s6.2 Typhoid-Fever Appendix

Appendix
Figure 1: Literature search for relevant systematic reviews. ....................................................................... 2

Table 1: Systematic Reviews Search Strategy ............................................................................................... 3
Table 2: Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria used
(description) .................................................................................................................................................. 5
Table 3: GRADE assessment-I ....................................................................................................................... 7
Table 3.1: Ciprofloxacin/Ofloxacin versus Chloramphenicol in the treatment of enteric fever .............. 7
Table 3.2: Gatifloxacin versus Chloramphenicol in the treatment of enteric fever ................................. 8
Table 3.3: Ciprofloxacin/Ofloxacin versus Cotrimoxazole in the treatment of enteric fever ................... 9
Table 3.4: Ciprofloxacin/Ofloxacin versus Ampicillin/Amoxicillin in the treatment of enteric fever ..... 10
Table 3.5: Ciprofloxacin/Ofloxacin versus Cefixime in the treatment of enteric fever .......................... 11
Table 3.6: Gatifloxacin versus Cefixime in the treatment of enteric fever ............................................ 13
Table 3.7: Ciprofloxacin/Ofloxacin versus Ceftriaxone in the treatment of enteric fever ..................... 14
Table 3.8: Ciprofloxacin/Ofloxacin versus Azithromycin in the treatment of enteric fever ................... 15
Table 3.9: Gatifloxacin versus Azithromycin in the treatment of enteric fever..................................... 17
Table 4: GRADE assessment-II .................................................................................................................... 18
Table 4.1: Azithromycin versus Chloramphenicol in the treatment of enteric fever ............................. 18
Table 4.2: Azithromycin versus Fluoroquinolones in the treatment of enteric fever ............................ 18
Table 4.3: Azithromycin versus Ceftriaxone in the treatment of enteric fever ...................................... 19
Table 5: Drug doses (Systematic reviews) .................................................................................................. 21
Figure 2: Literature search for additional RCTs .......................................................................................... 23
Table 6: Cochrane Risk of Bias assessment for additional RCTs ................................................................. 24
Table 7: Study characteristics and outcomes of additional RCTs ............................................................... 25
Figure 3: Flow chart- Guidelines ................................................................................................................. 27
Table 8: Search Strategy for Clinical Practice Guidelines............................................................................ 28
Table 9: AGREE II assessment ..................................................................................................................... 31
Table10: Current recommendations ........................................................................................................... 32
Table 10.1: Background document: The diagnosis, treatment and prevention of typhoid fever, WHO
2003 ........................................................................................................................................................ 32
Table 10.2: Evidence for Technical update of pocket book recommendations, Recommendations for
management of common childhood conditions, WHO 2012 ................................................................. 33
1
Figure 1: Literature search for relevant systematic reviews.
Medline Embase Cochrane

Identification
94 192 20
306 Records Identified

Discarded Duplicates, n=88
218 Records Screened by

Title and Abstract
Screening
Excluded, n=193
25 Articles accessed in Full-

Text for Eligibility
Excluded, n=13
Eligibility
Excluded n=10
Criteria:
12 Articles included for • Full text not available: 2
evaluation • Review protocol, no data: 1
• Withdrawn Cochrane reviews: 2
• Duplicate data: 1
• Cochrane reviews superseded by
Included
latest version, n =3
2 Articles Included in final • Duplicate information with included
assessment reviews and RCTs, n=1
2
Table 1: Systematic Reviews Search Strategy
1. Database: Medline (Ovid MEDLINE® Epub Ahead of Print, In-Process & Other Non-Indexed
Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) 1946 to present
Search Strategy:
1 meta-analysis.pt. (96288)
2 meta-analysis/ or systematic review/ or meta-analysis as topic/ or "meta analysis (topic)"/ or
"systematic review (topic)"/ or exp technology assessment, biomedical/ (123251)
3 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or
overview*))).ti,ab,kf,kw. (150749)
4 ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or
overview*))).ti,ab,kf,kw. (9372)
5 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool*
adj3 analy*)).ti,ab,kf,kw. (22116)
6 (data synthes* or data extraction* or data abstraction*).ti,ab,kf,kw. (22583)
7 (handsearch* or hand search*).ti,ab,kf,kw. (8330)
8 (random effect* or fixed effect*).ti,ab,kf,kw. (44886)
9 (met analy* or metanaly*).ti,ab,kf,kw. (331)
10 (meta-analy* or metaanaly* or systematic review*).mp,hw. (245076)
11 (medline or cochrane or pubmed or medlars or embase or cinahl).ti,ab,hw. (181899)
12 (cochrane or (health adj2 technology assessment) or evidence report).jw. (18368)
13 (comparative adj3 (efficacy or effectiveness)).ti,ab,kf,kw. (11789)
14 (outcomes research or relative effectiveness).ti,ab,kf,kw. (8316)
15 Typhoid Fever/ (10779)
16 Paratyphoid Fever/ (2318)
17 typhoid.ti,ab. (11419)
18 paratyphoid.ti,ab. (1641)
19 "enteric fever*".ti,ab. (1613)
20 "abdominal typhus".ti,ab. (121)
21 "salmonella typhi infection*".ti,ab. (166)
22 "salmonella paratyphi infection*".ti,ab. (10)
23 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 (391582)
24 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 (17163)
25 23 and 24 (107)
26 25 (107)
27 limit 26 to (english language and yr="1990 -Current") (94)
2. Database: Embase 1974 to present
Search Strategy:
1 meta-analysis/ or systematic review/ or meta-analysis as topic/ or "meta analysis (topic)"/ or
"systematic review (topic)"/ or exp technology assessment, biomedical/ (332297)
2 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or
overview*))).ti,ab,kw. (188337)
3 ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or
overview*))).ti,ab,kw. (11002)
3
4 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool*
adj3 analy*)).ti,ab,kw. (31471)
5 (data synthes* or data extraction* or data abstraction*).ti,ab,kw. (27911)
6 (handsearch* or hand search*).ti,ab,kw. (10125)
7 (random effect* or fixed effect*).ti,ab,kw. (59322)
8 (met analy* or metanaly*).ti,ab,kw. (777)
9 (meta-analy* or metaanaly* or systematic review*).mp,hw. (392927)
10 (medline or cochrane or pubmed or medlars or embase or cinahl).ti,ab,hw. (241287)
11 (cochrane or (health adj2 technology assessment) or evidence report).jw. (25663)
12 (comparative adj3 (efficacy or effectiveness)).ti,ab,kw. (16990)
13 (outcomes research or relative effectiveness).ti,ab,kw. (12118)
14 typhoid fever/ (9704)
15 paratyphoid fever/ (355)
22 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 (574941)
23 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 (12688)
24 22 and 23 (202)
25 24 (202)
3. The Cochrane Library: Cochrane Database of Systematic Reviews Issue 1 of 12, January 2019
#1 MeSH descriptor: [Typhoid Fever] explode all trees 244

