Antibacterials: MOA and spectrum of activity

target: cell membrane disruption

• polymyxins

• lipopeptides

target: DNA

• nitroimidazoles

• nitrofurans

target: DNA topoisomerases

• quinolones

target: mRNA synthesis

• rifamycins

target: protein synthesis

• translation (50S subunit)

  • macrolides

  • lincosamides

  • oxazolidinones

  • streptogramins

  • phenicols

• Translation (30S subunit)

  • aminoglycosides

  • tetracyclins

target: cell wall synthesis

• B-lactams

  • penicillins

  • cephalosporins

  • carbapenems

  • monobactams

• glycopeptides

• lipoglycopeptides

target: folic acid synthesis

• diaminopyrimidines

• sulfonamides

Gram-Positive Bacteria

• Have a thick peptidoglycan layer that provides support and protection.

• Have one cytoplasmic (inner) membrane.

• Do not have an outer membrane.

• Have a relatively small periplasmic space.

• Usually stain purple during the Gram-staining process.

Gram-Negative Bacteria

• Have a thin peptidoglycan layer.

• Have two membranes: an inner cytoplasmic membrane and an outer membrane.

• Have a larger periplasmic space between the two membranes.

• The outer membrane contains:

  • Lipopolysaccharides (LPS): Help protect the bacteria and can act as endotoxins.

  • Porins: Protein channels that allow certain substances to pass through.

  • Lipoproteins: Help connect the outer membrane to the peptidoglycan layer.

• Usually stain pink or red during Gram staining.

Peptidoglycan

• purpose is to help give the cell structural strenght and prevent it from bursting

• sugar backbone

  • mesh of repeating sugars of NAG and NAM

• Peptide chains

  • short chains of amino acids

  • attached to the NAM sugars (3-5 amino acids)

• cross-links

  • formed between amino acid chains

  • created by enzymes called transpeptidases

NAG

n-acetylglucosamine

NAM

N-acetylmuramic acid

B-lactam antibiotics examples

• penicillins

• cephalosporins

• carbapenems

• monobactams

beta lactams

• broad class on antibiotics

• all antibiotics have a common feature, the beta-lactam ring structure

  • a ring with 3-carbons and 1-nitrogen

B-lactam MOA

Inhibits bacterial cell wall synthesis by binding a transpeptidase called penicillin binding proteins (PBPs) preventing cross linking of cell wall components​

•To kill bacteria, beta-lactams work as cell wall synthesis inhibitors

•In normal cell wall synthesis (steps 1+2), you have sugar chains (NAG/NAM), with peptide side chains attached. Cross-linking forms between the peptide side chains to help give the cell wall strength and rigidity

•Penicillin binding proteins (PBPs) act as transpeptidases and transglycosylases to help cross-link the amino acid peptide chains

•In steps 3-5, you can see how beta-lactams work to prevent this activity, which interrupts the cross-linking and therefore interferes with cell wall synthesis

•Beta-lactams come in and bind to the PBP, which inactivates the PBP, therefore no transpeptidation and cross-linking occurs, and the cell wall becomes too weak to withstand pressure inside the bacteria and will lyse and die.

There are various PBPs that each have different functions and each beta-lactam has varying affinities for the PBPs

Mechanisms of Resistance to B-lactams: Beta-lactamases (ESBL, AmpC, KPC)

Break apart beta-lactam ring

Mechanisms of Resistance to B-lactams: PBP Mutations (MecA gene -> PBP2a)

Altered binding sites prevent drug attachment

Mechanisms of Resistance to B-lactams: Efflux Pumps

Remove drug that has entered the cell

Mechanisms of Resistance to B-lactams: Porin Channels

Prevent drug from entering the cell

B-lactamase Enzyme Types: Penicillinases

• Bacterial expression:

  • Most staphylococci and many gram-negatives

• Pearls:

  • Simple beta-lactamase inhibitors (BLIs) and most cephalosporins will overcome it

B-lactamase Enzyme Types: Cephalosporinases

• Bacterial expression:

  • Mostly gram-negatives

• Pearls:

  • Ex: AmpC, resistance to 1st and 2nd, sometimes 3rd gen cephalosporins

B-lactamase Enzyme Types: Extended Spectrum Beta Lactamases

• Bacterial expression:

