Publications by authors named "Fabrizio De Ponti"

159 Publications

Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction.

Expert Opin Pharmacother 2022 Feb 20;23(3):303-320. Epub 2022 Jan 20.

Cardiology Unit, IRCCS Azienda Ospedaliero-universitaria Di Bologna, Bologna, Italy.

Introduction: Sacubitril/valsartan is the first-in-class angiotensin-receptor neprilysin inhibitor approved in 2015 for the treatment of heart failure with reduced ejection fraction (HFrEF). On 16 February 2021, the Food and Drug Administration acknowledged that "Benefits are most clearly evident in patients with left ventricular ejection fraction below normal," thus potentially extending the use in subjects with heart failure and preserved ejection fraction (HFpEF).

Areas Covered: The authors outline the regulatory history, pharmacokinetics, pharmacodynamics, and risk-benefit profile of sacubitril/valsartan in HFrEF and HFpEF. A critical cross-trial comparison is presented, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), together with an insight into the latest European Society of Cardiology guidelines, where the new category of heart failure with mildly reduced ejection fraction is introduced.

Expert Opinion: Sacubitril/valsartan is a foundation of the pharmacological armamentarium in HFrEF to counteract the neuro-hormonal changes and reverse cardiac remodeling, together with beta-blockers, SGLT2i and mineralocorticoid receptor antagonists. The optimal sequence algorithm is an evolving issue, and the authors provide the reader with their personal perspective. A multidisciplinary management is encouraged to minimize the therapeutic inertia and manage tolerability issues, thus supporting adherence. Pragmatic trials, pharmacovigilance, and high-quality real-world evidence are crucial toward personalized safe prescribing of sacubitril/valsartan.
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http://dx.doi.org/10.1080/14656566.2022.2027909DOI Listing
February 2022

Development of a Network-Based Signal Detection Tool: The COVID-19 Adversome in the FDA Adverse Event Reporting System.

Front Pharmacol 2021 8;12:740707. Epub 2021 Dec 8.

Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

The analysis of pharmacovigilance databases is crucial for the safety profiling of new and repurposed drugs, especially in the COVID-19 era. Traditional pharmacovigilance analyses-based on disproportionality approaches-cannot usually account for the complexity of spontaneous reports often with multiple concomitant drugs and events. We propose a network-based approach on co-reported events to help assessing disproportionalities and to effectively and timely identify disease-, comorbidity- and drug-related syndromes, especially in a rapidly changing low-resources environment such as that of COVID-19. Reports on medications administered for COVID-19 were extracted from the FDA Adverse Event Reporting System quarterly data (January-September 2020) and queried for disproportionalities (Reporting Odds Ratio corrected for multiple comparisons). A network (the Adversome) was estimated considering events as nodes and conditional co-reporting as links. Communities of significantly co-reported events were identified. All data and scripts employed are available in a public repository. Among the 7,082 COVID-19 reports extracted, the seven most frequently suspected drugs (remdesivir, hydroxychloroquine, azithromycin, tocilizumab, lopinavir/ritonavir, sarilumab, and ethanol) have shown disproportionalities with 54 events. Of interest, myasthenia gravis with hydroxychloroquine, and cerebrovascular vein thrombosis with azithromycin. Automatic clustering identified 13 communities, including a methanol-related neurotoxicity associated with alcohol-based hand-sanitizers and a long QT/hepatotoxicity cluster associated with azithromycin, hydroxychloroquine and lopinavir-ritonavir interactions. Findings from the Adversome detect plausible new signals and iatrogenic syndromes. Our network approach complements traditional pharmacovigilance analyses, and may represent a more effective signal detection technique to guide clinical recommendations by regulators and specific follow-up confirmatory studies.
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http://dx.doi.org/10.3389/fphar.2021.740707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8694570PMC
December 2021

Impact of nephrotoxic drugs on urinary biomarkers of renal function in very preterm infants.

Pediatr Res 2021 Dec 11. Epub 2021 Dec 11.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Background: Following preterm birth, the immature kidney is exposed to several harmful conditions, with an increased risk of renal impairment. We aimed to assess urinary biomarkers of renal function in very preterm infants during early nephrotoxic treatments.

Methods: Infants ≤32 weeks' gestation and ≤1500 g were enrolled in this observational prospective study. Urine samples were collected on day 1(T1), 2-4(T2), 5-7(T3), 8-10(T4), 11-13(T5). The following urinary biomarkers were determined: osteopontin (uOPN), epidermal growth factor (uEGF), neutrophil gelatinase-associated lipocalin (uNGAL), cystatin C (uCysC). The infants were grouped according to their exposure to amikacin or ibuprofen during the study period and a between-group comparison of urinary biomarkers at each time point was performed.