#2 MeSH descriptor: [Paratyphoid Fever] explode all trees 30
#3 typhoid 592
#4 paratyphoid 164
#5 "enteric fever*" 84
#6 "abdominal typhus" 0
#7 "salmonella typhi infection*" 2
#8 "salmonella paratyphi infection*" 0
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 622
Search Results
Ovid Medline 94
Ovid Embase 192
The Cochrane Library 20
Total 306
Total after deduplication 218
4
Table 2: Grading of Recommendations, Assessment, Development and Evaluation
(GRADE) criteria used (description)
For each outcome, evidence from the systematic reviews were retrieved and assessed for the quality of
evidence using GRADE (Grading of Recommendations, Assessment, Development and Evaluation)
approach. The quality of data was evaluated based on the following criteria according to WHO guideline
for guideline development.
 Limitations of study in terms of design, conduct and analysis

o Limitations were considered in terms of study design, allocation concealment, blinding,
and loss to follow-up. 0.5 point deduction was made for the limitation in each item.
Although most of the studies did not included intention-to-treat analysis as they excluded
culture negative patients, no deductions were made because it is unlikey that this would
have biased the results in a given direction.
 Precision of results
o Precision were evaluated based on the confidence interval around the estimate of the
effect. Deductions of 0.5 or 1 points were made based on the magnitude of impreciseness
of effect.
 Consistency
o Consistency of results across the studies was evaluated based on the differences in
direction, size and significance of the difference in effects. Deduction of 0.5 or 1 points
were made based on the magnitude of inconsistency. 1 point deduction was made for the
effect based on only one study, 0.5 deduction if based on only one large trial.
 Generalizability/Directness
o Deduction of 0.5 or 1 point was made based on the generalizability of evidence with
respect to population of interest, antimicrobial drug resistance, interventions and its
application.
 Reporting bias.
o Studies were evaluated for the reporting of all the outcomes they have measured.
Downgrading of quality was done by 0.5 or 1 labels for selective reporting of outcomes,
Additional considerations included dose-response gradient, direction of plausible bias and magnitude of
the effect. The quality of evidence were then categorized into high, moderate, low or very low as defined
in the table below (Adapted from WHO guidelines for guideline development)
Criteria for quality assessment of quality of systematic reviews using GRADE approach.
Quality Definition Implication

High The guideline development group is very Further research is very unlikely to
confident that the true effect lies close to that change confidence in the estimate of
of the estimate of the effect effect
Moderate The guideline development group is Further research is likely to have an
moderately confident in the effect estimate: important impact on confidence in the
the true effect is likely to be close to the estimate of effect and may change the
estimate of the effect, but there is a possibility estimate
that it is substantially different
Low Confidence in the effect estimate is limited: Further research is very likely to have
the true effect may be substantially different an important impact on confidence in
from the estimate of the true effect the estimate of effect and is unlikely to
5
change the estimate
Very low The group has very little confidence in the Any estimate of effect is very uncertain
effect estimate: the true effect is likely to be
substantially different from the estimate of the
effect
6
Table 3: GRADE assessment-I
Table 3.1: Ciprofloxacin/Ofloxacin versus Chloramphenicol in the treatment of enteric fever
Population: Patients with typhoid fever
Intervention: Ciprofloxacin/Ofloxacin versus chloramphenicol
Reference: Effa et. al. [2011]
Limitations in methods Precisio Consiste Generaliza Report Overa Pooled
Based on methods of studies with ≥50% of the total weight of evidence n ncy bility ing ll effect
Outcome No. Tota Eve Desi Allocati Blind Loss bias qualit size
of l nts gn on ing to y (95%
studi sam total conceal follo CI)
es ple ment w-up
Ciprofloxacin versus chloramphenicol
FCT 2 147 NA RCT Unclear No No No No Mostly No Moder Mean

0 -0.5 -0.5 0 impreci inconsist adults, 0 ate differe
sion ency inadequate (Total nce
0 0 MDR/NaR -1.5) -
data 62.46(
-0.5 -75.52,
-
49.39)
Clinical 4 293 13 RCT Unclear No No Some Inconsist Mostly No Low RR
failure 0 -0.5 -0.5 0 Impreci ency adults, 0 (Total 0.24
sion -0.5 Inadequate -2.5) (0.07,
-0.5 MDR/NaR 0.82)
data
-0.5
Microbiolo 2 142 9 RCT Unclear No No High Inconsist Mostly No Low RR
gical 0 -0.5 -0.5 0 impreci ency adults, 0 (Total 0.05
failure sion 0 Inadequate -2.5 (0.00,
-1 MDR/NaR 0.81)
data
-0.5
Relapse 4 292 7 RCT Unclear No No Some Inconsist Mostly No Low RR
0 -0.5 -0.5 0 Impreci ency adults, 0 (Total 0.15
sion 0 Inadequate -2) (0.02,
-0.5 MDR/NaR 1.15)
data
-0.5
Serious 2 153 4 RCT Unclear No No High Inconsist Mostly No Very RR
adverse 0 -0.5 -0.5 0 Impreci ency adults, 0 Low 0.99
events sion -0.5 Inadequate (Total (0.18,
-1 MDR/NaR -3) 5.52)
data
-0.5
Non 4 253 56 RCT Unclear No No No Inconsist Mostly No Low RR 1
serious -0.5 -0.5 0 impreci ency adults, 0 (Total (0.61,
adverse sion -0.5 Inadequate -2.5) 1.64)
events 0.5 MDR/NaR
data
-0.5
Ofloxacin versus chloramphenicol
FCT 2 140 NA RCT Unclear No No No No Mostly No Moder Mean

0 -0.5 -0.5 0 impreci inconsist adults, 0 ate differe
sion ency inadequate (Total nce -
0 0 MDR/NaR -1.5) 75.85
data (-
-0.5 88.52,
-
63.17)
7
Clinical 4 247 13 RCT Unclear No No Some No Mostly No Low RR
failure 0 -0.5 -0.5 0 Impreci inconsist adults, 0 (Total 0.15
sion ency Inadequate -2) (0.03,
-0.5 0 MDR/NaR 0.64)
data
-0.5
Microbiolo 3 199 13 RCT Unclear No No Some No Mostly No Low RR
gical 0 -0.5 -0.5 0 impreci inconsist adults, 0 (Total 0.16
failure sion ency Inadequate -2) (0.02,
-0.5 0 MDR/NaR 1.07)
data
-0.5
Relapse 2 149 3 RCT Unclear No No High No Mostly No Low RR
0 -0.5 -0.5 0 impreci inconsist adults, 0 (total - 0.14
sion ency Inadequate 2.5) (0.01,
-1 -0 MDR/NaR 2.65)
data
-0.5
Serious 1 50 0 RCT Allocati No No High Only one Mostly No Very No
adverse 0 on -0.5 0 impreci study adults, 0 low estima
events conceale sion -1 Inadequate (Total te
d -1 MDR/NaR -3)
0 data
-0.5
Non 4 207 41 RCT Unclear No No No Inconsist Mostly No Low RR
serious 0 -0.5 -0.5 0 impreci ency adults, 0 (Total 1.06
adverse sion -0.5 Inadequate -2) (0.6,
events 0 MDR/NaR 1.87)
data
-0.5
- All the studies excluded culture negative patients and thus did not do ‘intention to treat’ analysis.
However, this applied to both intervention and comparator. It is unlikely that this would have
biased the results in a given direction. Therefore no points were deducted.
Table 3.2: Gatifloxacin versus Chloramphenicol in the treatment of enteric fever

