WHAT IS TYPHOID FEVER?
Typhoid and paratyphoid fever are bacterial infections caused by Salmonella enterica serovars Typhi and Paratyphi (S. Paratyphi), respectively. Typhoid fever, also known as enteric fever or simply typhoid, is estimated to cause millions of infections and deaths globally each year.
It is an acute, life-threatening systemic febrile illness transmitted via the oral fecal route. Importantly, children and immunocompromised patients are the most vulnerable populations. In many developing nations, typhoid fever remains a common bacterial infection characterized by a high grade, step-ladder fever (alternating rise and fall), chills, myalgia (muscle pain), altered bowel habits (constipation or diarrhea), headache, lethargy, cough, stomachache, and in some cases, rose-colored spots on the skin.
If left untreated, fatal complications may occur, including intestinal perforation, gastrointestinal hemorrhage, encephalitis, liver damage, inflammation of the heart, and cranial neuritis. These complications are often seen in patients who do not receive timely antimicrobial therapy.
Currently, the largest number of typhoid cases are reported from South Asia (India, Pakistan, and Bangladesh). Pakistan faces a particularly high incidence of typhoid fever. In fact, typhoid is endemic in Pakistan and shows sporadic or scattered occurrences, appearing irregularly across different regions.
CLASSIFICATION OF SALMONELLA BACTERIA
Salmonella is a genus divided into two main species. These are gram-negative, flagellated, facultatively anaerobic bacilli characterized by O (somatic), H (flagellar), and Vi antigens. They belong to the Enterobacteriaceae family.
The two species are:
1. Salmonella enterica
2. Salmonella bongori
Among these, Salmonella enterica is further subdivided into six subspecies comprising approximately 2,500 serotypes.
Broadly, these are classified as:
• Typhoidal serotypes:
These are human-restricted serotypes not found in animals. They cause systemic, complicated, and life-threatening febrile illnesses that require prompt antibiotic treatment. Transmission occurs only person to person via the oral fecal route or through asymptomatic carriers.
• Non-typhoidal serotypes:
In contrast, these infect both humans and animals worldwide. They cause gastroenteritis an inflammation of the GI tract leading to diarrhea, vomiting, and abdominal cramps lasting up to seven days. Also known as salmonellosis, this form is self-limiting, uncomplicated, and usually does not require hospitalization or antibiotic therapy.
INCUBATION PERIOD
After exposure to the organism, symptoms of typhoid fever typically appear after 7–14 days (the incubation period) or within one to three weeks. However, a larger infectious dose can shorten this period and lead to earlier symptom onset.
RISK FACTORS FOR TYPHOID FEVER
Several factors increase the risk of infection.
1. Poor hygiene practices: Lack of handwashing before meals and after defecation plays a major role. Since infected or carrier individuals shed bacteria in feces, contaminated hands can transfer pathogens to food, spreading infection.
2. Unsafe water sources: Consumption of water contaminated with sewage, used for drinking or irrigation, contributes to disease transmission.
3. Poor sanitation: Improper waste disposal and inadequate sewer systems promote the spread of infection.
4. Contaminated or undercooked food: Ingesting improperly cooked food allows bacteria to survive and cause illness.
5. Use of contaminated ice: Ice or ice cubes made from unsafe water can harbor Salmonella.
MULTIDRUG RESISTANT (MDR) TYPHOID
Over time, Salmonella Typhi has evolved resistance to commonly used antibiotics. MDR typhoid refers to typhoid fever resistant to first-line antibiotics such as ampicillin, cotrimoxazole, and chloramphenicol, with or without resistance to second-line therapies. This resistant strain was first reported in the 1960s and continues to challenge global public health efforts.
WHY SALMONELLA TYPHI SHOWS RESISTANCE IN MDR TYPHOID
The H58 clade a specific genetic variant of Salmonella Typhi contains resistance genes responsible for decreased antibiotic susceptibility. As a result, first-line drugs are becoming increasingly ineffective.
CIPROFLOXACIN RESISTANCE IN SOUTH ASIA
By the 1990s, resistance to ciprofloxacin had already emerged in South Asia. This occurred primarily because of widespread self-medication and irrational antibiotic use. Many individuals with diarrhea or gastroenteritis first take metronidazole, and when symptoms persist, they consume a few doses of ciprofloxacin, which may temporarily relieve symptoms but drives resistance.
