XDR typhoid fever outbreak was first reported in 2016 in the Sindh province of Pakistan. The epidemic is not over yet. XDR-Typhoid treatment is too costly. Hence, prevention via handwashing, hygienic water and food, and vaccination should be emphasized. In a Grand Round in 2013/ 2014, the microbiologists at Pakistan Institute of Medical Sciences Islamabad shared a one-year data in which 90% of the culture-positive patients with Salmonella typhi were resistant to quinolones (Ciprofloxacin). So, we were already dealing with quinolones-resistant Salmonella Typhi. The inappropriate use of Ceftriaxone resulted in the emergence of XDR-typhoid fever as we were already dealing with Salmonella typhi that was resistant to fluoroquinolones. The XDR-Typhoid fever has greatly increased the morbidity, mortality, and financial burden on the family and the government.

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What is the total cost of treating Typhoid Fever and XDR-Typhoid fever in particular?

Treatment of Typhoid fever with Ciprofloxacin (Ciproxin) 750 mg twice daily for 14 days costs the patient Rs. 1978 Treatment of Typhoid fever with Ceftriaxone (Rocephin) 2 gm twice daily for 14 days costs the patient Rs. 47768 Treatment of Typhoid fever with Cap. Azithromycin 500 mg once daily for 10 days costs the patient Rs. 566 Treatment of Typhoid fever with Injection Azithromycin 500 mg once daily for 10 days costs the patient Rs. 2960 Treatment of Typhoid fever with Meropenem 1 gm thrice daily for 14 days costs the patient Rs. 108906

Thus, the total expenses of treating XDR-Typhoid fever increases by 2.5 - 55 times.

This excludes the expenses of the hospital stay, treatment of any complications, the number of days the patient is off-work, and other supportive treatments.

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Definitions of typhoid fever according to drug resistance:

Definitions are important to decide the treatment regimen. According to the WHO, typhoid fever is classified as:

• Non-resistant typhoid fever:

Typhoid fever caused by Salmonella typhi and/or Salmonella paratyphi A, B, or C strains that are sensitive to first-line drugs and third-generation cephalosporins with or without resistance to second-line drugs.

• Multidrug-resistant (MDR) typhoid fever:

Typhoid fever caused by Salmonella typhi and/or Salmonella paratyphi A, B, or C strains that are resistant to first-line recommended drugs, with or without resistance to second-line drugs.

• Extensively drug-resistant (XDR) Typhoid fever:

Typhoid fever caused by Salmonella typhi strain that is resistant to all the recommended antibiotics for typhoid fever.

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What are the first-line and second-line drugs for typhoid fever?

The first-line drugs for the treatment of Salmonella typhi include:

• Chloramphenicol
• Ampicillin
• Trimethoprim-sulfamethoxazole
• Cefixime
• Ceftriaxone

Cefixime and Ceftriaxone are oral and parenteral third-generation cephalosporins respectively. Cefixime is recommended by the IAP ( International Academy of the Philippines) for uncomplicated Salmonella typhi infections. Ceftriaxone is recommended for complicated infections caused by Salmonella typhi.

Fluoroquinolones are considered second-line agents in the treatment of Salmonella typhi infection.

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Factors responsible for the emergence of XDR typhoid fever:

Since Salmonella typhi infection follows the ingestion of the bacteria (via the fecal-oral route), the disease spreads in areas with poor sanitation. Contaminated food items, milk, frozen fruit, close contact with a contaminated person, and most importantly, the use of contaminated water are responsible for most cases of typhoid fever. The contamination of water occurs due to the mixing of sewerage with drinking water. Secondly, the inappropriate use of antibiotics by healthcare providers is another factor responsible for the emergence of drug-resistant typhoid fever. Ciprofloxacin, moxifloxacin, ofloxacin, and recently gemifloxacin are all very commonly used for skin infections, upper and lower respiratory tract infections, and gastrointestinal infections. It should be noted that upper respiratory tract infections like tonsillitis and pharyngitis are mostly caused by viral infections. Similarly, diarrhea is commonly treated with ciprofloxacin. In most patients, diarrhea is self-limiting and needs oral rehydration therapy alone.

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XDR-Typhoid treatment 

Prior to initiating treatment, a few points are important to consider while treating a patient with Typhoid fever:

1. All patients should have blood cultures sent prior to initiating the treatment.

2. Patients who have received or are receiving antibiotics should also have at least one blood culture sent if the patient is symptomatic.

3. Patients should not be given the diagnosis of Typhoid fever based solely on the widely used test - the Typhidot test.

   • Rather, I suggest that the Typhidot test should be abandoned.

   • The Typhidot test is probably the number one cause of inappropriate use of antibiotics in afebrile patients in our setup.

