Key messages
• There may be no difference in the performance of ceftriaxone (a type of cephalosporin) compared with azithromycin, fluoroquinolones, or chloramphenicol (other antimicrobial medicines) for adults and children with enteric fever (typhoid fever).
• Cefixime (another type of cephalosporin) can also be used for treatment of enteric fever in adults and children but may not be as effective as fluoroquinolones.
• Policymakers and clinicians need to consider local antibiotic resistance patterns when considering treatment options for enteric fever.
What is enteric fever?
Enteric fever is a common term for two similar illnesses known individually as typhoid fever and paratyphoid fever. These illnesses only occur in people and are caused by bacteria known as Salmonellatyphi and Salmonella paratyphi A, B or C. These illnesses are most common in low- and middle-income countries where water and sanitation may be inadequate. Enteric fever typically causes fever and headache with diarrhoea, constipation, abdominal pain, nausea and vomiting, or loss of appetite. If left untreated, some people can develop serious complications and may die.
What are cephalosporins and how might they work?
The cephalosporins are a large family of antimicrobial medicines, which are commonly used to treat a variety of infectious diseases. Individual cephalosporins (such as cefixime and ceftriaxone) vary in the specific bacteria they can treat, how they are given - by mouth (orally) or injected (intravenously) - and when they were developed. Some cephalosporins can treat Salmonellatyphi and Salmonella paratyphi A, B, or C, the bacteria causing enteric (typhoid) fever.
In the past, enteric fever responded extremely well to other types of antimicrobial medicines, such as chloramphenicol. However, bacterial resistance to multiple antimicrobial medicines has become a major public health problem in many areas, especially Asia and Africa. Specific cephalosporins are now often used to treat enteric fever due to evolving drug resistance to other antimicrobials.
What did we want to find out?
We wanted to discover whether cephalosporins are better or worse in treating adults and children with enteric fever compared to other commonly given antimicrobials such as fluoroquinolones and azithromycin. To discover this, we wanted to know if treatment with cephalosporins would lead to persisting symptoms of disease (clinical failure), persisting Salmonellatyphi and Salmonella paratyphi A, B, or C bacteria in blood (microbiological failure), or return of symptoms or Salmonellatyphi and Salmonella paratyphi A, B, or C in the blood (relapse).
We also wanted to know how long cephalosporins take to reduce fever, if they reduce the length of time a patient needs to stay in hospital, whether patients' faeces (stool) would still carry the bacteria and thus remain infectious, and whether they cause any unwanted effects in patients.
What did we do?
We searched for studies that compared the treatment of a cephalosporin antimicrobial to another type of antimicrobial, or compared the treatment of a cephalosporin antimicrobial to another different cephalosporin antimicrobial, in adults or children who had enteric fever diagnosed through a laboratory test, such as blood culture.
What did we find?
We identified 27 studies involving 2231 adults and children from Africa, Asia, Europe, the Middle East, and the Caribbean that compared cephalosporin antimicrobial treatment in enteric fever with other antimicrobials.
Ceftriaxone was found to be an effective treatment for enteric fever, with few unwanted effects, and was similar to azithromycin, fluoroquinolones and chloramphenicol in its ability to treat enteric fever.
Cefixime can also be used to treat enteric fever but may not perform as well when compared to fluoroquinolone antimicrobials.
These findings only apply if the bacteria causing the enteric fever infection is vulnerable to the antimicrobial given to treat the infection; that is, the bacteria is not resistant to the antimicrobial.
What are the limitations of the evidence?
We have low confidence in our estimates, for these findings because of the low number of patients in the included studies. Also, in most included studies patients and doctors knew which antimicrobial the patient was receiving, which could have biased the results.
How up to date is this evidence?
These results are current up to 24 November 2021.
Based on very low- to low-certainty evidence, ceftriaxone is an effective treatment for adults and children with enteric fever, with few adverse effects. Trials suggest that there may be no difference in the performance of ceftriaxone compared with azithromycin, fluoroquinolones, or chloramphenicol. Cefixime can also be used for treatment of enteric fever but may not perform as well as fluoroquinolones.
We are unable to draw firm general conclusions on comparative contemporary effectiveness given that most trials were small and conducted over 20 years previously. Clinicians need to take into account current, local resistance patterns in addition to route of administration when choosing an antimicrobial.
Typhoid and paratyphoid (enteric fever) are febrile bacterial illnesses common in many low- and middle-income countries. The World Health Organization (WHO) currently recommends treatment with azithromycin, ciprofloxacin, or ceftriaxone due to widespread resistance to older, first-line antimicrobials. Resistance patterns vary in different locations and are changing over time. Fluoroquinolone resistance in South Asia often precludes the use of ciprofloxacin. Extensively drug-resistant strains of enteric fever have emerged in Pakistan. In some areas of the world, susceptibility to old first-line antimicrobials, such as chloramphenicol, has re-appeared. A Cochrane Review of the use of fluoroquinolones and azithromycin in the treatment of enteric fever has previously been undertaken, but the use of cephalosporins has not been systematically investigated and the optimal choice of drug and duration of treatment are uncertain.
