOO C C a a r r b b o o x x y y a a n n d d i i n n d d a a n n y y l l p p e e n n i i c c i i l l l l i i n n s s

C C a a r r b b e e n n i i c c i i l l l l i i n n

T T i i c c a a r r c c i i l l l l i i n n

WWiiddeerr ccoovveerraaggee ffoorr GG((--)) bbaacctteerriiaa iinncclluuddiinngg PPsseeuuddoommoonnaass aaeerruuggiinnoossaa PPOO

IIMM,,IIVV

E E x x t t e e n n d d e e d d s s p p e e c c t t r r u u m m u u r r e e i i d d o o p p e e n n i i c c i i l l l l i i n n s s

P P i i p p e e r r a a c c i i l l i i n n

WWiiddeerr ccoovveerraaggee ffoorr GG((--)) bbaacctteerriiaa iinncclluuddiinngg PPsseeuuddoommoonnaass aaeerruuggiinnoossaa;; aaccttiivvee aaggaaiinnsstt eenneetteerrooccooccccii,, BBaacctteerrooiiddeess sspppp.. IIMM,,IIVV

Classification of penicillins –based on antimicrobialspectrum with considerable overlap among classes

Infecting Organism Penicillin of Choice Gram positive Streptococcus pneumoniae Streptococcus pyogenes Streptococcus agalactiae Enterococcus faecalis Staphylococcus aureus

MRSA Staphylococcus epidermidis

MRSE Corynebacterium diphtheriae

Listeria monocytogenes

Penicillin GPenicillin GPenicillin GAmpicillinPenicillinase resistant penicillin

NonePenicillinase resistant penicillin

NonePenicillin G

AmpicillinGram negative Neisseria meningitidis Haemophilus influenzae Pseudomonaes aeruginosa Escherichia coli

Penicillin GAmpicillinPiperacillinAmpicillin


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Infecting Organism Penicillin of Choice

Anaerobic species

PeptostreptococcusPrevotella melaninogenicasClostridium tetani

Penicillin GPenicillin GPenicillin G

Treponema pallidumLeptospiraBacillus anthracis

Penicillin GPenicillin GPenicillin G

Bacterial meningitis (dueBacterial meningitis (dueto S. pneumoniae and N.to S. pneumoniae and N.meningitidis) High dosemeningitidis) High dosebenzylpenicillin IVbenzylpenicillin IV

Bone and joint infectionsBone and joint infectionsdue to S. aureus with IVdue to S. aureus with IVoxacillin then shift to oraloxacillin then shift to oral

cloxacillincloxacillin


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Skin and soft tissueSkin and soft tissue

infections due to S.infections due to S.

pyogenes and S. aureuspyogenes and S. aureus--

oral penicillin, cloxacillinoral penicillin, cloxacillin

Pharyngitis due to S.Pharyngitis due to S.

pyogenespyogenes-- Oral Pen VKOral Pen VK

Otitis mediaOtitis media-- due to H.due to H.

influenzae, S.influenzae, S.pneumoniae, S.pneumoniae, S.

pyogenespyogenes-- may give oralmay give oral

amoxycillinamoxycillin

GonorrheaGonorrhea--

penicillin no longerpenicillin no longerusedused

SyphillisSyphillis-- penicillinpenicillindrug of choicedrug of choice

EndocarditisEndocarditis-- IVIVpenicillin +penicillin +aminoglycosideaminoglycoside

PseudomonasPseudomonasaeruginosaaeruginosa--piperacillinpiperacillin


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1.allergic reactions1.allergic reactions -- anaphylaxis in 0.2%,anaphylaxis in 0.2%,skin rashes, fever, delayed type ofskin rashes, fever, delayed type of

serum sicknessserum sickness

2. hematologic toxicity2. hematologic toxicity – – 11--4%4%

3. renal toxicity3. renal toxicity – – 11--2%2%

4. CNS toxicity4. CNS toxicity -- rarerare

5. GI disturbance5. GI disturbance – – 22--5%5%

6. Elevated liver function tests6. Elevated liver function tests – – 11--4%4%

7. Electrolyte disturbances7. Electrolyte disturbances-- IV penicillinsIV penicillinswith large amounts if sodium orwith large amounts if sodium or

potassiumpotassium

List of cephalosporins according to the generationList of cephalosporins according to the generation

1st generation1st generation Cephalothin CephalexinCephalothin CephalexinCefazolin Cephapirin CephradineCefazolin Cephapirin CephradineCeftezole Cephradine CefadroxilCeftezole Cephradine Cefadroxil

