Efficacy and safety of clarithromycin for patients with sepsis or septic shock: a systematic review and meta-analysis

Abstract

Background: Clarithromycin exerts an immunomodulatory role in several human diseases. However, whether this effect improves the prognosis in patients with sepsis remains controversial, and higher levels of clinical evidence are urgently needed. To the best of our knowledge, no meta-analysis to date has reported the clinical efficacy and safety of clarithromycin in sepsis.

Methods: A comprehensive literature search of PubMed, EMBASE, and the Cochrane Library was conducted up to December 31, 2022. Only randomized controlled trials comparing the clinical efficacy and safety of clarithromycin with controls among patients with sepsis or septic shock were included. Data were pooled by applying a fixed-effects model and a relative risk (RR) estimate with 95% confidence intervals (CIs) using Review Manager (version 5.3; Cochrane Collaboration, Copenhagen, Denmark).

Results: Three randomized controlled trials involving a total of 910 patients were included. The pooled results confirmed that clarithromycin had no beneficial effect on progression to multiple organ dysfunction syndrome (RR: 1.51; 95% CI: 1.02-2.25; P = 0.04; I² = 0%), 28-day mortality (RR: 1.09; 95% CI: 0.87-1.36; P = 0.46; I² = 0%), and 90-day mortality (RR: 0.86; 95% CI: 0.71-1.03; P = 0.10; I² = 81%) in patients with sepsis or septic shock. Moreover, there was no difference in other serious adverse events between patients who received clarithromycin and those in the control group (RR: 1.02; 95% CI: 0.87-1.19; P = 0.83; I² = 18%).

Conclusion: Our meta-analysis did not reveal an improvement to short-term outcomes in patients with sepsis treated with clarithromycin. However, administration of clarithromycin did not increase the risk of adverse events.

Keywords

Clarithromycin / Meta-analysis / Outcomes / Sepsis / Septic shock

Conflict of interest statement

The authors declare no conflict of interest.

Author contributions

Zhao P and Yao R conceived the study. Yang J extracted all dada. Zhao P, Yao R, and Yang J undertook and refined the searches. Zhao P wrote the paper. Yao R and Yang J undertook the statistical analyses. Wen W, Yao Y, and Du X helped to revise the intellectual content. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the National Natural Sci-ence Foundation of China (no. 81871317) and Key Project of Mili-tary Medical Innovation Program (no. 18CXZ025).

Ethical approval of studies and informed consent

All studies included in this study followed the principles of the Declaration of Helsinki as revised in 2013.

Acknowledgments

None.

References

[1] Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315(8):801-810. doi:10.1001/jama.2016.0287

[2] Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020; 395(10219):200-211. doi:10.1016/s0140-6736(19)32989-7

[3] Marshall JC. Why have clinical trials in sepsis failed. Trends Mol Med. 2014; 20(4):195-203. doi:10.1016/j.molmed.2014.01.007

[4] Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021; 47(11):1181-1247. doi:10.1007/s00134-021-06506-y

[5] Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021; 49(11):e1063-e1143. doi:10.1097/ccm.0000000000005337

[6] Nair GB, Niederman MS. Year in review 2013: critical care—respiratory infections. Crit Care. 2014; 18(5):572. doi:10.1186/s13054-014-0572-3

[7] Phua J, Dean NC, Guo Q, Kuan WS, Lim HF, Lim TK. Severe community-acquired pneumonia: timely management measures in the first 24 hours. Crit Care. 2016; 20(1):237. doi:10.1186/s13054-016-1414-2

[8] Nie W, Li B, Xiu Q. β-Lactam/macrolide dual therapy versus β-lactam monotherapy for the treatment of community-acquired pneumonia in adults: a systematic review and meta-analysis. J Antimicrob Chemother. 2014; 69(6):1441-1446. doi:10.1093/jac/dku033

[9] Horita N, Otsuka T, Haranaga S, et al. Beta-lactam plus macrolides or beta-lactam alone for community-acquired pneumonia: a systematic review and meta-analysis. Respirology. 2016; 21(7):1193-1200. doi:10.1111/resp.12835

[10] Sjomina O, Vangravs R, Ļeonova E, et al. Clarithromycin-containing triple therapy for Helicobacter pylori eradication is inducing increased long-term resistant bacteria communities in the gut. Gut. 2023;gutjnl-2023-329792. doi:10.1136/gutjnl-2023-329792

[11] Phillips RO, Robert J, Abass KM, et al. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial. Lancet. 2020; 395(10232):1259-1267. doi:10.1016/s0140-6736(20)30047-7

[12] Tiwari T, Murphy TV, Moran J. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Recomm Rep. 2005; 54(RR-14):1-16

