Abstract
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.
Highlights
Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (C/A) are novel beta-lactam/beta-lactamase inhibitors (BL/ BLIs), respectively approved by the Food and Drug Administration (FDA) in 2014 and in 2015, and by the European Medicines Agency (EMA) in 2015 and in 2016, characterized by activity against multidrug-resistant (MDR) Gram-negative pathogens, including extensively drug- the risk-benefit ratio is generally favourable in severe MDR infections, the safety profile of these antibiotics still requires thorough investigation
No differences were found in serious adverse events (AEs) between novel BL/BLIs and controlled treatments in pivotal trials [2], being tolerability predictable and comparable to those seen with other beta-lactams, while real-world evidence is limited to the description of AEs reported with C/A [3]
Increased reporting was found for acute kidney injury (N = 24; reporting odds ratio (ROR) 5.50; 95% confidence interval (CI) 3.66– 8.27), agranulocytosis (12; 21.96; 12.40–38.87), pancytopenia (14; 10.50; 6.18–17.82) and renal failure (27; 7.88; 5.36–11.58) with C/T
Summary
Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (C/A) are novel beta-lactam/beta-lactamase inhibitors (BL/ BLIs), respectively approved by the Food and Drug Administration (FDA) in 2014 and in 2015, and by the European Medicines Agency (EMA) in 2015 and in 2016, characterized by activity against multidrug-resistant (MDR) Gram-negative pathogens, including extensively drug- the risk-benefit ratio is generally favourable in severe MDR infections, the safety profile of these antibiotics still requires thorough investigation. No differences were found in serious adverse events (AEs) between novel BL/BLIs and controlled treatments in pivotal trials [2], being tolerability predictable and comparable to those seen with other beta-lactams, while real-world evidence is limited to the description of AEs reported with C/A [3]. Given their expanding use at higher dosage in challenging scenarios, including patients affected by severe renal impairment [4], characterization of potential unexpected AEs with novel BL/BLIs becomes necessary. These post-marketing studies are suited to early detect rare, unexpected and delayed AEs, which cannot be fully appreciated in pivotal trials, and are recommended for real-time safety assessment of recently marketed drugs.
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