Beta-Lactam Antibiotics: Cell Wall Active Agents (Inhibitors) (5)

Beta-Lactam Families

Penicillins (PCNs)

Cephalosporins

Monobactams

Carbapenems

Penicillin Sub-Families

Natural Penicillins

Anti-Staphylococcal PCNs

AminoPCNs

Beta-lactam/Beta-lactamase Inhibitors

Cephalosporin Sub-Families

1st Generation

2nd Generation

3rd Generation

4th and Beyond Generations

What does penicillin mimic?

The D-Ala D-ala peptide in the peptidoglycan structure

Basic Peptidoglycan Structure

Alternating sugars NAG and NAM (backbone)

Peptide side chain hanging of NAM

Peptide ends in D-Ala D-ala

Transpeptidase

Enzyme that crosslinks peptidoglycan and creates the rigid, cross-linked peptidoglycan mesh providing the cell wall with mechanical strength

B-Lactam Core

Pharmacophore that lets drug interact with transpeptidase/PBP target

What type of inhibitor is penicillin?

Suicide Inhibitor (irreversible)

How does penicillin work?

It mimics D-Ala D-ala and once transpeptidase binds to it covalent inactivation occurs of the enzyme (suicide inhibition)

Factors determining the activity of beta-lactams

Binding affinity for the transpeptidase

Ability to penetrate the outer-membrane (gram-negatives)

Sensitivity to inactivation by B-lactamases

B-lactamase Resistance (to penicillins and cephalosporins)

There is a high conservation between B-lactamases and transpeptidases (commonly ancestry)

Also many bacteria already produce B-lactamase and also transfer of extra-chromosomal DNA (plasmid transfer) and allows resistance to spread between bacteria strains

B-lactamase

bacterial resistance enzyme whose job is to hydrolyze/open the β-lactam ring, which destroys the drug's active structure and makes the antibiotic ineffective.

B-lactamase Inhibitors

Sulfabactam with ampicillin (Unasyn)

Tazobactam with piperacillin (Zosyn)

Natural Penicillins

Narrow Spectrum

Penicillin G and V

Rapid resistance

Semi-Synthetic B-lactamase resistant Penicillins

Methicillin (historic)

Nafcillin

Oxacillin

Dicloaxicillin

Made to combat B-lactamases/resistance issues

Mechanisms of B-lactam Resistance (S. aureus)

Expression of blaZ gene to produce narrow spectrum beta-lactamase enzyme (PCN)

Expression of MecA gene with mutated PBP designated PBP2a with low affinity to beta-lactam antibiotics (MRSA) affects drug binding site/target

Penicillinase-Resistance PCNs: Drugs available

Nafcillin (IV)

Oxacillin (IV)

Dicloxacillin (PO)

Penicillinase-Resistance PCNs: Known for their....

Activity against Staphylococcus (methicillin susceptible organisms (MSSA)

Penicillinase-Resistance PCNs: Spectrum of Activity

G+: S. aureus, S. epidermidis, Streptococcus

Penicillinase-Resistance PCNs: ADRs

N/V/D, rash

Hypersensitivity reactions (most common with this class)

Rare: interstitial nephritis, increase in LFTs/hepatotoxicity

Neutropenia

Penicillinase-Resistance PCNs: PK/PD

Bactericidal

Nafcillin is hepatically metabolized; Oxacillin renally

Penicillinase-Resistance PCNs: Nafcillin DDIs

Induces CYP3A4, may decrease INR in patients on warfarin

Penicillinase-Resistance PCNs: Monitoring (long courses of tx)

CBC, serum creatinine, LFTs (AST/ALT)

Broad Spectrum Penicillins: Groups III and IV

Ampicillin (Omnipen, Principen, Amcil)

Amoxacillin (Moxilin, Moxatag, Trimox)

Aminopenicillins: Spectrum of Activity

G(+): Streptococcus, Enterococcus, Listeria monocytogenes

G(-): H. influenzae, E. coli, Proteus mirabilis (resistance is common though)

How do we improve coverage of anaerobes, MSSA and enteric gram negatives with Aminopenicillins?

