**6. Clinical management**

In primary care, a thorough history and clinical examination could be suggestive. Unstable patients or those at high risk of deterioration should be referred to secondary care for same day hospital assessment and treatment. The mainstay of enteric fever treatment is antibiotics. The route of administration is often oral and parenteral in primary and secondary care respectively. There are several options of antibiotics and first line choice is usually determined by national and local guidelines according to sensitivities and antibiotics resistance pattern. In most places, fluoroquinolones such as ciprofloxacin and ofloxacin are first line. Second line antibiotics include third generation cephalosporins such as ceftriaxone, ampicillin, co-amoxiclav and trimethoprim-sulphamethoxazole [7]. Over the years, several options of antibiotics have been preferred but have changed based on resistance patterns. Decades ago, top on the list of antibiotics were chloramphenicol, ampicillin and co-trimoxazole [7]. The resistance to these traditional antibiotics resulted in multidrug resistance (MDR) typically conferred via IncHI1 plasmids, harbouring resistance genes such as *catA*, *sul1*, *sul2*, *dfrA*, *bla*TEM-1, *strA*, *strB*, *tetA*, *tetB*, *tetC,* and *tetD* on composite transposons [7]. MDR strains were responsible for several

outbreaks of enteric fever in the 1980/1990s and led to the widespread use of fluoroquinolones as first-line therapy [7, 24]. In the event of MDR and fluoroquinolone resistance, third generation cephalosporins provided respite and an effective alternative. Unfortunately, there are now emerging resistant strains to fluroquinolone and cephalosporin especially in Africa, south-east Asia and the Indian subcontinent resulting in extreme drug-resistance [7]. Fluoroquinolone resistance occurs mainly via chromosomal mutations in the *gyrA*, *gyrB*, *parC,* and *parE* genes. The local pharmacologist or microbiologist should be involved in discussion of the treatment of such cases where recommendations can be made for the use of other options. Such options would likely include Azithromycin, tigecycline or the monobactam, Aztreonam. On a positive note, re-emerging sensitivity to the traditional antibiotics of chloramphenicol, ampicillin and co-trimoxazole is being reported after the prolonged decline in their use [25]. This makes a case for strict adherence to antibiotics stewardship and similar trend may be the case for lot of other infectious diseases which is worth exploring. It is inevitable that various forms of MDR may emerge in future and antibiotic guidelines have to evolve to reflect the trend.

Also, chronic carriers may be treated with a combination of medical and surgical interventions. About 80% clearance rate can be achieved with a 28- day course of ciprofloxacin 750 mg twice daily or norfloxacin 400 mg twice daily. Azithromycin may be beneficial in those with floroquinolone resistance. In chronic carriers with cholethiasis, cholecystectomy under antibiotic cover is indicated and those with schistosomal infection should be covered with praziquantel [7, 24].

#### **7. Prevention**

As earlier discussed, central to the transmission and pathogenesis of enteric fever is poor sanitation and hygiene standards and lack of access to safe drinking water. Therefore, public health interventions targeted at addressing these will go a long way in reducing the global burden of the disease.

Another factor responsible for high global burden is the emergence of antimicrobial resistance strains which result in treatment failure and increased carriage rate [7, 14, 16]. In light of this, it is totally rational that the development of a highly efficacious vaccine will significantly reduce global burden. This is highly important especially for endemic areas with high disease burden and those at high risk of complications especially young children. A number of typhoid vaccines have been developed over the years and others are still in various stages of development with varying degrees of efficacy. Examples include Ty21a and Vi-polysaccharide vaccines which have shown efficacy at 2 years of 58% (95% CI 40–71%) and 59% (95% CI 45–69%), respectively [7]. Typhoid conjugate vaccines (TCVs) have been developed using the Vi-polysaccharide vaccine covalently linked to a protein to enhance immunogenicity, antibody quality, magnitude and duration [7]. Recent studies have shown better and long-lasting immunogenicity from TCV than Vi alone. For instance a prototype Vi-rEPA vaccine made up of Vi covalently linked to rEPA, a recombinant exoprotein A from *Pseudomonas aeruginosa* demonstrated efficacy of up to 91% (95% CI 77–97%) at 2 years, when given as a two dose schedule in 2–5 year-old children and protection lasted at least 4 years [7, 26, 27].

