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Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)

  1. Emmanuel E Effa2,
  2. Zohra S Lassi1,
  3. Julia A Critchley3,
  4. Paul Garner4,
  5. David Sinclair4,
  6. Piero L Olliaro5,
  7. Zulfiqar A Bhutta1,*

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 1 FEB 2011

DOI: 10.1002/14651858.CD004530.pub4


How to Cite

Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD004530. DOI: 10.1002/14651858.CD004530.pub4.

Author Information

  1. 1

    Aga Khan University Hospital, Division of Women and Child Health, Karachi, Sindh, Pakistan

  2. 2

    University of Calabar Teaching Hospital, Internal Medicine, Calabar, Cross River State, Nigeria

  3. 3

    Newcastle University, Institute of Health and Society, Newcastle, Tyne and Wear, UK

  4. 4

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, Merseyside, UK

  5. 5

    World Health Organization, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland

*Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, Sindh, 74800, Pakistan. zulfiqar.bhutta@aku.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 5 OCT 2011

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

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

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
 

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.

 FigureFigure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing 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).

See Appendix 2 for further details on microbiological results and sensitivity.

 

Participants

Three trials were exclusively in children (Vinh 1996 VNM; Phuong 1999 VNM; Vinh 2005 VNM). Seven trials included both children and adults (Alam 1995 BGD; Tran 1995 VNM; Pandit 2007 NPL; Parry 2007 VNM;Rizvi 2007 PAK; Dolecek 2008 VNM; Arjyal 2011), 15 trials were exclusively in adults (Hajji 1988 MAR; Limson 1989 PHL; Gottuzzo 1992 N/A; Morelli 1992 ITA; Yousaf 1992 PAK; Wallace 1993 BHR; Smith 1994 VNM; Cristiano 1995 ITA; Unal 1996 TUR; Chinh 1997 VNM; Kalo 1997 ALB; Girgis 1999 EGY; Chinh 2000 VNM; Gasem 2003 IDN; Phongmany 2005 LAO), and five trial reports did not mention the participants' age of which one used the keyword "adult" (Flores 1994 MEX).

Eighteen trials were conducted specifically on participants with uncomplicated enteric fever or participants without major 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 (see Appendix 3 'Definitions of outcomes'). A full summary of adverse events as stated in the papers is summarized in Appendix 4 and Appendix 5.

Further details are presented in the Characteristics of included studies tables.

 

Excluded studies

Of the excluded studies, five were excluded as they used norfloxacin (Nalin 1987; Sarma 1991; Huai 2000; Bai 1995; ZhongYang 1997), and three involved fluoroquinolones no longer in clinical use (Abejar 1993; Arnold 1993; Tran 1994). (For further details see the Characteristics of excluded studies table).

 

Risk of bias in included studies

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

 

Allocation

The method used to generate the allocation sequence was at low risk of bias in sixteen trials, and unclear in ten.

Fourteen trials used an adequate method (sealed envelopes) to conceal allocation. The method used in the remaining 12 trials was unclear.

 

Blinding

Three trials were described as "double blinded" and 22 trials were open; one trial did not mention use of placebo, but we assumed it was open (Flores 1994 MEX). In one trial, blinding was unclear (Rizvi 2007 PAK).

 

Incomplete outcome data

There were incomplete long term outcome data reported for four trials (Smith 1994 VNM; Vinh 1996 VNM; Gasem 2003 IDN; Phongmany 2005 LAO). The reason for this was unclear.

 

Selective reporting

Most trials reported both efficacy and safety data. In one trial (Wallace 1993 BHR), there were no reports of adverse events while in another, the report was incomplete as only mortality and 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).

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.

 
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).

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.

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).

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)

 
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.

 

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.

 
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.

 

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).

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.

Fever Clearance and duration of hospital stay

Fever clearance time was significantly shorter for ofloxacin (MD -24.00, 95% CI -41.46 to -6.54, one trial, 91 participants,  Analysis 4.5). There was a statistically significant difference in the median time to fever clearance for gatifloxacin (92 hours vs 138 hours, P <0.0001) and ofloxacin (105 hours vs 201 hours, P <0.0001). This reductions for ofloxacin were also reflected in the shorter length of hospital stay in that group (MD -3.00, 95% CI -4.53 to -1.47, 80 participants, one trial,  Analysis 4.6).

 
Adverse events

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

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

 

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).

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).

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.

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).

 

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)

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).

 
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).

Convalescent faecal carriage was lower in the azithromycin group compared with ofloxacin (RR 13.52, 95% CI 2.64 to 69.36, 193 participants, 2 trials,  Analysis 6.4), but no difference has been shown between ciprofloxacin (64 participants, 1 trial,  Analysis 6.4), or gatifloxacin (268 participants, 1 trial,  Analysis 6.4)

 
Fever clearance time

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

 
Duration of hospitalization

There was a statistically significant reduction in the duration of hospital stay in the ofloxacin group (RR 1.01, 95% CI 0.19 to 1.83, 213 participants, two trials,  Analysis 6.6)

 
Adverse events

No significant difference in serious events has been seen between the ofloxacin with azithromycin groups (88 participants, 1 trial,  Analysis 6.7). Overall, non-serious adverse events were similar across all the trials (564 participants, four trials,  Analysis 6.8).

 

Head to head comparisons of different fluoroquinolones or different durations of treatment

Differences in efficacy between the different fluoroquinolones has not been demonstrated in head to head clinical trials.

The different fluoroquinolones have only been compared as part of multiple arm studies (Morelli 1992 ITA; Rizvi 2007 PAK). In these studies no clinical or microbiological failures, or relapses were seen in the fluoroquinolone treatment arms (see  Analysis 1.1;  Analysis 1.2;  Analysis 1.3).

None of the comparisons demonstrated one duration was 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.

 

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).

 

Comparison 14. Gatifloxacin versus cefixime

Compared to 7-days of cefixime, a 7-day course of gatifloxacin was shown to produce a statistically significant reduction in clinical failure (RR 0.04; 95% CI 0.01 to 0.31, 158 participants, one trial,  Analysis 13.1), and relapse (RR 0.2; 95% CI 0.04 to 0.93, 138 participants, one trial,  Analysis 13.1) in Nepal. There was however no difference in microbiological failure assessed at day 10 (158 participants, one trial,  Analysis 13.1). Gatifloxacin was associated with a statistically significant increase in adverse events (RR 19.25, 95% CI 2.66 to 139.30, 169 participants, one trial,  Analysis 13.1). The events were mainly vomiting and in two cases, this was severe enough to require intravenous fluids.