Intervention: Gatifloxacin versus chloramphenicol
Limitations in methods Precisio Consiste Generaliza Report Overal Pooled
Based on methods of studies with ≥50% of the total weight of evidence n ncy bility ing l effect
Outcome No. Tota Eve Desi Allocati Blindi Loss bias qualit size
of l nts gn on ng to y (95%
es ple ment w-up
FCT 0
Clinical 1 352 18 RCT Allocati No No No One Adults and No Moder OR

failure 0 on -0.5 0 Impreci study children, 0 ate 0.79(0.
conceale sion but High MDR (Total 32,
d 0 large prevalence -1) 1.96)
0 sample area, study
size after 2010
-0.5 0
Microbiolo 1 352 2 RCT Allocati No No High One Adults and No Low OR
gical 0 on -0.5 0 Impreci study children, 0 (Total 4.94
failure conceale sion but High MDR -2) (0.24,
d -1 large prevalence 102.24
0 sample area, study )
size after 2010
-0.5 0
8
Relapse 1 352 11 RCT Allocati No No Some One Adults and No Moder OR
0 on -0.5 0 Impreci study children, , 0 ate 0.56
conceale sion but High MDR (Total (0.17,
d -0.5 large prevalence -1.5) 1.90)
size after 2010
-0.5 0
Serious 0
adverse
events
Non 1 844* 158 RCT Allocati No No No One Adults and No Moder OR
serious 0 on -0.5 0 Impreci study children, , 0 ate 0.58
adverse conceale sion but High MDR (Total (0.44,
events d 0 large prevalence -1) 0.78)
size after 2010
-0.5 0
-ITT performed, hence no points deducted.
* Analysis performed on ITT (culture positive and negative patients together)
Table 3.3: Ciprofloxacin/Ofloxacin versus Cotrimoxazole in the treatment of enteric fever

Intervention: Ciprofloxacin/Ofloxacin versus cotrimoxazole
Limitations in methods Precisio Consiste Generaliza Report Over Pooled
Based on methods of studies with ≥50% of the total weight of evidence n ncy bility ing all effect
Outcome No. Tota Eve Desi Allocati Blindi Loss bias quali size
of l nts gn on ng to ty (95%
es ple ment w-up
Ciprofloxacin versus cotrimoxazole
FCT 1 92 NA RCT Unclear No No Some Only one Mostly No Very Mean

0 -0.5 -0.5 0 Impreci study adults, 0 low differe
sion -1 inadequate (total nce -
-0.5 MDR/NaR -3) 84.00
data (-
-0.5 99.72,
-68.28)
Clinical 2 132 15 RCT Unclear No No Some No Mostly No Low RR
failure 0 -0.5 -0.5 0 Impreci inconsist adults, 0 (Tot 0.06
sion ency inadequate al -2) (0.01,
-0.5 0 MDR/NaR 0.43)
data
-0.5
Microbiolo 2 132 15 RCT Unclear No No Some No Mostly No low RR
gical 0 -0.5 -0.5 0 Impreci inconsist adults, 0 (Tot 0.06
failure sion ency inadequate al -2) (0.01,
-0.5 0 MDR/NaR 0.43)
data
-0.5
Relapse 1 92 0 RCT Unclear No No No No Mostly No Very No
0 -0.5 -0.5 0 estimate estimate adults, 0 low estimat
-1 -1 inadequate (total e
MDR/NaR -3.5)
data
-0.5
Serious 0
adverse
events
9
Non 2 110 30 RCT Unclear No No Some No Mostly No Low RR
serious 0 -0.5 -0.5 0 imprecis inconsist adults, 0 (Tot 0.62
adverse ion ency inadequate al -2) (0.34,
events -0.5 0 MDR/NaR 1.12)
data
-0.5
Ofloxacin versus cotrimoxazole
FCT 1 92 NA RCT Unclear No No Some Only one Mostly No Very Mean

0 -0.5 -0.5 0 Impreci study adults, 0 low differe
sion -1 inadequate (total nce
-0.5 MDR/NaR -3) -96.00
data (-
-0.5 115.64
,-
76.36)
Clinical 1 99 13 RCT Unclear No No Large Only one Mostly No Very RR
failure 0 -0.5 -0.5 0 Impreci study adults, 0 low 0.04
sion -1 inadequate (Tot (0.00,
-1 MDR/NaR al - 0.59)
data 3.5)
-0.5
Microbiolo 1 99 13 RCT Unclear No No Large Only one Mostly No Very RR
gical 0 -0.5 -0.5 0 Impreci study adults, 0 low 0.04
failure sion -1 inadequate (Tot (0.00,
-1 MDR/NaR al - 0.59)
data 3.5)
-0.5
Relapse 1 89 0 RCT Unclear No No No No Mostly No Very No
0 -0.5 -0.5 0 estimate estimate adults, 0 low estimat
-1 -1 inadequate (total e
MDR/NaR -3.5)
data
-0.5
Serious 0
adverse
events
Non 1 67 23 RCT Unclear No No Some Only one Mostly No Very RR
serious 0 -0.5 -0.5 0 imprecis study adults, 0 low 0.92
adverse ion -1 inadequate (Tot (0.46,
events -0.5 MDR/NaR al -3) 1.83)
data
-0.5
Table 3.4: Ciprofloxacin/Ofloxacin versus Ampicillin/Amoxicillin in the treatment of enteric

fever
Intervention: Ofloxacin versus ampicillin/amoxycillin
Limitations in methods Precisio Consisten Generaliza Report Over Pool
Based on methods of studies with ≥50% of the total weight of evidence n cy bility ing all ed
Outcome No. Tota Eve Desi Allocatio Blindi Loss bias quali effec
of l nts gn n ng to ty t
studi sam total conceal follo size
es ple ment w-up (95
%
10
CI)
Ofloxacin versus ampicillin
FCT 0
Clinical 1 40 5 RCT Unclear No No Some Only one Adults only No Ver RR

failure 0 -0.5 -0.5 0 Imprecis study -0.5 0 low 0.09
ion -1 (Tota (0.0
-0.5 l -3) 1,
1.54
)
Microbiolo 1 50 9 RCT Unclear No No High Only one Adults only No Ver RR
gical 0 -0.5 -0.5 0 imprecis study -0.5 0 low 0.13
failure ion -1 (Tota (0.0
-1 l- 2,
3.5) 2.60
)
Relapse 0
Serious 0
adverse
events
Non 0
serious
adverse
events
Ofloxacin versus amoxicillin
FCT
Clinical 1 50 9 RCT Unclear No No Some Only one Adults only No Ver RR

failure 0 -0.5 -0.5 0 Imprecis study -0.5 0 low 0.13
ion -1 (Tota (0.0
-0.5 l -3) 2,
0.93
)
Microbiolo 1 50 9 RCT Unclear No No Some Only one Adults only No Ver RR
gical 0 -0.5 -0.5 0 Imprecis study -0.5 0 low 0.13
failure ion -1 (Tota (0.0
-0.5 l -3) 2,
0.93
)
Relapse 0
Serious 0
adverse
events
Non 2 90* 16 RCT Unclear No No Some Some Adults only No Low RR
serious 0 -0.5 -0.5 0 Imprecis inconsiste -0.5 0 (Tota 0.33
adverse ion ncy l- (0.1
events* -0.5 -0.5 2.5) 2,
0.93
)
- * This pools two trials (Flores 1994 MEX and Yousaf 1992 PAK).
Table 3.5: Ciprofloxacin/Ofloxacin versus Cefixime in the treatment of enteric fever

Intervention: Ciprofloxacin/Ofloxacin versus cefixime
11
es ple ment w-up
Ciprofloxacin versus cefixime
FCT 1 94 NA RCT Unclear No No No Only one Mostly No Low Mean