Add a beta-lactamase inhibitor such as sulbactam or clavulanate

Aminopenicillins + Beta-Lactamase Inhibitors (drugs)

Ampicillin + Sulbactam (Unasym)

Amoxacillin + Clavulanate (Augmentin)

Aminopenicillins + Beta-Lactamase Inhibitors: Spectrum of Activity

G(+): Streptococcus, Enterococcus, Listeria monocytogenes; Staphylococcal aureus (MSSA)

G(-): H. influenzae, E. coli, Proteus mirabilis, Klebsiella pneumoniae

Ampicillin-Sulfabactam ONLY: Acinteobacter spp.

Anaerobes: B. fragilis, oral anaerobes (Peptostreptococci)

Aminopenicillins + Beta-Lactamase Inhibitors: ADRs

Hypersensitivity reactions, including anaphylaxis

Nausea/vomiting/diarrhea (especially w clavulanate), enterocolitis, eosinophilia

Aminopenicillins + Beta-Lactamase Inhibitors: PK/PD

High PO bioavailability for BLs (50-80%), amoxicillin better than ampicillin

Renal excretion, dose adjustments needed for impairment

Aminopenicillins + Beta-Lactamase Inhibitors: Monitoring (long courses of tx)

Renal function; serum creatinine

Sulbactam-Durlobactam (XacDuro): Sulbactam

Sulbactam competitively and irreversibly binds to PBP1a, PBP1b, and PBP3 at high doses against A. baumannii

Sulbactam in this combination is not interchangeable with other B-lactamase inhibitors

Sulbactam-Durlobactam (XacDuro): Durlobactam

Durlobactam is a B-lactamase inhibitor with activity against a broad range of B-lactamases that chemically optimize to inhibit class D OXA carbapenemases

Lowers median sulbactam MICs by 32 against carbapenem-resistant Acinetobacter baumanii (CRAB)

Pivmecillinam (Pivya): MOA

Amidinopenicillin group

The pivalate ester prodrug of mecillinam which enhances bioavailability achieves very high urinary concentrations (good for UTIs)

Preferentially targets PBP2 unlike most beta-lactams

Pivmecillinam (Pivya): Spectrum of activity/general use

Used exclusively for UTIs

Broad coverage of common urinary pathogens: E. coli, K. pneumoniae, S. saprophyticus

Pivmecillinam (Pivya): What deficiency can it cause + DDI

Prolonged administration can cause carnitine deficiency

Avoid concomitant administration with valproic acid

Group 5 Penicillins: Ureidopenicillins (cyclic urea side chain): Drug + Info

Extended Sprectrum

Piperacillin + Tazobactam

Piperacillin is susceptible to B-lactamases (why given with tazobactam)

Piperacillin + Tazobactam: Spectrum of Activity

(G+): Streptococcus, Enterococcus spp, Staphylococcus aureus (MSSA), Listeria monocytogenes

(G-): H. influenzae, Enterobacterales (E. coli, Protus mirabilis, Salmonella spp, Shigella spp, Klebsiella spp, etc), Enterobacter spp, Psuedomonas aeruginosa, and SOME Acinetobacter spp.

Anaerobes: Bacteroides spp.

Piperacillin + Tazobactam: ADRs

Hypersensitivity reactions, anaphylaxis, N/V/D, can contribute to excess sodium (1.85 mEq Na+/gm), and thrombocytopenia (rare)

Piperacillin + Tazobactam: Key PK/PD

Renal excretions, dose adjustments needed for impairment

Higher doses or prolonged infusions may be needed for Pseudomonas aeruginosa

Piperacillin + Tazobactam: Monitoring (Long Term Tx)

Renal Function: serum creatinine and CBC

First Generation Cephalosporins

Cefazolin (Ancef/Kefazol) IV

Cephalexin (Keflex) PO

Cefadroxil (Duricef/Ultracef) PO

First Generation Cephalosporins: Spectrum of Activity

Activity against G+ organisms, limited in G- to Klebsiella, E. coli, and Proteus mirabilis

Second Generation Cephalosporins

Cefuroxime (Ceftin) PO/Inj

Cefaclor (Ceclor) PO cap

Cefprozil (Cefzil) Liq/tab

Second Generation Cephalosporins: Spectrum of Activity

Less activity against G+

Increased spectrum for G-

Klebsiella, E. coli, H. influenzae, Enterobacter, and Proteus sp.

Third Generation Cephalosporins

Cefotaxime (Claforan) Inj

Ceftriaxone (Rocephen) Inj/IV

Ceftazidime (Fortaz) IV/IM

Third Generation Cephalosporins: Spectrum of Activity

Less activity against G+

Increased spectrum for G-

Klebsiella, E. coli, H. influenzae, Enterobacter, and Proteus sp. BUT more resistant to beta-lactamases

What third generation cephalosporin has Pseudomonas coverage?

