Antimicrobials- Cell Wall Inhibitors

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Chemotherapy

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treatment of systemic infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the recipient

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Bactericidal

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Cause death of the microorganism
E.g. Penicillins, Aminoglycosides, cephalosporins

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Bacteriostatic

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Inhibits the growth of the microorganism
Sulfonamides, tetracyclines, erythromycin

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Peptidoglycan inhibitors

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Beta-lactam drugs
Vancomycin
bacitracin

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Nucleic acid synthesis inhibitors

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fluoroquinolones
rifamycins

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protein synthesis inhibitors

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aminoglycosides
tetracylcines
macrolides
chloramphenicol
lincosamides
oxazolidinones
streptogramins

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inhibition of folic acid synthesis

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sulfonamides
trimethoprim
pyrimethamine

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Structural features of Beta-lactam antibiotics

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Thiazolidine ring
betalactam ring

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MOA of Penicillins

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Bactericidal
-Interferes with the synthesis of the bacterial cell wall peptidoglycan
-Bind to and inactivate transpeptidase which results in loss of cell rigidity and cell death
- gram (+) bacteria w/ thick cell wall susceptible.

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transpeptidase

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a bacterial enzyme which cross links the peptidoglycan chains to form rigid cell walls

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Gram positive structure

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techoic acid
cell wall
surface protein

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Gram negative structure

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Outer membrane
LPS
porins
Lipid A

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Bacterial cell wall synthesis targets

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NAG and NAM cross bridge

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Mechanisms of Resistance of penicillins

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1. Beta-lactamases ex. Staph
2. Alteration of penicillin binding proteins ex. S. Aureus, MRSA, penicillin resistant pneumococci
3. Reduced permeability in G(-) cell membranes ex. pseudomonas

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Types and spectrum of activity of penicillins

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- Narrow spectrum (penicillinase susceptible)
- Narrow spectrum (penicillinase resistant)
- Broad spectrum (penicillinase susceptible)
- Extended spectrum or antipseudomonal (penicillinase susceptible)

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Narrow spectrum (penicillinase susceptible)

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Penicillin G (parenteral)
Penicillin V (oral

Strep, pneumococci, meningococci, treponema pallidum

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Narrow spectrum (penicillinase resistant):

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Methicillin, naficillin , oxacillin
Staphylococci (except MRSA)

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Broad spectrum (penicillinase susceptible):

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Ampicillin & Amoxicillin

Gram positive cocci, Haemophillus influenza, listeria monocytogenes, H.pylori

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Extended spectrum or antipseudomonal (penicillinase susceptible):

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Ticarcillin, piperacillin, azlocillin
Gram –ve rods..pseudomonasaeruginosa

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Repository penicillin G (long acting):

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Procaine and Benzathine penicillin G

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When do penicillins penetrate the CSF to a significant extent?

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inflammation

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Penicillin G is acid labile, therefore what is its route of administration?

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IM and IV

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_________ competitively inhibits the renal tubular secretion of penicillin.
Thus it increases the concentration of penicillin and prolongs it activity.

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Probenecid

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Uses of Penicillin G

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- Streptococcal, meningococcal, gram positive bacilli infections
- Drug of choice for syphilis (Treponema pallidum)

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Resistant to Penicillin G

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- Strains of pneumococci, Staph aureus and Neisseria gonorrhoeae are resistant

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Uses of methicillin, naficillin & oxacillin

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- resistant to inactivation by betalactamases
- Staph infections
- MRSA & MRSE (s. epidermidis) are resistant

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Uses of Ampicillin and Amoxicillin

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Infections due to enterococci, Listeria monocytogenes, E. coli, Proteus mirabilis, Haemophilus influenzae

Amoxicillin used in:
endocarditis before major procedures
H.pylori infection(peptic ulcers)

Activity enhanced if used in combination with beta lactamase inhibitors (clavulanic acid, sulbactum)- widens the spectrum

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Uses of piperacillin & ticarcillin

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Pseudomonas, Enterobacter infections

Synergistic action with aminoglycosides against pseudomonal and enterococal species

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Prophylactic penicillin for rheumatic fever

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benzathine penicillin

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Prophylactic penicillin for gonorrhea and syphillis in sexual partner

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Benzathine or procaine penicillin

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Bacterial endocarditis prophylaxis is indicated in patients with prosthetic heart valves, cyanotic heart disease, previous diagnosis of endocarditis- who are planning to undergo dental or respiratory tract or genitourinary or gastrointestinal procedures

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Amoxicillin or ampicillin

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Beta-Lactamase inhibitors

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Clavulanic acid, sulbactum, tazobactam

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-No antibacterial activity
-Potent and irreversible inhibitor of ß lactamase
-Available as fixed dose combinations:
Amoxicillin/ticarcillin +clavulanic acid
Ampicillin+sulbactum
Piperacillin+Tazobactum

Widens antibacterial spectrum

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Beta-lactamase inhibitors

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Uses of beta lactamase inhibitors

