PMID- 33415492
OWN - NLM
STAT- MEDLINE
DCOM- 20210907
LR  - 20210907
IS  - 1435-4373 (Electronic)
IS  - 0934-9723 (Print)
IS  - 0934-9723 (Linking)
VI  - 40
IP  - 6
DP  - 2021 Jun
TI  - Serious adverse events with novel beta-lactam/beta-lactamase inhibitor 
      combinations: a large-scale pharmacovigilance analysis.
PG  - 1169-1176
LID - 10.1007/s10096-020-04149-3 [doi]
AB  - 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.
FAU - Gatti, Milo
AU  - Gatti M
AUID- ORCID: 0000-0003-3018-3779
AD  - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater 
      Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. 
      milo.gatti2@unibo.it.
FAU - Raschi, Emanuel
AU  - Raschi E
AUID- ORCID: 0000-0003-0487-7996
AD  - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater 
      Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
FAU - De Ponti, Fabrizio
AU  - De Ponti F
AUID- ORCID: 0000-0002-0367-9595
AD  - Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater 
      Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
LA  - eng
PT  - Journal Article
PT  - Observational Study
DEP - 20210107
PL  - Germany
TA  - Eur J Clin Microbiol Infect Dis
JT  - European journal of clinical microbiology & infectious diseases : official 
      publication of the European Society of Clinical Microbiology
JID - 8804297
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Azabicyclo Compounds)
RN  - 0 (Cephalosporins)
RN  - 0 (Drug Combinations)
RN  - 0 (Lactams)
RN  - 0 (avibactam, ceftazidime drug combination)
RN  - 0 (beta-Lactamase Inhibitors)
RN  - 0 (ceftolozane, tazobactam drug combination)
RN  - 9M416Z9QNR (Ceftazidime)
RN  - SE10G96M8W (Tazobactam)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Agranulocytosis/*etiology
MH  - Anti-Bacterial Agents/*adverse effects/therapeutic use
MH  - Azabicyclo Compounds/adverse effects/therapeutic use
MH  - Ceftazidime/adverse effects/therapeutic use
MH  - Cephalosporins/adverse effects/therapeutic use
MH  - Drug Combinations
MH  - Drug Therapy, Combination/adverse effects
MH  - Female
MH  - Gram-Negative Bacterial Infections/*drug therapy
MH  - Humans
MH  - Lactams/*adverse effects/therapeutic use
MH  - Male
MH  - Microbial Sensitivity Tests
MH  - Middle Aged
MH  - Pancytopenia/etiology
MH  - Pharmacovigilance
MH  - Retrospective Studies
MH  - Tazobactam/adverse effects/therapeutic use
MH  - beta-Lactamase Inhibitors/*adverse effects/therapeutic use
PMC - PMC8139903
OTO - NOTNLM
OT  - Agranulocytosis
OT  - Ceftazidime-avibactam
OT  - Ceftolozane-tazobactam
OT  - Neurotoxicity
OT  - Safety profile
COIS- The authors declare that they have no conflict of interest.
EDAT- 2021/01/09 06:00
MHDA- 2021/09/08 06:00
PMCR- 2021/01/07
CRDT- 2021/01/08 06:15
PHST- 2020/10/23 00:00 [received]
PHST- 2020/12/28 00:00 [accepted]
PHST- 2021/01/09 06:00 [pubmed]
PHST- 2021/09/08 06:00 [medline]
PHST- 2021/01/08 06:15 [entrez]
PHST- 2021/01/07 00:00 [pmc-release]
AID - 10.1007/s10096-020-04149-3 [pii]
AID - 4149 [pii]
AID - 10.1007/s10096-020-04149-3 [doi]
PST - ppublish
SO  - Eur J Clin Microbiol Infect Dis. 2021 Jun;40(6):1169-1176. doi: 
      10.1007/s10096-020-04149-3. Epub 2021 Jan 7.