“Antimicrobial infections like XDR typhoid are not confined by borders. . .XDR typhoid is the final warning sign.”
Misbah Khan, The Lancet September 28, 2024
"The global burden of drug-resistant bacterial infections is staggering and only getting worse, with recent data in The Lancet indicating that nearly 40 million people will die from antimicrobial resistance by 2050."
Henry Skinner, PhD, AMR Action Fund CEO
Many infectious diseases experts consider the relentless emergence of antimicrobial resistance (AMR) the single biggest microbial threat to our species. According to a September 21, 2024 article in The Lancet, “Antimicrobial resistance at a cross roads: the cost of inaction,” public health authorities estimate that AMR will result in a global gross domestic product loss of $1 trillion annually by 2030. The human suffering and loss of life are, however, incalculable.
AMR isn’t new to Germ Gems’ readers; it has been a recurrent topic in previous posts. But what is relatively new is an alarming development—the emergence of extensively resistant typhoid (XDR typhoid). (See, “‘The final warning sign’: XDR typhoid,” The Lancet, September 28, 2024). In today’s post, I provide a brief review of typhoid fever and discuss what is being done to address the ongoing AMR crisis.
What is typhoid fever? The Gram-negative bacterium Salmonella typhi causes the disease typhoid fever, simply known as typhoid. Typhoid is contracted by ingesting food or water contaminated with the bacillus. An estimated 27 million cases of typhoid and 21,000 deaths occur annually worldwide.
Only humans can be infected; there are no known animal reservoirs. Humans are also the only carriers of typhoid. Chronic carriers of S. typhi commonly harbor the bacillus in the gall bladder. Asymptomatic carriers can excrete bacteria in their stools for a year or longer and represent a major public health challenge. (“Typhoid Mary,” an Irish-born American cook, was a notorious source of multiple outbreaks of typhoid fever in New York City in the early 20thcentury.)
Signs, symptoms, prevention, and treatment. Classically, untreated typhoid has three distinct stages. In the first week, fever, headache, and cough are common. The second week is characterized by high fever, exhaustion, delirium (giving typhoid the nickname of “nervous fever”), and abdominal distension. In the third week, high fever, rash, intestinal bleeding, and neuropsychiatric symptoms are manifest.
Anyone can get infected with typhoid. Safe drinking water and hygiene are key to preventing the disease. Two vaccines are also available. Travelers to countries with a high prevalence of typhoid are at increased risk. For these travelers, the Centers for Disease Control and Prevention recommends the typhoid vaccine but warns that the “vaccine is not 100% effective and is not a substitute for being careful about what you eat or drink.”
The mainstay of typhoid treatment is antibiotic therapy. Without effective treatment, the risk of dying from typhoid is as high as 20%. Where AMR is uncommon, fluroquinolones, like ciprofloxacin, or cephalosporins or macrolides are usually effective, reducing the risk of death to between 1% and 4%.
XDR typhoid is, however, a game changer. XDR typhoid is resistant to almost all antibiotics usually used to treat this serious bacterial infection thereby limiting treatment options and increasing the risk of death from typhoid.
Global burden of bacterial AMR. Pakistan has the highest rate of typhoid in south Asia, a problem that has escalated since the emergence of XDR typhoid. More than 15,000 cases of XDR typhoid have been officially reported in Pakistan. Writing in The Lancet in September, Misbah Khan states, “XDR typhoid is the final warning sign. After this we will enter a state where the superbug won’t respond to any drug at all. That means we will go back to when typhoid was a more deadly disease. And that really worries us.”
XDR typhoid is alarming; it is, however, only a tiny tip of a massive iceberg of bacterial AMR. A study published in The Lancet on September 28, 2024, “Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050,” provides the first comprehensive assessment of the global burden of AMR from 1990 to 2021. The report suggests that deaths from AMR infections could reach more than 39 million people by 2050. And as we approach that catastrophic death toll, deaths linked to these “superbugs” will grow from 4.7 million per year to 8.2 million per year.
Addressing the AMR crisis. The underlying reasons for mounting AMR are generally well recognized. They include the overprescribing of antibiotics when they’re not indicated, for example, to treat viral infections, and the addition of antibiotics to animal feed for growth promotion. Also, financial incentives often aren’t aligned with responsible use of antibiotics.
But AMR is now recognized as a global health emergency that is associated with increased mortality and longer hospitalization as well as a negative effect on the economics of communities, especially in low-income and middle-income countries. And significant steps are now being taken to address this global health threat.
There has been substantial investment in the research and development of new antibiotics. The World Health Organization (WHO) in partnership with the Global Antimicrobial Resistance Research & Development Hub recently published a report noting that since 2017, public and philanthropic investments in antibiotic research and development have reached $13.75 billion, led by contributions from G7 countries and the European Union. According to Samuel Kariuki of the Kenya Medical Research Institute, “If new antimicrobials are developed for currently antimicrobial-resistant Gram-negative bacteria, a forecasted 11.1 million AMR deaths could be averted by 2050.” (See, “Global burden of antimicrobial resistance and forecasts to 2050,” The Lancet, September 16, 2024).
In addition, on October 10, 2024, the WHO issued a report providing an in-depth evaluation of the potential role of vaccines in reducing AMR. According to the report, the introduction and deployment of 44 vaccines against 24 pathogens could avert more than half a million deaths from drug-resistant infections annually, cut AMR-related healthcare costs and productivity losses by billions of dollars, and reduce the number of antibiotics needed to treat infections by 2.5 doses billion annually.
On September 26, 2024, AMR experts met with world leaders in New York for the second “United Nations High-Level Meeting on AMR.” Ramanan Laxminarayan, PhD, MPH, founder and president of One Health Trust, a Princeton University research scholar and one of the attendees, stated: “I’m very hopeful that the world can tackle this problem because it’s a very solvable problem.” The fact that AMR is now on the radar screen of all the major stakeholders, including the WHO (United Nations), public health organizations in every country, as well as the pharmaceutical industry, may prove Dr. Laxminarayan right. I certainly hope so.
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