Results: Thirty-six infants were included. Urinary CysC, uOPN, and uNGAL rose significantly during ibuprofen or amikacin treatment, while no difference was observed for uEGF. After adjustment for possible influencing factors, amikacin administration was associated with higher uCysC at T1 (p = 0.007) and T2 (p = 0.016), whereas ibuprofen increased uOPN (p = 0.001) and uNGAL concentration (p = 0.009) at T3.

Conclusion: Nephrotoxic therapies induce molecule-specific change patterns of renal function biomarkers in treated preterm infants. Serial assessments of these biomarkers may aid to identify neonates at risk of renal impairment and to develop tailored therapeutic approaches.

Impact: Despite the wide use of nephrotoxic therapies in neonatal settings, little is known on their effect on renal function biomarkers in preterm infants. This study describes molecule-specific change patterns of urinary biomarkers during ibuprofen and amikacin administration, suggesting underlying pathophysiological effects on renal function. Given their low analytical costs and non-invasive collection, the urinary biomarkers investigated in this study represent a promising strategy for serial monitoring of renal function in at-risk neonates and may aid the early detection of renal function impairment at different kidney levels during nephrotoxic treatments.
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http://dx.doi.org/10.1038/s41390-021-01905-9DOI Listing
December 2021

Crystal nephropathy and amoxicillin: insights from international spontaneous reporting systems.

J Nephrol 2022 Apr 11;35(3):1017-1027. Epub 2021 Nov 11.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Background: A substantial increase in amoxicillin-induced crystal nephropathy was recently reported in France. Our study aims to further characterize this safety issue from a worldwide perspective.

Methods: We queried both the FDA Adverse Event Reporting System (FAERS) and the Eudravigilance databases, and performed disproportionality analysis, selecting only adverse events (AEs) related to crystal nephropathy where amoxicillin or amoxicillin/clavulanic acid were reported as suspect. In FAERS, the reporting odds ratios were calculated and deemed significant by the lower limit of the 95% confidence interval (LL95%CI) > 1, selecting all other drugs/events recorded in FAERS as comparator. Deduplication followed by case-by-case assessment and comparison between French and non-French cases were also performed in both databases.

Results: Overall, 57,754 and 84,764 AE reports with amoxicillin or amoxicillin/clavulanic acid were recorded in FAERS and Eudravigilance, respectively, with France accounting for 18.7% and 22.0% of cases. Specific AEs of interest were retrieved in 144 and 239 cases, respectively. Increased reporting was found in FAERS for crystalluria (N = 99; LL95%CI 53.18), crystal nephropathy (24; 27.01), medication crystal in urine present (9; 92.00), crystal urine (8; 11.90), and crystal urine present (4; 1.57). In FAERS and Eudravigilance databases, reports were classified as serious in 98.8% and 91.2% of cases, respectively. Acute kidney injury (AKI) was found in 81.2% and 71.1% of patients. Amoxicillin was mainly given intravenously, and a dose ≥ 12 g/day was administered in 50.0% and 19.7% of cases in the FAERS and Eudravigilance databases, respectively.

Conclusion: Although causal association cannot be firmly inferred, a consistent signal of crystal nephropathy with amoxicillin emerged, especially in France. Clinicians should monitor patients for possible early AKI onset, especially when dealing with intravenous administration of daily doses > 12 g.
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http://dx.doi.org/10.1007/s40620-021-01191-yDOI Listing
April 2022

Skin Toxicities with Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Signals from Disproportionality Analysis of the FDA Adverse Event Reporting System.

Am J Clin Dermatol 2022 Mar 26;23(2):247-255. Epub 2021 Oct 26.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.

Background: Cyclin-dependent kinase (CDK)-4/6 inhibitors have been associated with dermatologic reactions, especially alopecia, in pivotal trials.

Objective: We aimed to comprehensively describe skin toxicities with CDK4/6 inhibitors reported in the real world through the US FDA Adverse Event Reporting System (FAERS).

Methods: Cutaneous adverse events (AEs) were characterized in terms of spectrum and clinical features, including seriousness (with fatality proportion), latency, and discontinuation. Disproportionality analyses were performed through the reporting odds ratio (ROR) and 95% confidence interval (CI) by comparing CDK4/6 inhibitors with other anticancer drugs used in breast cancer.

