fluoroquinolones for treating typhoid and paratyph

Cochrane Database of Systematic Reviews

Fluoroquinolones for treating typhoid and paratyphoid fever

(enteric fever) (Review)

Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA

Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA.

Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever).

Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD004530.

DOI: 10.1002/14651858.CD004530.pub4.

www.cochranelibrary.com

Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.cochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 1 Clinical failure. . . . . . . . 70

Analysis 1.2. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 2 Microbiological failure. . . . . 71

Analysis 1.3. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 3 Relapse. . . . . . . . . . 73

Analysis 1.4. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 4 Convalescent faecal carriage. . . 74

Analysis 1.5. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 5 Fever clearance time. . . . . . 75

Analysis 1.6. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 6 Duration of hospitalization. . . 76

Analysis 1.7. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 7 Serious adverse events. . . . . 77

Analysis 1.8. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 8 Non-serious adverse events. . . 78

Analysis 2.1. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 1 Clinical Failure. . . . . . . . 79

Analysis 2.2. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 2 Microbiological failure. . . . . . 80

Analysis 2.3. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 3 Relapse. . . . . . . . . . . 81

Analysis 2.4. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 4 Convalescent faecal carriage. . . . 82

Analysis 2.5. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 5 Fever clearance time. . . . . . 82

Analysis 2.6. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 6 Non serious adverse events. . . . 83

Analysis 3.1. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 1 Clinical failure. . . . . . 84

Analysis 3.2. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 2 Microbiological failure. . . . 85

Analysis 3.3. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 3 Non-serious adverse events. . 86

Analysis 4.1. Comparison 4 Fluoroquinolone versus cefixime, Outcome 1 Clinical failure. . . . . . . . . . . 87

Analysis 4.2. Comparison 4 Fluoroquinolone versus cefixime, Outcome 2 Microbiological failure. . . . . . . . 88

Analysis 4.3. Comparison 4 Fluoroquinolone versus cefixime, Outcome 3 Relapse. . . . . . . . . . . . . 89

Analysis 4.4. Comparison 4 Fluoroquinolone versus cefixime, Outcome 4 Convalescent faecal carriage. . . . . . 90

Analysis 4.5. Comparison 4 Fluoroquinolone versus cefixime, Outcome 5 Fever clearance time. . . . . . . . . 90

Analysis 4.6. Comparison 4 Fluoroquinolone versus cefixime, Outcome 6 Duration of hospitalization. . . . . . 91

Analysis 4.7. Comparison 4 Fluoroquinolone versus cefixime, Outcome 7 Serious adverse Events. . . . . . . . 92

Analysis 4.8. Comparison 4 Fluoroquinolone versus cefixime, Outcome 8 Non-serious adverse events. . . . . . 93

Analysis 5.1. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 1 Clinical failure. . . . . . . . . . 94

Analysis 5.2. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 2 Microbiological failure. . . . . . . 95

Analysis 5.3. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 3 Relapse. . . . . . . . . . . . 96

Analysis 5.4. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 4 Convalescent faecal carriage. . . . . 97

Analysis 5.5. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 5 Fever clearance time. . . . . . . . 97

Analysis 5.6. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 6 Non-serious adverse events. . . . . 98

Analysis 6.1. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 1 Clinical failure. . . . . . . . . 99

Analysis 6.2. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 2 Microbiological failure. . . . . . 100

Analysis 6.3. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 3 Relapse. . . . . . . . . . . 101

Analysis 6.4. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 4 Convalescent faecal carriage. . . . 102

Analysis 6.5. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 5 Fever clearance time. . . . . . . 103

iFluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review)


Analysis 6.6. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 6 Duration of Hospitalization. . . . 104

Analysis 6.7. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 7 Serious adverse events. . . . . . 104

Analysis 6.8. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 8 Non-serious adverse events. . . . . 105

Analysis 7.1. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 1 Clinical failure. . . . . . . . . . 106

Analysis 7.2. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 2 Microbiological failure. . . . . . . 106

Analysis 7.3. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 3 Relapse. . . . . . . . . . . . . 107

Analysis 7.4. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 4 Convalecsent faecal carriage. . . . . . 108

Analysis 7.5. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 5 Fever clearance time. . . . . . . . 108

Analysis 7.6. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 6 Duration of hospitalization. . . . . . 109

Analysis 7.7. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 7 Serious adverse events. . . . . . . . 110

Analysis 7.8. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 8 Non-serious adverse events. . . . . . 110


Analysis 8.2. Comparison 8 Fluoroquinolone 3 days vs 5 days, Outcome 2 Fever Clearance time. . . . . . . . 112


Analysis 9.1. Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 1 Microbiological Failure. . . . . . . 113


Analysis 9.3. Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 3 Fever clearance time. . . . . . . . 114


Analysis 10.1. Comparison 10 Fluoroquinolone 7 days vs 10 days, Outcome 1 Microbiological failure. . . . . . 115

Analysis 10.2. Comparison 10 Fluoroquinolone 7 days vs 10 days, Outcome 2 Relapse. . . . . . . . . . . 115

Analysis 11.1. Comparison 11 Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days), Outcome 1 All

outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Analysis 12.1. Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 1 Relapse. . . . . . . . . . . 117

Analysis 12.2. Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 2 Fever clearance time. . . . . . . 117

Analysis 12.3. Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 3 Non-serious adverse events. . . . 118

Analysis 13.1. Comparison 13 Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days), Outcome 1 All outcomes. . 118

Analysis 14.1. Comparison 14 Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days), Outcome 1 All outcomes. 119

119APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

139WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

139HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

140CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

140DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

140SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

140DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

141NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

141INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiFluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review)


[Intervention Review]

Fluoroquinolones for treating typhoid and paratyphoid fever(enteric fever)

Emmanuel E Effa1, Zohra S Lassi2 , Julia A Critchley3, Paul Garner4, David Sinclair4, Piero L Olliaro5, Zulfiqar A Bhutta2

1Internal Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria. 2Division of Women and Child Health, Aga Khan

University Hospital, Karachi, Pakistan. 3Institute of Health and Society, Newcastle University, Newcastle, UK. 4International Health

Group, Liverpool School of Tropical Medicine, Liverpool, UK. 5UNICEF/UNDP/World Bank/WHO Special Programme for Research

and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland

Contact address: Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box

3500, Karachi, 74800, Pakistan. [email protected].

Editorial group: Cochrane Infectious Diseases Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2012.

Review content assessed as up-to-date: 1 February 2011.

Citation: Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA. Fluoroquinolones for treating ty-

phoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD004530. DOI:

10.1002/14651858.CD004530.pub4.


A B S T R A C T

Background

Typhoid and paratyphoid are febrile illnesses, due to a bacterial infection, which remain common in many low- and middle-income

countries. The World Health Organization (WHO) currently recommends the fluoroquinolone antibiotics in areas with known

resistance to the older first-line antibiotics.

Objectives

To evaluate fluoroquinolone antibiotics for treating children and adults with enteric fever.

Search methods

We searched The Cochrane Infectious Disease Group Specialized Register (February 2011); Cochrane Central Register of Controlled

Trials (CENTRAL), published in The Cochrane Library (2011, Issue 2); MEDLINE (1966 to February 2011); EMBASE (1974 to

February 2011); and LILACS (1982 to February 2011). We also searched the metaRegister of Controlled Trials (mRCT) in February

2011.

Selection criteria

Randomized controlled trials examining fluoroquinolone antibiotics, in people with blood, stool or bone marrow culture-confirmed

enteric fever.

Data collection and analysis

Two authors independently assessed the trial’s methodological quality and extracted data. We calculated risk ratios (RR) for dichotomous

data and mean difference for continuous data with 95% confidence intervals (CI).

Comparative effectiveness has been interpreted in the context of; length of treatment, dose, year of study, known levels of antibiotic

resistance, or proxy measures of resistance such as the failure rate in the comparator arm.

1Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review)


mailto:[email protected]

Main results

Twenty-six studies, involving 3033 patients, are included in this review.

Fluoroquinolones versus older antibiotics (chloramphenicol, co-trimoxazole, amoxicillin and ampicillin)

In one study from Pakistan in 2003-04, high clinical failure rates were seen with both chloramphenicol and co-trimoxazole, although

resistance was not confirmed microbiologically. A seven-day course of either ciprofloxacin or ofloxacin were found to be superior. Older

studies of these comparisons failed to show a difference (six trials, 361 participants).

In small studies conducted almost two decades ago, the fluoroquinolones were demonstrated to have fewer clinical failures than

ampicillin and amoxicillin (two trials, 90 participants, RR 0.11, 95% CI 0.02 to 0.57).

Fluoroquinolones versus current second-line options (ceftriaxone, cefalexin, and azithromycin)

The two studies comparing a seven day course of oral fluoroquinolones with three days of intravenous ceftriaxone were too small to

detect important differences between antibiotics should they exist (two trials, 89 participants).

In Pakistan in 2003-04, no clinical or microbiological failures were seen with seven days of either ciprofloxacin, ofloxacin or cefixime

(one trial, 139 participants). In Nepal in 2005, gatifloxacin reduced clinical failure and relapse compared to cefixime, despite a high

prevalence of NaR in the study population (one trial, 158 participants, RR 0.04, 95% CI 0.01 to 0.31).

Compared to a seven day course of azithromycin, a seven day course of ofloxacin had a higher rate of clinical failures in populations

with both multi-drug resistance (MDR) and nalidixic acid resistance (NaR) enteric fever in Vietnam in 1998-2002 (two trials, 213

participants, RR 2.20, 95% CI 1.23 to 3.94). However, a more recent study from Vietnam in 2004-05, detected no difference between

gatifloxacin and azithromycin with both drugs performing well (one trial, 287 participants).

Authors’ conclusions

Generally, fluoroquinolones performed well in treating typhoid, and maybe superior to alternatives in some settings. However, we were

unable to draw firm general conclusions on comparative contemporary effectiveness given that resistance changes over time, and many

studies were small. Policy makers and clinicians need to consider local resistance patterns in choosing a fluoroquinolone or alternative.

There is some evidence that the newest fluoroquinolone, gatifloxacin, remains effective in some regions where resistance to older

fluoroquinolones has developed. However, the different fluoroquinolones have not been compared directly in trials in these settings.

P L A I N L A N G U A G E S U M M A R Y

Fluoroquinolones for treating enteric fever

Researchers in The Cochrane Collaboration conducted a review of the effect of fluoroquinolone antibiotics in people enteric fever.

After searching for relevant studies, they identified 26 studies involving 3033 patients. Their findings are summarized below.

What is enteric fever and how might fluoroquinolones work?

Enteric fever is a common term for two similar clinical illnesses known individually as typhoid fever and paratyphoid fever. These 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.

In left untreated some people can develop serious complications and can be fatal.

The fluoroquinolones are a large family of antibiotic drugs, which are commonly used for a variety of infectious diseases. In the past,

enteric fever responded extremely well to fluoroquinolones, but drug resistance has become a major public health problem in many

areas especially Asia.

What the research says

Effect of using fluoroquinolones:

Generally, fluoroquinolones are effective in typhoid.

Policy makers and clinicians will need to consider local antibiotic resistance when considering treatment options for enteric fever.



One relatively new fluoroquinolone, gatifloxacin, seems to remain effective in some regions where resistance to older fluoroquinolones

has developed.

B A C K G R O U N D

Description of the condition

Enteric fever is a common term to encompass two similar clinical

illnesses, caused by different serotypes of the bacterium Salmonella

enterica. Typhoid fever (due to Salmonella typhi) is generally more

common, and more severe, but recent reports suggest that the rel-

ative frequency of paratyphoid fever (due to Salmonella paraty-

phi) may be increasing (Chandel 2000; Ahmad 2002; Butt 2005;

Ochiai 2005; Jesudason 2005; Woods 2006; Maskey 2008). In the

year 2000, there were an estimated 21.6 million cases of typhoid

fever, with 210,000 deaths, and 5.4 million cases of paratyphoid

fever (Ochiai 2008; Crump 2004).

The symptoms of enteric fever are generally non-specific and can

vary among different populations (Parry 2002). Common symp-

toms include fever, headache, and gastrointestinal complaints;

such as diarrhoea, constipation, abdominal pain, nausea and vom-

iting, or loss of appetite (Lee 2000; Richens 2000). Severe disease

occurs in 10 to15% of people, and complications such as; intesti-

nal perforation, intestinal bleeding, shock, pancreatitis (inflam-

mation of the pancreas), pneumonia, myocarditis (inflammation

of the heart muscles), meningitis (inflammation of the covering of

the brain), or psychosis (altered mental state) can occur, typically

after the illness has lasted more than two weeks (Parry 2002).

The bacteria may be shed in the faeces during the acute illness, dur-

ing convalescence, and occasionally for prolonged periods when

the person is labelled a ’chronic carrier’ (defined as excretion of

the bacterium in the stool or urine for more than one year (Bhan

2005)). Infection occurs when food or water contaminated with

faeces harbouring the bacteria are ingested. The organisms then

penetrate the intestinal lining, multiply in lymphoid tissues, and

are released into the blood stream from where they spread through-

out the body to various organs; most commonly the liver, spleen,

bone marrow, and gall bladder (Lesser 2001).

The enteric fevers remain a major health problem in low- and mid-

dle-income countries where water and sanitation services may be

inadequate. They are endemic throughout Asia (with the highest

incidence in South and Southeast Asia), the Middle East, Africa,

and South and Central America (Ivanoff 1995; Crump 2004). In

high-income countries, most cases occur in travellers returning

from these endemic areas (McNabb 2008). The highest incidence

has been reported in children between five and 10 years of age (Lin

2000; Siddiqui 2006; Sur 2006), and in those under five years of

age (Sinha 1999; Saha 2001; Saha 2003; Brooks 2005).

Diagnosis and treatment

The diagnosis of enteric fever can be difficult due to the non

specific nature of the symptoms. A definitive diagnosis is possible

when the organisms are isolated from blood, bone marrow or other

body fluids. Blood cultures are typically positive in 60 to 80%

of cases, while bone marrow cultures are more sensitive with 80

to 95% positive, even after prior antibiotic therapy (Parry 2002).

Serological tests, such as the Widal reaction, have been widely used

but these are non-specific, giving false positive results, and can be

difficult to interpret. More recently, there has been interest in the

use of DNA probes and polymerase chain reaction (PCR) testing

, but these are not widely available in enteric fever endemic areas

(Parry 2002).

Untreated the disease last 3 to 4 weeks with fever, septicaemia,

and a 10-30% mortality. Treatment is with antibiotics and most

patients are managed as outpatients.

Antibiotic resistance

Resistance of S. typhi and S. paratyphi to commonly used antibi-

otics has become problematic. Resistance to the highly effective

chloramphenicol in the 1970’s was associated with simultaneous

resistance to sulfonamides, tetracycline, and streptomycin; this led

to the use of alternative agents such as co-trimoxazole and amox-

icillin (Parry 2002). Subsequently, multi-drug resistant (MDR)

strains (resistant to chloramphenicol, ampicillin, co-trimoxazole

and streptomycin) emerged and are now prevalent in many parts

of the world.

In the Indian subcontinent and China, the frequency of MDR

strains ranges from 50% to 80% of all S. typhi isolates and

has reached 100% during outbreaks (Lee 2000). In sub-Saharan

Africa, MDR S. typhi has been found in 61% and 82.4% of iso-

lates in Nigeria and Kenya, respectively (Akinyemi 2005;Kariuki

2004). Surveillance studies can show considerable geographic dif-

ferences in the proportion of MDR isolates within the same region;

MDR S. typhi is far more common in India, Pakistan and Vietnam

than in areas of China and Indonesia (Ochiai 2008). Longitudinal

studies have also shown that the proportion of MDR strains can

decrease over time following changes in antibiotic use (Lakshmi



2006; Maskey 2008). Indeed several areas have reported a re-emer-

gence of strains susceptible to first-line antibiotics such as chlo-

ramphenicol (Takkar 1995; Sood 1999; Wasfy 2002; Rodrigues

2003; Butt 2005; Walia 2005; Mohanty 2006; Gupta 2009).

Infection with resistant strains can lead to higher treatment failure

rates, an increased risk of complications, and an increased potential

for transmission due to prolonged faecal carriage (Coovadia 1992;

Bhutta 1996; Mermin 1999; Rupali 2004; Walia 2005; Crump

2008).

The isolates that respond less well clinically to fluoroquinolones

are usually nalidixic acid resistant (NaR) by disc susceptibility test-

ing and have high minimum inhibitory concentrations (MICs) al-

though their breakpoints remain within the range set by the Clini-

cal and Laboratory Standard Institute (CLSI). Using current CLSI

disk breakpoints (CLSI 2007) means that fluoroquinolones may

continue to be used inappropriately thereby increasing the risks of

treatment failure. A key consideration now is the suggested need

to redefine breakpoints for isolates with reduced susceptibility to

fluoroquinolones in order to identify these strains, offer appropri-

ate therapy and stem the emergence of more resistant organisms

(Crump 2003, Parry 2010, BSAC 2011).

Description of the intervention

The fluoroquinolones are a large family of anti-infective drugs,

synthesized around a quinolone core, that possess a broad spectrum

of antibacterial activity (Congeni 2002).

Nalidixic acid, the prototype quinolone, was first introduced into

clinical use in 1962. Four generations of fluoroquinolones have

subsequently been developed, classified according to their spec-

trum of antibacterial activity, and used to treat a range of urinary

tract, respiratory, gastrointestinal, and sexually transmitted infec-

tions (Oliphant 2002):

• second generation; eg ciprofloxacin, ofloxacin, pefloxacin,

norfloxacin; broad gram-negative cover but limited activity

against gram-positive bacteria;

• third generation; eg levofloxacin, sparfloxacin, gatifloxacin,

moxifloxacin; improved activity against gram-positive bacteria;

• fourth generation; eg trovafloxacin, gemifloxacin; improved

activity against anaerobic bacteria.

Subsequently, several of these products have been withdrawn from

clinical use (Committee 2006), and norfloxacin is not generally

recommended for the treatment of enteric fever due to its poor

bioavailability (Miller 2000; Hooper 2000).

Adverse events

Fluoroquinolones generally have few adverse effects. The most

common are mild and self-limiting symptoms affecting either the

gastrointestinal system (nausea, vomiting or diarrhoea), or the

central nervous systems (headaches and dizziness) (Bertino 2000;

Oliphant 2002). Rare and serious adverse effects have been linked

to specific fluoroquinolone compounds and several have subse-

quently been withdrawn from clinical use: prolongation of the cor-

rected QT (QTc) interval with grepafloxacin, liver toxicity with

trovafloxacin, and anaphylaxis, haemolytic anaemia and renal fail-

ure with temafloxacin.(Bertino 2000; Fish 2001)

How the intervention might work

In the past, enteric fevers responded extremely well to the fluoro-

quinolones, but quinolone resistant strains of S. typhi, especially in

Asia, have become a major public health problem (Chuang 2009;

Parry 2010; Smith 2010; Parry 2010).The susceptibility of S. typhi

to the fluoroquinolones can be divided into three categories:

• fully susceptible; susceptible to both nalidixic acid and

ciprofloxacin;

• reduced susceptibility: NaR, but susceptible to

ciprofloxacin (Threlfall 1999; Ackers 2000; Crump 2003); or

• resistant: both NaR and ciprofloxacin resistant (Rupali

2004; Parry 2006; Kownhar 2007).

However, not all strains with reduced susceptibility to fluoro-

quinolones are NaR suggesting the likelihood of a new mecha-

nism of resistance unrelated to the principal mechanisms of re-

sistance already known (Threlfall 2003; Cooke 2006). There are

emerging reports of isolates with absolute fluoroquinolone resis-

tance (Harish 2004; Adachi 2005; Renuka 2005; Ahmed 2006;

Mohanty 2006; Walia 2006; Joshi 2007). To date, fluoroquinolone

resistance has been reported in several countries including India

(Renuka 2005,Gaind 2006, Kownhar 2007), Vietnam (Ahmed

2006), Kuwait (Dimitrov 2009), South Africa (Keddy 2010), UK

(Cooke 2007) and the USA (Medalla 2011). Most of those re-

ported in the UK and the USA have been imported from India,

Vietnam and Bangladesh.

There is current interest in gatifloxacin, which has been found

to be active against NaR strains. The alteration in its structure is

such that it may hypothetically make the drug less susceptible to

the mutations that caused resistance to the older fluoroquinolones

(Fukuda 2001). Studies of gatifloxacin suggest that there may be

fewer cardiac adverse effects than seen with older generation fluo-

roquinolones, but with a higher incidence of dysglycaemia (high

or low blood sugar) (Frothingham 2005; Park-Wyllie 2006), al-

though some authorities state this may be confined to the elderly,

and those with non-insulin dependent diabetes (Ambrose 2003).

Why it is important to do this review

This review aims to summarise trials comparing fluoroquinolones

and other antibiotics in treating enteric fever. Interpreting trial

data needs to take into account other factors, in particular the year

and location of the study, as antibiotic resistance (and therefore

efficacy), is dynamic and changes with time.

In the earlier version of this review, different generations of fluoro-

quinolones were combined in the analysis with sub groups accord-



ing to the prevalence of NaR strains (Thaver 2008). It was clear that

there were important differences between the fluoroquinolones,

and this update therefore seeks to group studies by each fluoro-

quinolone individually. As norfloxacin has poor bioavailability and

is no longer a credible treatment option, studies evaluating this

drug were excluded.

O B J E C T I V E S

To evaluate the fluoroquinolone antibiotics in the treatment of

enteric fever in children and adults.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Types of participants

People diagnosed with typhoid or paratyphoid fever based on mi-

crobiological confirmation from blood, stool or bone marrow.

Types of interventions

Intervention

Different fluoroquinolone antibiotics, excluding norfloxacin or

other fluoroquinolones not currently in use

Control

Any non-fluoroquinolone antibiotic used to treat enteric fever;

chloramphenicol, ampicillin, amoxicillin, cotrimoxazole, azithro-

mycin or cephalosporins.

An alternative fluoroquinolone, or a different treatment duration

of the same fluoroquinolone.

Types of outcome measures

Primary outcomes

• Clinical failure; defined as development of complications,

requiring a change of antibiotic therapy, or remaining

symptomatic beyond a time period specified by trial authors.

• Microbiological failure; defined as a positive culture from

blood, bone marrow, or any sterile anatomic site, beyond a time

period specified by trial authors.

• Relapse; defined as the recurrence of symptoms with a

positive culture from blood or bone marrow or any sterile

anatomic site, beyond a time period defined by trial authors.

Secondary outcomes

• Fever clearance time; defined as the time in hours/days

taken to clear fever from the start of the intervention or control

drug with the definition of fever clearance as specified by trial

authors.

• Length of hospital stay; defined as the time in days from

entry into trial until discharge.

• Convalescent faecal carriage; defined as a positive faecal

culture detected at any time after the end of treatment up to one

year of follow up.

Adverse events (as defined by trial authors)

• Serious adverse events; defined as adverse events leading to

death, inpatient hospitalization, prolonged hospitalization, or

life threatening, resulting in persistent or significant disability or

incapacity, such as joint disease, tendonitis and tendon rupture,

prolongation of QTc interval, seizures, nephrotoxicity,

haematological reactions, or severe dermatologic reactions.

• Other adverse events, such as nausea, diarrhoea, headache,

dizziness, mild photosensitivity, hepatic enzyme elevations, and

hypersensitivity reactions.

Search methods for identification of studies

Emmanuel Effa worked with Vittoria Lutje (Information Retrieval

Specialist, Cochrane Infectious Diseases Group) to identify all rel-

evant trials regardless of language or publication status.

Electronic searches

We searched the following databases using the search terms and

strategy described in Appendix 1: Cochrane Infectious Diseases

Group Specialized Register (February 2011); Cochrane Central

Register of Controlled Trials (CENTRAL), published in The

Cochrane Library (2011, Issue 2); MEDLINE (1966 to February

2011); EMBASE (1974 to Febrary 2011); and LILACS (1982 to

February 2011). We also searched the metaRegister of Controlled

Trials (mRCT) in February 2011 using the search term “(typhoid

fever) NOT vaccine”.

Searching other resources

Researchers



We contacted Christiane Dolecek (in October, 2010) who pro-

vided information on unpublished and ongoing trials.

Reference lists and review authors’ personal collections

We also checked the reference lists of all retrieved trials and

searched the review authors’ personal literature collections for rel-

evant trials.

Data collection and analysis

Selection of studies

Two review authors, Emmanuel E Effa (EEE) and Zohra S Lassi

(ZSL), independently assessed all the potential studies identified

by the search strategy and applied the inclusion criteria. Any

disagreements were resolved through discussion. The excluded

studies, and the reason for their exclusion are included in the

’Characteristics of excluded studies’.

Data extraction and management

For eligible studies, two review authors (EEE and ZSL) extracted

the data using a pre-tested data extraction form. For dichotomous

outcomes, such as clinical failure, we extracted the total number

of participants and number of participants that experienced the

event. For continuous outcomes, such as fever clearance time, we

extracted the total number of participants, arithmetic means, and

standard deviations. If the standard deviation was not reported,

we attempted to use the confidence interval or P value to derive

it. The extracted data were entered data into Review Manager 5.1.

and cross-checked by a second author for accuracy.

Assessment of risk of bias in included studies

Two review authors (EEE and ZSL) independently assessed the

risk of bias for each included trial using the Cochrane collabora-

tion’s ’Risk of bias’ tool as described in the Cochrane Handbook of

Systematic Reviews of Intervention (Higgins 2011).

We followed the guidance to assess whether adequate steps were

taken to reduce the risk of bias across six domains: sequence gen-

eration, allocation concealment, blinding (of participants, person-

nel and outcome assessors), incomplete outcome data, selective

outcome reporting and other sources of bias. We have categorized

our judgements as ’yes’ (low risk of bias), ’no’ (high risk of bias)

or ’unclear’. We compared our entries and resolved disagreements

by discussion.

The risk of bias judgements are displayed in a table and sum-

marised in Figure 1 and Figure 2.

Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Measures of treatment effect

Dichotomous data are presented and compared using risk ratios

(RR), and continuous data using a mean difference (MD). All re-

sults are presented with the corresponding 95% confidence inter-

val (CI).

