PCOL 2 - BETA-LACTAM AND OTHER CELL WALL- & MEMBRANE-ACTIVE ANTIBIOTICS

GUIDE QUESTIONS:

1. Which of the following may be considered as  mechanism/s of effect of Beta lactam antibiotics?

I.  Inhibition of activity of the transpeptidase  enzyme

II. Inhibition of formation of the 50S ribosomal subunit

III. Binding to the so-called PBPs and related proteins in the cell membrane

I and III

GUIDE QUESTIONS:

What is the primary role of agents such as  Tazobactam and Sulbactam in antibacterial therapy?

a. Increase in the oral bioavailability of the  Penicillins

b. Effective against most gram-negative aerobic bacteria

c. Effective  against  including Clostridia anaerobic bacteria

d. Minimize destruction of the Penicillins  by bacterial beta-lactamases

e. Improve CNS penetrability of Penicillins

Minimize destruction of the Penicillins  by bacterial beta-lactamases

Microorganisms of medical importance fall into four categories:_____

○ However, there are many antibiotics that work against more than 1 category of  microbes

bacteria, viruses, fungi, and parasites

____- introduced by Ehrlich, defines that active chemical moiety of the drug that binds to the microbial receptors

○ The microbial proteins targeted by the antibiotic are essential components of the biochemical reactions in the microbes, and the interference with these physiologic pathways kills the microorganisms

Pharmacophore

Classification of antibiotic is based on the following:

○ Class and spectrum of microorganisms it kills

○ Biochemical pathway it interferes with

○ Chemical structure of its pharmacophore

First broad classification of antibiotics are ___

antibacterial, antiviral, antifungal, and antiparasitic

Suffixes that indicates destruction of a type of microbe

-cide / -cidal

Suffixes that indicates inhibition, but not complete destruction, of a type of microbe

-stasis / -static

Active against one or few types of microorganism

NARROW-SPECTRUM ANTIBIOTICS

Active against several types of microorganisms

BROAD SPECTRUM ANTIBIOTICS

Penicillin’s basic structure is made-up of

thiazolidine ring + Beta lactam ring (6- aminopenicillanic acid/6-APA)

Penicillin
Hydrolysis of β-lactam part yields___ which lacks antibiotic activity

Penicilloic acid

Penicillin

Modification at ___ alters pharmacologic properties and resistance to β-lactamases

R-group

MOA:

● inhibits penicillin-binding proteins/PBP located in the bacterial cytoplasmic membrane

● Inhibits transpeptidation reaction

● Activation of autolytic enzyme

Pencillin

Mechanism of Resistance (MOR):

● Inactivation of antibiotic by β-lactamase (Penicillinase)

● Modification of target PBP

● Impaired penetration of drug to target PBP

● Antibiotic efflux

Pencillin

TOXICITY:

● Hypersensitivity, Complete cross-allergenicity with other Penicillins, GI disturbance

● Interstitial nephritis (Methicillin), Neutropenia  (Nafcillin)

● Pseudomembranous colitis and Rash (Ampicillin)

● Necrotizing enterocolitis (Co-amoxiclav)

Penicillin

What penicillin causes this toxicity?
Interstitial nephritis

Methicillin

What penicillin causes this toxicity?

Neutropenia

Nafcillin

What penicillin causes this toxicity?

Pseudomembranous colitis and Rash

Ampicillin

What penicillin causes this toxicity?

Necrotizing enterocolitis

Co-amoxiclav

CLASSES OF PENICILLINS: (3)

• Narrow Spectrum (Natural) Penicillins

• Penicillinase-Resistant / Antistaphylococcal Penicillins

• Aminopenicillins / Extended-Spectrum

Narrow Spectrum (Natural) Penicillins examples

Benzylpenicillin (Penicillin G) Benzocaine and Procaine, Phenoxymethylpenicillin (Pen V)

What penicillin class?

USES:

■ Mostly used against G (+) organisms (S. pneumoniae, S. pyogenes, Actinomyces)

■ Mostly used against G (-) cocci (N. meningitidis), Spirochetes (T. pallidum)

■ Bactericidal for gram (+) cocci, gram (+) rods, gram (-) cocci, spirochetes

■ DOC for Syphilis

Narrow Spectrum (Natural) Penicillins

What penicillin class?

