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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2011 Oct 5;2011(10):CD004530. doi: 10.1002/14651858.CD004530.pub4

Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)

Emmanuel E Effa 1, Zohra S Lassi 2, Julia A Critchley 3, Paul Garner 4, David Sinclair 4, Piero L Olliaro 5, Zulfiqar A Bhutta 2,
Editor: Cochrane Infectious Diseases Group
PMCID: PMC6532575  PMID: 21975746

Abstract

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.

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.

8 May 2019

No update planned

Other

An updated search (5 Sep, 2016) identified 4 studies for inclusion ('Studies awaiting classification’ section: Ali 2011; Arjyal 2016; Chandey 2012; Koirala 2013). In an external analysis for the WHO, inclusion of these 4 studies did not change the 2011 published version's results. The WHO used these results in 2017 (unpublished report for the WHO SAGE Typhoid Working Group, 2017).

Keywords: Adult, Child, Humans, Anti‐Bacterial Agents, Anti‐Bacterial Agents/adverse effects, Anti‐Bacterial Agents/therapeutic use, Fluoroquinolones, Fluoroquinolones/adverse effects, Fluoroquinolones/therapeutic use, Norfloxacin, Norfloxacin/therapeutic use, Paratyphoid Fever, Paratyphoid Fever/drug therapy, Randomized Controlled Trials as Topic, Treatment Outcome, Typhoid Fever, Typhoid Fever/drug therapy

Plain language summary

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.

Background

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 relative frequency of paratyphoid fever (due to Salmonella paratyphi) 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 symptoms include fever, headache, and gastrointestinal complaints; such as diarrhoea, constipation, abdominal pain, nausea and vomiting, or loss of appetite (Lee 2000; Richens 2000). Severe disease occurs in 10 to15% of people, and complications such as; intestinal perforation, intestinal bleeding, shock, pancreatitis (inflammation 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, during 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 throughout 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 middle‐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 antibiotics 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 amoxicillin (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 isolates in Nigeria and Kenya, respectively (Akinyemi 2005;Kariuki 2004). Surveillance studies can show considerable geographic differences 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‐emergence of strains susceptible to first‐line antibiotics such as chloramphenicol (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 testing and have high minimum inhibitory concentrations (MICs) although their breakpoints remain within the range set by the Clinical 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 appropriate 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 spectrum of antibacterial activity, and used to treat a range of urinary tract, respiratory, gastrointestinal, and sexually transmitted infections (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 subsequently been withdrawn from clinical use: prolongation of the corrected QT (QTc) interval with grepafloxacin, liver toxicity with trovafloxacin, and anaphylaxis, haemolytic anaemia and renal failure with temafloxacin.(Bertino 2000; Fish 2001)

How the intervention might work

In the past, enteric fevers responded extremely well to the fluoroquinolones, 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:

However, not all strains with reduced susceptibility to fluoroquinolones are NaR suggesting the likelihood of a new mechanism of resistance unrelated to the principal mechanisms of resistance already known (Threlfall 2003; Cooke 2006). There are emerging reports of isolates with absolute fluoroquinolone resistance (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 reported 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 fluoroquinolones, but with a higher incidence of dysglycaemia (high or low blood sugar) (Frothingham 2005; Park‐Wyllie 2006), although 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 fluoroquinolones were combined in the analysis with sub groups according 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 fluoroquinolone individually. As norfloxacin has poor bioavailability and is no longer a credible treatment option, studies evaluating this drug were excluded.

Objectives

To evaluate the fluoroquinolone antibiotics in the treatment of enteric fever in children and adults.

Methods

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 microbiological 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, azithromycin 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 relevant 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 provided 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 relevant 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 collaboration'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 generation, allocation concealment, blinding (of participants, personnel 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 summarised in Figure 1 and Figure 2.

1.

1

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

2.

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 results are presented with the corresponding 95% confidence interval (CI).

Unit of analysis issues

Trials including more than two comparison groups have been split and analysed as individual pair‐wise comparisons. When conducting 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 culture‐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.

Results

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 methodology 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 treatment 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 presenting to the outpatient or emergency department of the study hospital.

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 antibiotics, 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).

SeeAppendix 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 complications 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 diagnostic 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 antibiotics: chloramphenicol (eight trials), amoxicillin or ampicillin (two trials), co‐trimoxazole (three trials), azithromycin (four trials), ceftriaxone (two trials), and cefixime (three trials). Seven trials 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‐fluoroquinolone antibiotic treated the participants with the fluoroquinolone 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 failure (such as day two, the end of treatment, and some days after 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 confirmation 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 (seeAppendix 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 inFigure 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 associated data for one participant were reported (Phuong 1999 VNM).

Other potential sources of bias

Two trials were stopped early. One because of a significant difference 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 reducing clinical and microbiological treatment failures (eight trials, 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, demonstrated 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).

1.1. Analysis.

1.1

Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 1 Clinical failure.

1.2. Analysis.

1.2

Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 2 Microbiological failure.

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 remaining 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 difference in post‐treatment relapses or fecal carriage with any fluoroquinolone 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.

1.5. Analysis.

1.5

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

1.6. Analysis.

1.6

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

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 participants, one trial, Analysis 1.6). However, we note that ofloxacin was given only for three days compared to the 14 days of chloramphenicol, so this is perhaps unsurprising.

Adverse events

No difference has been shown between ciprofloxacin and chloramphenicol (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).

1.7. Analysis.

1.7

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

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 gastrointestinal 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 seventh days of the study. There was no difference in the number of participants with low blood sugar for both groups.

1.8. Analysis.

1.8

Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 8 Non‐serious adverse events.

The differences between the other fluoroquinolones and chloramphenicol 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 fluoroquinolones 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.

Clinical and microbiological response

Of the three trials, only Rizvi 2007 PAK reports any clinical failures 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 resistance, compared with no clinical failures following ciprofloxacin (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).

2.1. Analysis.

2.1

Comparison 2 Fluoroquinolone versus co‐trimoxazole, Outcome 1 Clinical Failure.

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)

2.5. Analysis.

2.5

Comparison 2 Fluoroquinolone versus co‐trimoxazole, Outcome 5 Fever clearance time.

Relapse and convalescent faecal carriage

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‐trimoxazole (219 participants, three trials, Analysis 2.6). The events were mainly gastrointestinal in nature and were self limiting.

2.6. Analysis.

2.6

Comparison 2 Fluoroquinolone versus co‐trimoxazole, Outcome 6 Non serious adverse events.

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 reported.

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.

Clinical and microbiological response

The risk of clinical or microbiological failure was significantly lower in the ofloxacin group compared to ampicillin or amoxicillin (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.

3.1. Analysis.

3.1

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

3.2. Analysis.

3.2

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

Relapse and convalescent faecal carriage

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.

3.3. Analysis.

3.3

Comparison 3 Fluroqunolone versus ampicillin/amoxicillin, Outcome 3 Non‐serious adverse events.

Fluoroquinolones versus second‐line antibiotics (cefixime, ceftriaxone, azithromycin)

Comparison 4. Fluoroquinolones versus cefixime

In one study from Pakistan in 2003‐04 no clinical or microbiological 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.

Clinical and microbiological response

Of the three tested fluoroquinolones, only gatifloxacin has demonstrated a statistically significant reduction in clinical failure compared to cefixime (RR 0.04, 95% CI 0.01 to 0.31, 158 participants, 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).

4.1. Analysis.

4.1

Comparison 4 Fluoroquinolone versus cefixime, Outcome 1 Clinical failure.

4.2. Analysis.

4.2

Comparison 4 Fluoroquinolone versus cefixime, Outcome 2 Microbiological failure.

Relapse and convalescent faecal carriage

Only gatifloxacin has demonstrated a statistically significant reduction in relapse (RR 0.20, 95% CI 0.04 to 0.93, 138 participants, one trial, Analysis 4.3). There were no reported incidents of faecal carriage.

4.3. Analysis.

4.3

Comparison 4 Fluoroquinolone versus cefixime, Outcome 3 Relapse.

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).

4.5. Analysis.

4.5

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

4.6. Analysis.

4.6

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

Adverse events

Serious adverse events were low in two trials comparing ofloxacin and gatifloxacin with cefixime but there was no significant difference between the comparisons (251 participants, two trials, Analysis 4.7).

4.7. Analysis.

4.7

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

Non‐serious adverse events appear to be higher with gatifloxacin than with cefixime (RR 20.92, 95% CI 2.9 to 150.90, 169 participants, 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.

4.8. Analysis.

4.8

Comparison 4 Fluoroquinolone versus cefixime, Outcome 8 Non‐serious adverse events.

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 intravenous ceftriaxone, and were too small to demonstrate important 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.

Clinical and microbiological response

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).

5.1. Analysis.

5.1

Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 1 Clinical failure.

5.2. Analysis.

5.2

Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 2 Microbiological failure.

Relapse and convalescent faecal carriage

The incidence of relapse and faecal carriage following treatment was very low with no differences between both groups (42 participants, one trial, Analysis 5.3; Analysis 5.4).

5.3. Analysis.

5.3

Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 3 Relapse.

5.4. Analysis.

5.4

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

Fever clearance and duration of hospitalization

Only Smith 1994 VNM reported adequate data for the fever clearance 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 respectively. No standard deviation was reported but the P value was given as 0.04.

5.5. Analysis.

5.5

Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 5 Fever clearance time.

Similarly, only Smith 1994 VNM reported the duration of hospitalization which averaged nine days (range: 6 to 13 days) in the ofloxacin group and 12 days (range: 7 to 23 days) in the ceftriaxone 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).

