Bacterial Cell Wall Bacterial Cell Wall InhibitorsInhibitors

ββ-lactam antibiotics-lactam antibiotics Contain a beta-lactam ring that is Contain a beta-lactam ring that is

part of their chemical structurepart of their chemical structure An intact beta-lactam ring is An intact beta-lactam ring is

essential for antibacterial activityessential for antibacterial activity Include: Penicillins, Include: Penicillins,

Cephalosporins, Carbapenems, Cephalosporins, Carbapenems, Carbacephems & MonobactamsCarbacephems & Monobactams

- The R in the structure of - The R in the structure of ββ-lactam -lactam antibiotic determines the antibiotic determines the characteristic of antimicrobial agent characteristic of antimicrobial agent e.g. narrow or broad spectrum; oral e.g. narrow or broad spectrum; oral vs parenteral administration; vs parenteral administration; sensitivity vs resisitence to sensitivity vs resisitence to ββ--lactamases…etclactamases…etc

- The - The ββ-lactam ring is the site of -lactam ring is the site of attack by gastric acidity and attack by gastric acidity and lactamases lactamases

Beta Lactams Mechanism of Action:Beta Lactams Mechanism of Action: Inhibit synthesis of bacterial cell Inhibit synthesis of bacterial cell

walls by binding to proteins in walls by binding to proteins in bacterial cell membranes e.g. PBP’sbacterial cell membranes e.g. PBP’s

Binding produces a defective cell Binding produces a defective cell wall that allows intracellular wall that allows intracellular contents to leak out (lysis)contents to leak out (lysis)

Most effective when bacterial cells Most effective when bacterial cells are dividingare dividing

Inhibitors of Cell Wall Inhibitors of Cell Wall SynthesisSynthesis

Bacteria that produce Bacteria that produce ββ-lactamase -lactamase (hydrolyze (hydrolyze ββ-lactam ring and hence -lactam ring and hence inactivation of antimicrobial) :inactivation of antimicrobial) :

Staph aureusStaph aureus

Moraxella catarrhlisMoraxella catarrhlis

Neisseria gonorrhoeaeNeisseria gonorrhoeae

EnterobacteriaceaeEnterobacteriaceae

Hemophilus influenzaeHemophilus influenzae

Bacteroides speciesBacteroides species

Penicillins (PNC’s)Penicillins (PNC’s)- Most widely used antibiotics, most - Most widely used antibiotics, most

effective, least toxic and cheapeffective, least toxic and cheap- Derivatives of 6-aminopenicillanic acid (ß-- Derivatives of 6-aminopenicillanic acid (ß-

lactam ring is important structure)lactam ring is important structure)- Derived from a fungus- Derived from a fungus- Prototype is Penicillin G- Prototype is Penicillin G- Widely distributed except in CSF (except if - Widely distributed except in CSF (except if

inflammation is present) and in inflammation is present) and in intraocular fluidintraocular fluid

- Most serious complication is - Most serious complication is hypersensitivity hypersensitivity

- Can cause seizures and nephropathy- Can cause seizures and nephropathy

- Natural penicillins:- Natural penicillins:

Benzylpenicillin=Penicillin G IM, IVBenzylpenicillin=Penicillin G IM, IV

Acid labile, short acting, given 4-6 Acid labile, short acting, given 4-6 times/daytimes/day

Depo IM forms to penicillin GDepo IM forms to penicillin G

Procaine penicillin given IM Procaine penicillin given IM twice/day, IV injection contraindicated twice/day, IV injection contraindicated (could lead to ↓ BP & convulsions)(could lead to ↓ BP & convulsions)

Benzathine penicillin given IM Benzathine penicillin given IM mainly used for rheumatic fever mainly used for rheumatic fever prophylaxisprophylaxis

Phenoxy methylpenicillin= Penicillin V Phenoxy methylpenicillin= Penicillin V OralOral

Natural penicillins are narrow spectrum Natural penicillins are narrow spectrum and penicillinase sensitiveand penicillinase sensitive