 

Comparison 15. Gatifloxacin versus azithromycin

No statistically significant difference has been shown in the risk of clinical or microbiological failure, or relapse, between a 7-day course of gatifloxacin and 7 days of azithromycin in Vietnam (287 participants, one trial,  Analysis 14.1). There is also no evidence of a difference in the incidence of adverse events (285 participants, one trial,  Analysis 14.1).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

 

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.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

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.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
Download statistical data

 
Comparison 1. Fluoroquinolone versus chloramphenicol

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ciprofloxacin versus chloramphenicol
4293Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.07, 0.82]

    1.2 Ofloxacin versus chloramphenicol
4249Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.03, 0.64]

    1.3 Pefloxacin versus chloramphenicol
2126Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Gatifloxacin versus chloramphenicol
1352Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.32, 1.96]

 2 Microbiological failure5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Ciprofloxacin versus chloramphenicol
2142Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.81]

    2.2 Ofloxacin versus chloramphenicol
3199Risk Ratio (M-H, Random, 95% CI)0.16 [0.02, 1.07]

    2.3 Pefloxacin versus chloramphenicol
2126Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.4 Gatifloxacin versus chloramphenicol
1352Risk Ratio (M-H, Random, 95% CI)4.94 [0.24, 102.24]

 3 Relapse6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Ciprofloxacin versus chloramphenicol
4292Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.15]

    3.2 Ofloxacin versus chloramphenicol
2149Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.65]

    3.3 Pefloxacin versus chloramphenicol
2126Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.21]

    3.4 Gatifloxacin versus chloramphenicol
1352Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.17, 1.90]

 4 Convalescent faecal carriage3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Ciprofloxacin versus chloramphenicol
150Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.01, 2.89]

    4.2 Ofloxacin versus chloramphenicol
160Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.98]

    4.3 Pefloxacin versus chloramphenicol
2126Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.02, 1.01]

    4.4 Gatifloxacin versus chloramphenicol
1273Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.82]

 5 Fever clearance time3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Ciprofloxacin versus chloramphenicol
2147Mean Difference (IV, Fixed, 95% CI)-62.46 [-75.52, -49.39]

    5.2 Ofloxacin versus chloramphenicol
2140Mean Difference (IV, Fixed, 95% CI)-75.85 [-88.52, -63.17]

 6 Duration of hospitalization2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Ciprofloxacin versus chloramphenicol
155Mean Difference (IV, Fixed, 95% CI)-0.40 [-1.63, 0.83]

    6.2 Ofloxacin versus chloramphenicol
150Mean Difference (IV, Fixed, 95% CI)-9.9 [-11.42, -8.38]

 7 Serious adverse events3203Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.18, 5.52]

    7.1 Ciprofloxacin versus chloramphenicol
2153Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.18, 5.52]

    7.2 Ofloxacin versus chloramphenicol
150Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Non-serious adverse events81410Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.61, 0.94]

    8.1 Ciprofloxacin versus chloramphenicol
4253Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.61, 1.64]

    8.2 Ofloxacin versus chloramphenicol
4207Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.60, 1.87]

    8.3 Pefloxacin versus chloramphenicol
2106Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.69, 2.52]

    8.4 Gatifloxacin versus chloramphenicol
1844Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.44, 0.78]

 
Comparison 2. Fluoroquinolone versus co-trimoxazole

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical Failure3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ciprofloxacin versus co-trimoxazole
2132Risk Ratio (M-H, Fixed, 95% CI)0.06 [0.01, 0.43]

    1.2 Ofloxacin versus co-trimoxazole
189Risk Ratio (M-H, Fixed, 95% CI)0.04 [0.00, 0.59]

    1.3 Pefloxacin versus co-trimoxazole
142Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Microbiological failure3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Ciprofloxacin versus co-trimoxazole
2132Risk Ratio (M-H, Fixed, 95% CI)0.06 [0.01, 0.43]

    2.2 Ofloxacin versus co-trimoxazole
189Risk Ratio (M-H, Fixed, 95% CI)0.04 [0.00, 0.59]

    2.3 Pefloxacin versus co-trimoxazole
142Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Relapse1181Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.1 Ciprofloxacin versus co-trimoxazole
192Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Ofloxacin versus co-trimoxazole
189Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Convalescent faecal carriage142Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Fever clearance time1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 ciprofloxacin versus co-trimoxazole
192Mean Difference (IV, Fixed, 95% CI)-84.0 [-99.72, -68.28]

    5.2 Ofloxacin versus co-trimoxazole
192Mean Difference (IV, Fixed, 95% CI)-96.0 [-115.64, -76.36]

 6 Non serious adverse events3219Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.46, 1.08]

    6.1 Ciprofloxacin versus co-trimoxazole
2110Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.34, 1.12]

    6.2 Ofloxacin versus co-trimoxazole
167Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.46, 1.83]

    6.3 Pefloxacin versus co-trimoxazole
142Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.14, 2.21]

 
Comparison 3. Fluroqunolone versus ampicillin/amoxicillin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure290Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.02, 0.57]

    1.1 Ofloxacin versus ampicillin
140Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.54]

    1.2 Ofloxacin versus amoxicillin
150Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.02, 0.93]

 2 Microbiological failure290Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.03, 0.68]

    2.1 Ofloxacin versus ampicillin/amoxicillin
140Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.60]

    2.2 Ofloxacin versus amoxicillin
150Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.02, 0.93]

 3 Non-serious adverse events290Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.12, 0.93]

    3.1 Ofloxacin versus amoxicillin
290Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.12, 0.93]

 
Comparison 4. Fluoroquinolone versus cefixime

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ciprofloxacin versus cefixime
194Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Ofloxacin versus cefixime
2173Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.02, 1.11]

    1.3 Gatifloxacin versus cefixime
1158Risk Ratio (M-H, Fixed, 95% CI)0.04 [0.01, 0.31]

 2 Microbiological failure3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Ciprofloxacin versus cefixime
194Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Ofloxacin versus cefixime
2173Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 4.66]

    2.3 Gatifloxacin versus cefixime
1158Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.01, 6.43]

 3 Relapse3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Ciprofloxacin versus cefixime
194Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Ofloxacin versus cefixime
2131Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.72]

    3.3 Gatifloxacin versus cefixime
1138Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.04, 0.93]

 4 Convalescent faecal carriage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Gatifloxacin versus cefixime
1147Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.01, 6.40]

 5 Fever clearance time1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Ciprofloxacin versus cefixime
194Mean Difference (IV, Fixed, 95% CI)-12.00 [-24.42, 0.42]

    5.2 Ofloxacin versus cefixime
191Mean Difference (IV, Fixed, 95% CI)-24.0 [-41.46, -6.54]

 6 Duration of hospitalization181Mean Difference (IV, Fixed, 95% CI)-3.0 [-4.53, -1.47]

    6.1 Ofloxacin versus cefixime
181Mean Difference (IV, Fixed, 95% CI)-3.0 [-4.53, -1.47]

 7 Serious adverse Events2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Ofloxacin versus cefixime
182Risk Ratio (M-H, Fixed, 95% CI)3.46 [0.15, 82.56]

    7.2 Gatifloxacin versus cefixime
1169Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.15, 18.11]

 8 Non-serious adverse events2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Ciprofloxacin versus cefixime
194Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.83, 2.95]

    8.2 Ofloxacin versus cefixime
191Risk Ratio (M-H, Fixed, 95% CI)1.70 [0.83, 3.49]

    8.3 Gatifloxacin versus cefixime
1169Risk Ratio (M-H, Fixed, 95% CI)20.92 [2.90, 150.90]

 
Comparison 5. Fluoroquinolone versus ceftriaxone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ciprofloxacin versus ceftriaxone
142Risk Ratio (M-H, Fixed, 95% CI)0.08 [0.01, 1.41]

    1.2 Ofloxacin versus ceftriaxone
147Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 1.46]

 2 Microbiological failure2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Ciprofloxacin versus ceftriaxone
142Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Ofloxacin versus ceftriaxone
147Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 8.80]

 3 Relapse2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Ciprofloxacin versus ceftriaxone
142Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 8.48]

    3.2 Ofloxacin versus ceftriaxone
123Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.02, 8.04]

 4 Convalescent faecal carriage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Ciprofloxacin versus ceftriaxone
142Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.02, 8.48]

 5 Fever clearance time147Mean Difference (IV, Fixed, 95% CI)-113.00 [-150.67, -79.33]

    5.1 Ofloxacin versus ceftriaxone
147Mean Difference (IV, Fixed, 95% CI)-113.00 [-150.67, -79.33]

 6 Non-serious adverse events147Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.06, 5.85]

    6.1 Ofloxacin versus ceftriaxone
147Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.06, 5.85]

 
Comparison 6. Fluoroquinolone versus azithromycin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Ciprofloxacin versus azithromycin
164Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Ofloxacin versus azithromycin
2213Risk Ratio (M-H, Fixed, 95% CI)2.20 [1.23, 3.94]