5.6. Analysis.

5.6

Comparison 5 Fluoroquinolone versus ceftriaxone, Outcome 6 Non‐serious adverse events.

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 gatifloxacin 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.

Clinical and microbiological response

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)

6.1. Analysis.

6.1

Comparison 6 Fluoroquinolone versus azithromycin, Outcome 1 Clinical failure.

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).

6.2. Analysis.

6.2

Comparison 6 Fluoroquinolone versus azithromycin, Outcome 2 Microbiological failure.

Relapse and convalescent faecal carriage

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).

6.3. Analysis.

6.3

Comparison 6 Fluoroquinolone versus azithromycin, Outcome 3 Relapse.

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)

6.4. Analysis.

6.4

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

Fever clearance time

No consistent statistically significant difference in fever clearance has been shown between any of the fluoroquinolones and azithromycin (564 participants, four trials, Analysis 6.5).

6.5. Analysis.

6.5

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

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)

6.6. Analysis.

6.6

Comparison 6 Fluoroquinolone versus azithromycin, Outcome 6 Duration of Hospitalization.

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).

6.7. Analysis.

6.7

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

6.8. Analysis.

6.8

Comparison 6 Fluoroquinolone versus azithromycin, Outcome 8 Non‐serious adverse events.

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).

1.3. Analysis.

1.3

Comparison 1 Fluoroquinolone versus chloramphenicol, Outcome 3 Relapse.

None of the comparisons demonstrated one duration was superior 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 percentage 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 outcomes 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 compared three days with five days of ofloxacin. The majority of S. typhi isolates (91%) were MDR. Some participants had NaR strains, although the precise number of these participants was not available.

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.

8.2. Analysis.

8.2

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

Comparison 9. Fluoroquinolone five days versus seven days

One trial made this comparison (Unal 1996 TUR) with pefloxacin. 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 resistant S. typhi some of whom were MDR. The proportion of participants with NaR strains was not reported.

There was no statistically significant difference in microbiological failure. There were no clinical failures or convalescent faecal carriers. 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 statistically 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 summarised 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 areas 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 gatifloxacin 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).

11.1. Analysis.

11.1

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

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.

13.1. Analysis.

13.1

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

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).

14.1. Analysis.

14.1

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

Discussion

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, although 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 difference.

In two small studies conducted almost two decades ago the fluoroquinolones were demonstrated to be more effective than ampicillin and amoxicillin.

Fluoroquinolones versus current second‐line options

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.

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 populations 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 azithromycin, 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 fluoroquinolone, have not been demonstrated in head to head clinical trials.

Adverse events

Overall, the adverse event profiles were similar for the fluoroquinolone and non‐fluoroquinolone antibiotics. They were mostly mild and self limiting.The risk of dysglycaemia with gatifloxacin 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 of evidence

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 comparison, 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 other studies or reviews

In our previous update (Thaver 2008), different types of fluoroquinolone 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 resistance across various regions over different times.

Authors' conclusions

Implications for practice.

Generally, fluoroquinolones performed well in the treating typhoid. Generally, fluoroquinolones performed well in the 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. In choosing any fluoroquinolone, clinicians need to take into account current, local resistance patterns.

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 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 therefore focus on re‐examining these relatively inexpensive alternatives in robust comparisons with fluoroquinolones in appropriate endemic populations.

Most of the studies were small . Given the importance of the study question, we would recommend multi‐centred, adequately powered 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 recruitment in trials and avoid the problem of syndromic treatment. In addition, it will reduce the widespread abuse of antibiotics, especially 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.

What's new

Date Event Description
5 October 2011 Amended Amendment made to acknowledgements

History

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  fluoroquinolone 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.

Notes

The Contact Editor for this review was Dr Mical Paul.

Acknowledgements

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 International 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.

Appendices

Appendix 1. Detailed Search Strategy

Search set CIDG SRa CENTRAL MEDLINEb EMBASEb LILACSb
1 typhoid fever fluoroquinolone QUINOLINES QUINOLONE DERIVED ANTIINFECTIVE AGENT typhoid
2 enteric fever amifloxacin QUINOLONES fluoroquinolones typhoid fever
3 paratyphoid fever balofloxacin ANTI‐INFECTIVE AGENTS, QUINOLONE amifloxacin enteric fever
4 Salmonella typhi cetefloxacin ANTI‐INFECTIVE AGENTS, FLUOROQUINOLONE BALOFLOXACIN Salmonella typhi
5 Salmonella paratyphi ciprofloxacin FLUOROQUINOLONES 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
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 OXOCIPROFLOXACIN
39 trovafloxacin oxociprofloxacin
40 1 ‐ 39/OR PEFLOXACIN
41 TYPHOID FEVER pefloxacin
42 typhoid fever PREMAFLOXACIN
43 enteric fever premafloxacin
44 PARATYPHOID FEVER PRULIFLOXACIN
45 paratyphoid fever prulifloxacin
46 SALMONELLA TYPHI 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 TYPHI
62 Salmonella typhi
63 SALMONELLA PARATYPHI
64 Salmonella paratyphi
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