2nd generation2nd generation Cefuroxime Cefuroxime axetilCefuroxime Cefuroxime axetilw/o anaerobic Cefamandole Cefaclor Cefonicid Cefprozilw/o anaerobic Cefamandole Cefaclor Cefonicid Cefprozil

Cefotiam Ceforanide Loracarbef*Cefotiam Ceforanide Loracarbef*with antianaerobic Cefoxitin Cefminox Cefotetan Cefmetazolewith antianaerobic Cefoxitin Cefminox Cefotetan Cefmetazole

3rd generation3rd generationw/o antiw/o anti--pseudomonal Cefotaxime Cefminoxime Cefiximepseudomonal Cefotaxime Cefminoxime Cefixime

Ceftizoxime Cefpodoxime CeftriaxoneCeftizoxime Cefpodoxime CeftriaxoneCeftibutenCeftibuten

with antiwith anti--pseudomonal Cefoperazone Cefpimizolepseudomonal Cefoperazone CefpimizoleCeftazidime Cefsulodin CefpiramideCeftazidime Cefsulodin Cefpiramide

4th generation4th generation Cefepime, cefpiromeCefepime, cefpirome

55thth generation cephalosporingeneration cephalosporin CeftobiproleCeftobiprole


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Classification of CephalosporinsClassification of Cephalosporins

Generation Prototype Drugs Useful Spectrum

First Cefazolin (IV)Cephalexin (PO) Gram positive Streptococci,Staph aureus, but no activityagainst Enterococci and Listeria

Second Cefuroxime (IV,PO)Cefaclor

Cefoxitin

Community acquired E. coli,Klebsiella, Proteus, H.influenzae, M. catarrhalis. Lessactive against gram(+)Has added activity againstBacteroides fragilis

Third Ceftriaxone (IV, IM)Cefotaxime (IV)Cefixime (PO)Ceftazidime

Enterobacteriaceae, Serratia,Neisseria gonorrhea; less activethan 1st gen against G(+) cocci- active against Pseudomonas

aeruginosaFourth Cefepime Comparable to 3rd gen but more

stable to β lactamases of G(-)

Fifth Ceftobiprole Activity against MRSA, Gram (-)including Pseudomonas

CefazolinCefazolin-- prophylaxis for surgeryprophylaxis for surgery

CefuroximeCefuroxime-- alternative to amoxycillin foralternative to amoxycillin forcommunity acquired pneumoniacommunity acquired pneumonia

CeftriaxoneCeftriaxone-- alternative to penicillin foralternative to penicillin formeningitismeningitis

CeftazidimeCeftazidime-- pseudomonas infectionspseudomonas infections

CefipimeCefipime-- nosocomial infectionsnosocomial infections


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Adverse effects of CephalosporinsAdverse effects of Cephalosporins

Hypersensitivity reactionsHypersensitivity reactions – – 11--3%; may3%; maycross react with penicillins in 5cross react with penicillins in 5--20%20%

HematologicHematologic-- 11--5%5%

diarrheadiarrhea-- 22--5%5%

abn liver function testsabn liver function tests-- 11--7%7%

biliary sludge (ceftriaxone)biliary sludge (ceftriaxone)-- 20%20%

interstitial nephritisinterstitial nephritis-- rarerare

CarbapenemsCarbapenems-- ErtapenemErtapenem

MeropenemMeropenemMech of ActionMech of Action-- high affinitity to PBP’shigh affinitity to PBP’s

and is not hydrolyzed by mostand is not hydrolyzed by most ββββββββlactamases; shows a postantibioticlactamases; shows a postantibioticeffect against gram negativeeffect against gram negativeorganismsorganisms

Ertapenem


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Spectrum of activitySpectrum of activity--most active drugmost active drugagainst a wide varietyagainst a wide varietyof bacteria includingof bacteria includingG(+), G(G(+), G(--), and), andanaerobic bacteria;anaerobic bacteria;reserved for seriousreserved for seriousinfections with multiinfections with multi--

drug resistant bacteriadrug resistant bacteriaor polymicrobialor polymicrobialinfectionsinfections

DrugDrug Gram positiveGram positive Gram negativeGram negative AnaerobesAnaerobes

MeropenemMeropenem Staph aureus Staph aureus (MSSA only)(MSSA only) StrepStrepagalactiae,agalactiae,