0 -0.5 -0.5 0 imprecis study adults, 0 (Tot differe
ion -1 inadequate al - nce
0 MDR/NaR 2.5) -12.00
data (-
-0.5 24.42,
-0.42)
Clinical 1 94 0 RCT Unclear No No No Only one Mostly No Very No
failure 0 -0.5 -0.5 0 estimate study adults, 0 low estimat
-1 -1 inadequate (Tot e
MDR/NaR al -
data 3.5)
-0.5
Microbiolo 1 94 0 RCT Unclear No No No Only one Mostly No Very No
gical 0 -0.5 -0.5 0 estimate study adults, 0 low estimat
failure -1 -1 inadequate (Tot e
MDR/NaR al -
data 3.5)
-0.5
Relapse 1 94 0 RCT Unclear No No No Only one Mostly No Very No
0 -0.5 -0.5 0 estimate study adults, 0 low estimat
-1 -1 inadequate (Tot e
MDR/NaR al -
data 3.5)
-0.5
Serious `0
adverse
events
Non 1 94 29 RCT Unclear No No No Only 1 Mostly No Low RR
serious 0 -0.5 -0.5 0 imprecis study adults, 0 (Tot 1.57
adverse ion -1 inadequate al - (0.83,
events 0 MDR/NaR 2.5) 2.59)
data
-0.5
Ofloxacin versus cefixime
FCT 1 91 NA RCT Unclear No No No Only one Mostly No Low Mean

0 -0.5 -0.5 0 imprecis study adults, 0 (Tot differe
ion -1 inadequate al- - nce
0 MDR/NaR 2.5) -24.00
data (-
-0.5 41.46,
-6.54)
Clinical 2 173 9 RCT Allocati No No Some Some Mostly No Low RR
failure 0 on -0.5 0 Impreci inconsist adults, 0 (Tot 0.14
conceale sion ency inadequate al -2) (0.02,
d -0.5 -0.5 MDR/NaR 1.11)
0 data
-0.5
Microbiolo 2 173 13 RCT Allocati No No Some Some Mostly No Low RR
gical 0 on -0.5 0 imprecis inconsist adults, 0 (Tot 0.23
failure conceale ion ency inadequate al -2) (0.01,
d -0.5 -0.5 MDR/NaR 4.66)
0 data
-0.5
Relapse 2 131 1 RCT Allocati No No High Some Mostly No Low RR
0 on -0.5 0 imprecis inconsist adults, 0 (total 0.33
conceale ion ency inadequate -2.5) (0.01,
12
d -1 -0.5 MDR/NaR 7.72)
0 data
-0.5
Serious 1 82 1 RCT Unclear No No High Only one Mostly No Very RR
adverse 0 -0.5 0 imprecis study adults, 0 low 3.46,
events ion -1 inadequate (Tot (0.15,
-1 MDR/NaR al -3) 82.56)
data
-0.5
Non 1 91 24 RCT Unclear No No No Only one Mostly No Low RR 1.7
serious 0 -0.5 -0.5 0 imprecis study adults, 0 (Tot (0.83,
adverse ion -1 inadequate al - 3.49)
events 0 MDR/NaR 2.5)
data
-0.5
Table 3.6: Gatifloxacin versus Cefixime in the treatment of enteric fever

Intervention: Gatifloxacin versus cefixime
Limitations in methods Precisio Consiste Generaliza Report Overal Pool
Based on methods of studies with ≥50% of the total weight of evidence n ncy bility ing l ed
Outcome No. Tota Eve Desi Allocati Blindi Loss bias quality effec
of l nts gn on ng to t size
studi sam total conceal follo (95%
es ple ment w-up CI)
FCT 0
Clinical 1 158 20 RCT Allocati No No, Some One Adults and No Moder OR
failure 0 on -0.5 0 Impreci study children, 0 ate 0.04
conceale sion but large high MDR (Total (0.01
d -0.5 sample prevalence -1.5) ,
0 size area, 0.31)
-0.5 published
in 2007
0
gical 0 on -0.5 0 Impreci study children, 0 (Total 0.27
failure conceale sion but large high MDR -2) (0.01
d -1 sample prevalence ,
0 size area, 6.43)
-0.5 published
in 2007
0
Relapse 1 138 8 RCT Allocati No No Some One Adults and No Moder OR
0 on -0.5 0 Impreci study children, 0 ate 0.20
conceale sion but large high MDR (Total (0.04
d -0.5 sample prevalence -1.5) ,
0 size area, 0.93)
-0.5 published
in 2007
0
Serious 1 169 3 RCT Allocati No No High One Adults and No Low OR
adverse 0 on -0.5 0 Impreci study children, 0 (Total 1.67
events conceale sion but large high MDR -2) (0.15
d -1 sample prevalence ,
0 size area, 18.11
13
-0.5 published )
in 2007
0
Non 1 169 26 RCT Allocati No No High One Adults and No Low OR
serious 0 on -0.5 0 Impreci study children, 0 (Total 20.92
adverse conceale sion but large high MDR -2) (2.90
events d -1 sample prevalence ,
0 size area, 150.9
-0.5 published 0)
in 2007
0
- The trial was stopped early by the data management and safety committee for large difference observed
in primary endpoint. No point was deducted because of the large sample size already attained at the time
of stopping of the trail.
Table 3.7: Ciprofloxacin/Ofloxacin versus Ceftriaxone in the treatment of enteric fever

Intervention: Ciprofloxacin/Ofloxacin versus ceftriaxone
Outcome No. Tota Eve Desi Allocati Blindi Loss bias qualit size
of l nts gn on ng to y (95%
es ple ment w-up
Ciprofloxacin versus ceftriaxone
FCT 0
Clinical 1 42 6 RCT Unclear No No Some Only Adult only, No Very RR

failure 0 -0.5 -0.5 0 impreci one >50% 0 low 0.08
sion study MDR (Total (0.01,
-0.5 -1 -0.5 -3) 1.41)
Microbiolo 1 42 0 RCT Unclear No No No Only Adult only, No Very No
gical 0 -0.5 -0.5 0 estimate one >50% 0 low estimat
failure -1 study MDR (Total e
-1 -0.5 -3.5)
Relapse 1 42 1 RCT Unclear No No Some Only Adult only, No Very RR
0 -0.5 -0.5 0 impreci one >50% 0 low 0.37
sion study MDR (Total (0.02,
-0.5 -1 -0.5 -3) 8.48)
Serious `0
adverse
events
Non 0
serious
adverse
events
Ofloxacin versus ceftriaxone
FCT 1 47 NA RCT Allocati No No No Only Adults No Moder Mean

0 on -0.5 0 impreci one only, High 0 ate differe
conceale sion study MDR (Total nce
d 0 -1 prevalence - -1.5) -
0 area, no 115.00
NaR (-
-0.5 150.67
14
,-
79.33)
Clinical 1 47 6 RCT Allocati No No Some Only Adults No Low RR
failure 0 on -0.5 0 Impreci one only, High 0 (Total 0.09
conceale sion study MDR -2) (0.01,
d -0.5 -1 prevalence 1.46)
0 area, no
NaR
-0.5
Microbiolo 1 47 1 RCT Allocati No No Some Only Adult only, No Low RR
gical 0 on -0.5 0 impreci one High MDR 0 (Total 0.38
failure conceale sion study prevalence -2) (0.02,
d -0.5 -1 area, no 8.8)
0 NaR
-0.5
Relapse 1 23 1 RCT Allocati No No Some Only Adult only, No Very RR
0 on -0.5 0 impreci one High MDR 0 low 0.36
conceale sion study prevalence (Total (0.02,
d -0.5 -1 area, no -2.5) 8.04)
0 NaR
-0.5
Serious O
adverse
events
Non 1 47 3 RCT Allocati No No Some Only Adult only, No Very RR
serious 0 on -0.5 0 impreci one High MDR 0 low 0.57
adverse conceale sion study prevalence (Total (0.06,
events d -0.5 -1 area, no -2.5) 5.85)
0 NaR
-0.5
Table 3.8: Ciprofloxacin/Ofloxacin versus Azithromycin in the treatment of enteric fever