Comparison Trial Participants Culture positive (site) S. Typhi/Paratyphi Number (%)a with MDR MDR defined asb Number (%*)a NaRc Notes on resistance
Fluoroquinolone vs chloramphenicol Cristiano 1995 ITA 60 enrolled and randomized 60 (blood) 60/0
Fluoroquinolone: 30
Chloramphenicol: 30
0 Not stated
No resistance to chloramphenicol, ampicillin, 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 chloramphenicol
12.8% resistant to ampicillin or co‐trimoxazole
Not stated
MIC range of ciprofloxacin was < 1
Arjyal 2011 853 enrolled and randomized 352 (blood) 124/53 Fluoroquinolone
125/50
Chloramphenicol
2(0.58%) both in the gatifloxacin arm Resistance to all first line antibiotics: chloramphenicol, amoxicillin and trimethoprim‐sulphamethoxazole 251(72.2%) Two S. Paratyphi isolates were chloramphenicol resistant.
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 chloramphenicol was 0.5 to 4 mg/L
Not stated
MIC ranges were: ofloxacin 0.03 to 0.25; pefloxacin 0.06 to 0.5; ciprofloxacin 0.016 to 0.063; enoxacin 0.25; norfloxacin 0.063 to 0.25
Phongmany 2005 LAO 107 enrolled and randomized 50 (blood) 50/0
Fluoroquinolone: 27
Chloramphenicol: 23
3/50 (6%)
Fluoroquinolone: 1/27
Chloramphenicol: 2/23
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) 0 Chloramphenicol resistance: 4/50
Fluoroquinolone: 1/27
Chloramphenicol: 3/23d
Ampicillin: 2/50
Fluoroquinolone: 1/27
Chloramphenicol: 1/23
Co‐trimoxazole: 1/50
Fluoroquinolone: 0/27
Chloramphenicol: 1/23
Yousaf 1992 PAK 85 enrolled and randomized 85 (not stated) Not stated Not stated Not stated Not stated
Fluoroquinolone vs ampicillin Flores 1994 MEX Not stated 40 (not stated) 40/0
Fluoroquinolone: 20
Ampicillin: 20
Not stated Not stated Not stated
Fluoroquinolone 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 resistant to co‐trimoxazole was in pefloxacin group
0
Limson 1989 PHL 53 enrolled and randomized 40 (blood) 28/12
Fluoroquinolone: 15/5
Co‐trimoxazole: 13/7
0 Not stated
No resistance to co‐trimoxazole
16 were resistant to chloramphenicol
Not stated
Fluoroquinolone vs azithromycin Dolecek 2008 VNM 358 enrolled and randomized 288 (blood or bone marrow) 282/5
Fluoroquinolone: 144/1
Azithromycin: 138/4
153 (58%) of 263 S. Typhi
Fluoroquinolone: 87/137
Azithromycin: 66/126
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) 253 (96%) of 263 S. Typhi
Fluoroquinolone: 132/137
Azithromycin: 121/126
All 5 S. Paratyphi were susceptible
Chinh 2000 VNM 97 enrolled and randomized 91 (blood) 86/2 68 (78%) of 87
Fluoroquinolone: 35
Azithromycin: 33
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) 46 (52.3%; of 87 strains evaluated)
Fluoroquinolone: 21
Azithromycin: 25
Girgis 1999 EGY 123 enrolled and randomized 64 (62 by blood, 2 by stool) 60/4
Fluoroquinolone: 34/2
Azithromycin: 26/2
21/64 (33%)
Fluoroquinolone: 15
Azithromycin: 6
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) Not stated
Parry 2007 VNM 160 enrolled and randomized (excluding fluoroquinolone with azithromycin combination arm) 130 (blood and/or bone marrow) 125/0
Fluoroquinolone: 63/0
Azithromycin: 62/0
110/125 (88%)
Fluoroquinolone: 57/63
Azithromycin: 53/62
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) 117/125 (94%)
Fluoroquinolone: 62/63
Azithromycin: 55/62
Fluoroquinolone vs cefixime Phuong 1999 VNM 138 enrolled and randomized 82 (blood) 82/0
Fluoroquinolone: 38
Cefixime: 44
70 (85%)
S. Typhi: 32
S. Paratyphi: 38
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) and tetracycline 0
Pandit 2007 NPL 390 enrolled and randomized 169 (blood) 119/50
Fluoroquinolone: 65/27
Cefixime: 54/23
0 Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) 136/163 (83%)
Fluoroquinolone: 71/89
Cefixime: 65/74
Fluoroquinolone vs ceftriaxone Smith 1994 VNM 60 enrolled and randomized 47 (44 by blood and/or bone marrow, 3 by stool) 41/6
Fluoroquinolone: 21/1
Ceftriaxone: 20/5
26 (55%)
Fluoroquinolone: 14
Ceftriaxone: 12
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) and tetracycline 0
Wallace 1993 BHR 43 enrolled and 42 randomized 42 (blood) 42/0
Fluoroquinolone: 20
Ceftriaxone: 22
22 (52%)
Fluoroquinolone: 11
Ceftriaxone: 11
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) Not stated
Different durations of fluoroquinolone Alam 1995 BGD 76 enrolled and randomized 72 (blood or bone marrow) 61/8
Fluoroquinolone 10‐day: 30/5
Fluoroquinolone 14‐day: 31/3
36/69 (52%)
Fluoroquinolone 10‐day: 18
Fluoroquinolone 14‐day: 18
Resistance to all drugs used conventionally against S. Typhi and S. Paratyphi 5/69 (7%)
Fluoroquinolone 10‐day: 2
Fluoroquinolone 14‐day: 3
(derived from data presented for MIC for ciprofloxacin)
Kalo 1997 ALB 30 (ampicillin‐resistant) enrolled and randomized 30 (blood) 30/0 12/30 (40%) Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) Not stated
Chinh 1997 VNM 107 enrolled and randomized 101 (blood) 95/5
Fluoroquinolone 2‐day: 43/4
Fluoroquinolone 3‐day: 52/1
75/95 (79%)
Fluoroquinolone 2‐day: 35
Fluoroquinolone 3‐day: 40
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) and tetracycline 5/95 (5%)
Fluoroquinolone 2‐day: 1
Fluoroquinolone 3‐day: 4
Tran 1995 VNM 438 enrolled, 425 randomized 228 (blood) 207/19
 (2 other Salmonella) 189
Fluoroquinolone 3‐day: 98
Fluoroquinolone 5‐day: 91
Resistant to standard antibiotics Few NaR strains present, number not stated
Unal 1996 TUR 46 randomized 46 (blood and/or bone marrow) 19/27
Fluoroquinolone 5‐day: 8/14
Fluoroquinolone 7‐day: 11/13
6/46 (13%)
Fluoroquinolone 5‐day: 3
Fluoroquinolone 7‐day: 3
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) Not stated
MIC for pefloxacin was 0.06 to 1
Vinh 1996 VNM 108 enrolled and randomized 100 (blood) 100/0
Fluoroquinolone 2‐day: 53
Fluoroquinolone 3‐day: 47
84
Fluoroquinolone 2‐day: 46
Fluoroquinolone 3‐day: 38
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) and tetracycline 13 (13%)
Fluoroquinolone 2‐day: 6
Fluoroquinolone 3‐day: 7
Vinh 2005 VNM 235 enrolled and randomized 202 (blood) 196/0
Fluoroquinolone 2‐day: 89
Fluoroquinolone 3‐day: 107
176/196 (90%)
Fluoroquinolone 2‐day: 82/89
Fluoroquinolone 3‐day: 94/107
Resistant to all 3 (chloramphenicol, ampicillin, co‐trimoxazole) 4/161 (2.5%)
Fluoroquinolone 2‐day: 1/72
Fluoroquinolone 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 failure Microbiological failure Relapse Fever clearance time Convalescent Faecal Carriage
Fluoroquinolones vs chloramphenicol Ciprofloxacin Gasem 2003 IDN Not afebrile within 7 days of treatment Blood culture positive at days 3 and 5 Reappearance of fever after defervescence during hospitalization (under 14 days) Defined as first day that temperature fell < 37.5 °C and remained below that level for ≥ 48 hours Outcome not reported
Ciprofloxacin Gottuzzo 1992 N/A "One participant who developed a gastrointestinal bleed in first 36 hours of treatment was considered a failure" Outcome not reported Not defined Outcome not reported Outcome not reported
Ciprofloxacin Morelli 1992 ITA Persistence of fever Outcome not reported Not defined Not defined 3 weeks during follow up
Ciprofloxacin and Ofloxacin and
Cotrimoxazole
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 after initial disappearance for at least 48 hours or reappearance of pathogen in blood and/or stool within three weeks after 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 treatment or continuation of symptoms and high tympanic temperature > 39 °C at 7 days after start of treatment or development of signs of severe disease Outcome not reported Outcome not reported Time from onset of treatment to first recording of a tympanic temperature < 38 °C (˜ 37.5 °C axillary) which remained < 38 °C for 48 hours ('Fever Clearance 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 treatment (the 2 relapses were blood culture negative and were stool culture positive before relapse) Not defined 30 days
Gatifloxacin Arjyal 2011 Not specifically defined but denoted as part of composite end point of treatment failure Positive blood culture for S.Typhi or S.Paratyphi A on day 8 Reappearance of culture confirmed or syndromic enteric fever on or after day 11 to day 31 in patients who were initially categorized as successfully treated Time from the first dose of treatment given until temperature was fro the first time ≤37.5oC and the patient remained afebrile for at least 48 hours Faecal carriage at the follow up visits at 1, 3 and 6 months.
Fluoroquinolone vs ampicillin Ofloxacin Flores 1994 MEX Persistence of signs and symptoms of infection 5‐7 days after the end of treatment. Persistence of S. Typhi from blood culture 5‐7 days after the end of treatment Outcome not reported Outcome not reported Outcome not reported
Yousaf 1992 PAK Persistence or reappearance of all presenting signs and symptoms or increase in severity of at least 1 sign or symptom or both Persistence of baseline pathogen at day 14 Outcome not reported Outcome not reported Outcome not reported
Fluoroquinolone vs co‐trimoxazole Pefloxacin Hajji 1988 MAR Fever and presence of clinical symptoms and positive cultures Positive cultures at days 4, 15, and 30 Reappearance of fever, clinical symptoms, and/or bacteraemia 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 improvement in symptoms after 5 days of therapy Positive cultures during and after therapy Outcome not reported Outcome not reported Outcome not reported
Fluoroquinolone vs azithromycin Gatifloxacin Dolecek 2008 VNM Persistence of fever and symptoms 2 days after the end of treatment, i.e. on day 10 Positive blood culture on day 7 to 9 after the start of treatment Symptoms and signs suggestive of
 typhoid fever within 1 month after completion of treatment (only culture positive data extracted) Time from start of antibiotic treatment to when the axillary temperature first fell ≤ 37. 5 °C and remained there for at least 48 hours Follow ups at 1, 3, and 6 months; participants who attended at least 2 consecutive follow‐up visits were evaluated
Ciprofloxacin Chinh 2000 VNM Persistence of fever and symptoms for > 5 days after the end of treatment or development of severe complications (severe gastrointestinal bleed, intestinal perforation, visible jaundice, myocarditis, renal failure, shock, coma) during treatment requiring change in treatment Isolation of S. Typhi/S. Paratyphi from blood or other sterile site after completion of treatment Recurrence of signs and symptoms suggestive of enteric fever after discharge at 4 to 6 weeks of follow up Time from start of treatment until body temperature 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 resolution of symptoms by day 7 or development of major complications of typhoid fever after 5 days of therapy Blood culture positive for S. Typhi/S. Paratyphi on day 10 Recurrence of fever with signs/symptoms of typhoid fever in 4 weeks of therapy completion and culture positive First day on which maximum temperature ≤ 38 °C and at this level for ≥ 48 hours 1 month
Ciprofloxacin Parry 2007 VNM Presence of fever and at least 1 other typhoid related symptom for > 7 days after start of treatment or development of severe complications (severe gastrointestinal bleeding, perforation, visible jaundice, myocarditis, pneumonia, renal failure, shock, or altered consciousness level, during treatment requiring change in therapy Isolation of S. Typhi or S. Paratyphi from blood or sterile site after completion of treatment Recurrence of symptoms or signs suggestive of enteric fever within 4‐week period after patient had been discharged well from hospital accompanied by positive blood culture for S. Typhi or S. Paratyphi Time from start of treatment until body temperature reached ≤ 37.5 °C and remained at this for 48 hours After end of initial 7‐day treatment and before hospital discharge (with isolate having the same susceptibility pattern as original isolate)
Fluoroquinolone vs cefixime Ofloxacin Phuong 1999 VNM Deterioration in clinical condition or failure of resolution of symptoms requiring further treatment Blood culture positive for S. Typhi after completion of treatment Symptoms suggestive of typhoid fever with a positive blood or bone marrow culture up to 4 weeks after discharge Time from onset of treatment until fever was 37.5 °C or below for at least 24 hours 1 month mostly, few seen after a longer period
Gatifloxacin Pandit 2007 NPL Any severe complication, persistence of fever (> 38 °C), persistence of symptoms for > 7 days after start of treatment, requiring additional or rescue treatment Blood culture positive on day 10 Fever with blood culture positive within a month of completing treatment (patients given rescue treatment or prolonged treatment were excluded) Time to 1st drop in oral temperature ≤ 37.5 °C remaining ≤ 37.5 °C for 48 hours 1 month
Fluoroquinolone vs ceftriaxone Ofloxacin Smith 1994 VNM Acute treatment failure as continuing symptoms and fever for at least 7 days after starting the treatment regimen Blood culture positive at day 8 Recurrence of fever and symptoms in the period up to 6 weeks after discharge with a positive blood or bone marrow culture b Time to defervescence 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 deteriorated clinically after 5 full days Blood culture positive at day 3 Readmission for typhoid within 2 months of discharge with stool or blood culture positive for S. Typhi of the same antibiogram (1 relapse had both stool and blood culture positive) Not defined Days 1, 7, and 28; results unclear
Different durations of fluoroquinolones   Alam 1995 BGD Lack of improvement or deterioration in clinical condition 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 culture after initial cure Time to return of oral temperature to ≤ 37.5 °C after initiation 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 hospitalization and 2 month follow up Outcome not reported Days 7 to 12
  Chinh 1997 VNM Continuing fever and symptoms for 7 days after the start of treatment or deterioration in clinical condition before 7 days that warranted further treatment Blood or bone marrow culture positive after end of treatment before discharge Recurrent fever and symptoms with bone marrow or blood culture positive mostly up to 6 weeks after discharge b Time at which fever fell below 37.5 °C for at least 24 hours Usually 6 weeks (occasionally up to 12 weeks)
  Tran 1995 VNM Persistent fever and symptoms for > 7 days after start of treatment Blood or bone marrow culture positive after end of treatment Symptoms since study with positive blood culture Not defined 1 month
  Unal 1996 TUR Continued or worsening symptoms after 7 days of therapy Failure to eradicate organism Similar signs and symptoms after apparently being cured for a month (the participant had a positive stool culture) Time for temperature to be below 37.5 °C for at least 48 hours 1 month; results unclear
  Vinh 1996 VNM Continued 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 Recurrence of fever and symptoms with positive blood or bone marrow culture up to 6 weeks (26 participants followed up to 12 weeks) after discharge Time from start of treatment until axillary temperature fell below 37.5 °C and remained below this level for > 48 hours 4 to 6 weeks (for 66 participants); and at 3 months (for 26 participants)
  Vinh 2005 VNM Fever and symptoms persisting for ≥ 7 days after start of therapy, or development of severe or complicated disease Blood culture positive for same organism between 7 to 28 days after completion of therapy Recurrence of typhoid fever symptoms usually with positive blood culture after hospital discharge until 28 days post discharge (only data for blood culture‐confirmed relapse extracted) Period from start of treatment until temperature remained at or below 37.5 °C for at least 48 hours Immediately after treatment