Ceftazidime (Fortaz)

What chemical feature is added to a Cephalosporin that differentiates it from other B-lactams?

A dihydrothiazine ring

Ceftazidime + Avibactam (Avycaz): about

First beta-lactamase inhibitor to cover Klebsiella pneumonia carbapenamase (KPC)

Ceftazidime + Avibactam (Avycaz): Spectrum of Activity

MDR (G-): Klebsiella, E. coli, H. influenzae, Enterobacteria and variable activity against P. aeruginosa

(G+): Streptococcus pneumoniae and pyogenes

Fourth Generation Cephalosporin:

Cefepime (Maxipime) IV

Cefepime: Spectrum of Activity

Pseudomonads

Enterobacteriaceae

(Broadest spectrum without a beta-lactamase inhibitor)

LAME: Bacterial Species 1-4th Generation Cephalosporins are not active against

Listeria monocytogenes

Atypicals (Mycoplasma+Chlamydia)

Methicillin resistant S. aureus (MRSA)

Enterococci

5th Generation Cephalosporins

Ceftaroline (Teflaro) IV

Ceftobiprole (Zevtera) IV

Ceftolozane [+Tazobactam] (Zerbaxa) IV

Ceftaroline (Teflaro): Spectrum of Activity

G(-): Klebsiella, E. coli, H. influenzae, Moraxella catarrhalis, and Proteus mirabilis

G(+): MRSA + VRSA, MSSA, Streptococcus

Ceftobiprole (Zevtera): Spectrum of Activity

MRSA (G+ activity)

P. aeruginosa (G- activity)

Ceftobiprole (Zevtera): About

Distinctive C3 pyrrolidinone-containing side chain is designed to increase affinity for penicillin-binding proteins including PBP2a in MRSA + PBP3 in P. aeruginosa

Pseudomonas aeruginosa

Causes clinical disease and a frequent nosocomial pathogen

Common cause of hospital acquired pneumonia, UTIs, surgical infections, and bacteremia

DTR P. aeruginosa

Non-susceptible to:

Piperacillin-tazobactam

Ceftazidime

Cefepime

Aztreonam

Meropenem

Imipenem/Cilastatin

Ciprofloxacin

Levofloxacin

P. aeruginosa Resistant Mechanisms

'Slow' porins

Reduction in number of porins

Many efflux pumps (6-12)

Variety of beta-lactamases: broad spectrum + metallo-beta lactase

Ceftolozane/Tazobactam (Zerbaxa)

2:1 combination

Indicated for complicated UTIs, intra-abdominal or ventilator associated bacterial pneumonia

More potent against AmpC beta-lactamases and Pan-beta-lactamases in P. aeruginosa and some ESBL

Cefiderocol (Fetroja): About

Siderophore cephalosporin

"Trojan-horse"

Catechol group + beta-lactam combination drug effective against Enterobacteriaceae, P. aeruginosa, and K. pneumoniae (note that bacteria have many ways to uptake iron, this stops 1 path)

Lyophilized powder + NaCl given by IV infusion (2g q8h over 3 hour infusion)

Cefiderocol (Fetroja): Use/Indication

Approved for complicated UTI infections

18+ for patients with limited or no alternative therapies

Extended Spectrum Beta-Lactamases (ESBLs): About

Beta-lactamases capable of inactivating penicillins, cephalosporins (minus cefepime) and aztreonam via hydrolysis

Carried on plasmids or arises from amino acid substitutions

Most prevalent in E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis

Extended Spectrum Beta-Lactamases (ESBLs): Are susceptible to?

Cephamycins, carbapenems, and usually to beta-lactamase inhibitors

Extended Spectrum Beta-Lactamases (ESBLs): Are resistant to?

