Safety and Efficacy of Nemonoxacin vs Levofloxacin in Patients With Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis of Randomized Control Trials

Community-acquired pneumonia is a leading cause of morbidity and mortality throughout the world, which incurs significant healthcare costs. The aim of his meta-analysis is to assess the clinical efficacy and safety of a novel non-fluorinated quinolone, nemonoxacin, compared with levofloxacin in treating community-acquired pneumonia (CAP). A recursive literature search was conducted using PubMed, Google Scholar, and Scopus up to August 2022. All randomized clinical trials comparing nemonoxacin to levofloxacin for community-acquired pneumonia were included. The patients selected for this study had mild to moderate CAP. Each individual received treatment with either nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) for a duration of 3-10 days. Four randomized control trials with a total of 1955 patients were included. Nemonoxacin and levofloxacin were found to have similar clinical cure rates in the treatment of CAP. There were no significant differences reported in the treatment-emergent adverse events between the two drugs (RR=0.95, 95% CI: 0.86, 1.08, I2=0%). However, the most frequent symptoms exhibited were gastrointestinal system-related. Both the dosages (500 mg and 750 mg) of nemonoxacin were found to have similar efficacy as that of levofloxacin. Our meta-analysis indicates that nemonoxacin is a well-tolerated and effective antibiotic therapy for the treatment of community-acquired pneumonia (CAP), with clinical success rates comparable to those of levofloxacin. Furthermore, the adverse effects associated with nemonoxacin are generally mild. Therefore, both the 500 mg and 750 mg dosages of nemonoxacin can be recommended as appropriate antibiotic therapy regimens for the treatment of CAP.

topoisomerase IV, exhibits potent in vitro and in vivo activities against community-acquired pneumonia pathogens, including multidrug-resistant Streptococcus pneumoniae, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and ertapenem-nonsusceptible Enterobacteriaceae [8][9][10]. The reduced incidence of toxic adverse effects is linked to the absence of fluorine moiety from nemonoxacin's quinolone structure [11]. Levofloxacin is a fluoroquinolone with broad-spectrum activity against several bacterial pathogens that cause CAP, including gram-positive and gram-negative bacteria, as well as antibiotic-resistant pathogens. It has proven to be an effective agent against penicillin-sensitive and penicillin-resistant Streptococcus pneumonia, which is by far the main causative agent of CAP [12]. Unlike levofloxacin, an additional characteristic of nemonoxacin is that it has shown poor activity against Mycobacterium tuberculosis (TB), multidrug-resistant TB, and non-multidrugresistant TB [13]. Thus, its use would not mask or delay the diagnosis of TB [14]. In 2010, a study was done in Taiwan, China, and South Africa that investigated the efficacy and safety of nemonoxacin compared to that of levofloxacin in CAP outpatients. It was reported that nemonoxacin was not inferior to levofloxacin in either the evaluable intent-to-treat population or the clinical per protocol (PPc) population [15][16][17]. Although both drugs have been established as effective treatments for CAP, the safety and efficacy of nemonoxacin compared with levofloxacin remain controversial. Both drugs have favorable outcomes in treating the notorious illness, CAP. Unfortunately, despite the beneficial effects, these drugs come with their personalized set of adverse outcomes.
Few studies have compared the safety and efficacy of nemonoxacin and levofloxacin [14][15][16][17]. As a consequence, there is a limited comparative profile of the potency and effectiveness of these drugs. To analyze the safety and efficacy, a larger sample size along with variable outcomes is required. Because the studies are conducted in heterogeneous populations, therefore sample size is not adequate to explicate the desired concerns. Therefore, we analyzed the recent results to find a comprehensive overview of the safety and efficacy of nemonoxacin versus levofloxacin in the treatment of CAP. This is the first recently updated meta-analysis to the best of our knowledge.

Review Materials and method
This systematic review and meta-analysis were conducted by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. An institutional review board (IRB) approval was not sought for this study as the data was publicly available.

