INTEGRATED ANTIBIOTIC SAFETY ASSESSMENT MODEL: CAUSALITY, SEVERITY, PREVENTABILITY AND SIGNAL DETECTION

Antibiotics are essential for the management of bacterial infections; however, their widespread and often inappropriate use is associated with adverse drug reactions (ADRs), medication errors, drug interactions, and other preventable harms. Conventional antibiotic safety assessment commonly evaluates causality, severity, preventability, and pharmacovigilance signals as separate domains, potentially limiting comprehensive interpretation and translation of safety findings into clinical action. This review proposes the Integrated Antibiotic Safety Assessment Model (IASAM), a multidimensional framework that combines these complementary domains within a unified and iterative assessment pathway. Causality assessment evaluates the likelihood that an antibiotic is responsible for an adverse event, severity assessment determines its clinical consequences, preventability assessment identifies potentially avoidable factors across the medication-use process, and signal detection examines patterns that may indicate emerging or disproportionate safety concerns at the population level. By integrating individual case assessment with population-level pharmacovigilance, IASAM aims to improve the identification, prioritization, and management of clinically significant and preventable antibiotic-related harm. The model provides a structured feedback loop linking safety assessment with risk mitigation, antimicrobial stewardship, quality improvement, and regulatory decision-making. Its potential applications extend across hospitals, pharmacovigilance centres, formulary committees, and public health programmes, including settings such as the Pharmacovigilance Programme of India. Emerging real-world data and artificial intelligence may further strengthen safety surveillance, although expert clinical judgment remains essential. IASAM represents a conceptual approach to bridge pharmacovigilance and antimicrobial stewardship; however, prospective validation is required to establish its reliability, reproducibility, clinical utility, and applicability across diverse healthcare settings and antibiotic classes.

• Phatak A, Nagari BG. Safety of medicines. Pharma Times., 2003; 35: 19-21.
• Shamna M, Dilip C, Ajmal M, Mohan PL, Shinu C, Jafer CP, et al. A prospective study on Adverse Drug Reactions of antibiotics in a tertiary care hospital. Saudi Pharm J., 2014; 22: 303-8.
• Stavreva G, Pendicheva D, Pandurska A, Marev R. Detection of adverse drug reactions to antimicrobial drugs in hospitalized patients. Trakia J Sci., 2008; 6(1): 7-9.
• Hussain MM, Girhepunje K, Pal R, Siddiqua SS. Incidence of adverse drug reactions in a tertiary care hospital: a systematic review and meta-analysis of prospective studies. Der Pharmacia Lettre., 2010; 2(3): 358-68.
• Jimmy J, Rao Padma GM, Jimmy B. Adverse drug reactions to fluoroquinolone antibiotics-analysis of reports received in a tertiary care hospital. Int J Risk Saf Med., 2008; 20: 169-80.
• Suthar JV, Desai SV. A study of adverse cutaneous drug reactions in outdoor patients attending to skin and V.D. Department of Shree Krishna Hospital, Karamsad. Int J Res Pharm Biomed Sci., 2011; 2(1): 274-9.
• Oshikoya KA, Njokanma OF, Chukwara HA, Ojo IO. Adverse drug reactions in Nigerian children. Paediatr. Perinat Drug Ther., 2007; 8: 81-8.
• Benjamin H, Louis MJ, Maryse LM. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol, 2002; 54: 665-70.
• Jonville-Bera AP, Giraudeau B, Blanc P, Beau Salinas F, Autret-Leca E. Frequency of adverse drug reactions in children: a prospective study. Br J Clin Pharmacol, 2002; 53: 207-10.
• Granowitz, Eric V, Brown, Richard B. Antibiotic adverse reactions and drug interactions. Crit Care Clin., 2008; 24: 421-42.
• Priyadharsini R, Adhithan SC, Sreenivasan S, Kumar. A study on adverse drug reactions in paediatric patients. J Pharmacol Pharmacother, 2011; 2(4): 277-80.
