First Reported Case of Ceftriaxone-Resistant Typhoid Fever in the Middle-East

Typhoid fever is a potential febrile illness, caused by Salmonella enterica serovar Typhi, which is most commonly seen in South-East Asia and Africa. Some cases can have a severe debilitating course, leading to life-threatening conditions. Its infection is restricted only to a human host with an incubation period of 6-30 days. This bacterium is transmitted through contaminated water and food, and tends to spread in the areas of poor sanitation. The escalating antimicrobial resistance in S. Typhi in the last few decades is a global concern in the management of typhoid.1 With reference to the reports from United States Communicable Disease Centre, about 26 million cases of typhoid fever occur worldwide each year, causing 2,15,000 deaths.2 Surveillance for Enteric Fever in Asia Project (SEAP) has established drug resistance to multiple antimicrobials including fluoroquinolones, chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole.3 During 2016-2018, several cases of cephalosporin resistant typhoid cases were reported in Pakistan.4 Later, there were many reported cases of international transmission of Extensively Drug Resistant (XDR) S. Typhi strain from the United States, United Kingdom and Australia. In the United States itself, 5 cases of XDR typhoid were reported in 2016-2018, who travelled to or from Pakistan during that period5. There has been no reported cases of ceftriaxone-resistant S. Typhi in the MiddleEast. This article describes a case of S. Typhi infection, who travelled from Pakistan.

with other supportive medications. From day 1 of admission, high-grade fever with shivering and severe headache was recorded every 6 hours which continued in spite of taking antipyretic medication. His serum C-reactive protein and liver enzymes were elevated. Radiological imaging of chest and abdomen were unremarkable (Table 1).
After 24 hours of admission, his blood culture which was performed by BD Phoenix M50 system showed the growth of gram-negative organism. Regarding antimicrobial stewardship, he was switched over to IV meropenam 1 gm thrice daily. Later, S. Typhi was isolated from the blood, which was resistant to all cephalosporins, so he was continued on injection (Inj) meropenem. After 48 hours of Inj. meropenem, the number of spikes of fever reduced and his blood pressure improved. On day 7 of Inj. meropenem, defervescence was started, and he became afebrile and was discharged from hospital on oral azithromycin. After 5 days of discharge, he was reviewed in the outpatient department and his clinical condition was shown to have improved significantly except for mild fatigue. His serum C-reactive protein level reduced to near normal ( Table 2).

Discussion
To the best of our knowledge, this is one of the first reported cases of ceftriaxone-resistant S. Typhi in the Middle East. Typhoid fever is caused by gram-negative organism, S. enterica serovar Typhi. It spreads through the food and water contaminated with human wastes. In the absence of sensitive antibiotics, typhoid fever will have a prolonged and debilitating course which may lead to the development of severe complications and death. 6 Salmonella Typhi had shown anti-microbial resistance to multiple drugs since 1970s relentlessly till the early 1990s. Fluroquinolones then emerged as the treatment of choice in 1990s. 7 Wide spread irrational use of these antibiotics led to reduced susceptibility to S. Typhi. Later, the outbreak of fluroquinolone resistant typhoid cases was reported in different parts of the world. Thus Inj. Ceftriaxone and oral Cefixime became the mainstay of the management of typhoid. 8 The outbreak of typhoid occurred in Pakistan during 2016-2018, isolated strains having haplotype-58 which were resistant to first-and second-line drugs and third generation cephalosporins (XDR). The XDR S. Typhi strain developed the resistance via a plasmid. In our case, S. Typhi showed resistance to cephalosporins but was susceptible to carbapenems, piperacillin-tazobactam and tigecycline. However, the sensitivity of azithromycin and other macrolides were not checked. Also, the genomic sequencing of S. Typhi could not be performed in our study.
Isolation of S. Typhi in blood and bone marrow remains the definitive diagnostic test for Typhoid fever, while the serological test is discouraged due to the lack of accuracy. 9 The delay in diagnosis and management of sensitive antibiotics can lead to many complications. The XDR salmonella are more prone to develop complications like massive gastrointestinal bleeding, thickening of ileo-caecal region, large soft tissue abscess and significant mesenteric lymphadenopathy. 10 In many developing countries, typhoid fever is a public health problem. 11 Unsafe water, poor sanitation, inadequate public health infrastructure and lack of awareness among public make the situation more abysmal. Safe drinking water, improved sanitation and public health infrastructure will play the key role in the control of the disease from the source. Due to an increase in immigration, there is a high probability of the spread of the disease world-wide. Sporadic cases are already reported in developed countries.
Vaccination is an important and effective tool in preventing this disease, especially when travelling to the typhoid endemic areas. The World Health Organization recommends two types of safe vaccines for typhoid-oral and injectable. 12 Oral vaccine is approved for people of 6 years and older. It should be taken at least 1 week prior to travel. The injectable vaccine Typhi IV is approved for 2-year-old individuals and older. Travellers should receive injections at least 2 weeks before departure.
Effective health education among public and health care workers is the cornerstone for the control of spread of the drug resistant typhoid. Frequent inspection in restaurants, health checkup among food handlers and enactment of the law are also very helpful in preventing food-borne diseases like typhoid. 13 In the last seven decades, the S. Typhi has shown resistance to multiple antibiotics by different mechanism. It also necessitated the judicial use of antibiotics by health care professionals under antimicrobial stewardship to prevent the development of its resistance and thus the global threat by the micro-organism to the human society at large. 1