Furthermore, physicians often prescribe ciprofloxacin empirically for broad bacterial coverage without proper laboratory confirmation. The misuse and overuse of broad-spectrum antibiotics remain major contributors to AMR in Salmonella Typhi.
EXTENSIVELY DRUG-RESISTANT (XDR) TYPHOID
More recently, extensively resistant forms of typhoid were first reported in Bangladesh and India, and later, a large number of XDR cases were recorded in Pakistan. XDR typhoid is resistant to nearly all recommended antibiotics, including ampicillin, cotrimoxazole, chloramphenicol, third-generation cephalosporins, and fluoroquinolones.
Alarmingly, Pakistani XDR strains remain susceptible to only one oral antibiotic azithromycin and to IV extended-spectrum beta lactam carbapenems and tigecycline (parenteral). This severely limits treatment options, increases hospitalization, and escalates healthcare costs.
MECHANISM OF ANTIBIOTIC RESISTANCE IN SALMONELLA TYPHI
Resistance occurs because Salmonella Typhi harbors plasmids carrying specific resistance genes, such as blaCTX-M15 (causing ceftriaxone resistance) and qnrs (causing fluoroquinolone resistance). Thus, horizontal gene transfer plays a crucial role in the spread of AMR.
CAUSES OF AMR IN SALMONELLA TYPHI IN PAKISTAN
Over recent decades, AMR has become increasingly prevalent in Salmonella enterica serovar Typhi. Since antimicrobial therapy is the cornerstone of treatment, these successive AMR waves have left few effective options, particularly for oral therapy. Consequently, XDR typhoid represents a serious public health concern in Pakistan.
CONTRIBUTION OF TYPHI DOT TEST IN THE EMERGENCE OF AMR
To understand how the Typhi Dot Test contributes to AMR in developing countries like Pakistan, it is important to first understand its procedure.
• The Typhi Dot Test is a dot ELISA that detects antibodies (IgM and IgG) against Salmonella Typhi outer membrane proteins. This qualitative test can become positive within 2–3 days after infection and is widely used in endemic regions.
Although it appears convenient and cost-effective, the test has low sensitivity and specificity, which often lead to misdiagnosis, inappropriate antibiotic use, and, ultimately, AMR.
INTERPRETATION OF TYPHI DOT TEST
• Positive IgM → Indicates early infection.
• Positive IgM and IgG → Indicates the middle phase of infection.
• Positive IgG only → Indicates past or chronic infection.
However, in practice, interpreting these results is often challenging, particularly in areas with high endemicity.
HOW MISINTERPRETATION LEADS TO MISDIAGNOSIS
In reality, IgG antibodies can persist for over two years after recovery from typhoid fever. This makes it difficult to differentiate between past and current infections. During reinfection, the stronger IgG response can mask the IgM response, leading to misinterpretation.
As a result, false-positive results from pre-existing immunity or cross-reactivity cause unnecessary antibiotic use, which in turn accelerates the development of AMR.
PRE-EXISTING IMMUNITY
Previous infection or immunization can produce pre-existing IgG antibodies, leading to false-positive Typhi Dot results. Therefore, such tests must be interpreted cautiously in endemic regions.
FINDINGS FROM THE PAKISTAN JOURNAL OF MEDICAL SCIENCES
According to a study published in the Pakistan Journal of Medical Sciences, Typhi Dot test results were compared with blood culture results in patients with acute febrile illness (≥3 days) at Civil Hospital Karachi. The study concluded that the Typhi Dot test is not as reliable as clinicians expect because of its low sensitivity and specificity.
Moreover, the O and H antigens of Salmonella Typhi can cross-react with antibodies from other Salmonella serotypes or gram-negative bacteria, resulting in false-positive results. Consequently, diseases such as malaria, dengue fever, tuberculosis, urinary tract infections, and even viral arthritis can yield false-positive Typhi Dot results.
CROSS REACTIVITY DURING DENGUE OUTBREAKS
During dengue outbreaks in Pakistan, many patients tested positive for Salmonella Typhi IgM despite negative cultures. This clearly demonstrates that immunoassays cannot differentiate between Salmonella Typhi and other febrile illnesses. Hence, inappropriate antibiotic administration based on false-positive results further worsens AMR.
ERRONEOUS MANAGEMENT DUE TO LACK OF DIFFERENTIAL DIAGNOSIS
In endemic areas, nonspecific symptoms of typhoid fever overlap with other febrile illnesses. As a result, patients presenting with fever for more than three days are often clinically misdiagnosed with typhoid. Immunoassays like the Widal or Typhi Dot test fail to differentiate between typhoid, salmonellosis, and other viral or bacterial infections.
