Adverse Drug Reactions Relevant to Drug Resistance and Ineffectiveness Associated with Meropenem, Linezolid, and Colistin: An Analysis Based on Spontaneous Reports from the European Pharmacovigilance Database

Antimicrobial resistance is considered one of the major threats to public health and is an important factor that influences the patient’s outcome in the intensive care unit. Pharmacovigilance can help raise awareness of potential drug resistance (DR) or ineffectiveness (DI) through adverse drug reaction reports that are submitted to different spontaneous reporting systems. Based on spontaneous Individual Case Safety Reports from EudraVigilance, we conducted a descriptive analysis of adverse drug reactions associated with meropenem, colistin, and linezolid, with a focus on DR and DI. Of the total adverse drug reactions (ADRs) reported for each analyzed antibiotic by 31 December 2022, between 2.38–8.42% and 4.15–10.14% of the reports were related to DR and DI, respectively. A disproportionality analysis was conducted to evaluate the frequency of reporting adverse drug reactions relevant to the DR and DI of the analyzed antibiotics compared to other antimicrobials. Based on the analysis of the collected data, this study underlines the importance of post-marketing drug safety monitoring in raising a warning signal regarding antimicrobial resistance, thereby potentially contributing to the reduction in antibiotic treatment failure in an intensive care setting.

[1]  J. Granton,et al.  Pharmacokinetic Alterations Associated with Critical Illness , 2023, Clinical Pharmacokinetics.

[2]  R. Birlutiu,et al.  Are There Any Changes in the Causative Microorganisms Isolated in the Last Years from Hip and Knee Periprosthetic Joint Infections? Antimicrobial Susceptibility Test Results Analysis , 2023, Microorganisms.

[3]  A. Rabaan,et al.  Global Prevalence of Colistin Resistance in Klebsiella pneumoniae from Bloodstream Infection: A Systematic Review and Meta-Analysis , 2022, Pathogens.

[4]  L. Rus,et al.  Microbial Resistance to Antibiotics and Effective Antibiotherapy , 2022, Biomedicines.

[5]  M. T. Herdeiro,et al.  Descriptive Analysis of Adverse Drug Reactions Reports of the Most Consumed Antibiotics in Portugal, Prescribed for Upper Airway Infections , 2022, Antibiotics.

[6]  C. Aurilio,et al.  Mechanisms of Action of Carbapenem Resistance , 2022, Antibiotics.

[7]  L. Härmark,et al.  Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre , 2021, Antibiotics.

[8]  K. Hardie,et al.  JMM Profile: Carbapenems: a broad-spectrum antibiotic , 2021, Journal of medical microbiology.

[9]  J. Roberts,et al.  A personalised approach to antibiotic pharmacokinetics and pharmacodynamics in critically ill patients. , 2021, Anaesthesia, critical care & pain medicine.

[10]  K. Allegaert,et al.  Pharmacokinetics of Antibiotics in Pediatric Intensive Care: Fostering Variability to Attain Precision Medicine , 2021, Antibiotics.

[11]  S. Mohapatra,et al.  Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions , 2021, Journal of biosciences.

[12]  Tasnim I. Lat,et al.  Gender Differences in Critical Illness and Critical Care Research , 2021, Clinics in Chest Medicine.

[13]  A. Spinewine,et al.  Clinical Use and Adverse Drug Reactions of Linezolid: A Retrospective Study in Four Belgian Hospital Centers , 2021, Antibiotics.

[14]  J. Habarugira,et al.  Pharmacovigilance network as an additional tool for the surveillance of antimicrobial resistance , 2021, Pharmacoepidemiology and drug safety.

[15]  T. Velkov,et al.  Rescuing the Last-Line Polymyxins: Achievements and Challenges , 2021, Pharmacological Reviews.

[16]  G. Onder,et al.  Adverse drug reactions in older adults: a narrative review of the literature , 2021, European Geriatric Medicine.

[17]  J. Qian,et al.  Comparisons of adverse event reporting for colistin versus polymyxin B using the US Food and Drug Administration Adverse Event Reporting System (FAERS) , 2021, Expert opinion on drug safety.

[18]  S. M. Nichelle,et al.  Meropenem use and therapeutic drug monitoring in clinical practice: a literature review , 2021, Journal of clinical pharmacy and therapeutics.

