What is the priority reason for the nurse to consider questioning in order for tetracycline in a child younger than eight years of age?

Cochrane Database Syst Rev. 2012 Oct; 2012(10): CD007179.

Abstract

Background

Brucellosis is the most common zoonotic infection in the world. Several antibiotics, separately or in combination, have been tried for treatment of human brucellosis. The inconsistencies between different treatment regimens warrants the need for a systematic review to inform clinical practice and future research.

Objectives

To evaluate the effects of various antibiotic regimens, monotherapy or in combination with other antibiotics, for treating human brucellosis.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS until May 2012. We browsed the abstract books of several international infectious diseases conferences. We also checked the reference lists of all studies identified

Selection criteria

We included the randomized controlled trials on the pharmaceutical interventions in treatment of acute, chronic, non‐complicated, and complicated human brucellosis. The outcomes of interest were relapse, persistence of symptoms at the end of treatment, and adverse drug effects.

Data collection and analysis

Two authors independently assessed the studies for inclusion, risk of bias, and extracted relevant data using pre‐designed extraction forms. The findings of homogenous studies were pooled using fixed‐effect meta‐analysis.

Main results

In total we included 25 studies comparing various antibiotic regimens. Methods of allocation and concealment were inadequately described in half the studies, and only three were blinded. In comparisons of doxycycline plus rifampicin versus doxycycline plus streptomycin we found eight studies with 694 participants. For treatment failure, the doxycycline plus rifampicin regimen was less effective (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.07 to 3.42, seven studies, 567 participants), relapse (RR 2.39, 95% CI 1.17 to 4.86), and minor adverse drug reactions (RR 1.38, 95% CI 0.99 to 1.92). In comparisons of doxycycline plus rifampicin against quinolone (ciprofloxacin or ofloxacin) plus rifampicin we found five studies of 336 participants. The pooled analysis did not demonstrate any significant difference between two regimens in terms of relapse and symptom persistence, but showed a non‐significant higher risk of minor adverse reactions in doxycycline plus rifampicin (RR 1.80, 95% CI 0.78 to 4.18). Other comparisons were reported in a few heterogenous studies, and the pooled analyses, where applied, did not show any significant difference.

Authors' conclusions

Doxycycline (six weeks) plus streptomycin (two or three weeks) regimen is more effective regimen than doxycycline plus rifampicin (six weeks) regimen. Since it needs daily intramuscular (IM) injection, access to care and cost are important factors in deciding between two choices. Quinolone plus rifampicin (six weeks) regimen is slightly better tolerated than doxycycline plus rifampicin, and low quality evidence did not show any difference in overall effectiveness.

Keywords: Humans, Anti‐Bacterial Agents, Anti‐Bacterial Agents/therapeutic use, Brucellosis, Brucellosis/drug therapy, Ciprofloxacin, Ciprofloxacin/therapeutic use, Doxycycline, Doxycycline/therapeutic use, Ofloxacin, Ofloxacin/therapeutic use, Randomized Controlled Trials as Topic, Rifampin, Rifampin/therapeutic use, Streptomycin, Streptomycin/therapeutic use

Antibiotics for treating human brucellosis

Brucellosis is a common infection caused by Brucella bacteria species and can infect both people and animals. It is spread by eating infected food products and through direct contact with infected animals. The bacterial infection can affect different tissues and organs and is treated using antibiotics. Current recommended treatment regimens involve the use of two or more antibiotics in order to avoid relapses occurring and to prevent prolonged use of these drugs, which may lead to problems of drug resistance arising. Drug resistance is a particularly important issue as most people infected with brucellosis live in low socioeconomic areas of developing countries, where tuberculosis is also an endemic health problem. Thus there are concerns over the potential increase in resistance to tuberculosis drugs due to their prolonged use in treating brucellosis.

This review evaluates different drug regimens for treatment of brucellosis in terms of treatment failure and side effects: doxycycline plus rifampicin, doxycycline plus streptomycin, quinolones plus rifampicin or doxycycline plus gentamycin.

Based on currently available evidence, there is probably a lower incidence of total drug treatment failure in people that take doxycycline plus streptomycin instead of doxycycline plus rifampicin to treat brucellosis. However, we are uncertain whether either one of these two treatment regimens results in people having fewer adverse drug reactions.

There may not be any difference between the two drug regimens, doxycycline plus rifampicin versus quinolones plus rifampicin, with respect to total treatment failure. Notably, use of doxycycline plus rifampicin instead of quinolones plus rifampicin may result in more people suffering adverse drug reactions.

Giving doxycycline plus gentamycin to people with brucellosis may reduce the incidence of total treatment failure compared to administration of doxycycline plus streptomycin. However, comparing these two drug regimens, there may not be any difference in the number of people that have drug reactions.

Importantly studies included in this review were limited to adult patients with brucellosis, and the findings of this review are not applicable to children, pregnant women, and patients with complications like spondylitis and neurobrucellosis. Some studies did not perform any explicit assessment of minor adverse reactions, so the findings regarding adverse drug reactions should be interpreted with caution.

Summary of findings

Summary of findings for the main comparison

Doxycycline+Rifampicin compared to Doxycycline+Streptomycin for human Brucellosis

Summary of findings 2

Doxycycline+Rifampicin compared to Quinolones+Rifampicin for human Brucellosis

Summary of findings 3

Doxycycline+Streptomycin compared to Doxycycline+Gentamycin for human Brucellosis

Background

Brucellosis is the most common zoonotic disease worldwide (Pappas 2005a) and an important health problem in the Middle East, Central Asia, Africa, and Latin America (Hall 1990; Solera 1997a; Hassanjani Roushan 2004). It has been imported to countries in other geographical areas through migration, travel, and infected food products (Pappas 2005a). Brucellosis is caused by intracellular bacteria from the genus Brucella. Several Brucella species have been identified; Brucella melitensis is the most common cause of human brucellosis (Corbel 1997), while B. abortus is the most common cause of infection in animals. Human infection with B. abortus is often subclinical and less severe than the disease caused by B. melitensis (WHO 2006). Human reaction to different species ranges from acute inflammation to chronic granulomatous infection. Transmission generally occurs through eating unpasteurized or raw milk, or other dairy products. Other possible routes of transmission are direct contact with infected animal parts, inhalation of infected particles, and accidental inoculation. In developed countries, it is mostly an occupational disease in veterinarians, microbiologic laboratories staff, dairy industry professionals, and abattoir workers.

Clinical presentation

People with brucellosis usually present with non‐specific symptoms like fever, sweating, fatigue, loss of appetite, and weight loss (WHO 2006). Diagnosis is made by isolation of Brucella bacteria or positive tests for anti‐Brucella antibodies plus compatible clinical findings (fever, sweats, arthralgias, hepatomegaly, splenomegaly, or signs of focal disease) (Sauret 2002). Depending on the time and also the adequacy of received treatment, complications can occur. Musculoskeletal complications are the most common, particularly osteoarticular disease, monoarthritis (one‐joint inflammation), low back pain, osteomyelitis (bone infection), and septic arthritis (joint infection) (Corbel 2005). The reproductive system is the second common site of focal brucellosis. Neurological symptoms like depression and lethargy are frequently seen (Corbel 2005). There is no universal definition for chronic brucellosis. Some experts suggest the term 'chronic brucellosis' in patients whose clinical symptoms persist for 12 months or more from the time of the diagnosis (WHO 2006). The mortality rate due to Brucella infection is low, but morbidity is high because this systemic infection involves many organs and tissues, often causing diminished activity.