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 chloramphenicol 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‐trimoxazole 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
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 azithromycin Chinh 2000 VNM Gastrointestinal bleeding (1 participant) Gastrointestinal bleeding (1 participant)
Dolecek 2008 VNM Gastrointestinal bleeding (4 participants)
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)
Pefloxacin: Skin Rash (2), headache (6), epigastric pain (10)
Diarrhoea (3), Mild epigastric pain (6),
abdominal pain (4)
Not reported not reported
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: Nausea/vomiting (10), diarrhoea (1), heartburn (2), headache/dizziness (3), anorexia (1), palpitation (1).
Ofloxacin: Nausea/vomiting (6), abdominal pain (1), heartburn (4), headache (2), palpitation (2)
Chloramphenicol: Nausea/vomiting(4), abdominal pain (1), cough (1), palpitation(1), anaemia(2) None reported None reported
Arjyal 2011 Number of patients with events (59/426)
Abdominal pain (8), acne (0),
 anorexia (1), diarrhoea (5),
 dizziness (2), nausea (9), oral candidiasis (0), vomiting (35),
 weakness (0)
Number of patients with events(99/418)
Abdominal pain (11), acne (2), anorexia (9), diarrhoea (24), dizziness (11), nausea (26), oral candidiasis (4), vomiting (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 discomfort/diarrhoea (1)
Dizziness (1)
Cotrimoxazole: nausea or abdominal discomfort (5)
Pruritus (1)
None None
Fluoroquinolone vs ampicillin/amoxicillin Yousaf 1992 PAK 3 reported adverse events. No specific event 11 events reported to be mostly diarrhoea, pruritus and rashes None reported None reported
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: nausea (1); vomiting (3); abdominal pain (4); skin rash (0) Azithromycin: nausea (5); vomiting (5); abdominal pain (4); skin rash (1) Ofloxacin: mild elevation in mean transaminase levels Azithromycin: mild elevation in mean transaminase levels
Dolecek 2008 VNM Gatifloxacin: vomiting (1); Diarrhoea (1) Azithromycin: jaundice (2) Gatifloxacin: mild elevations in median transaminase levels Azithromycin: mild elevations in median transaminase levels
Girgis 1999 EGY Ciprofloxacin: nausea or vomiting (4); lightheadedness (2); dry throat or mouth (4); loose stools (3); constipation (2) Azithromycin: nausea or vomiting (6); lightheadedness (2); dry throat or mouth (3); loose stools (3); constipation (2) Ciprofloxacin: thrombocytosis (1); mild increases in aspartate transaminases levels (3) Azithromycin: thrombocytosis (4); mild increase in aspartate amino transaminase levels (2)
Parry 2007 VNM Ofloxacin: joint discomfort 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 enzymes 3D: no significant increases in liver enzymes
Fluoroquinolone 3days vs 5days Tran 1995 VNM 3D: Insomnia (5), dizziness (5) epigastric pain (2), nausea (1), headache (1) 5D: Insomnia (5), dizziness (1) vomiting (1), rash (1) 3D: none 5D: none
Fluoroquinolone 5days vs 7days Unal 1996 TUR 5D: Nausea and vomiting (3) 7D: Nausea and vomiting (3) 5D: None 7D: Increased transaminase levels (1)
Fluoroquinolone 7days vs 10days Kalo 1997 ALB 7D Nausea/abdominal discomfort 10D: Nausea/ abdominal discomfortd 7D: None 10D:None
Fluoroquinolone 10days vs 14 days Alam 1995 BGD 10D: Eleven events occurred in four patients namely headache, malaise, dizziness, insomnia, skin rash, pruritus, lethargy, weakness 14D: Eighteen events occurred in nine patients namely headache, malaise, abdominal pain, dizziness, nausea, oral mucosal pain, insomnia, photosensitivity, vomiting, vertigo, joint pain palpitation, restlessness. 10D: Moderate eosinophilia (5) 14D: Transient elevation 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/dL

cLeucopenia 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

Data and analyses

Comparison 1. Fluoroquinolone versus chloramphenicol.

Outcome or subgroup title No. 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 4 249 Risk Ratio (M‐H, Fixed, 95% CI) 0.15 [0.03, 0.64]
1.3 Pefloxacin versus chloramphenicol 2 126 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Gatifloxacin versus chloramphenicol 1 352 Risk Ratio (M‐H, Fixed, 95% CI) 0.79 [0.32, 1.96]
2 Microbiological failure 5   Risk Ratio (M‐H, Random, 95% CI) Subtotals only
2.1 Ciprofloxacin versus chloramphenicol 2 142 Risk Ratio (M‐H, Random, 95% CI) 0.05 [0.00, 0.81]
2.2 Ofloxacin versus chloramphenicol 3 199 Risk Ratio (M‐H, Random, 95% CI) 0.16 [0.02, 1.07]
2.3 Pefloxacin versus chloramphenicol 2 126 Risk Ratio (M‐H, Random, 95% CI) 0.0 [0.0, 0.0]
2.4 Gatifloxacin versus chloramphenicol 1 352 Risk Ratio (M‐H, Random, 95% CI) 4.94 [0.24, 102.24]
3 Relapse 6   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
3.1 Ciprofloxacin versus chloramphenicol 4 292 Risk Ratio (M‐H, Fixed, 95% CI) 0.15 [0.02, 1.15]
3.2 Ofloxacin versus chloramphenicol 2 149 Risk Ratio (M‐H, Fixed, 95% CI) 0.14 [0.01, 2.65]
3.3 Pefloxacin versus chloramphenicol 2 126 Risk Ratio (M‐H, Fixed, 95% CI) 0.15 [0.02, 1.21]
3.4 Gatifloxacin versus chloramphenicol 1 352 Risk Ratio (M‐H, Fixed, 95% CI) 0.56 [0.17, 1.90]
4 Convalescent faecal carriage 3   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
4.1 Ciprofloxacin versus chloramphenicol 1 50 Risk Ratio (M‐H, Fixed, 95% CI) 0.16 [0.01, 2.89]
4.2 Ofloxacin versus chloramphenicol 1 60 Risk Ratio (M‐H, Fixed, 95% CI) 0.11 [0.01, 1.98]
4.3 Pefloxacin versus chloramphenicol 2 126 Risk Ratio (M‐H, Fixed, 95% CI) 0.13 [0.02, 1.01]
4.4 Gatifloxacin versus chloramphenicol 1 273 Risk Ratio (M‐H, Fixed, 95% CI) 0.32 [0.01, 7.82]
5 Fever clearance time 3   Mean Difference (IV, Fixed, 95% CI) Subtotals only
5.1 Ciprofloxacin versus chloramphenicol 2 147 Mean Difference (IV, Fixed, 95% CI) ‐62.46 [‐75.52, ‐49.39]
5.2 Ofloxacin versus chloramphenicol 2 140 Mean Difference (IV, Fixed, 95% CI) ‐75.85 [‐88.52, ‐63.17]
6 Duration of hospitalization 2   Mean Difference (IV, Fixed, 95% CI) Subtotals only
6.1 Ciprofloxacin versus chloramphenicol 1 55 Mean Difference (IV, Fixed, 95% CI) ‐0.40 [‐1.63, 0.83]
6.2 Ofloxacin versus 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]
7.1 Ciprofloxacin versus chloramphenicol 2 153 Risk Ratio (M‐H, Fixed, 95% CI) 0.99 [0.18, 5.52]
7.2 Ofloxacin versus chloramphenicol 1 50 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8 Non‐serious adverse events 8 1410 Risk Ratio (M‐H, Fixed, 95% CI) 0.76 [0.61, 0.94]
8.1 Ciprofloxacin versus chloramphenicol 4 253 Risk Ratio (M‐H, Fixed, 95% CI) 1.00 [0.61, 1.64]
8.2 Ofloxacin versus chloramphenicol 4 207 Risk Ratio (M‐H, Fixed, 95% CI) 1.06 [0.60, 1.87]
8.3 Pefloxacin versus chloramphenicol 2 106 Risk Ratio (M‐H, Fixed, 95% CI) 1.32 [0.69, 2.52]
8.4 Gatifloxacin versus chloramphenicol 1 844 Risk Ratio (M‐H, Fixed, 95% CI) 0.58 [0.44, 0.78]

