Acquired Pneumonia: a Systemic Review and Meta- Analysis of Randomized Controlled Trials

Home , Nemonoxacin

Journal name: Infection and Drug Resistance Article Designation: Original Research Year: 2019 Volume: 12 Infection and Drug Resistance Dovepress Running head verso: Chang et al Running head recto: Chang et al open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IDR.S193233

Open Access Full Text Article Original Research The efficacy and safety of nemonoxacin compared with levofloxacin in the treatment of community- acquired pneumonia: a systemic review and meta- analysis of randomized controlled trials

Shen-Peng Chang1 Objectives: This meta-analysis aims to assess the clinical efficacy and safety of nemonoxacin Hong-Zin Lee2 in comparison with levofloxacin in treating community-acquired pneumonia (CAP). Chih-Cheng Lai3 Materials and methods: The Pubmed, Embase, ClinicalTrials.gov., and the Cochrane data- Hung-Jen Tang4 bases were searched up to September 2018. Only randomized controlled trials (RCTs) evaluating nemonoxacin and levofloxacin in the treatment of CAP were included. The primary outcome 1Department of Pharmacy, Chi Mei Medical Center, Liouying, was the clinical cure rate, and the secondary outcomes included the microbiologic response Taiwan; 2School of Pharmacy, China rate and the risk of adverse events. Medical University, Taichung, Taiwan; For personal use only. Results: Three RCTs were included. Overall, nemonoxacin and levofloxacin had similar clini- 3Department of Intensive Care 2 Medicine, Chi Mei Medical Center, cal cure rates in the treatment of CAP (OR =1.05, 95% CI =0.67–1.64, I =0%). Nemonoxacin Liouying, Taiwan; 4Department of also had a microbiologic response rate similar to levofloxacin (OR= 0.89, 95% CI =0.44–1.81, Medicine, Chi Mei Medical Center, I2=0%). No significant differences were found in treatment-emergent adverse events between Tainan, Taiwan the two drugs (OR =1.08, 95% CI =0.81–1.43, I2=0%). In subgroup analysis, the similarities in the clinical cure rate, microbiologic response rate, and risk of adverse events of these two drugs remained unchanged with the dose of nemonoxacin (500 or 750 mg) and individual pathogens. Conclusion: The clinical and microbiologic efficacy of nemonoxacin is comparable to that of levofloxacin in the treatment of CAP, and this agent is as well tolerated as levofloxacin. Keywords: nemonoxacin, levofloxacin, community-acquired pneumonia

Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 25-Apr-2020 Introduction Community-acquired pneumonia (CAP) is a common type of infection that can be caused by a variety of microorganisms, including typical pathogens such as Strepto- coccus pneumoniae and Haemophilus influenza and atypical pathogens such as Myco- plasma pneumoniae, Chlamydia pneumoniae, and Legionella species.1,2 In the face of the high morbidity and mortality of this disease, an appropriate antibiotic is the key to treatment.3 Respiratory quinolones, including levofloxacin and moxifloxacin, have good in vitro and in vivo activity against typical and atypical CAP pathogens and are 3 Correspondence: Hung-Jen Tang recommended for treatment. Department of Medicine, Chi Mei Nemonoxacin is a recently developed novel quinolone. In contrast to other qui- Medical Center, No.901, Zhonghua nolones, nemonoxacin is a nonfluorinated C-8 methoxy quinolone which targets Road, Yongkang Dist., Tainan City 71004, Taiwan DNA gyrase and topoisomerase IV. Many in vitro studies have demonstrated its great Tel +886 6 281 2811 ext. 52 606 antibacterial activity.4–8 Nemonoxacin also displays good in vitro activity against Fax +886 6 283 2057 Email [email protected] some antibiotic-resistant pathogens such as methicillin-resistant Staphylococcus