Intervention: Ciprofloxacin/Ofloxacin versus azithromycin
es ple ment w-up
Ciprofloxacin versus azithromycin
FCT 1 64 NA RCT Allocati No No No Only one Adults No Low Mean

0 on -0.5 0 impreci study only, High 0 (Total differe
conceale sion -1 MDR -2) nce -
d 0 prevalence 12.00
0 area (-
-0.5 24.39,
-0.39)
Clinical 1 64 0 RCT Allocati No No No Only one Adults No Very No
failure 0 on -0.5 0 estimate study only, High 0 low estima
conceale -1 -1 MDR (Total te
d prevalence -3)
0 area
-0.5
15
Microbiolo 1 64 0 RCT Allocati No No No Only one Adults No Very No
gical 0 on -0.5 0 estimate study only, High 0 low estima
failure conceale -1 -1 MDR (Total te
d prevalence -3)
0 area
-0.5
Relapse 1 64 0 RCT Allocati No No No Only one Adults No Very No
0 on -0.5 0 estimate study only, High 0 low estima
conceale -1 -1 MDR (Total te
d prevalence -3)
0 area
-0.5
Serious 0
adverse
events
Non 1 64 31 RCT Allocati No No No Only one Adult only, No Low RR
serious 0 on -0.5 0 impreci study Inadequate 0 (Total 1.21
adverse conceale sion -1 MDR/NaR -2) (0.73,
events d 0 data 1.99)
0 -0.5
Ofloxacin versus azithromycin
FCT 2 213 NA RCT Allocati No No Some Inconsist Children No Moder Mean

0 on -0.5 0 impreci ency and adults, 0 ate differe
conceale sion -0.5 High (Total nce
d -0.5 MDR/NA -1.5) 30.41
0 R (-
prevalence 22.12,
area 82.93)
0
Clinical 2 213 42 RCT Allocati No No No No Children No High RR 2.2
failure 0 on -0.5 0 impreci inconsist and adults, 0 (Total (1.23,
conceale sion ency High -0.5) 3.94)
d 0 0 MDR/NA
0 R
prevalence
area
0
Microbiolo 2 213 7 RCT Allocati No No Some Inconsist Children No Moder RR
gical 0 on -0.5 0 impreci ency and adults, 0 ate 1.32
failure conceale sion 0.5 High (Total (0.30,
d 0.5 MDR/NA -0.5) 5.76)
0 R
prevalence
area
0
Relapse 2 163 2 RCT Allocati No No High Inconsist Children No Low RR
0 on -0.5 0 impreci ency and adults, 0 (Total 6.11
conceale sion -0.5 High -2) (0.31,
d -1 MDR/NA 119.33
0 R )
prevalence
area
0
Serious 1 88 2 RCT Allocati No No High Only one Children No Low RR
adverse 0 on -0.5 0 impreci study and adults, 0 (Total 1.00
events conceale sion -1 High -2.5) (0.06,
d -1 MDR/NA 15.49)
0 R
prevalence
area
0
Non 2 213 24 RCT Allocati No No Some Inconsist Children No Moder RR
serious 0 on -0.5 0 impreci ency and adults, 0 ate 0.56
adverse conceale sion 0.5 High (Total (0.27,
events d -0.5 MDR/NA -1.5) 1.16)
0 R
prevalence
area
16
0
Table 3.9: Gatifloxacin versus Azithromycin in the treatment of enteric fever

Intervention: Gatifloxacin versus azithromycin
Limitations in methods Precisio Consiste Generaliza Report Overal Pool
Based on methods of studies with ≥50% of the total weight of evidence n ncy bility ing l ed
Outcome No. Tota Eve Desi Allocati Blindi Loss bias quality effec
of l nts gn on ng to t
studi sam total conceal follo size
es ple ment w-up (95
%
CI)
FCT 0
Clinical 1 287 12 RCT Allocati No No Some One Adults and No Moder OR

failure 0 on -0.5 0 Imprecis study children, 0 ate 0.98
conceale ion but large high MDR (Total (0.3
d -0.5 sample prevalence -1.5) 2,
0 size area, 2.96
-0.5 published )
in 2008
0
gical 0 on -0.5 0 Imprecis study children, 0 (Total 0.64
failure conceale ion but large high MDR -2) (0.1
d -1 sample prevalence 1,
0 size area, 3.79
-0.5 published )
in 2008
0
Relapse 1 274 4 RCT Allocati No No High One Adults and No Low OR
0 on -0.5 0 Imprecis study children, 0 (Total 0.12
conceale ion but large high MDR -2) (0.0
d -1 sample prevalence 1,
0 size area, 2.20
-0.5 published )
in 2008
0
Serious 0
adverse
events
Non 1 287 3 RCT Allocati No No High One Adults and No Low OR
serious 0 on -0.5 0 Imprecis study children, 0 (Total 1.96
adverse conceale ion but large high MDR -2) (0.1
events d -1 sample prevalence 8,
0 size area, 21.3
-0.5 published 6)
in 2008
0
17
Table 4: GRADE assessment-II
Table 4.1: Azithromycin versus Chloramphenicol in the treatment of enteric fever
Intervention: Azithromycin versus chloramphenicol
es ple ment w-up
FCT 1 77 NA RCT Allocati No No Some Only Adults No Low Mean
0 on -0.5 0 Impreci one only, MDR 0 (Tota differe
conceale sion study around l- nce
d -0.5 -1 10%, 2.5) -4.8
0 published (-
in 1999 34.98,
-0.5 25.38)
Clinical 1 77 2 RCT Allocati No No Some Only Adults No Low OR
failure 0 on -0.5 0 Impreci one only, MDR 0 (Tota 0.16
conceale sion study around l- (0.01,
d -0.5 -1 10%, 2.5) 3.4)
0 published
in 1999
-0.5
Microbiolo 1 77 1 RCT Allocati No No Some Only Adults No Low OR
gical 0 on -0.5 0 Impreci one only, MDR 0 (Tota 0.27
failure conceale sion study around l- (0.01,
d -0.5 -1 10%, 2.5) 6.85)
0 published
in 1999
-0.5
Relapse 0
Serious 0
adverse
events
Non 1 77 5 RCT Allocati No No Some Only Adults No :ow OR
serious 0 on -0.5 0 Impreci one only, MDR 0 (Tota 10.41
adverse conceale sion study around l- (0.56,
events d -0.5 -1 10%, 2.5) 195.25
0 published )
in 1999
-0.5
Table 4.2: Azithromycin versus Fluoroquinolones in the treatment of enteric fever

Intervention: Azithromycin versus fluroquinolones (all fluroquinolones)
18
es ple ment w-up
FCT 4 564 NA RCT Allocati No No Some Some Both No Moder Mean
0 on -0.5 0 impreci inconsist adults and 0 ate differe
conceale sion ency children, (Total nce -
d -0.5 -0.5 High -1.5) 9.8 (-
0 MDR, 34.15.
NaR 14.56)
0
Clinical 4 564 54 RCT Allocati No No No Some Both No Moder OR
failure 0 on -0.5 0 impreci inconsist adults and 0 ate 0.48
conceale sion ency children, (Total (0.26,
d 0 -0.5 High -1) 0.89)
0 MDR,
NaR
0
Microbiolo 4 564 12 RCT Allocati No No Some Some Both No Moder OR
gical 0 on -0.5 0 impreci inconsist adults and 0 ate 1.01
failure conceale sion ency children, (Total (0.32,
d 0.5 -0.5 High -1.5) 3.19)
0 MDR,
NaR
0
Relapse 4 491 6 RCT Allocati No No Some No Both No Moder OR
0 on -0.5 0 Impreci inconsist adults and 0 ate 0.13
conceale sion ency children, (Total (0.01,
d -0.5 0 High -1) 01.08)
0 MDR,
NaR
0
Serious 3 Incomplete information
adverse
events
Non 0 1
serious
adverse
events
Table 4.3: Azithromycin versus Ceftriaxone in the treatment of enteric fever