Unit of analysis issues

Trials including more than two comparison groups have been split

and analysed as individual pair-wise comparisons. When conduct-

ing meta-analysis we have ensured that participants and cases in

the placebo group are not counted more than once, by dividing

the placebo cases and participants evenly between the intervention

groups.

Dealing with missing data

We were unable to conduct an intention-to-treat analysis on cul-

ture-positive cases since no further information was available for

culture-positive participants who were lost to follow up.

Assessment of heterogeneity

We assessed for heterogeneity by visually inspecting the forest plots

and by using the Chi2 test for homogeneity, using a 10% level of

statistical significance to indicate statistical heterogeneity.

Assessment of reporting biases

We planned to assess for the presence of publication bias by looking

for funnel plot asymmetry but this was not possible due to the low

number of trials.

Data synthesis

We analysed data using Review Manager 5.1.

We analysed data using pair-wise comparisons. we compared the

fluoroquinolones with each alternative antibiotic and subgrouped

by the specific fluoroquinolone. The data are organised into four

sections:

• fluoroquinolones versus first-line antibiotics (chloramphenicol,

co-trimoxazole, and ampicillin or amoxicillin);

• fluoroquinolones versus second-line antibiotics (cefixime,

ceftriaxone, azithromycin);

• comparison of different fluoroquinolones and different

durations of fluoroquinolones;

• a summary of the evidence for gatifloxacin

Where there is no statistical heterogeneity we have used the fixed-

effect model. Where statistical heterogeneity was detected, and

we still considered it appropriate to pool the data, we used the

random-effects model.

Subgroup analysis and investigation of heterogeneity

We planned to investigate heterogeneity by conducting subgroup

analyses according to; drug dose; severe or complicated enteric

fever (as defined by trialists) versus uncomplicated enteric fever;

and different time points for outcome measurements. This was not

possible due to the limited number of trials in each comparison.

We have instead commented on these factors within the text where

appropriate.

Sensitivity analysis

We planned to assess the robustness of the data by performing a

sensitivity analysis for each of the risk of bias assessment factors,

but were again unable to do this due to the low number of trials.

R E S U L T S

Description of studies

Results of the search

We assessed 72 trials for eligibility. Twenty-six were included and

36 excluded. Seven studies are awaiting classification and one trial

is ongoing.

Among the seven trials awaiting classification; we were unable to

retrieve full text copies for two (Flores 1991; Soewandojo 1992),

and four did not provide adequate information on the method-

ology for inclusion (Quintero 1988; Weng 1996, Xiao 1991, Yu

1998). (See the Characteristics of studies awaiting classification

table).

Included studies

The 26 trials included 3033 participants. Most trials were small

and lacked statistical power to detect differences between the treat-

ment regimens. The smallest trial had 23 participants and the

largest had 352 participants.



Trial setting

Nine trials were conducted in Vietnam, two trials in each of Italy,

Nepal and Pakistan, and one trial in each of Albania, Bahrain,

Bangladesh, Egypt, Guatemala, Indonesia, Laos, Morocco and

Turkey. We could not determine the location of one trial (Gottuzzo

1992 N/A).

Twenty-two of the 26 trials were conducted on inpatients. Alam

1995 BGD was conducted on both inpatients and outpatients.

Tran 1995 VNM was a community-based outpatient trial, while

Pandit 2007 NPL and Arjyal 2011 recruited outpatients present-

ing to the outpatient or emergency department of the study hos-

pital.

Twenty-two trial reports included data on the prevalence of MDR

strains among trial participants, and 13 trial reports included data

on the prevalence of NaR strains.

Of the 13 trials comparing fluoroquinolones with first-line antibi-

otics, MDR strains were only present in two trials (Phongmany

2005 LAO; Arjyal 2011), they were absent in seven trials, and four

trials did not report it (Gottuzzo 1992 N/A; Yousaf 1992 PAK;

Flores 1994 MEX; Rizvi 2007 PAK).

See Appendix 2 for further details on microbiological results and

sensitivity.

Participants

Three trials were exclusively in children (Vinh 1996 VNM;

Phuong 1999 VNM; Vinh 2005 VNM). Seven trials included

both children and adults (Alam 1995 BGD; Tran 1995 VNM;

Pandit 2007 NPL; Parry 2007 VNM;Rizvi 2007 PAK; Dolecek

2008 VNM; Arjyal 2011), 15 trials were exclusively in adults (Hajji

1988 MAR; Limson 1989 PHL; Gottuzzo 1992 N/A; Morelli

1992 ITA; Yousaf 1992 PAK; Wallace 1993 BHR; Smith 1994

VNM; Cristiano 1995 ITA; Unal 1996 TUR; Chinh 1997 VNM;

Kalo 1997 ALB; Girgis 1999 EGY; Chinh 2000 VNM; Gasem

2003 IDN; Phongmany 2005 LAO), and five trial reports did

not mention the participants’ age of which one used the keyword

“adult” (Flores 1994 MEX).

Eighteen trials were conducted specifically on participants with

uncomplicated enteric fever or participants without major com-

plications of enteric fever (Limson 1989 PHL; Gottuzzo 1992

N/A; Wallace 1993 BHR; Flores 1994 MEX; Tran 1995 VNM;

Unal 1996 TUR; Vinh 1996 VNM; Vinh 2005 VNM; Phuong

1999 VNM; Chinh 1997 VNM; Girgis 1999 EGY; Chinh 2000

VNM; Gasem 2003 IDN; Phongmany 2005 LAO; Pandit 2007

NPL; Parry 2007 VNM; Dolecek 2008 VNM; Arjyal 2011 ), and

one included only participants with severe enteric fever (Cristiano

1995 ITA). The remaining trials did not provide this information.

Most trials used blood cultures, bone marrow cultures, or both,

to confirm cases of enteric fever. In Rizvi 2007 PAK, a rapid di-

agnostic test - Dot Enzyme immunosorbent Assay - was also used

although all but one participant was culture positive.

Trials that included patients diagnosed clinically tended to report

outcomes only for culture-confirmed cases of enteric fever and

excluded culture-negative cases from their analysis, even if initially

enrolled in the study. Only Arjyal 2011 detailed analyses were

done both reporting culture positive cases only and intention to

treat which included patients randomized but who were culture

negative..

Interventions

Nineteen trials compared fluoroquinolones with alternative an-

tibiotics: chloramphenicol (eight trials), amoxicillin or ampicillin

(two trials), co-trimoxazole (three trials), azithromycin (four tri-

als), ceftriaxone (two trials), and cefixime (three trials). Seven tri-

als compared different fluoroquinolone treatment durations: two

days versus three days (three trials); three days versus five days (one

trial), five days versus seven days (one trial); seven days versus 10

days (one trial); and 10 days versus 14 days (one trial).

Most trials comparing fluoroquinolones with a non-fluoro-

quinolone antibiotic treated the participants with the fluoro-

quinolone for seven (eight trials) or 10 days (six trials) (range: three

to 15 days).

Outcomes

There were considerable variations regarding the time points at

which outcomes were measured, particularly microbiological fail-

ure (such as day two, the end of treatment, and some days af-

ter treatment) and relapse (such as during therapy or up to two

months after treatment completion). The precise descriptions also

varied considerably; for example, some trialists defined “relapse”

as the recurrence of similar signs and symptoms with confirma-

tion by blood and/or bone marrow culture (sterile site, as defined

in protocol), and others as confirmed by positive stool cultures

(non-sterile site) only. Some trialists did not explicitly state how

they confirmed relapse in their trial (see Appendix 3 ’Definitions

of outcomes’). A full summary of adverse events as stated in the

papers is summarized in Appendix 4 and Appendix 5.

Further details are presented in the Characteristics of included

studies tables.

Excluded studies

Of the excluded studies, five were excluded as they used norfloxacin

(Nalin 1987; Sarma 1991; Huai 2000; Bai 1995; ZhongYang

1997), and three involved fluoroquinolones no longer in clinical

use (Abejar 1993; Arnold 1993; Tran 1994). (For further details

see the Characteristics of excluded studies table).

Risk of bias in included studies

See summary of ’risk of bias’ assessment in Figure 2



Allocation

The method used to generate the allocation sequence was at low

risk of bias in sixteen trials, and unclear in ten.

Fourteen trials used an adequate method (sealed envelopes) to

conceal allocation. The method used in the remaining 12 trials

was unclear.

Blinding

Three trials were described as “double blinded” and 22 trials were

open; one trial did not mention use of placebo, but we assumed it

was open (Flores 1994 MEX). In one trial, blinding was unclear

(Rizvi 2007 PAK).

Incomplete outcome data

There were incomplete long term outcome data reported for four

trials (Smith 1994 VNM; Vinh 1996 VNM; Gasem 2003 IDN;

Phongmany 2005 LAO). The reason for this was unclear.

Selective reporting

Most trials reported both efficacy and safety data. In one trial

(Wallace 1993 BHR), there were no reports of adverse events while

in another, the report was incomplete as only mortality and associ-

ated data for one participant were reported (Phuong 1999 VNM).

Other potential sources of bias

Two trials were stopped early. One because of a significant dif-

ference in the primary outcome (Phongmany 2005 LAO), and

one due to apparent lower efficacy in the control group, the cost

of control drug and inconvenience of intravenous administration

(Wallace 1993 BHR). Two trials were funded by pharmaceutical

companies (Alam 1995 BGD; Girgis 1999 EGY)

Effects of interventions

Fluoroquinolones versus first-line antibiotics

(chloramphenicol, co-trimoxazole, and ampicillin or

amoxicillin)

Comparison 1. Fluoroquinolones versus chloramphenicol

Overall, a seven-day course of any fluoroquinolone appears at

least as effective as a 14-day course of chloramphenicol at reduc-

ing clinical and microbiological treatment failures (eight tri-

als, 916 participants). In the most recent study, from Pakistan

in 2003-04, high failure rates were seen with chloramphenicol,

and the fluoroquinolones used (ciprofloxacin and ofloxacin)

were superior.

Eight trials have compared four different fluoroquinolones with

chloramphenicol: Four trials used ciprofloxacin as the comparator

drug (Gottuzzo 1992 N/A; Morelli 1992 ITA; Gasem 2003 IDN;

Rizvi 2007 PAK), four trials used ofloxacin (Morelli 1992 ITA;

Yousaf 1992 PAK; Phongmany 2005 LAO; Rizvi 2007 PAK), two

used pefloxacin (Morelli 1992 ITA; Cristiano 1995 ITA), and one

trial assessed gatifloxacin (Arjyal 2011).

Two studies did not clarify the proportion of participants with

MDR strains (Gottuzzo 1992 N/A; Yousaf 1992 PAK), and seven

did not report NaR data. The dosing of fluoroquinolones varied

from trial to trial and is included in the forest plots as footnotes

to aid interpretation.

Clinical and microbiological response

Only one three-arm study, from Pakistan in 2003-04, demon-

strated a statistically significant benefit with fluoroquinolones

compared to chloramphenicol (Rizvi 2007 PAK). The incidence

of clinical and microbiological failure with chloramphenicol was

high in this trial (9/44) suggesting significant resistance, although

this was not confirmed microbiologically. Clinical failures were

lower with both ciprofloxacin (RR 0.05, 95% CI 0.00 to 0.81, 92

participants, one trial, Analysis 1.1; Analysis 1.2), and ofloxacin

(RR 0.05, 95% CI 0.00 to 0.86, 89 participants, one trial, Analysis

1.1; Analysis 1.2).

Conversely, the largest trial to date found no significant difference

between gatifloxacin and chloramphenicol in Nepal in 2006-08

(352 participants, one trial, Analysis 1.1; Analysis 1.2). The re-

maining older trials were too small to detect clinically important

differences between the treatment regimens should they exist.

Relapse and convalescent faecal carriage

The current trials have not shown a statistically significant differ-

ence in post-treatment relapses or fecal carriage with any fluoro-

quinolone compared to chloramphenicol ( participants, six trials,

Analysis 1.5; Analysis 1.6). The follow-up in the included trials

varied from two weeks to six months.

Fever clearance time

Fever clearance time was significantly longer with chloramphenicol

compared with ciprofloxacin (MD -62.46, 95% CI -75.52 to -

49.39, 147 participants, two trials, Analysis 1.5) and ofloxacin

(MD -75.85, 95% CI -88.52 to -63.17, 140 participants, two

trials, Analysis 1.5).

Duration of hospitalisation

Participants who had chloramphenicol in Phongmany 2005 LAO,

stayed a significantly longer number of days in hospital compared



with ofloxacin (MD -9.90, 95% CI -11.42 to -8.38, 60 partic-

ipants, one trial, Analysis 1.6). However, we note that ofloxacin

was given only for three days compared to the 14 days of chloram-

phenicol, so this is perhaps unsurprising.

Adverse events

No difference has been shown between ciprofloxacin and chlo-

ramphenicol (173 participants, two trials, Analysis 1.7), or

ofloxacin and chloramphenicol where no serious adverse events

were recorded (50 participants, one trial, Analysis 1.7).

Non-serious adverse events were significantly lower following

treatment with gatifloxacin than with chloramphenicol (RR 0.58,

95% CI 0.44 to 0.78, 844 participants, one trial, Analysis 1.8).

This data included all randomized participants including those

who were culture negative. The events were mainly gastrointesti-

nal in nature and the common ones included abdominal pains,

diarrhoea, nausea and vomiting. Elevated blood sugar was more

common in the gatifloxacin group between the second and sev-

enth days of the study. There was no difference in the number of

participants with low blood sugar for both groups.

The differences between the other fluoroquinolones and chloram-

phenicol did not reach statistical significance (Analysis 1.8).

Comparison 2. Fluoroquinolones versus cotrimoxazole

In one study, from an area of Pakistan in 2003-04, the fluo-

roquinolones used (ciprofloxacin and ofloxacin) were superior

to co-trimoxazole. Two small trials done in the 1980s, in the

absence of MDR strains, failed to show a difference with both

drugs performing well.

Three trials have compared three different fluoroquinolones with

cotrimoxazole: two trials used ciprofloxacin; Limson 1989 PHL;

Rizvi 2007 PAK, and one trial each assessed ofloxacin; Rizvi 2007

PAK, and pefloxacin; Hajji 1988 MAR.

Hajji 1988 MAR and Limson 1989 PHL both report the absence

of MDR strains and Hajji 1988 MAR also records that there were

no participants with NaR strains. Limson 1989 PHL and Rizvi

2007 PAK do not report the presence or absence of NaR strains.


Of the three trials, only Rizvi 2007 PAK reports any clinical fail-

ures at all. In this trial, from Pakistan in 2003-04, there was a

high incidence of clinical and microbiological failure following

treatment with co-trimoxazole (13/44) suggesting significant re-

sistance, compared with no clinical failures following ciprofloxa-

cin (RR 0.03, 95% CI 0.00 to 0.56, 92 participants, one trial,

Analysis 2.1) or ofloxacin (RR 0.04, 95% CI 0.00 to 0.59, 89

participants, one trial, Analysis 2.1).

The high failure rate with co-trimoxazole is the likely cause of the

longer fever clearance time observed by Rizvi 2007 PAK (Analysis

2.5)


Only Rizvi 2007 PAK assessed for relapses, and only Hajji 1988

MAR assessed for convalescent faecal carriage, but there were no

events in either trial.

Fever clearance and duration of hospitalisation

Not reported

Adverse events

Serious adverse events were not reported.

No statistically significant difference in non-serious events has

been shown between any individual fluoroquinolone and co-tri-

moxazole (219 participants, three trials, Analysis 2.6). The events

were mainly gastrointestinal in nature and were self limiting.

Comparison 3. Fluoroquinolones versus amoxicillin or

ampicillin

Two small studies conducted in the 1990s, found that ofloxacin

given for 10 to 14 days reduced clinical and microbiological

failures compared to a 10 to 14 day course of amoxicillin or

ampicillin. The prevalence of antibiotic resistance was not re-

ported.

One small trial has compared ofloxacin with ampicillin (Flores

1994 MEX), and another compared ofloxacin with amoxicillin

(Yousaf 1992 PAK)

There was no indication as to the presence or not of MDR or NaR

strains.


The risk of clinical or microbiological failure was significantly

lower in the ofloxacin group compared to ampicillin or amoxi-

cillin (RR 0.11, 95% CI 0.02 to 0.57, 90 participants, two trials,

Analysis 3.1; RR 0.13; 95% CI 0.03 to 0.68, 90 participants, two

trials, Analysis 3.2 respectively). It should be noted that these two

trials are almost 20 years old and may not be relevant today.


Not reported

Fever clearance and duration of hospitalization

Not reported



Adverse events

No serious adverse events occurred in either of the studies. Non-

serious events were significantly more following treatment with

ofloxacin compared to amoxicillin (RR 0.27; 95% CI 0.09 to 0.86,

50 participants, one trial, Analysis 3.3). The reported events were

mostly diarrhoea and skin rashes.

Fluoroquinolones versus second-line antibiotics

(cefixime, ceftriaxone, azithromycin)

Comparison 4. Fluoroquinolones versus cefixime

In one study from Pakistan in 2003-04 no clinical or microbio-

logical failures were seen with either ciprofloxacin, ofloxacin or

cefixime. In Nepal in 2005, gatifloxacin reduced clinical failure

and relapse compared to cefixime, despite a high prevalence of

NaR in the study population.

Three trials have compared a fluoroquinolone with cefixime. One

trial used ciprofloxacin as the comparator drug (Rizvi 2007 PAK),

two trials used ofloxacin (Phuong 1999 VNM; Rizvi 2007 PAK)

and one gatifloxacin (Pandit 2007 NPL).

In one trial, participants were mostly adults (Pandit 2007 NPL)

while one trial had only child participants (Phuong 1999 VNM).

The third trial included both adult and child participants (Rizvi

2007 PAK). One trial (Pandit 2007 NPL) had a high proportion

of NaR strains, but the other two trials did not report the presence

of these strains ( Phuong 1999 VNM; Rizvi 2007 PAK). In Pandit

2007 NPL, because of its wholly out patient status, community

medical auxiliaries conducted twice daily home-based assessments

and provided directly observed treatment with study drugs. All

participants were then compulsorily seen at the hospital on Day

10.


Of the three tested fluoroquinolones, only gatifloxacin has demon-

strated a statistically significant reduction in clinical failure com-

pared to cefixime (RR 0.04, 95% CI 0.01 to 0.31, 158 partici-

pants, one trial, Analysis 4.1). Microbiological failures were too

low across all three trials to demonstrate any significant differences

for any of the comparisons (379 participants, three trials, Analysis

4.2).


Only gatifloxacin has demonstrated a statistically significant re-

duction in relapse (RR 0.20, 95% CI 0.04 to 0.93, 138 partici-

pants, one trial, Analysis 4.3). There were no reported incidents

of faecal carriage.

Fever Clearance and duration of hospital stay

Fever clearance time was significantly shorter for ofloxacin (MD -

24.00, 95% CI -41.46 to -6.54, one trial, 91 participants, Analysis

4.5). There was a statistically significant difference in the median

time to fever clearance for gatifloxacin (92 hours vs 138 hours, P

<0.0001) and ofloxacin (105 hours vs 201 hours, P <0.0001). This

reductions for ofloxacin were also reflected in the shorter length

of hospital stay in that group (MD -3.00, 95% CI -4.53 to -1.47,

80 participants, one trial, Analysis 4.6).

Adverse events

Serious adverse events were low in two trials comparing ofloxacin

and gatifloxacin with cefixime but there was no significant dif-

ference between the comparisons (251 participants, two trials,

Analysis 4.7).

Non-serious adverse events appear to be higher with gatifloxacin

than with cefixime (RR 20.92, 95% CI 2.9 to 150.90, 169 par-

ticipants, one trial, Analysis 4.8). However it is not clear whether

adverse events were completely reported in this trial. No difference

has been shown between ciprofloxacin or ofloxacin and cefixime.

Comparison 5. Fluoroquinolones versus ceftriaxone

Two studies, conducted almost 20 years ago, compared five to

seven days of an oral fluoroquinolone with three days of intra-

venous ceftriaxone, and were too small to demonstrate impor-

tant differences if they exist. The prevalence of NaR strains was

either absent or unreported.

One trial has compared ciprofloxacin with ceftriaxone (Wallace

1993 BHR), and one trial compared ofloxacin (Smith 1994

VNM).

In both trials, over half of participants had MDR strains. There

were no participants with NaR strains in Smith 1994 VNM

whereas the proportion was not stated in Wallace 1993 BHR.

Sample sizes for these studies were quite small resulting in very

wide confidence intervals.


The proportion of clinical failures was lower with fluoroquinolones

but the result was not statistically significant (89 participants, two

trials, Analysis 5.1). Only one microbiological failure is reported

in either group (Analysis 5.2).


The incidence of relapse and faecal carriage following treatment

was very low with no differences between both groups (42 partic-

ipants, one trial, Analysis 5.3; Analysis 5.4).

Fever clearance and duration of hospitalization

Only Smith 1994 VNM reported adequate data for the fever clear-

ance time which was significantly shorter with ofloxacin (MD -

115.0; 95% CI -150.67 to -79.33, 47 participants, 1 trial, Analysis

5.5). In Wallace 1993 BHR, mean fever clearance times for the

ciprofloxacin and ceftriaxone groups were 4 and 5.2 days respec-

tively. No standard deviation was reported but the P value was

given as 0.04.



Similarly, only Smith 1994 VNM reported the duration of hos-

pitalization which averaged nine days (range: 6 to 13 days) in the

ofloxacin group and 12 days (range: 7 to 23 days) in the ceftriax-

one group. No values for standard deviation were reported but a

P value was given as 0.01.

Adverse events

No serious adverse events were reported. Non-serious events were

few, mild and self limiting in both groups in the only trial that

recorded them (47 participants, 1 trial, Analysis 5.6).

Comparison 6. Fluoroquinolones versus azithromycin

Azithromycin was superior to ofloxacin in reducing clinical

failures and convalescent faecal carriage in populations with

both MDR and NaR enteric fever in Vietnam. The most recent

study, also from Vietnam, found no difference between gati-

floxacin and azithromycin with both drugs performing well.

Four trials involving 564 participants made this comparison.

One trial each compared ciprofloxacin with azithromycin (Girgis

1999 EGY, 64 participants) and gatifloxacin with azithromycin

(Dolecek 2008 VNM, 287 participants). Two trials compared

ofloxacin with azithromycin (Chinh 2000 VNM, 88 participants

and Parry 2007 VNM, 125 participants).

In Girgis 1999 EGY, a third of participants were infected with

MDR strains. The proportion of NaR strains was not reported.

The other trials had varying proportions of participants with MDR

and NaR strains.


Treatment with azithromycin resulted in a statistically significant

decrease in clinical failures compared to ofloxacin (RR 2.20, 95%

CI 1.23 to 3.94, 213 participants, two trials, Analysis 6.1), but no

difference has been shown between ciprofloxacin (64 participants,

one trial, Analysis 6.1), or gatifloxacin (287 participants, one trial,

Analysis 6.1)

No statistically significant difference in microbiological failure has

been seen in any of the trials comparing fluoroquinolones with

azithromycin (564 participants, four trials, Analysis 6.2).


No statistically significant difference in relapse rate has been seen

in any of the trials comparing fluoroquinolones with azithromycin

(479 participants, 4 trials, Analysis 6.3).

Convalescent faecal carriage was lower in the azithromycin group

compared with ofloxacin (RR 13.52, 95% CI 2.64 to 69.36, 193

participants, 2 trials, Analysis 6.4), but no difference has been

shown between ciprofloxacin (64 participants, 1 trial, Analysis

6.4), or gatifloxacin (268 participants, 1 trial, Analysis 6.4)

Fever clearance time

No consistent statistically significant difference in fever clearance

has been shown between any of the fluoroquinolones and azithro-

mycin (564 participants, four trials, Analysis 6.5).

Duration of hospitalization

There was a statistically significant reduction in the duration of

hospital stay in the ofloxacin group (RR 1.01, 95% CI 0.19 to

1.83, 213 participants, two trials, Analysis 6.6)

Adverse events

No significant difference in serious events has been seen between

the ofloxacin with azithromycin groups (88 participants, 1 trial,

Analysis 6.7). Overall, non-serious adverse events were similar

across all the trials (564 participants, four trials, Analysis 6.8).

Head to head comparisons of different

fluoroquinolones or different durations of treatment

Differences in efficacy between the different fluoroquinolones

has not been demonstrated in head to head clinical trials.

The different fluoroquinolones have only been compared as part

of multiple arm studies (Morelli 1992 ITA; Rizvi 2007 PAK).

In these studies no clinical or microbiological failures, or relapses

were seen in the fluoroquinolone treatment arms (see Analysis 1.1;

Analysis 1.2; Analysis 1.3).

None of the comparisons demonstrated one duration was su-

perior to another for failure or relapse, even in the presence

of MDR and NaR strains. Studies were generally too small to

detect what might be important differences.

Comparison 7. Fluoroquinolones for two days versus three

days

Three trials made this comparison: one in adults (Chinh 1997

VNM) and two in children (Vinh 1996 VNM; Vinh 2005 VNM).

They were all ofloxacin trials. All three trials reported the percent-

age of participants with NaR and MDR strains. These were 2.5.%

and 90% (Vinh 2005 VNM), 5% and 79% (Chinh 1997 VNM),

and 13% and 84% (Vinh 1996 VNM), respectively.

There were no statistically significant differences for all the out-

comes in either groups of the trials. There were no serious adverse

events.

Comparison 8. Fluoroquinolones three days versus five days

Only one trial (Tran 1995 VNM) with over 70% children com-

pared three days with five days of ofloxacin. The majority of S. ty-

phi isolates (91%) were MDR. Some participants had NaR strains,

although the precise number of these participants was not avail-

able.



Fever clearance time was significantly shorter in the three day

group compared with the five day group (MD -12.0; 95% CI -

18.07 to -5.93,195 participants, one trial, Analysis 8.2). There

were no differences in the risk of relapse and adverse events in

either groups.

Comparison 9. Fluoroquinolone five days versus seven days

One trial made this comparison (Unal 1996 TUR) with pe-

floxacin. Thirteen percent of the strains were MDR. There was no

report of the proportion with NaR strains.

There were no clinical failures in either arm, and we did not detect a

statistically significant difference in microbiological failure, relapse

and fever clearance time. Adverse events were not serious and they

were similar in both groups.