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aureus, penicillin-resistant Streptococcus pneumoniae, and Data analysis ertapenem-non-susceptible Enterobacteriaceae.4,9–12 All of This study used the Cochrane Risk of Bias Assessment tool these findings suggest that nemonoxacin may play a role in to assess the quality of enrolled randomized controlled trials the treatment of CAP.13 Nemonoxacin exhibits poor activity (RCTs) and the risk of bias.19 The software Review Manager, against Mycobacterium tuberculosis (tuberculosis [TB]), version 5.3 was used to conduct the statistical analyses. The including both multidrug-resistant (MDR) TB and non- degree of heterogeneity was evaluated with the Q statistic MDR-TB.14 Thus, unlike levofloxacin and moxifloxacin, generated from the chi-squared test. The proportion of which are active against TB, nemonoxacin may bring an statistical heterogeneity was assessed by the I2 measure. additional benefit in the clinical setting of CAP as its use Heterogeneity was considered significant when the P-value would not mask or delay the diagnosis of TB.13,15 was <0.10 or the I2 was >50%. The random-effects model Recently, several clinical trials16–18 have investigated the was used when the data were significantly heterogeneous, clinical efficacy and safety of nemonoxacin in the treatment and the fixed-effect model was used when the data were of CAP. But there has been no systematic review or meta- homogenous. Pooled ORs and 95% CIs were calculated for analysis comparing the efficacy and safety of nemonoxacin outcome analyses. and other quinolones in treating CAP. Therefore, we per- formed a comprehensive meta-analysis to provide better Results evidence on the efficacy and safety of nemonoxacin in Study selection and characteristics treating CAP. The search program yielded 189 references, including 47 from PubMed, 111 from Embase, 19 from the Cochrane Materials and methods database, and 12 from ClinicalTrials.gov. Finally, three Study search and selection studies16–18 fulfilling the inclusion criteria were included All clinical studies were identified by a systematic review of in this meta-analysis (Figure 1). All studies were random-

For personal use only. the literature in the PubMed, Embase, ClinicalTrials.gov., and ized, double-blind, multicenter studies that were designed Cochrane databases until September 2018 using the follow- to compare the clinical efficacy and safety of nemonoxacin ing search terms – nemonoxacin, TG-873870, and Taigexyn. with levofloxacin for adult patients with CAP (Table 1). Only the clinical studies that compared the clinical efficacy Two studies16,17 assigned CAP patients to one of three treat- and adverse effects of nemonoxacin and other comparators ment groups (nemonoxacin 750 mg, nemonoxacin 500 mg, were included. Two reviewers (Chang and Lee) searched and and levofloxacin 500 mg) in a 1:1:1 ratio. Another study18 examined publications independently to avoid bias. When assigned patients in a 2:1 ratio to receive nemonoxacin they disagreed, the third author (Lai) resolved the issue. The 500 mg or levofloxacin 500 mg for 7–10 days. Most of the following data were extracted from every included study: year domains were classified as having a low risk of bias, except of publication, study design, sites and duration, antibiotic for incomplete outcome data in one study17 (Figures 2 and 3). regimens of nemonoxacin and comparators, outcomes, and Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 25-Apr-2020 adverse events. Clinical efficacy Overall, nemonoxacin had a clinical cure rate similar to Definitions and outcomes levofloxacin in the treatment of CAP (OR= 1.05, 95% CI The primary outcome was overall clinical cure with resolution =0.67–1.64, I2=0%; Figure 4). In addition, all the enrolled of clinical signs and symptoms of pneumonia, or recovery studies16–18 found no significant differences in the clinical to the pretreatment state as the test of cure (TOC). Second- cure rates of patients treated with nemonoxacin 500 mg and ary outcomes included the microbiologic response rate and levofloxacin 500 mg (OR= 1.01, 95% CI =0.62–1.65, I2=0%). adverse events. A microbiologic response was defined as Only two included studies16,17 compared the clinical cure rates eradication (the baseline pathogen was absent) and presumed of nemonoxacin 750 mg and levofloxacin 500 mg and no sig- eradication (if an adequate source specimen was not available nificant difference was found (OR= 1.09, 95% CI =0.58–2.05, to culture, but the patient was assessed as clinically cured) I2=0%). Nemonoxacin and levofloxacin exhibited similar at the TOC visit. Treatment-emergent adverse events were clinical responses against Streptococcus pneumoniae (OR recorded, irrespective of causality. Finally, we used the results =1.20, 95% CI =0.21–6.75, I2=0%), Haemophilus spp. (OR of intent-to-treat analysis for this meta-analysis. =0.77, 95% CI =0.16–3.63, I2=0%), Staphylococcus aureus