    1.3 Gatifloxacin versus azithromycin
1287Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.32, 2.96]

 2 Microbiological failure4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Ciprofloxacin versus azithromycin
164Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Ofloxacin versus azithromycin
2213Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.30, 5.76]

    2.3 Gatifloxacin versus azithromycin
1285Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.11, 3.79]

 3 Relapse4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Ciprofloxacin versus azithromycin
164Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Ofloxacin versus azithromycin
2163Risk Ratio (M-H, Fixed, 95% CI)6.11 [0.31, 119.33]

    3.3 Gatifloxacin versus azithromycin
1264Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 2.20]

 4 Convalescent faecal carriage4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Ciprofloxacin versus azithromycin
164Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Ofloxacin versus azithromycin
2193Risk Ratio (M-H, Fixed, 95% CI)13.52 [2.64, 69.36]

    4.3 Gatifloxacin versus azithromycin
1268Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.12, 69.82]

 5 Fever clearance time3Mean Difference (IV, Random, 95% CI)Subtotals only

    5.1 Ciprofloxacin versus azithromycin
164Mean Difference (IV, Random, 95% CI)-12.0 [-24.39, 0.39]

    5.2 Ofloxacin versus azithromycin
2213Mean Difference (IV, Random, 95% CI)30.41 [-22.12, 82.93]

 6 Duration of Hospitalization2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Ofloxacin versus azithromycin
2213Mean Difference (IV, Fixed, 95% CI)1.01 [0.19, 1.83]

 7 Serious adverse events188Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.06, 15.49]

    7.1 Ofloxacin versus azithromycin
188Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.06, 15.49]

 8 Non-serious adverse events4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Ciprofloxacin versus azithromycin
164Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.73, 1.99]

    8.2 Ofloxacin versus azithromycin
2213Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.27, 1.16]

    8.3 Gatifloxain versus azithromycin
1287Risk Ratio (M-H, Fixed, 95% CI)1.96 [0.18, 21.36]

 
Comparison 7. Fluoroquinolone 2 days vs 3 days

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical failure3396Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.54, 2.53]

 2 Microbiological failure2296Risk Ratio (M-H, Fixed, 95% CI)1.94 [0.44, 8.47]

 3 Relapse3312Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.14, 2.97]

 4 Convalecsent faecal carriage2262Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.01, 7.45]

 5 Fever clearance time3396Mean Difference (IV, Fixed, 95% CI)-5.41 [-14.59, 3.78]

 6 Duration of hospitalization3396Mean Difference (IV, Fixed, 95% CI)-0.33 [-0.73, 0.06]

 7 Serious adverse events3396Risk Ratio (M-H, Fixed, 95% CI)2.40 [0.22, 26.08]

 8 Non-serious adverse events2296Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.01, 3.61]

 
Comparison 8. Fluoroquinolone 3 days vs 5 days

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse1154Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.65]

 2 Fever Clearance time1195Mean Difference (IV, Fixed, 95% CI)-12.0 [-18.07, -5.93]

 3 Non-serious adverse events1425Risk Ratio (M-H, Fixed, 95% CI)1.73 [0.74, 4.03]

 
Comparison 9. Fluoroquinolone 5 days vs 7 days

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Microbiological Failure146Risk Ratio (M-H, Fixed, 95% CI)3.26 [0.14, 76.10]

 2 Relapse146Risk Ratio (M-H, Fixed, 95% CI)3.26 [0.14, 76.10]

 3 Fever clearance time146Mean Difference (IV, Fixed, 95% CI)-7.20 [-7.78, -6.62]

 4 Non-serious adverse events146Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.21, 3.25]

 
Comparison 10. Fluoroquinolone 7 days vs 10 days

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Microbiological failure130Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Relapse130Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All outcomes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Clinical failure (need for rescue medication or persistence of fever until day 10)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Microbiological failure (blood culture +ve on day 8)
1Risk 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)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Convalescent faecal carriage
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   1.5 Serious adverse events
0Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.6 Other adverse events (selected gastrointestinal adverse events)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 12. Fluoroquinolone 10 days vs 14 days

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Relapse169Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.01, 3.91]

 2 Fever clearance time169Mean Difference (IV, Fixed, 95% CI)-16.80 [-42.65, 9.05]

 3 Non-serious adverse events169Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.15, 1.27]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All outcomes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Clinical failure (need for rescue medication or persistence of fever until day 7)
1Risk 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)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Microbiological failure (blood culture +ve on day 10)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Serious adverse events
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.5 Other adverse events (may be incompletely reported)
1Risk 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 titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All outcomes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Clinical failure (need for rescue medication of persistence of fever until day 10)
1Risk 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)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Microbiological failure (blood culture +ve on day 7 to 9)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Convalescent faecal carriage
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   1.5 Serious adverse events
0Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.6 Other adverse events (may be incompletely reported)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
 

Appendix 1. Detailed Search Strategy


Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb

1typhoid feverfluoroquinoloneQUINOLINESQUINOLONE DERIVED ANTIINFECTIVE AGENTtyphoid

2enteric feveramifloxacinQUINOLONESfluoroquinolonestyphoid fever

3paratyphoid feverbalofloxacinANTI-INFECTIVE AGENTS, QUINOLONEamifloxacinenteric fever

4Salmonella typhicetefloxacinANTI-INFECTIVE AGENTS, FLUOROQUINOLONEBALOFLOXACINSalmonella typhi

5Salmonella paratyphiciprofloxacinFLUOROQUINOLONESbalofloxacinSalmonella paratyphi

6clinafloxacinfluoroquinolonesCETEFLOXACIN

7enoxacinamifloxacincetefloxacin

8fleroxacinbalofloxacinCIPROFLOXACIN

9gatifloxacincetefloxacinciprofloxacin

10gemifloxacinCIPROFLOXACINCLINAFLOXACIN

11grepafloxacinciprofloxacinclinafloxacin

12irloxacinclinafloxacinENOXACIN

13levofloxacinENOXACINenoxacin

14lomefloxacinenoxacinFLEROXACIN

15moxifloxacinFLEROXACINfleroxacin

16nordifloxacinfleroxacinGATIFLOXACIN

17norfleroxacingatifloxacingatifloxacin

18norfloxacingemifloxacinGEMIFLOXACIN

19ofloxacingrepafloxacingemifloxacin

20oxociprofloxacinirloxacinGREPAFLOXACIN

21pefloxacinlevofloxacingrepafloxacin

22premafloxacinlomefloxacinIRLOXACIN

23prulifloxacinmoxifloxacinirloxacin

24rufloxacinnordifloxacinLEVOFLOXACIN

25sitafloxacinnorfleroxacinlevofloxacin

26sparfloxacinNORFLOXACINLOMEFLOXACIN

27temafloxacinnorfloxacinlomefloxacin

28tosufloxacinofloxacinMOXIFLOXACIN

29trovafloxacinoxociprofloxacinmoxifloxacin

301/29 - ORPEFLOXACINNORDIFLOXACIN

31typhoid feverpefloxacinnordifloxacin

32enteric feverpremafloxacinNORFLEROXACIN

33paratyphoid feverprulifloxacinnorfleroxacin

34Salmonella typhirufloxacinNORFLOXACIN

35Salmonella paratyphisitafloxacinnorfloxacin

3631/35 - ORsparfloxacinOFLOXACIN

3730 and 36temafloxacinofloxacin

38tosufloxacinOXOCIPROFLOXACIN

39trovafloxacinoxociprofloxacin

401 - 39/ORPEFLOXACIN

41TYPHOID FEVERpefloxacin

42typhoid feverPREMAFLOXACIN

43enteric feverpremafloxacin

44PARATYPHOID FEVERPRULIFLOXACIN

45paratyphoid feverprulifloxacin

46SALMONELLA TYPHIRUFLOXACIN

47Salmonella typhirufloxacin

48SALMONELLA PARATYPHISITAFLOXACIN

49Salmonella paratyphisitafloxacin

50typhusSPARFLOXACIN

5141 - 50/ORsparfloxacin

5240 and 51TEMAFLOXACIN

53limit 52 to humantemafloxacin

54tosufloxacin

551 - 54/OR

56TYPHOID FEVER

57typhoid fever

58enteric fever

59PARATYPHOID FEVER

60paratyphoid fever

61SALMONELLA TYPHI

62Salmonella typhi

63SALMONELLA PARATYPHI

64Salmonella paratyphi

65typhus

6656 - 65/OR

6755 and 66

68limit 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


ComparisonTrialParticipantsCulture positive (site)S. Typhi/ParatyphiNumber (%)a with MDRMDR defined asbNumber (%*)a NaRcNotes on resistance