Considered drugs of choice to treat Considered drugs of choice to treat infections with G+ve Strep., infections with G+ve Strep., ββ-hemolytic -hemolytic type (most common microbe in tonsillitis)type (most common microbe in tonsillitis)

Have little effect if any against G-ve Have little effect if any against G-ve bacteriabacteria

- Narrow spectrum penicillinase - Narrow spectrum penicillinase resistant penicillins (Anti Staph resistant penicillins (Anti Staph penicillins):penicillins):

Nafcillin IM, IV Nafcillin IM, IV

Oxacillin IM, IV Oxacillin IM, IV

Cloxacillin OralCloxacillin Oral

Dicloxacillin OralDicloxacillin Oral

Flucloxacillin Oral & parenteralFlucloxacillin Oral & parenteral

- Broad spectrum penicillinase sensitive - Broad spectrum penicillinase sensitive PNCPNC’’s (amino PNCs (amino PNC’’s ):s ):

Ampicillin IM, IV, OralAmpicillin IM, IV, Oral

Amoxicillin Oral More potent, better Amoxicillin Oral More potent, better

bioavailability, longer DOAbioavailability, longer DOA

These PNCThese PNC’’s have very little effect, if any, s have very little effect, if any, against PNC ase producing bacteria e.g. against PNC ase producing bacteria e.g. H. influenza and against G-ve bacteria H. influenza and against G-ve bacteria e.g. E. coli, Proteus. No effect against e.g. E. coli, Proteus. No effect against PseudomonasPseudomonas

Amino PNC’s are widely used in Amino PNC’s are widely used in tonsillitis, otitis media, tonsillitis, otitis media, gonorrhea, respiratory gonorrhea, respiratory infections, shigella infections, infections, shigella infections, UTI’s…etcUTI’s…etc

Amoxicillin has good activity Amoxicillin has good activity against Helicobacter pylori (+ against Helicobacter pylori (+ PPI’s PPI’s ++ Clarithromycin Clarithromycin ++ Metronidazole)Metronidazole)

- Antipseudomonal PNC’s:- Antipseudomonal PNC’s:Piperacillin > Mezlocillin=Ticarcillin > Piperacillin > Mezlocillin=Ticarcillin >

CarbinicillinCarbinicillinAll are synergistic with aminoglycosides All are synergistic with aminoglycosides

against against PseudomonasPseudomonas- Amidinopenicillins:- Amidinopenicillins:Mecillinam (IM; IV) Pivmicillinam (oral)Mecillinam (IM; IV) Pivmicillinam (oral) Most potent PNC’s against enterobacteria Most potent PNC’s against enterobacteria ( Salmonella, E. coli, Klebsiella, ( Salmonella, E. coli, Klebsiella,

Shigella…), have little or no activity against Shigella…), have little or no activity against G+ve cocci or pseudomonas; synergistic with G+ve cocci or pseudomonas; synergistic with other other ββ-lactams but not with -lactams but not with aminoglycosidesaminoglycosides

MOA of Penicillins:MOA of Penicillins:Most bacteria have rigid cell walls that Most bacteria have rigid cell walls that

are not found in host cells (selective are not found in host cells (selective toxicity)toxicity)

PNC’s act by inhibiting transpeptidases, PNC’s act by inhibiting transpeptidases, the enzymes that catalyze the final the enzymes that catalyze the final cross-linking step in the synthesis of cross-linking step in the synthesis of peptidoglycan, thus leading to the lyses peptidoglycan, thus leading to the lyses of cell wall.of cell wall.

