Combination of vancomycin plus piperacillin and risk of acute kidney injury: a worldwide pharmacovigilance database analysis.

BACKGROUND: Excess of acute kidney injury (AKI) secondary to the association of vancomycin plus piperacillin is debated. OBJECTIVES: To detect a signal for an increased risk of AKI with the vancomycin and piperacillin combination compared with other vancomycin-based regimens. METHODS: Using VigiBase, the WHO global database of individual case safety reports (ICSR) from 1997 to 2019, we conducted a disproportionality analysis comparing the reporting of AKI cases between different vancomycin-based regimens (vancomycin plus piperacillin, cefepime or meropenem). To take into account a possible notoriety bias, we secondarily restricted the study period to before 2014, the date of the first publication of AKI in patients receiving vancomycin plus piperacillin. Results are expressed using the reporting OR (ROR) and its 95% CI. RESULTS: From 1997 to 2019, 53 701 ICSR concerning vancomycin have been registered in the database, including 6016 reports of AKI (11.2%), among which 925 (15.4%) were reported with vancomycin/piperacillin, 339 (5.6%) with vancomycin/cefepime and 197 (3.7%) with vancomycin/meropenem. ROR (95% CI) for AKI was 2.6 (2.4-2.8) for vancomycin/piperacillin, 2.5 (2.2-2.9) for vancomycin/cefepime and 0.5 (0.4-0.6) for vancomycin/meropenem versus other vancomycin-containing regimens. After restriction of the study period to 1997-2013, the ROR for AKI remains significant only for vancomycin/piperacillin [ROR (95% CI) = 2.1 (1.8-2.4)]. CONCLUSIONS: We found a disproportionality in reports of AKI in patients receiving vancomycin plus piperacillin compared with vancomycin in other regimens. This suggests a drug-drug interaction between these two antibiotics resulting in an increased risk of AKI.

Drug-induced fetal and offspring disorders, beyond birth defects.

Studies on drug utilization in western countries disclosed that about nine over ten women use at least one or more drugs during pregnancy. Determining whether a drug is safe or not in pregnant women is a challenge of all times. As a developing organism, the fetus is particularly vulnerable to effects of drugs used by the mother. Historically, research has predominantly focused on birth defects, which represent the most studied adverse pregnancy outcomes. However, drugs can also alter the ongoing process of pregnancy and impede the general growth of the fetus. Finally, adverse drug reactions can theoretically damage all developing systems, organs or tissues, such as the central nervous system or the immune system. This extensive review focuses on different aspects of drug-induced damages affecting the fetus or the newborn/infant, beyond birth defects, which are not addressed here.

In Utero Exposure to Antibiotics and Risk of Serious Infections in the First Year of Life.

INTRODUCTION AND OBJECTIVE: Given the high prevalence of antibiotic prescription during pregnancy in France and previous studies suggesting an increased risk of infection in offspring with such exposures, our study aimed to investigate the association between prenatal exposure to systemic antibiotics and serious infections in full-term infants during their first year of life. METHODS: We conducted a retrospective population-based cohort study on singleton, full-term liveborn non-immunocompromised infants, using the French National Health Data System (SNDS) between 2012 and 2021. Systemic antibiotic dispensing in ambulatory care settings during pregnancy defined the exposure. Outcomes concerned serious infections (i.e., infections requiring hospitalization) in offspring identified between 3 and 12 months of life, hence excluding infections of maternal origin. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariate models to control for potential confounders. RESULTS: Of 2,836,630 infants included, 39.6% were prenatally exposed to systemic antibiotics. Infants prenatally exposed to antibiotics had a higher incidence of serious infections compared with unexposed infants {aOR 1.12 [95% confidence interval (95% CI) 1.11-1.13]}. Similar associations were observed according to the timing of exposure during pregnancy, antibiotic class, and site of infections. The strongest association was observed when infants were prenatally exposed to three or more antibiotic courses during pregnancy [aOR 1.21 (95% CI 1.19-1.24)]. Limitations include residual confounders, such as genetic susceptibility to infections and the role of the underlying pathogen agent. CONCLUSION: Prenatal exposure to systemic antibiotics is very common and is associated with a weak yet significant associations with subsequent serious infectious events during the first year of life. While our study revealed associations, it is important to note that causation cannot be established, given the acknowledged limitations, including potential confounding by indication.

De Novo Vogt-Koyanagi-Harada Disease following Covid-19 Vaccine: A Case Report and Literature Overview.

PURPOSE: To describe a case of Vogt-Koyanagi-Harada (VKH) disease after a Covid-19 mRNA vaccine (tozinameran) and to present the results of a pharmacovigilance disproportionality study. METHODS: A retrospective chart review and a pharmacovigilance disproportionality study using the WHO global individual case safety reports database (VigiBase). RESULTS: A 57-year-old female with no medical history developed a VKH disease 3 weeks after Covid-19 mRNA vaccine. Symptoms at onset were headaches and blurred vision associated with aseptic meningitis and bilateral diffuse granulomatous panuveitis with serous retinal detachment. One month from diagnosis and glucocorticoids treatment, the patient recovered. Five similar cases have been reported in VigiBase. VKH disease is disproportionately reported with tozinameran and other vaccines. CONCLUSION: VKH disease is disproportionately reported with tozinameran, suggesting a possible safety signal. Cases after vaccination support the screening for any possible immune triggers such as vaccines when assessing patients with VKH disease.

Drug-induced IgA vasculitis in children and adults: Revisiting drug causality using a dual pharmacovigilance-based approach.

OBJECTIVES: IgA vasculitis (IgAV) is an immune complex small-vessel vasculitis. Drug-induced IgAV cases were rarely reported in the literature. Drug causality assessment is challenging as many other etiological factors can be involved. We performed a pharmacovigilance study to identify the main drugs reported to induce IgAV. METHODS: We used the French pharmacovigilance database (FPVD) and the WHO global individual case safety reports database (VigiBase) to retrieve IgAV cases. Cases from the FPVD were reviewed by two investigators using predefined criteria. Disproportionality analyses (case - non-case approach) were conducted in VigiBase to identify drugs significantly associated with IgAV reporting. RESULTS: Of the 467 IgAV cases retrieved from the FPVD, 115 (47 children and 68 adults) have been assessed as definite or probable, reported with 178 suspected drugs. Overall IgAV cases were mainly male (58%), with a median age of 33.5 (8.0-63.3) years. No death was reported. Besides, we identified 1558 possible IgAV cases in VigiBase. Among them, 40 were associated with a disproportionality in IgAV reporting. Drugs were mainly vaccines, antibiotics and TNF-α blockers, these finding being consistent in both databases. IgAV reporting with TNF-α blockers was significantly associated with their use in inflammatory bowel diseases, psoriasis or ankylosing spondylitis compared to other indications. CONCLUSIONS: Our systematic study enables the identification of culprit drugs in drug-induced IgAV. These results strengthen the immune pathophysiology of IgAV and the role of underlying disease. The list of suspected drugs may be useful for physicians to manage patients with IgAV and consider appropriate drug discontinuation. KEY MESSAGES: What is already known about this subject? IgA vasculitis has multifactorial etiology. To date, possible culprit drugs have been reported only in case reports. What does this study add? Using a dual pharmacovigilance-based approach, we identified drugs associated with the occurrence of IgA vasculitis, such as all types of vaccines, major antibiotics and immunomodulatory agents, mainly TNF-α blockers. How might this impact on clinical practice or future developments? Physicians should be aware of drug-induced IgA vasculitis and we provide evidence on the most frequent implicated drugs.