Cell Wall Synthesis Cell Wall Synthesis InhibitorsInhibitors

By By

S.Bohlooli, PhDS.Bohlooli, PhD

Inhibitors of Cell Wall SynthesisInhibitors of Cell Wall Synthesis

PenicillinsPenicillins CephalosporinsCephalosporins MonobactamsMonobactams CarbapenemsCarbapenems Glycopeptides Other Cell Wall- or Membrane-Active Agents

Chemical StructureChemical Structure

Chemical StructureChemical Structure

PenicillinsPenicillins

In 1928, Alexander Fleming was researching In 1928, Alexander Fleming was researching vaccines and noticed a culture of staphlococci had vaccines and noticed a culture of staphlococci had undergone lysis from contamination with a moldundergone lysis from contamination with a mold

Fleming finally isolated the mold, Fleming finally isolated the mold, Penicillium Penicillium notatumnotatum, and found that the fluid beneath it possessed , and found that the fluid beneath it possessed antibacterial propertiesantibacterial properties

Basic structure consists of thiazolidine ring connected Basic structure consists of thiazolidine ring connected to to -lactam ring, to which is attached a side chain-lactam ring, to which is attached a side chain

Structure of penicillins and products of their enzymatic hydrolysis.

Chemical structure ,major variantsChemical structure ,major variants

Chemical structure ,major variantsChemical structure ,major variants

Cell envelope of a gram-negative bacterium

Biosynthesis of cell wall peptidoglycan

Mechanism of ActionMechanism of Action

Interferes with last step of bacterial cell wall Interferes with last step of bacterial cell wall synthesis, causing cell lysissynthesis, causing cell lysis

BactericidalBactericidal Only effective against rapidly growing Only effective against rapidly growing

organisms that synthesize a peptidoglycan cell organisms that synthesize a peptidoglycan cell wallwall

Inactive against mycobacteria, fungi, virusesInactive against mycobacteria, fungi, viruses

Mechanism of ActionMechanism of Actionway of being bactericideway of being bactericide

Penicillin binding proteinsPenicillin binding proteins Enzymes involved in forming cross linkages between Enzymes involved in forming cross linkages between

peptidoglycan chains inactivated by penicillinpeptidoglycan chains inactivated by penicillin Inhibition of transpeptidaseInhibition of transpeptidase

Hinders last step in formation of cross links needed for cell Hinders last step in formation of cross links needed for cell wall integritywall integrity

AutolysinsAutolysins Normally degrade cell wall, but penicillin prevents new Normally degrade cell wall, but penicillin prevents new

synthesissynthesis

Antibacterial SpectrumAntibacterial Spectrum

Natural penicillinsNatural penicillins Antistaphylococcal penicillinsAntistaphylococcal penicillins Extended spectrum penicillinsExtended spectrum penicillins Antipseudomonal penicillinsAntipseudomonal penicillins

Natural PenicillinsNatural Penicillins

Penicillin G (Benzylpenicillin)Penicillin G (Benzylpenicillin) Gram +/- cocci, Gram + bacilli, spirochetes, Gram +/- cocci, Gram + bacilli, spirochetes,

anaerobesanaerobes Susceptible to inactivation by Susceptible to inactivation by -lactamase-lactamase

Penicillin VPenicillin V Similar spectrumSimilar spectrum More acid stable than Pen GMore acid stable than Pen G Higher minimum inhibitory concentrationHigher minimum inhibitory concentration

Bacteria Susceptible to PenicillinBacteria Susceptible to Penicillin

Strep pneumoniaStrep pneumonia Major cause of bacterial pneumonia in all agesMajor cause of bacterial pneumonia in all ages

GonorrheaGonorrhea Neisseria gonorrhea and meningitidisNeisseria gonorrhea and meningitidis

SyphilisSyphilis Treponema pallidumTreponema pallidum

Antistaphylococcal penicillinsAntistaphylococcal penicillins

MethicillinMethicillin NafcillinNafcillin OxacillinOxacillin DicloxacillinDicloxacillin All are penicillinase-resistant penicillins used All are penicillinase-resistant penicillins used

in penicillinase-producing staphylococciin penicillinase-producing staphylococci Methicillin-resistant staph aureusMethicillin-resistant staph aureus