Therefore, misdiagnosis and inappropriate antibiotic therapy contribute directly to the development and spread of resistant Salmonella Typhi strains.
HOW BROAD-SPECTRUM ANTIBIOTICS INCREASE THE RISK OF TYPHOID
Under normal conditions, gastric acidity, intestinal motility, and gut flora act as natural defenses against infections. However, malnutrition and the excessive use of broad-spectrum antibiotics disturb gut flora and reduce resistance to infection, thereby increasing susceptibility to typhoid.
STEPS TAKEN IN PAKISTAN TO STOP XDR SPREAD
Recognizing the threat, Pakistan has implemented several measures to control XDR typhoid.
1. National Institute of Health (NIH) directives:
The NIH has instructed healthcare facilities not to use Widal or Typhi Dot tests for diagnosis due to their false-positive rates. Instead, only blood culture should be used for confirmation. The use of outdated diagnostic tests has been linked to the surge of XDR typhoid cases.
2. Mass Vaccination:
There are three main vaccines for typhoid fever:
• Live attenuated oral vaccine
• Inactivated (killed) vaccine
• Typhoid conjugate vaccine (TCV)
Pakistan became the first country to introduce TCV into its routine immunization program. Currently, all children aged 9 months to 15 years are advised to receive 0.5 mL of TCV intramuscularly, regardless of prior vaccination status.
CONCLUSION
The increasing number of XDR typhoid cases in South Asia underscores the urgent need for continuous genomic surveillance and a strong national reporting network. All healthcare sectors public and private must coordinate to share case data with health authorities.
Although vaccination offers short- to medium-term control by reducing antibiotic demand, responsible antibiotic use is essential. Unfortunately, azithromycin, the last oral treatment option for XDR typhoid, has been overprescribed, particularly during the COVID-19 pandemic.
To combat AMR, Pakistan must strengthen antibiotic stewardship, enforce prescription regulations, and discourage the use of immunoassays like Widal and Typhi Dot for diagnosis. Ultimately, ensuring access to safe drinking water, improving sanitation, promoting vaccination, and discouraging unnecessary antibiotic use will be key to preventing future outbreaks.
FREQUENTLY ASKED QUESTIONS (FAQs)
1. What are Widal and Typhi Dot tests used for?
Both tests are serological (blood-based) immunoassays used to detect antibodies against Salmonella typhi, the bacteria responsible for typhoid fever.
2. Why are these tests linked to antimicrobial resistance (AMR)?
In regions where typhoid is common, Widal and Typhi Dot tests are often used as quick diagnostic tools sometimes without confirmation by culture tests. False positive results can lead to unnecessary antibiotic use, which promotes antimicrobial resistance.
3. Are these tests still recommended for typhoid diagnosis?
Modern clinical guidelines suggest that Widal and Typhi Dot tests have limited accuracy and should not be used alone. Blood culture remains the gold standard for typhoid confirmation.
4. How can healthcare professionals help reduce AMR?
By using reliable diagnostic methods, avoiding empirical antibiotic prescriptions, and following evidence-based treatment guidelines, clinicians can help slow down AMR development.
5. What should patients do to prevent antibiotic misuse?
Patients should never self-medicate or demand antibiotics without proper testing. Completing the full prescribed course and following medical advice are essential to prevent resistance.
DISCLAIMER
This content is intended for educational and informational purposes only. It should not replace professional medical advice, diagnosis, or treatment. Healthcare professionals should consult current clinical guidelines before making diagnostic or therapeutic decisions.
CALL TO ACTION
Antimicrobial resistance threatens global health and inappropriate use of outdated tests like Widal and Typhi Dot worsens the problem.
Let’s advocate for accurate diagnostics, rational antibiotic use, and stronger public health awareness.
Share this article to raise awareness about responsible antibiotic use and the importance of evidence-based diagnostics.
REFERENCES
1. World Health Organization (WHO). Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report 2024.
2. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States, 2023.
3. Ochiai RL et al. “The decline of the Widal test and rise of molecular diagnostics in typhoid fever.” Clin Infect Dis. 2021.
4. Akhtar S. Evaluation of Typhi Dot Test and Its Role in Misdiagnosis of Typhoid Fever in Pakistan. Pak J Med Sci. 2022. 5. WHO. Typhoid and Paratyphoid Fever – Laboratory Diagnosis and Case Management Guidelines.