Results: As of December 2020, a total of 7986 cutaneous events were reported with CDK4/6 inhibitors (15% of total AEs with CDK4/6 inhibitors), mainly by consumers (39.6%), with 43.5% classified as serious and 25% requiring discontinuation. In 49% of the cases, five or more noncutaneous events were co-reported. The most frequently reported cutaneous events were alopecia (N = 3528), rash (N = 1493), and pruritus (N = 1211): rashes were recorded in the first month (median onset 28 days), whereas alopecia and nail alterations were recorded after a median of 67 and 112 days, respectively. Several cutaneous AEs were associated with increased reporting, including vitiligo (N = 6; ROR 8.88; 95% CI 2.95-22.46) and bullous dermatitis with ribociclib (N = 7; ROR 2.90; 95% CI 1.13-6.27); erythema multiforme with abemaciclib (N = 9; ROR 5.80; 95% CI 2.57-11.48); onychoclasis (N = 142, ROR 2.27; 95% CI 1.83-2.79) and trichorrhexis (N = 22; ROR 3.27; 95% CI 1.78-5.93) with palbociclib.

Conclusions: Although causality cannot be demonstrated, a diverse reporting pattern of cutaneous AEs emerged from FAERS, including dermal/epidermal conditions, hair/nail disorders, and serious bullous conditions, with variable onsets and a remarkable proportion of discontinuations. The potential differential reporting among CDK4/6 inhibitors deserves further investigation.
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http://dx.doi.org/10.1007/s40257-021-00645-0DOI Listing
March 2022

Adverse events with sacubitril/valsartan in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system.

Eur J Prev Cardiol 2021 08 20;28(9):983-989. Epub 2020 Apr 20.

Department of Medical and Surgical Sciences, University of Bologna, Italy.

Aims: The aim of this study was to characterise clinical priority of adverse events with sacubitril/valsartan for targeting preventive measures.

Methods: We used the US Food and Drug Administration adverse event reporting system (worldwide pharmacovigilance database) to compare adverse events recording sacubitril/valsartan as suspect with other cardiovascular drugs. Disproportionality analyses were performed by calculating the reporting odds ratios, deemed significant when the lower limit of the 95% confidence interval was greater than 1. Clinical priority was assigned to adverse events with significant disproportionality by scoring (range 0-10 points) five features (number of events, magnitude of the lower limit of the 95% confidence interval, mortality frequency, important/designated medical event, biological plausibility).

Results: Sacubitril/valsartan was recorded in 20,021 reports, with 178 adverse events associated with significant disproportionality: 71.9%, 25.9% and 2.2% were classified as weak, moderate and strong clinical priorities, respectively. Increased reporting emerged for several cardiovascular adverse events, including 'renal failure' (N = 388; lower limit of the 95% confidence interval 2.26), 'hyperkalaemia' (314; 2.42) and 'angioedema' (309; 1.56). Sudden cardiac death (priority score 9 points) was the only designated medical event with strong clinical priority. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration (average onset 124 days), with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, loop diuretics) in 26.2% of records.

Conclusion: The increased cardiovascular reporting of sacubitril/valsartan in the real world was largely predictable from pre-approval evidence, underlying disease and likely patients' comorbidities. The unexpected reporting of sudden cardiac death occurred well before the complete development of positive electrical remodelling induced by sacubitril/valsartan, and calls for stringent clinical monitoring (to reduce the pro-arrhythmic burden related to co-medications), and further investigation on appropriate combination with other preventive measures.
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http://dx.doi.org/10.1177/2047487320915663DOI Listing
August 2021

Serious adverse events with tedizolid and linezolid: pharmacovigilance insights through the FDA adverse event reporting system.

Expert Opin Drug Saf 2021 Nov 19;20(11):1421-1431. Epub 2021 Jul 19.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

BackgroundTo investigate the adverse event (AE) profile of tedizolid and linezolid in post-marketing surveillance.Research design and methodsWe queried the worldwide FDA Adverse Event Reporting System and selected all records where tedizolid and linezolid were reported as suspect by removing potential duplicates. Disproportionality analysis was performed investigating designated medical events (DMEs) and specific AEs of clinical interest reported with tedizolid. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL95%CI)>1, using linezolid as comparator. Case-by-case assessment of AEs reported in at least three cases with tedizolid was performed.ResultsOverall, 271 and 11,259 reports mentioning respectively tedizolid and linezolid were recorded, of which respectively 59 and 4,473 patients with DMEs or selected AEs were found. No difference emerged for the selected AEs except for increased reporting of (N = 3; LL95%CI = 1.06) with tedizolid considering reports collected after 2014. Extensive off-label use in terms of therapeutic indications (83.6%) and treatment duration was reported with tedizolid.ConclusionsSimilar AE reporting between the two oxazolidinones was found. Considering limitations of pharmacovigilance, this hypothesis of comparable safety profile should be tested prospectively through dedicated real-world studies.
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http://dx.doi.org/10.1080/14740338.2021.1956461DOI Listing
November 2021

European List of Essential Medicines for Medical Education: a protocol for a modified Delphi study.