To evaluate the effectiveness of cephalosporins for treating enteric fever in children and adults compared to other antimicrobials.
We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, the WHO ICTRP and ClinicalTrials.gov up to 24 November 2021. We also searched reference lists of included trials, contacted researchers working in the field, and contacted relevant organizations.
We included randomized controlled trials (RCTs) in adults and children with enteric fever that compared a cephalosporin to another antimicrobial, a different cephalosporin, or a different treatment duration of the intervention cephalosporin. Enteric fever was diagnosed on the basis of blood culture, bone marrow culture, or molecular tests.
We used standard Cochrane methods. Our primary outcomes were clinical failure, microbiological failure and relapse. Our secondary outcomes were time to defervescence, duration of hospital admission, convalescent faecal carriage, and adverse effects. We used the GRADE approach to assess certainty of evidence for each outcome.
We included 27 RCTs with 2231 total participants published between 1986 and 2016 across Africa, Asia, Europe, the Middle East and the Caribbean, with comparisons between cephalosporins and other antimicrobials used for the treatment of enteric fever in children and adults. The main comparisons are between antimicrobials in most common clinical use, namely cephalosporins compared to a fluoroquinolone and cephalosporins compared to azithromycin.
Cephalosporin (cefixime) versus fluoroquinolones
Clinical failure, microbiological failure and relapse may be increased in patients treated with cefixime compared to fluoroquinolones in three small trials published over 14 years ago: clinical failure (risk ratio (RR) 13.39, 95% confidence interval (CI) 3.24 to 55.39; 2 trials, 240 participants; low-certainty evidence); microbiological failure (RR 4.07, 95% CI 0.46 to 36.41; 2 trials, 240 participants; low-certainty evidence); relapse (RR 4.45, 95% CI 1.11 to 17.84; 2 trials, 220 participants; low-certainty evidence). Time to defervescence in participants treated with cefixime may be longer compared to participants treated with fluoroquinolones (mean difference (MD) 1.74 days, 95% CI 0.50 to 2.98, 3 trials, 425 participants; low-certainty evidence).
Cephalosporin (ceftriaxone) versus azithromycin
Ceftriaxone may result in a decrease in clinical failure compared to azithromycin, and it is unclear whether ceftriaxone has an effect on microbiological failure compared to azithromycin in two small trials published over 18 years ago and in one more recent trial, all conducted in participants under 18 years of age: clinical failure (RR 0.42, 95% CI 0.11 to 1.57; 3 trials, 196 participants; low-certainty evidence); microbiological failure (RR 1.95, 95% CI 0.36 to 10.64, 3 trials, 196 participants; very low-certainty evidence). It is unclear whether ceftriaxone increases or decreases relapse compared to azithromycin (RR 10.05, 95% CI 1.93 to 52.38; 3 trials, 185 participants; very low-certainty evidence). Time to defervescence in participants treated with ceftriaxone may be shorter compared to participants treated with azithromycin (mean difference of −0.52 days, 95% CI −0.91 to −0.12; 3 trials, 196 participants; low-certainty evidence).
Cephalosporin (ceftriaxone) versus fluoroquinolones
It is unclear whether ceftriaxone has an effect on clinical failure, microbiological failure, relapse, and time to defervescence compared to fluoroquinolones in three trials published over 28 years ago and two more recent trials: clinical failure (RR 3.77, 95% CI 0.72 to 19.81; 4 trials, 359 participants; very low-certainty evidence); microbiological failure (RR 1.65, 95% CI 0.40 to 6.83; 3 trials, 316 participants; very low-certainty evidence); relapse (RR 0.95, 95% CI 0.31 to 2.92; 3 trials, 297 participants; very low-certainty evidence) and time to defervescence (MD 2.73 days, 95% CI −0.37 to 5.84; 3 trials, 285 participants; very low-certainty evidence). It is unclear whether ceftriaxone decreases convalescent faecal carriage compared to the fluoroquinolone gatifloxacin (RR 0.18, 95% CI 0.01 to 3.72; 1 trial, 73 participants; very low-certainty evidence) and length of hospital stay may be longer in participants treated with ceftriaxone compared to participants treated with the fluoroquinolone ofloxacin (mean of 12 days (range 7 to 23 days) in the ceftriaxone group compared to a mean of 9 days (range 6 to 13 days) in the ofloxacin group; 1 trial, 47 participants; low-certainty evidence).