Strep pneumoniae Strep pneumoniae (including penicillin(including penicillin

resistant strains)resistant strains)Strep pyogenes Strep pyogenes

E. coli, H.E. coli, H.influenzae influenzae ,,

Klebsiella Klebsiella

M. catarrhalis,M. catarrhalis,Proteus mirabilis Proteus mirabilis

PseudomonasPseudomonasaeruginosa,aeruginosa,

including ESBLincluding ESBLproducingproducing

organismsorganisms

Bacteroides sppBacteroides sppincluding fragilis including fragilis

ClostridiumClostridium

clostridioforme clostridioforme Peptostreptococc Peptostreptococc

usus speciesspeciesPorphyromonasPorphyromonas

asaccharolytica asaccharolytica Prevotella bivia Prevotella bivia

ErtapenemErtapenem Staph aureus Staph aureus

(MSSA only)(MSSA only) StrepStrepagalactiae,agalactiae,Strep pneumoniae Strep pneumoniae

(penicillin(penicillinsusceptible isolatessusceptible isolates

only)only) StrepStreppyogenes pyogenes

E. coli, H. influenzae E. coli, H. influenzae

(Beta(Beta--lactamaselactamasenegative isolatesnegative isolates

only),only), K.K.

pneumoniae pneumoniae M. catarrhalis,M. catarrhalis,

Proteus mirabilis Proteus mirabilis

Bacteroides sppBacteroides spp

including fragilis including fragilis ClostridiumClostridium

clostridioforme clostridioforme

Peptostreptococc Peptostreptococc usus speciesspecies

PorphyromonasPorphyromonasasaccharolytica asaccharolytica

Prevotella bivia Prevotella bivia


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DrugsDrugs preparatpreparat

ionsionsHalfHalf--lifelife

DosingDosing EliminationElimination

MeropenemMeropenem IVIV 1 hr1 hr Q 8hrsQ 8hrs RenalRenal

ErtapenemErtapenem IV, IMIV, IM 4 hrs4 hrs Q 24Q 24hrshrs

RenalRenal

Complicated IntraComplicated Intra--abdominal/pelvicabdominal/pelvic

InfectionsInfections..

Complicated Skin and Skin StructureComplicated Skin and Skin StructureInfections,Infections, including diabetic foot infectionsincluding diabetic foot infectionswithout osteomyelitiswithout osteomyelitis

Community Acquired PneumoniaCommunity Acquired Pneumonia

Complicated UTI including pyelonephritisComplicated UTI including pyelonephritis

PreventionPrevention-- in adults for thein adults for the prophylaxis ofprophylaxis ofelective colorectal surgeryelective colorectal surgery

Cannot be used for CNS infectionsCannot be used for CNS infections


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1.1. Documented multidrug resistant gramDocumented multidrug resistant gram--negative infections due to organisms provennegative infections due to organisms provenor suspected to be susceptible toor suspected to be susceptible tocarbapenems.carbapenems.

2.2. Polymicrobial infections (e.g., mixed aerobicPolymicrobial infections (e.g., mixed aerobicand anaerobic infections) in which otherand anaerobic infections) in which otheragents have insufficient activity or areagents have insufficient activity or are

contraindicated due to toxic potential.contraindicated due to toxic potential.-- May be used for CNS infectionsMay be used for CNS infections

Adverse effectsAdverse effects

immediate hypersensitivity;immediate hypersensitivity;

rapid infusion can cause nausea andrapid infusion can cause nausea andvomiting;vomiting;

seizures in 0.4seizures in 0.4--1.5% of patients1.5% of patients

given Imipenem; Meropenem is lessgiven Imipenem; Meropenem is lessseizuregenicseizuregenic

candidemia may occurcandidemia may occur


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1. RIGHT DIAGNOSIS1. RIGHT DIAGNOSIS

2. RIGHT DRUG2. RIGHT DRUG

3. PROPER DRUG3. PROPER DRUGADMINISTRATIONADMINISTRATION

4. PREVENT/MINIMIZE ADVERSE4. PREVENT/MINIMIZE ADVERSE

DRUG REACTIONDRUG REACTION

Cell wall inhibitors are one of the mostCell wall inhibitors are one of the mostimportant weapons in theimportant weapons in thearmamentarium of physicians againstarmamentarium of physicians againstbacterial infectionsbacterial infections

To preserve their usefulness, rationalTo preserve their usefulness, rational

antibiotic use must be exercisedantibiotic use must be exercised-- if notif notresistance will be commonplaceresistance will be commonplace

beta lactam antibiotics lu iv

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