BMJ Open 2021 05 4;11(5):e045635. Epub 2021 May 4.

Department of Internal Medicine, Section Pharmacotherapy, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands.

Introduction: Junior doctors are responsible for a substantial number of prescribing errors, and final-year medical students lack sufficient prescribing knowledge and skills just before they graduate. Various national and international projects have been initiated to reform the teaching of clinical pharmacology and therapeutics (CP&T) during undergraduate medical training. However, there is as yet no list of commonly prescribed and available medicines that European doctors should be able to independently prescribe safely and effectively without direct supervision. Such a list could form the basis for a European Prescribing Exam and would harmonise European CP&T education. Therefore, the aim of this study is to reach consensus on a list of widely prescribed medicines, available in most European countries, that European junior doctors should be able to independently prescribe safely and effectively without direct supervision: the European List of Essential Medicines for Medical Education.

Methods And Analysis: This modified Delphi study will recruit European CP&T teachers (expert group). Two Delphi rounds will be carried out to enable a list to be drawn up of medicines that are available in ≥80% of European countries, which are considered standard prescribing practice, and which junior doctors should be able to prescribe safely and effectively without supervision.

Ethics And Dissemination: The study has been approved by the Medical Ethics Review Committee of VU University Medical Center (no. 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical Education (approved project no. NVMO-ERB 2020.4.8). The European List of Essential Medicines for Medical Education will be presented at national and international conferences and will be submitted to international peer-reviewed journals. It will also be used to develop and implement the European Prescribing Exam.
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http://dx.doi.org/10.1136/bmjopen-2020-045635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098946PMC
May 2021

Thromboembolic Events with Cyclin-Dependent Kinase 4/6 Inhibitors in the FDA Adverse Event Reporting System.

Cancers (Basel) 2021 Apr 7;13(8). Epub 2021 Apr 7.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.

We analyzed thromboembolic events, recognized (AESIs), with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system.

Methods: Thromboembolic events were characterized in terms of spectrum [venous and arterial thromboembolism (VTE; ATE)] and clinical features by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment.

Results: A total of 1722 thromboembolic events were retained. Increased VTE reporting emerged for CDK4/6 inhibitors in the exploratory analyses ( = 659; ROR = 1.51; 95% CI = 1.39-1.63), with consistent disproportionality in the consolidated analyses (e.g., deep vein thrombosis with abemaciclib: 17; 1.98; 1.22-3.19). Higher-than-expected ATE reporting was found for ribociclib, including myocardial infarction (41; 1.82; 1.33-2.48), with rapid onset (median latency 1 vs. 6 months for other CDK4/6 inhibitors). Causality was highly probable or probable in 83.2% of cases, with a negligible proportion of pre-existing drug- and patient-related risk factors except for cardiovascular comorbidities (26%).

Conclusions: Although causal association cannot be firmly inferred, oncologists should proactively monitor the occurrence of VTE with CDK4/6 inhibitors. The unexpected distinctive increased ATE reporting with ribociclib deserves urgent clarification though large comparative population-based studies. We support pharmacovigilance for the post-marketing characterization of AESIs, thus promoting real-time safe prescribing in oncology.
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http://dx.doi.org/10.3390/cancers13081758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067683PMC
April 2021

Clinically Significant Drug Interactions Between Psychotropic Agents and Repurposed COVID-19 Therapies.

CNS Drugs 2021 04 18;35(4):345-384. Epub 2021 Apr 18.

Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Massarenti, 9, 40138, Bologna, Italy.