• Jung IY, Kim JJ, Lee SJ, et al. Antibiotic-related adverse drug reactions at a tertiary care hospital in South Korea. BioMed Res Int., 2017; 2017.
• Sokolewicz EM, Rogowska M, Lewandowski M, Puchowska M, Piechota D, Bara´ nska-Rybak W. Antibiotic-related adverse drug reactions in patients treated on the Dermatology ward of medical University of Gda´ nsk. Antibiotics, 2021; 10(10): 1144.
• Watson S, Caster O, Rochon PA, den Ruijter H. Reported adverse drug reactions in women and men: aggregated evidence from globally collected individual case reports during half a century. EClinicalMedicine, 2019; 17: 100188.
• Brabete AC, Greaves L, Maximos M, Huber E, Li A, Lˆ e ML. A Sex-and gender-based analysis of adverse drug reactions: a Scoping review of pharmacovigilance Databases. Pharmaceuticals, 2022; 15(3): 298.
• Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol, 2001; 2(6):           349–351.
• Sundaran S, Udayan A, Hareendranath K, et al. Study on the classification, causality, preventability and severity of adverse drug reaction using spontaneous reporting system in hospitalized patients. Pharmacy, 2018; 6(4): 108.
• Suh DC, Woodall BS, Shin SK, Santis ER. Clinical and economic impact of adverse drug reactions in hospitalized patients. Ann Pharmacother, 2000; 34(12): 1373–1379.
• Gonz´alez-García R, Albanell-Fern´andez M, Aranda L, et al. Evaluation of desensitization protocols to betalactam antibiotics. J Clin Pharm Therapeut, 2022; 47(5): 592–599.
• Chastain DB, Hutzley VJ, Parekh J, Alegro JV. Antimicrobial desensitization: a review of published protocols. Pharmacy, 2019; 7(3): 112.
• Oshikoya KA, Ogunyinka IA, Ogar CK, Abiola A, Ibrahim A, Oreagba IA. Severe cutaneous adverse drug reactions manifesting as Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the national pharmacovigilance center in Nigeria: a database review from 2004 to 2017. Therapeutic Advances in Drug Safety, 2020; (1): 2042098620905998. 
• Lian BS, Lee HY. Managing the ADR of Stevens-Johnson syndrome/toxic epidermal necrolysis. Expet Opin Drug Saf., 2022; 21(8): 1039–1046.
• Al Aboud DM, Nessel TA, Hafsi W. Cutaneous Adverse Drug Reaction. StatPearls [Internet] StatPearls Publishing, 2021.
• Maker JH, Stroup CM, Huang V, James SF. Antibiotic hypersensitivity mechanisms. Pharmacy, 2019; 7(3): 122.
• Dilley M, Geng B. Immediate and delayed hypersensitivity reactions to antibiotics: aminoglycosides, clindamycin, linezolid, and metronidazole. Clin Rev Allergy Immunol, 2022; 62(3): 463–475.
• Joerg L, Hasler S, Gschwend A, et al. 75% negative skin test results in patients with suspected hypersensitivity to beta-lactam antibiotics: Influencing factors and interpretation of test results. World Allergy Organization Journal, 2021; 14(11): 100602.
• Choi JY, Choi JH, Kim MG, Rhie SJ. Signal detection of adverse drug reactions of cephalosporins using data from a national pharmacovigilance database. Pharmaceuticals, 2021; 14(5): 425.
• Mhaidat NM, Al-Azzam S, Banat HA, et al. Reporting antimicrobial-related adverse drug events in Jordan: an analysis from the VigiBase database. Antibiotics, 2023; 12(3): 624.
• Kongkaew C, Noyce PR, Ashcroft DM. Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Ann Pharmacother, 2008; 42(7): 1017-25.
• Ramesh M, Pandit J, Parthasarathi G. Adverse drug reactions in a South Indian hospital— their severity and cost involved. Pharmacoepidemiol Drug Saf., 2003; 12(8): 687 92.
• Naranjo CA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther, 1981; 30: 239245.