1.4. Analysis.

1.4

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

Comparison 2. Fluoroquinolone versus co‐trimoxazole.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Clinical Failure 3   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
1.1 Ciprofloxacin versus co‐trimoxazole 2 132 Risk Ratio (M‐H, Fixed, 95% CI) 0.06 [0.01, 0.43]
1.2 Ofloxacin versus co‐trimoxazole 1 89 Risk Ratio (M‐H, Fixed, 95% CI) 0.04 [0.00, 0.59]
1.3 Pefloxacin versus co‐trimoxazole 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Microbiological failure 3   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
2.1 Ciprofloxacin versus co‐trimoxazole 2 132 Risk Ratio (M‐H, Fixed, 95% CI) 0.06 [0.01, 0.43]
2.2 Ofloxacin versus co‐trimoxazole 1 89 Risk Ratio (M‐H, Fixed, 95% CI) 0.04 [0.00, 0.59]
2.3 Pefloxacin versus co‐trimoxazole 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Relapse 1 181 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.1 Ciprofloxacin versus co‐trimoxazole 1 92 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Ofloxacin versus co‐trimoxazole 1 89 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4 Convalescent faecal carriage 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5 Fever clearance time 1   Mean Difference (IV, Fixed, 95% CI) Subtotals only
5.1 ciprofloxacin versus co‐trimoxazole 1 92 Mean Difference (IV, Fixed, 95% CI) ‐84.0 [‐99.72, ‐68.28]
5.2 Ofloxacin versus co‐trimoxazole 1 92 Mean Difference (IV, Fixed, 95% CI) ‐96.0 [‐115.64, ‐76.36]
6 Non serious adverse events 3 219 Risk Ratio (M‐H, Fixed, 95% CI) 0.70 [0.46, 1.08]
6.1 Ciprofloxacin versus co‐trimoxazole 2 110 Risk Ratio (M‐H, Fixed, 95% CI) 0.62 [0.34, 1.12]
6.2 Ofloxacin versus co‐trimoxazole 1 67 Risk Ratio (M‐H, Fixed, 95% CI) 0.92 [0.46, 1.83]
6.3 Pefloxacin versus co‐trimoxazole 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.56 [0.14, 2.21]

2.2. Analysis.

2.2

Comparison 2 Fluoroquinolone versus co‐trimoxazole, Outcome 2 Microbiological failure.

2.3. Analysis.

2.3

Comparison 2 Fluoroquinolone versus co‐trimoxazole, Outcome 3 Relapse.

2.4. Analysis.

2.4

Comparison 2 Fluoroquinolone versus co‐trimoxazole, Outcome 4 Convalescent faecal carriage.

Comparison 3. Fluroqunolone versus ampicillin/amoxicillin.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Clinical failure 2 90 Risk Ratio (M‐H, Fixed, 95% CI) 0.11 [0.02, 0.57]
1.1 Ofloxacin versus ampicillin 1 40 Risk Ratio (M‐H, Fixed, 95% CI) 0.09 [0.01, 1.54]
1.2 Ofloxacin versus amoxicillin 1 50 Risk Ratio (M‐H, Fixed, 95% CI) 0.13 [0.02, 0.93]
2 Microbiological failure 2 90 Risk Ratio (M‐H, Fixed, 95% CI) 0.13 [0.03, 0.68]
2.1 Ofloxacin versus ampicillin/amoxicillin 1 40 Risk Ratio (M‐H, Fixed, 95% CI) 0.14 [0.01, 2.60]
2.2 Ofloxacin versus amoxicillin 1 50 Risk Ratio (M‐H, Fixed, 95% CI) 0.13 [0.02, 0.93]
3 Non‐serious adverse events 2 90 Risk Ratio (M‐H, Fixed, 95% CI) 0.33 [0.12, 0.93]
3.1 Ofloxacin versus amoxicillin 2 90 Risk Ratio (M‐H, Fixed, 95% CI) 0.33 [0.12, 0.93]

Comparison 4. Fluoroquinolone versus cefixime.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Clinical failure 3   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
1.1 Ciprofloxacin versus cefixime 1 94 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Ofloxacin versus cefixime 2 173 Risk Ratio (M‐H, Fixed, 95% CI) 0.14 [0.02, 1.11]
1.3 Gatifloxacin versus cefixime 1 158 Risk Ratio (M‐H, Fixed, 95% CI) 0.04 [0.01, 0.31]
2 Microbiological failure 3   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
2.1 Ciprofloxacin versus cefixime 1 94 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Ofloxacin versus cefixime 2 173 Risk Ratio (M‐H, Fixed, 95% CI) 0.23 [0.01, 4.66]
2.3 Gatifloxacin versus cefixime 1 158 Risk Ratio (M‐H, Fixed, 95% CI) 0.27 [0.01, 6.43]
3 Relapse 3   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
3.1 Ciprofloxacin versus cefixime 1 94 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Ofloxacin versus cefixime 2 131 Risk Ratio (M‐H, Fixed, 95% CI) 0.33 [0.01, 7.72]
3.3 Gatifloxacin versus cefixime 1 138 Risk Ratio (M‐H, Fixed, 95% CI) 0.20 [0.04, 0.93]
4 Convalescent faecal carriage 1   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
4.1 Gatifloxacin versus cefixime 1 147 Risk Ratio (M‐H, Fixed, 95% CI) 0.27 [0.01, 6.40]
5 Fever clearance time 1   Mean Difference (IV, Fixed, 95% CI) Subtotals only
5.1 Ciprofloxacin versus 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
7.1 Ofloxacin versus cefixime 1 82 Risk Ratio (M‐H, Fixed, 95% CI) 3.46 [0.15, 82.56]
7.2 Gatifloxacin versus cefixime 1 169 Risk Ratio (M‐H, Fixed, 95% CI) 1.67 [0.15, 18.11]
8 Non‐serious adverse events 2   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
8.1 Ciprofloxacin versus cefixime 1 94 Risk Ratio (M‐H, Fixed, 95% CI) 1.57 [0.83, 2.95]
8.2 Ofloxacin versus cefixime 1 91 Risk Ratio (M‐H, Fixed, 95% CI) 1.70 [0.83, 3.49]
8.3 Gatifloxacin versus cefixime 1 169 Risk Ratio (M‐H, Fixed, 95% CI) 20.92 [2.90, 150.90]

4.4. Analysis.

4.4

Comparison 4 Fluoroquinolone versus cefixime, Outcome 4 Convalescent faecal carriage.

Comparison 5. Fluoroquinolone versus ceftriaxone.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Clinical failure 2   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
1.1 Ciprofloxacin versus ceftriaxone 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.08 [0.01, 1.41]
1.2 Ofloxacin versus ceftriaxone 1 47 Risk Ratio (M‐H, Fixed, 95% CI) 0.09 [0.01, 1.46]
2 Microbiological failure 2   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
2.1 Ciprofloxacin versus ceftriaxone 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Ofloxacin versus ceftriaxone 1 47 Risk Ratio (M‐H, Fixed, 95% CI) 0.38 [0.02, 8.80]
3 Relapse 2   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
3.1 Ciprofloxacin versus ceftriaxone 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.37 [0.02, 8.48]
3.2 Ofloxacin versus ceftriaxone 1 23 Risk Ratio (M‐H, Fixed, 95% CI) 0.36 [0.02, 8.04]
4 Convalescent faecal carriage 1   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
4.1 Ciprofloxacin versus ceftriaxone 1 42 Risk Ratio (M‐H, Fixed, 95% CI) 0.37 [0.02, 8.48]
5 Fever clearance time 1 47 Mean Difference (IV, Fixed, 95% CI) ‐113.00 [‐150.67, ‐79.33]
5.1 Ofloxacin versus ceftriaxone 1 47 Mean Difference (IV, Fixed, 95% CI) ‐113.00 [‐150.67, ‐79.33]
6 Non‐serious adverse events 1 47 Risk Ratio (M‐H, Fixed, 95% CI) 0.57 [0.06, 5.85]
6.1 Ofloxacin versus ceftriaxone 1 47 Risk Ratio (M‐H, Fixed, 95% CI) 0.57 [0.06, 5.85]

