Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study

Abstract

BackgroundThe management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections.MethodsThree spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999–2008 vs. 2009–2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009–2017) was investigated for both Italy and UK.ResultsA total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found.ConclusionKPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues.

Serious adverse events with novel beta-lactam/beta-lactamase inhibitor combinations: a large-scale pharmacovigilance analysis

“…Although the risk-benefit ratio is generally favourable in severe MDR infections, the safety profile of these antibiotics still requires thorough investigation. Specifically, 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]. However, 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.…”

Hospital-Acquired Infections Caused by Carbapenem-Resistant Enterobacteriaceae: An Observational Study

“…During the literature search, 1094 retrieved articles were identified as relevant for screening, and among them, 49 papers were eligible for full-text screening, with a total of 14 articles [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] meeting the inclusion criteria ( Figure 1 ).…”

“…From the included articles, 1083 contained CRE E. coli and 2053 contained CRKP from more than 63 patients hospitalized for more than two days in a UK hospital between 2009 and 2021. Three studies [ 17 , 18 , 19 ] reported CRKP but not CRE E. coli . In contrast, for those who identified both resistant species, only four studies from three hospitals in Manchester showed a higher percentage of patients with CRE E. coli than CRKP.…”

“…Eleven studies [ 17 , 18 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 28 , 29 ] quantitatively reported the type of carbapenemase, mainly KPC, NDM, and OXA-48-like, produced by either CRE E. coli or CRKP. The total number of reported CRKP and CRE E. coli cases carrying one of the major carbapenemases was 2756, 35% of which were CRE E. coli and 65% were CRKP ( Table 2 ).…”

Off-Label Use of Ceftazidime/Avibactam for the Treatment of Pan-Drug-Resistant Klebsiella pneumoniae in a Neonate: Case Report and Literature Review

“…Blood electrolytes and urine analysis were monitored daily. Generally, CAZ-AVI has a favorable risk–benefit profile [ 34 ]. In our case, the patient tolerated CAZ-AVI very well with no severe adverse events detected.…”