Search Strategy
To retrieve all relevant articles, a literature review was conducted from inception to 13th February 2023 on PubMed, Google Scholar, and Scopus using a formulated search string. The search string was constructed based on different criteria of this study, using and combining key terms such as community-acquired pneumonia, pneumonia, CAP, nemonoxacin, quinolone, non-fluorinated quinolone, levofloxacin, ofloxacin, which resulted in the formation of the following Medical Subject Heading (MeSH) [CAP]]. The detailed search strategy is given in the table in the appendix. The search string compared the safety and efficacy of the two quinolone drugs, namely nemonoxacin (given in two different dosages, 500 mg and 750 mg) versus levofloxacin (500 mg) administered to patients [who also had several different underlying disorders] suffering from communityacquired pneumonia. All articles were then transferred to EndNote™ X7 for the removal of duplicate studies. Two independent reviewers (AS and AI) screened the remaining articles based on the title and abstract before conducting a full-text screening. A third reviewer (AA) was consulted in the case of disparities. Studies were initially shortlisted based on title and abstract, after which the full text was assessed for eligibility. The references of the selected studies were also reviewed thoroughly.

Eligibility Criteria
Inclusion criteria: The meta-analysis included studies that met specific criteria. Firstly, the studies must have been published in English and have full text readily available for review. Secondly, all studies had to be randomized control trials (RCT), with patients of any age, ethnicity, and body mass index suffering from community-acquired pneumonia and any of the following underlying disorders: hypertension, diabetes mellitus, chronic obstructive pulmonary disease (COPD), chronic bronchitis (CB), hepatitis B, hyperlipidemia, allergic rhinitis, and tuberculosis. Thirdly, the studies had to involve treatment with quinolones, namely nemonoxacin and levofloxacin, with different dosages of 500 mg and 750 mg for nemonoxacin and 500 mg for levofloxacin. The studies assessed common treatment-emergent adverse events (TEAEs) such as ventral nervous system (CNS), red blood cells (RBCs), white blood cells (WBCs), platelets, gastrointestinal tract (GIT), cardiovascular and liver enzymes, and drug-related TEAEs such as RBCs, WBCs, platelets, and gastrointestinal tract. Additionally, the studies underwent a comprehensive evaluation to ascertain whether they provided sufficient information on each drug group's safety, efficacy, and side effect profile independently.
Exclusion criteria: Certain types of studies were excluded to ensure the quality of the meta-analysis. These included reviews, editorials, protocols, case reports, and studies without comparison and outcomes. Only studies that had a placebo and control group were included. Duplicates of previous publications should have been considered. In addition, studies that did not provide sufficient data for estimating a mean difference (MD) with a 95% confidence interval (CI) were excluded from the meta-analysis. These exclusion criteria were implemented to ensure the validity and reliability of the findings in the meta-analysis.

Data Extraction
The studies done by the data extraction team (AS and AI) that were to be included in the meta-analysis had the first author's name, the year in which the relevant randomized control trial was published, type and phase of the RCT trial, duration of RCT trial study, race and ethnicity, underlying comorbidities, dosages of drugs administered, the total number of patients included in the study, and several patients in individual groups (nemonoxacin 500 mg and 750 mg) and levofloxacin (750 mg). Outcomes of interest include common and drug-related TEAEs. Common TEAEs can be defined as neutropenia, thrombocytopenia, diarrhea, nausea, vomiting, stomach upset/abdominal discomfort, abnormal liver functions, elevated serum aspartate transaminase (AST), elevated alanine transaminase (ALT), QT prolongation, headache, skin rash, dizziness, and leukopenia. Drug-related TEAEs are defined as neutropenia, thrombocytopenia, anemia, diarrhea, nausea, and headache.

Quality Assessment and Risk of Bias
The Cochrane method was used for the evaluation of selected RCTs.

Statistical Analysis
Only comparative studies were analyzed statistically using Review Manager 5.4.1 (The Nordic Cochrane Centre, Denmark) and comprehensive meta-analysis. This meta-analysis provides a pooled effect of relative risks (RRs) for dichotomous outcomes and weighted mean differences (WMDs) for continuous outcomes calculated utilizing the generic-inverse variance with a random-effects model. Forest plots were used to display the results of pooled analyses. To assess publication bias, funnel plots were constructed for the two main outcomes. Low (25%), moderate (25-75%), and high (>75%) levels of heterogeneity were determined using Higgin's I 2 test. All analyses were considered significant if the p-value was less than 0.05.
Since the data was compiled and synthesized from earlier clinical trials for which the researchers had already received informed consent, no ethics committee approval was required for this study.