Comparison 10. Fluoroquinolone seven days versus 10 or 14

days

One trial compared pefloxacin for seven days with 10 days (Kalo

1997 ALB) in a population wholly infected with ampicillin resis-

tant S. typhi some of whom were MDR. The proportion of par-

ticipants with NaR strains was not reported.

There was no statistically significant difference in microbiological

failure. There were no clinical failures or convalescent faecal car-

riers. Adverse events were mild and self limiting.

Comparison 11. Fluoroquinolone 10 days versus 14 days

One trial, with 7% of the participants infected with NaR strains,

made this comparison (Alam 1995 BGD). There was no statisti-

cally significant difference in relapse or fever clearance time. There

were no clinical or microbiological failures, or convalescent faecal

carriers. Adverse events (gastrointestinal symptoms, headache and

rashes in both arms, and one case of joint pain in the 14-day arm)

were mild and self limiting.

Summary of gatifloxacin comparisons

In the light of the emerging interest in gatifloxacin, we have sum-

marised the results in this section for this one drug.

One trial each compared gatifloxacin with chloramphenicol

(Arjyal 2011), cefixime (Pandit 2007 NPL) and azithromycin

(Dolecek 2008 VNM). All the trials had a majority of participants

infected with NaR strains equally distributed between groups. In

Pandit 2007 NPL and Arjyal 2011, MDR strains were negligible

(0.58% and 0% respectively). All the trials were conducted in ar-

eas previously known to have a high prevalence of MDR and NaR

salmonella isolates.

Comparison 13. Gatifloxacin versus chloramphenicol

No statistically significant difference has been shown in the risk

of clinical or microbiological failure, or relapse, between a 7-day

course of gatifloxacin and 14 days of chloramphenicol in Nepal

(352 participants, one trial, Analysis 11.1). Treatment with gati-

floxacin may however be associated with fewer adverse events (RR

0.58, 95% CI 0.44 to 0.78, 844 participants, one trial, Analysis

11.1).

Comparison 14. Gatifloxacin versus cefixime

Compared to 7-days of cefixime, a 7-day course of gatifloxacin was

shown to produce a statistically significant reduction in clinical

failure (RR 0.04; 95% CI 0.01 to 0.31, 158 participants, one trial,

Analysis 13.1), and relapse (RR 0.2; 95% CI 0.04 to 0.93, 138

participants, one trial, Analysis 13.1) in Nepal. There was however

no difference in microbiological failure assessed at day 10 (158

participants, one trial, Analysis 13.1). Gatifloxacin was associated

with a statistically significant increase in adverse events (RR 19.25,

95% CI 2.66 to 139.30, 169 participants, one trial, Analysis 13.1).

The events were mainly vomiting and in two cases, this was severe

enough to require intravenous fluids.

Comparison 15. Gatifloxacin versus azithromycin

No statistically significant difference has been shown in the risk

of clinical or microbiological failure, or relapse, between a 7-day

course of gatifloxacin and 7 days of azithromycin in Vietnam (287

participants, one trial, Analysis 14.1). There is also no evidence of

a difference in the incidence of adverse events (285 participants,

one trial, Analysis 14.1).

D I S C U S S I O N

Summary of main results

Fluoroquinolones versus older antibiotics

In one study from Pakistan in 2003-04, high clinical failure rates

were seen with both chloramphenicol and co-trimoxazole, al-

though resistance was not confirmed microbiologically. A seven

day course of either ciprofloxacin or ofloxacin was found to be

superior. Older studies of these comparisons failed to show a dif-

ference.

In two small studies conducted almost two decades ago the fluo-

roquinolones were demonstrated to be more effective than ampi-

cillin and amoxicillin.



Fluoroquinolones versus current second-line options

The two studies comparing a seven day course of oral fluoro-

quinolones with three days of intravenous ceftriaxone were too

small to detect important differences between antibiotics should

they exist.

In Pakistan in 2003-04 no clinical or microbiological failures were

seen with seven days of either ciprofloxacin, ofloxacin or cefixime.

In Nepal in 2005, gatifloxacin reduced clinical failure and relapse

compared to cefixime, despite a high prevalence of NaR in the

study population.

Compared to a seven day course of azithromycin, a seven day

course of ofloxacin had a higher rate of clinical failures in pop-

ulations with both MDR and NaR enteric fever in Vietnam in

1998-2002. However, the most recent study, also from Vietnam

in 2004-05, found no difference between gatifloxacin and azithro-

mycin, with both drugs performing well.

Fluoroquinolones versus alternative fluoroquinolones

Differences in efficacy between the available fluoroquinolones, or

between different durations of treatment with an individual fluo-

roquinolone, have not been demonstrated in head to head clinical

trials.

Adverse events

Overall, the adverse event profiles were similar for the fluo-

roquinolone and non-fluoroquinolone antibiotics. They were

mostly mild and self limiting.The risk of dysglycaemia with gati-

floxacin has been reported in several studies (Frothingham 2005,

Park-Wyllie 2006). However, in the three studies included in this

review which report on dysglycaemia ( Pandit 2007 NPL; Dolecek

2008 VNM; Arjyal 2011), no difference was detected in the risk

of hypoglycaemia or hyperglycaemia among those studied

Overall completeness and applicability ofevidence

Most of the included trials were conducted on inpatients and may

not be representative of the majority of settings where most enteric

fever is managed as outpatients. The data are likely to represent a

subset of patients with more severe illness who may respond less

favourably to conventional therapy.

The changing epidemiology of resistance patterns across various

regions precludes any generalization of the results of the included

studies. Indeed, some included studies are nearly two decades old

and thus may not be useful in informing practice.

In addition, overall, there are too few studies in each compari-

son, and the studies themselves are too small, to make any firm

conclusions on the prescience or absence of important differences

between the different treatment options.

Potential biases in the review process

Although we found several trials from China, and published in

the Chinese language, we were unable to extract adequate details

on the trial methodology to allow inclusion. These studies are

listed in the ’Studies awaiting assessment’ table. A recent study of

over 30,000 apparent RCTs in China showed that only 6.8% were

authentic RCTs (Wu 2009).

Agreements and disagreements with otherstudies or reviews

In our previous update (Thaver 2008), different types of fluoro-

quinolone were combined in the meta analyses in spite of their

dissimilarity. In this revision, we have analysed them separately

with the intention of highlighting the effectiveness of different

fluoroquinolones. We also considered the changing pattern of re-

sistance across various regions over different times.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Generally, fluoroquinolones performed well in the treating ty-

phoid. Generally, fluoroquinolones performed well in the treating

typhoid, and maybe superior to alternatives in some settings. How-

ever, we were unable to draw firm general conclusions on com-

parative contemporary effectiveness given that resistance changes

over time, and many studies were small. In choosing any fluoro-

quinolone, clinicians need to take into account current, local re-

sistance patterns.

There is some evidence that the newest fluoroquinolone, gati-

floxacin, remains effective in some regions where resistance to older

fluoroquinolones has developed. However, the different fluoro-

quinolones have not been compared directly in head to head trials.

Implications for research

The re-emergence of chloramphenicol sensitive strains in some

regions may suggest a similar trend for other first line drugs which

had been abandoned following prevalent MDR. Trials may there-

fore focus on re-examining these relatively inexpensive alternatives

in robust comparisons with fluoroquinolones in appropriate en-

demic populations.

Most of the studies were small . Given the importance of the study

question, we would recommend multi-centred, adequately pow-

ered trials, with robust methods and analytical design. Given the

nature of the disease and the importance of accurate diagnoses,

we would recommend the development of robust diagnostic tests

and gold standards for defining disease and resistance patterns,



based on molecular methods if possible. Rapid diagnostic tests for

diagnosing enteric fever should be made more widely available in

endemic areas; this will ensure more efficient participant recruit-

ment in trials and avoid the problem of syndromic treatment. In

addition, it will reduce the widespread abuse of antibiotics, espe-

cially the use of fluoroquinolones for suspected typhoid fever.

Definitions of outcomes and their measurement should also be

standardized to make more effective comparisons and adaptability

across regions.

A C K N O W L E D G E M E N T S

Emmanuel Effa’s fellowship to Liverpool School of Tropical

Medicine, and the update of this review was supported by a grant

from the World Health Organization. The Cochrane Infectious

Diseases Group is funded by the UK Department for Interna-

tional Development (DFID) for the benefit of low- and middle-

countries.

We acknowledge Vittoria Lutje, Trials Search Co-ordinator for the

CIDG for assistance with the searches as well as staff of the CIDG

for assistance during the process of updating the review.

The Contact Editor for this review was Dr Mical Paul.

Thanks to Durrane Thaver, who wrote the original and first update

of this review. She is fondly remembered by all of us that knew

her.

R E F E R E N C E S

References to studies included in this review

Alam 1995 BGD {published data only}

Alam MN, Haq SA, Das KK, Baral PK, Mazid MN,

Siddique RU, et al. Efficacy of ciprofloxacin in enteric

fever: comparison of treatment duration in sensitive and

multidrug resistant salmonella. American Journal of Tropical

Medicine and Hygiene 1995;53(3):306–11.

Arjyal 2011 {published data only}

Arjyal A, Basnyat B, Koirala S, Karkey A, Dongol S,

Agrawaal KK, Shakya N, Shrestha K, Sharma M, Lama S,

Shrestha K, Khatri NS, Shrestha U, Campbell JI, Baker

S, Farrar J, Wolbers M, Dolecek C. Gatifloxacin versus

choramphenicol: An open, randomized controlled trial in

the treatment of uncomplicated enteric fever. Lancet Infect

Dis 2011;11(6):445–454.

Chinh 1997 VNM {published data only}

Chinh NT, Solomon T, Mai XT, Nguyen TL, Nguyen TT,

Wain J, et al. Short courses of ofloxacin for the treatment

of enteric fever. Transactions of the Royal Society of Tropical


Chinh 2000 VNM {published data only}

Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX,

Diep TS, et al. A randomized controlled comparison of

azithromycin and ofloxacin for treatment of multidrug-

resistant or nalidixic acid-resistant enteric fever.

Antimicrobial agents and chemotherapy 2000;44(7):1855–9.

Cristiano 1995 ITA {published data only}

Cirstiano P, Imparato L, Carpinelli C, Lauria F, Iovene MR,

Corrado MF, et al. Pefloxacin versus chloramphenicol in the

therapy of typhoid fever. Infection 1995;23(2):103–6.

Dolecek 2008 VNM {published data only}

Dolecek C, La TTP, Rang NN, Phuong LT, Tuan PQ,

DU DC, et al. A multi-center randomised controlled trial

of gatifloxacin versus azithromycin for the treatment of

uncomplicated typhoid and paratyphoid fever in children

and adults in Vietnam. PLoS ONE 2008;3(5):e2188.

Flores 1994 MEX {published data only}

Flores GR, Dorantes F, Aviles J. Safety and efficacy of oral

ofloxacin vs oral ampicillin in the management of typhoid.

Investigacion Medica Internacional 1994;21(2):88–92.

Gasem 2003 IDN {published data only}

Gasem MH, Keuter M, Dolmans WM, Van Der Ven-

Jongekrijg J, Djokomoeljanto R, Van Der Meer JW.

Persistence of Salmonellae in blood and bone marrow:

randomized controlled trial comparing ciprofloxacin

and chloramphenicol treatments against enteric fever.

Antimicrobial Agents and Chemotherapy 2003;47(5):

1727–31.

Girgis 1999 EGY {published data only}

Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM,

Tribble D, et al. Azithromycin versus ciprofloxacin for

treatment of uncomplicated typhoid fever in a randomized

trial in Egypt that included patients with multidrug

resistance. Antimicrobial Agents And Chemotherapy 1999;43

(6):1441–4.

Gottuzzo 1992 N/A {published data only}

Gottuzzo E, Carillo C. Typhoid fever. Evaluation of

the efficacy and safety of ciprofloxacin in comparison

with chloramphenicol. In: HL Dupont editor(s). Use

of quinolones in travel medicine. Second Conference on

International Travel Medicine, Atlanta, Georgia 1991. Berlin,

Germany: Springer-Verlag, 1992:16–22.

Hajji 1988 MAR {published data only}

Hajji M, el Mdaghri N, Benbachir M, el Filali KM,

Himmich H. Prospective randomized comparative trial of

pefloxacin versus cotrimoxazole in the treatment of typhoid

fever in adults. European Journal of Clinical Microbiology

and Infectious Diseases 1988;7(3):361–3.



Kalo 1997 ALB {published data only}

Kalo T, Davachi F, Nushi A, Dedja S, Karapici L, Como N,

et al. Therapeutic efficacy of perfloxacin in treatment of

ampicillin-resistant typhoid fever in 7 days versus 10 days.

International Journal of Infectious Diseases 1997;2(1):12–4.

Limson 1989 PHL {published data only}

Limson BM, Littaua RT. Comparative study of ciprofloxacin

versus co-trimoxazole in the treatment of Salmonella enteric

fever. Infection 1989;17(2):105–6.

Morelli 1992 ITA {published data only}

Morelli G, Mazzoli S, Tortoli E, Simonetti MT, Perruna F,

Postiglione A. Fluoroquinolones versus chloramphenicol in

the therapy of typhoid fever: a clinical and microbiological

study. Current Therapeutic Research 1992;52(4):532–42.

Pandit 2007 NPL {published data only}

Pandit, A, Arjyal, A, Day JN, Paudyal B, et al. An open

randomized comparison of gatifloxacin versus cefixime for

the treatment of uncomplicated enteric fever. PLoS ONE

2007;2(6):e542.

Parry 2007 VNM {published data only}

Parry CM, Ho VA, Phuong le T, Bay PV, Lanh MN, Tung

le T, et al. Randomized controlled comparison of ofloxacin,

azithromycin, and an ofloxacin-azithromycin combination

for treatment of multidrug-resistant and nalidixic acid-

resistant typhoid fever. Antimicrobial Agents Chemotherapy

2007;51(3):819–25.

Phongmany 2005 LAO {published data only}

Phongmany S, Phetsouvanh R, Sisouphone S, Darasavath

C, Vongphachane P, Rattanavong O, et al. A randomized

comparison of oral chloramphenicol versus ofloxacin in

the treatment of uncomplicated typhoid fever in Laos.

Transactions of the Royal Society of Tropical Medicine and

Hygiene 2005;99(6):451–8.

Phuong 1999 VNM {published data only}

Phuong CXT, Kneen R, Nguyen TA, Truong DL, White

NJ, Parry CM. A comparative study of ofloxacin and

cefixime for treatment of typhoid fever in children. The

Dong Nai Pediatric Center Typhoid Study Group. Pediatric

Infectious Disease Journal 1999;18(3):245–8.

Rizvi 2007 PAK {published data only}

Rizvi Q. Effeciveness of anti-typhoid drugs currently used

in Pakistan. Pakistan Journal of Surgery 2007;23(1):57–64.

Smith 1994 VNM {published data only}

Smith MD, Duong NM, Hoa NT, Wain J, Ha HD, Diep

TS, et al. Comparison of ofloxacin and ceftriaxone for

short-course treatment of enteric fever. Antimicrobial Agents

and Chemotherapy 1994;38(8):1716–20.

Tran 1995 VNM {published data only}

Tran TH, Bethell DB, Nguyen TT, Wain J, To SD, Le TP,

et al. Short course of ofloxacin for treatment of multidrug-

resistant typhoid. Clinical Infectious Diseases 1995;20(4):

917–23.

Unal 1996 TUR {published data only}

Unal S, Hayran M, Tuncer S, Gur D, Uzun O, Akova M,

et al. Treatment of enteric fever with pefloxacin for 7 days

versus 5 days: a randomized clinical trial. Antimicrobial

Agents and Chemotherapy 1996;40(12):2898–900.

Vinh 1996 VNM {published data only}

Vinh H, Wain J, Vo TN, Cao NN, Mai TC, Bethell D, et al.

Two or three days of ofloxacin treatment for uncomplicated

multidrug-resistant typhoid fever in children. Antimicrobial

Agents and Chemotherapy 1996;40(4):958–61.

Vinh 2005 VNM {published data only}

Vinh H, Duong NM, Phuong lT, Truong NT, Bay PV,

Wain J, et al. Comparative trial of short-course ofloxacin

for uncomplicated typhoid fever in Vietnamese children.

Annals of Tropical Paediatrics 2005;25(1):17–22.

Wallace 1993 BHR {published data only}

Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall

EJ, Rowe B, et al. Ciprofloxacin versus ceftriaxone in the

treatment of multiresistant typhoid fever. European Journal

of Clinical Microbiology and Infectious Diseases 1993;12(12):

907–10.

Yousaf 1992 PAK {published data only}

Yousaf MH, Hasnain SS, Mohsin A, Ara N. A comparative

study of efficacy and safety of three antimicrobials

in the treatment of enteric fever. Pakistan Journal of

Gastroenterology 1992;6(2):46–8.

References to studies excluded from this review

Abejar 1993 {published data only}

Abejar NH, Dimaano EM, Cabanban AB. Fleroxacin versus

chloramphenicol in enteric fever. An open, randomized,

parallel study. Philippine Journal of Internal Medicine 1993;

31(6):327–30.

Agalar 1997 {published data only}

Agalar C, Usubutun S, Tutuncu E, Turkyilmaz R.

Comparison of two regimens for ciprofloxacin treatment of

enteric infections. European Journal of Clinical Microbiology

and Infectious Diseases 1997;16(11):803–6.

Akhtar 1989 {published data only}

Akhtar MA, Karamat KA, Malik AZ, Hashmi A, Khan

QM, Rasheed P. Efficacy of ofloxacin in typhoid fever,

particularly in drug resistant cases. Reviews of Infectious

Diseases 1989;2 Suppl 5:1193.

Akhtar 1992 {published data only}

Akhtar MA, Hussain A, Karamat KA, Naqi N, Zubdi N.

Role of ciprofloxacin in typhoid fever. Journal of Pakistan

Medical Association 1992;42(1):9–10.

Arnold 1993 {published data only}

Arnold K, Hong C, Nelwan R, Trujillo Z, Kadio A, Barros

M, et al. Randomized comparative study of fleroxacin and

chloramphenicol in typhoid fever. American Journal of

Medicine 1993;94(3A):195S–200S.

Bai 1995 {published data only}

Bai YM, Lin JB, Duan MT, Zhang Y, Liang B. Comparison

of therapeutic effect of enoxacin and norfloxacin in the

treatment of typhoid fever. Zhonghua Chuan Ran Bing

Za Zhi [Chinese Journal of Infectious Diseases] 1995;13(2):

117–8.



Bavdekar 1991 {published data only}

Bavdekar A, Chaudhari M, Bhave S, Pandit A. Ciprofloxacin

in typhoid fever. Indian Journal Pediatrics 1991;58(3):

335–9.

Bethell 1996 {published data only}

Bethell DB, Day NP, Dung NM, McMullin C, Loan HT,

Tam DT, et al. Pharmacokinetics of oral and intravenous

ofloxacin in children with multidrug-resistant typhoid

fever. Antimicrobial Agents and Chemotherapy 1996;40(9):

2167–72.

Chakravorty 1991 {published data only}

Chakravorty B, Jain N, Gupta B, Rajvanshi P, Sen MK,

Krishna A. Chloramphenicol resistant enteric fever. Journal

of Indian Medical Association 1993;91(1):10–13.

Chukwani 1998 {published data only}

Chukwani CM, Onyemelukwe GC, Okonkwo PO,

Coker HAB, Ifudu ND. Fleroxacin vs ciprofloxacin in the

management of typhoid fever. Clinical Drugs Investigation

1998;16(4):279–88.

Daga 1994 {published data only}

Daga MK, Sarin K, Sarkar R. A study of culture positive

multidrug resistant enteric fever - changing pattern

and emerging resistance to ciprofloxacin. Journal of the

Association of Physicians of India 1994;42(8):599–600.

Duong 1995 {published data only}

Duong NM, Chau NVV, Anh DCV, Hoa NTT, Tam DTH,

Hai DT, et al. Short course fleroxacin in the treatment of

typhoid fever. JAMA Southeast Asia 1995;11 Suppl:21–5.

Hou 1993 {published data only}

Hou SR. Clinical study of Chinese ofloxacin. Zhonghua Yi

Xue Za Zhi 1993;73(4):255–6.

Huai 2000 {published data only}

Huai Y, Zhu Q, Wang X. Ceftriaxone vs. norfloxacin in

the treatment of resistant typhoid fever in 60 children.

Zhonghua Er Ke Za Zhi [Chinese Journal of Pediatrics] 2000;

38(6):386–8.

Jia 1994 {published data only}

Jia FZ, Zhu JQ, Huang SY, Chen HK, Bai JY, Li ZC, et al.

Clinical study on therapy of typhoid fever with pefloxacin.

Zhonghua Chuan Ran Bing Za Zhi [Chinese Journal of

Infectious Diseases] 1994;12 Suppl 3:134–6.

Jinlong 1998 {published data only}

Jinlong Z, Wennan H, Guosheng M, Zhigang H, Jianping

Z. Evaluation of effectiveness of ofloxacin and S-(-)

ofloxacin in treating typhoid fever. Zhonghua Chuan Ran

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(4):237.

Kumar 2007 {published data only}

Kumar R, Gupta N. Multidrug-resistant typhoid fever.

Indian Journal of Pediatrics 2007;74(1):39–42.

Liberti 2000 {published data only}

Liberti A, Loiacono L. Ciprofloxacin versus chloramphenicol

in the treatment of salmonella infection. International

Journal of Antimicrobial Agents 2000;16(3):347–8.

Lu 1995 {published data only}

Lu Y, Zhang H, Mu G, Qiu D, Hu P. Clinical study

of intravenous enoxacin versus cefotaxime in aute [sic]

infectious diseases. Zhongguo Kang Sheng Su Za Zhi [Chinese

Journal of Antibiotics] 1995;20(2):123–8.

Nalin 1987 {published data only}

Nalin DR, Hoagland VL, Acuna G, Bran JL, Carrilo

C, Gotuzzo E, et al. Clinical trial of norfloxacin versus

chloramphenicol therapy for acute typhoid fever. Progress

in antimicrobial and anti-cancer chemotherapy. Proceedings

of the 15th International Congress of Chemotherapy; 1987

July 19-24; Istanbul. Copenhagen, Munksgaard, 1987:

1174–5.

Nelwan 1995 {published data only}

Nelwan RH, Hendarwanto, Zulkarnain I, Gunawan J,

Supandiman I, Yusuf H, et al. A comparative study of short

course ciprofloxacin treatment in typhoid and paratyphoid

fever. Drugs 1995;49 Suppl 2:463–5.

Peyramond 1986 {published data only}

Peyramond D, Tiguad S, Lucht F, Vedrinne JM, Salord

F, Bertrand JL. Clinical evaluation of ofloxacin in the

treatment of various infections [Bilan d’utilisation de

l’ofloxacine dans le traitement d’infections variées].

Pathologie-Biologie 1986;34(5):471–5.

Sarma 1991 {published data only}

Sarma PS, Durairaj P. Randomized treatment of patients

with typhoid and paratyphoid fevers using norfloxacin or

chloramphenicol. Transactions of the Royal Society of Tropical


Secmeer 1997 {published data only}

Secmeer G, Kanra G, Figen G, Akan O, Ceyhan M, Ecevit

Z. Ofloxacin versus co-trimoxazole in the treatment of

typhoid fever in children. Acta Paediatrica Japonica 1997;

39(2):218–21.

Singh 1993 {published data only}

Singh CP, Singh N, Brar GK, Lal G, Kumar H. Efficacy of

ciprofloxacin and norfloxacin in multidrug resistant enteric

fever in adults. Journal of the Indian Medical Association

1993;91(6):156–7.

Suhendro 2007 {published data only}

Suhendro, Chen K, Pohan HT. Open study on efficacy and

tolerability of ciprofloxacin XR compared with ciprofloxacin

BID in the treatment of typhoid fever. Acta Medica

Indonesiana 2007;39(1):22–6.

Takkar 1994 {published data only}

Takkar VP, Kumar R, Khurana S, Takkar R. Comparison

of ciprofloxacin versus cephelexin and gentamicin in the

treatment of multi-drug resistant typhoid fever. Indian

Pediatrics 1994;31(2):200–1.

Tanphaichitra 1986 {published data only}

Tanphaichitra D, Sahaphong S, Srimuang S. Ofloxacin,

a new quinolone in the treatment of genitourinary and

enteric infections. Infection 1986;14 Suppl 4:321–3.

Tran 1994 {published data only}

Tran TH, Nguyen MD, Huynh DH, Nguyen TT, To SD,

Le TP, et al. A randomized comparative study of fleroxacin



and ceftriaxone in enteric fever. Transactions of the Royal

Society of Tropical Medicine and Hygiene 1994;88(4):464–5.

Uwaydah 1992 {published data only}

Uwaydah AK, al Soub H, Matar I. Randomized prospective

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Wain 1997 {published data only}

Wain J, Hoa NTT, Chinh NT, Vinh H, Everett J, Diep

TS, et al. Quinolone-resistant Salmonella typhi in Viet

Nam: molecular basis of resistance and clinical response to

treatment. Clinical Infectious Diseases 1997;25(6):1404–10.

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Weng YL, Jia FZ. Clinical efficacy evaluation of

fluoroquinolones in typhoid fever (clinical analysis of 391

cases). Chinese Journal of Clinical Pharmacology 1996;12(3):

142–7.

Yang 1991 {published data only}

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Zavala 1989 {published data only}

Zavala-Trujillo I, Nava-Zavala A, Marcano MG, Renteria

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Alam 1995 BGD

Methods Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: open

Inclusion of all randomized culture-positive participants in the final analysis: 64/72 (88.