As many patients with underlying psychiatric disorders may be infected with COVID-19, and COVID-19-affected subjects may frequently experience a new onset of psychiatric manifestations, concomitant use of psychotropic medications and COVID-19 therapies is expected to be highly likely and raises concerns of clinically relevant drug interactions. In this setting, four major mechanisms responsible for drug interactions involving psychotropic agents and COVID-19 therapies may be identified: (1) pharmacokinetic drug-drug interactions mainly acting on cytochrome P450; (2) pharmacodynamic drug-drug interactions resulting in additive or synergistic toxicity; (3) drug-disease interactions according to stage and severity of the disease; and (4) pharmacogenetic issues associated with polymorphisms of cytochrome P450 isoenzymes. In this review, we summarise the available literature on relevant drug interactions between psychotropic agents and COVID-19 therapies, providing practical clinical recommendations and potential management strategies according to severity of illness and clinical scenario.
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http://dx.doi.org/10.1007/s40263-021-00811-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053373PMC
April 2021

Drug Repurposing in the COVID-19 Era: Insights from Case Studies Showing Pharmaceutical Peculiarities.

Pharmaceutics 2021 Feb 25;13(3). Epub 2021 Feb 25.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy.

COVID-19 may lead to severe respiratory distress syndrome and high risk of death in some patients. So far (January 2021), only the antiviral remdesivir has been approved, although no significant benefits in terms of mortality and clinical improvement were recently reported. In a setting where effective and safe treatments for COVID-19 are urgently needed, drug repurposing may take advantage of the fact that the safety profile of an agent is already well known and allows rapid investigation of the efficacy of potential treatments, at lower costs and with reduced risk of failure. Furthermore, novel pharmaceutical formulations of older agents (e.g., aerosolized administration of chloroquine/hydroxychloroquine, remdesivir, heparin, pirfenidone) have been tested in order to increase pulmonary delivery and/or antiviral effects of potentially active drugs, thus overcoming pharmacokinetic issues. In our review, we will highlight the importance of the drug repurposing strategy in the context of COVID-19, including regulatory and ethical aspects, with a specific focus on novel pharmaceutical formulations and routes of administration.
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http://dx.doi.org/10.3390/pharmaceutics13030302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996547PMC
February 2021

Fluoroquinolones and Aortic Disease.

JAMA Intern Med 2021 06;181(6):881

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1001/jamainternmed.2020.9226DOI Listing
June 2021

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

Eur J Clin Microbiol Infect Dis 2021 Jun 7;40(6):1169-1176. Epub 2021 Jan 7.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.

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.
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http://dx.doi.org/10.1007/s10096-020-04149-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139903PMC
June 2021

Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment.

Breast Cancer Res Treat 2021 Feb 5;186(1):219-227. Epub 2020 Nov 5.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Purpose: We assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS).

Methods: Reports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases.

Results: ILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28-1.74), and abemaciclib vs other anticancer agents (4.70; 3.62-5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07-1.77) and ribociclib (2.39; 1.34-3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases.

Conclusions: Increased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.
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http://dx.doi.org/10.1007/s10549-020-06001-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641870PMC
February 2021

SGLT2 inhibitors for heart failure with reduced ejection fraction: a real EMPEROR?

Expert Opin Pharmacother 2021 Apr 13;22(5):647-650. Epub 2020 Nov 13.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

: In individuals with type 2 diabetes mellitus, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and serious adverse renal events, both in randomized controlled trials and observational studies.: In this paper, the authors critically discuss the rationale, results, and implications of the recent placebo-controlled EMPEROR-Reduced trial [NCT03057977], which evaluated empagliflozin in subjects with chronic heart failure and a reduced ejection fraction (HFrEF), with or without diabetes. A parallel with the DAPA-HF trial, investigating dapagliflozin in a similar albeit not fully overlapping population, is also provided. The authors finally provide the reader with their expert perspectives.: EMPEROR-Reduced confirmed and extended the findings from DAPA-HF, especially on renal outcomes, thus strengthening the rationale for considering SGLT2 inhibitors among established treatments in HFrEF. Forthcoming guidelines supported by the knowledge of the clinical pharmacology of SGLT2 inhibitors will hopefully assist cardiologists, nephrologists, and general practitioners in selecting the target population and promoting safe prescribing.
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http://dx.doi.org/10.1080/14656566.2020.1846719DOI Listing
April 2021

Ceftolozane/tazobactam exposure in critically ill patients undergoing continuous renal replacement therapy: a PK/PD approach to tailor dosing.

J Antimicrob Chemother 2021 01;76(1):199-205

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Objectives: To investigate the influence of continuous renal replacement therapy (CRRT) intensity on the clearance of ceftolozane/tazobactam in critical care patients, and to evaluate if the reported doses would achieve an optimal pharmacokinetic/pharmacodynamic (PK/PD) target against Pseudomonas aeruginosa exhibiting different MICs.