Disruption of the cell wall causes death of Disruption of the cell wall causes death of the bacterial cell (Bactericidal Effect)the bacterial cell (Bactericidal Effect)

Pharmacokinetics of PNCPharmacokinetics of PNC’’s:s:Bind plasma proteins, widely distributed, theirBind plasma proteins, widely distributed, their

concentrations in ocular fluid, joints and CSFconcentrations in ocular fluid, joints and CSF

are poor (do not cross BBB unless meninges are poor (do not cross BBB unless meninges are inflamed), do not cross the placenta are inflamed), do not cross the placenta

Metabolized by the liver and excreted by Metabolized by the liver and excreted by glomerular filtration and tubular secretionglomerular filtration and tubular secretion

Probenecid inhibits tubular secretion of PNCProbenecid inhibits tubular secretion of PNC’’s s (nafcillin & oxacillin are mainly excreted by (nafcillin & oxacillin are mainly excreted by the liver)the liver)

Indications for Penicillin’s:Indications for Penicillin’s:- More effective in treating gram+ - More effective in treating gram+

infectionsinfections- Used to treat infections of the skin, GU, - Used to treat infections of the skin, GU,

GI, respiratory tract and soft tissuesGI, respiratory tract and soft tissues- Selection depends on the organism and - Selection depends on the organism and

severity of the infection e.g. anti-staph severity of the infection e.g. anti-staph vs. anti - pseudomonalvs. anti - pseudomonal

** Combination of PNC’s or a ** Combination of PNC’s or a cephalosporin with a potent inhibitor cephalosporin with a potent inhibitor of lactamasesof lactamases

ββ-lactemase inhibitors:-lactemase inhibitors:

Have no antibacterial activity, increase Have no antibacterial activity, increase potency and etend spectrum of activity potency and etend spectrum of activity of combined antibioticof combined antibiotic

Clavulinic acid, Sulbactam, TazobactamClavulinic acid, Sulbactam, Tazobactam

(Augmentin(Augmentin® ® =amoxicillin/clavulinate)=amoxicillin/clavulinate)

(Unasyn(Unasyn®®=ampicillin/sulbactam) =ampicillin/sulbactam)

(Zosyn(Zosyn®®=piperacillin/tazobactam)…etc=piperacillin/tazobactam)…etc

Mechanisms of resistance to PNC’s:Mechanisms of resistance to PNC’s:

- Altered penicillin binding proteins - Altered penicillin binding proteins (PBPs) (PBPs)

- Production of beta-lactamase - Production of beta-lactamase (penicillinases)(penicillinases)

- Decreased penetration/increased efflux - Decreased penetration/increased efflux (pseudomonas)(pseudomonas)

Preparations to PNCPreparations to PNC’’s :s :

Oral, parenteral, intrathecal, topical, Oral, parenteral, intrathecal, topical, intra – articularintra – articular

Side effects to PNC’s:Side effects to PNC’s:

- Allergy ( Most frequent and - Allergy ( Most frequent and dangerous )dangerous )

Type Type I allergic reactions. I allergic reactions. Early onset Early onset ( immune Ig E mediated )( immune Ig E mediated )

Type Type II allergic reactions. II allergic reactions. Late onset Late onset ( 2-10 days ). May manifest as ( 2-10 days ). May manifest as eosinophilia, hemolytic anemia, eosinophilia, hemolytic anemia, interstitial nephritis or serum interstitial nephritis or serum sickness (fever; arthralgia; malaise…) sickness (fever; arthralgia; malaise…)

- Nonallergic ampicillin rash, occurs - Nonallergic ampicillin rash, occurs only once (more common in pts with only once (more common in pts with acute leukemias; mononucleosis, acute leukemias; mononucleosis, lymphomas, cytomegaloviral lymphomas, cytomegaloviral infections…)infections…)

- Neurotoxicity (more common with - Neurotoxicity (more common with oxacillin)oxacillin)

- Hepatotoxicity (IV oxacillin)- Hepatotoxicity (IV oxacillin)- Bone marrow depression (reversible) - Bone marrow depression (reversible)

(IV nafcillin)(IV nafcillin)- Nephrotoxicity (Methicillin)- Nephrotoxicity (Methicillin)

Other restrictions in the use of Other restrictions in the use of PNC’s:PNC’s:

- Na+ penicillins → restricted use in - Na+ penicillins → restricted use in pts with hypertension or heart pts with hypertension or heart failurefailure

- K+ Penicillins →restricted use in - K+ Penicillins →restricted use in pts with renal failurepts with renal failure

- Absolute contraindications to all - Absolute contraindications to all PNC’s in pts with history of allergyPNC’s in pts with history of allergy