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Records identified through database searching n=189

Identification Duplicated records excluded n=69

Records after duplicates removed n=120

Excluded by title and abstract n=116 Screening Full-text articles assessed for eligibility n=4

Articles excluded

Eligibility 1:subgroup analysis of Yuan et al, 2017 Studies included in qualitative synthesis n=3 d

Studies included in Include meta-analysis n=3

Figure 1 Flow diagram of the study selection process.

Table 1 Characteristics of included studies Study, Study Study Study Study No of patients Dose regimen published design site period population Nemonoxacin Comparator Nemonoxacin Comparator year van Multicenter, South 2006– Mild to 89 (500 mg) 90 Nemonoxacin Levofloxacin For personal use only. Rensburg randomized, double- Africa, 2007 moderate 86 (750 mg) 750 mg or 500 500 mg/day et al, blind, non-inferiority Taiwan CAP mg/day for 7 for 7 days 201017 trial days Liu et al, Multicenter, China 2009– Chinese 65 (500 mg) 62 Nemonoxacin Levofloxacin 201716 randomized, double- 2010 patients 65 (750 mg) 750 or 500 mg/ 500 mg/day blind, non-inferiority with mild to day for 7–10 for 7–10 days trial moderate days CAP Yuan et al, Multicenter, China, 2011– Chinese 357 (500 mg) 175 Nemonoxacin Levofloxacin 201718 randomized, Taiwan 2012 patients with 500 mg/day for 500 mg/day double-blind, , non- CAP 7–10 days for 7–10 days inferiority trial Abbreviation: CAP, community-acquired pneumonia Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 25-Apr-2020

(OR =2.29, 95% CI =0.12–41.98, I2=0%), and atypical patho- Adverse events gens (OR =0.80, 95% CI =0.17–1.92, I2=0%). No significant differences were found for treatment-emergent adverse events in overall and subgroup comparisons Microbiologic response (nemonoxacin at 500 or 750 mg vs levofloxacin 500 mg: Nemonoxacin had a microbiologic response rate similar to OR =1.08, 95% CI =0.81–1.43, I2=0%, Figure 6; nemonoxa- levofloxacin in the treatment of CAP (OR= 0.89, 95% CI cin at 500 mg vs levofloxacin 500 mg: OR= 0.95, 95% CI =0.44–1.81, I2=0%; Figure 5). Three enrolled studies16–18 =0.71–1.28, I2=0%; nemonoxacin at 750 mg vs levofloxacin compared the microbiologic response of nemonoxacin 500 500 mg: OR =1.46, 95% CI =0.92–2.31, I2=0%). mg with levofloxacin 500 mg and found no significant differences (OR =0.83, 95% CI =0.39–1.77, I2=0%). Two included Comparison between nemonoxacin studies16,17 compared the microbiologic response between dosages of 750 and 500 mg nemonoxacin 750 mg and levofloxacin 500 mg and found no In subgroup analysis, there were no significant differences significant difference (OR= 0.98, 95% CI =0.33–2.90, I2=0%). in the clinical cure rate (OR =0.99, 95% CI =0.33–2.99,

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Random sequence generation (selection bias)

Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias

0% 25% 50% 75% 100% Low risk of bias Unclear risk of bias High risk of bias

Figure 2 Summary of risk of bias.

