Adjuvant β-Lactam Therapy Combined with Vancomycin or Daptomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: a Systematic Review and Meta-analysis.

CLINICAL THERAPEUTICS crossm Adjuvant ␤-Lactam Therapy Combined with Vancomycin or Daptomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: a Systematic Review and Meta-analysis Chunjiang Wang,a Chao Ye,b Linglong Liao,c Zhaohui Wang,b Ying Hu,b Chao Deng,d Liang Liue a Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China b Department of Pharmacy, People’s Hospital of Ningxiang City, Hunan University of Chinese Medicine, Changsha, Hunan, China c Gastroenterology, Zengcheng District People’s Hospital of Guangzhou, Guangzhou, Guangdong, China d Department of Pharmacy, Jingshan Union Hospital of Huazhong University of Science and Technology, Jingshan, Hubei, China e Neurosurgery, People’s Hospital of Ningxiang City, Hunan University of Chinese Medicine, Changsha, Hunan, China ABSTRACT Infections due to methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) seriously threaten public health due to poor outcomes and high mortality. The objective of this study is to perform a systematic review and meta-analysis of the current evidence on adjuvant ␤-lactam (BL) therapy combined with vancomycin (VAN) or daptomycin (DAP) for MRSAB. PubMed, Embase, and Cochrane Library were systematically searched for publications reporting clinical outcomes of BLs⫹VAN or BLs⫹DAP for adult patients with MRSAB through 5 April 2020. Meta-analysis techniques were applied using random effects modeling. Three randomized controlled trials and 12 retrospective cohort studies were identified, totaling 2,594 patients. Combination treatment significantly reduced the risk of clinical failure (risk ratio [RR] ⫽ 0.80; 95% confidence interval [CI], 0.66 to 0.96; P ⫽ 0.02; I2 ⫽ 39%), bacteremia recurrence (RR ⫽ 0.66; 95% CI, 0.50 to 0.86; P ⫽ 0.002; I2 ⫽ 0%), and persistent bacteremia (RR ⫽ 0.65; 95% CI, 0.55 to 0.76; P ⬍ 0.00001; I2 ⫽ 0%) and shortened the duration of bacteremia (standardized mean difference [SMD] ⫽ – 0.37; 95% CI, – 0.48 to – 0.25; P ⬍ 0.00001; I2 ⫽ 0%). There was no significant difference in the risk of crude mortality, nephrotoxicity, or thrombocytopenia between groups. Notably, combination treatment might nonsignificantly increase the risk of Clostridium difficile infection (CDI) (RR ⫽ 2.13; 95% CI, 0.98 to 4.63; P ⫽ 0.06; I2 ⫽ 0%). Subgroup analysis suggested that DAP⫹BLs could reduce crude mortality (RR ⫽ 0.53; 95% CI, 0.28 to 0.98; P ⫽ 0.04; I2 ⫽ 0%). The meta-analysis suggested that although combination therapy with BLs could improve some microbial outcomes, it could not reduce crude mortality but might increase the risk of CDI and should be applied very cautiously. Regarding mortality reduction, the combination of DAP⫹cephalosporins appears more promising. KEYWORDS methicillin-resistant Staphylococcus aureus, bacteremia, ␤-lactams, vancomycin, daptomycin, combination therapy, meta-analysis S taphylococcus aureus is an important human pathogen and one of the leading causes of both nosocomial and community-acquired bacteremia worldwide. Staphylococcus aureus bacteremia (SAB) is a common cause of bloodstream infections, with an annual population-based incidence rate ranging from 20 to 30 cases/100,000 population in higher income countries (1). Even with adherence to current standards of care, all-cause mortality is still high. Case fatality rates for SAB remain stable between 15% and 50% (2). SAB carries a high risk of complications, such as endocarditis, septic shock, and disseminated infection (3), which are associated with a high risk of relapse November 2020 Volume 64 Issue 11 e01377-20 Antimicrobial Agents and Chemotherapy Citation Wang C, Ye C, Liao L, Wang Z, Hu Y, Deng C, Liu L. 2020. Adjuvant β-lactam therapy combined with vancomycin or daptomycin for methicillin-resistant Staphylococcus aureus bacteremia: a systematic review and metaanalysis. Antimicrob Agents Chemother 64:e01377-20. https://doi.org/10.1128/AAC .01377-20. Copyright © 2020 Wang et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Chao Ye, . Received 30 June 2020 Returned for modification 20 July 2020 Accepted 7 August 2020 Accepted manuscript posted online 24 August 2020 Published 20 October 2020 aac.asm.org 1 Wang et al. Antimicrobial Agents and Chemotherapy and death from metastatic disease. Importantly, infection due to methicillin-resistant Staphylococcus aureus (MRSA) complicates therapy and has been identified as an independent risk factor for mortality (4, 5). Vancomycin (VAN) and daptomycin (DAP) are the only agents currently approved for treating MRSA bacteremia (MRSAB) (5). However, each agent has limitations. Specifically, a number of issues hamper the utility of VAN, including slow bactericidal activity, low tissue penetration, and increasing reports of resistance and failure (6, 7). While DAP has been effective against MRSAB, unsusceptible isolates and treatment failures have been noted (8, 9). Considerable efforts have been made to improve MRSAB treatment results and outcomes. Combinations of VAN or DAP with other antibacterial agents are being increasingly used to treat serious MRSA infections. Combination therapy with an active ␤-lactam (BL) early in the course of MRSAB has been suggested as a possible treatment strategy due to the observed synergy between glycopeptides and BLs (10–13). This phenomenon has been termed the ‘‘see-saw’’ effect, where, in the presence of glycopeptide or lipoglycopeptide, susceptibility to BLs improves (14–17). In recent years, an increasing number of studies have evaluated the effectiveness and safety of VAN or DAP combined with BLs in the treatment of MRSAB, especially at the beginning of 2020 (as of April 2020), and three clinical studies have been reported (18–20). However, the efficacy and safety of BLs as an adjuvant therapy for MRSAB are still ongoing matters of debate. Therefore, we decided to update the existing evidence to better determine the clinical effectiveness and safety of adjuvant BLs in the treatment of MRSAB with respect to crude mortality, nephrotoxicity, and Clostridium difficile infection (CDI), among others. RESULTS Identified studies. A total of 1,344 relevant studies were initially identified. After removing duplicate documents and screening the titles and abstracts, we determined that 34 studies were to be subject to a full-text assessment (Fig. 1). After applying the inclusion/exclusion criteria, a total of 15 studies (6, 18–31) comprising a total of 2,594 patients were included (1,189 patients in the standard therapy [STAN] group and 1,405 patients in the STAN therapy combined with ␤-lactams [COMBO] group), including 7 studies (21–27) based on the combination of VAN, 5 studies (6, 28–31) based on the combination of DAP, and 3 studies (18–20) based on the combination of daptomycin or vancomycin. Among the included studies, the ␤-lactam of choice was ceftaroline i (...truncated)