Fluoroquinolone vs chloramphenicolCristiano 1995 ITA60 enrolled and randomized60 (blood)60/0

Fluoroquinolone: 30

Chloramphenicol: 30
0Not stated

No resistance to chloramphenicol, ampicillin, or co-trimoxazole
Not stated

MIC range of pefloxacin was < 0.016 to 0.5

Gasem 2003 IDN100 enrolled and randomized55 (blood and/or bone marrow)50/50Not stated

No resistance to chloramphenicol

12.8% resistant to ampicillin or co-trimoxazole
Not stated

MIC range of ciprofloxacin was < 1

Arjyal 2011853 enrolled and randomized352 (blood)124/53 Fluoroquinolone

125/50

Chloramphenicol
2(0.58%) both in the gatifloxacin armResistance to all first line antibiotics: chloramphenicol, amoxicillin and trimethoprim-sulphamethoxazole251(72.2%)Two S. Paratyphi isolates were chloramphenicol resistant.

Gottuzzo 1992 N/ANot stated98 (not stated)Not statedNot statedNot statedNot stated

Morelli 1992 ITA156 enrolled and randomized156 (blood)156/00Not 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 LAO107 enrolled and randomized50 (blood)50/0

Fluoroquinolone: 27

Chloramphenicol: 23
3/50 (6%)

Fluoroquinolone: 1/27

Chloramphenicol: 2/23
Resistant to all 3 (chloramphenicol, ampicillin, co-trimoxazole)0Chloramphenicol 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 PAK85 enrolled and randomized85 (not stated)Not statedNot statedNot statedNot stated

Fluoroquinolone vs ampicillinFlores 1994 MEXNot stated40 (not stated)40/0

Fluoroquinolone: 20

Ampicillin: 20
Not statedNot statedNot stated

Fluoroquinolone vs co-trimoxazoleHajji 1988 MAR77 enrolled and randomized42 (blood and/or stool)28/4 (from blood culture)0Not stated

1 isolate resistant to co-trimoxazole was in pefloxacin group
0

Limson 1989 PHL53 enrolled and randomized40 (blood)28/12

Fluoroquinolone: 15/5

Co-trimoxazole: 13/7
0Not stated

No resistance to co-trimoxazole

16 were resistant to chloramphenicol
Not stated

Fluoroquinolone vs azithromycinDolecek 2008 VNM358 enrolled and randomized288 (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 VNM97 enrolled and randomized91 (blood)86/268 (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 EGY123 enrolled and randomized64 (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 VNM160 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 cefiximePhuong 1999 VNM138 enrolled and randomized82 (blood)82/0

Fluoroquinolone: 38

Cefixime: 44
70 (85%)

S. Typhi: 32

S. Paratyphi: 38
Resistant to all 3 (chloramphenicol, ampicillin, co-trimoxazole) and tetracycline0

Pandit 2007 NPL390 enrolled and randomized169 (blood)119/50

Fluoroquinolone: 65/27

Cefixime: 54/23
0Resistant to all 3 (chloramphenicol, ampicillin, co-trimoxazole)136/163 (83%)

Fluoroquinolone: 71/89

Cefixime: 65/74

Fluoroquinolone vs ceftriaxoneSmith 1994 VNM60 enrolled and randomized47 (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 tetracycline0

Wallace 1993 BHR43 enrolled and 42 randomized42 (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 fluoroquinoloneAlam 1995 BGD76 enrolled and randomized72 (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. Paratyphi5/69 (7%)

Fluoroquinolone 10-day: 2

Fluoroquinolone 14-day: 3

(derived from data presented for MIC for ciprofloxacin)

Kalo 1997 ALB30 (ampicillin-resistant) enrolled and randomized30 (blood)30/012/30 (40%)Resistant to all 3 (chloramphenicol, ampicillin, co-trimoxazole)Not stated

Chinh 1997 VNM107 enrolled and randomized101 (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 tetracycline5/95 (5%)

Fluoroquinolone 2-day: 1

Fluoroquinolone 3-day: 4

Tran 1995 VNM438 enrolled, 425 randomized228 (blood)207/19
(2 other Salmonella)
189

Fluoroquinolone 3-day: 98

Fluoroquinolone 5-day: 91
Resistant to standard antibioticsFew NaR strains present, number not stated

Unal 1996 TUR46 randomized46 (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 VNM108 enrolled and randomized100 (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 tetracycline13 (13%)

Fluoroquinolone 2-day: 6

Fluoroquinolone 3-day: 7

Vinh 2005 VNM235 enrolled and randomized202 (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


ComparisonSpecific FQTrialClinical failureMicrobiological failureRelapseFever clearance timeConvalescent Faecal Carriage

Fluoroquinolones vs chloramphenicolCiprofloxacinGasem 2003 IDNNot afebrile within 7 days of treatmentBlood culture positive at days 3 and 5Reappearance 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 hoursOutcome not reported

CiprofloxacinGottuzzo 1992 N/A"One participant who developed a gastrointestinal bleed in first 36 hours of treatment was considered a failure"Outcome not reportedNot definedOutcome not reportedOutcome not reported

CiprofloxacinMorelli 1992 ITAPersistence of feverOutcome not reportedNot definedNot defined3 weeks during follow up

Ciprofloxacin and Ofloxacin and

Cotrimoxazole
Rizvi 2007 PAKNo significant response to therapyPersistence of S. Typhi and S. Paratyphi on day 7 or 14 or recurrence of the initial pathogen at the end of treatmentReapperance 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 definedNot reported

OfloxacinPhongmany 2005 LAOContinuation 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 diseaseOutcome not reportedOutcome not reportedTime 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

PefloxacinCristiano 1995 ITANot definedBlood 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 defined30 days

GatifloxacinArjyal 2011Not specifically defined but denoted as part of composite end point of treatment failurePositive blood culture for S.Typhi or S.Paratyphi A on day 8Reappearance of culture confirmed or syndromic enteric fever on or after day 11 to day 31 in patients who were initially categorized as successfully treatedTime 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 hoursFaecal carriage at the follow up visits at 1, 3 and 6 months.

