Heterogeneity in the Identification of Potential Drug‐Drug Interactions in the Intensive Care Unit: A Systematic Review, Critical Appraisal, and Reporting Recommendations

Abstract

Patients admitted to the intensive care unit (ICU) are frequently exposed to potential drug‐drug interactions (pDDIs). However, reported frequencies of pDDIs in the ICU vary widely between studies. This can be partly explained by significant variation in their methodological approach. Insight into methodological choices affecting pDDI frequency would allow for improved comparison and synthesis of reported pDDI frequencies. This study aimed to evaluate the association between methodological choices and pDDI frequency and formulate reporting recommendations for pDDI frequency studies in the ICU. The MEDLINE database was searched to identify papers reporting pDDI frequency in ICU patients. For each paper, the pDDI frequency and methodological choices such as pDDI definition and pDDI knowledge base were extracted, and the risk of bias was assessed. Each paper was categorized as reporting a low, medium, or high pDDI frequency. We sought associations between methodological choices and pDDI frequency group. Based on this comparison, reporting recommendations were formulated. Analysis of methodological choices showed significant heterogeneity between studies, and 65% of the studies had a medium to high risk of bias. High risk of bias, small sample size, and use of drug prescriptions instead of administrations were related to a higher pDDI frequency. The findings of this review may support researchers in designing a reliable methodology assessing pDDI frequency in ICU patients. The reporting recommendations may contribute to standardization, comparison, and synthesis of pDDI frequency studies, ultimately improving knowledge about pDDIs in and outside the ICU setting.

The Issue of Pharmacokinetic-Driven Drug-Drug Interactions of Antibiotics: A Narrative Review

“…Patients admitted to the ICU are at high risk for pDDIs due to the significant number of drugs prescribed and the complexity of drug regimens in this clinical setting [ 7 , 8 ]. As a consequence, an analysis of risk factors for adverse events in ICU patients reported that an increasing number of medications and DDIs was associated with a higher risk of injury [ 20 ].…”

“…According to available literature with regard to DDIs specifically involving anti-infective agents, a significant number of patients experienced at least one DDI during their ICU admission, with the antifungal drug fluconazole ranking in the top-ten DDIs, followed by aminoglycosides and macrolides [ 7 , 8 ]. More recently, Kusku and co-workers [ 21 ] analyzed data from 5 different hospitals and reported that DDIs with antimicrobial agents represented 26% of all interactions, with 42% and 38% of them “contraindicated” and “major”, respectively according to the Micromedex online reference system.…”

“…Similarly, Mehralian and co-workers in their cross-sectional prospective study found that 60% of ICU patients had at least one DDI [ 22 ]; nearly 87% of them, involving mainly antibiotics, were scored as harmful. Of particular relevance, DDIs involving metronidazole, azoles, azithromycin, and quinolones have been associated with QT prolongation [ 7 , 23 ].…”

“…However, it must be considered that ICU patients are usually elderly, with multi-comorbidities and on heavy polypharmacy [ 5 , 6 ]. For these reasons, pDDIs are likely to take place in the ICU setting when antibiotic therapies are added on the top of an important background of maintenance medications, eventually leading to treatment failure or development of drug-related toxicity [ 7 , 8 ].…”

“…The most frequent pharmacokinetic-driven pDDIs in ICU involve the inhibition or induction of drug metabolizing enzymes [ 7 , 8 ]. The most common are those affecting drug metabolism due to induction or inhibition of the cytochrome P450 (CYP) leading to abnormal drug exposure; among the different CYP isoforms, CYP3A, CYP2D6, and CYP2B6 are those most frequently involved in DDIs [ 9 ].…”