Approach

The outcome of typhoid infection is usually good when effective antimicrobial therapy is provided in a timely manner, with a fatality rate of <1% and a low rate of serious complications. However, even with proper antimicrobial treatment, bacteraemia and fever clearance times are slow. This reflects the relative difficulty in eradicating the organism from its intracellular niche.

When considering treatment options, the country in which the disease was acquired, with its known antibiotic resistance patterns, should be taken into account together with disease severity.[13][65]​​​ Consult local guidelines, where available.

Presumptive treatment

Empirical antibiotic therapy should be started while waiting for definitive diagnosis and drug sensitivity testing results. Resistance to antimicrobial therapy has been increasing in strains of Salmonella typhi and S paratyphi. Multidrug-resistant strains, which are resistant to amoxicillin, chloramphenicol, and trimethoprim/sulfamethoxazole, emerged in the late 1980s and became prevalent worldwide. Fluoroquinolones were widely introduced and were considered the optimal treatment for typhoid fever due to high efficacy and having a short orally administered course.[66] However, widespread use has led to the emergence of fluoroquinolone-resistant S typhi and S paratyphi strains. Initially, nalidixic acid-resistant strains emerged, followed by fully fluoroquinolone-resistant strains. These strains are prevalent in Asia, and have also emerged in Africa and Latin America.[13][67][68]​​​​ 

Azithromycin and third-generation cephalosporins (e.g., ceftriaxone, cefixime) have low rates of resistance globally, and are therefore generally recommended as empirical treatment for enteric fever.[13]​​[38]​​[40][69][70][71]

Because ceftriaxone failure is common and mean defervescence is long (despite in vitro sensitivity), there has been a move towards a combined therapy approach with ceftriaxone and azithromycin, especially in patients living in the Indian subcontinent. The rationale behind this approach, which is the lead author's preference, is that typhoid bacteria shift between the blood and the intracellular compartments, and since ceftriaxone is highly active in blood, and azithromycin in the intracellular compartment, the combination may confer a clinical benefit.[72]

One study of Israeli travellers in Nepal found that combination treatment with ceftriaxone and azithromycin nearly halved the fever clearance time compared with ceftriaxone alone; the study included 37 travellers who all had isolates resistant to nalidixic acid but were sensitive to ciprofloxacin.[72] The potential benefit of combination therapy over monotherapy has since been demonstrated in one open-label prospective trial in the local population in Nepal.[73] In this trial, combination therapy of ceftriaxone or cefixime and azithromycin resulted in shorter fever clearance time and no late relapses were recorded. Further clinical trials of this combined regimen therapy are ongoing.

An outbreak of typhoid fever caused by a strain of extensively drug-resistant (XDR) S typhi, resistant to chloramphenicol, ampicillin, trimethoprim/sulfamethoxazole, fluoroquinolones, and ceftriaxone, emerged in Pakistan in 2016.[19] ​XDR S typhi has since been documented in other countries, including the US, mostly associated with travel to Pakistan but also in patients who report no history of international travel in the 30 days before their illness and no close contact with anyone ill.[13][20][21][22][23]​​[24]​ The US Centers for Disease Control and Prevention (CDC) recommends that patients with suspected typhoid fever who have travelled to Pakistan or Iraq, or who did not travel internationally before their illness began, should be treated with azithromycin for uncomplicated illness and with a carbapenem antibiotic for severe or complicated disease.[40]

Treatment upon receipt of sensitivity assays

The antibiotic treatment regimen may be adjusted once antimicrobial sensitivity results are available.

Ciprofloxacin is widely considered the treatment of choice in adults with infections that are susceptible to fluoroquinolones. However, if the patient is already taking azithromycin and/or a cephalosporin and is responding to treatment, there is no need to change.

Chloramphenicol, ampicillin, or trimethoprim/sulfamethoxazole may be appropriate alternatives for treatment of infection that is not multidrug-resistant (as resistance has declined over time while other antibiotics have been widely used).

If the strain is resistant to fluoroquinolones, treatment with a third-generation cephalosporin, preferably with concomitant azithromycin, is recommended.

Response to treatment has become slower in recent years, even when the pathogen is sensitive to fluoroquinolones or ceftriaxone in vitro.[74][75]

Clinicians should be aware that rarely fluoroquinolones have been associated with disabling and potentially irreversible musculoskeletal or nervous system adverse events.[76][77]

Azithromycin has shown similar results in comparison to ciprofloxacin and ofloxacin, and oral azithromycin has been shown to be comparable to ceftriaxone in uncomplicated typhoid infection in children and adolescents.[78][79][80]​ There were no serious adverse events reported in any of the trials.[81]

Antimicrobial treatment should always be accompanied by supportive care, including antipyretics and hydration.

Treatment of extensively drug-resistant (XDR) infection

Patients with confirmed XDR typhoid fever may continue to be treated with azithromycin and meropenem, either as monotherapy or in combination.[13]​​[38][40]​​​[69][70]​​​​​ The emergence of a carbapenem-resistant strain is a possibility. Co-isolation of ceftriaxone-resistant S typhi and carbapenemase-producing Enterobacteriaceae in a single traveller to Pakistan was reported in 2019.[22]

Persistence of fever

Fever clearance times can be slow and patients may continue to have fever for around five days after starting antibiotic treatment.[13]​​[38][40]​​​​[69][70]​​​ If fever persists and the patient is receiving monotherapy (azithromycin or a cephalosporin) then combination antibiotic therapy may be considered at this point. If there is persistent fever as well as persistence of other symptoms after seven days then the antibiotic regimen may be failing. Verify that the pathogen is not XDR, particularly if the patient has recently returned from Pakistan or neighbouring countries, otherwise perform tests for metastatic infection.

Encephalopathic complications

Patients with encephalopathic complications such as delirium, obtundation, stupor, coma, or shock may benefit from the prompt administration of dexamethasone.[39][82]​​

Dexamethasone may rarely be contraindicated (e.g., in patients with structural brain lesions).

Complications such as encephalopathy are more likely in patients presenting later in the course of their illness.[83]

Metastatic infection

Secondary metastatic foci may occur in many organs: for example, splenic abscesses, endocarditis, osteomyelitis, arthritis, and acute cholecystitis. In these cases a prolonged antibiotic course might be needed, and sometimes additional surgical intervention (e.g., cholecystectomy).

Relapse

Relapse may occur, even with appropriate antimicrobial therapy in S typhi and S paratyphi.[14] This reflects the difficulty of eradicating the organism. It is important to note that the relapse organism invariably has the same sensitivity pattern as the initial infecting isolate. In these cases, repeat antibiotic courses are needed.

Chronic carriage

Some patients become chronic carriers, defined as continuing to excrete the organism in stool for more than a year but remaining asymptomatic (though able to transmit infection). Prolonged antimicrobial treatment is usually required.[40]​ Cholecystectomy may also be considered in some cases.[38][69][70]

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