Comparative Efficacy of Gatifloxacin versus Ceftriaxone for Uncomplicated Enteric Fever
Introduction
Enteric (typhoid) fever, a systemic infection caused by the Salmonella enterica serovars Typhi and Paratyphi A, B, and C, is a leading cause of febrile disease in many low-income countries.
Aim
To test the hypothesis that gatifloxacin is superior to ceftriaxone in treating enteric fever
Patient Profile
Children (aged 2–13 years) and adult (aged 14–45 years) with suspected enteric fever
Methods
- Open-label, randomised, controlled, superiority trial
- Followed up duration: 28 days
- The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following:
- fever clearance time of more than 7 days after treatment initiation
- the need for rescue treatment on day 8
- microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8
- or relapse or disease-related complications within 28 days of treatment initiation
- Secondary endpoints were fever clearance time only; time to relapse until day 28 or at any time during followup; confirmed and syndromic relapse until day 28; confirmed or syndromic relapse at any time; and faecal carriage of S Typhi or S Paratyphi at 1 month, 3 months, or 6 months after randomisation assessed in culture-positive patients only.
Results
Primary Outcome
- 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
- The most common cause of treatment failure in culture-negative patients treated with ceftriaxone was fever for more than 7 days (12 [80%] of 15 patients) and nine [60%] of 15 received rescue treatment
Secondary endpoint
- Fever clearance times did not differ between the two treatment groups
Table 1: Fever clearance time (secondary endpoint) overall and in predefined subgroups
|
|
Gatifloxacin |
Ceftriaxone |
Acceleration factor p value |
Heterogeneity test (p-interaction value) | ||
|
n |
Median days |
n |
Median days |
|
| |
|
All patients (modified intention-to-treat population) |
120 |
2·43 |
119 |
2·93 |
0.89; p=0·31 |
|
|
Culture-negative or culture-positive population |
|
|
|
|
|
<0·0001 |
|
Culture negative |
58 |
1·12 |
65 |
3·03 |
0·44; p<0·0001 |
|
|
Culture positive |
62 |
4·21 |
54 |
2·78 |
1·42; p=0·001 |
|
|
Pathogen (culture-confirmed population) |
|
|
|
|
|
0·57 |
|
Salmonella Paratyphi A |
19 |
3·68 |
16 |
2·24 |
1·31; p=0·19 |
|
|
Salmonella Typhi |
43 |
4·51 |
38 |
3·03 |
1·47; p=0·002 |
|
|
Age (modified intention-to-treat population) |
|
|
|
|
|
0·29 |
|
<16 years |
32 |
3·02 |
36 |
2·23 |
1·08; p=0·72 |
|
|
≥16 years |
88 |
2·22 |
83 |
3·25 |
0·83; p=0·16 |
|
|
Age (culture-confirmed population) |
|
|
|
|
|
0·46 |
|
<16 years |
21 |
3·82 |
16 |
3·04 |
1·26; p=0·18 |
|
|
≥16 years |
41 |
4·43) |
38 |
2·66 |
1·51; p=0·003 |
|
|
Sex (modified intention-to-treat population) |
|
|
|
|
|
0·99 |
|
Female |
21 |
2·41 |
38 |
2·78 |
0·89 (0·56–1·41); p=0·61 |
|
|
Male |
99 |
2·44 |
81 |
2·99 |
0·89 (0·68–1·14); p=0·35 |
|
|
Sex (culture-confirmed population) |
|
|
|
|
|
0·68 |
|
Female |
11 |
4·27 |
17 |
3·06 |
1·25; p=0·25 |
|
|
Male |
51 |
4·18 |
37 |
2·66 |
1·46; p=0·004 |
|
|
Recruitment date (modified intention-to-treat population) |
|
|
|
|
|
0·09 |
|
Before April 1, 2013 |
62 |
2·30 |
59 |
2·79 |
0·74; p=0·08 |
|
|
April 1, 2013, or later |
58 |
2·60 |
60 |
3·05 |
1·09; p=0·56 |
|
|
Recruitment date (culture-confirmed population) |
|
|
|
|
|
0·12 |
|
Before April 1, 2013 |
33 |
3·88 |
28 |
2·54 |
1·21; p=0·22 |
|
|
April 1, 2013, or later |
29 |
4·68 |
26 |
3·00 |
1·68; p=0·0004 |
|
|
MIC against ciprofloxacin (culture-confirmed population) |
|
|
|
|
|
0·02 |
|
<0·12 ?g/mL |
4 |
2·55 |
3 |
4·98 |
0·58; p=0·028 |
|
|
0·12–2·00 ?g/mL |
45 |
3·88 |
46 |
2·63 |
1·24; p=0·06 |
|
|
>2·00 ?g/mL* |
10 |
8·20 |
4 |
3·66 |
2·36; p=<0·0001 |
|
|
MIC against gatifloxacin (culture-confirmed population) |
|
|
|
|
|
0·049 |
|
≤1·00 ?g/mL |
49 |
3·76 |
49 |
2·75 |
1·17; p=0·15 |
|
|
>1·00 ?g/mL |
10 |
8·20 |
4 |
3·66 |
2·36; p<0·0001 |
|
Safety
- No serious events were reported.
- 122 adverse events occurred in the gatifloxacin group
- 120 in the ceftriaxone group no serious adverse events
- The most common adverse events reported were
- Vomiting (in 27 [23%] of 120 patients receiving gatifloxacin and 17 [14%] of 119 receiving ceftriaxone; p=0.13)
- Cough (which did significantly differ between groups: in 15 [12%] patients receiving gatifloxacin and 29 [24%] patients receiving ceftriaxone; p=0?02).
Conclusion
- In culture-negative patients with suspected enteric fever gatifloxacin out-performed ceftriaxone with median fever clearance times of 1.12 days and 3.03, respectively
- Ceftriaxone was suboptimum in a high proportion of patients with culture-negative enteric fever
Reference
Lancet Infect Dis. 2016; 16: 535–45
