Drug Resistant Salmonella - MDR and NARST

1. Introduction

Enteric fever, caused by Salmonella enterica serovar Typhi (S. Typhi) and Paratyphi, remains a significant global health burden. The management of this condition has been increasingly complicated by the evolution of antimicrobial resistance. The emergence of Multidrug-Resistant (MDR) strains and subsequent fluoroquinolone resistance (NARST) represents a major therapeutic challenge, particularly in developing regions like the Indian subcontinent.

2. Definitions

A. Multidrug Resistant Salmonella Typhi (MDR-ST)

Definition: MDR-ST is defined as S. Typhi strains that demonstrate simultaneous resistance to the three formerly recommended first-line antimicrobial agents used for treatment. These three antibiotics are:

1. Ampicillin
2. Chloramphenicol
3. Trimethoprim-Sulfamethoxazole (TMP-SMX).

Clinical Context: MDR-ST strains emerged prominently in the late 1980s and 1990s. In children, MDR-ST is associated with a more severe clinical illness, higher rates of toxicity, complications, and higher case fatality rates compared to non-MDR strains.

B. Nalidixic Acid Resistant Salmonella Typhi (NARST)

Definition: NARST refers to S. Typhi isolates that are resistant to nalidixic acid. Clinical Significance:

• Surrogate Marker: Resistance to nalidixic acid serves as a surrogate marker for reduced susceptibility to fluoroquinolones (e.g., ciprofloxacin, ofloxacin).
• Therapeutic Implications: Even if a NARST isolate appears susceptible to ciprofloxacin in vitro using standard breakpoints, it is associated with a delayed clinical response and a significantly higher rate of treatment failure (up to 30-fold higher risk of requiring retreatment). Consequently, if a culture shows resistance to nalidixic acid, quinolones should generally not be used for treatment, irrespective of the ciprofloxacin sensitivity report.

3. Mechanisms of Development of Drug Resistance

The development of drug resistance in S. Typhi is a multifactorial process involving genetic adaptation and selective pressure from antibiotic use.

A. Plasmid-Mediated Resistance (MDR Development)

The primary mechanism for the development of MDR-ST is the acquisition of plasmids.

• Transferable Resistance: Antibiotic resistance is typically transferable between organisms via plasmids that carry genes encoding resistance factors.
• Mechanism: Many strains of S. Typhi developed plasmid-mediated multidrug resistance specifically to ampicillin, chloramphenicol, and TMP-SMX.
• Hybrid Plasmids: Serotype-specific virulence plasmids can form hybrid plasmids through recombination with resistance plasmids. They may also acquire gene cassettes consisting of multiple resistance genes, providing the virulent strain with a survival advantage in an environment with high drug pressure.

B. Chromosomal Mutations (Fluoroquinolone Resistance)

Unlike the plasmid-mediated resistance seen in MDR strains, resistance to quinolones (NARST) is primarily chromosomally acquired.

• Target Mutation: The resistance is typically caused by point mutations in the gyrA gene. This gene encodes DNA gyrase, the target enzyme for quinolones.
• Selective Pressure: The widespread and indiscriminate use of fluoroquinolones in both human medicine and animal husbandry has driven this selection. New minimum inhibitory concentration (MIC) breakpoints have been established to better identify these strains, as isolates with MICs between 0.06 µg/mL and 1 µg/mL (often flagged by nalidixic acid resistance) are associated with clinical failure.

C. Mechanisms for Extensively Drug-Resistant (XDR) Strains

While the question focuses on MDR and NARST, the evolution has continued toward XDR strains (resistant to chloramphenicol, ampicillin, TMP-SMX, fluoroquinolones, and third-generation cephalosporins).

• Genetic Acquisition: Recent XDR isolates have been found to possess a combination of resistance genes including blaTEM1 (beta-lactamase), dhfR7, sul1, catA1, qnrS, and blaCTX-M-15 (Extended-Spectrum Beta-Lactamase), alongside the gyrA point mutation.
• Enzymatic Inactivation: Resistance to third-generation cephalosporins is mediated by the production of Extended-Spectrum Beta-Lactamases (ESBLs) such as SHV-12, CTX-M types, or AmpC beta-lactamases (e.g., ACC-1).

D. Role of Environmental and Host Factors

• Antibiotic Misuse: The misuse of antimicrobial agents in humans and the subtherapeutic use of antibiotics in animals raised for food alter competing gastrointestinal flora and induce multidrug-resistant strains.
• Biofilms: Salmonella can form biofilms, which increase resistance to disinfectants and antibiotics, contributing to persistence and chronic carriage.