Study Selection
By applying the search strategy, an extensive search was conducted on three databases (PubMed, Google Scholar, and Scopus), which yielded a total of 1975 results. Implementing the inclusion and exclusion criteria, a total of four studies were excluded in the process of title and abstract screening. The remaining records then underwent full-text review; at last, only four randomized controlled trials that were deemed fit according to our inclusion criteria were inducted for this meta-analysis. The selection process is summarized in Figure 1.

Baseline Characteristics
The selected four RCTs included patients with community-acquired pneumonia, with several underlying diseases (such as hypertension [HTN], DM, COPD, CB, hepatitis B, hyperlipidemia, allergic rhinitis, and tuberculosis), with 1322 patients receiving nemonoxacin (500 mg and 750 mg) and 633 patients receiving levofloxacin (500 mg). The characteristics of the individual studies are summarized in the tables in the appendix. At least two outcomes, namely common TEAEs (sub-classified into the cardiovascular system (CVS), CNS, GIT, liver enzymes, and dermatology) and drug-related TEAEs (GIT and derma), were evaluated in the four studies involving CAP treated with the aforementioned quinolones. The patients participating in each trial were orally administered both quinolones. In three [14][15][16][17] of the four studies, three different dosages (nemonoxacin 500 mg, 750 mg, and levofloxacin 750 mg) were administered, whereas, in one [16], only two dosages (nemonoxacin 500 mg and levofloxacin 750 mg) were administered. None of the studies included a control group.
Regarding the phases, Van Rensburg et al. [14] study was in the second phase, whereas Liu et al. [15] and Yuan et al. [16] studies were in the third phase trials. Finally, Cheng et al. [17] study is a mixture of the second and third phase trial. Regarding the time duration for the RCT, Van Rensburg et al. [14] study was seven days, whereas Liu et al. [15] and Yuan et al. [16] studies were done in 7-10 days. Lastly, Cheng et al. [17] study was done in 3-10 days. As indicated by the research type, Table 1 provides information on the baseline characteristics of the included patients.  RCT-randomized controlled trial; SD -standard deviation

Quality Assessment and Publication Bias
Quality assessment of all the RCTs was done by using the Cochrane Collaboration tool for assessing the risk of bias in randomized trials, which showed that Yuan et al. [16] study was found to be low-risk in selection bias, performance bias, detection bias, and attrition bias. Liu et al. [15] study was found to be low-risk in selection bias, performance bias, detection bias, attrition bias as well as reporting bias. Cheng et al. [17] study was found to be low risk in selection bias, performance bias, detection bias, and attrition bias and was found to be high risk in reporting bias. Van Rensburg et al. [14] study was found to be low risk in selection bias, performance bias, detection bias, and reporting bias, although it was found to be high risk in attrition bias, as shown in Figure 2. Funnel plots of the main outcomes showed that this study has no publication bias, as shown in Figures

Outcomes
All of the studies recruited in this research [14][15][16][17] exhibit a range of side effects of the drugs used. Although these studies have some differences, they share similar outcomes as well. Tables 2 and 3 summarize outcomes on an individual study basis.
Abnormal liver

Common TEAEs
When we compare the safety and efficacy of the two drug regimens, levofloxacin has slightly less risk of inducing common TEAEs as compared to nemonoxacin (RR=0.96 [0.86,1.08], p=0.53, I 2 =0%) as shown in Figure 5. Overall, this adverse event is statistically insignificant as an outcome. GIT-associated adverse events: All four recruited studies [14][15][16][17]  ). Based on the relative risk comparing levofloxacin and nemonoxacin, levofloxacin has a reduced risk of a headache than nemonoxacin. The adverse event of dizziness was found in three out of four studies [14,16,17]. The TEAE plot showed that it was not significant (RR=0.50 [0.23, 1.08], p=0.08, I 2 =0%). The relative risk, while comparing levofloxacin with nemonoxacin, shows that levofloxacin had lesser incidences of dizziness compared to the other drug. The overall analysis based on the p-value of the two plots revealed that CNS-based effects in both groups are nearly the same and insignificant.
Skin-related TEAEs: The data on skin rash was reported in two out of four studies [16,17], and the pooled analysis revealed (RR=4.19 [1.27, 13.84], p=0.02, I 2 =0%) that there is a significantly increased risk of this particular adverse effect. Therefore, skin-related TEAEs were significantly reported in the group taking the levofloxacin regimen.