[13] Tsiakos K, Tsakiris A, Tsibris G, et al. Early start of oral clarithromycin is associated with better outcome in COVID-19 of moderate severity: the ACHIEVE open-label single-arm trial. Infect Dis Ther. 2021; 10(4):2333-2351. doi:10.1007/s40121-021-00505-8

[14] Tagliabue C, Salvatore CM, Techasaensiri C, et al. The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection. J Infect Dis. 2008; 198(8):1180-1188. doi:10.1086/591915

[15] Kyriazopoulou E, Sinapidis D, Halvatzis S, et al. Survival benefit associated with clarithromycin in severe community-acquired pneumonia: a matched comparator study. Int J Antimicrob Agents. 2020; 55(1):105836. doi:10.1016/j.ijantimicag.2019.10.017

[16] Karakike E, Scicluna BP, Roumpoutsou M, et al. Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial. Crit Care. 2022; 26(1):183. doi:10.1186/s13054-022-04055-4

[17] Wu T, Hu C, Huang W, Xu Q, Hu B, Li J. Effect of combined hydrocortisone, ascorbic acid and thiamine for patients with sepsis and septic shock: a systematic review and meta-analysis. Shock. 2021; 56(6):880-889. doi:10.1097/shk.0000000000001781

[18] Zhao P, Yang X, Yan Y, Yang J, Li S, Du X. Effect of radical lymphadenectomy in colorectal cancer with para-aortic lymph node metastasis: a systematic review and meta-analysis. BMC Surg. 2022; 22(1):181. doi:10.1186/s12893-022-01631-x

[19] Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003; 29(4):530-538. doi:10.1007/s00134-003-1662-x

[20] Li Z, Zhang X, Wu Y, et al. Hydrocortisone, vitamin C, and thiamine may not improve the outcome of patients with sepsis or septic shock: a systematic review and meta-analysis. Emerg Crit Care Med. 2023; 3(3). doi:10.1097/ec9.0000000000000072

[21] Giamarellos-Bourboulis EJ, Pechère JC, Routsi C, et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis. 2008; 46(8):1157-1164. doi:10.1086/529439

[22] Giamarellos-Bourboulis EJ, Mylona V, Antonopoulou A, et al. Effect of clarithromycin in patients with suspected gram-negative sepsis: results of a randomized controlled trial. J Antimicrob Chemother. 2014; 69(4):1111-1118. doi:10.1093/jac/dkt475

[23] Vázquez-Laslop N, Mankin AS. How macrolide antibiotics work. Trends Biochem Sci. 2018; 43(9):668-684. doi:10.1016/j.tibs.2018.06.011

[24] Venditto VJ, Feola DJ. Delivering macrolide antibiotics to heal a broken heart—and other inflammatory conditions. Adv Drug Deliv Rev. 2022; 184:114252. doi:10.1016/j.addr.2022.114252

[25] Tita ATN, Carlo WA, McClure EM, et al. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023; 388(13):1161-1170. doi:10.1056/NEJMoa2212111

[26] Behal ML, Nguyen JL, Li X, Feola DJ, Neyra JA, Flannery AH. Azithromycin and major adverse kidney events in critically ill patients with sepsis-associated acute kidney injury. Shock. 2022; 57(4):479-485. doi:10.1097/shk.0000000000001883

[27] Vardakas KZ, Trigkidis KK, Falagas ME. Fluoroquinolones or macrolides in combination with β-lactams in adult patients hospitalized with community acquired pneumonia: a systematic review and meta-analysis. Clin Microbiol Infect. 2017; 23(4):234-241. doi:10.1016/j.cmi.2016.12.002

[28] Chatzakis C, Papatheodorou S, Sarafidis K, Dinas K, Makrydimas G, Sotiriadis A. Effect on perinatal outcome of prophylactic antibiotics in preterm prelabor rupture of membranes: network meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2020; 55(1):20-31. doi:10.1002/uog.21884

[29] Basu S, Smith S. Macrolides for the prevention and treatment of feeding intolerance in preterm low birth weight infants: a systematic review and meta-analysis. Eur J Pediatr. 2021; 180(2):353-378. doi:10.1007/s00431-020-03814-1

[30] Corrales-Medina VF, Musher DM. Immunomodulatory agents in the treatment of community-acquired pneumonia: a systematic review. J Infect. 2011; 63(3):187-199. doi:10.1016/j.jinf.2011.06.009

[31] Spyridaki A, Raftogiannis M, Antonopoulou A, et al. Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by gram-negative bacteria: results from a randomized clinical study. Antimicrob Agents Chemother. 2012; 56(7):3819-3825. doi:10.1128/aac.05798-11