In England, the two main vaccines available are the Vi vaccine given as a single injection and the Ty21a vaccine available in the form of three capsules to be taken on alternate days. It is also available in combination with hepatitis A vaccine with protection lasting 1 year and 3 years for hepatitis A and Typhoid respectively [28]. Vaccination is highly recommended for people who are travelling to high risk areas including the Indian subcontinent, Africa, South America, South and South-east

#### *Enteric Fever in Primary Care DOI: http://dx.doi.org/10.5772/intechopen.96047*

Asia [28]. The Ty21a being live-attenuated, should not be given to immunocompromised patients or children below six years of age. However, the Vi vaccine can be given from the age of 2 years [28].

The World Health Organisation (WHO) strategic Group of Experts on immunisation, in October, 2017, recommended the inclusion of TCVs in vaccination programme schedules in endemic countries from 6 month of age and catch-up vaccinations in children and adolescents up to 15 years old where it is feasible and appropriate [7, 29]. However, this is yet to be implemented in most of these countries due to several factors including lack of political will, poor funding and in some cases poor uptake due to local cultural beliefs.

In 2008, the Vaccine Alliance (Gavi) made TCVs a priority as part of the typhoid investment initiative but did not make any financial commitments due to unavailability of a suitable vaccine [29], however, with the development of promising vaccine candidates with clinically appreciable efficacy albeit in the short- tomedium term, in November 2017, Gavi committed an \$85 million funding window to support the roll out of these vaccines in eligible countries between 2019 and 2020 [7, 29] and in In January 2018, the WHO prequalified the TYPBAR-TCV. Since then, three countries have applied for support from Gavi, which includes a request for TCV use in response to an outbreak. The first Gavi-supported introduction of the TCV began in 2019 with Pakistan being the first country to request the vaccine in response to widespread transmission of an of extreme drug resistant strain (XDR) of *Salmonella typhi*. Following on this in the same year, Zimbabwe also applied for the TCV to combat an outbreak of drug resistant strains in Harare and was the first non-research use of the TCV in sub-Saharan Africa [29]. It is hoped that many more countries will apply for vaccine support and increase coverage to enhance reduction in global disease burden.

Another important factor driving an increase in disease burden is antibiotics resistance. This is mainly in endemic countries where the implementation of antibiotic stewardship is still a huge challenge. In these areas, a lot of antibiotics can be bought over-the-counter and patients often get them from the local chemist or patent medicine store without having to see a clinician. This has fostered the propagation of drug resistant strains of *Salmonella typhi* and *paratyphi* resulting in treatment failure, increased morbidity and mortality and increased tendency for chronic carriage. To mitigate this, there has to be a deliberate policy in these countries to better control access to antimicrobials, improved access to rapid diagnostic tests and public sanitation measures like clean, safe water, running pipe-borne water, clean toilet and waste disposal facilities.

### **8. Conclusion and recommendation**

In conclusion, enteric fever caused by *Salmonella typhi* and *paratyphi* is still a huge global challenge and remains of major public health concern especially in low resource settings. The fundamental reasons for this unrelenting disease burden are multifactorial. Major factors include poor hygiene and sanitation measures, lack of access to portable drinking water, antibiotics resistance and poor access to vaccines. There has to be a strong political will for disease surveillance and primary care interventions such as ensuring the typhoid vaccines are included in routine immunisation schedules in endemic countries especially for children. The traditional typhoid vaccines held some challenges including convenience of administration and poor immunogenicity. However, the TCVs with better administration convenience especially in children as young as six months and longer-term protection, hold huge promise for the future of typhoid vaccine prophylaxis. Also, more countries need

to seize the opportunity for vaccine support provided by Gavi to improve vaccine uptake. There also has to be increased investment in research and development into novel vaccines and diagnostic tools which are accessible, available, reliable and affordable. With the aforementioned and improved commitment to environmental, food and hygiene status, we will hopefully combat this scourge and forge a better, healthier future with enteric fever disease burden reduced to the barest minimum.
