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. 2022 Nov 24;11(11):CD010452.
doi: 10.1002/14651858.CD010452.pub2.

Treatment of enteric fever (typhoid and paratyphoid fever) with cephalosporins

Rebecca Kuehn  1 , Nicole Stoesser  2 , David Eyre  3 , Thomas C Darton  4 , Buddha Basnyat  2   5 , Christopher Martin Parry  1   2
Affiliations

Treatment of enteric fever (typhoid and paratyphoid fever) with cephalosporins

Rebecca Kuehn et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To evaluate the effectiveness of cephalosporins for treating enteric fever in children and adults compared to other antimicrobials.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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).

Authors' conclusions: 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.

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Conflict of interest statement

RK is a Cochrane Infectious Diseases Group Research Associate, and was not involved in the editorial process. She has no known conflicts of interest.

NS has no known conflicts of interest.

DE has received grants from the NIHR, Gilead Sciences, and the Robertson Foundation, and has no known conflicts of interest.

TD is a previous contributor to WHO Guidance for the Surveillance of Vaccine Preventable Diseases (typhoid), and has no known conflicts of interest.

BB is a co‐author on two trials included in this review (Arjyal 2016; Pandit 2007).

CP is a co‐author on the following trial included in this review (Cao 1999).

Figures

1
1
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial
1.1
1.1. Analysis
Comparison 1: Cefixime versus fluoroquinolone, Outcome 1: Clinical failure
1.2
1.2. Analysis
Comparison 1: Cefixime versus fluoroquinolone, Outcome 2: Microbiological failure
1.3
1.3. Analysis
Comparison 1: Cefixime versus fluoroquinolone, Outcome 3: Relapse
1.4
1.4. Analysis
Comparison 1: Cefixime versus fluoroquinolone, Outcome 4: Time to defervescence
2.1
2.1. Analysis
Comparison 2: Ceftriaxone versus azithromycin, Outcome 1: Clinical failure
2.2
2.2. Analysis
Comparison 2: Ceftriaxone versus azithromycin, Outcome 2: Microbiological failure
2.3
2.3. Analysis
Comparison 2: Ceftriaxone versus azithromycin, Outcome 3: Relapse
2.4
2.4. Analysis
Comparison 2: Ceftriaxone versus azithromycin, Outcome 4: Time to defervescence
3.1
3.1. Analysis
Comparison 3: Ceftriaxone versus fluoroquinolone, Outcome 1: Clinical failure
3.2
3.2. Analysis
Comparison 3: Ceftriaxone versus fluoroquinolone, Outcome 2: Microbiological failure
3.3
3.3. Analysis
Comparison 3: Ceftriaxone versus fluoroquinolone, Outcome 3: Relapse
3.4
3.4. Analysis
Comparison 3: Ceftriaxone versus fluoroquinolone, Outcome 4: Time to defervescence
3.5
3.5. Analysis
Comparison 3: Ceftriaxone versus fluoroquinolone, Outcome 5: Convalescent faecal carriage
4.1
4.1. Analysis
Comparison 4: Ceftriaxone versus cefixime, Outcome 1: Clinical failure
4.2
4.2. Analysis
Comparison 4: Ceftriaxone versus cefixime, Outcome 2: Microbiological failure
4.3
4.3. Analysis
Comparison 4: Ceftriaxone versus cefixime, Outcome 3: Relapse
4.4
4.4. Analysis
Comparison 4: Ceftriaxone versus cefixime, Outcome 4: Time to defervescence
5.1
5.1. Analysis
Comparison 5: Ceftriaxone versus chloramphenicol, Outcome 1: Clinical failure
5.2
5.2. Analysis
Comparison 5: Ceftriaxone versus chloramphenicol, Outcome 2: Microbiological failure
5.3
5.3. Analysis
Comparison 5: Ceftriaxone versus chloramphenicol, Outcome 3: Relapse
5.4
5.4. Analysis
Comparison 5: Ceftriaxone versus chloramphenicol, Outcome 4: Time to defervescence
5.5
5.5. Analysis
Comparison 5: Ceftriaxone versus chloramphenicol, Outcome 5: Convalescent faecal carriage
6.1
6.1. Analysis
Comparison 6: Cefixime versus chloramphenicol, Outcome 1: Clinical failure
6.2
6.2. Analysis
Comparison 6: Cefixime versus chloramphenicol, Outcome 2: Microbiological failure
6.3
6.3. Analysis
Comparison 6: Cefixime versus chloramphenicol, Outcome 3: Time to defervescence
7.1
7.1. Analysis
Comparison 7: Cefoperazone versus chloramphenicol, Outcome 1: Clinical failure
7.2
7.2. Analysis
Comparison 7: Cefoperazone versus chloramphenicol, Outcome 2: Relapse
7.3
7.3. Analysis
Comparison 7: Cefoperazone versus chloramphenicol, Outcome 3: Time to defervescence
7.4
7.4. Analysis
Comparison 7: Cefoperazone versus chloramphenicol, Outcome 4: Convalescent faecal carriage
8.1
8.1. Analysis
Comparison 8: Cefixime versus cefpodoxime, Outcome 1: Clinical failure
8.2
8.2. Analysis
Comparison 8: Cefixime versus cefpodoxime, Outcome 2: Time to defervescence
9.1
9.1. Analysis
Comparison 9: Cefixime versus aztreonam, Outcome 1: Relapse
9.2
9.2. Analysis
Comparison 9: Cefixime versus aztreonam, Outcome 2: Time to defervesence
10.1
10.1. Analysis
Comparison 10: Ceftriaxone versus aztreonam, Outcome 1: Relapse
10.2
10.2. Analysis
Comparison 10: Ceftriaxone versus aztreonam, Outcome 2: Time to defervesence
11.1
11.1. Analysis
Comparison 11: Short versus long course ceftriaxone, Outcome 1: Clinical failure
11.2
11.2. Analysis
Comparison 11: Short versus long course ceftriaxone, Outcome 2: Relapse
11.3
11.3. Analysis
Comparison 11: Short versus long course ceftriaxone, Outcome 3: Time to defervescence
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD010452

References

References to studies included in this review

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References to studies awaiting assessment

Amin 2021 {published data only}
    1. Amin MR, Das SK, Kabir A, Islam MR, Ahmed SM, Hasan MJ. Open label randomized controlled comparison of three alternative regimes of ciprofloxacin, azithromycin and cefixime for treatment of uncomplicated typhoid fever in Bangladesh. Mymensingh Medical Journal 2021;30(3):725-37. - PubMed
Hamidullah 2019 {published data only}
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Thapaet 2019 {published data only}
    1. Thapaet RK, Raghu PS, Khanal DP. Efficacy of azithromycin and ceftriaxone for the treatment of enteric fever in two tertiary care hospitals of Kathmandu Nepal. Journal of Global Trends in Pharmaceutical Sciences 2019;10(3):6361-7.

References to ongoing studies

NCT04349826 {unpublished data only}
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References to other published versions of this review

Stoesser 2013
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