Drug-related TEAEs
Drug-related common TEAEs were reported in three out of the four papers [14,16,17]. Pooling of these studies demonstrated that the comparison of levofloxacin and nemonoxacin was not significantly causing any statistical difference between the two groups (RR=1.42 [0.58,3.46], p=0.44, I 2 =95%) as shown in Figure 6. Therefore, drug-related TEAEs in both groups are nearly the same. Moreover, based on the p-value, the overall effect of this outcome appears to be insignificant.

RR -relative risk, CI -confidence interval
Drug-related hematological adverse events: To evaluate the influence of drug-related TEAEs blood disorders, the data was reported by two out of four studies [14,17]. The effect on blood-related disorders was examined by the following parameter group. However, this risk was insignificant based on the p-value deduced from the forest plot. p=0.53, I 2 =0%) that there was an increased risk of neutropenia in the group being treated with nemonoxacin as compared to the other group. The pooled analysis revealed that there was a reduced risk of this drugrelated TEAE in the patients on the levofloxacin regimen as compared to nemonoxacin. The overall analysis and the p-value show no statistically significant difference between the two drugs.
Drug-related GIT adverse events: The occurrence of drug-related TEAEs, namely nausea and diarrhea, was reported by two out of four studies [14,17]

Discussion
Community-acquired pneumonia (CAP) is a cause of substantial morbidity, mortality, and resource utilization worldwide [19]. In the RCTs included in our study, the diagnostic criteria for CAP were as follows: patients having fever and/or a WBC count >10,000/mm 3 , and/or a neutrophil count >70% and at least three of the following symptoms -cough, purulent sputum, dyspnea or tachypnea, chest pain, evidence of pulmonary consolidation. Only the cases of the patients suitable for being managed with outpatient therapy with an oral antimicrobial agent were considered and included. Despite the advancements in the treatment of CAP, antimicrobial management is still controversial [20]. The antibiotics used in the RCTs were confirmed with the guidelines of the Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) [21] and the Canadian Infectious Disease Society (CIDS)/Canadian Thoracic Society (CTS).
After an initial assessment of severity, the patients classified as having mild to moderate cases were managed orally.
Our primary outcome analysis based on four RCTs [14][15][16][17] validates that nemonoxacin and levofloxacin are parallel concerning mortality reduction and clinical response in the treatment of CAP. Notably, the clinical cure rates of nemonoxacin were on par with levofloxacin in CAP patients. In the same way, the clinical failure rates were also indistinguishable. Furthermore, both dosages (500 mg and 750 mg) of nemonoxacin were found to be comparable with levofloxacin (750 mg). Lastly, the clinical efficacy of nemonoxacin was analogous to levofloxacin in the treatment of CAP. This meta-analysis aims to compare the efficacy as well as the safety of nemonoxacin and levofloxacin. Our efficacy findings are supported by a previous metaanalysis [22] that evaluated the same antibiotics for the treatment of CAP. However, the previous metaanalysis was based on three RCTs, while this updated meta-analysis is based on four RCTs. Moreover, the previous meta-analysis has mentioned safety concerns as the primary outcome and microbiological response as the secondary outcome [22]. Alternatively, this is the only detailed meta-analysis focused on the safety and efficacy of nemonoxacin and levofloxacin. Three [14][15][16] out of four of our included RCTs have mentioned the safety and efficacy along with the microbiological response acquired from these drugs. On the other hand, Cheng et al. [17] have focused mainly on the clinical cure rates, that is, the safety concerns associated with quinolones.
The adverse reactions of the intervention mainly involve gastrointestinal, hepatic, cardiac, hematologic, and neurological-related symptoms [23]. It was observed that the most frequent adverse event in the gastrointestinal system was nausea, as reported by all four RCTs [14][15][16][17]. Vomiting and epigastric pain were reported by three RCTs and occurred almost evenly in both groups. Diarrhea, nonetheless, was reported by two RCTs [14,17] but was more commonly reported by the nemonoxacin group. It was observed that diarrhea and nausea were drug-related TEAEs, and, therefore, were resolved with the discontinuity of the drug. Henceforth, it is suggested to manage the preventive workup at the earliest possible interval. The overall results, however, favored the safety of the drug. Similar to other quinolones, hepatotoxic side effects, which consist mainly of elevated AST, ALT, and liver function tests (LFTs), were not found to be reported as drugrelated TEAE, although a larger, but not significant, increase of ALT was noted in patients treated with nemonoxacin.