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ß lactamase producing staphylococci, H.influenza, N.gonorrhoea, E.coli, Proteus

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ADR Penicillins

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Relatively safe
Hypersensitivity:
-5-7% incidence
-Severity varies from urticarial skin rashes to acute anaphylaxis
-Cross-sensitivity between individual penicillins possible

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ADR methicillin

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interstitial nephritis

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ADR ampicillin

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maculopapular rash
diarrhea- pseudomembranous enterocolitis

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Isolated from fungus Cephalosporium

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Cephalosporins

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MOA of cephalosporins

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-Similar to that of penicillins
-All cephalosporins are bactericidal
-Less susceptible to inactivation by penicillinases
-Some bacteria produce cephalosporinase (another type of beta-lactamase)
-Resistance also possible due to decrease in membrane permeability & change in structure of PBP

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1st generation cephalosporins

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Cephalexin(oral), Cefazolin (parenteral)

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Uses of 1st generation cephalosporins

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Spectrum: Gram +ve cocci, klebsiella pneumoniae

Use:
Cefazolin in surgical prophylaxis
Klebsiella pneumonia

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2nd generation cephalosporins

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Cefoxitin, Cefotetan, Cefaclor, Cefamandole & Cefuroxime

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Uses of 2nd generation cephalosporins

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More active on Gram –ve bacteria
Except Cefuroxime others do NOT enter CSF

Uses:
Cefoxitin, cefotetan- Bacteroids fragilis

Cefuroxime, cefachlor, cefamandole – H.influenza

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3rd generation cephalosporins

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Cefotaxime, Ceftriaxone(IM), Ceftazidime, cefoperazone, Cefixime (oral)

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Uses of 3rd generation cephalosporins

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Increased activity againist Gram –ve bacteria
Good penetration into BBB (except Cefoperazone & Cefixime)

Cefoperazone, Ceftazidime –good activity against Pseudomonas

Ceftriaxone (parenteral) & Cefixime (oral) – Rx of gonorrhoea

Cefriaxone, cefaperazone- Rx of S.typhi

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4th generation cephalosporins

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Cefipime (IV), cefpirome

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4th generation cephalosporins

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-Resistant to inactivation by beta lactamases
-Excellent penetration into gram negative bacteria
-Wider spectrum than 3rd generation (both Gram positive & negative)

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ADR of Cephalosporins

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Hypersensitivity reactions- 2 % rashes, fever—common

Cross-hypersensitivity between cephalosporins completely possible

Cross-reaction between penicillins is less likely (5-10%) caution still needed

History of anaphylaxis to penicillin is a contraindication for cephalosporin

Superinfection- diarrhea

If given with aminoglycosides- Increased chances of nephrotoxicity

Cefamandole, Cefoperazone & Cefotetan contain methylthiotetrazole group (MTT group)
-This may cause dusulfiram like reactions with ethanol

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Monobactams

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Aztreonam (IV)
-structure has a single ring

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Uses of Monobactams

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-Active only against gram –ve rods
-No effect on gram +ve bacteria and anerobes

Used in gram –ve infections especially in patients allergic to Penicillins/Cephalosporins

-Same MOA as penicillins & cephalosporins
-Resistant to ß-lactamases

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ADR of Monobactams

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No cross hypersensitivity reaction between penicillins and aztreonam

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Carbapenems

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Imipenem , Meropenem, ertapenem

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A/E: GI distress, skin rash, in high doses- seizures)

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Carbepenems

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Broad spectrum: gram +ve & –ve bacteria, anaerobes-Bact.fragilis, clostridia

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Carbapenems

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-Imipenem is rapidly inactivated by renal dehydropeptidase I
-Imipenem is combined with cilastatin to prevent hydrolysis by enzymes in the renal brush border
-Cilastatin is an inhibitor of renal dehydropeptidase
-Cilastatin thus increases the plasma ½ life of imipenem

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Carbapenems

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MOA of vancomycin

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Acts by binding to D-Ala-D-Ala terminal of the nascent peptidoglycan pentapeptide side chain

This leads to inhibition of transglycosilation and in turn prevents the peptidoglycan chain elongation

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Mechanism of resistance to vancomycin

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-Occurs in strains of enterococci and staphylococci (VRE and VRSA)
-Resistance involves a decreased affinity of vancomycin for the binding site
-This is because of replacement of the terminal D-Ala by D-Lactate

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Spectrum:
MRSA, enterococci, Clostridium difficile

No activity against gram-negative

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Vancomycin

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Uses of vancomycin

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MRSA infections given by slow I.V infusion

Antibiotic associated enterocolitis(C. difficile)- oral vancomycin

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ADR of vancomycin

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Adverse effects:
-Red mans syndrome because of release of histamine (flushing, redness of face, hypotension), this can be prevented by pretreatment with antihistamines.
-Nephrotoxicity
-Ototoxicity
(can become addtitive if used with aminoglycosides)