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Novel ?-Lactam/?-Lactamase inhibitor combinations vs alternative antibiotics in the treatment of complicated urinary tract infections: A meta-analysis of randomized controlled trials.

ABSTRACT: OBJECTIVES:This meta-analysis assessed the efficacy and safety of novel ?-lactam/?-lactamase inhibitor combinations in the treatment of complicated urinary tract infection (cUTI)/acute pyelonephritis (APN). METHODS:PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid MEDLINE, and Embase databases were accessed until November 21, 2019. In this meta-analysis, only randomized controlled trials comparing the treatment efficacy of novel ?-lactam/?-lactamase inhibitor combinations with other antibiotics for cUTI/APN in adult patients were included. The outcomes included the clinical and microbiological responses, and risk of adverse events (AEs). RESULTS:Overall, the experimental group treated with a novel ?-lactam/?-lactamase inhibitor combination and the control group comprised 1346 and 1376 patients, respectively. No significant difference in the clinical response rate at test-of-cure was observed between the novel ?-lactam/?-lactamase inhibitor combination and comparators among the microbiological modified intent-to-treat population (89.1% vs 88.3%, OR, 1.04; 95% confidence interval [CI], 0.76-1.42; I?=?28%) and the microbiologically evaluable population (95.2% vs 94.7%, OR, 1.12; 95% CI, 0.68-1.84; I?=?0%). Additionally, the novel ?-lactam/?-lactamase inhibitor combination was associated with a better microbiological response at test-of-cure than the comparators among the microbiological modified intent-to-treat population (74.4% vs 68.5%, OR, 1.34; 95% CI, 1.04-1.72; I?=?45%) and microbiologically evaluable population (80.1% vs 72.5%, OR, 1.49; 95% CI, 1.06-2.10; I?=?58%). Finally, the risk of AEs associated with the novel ?-lactam/?-lactamase inhibitor combination was similar to that associated with the comparators (treatment-emergent adverse events [TEAE], OR, 1.04; 95% CI, 0.87-1.23; I?=?19%; serious AEs, OR, 1.21; 95% CI, 0.82-1.76; I?=?0%; treatment discontinuation for drug-related TEAE, OR, 077; 95% CI, 0.38-1.56, I?=?5%). The all-cause mortality did not differ between the novel ?-lactam/?-lactamase inhibitor combination and comparators (OR, 1.19; 95% CI, 0.37-3.81; I?=?0%). CONCLUSIONS:The clinical and microbiological responses of novel ?-lactam/?-lactamase inhibitor combinations in the treatment of cUTI/APN are similar to those of other available antibiotics. These combinations also share a safety profile similar to that of other antibiotics.

SUBMITTER: Lu LC

PROVIDER: S-EPMC7220034 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Novel β-Lactam/β-Lactamase inhibitor combinations vs alternative antibiotics in the treatment of complicated urinary tract infections: A meta-analysis of randomized controlled trials.

Lu Li-Chin LC Lai Chih-Cheng CC Chang Shen-Peng SP Lan Shao-Huan SH Hung Shun-Hsing SH Lin Wei-Ting WT

Medicine 20200501 19

<h4>Objectives</h4>This meta-analysis assessed the efficacy and safety of novel β-lactam/β-lactamase inhibitor combinations in the treatment of complicated urinary tract infection (cUTI)/acute pyelonephritis (APN).<h4>Methods</h4>PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid MEDLINE, and Embase databases were accessed until November 21, 2019. In this meta-analysis, only randomized controlled trials comparing the treatment efficacy of novel β-lactam/β-lactamase inh ...[more]

PMID: 32384444

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Project description:Recently, several β-lactam (BL)/β-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their in vitro activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine β-lactamase) and metallo-β-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of β-lactamase inhibition by various BLIs in biochemical assays using purified β-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-β-lactamases and (ii) to compare the in vitro potency of XER in combination with multiple β-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 µg/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in Enterobacterales, e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified β-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 µg/mL) was the most potent combination against MBL-negative CRE with MIC90 values of 0.125 µg/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC90 of 1 µg/mL) being at least 16-fold more potent than FEP-TAN (MIC90 of 16 µg/mL). MEM-XER MIC values were ≤8 µg/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 µg/mL. Xeruborbactam also significantly enhanced potency of other β-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of Enterobacterales that carried various class A, class C, and class D extended-spectrum β-lactamases and carbapenem-resistant Enterobacterales, including metallo-β-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.

Project description:The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.

Dataset Information

Novel ?-Lactam/?-Lactamase inhibitor combinations vs alternative antibiotics in the treatment of complicated urinary tract infections: A meta-analysis of randomized controlled trials.

Publications

Novel β-Lactam/β-Lactamase inhibitor combinations vs alternative antibiotics in the treatment of complicated urinary tract infections: A meta-analysis of randomized controlled trials.

Similar Datasets

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