9%)

Participants 69 analysed : 35 in 10-day group: 34 in 14-day group

Adults (18 to 65 years) and 11 children (< 18 years)

Both outpatients and inpatients (ciprofloxacin 10-day group had 20 outpatients and 14

inpatients, ciprofloxacin 14-day group had 21 outpatients and 14 inpatients)

Inclusion criteria: blood or bone marrow culture positive for S. typhi or S. paratyphi

Exclusion criteria: hypersensitivity to quinolones; severe renal disease; pregnant or lac-

tating; patients < 18 years were randomized only if had MDR strain

Interventions 1. Ciprofloxacin (500 mg oral twice daily for 10 days)

2. Ciprofloxacin (500 mg oral twice daily for 14 days)

Outcomes 1. Clinical failure

2. Microbiological failure

3. Relapse

4. Fever clearance time

5. Convalescent faecal carriage

6. Serious adverse events

7. Other adverse events

Notes Location: Bangladesh

Date: 1992-3

Severity of illness at entry: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk “Patients randomly assigned to two regi-

mens”

Allocation concealment (selection bias) Unclear risk Not stated

Blinding (performance bias and detection

bias)

All outcomes

Unclear risk Not stated

Incomplete outcome data (attrition bias)

All outcomes(short term)

Low risk Data was reported for all the patients in

short term follow-up



Alam 1995 BGD (Continued)


All outcomes(long term)

Low risk Data was missed for 3, 22 and 32 patients

on 2, 6 and 12 months respectively for pa-

tients in 10 days treatment

Whereas data was missing for 2, 20 and 31

patients on 2, 6, and 12 months respec-

tively for those on 14 days treatment. miss-

ing outcome data balanced between groups

Selective reporting (reporting bias) High risk Efficacy and adverse events reported

Other bias High risk Supported by research grant from Beximco

pharmaceuticals ltd

Arjyal 2011

Methods Generation of allocation sequence: blocks of 50

Allocation concealment: sealed envelops

Blinding: non-blinded

Inclusion of all randomized culture-positive participants in the final analysis: 348/352

(98.9%)

Participants 352 analysed: 175 in chloramphenicol: 177 in gatifloxacin

Adults and children: chloramphenicol 15 yrs (8-22) and in gatifloxacin 16 yrs (9-22)

Outpatients

Inclusion criteria: Patients with fever for more than 3 days who were clinically diagnosed

to have enteric fever patients who received amoxicillin or co-trimoxazole were included

as long as they did not show evidence of clinical response

Exclusion criteria: pregnancy or lactation, age under 2 years and weight less than 10

kg, shock, jaundice, gastrointestinal bleeding or any other signs of severe typhoid fever,

hypersensitivity, known previous treatment with a quinolone antibiotic or 3rd generation

cephalosporin or macrolide within one week of hospital admission

Interventions 1. Gatifloxacin (10 mg/kg/day in a single oral dose for 7 days)

2. Chloramphenicol (75 mg/kg/day in four divided oral doses for 14 days)



3. Relapse

4. enteric fever complications



Notes Location: Nepal

Date: May 2006 - August 2008


Risk of bias



Arjyal 2011 (Continued)



bias)

Low risk “Patients were randomly allocated to one

of two treatments. Randomization was per-

formed in blocks of 50..”

Allocation concealment (selection bias) Low risk “The random allocations were placed in

sealed opaque envelopes”


bias)

All outcomes

High risk Open study for participants and investiga-

tors but final outcome assessors blinded



Low risk Missing data balanced across both groups



Low risk Missing data balanced across groups

Selective reporting (reporting bias) Low risk Efficacy and safety data reported

Other bias Low risk Study seems free from other bias

Chinh 1997 VNM

Methods Generation of allocation sequence: blocks

Allocation concealment: sealed envelopes

Blinding: open


(93.5%)

Participants 100 analysed: 47 in 2-day group: 53 in 3-day group

Mean age in 2-day group was 25.3 (8.9) and 3 days group 24.2 (7.1); adults >15 yrs

Inpatients

Inclusion criteria: clinically suspected uncomplicated enteric fever were included

Exclusion criteria: pregnant, had severe disease required intensive care, had known hy-

persensitivity to quinolones or had treatment with quinolones in the week before ad-

mission, those who had received previous treatment with chloramphenicol, ampicillin,

cephalosporins or trimethoprim-sulphamethoxazole were also excluded

Interventions 1. Ofloxacin (15 mg/kg/day for two days)

2. Ofloxacin (10 mg/kg/day for three days)



3. Relapse




Chinh 1997 VNM (Continued)

Notes Location: Viet Nam

Date: November 1993 - December 1995


Risk of bias



bias)

Low risk “ patients were allocated at random...Ran-

domization was in blocks”

Allocation concealment (selection bias) Low risk “Treatment codes were contained in serially

numbered sealed envelopes...”


bias)

All outcomes

High risk “ in an open, randomised ?”



Low risk All outcome data addressed



Low risk 50% of outcome data at follow up pre-

sented but results unlikely to affect ob-

served effect size

Selective reporting (reporting bias) Low risk Efficacy and adverse events reported


Chinh 2000 VNM

Methods Generation of allocation sequence: computer-generated


Blinding: open


(42%)

Participants 88 analysed : 44 in ofloxacin group; 44 in azithromycin group

Adult inpatients aged >15 years

Inclusion criteria: clinical with blood culture positive for S. Typhi or S. Paratyphi

Exclusion criteria: severe or complicated disease; significant underlying disease; hyper-

sensitivity to either trial drug; pregnant; history of treatment with fluoroquinolone or

third-generation cephalosporins or macrolides within 1 week of admission

Interventions 1. Ofloxacin (200 mg oral twice daily for 5 days at 8 mg/kg/day)

2. Azithromycin (1 gm oral daily for 5 days at 20 mg/kg/day)



Chinh 2000 VNM (Continued)



3. Relapse

4. Fever clearance time (mean and 95% confidence intervals; SD calculated by review

author)

5. Complications

6. Length of hospitalization (mean and 95% confidence interval; SD calculated by review

author)



9. Other adverse events (number of events stated)

Notes Location: Vietnam

Date: not available

Severity of illness at entry: all uncomplicated

Author provided further information

Risk of bias



bias)

Low risk “Patients were allocated to one of two treat-

ment groups in an open randomised com-

parison” Computer generated randomiza-

tion list. Information from trial authors

Allocation concealment (selection bias) Low risk “The treatment allocations were kept in se-

rially numbered sealed envelopes”


bias)

All outcomes

High risk Open comparison



Low risk outcomes were presented for all ran-

domised



Low risk 9/44 from ofloxacin group and 10/44 from

azithromycin group were missing from the

long term treatment but unlikely to affect

estimate of effect

Selective reporting (reporting bias) Low risk Efficacy and adverse event data reported




Cristiano 1995 ITA



Blinding: open

Inclusion of all randomized culture-positive participants in the final analysis: 100%

Participants 60 analysed: 30 in pefloxacin group; 30 in chloramphenicol group

Adult inpatients aged 17 to 64 years

Inclusion criteria: Severe culture-positive typhoid sepsis

Exclusion criteria: Received any known or presumed antibiotic active against S. Typhi,

allergy to pyridoxine-carboxylic acid derivatives or to chloramphenicol

Interventions 1. Pefloxacin (1200 mg intravenous in 3 divided doses every 8 hours for 5 days, and

orally for the next 10 days)

2. Chloramphenicol (2 g in 4 divided doses every 6 hours for 15 days)



3. Relapse

4. Fever clearance time (no SD)


6. Length of hospitalisation (no SD)



Notes Location: Italy

Date: 1991-3

Severity of illness at entry: all severe

Risk of bias



bias)

Low risk “The enrolled patients were randomly as-

signed (by means of a computerized list..”

Allocation concealment (selection bias) Unclear risk No information provided


bias)

All outcomes

High risk “..an open, randomised clinical study”



Low risk No pre specified outcomes but all relevant

outcome data accounted for



Low risk No pre specified outcomes but all relevant

outcome data accounted for




Cristiano 1995 ITA (Continued)

Other bias Unclear risk Pefloxacin was supplied by Rhone-poulenc

Pharma Italy S.P.A. Milan, Italy

Dolecek 2008 VNM

Methods Generation of allocation sequence: computer-generated, block randomization


Blinding: open


(93%)

Participants 285 analysed: 145 in gatifloxacin group; 140 in azithromycin group

Adult and children inpatients aged 1 to 41 years (210/287 (73%) participants below the

age of 15 years)

Inclusion criteria: clinical or culture-positive enteric fever

Exclusion criteria: no consent; pregnancy; age < 6 months; history of hypersensitivity

to either of the trial drugs; any signs of severe typhoid fever or previous reported treat-

ment with a fluoroquinolone antibiotics; a third-generation cephalosporin or macrolide

antibiotic within 1 week before to hospital admission

Interventions 1. Gatifloxacin (10 mg/kg/day oral once daily for 7 days)

2. Azithromycin (20 mg/kg/day oral once daily for 7 days)



3. Relapse


5. Complications

6. Length of hospitalization




Notes Location: Vietnam (multi-centre, 3 hospitals)

Date: 2004-5


Received as an unpublished trial (with additional data), but reference updated to current

citation upon publication

Risk of bias



bias)

Low risk “An independent administrator from the

study generated the random number se-

quence in excel using RAND function”



Dolecek 2008 VNM (Continued)

Allocation concealment (selection bias) Low risk “..assignments were folded and kept in

opaque, sealed, sequentially numbered en-

velopes at all three study sites?”


bias)

All outcomes

High risk Open label study



Low risk No loss to follow up and data was analysed

for all the participants randomized



Low risk In Gatifloxocin group 7, 8, and 80 partici-

pants were lost to follow-up and in Azithro-

mycin group 5, 11 and 79participants were

lost to follow-up. Unlikely to affect ob-

served effect size as loss is similar

Selective reporting (reporting bias) Low risk Report includes all pre specified outcomes

including efficacy and safety data


Flores 1994 MEX



Blinding: open


Participants 40 analysed: 20 in ofloxacin group; 20 in ampicillin group

Adult male or females; most probably inpatients.

Inclusion criteria: Age over 16 with clinical features of typhoid fever as well as positive

blood cultures for S. typhi

Exclusion criteria: Previous adverse reactions, complicated disease, severe renal insuffi-

ciency, severe neutropenia, requirement of concomitant systemic antimicrobial, convul-

sions, grave psychiatric disorders, pregnancy or lactation

Interventions 1. Ampicillin (1 g every 6 hours for 10 days)

2. Ofloxacin (400 mg every 12 hours for 10 days)




Notes Location: Mexico

Date: not reported




Flores 1994 MEX (Continued)

Risk of bias



bias)

Unclear risk ’A comparative open study with groups as-

signed randomly...’



bias)

All outcomes

High risk Open study



High risk Relapse and fever clearance times not re-

ported



High risk Convalescent faecal carriage not reported


Other bias Unclear risk Language

Gasem 2003 IDN

Methods Generation of allocation sequence: random-number table


Blinding: open


Participants 55 analysed: 28 in ciprofloxacin group; 27 in chloramphenicol group

Adult inpatients

Inclusion criteria: clinical and ≥14 years

Exclusion criteria: severe complications; treatment with chloramphenicol, ciprofloxa-

cin, other fluoroquinolones before admission; history of allergy to chloramphenicol/

quinolone; malaria or other infection; white blood cell count < 2000/mL; pregnant or

lactating


2. Chloramphenicol (500 mg oral 4 times a day for 14 days)


2. Microbiological response to treatment at day 3 or day 5

3. Relapse


5. Complications




Gasem 2003 IDN (Continued)



Notes Location: Indonesia

Date: not reported

Severity of illness at entry: none had severe complications on enrolment

Risk of bias



bias)

Low risk “..patients were randomly assigned to ei-

ther..” “....The distribution of the en-

velopes was derived from a randomly per-

muted table..”

Allocation concealment (selection bias) Low risk “..treatment group by means of sealed en-

velopes containing the names of the study

drugs.?”


bias)

All outcomes

High risk “..randomised, open-label, parallel con-

trolled trial”



Low risk Outcome data addressed, no information

on loss to follow-up



High risk No data provided



Girgis 1999 EGY

Methods Generation of allocation sequence: random-number list, block randomization


Blinding: open


Participants 64 analysed: 28 in ciprofloxacin group; 36 in azithromycin group

Adult inpatients aged > 18 years

Inclusion criteria: clinical

Exclusion criteria: pregnant or lactating; allergy to ciprofloxacin or erythromycin/other

macrolides; those with complications of typhoid fever; inability to swallow medications;

significant underlying illness; treatment within past 4 days with an antibiotic with po-

tential efficacy against S. Typhi



Girgis 1999 EGY (Continued)


2. Azithromycin (1 g oral once daily for the first day followed by oral 500 mg once daily

for total duration of 7 days)



3. Relapse


5. Complications


7. Cost of treatment




Notes Location: Egypt

Date: 1997-8



Risk of bias



bias)

Low risk “..each subject was randomly assigned.. as-

signments, determined by block randomi-

sation based on a random number list”

Allocation concealment (selection bias) Low risk ”Treatment assignments..were sealed in en-

velopes”


bias)

All outcomes









Other bias High risk Supported by an unrestricted grant from

Pfizer



Gottuzzo 1992 N/A



Blinding: double


(97%)

Participants 98 analysed: 49 in ciprofloxacin group; 49 in chloramphenicol group

Adult inpatients

Inclusion criteria: clinical with culture positive for S. typhi or S. paratyphi

Interventions 1. Ciprofloxacin (500 mg oral every 12 hours for 10 days)

2. Chloramphenicol (750 mg oral every 6 hours for 14 days)


2. Relapse

Notes Location: not available

Date: not available


Risk of bias



bias)

Unclear risk Randomized study but mode of generation

of sequence not stated



bias)

All outcomes

Low risk Double blind. Placebos given during re-

maining days of therapy in the longer arm



High risk Fever clearance time not reported for com-

parison arm



Low risk Relevant data reported





Hajji 1988 MAR



Blinding: open


Participants 42 analysed: 24 in pefloxacin group; 18 in co-trimoxazole group



Exclusion criteria: not reported

Interventions 1. Pefloxacin (400 mg oral twice daily for 14 days)

2. Co-trimoxazole (160/800 mg oral twice daily for 14 days)

5 participants were given intravenous pefloxacin for mean 4.8 days; 4 were given intra-

muscular co-trimoxazole for mean 6 days

Outcomes 1. Cure

2. Relapse

3. Fever clearance time (no SD, non-exact P value)

4. Chronic carrier state

5. Serious Adverse events

Notes Location: Morocco

Date: 1984-5

Severity of illness at entry: comatose or neurological disorders in 3 participants in pe-

floxacin group and 2 participants in co-trimoxazole group


Risk of bias



bias)

Unclear risk “A comparative open and randomised trial.

.”



bias)

All outcomes











Hajji 1988 MAR (Continued)

Other bias Unclear risk Insufficient information to assess whether

an important risk of bias exists

Kalo 1997 ALB



Blinding: open


Participants 30 analysed: 15 in 7-day group; 15 in 10-day group


Inclusion criteria: blood-culture positive; ampicillin-resistant S. typhi

Exclusion criteria: received quinolones within 2 weeks before hospitalization

Interventions 1. Perfloxacin (400 mg oral twice daily for 7 days)

2. Perfloxacin (400 mg oral twice daily for 10 days)



3. Relapse



Notes Location: Albania

Date: 1992-4


Risk of bias



bias)

Unclear risk The patients were divided into two groups

Allocation concealment (selection bias) Unclear risk No information available


bias)

All outcomes










Kalo 1997 ALB (Continued)




Limson 1989 PHL



Blinding: open


Participants 40 analysed: 20 in ciprofloxacin group; 20 in co-trimoxazole group



Exclusion criteria: complications; drug allergy; renal impairment


2. Co-trimoxazole (160/800 mg oral twice daily for 14 days)





Notes Location: Philippines

Date: not reported


Risk of bias



bias)

Low risk “Patients were randomly assigned.. using a

table of random numbers”



bias)

All outcomes




Low risk All outcome data reported



Low risk All outcome data reported



Limson 1989 PHL (Continued)

Selective reporting (reporting bias) Low risk Safety and efficacy reported



Morelli 1992 ITA



Blinding: open


Participants 156 analysed: 30 each in ofloxacin and chloramphenicol groups; 36 in pefloxacin group;

20 each in ciprofloxacin,

enoxacin, and norfloxacin groups


Inclusion criteria: blood culture positive for S. typhi; high fever for not more than 5 days;

toxic symptomatology

Exclusion criteria: hypersensitivity or allergy to fluoroquinolone or antibiotic treatment

Interventions 1. Ofloxacin (300 mg oral every 8 hours for 15 days)

2. Pefloxacin (400 mg oral every 8 hours for 15 days)

3. Ciprofloxacin (500 mg oral every 8 hours for 15 days)

4. Enoxacin (300 mg oral every 8 hours for 15 days)

5. Norfloxacin (400 mg oral every 8 hours for 15 days)



2. Relapse




Notes Location: Italy

Date: 1985-90


We prepared different comparisons with these data: a combination of all 5 fluoro-

quinolone groups vs the chloramphenicol

group; and norfloxacin vs ofloxacin, pefloxacin, and enoxacin

Risk of bias



bias)

Low risk “..patients in this open study were ran-

domly assigned, by means of a computer-

ized list”



Morelli 1992 ITA (Continued)



bias)

All outcomes











Pandit 2007 NPL

Methods Generation of allocation sequence: computer-generated, block randomization


Blinding: open


(87%)

Participants 158 analysed: 88 in gatifloxacin group; 70 in cefixime group

Adults and children outpatients aged 2.75 to 50 years (60/169 (35.5%) were children

aged < 14 years)


Exclusion criteria: not residing 2.5 km radius from hospital; age not between 2 to 65

years; not willing to give informed consent; not able to take oral medications; pregnant

or lactating; history of seizures; not able to stay in city for treatment duration; known

contraindication to cephalosporins or fluoroquinolones; complicated typhoid fever or

received third-generation cephalosporins, fluoroquinolones, or macrolide in week before

presentation to clinic

Interventions 1. Gatifloxacin (10 mg/kg/day in single dose oral for 7 days)

2. Cefixime (20 mg/kg/day in 2 divided doses oral for 7 days)



3. Relapse



6. Complications


8 Other adverse events



Pandit 2007 NPL (Continued)

Notes Location: Nepal

Date: 2005



Risk of bias



bias)

Low risk “Patients were randomised in blocks from

a computer generated randomisation list”

Allocation concealment (selection bias) Low risk “Treatment allocations were kept in sealed

opaque envelopes..”


bias)

All outcomes

High risk Open label study



Low risk Relevant outcome data addressed



Low risk Missing outcome data at 1, 3 and 6 months

(22/169, 28/169 and 39/169 respectively)

unlikely to affect effect estimate

Selective reporting (reporting bias) Low risk Report includes all pre specified outcomes

Other bias Low risk Study seems free of other bias

Parry 2007 VNM



Blinding: open


(88%)

Participants 125 analysed: 63 in ofloxacin group; 62 in azithromycin group

Adults and children inpatients 3 to 42 years (87% (163/187) were children < 15 years

for all three arms)


Exclusion criteria: severe or complicated disease; inability to swallow oral medications;

history of significant underlying disease or hypersensitivity to either of trial drugs; preg-

nant or lactating; history of treatment



Parry 2007 VNM (Continued)

Interventions 1. Ofloxacin (20 mg/kg/day in 2 divided doses oral for 7 days)

2. Azithromycin (10 mg/kg/day once a day oral for 7 days)

Comparison not included in this review:

3. Ofloxacin-azithromycin (15 mg/kg/day in 2 divided doses oral ofloxacin for 7 days

and 10 mg/kg/day once a day

oral azithromycin for first 3 days)



3. Relapse


author)

5. Complications

6. Length of hospitalization (mean and 95% confidence intervals; SD calculated by

review author)



9. Other adverse events (numbers not stated)


Date: 1998-2002



Risk of bias



bias)

Low risk Computer generated randomization list

Allocation concealment (selection bias) Low risk “Treatment allocations were kept in serially

numbered sealed envelopes”


bias)

All outcomes

High risk “an open randomised comparison.”






Low risk Incomplete outcome data unlikely to affect

observed effect size


Other bias Low risk Study seems free of other bias



Phongmany 2005 LAO

Methods Generation of allocation sequence: random-number table, block randomization


Blinding: open


(96%)

Participants 50 analysed: 27 in ofloxacin group; 23 in chloramphenicol group


Inclusion criteria: clinical or blood culture positive typhoid fever

Exclusion criteria: age <15 years; pregnant; lactating; not able to take oral medication;

not willing to give informed consent; not able to stay in hospital for the duration of

treatment; known to have contraindications to chloramphenicol or ofloxacin; severe

typhoid fever; or intractable vomiting

Interventions 1. Ofloxacin (15 mg/kg/day in 2 divided doses oral for 3 days)

2. Chloramphenicol (50 mg/kg/day oral in 4 divided doses for 14 days)



3. Complications




Notes Location: Laos

Date: 2001-3



Risk of bias



bias)

Low risk “..randomised in blocks of 10 from a ran-

dom number table”

Allocation concealment (selection bias) Low risk “Treatment allocations kept in sealed

opaque envelopes”


bias)

All outcomes

High risk “..prospective randomised open-label con-

trolled trial”






High risk Patients not followed up after discharge.

No data for long term outcomes like relapse

and convalescent faecal carriage



Phongmany 2005 LAO (Continued)


Other bias High risk Trial stopped early because of apparently

significant difference in primary outcome

Phuong 1999 VNM



Blinding: open


(49%)

Participants 82 analysed: 38 in ofloxacin group; 44 in cefixime group

Children inpatients aged < 15 years

Inclusion criteria: fever and no obvious source of infection for > 7 days or < 7 days if

family history of typhoid fever

Exclusion criteria: severe disease; hypersensitivity to quinolones or third-generation

cephalosporins; received either drug during this illness; or responded to ampicillin, chlo-

ramphenicol, or co-trimoxazole

Interventions 1. Ofloxacin (10 mg/kg/day oral in 2 divided doses for 5 days)

2. Cefixime (20 mg/kg/day oral in 2 divided doses for 7 days)



3. Relapse


5. Complications






Date: 1995-6



Risk of bias



bias)

Low risk “..Patients were randomised to receive

ofloxacin.or cefixime...” Computer gener-

ated list



Phuong 1999 VNM (Continued)

Allocation concealment (selection bias) Low risk “treatment codes were contained in serially

numbered sealed envelops ..”


bias)

All outcomes




Low risk All pre specified outcome data addressed



Low risk All data reported

Selective reporting (reporting bias) High risk Incomplete report of adverse events. Only

mortality and associated data for one pa-

tient reported

Other bias Unclear risk No information on ethical clearance

Rizvi 2007 PAK



Blinding: Unclear


(70%) on Typhi Dot and 87/227 (38.3%) on Widal test

Participants 227 analysed: 48 in ciprofloxacin, 45 in ofloxacin, 46 in cefixime, 44 in chloramphenicol

and 44 in co-trimoxazole

>12 yrs of age

Both outpatients and inpatients: hospitalised for 24 hours and then attended clinics for

assessments

Inclusion criteria: above 12 yrs of age with clinically and bacteriologically proven diag-

nosis of typhoid fever, either on positive blood or stool culture or by positive Typhi-Dot

test

Exclusion criteria: patients with signs and symptoms similar to those of typhoid fever

but proved bacteriologically to be caused by other organism were excluded. Patients with

salmonellosis caused by organisms other than S. typhi and S. paratyphi were not included.

Pregnant women and patients with previously known hypersensitivity to any of the trial

drugs were also not included


2. Ofloxacin (200 mg oral twice daily for 7 days)

3. Cefixime (200 mg oral twice daily for 7 days)

4. Chloramphenicol (750 mg oral 6 hourly for 14 days)

5. Cotrimoxazole (960 mg oral twice daily for 14 days)



Rizvi 2007 PAK (Continued)

Outcomes 1. Clinical cure


3. Relapse

4. Clinical Failure

5. Fever Clearance

6. Adverse events

Notes Location: Pakistan

Date: Jan 2003 to Jan 2004


Risk of bias



bias)

Unclear risk “The patients were randomly assigned to

one of the following”



bias)

All outcomes

Unclear risk Not stated



Low risk Relevant outcomes addressed



Low risk outcomes data presented

Selective reporting (reporting bias) Low risk No selective reporting



Smith 1994 VNM



Blinding: open


Participants 47 analysed: 22 in ofloxacin group; 25 in ceftriaxone group


Inclusion criteria: clinical or culture positive for enteric fever

Exclusion criteria: hypersensitivity to beta-lactam antibiotics or quinolones; previous

treatment with broad-spectrum cephalosporins or quinolone within 1 week of hospital

admission; those who responded to ampicillin, chloramphenicol, or co-trimoxazole



Smith 1994 VNM (Continued)

Interventions 1. Ofloxacin (200 mg oral every 12 hours for 5 days)

2. Ceftriaxone (3 g intravenous once a day for 3 days)



3. Relapse


5. Complications

6. Length of hospitalization (mean and range)





Date: 1992-3



Risk of bias



bias)

Unclear risk “Patients were randomised to receive?.”

Allocation concealment (selection bias) Low risk “Treatment codes were contained in indi-

vidual sealed envelopes?..”


bias)

All outcomes

High risk “...open, randomised comparison...”



Low risk All primary outcome data reported.



Unclear risk Specific numbers for post discharge follow

up not reported


Other bias Unclear risk No information given on ethical clearance

for undertaking this study



Tran 1995 VNM



Blinding: open

Inclusion of all randomized culture-positive participants in the final analysis: 50% (114/

228)


Adults and children outpatients (180 culture positive were aged < 17 years)


Exclusion criteria: unable to take oral medications due to vomiting; severe disease; shock;

impaired consciousness; bleeding; peritonitis; pregnant; neonates; received a fluoro-

quinolone

Interventions 1. Ofloxacin (15 mg/kg/day oral for 3 days)

2. Ofloxacin (10 mg/kg/day oral for 5 days)



3. Relapse






Date: 1993-3



Risk of bias



bias)

Low risk “Patients were randomised to receive.. “

Computer generated

Allocation concealment (selection bias) Low risk “Treatment allocation were kept in sealed

envelopes ...”


bias)

All outcomes

High risk open label






Low risk 291/425 overall but 81, 78 and 132 for D3,

D5

and blood culture negative arms respec-



Tran 1995 VNM (Continued)

tively but unlikely to affect measured effect

size


Other bias High risk Ofloxacin was provided by Professor A

Bryskier of Roussel-UCLAF Pharmaceuti-

cals, Paris

Unal 1996 TUR



Blinding: open


(100%)

Participants 46 analysed: 22 in 5-day group: 24 in 7-day group

Mean age was 24 years (18-40 years ) in 5 days and 26 years (18-68) in 7 days group

inpatients

Inclusion criteria: All patients with febrile disease and at least one positive blood and/or

bone marrow culture for salmonella

Exclusion criteria: Patients under 16 years of age, pregnant and lactating women, those

with jaundice and hepatic failure, and the patients who had received any antibiotic within

the last 2 weeks

Interventions 1. Pefloxacin (400 mg oral twice daily for 5 days)

2. Pefloxacin (400 mg oral twice daily for 7 days



3. Relapse

4. Clinical cure


Notes Location: Turkey

Date: June 1992 to October 1994


Risk of bias



bias)

Unclear risk “..were randomised to receive pefloxacin

for 5 days..”