The cardio-toxic side effects include QT interval prolongation and bundle branch blockage [24]. According to Pharmacovigilance Working Party (PhVWP) [25], some fluoroquinolones can cause torsade's de points, especially those that favor QT interval prolongation. When reviewed for safety in this aspect, it was concluded that the fluoroquinolone levofloxacin had a low potential of causing this outcome with no reported cases of torsade's de points [25]. Regarding the bundle branch blockage, only four patients from the nemonoxacin group reported it, contrary to the levofloxacin group, where no such findings were observed. It is recommended to consider the actual condition of the patient's body thoroughly so that there is an immediate adjustment of the medication regimen or stoppage of the treatment [26]. The hematologic adverse events consist of drug-related TEAE, which includes neutropenia and thrombocytopenia, and common TEAE, which includes leukopenia and skin rash. No such effects were significantly reported by either of the groups. Lastly, a few neurological symptoms, mainly dizziness and headache, were also reported by some patients in various studies [27].
We found a few differences in the drug-related TEAE. The most significant difference was found concerning intestinal events. In contrast to Cheng et al. [17] study, which reported more cases of drug-related diarrhea in the nemonoxacin group and, therefore, favored levofloxacin, the study by van Rensburg et al. [14] reported more such cases in the levofloxacin group, hence favoring nemonoxacin. However, as only two studies have reported diarrhea [14,17] as a drug-related TEAE with variable outcomes, we can conclude that this may have been an outcome of high-observed heterogeneity and, hence, have precluded the detection of this side effect with levofloxacin.
There is an association found between nausea and thrombocytopenia in patients treated with nemonoxacin [28]. However, when compared with levofloxacin, we deduced that it was more frequent in nemonoxacin. Neutropenia was seen in the nemonoxacin group, but a significant conclusion cannot be procured as individual differences between the 1260 patients were minimal. Finally, the overall drug-related TEAE further affirms a non-significant difference in the drug safety profiles.
The core strength of our research is that it is solely based on RCTs; therefore, there is a reduced risk of bias. Moreover, this updated meta-analysis has focused mainly on safety and efficacy by analyzing the TEAEs of the respective drugs. Furthermore, the robustness of this meta-analysis can be considered more convincing than individual RCTs. Lastly, this meta-analysis can resolve the dissimilitude between the studies, which can help in yielding conclusive results for the greater good of pharmacotherapy in patients suffering from CAP.
Conversely, there are certain limitations to this study. Firstly, a limited number of studies were included in this meta-analysis; therefore, the risk of heterogeneity may be underestimated. Secondly, the results of this analysis cannot be generalized to the unselected population due to the narrow inclusion criteria of RCTs. In addition, the degree of severity of CAP in this study was mild to moderate. Therefore, further studies are required to evaluate the use of nemonoxacin in severe CAP. Thirdly, this meta-analysis is based on the use of oral nemonoxacin. Further investigations are required for the safety and efficacy of intravenous nemonoxacin.

Conclusions
Succinctly, 500 mg or 750 mg of oral nemonoxacin administered once daily for seven to 10 days showed robust clinical efficacy in treating adult CAP. Moreover, although nearly all treatment-emergent adverse events are higher in the nemonoxacin group, statistically, we should consider it equally well tolerated as levofloxacin because the differences are not significant. Thus, nemonoxacin can be recommended as an appropriate antibiotic therapy for mild to moderate CAP.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.