Fluoroquinolone vs ampicillinOfloxacinFlores 1994 MEXPersistence 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 treatmentOutcome not reportedOutcome not reportedOutcome not reported

Yousaf 1992 PAKPersistence or reappearance of all presenting signs and symptoms or increase in severity of at least 1 sign or symptom or bothPersistence of baseline pathogen at day 14Outcome not reportedOutcome not reportedOutcome not reported

Fluoroquinolone vs co-trimoxazolePefloxacinHajji 1988 MARFever and presence of clinical symptoms and positive culturesPositive cultures at days 4, 15, and 30Reappearance of fever, clinical symptoms, and/or bacteraemia at days 4, 15, and 30Time for rectal temperature to be sustained ≤ 37.5 °C for ≥ 2 days30 days

CiprofloxacinLimson 1989 PHLPersistent fever or no improvement in symptoms after 5 days of therapyPositive cultures during and after therapyOutcome not reportedOutcome not reportedOutcome not reported

Fluoroquinolone vs azithromycinGatifloxacinDolecek 2008 VNMPersistence of fever and symptoms 2 days after the end of treatment, i.e. on day 10Positive blood culture on day 7 to 9 after the start of treatmentSymptoms 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 hoursFollow ups at 1, 3, and 6 months; participants who attended at least 2 consecutive follow-up visits were evaluated

CiprofloxacinChinh 2000 VNMPersistence 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 treatmentIsolation of S. Typhi/S. Paratyphi from blood or other sterile site after completion of treatmentRecurrence of signs and symptoms suggestive of enteric fever after discharge at 4 to 6 weeks of follow upTime from start of treatment until body temperature fell < 37.5 °C and remained at ≤ 37.5 °C for 48 hoursDays 2 to 3 after end of treatment

CiprofloxacinGirgis 1999 EGYLack of resolution of symptoms by day 7 or development of major complications of typhoid fever after 5 days of therapyBlood culture positive for S. Typhi/S. Paratyphi on day 10Recurrence of fever with signs/symptoms of typhoid fever in 4 weeks of therapy completion and culture positiveFirst day on which maximum temperature ≤ 38 °C and at this level for ≥ 48 hours1 month

CiprofloxacinParry 2007 VNMPresence 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 therapyIsolation of S. Typhi or S. Paratyphi from blood or sterile site after completion of treatmentRecurrence 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. ParatyphiTime from start of treatment until body temperature reached ≤ 37.5 °C and remained at this for 48 hoursAfter end of initial 7-day treatment and before hospital discharge (with isolate having the same susceptibility pattern as original isolate)

Fluoroquinolone vs cefiximeOfloxacinPhuong 1999 VNMDeterioration in clinical condition or failure of resolution of symptoms requiring further treatmentBlood culture positive for S. Typhi after completion of treatmentSymptoms suggestive of typhoid fever with a positive blood or bone marrow culture up to 4 weeks after dischargeTime from onset of treatment until fever was 37.5 °C or below for at least 24 hours1 month mostly, few seen after a longer period

GatifloxacinPandit 2007 NPLAny severe complication, persistence of fever (> 38 °C), persistence of symptoms for > 7 days after start of treatment, requiring additional or rescue treatmentBlood culture positive on day 10Fever 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 hours1 month

Fluoroquinolone vs ceftriaxoneOfloxacinSmith 1994 VNMAcute treatment failure as continuing symptoms and fever for at least 7 days after starting the treatment regimenBlood culture positive at day 8Recurrence of fever and symptoms in the period up to 6 weeks after discharge with a positive blood or bone marrow culture bTime to defervescence to < 37.5 °C for at least 48 hours4 to 6 weeks

CiprofloxacinWallace 1993 BHRFever > 38 °C after 7 days of therapy or who deteriorated clinically after 5 full daysBlood culture positive at day 3Readmission 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 definedDays 1, 7, and 28; results unclear

Different durations of fluoroquinolonesAlam 1995 BGDLack of improvement or deterioration in clinical condition during treatmentGrowth 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 cureTime to return of oral temperature to ≤ 37.5 °C after initiation of therapy and remained so for at least 48 hoursSecond follow up (at 2 months)

Kalo 1997 ALBFever at day 5Blood culture positive at day 4Relapse during hospitalization and 2 month follow upOutcome not reportedDays 7 to 12

Chinh 1997 VNMContinuing fever and symptoms for 7 days after the start of treatment or deterioration in clinical condition before 7 days that warranted further treatmentBlood or bone marrow culture positive after end of treatment before dischargeRecurrent fever and symptoms with bone marrow or blood culture positive mostly up to 6 weeks after discharge bTime at which fever fell below 37.5 °C for at least 24 hoursUsually 6 weeks (occasionally up to 12 weeks)

Tran 1995 VNMPersistent fever and symptoms for > 7 days after start of treatmentBlood or bone marrow culture positive after end of treatmentSymptoms since study with positive blood cultureNot defined1 month

Unal 1996 TURContinued or worsening symptoms after 7 days of therapyFailure to eradicate organismSimilar 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 hours1 month; results unclear

Vinh 1996 VNMContinued fever and symptoms for > 7 days after treatmentPositive blood culture or bone marrow culture for S. Typhi taken > 48 hours after the last dose of treatmentRecurrence of fever and symptoms with positive blood or bone marrow culture up to 6 weeks (26 participants followed up to 12 weeks) after dischargeTime from start of treatment until axillary temperature fell below 37.5 °C and remained below this level for > 48 hours4 to 6 weeks (for 66 participants); and at 3 months (for 26 participants)

Vinh 2005 VNMFever and symptoms persisting for ≥ 7 days after start of therapy, or development of severe or complicated diseaseBlood culture positive for same organism between 7 to 28 days after completion of therapyRecurrence 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 hoursImmediately 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


ComparisonTrialInterventionControl

Fluoroquinolone vs chloramphenicolYousaf 1992 PAKNone reportedNone reported

Gottuzzo 1992 N/AGastrointestinal bleeding(1)Severe leukopenia(1)

Cristiano 1995 ITASkin rash (1)None

Morelli 1992 ITACiprofloxacin: Rash (2)

Pefloxacin: Rash (2)
None

Gasem 2003 IDNCiprofloxacin: NoneChloramphenicol: Intestinal bleeding (1 participant)

Rash (1)

Phongmany 2005 LAONoneNone

Rizvi 2007 PAKCiprofloxacin: palpitation (1) ????

Ofloxacin: palpitation (2)
palpitation (1)

Arjyal 2011noneOral candidiasis (4)

Fluoroquinolone vs co-trimoxazoleHajji 1988 MARPefloxacin: Phototoxicity (1)Rash (1)

Limson 1989 PHLNoneNone

Fluoroquinolone vs ampicillin/amoxicillinYousaf 1992 PAKNone reportedNone reported

Flores 1994 MEXNone reportedNone reported

Fluoroquinolone vs cefiximePhuong 1999 VNMOfloxacin: Death (1)None

Pandit 2007 NPLExcessive vomiting requiring

intravenous therapy(1)
Death(1)

Fluoroquinolone vs ceftriaxoneWallace 1993 BHRNot reportedNot reported

Smith 1994 VNMNone reportedNone reported

Fluoroquinolone vs azithromycinChinh 2000 VNMGastrointestinal bleeding (1 participant)Gastrointestinal bleeding (1 participant)

Dolecek 2008 VNMGastrointestinal bleeding (4 participants)

Rash (1)
None

Girgis 1999 EGYNoneNone

Parry 2007 VNMNoneNone



 

Appendix 5. Non-serious adverse events


ComparisonTrialClinical adverse events aLaboratory adverse events a


InterventionControlInterventionControl

Fluoroquinolone vs chloramphenicolYousaf 1992 PAK3 reported adverse events. No specific event4 reported adverse events. No specific eventNone reportedNone reported

Gottuzzo 1992 N/ARash (1)NoneNoneleukopenia (11)

Cristiano 1995 ITANausea (3), mild and transient epigastric pain (3), transient skin rash (1)Mild and transient epigastric pain (5)NoneNone

Morelli 1992 ITACiprofloxacin: 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 reportednot reported