CephalosporinsCephalosporinsDerivatives of 7-aminocephalosporanic Derivatives of 7-aminocephalosporanic

acidacid ββ- lactam antibiotics, Cidal- lactam antibiotics, CidalSemisyntheticSemisyntheticBroad spectrumBroad spectrumInhibitors of microbial cell wall synthesisInhibitors of microbial cell wall synthesisDiffer in pharmacokinetic properties and Differ in pharmacokinetic properties and

spectrum of activityspectrum of activityClassified into 1Classified into 1stst 2 2ndnd 3 3rdrd and 4 and 4thth generations generations

* First generation* First generationCefadroxil Cefadroxil Cefalexin Cefalexin Oral OralCefazolin Cefazolin IM, IVIM, IVCephapirinCephapirinCephradineCephradineCephaloridine Cephaloridine * Second generation* Second generationCefaclorCefaclor Oral OralCephamandole Cephamandole IM, IV IM, IV

CephmetazoleCephmetazole

CefonicidCefonicid

CefotetanCefotetan

CefoxitinCefoxitin

CefprozilCefprozil

CefuroximeCefuroxime

Cefuroxime axetilCefuroxime axetil

LoracarbefLoracarbef

* Third generation* Third generation

CefiximeCefixime Oral Oral

Cefoperazone IM, IVCefoperazone IM, IV

Cefdinir CefpodoximeCefdinir Cefpodoxime

Cefotaxims CeftazidimeCefotaxims Ceftazidime

CeftriaxoneCeftriaxone Ceftibuten Ceftizoxime Ceftibuten Ceftizoxime

* Fourth generation* Fourth generation

CefepimeCefepime IM, IV IM, IV

11stst generation cephalosporins have the best generation cephalosporins have the best activity against G +ve microorganisms, lessactivity against G +ve microorganisms, less resistant to resistant to ββ- lactamases, and do not cross - lactamases, and do not cross readily the BBB as compared to 2readily the BBB as compared to 2ndnd, 3, 3rdrd and and 44thth generations generationsCephalosporins never considered drugs of Cephalosporins never considered drugs of choice for any infection, however they are choice for any infection, however they are

highly effective in upper and lower highly effective in upper and lower respiratory infection, H. influenza, UTIrespiratory infection, H. influenza, UTI’’s, s, dental infections, severe systemic dental infections, severe systemic infection...infection...

** Among cephalosporins:** Among cephalosporins:

- Cefoxitin (2- Cefoxitin (2ndnd) has the best activity ) has the best activity against Bacteroids fragilisagainst Bacteroids fragilis

- Cefamandole (2- Cefamandole (2ndnd) has the best ) has the best activity against H. Influenzaactivity against H. Influenza

- Cefoperazone (3- Cefoperazone (3rdrd), Ceftazidine (3), Ceftazidine (3rdrd) ) and Cefepime (4and Cefepime (4thth) have the best ) have the best activity against P. aeruginosa activity against P. aeruginosa infectionsinfections

Side effects to cephalosporins:Side effects to cephalosporins:

- Allergy- Allergy

Cross allergy with penicillins ( 10% )Cross allergy with penicillins ( 10% )

- Hepatotoxicity- Hepatotoxicity

- Nephrotoxicity- Nephrotoxicity

Mostly seen with Cephaloridine (1Mostly seen with Cephaloridine (1stst))

↑ ↑ with concomitant aminoglycosides usewith concomitant aminoglycosides use

- Hemolytic anemia- Hemolytic anemia

All cephalosporins are excreted by the kidney All cephalosporins are excreted by the kidney except except

Ceftriaxone (3Ceftriaxone (3rdrd) which is excreted by the liver) which is excreted by the liver

Other Other ββ- lactam antibiotics:- lactam antibiotics:- Carbapenems- Carbapenems e.g. Imipenem, Meropenem e.g. Imipenem, Meropenem* Imipenem* ImipenemHas the broadest spectrum of activity of all Has the broadest spectrum of activity of all

ββ--lactam antibiotics, effective against most G lactam antibiotics, effective against most G