Treatment

Brucellosis is treated with antibiotics, although the most effective antibiotic regimens and treatment durations are unclear (Cisneros 1990; Karabay 2004). There are some limitations in choosing the best regimen: the choice of antibiotics that act intracellularly (eg doxycycline) are limited (Agalar 1999); and prolonged treatment needed to prevent relapse may increase the occurrence of adverse reactions (including gastric discomfort, hepatotoxicity (liver toxicity), nephrotoxicity (kidney toxicity), and allergic reactions), and may reduce adherence to the treatment. Regimens that combine two or more antibiotics are now recommended by most experts due to high relapse rates with monotherapy (Agalar 1999; Pappas 2005b). In addition, since the majority of brucellosis cases are in low socioeconomic areas of developing countries, where tuberculosis is also an endemic health problem, the overlap between treatment regimens of two diseases have raised concerns over the potential increase in resistance to tuberculosis drugs due to their prolonged use in brucellosis treatment (Ariza 2007). The significant health consequences of multiple drug resistant tuberculosis has resulted in calls for new drug regimens and shorter brucellosis drug treatment regimens.

In 1971, the World Health Organization (WHO) suggested a 21‐day regimen of tetracycline plus streptomycin as the treatment of choice for human brucellosis (WHO 1971). Although this regimen was successful in reducing the early symptoms, it failed to treat the disease completely, and immediate relapse was observed in some patients (Ariza 1985; Cisneros 1990). Accordingly, in 1986 the Joint Food and Agriculture Organization of the United Nations (FAO)/ WHO Expert Committee on Brucellosis proposed two new regimens: rifampicin (600 to 900 mg/day orally) plus doxycycline (200 mg/day orally) for six weeks; and doxycycline (200 mg/day orally) for 45 days plus streptomycin (1 g/day intramuscularly) for two to three weeks (WHO 1986). However, later studies showed a treatable but high rate of relapse for the mentioned regimens. The rifampicin plus doxycycline regimen is the most popular treatment, and favourable to the more effective regimen of streptomycin plus doxycycline, possibly because its lower price and ease of administration (Pappas 2005b; Pappas 2007); while streptomycin requires parenteral administration in a hospital setting or in an appropriately set‐up primary care network, both of which are restricted in lower income countries (Pappas 2005a). The above‐mentioned treatment regimens were replicated in the 2006 WHO recommendations (WHO 2006). Streptomycin plus doxycycline regimen was stated as the gold standard for the treatment of brucellosis by the recommendations developed through an international consensus meeting of experts in Ioannina, Greece (Ariza 2007). Streptomycin plus doxycycline was considered superior to the doxycycline plus rifampicin regimen by the Ioannina expert panel, because of its higher effectiveness, some supporting evidence of pharmacokinetics, and its lack of overlap with tuberculosis treatments. However, the expert panel suggested the need for further studies on the potential side effects of aminoglycoside‐containing regimens.

Other antibiotic formulations, including quinolones (eg ciprofloxacin and ofloxacin) and trimethoprim/sulphamethoxazole (co‐trimoxazole), have been used (Pappas 2005b; WHO 2006). However, questions remain about their effectiveness (Pappas 2006; WHO 2006). In addition, monotherapy with tetracyclines has been considered another less costly and easier to administer by some authors; while the evidence on its comparative effectiveness with combination therapies is scarce and controversial (Solera 2010).

Treatment protocols may differ in children aged less than eight years and pregnant women, because of adverse reactions of some medications, including inhibition of bone growth due to tetracycline treatment in children and teratogenic potential of some drugs, such as streptomycin (WHO 2006).

Rationale for the review

Despite years of research on the treatment of human brucellosis, the choice of antibiotics and the optimal duration of treatment have remained controversial (Ariza 2007). Skalsky 2008 conducted a systematic review on the effectiveness of antibiotic regimens in treating human brucellosis. Despite the comprehensiveness of the search and rigor of quality assessment, the study had some limitations. The authors pooled studies based on drug classes (eg comparing all quinolone and non‐quinolone based regimens, no matter with what other antibiotic they were administered), and did not take the within class heterogeneity into account. In addition, they pooled spondylitis cases with non‐complicated brucellosis, despite differences in the treatment duration in many studies. In addition, while they stated that they used a modified intention‐to‐treat analysis, in which all drop outs were counted as failure, it seems that they did not apply that rule consistently to all included studies. For instance, 16 patients who were withdrawn from the Ariza 1992 trial were not considered as failure in the meta‐analysis. Moreover, they limited the review to a few comparisons among different combinations of treatment regimens. Solis Garcia del Pozo 2012 conducted a more recent systematic review on the same issue, trying to address the limitations of the Skalsky 2008 study. However, we believe that the authors misclassified several studies. For example, even though they stated that the meta‐analyses were done only on randomized controlled trials, several quasi and non‐randomized studies were also included (eg Ariza 1985b; Saltoglu 2002; Solera 1991; Solera 1995). In addition, despite stating that they excluded studies with less than six months follow‐up, Karabay 2004 with three months follow‐up was still used in the analysis. Moreover, they combined the results of Keramat 2009 study (with 38% of included patients suffering from spondylitis) with the studies on non‐complicated brucellosis.

The inconsistencies among different treatment regimens and lack of high quality reviews comparing various treatment regimens (especially comparisons other than doxycycline plus streptomycin versus doxycycline plus rifampicin) demonstrate the need for a more comprehensive systematic review. We aimed to collate the evidence on the effectiveness of the frequently used regimens for treating human brucellosis, to inform practice and research priorities.

Objectives

To evaluate the effects of various antibiotic regimens, monotherapy or in combination with other antibiotics, for treating human brucellosis in terms of treatment failure and side effects.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials. Non‐randomized and quasi‐randomized trials were excluded.

Types of participants

People with brucellosis diagnosed by the presence of compatible clinical findings (fever, sweats, arthralgias, hepatomegaly, splenomegaly, or signs of focal disease) with:

• isolation of Brucella species from blood, other tissues, or fluids.

• or standard tube agglutination titres of 1/160, or more for anti‐Brucella antibodies.

Patients with brucellosis spondylitis were excluded, because of the considerable differences in the treatment principles of spinal complications.

Types of interventions

Interventions

Combination of doxycycline and rifampicin, doxycycline and streptomycin, quinolones and rifampicin, doxycycline and gentamycin, and other combinations, with any dosage for any period of treatment.

Control

Placebo, or other antibiotics given alone or in combination.

Types of outcome measures

Primary

Total treatment failure, defined as:

• the relapse of symptoms and signs of the disease accompanied by increasing serological tests and/or a positive culture after the end of treatment or

• persistence of disease symptoms or signs after the end of treatment

Secondary

• Time to defervescence, defined as the number of days after the beginning of treatment until the fever ends.

Adverse drug reactions

• Serious adverse reactions, including those that result in death, hospitalisation, prolongation of hospital stay, discontinuation of treatment, or persistent or significant long‐term disability.

• Minor adverse reactions, including gastrointestinal upset, central nervous system events, hepatotoxicity, nephrotoxicity, ototoxicity, or dermatitis. 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

Databases

We searched the following databases using the search terms and strategy described in Table 9: Cochrane Infectious Diseases Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) issue, published in The Cochrane Library (2012, issue 2), MEDLINE (9 May 2012), EMBASE (9 May 2012), and LILACS (9 May 2012).

Table 1

Detailed search strategies

The electronic search was updated by the Cochrane Infectious Diseases Group on 9 May 2012.

We also searched the International Clinical Trials Registry Platform Search Portal (http://www.who.int/trialsearch/) for ongoing and unpublished trials until 9 May 2012, using 'brucellosis' as the search term.

Conference proceedings

We searched the following conference proceedings for relevant abstracts from year 2000 to 2008: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Annual meetings of the Infectious Diseases Society of America (IDSA); and European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Researchers and pharmaceutical companies

We contacted individual researchers working in the field and pharmaceutical companies including Bayer, Aventis, Novartis, and CollaGenex for unpublished and ongoing trials.

Reference lists

We checked the reference lists of all studies identified by the above methods, looking for cited relevant studies.

