(3) Antibacterials III (The β-Lactams)

 What are the largest group of antibiotics physicians can choose from?

β-LACTAMS

Since about 2015, β-lactam/β-lactamase inhibitor combinations have…

increased

β-LACTAMS

Main Classes

• Penicillins

• Cephalosporins / cephamycins

• Carbapenems

• Monobactams

• β-lactam / β-lactamase inhibitor combinations

Main Classes

important update

Cefiderocol

• newer special cephalosporin

• uses iron transporter to enter bacteria

General big-picture facts about β-lactams

• β-lactams = cell wall inhibitors

• largest antibiotic class

Bacterial cell wall basics - topic overview

• Gram-positive

• Gram-negative

Bacterial cell wall basics

Gram-positive

• Thick peptidoglycan layer

• One membrane

Bacterial cell wall basics

Gram-negative

• Thin peptidoglycan

• Two membranes

  • outer membrane

  • inner membrane

• Outer membrane has:

  • porins

    • channels for entry

Gram-negative resistance often:

• ↓ porins = ↓ antibiotic entry

Peptidoglycan structure

overview

• sugars

• peptides

Peptidoglycan structure

Sugar components

• NAG = N-acetylglucosamine

• NAM = N-acetylmuramic acid

Peptidoglycan structure

Peptide side chains

• Peptides are attached to the sugar backbone.- NAM

• Peptides end in:

  • D-Ala-D-Ala

 

PEPTIDOGLYCAN STRUCTURE

Normal bacterial process

• Bacteria cleave last D-Ala

• Cross-link cell wall

• Cross-linking = wall strength

β-LACTAM MECHANISM OF ACTION Main Target =

PBP = Penicillin Binding Proteins

PBP = Penicillin Binding Proteins

• enzymes in membrane

• make cell wall cross-links

β-LACTAM MECHANISM OF ACTION

β-lactams act like:

D-Ala-D-Ala analog

β-LACTAM MECHANISM OF ACTION

What happens?

• drug binds PBP

• blocks transpeptidation

• no cross-linking

• weak wall

• cell lyses

β-LACTAM MECHANISM OF ACTION

β-lactams:

• inhibit peptidoglycan synthesis

• bactericidal

 PBP EFFECTS: what happens to bacteria when different PBPs (penicillin-binding proteins) are blocked?

• PBP1 → lysis

• PBP3 → filament formation / bacteria cannot divide

• PBP2 → cell becomes round / oval

How antibiotics physically get inside bacteria to reach their target (PBPs)? - GIVE ME OVERVIEW OF BACTERIA WE TALK ABOUT

• Gram Positive

• Gram Negative

DRUG ENTRY

Gram Positive

β-lactams:

• easily reach PBP

Glycopeptides (vancomycin):

• also can enter

DRUG ENTRY

Gram Negative

β-lactams:

• enter through porins

• cross periplasm

• bind PBPs

Glycopeptides:

• TOO BIG

• cannot enter

β-lactams important for Gram-negative because:

can pass porins

WHY SO MANY β-LACTAM GENERATIONS?

• bacterial resistance

• improve efficacy

WHY SO MANY β-LACTAM GENERATIONS?

Professor said:

• bacteria always evolve resistance

• many newer drugs are “me-too drugs” similar to older drugs

Give me Penicillin generations…

1ST GEN PENICILLINS

2ND GEN: ANTI-STAPH PENICILLINS

3RD GEN: AMINOPENICILLINS

4TH GEN PENICILLINS (EXTENDED / EXPANDED)

PENICILLINS - 1ST GEN PENICILLINS

Drugs

• Penicillin G = IV

• Penicillin V = oral

PENICILLINS - 1ST GEN PENICILLINS

Coverage

• most Streptococci

• oral anaerobes

PENICILLINS - 1ST GEN PENICILLINS

Weakness

• poor Gram-negative rod coverage

• hydrolyzed by β-lactamases

PENICILLINS - 1ST GEN PENICILLINS

Resistant bugs

• S. aureus (>90%)