Extended Spectrum PenicillinsExtended Spectrum Penicillins

AmpicillinAmpicillin AmoxicillinAmoxicillin Activity against haemophilus influenza, Activity against haemophilus influenza,

proteus mirabilis, E. coli, and neisseria speciesproteus mirabilis, E. coli, and neisseria species Resistance due to plasmid mediated Resistance due to plasmid mediated

penicillinasepenicillinase May use clavulanic acid or sulbactam to May use clavulanic acid or sulbactam to

extend the antibacterial activityextend the antibacterial activity

Antipseudomonas PenicillinsAntipseudomonas Penicillins

CarbenicillinCarbenicillin TicarcillinTicarcillin PiperacillinPiperacillin AzlocillinAzlocillin MezlocillinMezlocillin Effective against pseudomonas aeroginosa and Effective against pseudomonas aeroginosa and

other gram negativesother gram negatives

Penicillins and AminoglycosidesPenicillins and Aminoglycosides

SynergisticSynergistic Inactivate each other if placed in same IV fluid Inactivate each other if placed in same IV fluid

bag because of positively charged bag because of positively charged aminoglycosides and negative penicillinsaminoglycosides and negative penicillins

Specific Indications for PenicillinSpecific Indications for Penicillin Narrow-spectrum bactericidalNarrow-spectrum bactericidal Most Gm+ cocci and rods and anaerobesMost Gm+ cocci and rods and anaerobes Intravenous: Pen G (potassium or sodium)Intravenous: Pen G (potassium or sodium) Intramuscular: Benzathine or procaine Pen GIntramuscular: Benzathine or procaine Pen G Oral: Pen VOral: Pen V Pen V, G well distributed in soft tissuesPen V, G well distributed in soft tissues Bone level is fraction of plasma concentrationBone level is fraction of plasma concentration Excreted primarily via kidneysExcreted primarily via kidneys

Bacterial ResistanceBacterial Resistance

1.1. -lactamase activity-lactamase activity• Hydrolyzes cyclic amide bond of Hydrolyzes cyclic amide bond of -lactam ring-lactam ring• Usually acquired by transfer of plasmidsUsually acquired by transfer of plasmids

2.2. Decreased permeability to drugDecreased permeability to drug

3.3. Altered penicillin binding proteinsAltered penicillin binding proteins• May require greater antibiotic concentrationsMay require greater antibiotic concentrations

4.4. Efflux Efflux

-lactamase Inhibitors-lactamase Inhibitors Clavulanic acid: product of streptomyces Clavulanic acid: product of streptomyces

clavuligerusclavuligerus Irreversibly binds Irreversibly binds -lactamases and inactivates -lactamases and inactivates

themthem Augmentin: amoxicillin + clavulanic acidAugmentin: amoxicillin + clavulanic acid Timentin: ticarcillin + clavulanic acidTimentin: ticarcillin + clavulanic acid Unasyn: ampicillin + sulbactamUnasyn: ampicillin + sulbactam

PharmacokineticsPharmacokinetics

AdministrationAdministration Oral, IV, IMOral, IV, IM

AbsorptionAbsorption Amoxicillin most completely absorbedAmoxicillin most completely absorbed Pen G absorption impeded by food in stomachPen G absorption impeded by food in stomach Administered at least 1–2 hours before or after a

meal. DistributionDistribution

All cross placentaAll cross placenta Minimal penetration into bone and CSFMinimal penetration into bone and CSF

Pharmacokinetics (con’t)Pharmacokinetics (con’t)

MetabolismMetabolism Minimal, except in renal failureMinimal, except in renal failure

ExcretionExcretion KidneyKidney Adjust dose in renal compromiseAdjust dose in renal compromise Probenecid inhibits penicillin secretionProbenecid inhibits penicillin secretion

Adverse ReactionsAdverse Reactions Hypersensitivity- 1-10% patients treatedHypersensitivity- 1-10% patients treated

Penicilloic acid- hapten for immune reactionPenicilloic acid- hapten for immune reaction Urticaria to angioedema to anaphylaxisUrticaria to angioedema to anaphylaxis -lactam cross reactivity-lactam cross reactivity

Diarrhea- disruption of flora- ampicillinDiarrhea- disruption of flora- ampicillin Nephritis- methicillinNephritis- methicillin Neurotoxicity- intrathecal or seizure disordersNeurotoxicity- intrathecal or seizure disorders Platelet dysfunction- carbenicillin, ticarcillinPlatelet dysfunction- carbenicillin, ticarcillin Cation toxicity- watch sodium (congenstive heart failure) Cation toxicity- watch sodium (congenstive heart failure)

and potassium (cardiac toxicity esp in renal failure pts)and potassium (cardiac toxicity esp in renal failure pts) Skin rashes-ampicillin and amoxicillin

Allergic ReactionsAllergic Reactions

Acute (< 30 min)Acute (< 30 min) Urticaria, angioedema, bronchoconstriction, GI, shockUrticaria, angioedema, bronchoconstriction, GI, shock

Accelerated (30 min-48 hrs)Accelerated (30 min-48 hrs) Urticaria, pruritis, wheezing, mild laryngeal edema, Urticaria, pruritis, wheezing, mild laryngeal edema,

local inflammatory reactionslocal inflammatory reactions Delayed (> 2 days)Delayed (> 2 days)