Data collection and analysis

Selection of studies

Two authors independently checked the results of the literature search for potentially relevant trials following the inclusion criteria, and determined the eligibility for obtaining full articles. If it was obvious from the abstract that the study did not meet the selection criteria, we excluded the study. If it was unclear from the abstract whether the study met the selection criteria, or it was included by each author, then we retrieved the full text article. Two authors independently assessed the full‐text articles for inclusion using the study eligibility criteria. We resolved disagreements in a consensus meeting, or by seeking the opinion of a third author. We scrutinized each trial report to find potential duplicates. We have listed the excluded studies along with the reason for exclusion in the Characteristics of excluded studies. If eligibility was unclear, we attempted to contact the trial authors for further information, and a final decision made to include or exclude.

Data extraction and management

Two authors independently extracted data using a pre‐designed data extraction form. We resolved disagreements by consensus or by consulting a third author.

We used an available case analysis, ie all patients with a measured outcome were included in the analysis. For studies in which patients with spondylitis were also included, we extracted the data for the subgroup without spondylitis and, if available, we used this data in the analysis.

We extracted data for dichotomous outcomes, such as relapse rate and therapeutic failure, by recording the total number of participants randomized, those that experienced outcomes, and the number analysed. For continuous outcomes, such as time to defervescence, we extracted the total number of participants analysed, arithmetic means, and the standard deviations. If the number of participants randomized to each group was not identical to the number analysed for a given outcome, we calculated the percentage of participants lost to follow‐up. We attempted to contact trial authors where published data were unclear or missing.

Assessment of risk of bias in included studies

Two authors independently assessed the risk of bias using the Cochrane Collaboration Risk of Bias form. We resolved disagreements through consensus or by consulting a third author. We assessed six components of risk of bias for each study: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. For each component, the judgment of "yes", "no", or "unclear" was made, which represented either a high, low, or unclear risk of bias.

Assessment of reporting biases

We intended to explore the presence of reporting biases using funnel plots but we were unable to do so due to the nature of the data and the limited number of included studies.

Data synthesis

We used Review Manager (RevMan) to analyse data. We used risk ratio (RR) as a measure of effect for dichotomous data, and the weighted mean difference for continuous data. The results were presented with 95% CI. If we suspected the data were skewed and inappropriately summarized as means and standard deviations, we did not combine the data in a meta‐analysis.

For each outcome, we stratified the analyses by comparison (ie we did not combine trials with different control groups). For total treatment failure and relapse, we also stratified the analyses by follow‐up time (less than six months versus greater than six months). For adverse drug reactions, we stratified the analyses by severity, classified as serious, minor (mild and moderate), and all adverse reactions. We combined trials within the same strata using meta‐analysis.

For dichotomous outcomes, where data available, the number of patients randomized was used as the denominator, and all missing data were considered as

To check for heterogeneity, we visually examined the forest plots, used the Chi2 test with 10% level of statistical significance and performed the I2 statistic (50% represents moderate level of heterogeneity). Where the number of trials permitted, we planned to explore the following potential sources of heterogeneity in subgroup analyses: Brucella species (B. melitensis or B. abortus); antibiotic dose; treatment duration; follow‐up duration (less than six months; six months or more); participant age (less than eight years versus older); pregnancy; and local organ involvements (central nervous system involvement, endocarditis).

Sensitivity analysis

We intended to perform a sensitivity analysis to assess the role of adequate allocation concealment and other quality indicators, but we were unable to do so due to the limited number of included studies.

Results

Description of studies

Included studies

We included 25 randomized controlled trials. All of the studies used a combination of clinical assessment, culture, and serology to diagnose brucellosis. Fifteen studies diagnosed the brucellosis by a positive culture or a combination of clinical features (including fever, sweats, arthralgia, hepatomegaly, splenomegaly) and a standard tube agglutination titre (STAT) of 1/160 or more. Acocella 1989 used a Standard tube agglutination test above 125 International Units (IU), and Alavi 2007 a STAT titre of 1/80; which are in both studies a more sensitive and less specific serologic cut‐point. Conversely, Hassanjani Roushan 2006, and Hassanjani Roushan 2010 used a titer of 1/320 or more for STAT, as diagnostic cut‐point. The Lang 1990, Lang 1992, and Rodriguez Zapata 1987 studies used the Rose‐Bengal and a four‐fold increase in hemagglutination titres as serologic criteria. The Agalar 1999, Buzon 1982, and Sarmadian 2009 did not specify the serologic criteria . The percentage of positive culture for brucellosis ranged between 60 to 75% of participants in included studies, apart from Agalar 1999 which excluded all patients with negative culture. In most of the studies B. melitensis was the only detected Brucella species in cultures. Patients with neurobrucellosis or endocarditis were excluded from most of the studies, excluding Colmenero 1994, Karabay 2004, and Rodriguez Zapata 1987. Agalar 1999 reported no occurrence of endocarditis. All studies were restricted to adult patients, but the minimum age varied from six years (Lang 1992) to 18 years (Lang 1990;Solera 2004). Pregnant women were excluded. Details about each included trial are given in the table of Characteristics of included studies.

Doxycycline plus rifampicin regimen was compared with doxycycline plus streptomycin in eight studies (Acocella 1989;Ariza 1992;Colmenero 1989;Colmenero 1994;Ersoy 2005;Hashemi 2012; Montejo 1993b;Rodriguez Zapata 1987 ). It was compared with a combination of a quinolone (ciprofloxacin or ofloxacin) with rifampicin in six studies (Agalar 1999;Akova 1993;Ersoy 2005;Hashemi 2012; Karabay 2004;Sarmadian 2009). Some studies compared it with other antibiotic combinations: with tetracycline plus streptomycin (Acocella 1989), with doxycycline plus co‐trimoxazole (Alavi 2007), with doxycycline plus ciprofloxacin (Kalo 1996;Sarmadian 2009), with ciprofloxacin (Lang 1990), with co‐trimoxazole (Montejo 1993a), and with doxycycline plus rifampicin plus amikacin (Ranjbar 2007).

Only nine studies defined the relapse based on the presence of both clinical and serologic conditions (Agalar 1999; Alavi 2007; Ersoy 2005; Hashemi 2012; Hassanjani Roushan 2004; Hassanjani Roushan 2006; Hassanjani Roushan 2010; Karabay 2004; Lang 1990). The rest of the studies defined it based on reappearance of clinical signs and symptoms, or the presence of either clinical, serologic, or bacteriologic criteria.

Risk of bias in included studies

Details of the risk of bias of included studies are provided in Figure 1 and Figure 2.

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

Risk of Bias summary: review authors' judgements about each Risk of Bias item for each included study.

Blinding

Most studies were open, and the patients, care providers, and outcome assessors were not blinded; except in Ariza 1992, McDevitt 1970, and Solera 2004 in which patients and investigators were kept blinded to treatments.

Incomplete outcome data

Generally, studies reported the number of patients missed during the study period. However, because of the low proportion of the primary outcome (total treatment failure), the percentage of missing outcomes compared with observed event risk was high enough to induce bias in intervention effect estimate in most of the studies. The percentage of patients lost to follow‐up was considerable among the studies, and some mistakenly defined the non‐compliant patients or who developed complications as excluded. Most of the studies did not explicitly report the number of patients missed at each follow‐up session.

Other potential sources of bias

The provided information in most of the studies was not sufficient to assess these sources of bias. Acocella 1989 had a considerable baseline imbalance between study groups.

Effects of interventions

See: Table 1; Table 2; Table 3

1. Doxycycline plus rifampicin versus doxycycline plus streptomycin

Six studies used 1 g/day of streptomycin for 21 days, administered intramuscularly (Acocella 1989;Colmenero 1989;Colmenero 1994;Ersoy 2005;Hashemi 2012; Rodriguez Zapata 1987). Ariza 1992, and Montejo 1993b applied it for two weeks. In the doxycycline plus streptomycin arm, most studies administered 200 mg/day of doxycyline for six weeks, except for Colmenero 1989 which used it for 30 days, and Ersoy 2005 who used a dosage of 100 mg/day of doxycycline for six weeks.