• Bacteroides fragilis

• Prevotella

PENICILLINS - 1ST GEN PENICILLINS

Important:

penicillin no longer useful for gonorrhea

2ND GEN: ANTI-STAPH PENICILLINS

Drugs

• Methicillin

• Nafcillin

• Oxacillin

• Dicloxacillin

• Cloxacillin

2ND GEN: ANTI-STAPH PENICILLINS

Coverage

• Strep

• MSSA

2ND GEN: ANTI-STAPH PENICILLINS

NOT active against:

• MRSA

• Enterococci

• anaerobes

• Listeria

2ND GEN: ANTI-STAPH PENICILLINS

Important

anti-staph penicillins = MSSA only

3RD GEN: AMINOPENICILLINS

Drugs

• Amoxicillin

• Ampicillin

• Pivmecillinam (new FDA 2024)

3RD GEN: AMINOPENICILLINS

Coverage

• Strep

• basic Gram-negatives

3RD GEN: AMINOPENICILLINS

Pivmecillinam:

• uncomplicated UTI

• Covers:

  • E. coli

  • Proteus mirabilis

  • S. saprophyticus

3RD GEN: AMINOPENICILLINS

Important PK:

• Amoxicillin = better oral bioavailability

• Ampicillin = only ~40% oral absorbed

4TH GEN PENICILLINS (EXTENDED / EXPANDED)

Drugs

• Piperacillin

• Ticarcillin

4TH GEN PENICILLINS (EXTENDED / EXPANDED)

Coverage

• broader Gram-negatives

• Pseudomonas

4TH GEN PENICILLINS (EXTENDED / EXPANDED)

Important

• usually used WITH inhibitor

4TH GEN PENICILLINS (EXTENDED / EXPANDED)

Example:

• Piperacillin/tazobactam

4TH GEN PENICILLINS (EXTENDED / EXPANDED)

Important

piperacillin = Pseudomonas coverage

PENICILLIN PHARMACOLOGY

topic overview

• Absorption

• Distribution

• Protein Binding

• Excretion

PENICILLIN PHARMACOLOGY

Absorption

Poor:

• Pen G

• Ampicillin

Best oral:

• Pen V

• Amoxicillin

PENICILLIN PHARMACOLOGY

Distribution

• good overall

• poor CNS / eye

PENICILLIN PHARMACOLOGY

Protein binding

~50%

PENICILLIN PHARMACOLOGY

Excretion

• renal

• unchanged drug

PENICILLIN + PROBENECID

Concept

probenecid:

• competes for renal tubular secretion

• probenecid prolongs penicillin action

PENICILLIN + PROBENECID

Result

• slows penicillin excretion

• prolongs blood level

PENICILLIN ADVERSE EFFECTS

topic overview

• main

• severe

• other

PENICILLIN ADVERSE EFFECTS

Main

allergy

PENICILLIN ADVERSE EFFECTS - MAIN

Important stats:

• 10% report allergy

• true allergy closer to ~1%

PENICILLIN ADVERSE EFFECTS - MAIN

Important:

many rashes = viral rash, not allergy

PENICILLIN ADVERSE EFFECTS

Severe:

• anaphylaxis → epinephrine

PENICILLIN ADVERSE EFFECTS

Other:

• superinfection

Rare:

• seizures (high dose)

• bleeding

• neutropenia

• hepatic toxicity

CEPHALOSPORINS

Important

• alternatives to penicillins

• semisynthetic

• bactericidal

CEPHALOSPORINS

Key feature:

2 side chains = easier to modify

CEPHALOSPORINS

 CROSS ALLERGY

about 5–15% of people with penicillin allergy may also react to cephalosporins

CEPHALOSPORINS-CROSS ALLERGY

Important:

• NOT every penicillin allergy means cephalosporin allergy

• ask what reaction happened

CEPHALOSPORINS

what is rare?

