METHODS: We selected randomized controlled trials, assessing efficacy of antibiotics for the treatment of leptospirosis as a case study. A pairwise meta-analysis was conducted using a random effect model, assuming that different studies assessed different but related treatment effects. The analysis was then extended to a network meta-analysis, which consists of direct and indirect evidence in a network of antibiotics trials, using a suite of multivariate meta-analysis routines of STATA (mvmeta command). We also assessed an assumption of 'consistency' that estimates of treatment effects from direct and indirect evidence are in agreement.
RESULTS: Seven randomised controlled trials were identified for this analysis. These RCTs assessed the efficacy of antibiotics such as penicillin, doxycycline and cephalosporin for the treatment of human leptospirosis. These studies made comparisons between antibiotics (i.e. an antibiotic versus alternative antibiotic) in the primary study and a placebo, except for cephalosporin. These studies were sufficient to allow the creation of a network for the network meta-analysis; a closed loop in which three comparator antibiotics were connected to each other through a polygon. The comparison of penicillin versus the placebo has the largest contribution to the entire network (31.8%). The assessment of rank probabilities indicated that penicillin presented the greatest likelihood of improving efficacy among the evaluated antibiotics for treating leptospirosis.
CONCLUSIONS: Findings suggest that network meta-analysis, a meta-analysis comparing multiple treatments, is feasible and should be considered as better precision of effect estimates for decisions when several antibiotic options are available for the treatment of leptospirosis.
METHODS: Two independent reviewers (KY and SJ) screened two electronic databases, PubMed and Scopus, for randomized clinical trials on the use of systemic doxycycline as an adjunct to scaling and root planing in improving periodontal status and glycemic control in diabetic patients with periodontitis using predetermined selection criteria within a 3-month period. The reviewers independently did data screening, data selection, data extraction and risk of bias. Quality of studies involved was analysed using the revised Cochrane Risk of Bias 2.0. Weighted standard mean differences (SMD) and 95% confidence intervals were calculated using a random effects meta-analysis model. Publication bias was evaluated using funnel plot. Quality of evidence was evaluated by Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
RESULTS: Electronic searches provided 1358 records and six studies were selected. The meta-analyses indicated that there was no statistically significant difference in the improvement of periodontal status with the use of systemic doxycycline as an adjunct for scaling and root planing (SRP). SMD of clinical attachment levels (- 0.22 [- 0.52, 0.08]) and HbA1c levels (- 0.13 [- 0.41, 0.15]) were calculated. Overall risk of bias is high in 2 out of 6 studies involved.
CONCLUSION: Systemic doxycycline when used in addition to scaling and root planing yields no significant improvement of clinical attachment levels for periodontal status and reduction of HbA1c levels in treatment of diabetic patients with periodontitis when comparing the test group to the control group.
OBJECTIVES: To assess and compare the effects of different antibiotic regimens for treatment of scrub typhus.
SEARCH METHODS: We searched the following databases up to 8 January 2018: the Cochrane Infectious Diseases Group specialized trials register; CENTRAL, in the Cochrane Library (2018, Issue 1); MEDLINE; Embase; LILACS; and the metaRegister of Controlled Trials (mRCT). We checked references and contacted study authors for additional data. We applied no language or date restrictions.
SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs comparing antibiotic regimens in people with the diagnosis of scrub typhus based on clinical symptoms and compatible laboratory tests (excluding the Weil-Felix test).
DATA COLLECTION AND ANALYSIS: For this update, two review authors re-extracted all data and assessed the certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for dichotomous outcomes when appropriate, and elsewhere tabulated data to facilitate narrative analysis.
MAIN RESULTS: We included six RCTs and one quasi-RCT with 548 participants; they took place in the Asia-Pacific region: Korea (three trials), Malaysia (one trial), and Thailand (three trials). Only one trial included children younger than 15 years (N = 57). We judged five trials to be at high risk of performance and detection bias owing to inadequate blinding. Trials were heterogenous in terms of dosing of interventions and outcome measures. Across trials, treatment failure rates were low.Two trials compared doxycycline to tetracycline. For treatment failure, the difference between doxycycline and tetracycline is uncertain (very low-certainty evidence). Doxycycline compared to tetracycline may make little or no difference in resolution of fever within 48 hours (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.90 to 1.44, 55 participants; one trial; low-certainty evidence) and in time to defervescence (116 participants; one trial; low-certainty evidence). We were unable to extract data for other outcomes.Three trials compared doxycycline versus macrolides. For most outcomes, including treatment failure, resolution of fever within 48 hours, time to defervescence, and serious adverse events, we are uncertain whether study results show a difference between doxycycline and macrolides (very low-certainty evidence). Macrolides compared to doxycycline may make little or no difference in the proportion of patients with resolution of fever within five days (RR 1.05, 95% CI 0.99 to 1.10; 185 participants; two trials; low-certainty evidence). Another trial compared azithromycin versus doxycycline or chloramphenicol in children, but we were not able to disaggregate date for the doxycycline/chloramphenicol group.One trial compared doxycycline versus rifampicin. For all outcomes, we are uncertain whether study results show a difference between doxycycline and rifampicin (very low-certainty evidence). Of note, this trial deviated from the protocol after three out of eight patients who had received doxycycline and rifampicin combination therapy experienced treatment failure.Across trials, mild gastrointestinal side effects appeared to be more common with doxycycline than with comparator drugs.
AUTHORS' CONCLUSIONS: Tetracycline, doxycycline, azithromycin, and rifampicin are effective treatment options for scrub typhus and have resulted in few treatment failures. Chloramphenicol also remains a treatment option, but we could not include this among direct comparisons in this review.Most available evidence is of low or very low certainty. For specific outcomes, some low-certainty evidence suggests there may be little or no difference between tetracycline, doxycycline, and azithromycin as treatment options. Given very low-certainty evidence for rifampicin and the risk of inducing resistance in undiagnosed tuberculosis, clinicians should not regard this as a first-line treatment option. Clinicians could consider rifampicin as a second-line treatment option after exclusion of active tuberculosis.Further research should consist of additional adequately powered trials of doxycycline versus azithromycin or other macrolides, trials of other candidate antibiotics including rifampicin, and trials of treatments for severe scrub typhus. Researchers should standardize diagnostic techniques and reporting of clinical outcomes to allow robust comparisons.
CASE PRESENTATION: Here, we report two cases of melioidosis from Nepal. Both of them were diabetic male who presented themselves with fever, multiple abscesses and developed sepsis. They were treated with multiple antimicrobial agents including antitubercular drugs before being correctly diagnosed as melioidosis. Consistent with this, both patients were farmer by occupation and also reported travelling to Malaysia in the past. The diagnosis was made consequent to the isolation of B. pseudomallei from pus samples. Accordingly, they were managed with intravenous meropenem followed by oral doxycycline and cotrimoxazole.
CONCLUSION: The case reports raise serious concern over the existing unawareness of melioidosis in Nepal. Both of the cases were left undiagnosed for a long time. Therefore, clinicians need to keep a high index of suspicion while encountering similar cases. Especially diabetic-farmers who present with fever and sepsis and do not respond to antibiotics easily may turn out to be yet another case of melioidosis. Ascertaining the travel history and occupational history is of utmost significance. In addition, the microbiologist should be trained to correctly identify B. pseudomallei as it is often confused for other Burkholderia species. The organism responds only to specific antibiotics; therefore, correct and timely diagnosis becomes crucial for better outcomes.