NOTE:

■ Inactivated by penicillinase

■ Susceptible to hydrolysis → cannot be formulated in aqueous solution

■ Unstable in acidic medium (May be destroyed in stomach)

■ Probenecid blocks renal tubular secretion

Narrow Spectrum (Natural) Penicillins

Penicillinase-Resistant / Antistaphylococcal Penicillins examples

CLOXACILLIN, OXACILLIN, NAFCILLIN, DICLOXACILLIN, METHICILLIN (CONDoM)

Penicillinase-Resistant / Antistaphylococcal Penicillins is also known as

Isoxazolyl penicillins 

What penicillin class?
USES:

■ Staphylococcus aureus (MSSA)

Penicillinase-Resistant / Antistaphylococcal Penicillins

What penicillin class?

NOTE:

■ Penicillinase resistant because

■ Probenecid blocks renal tubular secretion

Penicillinase-Resistant / Antistaphylococcal Penicillins

Aminopenicillins / Extended-Spectrum examples

AMPICILLIN (IV), AMOXICILLIN (PO)

What penicillin class?

USES:

■ Pen G coverage + Extended-spectrum – HHELPSS kill enterococci

■ H. influenzae, H. pylori, E. coli, Listeria, Proteus, Salmonella, Shigella, enterococci

Aminopenicillins / Extended-Spectrum

What penicillin class?

NOTE:

■ Inactivated by Penicillinase

■ Potentiation effect with beta-lactamase inhibitors

■ Synergistic with aminoglycosides

■ Probenecid blocks renal tubular secretion

Aminopenicillins / Extended-Spectrum

Potentiation effect with beta-lactamase inhibitors

● Ampicillin + ___= ___

Sulbactam, Unasyn

Potentiation effect with beta-lactamase inhibitors

● Amoxicillin + ____=____

Clavulanic acid,Augmentin

(1 + 1 = 2)

● Effect of substance A + B is equal to the sum of their effect

● Alcohol + H1 antagonist

ADDITIVE

(1 + 1 > 2)

● Effect of substance A + B is greater than the sum of their effect

● Sulfamethoxazole + Trimethoprim; PENS + Aminoglycosides

SYNERGISTIC

(1 + 0 > 2)

● Similar to synergism but substance B has no therapeutic action alone

● Levodopa + Carbidopa; Amoxicillin + Clavulanic acid

POTENTIATION

(1 + 1 < 2)

● Effect of substance A + B is less than the sum of their effects

● Ethanol antidote from methanol poisoning

ANTAGONISTIC

Antipseudomonal Penicillins examples

○ Carboxypenicillins [CARBENICILLIN, TICARCILLIN]

○ Ureidopenicillins [PIPERACILLIN]

What Antipseudomonal Penicillins?

CARBENICILLIN, TICARCILLIN

Carboxypenicillins

What Antipseudomonal Penicillins?

PIPERACILLIN

Ureidopenicillins

What penicillin class?

USES:

■ Greater activity against Gram (-) infections

■ Pen G coverage + Pseudomonas, Enterobacter, Klebsiella

Antipseudomonal Penicillins

What penicillin class?

NOTE:

■ Inactivated by penicillinase

■ Potentiation effect with beta-lactamase inhibitors

● Piperacillin + Tazobactam → Zosyn

■ Synergistic with aminoglycosides

Antipseudomonal Penicillins

Antipseudomonal Penicillins
Potentiation effect with beta-lactamase inhibitors example

Piperacillin + Tazobactam → Zosyn

Antipseudomonal Penicillins are synergistic with?

aminoglycosides

Chemistry:

● Similar to PENS but more stable to β-lactamases → broader spectrum

● Basic structure is made-up of

○ dihydrothiazine ring + beta-lactam ring (7 aminocephalosporanic acid)

● Modification at position 7 of β-lactam → alteration of antibacterial activity

● Substitution at position 3 of dihydrothiazine ring → alters pharmacokinetic properties

CEPHALOSPORINS

CEPHALOSPORINS

● Basic structure is made-up of ___

dihydrothiazine ring + beta-lactam ring (7 aminocephalosporanic acid)