Comparison 6. Fluoroquinolone versus azithromycin.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Clinical failure 4   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
1.1 Ciprofloxacin versus azithromycin 1 64 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Ofloxacin versus azithromycin 2 213 Risk Ratio (M‐H, Fixed, 95% CI) 2.20 [1.23, 3.94]
1.3 Gatifloxacin versus azithromycin 1 287 Risk Ratio (M‐H, Fixed, 95% CI) 0.98 [0.32, 2.96]
2 Microbiological failure 4   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
2.1 Ciprofloxacin versus azithromycin 1 64 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Ofloxacin versus azithromycin 2 213 Risk Ratio (M‐H, Fixed, 95% CI) 1.32 [0.30, 5.76]
2.3 Gatifloxacin versus azithromycin 1 285 Risk Ratio (M‐H, Fixed, 95% CI) 0.64 [0.11, 3.79]
3 Relapse 4   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
3.1 Ciprofloxacin versus azithromycin 1 64 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Ofloxacin versus azithromycin 2 163 Risk Ratio (M‐H, Fixed, 95% CI) 6.11 [0.31, 119.33]
3.3 Gatifloxacin versus azithromycin 1 264 Risk Ratio (M‐H, Fixed, 95% CI) 0.12 [0.01, 2.20]
4 Convalescent faecal carriage 4   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
4.1 Ciprofloxacin versus azithromycin 1 64 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Ofloxacin versus azithromycin 2 193 Risk Ratio (M‐H, Fixed, 95% CI) 13.52 [2.64, 69.36]
4.3 Gatifloxacin versus azithromycin 1 268 Risk Ratio (M‐H, Fixed, 95% CI) 2.87 [0.12, 69.82]
5 Fever clearance time 3   Mean Difference (IV, Random, 95% CI) Subtotals only
5.1 Ciprofloxacin versus azithromycin 1 64 Mean Difference (IV, Random, 95% CI) ‐12.0 [‐24.39, 0.39]
5.2 Ofloxacin versus 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
6.1 Ofloxacin versus azithromycin 2 213 Mean Difference (IV, Fixed, 95% CI) 1.01 [0.19, 1.83]
7 Serious adverse events 1 88 Risk Ratio (M‐H, Fixed, 95% CI) 1.0 [0.06, 15.49]
7.1 Ofloxacin versus azithromycin 1 88 Risk Ratio (M‐H, Fixed, 95% CI) 1.0 [0.06, 15.49]
8 Non‐serious adverse events 4   Risk Ratio (M‐H, Fixed, 95% CI) Subtotals only
8.1 Ciprofloxacin versus azithromycin 1 64 Risk Ratio (M‐H, Fixed, 95% CI) 1.21 [0.73, 1.99]
8.2 Ofloxacin versus azithromycin 2 213 Risk Ratio (M‐H, Fixed, 95% CI) 0.56 [0.27, 1.16]
8.3 Gatifloxain versus azithromycin 1 287 Risk Ratio (M‐H, Fixed, 95% CI) 1.96 [0.18, 21.36]

Comparison 7. Fluoroquinolone 2 days vs 3 days.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Clinical failure 3 396 Risk Ratio (M‐H, Fixed, 95% CI) 1.16 [0.54, 2.53]
2 Microbiological failure 2 296 Risk Ratio (M‐H, Fixed, 95% CI) 1.94 [0.44, 8.47]
3 Relapse 3 312 Risk Ratio (M‐H, Fixed, 95% CI) 0.65 [0.14, 2.97]
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]
7 Serious adverse events 3 396 Risk Ratio (M‐H, Fixed, 95% CI) 2.40 [0.22, 26.08]
8 Non‐serious adverse events 2 296 Risk Ratio (M‐H, Fixed, 95% CI) 0.18 [0.01, 3.61]

7.1. Analysis.

7.1

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

7.2. Analysis.

7.2

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

7.3. Analysis.

7.3

Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 3 Relapse.

7.4. Analysis.

7.4

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

7.5. Analysis.

7.5

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

7.6. Analysis.

7.6

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

7.7. Analysis.

7.7

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

7.8. Analysis.

7.8

Comparison 7 Fluoroquinolone 2 days vs 3 days, Outcome 8 Non‐serious adverse events.

Comparison 8. Fluoroquinolone 3 days vs 5 days.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Relapse 1 154 Risk Ratio (M‐H, Fixed, 95% CI) 0.32 [0.01, 7.65]
2 Fever Clearance time 1 195 Mean Difference (IV, Fixed, 95% CI) ‐12.0 [‐18.07, ‐5.93]
3 Non‐serious adverse events 1 425 Risk Ratio (M‐H, Fixed, 95% CI) 1.73 [0.74, 4.03]

8.1. Analysis.

8.1

Comparison 8 Fluoroquinolone 3 days vs 5 days, Outcome 1 Relapse.

8.3. Analysis.

8.3

Comparison 8 Fluoroquinolone 3 days vs 5 days, Outcome 3 Non‐serious adverse events.

Comparison 9. Fluoroquinolone 5 days vs 7 days.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Microbiological Failure 1 46 Risk Ratio (M‐H, Fixed, 95% CI) 3.26 [0.14, 76.10]
2 Relapse 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]
4 Non‐serious adverse events 1 46 Risk Ratio (M‐H, Fixed, 95% CI) 0.82 [0.21, 3.25]

9.1. Analysis.

9.1

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

9.2. Analysis.

9.2

Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 2 Relapse.

9.3. Analysis.

9.3

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

9.4. Analysis.

9.4

Comparison 9 Fluoroquinolone 5 days vs 7 days, Outcome 4 Non‐serious adverse events.

Comparison 10. Fluoroquinolone 7 days vs 10 days.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Microbiological failure 1 30 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Relapse 1 30 Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]

10.1. Analysis.

10.1

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

10.2. Analysis.

10.2

Comparison 10 Fluoroquinolone 7 days vs 10 days, Outcome 2 Relapse.

Comparison 11. Gatifloxacin (OD for 7 days) vs chloramphenicol (QDS for 14 days).

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
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   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.3 Relapse (reappearance of culture confirmed or syndromic enteric fever on days 11 to 31) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Convalescent faecal carriage 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
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) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 12. Fluoroquinolone 10 days vs 14 days.

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 Relapse 1 69 Risk Ratio (M‐H, Fixed, 95% CI) 0.19 [0.01, 3.91]
2 Fever clearance time 1 69 Mean Difference (IV, Fixed, 95% CI) ‐16.80 [‐42.65, 9.05]
3 Non‐serious adverse events 1 69 Risk Ratio (M‐H, Fixed, 95% CI) 0.43 [0.15, 1.27]

12.1. Analysis.

12.1

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

12.2. Analysis.

12.2

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

12.3. Analysis.

12.3

Comparison 12 Fluoroquinolone 10 days vs 14 days, Outcome 3 Non‐serious adverse events.

Comparison 13. Gatifloxacin (OD for 7 days) vs cefixime (BD for 7 days).

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
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 7) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Relapse (fever plus +ve blood culture within 1 month of successful treatment) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.3 Microbiological failure (blood culture +ve on day 10) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Serious adverse events 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.5 Other adverse events (may be incompletely reported) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 14. Gatifloxacin (OD for 7 days) vs azithromycin (OD for 7 days).

Outcome or subgroup title No. of studies No. of participants Statistical method Effect size
1 All outcomes 1   Risk Ratio (M‐H, Fixed, 95% CI) Totals not selected
1.1 Clinical failure (need for rescue medication of persistence of fever until day 10) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Relapse (symptoms and signs of typhoid fever within 1 month of successful treatment) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.3 Microbiological failure (blood culture +ve on day 7 to 9) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Convalescent faecal carriage 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.5 Serious adverse events 0   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.6 Other adverse events (may be incompletely reported) 1   Risk Ratio (M‐H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Characteristics of studies

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 lactating; 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 regimens”
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
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk Data was missed for 3, 22 and 32 patients on 2, 6 and 12 months respectively for patients in 10 days treatment.
Whereas data was missing for 2, 20 and 31 patients on 2, 6, and 12 months respectively for those on 14 days treatment. missing 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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. enteric fever complications
5. Fever clearance time
5. Convalescent faecal carriage
Notes Location: Nepal
Date: May 2006 ‐ August 2008
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “Patients were randomly allocated to one of two treatments. Randomization was performed in blocks of 50..”
Allocation concealment (selection bias) Low risk “The random allocations were placed in sealed opaque envelopes”
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study for participants and investigators but final outcome assessors blinded
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk Missing data balanced across both groups
Incomplete outcome data (attrition bias) 
 All outcomes(long term) 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
Inclusion of all randomized culture‐positive participants in the final analysis: 100/107 (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 hypersensitivity to quinolones or had treatment with quinolones in the week before admission, 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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
Notes Location: Viet Nam
Date: November 1993 ‐ December 1995
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “ patients were allocated at random...Randomization was in blocks”
Allocation concealment (selection bias) Low risk “Treatment codes were contained in serially numbered sealed envelopes...”
Blinding (performance bias and detection bias) 
 All outcomes High risk “ in an open, randomised ?”
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk 50% of outcome data at follow up presented but results unlikely to affect observed effect size
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias Low risk Study seems free from other bias

Chinh 2000 VNM.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 38/91 (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; hypersensitivity 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)
Outcomes 1. Clinical failure
2. Microbiological failure
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)
7. Convalescent faecal carriage
8. Serious adverse events
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 Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “Patients were allocated to one of two treatment groups in an open randomised comparison" Computer generated randomization list. Information from trial authors
Allocation concealment (selection bias) Low risk “The treatment allocations were kept in serially numbered sealed envelopes”
Blinding (performance bias and detection bias) 
 All outcomes High risk Open comparison
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk outcomes were presented for all randomised
Incomplete outcome data (attrition bias) 
 All outcomes(long term) 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
Other bias Low risk Study seems free from other bias