Allocation concealment (selection bias) Unclear risk “..were randomised to receive pefloxacin

for 5 days..”



Unal 1996 TUR (Continued)


bias)

All outcomes

Unclear risk Open study



Unclear risk All outcome data addressed



Unclear risk All outcome data addressed

Selective reporting (reporting bias) Unclear risk Efficacy and adverse events reported



Vinh 1996 VNM



Blinding: open


(26%)


Children inpatients aged 1 to 15 years

Inclusion criteria: clinical or blood culture positive for S. typhi

Exclusion criteria: severe disease; complications, such as reduced level of consciousness,

jaundice, shock, gastrointestinal bleed, clinical signs of intestinal perforation, prostate,

and vomiting; unable to take oral medication; allergic to fluoroquinolones; received

antibiotics that had efficacy against this organism


2. Ofloxacin (15 mg/kg/day oral in 2 divided doses for 3 days)



3. Relapse


5. Complications






Date: not reported





Vinh 1996 VNM (Continued)

Risk of bias



bias)

Low risk “Patients were randomised to receive either

ofloxacin?” Computer generated

Allocation concealment (selection bias) Low risk “After enrolment in the study, a sealed en-

velope containing the treatment regimen to

be given was opened”


bias)

All outcomes

High risk open study






Unclear risk No data for 34 and 74 subjects at the 1 and

3 month follow up respectively. No indica-

tion how these were handled




Vinh 2005 VNM



Blinding: open


(97%)

Participants 196 analysed: 89 in ofloxacin 2-day group; 107 in ofloxacin 3-day group

Children inpatients aged < 15 years


Exclusion criteria: no informed consent from parent or guardian; previous treatment

active against S. Typhi or S. Paratyphi (but those with no response to chloramphenicol,

ampicillin, or co-trimoxazole were included); severe or complicated disease


2. Ofloxacin (10 mg/kg/day oral in 2 divided doses for 3 days)



3. Relapse



Vinh 2005 VNM (Continued)


author)

5. Complications

6. Length of hospitalization (mean and 95% confidence intervals; SD calculated by

review author)





Date: 1994-6



Risk of bias



bias)

Low risk “A computer-generated, randomised

treatment allocation was..”

Allocation concealment (selection bias) Low risk “Randomized treatment allocation was

contained in serially numbered sealed en-

velopes..”


bias)

All outcomes




Low risk All outcomes addressed



High risk Data for 6 culture positive children ran-

domized to 2-day treatment excluded from

analysis






Wallace 1993 BHR



Blinding: open


6%)

Participants 42 analysed: 20 in ciprofloxacin group; 22 in ceftriaxone group

Adult inpatients

Inclusion criteria: blood culture positive for S. Typhi

Exclusion criteria: only positive Widal and/or a positive stool culture; age < 16 years;

unable to take oral medications; possible proven pregnancy; and lack of fever at admission


2. Ceftriaxone (3 g/day intravenous for 7 days)



3. Relapse

4. Fever clearance time (SD not reported)


6. Complication

Notes Location: Bahrain

Date: not reported


Risk of bias



bias)

Unclear risk “..patients were randomised to receive” No

indication as to how sequence was gener-

ated



bias)

All outcomes








Selective reporting (reporting bias) High risk No report of adverse events



Wallace 1993 BHR (Continued)

Other bias High risk Trial stopped early because of apparent

lower efficacy in the control group, cost of

control drug and inconvenience of intra-

venous administration

Yousaf 1992 PAK



Blinding: open


4%)

Participants 75 analysed a : 25 in ofloxacin group; 25 in chloramphenicol group; 25 in amoxicillin

group

Adult inpatients

Inclusion criteria: culture positive

Exclusion criteria: if received previous antibiotic therapy known to be effective against

S. Typhi

Interventions 1. Ofloxacin (200 mg oral twice daily for 14 days)

2. Chloramphenicol (50 mg/kg/day, then 30 mg/kg/day when afebrile for 14 days)

3. Amoxicillin (4 to 6 g/day oral for 14 days)




Notes Location: Pakistan

Date: 1989-92


Risk of bias



bias)

Unclear risk ’The patients were randomly divided into

three groups...’

Allocation concealment (selection bias) Unclear risk unclear


bias)

All outcomes




Low risk Relevant short term outcomes reported



Yousaf 1992 PAK (Continued)



High risk Long term outcomes not reported




Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Abejar 1993 One arm allocated to fleroxacin which is no longer in clinical use

Agalar 1997 Not a randomized controlled trial because 1 group consisted of participants admitted in 1994 and the other

group of participants admitted in 1995

Akhtar 1989 No mention of randomization

Akhtar 1992 Quasi-randomized controlled trial: participants were allocated alternatively to either ciprofloxacin group or

chloramphenicol group, and resistance strains assigned to a third ciprofloxacin group; author provided this

additional information

Arnold 1993 One arm allocated to fleroxacin which is no longer in clinical use

Bai 1995 One arm allocated to norfloxacin which is no longer recommended for use by the WHO and the other arm

enoxacin which is no longer in clinical use

Bavdekar 1991 Interventions not randomly assigned

Bethell 1996 Children from the Vinh 1996 VNM trial (which is included in this review) were entered into this pharma-

cokinetic study of oral vs intravenous ofloxacin

Chakravorty 1991 All treated with chloramphenicol; some switched over to another drug based on culture results

Chukwani 1998 2 different fluoroquinolone drugs were given for different durations (one for 7 days and one for 14 days) in

this randomized controlled trial

Daga 1994 Treatment assigned depending on treatment already taken, clinical course, and complications

Duong 1995 One arm allocated to fleroxacin which is no longer in clinical use

Hou 1993 Randomized controlled trial comparing Chinese ofloxacin with Japanese ofloxacin



(Continued)

Huai 2000 One arm allocated to fleroxacin which is no longer in clinical use

Jia 1994 One arm allocated to norfloxacin which is no longer recommended for use by the WHO

Jinlong 1998 Quasi-randomized controlled trial

Kumar 2007 Described as a randomized controlled parallel study of ofloxacin vs ceftriaxone in 93 children with multi-

drug resistant typhoid fever proven by blood culture. The main outcome reported for both arms is mean fever

clearance time; however the number of children in each arm is not available. We have contacted the author for

additional information (December 2007) and will include this study if further information becomes available

Liberti 2000 No mention of randomization

Lu 1995 A total of 130 participants with any infectious disease were randomized into 2 groups (enoxacin and cefotaxime)

; there were only 2 participants with enteric fever in enoxacin group and 1 participant with enteric fever in

cefotaxime group

Nalin 1987 One arm allocated to norfloxacin which is no longer recommended for use by the WHO

Nelwan 1995 Randomized controlled trial comparing 3 days with 6 days of ciprofloxacin that included 20 participants with

serologically confirmed enteric fever (of a total of 59 participants randomized). We contacted the author (17

December 2003) to obtain additional data for blood culture confirmed cases and will include this in future

updates should it become available

Peyramond 1986 Not a randomized controlled trial

Sarma 1991 One arm allocated to norfloxacin which is no longer recommended for use by the WHO

Secmeer 1997 No randomization; allocation based on co-trimoxazole susceptibility

Singh 1993 No mention of randomization

Suhendro 2007 Compares 2 different formulations of ciprofloxacin; described as a prospective, open labelled, clinical trial,

comparing safety and efficacy of extended-release ciprofloxacin 1000 mg once daily (Ciprofloxacin XR) and

ciprofloxacin intermediate release 500 mg 2 times daily (Ciprofloxacin bid) in adults with typhoid fever

Takkar 1994 Not randomized

Tanphaichitra 1986 Randomized controlled trial of gonorrhoea; part of the report, but not part of the trial, were 8 participants

with enteric fever that treated with ofloxacin

Tran 1994 One arm allocated to fleroxacin which is no longer in clinical use

Uwaydah 1992 Compares 2 ciprofloxacin doses, not durations

Wain 1997 Study on S. Typhi isolates from blood cultures of participants included in 3 trials included in this review:

Smith 1994 VNM; Vinh 1996 VNM; and Nguyen 1997



(Continued)

Weng 1996a A description of likely several trials involving fluoroquinolones

Yang 1991 One group given fleroxacin which is no longer in clinical use

Zavala 1989 No mention of randomization

Zhang 1991 Randomized controlled trial including several infections; randomization not applied to the 63 typhoid partic-

ipants treated with enoxacin

ZhongYang 1997 Randomized controlled trial comparing ofloxacin with norfloxacin for 14 days

Characteristics of studies awaiting assessment [ordered by study ID]

Bran 1991



Blinding: double


Participants 102 analysed a : 51 in ciprofloxacin group; 51 in chloramphenicol group; only the total number of participants (102)

was provided, but we assumed 51 in each group

Age not mentioned (adult dosages used); most probably inpatients

Inclusion criteria: blood and/or bone marrow culture positive for S. Typhi




Outcomes 1. Microbiological failure





Notes Location: Guatemala

Date: not reported


Conference abstract



Flores 1991

Methods NA

Participants NA

Interventions NA

Outcomes NA

Notes Unable to retrieve this study

Quintero 1988

Methods Reported as a double blind study but exact methods are unclear

Participants 26 participants: 13 in each group

Age not mentioned (adult dosages used); most probably inpatients

Inclusion criteria: not reported


Interventions 1. Ciprofloxacin (750 mg oral 3 times a day for unknown duration)

2. Chloramphenicol (750 mg oral 4 times a day for unknown duration)




Notes Location: Mexico

Date: not reported


Conference abstract

Soewandojo 1992

Methods NA

Participants NA

Interventions NA

Outcomes NA

Notes Unable to retrieve this study



Weng 1996

Methods Unclear

Participants Children and adults aged 14 to years

Interventions Several different fluoroquinolones given orally and parenterally

Outcomes Cure and efficiency rate

Fever clearance

Bacterial clearance rate

Notes Chinese language, unclear if randomized trials

Xiao 1991

Methods Unclear

Participants Adult and children inpatients aged 11 to 62 years

Inclusion criteria: clinical with blood or bone marrow culture positive for S. Typhi

Exclusion criteria: not mentioned

Interventions We evaluated 3 of the available 5 groups:

1. Norfloxacin (300 to 400 mg oral thrice a day for 14 days)

2. Pefloxacin (400 mg oral twice daily for 14 days)

3. Ofloxacin (300 mg oral twice daily for 14 days)



Notes Location: China (Chinese language)

Date: not reported

Yu 1998



Blinding: open


Participants 80 analysed: 40 in levofloxacin group; 40 in cefixime group

Adult aged 18 to 65 years; most probably inpatients

Inclusion criteria: clinical with blood or bone marrow culture positive for S. Typhi or S. Paratyphi

Exclusion criteria: not mentioned

Interventions 1. Levofloxacin (200 mg oral twice a day for 10 days)

2. Cefixime (200 mg oral twice a day for 10 days)





Yu 1998 (Continued)

3. Relapse


5. Complications



Notes Location: China (Chinese language)

Date: not reported

Severity of illness at entry: included ’mild, common, and severe’ types (1 ’severe type’ illness in levofloxacin group

and 2 in cefixime group)

Characteristics of ongoing studies [ordered by study ID]

ISRCTN66534807

Trial name or title “A randomised clinical trial of Azithromycin versus Ofloxacin in the treatment of adults with uncomplicated

typhoid fever at Mahosot Hospital, Vientiane, Lao People’s Democratic Republic (PDR)”

Methods “randomised clinical trial”

Participants Inclusion criteria: adult (≥15 years) non-pregnant patients with suspected or blood-culture proven typhoid;

fever > 37.5 °C; informed written consent to the study; able to stay in hospital for 7 days; able to take oral

medication; bodyweight > 40 kg; likely to be able to complete 6 months’ follow up; none of the exclusion

criteria

Exclusion criteria: known hypersensitivity to ofloxacin or azithromycin; administration of chloramphenicol,

co-trimoxazole, ampicillin, azithromycin, or a fluoroquinolone during previous week; pregnancy or breast-

feeding; contraindications to ofloxacin or azithromycin; evidence for severe typhoid

Interventions 1. Ofloxacin 7.5 mg/kg every 12 hours for 3 days

2. Azithromycin 20 mg/kg every 24 hours for 3 days

Outcomes 1. Fever clearance time

2. Cure

3. Relapse

4. Faecal carriage

Starting date 1 May 2004

Anticipated end date: 31 December 2007

Contact information Dr Paul Newton ([email protected]), Microbiology laboratory, Ministry of Health, Mahosot Hospital,

Vientiane, Laos

Notes Location: Laos

Registration number: ISRCTN66534807

Source of funding: The Wellcome Trust (UK)

Percentage of children in trial: none

E-mail update by Dr Newton on 5 December 2007: on hold because of considerable decline in incidence of



ISRCTN66534807 (Continued)

typhoid in Vientiane



D A T A A N D A N A L Y S E S

Comparison 1. Fluoroquinolone versus chloramphenicol

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Clinical failure 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 Ciprofloxacin versus

chloramphenicol

4 293 Risk Ratio (M-H, Fixed, 95% CI) 0.24 [0.07, 0.82]

1.2 Ofloxacin versus

chloramphenicol


1.3 Pefloxacin versus

chloramphenicol


1.4 Gatifloxacin versus

chloramphenicol


2 Microbiological failure 5 Risk Ratio (M-H, Random, 95% CI) Subtotals only


chloramphenicol

2 142 Risk Ratio (M-H, Random, 95% CI) 0.05 [0.00, 0.81]


chloramphenicol



chloramphenicol



chloramphenicol


3 Relapse 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


chloramphenicol



chloramphenicol



chloramphenicol



chloramphenicol


4 Convalescent faecal carriage 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


chloramphenicol



chloramphenicol



chloramphenicol



chloramphenicol


5 Fever clearance time 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only


chloramphenicol

2 147 Mean Difference (IV, Fixed, 95% CI) -62.46 [-75.52, -49.

39]


chloramphenicol


17]

6 Duration of hospitalization 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only




chloramphenicol

1 55 Mean Difference (IV, Fixed, 95% CI) -0.40 [-1.63, 0.83]


chloramphenicol

1 50 Mean Difference (IV, Fixed, 95% CI) -9.9 [-11.42, -8.38]

7 Serious adverse events 3 203 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.18, 5.52]


chloramphenicol



chloramphenicol


8 Non-serious adverse events 8 1410 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.61, 0.94]


chloramphenicol



chloramphenicol



chloramphenicol



chloramphenicol


Comparison 2. Fluoroquinolone versus co-trimoxazole


studies

No. of


1 Clinical Failure 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


co-trimoxazole



co-trimoxazole



co-trimoxazole


2 Microbiological failure 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


co-trimoxazole



co-trimoxazole



co-trimoxazole


3 Relapse 1 181 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]


co-trimoxazole



co-trimoxazole


4 Convalescent faecal carriage 1 42 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]


5.1 ciprofloxacin versus

co-trimoxazole


28]


co-trimoxazole


36]



6 Non serious adverse events 3 219 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.46, 1.08]


co-trimoxazole



co-trimoxazole



co-trimoxazole


Comparison 3. Fluroqunolone versus ampicillin/amoxicillin


studies

No. of


1 Clinical failure 2 90 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.02, 0.57]


ampicillin



amoxicillin


2 Microbiological failure 2 90 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.03, 0.68]


ampicillin/amoxicillin



amoxicillin




amoxicillin


Comparison 4. Fluoroquinolone versus cefixime


studies

No. of




cefixime


1.2 Ofloxacin versus cefixime 2 173 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.02, 1.11]


cefixime




cefixime




cefixime






cefixime




cefixime




cefixime




cefixime

1 94 Mean Difference (IV, Fixed, 95% CI) -12.00 [-24.42, 0.

42]

5.2 Ofloxacin versus cefixime 1 91 Mean Difference (IV, Fixed, 95% CI) -24.0 [-41.46, -6.54]

6 Duration of hospitalization 1 81 Mean Difference (IV, Fixed, 95% CI) -3.0 [-4.53, -1.47]

6.1 Ofloxacin versus cefixime 1 81 Mean Difference (IV, Fixed, 95% CI) -3.0 [-4.53, -1.47]

7 Serious adverse Events 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



cefixime


8 Non-serious adverse events 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


cefixime




cefixime


Comparison 5. Fluoroquinolone versus ceftriaxone


studies

No. of




ceftriaxone



ceftriaxone




ceftriaxone



ceftriaxone




ceftriaxone



ceftriaxone




ceftriaxone




5 Fever clearance time 1 47 Mean Difference (IV, Fixed, 95% CI) -113.00 [-150.67, -

79.33]


ceftriaxone

1 47 Mean Difference (IV, Fixed, 95% CI) -113.00 [-150.67, -

79.33]



ceftriaxone


Comparison 6. Fluoroquinolone versus azithromycin


studies

No. of




azithromycin



azithromycin



azithromycin




azithromycin



azithromycin



azithromycin




azithromycin



azithromycin



azithromycin




azithromycin



azithromycin



azithromycin


5 Fever clearance time 3 Mean Difference (IV, Random, 95% CI) Subtotals only


azithromycin

1 64 Mean Difference (IV, Random, 95% CI) -12.0 [-24.39, 0.39]


azithromycin

2 213 Mean Difference (IV, Random, 95% CI) 30.41 [-22.12, 82.

93]

6 Duration of Hospitalization 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only


azithromycin

2 213 Mean Difference (IV, Fixed, 95% CI) 1.01 [0.19, 1.83]





azithromycin


8 Non-serious adverse events 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only


azithromycin



azithromycin


8.3 Gatifloxain versus

azithromycin


Comparison 7. Fluoroquinolone 2 days vs 3 days


studies

No. of


1 Clinical failure 3 396 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.54, 2.53]



4 Convalecsent faecal carriage 2 262 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.01, 7.45]

5 Fever clearance time 3 396 Mean Difference (IV, Fixed, 95% CI) -5.41 [-14.59, 3.78]

6 Duration of hospitalization 3 396 Mean Difference (IV, Fixed, 95% CI) -0.33 [-0.73, 0.06]





studies

No. of



2 Fever Clearance time 1 195 Mean Difference (IV, Fixed, 95% CI) -12.0 [-18.07, -5.93]




studies

No. of


1 Microbiological Failure 1 46 Risk Ratio (M-H, Fixed, 95% CI) 3.26 [0.14, 76.10]


3 Fever clearance time 1 46 Mean Difference (IV, Fixed, 95% CI) -7.20 [-7.78, -6.62]






studies

No. of




Comparison 11. Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days)


studies

No. of


1 All outcomes 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

1.1 Clinical failure (need

for rescue medication or

persistence of fever until day

10)

1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

1.2 Microbiological failure

(blood culture +ve on day 8)


1.3 Relapse (reappearance of

culture confirmed or syndromic

enteric fever on days 11 to 31)


1.4 Convalescent faecal

carriage


1.5 Serious adverse events 0 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

1.6 Other adverse events

(selected gastrointestinal

adverse events)




studies

No. of



2 Fever clearance time 1 69 Mean Difference (IV, Fixed, 95% CI) -16.80 [-42.65, 9.

05]




Comparison 13. Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days)


studies

No. of




for rescue medication or

persistence of fever until day 7)


1.2 Relapse (fever plus +ve

blood culture within 1 month

of successful treatment)



(blood culture +ve on day 10)



1.5 Other adverse events (may

be incompletely reported)


Comparison 14. Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days)


studies

No. of




for rescue medication of

persistence of fever until day

10)


1.2 Relapse (symptoms and

signs of typhoid fever within 1

month of successful treatment)



(blood culture +ve on day 7 to

9)


1.4 Convalescent faecal

carriage



1.6 Other adverse events (may

be incompletely reported)




Analysis 1.1. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 1 Clinical failure.

Review: Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)

Comparison: 1 Fluoroquinolone versus chloramphenicol

Outcome: 1 Clinical failure

Study or subgroup Fluoroquinolone Chloramphenicol Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Ciprofloxacin versus chloramphenicol

Gottuzzo 1992 N/A (1) 1/48 0/48 4.0 % 3.00 [ 0.13, 71.85 ]

Morelli 1992 ITA (2) 0/20 0/30 Not estimable

Gasem 2003 IDN (3) 1/28 2/27 16.4 % 0.48 [ 0.05, 5.01 ]

Rizvi 2007 PAK (4) 0/48 9/44 79.6 % 0.05 [ 0.00, 0.81 ]

Subtotal (95% CI) 144 149 100.0 % 0.24 [ 0.07, 0.82 ]

Total events: 2 (Fluoroquinolone), 11 (Chloramphenicol)

Heterogeneity: Chi2 = 4.03, df = 2 (P = 0.13); I2 =50%

Test for overall effect: Z = 2.28 (P = 0.023)

2 Ofloxacin versus chloramphenicol

Yousaf 1992 PAK (5) 1/25 2/25 15.1 % 0.50 [ 0.05, 5.17 ]


Phongmany 2005 LAO (7) 0/27 1/23 12.2 % 0.29 [ 0.01, 6.69 ]

Rizvi 2007 PAK (8) 0/45 9/44 72.7 % 0.05 [ 0.00, 0.86 ]

Subtotal (95% CI) 127 122 100.0 % 0.15 [ 0.03, 0.64 ]


Heterogeneity: Chi2 = 1.75, df = 2 (P = 0.42); I2 =0.0%


3 Pefloxacin versus chloramphenicol


Cristiano 1995 ITA (10) 0/30 0/30 Not estimable

Subtotal (95% CI) 66 60 Not estimable


Heterogeneity: not applicable

Test for overall effect: not applicable

4 Gatifloxacin versus chloramphenicol

Arjyal 2011 (11) 8/177 10/175 100.0 % 0.79 [ 0.32, 1.96 ]

Subtotal (95% CI) 177 175 100.0 % 0.79 [ 0.32, 1.96 ]




0.001 0.01 0.1 1 10 100 1000

Favours fluoroquinolone Favours chloramphenicol



(1) Ciprofloxacin 500mg BD for 10 days vs Chloramphenicol 750mg QDS for 14 days

(2) Ciprofloxacin 500mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days



(5) Ofloxacin 200mg BD for 14 days vs Chloramphenicol 50mg/kg/day for 14 days

(6) Ofloxacin 300mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days

(7) Ofloxacin 15mg/kg in 2 divided doses for 3 days vs Cloramphenicol 50mg/kg in 4 divided doses for 14 days

(8) Ofloxacin 200mg BD for 7 days vs Chloramphenicol 750mg QDS for 14 days

(9) Pefloxacin 400mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days

(10) Pefloxacin 400mg (IV) TDS for 5 days vs Chloramphenicol 500mg (PO) QDS for 15 days

(11) Gatifloxacin 10mg/kg OD for 7 days vs Chloramphenicol 75mg/kg in 4 divided doses for 14 days

Analysis 1.2. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 2 Microbiological failure.



Outcome: 2 Microbiological failure


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI



Rizvi 2007 PAK 0/48 9/44 100.0 % 0.05 [ 0.00, 0.81 ]

Subtotal (95% CI) 68 74 100.0 % 0.05 [ 0.00, 0.81 ]





Yousaf 1992 PAK 1/25 3/25 60.2 % 0.33 [ 0.04, 2.99 ]


Rizvi 2007 PAK 0/45 9/44 39.8 % 0.05 [ 0.00, 0.86 ]

0.001 0.01 0.1 1 10 100 1000


(Continued . . . )



(. . . Continued)Study or subgroup Fluoroquinolone Chloramphenicol Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Subtotal (95% CI) 100 99 100.0 % 0.16 [ 0.02, 1.07 ]


Heterogeneity: Tau2 = 0.31; Chi2 = 1.19, df = 1 (P = 0.28); I2 =16%




Cristiano 1995 ITA 0/30 0/30 Not estimable






Arjyal 2011 2/177 0/175 100.0 % 4.94 [ 0.24, 102.24 ]

Subtotal (95% CI) 177 175 100.0 % 4.94 [ 0.24, 102.24 ]




0.001 0.01 0.1 1 10 100 1000


(1) Ciprofloxacin 500mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days

(2) Ofloxacin 300mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days

(3) Pefloxacin 400mg TDS for 15 days vs Chloramphenicol 500mg QDS for 15 days



Analysis 1.3. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 3 Relapse.



Outcome: 3 Relapse




Morelli 1992 ITA 0/20 3/30 38.8 % 0.21 [ 0.01, 3.87 ]

Gottuzzo 1992 N/A 0/47 4/48 61.2 % 0.11 [ 0.01, 2.05 ]

Gasem 2003 IDN (1) 0/28 0/27 Not estimable

Rizvi 2007 PAK 0/48 0/44 Not estimable

Subtotal (95% CI) 143 149 100.0 % 0.15 [ 0.02, 1.15 ]





Morelli 1992 ITA 0/30 3/30 100.0 % 0.14 [ 0.01, 2.65 ]

Rizvi 2007 PAK 0/45 0/44 Not estimable

Subtotal (95% CI) 75 74 100.0 % 0.14 [ 0.01, 2.65 ]





Morelli 1992 ITA 0/36 3/30 60.4 % 0.12 [ 0.01, 2.23 ]

Cristiano 1995 ITA 0/30 2/30 39.6 % 0.20 [ 0.01, 4.00 ]

Subtotal (95% CI) 66 60 100.0 % 0.15 [ 0.02, 1.21 ]





Arjyal 2011 4/177 7/175 100.0 % 0.56 [ 0.17, 1.90 ]

Subtotal (95% CI) 177 175 100.0 % 0.56 [ 0.17, 1.90 ]




0.001 0.01 0.1 1 10 100 1000


(1) Gasem 2003 IDN reports that no relapses were observed but patients were not routinely monitored after day 14.



Analysis 1.4. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 4 Convalescent faecal

carriage.