Intervention: Azithromycin versus ceftriaxone
Limitations in methods Precisio Consiste Generaliza Report Overa Pooled
Based on methods of studies with ≥50% of the total weight of evidence n ncy bility ing ll effect
es ple ment w-up
FCT 2 132 NA RCT Allocati No No Some No Adults No Moder Mean
0 on -0.5 0 impreci inconsist only, 0 ate differe
conceale sion ency MDR<20 (Total nce -
d -0.5 0 %, -1.5) 9.12
0 published (-1.11,
2000, 2005 19.36)
-0.5
19
Clinical 2 132 7 RCT Allocati No No Some No Adults No Low OR
failure 0 on -0.5 0 impreci inconsist only, 0 (Total 2.58
conceale sion ency MDR<20 -2) (0.48,
d -1 0 %, 13.87)
0 published
2000, 2004
-0.5
Microbiolo 2 132 3 RCT Allocati No No Some Inconsist Adults No Low OR
gical 0 on -0.5 0 Impreci ency only, 0 (Total 0.58
failure conceale sion -0.5 MDR<20 -2.5) (0.07,
d -1 %, 4.62)
0 published
2000, 2004
-0.5
Relapse 2 132 9 RCT Allocati No No Some No Adults No Moder OR
0 on -0.5 0 Impreci inconsist only, 0 ate 0.09
conceale sion ency MDR<20 (Total (0.01,
d -0.5 0 %, -1.5) 0.70)
0 published
2000, 2004
-0.5
Serious 0
adverse
events
Non 0
serious
adverse
events
20
Table 5: Drug doses (Systematic reviews)
Table 5.1: Drug doses of ciprofloxacin, ofloxacin, chloramphenicol, cefixime, ceftriaxone and
azithromycin used in RCTs comparing the treatment effect of respective drugs. Source: Effa et. al. 2011
Author, Year of Interventions Dose

publication, Country
Chinh et. al. 2000, Ofloxacin 200 mg oral twice daily for 5 days at 8mg/kg/day
Vietnam
Azithromycin 1 gm oral daily for 5 days at 20mg/kg/day
Gasem et al. 2003, Ciprofloxacin 500 mg oral twice daily for 7 days
Indonesia
Chloramphenicol 500 mg oral 4 times a day for 14 days
Girgis et. al. 1999, Ciprofloxain 500 mg oral twice daily for 7 days
Egypt
Azithromycin 1 g oral once daily for the first day followed by oral 500 mg
once daily for total duration of 7 days.
Gottuzzo et. al. 1992, Ciprofloxacin 500 mg oral every 12 hours for 10 days
NA
Chloramphenicol 750 mg oral every 6 hours for 14 days
Morelli et. al. 1992, Ofloxacin 300 mg oral every 8 hours for 15 days
Italy
Ciprofloxacin 500 mg oral every 8 hours for 15 days
Chloramphenicol 500 mg oral every 6 hours for 15 days
Parry et. al. 2007, Ofloxacin 20mg/kg/day in 2 divided doses oral for 7 days
Vietnam
Azithromycin 10mg/kg/day once a day oral for 7 days
Ofloxacin- 15mg/kg/day in 2 divided doses oral ofloxacin for 7 days and
azithromycin 10mg/kg/day once a day oral azithromycin for first 3 days
Phongmany et. al. 2005, Ofloxacin 15mg/kg/day in 2 divided doses oral for 3 days
Lao
Chloramphenicol 50mg/kg/day oral in 4 divided doses for 14 days
Phong et. al. 1999, Ofloxacin 10mg/kg/day oral in 2 divided doses for 5 days
Vietnam
Cefixime 30mg/kg/day oral in 2 divided doses for 7 days
Rizvi et. al. 2007, Ciprofloxacin 500 mg oral twice daily for 7 days
Pakistan
Ofloxacin 200 mg oral twice daily for 7 days
Cefixime 200 mg oral twice daily for 7 days
Chloramphenicol 750 mg oral 6 hourly for 14 days
Smith et. al. 1994, Ofloxacin 200 mg oral every 12 hours for 5 days
Vietnam
Ceftriaxone 3 g intravenous once a day for 3 days
Wallace et. al. 1993, Ciprofloxacin 500 mg oral twice daily for 7 days
Bahrain
Ceftriaxone 3 g/day intravenous for 7 days
21
Yousaf et. al. 1992, Ofloxacin 200 mg oral twice daily for 14 days
Pakistan
Chloramphenicol 50mg/kg/day, then 30mg/kg/day when afebrile for 14 days
Table 5.2: Drug doses of ciprofloxacin, ofloxacin, chloramphenicol, ceftriaxone and azithromycin used in
RCTs comparing the treatment effect of respective drugs. Source: Effa et. al. 2008
(Duplicates with Effa et. al. 2011 are excluded in the table)
Author, Year of Interventions Dose

publication, Country
Butler et. al. 1999, Azithromycin 500 mg oral once daily for 7 days
India Chloramphenicol 2 to 3 g oral in 4 divided doses for 14 days
Frenck et. al. 2000, Azithromycin 20mg/kg/day oral with a maximum of 500mg/day for
Egypt 7 days
Ceftriaxone 75mg/kg/day intramuscular with a maximum of 2.5
g/day daily for 7 days
Frenck et. al. 2000, Azithromycin 20mg/kg/day oral with a maximum of 1000mg/day
Egypt for 5 days
Ceftriaxone 75mg/kg/day intravenous with a maximum of 2.5
g/day daily for 5 days
22
Figure 2: Literature search for additional RCTs
Records identified through

PubMed search
(n=341)
Excluded on screening titles and

abstract, n=274
Studies retained for further
review
(n=67)
Exclusion on full text review, n=23
Indentified enteric fever

treatment study
(n=44)
Duplicates with relevant Cochrane
reviews and meta-analysis, n=22
Evaluated for data on • Compared interventions not in

clinical use, n=8 (Norfloxacin-1,
treatment effects (n=22) Aztreonam-3, Fleroxacin-3,
Flurazolidone-1)
• Comparison between different
treatment duration with same
drug, n=1
• Sample size in each arm not
Included in analysis (n=12)
specified, n=1
Figure 2. Flow chart showing systematic search of additional RCTs on enteric fever treatments.
23
Table 6: Cochrane Risk of Bias assessment for additional RCTs
Author, Random Allocation Blinding Incomplete Incomplete Selective Other