Cristiano 1995 ITA.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: unclear
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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time (no SD)
5. Convalescent faecal carriage
6. Length of hospitalisation (no SD)
7. Serious adverse events
8. Other adverse events
Notes Location: Italy
Date: 1991‐3
Severity of illness at entry: all severe
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “The enrolled patients were randomly assigned (by means of a computerized list..”
Allocation concealment (selection bias) Unclear risk No information provided
Blinding (performance bias and detection bias) 
 All outcomes High risk “..an open, randomised clinical study”
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk No pre specified outcomes but all relevant outcome data accounted for
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk No pre specified outcomes but all relevant outcome data accounted for
Selective reporting (reporting bias) Low risk Efficacy and safety data reported
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
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 268/288 (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 treatment 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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Complications
6. Length of hospitalization
7. Convalescent faecal carriage
8. Serious adverse events
9. Other adverse events
Notes Location: Vietnam (multi‐centre, 3 hospitals)
Date: 2004‐5
Severity of illness at entry: all uncomplicated
Received as an unpublished trial (with additional data), but reference updated to current citation upon publication
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “An independent administrator from the study generated the random number sequence in excel using RAND function”
Allocation concealment (selection bias) Low risk “..assignments were  folded and kept in opaque, sealed, sequentially numbered envelopes at all three study sites?”
Blinding (performance bias and detection bias) 
 All outcomes High risk Open label study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk No loss to follow up and data was analysed for all the participants randomized
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk In Gatifloxocin group 7, 8, and 80 participants were lost to follow‐up and in Azithromycin group 5, 11 and 79participants were lost to follow‐up. Unlikely to affect observed effect size as loss is similar
Selective reporting (reporting bias) Low risk Report includes all pre specified outcomes including efficacy and safety data
Other bias Low risk Study seems free from other bias

Flores 1994 MEX.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
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 insufficiency, severe neutropenia, requirement of concomitant systemic antimicrobial, convulsions, 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)
Outcomes 1. Clinical failure
 2. Microbiological failure
 3. Serious adverse events
Notes Location: Mexico
Date: not reported
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk 'A comparative open study with groups assigned randomly...'
Allocation concealment (selection bias) Unclear risk Not stated
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) High risk Relapse and fever clearance times not reported
Incomplete outcome data (attrition bias) 
 All outcomes(long term) High risk Convalescent faecal carriage not reported
Selective reporting (reporting bias) Low risk Efficacy and safety data reported
Other bias Unclear risk Language

Gasem 2003 IDN.

Methods Generation of allocation sequence: random‐number table
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
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, ciprofloxacin, other fluoroquinolones before admission; history of allergy to chloramphenicol/quinolone; malaria or other infection; white blood cell count < 2000/mL; pregnant or lactating
Interventions 1. Ciprofloxacin (500 mg oral twice daily for 7 days)
2. Chloramphenicol (500 mg oral 4 times a day for 14 days)
Outcomes 1. Clinical failure
2. Microbiological response to treatment at day 3 or day 5
3. Relapse
4. Fever clearance time
5. Complications
6. Length of hospitalization
7. Serious adverse events
8. Other adverse events
Notes Location: Indonesia
Date: not reported
Severity of illness at entry: none had severe complications on enrolment
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “..patients were randomly assigned to either..”  “....The distribution of the envelopes was derived from a randomly permuted table..”
Allocation concealment (selection bias) Low risk “..treatment group by means of sealed envelopes containing the names of the study drugs.?”
Blinding (performance bias and detection bias) 
 All outcomes High risk “..randomised, open‐label, parallel controlled trial”
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk Outcome data addressed, no information on loss to follow‐up
Incomplete outcome data (attrition bias) 
 All outcomes(long term) High risk No data provided
Selective reporting (reporting bias) Low risk Efficacy and safety data reported
Other bias Low risk Study seems free from other bias

Girgis 1999 EGY.

Methods Generation of allocation sequence: random‐number list, block randomization
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
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 potential efficacy against S. Typhi
Interventions 1. Ciprofloxacin (500 mg oral twice daily for 7 days)
2. Azithromycin (1 g oral once daily for the first day followed by oral 500 mg once daily for total duration of 7 days)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Complications
6. Length of hospitalization
7. Cost of treatment
8. Convalescent faecal carriage
9. Serious adverse events
10. Other adverse events (number of events stated)
Notes Location: Egypt
Date: 1997‐8
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “..each subject was randomly assigned.. assignments, determined by block randomisation based on a random number list”
Allocation concealment (selection bias) Low risk "Treatment assignments..were sealed in envelopes”
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All outcome data addressed
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias High risk Supported by an unrestricted grant from Pfizer

Gottuzzo 1992 N/A.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: double
Inclusion of all randomized culture‐positive participants in the final analysis: 95/98 (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)
Outcomes 1. Clinical failure
2. Relapse
Notes Location: not available
Date: not available
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Randomized study but mode of generation of sequence not stated
Allocation concealment (selection bias) Unclear risk Not stated
Blinding (performance bias and detection bias) 
 All outcomes Low risk Double blind. Placebos given during remaining days of therapy in the longer arm
Incomplete outcome data (attrition bias) 
 All outcomes(short term) High risk Fever clearance time not reported for comparison arm
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk Relevant data reported
Selective reporting (reporting bias) Low risk Efficacy and adverse event data reported
Other bias Low risk Study seems free from other bias

Hajji 1988 MAR.

Methods Generation of allocation sequence: random‐number table
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
Participants 42 analysed: 24 in pefloxacin group; 18 in co‐trimoxazole group
Adult inpatients aged > 16 years
Inclusion criteria: clinical
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 intramuscular 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 pefloxacin group and 2 participants in co‐trimoxazole group
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk “A comparative open and randomised trial..”
Allocation concealment (selection bias) Unclear risk Not stated
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All outcome data addressed
Selective reporting (reporting bias) Low risk Efficacy and adverse event data reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Kalo 1997 ALB.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
Participants 30 analysed: 15 in 7‐day group; 15 in 10‐day group
Adult inpatients aged 16 to 42 years
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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Convalescent faecal carriage
5. Serious adverse events
Notes Location: Albania
Date: 1992‐4
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk The patients were divided into two groups
Allocation concealment (selection bias) Unclear risk No information available
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All outcome data addressed
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Limson 1989 PHL.

Methods Generation of allocation sequence: random‐number table
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
Participants 40 analysed: 20 in ciprofloxacin group; 20 in co‐trimoxazole group
Adult inpatients aged 18 to 77 years
Inclusion criteria: clinical
Exclusion criteria: complications; drug allergy; renal impairment
Interventions 1. Ciprofloxacin (500 mg oral twice daily for 10 days)
2. Co‐trimoxazole (160/800 mg oral twice daily for 14 days)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Serious adverse events
4. Other adverse events
Notes Location: Philippines
Date: not reported
Severity of illness at entry: all uncomplicated
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “Patients were randomly assigned.. using a table of random numbers”
Allocation concealment (selection bias) Unclear risk Not stated
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data reported
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All outcome data reported
Selective reporting (reporting bias) Low risk Safety and efficacy reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Morelli 1992 ITA.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
Participants 156 analysed: 30 each in ofloxacin and chloramphenicol groups; 36 in pefloxacin group; 20 each in ciprofloxacin,
enoxacin, and norfloxacin groups
Adult inpatients aged 16 to 60 years
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)
6. Chloramphenicol (500 mg oral every 6 hours for 15 days)
Outcomes 1. Clinical failure
2. Relapse
3. Fever clearance time (no SD)
4. Convalescent faecal carriage
5. Other adverse events (number of events stated)
Notes Location: Italy
Date: 1985‐90
Severity of illness at entry: not reported
We prepared different comparisons with these data: a combination of all 5 fluoroquinolone groups vs the chloramphenicol
group; and norfloxacin vs ofloxacin, pefloxacin, and enoxacin
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “..patients in this open study were randomly assigned, by means of a computerized list”
Allocation concealment (selection bias) Unclear risk Not stated
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All outcome data addressed
Selective reporting (reporting bias) Low risk Efficacy and adverse event data reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Pandit 2007 NPL.

Methods Generation of allocation sequence: computer‐generated, block randomization
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 147/169 (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)
Inclusion criteria: clinical
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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Convalescent faecal carriage
6. Complications
7. Serious adverse events
8 Other adverse events
Notes Location: Nepal
Date: 2005
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection 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..”
Blinding (performance bias and detection bias) 
 All outcomes High risk Open label study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk Relevant outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) 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.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 114/130 (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)
Inclusion criteria: clinical
Exclusion criteria: severe or complicated disease; inability to swallow oral medications; history of significant underlying disease or hypersensitivity to either of trial drugs; pregnant or lactating; history of treatment
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)
Outcomes 1. Clinical failure
2. Microbiological failure
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 intervals; SD calculated by review author)
7. Convalescent faecal carriage
8. Serious adverse events
9. Other adverse events (numbers not stated)
Notes Location: Vietnam
Date: 1998‐2002
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Computer generated randomization list
Allocation concealment (selection bias) Low risk “Treatment allocations were kept in serially numbered sealed envelopes”
Blinding (performance bias and detection bias) 
 All outcomes High risk “an open randomised comparison.”
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk Incomplete outcome data unlikely to affect observed effect size
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias Low risk Study seems free of other bias

Phongmany 2005 LAO.