CEPHALOSPORINS

● Modification at position (1)____→ alteration of antibacterial activity

● Substitution at position (2)____→ alters pharmacokinetic properties

(1) 7 of β-lactam

(2) 3 of dihydrothiazine ring

MOA:

● Inhibit bacterial cell wall synthesis in a similar manner to that of PENS

CEPHALOSPORINS

MOR:

● Inactivation of antibiotic by β-lactamase (Cephalosporinase)

● Modification of target PBP

CEPHALOSPORINS

TOXICITY:

● Hypersensitivity, Complete cross-allergenicity (Partial with Penicillins, complete with cephalosporins), GI upset, Disulfiram-like reaction

● Increases nephrotoxicity of aminoglycosides

CEPHALOSPORINS

CEPHALOSPORINS 1st-4th gen do not cover

(LAME)

○ Listeria

○ Atypicals (Chlamydia, Mycoplasma)

○ MRSA

○ Enterococci

CEPHALOSPORINS GENERAL RULE: Spectrum

○1._____ are predominantly active against G (+) organisms

○ 2. _____ progressively more active against Gram (-) organisms and reduced G (+) activity (EXCEPT 4th Gen)

1. 1st gen;

2. Succeeding generations

First Generation Cephalosporins examples

CEFALEXIN, CEFADROXIL, CEPHALOTIN, CEPHRADINE, CEFAZOLIN (Fa, Pha)

What Cephalosporin generation?

USES:

○ (+) PEcK (Gram (+) cocci, Proteus mirabilis, E. coli, Klebsiella pneumoniae)

○ Surgical prophylaxis (Cefazolin)

First Generation

What first gen cephalosporin is used for Surgical prophylaxis

Cefazolin

Second Generation Cephalosporin examples

CEFUROXIME, CEFOXITIN, CEFOTETAN, CEFAMANDOLE, CEFACLOR, LORACARBEF, CEFPROZIL (Fu, Fo)

What Cephalosporin generation?

USES:

○ slightly less G (+) activity than 1st gen but have and extended G (-) activity

○ (+) HENS PEcK (H. influenzae, Enterobacter, Neisseria, Serratia)

○ B. fragilis (Cefotetan, Cefoxitin)

Second Generation

What 2nd gen cephalosporin is used for B. fragilis

Cefotetan, Cefoxitin

Third generation cephalosporin example:

[CEFTRIAXONE, CEFTAZIDIME*, CEFDINIR, CEFTIBUTEN, MOXOLACTAM, CEFIXIME**, CEFOPERAZONE*, CEFOTAXIME

What generation of cephalosporin?
USES:

○ Expanded gram (-) coverage but decreased gram (+) activity

○ Serious gram negative infections resistant to other β-lactams

○ HENS PEcK + Acinobacter + Pseudomonas*

○ Pseudomonas (Ceftazidime and Cefoperazone*)

○ DOC for gonorrhea (Ceftriaxone and Cefixime)

Third Generation

What generation of cephalosporin?

NOTE:

○ All are renally excreted except Cefoperazone and Ceftriaxone

○ All can penetrate the BBB except Cefoperazone and Cefixime

○ Can cross BBB (Ceftriaxone)

Third Generation

What Third Generation cephalosporin is a DOC for gonorrhea

Ceftriaxone and Cefixime

What Third Generation cephalosporin can cross BBB

Ceftriaxone

Fourth Generation caphalosporin examples

CEFEPIME, CEFPIROME

What generation of cephalosporin?

USES:

○ Gram (-) organisms with increase activity against

Pseudomonas and Gram (+)

○ (+) HENS PEcK + Acinetobacter + Pseudomonas

Fourth Generation

Fifth Generation cephalosporin example

CEFTOBIPROLE, CEFTAROLINE]

What generation of cephalosporin?

USES:

○ Broad gram (+) and gram (-) coverage

○ (+) HENS PEcK + MRSA

○ Covers MRSA and Enterococcus faecalis

○ No activity against Pseudomonas

Fifth Generation

What cephalosporin?

