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Resistant Phenotypes of Gram Negative Bacteria

We have a series of short cases & questions (5) on resistant phenotypes of gram-negative bacteria. There are a four major types of gram-negative resistance mechanisms:

1. Enzymatic degradation
2. Change in binding site (e.g. MecA)
3. Loss of porin channels
4. Efflux pumps.

Today we are focusing mostly on #1 and #3. Our first 4 cases will illustrate common patterns related to enzymatic degradation.

Enzymatic Degradation

β-lactam antibiotics are inactivated by a large number of enzymes known as β-lactamases. The most widely used classification of β-lactamases is the Ambler classification. This classification breaks up β-lactamases into 4 classes A, B, C, and D based on the type of enzyme (serine β-lactamases versus metallo β-lactamases). See this brief commentary on the classification from the Journal of Antimicrobial Chemotherapy, 2005. https://doi.org/10.1093/jac/dki130

While the Ambler classification is helpful, it helps to be able to identify different phenotypes in clinical practice based on susceptibility patterns, organism, and epidemiology. This awesome infographic was prepared by @sukritibanthiya.

Case 1

AmpC β-lactamases (Class C); Case 1

Historically, the mnemonic for remembering AmpC produces was the “SPACE” organisms mnemonic.

• Serratia
• Pseudomonas
• Acinetobacter
• Citrobacter
• Enterobacter

We like another mnemonic too: AMPCHES (pronounced “Amp- Cheese”)

(Credit to Dr. Arias @SuperBugDoc). Add A: Aeromonas/Acinetobacter

Key identifiers:

• AmpC producers are reliably R to Cephamycins (cefoxitin).
• Cefepime can overcome inactivation by AmpC, and activity is retained.
• Phenotypes: Derepressed (low vs. high level production) vs. inducible production (repressed)
  • Some bacteria have a basal level of minimal production irrespective of whether or not β-lactams are present (<3%🦠)
  • Others have AmpC production that is inducible– that is their baseline production transiently & reversibly increases in response to the presence of β-lactam antibiotics. Most isolates have this reversible increase in production.
  • Others have constitutively derepressed production of AmpC. These isolates always produce high quantities of AmpC irrespective of presence of β-lactams. These are also known as “stably derepressed”.

Case 2

ESBL-producing; Case 2

Key identifiers:

• ESBL producers are resistant to Ceftriaxone and PCN resistant.
• Cephamycins (cefoxitin) susceptible.
• Cefepime often tests susceptible.
  • Some institutions won’t report Cefepime because of possible worsening outcomes

Molecular dx: CTX-M (most frequent US), TEM, SHV

Case 3

What is the mechanism of resistance of this K. pneumoniae?

Serine carbapenemases: KPC (class-A), OXA-48 (class-D); Case 3

Key identifiers:

• Resistant to all traditional β-lactams, including carbapenems.
• Inhibited by avibactam (Avycaz), vaborbactam (Vabomere), relebactam (Recabrio).

Molecular diagnosis: KPC, OXA-48

Case 4

Extended panel: Cefiderocol-S.
Exploratory: In vitro synergy of ceftazidime/avibactam and Aztreonam using Agar-Etest methods-S.

What is the mechanism of resistance of this K.pneumoniae?

Metallo-β-lactamases: (NDM, VIM, IMP); Case 4

Key identifiers:

• Resistant to all β-lactams.
• MBL dont hydrolyze Aztreonam, but organisms usually co-carry other β -lactamases (i.e. AmpC). Thus, combination Aztreonam–Avibactam can have activity.

Molecular dx: NDM, VIM, IMP

Case 5

Which mechanism of resistance is likely expressed in this PSAR isolate?

OprD-mediated; Case 5

Organisms: Pseudomonas aeruginosa
OprD is porin that facilitates diffusion of carbapenems into the cell. Decreased expression results in resistance.

Key identifiers:

• Resistant to carbapenems, especially imipenem

That is it! Hope you enjoy it. Thanks for the feedback and for sharing!

Authors: @LeMiguelChavez @InfectiousDan
Infographic: @sukritibanthiya

Originally tweeted by Infectious Diseases Fellows Network (@ID_fellows) on 11 May, 2021.