All clinical studies were identified through a systematic search of the PubMed, Embase, ClinicalTrials.gov, and Cochrane databases from their inception until April 2022; the following search terms were used: “CSE-1034,” “Elores,” and “RCT.” Randomized controlled studies that compared the clinical efficacy and adverse effects of CSE-1034 and comparators in treating adult patients with acute bacterial infections were included. Articles published in all languages were eligible for inclusion. However, we excluded articles that reported in pharmacokinetic-pharmacodynamic, vitro study, or conference papers. Two reviewers (Lan and Chang) searched and examined publications independently to avoid bias. Any disagreement was resolved and decided by a third reviewer (Lai). The following data were extracted from the included studies: authorship, year of publication, study design, countries, antibiotic regimens of CSE-1034 and comparators, and clinical and microbiological outcomes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol of the review and meta-analysis was registered at PROSPERO [CRD42022308798].

The primary outcome was the clinical cure rate at the end of treatment ([EOT], 5-14 days after randomization); the clinical cure was defined as the resolution of clinical signs and symptoms of acute bacterial infection without the necessity of further antimicrobial therapy. The secondary outcomes were clinical cure rate at test-of-cure ([TOC], 8-12 days after EOT) and at late follow-up ([LFU], 5-9 days after TOC) and microbiological eradication rate at EOT (defined as the absence of admission pathogens).

We used the Cochrane risk-of-bias tool to assess the quality of the included RCTs and the risk of bias ( 8 ). Statistical analyses were conducted through random-effect model analysis using Review Manager (version 5.3). The degree of heterogeneity was evaluated with the Q statistic generated from the χ( 2 ) test. The proportion of statistical heterogeneity was assessed using the I ( 2 ) measure. Heterogeneity was considered significant when P was <.10 or I ( 2 ) was >50%. Pooled risk ratios (RRs) and the corresponding 95% confidence intervals (CIs) were calculated for outcome analyses.

The present search yielded 75 references. After excluding 35 duplicates, we screened the remaining 40 references. Among the screened references, we retrieved 7 for full-text review. Finally, 5 studies ( 5 – 7 , 9 , 10 ) fulfilling the inclusion criteria were included in this meta-analysis (Figure-1). All the studies involved multicenter designs and were conducted in India to compare the clinical efficacy and safety of CSE- 1034 and other comparators for adult patients with acute bacterial infection (Table-1). Two studies ( 5 , 6 ) focused on UTIs, one of which used ceftriaxone as a comparator, and the other used meropenem. Each study ( 7 , 10 ) compared the usefulness of CSE-1034 and ceftriaxone in treating community-acquired pneumonia, skin and skin structure infection (SSSI), and bone and joint infection (BJI). Another study ( 9 ) assessed the efficacy of CSE-1034 in managing lower respiratory tract infections and UTIs. Overall, a total of 950 patients (n:638 in the UTI group, n:186 in the lower respiratory tract infection group, n:70 in the BJI group, and n:56 in SSSI) were included in this meta-analysis, and 478 and 472 patients received CSE-1034 and the relevant comparator, respectively. Four studies had a high risk of bias in the following domains, including allocation concealment, blinding of participants and personnel, and blinding of outcome assessment (Figure-2). Overall, CSE-1034 had a higher clinical cure rate at EOT than did its comparator (95.3% [384/403] vs. 81.0% [319/394], RR, 1.20; 95% CI, 1.04-1.39; I ( 2 ) = 92%; Figure 3). Additionally, the clinical cure rates of CSE-1034 at LFU and TOC were higher than those of the comparator (LFU: RR, 4.32; 95%CI, 2.21-10.55; I ( 2 )=0%; TOC: RR, 7.54; 95%CI, 1.90-29.97; I ( 2 )=44%) in the pooled analysis of 3 studies that reported these outcomes. This trend was observed in the subgroup analysis of patients with lower respiratory tract infections (100% [92/92] vs. 89.8% [74/91], RR, 1.22; 95%CI, 1.10-1.35; I ( 2 )=0%). In the patients with BJIs and SSSIs, CES-1034 was associated with a higher cure rate than the comparator (Figure-3). However, in the subgroup with UTIs, no significant difference in clinical cure rate was observed between CSE- 1034 and the comparator (99.1% [234/246] vs. 89.8% [225/242], RR,1.15; 95%CI, 0.97-1.14; I ( 2 )=81%; Figure 3). In contrast, the overall clinical failure rate of CSE-1034 was also lower than that of the comparators (RR, 0.04; 95%CI, 0.01-0.13; I ( 2 )=0%). Additionally, in the pooled analysis of 4 studies using ceftriaxone as a comparator, CSE- 1034 exhibited a higher clinical cure rate (94.8% (312/329) vs. 77.2% 251/325), RR, 1.25; 95%CI, 1.07-1.45; I ( 2 )=86%).

Overall, CSE-1034 had a higher microbiological eradication rate at EOT than the comparator (92.9% [315/339] vs. 71.1% [216/304], RR, 1.53; 95%CI,1.06-2.21; I ( 2 )=97%; Figure-4). Additionally, the microbiological eradication rates of CSE- 1034 were similar to those of the comparator at LFU (RR, 2.98; 95% CI, 0.44-20.08; I ( 2 )=74%) but higher than those of the comparator at TOC (RR,5.42; 95%CI, 1.88-15.56; I ( 2 )=37%) in a pooled analysis of 3 studies reported the outcomes. In the subgroup of patients with lower respiratory tract infections, the microbiological eradication rate was higher for CSE-1034 than for the comparator (95.7% [67/70] vs. 61% [25/41], RR, 1.15; 95%CI, 1.19-1.93; I ( 2 )=0%; Figure-4), and the similar trend was observed for patients with BJI and SSSIs. In contrast, no difference was observed in the subgroup analysis of patients with UTIs (96.1% [196/204] vs. 87.1% [176/202], RR, 110; 95%CI, 0.91-1.34; I ( 2 )=92%; Figure-4). In the pooled analysis of four studies using ceftriaxone as comparator, CSE-1034 exhibited a higher eradication rate (91.3% [242/265] vs. 63.0% [148/235], RR, 1.58; 95%CI, 1.19-2.09; I ( 2 )=86%). CSE-1034 showed a similar eradication rate to the comparator against Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumanii, Enterobacter spp., Proteus spp., Pseudomonas aeruginosa.