• Pharmacovigilance Programme of India for Assuring Drug Safety. http://www.cdsco.nic.in/ pharmacovigilance.htm [Last accessed on 2019 Mar 23].
• Pharmacovigilance, WHO; 2014. Available from: http:// www.who.int/medicines/areas/quality safety/safety efficacy/ pharmvigi/en 8. R AK, V MJ, M V, K RKP. A retrospective study of Adverse Drug Reactions reported in a tertiary care hospital. Natl J Physiol Pharm Pharmacol. (2023), [cited December 23, 2024]; 13(11): 2328 2332. doi:10.5455/njppp.2023.13.04196202320042023
• H¨ armark L, Van Grootheest AC. Pharmacovigilance: Methods, recent developments and future per spectives. Eur J ClinPharmacol, 2008; 64: 743-52.
• Shajahan J, Parathoduvil AA, Purushothaman S. An analysis of seriousness, predictability and pre ventability of Adverse Drug Reactions reported at a tertiary care teaching hospital in Kerala, India: a retrospective observational record based study. Int J Basic ClinPharmacol, 2018; 7: 2433-8
• Shamna M, Dilip C, Ajmal M, Mohan PL, Shinu C, Jafer CP, et al. A prospective study on Adverse Drug Reactions of antibiotics in a tertiary care hospital. Saudi Pharm J., 2013; 22: 303-8.
• Rani S, Sharma B, Tarun, Kumar S, Saini R. Antibiotics-related Adverse Drug Reactions at a tertiary care hospital in North India. Int J Basic ClinPharmacol, 2019; 8: 2288-93.
• BharathiAT, Sivasankari N, Rajeswari H, Sreelekha B. Retrospective study on adverse drug reaction in a tertiary care hospital. Int J Pharm Bio Sci., 2016; 7: 294-8.
• Jung IY, Kim JJ, Lee SJ, Kim J, Seong H, Jeong W, et al. Antibiotic-related Adverse Drug Reactions at a tertiary care hospital in South Korea. Biomed Res Int., 2017; 2017: 4304973.
• Godlewska, A.; Pawlak, K.; Jańczewski, D. Phospholipid composition changes in bacterial membranes: A molecular mechanism of antibiotic resistance. Adv. Colloid Interface Sci., 2026; 348: 103738.
• Radka, C.D.; Rock, C.O. Mining fatty acid biosynthesis for new antimicrobials. Annu. Rev. Microbiol, 2022; 76: 281–304.
• Liebisch, G.; Vizcaíno, J.A.; Köfeler, H.; Trötzmüller, M.; Griffiths, W.J.; Schmitz, G.; Spener, F.; Wakelam, M.J.O. Shorthand notation for lipid structures derived from mass spectrometry. J. Lipid Res., 2013; 54: 1523–1530.
• Ni, Z.; Angelidou, G.; Lange, M.; Hoffmann, R.; Fedorova, M. LipidHunter identifies phospholipids by high-throughput processing of LC-MS and shotgun lipidomics datasets. Anal. Chem., 2017; 89: 8800–8807.
• Cronan, J.E.; Luk, T. Advances in the structural biology, mechanism, and physiology of cyclopropane fatty acid modifications of bac terial membranes. Microbiol. Mol. Biol. Rev., 2022; 86: e00013-22.
• Kolbeck, S.; Kienberger, H.; Kleigrewe, K.; Hilgarth, M.; Vogel, R.F. Effect of high levels of CO2 and O2 on membrane fatty acid profile and membrane physiology of meat spoilage bacteria. Eur. Food Res. Technol, 2021; 247: 999–1011.
• Karlinsey, J.E.; Fung, A.M.; Johnston, N.; Goldfine, H.; Libby, S.J.; Fang, F.C. Cyclopropane fatty acids are important for Salmonella enterica serovar Typhimurium virulence. Infect. Immun., 2022; 90: e00479-21.
• Romantsov, T.; Guan, Z.; Wood, J.M. Cardiolipin and the osmotic stress responses of bacteria. Biochim. Biophys. Acta (BBA) Biomembr, 2009; 1788: 2092–2100.