An infectious disease consultation is requested for a 54-year-old male patient currently receiving mechanical ventilation in the intensive care unit. He developed a new-onset fever and increased purulent endotracheal secretions on hospital day 7. A chest radiograph demonstrates a new right lower lobe infiltrate. Tracheal aspirate cultures grow *Klebsiella pneumoniae*. The antimicrobial susceptibility report is provided below:
| Antimicrobial Agent | Interpretation |
|---|---|
| Ampicillin | Resistant |
| Ceftriaxone | Resistant |
| Ceftazidime | Resistant |
| Cefepime | Susceptible |
| Imipenem | Susceptible |
Based on the susceptibility profile, which of the following is the most likely molecular mechanism underlying this pathogen's resistance to third-generation cephalosporins?
- Hydrolysis of the cyclic amide bond by an acquired enzymeAnswer
- BStructural modification of membrane-bound transpeptidases
- CActive transport of the medication out of the bacterial periplasm
- DSubstitution of a terminal D-lactate for D-alanine in cell wall precursors
- ECovalent modification of the antimicrobial agent via acetylation
Answer
The mechanism is the hydrolysis of the cyclic amide bond by an acquired enzyme (beta-lactamase production).
The patient is infected with an Extended-Spectrum Beta-Lactamase (ESBL) producing strain of *Klebsiella pneumoniae*, evidenced by resistance to third-generation cephalosporins but susceptibility to carbapenems. The fundamental mechanism of all beta-lactamases is the targeted hydrolysis of the beta-lactam ring (a cyclic amide bond) of the antibiotic, rendering it incapable of inhibiting bacterial cell wall synthesis.
Step-by-Step Solution
Key Concept
Extended-spectrum beta-lactamases (ESBLs) produced by Gram-negative bacilli (like Klebsiella) confer resistance to most penicillins and cephalosporins by hydrolyzing the beta-lactam ring, requiring treatment with carbapenems.