Gasem 2003 IDNNoneskin rash (1)None reportedNone reported

Phongmany 2005 LAONone reportedNone reportedNone reportedNone reported

Rizvi 2007 PAKCiprofloxcin: 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 reportedNone reported

Arjyal 2011Number 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 cotrimoxazoleHajji 1988 MARPhotosensitivity (1)Generalized rash (1)Mild and transient rise in transaminases (2)Mild and transient rise in transaminases (3)

Limson 1989 PHLCiprofloxacin

Abdominal discomfort/diarrhoea (1)

Dizziness (1)
Cotrimoxazole: nausea or abdominal discomfort (5)

Pruritus (1)
NoneNone

Fluoroquinolone vs ampicillin/amoxicillinYousaf 1992 PAK3 reported adverse events. No specific event11 events reported to be mostly diarrhoea, pruritus and rashesNone reportedNone reported

Flores 1994 MEXModerate nausea (1)Epigastric pain (1)None reportedNone reported

Fluoroquinolone vs cefiximePhuong 1999 VNMNot reportedNot reportedNot reportedNot reported

Pandit 2007 NPLNausea/occasional vomiting (23)Erythematous skin rash(1)NoneNone

Fluoroquinolone vs ceftriaxoneWallace 1993 BHRNot reportedNot reportedNot reportedNot reported

Smith 1994 VNMPruritus (1)skin rashes (2)NoneNone

Fluoroquinolone vs azithromycinChinh 2000 VNMOfloxacin: 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 levelsAzithromycin: mild elevation in mean transaminase levels

Dolecek 2008 VNMGatifloxacin: vomiting (1); Diarrhoea (1)Azithromycin: jaundice (2)Gatifloxacin: mild elevations in median transaminase levelsAzithromycin: mild elevations in median transaminase levels

Girgis 1999 EGYCiprofloxacin: 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 VNMOfloxacin: joint discomfortAzithromycin: joint discomfort (1)Ofloxacin: noneAzithromycin: none

Fluoroquinolones 2days vs 3daysChinh 1997 VNM2D: none3D: none2D: none3D: none

Vinh 1996 VNM2D: none3D: none2D: none3D: none

Vinh 2005 VNM2D: none3D: none2D: no significant increases in liver enzymes3D: no significant increases in liver enzymes

Fluoroquinolone 3days vs 5daysTran 1995 VNM3D: Insomnia (5), dizziness (5) epigastric pain (2), nausea (1), headache (1)5D: Insomnia (5), dizziness (1) vomiting (1), rash (1)3D: none5D: none

Fluoroquinolone 5days vs 7daysUnal 1996 TUR5D: Nausea and vomiting (3)7D: Nausea and vomiting (3)5D: None7D: Increased transaminase levels (1)

Fluoroquinolone 7days vs 10daysKalo 1997 ALB7D Nausea/abdominal discomfort10D: Nausea/ abdominal discomfortd7D: None10D:None

Fluoroquinolone 10days vs 14 daysAlam 1995 BGD10D: Eleven events occurred in four patients namely headache, malaise, dizziness, insomnia, skin rash, pruritus, lethargy, weakness14D: 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

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

Last assessed as up-to-date: 1 February 2011.


DateEventDescription

5 October 2011AmendedAmendment made to acknowledgements



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

Protocol first published: Issue 4, 2003
Review first published: Issue 2, 2005


DateEventDescription

9 August 2011New citation required and conclusions have changedA 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.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

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.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

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

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms
 

Internal sources

  • University of Calabar Teaching Hospital, Calabar, Nigeria.
  • Nigeria branch of South African Cochrane centre, Nigeria.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

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

 