1.1 Total treatment failure

The pooled analysis of six trials (n = 490, Figure 3) did not show any significant difference in total treatment failure between doxycycline plus rifampicin and doxycycline plus streptomycin in short‐term follow‐up (Acocella 1989, Ariza 1992, Colmenero 1994, Ersoy 2005, Hashemi 2012, Rodriguez Zapata 1987). But in follow‐ups of longer than six months in duration, pooling the results of seven studies (n = 567) showed that the doxycycline plus rifampicin regimen resulted in significantly more treatment failures with a fixed‐effect Mantel‐Hanszel RR of 1.91 (95% CI 1.07 to 3.42, Analysis 1.1: subgroup 2) (Acocella 1989, Ariza 1992, Colmenero 1989, Colmenero 1994, Ersoy 2005, Montejo 1993b, Rodriguez Zapata 1987). The point estimates were all placed on one side of the no‐effect line, and were not significantly heterogeneous.

Forest plot of comparison: 1 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Streptomycin(DS), outcome: 1.1 Total treatment failure.

Comparison 1 Doxycycline plus rifampicin (DR) versus doxycycline plus streptomycin (DS), Outcome 1 Total treatment failure.

Following visual inspection of the forest plot, the point estimates of RR for two studies with different doxycycline plus streptomycin regimens (Colmenero 1989, Ersoy 2005), or with different durations of streptomycin administration (Ariza 1992; Montejo 1993b) did not differ from the other studies. Ariza 1992, Colmenero 1994, and Rodriguez Zapata 1987 also included seven, two, and two patients with spondylitis respectively. That subgroup was removed from the analysis, since the information regarding the relapse and treatment failure was available for it.

1.2 Relapse

The pooled analysis of relapse in seven studies (n = 567, Figure 4) showed that doxycycline plus rifampicin regimen resulted in more relapses than doxycycline plus streptomycin during follow‐up periods of more than six months, with the fixed‐effect Mantel‐Hanszel RR of 2.39 (95% CI 1.17 to 4.86, Analysis 1.2: subgroup 2) (Acocella 1989, Ariza 1992, Colmenero 1989, Colmenero 1994, Ersoy 2005, Montejo 1993b, Rodriguez Zapata 1987). The pooled analysis of relapse rate during follow‐ups shorter than six months in five studies (n = 413) did not show any significant difference.

Forest plot of comparison: 1 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Streptomycin(DS), outcome: 1.2 Relapse.

Comparison 1 Doxycycline plus rifampicin (DR) versus doxycycline plus streptomycin (DS), Outcome 2 Relapse.

1.3 Persistence of symptoms

The pooled analysis of persistence of symptoms in eight studies (n = 696, Figure 5) did not show any significant difference between two regimens, with the fixed‐effect Mantel‐Hanszel RR of 1.69 (95% CI 0.79 to 3.59, Analysis 1.3) (Acocella 1989;Ariza 1992;Colmenero 1989;Colmenero 1994;Ersoy 2005;Hashemi 2012; Montejo 1993b;Rodriguez Zapata 1987). The variation among studies was not significantly greater than by chance. Montejo 1993b defined the persistence of symptoms as if the symptoms did not resolve two weeks after treatment had begun, which was slightly different from other studies (persistence after the end of treatment).

Forest plot of comparison: 1 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Streptomycin(DS), outcome: 1.3 Persistence of symptoms.

Comparison 1 Doxycycline plus rifampicin (DR) versus doxycycline plus streptomycin (DS), Outcome 3 Persistence of symptoms.

1.4 Adverse drug reactions

We divided adverse drug effects into two subgroups of serious adverse reactions, including those that resulted in death, hospitalisation, prolongation of hospital stay, discontinuation of treatment, or persistent or significant long‐term disability, and minor adverse reactions. Only two studies reported cases of serious adverse reactions, resulted in the change of treatment regimen (Acocella 1989;Ersoy 2005), which did not differ in two study groups. Five studies observed minor adverse drug effects, mainly gastro‐intestinal complaints (Ariza 1992;Colmenero 1989;Ersoy 2005;Hashemi 2012; Rodriguez Zapata 1987). Pooled analysis of minor adverse drug reactions of five studies (n = 473, Figure 6) did not show a significantly higher risk of minor drug reactions in doxycycline plus rifampicin than doxycycline plus streptomycin, with fixed‐effect Mantel‐Hanszel RR of 1.38 (95% CI 0.99 to 1.92, Analysis 1.4: subgroup 2).

Forest plot of comparison: 1 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Streptomycin(DS), outcome: 1.4 Adverse drug reactions.

Comparison 1 Doxycycline plus rifampicin (DR) versus doxycycline plus streptomycin (DS), Outcome 4 Adverse drug reactions.

1.5 Time to defervescence

Two studies reported the average time to defervescence (Ariza 1992;Colmenero 1989). None of them reported the standard deviation of measure, so meta‐analysis was not possible. The average time to defervescence in doxycycline plus rifampicin and doxycycline plus streptomycin groups was 4.2 and 3.2 days in Ariza 1992, and 3.5 and 3.5 days in Colmenero 1989 respectively.

2. Doxycycline plus rifampicin versus quinolone plus rifampicin

Five studies compared doxycycline plus rifampicin with a combination of a quinolone (ciprofloxacin or ofloxacin) with rifampicin (Agalar 1999;Akova 1993;Ersoy 2005;Hashemi 2012; Karabay 2004). Three studies used the combination of ofloxacin 400 mg/day with rifampicin 600 mg/day for six weeks (Akova 1993;Ersoy 2005;Karabay 2004). Hashemi 2012 administered ofloxacin 800 mg/day for six weeks, combined with 15 mg/kg/day of rifampicin. Agalar 1999 administered ciprofloxacin 1 g/day and rifampicin 600 mg/day for 30 days. Akova 1993 included six patients with spondylitis who were excluded from the analysis.

2.1 Total treatment failure

The pooled analysis of total treatment failure of five studies (n = 333, Figure 7) for short term follow‐up did not show any significant difference between two regimens, with a fixed‐effect Mantel‐Hanszel RR of 1.41(95% CI 0.87 to 2.28, Analysis 2.1: subgroup 1). Furthermore, pooling of the results for the follow‐up durations longer than six months did not show any significant difference (RR 0.94, 95% CI 0.45 to 1.98, 181 participants, three trials, Analysis 2.1: subgroup 2). In short‐term follow‐up, Hashemi 2012, which used a doubled daily dose of ofloxacin, showed a considerably better point estimates for the ofloxacin plus rifampicin treatment, in comparison to the other four studies. Agalar 1999, which used ciprofloxacin, did not show any considerable difference in comparison to other studies using ofloxacin.

Forest plot of comparison: 2 Doxycycline plus Rifampicin(DR) versus Quinolones plus Rifampicin(QR), outcome: 2.1 Total treatment failure.

Comparison 2 Doxycycline plus rifampicin (DR) versus quinolones plus rifampicin (QR), Outcome 1 Total treatment failure.

2.2 Relapse

The pooled analysis of short‐term and long‐term follow‐ups of risk of relapse (Figure 8) did not show any significant difference between two regimens, with a fixed‐effect Mantel‐Hanszel RR of 0.95 (95% CI 0.40 to 2.27, 181 participants, three trials, Analysis 2.2: subgroup 2) for long‐term follow‐up. In short‐term follow‐up, Hashemi 2012, showed a considerably better point estimates in favour of ofloxacin plus rifampicin treatment, in comparison to the other three studies.

Forest plot of comparison: 2 Doxycycline plus Rifampicin(DR) versus Quinolones plus Rifampicin(QR), outcome: 2.2 Relapse.

Comparison 2 Doxycycline plus rifampicin (DR) versus quinolones plus rifampicin (QR), Outcome 2 Relapse.