publication sequence concealment outcome outcome reporting bias
year generation data (short data (long
term) term
Girgis et. Low risk Unclear risk High risk Low risk High risk Low risk Low risk
al. 1990
Lasserre Low risk Unclear risk High risk Low risk High risk Low risk Low risk
et. al. 1991
Islam et. Low risk Low risk High risk Low risk Low risk Low risk Low risk
al. 1993
Bhutta et. Unclear Unclear risk High risk Low risk High risk Low risk Low risk
al. 1994 risk
Acharya Low risk Low risk High risk Low risk High risk Low risk Low risk
et. al. 1995
Girgis et. Low risk Unclear risk High risk Low risk High risk Low risk Low risk
al. 1995
Memon et. Unclear Unclear risk High risk Low risk Low risk Low risk Low risk
al. 1997 risk
Malik et. Unclear Unclear risk High risk Low risk High risk Low risk Low risk
al. 1998 risk
Tatli et. al. Unclear Unclear risk High risk Low risk Low risk Low risk Low risk
2003 risk
Shakur Low risk Low risk Low risk Low risk High risk Low risk Low risk
2007
Koirala et. Low risk Low risk High risk Low risk Low risk Low risk Low risk
al. 2013
Arjyal et. Low risk Low risk High risk Low risk Low risk Low risk Low risk
al. 2016
24
Table 7: Study characteristics and outcomes of additional RCTs
n (%) CLF
Author,
(mean)
CARR
n (%)
n (%)
n (%)
MCF
FU%
FUD
REL
Publicatio Age
FCT
n year, Mean
country No. Drugs- Dose Duration (Range) Age Groups MDR % NAR%
Girgis et. Ceftriaxone 60-80mg/kg/d (max 4g) im
al. 1990, 25 od 5 -7 NS NS 3.9 0 0 0 NS 28 NS
Egypt
13.65 Children
30 Chloramphenicol 50-80mg/kg/d qid 12-14 (5-32) Adult NS NS 6.5 0 0 3 (10) NS 28 NS
Lasserre Chloramphenicol 23
et. al.
1991, 20 2000-3000mg/d qid 14 (15-40) NS NS 8 1 (5) NS 3 (15) NS 21 NS
Philippine 29
s
19 Ceftriaxone 3000mg/d od 3 (15-50) NS NS 7 0 NS 2 (10) NS 21 NS
27
20 Ceftriaxone 4000mg/d od 3 (15-58) Adults NS NS 7 0 NS 0 NS 21 NS
Ceftriaxone 75mg/kg/d (child); 18
Islam et. 6
al. 28 4000mg/d (adult)od 5 (3-35) NS NS 7.5 (21) 0 1 0 7 61
1993,
Chloramphenicol 60 mg/kg/d 18
Banglades Children 3
h 31 then 40mg/kg/d qid 14 (2-35) Adults NS NS 7 (10) 0 2 1 (3) 7 74
7
3
Bhutta et. 25 Cefixime 10mg/kd/d bid 14 (0.5-13) 100 NS 8.3 (12) 1 (4) 1 (4) NS 84 NS
al. 1994, 3
Pakistan 25 Ceftriaxone 65mg/kg/d iv od 14 8 Children 100 NS 8 (12) 2 (8) 3 (12) NS 84 NS
Ceftriaxone 50mg/kg/d
4
Acharya 23 (max 2000mg) od 3 18 NS NS NS (17) 0 1(4) 0 21 NS
et. al.
1995, Chloramphenicol 60mg/kg/d till Children 3
Nepal 23 defervescence then40 mg/kg/d qid 14 19 Adults NS NS NS (13) 0 0 0 21 NS
Girgis et. 50 Cefixime 15-20mg/kg/d bid 14 10 100 NS 5.5 0 NS 3 (6) NS 28 NS
al. 1995,
43 Ceftriaxone 50-70mg/kg/d, od 5 10 Children 100 NS 3.9 0 NS 2 (5) NS 28 NS
25
Egypt max4000mg
Aztreonam 150-200mg/kg/d tid
31 max8000mg 7 9 100 NS 5.3 0 NS 2 (6) NS 28 NS
31(7
Memon et. 44 Chloramphenicol 100mg/kg/d qid 14 5 NS 4.4 0) NS 0 NS 14 100
al. 1997,
Pakistan 41 Cefixime 10-12mg/kg/d bid 14 6 Children 78 NS 5.6 2(5) NS 0 NS 14 100
2
Malik et. 20 Cefixime 10mg/kg/d bid 14 6.2 NS NS 5.05 (10) NS NS NS 28 NS
al. 1998, 11
Pakistan 20 Chloramphenicol 50mg/kg/d qid 14 (2-12) Children NS NS 5.5 (55) NS NS NS 28 NS
until 5 days
Tatli et. al. after
2003, defervescenc
Turkey 36 Ceftriaxone 75mg/kg/d bid (max 2 gm) e 10.7 (4.5-15) 0 NS 5.4 0 0 0 0 28 83
Chloramphenicol 75mg/kg/d qid (max
36 2gm) 14 9.8 Children 0 NS 4.2 0 0 4 (14) 0 28 78
Shakur et. Cefpodoxime proxetil

al.
2007, 21 16mg/kg/d bid 10 5 (0.5-12) NS NS 4.9 1 (5) 0 NS NS NS NS
Banglades
h
19 Cefixime 20mg/kg/d bid 10 4 Children NS NS 4.3 1(5) 0 NS NS NS NS
Koirala et. *
al. 109 Gatifloxacin 10mg/kg/d od 7 17 3.3 5 (5) 0 4 (4) 0 180 60
2013, Children
Nepal 109 Ofloxacin 20mg/kg/d bid 7 16 Adults 0 82 4.7* 8 (8) 1 6 (6) 1 (1) 180 68
Arjyal et. 62 Gatifloxacin 10mg/kg/d od po 7 Children NS NS 4.21* 16 2 4 2 180 39
al. 2016,
Nepal
54 Ceftriaxone 60 mg/kg/d od iv (max 2 gm) 7 Adults NS NS 2.78* 4 1 1 0 180 41%
26
Figure 3: Flow chart- Guidelines
Medline Embase
Identification
95 301
396 records identified

Discarded duplicates.
n=75
321 records screened by

title and abstract
Screening
Exclude, n=312
9 records accessed in full-

text for eligibility
Excluded n=6
• Not enteric fever guideline, n=3
• Travel medicine=1
Eligibility
• No recommendation on
antimicrobial treatment, n=1
3 records eligible • Full document not accessible, n=1
Additional records identified through