Methods: The MEDLINE-PubMed database was searched from inception to January 2020 to retrieve observational studies or case reports investigating the PK behaviour of ceftolozane/tazobactam during CRRT. Relevant CRRT settings and PK variables were extracted, and the influence of CRRT intensity on ceftolozane/tazobactam total clearance (CLtot) was determined by simple linear regression. The optimal PK/PD target for the reported doses was deemed to be achieved when ceftolozane trough concentrations (Cmin) were above the MIC (less intensive target) or four times the MIC (intensive target) for P. aeruginosa.

Results: Data from six studies including 11 patients (mean age 56.6 years) were analysed. Mean blood flow rate and effluent flow rate were 161.8 mL/min and 2383.4 mL/h, respectively. Ceftolozane Cmin ranged from 25.8 to 79.4 mg/L. A significant correlation was found for ceftolozane CLtot and effluent flow rate (P = 0.027). The intensive PK/PD target was achieved by 100% and 50% of the reported doses for MIC, respectively, up to 4 and 8 mg/L.

Conclusions: A significant correlation between effluent flow rate and ceftolozane clearance during CRRT could be identified. Higher dosing regimens coupled with continuous/extended infusion may be required in the case of higher CRRT intensity, deep-seated infections or poorly susceptible isolates. Larger studies assessing ceftolozane PK in different CRRT settings are warranted.
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http://dx.doi.org/10.1093/jac/dkaa416DOI Listing
January 2021

Risk of hospitalization from drug-drug interactions in the Elderly: real-world evidence in a large administrative database.

Aging (Albany NY) 2020 Oct 5;12(19):19711-19739. Epub 2020 Oct 5.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

The aim of this study was to assess the risk of hospitalization associated with the concomitant prescription of 10 highly prevalent drug-drug interactions (DDIs) among all individuals aged ≥65 residing in Bologna's area, Italy. We used incidence density sampling, and the effect of current (last month) and past (≥30 days before) exposure to DDI was investigated through conditional multivariable logistic regression analysis. Two DDIs were associated with increased hospitalization due to DDI related conditions: ACE-inhibitors/ diuretics plus glucocorticoids (current DDI: OR 2.36, 95% CI 1.94-2.87; past DDI: OR 1.36, 95% CI 1.12-1.65) and antidiabetic therapy plus current use of fluoroquinolones (OR 4.43, 95% CI 1.61-11.2). Non-Steroidal Anti-inflammatory Drugs (NSAIDs) increased the risk of re-bleeding in patients taking Selective Serotonin Reuptake Inhibitors (OR 5.56, 95% CI 1.24-24.9), while no significant effect was found in those without a history of bleeding episodes. Concomitant prescription of NSAIDs and ACE-inhibitors/diuretics in patients with a history of high-risk conditions was infrequent. Within the pattern of drug prescriptions in the older population of Bologna's area, we distinguished DDIs with actual clinical consequences from others that might be considered generally safe. Observed prescribing habits of clinicians reflect awareness of potential interactions in patients at risk.
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http://dx.doi.org/10.18632/aging.104018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732312PMC
October 2020

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis.

Eur J Clin Pharmacol 2021 Feb 8;77(2):233-239. Epub 2020 Sep 8.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio, 48, 40126, Bologna, Italy.

Purpose: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents.

Methods: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (V), and lipophilicity) and PD (values of binding affinity (Ki) and IC for serotonin reuptake transporter (SERT) and 5-HT) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index).

Results: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large V (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for V/Ki SERT ratio (p = 0.05).

Discussion: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.
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http://dx.doi.org/10.1007/s00228-020-02990-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803711PMC
February 2021

Baricitinib, JAK inhibitors and liver injury: a cause for concern in COVID-19?

Expert Opin Drug Saf 2020 10 25;19(10):1367-1369. Epub 2020 Aug 25.

Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna , Bologna, Italy.

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http://dx.doi.org/10.1080/14740338.2020.1812191DOI Listing
October 2020

Assessment of adverse reactions to α-lipoic acid containing dietary supplements through spontaneous reporting systems.

Clin Nutr 2021 03 29;40(3):1176-1185. Epub 2020 Jul 29.

Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Background & Aims: Alpha-lipoic acid (ALA)-containing dietary supplements are widely used in clinical practice, although their safety assessment is under-investigated. We characterize the safety profile of ALA-containing products by analysing spontaneous reports of suspected adverse reactions (ARs).

Methods: Suspected ARs to ALA-containing products were extracted from the Italian Phytovigilance System (IPS), and scrutinized in terms of seriousness and causality (through WHO UMC system), with a specific focus on important (IMEs) and designated medical events (DMEs). To characterize the reporting profile from an international perspective, the WHO-VigiBase was also queried.