Resistance to 1st,2nd, 3rd generation cephalosporins and monobactams

Carbapenems: about them (general)

Broad-spectrum against most aerobic and anaerobic gram positives and negatives

Broadest activity of the beta-lactams (note that ertapenem has a different spectrum)

As a class do not cover atypical organisms, MRSA, or VRE

Carapenem (drugs)

Imipenem, Ertapenem, and Meropenem (all are IV only)

Imipenem/cilastatin/Meropenem: Spectrum of Activity

(G+): Streptococci spp, some Staphylococci spp, (NOT MRSA), E. faecalis (not VRE)

(G-): Acinetobacter spp, Citrobacter spp, Enterobacter cloacae, E. coli, H. influenzae, K. pneumoniae, and P. aeruginosa

Anaerobes: gram positive and gram negative

Ertapenem: Spectrum of Activity

(G+): Streptococci spp, some Staphylococci spp, (NOT MRSA), E. faecalis (not VRE)

(G-): Citrobacter spp, E. coli, H. influenzae, and K. pneumoniae,

Anaerobes: gram positive and gram negative

Carapenems: ADRs

Cross-reactivity (allergy) with penicillin

Hypersensitivity reactions

Seizure risk - meropenem seizure risk lower than imipenem/cilastatin

Reports of DRESS: drug rash, eosinophilia, systemic syndromes

Carapenems: DDIs

Decreases valproic acid concentrations → CONTRAINDICATED, avoid concomitant use

Carapenems: Key PK/PD

Cilastatin is a dehydropeptidase inhibitor to prevent degradation within renal tubules

Renally excreted, requires dose adjustment for renal impairment

Thiopenems/Oral Carbapenems: About

Broad spectrum agents, want to wait until they are needed (last-line agents)

Thiopenems/Oral Carbapenems: Drugs

Tebipenem and Sulopenem

Oral Carbapenems: Spectrum of Activity

Good coverage of enteric gram-negative rods including ESBL producing organisms, streptococcal spp and MSSA

No coverage of Pseudomonas aeruginosa

Oral Carbapenems: Indicated for?

Only approved for UTI due to limited PK/PD data as of current

Sulopenem requires co-administration with Probenecid

Both drugs are prodrugs

Carbapenem Resistant Enterobacterales (CREs)

Member of the enterobacterales order (E. coli, K. pneumoniae, Enterobacter spp, etc) and is resistant to at least one carbapenem antibiotic or produces a carbapenemase enzyme

A CRE isolate can be resistant to some carbapenems (ertapenem) but not others (meropenem)

Klebsiella pneumoniae Carbapenemase (KPC)

One of the most common, widespread carbapenemases

Class A

Encoded by the gene, blaKPC

Mode of acquisition → plasmid

Possible KPC Pathogens:

Klebsiella spp

P. aeruginosa

E. coli

Acinetobacter baumannii

Enterobacter spp

Carbapenems + Beta-Lactamase Inhibitor Combinations: about

Combinations of existing carbapenems with broad spectrum beta-lactamase inhibitors

Carbapenems + Beta-Lactamase Inhibitor Combinations: Drugs

Meropenem/Vaborbactam (Vabomere)

Imipenem/Cilstatin/Relebactam (Recarbio)*

Carbapenems + Beta-Lactamase Inhibitor Combinations: Indicated for/Use?

Expand spectrum of activity to include all the pathogens that the carbapenems cover + KPCs (Vabomere) and KPCs+DTR-Pseudomonas (Recarbio)

Generally reserved for these specific MDR scenarios

Monobactam Drug

Aztreonam (Azactam)

Aztreonam: spectrum of activity

Aerobic gram-negative rods (Pseudomonas and Neisseria)

Pseudomonas aeruginosa, Enterobacteriaceae, E. coli, H. influenzae, P, mirabilis, Proteus, Providencia spp, Salmonella spp, Serratia spp, Shigella spp, and Klebsiella spp

No activity against gram positive cocci or anaerobes

Aztreonam: About/Use

Susceptible to beta-lactamases, but maintain activity against the metallo-beta-lactamases

Reserved for gram-negative infections in severely PCN-allergic patients

Aztreonam: ADRs

Rash, urticaria, immediate hypersensitivity, GI (D/N)

Cross-reactivity in PCN allergy unlikely (except ceftazidime, cefiderocol)

Aztreonam: Key PK/PD

Renal excretion, dose adjustments required for renal impairment

Aztreonam: Monitoring

For long courses of treatment: renal function; serum creatinine

Drugs that cover P. aeruginosa

Polymyxins (other lecture)

Piperacillin + tazobactam

Ceftazidime

Ceftobiprole

Ceftolozane + tazobactam

Cefiderocol*

Cefepime

Imipenem/Cilastatin

Meropenem

Aztreonam

Imipenem/Cilastatin/Relebactam