   • Furthermore, patients continue to take antibiotics for months based on a positive Typhidot test.

4. Patients who do have typhoid fever should be asked to continue the recommended treatment despite the failure of the symptoms to resolve by up to four days of treatment initiation (unless the blood cultures are positive for XDR-Typhoid)

   • Unlike other bacterial infections where appropriate antibiotics initiation results in defervescence within 48 to 72 hours, it takes 4 - 5 days for the fever to improve in patients with typhoid fever.

5. Patients should be advised antibiotics at the recommended dosages and for the appropriate duration. Examples include:

   • Ciprofloxacin 750 mg twice daily for 10 - 14 days

   • Moxifloxacin 400 mg once a day for 10 - 14 days

   • Ceftriaxone 2 gm intravenously twice daily for 10 - 14 days

   • Cefixime 20 mg/kg once or twice daily for 10 - 14 days

6. Patients whose cultures are awaited or those who do not respond to the usual treatment should not be started empirically on a combination of a drug used to treat MDR and XDR typhoid fever. Even some doctors may prescribe these combinations from the start. Examples of commonly prescribed inappropriate combinations are:

   • Cefixime and Azithromycin

   • Ceftriaxone and Azithromycin

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How to treat XDR-Typhoid fever?

After receiving the blood cultures report, the patient should be immediately started on the appropriate antibiotics. The usual regimen is a combination of a carbapenem and azithromycin:

• Injection Meropenem 1 gm thrice daily for 10 - 14 days plus Injection/ cap. azithromycin 500 mg once a day for 10 - 14 days.

The Pakistan Society of Infectious diseases recommends monotherapy with injection Meropenem 1 gm thrice daily for 14 days.

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What if Salmonella acquires resistant to meropenem and azithromycin:

This is a grave situation and we should be prepared for the emergence of carbapenems resistant Salmonella typhi infections. The importance of prevention needs special emphasis here. Typhoid fever, unlike other infectious diseases, is being seen as commonly in patients with good socioeconomic status as the middle and the lower socioeconomic class. This is because of the increased frequency of intake of Junk food and hotelling. So, the primary concern is the intake of unhygienic food items.

Frequent hand washing especially prior to meals and the intake of properly cooked hygienic foods should be emphasized.

This message needs to be spread via newspapers, schools, mosques, and hospitals.

Furthermore, the WHO has recently recommended the administration of "Typhoid Conjugate Vaccine" in areas of high prevalence.

Pakistan is the first country to add the Typhoid conjugate vaccine in its routine schedule of immunization. The WHO Prefers the "Typhoid Conjugate Vaccine" over other typhoid vaccines because of its higher immunogenicity. The Typhoid Conjugate Vaccine (Typbar-TCV) reduced the risk of culture-confirmed typhoid fever substantially in a study in Nepal. The efficacy of the Typbar-TCV vaccine was 82% compared to the placebo vaccine.

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Vi-TT Typhoid Conjugate Vaccine (TCV):

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The TCV consists of the Vi polysaccharide antigen that is linked to the tetanus toxoid protein.

Dose: Typbar-TCV is administered as a single intramuscular dose.

Duration: Although data is limited, it is thought to be effective for up to five years after which the vaccine should be readministered.

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Novel treatments in patients with XDR-Typhoid fever:

Other than the above-mentioned antibiotics, the following investigational drugs may be used in super-refractory Salmonella Typhi. A case report of Splenic abscesses caused by Salmonella Typhi was effectively treated with four weeks of Piperacillin-Tazobactam¹. Four patients with Salmonella Typhi infections who failed to respond to chloramphenicol were successfully treated with aztreonam in a case series². Other studies have evaluated the role of the novel carbapenems (Ertapenem) and Tigecycline in the treatment of XDR-Typhoid fever³. The fourth-generation cephalosporins (Cefepime) and the fifth-generation cephalosporin (Ceftaroline) have also been studied in the treatment of XDR-Typhoid fever. However, because of cross-resistance with cefixime and ceftriaxone, they are of limited benefit in these patients. Lastly, Chloramphenicol has not been used for decades and the resistance to chloramphenicol might have gone down. This might lead to the revival of old antibiotics such as chloramphenicol.

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References:

1. Khan FY. Typhoid Splenic Abscess: A Case Report and Literature Review.
2. Farid Z, Girgis NI, Kamal M, Bishay E, Kilpatrick ME. Successful aztreonam treatment of acute typhoid fever after chloramphenicol failure. Scandinavian journal of infectious diseases. 1990 Jan 1;22(4):505-6.
3. Su LH, Wu TL, Chiu CH. Development of carbapenem resistance during therapy for non‐typhoid Salmonella infection. Clinical Microbiology and Infection. 2012 Apr;18(4):E91-4.