Results: From March 2002 to February 2020, out of 2147 total reports, 116 reports concerning 212 ARs to ALA-containing products were collected. Women were involved in 68.1% of cases. Skin (44.9%) and gastrointestinal disorders (10.8%) were the most frequently represented ARs. Causality assessment resulted as definite (15), probable (35), possible (24), unlikely (5), and unclassifiable (37). In 70% of cases, events occurred within 30 days of ALA use. Forty-five reports were serious (38.8%), being insulin autoimmune syndrome the most frequently reported (N = 10). IMEs were recorded in 20 cases, including four DMEs (3 angioedema and one anaphylactic shock). Similar distribution emerged from the 5641 reports in the WHO-VigiBase.

Conclusions: The remarkable reporting of unpredictable skin, immune and hepatic ARs, coupled with seriousness, strong causality and early onset, calls for a) careful risk-benefit assessment of ALA-containing products by regulators; b) awareness and monitoring by clinicians and c) continuous vigilance of their safety profile through valuable spontaneous reporting systems such as IPS.
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http://dx.doi.org/10.1016/j.clnu.2020.07.028DOI Listing
March 2021

Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis.

Drug Saf 2020 12;43(12):1277-1285

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.

Introduction: The European Medicines Agency has suspended the use of ulipristal acetate (UPA) in the treatment of uterine fibroids and is reassessing its association with a risk of liver injury.

Objectives: Our objectives were to characterize the post-marketing reporting of drug-induced liver injury (DILI) with UPA and investigate the underlying pharmacological basis.

Methods: We queried the worldwide FDA Adverse Event Reporting System and performed a disproportionality analysis, selecting only hepatic designated medical events (DMEs) where UPA was reported as suspect. The reporting odds ratios (RORs) were calculated, and we considered a lower limit of the 95% confidence interval (LL95% CI) > 1 as significant. Physiochemical/pharmacokinetic features were extracted to assess the risk of hepatotoxicity by applying predictive DILI risk models. Mifepristone and leuprolide were selected as comparators.

Results: A significantly higher proportion of liver disorders was reported for UPA than for mifepristone (2.9 vs. 0.8%; p < 0.00001) and leuprolide (2.9 vs. 1.6%; p = 0.015). As regards hepatic DMEs, statistically significant RORs were found for autoimmune hepatitis (N = 5; LL95% CI 16.8), DILI (n = 5; LL95% CI 5.9), and acute hepatic failure (N = 5; LL95% CI 9.3). No signals of DILI emerged for mifepristone and leuprolide acetate. UPA and mifepristone showed high lipophilicity and hepatic metabolism (predicted intermediate DILI risk). Leuprolide exhibited contrasting features, resulting in no DILI concern. Inhibition of different liver transporters and the presence of a reactive metabolite were also recognised for UPA.

Conclusion: Different drug properties previously linked to the occurrence of DILI may partially explain the reporting pattern observed with UPA. Our "bedside-to-bench" approach may support regulators in the risk-benefit assessment of UPA.
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http://dx.doi.org/10.1007/s40264-020-00975-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686198PMC
December 2020

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance.

Target Oncol 2020 08;15(4):449-466

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.

The advent of immune checkpoint inhibitors (ICIs) caused a paradigm shift both in drug development and clinical practice; however, by virtue of their mechanism of action, the excessively activated immune system results in a multitude of off-target toxicities, the so-called immune-related adverse events (irAEs), requiring new skills for timely diagnosis and a multidisciplinary approach to successfully manage the patients. In the recent past, a plethora of large-scale pharmacovigilance analyses have characterized various irAEs in terms of spectrum and clinical features in the real world. This review aims to summarize and critically appraise the current landscape of pharmacovigilance studies, thus deriving take-home messages for oncologists. A brief primer to study design, conduction, and data interpretation is also offered. As of February 2020, 30 real-world postmarketing studies have characterized multiple irAEs through international spontaneous reporting systems, namely WHO Vigibase and the US FDA Adverse Event Reporting System. The majority of studies investigated a single irAE and provided new epidemiological evidence about class-specific patterns of irAEs (i.e. anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] versus anti-programmed cell death 1 [PD-1] receptor, and its ligand [PD-L1]), kinetics of appearance, co-occurrences (overlap) among irAEs, and fatality rate. Oncologists should be aware of both strengths and limitations of these pharmacovigilance analyses, especially in terms of data interpretation. Optimal management (including rechallenge), predictivity of irAEs (as potential biomarkers of effectiveness), and comparative safety of ICIs (also in terms of combination regimens) represent key research priorities for next-generation real-world studies.
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http://dx.doi.org/10.1007/s11523-020-00738-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434791PMC
August 2020

Serious adverse events with tocilizumab: Pharmacovigilance as an aid to prioritize monitoring in COVID-19.