Outcome: 4 Convalescent faecal carriage




Morelli 1992 ITA 0/20 4/30 100.0 % 0.16 [ 0.01, 2.89 ]

Subtotal (95% CI) 20 30 100.0 % 0.16 [ 0.01, 2.89 ]





Morelli 1992 ITA 0/30 4/30 100.0 % 0.11 [ 0.01, 1.98 ]

Subtotal (95% CI) 30 30 100.0 % 0.11 [ 0.01, 1.98 ]





Morelli 1992 ITA 0/36 4/30 66.2 % 0.09 [ 0.01, 1.66 ]

Cristiano 1995 ITA 0/30 2/30 33.8 % 0.20 [ 0.01, 4.00 ]

Subtotal (95% CI) 66 60 100.0 % 0.13 [ 0.02, 1.01 ]





Arjyal 2011 0/139 1/134 100.0 % 0.32 [ 0.01, 7.82 ]

Subtotal (95% CI) 139 134 100.0 % 0.32 [ 0.01, 7.82 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 1.5. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 5 Fever clearance time.



Outcome: 5 Fever clearance time

Study or subgroup Fluoroquinolone ChloramphenicolMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI


Gasem 2003 IDN (1) 28 122.4 (33.6) 27 136.8 (52.8) 31.0 % -14.40 [ -37.88, 9.08 ]

Rizvi 2007 PAK (2) 48 72 (24) 44 156 (48) 69.0 % -84.00 [ -99.72, -68.28 ]

Subtotal (95% CI) 76 71 100.0 % -62.46 [ -75.52, -49.39 ]

Heterogeneity: Chi2 = 23.30, df = 1 (P<0.00001); I2 =96%

Test for overall effect: Z = 9.37 (P < 0.00001)


Phongmany 2005 LAO 27 55 (20.1) 21 93.5 (46.8) 35.1 % -38.50 [ -59.90, -17.10 ]

Rizvi 2007 PAK 48 60 (24) 44 156 (48) 64.9 % -96.00 [ -111.72, -80.28 ]

Subtotal (95% CI) 75 65 100.0 % -75.85 [ -88.52, -63.17 ]



Test for subgroup differences: Chi2 = 2.08, df = 1 (P = 0.15), I2 =52%

-100 -50 0 50 100


(1) Days

(2) Days



Analysis 1.6. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 6 Duration of

hospitalization.



Outcome: 6 Duration of hospitalization

Study or subgroup Fluoroquinolone ChloramphenicolMean


Difference



Gasem 2003 IDN (1) 28 11.7 (2) 27 12.1 (2.6) 100.0 % -0.40 [ -1.63, 0.83 ]

Subtotal (95% CI) 28 27 100.0 % -0.40 [ -1.63, 0.83 ]




Phongmany 2005 LAO 27 8.9 (2.33) 23 18.8 (3.04) 100.0 % -9.90 [ -11.42, -8.38 ]

Subtotal (95% CI) 27 23 100.0 % -9.90 [ -11.42, -8.38 ]




-100 -50 0 50 100


(1) Days



Analysis 1.7. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 7 Serious adverse events.



Outcome: 7 Serious adverse events




Gottuzzo 1992 N/A 2/49 1/49 39.6 % 2.00 [ 0.19, 21.34 ]

Gasem 2003 IDN 0/28 1/27 60.4 % 0.32 [ 0.01, 7.57 ]

Subtotal (95% CI) 77 76 100.0 % 0.99 [ 0.18, 5.52 ]





Phongmany 2005 LAO 0/27 0/23 Not estimable





Total (95% CI) 104 99 100.0 % 0.99 [ 0.18, 5.52 ]




Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours fluoroquinolones Favours chloramphenicol



Analysis 1.8. Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 8 Non-serious adverse

events.



Outcome: 8 Non-serious adverse events




Morelli 1992 ITA 18/20 4/10 3.5 % 2.25 [ 1.04, 4.87 ]

Gottuzzo 1992 N/A 0/49 10/49 6.9 % 0.05 [ 0.00, 0.79 ]

Gasem 2003 IDN 0/28 1/27 1.0 % 0.32 [ 0.01, 7.57 ]

Rizvi 2007 PAK 18/48 5/22 4.5 % 1.65 [ 0.70, 3.87 ]

Subtotal (95% CI) 145 108 15.9 % 1.00 [ 0.61, 1.64 ]





Morelli 1992 ITA 10/30 5/10 4.9 % 0.67 [ 0.30, 1.48 ]

Yousaf 1992 PAK 3/25 4/25 2.6 % 0.75 [ 0.19, 3.01 ]

Phongmany 2005 LAO 0/27 0/23 Not estimable

Rizvi 2007 PAK 15/45 4/22 3.5 % 1.83 [ 0.69, 4.88 ]

Subtotal (95% CI) 127 80 11.1 % 1.06 [ 0.60, 1.87 ]





Morelli 1992 ITA 18/36 4/10 4.1 % 1.25 [ 0.55, 2.86 ]

Cristiano 1995 ITA 7/30 5/30 3.3 % 1.40 [ 0.50, 3.92 ]

Subtotal (95% CI) 66 40 7.4 % 1.32 [ 0.69, 2.52 ]





Arjyal 2011 59/426 99/418 65.6 % 0.58 [ 0.44, 0.78 ]

Subtotal (95% CI) 426 418 65.6 % 0.58 [ 0.44, 0.78 ]




0.002 0.1 1 10 500


(Continued . . . )



(. . . Continued)Study or subgroup Fluoroquinolone Chloramphenicol Risk Ratio Weight Risk Ratio


Total (95% CI) 764 646 100.0 % 0.76 [ 0.61, 0.94 ]





0.002 0.1 1 10 500


Analysis 2.1. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 1 Clinical Failure.


Comparison: 2 Fluoroquinolone versus co-trimoxazole

Outcome: 1 Clinical Failure

Study or subgroup Fluoroquinolone Cotrimoxazole Risk Ratio Weight Risk Ratio


1 Ciprofloxacin versus co-trimoxazole

Limson 1989 PHL (1) 0/20 2/20 15.1 % 0.20 [ 0.01, 3.92 ]

Rizvi 2007 PAK (2) 0/48 13/44 84.9 % 0.03 [ 0.00, 0.56 ]

Subtotal (95% CI) 68 64 100.0 % 0.06 [ 0.01, 0.43 ]

Total events: 0 (Fluoroquinolone), 15 (Cotrimoxazole)



2 Ofloxacin versus co-trimoxazole

Rizvi 2007 PAK (3) 0/45 13/44 100.0 % 0.04 [ 0.00, 0.59 ]

Subtotal (95% CI) 45 44 100.0 % 0.04 [ 0.00, 0.59 ]




3 Pefloxacin versus co-trimoxazole

Hajji 1988 MAR (4) 0/24 0/18 Not estimable





0.005 0.1 1 10 200

Favours fluoroquinolone Favours cotrimoxazole



(1) Ciprofloxacin 500 mg BD for 10 days vs Co-trimoxazole 160/800 mg BD for 14 days

(2) Ciprofloxacin 500mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 days

(3) Ofloxacin 200mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 days

(4) Pefloxacin 400 mg BD for 14 days vs Co-trimoxazole 160/800 mg BD for 14 days

Analysis 2.2. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 2 Microbiological failure.







Limson 1989 PHL (1) 0/20 2/20 15.1 % 0.20 [ 0.01, 3.92 ]

Rizvi 2007 PAK (2) 0/48 13/44 84.9 % 0.03 [ 0.00, 0.56 ]

Subtotal (95% CI) 68 64 100.0 % 0.06 [ 0.01, 0.43 ]





Rizvi 2007 PAK (3) 0/45 13/44 100.0 % 0.04 [ 0.00, 0.59 ]

Subtotal (95% CI) 45 44 100.0 % 0.04 [ 0.00, 0.59 ]





Hajji 1988 MAR (4) 0/24 0/18 Not estimable





0.001 0.01 0.1 1 10 100 1000




(1) Ciprofloxacin 500 mg BD for 10 days vs Co-trimoxazole 160/800 mg BD for 14 days


(3) Ofloxacin 200mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 ays

(4) Pefloxacin 400 mg BD for 14 days vs Co-trimoxazole 160/800 mg BD for 14 days

Analysis 2.3. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 3 Relapse.



Outcome: 3 Relapse




Rizvi 2007 PAK (1) 0/48 0/44 Not estimable











Total (95% CI) 93 88 Not estimable




Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01 0.1 1 10 100

Favours fluoroqunolone Favours cotrimoxazole


(2) Ofloxacin 200mg BD for 7 days vs Co-trimoxazole 960mg BD for 14 days



Analysis 2.4. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 4 Convalescent faecal

carriage.






Hajji 1988 MAR 0/24 0/18 Not estimable






0.01 0.1 1 10 100

Favours Pefloxacin Favours Cotrimoxazole

Analysis 2.5. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 5 Fever clearance time.




Study or subgroup Fluoroquinolone CotrimoxazoleMean


Difference


1 ciprofloxacin versus co-trimoxazole

Rizvi 2007 PAK 48 72 (24) 44 156 (48) 100.0 % -84.00 [ -99.72, -68.28 ]

Subtotal (95% CI) 48 44 100.0 % -84.00 [ -99.72, -68.28 ]




Rizvi 2007 PAK 48 60 (48) 44 156 (48) 100.0 % -96.00 [ -115.64, -76.36 ]

Subtotal (95% CI) 48 44 100.0 % -96.00 [ -115.64, -76.36 ]



Test for subgroup differences: Chi2 = 0.87, df = 1 (P = 0.35), I2 =0.0%

-100 -50 0 50 100




Analysis 2.6. Comparison 2 Fluoroquinolone versus co-trimoxazole, Outcome 6 Non serious adverse events.



Outcome: 6 Non serious adverse events




Limson 1989 PHL 5/20 6/20 17.8 % 0.83 [ 0.30, 2.29 ]

Rizvi 2007 PAK 10/48 9/22 36.7 % 0.51 [ 0.24, 1.07 ]

Subtotal (95% CI) 68 42 54.5 % 0.62 [ 0.34, 1.12 ]





Rizvi 2007 PAK 15/45 8/22 31.9 % 0.92 [ 0.46, 1.83 ]

Subtotal (95% CI) 45 22 31.9 % 0.92 [ 0.46, 1.83 ]





Hajji 1988 MAR 3/24 4/18 13.6 % 0.56 [ 0.14, 2.21 ]

Subtotal (95% CI) 24 18 13.6 % 0.56 [ 0.14, 2.21 ]




Total (95% CI) 137 82 100.0 % 0.70 [ 0.46, 1.08 ]





0.05 0.2 1 5 20




Analysis 3.1. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 1 Clinical failure.


Comparison: 3 Fluroqunolone versus ampicillin/amoxicillin


Study or subgroup Fluoroquinolone Ampicillin/Amoxycillin Risk Ratio Weight Risk Ratio


1 Ofloxacin versus ampicillin

Flores 1994 MEX (1) 0/20 5/20 40.7 % 0.09 [ 0.01, 1.54 ]

Subtotal (95% CI) 20 20 40.7 % 0.09 [ 0.01, 1.54 ]

Total events: 0 (Fluoroquinolone), 5 (Ampicillin/Amoxycillin)



2 Ofloxacin versus amoxicillin

Yousaf 1992 PAK (2) 1/25 8/25 59.3 % 0.13 [ 0.02, 0.93 ]

Subtotal (95% CI) 25 25 59.3 % 0.13 [ 0.02, 0.93 ]




Total (95% CI) 45 45 100.0 % 0.11 [ 0.02, 0.57 ]





0.005 0.1 1 10 200

Favours fluoroquinolone Favours ampicillin

(1) Ofloxacin 400 mg BD 10 days vs Ampicillin 1 g QDS for 10 days

(2) Ofloxacin 200 mg oral BD for 14 days vs Amoxicillin 4 to 6 g/day for 14 days



Analysis 3.2. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 2 Microbiological failure.






1 Ofloxacin versus ampicillin/amoxicillin

Flores 1994 MEX (1) 0/20 3/20 30.4 % 0.14 [ 0.01, 2.60 ]

Subtotal (95% CI) 20 20 30.4 % 0.14 [ 0.01, 2.60 ]





Yousaf 1992 PAK (2) 1/25 8/25 69.6 % 0.13 [ 0.02, 0.93 ]

Subtotal (95% CI) 25 25 69.6 % 0.13 [ 0.02, 0.93 ]




Total (95% CI) 45 45 100.0 % 0.13 [ 0.03, 0.68 ]





0.001 0.01 0.1 1 10 100 1000

Favours fluoroquinolone Favours ampicillin

(1) Ofloxacin 400 mg BD 10 days vs Ampicillin 1 g QDS for 10 days

(2) Ofloxacin 200 mg oral BD for 14 days vs Amoxicillin 4 to 6 g/day for 14 days



Analysis 3.3. Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 3 Non-serious adverse

events.







Flores 1994 MEX 1/20 1/20 8.3 % 1.00 [ 0.07, 14.90 ]

Yousaf 1992 PAK 3/25 11/25 91.7 % 0.27 [ 0.09, 0.86 ]

Total (95% CI) 45 45 100.0 % 0.33 [ 0.12, 0.93 ]





0.01 0.1 1 10 100

Favours fluoroqunolone Favours ampicillin



Analysis 4.1. Comparison 4 Fluoroquinolone versus cefixime, Outcome 1 Clinical failure.


Comparison: 4 Fluoroquinolone versus cefixime


Study or subgroup Fluoroquinolone Cefixime Risk Ratio Weight Risk Ratio


1 Ciprofloxacin versus cefixime



Total events: 0 (Fluoroquinolone), 0 (Cefixime)



2 Ofloxacin versus cefixime

Phuong 1999 VNM (2) 1/38 8/44 100.0 % 0.14 [ 0.02, 1.11 ]


Subtotal (95% CI) 83 90 100.0 % 0.14 [ 0.02, 1.11 ]




3 Gatifloxacin versus cefixime

Pandit 2007 NPL (4) 1/88 19/70 100.0 % 0.04 [ 0.01, 0.31 ]

Subtotal (95% CI) 88 70 100.0 % 0.04 [ 0.01, 0.31 ]




0.005 0.1 1 10 200

Favours fluoroquinolone Favours cefixime

(1) Ciprofloxacin 500mg BD for 7 days vs Cefixime 200mg BD for 7 days

(2) Ofloxacin 10mg/kg in 2 divided doses for 5 days vs Cefixime 20mg/kg in 2 divided doses for 7 days

(3) Ofloxacin 200 mg BD for 7 days vs Cefixime 200 mg BD for 7 days)

(4) Gatifloxacin 10mg/kg/day in single oral dose for 7 days vs Cefixime 20mg/kg in 2 divided doses oral for 7 days



Analysis 4.2. Comparison 4 Fluoroquinolone versus cefixime, Outcome 2 Microbiological failure.













Phuong 1999 VNM (2) 0/38 2/44 100.0 % 0.23 [ 0.01, 4.66 ]


Subtotal (95% CI) 83 90 100.0 % 0.23 [ 0.01, 4.66 ]





Pandit 2007 NPL (4) 0/88 1/70 100.0 % 0.27 [ 0.01, 6.43 ]

Subtotal (95% CI) 88 70 100.0 % 0.27 [ 0.01, 6.43 ]




0.002 0.1 1 10 500




(3) Ofloxacin 200 mg BD for 7 days vs Cefixime 200 mg BD for 7 days




Analysis 4.3. Comparison 4 Fluoroquinolone versus cefixime, Outcome 3 Relapse.



Outcome: 3 Relapse










Phuong 1999 VNM (2) 0/20 1/20 100.0 % 0.33 [ 0.01, 7.72 ]


Subtotal (95% CI) 65 66 100.0 % 0.33 [ 0.01, 7.72 ]





Pandit 2007 NPL (4) 2/87 6/51 100.0 % 0.20 [ 0.04, 0.93 ]

Subtotal (95% CI) 87 51 100.0 % 0.20 [ 0.04, 0.93 ]




0.01 0.1 1 10 100




(3) Ofloxacin 200 mg BD for 7 days vs Cefixime 200 mg BD for 7 days




Analysis 4.4. Comparison 4 Fluoroquinolone versus cefixime, Outcome 4 Convalescent faecal carriage.







Pandit 2007 NPL 0/82 1/65 100.0 % 0.27 [ 0.01, 6.40 ]

Subtotal (95% CI) 82 65 100.0 % 0.27 [ 0.01, 6.40 ]




0.001 0.01 0.1 1 10 100 1000


Analysis 4.5. Comparison 4 Fluoroquinolone versus cefixime, Outcome 5 Fever clearance time.




Study or subgroup Fluoroquinolone CefiximeMean


Difference



Rizvi 2007 PAK 48 72 (24) 46 84 (36) 100.0 % -12.00 [ -24.42, 0.42 ]

Subtotal (95% CI) 48 46 100.0 % -12.00 [ -24.42, 0.42 ]




Rizvi 2007 PAK 45 60 (48) 46 84 (36) 100.0 % -24.00 [ -41.46, -6.54 ]

Subtotal (95% CI) 45 46 100.0 % -24.00 [ -41.46, -6.54 ]




-200 -100 0 100 200

Favours Fluoroquinolone Favours Cefixime



Analysis 4.6. Comparison 4 Fluoroquinolone versus cefixime, Outcome 6 Duration of hospitalization.




Study or subgroup Fluoroquinolone CefiximeMean


Difference



Phuong 1999 VNM 37 11 (3) 44 14 (4) 100.0 % -3.00 [ -4.53, -1.47 ]

Total (95% CI) 37 44 100.0 % -3.00 [ -4.53, -1.47 ]




-10 -5 0 5 10




Analysis 4.7. Comparison 4 Fluoroquinolone versus cefixime, Outcome 7 Serious adverse Events.



Outcome: 7 Serious adverse Events




Phuong 1999 VNM 1/38 0/44 100.0 % 3.46 [ 0.15, 82.56 ]

Subtotal (95% CI) 38 44 100.0 % 3.46 [ 0.15, 82.56 ]





Pandit 2007 NPL 2/92 1/77 100.0 % 1.67 [ 0.15, 18.11 ]

Subtotal (95% CI) 92 77 100.0 % 1.67 [ 0.15, 18.11 ]




0.01 0.1 1 10 100




Analysis 4.8. Comparison 4 Fluoroquinolone versus cefixime, Outcome 8 Non-serious adverse events.







Rizvi 2007 PAK 18/48 11/46 100.0 % 1.57 [ 0.83, 2.95 ]

Subtotal (95% CI) 48 46 100.0 % 1.57 [ 0.83, 2.95 ]





Rizvi 2007 PAK 15/45 9/46 100.0 % 1.70 [ 0.83, 3.49 ]

Subtotal (95% CI) 45 46 100.0 % 1.70 [ 0.83, 3.49 ]





Pandit 2007 NPL 25/92 1/77 100.0 % 20.92 [ 2.90, 150.90 ]

Subtotal (95% CI) 92 77 100.0 % 20.92 [ 2.90, 150.90 ]




0.05 0.2 1 5 20




Analysis 5.1. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 1 Clinical failure.


Comparison: 5 Fluoroquinolone versus ceftriaxone


Study or subgroup Fluoroquinolone Ceftriaxone Risk Ratio Weight Risk Ratio


1 Ciprofloxacin versus ceftriaxone

Wallace 1993 BHR (1) 0/20 6/22 100.0 % 0.08 [ 0.01, 1.41 ]

Subtotal (95% CI) 20 22 100.0 % 0.08 [ 0.01, 1.41 ]

Total events: 0 (Fluoroquinolone), 6 (Ceftriaxone)



2 Ofloxacin versus ceftriaxone

Smith 1994 VNM (2) 0/22 6/25 100.0 % 0.09 [ 0.01, 1.46 ]

Subtotal (95% CI) 22 25 100.0 % 0.09 [ 0.01, 1.46 ]




0.002 0.1 1 10 500

Favours fluoroquinolone Favours ceftriaxone

(1) Ciprofloxacin 500 mg BD for 7 days vs Ceftriaxone 3 g/day IV for 7 days

(2) Ofloxacin 200 mg BD for 5 days vs Ceftriaxone 3 g IV OD for 3 days



Analysis 5.2. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 2 Microbiological failure.







Wallace 1993 BHR (1) 0/20 0/22 Not estimable






Smith 1994 VNM (2) 0/22 1/25 100.0 % 0.38 [ 0.02, 8.80 ]

Subtotal (95% CI) 22 25 100.0 % 0.38 [ 0.02, 8.80 ]




0.01 0.1 1 10 100






Analysis 5.3. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 3 Relapse.



Outcome: 3 Relapse




Wallace 1993 BHR (1) 0/20 1/22 100.0 % 0.37 [ 0.02, 8.48 ]

Subtotal (95% CI) 20 22 100.0 % 0.37 [ 0.02, 8.48 ]





Smith 1994 VNM (2) 0/11 1/12 100.0 % 0.36 [ 0.02, 8.04 ]

Subtotal (95% CI) 11 12 100.0 % 0.36 [ 0.02, 8.04 ]




0.01 0.1 1 10 100






Analysis 5.4. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 4 Convalescent faecal carriage.







Wallace 1993 BHR 0/20 1/22 100.0 % 0.37 [ 0.02, 8.48 ]

Subtotal (95% CI) 20 22 100.0 % 0.37 [ 0.02, 8.48 ]




0.01 0.1 1 10 100


Analysis 5.5. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 5 Fever clearance time.




Study or subgroup Fluoroquinolone CeftriaxoneMean


Difference



Smith 1994 VNM 22 81 (25) 25 196 (87) 100.0 % -115.00 [ -150.67, -79.33 ]

Total (95% CI) 22 25 100.0 % -115.00 [ -150.67, -79.33 ]




-100 -50 0 50 100




Analysis 5.6. Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 6 Non-serious adverse events.







Smith 1994 VNM 1/22 2/25 100.0 % 0.57 [ 0.06, 5.85 ]

Total (95% CI) 22 25 100.0 % 0.57 [ 0.06, 5.85 ]





0.01 0.1 1 10 100




Analysis 6.1. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 1 Clinical failure.


Comparison: 6 Fluoroquinolone versus azithromycin


Study or subgroup Fluoroquinolone Azithromycin Risk Ratio Weight Risk Ratio


1 Ciprofloxacin versus azithromycin

Girgis 1999 EGY (1) 0/28 0/36 Not estimable


Total events: 0 (Fluoroquinolone), 0 (Azithromycin)



2 Ofloxacin versus azithromycin

Chinh 2000 VNM (2) 6/44 2/44 15.3 % 3.00 [ 0.64, 14.06 ]

Parry 2007 VNM (3) 23/63 11/62 84.7 % 2.06 [ 1.10, 3.85 ]

Subtotal (95% CI) 107 106 100.0 % 2.20 [ 1.23, 3.94 ]




3 Gatifloxacin versus azithromycin

Dolecek 2008 VNM (4) 6/145 6/142 100.0 % 0.98 [ 0.32, 2.96 ]

Subtotal (95% CI) 145 142 100.0 % 0.98 [ 0.32, 2.96 ]




0.01 0.1 1 10 100

Favours fluoroquinolone Favours azithromycin

(1) Ciprofloxacin 500 mg BD for 7 days vs Azithromycin 1 g OD followed by 500 mg OD for 6 days

(2) Ofloxacin 200 mg BD for 5 days vs Azithromycin 1 gm OD for 5 days

(3) Ofloxacin 10 mg/kg BD for 7 days vs Azithromycin 10 mg/kg OD for 7 days

(4) Gatifloxacin 10 mg/kg OD for 7 days vs Azithromycin 20 mg/kg OD for 7 days



Analysis 6.2. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 2 Microbiological failure.













Chinh 2000 VNM (2) 2/44 1/44 33.2 % 2.00 [ 0.19, 21.26 ]

Parry 2007 VNM (3) 2/63 2/62 66.8 % 0.98 [ 0.14, 6.77 ]

Subtotal (95% CI) 107 106 100.0 % 1.32 [ 0.30, 5.76 ]





Dolecek 2008 VNM (4) 2/145 3/140 100.0 % 0.64 [ 0.11, 3.79 ]

Subtotal (95% CI) 145 140 100.0 % 0.64 [ 0.11, 3.79 ]




0.01 0.1 1 10 100

Favours fluoroquinolone Favours azthithromycin







Analysis 6.3. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 3 Relapse.



Outcome: 3 Relapse










Chinh 2000 VNM (2) 2/17 0/21 100.0 % 6.11 [ 0.31, 119.33 ]

Parry 2007 VNM (3) 0/62 0/63 Not estimable

Subtotal (95% CI) 79 84 100.0 % 6.11 [ 0.31, 119.33 ]





Dolecek 2008 VNM (4) 0/127 4/137 100.0 % 0.12 [ 0.01, 2.20 ]

Subtotal (95% CI) 127 137 100.0 % 0.12 [ 0.01, 2.20 ]




0.005 0.1 1 10 200








Analysis 6.4. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 4 Convalescent faecal carriage.







Girgis 1999 EGY 0/28 0/36 Not estimable






Chinh 2000 VNM 8/35 0/34 33.6 % 16.53 [ 0.99, 275.62 ]

Parry 2007 VNM 12/62 1/62 66.4 % 12.00 [ 1.61, 89.51 ]

Subtotal (95% CI) 97 96 100.0 % 13.52 [ 2.64, 69.36 ]





Dolecek 2008 VNM 1/137 0/131 100.0 % 2.87 [ 0.12, 69.82 ]

Subtotal (95% CI) 137 131 100.0 % 2.87 [ 0.12, 69.82 ]




0.001 0.01 0.1 1 10 100 1000




Analysis 6.5. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 5 Fever clearance time.




Study or subgroup Fluoroquinolone AzithromycinMean


Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI


Girgis 1999 EGY 28 79.2 (24) 36 91.2 (26.4) 100.0 % -12.00 [ -24.39, 0.39 ]

Subtotal (95% CI) 28 36 100.0 % -12.00 [ -24.39, 0.39 ]




Chinh 2000 VNM 44 134 (76.14) 44 130 (46.61) 50.7 % 4.00 [ -22.38, 30.38 ]

Parry 2007 VNM 63 196.8 (97.18) 62 139.2 (67.49) 49.3 % 57.60 [ 28.31, 86.89 ]

Subtotal (95% CI) 107 106 100.0 % 30.41 [ -22.12, 82.93 ]

Heterogeneity: Tau2 = 1234.23; Chi2 = 7.10, df = 1 (P = 0.01); I2 =86%


-100 -50 0 50 100




Analysis 6.6. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 6 Duration of Hospitalization.