2.3 Persistence of symptoms

The pooled estimate of the risk of symptom persistence at the end of treatment in three studies (n = 267, Figure 9) was not statistically significant, with a fixed‐effect Mantel‐Hanszel RR of 1.80 (95% CI 0.72 to 4.53, Analysis 2.3). Again, the findings of Hashemi 2012 study was in favour of ofloxacin plus rifampicin treatment, considerably different from the other two studies.

Forest plot of comparison: 2 Doxycycline plus Rifampicin(DR) versus Quinolones plus Rifampicin(QR), outcome: 2.3 Persistence of symptoms.

Comparison 2 Doxycycline plus rifampicin (DR) versus quinolones plus rifampicin (QR), Outcome 3 Persistence of symptoms.

2.4 Adverse drug reactions

Serious drug effects, leading to the change of treatment regimen, was only reported in Ersoy 2005 (three events). The pooled estimate of the random effect analysis of minor adverse reactions in four studies (n = 296, Figure 10) was not significant, with a Mantel‐Hanszel RR of 1.80 (95% CI 0.78 to 4.18, Analysis 2.4: subgroup 2). Hashemi 2012 was the only study reporting a higher proportion of minor adverse drug reactions in ofloxacin plus rifampicin group, compared to the doxycycline plus rifampicin. The observed adverse reactions were mainly gastrointestinal upset.

Forest plot of comparison: 2 Doxycycline plus Rifampicin(DR) versus Quinolones plus Rifampicin(QR), outcome: 2.4 Adverse drug reactions.

Comparison 2 Doxycycline plus rifampicin (DR) versus quinolones plus rifampicin (QR), Outcome 4 Adverse drug reactions.

2.5 Time to defervescence

Three studies reported the average time to defervescence. Akova 1993, which only reported the means, showed 5.1 and 6.3 days for defervescence in doxycycline plus rifampicin and quinolone plus rifampicin groups. The meta‐analysis on two studies (n = 69, Figure 11) showed a significantly shorter fever duration in quinolone plus rifampicin group, with a fixed‐effect WMD of 1.2 days (95% CI 0.55 to 1.85, Analysis 2.5) (Agalar 1999;Karabay 2004).

Forest plot of comparison: 2 Doxycycline plus Rifampicin(DR) versus Quinolones plus Rifampicin(QR), outcome: 2.5 Time to defervescence (days).

Comparison 2 Doxycycline plus rifampicin (DR) versus quinolones plus rifampicin (QR), Outcome 5 Time to defervescence (days).

3. Doxycycline plus streptomycin versus quinolone plus rifampicin

Ersoy 2005 compared doxycycline plus streptomycin for 45 days with a combination of ofloxacin 400 mg/day with rifampicin 600mg/day for 45 days. Hashemi 2012 compared a six‐week treatment with doxycycline plus streptomycin with a combination of ofloxacin 800 mg daily plus rifampicin 15 mg/kg daily for six weeks.

3.1 Total treatment failure

The pooled analysis of short‐term follow‐up in two studies (n = 202, Figure 12) did not show any significant difference between two treatment regimens, with a fixed‐effect Mantel‐Hanszel RR of 0.69 (95% CI: 0.33 to 1.44). Ersoy 2005 did not show a significant difference in long term follow‐ups between two regimens, with a RR of 0.73 (95% CI 0.23 to 2.29, Analysis 3.1).

Forest plot of comparison: 3 Doxycycline plus Streptomycin(DS) versus Quinolones plus Rifampicin(QR), outcome: 3.1 Total treatment failure.

Comparison 3 Doxycycline plus streptomycin (DS) versus quinolones plus rifampicin (QR), Outcome 1 Total treatment failure.

3.2 Relapse

Hashemi 2012 reported the relapse rate for the short‐term follow‐up (Figure 13), which was not significantly different in two treatment regimens (RR 0.59, 95% CI 0.15 to 1.37). Ersoy 2005 only reported the relapse rate at long‐term follow‐up, with no significant difference (RR 0.77, 95% CI 0.20 to 2.98, Analysis 3.2: subgroup 2).

Forest plot of comparison: 3 Doxycycline plus Streptomycin(DS) versus Quinolones plus Rifampicin(QR), outcome: 3.2 Relapse.

Comparison 3 Doxycycline plus streptomycin (DS) versus quinolones plus rifampicin (QR), Outcome 2 Relapse.

3.3 Persistence of symptoms

The pooled analysis of the persistence of symptoms at the end of treatment was not significant (Figure 14), with a fixed‐effect Mantel‐Hanszel RR of 0.74 (95% CI 0.17 to 3.17, Analysis 3.3).

Forest plot of comparison: 3 Doxycycline plus Streptomycin(DS) versus Quinolones plus Rifampicin(QR), outcome: 3.3 Persistence of symptoms.

Comparison 3 Doxycycline plus streptomycin (DS) versus quinolones plus rifampicin (QR), Outcome 3 Persistence of symptoms.

3.4 Adverse drug reactions

Serious drug reactions were reported in Ersoy 2005 (one event in quinolone plus rifampicin group). The pooled analysis of minor adverse reactions in two studies (n = 202) did not show any significant difference in two treatment regimens, with a fixed‐effect Mantel‐Hanszel RR of 1.15 (95% CI 0.65 to 2.01). The side effects were mainly gastrointestinal upset.

3.5 Time to defervescence

Time to defervescence was not reported in any of the studies.

4. Doxycycline plus rifampicin versus doxycycline plus quinolone

Two studies compared doxycycline plus rifampicin with a combination of a quinolone (ciprofloxacin or ofloxacin) with doxycyline (Kalo 1996;Sarmadian 2009). Both used ciprofloxacin 1g/day as the quinolone, in combination with rifampicin 600 mg/day. The duration of treatment was six weeks in Kalo 1996, and eight weeks in Sarmadian 2009.

4.1 Total treatment failure

Sarmadian 2009 reported the total treatment failure for short‐term follow‐up, and did not show any significant difference (RR 0.78, 95% CI 0.32 to 1.88, Analysis 4.1, Figure 15).

Forest plot of comparison: 4 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Quinolone(DQ), outcome: 4.1 Total treatment failure.

Comparison 4 Doxycycline plus rifampicin (DR) versus doxycycline plus quinolone (DQ), Outcome 1 Total treatment failure.

4.2 Relapse

The pooled analysis of short‐term follow‐ups of risk of relapse in two studies (Figure 16) did not show any significant difference between two regimens, with a fixed‐effect Mantel‐Hanszel RR of 1.5 (95% CI 0.26 to 8.55, 104 participants, two trials, Analysis 4.2: subgroup 1) for short‐term follow‐up.

Forest plot of comparison: 4 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Quinolone(DQ), outcome: 4.2 Relapse.

Comparison 4 Doxycycline plus rifampicin (DR) versus doxycycline plus quinolone (DQ), Outcome 2 Relapse.

4.3 Persistence of symptoms

Sarmadian 2009 did not show any significant difference for the symptom persistence at the end of treatment (RR 0.6, 95% CI 0.22 to 1.75, Analysis 4.3, Figure 17).

Forest plot of comparison: 4 Doxycycline plus Rifampicin(DR) versus Doxycycline plus Quinolone(DQ), outcome: 4.3 Persistence of symptoms.

Comparison 4 Doxycycline plus rifampicin (DR) versus doxycycline plus quinolone (DQ), Outcome 3 Persistence of symptoms.

4.4 Adverse drug reactions

None of the studies reported the occurrence of adverse reactions.

4.5‐time to defervescence

Only Kalo 1996 reported the mean time to defervescence. The average febrile duration was four or five days in doxycycline plus rifampicin and quinolone plus doxycycline groups respectively. The study did not report the standard deviation values.

5 Doxycycline plus streptomycin versus doxycycline plus gentamycin

Two studies compared doxycycline plus streptomycin and doxycycline plus gentamycin regimens. Hassanjani Roushan 2006 (n = 191) compared a doxycycline plus streptomycin (45 and 14 days) regimen with a doxycycline plus gentamicin (45 and 7 days) regimen. In another study, Hassanjani Roushan 2010 (n = 154) compared a doxycycline plus streptomycin (45 and 14 days) regimen with a doxycycline plus gentamicin (56 and 5 days) regimen.