Severe ceph anaphylaxis:

CEPHALOSPORINS

give me the generations! - OVERVIEW

1ST GEN CEPHALOSPORINS

2ND GEN CEPHALOSPORINS

3RD GEN CEPHALOSPORINS

4TH GEN CEPHALOSPORIN

5TH GEN / ADVANCED CEPHALOSPORINS

1ST GEN CEPHALOSPORINS

Drugs

• Cefazolin

• Cephalexin

1ST GEN CEPHALOSPORINS

Coverage

Gram positive:

• staph

• strep

NOT:

• enterococci

Limited Gram negative:

• E. coli

• Klebsiella

• Proteus

1ST GEN CEPHALOSPORINS

Uses

• skin / soft tissue

• strep pneumonia

• UTI

• surgical prophylaxis

1ST GEN CEPHALOSPORINS

NOT for

• meningitis

• nosocomial infections

1ST GEN CEPHALOSPORINS

important

cefazolin = surgery prophylaxis

2ND GEN CEPHALOSPORINS

drugs

Cephamycins

• Cefoxitin

• Cefotetan

2ND GEN CEPHALOSPORINS

coverage

Better Gram-negative

• E. coli

• Klebsiella

2ND GEN CEPHALOSPORINS- Cephamycins

Good for:

anaerobes / B. fragilis

2ND GEN CEPHALOSPORINS

Uses

• sinusitis

• otitis media

• URI

• prophylaxis

2ND GEN CEPHALOSPORINS

DO NOT use:

• Enterococcus

• Enterobacter

• Pseudomonas

2ND GEN CEPHALOSPORINS

important

cephamycins cover anaerobes

3RD GEN CEPHALOSPORINS

Includes:

• Ceftriaxone

• Cefotaxime

• Ceftazidime

3RD GEN CEPHALOSPORINS

Important:

• Ceftazidime = weaker Gram positive + Pseudomonas

• Ceftriaxone / cefotaxime = strong pneumococcus

3RD GEN CEPHALOSPORINS

Uses:

• meningitis

• Lyme

• gonorrhea (if susceptible)

• community respiratory infections

• HACEK endocarditis

3RD GEN CEPHALOSPORINS

HACEK:

• Haemophilus

• Aggregatibacter

• Cardiobacterium

• Eikenella

• Kingella

4TH GEN CEPHALOSPORIN

drug

 CEFEPIME

4TH GEN CEPHALOSPORIN

key

• only US 4th gen

• zwitterion

 4TH GEN CEPHALOSPORIN

Why matters:

• enters Gram-negative faster

 4TH GEN CEPHALOSPORIN

Benefits:

• better porin penetration

• more PBP targets

• better AmpC stability

 4TH GEN CEPHALOSPORIN

BUT:

can still be hydrolyzed by ESBLs

4TH GEN CEPHALOSPORIN

Good:

• resistant hospital bugs

5TH GEN / ADVANCED CEPHALOSPORINS

Important names:

• Ceftaroline

• Ceftobiprole

• Ceftolozane

• Cefiderocol

5TH GEN / ADVANCED CEPHALOSPORINS

Ceftaroline

covers MRSA

5TH GEN / ADVANCED CEPHALOSPORINS

Ceftobiprole

• covers MRSA

• not for VAP

5TH GEN / ADVANCED CEPHALOSPORINS

Ceftolozane/tazobactam

resistant Pseudomonas

5TH GEN / ADVANCED CEPHALOSPORINS

Cefiderocol

• siderophore cephalosporin

• uses iron transporter

• Trojan horse entry

• still binds PBP

Professor also showed:

• resistance to cefiderocol already reported

✅ ON EXAM ⭐

cefiderocol = iron transporter trick

 

MONOBACTAM

drug

 AZTREONAM

MONOBACTAM

Key:

• only one ring

MONOBACTAM

Coverage:

• ONLY aerobic Gram-negative

MONOBACTAM

Similar to:

3rd gen cephs

MONOBACTAM

NOT active:

• ESBL

• AmpC

MONOBACTAM

Route:

• IV

• IM for UTI possible

MONOBACTAM

Pearl:

• good for penicillin allergy

• Gram-negative only

CARBAPENEMS

Drugs:

• Imipenem

• Meropenem

• Ertapenem

• Doripenem

CARBAPENEMS

Important:

• broad-spectrum

• penetrate tissues / fluids well

CARBAPENEMS

Use:

• severe resistant hospital infections

β-LACTAMASE INHIBITOR COMBINATIONS

Core concept:

• β-lactam kills

• inhibitor protects drug