Skin rashSkin rash Oral glossitis, flurred tongue, black and brown tongue, Oral glossitis, flurred tongue, black and brown tongue,

cheilosis, severe stomatitis with loss buccal mucosacheilosis, severe stomatitis with loss buccal mucosa

Allergic ReactionsAllergic Reactions

Mild: Diphenhydramine 25-50 mg IV/IM/POMild: Diphenhydramine 25-50 mg IV/IM/PO Severe: Epinephrine 0.03-0.05 mgSevere: Epinephrine 0.03-0.05 mg Skin tests: benzylpenicilloyl-polylysineSkin tests: benzylpenicilloyl-polylysine

CephalosporinsCephalosporins

Cephalosporium acremonium, first source, Cephalosporium acremonium, first source, isolated in 1948isolated in 1948

-lactam antibiotics-lactam antibiotics Related to penicillins structurally and Related to penicillins structurally and

functionallyfunctionally More resistant to More resistant to -lactamases-lactamases

Antibacterial SpectrumAntibacterial Spectrum

First generationFirst generation Second generationSecond generation Third generationThird generation Fourth generationFourth generation Increased generation number, increased gram Increased generation number, increased gram

negative bacterial susceptibility, increased negative bacterial susceptibility, increased --lactamase resistance, decreased efficacy lactamase resistance, decreased efficacy against gram +against gram +

First GenerationFirst Generation

Gram + cocci, gram - bacilli, oral anaerobesGram + cocci, gram - bacilli, oral anaerobes Staphylococcus aureus, Proteus mirabilis, E. Staphylococcus aureus, Proteus mirabilis, E.

coli, Klebsiella pneumoniacoli, Klebsiella pneumonia Cefazolin, Cephalothin (parenteral)Cefazolin, Cephalothin (parenteral) Cephalexin, Cefadroxil, Cephradine (oral)Cephalexin, Cefadroxil, Cephradine (oral)

Second GenerationSecond Generation

Less active against G+, more G-Less active against G+, more G- Haemophilus influenzae, Enterobacter Haemophilus influenzae, Enterobacter

aerogenes, Neisseriaaerogenes, Neisseria Cefaclor, Cefuroxime axetil (Oral) Cefaclor, Cefuroxime axetil (Oral) Cefamandole, Cefonicid, Cefuroxime, Cefamandole, Cefonicid, Cefuroxime,

Cefotetan, Ceforanide (Parenteral)Cefotetan, Ceforanide (Parenteral) Cefoxitin- Bacteroides fragilisCefoxitin- Bacteroides fragilis Used with aminoglycosides for G - bacilliUsed with aminoglycosides for G - bacilli

Third GenerationThird Generation

More Gm – bacilli, Serratia marcescensMore Gm – bacilli, Serratia marcescens Cefixime (Oral)Cefixime (Oral) CefotaximeCefotaxime CeftizoximeCeftizoxime CeftazidimeCeftazidime CefoperazoneCefoperazone CeftriaxoneCeftriaxone CefpodoximeCefpodoxime

Fourth GenerationFourth Generation

Similar spectrum to third generationSimilar spectrum to third generation More resistance to More resistance to -lactamases-lactamases Cefepime hydrochlorideCefepime hydrochloride

Cephalosporins Active Against Methicillin-Resistant Staphylococci

Ceftaroline fosamil Ceftobiprole medocaril Binding to penicillin-binding protein 2a

ResistanceResistance

Similar to penicillinsSimilar to penicillins Limited cross resistance with penicillin, except Limited cross resistance with penicillin, except

with staph and strep pneumoniawith staph and strep pneumonia

PharmacokineticsPharmacokinetics

AdministrationAdministration DistributionDistribution

Distributed well through body fluidsDistributed well through body fluids Only third generation well into CSFOnly third generation well into CSF

ExcretionExcretion Renal eliminationRenal elimination Cefoperazone and ceftriaxone excreted through Cefoperazone and ceftriaxone excreted through

bile and fecesbile and feces

General Therapeutic UsesGeneral Therapeutic Uses

Acute respiratory infectionAcute respiratory infection First and second generationFirst and second generation

Gonorrhea and H. influenzaGonorrhea and H. influenza CeftriaxoneCeftriaxone

Enterobacter, Serratia, E.Coli, Providencia, Enterobacter, Serratia, E.Coli, Providencia, SalmonellaSalmonella Third generationThird generation

Gram negative meningitis and septicemiaGram negative meningitis and septicemia Third generationThird generation

Adverse EffectsAdverse Effects

Allergy- 15% cross sensitivity with Pen allergyAllergy- 15% cross sensitivity with Pen allergy 1-2% without Pen allergy1-2% without Pen allergy