Solera 2004 (n = 146) compared two durations of doxycycline therapy (30 days versus 45 days) as a part of doxycycline plus gentamycin regimen with each other.

5.1 Total treatment failure

The pooled analysis of total treatment failure of two studies (n = 345, Figure 18) for short term and long term follow‐ups did not show any significant difference between two regimens, with a fixed‐effect Mantel‐Hanszel RR of 1.96 (95% CI 0.85 to 4.49, Analysis 5.1: subgroup 1) and 1.85 (95% CI 0.84 to 4.08, Analysis 5.1: subgroup 2) respectively. The point estimate of total treatment failure was in favour of doxycycline plus gentamycin regimen.

Forest plot of comparison: 5 Doxycycline plus Streptomycin(DS) versus Doxycyline plus gentamycin(DG), outcome: 5.1 Total treatment failure.

Comparison 5 Doxycycline plus streptomycin (DS) versus doxycyline plus gentamycin (DG), Outcome 1 Total treatment failure.

5.2 Relapse

The pooled analysis of short‐term and long‐term follow‐ups of risk of relapse in two studies (Figure 19) did not show any significant difference between two regimens, with a fixed‐effect Mantel‐Hanszel RR of 1.83 (95% CI 0.54 to 6.12, 345 participants, two trials, Analysis 5.2: subgroup 1) and 1.67 (95% CI 0.56 to 5.0, 345 participants, two trials, Analysis 5.2: subgroup 2) respectively, in favour of doxycycline plus gentamycin regimen.

Forest plot of comparison: 5 Doxycycline plus Streptomycin(DS) versus Doxycyline plus gentamycin(DG), outcome: 5.2 Relapse.

Comparison 5 Doxycycline plus streptomycin (DS) versus doxycyline plus gentamycin (DG), Outcome 2 Relapse.

Comparing two doxycycline plus gentamycin regimens, Solera 2004 reported 15 cases of relapse in the group treated with doxycycline for 30 days, versus 9 cases in the group treated for 45 days, at one year follow‐up.

5.3 Persistence of symptoms

The pooled estimate of the risk of symptom persistence at the end of treatment in two studies (n = 345, Figure 20) did not significantly differ, with a fixed‐effect Mantel‐Hanszel RR of 2.09 (95% CI 0.64 to 6.79, Analysis 5.3).

Forest plot of comparison: 5 Doxycycline plus Streptomycin(DS) versus Doxycyline plus gentamycin(DG), outcome: 5.3 Persistence of symptoms.

Comparison 5 Doxycycline plus streptomycin (DS) versus doxycyline plus gentamycin (DG), Outcome 3 Persistence of symptoms.

5.4 Adverse drug reactions

Only minor adverse effects occurred in both studies, which did not warrant change in treatment regimen. The pooled estimate of the risk of minor adverse reactions (Figure 21) was 0.85 (95% CI 0.60 to 1.22, Analysis 5.4: subgroup 2). The most frequent adverse reactions in both studies were photosensitivity and abdominal discomfort. Hassanjani Roushan 2006 reported two cases of ototoxicity in doxycycline plus streptomycin group.

Forest plot of comparison: 5 Doxycycline plus streptomycin(DS) versus doxycyline plus gentamycin (DG), outcome: 5.4 Adverse drug reactions.

Comparison 5 Doxycycline plus streptomycin (DS) versus doxycyline plus gentamycin (DG), Outcome 4 Adverse drug reactions.

Comparing two doxycycline plus gentamycin regimens, Solera 2004 did not report any serious adverse reactions in neither groups. They detected 29 minor adverse reactions in 30‐day doxycycline treatment and 28 in 45‐day treatment (mainly photosensitivity and epigastric pain).

6 Doxycycline plus rifampicin versus other regimens

Ranjbar 2007 (n = 220) reported the comparison between doxycycline plus rifampicin (eight weeks) and doxycycline plus rifampicin plus amikacin (amikacin 20 mg/day IM for seven days added to the regimen). Lang 1990 (n = 10) compared doxycycline plus rifampicin regimen with two dosages of ciprofloxacin monotherapy.

6.1‐Total treatment failure

In Ranjbar 2007, at six‐month follow‐up, doxycycline plus rifampicin regimen showed a higher risk of total treatment failure compared to the amikacin added regimen, with a Mantel‐Hanszel RR of 1.48 (95% CI 1.02 to 2.15).

In Lang 1990, no failure was observed in doxycycline plus rifampicin regimen. While five out of six patients in ciprofloxacin monotherapy groups relapsed a few weeks after treatment.

6.2 Relapse

In Ranjbar 2007, at six‐month follow‐up, the relapse was seen in nine patients in doxycycline plus rifampicin group and six patients in the amikacin added group, with a Mantel‐Hanszel RR of 1.5 (95% CI 0.55 to 4.07).

Lang 1990 reported no relapse in doxycycline plus rifampicin group in one year follow‐up. But three patients in group 1gr bd ciprofloxacin and two patients in 750 mg bd ciprofloxacin groups showed the signs of relapse during one month after treatment, resulting in the termination of the study.

6.3 Persistence of symptoms

In Ranjbar 2007, persistence of symptoms at the eighth week after beginning of treatments was seen in 37 patients in doxycycline plus rifampicin group and in 25 patients in amikacin added group, with a Mantel‐Hanszel RR of 1.48 (95% CI 0.96 to 2.28).

6.4 Adverse drug reactions

Ranjbar 2007 did not report any serious adverse reactions, but they reported minor reactions in four cases of doxycycline plus rifampicin, and six cases of amikacin added group. Two patients in doxycycline plus rifampicin had mild gastric complaints, one patient had vomiting, and one had genital candidiasis. In the amikacin added group, four patients had mild gastric complaints and two had phototoxicity.

Lang 1990 reported no serious adverse reactions in any groups. They reported a transient increase in hepatocellular enzymes in all treatment groups.

7 Tetracycline plus streptomycin versus other regimens

Acocella 1989 (n = 146) reported the comparison between a regimen consisting of tetracycline 2 g/day for 21 days, plus streptomycin 1g/day for the first two weeks with doxycycline plus rifampicin (45 days) and doxycycline plus streptomycin (45 and 21 days). The sample size in tetracycline plus streptomycin group was considerably smaller than other two groups.

7.1 Total treatment failure

During the one‐year follow‐up, total treatment failure was seen in 11 (41%) patients in the tetracycline plus streptomycin group, which was higher than the doxycycline plus rifampicin and the doxycycline plus streptomycin groups, with 3 (5%) and 2 (4%) cases respectively.

7.2 Relapse

During the six‐month follow‐up, relapse was seen in six (22%) patients in the tetracycline plus streptomycin group, which was higher than the doxycycline plus rifampicin and doxycycline plus streptomycin groups with 2 (4%) and 0 cases respectively. The relapse rates at 1 year follow‐up were 22%, 6%, and 0% in the three groups respectively.

7.3 Persistence of symptoms

Persistence of symptoms at the end of treatment was seen in 4, 0, and 1 patient in the tetracycline plus streptomycin, doxycycline plus rifampicin, and doxycycline plus streptomycin groups respectively.

7.4 Adverse drug reactions

Serious drug reactions leading in treatment regimen change were seen in one patient in doxycycline plus streptomycin (vertigo related to streptomycin), and one patient in tetracycline plus streptomycin group (lupus‐like rash on the face and erythema related to tetracycline).

8 Doxycycline plus streptomycin versus other regimens

Lang 1992 (n = 18) compared doxycycline plus streptomycin regimen (28 and 14 days) with a monotherapy with ceftriaxone maximum 2 g daily for at least two weeks. The initial goal was to include 66 patients but the study was discontinued early after evaluation of the first 18, because six out of eight patients in the ceftriaxone group showed treatment failure, and were switched to the other group after one week. Out of two who responded initially in ceftriaxone group, one developed relapse three weeks after completion of therapy. In contrast, all 10 patients in the doxycycline plus streptomycin group responded well to the therapy and did not show any signs of relapse or therapeutic failure during the six month follow‐up. No adverse reaction was seen in either group.

