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Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial.

Arjyal A, Basnyat B, Nhan HT, Koirala S, Giri A, Joshi N, Shakya M, Pathak KR, Mahat SP, Prajapati SP, Adhikari N, Thapa R, Merson L, Gajurel D, Lamsal K, Lamsal D, Yadav BK, Shah G, Shrestha P, Dongol S, Karkey A, Thompson CN, Thieu NT, Thanh DP, Baker S, Thwaites GE, Wolbers M, Dolecek C - Lancet Infect Dis (2016)

Bottom Line: Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever.In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08-0·73]; p=0·01).Wellcome Trust and Li Ka Shing Foundation.

View Article: PubMed Central - PubMed

Affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.

No MeSH data available.


Related in: MedlinePlus

Time to treatment failure and fever clearance timeTime to treatment failure shown in the (A) modified intention to treat, (B) culture-confirmed, and (C) culture-negative populations. Fever clearance times shown in the (D) modified intention to treat, (E) culture-confirmed, and (F) culture-negative populations. Fever clearance times were interval-censored; because numbers at risk are not well defined in this setting they are not shown for graphs D, E, or F. HR=hazard ratio. AF=acceleration factor.
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fig2: Time to treatment failure and fever clearance timeTime to treatment failure shown in the (A) modified intention to treat, (B) culture-confirmed, and (C) culture-negative populations. Fever clearance times shown in the (D) modified intention to treat, (E) culture-confirmed, and (F) culture-negative populations. Fever clearance times were interval-censored; because numbers at risk are not well defined in this setting they are not shown for graphs D, E, or F. HR=hazard ratio. AF=acceleration factor.

Mentions: Treatment failure in the modified ITT population was similar between treatment groups: 18 (15%) of 120 patients who received gatifloxacin had treatment failure, compared with 19 (16%) of 119 who received ceftriaxone (hazard ratio [HR] of time to failure 1·04 [95% CI 0·55–1·98]; p=0·91 [table 3]). Details for each event in the composite endpoint are in the appendix. However, there was significant heterogeneity in the primary outcome between the subpopulations of blood culture-confirmed and culture-negative patients (pinteraction<0·0001; table 3, figure 2). In the culture-confirmed population, 16 (26%) of 62 patients given gatifloxacin had treatment failure, compared with four (7%) of 54 patients given ceftriaxone (HR 0·24 [95% CI 0·08–0·73, p=0·01; table 3, absolute risks of failure in appendix). For the four patients with treatment failure in the ceftriaxone group, MICs against ceftriaxone ranged from 0–0·2 μg/mL, and were similar to MICs in patients without treatment failure. Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones. None of the subgroup analyses for culture-positive patients showed significant treatment effect heterogeneity of the primary endpoint (table 3).


Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre, randomised controlled trial.

Arjyal A, Basnyat B, Nhan HT, Koirala S, Giri A, Joshi N, Shakya M, Pathak KR, Mahat SP, Prajapati SP, Adhikari N, Thapa R, Merson L, Gajurel D, Lamsal K, Lamsal D, Yadav BK, Shah G, Shrestha P, Dongol S, Karkey A, Thompson CN, Thieu NT, Thanh DP, Baker S, Thwaites GE, Wolbers M, Dolecek C - Lancet Infect Dis (2016)

Time to treatment failure and fever clearance timeTime to treatment failure shown in the (A) modified intention to treat, (B) culture-confirmed, and (C) culture-negative populations. Fever clearance times shown in the (D) modified intention to treat, (E) culture-confirmed, and (F) culture-negative populations. Fever clearance times were interval-censored; because numbers at risk are not well defined in this setting they are not shown for graphs D, E, or F. HR=hazard ratio. AF=acceleration factor.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835582&req=5

fig2: Time to treatment failure and fever clearance timeTime to treatment failure shown in the (A) modified intention to treat, (B) culture-confirmed, and (C) culture-negative populations. Fever clearance times shown in the (D) modified intention to treat, (E) culture-confirmed, and (F) culture-negative populations. Fever clearance times were interval-censored; because numbers at risk are not well defined in this setting they are not shown for graphs D, E, or F. HR=hazard ratio. AF=acceleration factor.
Mentions: Treatment failure in the modified ITT population was similar between treatment groups: 18 (15%) of 120 patients who received gatifloxacin had treatment failure, compared with 19 (16%) of 119 who received ceftriaxone (hazard ratio [HR] of time to failure 1·04 [95% CI 0·55–1·98]; p=0·91 [table 3]). Details for each event in the composite endpoint are in the appendix. However, there was significant heterogeneity in the primary outcome between the subpopulations of blood culture-confirmed and culture-negative patients (pinteraction<0·0001; table 3, figure 2). In the culture-confirmed population, 16 (26%) of 62 patients given gatifloxacin had treatment failure, compared with four (7%) of 54 patients given ceftriaxone (HR 0·24 [95% CI 0·08–0·73, p=0·01; table 3, absolute risks of failure in appendix). For the four patients with treatment failure in the ceftriaxone group, MICs against ceftriaxone ranged from 0–0·2 μg/mL, and were similar to MICs in patients without treatment failure. Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones. None of the subgroup analyses for culture-positive patients showed significant treatment effect heterogeneity of the primary endpoint (table 3).

Bottom Line: Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever.In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08-0·73]; p=0·01).Wellcome Trust and Li Ka Shing Foundation.

View Article: PubMed Central - PubMed

Affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.

No MeSH data available.


Related in: MedlinePlus