  • Gram-negatives

• Pearls:

  • Hydrolyzes many beta-lactams and some BLIs may not inhibit the enzyme

B-lactamase Enzyme Types: Carbapenemases

• Bacterial expression:

  • Gram-negative Enterobacterales

• Pearls:

  • Hydrolyze carbapenems, not common

Penicillins: Natural

• penicillin G

• Penicillin V

Penicillins: Anti-staphlococcal

• methicillin

• oxacillin

• nafcillin

Penicillins: aminopenicillins

• ampicillin

• amoxicillin

Penicillins: beta-lactamase inhibitor

• clavulanic acid

• sulbactam

• tazobactam

Natural Penicillins

• Gram positive coverage:

  • S. Pyogenes (group A strep)

  • S. agalactiae (group B strep)

  • S. pneumonia

• Gram negative coverage:

  • limited, not routinely used

  • pasteurella

• Anaerobe coverage:

  • limited

  • actionmyces, clostridium, c. acnes, pepto

• Other:

  • IM and IV for syphilis

  • Does not cover methicillin susceptible staph aureus

Anti-staph penicillins

• Gram positive coverage:

  • staph (not MRSA)

  • GAS

  • GBS

• Gram negative coverage:

  • does not cover

• Anaerobe coverage:

  • no coverage

Aminopenicillins

• Gram positive coverage:

  • GAS
    GBS
    S. pneumo

  • E. faecalis

• Gram negative coverage:

  • E. coli

  • proteus

• Anaerobe coverage:

  • limited

• Other

  • listeria

Beta Lactamase inhibitor

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S. Pneumo

  • E. faecalis

• Gram negative coverage:

  • E. coli

  • proteus

  • klebsiella

• Anaerobe coverage:

  • B. fragilis

• Other

  • sulbactam for acinetobacter

Extended Spectrum (Piperacillin-tazobactam)

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S. Pneumo

  • E. faecalis

• Gram negative coverage:

  • pseudomonas

  • E. coli

  • Klebsiella

  • Proteus Morganella

  • Providencia

• Anaerobe coverage:

  • B. Fragilis

• Other

  • increased SCr with vancomyin

1st Gen Cephalosporins

• IV

  • cefazolin

• PO

  • cephalexin

  • cefadroxil

2nd gen cephalosporins

• IV

  • Cefuroxime

  • Cephamycins

    • cefoxitin

    • cefotetan

• PO

  • cefuroxime

3rd gen cephalosporins

• IV

  • ceftriaxone

  • cefotaxime

  • ceftazidime

• PO

  • Cefdinir

  • Cepodoxime

  • Cefixime

4th gen cephalosporins

• IV

  • cefepime

5th gen cephalosporin

• IV

  • ceftaroline

  • ceftobiprole

1st generation coverage

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S. pneumo

• Gram negative coverage:

  • E. coli

  • proteus

  • klebsiella

• Anaerobes coverage:

  • none

• Other:

  • does not cover enterococcus

2nd generation coverage

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S. pneumo

• Gram negative coverage:

  • E. coli

  • proteus

  • klebsiella

• Anaerobes coverage:

  • Cephamycins

• Other:

  • does not cover enterococcus

  • less active against gram + than first gen, but more active against gram negative

3rd generation coverage

• Gram positive coverage:

  • MSSA

  • Ceftazidime

  • GAS

  • GBS

  • S. pneumo

• Gram negative coverage:

  • E. coli

  • ceftazidime

  • pseudomonas

  • proteus

  • klebsiella

• Anaerobes coverage: limited

• Other:

  • does not cover enterococcus

  • gonorrhea, meningitis

4th generation coverage

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S. pneumo

• Gram negative coverage:

  • E. coli

  • Proteus

  • Klebsiella

  • Serratia

  • Pseudomonas

  • Citrobacter

  • Enterobacter

  • Morganella

  • Providencia

• Anaerobes coverage: limited

• Other:

  • does not cover enterococcus

5th generation coverage

• Gram positive coverage:

  • MRSA

  • GAS

  • GBS

  • S. pneumo

  • Ceftobiprole

  • E. faecalis

• Gram negative coverage:

  • E. coli (not its main use)