Discussion Several findings from this meta-analysis based on three RCTs showed that nemonoxacin has a clinical efficacy similar to levofloxacin in the treatment of adult patients with CAP. First, the clinical cure rate of nemonoxacin in treating CAP ) was as good as levofloxacin. Second, the microbiologic response rate of nemonoxacin was similar to levofloxacin. )

) Third, subgroup analysis of different pathogens, including For personal use only. Streptococcus pneumoniae, Haemophilus spp., Staphylococ- ) ) cus aureus, and atypical pathogens, showed no significant ) differences in the clinical efficacy of these two drugs in the treatment of CAP. Finally, both the 500 and 750 mg dosages of nemonoxacin had clinical and microbiologic responses similar to levofloxacin. All of these findings are supported by in vitro and in vivo studies7,12,20 showing that the activity of nemonoxacin is comparable to levofloxacin. Therefore, based on the findings of these analyses, it is suggested that nemonoxacin can play an important role similar to levofloxa- Random sequence generation (selection bias Allocation concealment (selection bias Blinding of participants and personnel (performance bias Blinding of outcome assessment (detection bias Incomplete outcome data (attrition bias Selective reporting (reporting bias Other bias Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 25-Apr-2020 cin in the treatment of CAP. Liu et al, 2017 The risk of adverse events is another important concern in the treatment of CAP with this novel antimicrobial agent. Rensburg et al, 2010 Most of the treatment-emergent adverse events among Yuan et al, 2017 nemonoxacin users were mild, and nausea, vomiting, leu- kopenia, and abnormal liver function were the most com- Figure 3 Risk of bias per study and domain. mon adverse events. In this analysis, the pooled risks of treatment-emergent adverse effects were similar between nemonoxacin and levofloxacin. Even with a higher dose of I2=57%) and microbiologic response rate (OR =1.38, nemonoxacin (750 mg), there was no significance difference 95% CI =0.49–3.95, I2=0%) between different doses of in the safety between these two drugs. All of these findings nemonoxacin (750 and 500 mg). However, the 750 mg dos- suggest that nemonoxacin is as safe as levofloxacin in the age of nemonoxacin had a higher risk of treatment-emergent treatment of CAP. adverse events than the 500 mg dose (OR =1.63, 95% CI We also found that there were no significant differences in =1.03–2.58, I2=0%). the clinical cure and microbiologic response rates between the

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Nemonoxacin Levofloxacin OR OR Study or subgroup Events Total Events TotalWeight (%) M-H, fixed, 95% Cl M-H, fixed, 95% Cl Rensburg 2010 138 175 72 90 54.2 0.93 (0.50–1.75) Liu 2017 104 115 46 52 16.3 1.23 (0.43–3.54) Yuan 2017 300 318 143 153 29.5 1.17 (0.52–2.59)

Total (95% Cl) 608 295 100.0 1.05 (0.67–1.64) Total events 542 261 Heterogeneity: 2=0.29, df=2 (P=0.86); I2=0% 0.01 0.1 110 100 Test for overall effect: Z=0.21 (P=0.83) Favors (experimental) Favors (control)

Figure 4 The overall clinical cure rates of nemonoxacin and levofloxacin in the treatment of community-acquired pneumonia.

Experimental Control OR OR Study or subgroup Events Total Events TotalWeight (%) M-H, fixed, 95% Cl M-H, fixed, 95% Cl Rensburg 2010 76 87 46 50 44.8 0.60 (0.18–2.00) Liu 2017 30 36 16 20 20.8 1.25 (0.31–5.08) Yuan 2017 105 114 55 60 34.5 1.06 (0.34–3.32)

Total (95% Cl) 237 130 100.0 0.89 (0.44–1.81) Total events 211117 Heterogeneity: 2=0.73, df=2 (P=0.70): I2=0% 0.01 0.1 110 100 Test for overall effect: Z=0.31 (P=0.76) Favors (experimental) Favors (control)

Figure 5 The overall microbiologic response rates of nemonoxacin and levofloxacin in the treatment of community-acquired pneumonia.

