Question:

A 12-year-old boy is brought to the emergency department due to a skin infection. Temperature is 38.4 C (101.1 F). Physical examination shows an area of erythema, warmth, and tenderness on his right distal leg. Laboratory results are notable for leukocytosis. The patient is started on intravenous nafcillin. Two days later, he shows limited response to antibiotic therapy. Light microscopy of pus obtained from the site shows gram-positive cocci in clusters, and sensitivity testing demonstrates little response to nafcillin but good response to vancomycin. Which of the following is the most likely explanation for nafcillin treatment failure in this patient?

Active drug transport out of the cell

Enzymatic degradation of the drug

Mutation in DNA gyrase

Mutation in RNA polymerase

Poor interaction with binding proteins

Welcome to USMLEPREPS!

Master your USMLE exams with our comprehensive question bank.

Subscribe to our Life Time Plan for unlimited access to Step 1, Step 2, and Step 3 preparation materials.

Don't miss this offer!

Hurry up!

: : Get The Offer

Unlimited Access Step ( one, two and three ).

Priority Access To New Features.

Free Lifetime Updates Facility.

Dedicated Support.

Explanation:

Common antibiotic resistance mechanisms
Penicillins	Beta-lactamase, ESBL Mutated PBP Mutated porin protein
Vancomycin	Mutated peptidoglycan cell wall Impaired influx/increased efflux
Quinolones	Mutated DNA gyrase Impaired influx/increased efflux
Aminoglycosides	Aminoglycoside-modifying enzymes Mutated ribosomal subunit protein Mutated porin protein
Tetracyclines	Impaired influx/increased efflux Inactivated enzyme
Rifamycins	Mutated RNA polymerase
ESBL = extended-spectrum beta-lactamase; PBP = penicillin-binding protein.

The presence of gram-positive cocci in clusters that do not respond to nafcillin but show sensitivity to vancomycin suggests infection with methicillin-resistant Staphylococcus aureus (MRSA). S aureus is a common cause of skin infections in the United States. Most skin infections are minor, but S aureus can cause serious infections (eg, surgical wound infections, bloodstream infections in the presence of central intravenous catheters, pneumonia).

S aureus strains that are resistant to oxacillin, nafcillin, and methicillin have been historically termed MRSA, but they are also resistant to all β-lactam agents, including penicillin, cephalosporins (except ceftaroline, a fifth-generation cephalosporin), and carbapenems. Methicillin (nafcillin) resistance is typically mediated by alterations in the structure of penicillin-binding proteins (PBP), the enzymes involved in cell wall synthesis. Altered PBPs, especially PBP2a, have greatly reduced affinity for β-lactam antimicrobial agents (except ceftaroline).

(Choice A) Resistance to tetracycline and sulfonamides is due at least in part to a decrease in the levels of drug accumulation due to decreased uptake and/or increased efflux.

(Choice B) Approximately 95% of S aureus isolates in the United States produce penicillinase, which causes penicillin resistance by breaking penicillin's β-lactam ring. However, nafcillin is penicillinase-stable (along with oxacillin and methicillin).

(Choices C and D) Mutations in DNA gyrase cause resistance to quinolone antibiotics. Mutations in RNA polymerase cause resistance to rifampin.

Educational objective:
Methicillin-resistant Staphylococcus aureus is resistant to all β-lactam antibiotics, including beta-lactamase-resistant antibiotics, as it has an altered penicillin-binding protein that does not bind β-lactams effectively.