+ve & - ve bacteria and anaerobes, given +ve & - ve bacteria and anaerobes, given IM, IV; IM, IV; ββ-lactamase resistant-lactamase resistant

More potent against E. faecalis, B. fragilis More potent against E. faecalis, B. fragilis and pseudomonas aeroginosa as and pseudomonas aeroginosa as compared to 3compared to 3rdrd generation cephalosporin generation cephalosporin

Some consider imipenem the drug of choice Some consider imipenem the drug of choice in the management of polymicrobial in the management of polymicrobial pulmonary, intraabdominal and tissue pulmonary, intraabdominal and tissue infectionsinfections

Imipenem is metabolized and excreted by Imipenem is metabolized and excreted by the kidney. It is metabolized in kidney by the kidney. It is metabolized in kidney by the enzyme dehydropeptidase I; so it is the enzyme dehydropeptidase I; so it is combined with combined with CilastatinCilastatin (inhibitor to (inhibitor to dehydrpeptidase I) to decrease rapid dehydrpeptidase I) to decrease rapid metabolic clearance of imipenemmetabolic clearance of imipenem

Seizures are major side effect to imipenemSeizures are major side effect to imipenem

* Meropenem; * Meropenem; has similar activity to has similar activity to imipenem; but resistant to imipenem; but resistant to metabolism by dehydropeptidase I (no metabolism by dehydropeptidase I (no need to combine it with cilastatin) need to combine it with cilastatin) and incidence of seizures is less than and incidence of seizures is less than imipenemimipenem

- Carbacephems- Carbacephems e.g. Loracarbef Oral e.g. Loracarbef Oral Spectrum of activity similar to 2Spectrum of activity similar to 2ndnd

generation cephalosporin particularly generation cephalosporin particularly cefaclor and cefprozil; effective orally; cefaclor and cefprozil; effective orally; excreted renallyexcreted renally

- Monobactams- Monobactams e.g. Aztreonam IM, IV e.g. Aztreonam IM, IV

Has excellent activity against G -ve Has excellent activity against G -ve bacteriabacteria

little if any effect against G +ve MO’slittle if any effect against G +ve MO’s

ββ-lactamase resistant-lactamase resistant

Considered a substitute to aminoglycosides Considered a substitute to aminoglycosides to treat G-ve infections (less toxic)to treat G-ve infections (less toxic)

Rarely, causes allergic reactions in pts with Rarely, causes allergic reactions in pts with type I allergy to other type I allergy to other ββ- lactam - lactam antibioticsantibiotics

Vancomycin & TeicoplaninVancomycin & TeicoplaninGlycopeptide (Large Molecules)Glycopeptide (Large Molecules)Prevent crosslinking of peptidoglycansPrevent crosslinking of peptidoglycansBactericidalBactericidalNarrow spectrum of activity effective Narrow spectrum of activity effective

against G+ve bacteria especially against G+ve bacteria especially methicillin resistant Staph aureus methicillin resistant Staph aureus (MRSA)(MRSA)

Alternatives to PNC’s to treat G+ve Strep & Alternatives to PNC’s to treat G+ve Strep & Staph infections in pts allergic to PNC’sStaph infections in pts allergic to PNC’s

Given IV (oral absorption is poor)Given IV (oral absorption is poor)

Considered drug of choice Considered drug of choice ++ metronidazole metronidazole to treat pseudomembranous to treat pseudomembranous colitis=antibiotic associated colitis colitis=antibiotic associated colitis (Clostridium difficille colitis; Staph (Clostridium difficille colitis; Staph enterocolitis) and in this case vancomycin enterocolitis) and in this case vancomycin could be given orally (IV in life could be given orally (IV in life threatening cases)threatening cases)

Teicoplanin is given IMTeicoplanin is given IMSide effects:Side effects:Rapid IV → flushing, tachycardia, ↓ BPRapid IV → flushing, tachycardia, ↓ BPThrombophlebitis, ototoxicity, circumoral Thrombophlebitis, ototoxicity, circumoral

parasthesia…parasthesia…