Drug-Resistant Typhoid Fever: A Growing Global Threat

For centuries, typhoid fever was one of the most feared infectious diseases. While often perceived as a problem of the past in developed countries, this ancient infection continues to pose a serious global threat, largely due to the increasing resistance to antibiotics. Recent research highlights a concerning trend: the bacterium responsible for typhoid fever is evolving widespread drug resistance, rapidly replacing strains that are susceptible to treatment.

The Rise of Extensively Drug-Resistant (XDR) Typhi

Typhoid fever is caused by the bacterium Salmonella enterica serovar Typhi (S. Typhi). Currently, antibiotics are the only effective therapy. Yet, over the past three decades, resistance to oral antibiotics has increased significantly and spread across several regions of the world. A 2022 study, involving the sequencing of nearly 3,500 S. Typhi strains collected between 2014 and 2019 in Nepal, Bangladesh, Pakistan, and India, revealed a rise in extensively drug-resistant (XDR) strains.

XDR Typhi strains are not only resistant to first-line antibiotics – such as ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole – but are also developing resistance to newer drugs, including fluoroquinolones and third-generation cephalosporins. This expanding resistance is particularly alarming since it limits treatment options and increases the risk of severe illness and death.

Global Spread and Risk Factors

The spread of these resistant strains is happening at a rapid rate internationally. While most cases originate in South Asia, documented instances of cross-border transmission have been reported since approximately 1990. Resistant strains have been exported to Southeast Asia, eastern and southern Africa, and have also been detected in the United Kingdom, the United States, and Canada [1].

According to Jason Andrews of Stanford University, the speed at which highly resistant strains have emerged and spread is a serious cause for concern, emphasizing the urgent need to strengthen prevention measures, especially in the countries most at risk [1].

The Emergence of REPJPP01 and Ceftriaxone Resistance

A particularly concerning strain, REPJPP01, emerged in Pakistan in 2016 and became the dominant genotype in the country by 2019. This strain is notable for its unusual resistance pattern, being the first Salmonella Typhi strain in Pakistan to demonstrate resistance to ceftriaxone, an antibiotic commonly recommended for typhoid fever treatment [2]. Most REPJPP01 isolates are also resistant to ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole [2].

The Centers for Disease Control and Prevention (CDC) has been monitoring REPJPP01 since 2018, as it has caused illnesses in travelers to Pakistan and neighboring countries, as well as in individuals who have not traveled internationally [2].

Azithromycin: A Diminishing Option

Currently, azithromycin remains one of the few effective oral antibiotics against typhoid fever. However, research indicates the spread of mutations that confer resistance to azithromycin, potentially threatening the effectiveness of all oral antimicrobials. If these mutations combine with XDR strains, therapeutic options could be drastically reduced [4].

Global Impact and Prevention Strategies

If left untreated, typhoid fever can be fatal in up to 20% of cases. As of 2024, over 13 million cases have been reported worldwide [4].

Prevention strategies are crucial in combating the spread of drug-resistant typhoid. These include vaccination and practicing safe eating and drinking habits, especially when traveling to high-risk areas. The World Health Organization (WHO) has prequalified four typhoid conjugate vaccines as of April 2025, which are being introduced into childhood immunization programs in endemic countries [4].

South Asia accounts for approximately 70% of global cases, but in a globalized world, resistant variants can spread rapidly, as demonstrated by the COVID-19 pandemic. A study conducted in India in 2021 estimated that vaccinating children in urban areas could prevent up to 36% of cases and deaths [4]. Pakistan was the first country to introduce routine typhoid vaccination, followed by other nations planning similar initiatives.

Antibiotic resistance is now a leading cause of death globally, with a greater impact than HIV/AIDS or malaria. Expanding access to vaccines and investing in research into recent antibiotics are key strategies to prevent typhoid fever from becoming the world’s next major health emergency.