A 68-year-old man with diabetes mellitus type 2 presents to the emergency department with fever (39.2°C), dysuria, and flank pain. Urine culture grows a gram-negative rod that is lactose-fermenting, indole-positive, and motile. On blood culture, the same organism is isolated. The isolate is resistant to ampicillin and cephalothin but susceptible to ceftriaxone and fluoroquinolones. ESBL testing is negative. Which of the following genetic mechanisms BEST explains this antibiotic resistance pattern?

Question

Accepted Answer

C. Chromosomal mutation in ampC gene promoter leading to derepression of AmpC production. ## Clinical Context The patient presents with community-acquired urosepsis from E. coli. The resistance pattern is key: **resistant to ampicillin and first-generation cephalosporins (cephalothin), but susceptible to third-generation cephalosporins (ceftriaxone) and fluoroquinolones**. ESBL is negative, ruling out extended-spectrum beta-lactamase. ## Mechanism Analysis **Key Point:** This resistance pattern is pathognomonic for **AmpC beta-lactamase** produced by E. coli, specifically due to derepression of the chromosomal ampC gene. ### Why AmpC Derepression (Option 2)? E. coli carries a chromosomal ampC gene that encodes an AmpC-type beta-lactamase. Under normal conditions, this gene is repressed by the ampD gene product. However, mutations in the ampC promoter region (or loss of ampD function) lead to **constitutive, high-level expression** of AmpC. AmpC beta-lactamases: - Hydrolyze **all beta-lactams except carbapenems and fourth-generation cephalosporins** - Are **NOT inhibited by clavulanic acid** (unlike TEM/SHV ESBLs) - Confer resistance to ampicillin, amoxicillin-clavulanate, and cephalothin - **Spare third-generation cephalosporins** (ceftriaxone, cefotaxime) because these are poor substrates - Are chromosomally encoded, not plasmid-mediated in E. coli **High-Yield:** The susceptibility to **ceftriaxone despite ampicillin resistance** is the diagnostic clue. This pattern does NOT fit ESBL (which would be inhibited by clavulanic acid and resistant to ceftriaxone) and does NOT fit simple PBP mutations. ## Why Each Distractor Is Wrong ### Option 0: PBP Mutations PBP mutations cause broad resistance to all beta-lactams, including third-generation cephalosporins. This patient is susceptible to ceftriaxone, so PBP mutation is unlikely. PBP mutations are also rare in E. coli (more common in S. pneumoniae and N. gonorrhoeae). ### Option 1: Plasmid-Mediated AmpC While plasmid-mediated AmpC (pAmpC) exists and can be found in E. coli, it is far less common than chromosomal AmpC derepression in community-acquired infections. The clinical presentation (urosepsis, likely community-acquired) and the absence of ESBL make chromosomal AmpC derepression the most likely mechanism. Additionally, plasmid-mediated AmpC is more commonly associated with Klebsiella and other Enterobacteriaceae in healthcare settings. ### Option 3: OmpF Loss-of-Function Outer membrane porin mutations reduce beta-lactam penetration but do NOT cause the specific resistance pattern seen here. OmpF loss would cause resistance to multiple drug classes and would not explain the selective susceptibility to ceftriaxone. This mechanism is also rare in E. coli and more relevant in Pseudomonas aeruginosa. ## Mermaid Diagram: E. coli Resistance Mechanisms ```mermaid flowchart TD A["E. coli with Beta-lactam Resistance"]:::outcome --> B{"ESBL Test Result?"}:::decision B -->|Positive| C["ESBL: TEM/SHV/CTX-M"]:::outcome C --> C1["Inhibited by clavulanic acid
Resistant to 3rd-gen cephalosporins"] B -->|Negative| D{"Cephalothin Resistant
but Ceftriaxone Susceptible?"}:::decision D -->|Yes| E["AmpC Derepression
Chromosomal ampC mutation"]:::action E --> E1["NOT inhibited by clavulanic acid
Spares 3rd-gen cephalosporins"] D -->|No| F["PBP mutation or
Porin loss"]:::outcome ``` ## Clinical Pearl **High-Yield:** In clinical practice, the **cephalothin-resistant, ceftriaxone-susceptible** pattern in E. coli strongly suggests **AmpC derepression**. This is often seen in community-acquired UTIs and intra-abdominal infections. Always request **AmpC detection** (e.g., by disk approximation test or molecular methods) when this pattern is observed, as it has implications for empiric therapy selection. ## Textbook Correlation AmpC beta-lactamases and their genetic basis are covered in detail in standard microbiology references. The distinction between ESBL and AmpC is a high-yield topic for NEET PG because it directly impacts antibiotic selection in clinical practice. ![E. coli & Klebsiella: Antibiotic Resistance Mechanisms diagram](https://mmcphlazjonnzmdysowq.supabase.co/storage/v1/object/public/blog-images/explanation/2603.webp)

Answer

A. Chromosomal mutation in penicillin-binding proteins (PBPs) with altered affinity for beta-lactams

Answer

B. Altered outer membrane permeability due to loss-of-function mutation in OmpF porin

Answer

D. Plasmid-mediated production of AmpC beta-lactamase with constitutive expression

Explanation

Clinical Context

Mechanism Analysis

Why AmpC Derepression (Option 2)?

Why Each Distractor Is Wrong

Option 0: PBP Mutations

Option 1: Plasmid-Mediated AmpC

Option 3: OmpF Loss-of-Function

Mermaid Diagram: E. coli Resistance Mechanisms

Clinical Pearl

Textbook Correlation

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