  • proteus

  • klebsiella

• Anaerobes coverage:

  • limited

• Other:

  • mainly for G+/staph bacteremia and skin infections, pneumonia

Cefiderocol

• siderophore cephalosporin

• mimics a natural bacterial siderophore bound to iron and tricks the bacteria into up taking it via active transport

• once inside primarily binds PBP3

Cefiderocol coverage

• broad gram-negative coverage

  • pseudomonas

  • stenotrophomonas

  • resistant organisms

meropenem and imipenem coverage

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S. pneumo

  • E.faecalis

• Gram negative coverage:

  • serratia

  • pseudomonas

  • acinetobacter

  • citrobacter

  • enterobacter

  • morganella

  • providencia

  • ESBLs

• Anaerobes coverage:

  • ++

Ertapenem coverage

• Gram positive coverage:

  • MSSA

  • GAS

  • GBS

  • S.pneumo

• Gram negative coverage:

  • serratia

  • citrobacter

  • enterobacter

  • morganella

  • providencia

  • ESBL

• Anaerobes coverage:

• Other:

  • does not cover enterococcus

  • does not cover pseudomonas or acinetobacter

Aztreonam

• only monobactam

• used in patients with true severe beta-lactam allergies

• no gram positive or anerobic activity

• broad gram-negative coverage including pseudomonas

Beta-lactamase inhibitors

• MOA: bind beta-lactamases as decoys, allowing the active drug to bind its targets

• Increased gram-negative coverage against specific pathogens/resistance mechanisms 

examples of beta-lactamase inhibitors (for resistant bacteria)

• Amoxicillin/clavulanate

• Piperacillin/tazobactam

• Ceftazidime/avibactam

• Meropenem/vaborbactam

• Aztreonam/avibactam

• Cefepime/zidebactam

• Ceftolozane/tazobactam

• Sulbactam/durlobactam

vancomycin MOA

• Inhibits peptidoglycan synthesis by binding and blocking cross-linking of D-ala-D-ala binding sites

Vancomycin resistance

• Commonly seen in E. faecalis and faecium; “VRE”

• Mechanism

  • VanA or B gene presence

  • D-ala-D-ala mutation into D-ala-D-lac

  • Vancomycin is unable to bind

Vancomycin spectrum of activity

• Gram positive only

  • Staphylococcus spp.

    • MSSA, MRSA, CoNS

  • Strep spp.

  • E. faecalis/faecium

  • corynebacterium

  • anaerobes

    • C. diff (oral only)

    • Actinomyce

    • peptostreptococcus

    • cutibacterium acnes

• Massive structure

Dalbavancin

• Lipoglycopeptide

• MOA is similar to vancomycin

  • binding and blocking cross-linking of D-ala D-ala binding sites to inhibits peptidoglycan synthesis

• Dalbavancin features a lipophilic tail

  • allows drug molecule to embed into the cell membrane

• Very long-acting agent

• active against:

  • Staph spp (including MRSA), strep spp.m E. faecalis

  • active against vanB carrying VRE strains

• Half life 346 hrs

Oritavancin

• MOA:

  • Inhibits cell wall synthesis by inhibiting peptidoglycan extension, preventing crosslinking of cell wall components, and disrupts the bacterial cell membrane by anchoring a lipid tail into it

• Another long-acting lipoglycopeptide agent

• Active against:

  • S. aureus (MSSA, MRSA)

  • Strep spp.

  • Enterococcus spp

    • Including Vancomycin-resistant Enterococcus (vanA and vanB)

• Transglycosylation (peptide chain extension), transpeptidation (cross-linking), disrupts cell membrane (increased permeability)

Telavacin

• MOA: similar to oritavancin mechanism

• Short-acting, once daily infusion

• Active against:

  • Staph spp. (MSSA/MRSA)

  • Strep spp.

  • E. faecalis

    • Active against vanB carrying VRE strains

Daptomycin

• MOA: Uses calcium ions to bind to the cell membrane forming a channel causing depolarization, ion efflux, cell death

• Gram positive only

  • Staph, strep, E. faecalis/faecium, corynebacterium  

  • Including VRE!

• Resistance (rare)

  • Cell wall remodeling, thickening, including upregulating positive ion production (repulsion)