9 Co‐trimoxazole versus other regimens

Alavi 2007 (n = 102) compared doxycycline plus rifampicin regimen with doxycycline plus co‐trimoxazole. The follow‐up period was about three months in this study.

Montejo 1993a (n = 200) reported the comparison between doxycycline plus rifampicin regimen administered for 28 days with co‐trimoxazole (six months) and doxycycline (six weeks) monotherapy.

Buzon 1982 (n = 84) reported the comparison of a regimen consisting of tetracycline plus rifampicin for four weeks with a six month treatment with co‐trimoxazole.

Hassanjani Roushan 2004 (n = 280) compared co‐trimoxazole plus doxycycline for eight weeks with co‐trimoxazole plus rifampicin for eight weeks.

Hassanjani Roushan 2005 (n = 79) compared two regimens of co‐trimoxazole plus rifampicin administered for six and eight weeks.

9.1 Total treatment failure

In Alavi 2007, the risk of total treatment failure was higher in doxycycline plus rifampicin group compared to doxycycline plus co‐trimoxazole, with a Mantel‐Hanszel RR of 2.8 (95% CI 0.95 to 8.24).

In Montejo 1993a, at one year follow‐up, total treatment failure was higher among doxycycline plus rifampicin (30 days) than doxycycline alone (6 weeks) group, with a Mantel‐Hanszel RR of 1.64 (95% CI 0.79 to 3.39). The risk of total treatment failure was also higher in the doxycycline plus rifampicin (30 days) group than co‐trimoxazole alone (six months) group, with a M‐H RR of 2.46 (95% CI 1.02 to 5.94).

In Buzon 1982, at six‐month follow‐up, total treatment failure was seen in 17 (45%) patients in co‐trimoxazole group and 8 (17%) patients in tetracycline plus rifampicin group.

In Hassanjani Roushan 2004, at one year follow‐up, total treatment failure was seen in 22 cases of co‐trimoxazole plus doxycycline, and 37 cases of co‐trimoxazole plus rifampicin group, with a Mantel‐Hanszel RR of 0.59 (95% CI 0.39 to 0.9).

At one‐year follow‐up, Hassanjani Roushan 2005 reported six cases of total treatment failure in the six‐week group, and one in the eight‐week group, with a Mantel‐Hanszel RR of 5.56 (95% CI 0.7 to 44.09).

9.2 Relapse

At the six month follow‐up, Alavi 2007 reported six cases of relapse in the doxycycline plus rifampicin group, and three in the doxycycline plus co‐trimoxazole group.

In Montejo 1993a, at one year follow‐up, relapse was reported in 14 cases of doxycycline plus rifampicin (30 days) group, two cases of co‐trimoxazole alone (six months), and 10 cases of doxycycline alone.

Buzon 1982 did not report the frequency of relapse in the study groups.

At 12 month follow‐up, Hassanjani Roushan 2004 reported 10 cases of symptom persistence in co‐trimoxazole plus doxycycline group, and 14 cases in co‐trimoxazole plus rifampicin group, with a Mantel‐Hanszel RR of 0.71 (95% CI 0.34 to 1.5).

At one year follow‐up, Hassanjani Roushan 2005 reported three cases of relapse in the six week group, and only one case of relapse in the eight week group.

9.3 Persistence of symptoms

Alavi 2007 reported five cases of symptom persistence in doxycycline plus rifampicin group, and one in the doxycycline plus co‐trimoxazole group.

Montejo 1993a reported symptom persistence in one patient of doxycycline plus rifampicin (30 days) group, four patients in co‐trimoxazole alone (six months), and no one in the doxycycline alone group.

Buzon 1982 did not report the frequency of symptom persistence in the study groups.

Hassanjani Roushan 2004 reported 12 cases of relapse in co‐trimoxazole plus doxycycline group, and 23 cases in co‐trimoxazole plus rifampicin group, with a Mantel‐Hanszel RR of 0.52 (95% CI 0.28 to 0.96).

Hassanjani Roushan 2005 reported three cases of persistence of symptoms in the six week group, and nobody in the eight week group.

9.4 Adverse drug reactions

Alavi 2007 did not address the assessment of adverse reactions.

Montejo 1993a did not report the rate of adverse reactions in each group separately.

In Buzon 1982, serious adverse reactions warranting the change in regimen happened in eight cases in co‐trimoxazole group and no one in the tetracycline plus rifampicin group.

Hassanjani Roushan 2004 reported two cases of adverse reaction in cotrimoxazole plus doxycycline group (erythema multiform in one case, vomiting in one case), and seven cases in co‐trimoxazole plus rifampin group (three cases had skin rash and four experienced vomiting).

Hassanjani Roushan 2005 did not address the assessment of adverse reactions.

10 Ampicillin versus other regimens

McDevitt 1970 (n = 54) conducted a double‐blind study to compare ampicillin 1 g four times a day orally for 28 days with placebo. They did not report the relapse and persistence of symptoms as study outcomes. At one month follow‐up, a total of six patients in the ampicillin group and seven patients in the placebo group subjectively felt better.

Discussion

Summary of main results

The meta‐analysis showed that, in adult patients suffering from brucellosis, doxycycline plus rifampicin regimen administered for six weeks results in slightly more treatment failure (relapse and persistence of symptoms) than the regimen consisting of doxycycline for six weeks and streptomycin for two or three weeks, with a Number Needed to Treat (NNT) of 18, as well as a non‐significant more minor adverse reactions with a Number Needed to Harm (NNH) of 13. These findings are based on pooling of the findings from seven and five low quality, randomized controlled trials respectively.

In addition, the meta‐analysis of three small studies showed that doxycycline plus rifampicin regimen for six weeks results in a slightly more minor adverse reactions (NNH = 7) and fairly longer fever duration (approximately one day) than the regimen consisting of a quinolone (ofloxacin or ciprofloxacin) and rifampicin administered for six weeks. Pooling of the results of three small studies did not show any significant difference in terms of total treatment failure between two regimens. The quality of evidence was low.

Adding another antibiotic, eg amikacin (Ranjbar 2007), to the doxycycline plus rifampicin regimen may have some beneficial effects on the relapse and treatment failure rates. However, this finding is only based on a single low quality randomized controlled trial.

Current evidence is not enough to compare various dosages and treatment durations in doxycycline plus rifampicin regimens. Only one study (Montejo 1993a) showed that, the regimen lasted for 30 days is significantly less effective than the doxycycline monotherapy for six weeks.

The evidence is not also sufficient to compare the effectiveness of quinolone plus rifampicin with doxycyline plus streptomycin. Based on the current available evidence, it is not possible to draw firm conclusions on the effectiveness of other antibiotic combinations, including doxycycline plus quinolone, tetracycline plus streptomycin, co‐trimoxazole plus rifampicin, and co‐trimoxazole plus doxycycline.

The meta‐analysis of two studies on comparing doxycyline plus gentamycin with doxycycline plus streptomycin showed a slight non‐significant superiority of doxycycline plus gentamycin in terms of treatment failure (NNT = 23). However, doxycycline plus gentamycin showed a modestly higher risk of minor adverse reactions (NNH = 24).

Overall completeness and applicability of evidence

All included studies were limited to adult patients with brucellosis, and current findings are not applicable to children, pregnant women, and patients with complications like spondylitis and neurobrucellosis. The dosages and treatment durations were quite homogenous among studies assessing the effect of doxycycline plus rifampicin and doxycycline plus streptomycin. In terms of outcomes, some studies did not perform any explicit assessment of minor adverse reactions, so the findings regarding adverse drug reactions should be interpreted with caution. We excluded all studies which included only the patients with spondylitis, or the studies in which separate information were not provided for the patients without spondylitis. The reason is that, spinal and neurological complications of brucellosis do not respond well to conventional treatment regimens, and generally require longer treatment durations, which is an important source of heterogeneity.