Outcome: 6 Duration of Hospitalization

Study or subgroup Fluoroquinolone AzithromycinMean


Difference



Chinh 2000 VNM 44 10.5 (3.38) 44 9.6 (2.37) 44.8 % 0.90 [ -0.32, 2.12 ]

Parry 2007 VNM 63 13.7 (3.85) 62 12.6 (2.21) 55.2 % 1.10 [ 0.00, 2.20 ]

Subtotal (95% CI) 107 106 100.0 % 1.01 [ 0.19, 1.83 ]




-2 -1 0 1 2


Analysis 6.7. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 7 Serious adverse events.







Chinh 2000 VNM 1/44 1/44 100.0 % 1.00 [ 0.06, 15.49 ]

Total (95% CI) 44 44 100.0 % 1.00 [ 0.06, 15.49 ]





0.01 0.1 1 10 100

Favours fluoroqunolone Favours azithromycin



Analysis 6.8. Comparison 6 Fluoroquinolone versus azithromycin, Outcome 8 Non-serious adverse events.







Girgis 1999 EGY 15/28 16/36 100.0 % 1.21 [ 0.73, 1.99 ]

Subtotal (95% CI) 28 36 100.0 % 1.21 [ 0.73, 1.99 ]





Chinh 2000 VNM 8/44 15/44 93.7 % 0.53 [ 0.25, 1.13 ]

Parry 2007 VNM 1/63 1/62 6.3 % 0.98 [ 0.06, 15.39 ]

Subtotal (95% CI) 107 106 100.0 % 0.56 [ 0.27, 1.16 ]




3 Gatifloxain versus azithromycin

Dolecek 2008 VNM 2/145 1/142 100.0 % 1.96 [ 0.18, 21.36 ]

Subtotal (95% CI) 145 142 100.0 % 1.96 [ 0.18, 21.36 ]




0.02 0.1 1 10 50




Analysis 7.1. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 1 Clinical failure.


Comparison: 7 Fluoroquinolone 2 days vs 3 days


Study or subgroup FQ 2D FQ 3D Risk Ratio Weight Risk Ratio


Chinh 1997 VNM 1/47 6/53 49.5 % 0.19 [ 0.02, 1.50 ]

Vinh 1996 VNM 6/53 2/47 18.6 % 2.66 [ 0.56, 12.55 ]

Vinh 2005 VNM 6/89 4/107 31.9 % 1.80 [ 0.53, 6.19 ]

Total (95% CI) 189 207 100.0 % 1.16 [ 0.54, 2.53 ]

Total events: 13 (FQ 2D), 12 (FQ 3D)




0.01 0.1 1 10 100

Favours 2D Favours 3D

Analysis 7.2. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 2 Microbiological failure.






Vinh 1996 VNM 0/53 1/47 63.6 % 0.30 [ 0.01, 7.10 ]

Vinh 2005 VNM 4/89 1/107 36.4 % 4.81 [ 0.55, 42.25 ]

Total (95% CI) 142 154 100.0 % 1.94 [ 0.44, 8.47 ]





0.01 0.1 1 10 100




Analysis 7.3. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 3 Relapse.



Outcome: 3 Relapse



Chinh 1997 VNM 0/24 1/26 34.6 % 0.36 [ 0.02, 8.43 ]

Vinh 1996 VNM 0/34 0/32 Not estimable

Vinh 2005 VNM 2/89 3/107 65.4 % 0.80 [ 0.14, 4.69 ]

Total (95% CI) 147 165 100.0 % 0.65 [ 0.14, 2.97 ]





0.01 0.1 1 10 100




Analysis 7.4. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 4 Convalecsent faecal carriage.



Outcome: 4 Convalecsent faecal carriage



Vinh 1996 VNM 0/34 1/32 100.0 % 0.31 [ 0.01, 7.45 ]


Total (95% CI) 123 139 100.0 % 0.31 [ 0.01, 7.45 ]





0.01 0.1 1 10 100


Analysis 7.5. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 5 Fever clearance time.




Study or subgroup FQ 2D FQ 3DMean


Difference


Chinh 1997 VNM 47 97 (33) 53 97 (44) 36.8 % 0.0 [ -15.14, 15.14 ]

Vinh 1996 VNM 53 100 (64) 47 107 (60) 14.3 % -7.00 [ -31.31, 17.31 ]

Vinh 2005 VNM 89 92 (48.13) 107 101 (44.86) 49.0 % -9.00 [ -22.12, 4.12 ]

Total (95% CI) 189 207 100.0 % -5.41 [ -14.59, 3.78 ]




-100 -50 0 50 100




Analysis 7.6. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 6 Duration of hospitalization.






Difference


Chinh 1997 VNM 47 7.6 (1.4) 53 7.8 (1.6) 45.4 % -0.20 [ -0.79, 0.39 ]

Vinh 1996 VNM 53 12.1 (2.3) 47 12.7 (3.5) 11.3 % -0.60 [ -1.78, 0.58 ]

Vinh 2005 VNM 89 7.6 (2.17) 107 8 (2.11) 43.2 % -0.40 [ -1.00, 0.20 ]

Total (95% CI) 189 207 100.0 % -0.33 [ -0.73, 0.06 ]




-4 -2 0 2 4




Analysis 7.7. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 7 Serious adverse events.




Study or subgroup FQ 2D Fq 3D Risk Ratio Weight Risk Ratio


Chinh 1997 VNM 0/47 0/53 Not estimable


Vinh 2005 VNM 2/89 1/107 100.0 % 2.40 [ 0.22, 26.08 ]

Total (95% CI) 189 207 100.0 % 2.40 [ 0.22, 26.08 ]

Total events: 2 (FQ 2D), 1 (Fq 3D)




0.005 0.1 1 10 200


Analysis 7.8. Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 8 Non-serious adverse events.




Study or subgroup Fluoroquinolone 2D Fluoroquinolone 3D Risk Ratio Weight Risk Ratio


Vinh 1996 VNM 0/53 2/47 100.0 % 0.18 [ 0.01, 3.61 ]


Total (95% CI) 142 154 100.0 % 0.18 [ 0.01, 3.61 ]

Total events: 0 (Fluoroquinolone 2D), 2 (Fluoroquinolone 3D)




0.01 0.1 1 10 100

Favours FQ 2D Favours FQ 3D






Outcome: 1 Relapse



Tran 1995 VNM 0/79 1/75 100.0 % 0.32 [ 0.01, 7.65 ]

Total (95% CI) 79 75 100.0 % 0.32 [ 0.01, 7.65 ]





0.01 0.1 1 10 100




Analysis 8.2. Comparison 8 Fluoroquinolone 3 days vs 5 days, Outcome 2 Fever Clearance time.



Outcome: 2 Fever Clearance time



Difference


Tran 1995 VNM 103 60 (21.6) 92 72 (21.6) 100.0 % -12.00 [ -18.07, -5.93 ]

Total (95% CI) 103 92 100.0 % -12.00 [ -18.07, -5.93 ]




-100 -50 0 50 100








Tran 1995 VNM 14/214 8/211 100.0 % 1.73 [ 0.74, 4.03 ]

Total (95% CI) 214 211 100.0 % 1.73 [ 0.74, 4.03 ]





0.05 0.2 1 5 20




Analysis 9.1. Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 1 Microbiological Failure.



Outcome: 1 Microbiological Failure



Unal 1996 TUR 1/22 0/24 100.0 % 3.26 [ 0.14, 76.10 ]

Total (95% CI) 22 24 100.0 % 3.26 [ 0.14, 76.10 ]





0.01 0.1 1 10 100





Outcome: 2 Relapse



Unal 1996 TUR 1/22 0/24 100.0 % 3.26 [ 0.14, 76.10 ]

Total (95% CI) 22 24 100.0 % 3.26 [ 0.14, 76.10 ]





0.01 0.1 1 10 100










Difference


Unal 1996 TUR 22 74.4 (1) 24 81.6 (1) 100.0 % -7.20 [ -7.78, -6.62 ]

Total (95% CI) 22 24 100.0 % -7.20 [ -7.78, -6.62 ]




-100 -50 0 50 100








Unal 1996 TUR 3/22 4/24 100.0 % 0.82 [ 0.21, 3.25 ]

Total (95% CI) 22 24 100.0 % 0.82 [ 0.21, 3.25 ]





0.01 0.1 1 10 100




Analysis 10.1. Comparison 10 Fluoroquinolone 7 days vs 10 days, Outcome 1 Microbiological failure.




Study or subgroup FQ 7D FQ 10D or 14D Risk Ratio Weight Risk Ratio


Kalo 1997 ALB 0/15 0/15 Not estimable


Total events: 0 (FQ 7D), 0 (FQ 10D or 14D)




0.01 0.1 1 10 100

Favours 7D Favours 10 or 14D




Outcome: 2 Relapse

Study or subgroup FQ 7D FQ 10 or 14D Risk Ratio Weight Risk Ratio


Kalo 1997 ALB 0/15 0/15 Not estimable


Total events: 0 (FQ 7D), 0 (FQ 10 or 14D)




0.01 0.1 1 10 100

Favours 7 Favours 10 or 14D



Analysis 11.1. Comparison 11 Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days), Outcome

1 All outcomes.


Comparison: 11 Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days)

Outcome: 1 All outcomes

Study or subgroup Gatifloxacin Chloramphenicol Risk Ratio Risk Ratio


1 Clinical failure (need for rescue medication or persistence of fever until day 10)

Arjyal 2011 (1) 8/177 10/175 0.79 [ 0.32, 1.96 ]

2 Microbiological failure (blood culture +ve on day 8)

Arjyal 2011 2/177 0/175 4.94 [ 0.24, 102.24 ]

3 Relapse (reappearance of culture confirmed or syndromic enteric fever on days 11 to 31)

Arjyal 2011 4/177 7/175 0.56 [ 0.17, 1.90 ]

4 Convalescent faecal carriage

Arjyal 2011 (2) 0/154 1/156 0.34 [ 0.01, 8.22 ]

5 Serious adverse events

6 Other adverse events (selected gastrointestinal adverse events)

Arjyal 2011 (3) 59/426 99/418 0.58 [ 0.44, 0.78 ]

0.005 0.1 1 10 200

Favours gatifloxacin Favours chloramphenicol

(1) This data includes culture positive patients only

(2) 3 patients in the chloramphenicol arm had positive stool cuture during convalescence but only one remained positive at 3 months

(3) Note: The adverse event data from Arjyal 2010 includes all randomized patients including test negative






Outcome: 1 Relapse



Alam 1995 BGD 0/35 2/34 100.0 % 0.19 [ 0.01, 3.91 ]

Total (95% CI) 35 34 100.0 % 0.19 [ 0.01, 3.91 ]





0.005 0.1 1 10 200








Difference


Alam 1995 BGD 35 100.8 (45.6) 34 117.6 (62.4) 100.0 % -16.80 [ -42.65, 9.05 ]

Total (95% CI) 35 34 100.0 % -16.80 [ -42.65, 9.05 ]




-100 -50 0 50 100










Alam 1995 BGD 4/35 9/34 100.0 % 0.43 [ 0.15, 1.27 ]

Total (95% CI) 35 34 100.0 % 0.43 [ 0.15, 1.27 ]





0.01 0.1 1 10 100


Analysis 13.1. Comparison 13 Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days), Outcome 1 All

outcomes.


Comparison: 13 Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days)


Study or subgroup Gatifloxacin Cefixime Risk Ratio Risk Ratio


1 Clinical failure (need for rescue medication or persistence of fever until day 7)

Pandit 2007 NPL (1) 1/88 19/70 0.04 [ 0.01, 0.31 ]

2 Relapse (fever plus +ve blood culture within 1 month of successful treatment)

Pandit 2007 NPL 2/87 6/51 0.20 [ 0.04, 0.93 ]

3 Microbiological failure (blood culture +ve on day 10)

Pandit 2007 NPL 0/88 1/70 0.27 [ 0.01, 6.43 ]


Pandit 2007 NPL (2) 2/92 1/77 1.67 [ 0.15, 18.11 ]

5 Other adverse events (may be incompletely reported)

Pandit 2007 NPL (3) 23/92 1/77 19.25 [ 2.66, 139.30 ]

0.001 0.01 0.1 1 10 100 1000

Favours gatifloxacin Favours cefixime



(1) This data includes culture positive patients only

(2) 2 patients developed severe vomiting requiring IV reydration in the gatifloxacin group, 1 patient died in the cefixime group

(3) 23 patients in the gatifloxacin developed vomiting, 1 patient in the cefixime group developed a rash

Analysis 14.1. Comparison 14 Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days), Outcome 1 All

outcomes.


Comparison: 14 Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days)


Study or subgroup Gatifloxacin Azithromycin Risk Ratio Risk Ratio


1 Clinical failure (need for rescue medication of persistence of fever until day 10)

Dolecek 2008 VNM (1) 6/145 6/140 0.97 [ 0.32, 2.92 ]

2 Relapse (symptoms and signs of typhoid fever within 1 month of successful treatment)

Dolecek 2008 VNM 4/137 0/127 8.35 [ 0.45, 153.52 ]

3 Microbiological failure (blood culture +ve on day 7 to 9)

Dolecek 2008 VNM 2/145 3/140 0.64 [ 0.11, 3.79 ]

4 Convalescent faecal carriage

Dolecek 2008 VNM (2) 1/137 0/131 2.87 [ 0.12, 69.82 ]


6 Other adverse events (may be incompletely reported)

Dolecek 2008 VNM (3) 2/145 1/141 1.94 [ 0.18, 21.21 ]

0.005 0.1 1 10 200

Favours gatifloxacin Favours azithromycin

(1) This data incudes culture positive patients only

(2) Only 1 patient was shown to be a persistent carrier during follow-up

(3) One patient developed vomiting on day 3 and 1 diarrhoea on day 4 in gatifloxacin group, one patient developed a rash in azithromycin group



A P P E N D I C E S

Appendix 1. Detailed Search Strategy

Search set CIDG SRa CENTRAL MEDLINEb EMBASEb LILACSb

1 typhoid fever fluoroquinolone QUINOLINES QUINOLONE

DERIVED ANTIIN-

FECTIVE AGENT

typhoid

2 enteric fever amifloxacin QUINOLONES fluoroquinolones typhoid fever

3 paratyphoid fever balofloxacin ANTI-IN-

FECTIVE AGENTS,

QUINOLONE

amifloxacin enteric fever

4 Salmonella typhi cetefloxacin ANTI-INFECTIVE

AGENTS, FLUO-

ROQUINOLONE

BALOFLOXACIN Salmonella typhi

5 Salmonella paratyphi ciprofloxacin FLUORO-

QUINOLONES

balofloxacin Salmonella paratyphi

6 - clinafloxacin fluoroquinolones CETEFLOXACIN -

7 - enoxacin amifloxacin cetefloxacin -

8 - fleroxacin balofloxacin CIPROFLOXACIN -

9 - gatifloxacin cetefloxacin ciprofloxacin -

10 - gemifloxacin CIPROFLOXACIN CLINAFLOXACIN -

11 - grepafloxacin ciprofloxacin clinafloxacin -

12 - irloxacin clinafloxacin ENOXACIN -

13 - levofloxacin ENOXACIN enoxacin -

14 - lomefloxacin enoxacin FLEROXACIN -

15 - moxifloxacin FLEROXACIN fleroxacin -

16 - nordifloxacin fleroxacin GATIFLOXACIN -

17 - norfleroxacin gatifloxacin gatifloxacin -

18 - norfloxacin gemifloxacin GEMIFLOXACIN -



(Continued)

19 - ofloxacin grepafloxacin gemifloxacin -

20 - oxociprofloxacin irloxacin GREPAFLOXACIN -

21 - pefloxacin levofloxacin grepafloxacin -

22 - premafloxacin lomefloxacin IRLOXACIN -

23 - prulifloxacin moxifloxacin irloxacin -

24 - rufloxacin nordifloxacin LEVOFLOXACIN -

25 - sitafloxacin norfleroxacin levofloxacin -

26 - sparfloxacin NORFLOXACIN LOMEFLOXACIN -

27 - temafloxacin norfloxacin lomefloxacin -

28 - tosufloxacin ofloxacin MOXIFLOXACIN -

29 - trovafloxacin oxociprofloxacin moxifloxacin -

30 - 1/29 - OR PEFLOXACIN NORDIFLOXACIN -

31 - typhoid fever pefloxacin nordifloxacin -

32 - enteric fever premafloxacin NORFLEROXACIN -

33 - paratyphoid fever prulifloxacin norfleroxacin -

34 - Salmonella typhi rufloxacin NORFLOXACIN -

35 - Salmonella paratyphi sitafloxacin norfloxacin -

36 - 31/35 - OR sparfloxacin OFLOXACIN -

37 - 30 and 36 temafloxacin ofloxacin -

38 - - tosufloxacin OXO-

CIPROFLOXACIN

-

39 - - trovafloxacin oxociprofloxacin -

40 - - 1 - 39/OR PEFLOXACIN -

41 - - TYPHOID FEVER pefloxacin -

42 - - typhoid fever PREMAFLOXACIN -



(Continued)

43 - - enteric fever premafloxacin -

44 - - PARATYPHOID

FEVER

PRULIFLOXACIN -

45 - - paratyphoid fever prulifloxacin -

46 - - SALMONELLA TY-

PHI

RUFLOXACIN -

47 - - Salmonella typhi rufloxacin -

48 - - SALMONELLA

PARATYPHI

SITAFLOXACIN -

49 - - Salmonella paratyphi sitafloxacin -

50 - - typhus SPARFLOXACIN -

51 - - 41 - 50/OR sparfloxacin -

52 - - 40 and 51 TEMAFLOXACIN -

53 - - limit 52 to human temafloxacin -

54 - - - tosufloxacin -

55 - - - 1 - 54/OR -

56 - - - TYPHOID FEVER -

57 - - - typhoid fever -

58 - - - enteric fever -

59 - - - PARATYPHOID

FEVER

-

60 - - - paratyphoid fever -

61 - - - SALMONELLA TY-

PHI

-

62 - - - Salmonella typhi -

63 - - - SALMONELLA

PARATYPHI

-

64 - - - Salmonella paratyphi -



(Continued)

65 - - - typhus -

66 - - - 56 - 65/OR -

67 - - - 55 and 66 -

68 - - - limit 67 to human -

aCochrane Infectious Diseases Group Specialized Register.bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre

2011); upper case: MeSH or EMTREE heading; lower case: free text term.

Appendix 2. Description of drug resistance by study

Compari-

son

Trial Partici-

pants

Culture

positive

(site)

S. Typhi/

Paratyphi

Number

(%)a with

MDR

MDR

defined asbNumber

(%*)a NaRc

Notes on re-

sistance

Fluoro-

quinolone vs

chloram-

phenicol

Cristiano

1995 ITA

60

enrolled and

randomized

60 (blood) 60/0

Fluoro-

quinolone:

30

Chloram-

phenicol: 30

0 Not stated

No

resistance to

chloram-

phenicol,

ampi-

cillin, or co-

trimoxazole

Not stated

MIC range

of pefloxacin

was < 0.016

to 0.5

-

Gasem 2003

IDN

100

enrolled and

randomized

55 (blood

and/or bone

marrow)

50/5 0 Not stated

No

resistance to

chloram-

phenicol

12.

8% resistant

to ampicillin

or co-

trimoxazole

Not stated

MIC range

of ciproflo-

xacin was < 1

-

Arjyal 2011 853

enrolled and

randomized

352 (blood) 124/53 Flu-

oro-

quinolone

125/50

Chloram-

phenicol

2(0.

58%) both

in the gati-

floxacin arm

Resistance

to all first

line antibi-

otics: chlo-

rampheni-

col, amoxi-

cillin and

trimetho-

251(72.2%) Two

S. Paratyphi

isolates were

chloram-

phenicol re-

sistant.



(Continued)

prim-sul-

phamethox-

azole

Gottuzzo

1992 N/A

Not stated 98 (not

stated)

Not stated Not stated Not stated Not stated -

Morelli

1992 ITA

156

enrolled and

randomized

156 (blood) 156/0 0 Not stated

MIC range

for chloram-

phenicol

was 0.5 to 4

mg/L

Not stated

MIC

ranges were:

ofloxacin 0.

03 to 0.25;

pefloxacin 0.

06 to 0.5; ci-

profloxa-

cin 0.016 to

0.063;

enoxacin 0.

25; nor-

floxacin 0.

063 to 0.25

-

Phongmany

2005 LAO

107

enrolled and

randomized

50 (blood) 50/0

Fluoro-

quinolone:

27

Chloram-

phenicol: 23

3/50 (6%)

Fluoro-

quinolone:

1/27

Chloram-

phenicol: 2/

23

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

0 Chloram-

phenicol re-

sistance: 4/

50

Fluoro-

quinolone:

1/27

Chloram-

phenicol: 3/

23d

Ampicillin:

2/50

Fluoro-

quinolone:

1/27

Chloram-

phenicol: 1/

23

Co-trimoxa-

zole: 1/50

Fluoro-

quinolone:

0/27

Chloram-

phenicol: 1/

23



(Continued)

Yousaf 1992

PAK

85

enrolled and

randomized

85 (not

stated)

Not stated Not stated Not stated Not stated -

Fluoro-

quinolone vs

ampicillin

Flores 1994

MEX

Not stated 40 (not

stated)

40/0

Fluoro-

quinolone:

20

Ampicillin:

20

Not stated Not stated Not stated -

Fluoro-

quinolone vs

co-

trimoxazole

Hajji 1988

MAR

77

enrolled and

randomized

42

(blood and/

or stool)

28/4

(from blood

culture)

0 Not stated

1 isolate re-

sistant to co-

trimox-

azole was in

pefloxacin

group

0 -

Limson

1989 PHL

53

enrolled and

randomized

40 (blood) 28/12

Fluoro-

quinolone:

15/5

Co-trimoxa-

zole: 13/7

0 Not stated

No resis-

tance to co-

trimoxazole

16 were re-

sistant

to chloram-

phenicol

Not stated -

Fluoro-

quinolone vs

azithromy-

cin

Dolecek

2008 VNM

358

enrolled and

randomized

288 (blood

or bone

marrow)

282/5

Fluoro-

quinolone:

144/1

Azithromy-

cin: 138/4

153 (58%)

of 263 S. Ty-

phi

Fluoro-

quinolone:

87/137

Azithromy-

cin: 66/126

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

253 (96%)

of 263 S. Ty-

phi

Fluoro-

quinolone:

132/137

Azithro-

mycin: 121/

126

All 5

S. Paratyphi

were suscep-

tible

Chinh 2000

VNM

97

enrolled and

randomized

91 (blood) 86/2 68 (78%) of

87

Fluoro-

quinolone:

35

Azithromy-

cin: 33

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

46 (52.3%;

of 87 strains

evaluated)

Fluoro-

quinolone:

21

Azithromy-

cin: 25

-



(Continued)

Girgis 1999

EGY

123

enrolled and

randomized

64 (62 by

blood, 2 by

stool)

60/4

Fluoro-

quinolone:

34/2

Azithromy-

cin: 26/2

21/64

(33%)

Fluoro-

quinolone:

15

Azithromy-

cin: 6

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

Not stated -

Parry 2007

VNM

160

enrolled and

random-

ized (exclud-

ing fluoro-

quinolone

with

azithromy-

cin combi-

nation arm)

130 (blood

and/or bone

marrow)

125/0

Fluoro-

quinolone:

63/0

Azithromy-

cin: 62/0

110/125

(88%)

Fluoro-

quinolone:

57/63

Azithromy-

cin: 53/62

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

117/125

(94%)

Fluoro-

quinolone:

62/63

Azithromy-

cin: 55/62

-

Fluoro-

quinolone vs

cefixime

Phuong

1999 VNM

138

enrolled and

randomized

82 (blood) 82/0

Fluoro-

quinolone:

38

Cefixime:

44

70 (85%)

S. Typhi: 32

S. Paratyphi:

38

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

and tetracy-

cline

0 -

Pandit 2007

NPL

390

enrolled and

randomized

169 (blood) 119/50

Fluoro-

quinolone:

65/27

Cefixime:

54/23

0 Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

136/163

(83%)

Fluoro-

quinolone:

71/89

Cefixime:

65/74

-

Fluoro-

quinolone vs

ceftriaxone

Smith 1994

VNM

60

enrolled and

randomized

47

(44 by blood

and/or bone

marrow, 3

by stool)

41/6

Fluoro-

quinolone:

21/1

Ceftriaxone:

20/5

26 (55%)

Fluoro-

quinolone:

14

Ceftriaxone:

12

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

and tetracy-

cline

0 -

Wallace

1993 BHR

43 enrolled

and 42 ran-

domized

42 (blood) 42/0

Fluoro-

quinolone:

20

22 (52%)

Fluoro-

quinolone:

11

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

Not stated -



(Continued)

Ceftriaxone:

22

Ceftriaxone:

11

cillin, co-tri-

moxazole)

Dif-

ferent dura-

tions of fluo-

roquinolone

Alam 1995

BGD

76

enrolled and

randomized

72 (blood or

bone

marrow)

61/8

Fluoro-

quinolone

10-day: 30/

5

Fluoro-

quinolone

14-day: 31/

3

36/69

(52%)

Fluoro-

quinolone

10-day: 18

Fluoro-

quinolone

14-day: 18

Resistance

to all drugs

used

convention-

ally against

S. Typhi and

S. Paratyphi

5/69 (7%)

Fluoro-

quinolone

10-day: 2

Fluoro-

quinolone

14-day: 3

(derived

from data

presented

for MIC for

ciprofloxa-

cin)

-

Kalo 1997

ALB

30

(ampicillin-

resistant)

enrolled and

randomized

30 (blood) 30/0 12/30

(40%)

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

Not stated -

Chinh 1997

VNM

107

enrolled and

randomized

101 (blood) 95/5

Fluoro-

quinolone

2-day: 43/4

Fluoro-

quinolone

3-day: 52/1

75/95

(79%)

Fluoro-

quinolone

2-day: 35

Fluoro-

quinolone

3-day: 40

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

and tetracy-

cline

5/95 (5%)

Fluoro-

quinolone

2-day: 1

Fluoro-

quinolone

3-day: 4

-

Tran 1995

VNM

438 en-

rolled, 425

randomized

228 (blood) 207/19

(2 other

Salmonella)

189

Fluoro-

quinolone

3-day: 98

Fluoro-

quinolone

5-day: 91

Resistant to

standard an-

tibiotics

Few

NaR strains

present,

number not

stated

-

Unal 1996

TUR

46 random-

ized

46 (blood

and/or bone

marrow)

19/27

Fluoro-

quinolone

5-day: 8/14

Fluoro-

quinolone

7-day: 11/

13

6/46 (13%)

Fluoro-

quinolone

5-day: 3

Fluoro-

quinolone

7-day: 3

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

Not stated

MIC for pe-

floxacin was

0.06 to 1

-



(Continued)

Vinh 1996

VNM

108

enrolled and

randomized

100 (blood) 100/0

Fluoro-

quinolone

2-day: 53

Fluoro-

quinolone

3-day: 47

84

Fluoro-

quinolone

2-day: 46

Fluoro-

quinolone

3-day: 38

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

and tetracy-

cline

13 (13%)

Fluoro-

quinolone

2-day: 6

Fluoro-

quinolone

3-day: 7

-

Vinh 2005

VNM

235

enrolled and

randomized

202 (blood) 196/0

Fluoro-

quinolone

2-day: 89

Fluoro-

quinolone

3-day: 107

176/196

(90%)

Fluoro-

quinolone

2-day: 82/

89

Fluoro-

quinolone

3-day: 94/

107

Resistant to

all 3 (chlo-

rampheni-

col, ampi-

cillin, co-tri-

moxazole)

4/161 (2.