Notes

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Notes
  18. Index terms

The Contact Editor for this review was Dr Mical Paul.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
  25. References to other published versions of this review
Alam 1995 BGD {published data only}
  • Alam MN, Haq SA, Das KK, Baral PK, Mazid MN, Siddique RU, et al. Efficacy of ciprofloxacin in enteric fever: comparison of treatment duration in sensitive and multidrug resistant salmonella. American Journal of Tropical Medicine and Hygiene 1995;53(3):306-11.
Arjyal 2011 {published data only}
  • Arjyal A, Basnyat B, Koirala S, Karkey A, Dongol S, Agrawaal KK, Shakya N, Shrestha K, Sharma M, Lama S, Shrestha K, Khatri NS, Shrestha U, Campbell JI, Baker S, Farrar J, Wolbers M, Dolecek C. Gatifloxacin versus choramphenicol: An open, randomized controlled trial in the treatment of uncomplicated enteric fever. Lancet Infect Dis 2011;11(6):445-454.
Chinh 1997 VNM {published data only}
  • Chinh NT, Solomon T, Mai XT, Nguyen TL, Nguyen TT, Wain J, et al. Short courses of ofloxacin for the treatment of enteric fever. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91(3):347-9.
Chinh 2000 VNM {published data only}
  • Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, et al. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrobial agents and chemotherapy 2000;44(7):1855-9.
Cristiano 1995 ITA {published data only}
Dolecek 2008 VNM {published data only}
  • Dolecek C, La TTP, Rang NN, Phuong LT, Tuan PQ, DU DC, et al. A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid and paratyphoid fever in children and adults in Vietnam. PLoS ONE 2008;3(5):e2188.
Flores 1994 MEX {published data only}
  • Flores GR, Dorantes F, Aviles J. Safety and efficacy of oral ofloxacin vs oral ampicillin in the management of typhoid. Investigacion Medica Internacional 1994;21(2):88-92.
Gasem 2003 IDN {published data only}
  • Gasem MH, Keuter M, Dolmans WM, Van Der Ven-Jongekrijg J, Djokomoeljanto R, Van Der Meer JW. Persistence of Salmonellae in blood and bone marrow: randomized controlled trial comparing ciprofloxacin and chloramphenicol treatments against enteric fever. Antimicrobial Agents and Chemotherapy 2003;47(5):1727-31.
Girgis 1999 EGY {published data only}
  • Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM, Tribble D, et al. Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrobial Agents And Chemotherapy 1999;43(6):1441-4.
Gottuzzo 1992 N/A {published data only}
  • Gottuzzo E, Carillo C. Typhoid fever. Evaluation of the efficacy and safety of ciprofloxacin in comparison with chloramphenicol. In: HL Dupont editor(s). Use of quinolones in travel medicine. Second Conference on International Travel Medicine, Atlanta, Georgia 1991. Berlin, Germany: Springer-Verlag, 1992:16-22.
Hajji 1988 MAR {published data only}
  • Hajji M, el Mdaghri N, Benbachir M, el Filali KM, Himmich H. Prospective randomized comparative trial of pefloxacin versus cotrimoxazole in the treatment of typhoid fever in adults. European Journal of Clinical Microbiology and Infectious Diseases 1988;7(3):361-3.
Kalo 1997 ALB {published data only}
  • Kalo T, Davachi F, Nushi A, Dedja S, Karapici L, Como N, et al. Therapeutic efficacy of perfloxacin in treatment of ampicillin-resistant typhoid fever in 7 days versus 10 days. International Journal of Infectious Diseases 1997;2(1):12-4.
Limson 1989 PHL {published data only}
Morelli 1992 ITA {published data only}
  • Morelli G, Mazzoli S, Tortoli E, Simonetti MT, Perruna F, Postiglione A. Fluoroquinolones versus chloramphenicol in the therapy of typhoid fever: a clinical and microbiological study. Current Therapeutic Research 1992;52(4):532-42.
Pandit 2007 NPL {published data only}
  • Pandit, A, Arjyal, A, Day JN, Paudyal B, et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS ONE 2007;2(6):e542.
Parry 2007 VNM {published data only}
  • Parry CM, Ho VA, Phuong le T, Bay PV, Lanh MN, Tung le T, et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrobial Agents Chemotherapy 2007;51(3):819-25.
Phongmany 2005 LAO {published data only}
  • Phongmany S, Phetsouvanh R, Sisouphone S, Darasavath C, Vongphachane P, Rattanavong O, et al. A randomized comparison of oral chloramphenicol versus ofloxacin in the treatment of uncomplicated typhoid fever in Laos. Transactions of the Royal Society of Tropical Medicine and Hygiene 2005;99(6):451-8.
Phuong 1999 VNM {published data only}
  • Phuong CXT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group. Pediatric Infectious Disease Journal 1999;18(3):245-8.
Rizvi 2007 PAK {published data only}
  • Rizvi Q. Effeciveness of anti-typhoid drugs currently used in Pakistan. Pakistan Journal of Surgery 2007;23(1):57-64.
Smith 1994 VNM {published data only}
  • Smith MD, Duong NM, Hoa NT, Wain J, Ha HD, Diep TS, et al. Comparison of ofloxacin and ceftriaxone for short-course treatment of enteric fever. Antimicrobial Agents and Chemotherapy 1994;38(8):1716-20.
Tran 1995 VNM {published data only}
  • Tran TH, Bethell DB, Nguyen TT, Wain J, To SD, Le TP, et al. Short course of ofloxacin for treatment of multidrug-resistant typhoid. Clinical Infectious Diseases 1995;20(4):917-23.
Unal 1996 TUR {published data only}
  • Unal S, Hayran M, Tuncer S, Gur D, Uzun O, Akova M, et al. Treatment of enteric fever with pefloxacin for 7 days versus 5 days: a randomized clinical trial. Antimicrobial Agents and Chemotherapy 1996;40(12):2898-900.
Vinh 1996 VNM {published data only}
  • Vinh H, Wain J, Vo TN, Cao NN, Mai TC, Bethell D, et al. Two or three days of ofloxacin treatment for uncomplicated multidrug-resistant typhoid fever in children. Antimicrobial Agents and Chemotherapy 1996;40(4):958-61.
Vinh 2005 VNM {published data only}
  • Vinh H, Duong NM, Phuong lT, Truong NT, Bay PV, Wain J, et al. Comparative trial of short-course ofloxacin for uncomplicated typhoid fever in Vietnamese children. Annals of Tropical Paediatrics 2005;25(1):17-22.
Wallace 1993 BHR {published data only}
  • Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall EJ, Rowe B, et al. Ciprofloxacin versus ceftriaxone in the treatment of multiresistant typhoid fever. European Journal of Clinical Microbiology and Infectious Diseases 1993;12(12):907-10.
Yousaf 1992 PAK {published data only}
  • Yousaf MH, Hasnain SS, Mohsin A, Ara N. A comparative study of efficacy and safety of three antimicrobials in the treatment of enteric fever. Pakistan Journal of Gastroenterology 1992;6(2):46-8.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
  25. References to other published versions of this review
Abejar 1993 {published data only}
  • Abejar NH, Dimaano EM, Cabanban AB. Fleroxacin versus chloramphenicol in enteric fever. An open, randomized, parallel study. Philippine Journal of Internal Medicine 1993;31(6):327-30.
Agalar 1997 {published data only}
  • Agalar C, Usubutun S, Tutuncu E, Turkyilmaz R. Comparison of two regimens for ciprofloxacin treatment of enteric infections. European Journal of Clinical Microbiology and Infectious Diseases 1997;16(11):803-6.
Akhtar 1989 {published data only}
  • Akhtar MA, Karamat KA, Malik AZ, Hashmi A, Khan QM, Rasheed P. Efficacy of ofloxacin in typhoid fever, particularly in drug resistant cases. Reviews of Infectious Diseases 1989;2 Suppl 5:1193.
Akhtar 1992 {published data only}
  • Akhtar MA, Hussain A, Karamat KA, Naqi N, Zubdi N. Role of ciprofloxacin in typhoid fever. Journal of Pakistan Medical Association 1992;42(1):9-10.
Arnold 1993 {published data only}
  • Arnold K, Hong C, Nelwan R, Trujillo Z, Kadio A, Barros M, et al. Randomized comparative study of fleroxacin and chloramphenicol in typhoid fever. American Journal of Medicine 1993;94(3A):195S-200S.
Bai 1995 {published data only}
  • Bai YM, Lin JB, Duan MT, Zhang Y, Liang B. Comparison of therapeutic effect of enoxacin and norfloxacin in the treatment of typhoid fever. Zhonghua Chuan Ran Bing Za Zhi [Chinese Journal of Infectious Diseases] 1995;13(2):117-8.
Bavdekar 1991 {published data only}
  • Bavdekar A, Chaudhari M, Bhave S, Pandit A. Ciprofloxacin in typhoid fever. Indian Journal Pediatrics 1991;58(3):335-9.
Bethell 1996 {published data only}
  • Bethell DB, Day NP, Dung NM, McMullin C, Loan HT, Tam DT, et al. Pharmacokinetics of oral and intravenous ofloxacin in children with multidrug-resistant typhoid fever. Antimicrobial Agents and Chemotherapy 1996;40(9):2167-72.
Chakravorty 1991 {published data only}
  • Chakravorty B, Jain N, Gupta B, Rajvanshi P, Sen MK, Krishna A. Chloramphenicol resistant enteric fever. Journal of Indian Medical Association 1993;91(1):10-13.