Methods Generation of allocation sequence: random‐number table, block randomization
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 48/50 (96%)
Participants 50 analysed: 27 in ofloxacin group; 23 in chloramphenicol group
Adult inpatients aged > 15 years
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)
Outcomes 1. Clinical failure
2. Fever clearance time
3. Complications
4. Length of hospitalization
5. Serious adverse events
6. Other adverse events
Notes Location: Laos
Date: 2001‐3
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “..randomised in blocks of 10 from a random number table”
Allocation concealment (selection bias) Low risk “Treatment allocations kept in sealed opaque envelopes”
Blinding (performance bias and detection bias) 
 All outcomes High risk “..prospective randomised open‐label controlled trial”
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) High risk Patients not followed up after discharge. No data for long term outcomes like relapse and convalescent faecal carriage.
Selective reporting (reporting bias) Low risk Efficacy and adverse event data reported
Other bias High risk Trial stopped early because of apparently significant difference in primary outcome

Phuong 1999 VNM.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 40/82 (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, chloramphenicol, 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)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Complications
6. Length of hospitalization
7. Convalescent faecal carriage
8. Serious adverse events
9. Other adverse events
Notes Location: Vietnam
Date: 1995‐6
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk "..Patients were randomised to receive ofloxacin.or cefixime..." Computer generated list
Allocation concealment (selection bias) Low risk “treatment codes were contained in serially numbered sealed envelops ..”
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All pre specified outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All data reported
Selective reporting (reporting bias) High risk Incomplete report of adverse events. Only mortality and associated data for one patient reported
Other bias Unclear risk No information on ethical clearance

Rizvi 2007 PAK.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: Unclear
Inclusion of all randomized culture‐positive participants in the final analysis: 159/227 (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 diagnosis 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.
Interventions 1. Ciprofloxacin (500 mg oral twice daily for 7 days)
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)
Outcomes 1. Clinical cure
2. Microbiological failure
3. Relapse
4. Clinical Failure
5. Fever Clearance
6. Adverse events
Notes Location: Pakistan
Date: Jan 2003 to Jan 2004
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk “The patients were randomly assigned to one of the following”
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 Relevant outcomes addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk outcomes data presented
Selective reporting (reporting bias) Low risk No selective reporting
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Smith 1994 VNM.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 50%
Participants 47 analysed: 22 in ofloxacin group; 25 in ceftriaxone group
Adult inpatients aged 15 to 63 years
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
Interventions 1. Ofloxacin (200 mg oral every 12 hours for 5 days)
2. Ceftriaxone (3 g intravenous once a day for 3 days)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Complications
6. Length of hospitalization (mean and range)
7. Convalescent faecal carriage
8. Serious adverse events
9. Other adverse events
Notes Location: Vietnam
Date: 1992‐3
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk “Patients were randomised to receive?.”
Allocation concealment (selection bias) Low risk “Treatment codes were contained in individual sealed envelopes?..”
Blinding (performance bias and detection bias) 
 All outcomes High risk "...open, randomised comparison..."
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All primary outcome data reported.
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Unclear risk Specific numbers for post discharge follow up not reported
Selective reporting (reporting bias) Low risk Efficacy and safety data reported
Other bias Unclear risk No information given on ethical clearance for undertaking this study

Tran 1995 VNM.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 50% (114/228)
Participants 228 analysed: 118 in 3‐day group; 110 in 5‐day group
Adults and children outpatients (180 culture positive were aged < 17 years)
Inclusion criteria: clinical
Exclusion criteria: unable to take oral medications due to vomiting; severe disease; shock; impaired consciousness; bleeding; peritonitis; pregnant; neonates; received a fluoroquinolone
Interventions 1. Ofloxacin (15 mg/kg/day oral for 3 days)
2. Ofloxacin (10 mg/kg/day oral for 5 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: Vietnam
Date: 1993‐3
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “Patients were randomised to receive.. “ Computer generated
Allocation concealment (selection bias) Low risk “Treatment allocation were kept in sealed envelopes  ...”
Blinding (performance bias and detection bias) 
 All outcomes High risk open label
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk 291/425 overall but 81, 78 and 132 for D3, D5
and blood culture negative arms respectively but unlikely to affect measured effect size.
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias High risk Ofloxacin was provided by Professor A Bryskier of Roussel‐UCLAF Pharmaceuticals, Paris

Unal 1996 TUR.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 46/46 (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
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Clinical cure
5. Fever clearance time
Notes Location: Turkey
Date: June 1992 to October 1994
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection 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..”
Blinding (performance bias and detection bias) 
 All outcomes Unclear risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Unclear risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Unclear risk All outcome data addressed
Selective reporting (reporting bias) Unclear risk Efficacy and adverse events reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Vinh 1996 VNM.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 26/100 (26%)
Participants 100 analysed: 53 in 2‐day group; 47 in 3‐day group
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
Interventions 1. Ofloxacin (15 mg/kg/day oral in 2 divided doses for 2 days)
2. Ofloxacin (15 mg/kg/day oral in 2 divided doses for 3 days)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time
5. Complications
6. Length of hospitalization
7. Convalescent faecal carriage
8. Serious adverse events
9. Other adverse events
Notes Location: Vietnam
Date: not reported
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection 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 envelope containing the treatment regimen to be given was opened”
Blinding (performance bias and detection bias) 
 All outcomes High risk open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Unclear risk No data for 34 and 74 subjects at the 1 and 3 month follow up respectively. No indication how these were handled.
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Vinh 2005 VNM.

Methods Generation of allocation sequence: computer‐generated
Allocation concealment: sealed envelopes
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 196/202 (97%)
Participants 196 analysed: 89 in ofloxacin 2‐day group; 107 in ofloxacin 3‐day group
Children inpatients aged < 15 years
Inclusion criteria: clinical
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
Interventions 1. Ofloxacin (10 mg/kg/day oral in 2 divided doses for 2 days)
2. Ofloxacin (10 mg/kg/day oral in 2 divided doses for 3 days)
Outcomes 1. Clinical failure
2. Microbiological failure
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 intervals; SD calculated by review author)
7. Convalescent faecal carriage
8. Serious adverse events
9. Other adverse events
Notes Location: Vietnam
Date: 1994‐6
Severity of illness at entry: all uncomplicated
Author provided further information
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection 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 envelopes..”
Blinding (performance bias and detection bias) 
 All outcomes High risk open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcomes addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) High risk Data for 6 culture positive children randomized to 2‐day treatment excluded from analysis
Selective reporting (reporting bias) Low risk Efficacy and adverse events reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

Wallace 1993 BHR.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 41/42 (97.6%)
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
Interventions 1. Ciprofloxacin (500 mg oral twice daily for 7 days)
2. Ceftriaxone (3 g/day intravenous for 7 days)
Outcomes 1. Clinical failure
2. Microbiological failure
3. Relapse
4. Fever clearance time (SD not reported)
5. Convalescent faecal carriage
6. Complication
Notes Location: Bahrain
Date: not reported
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk “..patients were randomised to receive” No indication as to how sequence was generated
Allocation concealment (selection bias) Unclear risk Not stated
Blinding (performance bias and detection bias) 
 All outcomes High risk Open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk All outcome data addressed
Incomplete outcome data (attrition bias) 
 All outcomes(long term) Low risk All outcome data addressed
Selective reporting (reporting bias) High risk No report of adverse events
Other bias High risk Trial stopped early because of apparent lower efficacy in the control group, cost of control drug and inconvenience of intravenous administration.

Yousaf 1992 PAK.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 75/85 (88.4%)
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)
Outcomes 1. Clinical failure
 2. Microbiological failure
 3. Other adverse events
Notes Location: Pakistan
Date: 1989‐92
Severity of illness at entry: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk 'The patients were randomly divided into three groups...'
Allocation concealment (selection bias) Unclear risk unclear
Blinding (performance bias and detection bias) 
 All outcomes High risk open study
Incomplete outcome data (attrition bias) 
 All outcomes(short term) Low risk Relevant short term outcomes reported
Incomplete outcome data (attrition bias) 
 All outcomes(long term) High risk Long term outcomes not reported
Selective reporting (reporting bias) Low risk Efficacy and safety data reported
Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists

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 pharmacokinetic 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
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
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 participants 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.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: double
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
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
Exclusion criteria: not reported
Interventions 1. Ciprofloxacin (500 mg oral twice daily for 10 days)
 2. Chloramphenicol (750 mg oral every 6 hours for 14 days)
Outcomes 1. Microbiological failure
 2. Fever clearance time (no SD)
 3. Convalescent faecal carriage
 4. Serious adverse events
 5. Other adverse events
Notes Location: Guatemala
Date: not reported
Severity of illness at entry: 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
Exclusion 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)
Outcomes 1. Clinical failure
 2. Fever clearance time
 3. Serious adverse events
Notes Location: Mexico
Date: not reported
Severity of illness at entry: 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)
Outcomes 1. Clinical failure
 2. Fever clearance time
Notes Location: China (Chinese language)
Date: not reported

Yu 1998.

Methods Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: open
Inclusion of all randomized culture‐positive participants in the final analysis: 100%
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)
Outcomes 1. Clinical failure
 2. Microbiological failure
 3. Relapse
 4. Fever clearance time
 5. Complications
 6. Convalescent faecal carriage
 7. Other adverse events
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 breastfeeding; 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 (paul@tropmedres.ac), 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 typhoid in Vientiane

Differences between protocol and review

We changed the intervention from 'Fluoroquinolone antibiotic' to 'Different fluoroquinolone antibiotic excluding norfloxacin or other fluoroquinolones not currently in use'

Contributions of authors

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.

Sources of support

Internal sources

  • University of Calabar Teaching Hospital, Calabar, Nigeria.

  • Nigeria branch of South African Cochrane centre, Nigeria.

External sources

  • No sources of support supplied

Declarations of interest

None known. Professor ZA Bhutta has been part of trials of treatment for typhoid therapy in children, none of which involved fluoroquinolones.

Unchanged

References

References to studies included in this review

Alam 1995 BGD {published data only}

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Pandit 2007 NPL {published data only}

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Parry 2007 VNM {published data only}

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Smith 1994 VNM {published data only}

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Unal 1996 TUR {published data only}

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Nelwan 1995 {published data only}

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Flores 1991 {published data only}

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Soewandojo 1992 {published data only}

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Weng 1996 {published data only}

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