5%)

Fluoro-

quinolone

2-day: 1/72

Fluoro-

quinolone

3-day: 3/89

-

MDR: multiple-drug-resistant strain; MIC: minimum inhibitory concentration; NaR: nalidixic acid resistant strain.aCalculation: number with MDR or NaR divided by number culture positive.bAs stated or implied in text of report.cOr MIC of fluoroquinolone if available (all ranges in mg/L).dThese participants were switched to fluoroquinolone when organisms were found resistant to assigned drug.

Appendix 3. Definitions of outcomes

Comparison Specific FQ Trial Clinical fail-

ure

Microbiolog-

ical failure

Relapse Fever clear-

ance time

Conva-

lescent Faecal

Carriage

Fluoro-

quinolones vs

chloram-

phenicol

Ciprofloxacin Gasem 2003

IDN

Not

afebrile within

7 days of treat-

ment

Blood cul-

ture positive at

days 3 and 5

Reappearance

of fever after

defervescence

during hospi-

talization (un-

der 14 days)

De-

fined as first

day that tem-

perature fell <

37.5 °C and

remained be-

low that level

for ≥ 48 hours

Outcome not

reported

Ciprofloxacin Gottuzzo

1992 N/A

“One partici-

pant who de-

veloped a gas-

trointestinal

bleed in first

Outcome not

reported

Not defined Outcome not

reported

Outcome not

reported



(Continued)

36

hours of treat-

ment was con-

sidered a fail-

ure”

Ciprofloxacin Morelli 1992

ITA

Persistence of

fever

Outcome not

reported

Not defined Not defined 3 weeks dur-

ing follow up

Ciprofloxacin

and Ofloxacin

and

Cotrimoxa-

zole

Rizvi 2007

PAK

No significant

response to

therapy

Persistence of

S. Typhi and

S. Paratyphi

on day 7 or 14

or recurrence

of the initial

pathogen

at the end of

treatment

Reapperance

of signs and

symptoms af-

ter initial dis-

appearance

for at least 48

hours or reap-

pearance

of pathogen in

blood and/

or stool within

three weeks af-

ter end of

treatment

Reported but

not defined

Not reported

Ofloxacin Phongmany

2005 LAO

Continuation

of symptoms

and tympanic

temperature >

38 °C for >

10 days after

start of treat-

ment or con-

tinuation

of symptoms

and high tym-

panic temper-

ature > 39 °C

at 7 days after

start of treat-

ment or de-

velopment of

signs of severe

disease

Outcome not

reported

Outcome not

reported

Time from

onset of treat-

ment

to first record-

ing of a tym-

panic temper-

ature < 38 °C

(~ 37.5 °C ax-

illary) which

remained < 38

°C

for 48 hours

(’Fever Clear-

ance Time

38’)

Outcome not

reported

Pefloxacin Cristiano

1995 ITA

Not defined Blood culture

positive at end

of treatment

(at 15 days)

Within

30 days after

end of treat-

ment (the 2

relapses were

Not defined 30 days



(Continued)

blood culture

negative

and were stool

culture

positive before

relapse)

Gatifloxacin Arjyal 2011 Not

specifically de-

fined but de-

noted as part

of composite

end point of

treatment fail-

ure

Positive blood

culture for S.

Typhi

or S.Paratyphi

A on day 8

Reappear-

ance of culture

confirmed or

syndromic en-

teric fever on

or after day 11

to day 31 in

patients who

were initially

categorized

as successfully

treated

Time from the

first

dose of treat-

ment given

until temper-

ature was fro

the first time

≤37.5oC and the pa-

tient remained

afebrile for at

least 48 hours

Faecal carriage

at the follow

up visits at 1, 3

and 6 months

Fluoro-

quinolone vs

ampicillin

Ofloxacin Flores 1994

MEX

Persis-

tence of signs

and symptoms

of infection 5-

7 days after the

end of treat-

ment

Persistence of

S. Typhi from

blood culture

5-7 days af-

ter the end of

treatment

Outcome not

reported

Outcome not

reported

Outcome not

reported

Yousaf 1992

PAK

Persistence or

reappear-

ance of all pre-

senting signs

and symptoms

or increase in

severity of at

least 1 sign

or symptom or

both

Persis-

tence of base-

line pathogen

at day 14

Outcome not

reported

Outcome not

reported

Outcome not

reported

Fluoro-

quinolone

vs co-trimoxa-

zole

Pefloxacin Hajji 1988

MAR

Fever and

presence of

clinical symp-

toms and pos-

itive cultures

Positive cul-

tures at days 4,

15, and 30

Reappearance

of fever, clini-

cal symptoms,

and/or bacter-

aemia at days

4, 15, and 30

Time for rectal

temperature

to be sustained

≤ 37.5 °C for

≥ 2 days

30 days

Ciprofloxacin Limson 1989

PHL

Persistent

fever or no im-

provement in

symptoms af-

Positive

cultures dur-

ing and after

therapy

Outcome not

reported

Outcome not

reported

Outcome not

reported



(Continued)

ter 5 days of

therapy

Fluoro-

quinolone vs

azithromycin

Gatifloxacin Dolecek 2008

VNM

Persis-

tence of fever

and symptoms

2 days after the

end of treat-

ment, i.e. on

day 10

Positive blood

culture on day

7 to 9 after the

start of treat-

ment

Symptoms

and signs sug-

gestive of

typhoid fever

within

1 month after

completion of

treatment

(only culture

positive data

extracted)

Time from

start of antibi-

otic treatment

to

when the ax-

illary temper-

ature first fell

≤ 37. 5 °C

and remained

there for at

least 48 hours

Follow ups at

1, 3, and 6

months; par-

tic-

ipants who at-

tended at least

2 consecutive

follow-up vis-

its were evalu-

ated

Ciprofloxacin Chinh 2000

VNM

Persis-

tence of fever

and symptoms

for > 5 days af-

ter the end of

treat-

ment or de-

velopment of

severe compli-

cations (severe

gastrointesti-

nal bleed, in-

testinal perfo-

ration, visible

jaundice, my-

ocarditis, renal

failure, shock,

coma) during

treatment re-

quir-

ing change in

treatment

Isolation of S.

Ty-

phi/S. Paraty-

phi from

blood or other

sterile site after

completion of

treatment

Recur-

rence of signs

and symptoms

suggestive

of enteric fever

after discharge

at 4 to 6 weeks

of follow up

Time

from start of

treatment un-

til body tem-

perature fell <

37.5 °C and

remained at ≤

37.5 °C for 48

hours

Days 2 to 3

after end of

treatment

Ciprofloxacin Girgis 1999

EGY

Lack of resolu-

tion of symp-

toms by day

7 or develop-

ment of ma-

jor complica-

tions of ty-

phoid fever af-

ter 5 days of

therapy

Blood culture

pos-

itive for S. Ty-

phi/S. Paraty-

phi on day 10

Recur-

rence of fever

with signs/

symptoms of

typhoid fever

in 4 weeks of

therapy com-

ple-

tion and cul-

ture positive

First day on

which max-

imum temper-

ature ≤ 38

°C and at this

level for ≥ 48

hours

1 month



(Continued)

Ciprofloxacin Parry 2007

VNM

Pres-

ence of fever

and at least 1

other typhoid

related symp-

tom for

> 7 days after

start of treat-

ment or devel-

opment of se-

vere complica-

tions (se-

vere gastroin-

testinal bleed-

ing, perfo-

ration, visible

jaundice, my-

ocardi-

tis, pneumo-

nia, renal fail-

ure, shock,

or altered con-

scious-

ness level, dur-

ing treatment

requir-

ing change in

therapy

Isolation of S.

Typhi

or S. Paratyphi

from blood or

sterile site after

completion of

treatment

Recurrence of

symptoms or

signs sugges-

tive of enteric

fever within 4-

week pe-

riod after pa-

tient had been

discharged

well from hos-

pital ac-

companied by

positive blood

culture for S.

Typhi or S.

Paratyphi

Time

from start of

treatment un-

til body tem-

perature

reached ≤ 37.

5 °C and re-

mained at this

for 48 hours

After end

of initial 7-day

treatment and

before hos-

pital discharge

(with

isolate having

the same sus-

ceptibility pat-

tern as original

isolate)

Fluoro-

quinolone vs

cefixime

Ofloxacin Phuong 1999

VNM

De-

terioration in

clinical condi-

tion or failure

of resolution

of symptoms

requiring fur-

ther treatment

Blood culture

positive for S.

Typhi after

completion of

treatment

Symp-

toms sugges-

tive of typhoid

fever with a

positive blood

or bone mar-

row culture up

to 4 weeks af-

ter discharge

Time

from onset of

treatment un-

til fever was

37.5 °C or be-

low for at least

24 hours

1

month mostly,

few seen after a

longer period

Gatifloxacin Pandit 2007

NPL

Any

severe compli-

cation, persis-

tence of

fever (> 38 °C)

, persistence of

symptoms for

> 7 days after

start of treat-

Blood culture

positive on

day 10

Fever with

blood culture

pos-

itive within a

month

of completing

treatment (pa-

tients given

rescue treat-

Time

to 1st drop in

oral tempera-

ture ≤ 37.5

°C remaining

≤ 37.5 °C for

48 hours

1 month



(Continued)

ment, requir-

ing additional

or rescue treat-

ment

ment or pro-

longed treat-

ment were ex-

cluded)

Fluoro-

quinolone vs

ceftriaxone

Ofloxacin Smith 1994

VNM

Acute treat-

ment failure as

continu-

ing symptoms

and fever for at

least 7 days af-

ter starting the

treatment reg-

imen

Blood culture

positive at day

8

Recur-

rence of fever

and symptoms

in the period

up to 6 weeks

after discharge

with a posi-

tive blood or

bone marrow

culture b

Time to defer-

vescence to <

37.5 °C for at

least 48 hours

4 to 6 weeks

Ciprofloxacin Wallace 1993

BHR

Fever > 38 °C

after 7 days of

therapy

or who dete-

riorated clini-

cally after 5

full days

Blood culture

positive at day

3

Read-

mission for ty-

phoid within

2 months of

discharge with

stool or blood

culture

positive

for S. Typhi of

the same an-

tibiogram

(1 relapse had

both stool and

blood culture

positive)

Not defined Days 1, 7, and

28; results un-

clear

Different du-

rations of fluo-

roquinolones

Alam 1995

BGD

Lack of im-

provement or

deterioration

in clinical con-

dition during

treatment

Growth

of S. Typhi or

S. Paratyphi in

blood in first

follow up (day

3)

Recurrence of

febrile illness

with growth of

S. Typhi or S.

Paratyphi

in blood cul-

ture after ini-

tial cure

Time to return

of

oral tempera-

ture to ≤ 37.5

°C after initia-

tion of therapy

and remained

so for at least

48 hours

Second

follow up (at 2

months)

Kalo 1997

ALB

Fever at day 5 Blood culture

positive at day

4

Relapse

during hospi-

talization and

2 month fol-

low up

Outcome not

reported

Days 7 to 12



(Continued)

Chinh 1997

VNM

Contin-

uing fever and

symptoms for

7 days after the

start of treat-

ment or de-

terioration in

clinical condi-

tion before 7

days that war-

ranted further

treatment

Blood or bone

marrow cul-

ture positive

after end of

treatment be-

fore discharge

Re-

current fever

and symptoms

with

bone marrow

or blood cul-

ture posi-

tive mostly up

to 6 weeks af-

ter discharge b

Time at which

fever fell be-

low 37.5 °C

for at least 24

hours

Usually

6 weeks (occa-

sionally up to

12 weeks)

Tran 1995

VNM

Persis-

tent fever and

symptoms for

> 7 days after

start of treat-

ment

Blood or bone

marrow

culture pos-

itive after end

of treatment

Symptoms

since study

with positive

blood culture

Not defined 1 month

Unal 1996

TUR

Contin-

ued or worsen-

ing symptoms

after 7 days of

therapy

Fail-

ure to eradi-

cate organism

Similar signs

and symptoms

after

apparently be-

ing cured for

a month (the

participant

had a positive

stool culture)

Time for tem-

perature to be

below 37.5 °C

for at least 48

hours

1 month; re-

sults unclear

Vinh 1996

VNM

Contin-

ued fever and

symptoms for

> 7 days after

treatment

Positive blood

culture or

bone marrow

culture for S.

Typhi taken >

48 hours after

the last dose of

treatment

Recur-

rence of fever

and symptoms

with pos-

itive blood or

bone marrow

culture up to 6

weeks (26 par-

ticipants fol-

lowed up to

12 weeks) af-

ter discharge

Time from

start of treat-

ment until ax-

illary tempera-

ture fell below

37.5 °C and

remained be-

low this level

for > 48 hours

4 to 6 weeks

(for 66 par-

ticipants); and

at 3 months

(for 26 partic-

ipants)

Vinh 2005

VNM

Fever

and symptoms

persisting for

≥ 7 days after

start of ther-

apy, or devel-

Blood culture

pos-

itive for same

organism

between 7 to

28 days after

Recurrence of

typhoid fever

symptoms

usu-

ally with posi-

tive blood cul-

Pe-

riod from start

of treatment

until tempera-

ture remained

at or below 37.

Im-

mediately af-

ter treatment



(Continued)

opment of se-

vere or com-

plicated

disease

completion of

therapy

ture after hos-

pital discharge

until 28 days

post discharge

(only data for

blood culture-

con-

firmed relapse

extracted)

5 °C for at

least 48 hours

S. Typhi/S. Paratyphi: Salmonella enterica serovar Typhi/Paratyphi.aAll definitions as stated or implied by trial authors.bWith an organism with the same sensitivity pattern, ribotype, and plasmid profile as the original isolate.

Appendix 4. Serious adverse events

Comparison Trial Intervention Control

Fluoroquinolone vs chloram-

phenicol

Yousaf 1992 PAK None reported None reported

Gottuzzo 1992 N/A Gastrointestinal bleeding(1) Severe leukopenia(1)

Cristiano 1995 ITA Skin rash (1) None

Morelli 1992 ITA Ciprofloxacin: Rash (2)

Pefloxacin: Rash (2)

None

Gasem 2003 IDN Ciprofloxacin: None Chloramphenicol: Intestinal

bleeding (1 participant)

Rash (1)

Phongmany 2005 LAO None None

Rizvi 2007 PAK Ciprofloxacin: palpitation (1) ????

Ofloxacin: palpitation (2)

palpitation (1)

Arjyal 2011 none Oral candidiasis (4)

Fluoroquinolone vs co-trimox-

azole

Hajji 1988 MAR Pefloxacin: Phototoxicity (1) Rash (1)

Limson 1989 PHL None None

Fluoroquinolone vs ampicillin/

amoxicillin

Yousaf 1992 PAK None reported None reported

Flores 1994 MEX None reported None reported



(Continued)

Fluoroquinolone vs cefixime Phuong 1999 VNM Ofloxacin: Death (1) None

Pandit 2007 NPL Excessive vomiting requiring

intravenous therapy(1)

Death(1)

Fluoroquinolone vs ceftriaxone Wallace 1993 BHR Not reported Not reported

Smith 1994 VNM None reported None reported

Fluoroquinolone vs azithromy-

cin

Chinh 2000 VNM Gastrointestinal bleeding (1 partic-

ipant)

Gastrointestinal bleeding (1 partic-

ipant)

Dolecek 2008 VNM Gastrointestinal bleeding (4 partic-

ipants)

Rash (1)

None

Girgis 1999 EGY None None

Parry 2007 VNM None None

Appendix 5. Non-serious adverse events

Comparison Trial Clinical adverse events a Laboratory adverse events a

Intervention Control Intervention Control

Fluoroquinolone vs

chloramphenicol

Yousaf 1992 PAK 3 reported adverse

events. No specific

event

4 reported adverse

events. No specific

event

None reported None reported

Gottuzzo 1992 N/A Rash (1) None None leukopenia (11)

Cristiano 1995 ITA Nausea (3)

, mild and transient

epigastric pain (3),

transient skin rash

(1)

Mild and transient

epigastric pain (5)

None None

Morelli 1992 ITA Ciprofloxacin: Skin

rash (2), dizziness

(4), flushing (4),

epigastric pain (8)

Ofloxacin:

Mild epigastric pain

(4), flushing (4),

headache (2)

Diarrhoea (3), Mild

epigastric pain (6),

abdominal pain (4)

Not reported not reported



(Continued)

Pefloxacin: Skin

Rash (2), headache

(6), epigastric pain

(10)

Gasem 2003 IDN None skin rash (1) None reported None reported

Phongmany 2005

LAO

None reported None reported None reported None reported

Rizvi 2007 PAK Ciprofloxcin: Nau-

sea/

vomiting (10), diar-

rhoea (1), heartburn

(2), headache/dizzi-

ness (3), anorexia

(1), palpitation (1)

Ofloxacin: Nausea/

vomiting

(6), abdominal pain

(1), heartburn (4),

headache (2), palpi-

tation (2)

Chlo-

ramphenicol: Nau-

sea/vomiting(4), ab-

dominal pain (1),

cough (1), palpita-

tion(1), anaemia(2)


Arjyal 2011 Number of

patients with events

(59/426)

Abdominal pain (8)

, acne (0),

anorexia (1), diar-

rhoea (5),

dizziness (2), nausea

(9), oral candidiasis

(0), vomiting (35),

weakness (0)

Number of

patients with events

(99/418)

Ab-

dominal pain (11)

, acne (2), anorexia

(9), diarrhoea (24),

dizziness (11), nau-

sea (26), oral can-

didiasis (4), vomit-

ing (36),

weakness (4)

Dysglycaemiab

Hyperglycaemia: 1/

400

Hypoglycaemia: 2/

400

Leucopeniac

Grade 1:1/188

Grade 2: 1/188

Dysglycaemiab

Hyperglycaemia: 0/

402

Hypoglycaemia: 2/

402

Leucopeniac

Grade 1:4/403

Grade 2: 3/403

Fluoroquinolone vs

cotrimoxazole

Hajji 1988 MAR Photosensitivity (1) Generalized rash (1) Mild and transient

rise in transaminases

(2)

Mild and transient

rise in transaminases

(3)

Limson 1989 PHL Ciprofloxacin

Abdominal discom-

fort/diarrhoea (1)

Dizziness (1)

Cotrimox-

azole: nausea or ab-

dominal discomfort

(5)

Pruritus (1)

None None

Fluoroquinolone

vs ampicillin/amox-

icillin

Yousaf 1992 PAK 3 reported adverse

events. No specific

11 events reported

to be mostly diar-




(Continued)

event rhoea, pruritus and

rashes

Flores 1994 MEX Moderate nausea (1) Epigastric pain (1) None reported None reported

Fluoroquinolone vs

cefixime

Phuong 1999 VNM Not reported Not reported Not reported Not reported

Pandit 2007 NPL Nausea/occasional

vomiting (23)

Erythematous skin

rash(1)

None None

Fluoroquinolone vs

ceftriaxone

Wallace 1993 BHR Not reported Not reported Not reported Not reported

Smith 1994 VNM Pruritus (1) skin rashes (2) None None

Fluoroquinolone vs

azithromycin

Chinh 2000 VNM Ofloxacin: nau-

sea (1); vomiting (3)

; abdominal pain (4)

; skin rash (0)

Azithromycin: nau-

sea (5); vomiting (5)

; abdominal pain (4)

; skin rash (1)

Ofloxacin: mild ele-

vation in mean

transaminase levels

Azithromycin: mild

elevation in mean

transaminase levels

Dolecek 2008

VNM

Gatifloxacin: vomit-

ing (1); Diarrhoea

(1)

Azithromycin: jaun-

dice (2)

Gat-

ifloxacin: mild ele-

vations in median

transaminase levels

Azithromycin: mild

elevations

in median transam-

inase levels

Girgis 1999 EGY Ciprofloxacin: nau-

sea or vomiting (4);

lightheadedness (2);

dry throat or mouth

(4); loose stools (3);

constipation (2)

Azithromycin: nau-

sea or vomiting (6);

lightheadedness (2);

dry throat or mouth

(3); loose stools (3);

constipation (2)

Ciprofloxacin:

thrombocytosis (1)

; mild increases in

aspartate transami-

nases levels (3)

Azithro-

mycin: thrombocy-

tosis (4); mild in-

crease in aspartate

amino transaminase

levels (2)

Parry 2007 VNM Ofloxacin: joint dis-

comfort

Azithromycin: joint

discomfort (1)

Ofloxacin: none Azithromycin: none

Fluoroquinolones

2days vs 3days

Chinh 1997 VNM 2D: none 3D: none 2D: none 3D: none

Vinh 1996 VNM 2D: none 3D: none 2D: none 3D: none

Vinh 2005 VNM 2D: none 3D: none 2D: no significant

increases in liver en-

zymes

3D: no significant

increases in liver en-

zymes

Fluoroquinolone

3days vs 5days

Tran 1995 VNM 3D: Insomnia (5),

dizziness (5) epigas-

tric pain (2), nausea

(1), headache (1)

5D: Insomnia (5),

dizziness (1) vomit-

ing (1), rash (1)

3D: none 5D: none



(Continued)

Fluoroquinolone

5days vs 7days

Unal 1996 TUR 5D: Nausea and

vomiting (3)

7D: Nausea and

vomiting (3)

5D: None 7D:

Increased transami-

nase levels (1)

Fluoroquinolone

7days vs 10days

Kalo 1997 ALB 7D Nausea/abdom-

inal discomfort

10D: Nausea/ ab-

dominal discomfortd

7D: None 10D:None

Fluoroquinolone

10days vs 14 days

Alam 1995 BGD 10D: Eleven events

occurred in four pa-

tients namely

headache, malaise,

dizziness, insomnia,

skin rash, pruritus,

lethargy, weakness

14D:

Eighteen events oc-

curred in nine pa-

tients namely

headache, malaise,

ab-

dominal pain, dizzi-

ness, nausea, oral

mucosal pain, in-

somnia, photosensi-

tivity, vomiting, ver-

tigo, joint pain pal-

pitation, restlessness

10D: Moderate

eosinophilia (5)

14D: Transient ele-

vation of urea and

creatinine (1)

Moderate

eosinophilia (3)

aNumber of participants with adverse event.bHyperglycaemia grade 2 defined as non-fasting plasma glucose level between 161 and 250 mg/dL; hypoglycaemia grade 2 defined as

non-fasting plasma glucose between 40 and 54 mg/dLcLeucopenia GRADE 1:WBC count 2000-2500/mm3 and GRADE 2: WBC count 1500-1999/mm3

dTotal number with listed adverse events was four but no specific number for each group

W H A T ’ S N E W

Last assessed as up-to-date: 1 February 2011.

Date Event Description

5 October 2011 Amended Amendment made to acknowledgements



H I S T O R Y

Protocol first published: Issue 4, 2003

Review first published: Issue 2, 2005

Date Event Description

9 August 2011 New citation required and conclusions have changed A new search was conducted and the structure of the review

altered. In previous versions the different types of fluoro-

quinolone were combined in the meta analyses in spite of

their dissimilarity. In this revision, we have analysed them

separately with the intention of highlighting the effective-

ness of different fluoroquinolones

C O N T R I B U T I O N S O F A U T H O R S

Emmanuel Effa and Zohra Lassi , considered the new search, extracted and enter data, updated the risk of bias assessment and Dave

Sinclair co-extracted data, assisted with restructuring and writing up of the review. Julia Critchley provided technical inputs and assisted

with the restructuring of the review. Prof Zulfiquar Bhutta, Prof Paul Garner, and Piero Olliaro guided the restructuring, examined the

data, provided technical direction and edited the manuscript. All authors contributed to the final manuscript.

D E C L A R A T I O N S O F I N T E R E S T

None known. Professor ZA Bhutta has been part of trials of treatment for typhoid therapy in children, none of which involved

fluoroquinolones.

S O U R C E S O F S U P P O R T

Internal sources

• University of Calabar Teaching Hospital, Calabar, Nigeria.

• Nigeria branch of South African Cochrane centre, Nigeria.

External sources

• No sources of support supplied



D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We changed the intervention from ’Fluoroquinolone antibiotic’ to ’Different fluoroquinolone antibiotic excluding norfloxacin or other

fluoroquinolones not currently in use’

N O T E S

The Contact Editor for this review was Dr Mical Paul.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Anti-Bacterial Agents [adverse effects; ∗therapeutic use]; Fluoroquinolones [adverse effects; ∗therapeutic use]; Norfloxacin [therapeutic

use]; Paratyphoid Fever [∗drug therapy]; Randomized Controlled Trials as Topic; Treatment Outcome; Typhoid Fever [∗drug therapy]

MeSH check words

Adult; Child; Humans



fluoroquinolones for treating typhoid and paratyph

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