Quality of the evidence

All studies were randomized controlled trials. However, more than half of studies did not describe the methods of allocation and concealment sufficiently. In addition, only three studies were blinded, and patients and care providers were not aware of group allocation. The definition of relapse and treatment failure in most of studies was based on objective bacteriological or serological measures, which were not very sensitive to masking of group allocation.

Some studies did not explicitly describe missing patients at each follow‐up session. Since the effect of treatment is assessed by the frequency of relapse and persistence of symptoms, detailed reporting of missing data is of special importance. Lack of sufficient reporting of missing data in some studies affects the overall quality of evidence.

Potential biases in the review process

Our search strategy was comprehensive, and was not limited to language and publication status. We covered the major international and local bibliographic databases, specialty journals, grey literature, and conferences in the field. We used a clear inclusion criteria and thorough quality assessment methodology to appraise the studies. Some information were missing in a few studies which were mainly published in the form of abstracts. This was reflected in the risk of bias tables. Two independent reviewers screened and appraised the studies, and extracted data, using pre‐designed assessment and data extraction forms. However, since brucellosis is the disease of the developing world, publication bias seems likely.

Agreements and disagreements with other studies or reviews

We showed that, doxycycline plus streptomycin regimen is superior to doxycycline plus rifampicin and other alternatives. This finding is consistent with the recommendations of Ioannina expert panel (Ariza 2007). WHO guidelines on treatment of human brucellosis recommended both regimens, doxycycline plus rifampicin and doxycycline plus streptomycin, as equally effective in uncomplicated brucellosis (WHO 2006). This recommendation is based on expert opinions and contradicts with the findings of current systematic review. Doxycycline plus streptomycin results in a significantly lower rate of relapse, symptom persistence, and adverse drug reactions in comparison to doxycycline plus rifampicin regimen. Skalsky 2008 and Solis Garcia del Pozo 2012 in a systematic review on treatment of human brucellosis similarly showed the superiority of doxycycline plus streptomycin regimen. Despite superiority in effectiveness, it has been shown that, practitioners prefer the doxycycline plus rifampicin regimen over doxycycline plus streptomycin because of the ease of administration and lower costs (Pappas 2007). Shorter treatment durations for streptomycin administration may improve the adherence. We found that the administration of streptomycin for two or three weeks yielded fairly similar results, which was consistent with the findings of Solis Garcia del Pozo 2012. On the other hand, the non‐significant superiority of five or seven days of gentamycin administration as an alternative to streptomycin is worth more attention.These findings should be investigated in future studies, in order to find a regimen which is both effective and is tolerated well.

We did not find any significant difference in total treatment failure between doxycycline plus rifampicin and quinolone plus rifampicin treatments, and showed non‐significant favourable results for quinolone plus rifampicin in terms of side effects, and a significant shorter time to defervescence. Based on these findings, there is not sufficient evidence for inferiority of quinolone‐containing regimens compared to other drug treatments. Ioannina expert panel did not support wide use of quinolone‐containing regimens, due to the lack of convincing evidence of efficacy, higher cost, and the risk of resistance to quinolones in the community (Ariza 2007). Skalsky 2008 pooled all the studies with the regimens containing quinolones and compared them with non‐quinolone regimens. They showed a significant difference in favour of non‐quinolone regimens in terms of total treatment failure. Based on this comparison they did not recommend quinolones as a treatment option for treating human brucellosis. However, quinolone and non‐quinolone groups were obviously heterogeneous regarding treatment duration and other administered drugs. While Solis Garcia del Pozo 2012 did not show any difference between doxycycline plus rifampicin and quinolone plus rifampicin treatments.

Authors' conclusions

Where applicable, doxycycline (six weeks) plus streptomycin (two or three weeks) regimen is more effective and more tolerable regimen than doxycycline plus rifampicin (six weeks). Since daily IM injection is required, access to care and cost are important factors in deciding between two choices.

It seems that the doxycycline plus rifampicin regimen should be administered long enough to be effective, and one month is not an adequate treatment duration.

Based on low quality evidence, quinolone plus rifampicin (six weeks) regimen did not have any difference with doxycycline plus rifampicin, in terms of overall effectiveness, and was slightly better tolerated.

Monotherapy is not recommended in treatment of brucellosis.

Most of the trials in the field of brucellosis have several weaknesses in terms of design and reporting. The details of random allocation and concealment were not reported in many studies. In addition, since the outcomes of interest ie symptom persistence, relapse, and adverse drug effects, does not occur frequently, even a small number of missing values may affect the dependability of findings. We suggest conducting large, well‐designed, randomized controlled trials with more precise definitions of the disease, study population, treatment regimens, outcomes, and long enough follow‐ups,especially on the effectiveness of shorter durations of streptomycin treatment (eg two weeks), short‐term administration of gentamycin as an alternative to streptomycin, and newer generations of quinolone containing regimens. More detailed reporting of the reasons for patient drop‐outs is also recommended.

We recommend a cost‐effectiveness analysis to formally compare doxycycline plus rifampicin and doxycycline plus streptomycin regimens, since the latter is more effective and also more costly.

Given that a noticeable percentage of relapse happened later than six months after beginning of treatment, we suggest brucellosis trials to follow patients for at least one year. Six month follow‐up is insufficient in assessing the overall effectiveness of treatment regimens.

We also recommend high quality randomized controlled trials on the treatment of childhood and complicated brucellosis (e.g. spondylitis), since there is no convincing evidence on the effectiveness of pharmaceutical treatments on these sub‐populations.

Acknowledgements

We thank Dr Mahtab Rabbani‐Anari for her contributions in developing the protocol and assessing some studies. We thank Dr Arash Rashidian (Center for Academic and Health Policy, Tehran University of Medical Sciences) and Dr Sirus Jafari (Infectious Diseases Department, Imam Khomeini hospital) for commenting on the draft protocol. The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of developing countries.

Data and analyses

Comparison 1

Doxycycline plus rifampicin (DR) versus doxycycline plus streptomycin (DS)

Comparison 2

Doxycycline plus rifampicin (DR) versus quinolones plus rifampicin (QR)

Comparison 3

Doxycycline plus streptomycin (DS) versus quinolones plus rifampicin (QR)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total treatment failure	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Follow up duration less than 6 months	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.33, 1.44]
1.2 Follow up duration more than 6 months	1	73	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.23, 2.29]
2 Relapse	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 Follow up duration less than 6 months	1	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.15, 2.37]
2.2 Follow up duration more than 6 months	1	73	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.20, 2.98]
3 Persistence of symptoms	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.23, 3.00]
4 Adverse drug reactions Open in a separate window Analysis 3.4 Comparison 3 Doxycycline plus streptomycin (DS) versus quinolones plus rifampicin (QR), Outcome 4 Adverse drug reactions.	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 Severe (drug regimen changed)	1	73	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.02, 10.08]
4.2 Minor (drug regimen did not change)	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.65, 2.01]
4.3 All adverse reactions	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.63, 1.90]

Comparison 4

Doxycycline plus rifampicin (DR) versus doxycycline plus quinolone (DQ)

Comparison 5

Doxycycline plus streptomycin (DS) versus doxycyline plus gentamycin (DG)

History

Protocol first published: Issue 2, 2008 Review first published: Issue 10, 2012

Differences between protocol and review

The contact reviewer changed. Two authors of the protocol were acknowledged for their contributions.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of studies awaiting assessment [ordered by study ID]

Contributions of authors

All authors participated in the preparation of the protocol, assessing the quality of studies, and data extraction. RYN performed all the analyses. All authors commented and endorsed the final review contents.

Sources of support

Internal sources

• Tehran University of Medical Sciences, Iran.

External sources

• No sources of support supplied

Declarations of interest

None known.

References

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