Disulfiram-like effectDisulfiram-like effect Cefamandole, cefoperazone when ingested with alcohol Cefamandole, cefoperazone when ingested with alcohol

block second step in oxidation and aldehyde accumulationblock second step in oxidation and aldehyde accumulation BleedingBleeding

Cefamandole, cefoperazone- anti-vitamin K effectsCefamandole, cefoperazone- anti-vitamin K effects Renal, hepatic dysfunctionRenal, hepatic dysfunction

CarbapenemsCarbapenems Synthetic Synthetic -lactam antibiotics-lactam antibiotics Differ from penicillin in sulfur atom of Differ from penicillin in sulfur atom of

thiazolidine ringthiazolidine ring ImipenemImipenem

Combined with cilastin- broadest spectrum Combined with cilastin- broadest spectrum --lactam antibiotic available against penicillinase-lactam antibiotic available against penicillinase-producing Gram + and -, anaerobes, and producing Gram + and -, anaerobes, and pseudomonaspseudomonas

Resists Resists -lactamase hydrolysis-lactamase hydrolysis Meropenem, Meropenem, doripenem, ertapenem

Greater activity against gram-negative aerobes

CarbapenemsCarbapenems

Intravenous useIntravenous use Penetrates well into CNSPenetrates well into CNS Excreted by kidneysExcreted by kidneys Toxic metabolite may cause nephrotoxicityToxic metabolite may cause nephrotoxicity

Administered with cilastin to prevent cleavage and Administered with cilastin to prevent cleavage and toxic metabolite formationtoxic metabolite formation

Nausea, vomiting, diarrhea, seizures, Nausea, vomiting, diarrhea, seizures, eosinophilia, and neutropeniaeosinophilia, and neutropenia

MonobactamsMonobactams

Narrow spectrum- enterobacteriaceae, Narrow spectrum- enterobacteriaceae, pseudomonas; no gram + or anaerobic activitypseudomonas; no gram + or anaerobic activity

Resistant to Resistant to -lactamase-lactamase Aztreonam IV or IMAztreonam IV or IM Phlebitis, skin rash, abnormal liver function Phlebitis, skin rash, abnormal liver function

teststests Little cross reactivity with penicillinLittle cross reactivity with penicillin

VancomycinVancomycin

It binds firmly to the D-Ala-D-Ala terminus and It binds firmly to the D-Ala-D-Ala terminus and inhibits transglycosylase. inhibits transglycosylase.

Narrow-spectrum against methicillin-resistant Narrow-spectrum against methicillin-resistant staphylococci and pseudomembranous colitis caused staphylococci and pseudomembranous colitis caused by clostridium difficileby clostridium difficile

Prophylaxis for subacute bacterial endocarditis in Prophylaxis for subacute bacterial endocarditis in penicillin allergic patients for high risk surgerypenicillin allergic patients for high risk surgery

Oral route only for P. colitisOral route only for P. colitis IV for systemic infectionsIV for systemic infections

VancomycinVancomycin

Minimal resistant bacteria, but not vancomycin Minimal resistant bacteria, but not vancomycin resistant enterococci (VRE)resistant enterococci (VRE)

Renal eliminationRenal elimination Fever, chills, phlebitis at infusion site, rash Fever, chills, phlebitis at infusion site, rash

with chronic administration, ototoxicity with chronic administration, ototoxicity (cochlear damage above 80 (cochlear damage above 80 g/ml), g/ml), nephrotoxicitynephrotoxicity

Slow IV administration- fast causes histamine Slow IV administration- fast causes histamine release (“red man syndrome”), hypotensionrelease (“red man syndrome”), hypotension

Newer glycopeptide antibiotics

Teicoplanin It can be given intramuscularly

Dalbavancin Derived from teicoplanin Effectrive on methicillin-resistant and vancomycin-

intermediate S aureus Telavancin

Derived from vancomycin active versus gram-positive bacteria including strains with reduced susceptibility to vancomycin

Other Cell Wall- or Membrane-Active Agents

Daptomycin Novel cyclic lipopeptide Similar to that of vancomycin Active against vancomycin-resistant strains of enterococci

and S aureus Fosfomycin

Analog of phosphoenolpyruvate Active against both gram-positive and gram-negative

Cycloserine Bacitracin

Mechanism of action of daptomycin

BacitracinBacitracin

Bacitracin inhibits cell wall synthesis by interfering Bacitracin inhibits cell wall synthesis by interfering with dephosphorlyation in cycling of the lipid carrierwith dephosphorlyation in cycling of the lipid carrier

Effective against Gram positive microorganismsEffective against Gram positive microorganisms Topical application due to nephrotoxicityTopical application due to nephrotoxicity Often used for traumatic abrasionsOften used for traumatic abrasions