other searches, n=1
Included
4 treatment guidelines
included in assessment
Figure 3: Flow chart showing systematic search for relevant guidelines in the treatment of enteric fever.
27
Table 8: Search Strategy for Clinical Practice Guidelines
Search Strategies
1. Database: Medline (Ovid MEDLINE® Epub Ahead of Print, In-Process & Other Non-Indexed
Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) 1946 to present
Search Strategy:
1 exp clinical pathway/ (6141)
2 exp clinical protocol/ (156551)
3 exp consensus/ (9839)
4 exp consensus development conference/ (11218)
5 exp consensus development conferences as topic/ (2650)
6 critical pathways/ (6141)
7 exp guideline/ (31391)
8 guidelines as topic/ (37436)
9 exp practice guideline/ (24661)
10 practice guidelines as topic/ (107678)
11 health planning guidelines/ (4019)
12 (guideline or practice guideline or consensus development conference or consensus development
conference, NIH).pt. (40210)
13 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw.
(28042)
14 (standards or guideline or guidelines).ti,kf,kw. (98978)
15 ((practice or treatment* or clinical) adj guideline*).ab. (34831)
16 (CPG or CPGs).ti. (5374)
17 consensus*.ti,kf,kw. (22821)
18 consensus*.ab. (134663)
19 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or
protocol*)).ti,ab,kf,kw. (17871)
20 recommendat*.ti,kf,kw. (36523)
21 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or
plans)).ti,ab,kf,kw. (49783)
22 (algorithm* adj2 (pharmacotherap* or chemotherap* or chemotreatment* or therap* or treatment*
or intervention*)).ti,ab,kf,kw. (8555)
23 Typhoid Fever/ (10779)
24 Paratyphoid Fever/ (2318)
31 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or
20 or 21 or 22 (645125)
32 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 (17163)
33 31 and 32 (115)
34 33 (115)
28
2. Database: Embase 1974 to present
Search Strategy:
1 exp consensus/ (58988)
2 consensus development/ (22852)
3 clinical pathway/ (7946)
4 exp practice guideline/ (484072)
5 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kw. (40208)
6 (standards or guideline or guidelines).ti,kw. (137304)
7 ((practice or treatment* or clinical) adj guideline*).ab. (51801)
8 (CPG or CPGs).ti. (6459)
9 consensus*.ti,kw. (28636)
10 consensus*.ab. (180404)
11 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kw.
(27623)
12 recommendat*.ti,kw. (46079)
13 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or
plans)).ti,ab,kw. (85398)
14 (algorithm* adj2 (pharmacotherap* or chemotherap* or chemotreatment* or therap* or treatment*
or intervention*)).ti,ab,kw. (12804)
15 typhoid fever/ (9704)
16 paratyphoid fever/ (355)
23 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 (894730)
24 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 (12688)
25 23 and 24 (340)
26 25 (340)
Search Results
Ovid Medline 95
Ovid Embase 301
Total 396
Total after deduplication 321
Following additional searches were performed. Screening was done for first 100 hits for each of the
search results.
Google
Guideline* “enteric fever*”
29
guideline* typhoid
"treatment recommendation*" "enteric fever*"
“treatment recommendation*” typhoid
Google site specific searches – WHO https://www.who.int/

guideline* "enteric fever*" site:.who.int/
guideline* typhoid site:.who.int/
Google site specific searches – Infectious Diseases Society of America (IDSA) https://www.idsociety.org/
guideline* "enteric fever*" site:.idsociety.org
guideline* typhoid site:.idsociety.org
Google Scholar
(guideline*|"treatment recommendation*"|consensus)(typhoid|paratyphoid|"enteric fever*"|"abdominal
typhus"|"salmonella typhi infection*"|"salmonella paratyphi infection*")
30
Table 9: AGREE II assessment
Appraisal of clinical practice guidelines using Appraisal of Guidelines for Research and Evaluation
(AGREE) II instrument.
Guidelin Scope Stakehold Rigor and Clarity of Editorial Overall Recommendati

es and er developme presentati independen score on for use
purpos involveme nt on ce (=Sum
e nt of
domain
scores/
5)
WHO 97% 44% 17% 94% 29% 56% No
2003
WHO 100% 67% 81% 97% 96% 88% Yes, with
2012 modification
API 2015 69% 47% 21% 72% 12% 44% No
IAP 2006 58% 44% 5% 28% 8% 29% No
WHO 2003: Background document: The diagnosis, treatment and prevention of typhoid fever, WHO,
2003
WHO 2012: Evidence for technical update of pocket book recommendations, Recommendations for
management of common childhood conditions, WHO, 2012
API 2015: API recommendation for the management of typhoid fever, 2015
IAP 2006: IAP Task force report: Management of enteric fever in children, 2006
Notes:
- Score for each domain was calculated following the methodology laid by the AGREE instrument.
-Overall score was calculated by adding the component domain scores and dividing it by 5.
31
Table10: Current recommendations
Table 10.1: Background document: The diagnosis, treatment and prevention of typhoid
fever, WHO 2003
32
Table 10.2: Evidence for Technical update of pocket book recommendations,
Recommendations for management of common childhood conditions, WHO 2012
a) Children with typhoid fever should be treated with a fluoroquinolone (i.e. ciprofloxacin, gatifloxacin, ofloxacin,
and perfloxacin) as a first line treatment for 7–10 days.
— Ciprofloxacin: orally 15 mg/kg per dose twice daily for 7–10 days.
(Strong recommendation; moderate quality evidence)
b) If the response to treatment is poor, consider drug-resistant typhoid and treat with a second line antibiotic like 3rd
generation cephalosporins or azithromycin.
— Cetriaxone IV: 80 mg/kg per day for 5–7 days
OR
— Azithromycin: 20 mg/kg per day for 5–7 days
(Strong recommendation, moderate quality evidence)
c) Where drug resistance to antibiotics among salmonella isolates is known, follow the national guidelines according
to local susceptibility data.
(Strong recommendation, moderate quality evidence)
33

s6.2 Typhoid-Fever Appendix

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Appendix

Figure 1: Literature search for relevant systematic reviews. ....................................................................... 2

Medline Embase Cochrane

306 Records Identified

218 Records Screened by

25 Articles accessed in Full-

2. Database: Embase 1974 to present

#1 MeSH descriptor: [Typhoid Fever] explode all trees 244

 Limitations of study in terms of design, conduct and analysis

Quality Definition Implication

FCT 2 147 NA RCT Unclear No No No No Mostly No Moder Mean

FCT 2 140 NA RCT Unclear No No No No Mostly No Moder Mean

Table 3.2: Gatifloxacin versus Chloramphenicol in the treatment of enteric fever

Clinical 1 352 18 RCT Allocati No No No One Adults and No Moder OR

Table 3.3: Ciprofloxacin/Ofloxacin versus Cotrimoxazole in the treatment of enteric fever

FCT 1 92 NA RCT Unclear No No Some Only one Mostly No Very Mean

FCT 1 92 NA RCT Unclear No No Some Only one Mostly No Very Mean

Table 3.4: Ciprofloxacin/Ofloxacin versus Ampicillin/Amoxicillin in the treatment of enteric

Clinical 1 40 5 RCT Unclear No No Some Only one Adults only No Ver RR

Clinical 1 50 9 RCT Unclear No No Some Only one Adults only No Ver RR

Table 3.5: Ciprofloxacin/Ofloxacin versus Cefixime in the treatment of enteric fever

FCT 1 94 NA RCT Unclear No No No Only one Mostly No Low Mean

FCT 1 91 NA RCT Unclear No No No Only one Mostly No Low Mean

Table 3.6: Gatifloxacin versus Cefixime in the treatment of enteric fever

Table 3.7: Ciprofloxacin/Ofloxacin versus Ceftriaxone in the treatment of enteric fever

Clinical 1 42 6 RCT Unclear No No Some Only Adult only, No Very RR

FCT 1 47 NA RCT Allocati No No No Only Adults No Moder Mean

Table 3.8: Ciprofloxacin/Ofloxacin versus Azithromycin in the treatment of enteric fever

FCT 1 64 NA RCT Allocati No No No Only one Adults No Low Mean

FCT 2 213 NA RCT Allocati No No Some Inconsist Children No Moder Mean

Table 3.9: Gatifloxacin versus Azithromycin in the treatment of enteric fever

Clinical 1 287 12 RCT Allocati No No Some One Adults and No Moder OR

Table 4.2: Azithromycin versus Fluoroquinolones in the treatment of enteric fever

Table 4.3: Azithromycin versus Ceftriaxone in the treatment of enteric fever

Author, Year of Interventions Dose

Author, Year of Interventions Dose

Records identified through

Excluded on screening titles and

Indentified enteric fever

Evaluated for data on • Compared interventions not in

Author, Random Allocation Blinding Incomplete Incomplete Selective Other

Shakur et. Cefpodoxime proxetil

396 records identified

321 records screened by

9 records accessed in full-

Additional records identified through

Google site specific searches – WHO https://www.who.int/

Guidelin Scope Stakehold Rigor and Clarity of Editorial Overall Recommendati

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