For personal use only. Experimental Control OR OR Study or subgroup Events Total Events TotalWeight (%) M-H, fixed, 95% Cl M-H, fixed, 95% Cl Rensburg 2010 88 175 44 90 31.0 0.06 (0.64–1.76) Liu 2017 40 121 14 56 13.8 1.48 (0.73–3.02) Yuan 2017 118 356 57 171 55.2 0.99 (0.67–1.46)

Total (95% Cl) 652 317 100.0 1.08 (0.81–1.43) Total events 246 115 Heterogeneity: 2=0.95, df=2 (P=0.62): I2=0% 0.01 0.1 110 100 Test for overall effect: Z=0.53 (P=0.60) Favors (experimental) Favors (control)

Figure 6 The overall risks of treatment-emergent adverse events for nemonoxacin and levofloxacin in the treatment of community-acquired pneumonia. Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 25-Apr-2020

nemonoxacin dosages of 500 and 750 mg. However, the 750 organisms, especially for antibiotic-resistant pathogens. mg dosage had a significantly higher risk of adverse effects Finally, the numbers of studies and patients were limited in than the 500 mg dosage. Nemonoxacin 500 mg regimen may this meta-analysis, and therefore, the formal test for hetero- be adequate for the treatment of CAP. geneity may be underestimating the degree of heterogeneity. This meta-analysis has one major strength. Only RCTs In addition, only Asians and Africans were enrolled in these were included, so the risk of bias is minimized, and the level three RCTs. Therefore, these findings may not be generalized of evidence is strong. However, this meta-analysis also has to other countries. Further large-scale study is warranted. several limitations. First, most cases of CAP in this meta- In conclusion, based on the findings of this meta-analysis analysis were mild to moderate, and all patients in these three of three RCTs, the clinical and microbiologic efficacy of RCTs received only oral nemonoxacin. Therefore, further nemonoxacin is as good as levofloxacin in the treatment of study is needed to investigate the use of nemonoxacin in CAP, and this antibiotic is as well tolerated as levofloxacin. severe CAP. Second, we did not evaluate the association Thus, nemonoxacin can be recommended as an appropriate between in vitro activity and the in vivo response of different antibiotic therapy for CAP.