● MOA: Bins to PBP; (-) transpeptidation

● USES:

○ Gram (-) coverage; no gram (+) activity or anaerobes

○ No cross-allergenicity with penicillins

● TOX: GI Upset

AZTREONAM

CARBAPENEMS examples

DORIPENEM, IMIPENEM, MEROPENEM*, ERTAPENEM**

● MOA: Binds to PBP; (-) transpeptidation

CARBAPENEMS

USES:

○ Life threatening infections

○ Gram (+) cocci, gram (-) rods, and anaerobes

CARBAPENEMS

TOX:

○ GI Upset, Rash

○ Seizure (except Meropenem*)

CARBAPENEMS

CARBAPENEMS causes seizure except

Meropenem

This carbapenem is hydrolyzed by renal enzyme (dehydropeptidase) → Cilastatin

Imipenem

All has Pseudomonas coverage except for this carbapenem

Ertapenem

BETA-LACTAMASE INHIBITORS examples

CLAVULANIC ACID, AVIBACTAM, SULBACTAM, TAZOBACTAM

● MOA: Binds to β-lactamases

● USES: Binds to β-lactamases

● TOX: Hypersensitivity, Cholestatic jaundice

BETA-LACTAMASE INHIBITORS

NOTE:

○ Amoxicillin + Clavulanic acid (Augmentin)

○ Ampicillin + Sulbactam (Unasyn)

○ Ceftazidime + Avibactam

○ Piperacillin + Tazobactam

BETA-LACTAMASE INHIBITORS

Glycopeptide Antibiotics examples

VANCOMYCIN, TEICOPLANIN, DALBAVANCIN, TELAVANCIN

MOA:

○ (-) cell wall synthesis by binding to the D-ala-D ala terminus of nascent peptidoglycan

Glycopeptide Antibiotics

USES:

○ Gram (+) microorganisms only

○ Reserved for multidrug-resistant organisms (MRSA, C. difficile)

Glycopeptide Antibiotics

TOXICITY:

○ Nephrotoxicity

○ Ototoxicity

○ Thrombophlebitis

○ Diffuse Flushing (Red Man Syndrome)

Glycopeptide Antibiotics

MECHANISM OF RESISTANCE:

○ Modification of D-ala-D-ala to D-ala-D-lac

Glycopeptide Antibiotics

Peptide Antibiotics examples

BACITRACIN

MOA:

○ Interferes with the late stage in cell wall synthesis in gram (+) organisms

BACITRACIN

● USES:

○ Gram (+) microorganisms

● TOXICITY:

○ Nephrotoxicity

● NOTE:

○ Reserved for topical use only because of its

marked nephrotoxicity

BACITRACIN

● MOA:

○ Disrupts cell membrane of gram (+) cocci by creating transmembrane channels

DAPTOMYCIN

USES:

○ S. aureus skin infections (especially MRSA), bacteremia, endocarditis, VRE

DAPTOMYCIN

TOXICITY:

○ Myopathy

○ Rhabdomyolysis

DAPTOMYCIN

MOA:

○ Cation polypeptides that bind to phospholipids on cell membranes of gram (-) bacteria

○ Disrupt cell membrane integrity →leakage of cellular components→cell death

POLYMYXIN B, POLYMYXIN E

USES:

○ Salvage therapy for multidrug-resistant gram (-) bacteria (e.g. P. aeruginosa, E. coli, K. pneumoniae)

○ Polymyxin B – component of a triple antibiotic ointment used for superficial skin infections

POLYMYXIN B, POLYMYXIN E

component of a triple antibiotic ointment used for superficial skin infections

POLYMYXIN B

TOXICITY:

○ Nephrotoxicity, Neurotoxicity (e.g. slurred speech, weakness, paresthesias), Respiratory failure

POLYMYXIN B, POLYMYXIN E

What microorganism formed Bacitracin

Bacillus subtilis

What microorganism formed Griseofulvin

Penicillium griseofulvum

What microorganism formed Penicillin

 Penicillium notatum

What microorganism formed Vancomycin

Streptococcus orientalis

What microorganism formed Erythromycin

Streptomyces erythreus

What microorganism formed Streptomycin

Streptomyces griseus

What microorganism formed Cycloserine

Streptomyces orchidaceus