[19]  C. Ayoub Moubareck,et al.  Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance , 2020, Membranes.

[20]  Sumana Mahadevaiah,et al.  Healthcare-associated Infection in Intensive Care Units: Overall Analysis of Patient Criticality by Acute Physiology and Chronic Health Evaluation IV Scoring and Pathogenic Characteristics , 2020, Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine.

[21]  A. A. Elshamy,et al.  A review on bacterial resistance to carbapenems: epidemiology, detection and treatment options , 2020, Future science OA.

[22]  M. Bue,et al.  Population pharmacokinetics of piperacillin in plasma and subcutaneous tissue in patients on continuous renal replacement therapy. , 2020, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[23]  M. Antonelli,et al.  Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial , 2019, Critical Care.

[24]  P. Collignon,et al.  Socioeconomic Enablers for Contagion: Factors Impelling the Antimicrobial Resistance Epidemic , 2019, Antibiotics.

[25]  S. Hashemian,et al.  Linezolid: a review of its properties, function, and use in critical care , 2018, Drug design, development and therapy.

[26]  J. Dogné,et al.  EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection , 2018, Drug Safety.

[27]  Roger L. Nation,et al.  Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B? , 2016, Antimicrobial Agents and Chemotherapy.

[28]  Y. Carmeli,et al.  The negative impact of antibiotic resistance. , 2016, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[29]  G. Meletis,et al.  Carbapenem resistance: overview of the problem and future perspectives , 2016, Therapeutic advances in infectious disease.

[30]  M. Antonelli,et al.  Safety and efficacy of colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia as part of a macro-project funded by the Seventh Framework Program of the European Commission studying off-patent antibiotics: study protocol for a randomized controlled trial , 2015, Trials.

[31]  G. Barton,et al.  Pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient , 2015, Journal of the Intensive Care Society.

[32]  J. Bosso,et al.  Adverse Reactions Associated with Systemic Polymyxin Therapy , 2015, Pharmacotherapy.

[33]  C. Llor,et al.  Antimicrobial resistance: risk associated with antibiotic overuse and initiatives to reduce the problem , 2014, Therapeutic advances in drug safety.

[34]  B. Creagh-Brown,et al.  Increasing age of patients admitted to intensive care, and association between increased age and greater risk of post-ICU death , 2014, Critical Care.

[35]  S. Pal,et al.  WHO programme for international drug monitoring , 2013 .

[36]  K. Long,et al.  Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome , 2011, Antimicrobial Agents and Chemotherapy.

[37]  Robert A. Bonomo,et al.  Carbapenems: Past, Present, and Future , 2011, Antimicrobial Agents and Chemotherapy.

[38]  Jordi Rello,et al.  International study of the prevalence and outcomes of infection in intensive care units. , 2009, JAMA.

[39]  Bogdan Ioan Coculescu.  Antimicrobial resistance induced by genetic changes , 2009, Journal of medicine and life.

[40]  J. Roberts,et al.  Pharmacokinetic issues for antibiotics in the critically ill patient , 2009, Critical care medicine.

[41]  D. Paterson,et al.  Antibiotic resistance—What’s dosing got to do with it? , 2008, Critical care medicine.

[42]  G. Wood,et al.  Pharmacokinetic changes in critical illness. , 2006, Critical care clinics.

[43]  H. Gold,et al.  Antimicrobial resistance to linezolid. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  J. Boyce,et al.  Mechanisms of Polymyxin Resistance. , 2019, Advances in experimental medicine and biology.

[45]  D. Moga,et al.  Pharmacoepidemiology and pharmacovigilance , 2019, Remington.

[46]  J. Rolain,et al.  Emergence of colistin-resistant bacteria in humans without colistin usage: a new worry and cause for vigilance. , 2016, International journal of antimicrobial agents.

[47]  Screening for adverse reactions in EudraVigilance , 2016 .

[48]  Arti Kapi.  The evolving threat of antimicrobial resistance: Options for action , 2014 .

[49]  Canary Wharf,et al.  Guidelines on good pharmacovigilance practices (GVP) , 2012 .

[50]  D. Mattison,et al.  Sex Differences in Pharmacokinetics and Pharmacodynamics , 2009, Clinical pharmacokinetics.

[51]  R. Jones,et al.  Oxazolidinones: a review. , 2000, Drugs.