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10. Chen YH, Liu CY, Lu JJ, King CH, Hsueh PR. In vitro activity of Disclosure nemonoxacin (TG-873870), a novel non-fluorinated quinolone, against The authors report no conflicts of interest in this work. clinical isolates of Staphylococcus aureus, enterococci and Strepto- coccus pneumoniae with various resistance phenotypes in Taiwan. J Antimicrob Chemother. 2009;64(6):1226–1229. References 11. Hsu MS, Liao CH, Liu CY, Yang CJ, Huang YT, Hsueh PR. In vitro 1. Peto L, Nadjm B, Horby P, et al. The bacterial aetiology of adult susceptibilities of clinical isolates of ertapenem-non-susceptible community-acquired pneumonia in Asia: a systematic review. Trans R Enterobacteriaceae to nemonoxacin, tigecycline, fosfomycin and other Soc Trop Med Hyg. 2014;108(6):326–337. antimicrobial agents. Int J Antimicrob Agents. 2011;37(3):276–278. 2. Woodhead M. Community-acquired pneumonia in Europe: causative 12. Li CR, Li Y, Li GQ, et al. In vivo antibacterial activity of nemonoxa- pathogens and resistance patterns. Eur Respir J Suppl. 2002;36: cin, a novel non-fluorinated quinolone. J Antimicrob Chemother. 20S–27S. 2010;65(11):2411–2415. 3. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases 13. Huang CH, Lai CC, Chen YH, Hsueh PR. The potential role of nemonox- Society of America/American Thoracic Society consensus guidelines acin for treatment of common infections. Expert Opin Pharmacother. on the management of community-acquired pneumonia in adults. Clin 2015;16(2):263–270. Infect Dis. 2007;44(Suppl 2):S27–S72. 14. Tan CK, Lai CC, Liao CH, et al. Comparative in vitro activities of the 4. Li ZX, Liu YN, Wang R, Li AM. Nemonoxacin has potent activity new quinolone nemonoxacin (TG-873870), gemifloxacin and other against gram-positive, but not gram-negative clinical isolates. Clin Ter. quinolones against clinical isolates of Mycobacterium tuberculosis. J 2015;166(6):e374–380. Antimicrob Chemother. 2009;64(2):428–429. 5. Lai CC, Liu WL, Ko WC, et al. Multicenter study in Taiwan of the 15. Lai CC, Lee KY, Lin SW, et al. Nemonoxacin (TG-873870) for treat- in vitro activities of nemonoxacin, tigecycline, doripenem, and other ment of community-acquired pneumonia. Expert Rev Anti Infect Ther. antimicrobial agents against clinical isolates of various Nocardia spe- 2014;12(4):401–417. cies. Antimicrob Agents Chemother. 2011;55(5):2084–2091. 16. Liu Y, Zhang Y, Wu J, et al. A randomized, double-blind, multicenter 6. Yang JC, Lee PI, Hsueh PR. In vitro activity of nemonoxacin, tige- Phase II study comparing the efficacy and safety of oral nemonoxacin cycline, and other antimicrobial agents against Helicobacter pylori with oral levofloxacin in the treatment of community-acquired pneu- isolates in Taiwan, 1998–2007. Eur J Clin Microbiol Infect Dis. monia. J Microbiol Immunol Infect. 2017;50(6):811–820. 2010;29(11):1369–1375. 17. van Rensburg DJ, Perng RP, Mitha IH, et al. Efficacy and safety of 7. Lauderdale TL, Shiau YR, Lai JF, Chen HC, King CH. Comparative in nemonoxacin versus levofloxacin for community-acquired pneumonia. vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated Antimicrob Agents Chemother. 2010;54(10):4098–4106. quinolone, and other quinolones against clinical isolates. Antimicrob 18. Yuan J, Mo B, Ma Z, et al. Safety and efficacy of oral nemonoxacin Agents Chemother. 2010;54(3):1338–1342. versus levofloxacin in treatment of community-acquired pneumonia: a 8. Chotikanatis K, Kohlhoff SA, Hammerschlag MR. In vitro activity Phase 3, multicenter, randomized, double-blind, double-dummy, active- For personal use only. of nemonoxacin, a novel nonfluorinated quinolone antibiotic, against controlled, non-inferiority trial. J Microbiol Immunol Infect. 2017;pii: Chlamydia trachomatis and Chlamydia pneumoniae. Antimicrob Agents S1684-1182(17):30151–30152. Chemother. 2014;58(3):1800–1801. 19. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Col- 9. Chen YH, Liu CY, Ko WC, et al. Trends in the susceptibility of meth- laboration’s tool for assessing risk of bias in randomised trials. BMJ. icillin-resistant Staphylococcus aureus to nine antimicrobial agents, 2011;343(oct18 2):d5928. including ceftobiprole, nemonoxacin, and tyrothricin: results from the 20. Li ZX, Liu YN, Wang R, Li AM. Nemonoxacin has potent activity Tigecycline In Vitro Surveillance in Taiwan (TIST) study, 2006–2010. against gram-positive, but not gram-negative clinical isolates. Clin Ter. Eur J Clin Microbiol Infect Dis. 2014;33(2):233–239. 2015;166(6):e374–e380. Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 54.70.40.11 on 25-Apr-2020

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