Chukwani 1998 {published data only}
  • Chukwani CM, Onyemelukwe GC, Okonkwo PO, Coker HAB, Ifudu ND. Fleroxacin vs ciprofloxacin in the management of typhoid fever. Clinical Drugs Investigation 1998;16(4):279-88.
Daga 1994 {published data only}
  • Daga MK, Sarin K, Sarkar R. A study of culture positive multidrug resistant enteric fever - changing pattern and emerging resistance to ciprofloxacin. Journal of the Association of Physicians of India 1994;42(8):599-600.
Duong 1995 {published data only}
  • Duong NM, Chau NVV, Anh DCV, Hoa NTT, Tam DTH, Hai DT, et al. Short course fleroxacin in the treatment of typhoid fever. JAMA Southeast Asia 1995;11 Suppl:21-5.
Hou 1993 {published data only}
  • Hou SR. Clinical study of Chinese ofloxacin. Zhonghua Yi Xue Za Zhi 1993;73(4):255-6.
Huai 2000 {published data only}
  • Huai Y, Zhu Q, Wang X. Ceftriaxone vs. norfloxacin in the treatment of resistant typhoid fever in 60 children. Zhonghua Er Ke Za Zhi [Chinese Journal of Pediatrics] 2000;38(6):386-8.
Jia 1994 {published data only}
  • Jia FZ, Zhu JQ, Huang SY, Chen HK, Bai JY, Li ZC, et al. Clinical study on therapy of typhoid fever with pefloxacin. Zhonghua Chuan Ran Bing Za Zhi [Chinese Journal of Infectious Diseases] 1994;12 Suppl 3:134-6.
Jinlong 1998 {published data only}
  • Jinlong Z, Wennan H, Guosheng M, Zhigang H, Jianping Z. Evaluation of effectiveness of ofloxacin and S-(-) ofloxacin in treating typhoid fever. Zhonghua Chuan Ran Bing Za Zhi [Chinese Journal of Infectious Diseases] 1998;16(4):237.
Kumar 2007 {published data only}
Liberti 2000 {published data only}
Lu 1995 {published data only}
  • Lu Y, Zhang H, Mu G, Qiu D, Hu P. Clinical study of intravenous enoxacin versus cefotaxime in aute [sic] infectious diseases. Zhongguo Kang Sheng Su Za Zhi [Chinese Journal of Antibiotics] 1995;20(2):123-8.
Nalin 1987 {published data only}
  • Nalin DR, Hoagland VL, Acuna G, Bran JL, Carrilo C, Gotuzzo E, et al. Clinical trial of norfloxacin versus chloramphenicol therapy for acute typhoid fever. Progress in antimicrobial and anti-cancer chemotherapy. Proceedings of the 15th International Congress of Chemotherapy; 1987 July 19-24; Istanbul. Copenhagen, Munksgaard, 1987:1174-5.
Nelwan 1995 {published data only}
  • Nelwan RH, Hendarwanto, Zulkarnain I, Gunawan J, Supandiman I, Yusuf H, et al. A comparative study of short course ciprofloxacin treatment in typhoid and paratyphoid fever. Drugs 1995;49 Suppl 2:463-5.
Peyramond 1986 {published data only}
  • Peyramond D, Tiguad S, Lucht F, Vedrinne JM, Salord F, Bertrand JL. Clinical evaluation of ofloxacin in the treatment of various infections [Bilan d'utilisation de l'ofloxacine dans le traitement d'infections variées]. Pathologie-Biologie 1986;34(5):471-5.
Sarma 1991 {published data only}
  • Sarma PS, Durairaj P. Randomized treatment of patients with typhoid and paratyphoid fevers using norfloxacin or chloramphenicol. Transactions of the Royal Society of Tropical Medicine and Hygiene 1991;85(5):670-1.
Secmeer 1997 {published data only}
Singh 1993 {published data only}
  • Singh CP, Singh N, Brar GK, Lal G, Kumar H. Efficacy of ciprofloxacin and norfloxacin in multidrug resistant enteric fever in adults. Journal of the Indian Medical Association 1993;91(6):156-7.
Suhendro 2007 {published data only}
  • Suhendro, Chen K, Pohan HT. Open study on efficacy and tolerability of ciprofloxacin XR compared with ciprofloxacin BID in the treatment of typhoid fever. Acta Medica Indonesiana 2007;39(1):22-6.
Takkar 1994 {published data only}
  • Takkar VP, Kumar R, Khurana S, Takkar R. Comparison of ciprofloxacin versus cephelexin and gentamicin in the treatment of multi-drug resistant typhoid fever. Indian Pediatrics 1994;31(2):200-1.
Tanphaichitra 1986 {published data only}
  • Tanphaichitra D, Sahaphong S, Srimuang S. Ofloxacin, a new quinolone in the treatment of genitourinary and enteric infections. Infection 1986;14 Suppl 4:321-3.
Tran 1994 {published data only}
  • Tran TH, Nguyen MD, Huynh DH, Nguyen TT, To SD, Le TP, et al. A randomized comparative study of fleroxacin and ceftriaxone in enteric fever. Transactions of the Royal Society of Tropical Medicine and Hygiene 1994;88(4):464-5.
Uwaydah 1992 {published data only}
  • Uwaydah AK, al Soub H, Matar I. Randomized prospective study comparing two dosage regimens of ciprofloxacin for the treatment of typhoid fever. Journal of Antimicrobial Chemotherapy 1992;30(5):707-11.
Wain 1997 {published data only}
  • Wain J, Hoa NTT, Chinh NT, Vinh H, Everett J, Diep TS, et al. Quinolone-resistant Salmonella typhi in Viet Nam: molecular basis of resistance and clinical response to treatment. Clinical Infectious Diseases 1997;25(6):1404-10.
Weng 1996a {published data only}
  • Weng YL, Jia FZ. Clinical efficacy evaluation of fluoroquinolones in typhoid fever (clinical analysis of 391 cases). Chinese Journal of Clinical Pharmacology 1996;12(3):142-7.
Yang 1991 {published data only}
  • Yang JG, Wa XL, Shen XJ, Wang KL, Zhu XB, Chen ZY. Short course of ofloxacin in the treatment of 28 patients of typhoid fever. Xin Yao Yu Lin Chuang [New Drugs and Clinical Remedies] 1991;11(2):79-80.
Zavala 1989 {published data only}
  • Zavala-Trujillo I, Nava-Zavala A, Marcano MG, Renteria M. Fleroxacin in the treatment of enteric fever and salmonellosis in adults. Reviews of Infectious Diseases 1989;2 Suppl 5:1188-9.
Zhang 1991 {published data only}
  • Zhang YY, Zhun BY, Jiang SC. Clinical evaluation of enoxacin. Zhonghua Nei Ke Za Zhi [Chinese Journal of Internal Medicine] 1991;30(8):480-3, 521.
ZhongYang 1997 {published data only}
  • ZhongYang H, Zheng L, Xinchung L, Hanjun H, Yi L X. Compared observation on therapeutic effect of ofloxacin and norfloxacin in treatment of typhoid fever. Zhonghua Chuan Ran Bing Za Zhi [Chinese Journal of Infectious Diseases] 1997;15(4):229-30.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
  25. References to other published versions of this review
Bran 1991 {published data only}
  • Bran JL, Garcia JF, Mendez O. Comparative, double blind study of chloramphenicol and ciprofloxacin in the treatment of typhoid fever (abstract 751). Proceedings of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy; 1991 Sept 29-Oct 2; Chicago, Illinois. Washington, DC: American Society of Microbiology, 1991:224.
Flores 1991 {published data only}
  • Flores GR. Pharmacological treatment of typhoid fever: A comparative study of ciprofloxacin versus trimethoprim-sulfamethoxazole [Tratamiento farmacológico del paciente con fiebre tifoidea: estudio comparativo entre ciprofloxacina y trimetoprim-sulfametoxazol]. Investigacion Medica International 1991;17(4):185-8.
Quintero 1988 {published data only}
  • Quintero-Perez NP, Andrea-Villanueva J, Leon-Garnica M, Bertin-Montano M, Chagollan-Rodriguez E, Rodiguez-Noriega E. Comparative double blind efficacy and safety study of ciprofloxacin with chloramphenicol in the treatment of typhoid fever. Abstract number 385. Programs and abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1988 Oct 23-26; Los Angeles, California. Washington, DC: American Society for Microbiology, 1988:177.
Soewandojo 1992 {published data only}
  • Soewandojo E, Suharto JR. Comparative study of ciprofloxacin vs chloramphenicol in patients with typhoid fever. Typhoid fever, profile, diagnosis and treatment in 1990. Proceedings of the 1st ISAC International Symposium. Jakarta: Acta Medica Indonesia, 1992:119-25.
Weng 1996 {published data only}
  • Weng Y-L, Jia F-Z. Clinical efficacy evaluation of fluoroquinolones in typhoid fever (clinical analysis of 391 cases). Zhongguo Lin Chuang Yao Li Xue Za Zhi [Chinese Journal of Clinical Pharmacology] 1996;12(3):142-7.
Xiao 1991 {published data only}
  • Xiao YH, Wang QN, Du JZ, Zheng XP, Li ZZ, Qui J, et al. Clinical and laboratory study of the fluoroquinolone antibiotics in the treatment of multiresistant typhoid fever. Sichuan I Hseuh 1991;12(4):196-8.
Yu 1998 {published data only}
  • Yu Y-S, Zheng J-C, Gan M-J, Ma Y-L. Clinical study on the efficacy and safety of the levofloxacin used to treat the patients with typhoid fever or paratyphoid fever. Zhongguo Lin Chuang Yao Li Xue Za Zhi [Chinese Journal of Clinical Pharmacology] 1998;14(2):70-4.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Notes
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
  25. References to other published versions of this review
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Akinyemi 2005
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