Br J Clin Pharmacol 2021 03 26;87(3):1533-1540. Epub 2020 Jul 26.

Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.
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http://dx.doi.org/10.1111/bcp.14459DOI Listing
March 2021

Biomarkers of Kidney Injury in Very-low-birth-weight Preterm Infants: Influence of Maternal and Neonatal Factors.

In Vivo 2020 May-Jun;34(3):1333-1339

Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, St. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy

Background/aim: Acute kidney injury is an important cause of mortality in very-low-birth-weight (VLBW) preterm infants. As in the general population, the detection of renal damage cannot rely on the measurement of serum creatinine, since it has been demonstrated to be a weak predictor and a delayed indicator of kidney function deterioration. However, several candidate biomarkers have failed to prove sufficient specificity and sensitivity for a routine clinical use because of the poor awareness of their biological role. This study was aimed to investigate the impact of different maternal and neonatal conditions on several renal biomarkers in VLBW preterm infants during the first week of life.

Patients And Methods: Preterm infants<32 weeks' gestation and <1500g were enrolled. We measured urinary biomarkers kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, epidermal growth factor (EGF) and osteopontin (OPN) on the 1, 3, and 7 day after birth.

Results: Thirty-tree infants were included. The multivariate analysis showed a significant association between gestational age, the presence of patent ductus arteriosus, antenatal maternal hypertension and the levels of urinary biomarkers.

Conclusion: There is a possible relation between early biomarkers of renal injury and antenatal, perinatal and post-natal characteristics in VLBW preterm infants during the first week of life.
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http://dx.doi.org/10.21873/invivo.11910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279835PMC
February 2021

Assessing the association between fluoroquinolones and emerging adverse drug reactions raised by regulatory agencies: An umbrella review.

Eur J Intern Med 2020 05 23;75:60-70. Epub 2020 Jan 23.

Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.

Background: Regulatory agencies warned against fluoroquinolones for the management of minor infections because of the risk of emerging adverse events (collagen-associated adverse events, neuropsychiatric toxicity and long-term disability). We aimed to assess quality and credibility of evidence as well as causality regarding these putative associations.

Methods: MEDLINE, Scopus, Web of Science and PROSPERO were searched, from inception to August 2019, for systematic reviews with meta-analyses investigating emerging adverse events. Two investigators extracted data to grade quality (through validated AMSTAR-2 tool), rank credibility of the evidence (convincing, highly suggestive, suggestive, weak) through adapted criteria including E-value calculation, and assess causality (Hill's criteria).

Results: Seven systematic reviews of observational studies providing 16 risk estimates [seven, five and four, respectively, for aortic aneurysm/dissection (AAD), retinal detachment (RD) and any tendon disorders (ATD)] met inclusion criteria. No systematic reviews with meta-analysis investigating the risk of neuropsychiatric toxicity or long-term disability were found. The associations between fluoroquinolones and AAD/ATD showed highly suggestive credibility and were supported by strong evidence of causality (double increased risk, especially within first 2 months of treatment). Conflicting data concerning the emergence of RD were retrieved, resulting in weak evidence of causality. Quality of the evidence ranged from high to low for AAD, from moderate to critically low for RD, and it was moderate for ATD.

Conclusion: Our analysis supports credible, plausible and highly suggestive associations with AAD (rare occurrence but strong causality) and ATD. Limitations of both umbrella reviews and observational evidence should be considered.
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http://dx.doi.org/10.1016/j.ejim.2020.01.009DOI Listing
May 2020

Reduced neuropsychiatric events as "beneficial reactions" to drugs: Seek associations with caution.

Brain Behav Immun 2020 02 19;84:275-276. Epub 2019 Nov 19.

Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy.

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http://dx.doi.org/10.1016/j.bbi.2019.11.011DOI Listing
February 2020

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

BMC Pharmacol Toxicol 2019 11 12;20(1):65. Epub 2019 Nov 12.

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.

Background: The 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.

Methods: Three 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.

Results: A 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.

Conclusion: KPC 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.
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http://dx.doi.org/10.1186/s40360-019-0364-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852729PMC
November 2019
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