Efficacy of drug treatment for severe melioidosis and eradication treatment of melioidosis: A systematic review and network meta-analysis

Background: This systematic review and network meta-analysis (NMA) aimed to compare the efficacy of all available treatments for severe melioidosis in decreasing hospital mortality and to identify eradication therapies with low disease recurrence rates and minimal risk of adverse drug events (AEs). Methodology: Relevant randomized controlled trials (RCT) were searched from Medline and Scopus databases from their inception until July 31, 2022. RCTs that compared the efficacy between treatment regimens for severe melioidosis or eradication therapy of melioidosis, measured outcomes of in-hospital mortality, disease recurrence, drug discontinuation, or AEs, were included for review. A two-stage NMA with the surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of treatment regimens. Principal findings: Fourteen RCTs were included in the review. Ceftazidime plus granulocyte colony-stimulating factor (G-CSF), ceftazidime plus trimethoprim-sulfamethoxazole (TMP-SMX), and cefoperazone-sulbactam plus TMP-SMX had a lower mortality rate than other treatments and were ranked as the top three most appropriate treatments for severe melioidosis with the SUCRA of 79.7%, 66.6%, and 55.7%, respectively. However, these results were not statistically significant. For eradication therapy, treatment with doxycycline monotherapy for 20 weeks was associated with a significantly higher risk of disease recurrence than regimens containing TMP-SMX (i.e.,TMP-SMX for 20 weeks, TMP-SMX plus doxycycline plus chloramphenicol for more than 12 weeks, and TMP-SMX plus doxycycline for more than 12 weeks). According to the SUCRA, TMP-SMX for 20 weeks was ranked as the most efficacious eradication treatment (87.7%) with the lowest chance of drug discontinuation (86.4%), while TMP-SMX for 12 weeks had the lowest risk of AEs (95.6%). Conclusion: Our results found a non-significant benefit of ceftazidime plus G-CSF and ceftazidime plus TMP-SMX over other treatments for severe melioidosis. TMP-SMX for 20 weeks was associated with a lower recurrence rate and minimal risk of adverse drug events compared to other eradication treatments. However, the validity of our NMA may be compromised by the limited number of included studies and discrepancies in certain study parameters. Thus, additional well-designed RCTs are needed to improve the therapy of melioidosis. Author summary: Melioidosis is a life-threatening infectious disease with a case fatality rate of 21% in Thailand. Furthermore, among patients who survive the acute disease, approximately 23% experience disease recurrence within one year. Despite the high efficacy of currently recommended mono-antibiotic therapies such as ceftazidime or meropenem, the mortality rate in patients with severe melioidosis remains high, ranging from 6%-37%. Thus, several drugs, such as granulocyte stimulating factor (G-CSF) and trimethoprim-sulfamethoxazole (TMP-SMX), have been added to antibiotic monotherapy to enhance its efficacy. However, the efficacy of combined treatments over monotherapies in decreasing mortality rates remains unclear. Additionally, several regimens are available for eradication therapy, which aim to prevent disease recurrence but their efficacy and potential risk of adverse drug events differ. Thus, we conducted a systematic review and network meta-analysis with the aims of comparing the hospital mortality among all available treatments for severe melioidosis, and identifying eradication therapies that effectively decrease disease recurrence, while also minimizing the risk of adverse drug events. Our findings suggest that ceftazidime plus G-CSF and ceftazidime plus TMP-SMX have lower mortality rates than other medications for treating severe melioidosis. However, this effect did not reach statistical significance. For eradication, TMP-SMX for 20 weeks was associated with a lower recurrence rate and a lower risk of adverse drug events when compared to other regimens. However, the validity of our analyses may be compromised due to the low number of included studies and dissimilarity in some factors among the included studies. These findings will be beneficial for clinicians in selecting the appropriate medications for treating severe melioidosis and preventing disease recurrence. In addition, this study suggests that additional well-designed clinical trials are necessary to improve the treatment of melioidosis.