Fosfomycin is a bactericidal antibiotic agent able to inhibit an enzyme-catalyzed reaction in the first step of the synthesis of the bacterial cell wall. Its intravenous (IV) formulation, fosfomycin disodium, is currently being used in several clinical conditions with positive results in terms of efficacy and safety (Shorr et al., 2017). However, this IV formulation can be associated with different adverse drug reactions (ADRs) that include angioedema, aplastic anemia, cholestatic jaundice, and hepatic necrosis (Michalopoulos et al., 2011; Pyrpasopoulou et al., 2018). In addition, the IV formulation is associated with a high sodium intake which represents a life-threatening clinical condition and is a limitation, especially for patients with heart failure or those on hemodialysis (Iarikov et al., 2015; Putensen et al., 2019). Hypernatremia, defined as a serum sodium level >145 mmol/L, is relatively common among the elderly and critically ill patients. Its frequency among hospitalized patients ranges from 0.3 to 3.5% (Aiyagari et al., 2006; Salahudeen et al., 2013; Thongprayoon et al., 2020). If this condition is not promptly recognized and treated, clinical consequences can be irreversible, leading to cell and organ damage and high mortality (Qian, 2019).

Considering the clinical significance of hypernatremia and given that the real frequency of IV fosfomycin-induced hypernatremia in clinical practice is still not well defined (being mostly known only in patients in intensive care units—ICUs) (Putensen et al., 2019), we carried out a pharmacovigilance study through the analysis of data collected in the European spontaneous reporting system (the EudraVigilance database) with the aim to assess the amount of Individual Case Safety Reports (ICSRs) reporting cases of fosfomycin-induced hypernatremia on a European level. In addition, we carried out a retrospective medical records review study with the aim to identify cases of fosfomycin-induced hypernatremia among patients who had received the drug in two hospitals in the south of Italy. Moreover, we used data from the retrospective medical records review to secondarily assess the impact of a regional training campaign related to the correct drug preparation on the reduction of fosfomycin-induced hypernatremia cases caused by reconstitution errors.

In light of these data and literature evidence on antimicrobial stewardship too (Munez Rubio et al., 2019), antibiotics require an active follow-up from clinicians and hospital pharmacists not only to avoid an inappropriate use of these antibiotics and, therefore, the onset of resistance but also to minimize the risk of ADR. As we previously strongly suggested for antivirals (Nappi et al., 2019), a close collaboration among ID specialists, clinicians, and hospital pharmacists should be managed throughout the creation of a network that will allow greater monitoring of the safety profile of antibiotics.

From our retrospective medical record review study, we observed that 11 patients treated with fosfomycin experienced hypernatremia, while from the EV analysis, 25 ICSRs related to fosfomycin-induced hypernatremia were identified. Hypernatremia is generally induced by fluid and sodium imbalance. In critically ill patients, this adverse event can be multifactorial, but its development is the result of sodium overload or a loss of free water (Qian, 2019). Hypernatremia can also have an iatrogenic origin, especially in ill patients treated with fosfomycin. Indeed, fosfomycin is one of the most sodium-rich antibiotics that contained 0.33 g of sodium for each gram of IV fosfomycin. Therefore, hypernatremia is a common adverse event with IV fosfomycin, especially when it is given in high doses or for prolonged periods (Shorr et al., 2017). Indeed, to reduce the risk of wrong reconstitution and preparation of IV fosfomycin, a surveillance and training campaign was performed in our territory. However, after the campaign, four cases of hypernatremia were still reported, thus highlighting the need for further policy decision making.

Overall, our results showed that fosfomycin is a well-tolerated agent associated with a low frequency of suspension. Indeed, only four out of 62 patients suspended the treatment because of ADRs and only one patient because of hypernatremia. This result highlights that when good monitoring of the electrolyte disorder is performed and close collaboration is established among ID specialists and hospital pharmacists, we can have an optimization of the efficacy and safety of the therapy with fosfomycin. Indeed, close patient monitoring not only can avoid an unnecessary drug withdrawal but also reduce the burden associated with the development of severe hypernatremia-related complications such as the subarachnoid or subdural hemorrhage, which can cause permanent brain damage and major cardiovascular events (including fatal coronary heart disease, non-fatal myocardial infarction, and stroke) (Tsegka et al., 2021; Wannamethee et al., 2016). Moreover, the good safety profile of fosfomycin-related hypernatremia can be assumed by the low number of ICSRs (n = 25) that were retrieved from the European database EV.

Regarding the severity of hypernatremia, from the retrospective medical record review, we found that only one patient had severe hypernatremia, and from the EV analysis, we found that most cases were reported as serious. In this regard, it should be worth noting that the classification of seriousness in pharmacovigilance follows different criteria from those used in the clinical setting to establish the severity of hypernatremia. In the evaluation of seriousness, we should also consider the reporting bias of serious ADRs due to mandatory reporting obligations and that healthcare professionals are more prone to report serious ADRs. Indeed, the primary source for the reporting of ADRs was the healthcare professional in all ICSRs. Finally, according to our results, literature clinical data classified fosfomycin-induced hypernatremia in most cases as mild (Tsegka et al., 2021). From the disproportionality analysis, we found that fosfomycin was associated with a 25-times higher reporting frequency of hypernatremia compared to gentamicin. Indeed, according to the literature, gentamicin is associated with the occurrence of electrolyte and acid-base disorders, mainly due to the increase in the excretion of sodium and magnesium (Scoglio et al., 2021). Therefore, this antibiotic can exert opposite effects in regulating sodium levels.

Further active trial and audit are mandatory to improve the use of antibiotics in terms of preparation, administration, and monitoring in antimicrobial stewardship programs. In conclusion, intravenous fosfomycin, despite its efficacy and relative safety, may need a more careful follow-up by clinicians and hospital pharmacists, particularly in those wards not familiar with antibiotics use. Indeed, the lack of close surveillance of hypernatremia may result in an increase in healthcare costs, not only due to prolonged hospitalization but also for possible complications related to unnecessary drug withdrawal.

This is a retrospective analysis of medical records related to patients who experienced hypernatremia after having received fosfomycin. The limited number of patients included in the study (n = 62) together with the absence of a control group did not allow us to draw firm conclusions. Indeed, because of the nature of the study, we could not rule out the presence of other confounding variables that might have affected our results. Larger sample-sized and controlled studies are required in order to better assess the safety profile of intravenous fosfomycin.

The second part of our study was based on data from the European spontaneous reporting system. In this regard, it is well known that all spontaneous reporting systems carry some intrinsic limitations, such as under-reporting. Indeed, we found analyzed data related to only 25 ICSRs reporting the association between fosfomycin/hypernatremia. Another important limitation of such systems is represented by the poor quality of information listed in each ICSR. As we used EV data obtained from the EMA website (www.adrreports.eu), we cannot exclude that important clinical data were not listed in evaluated ICSRs. Therefore, the effects of concomitant illnesses or therapy cannot be fully excluded in this analysis. Thus, we are aware that the real safety profile of fosfomycin in terms of hypernatremia occurrence needs to be confirmed by the results obtained from ad hoc studies.

We carried out two separate studies, both in real-life settings, with the aim to evaluate the fosfomycin-induced hypernatremia. Our results primarily showed that fosfomycin is safe and associated with a low frequency of suspension due to ADRs. Indeed, only four patients suspended the treatment due to ADRs. Moreover, this study demonstrated that surveillance and training campaigns on the correct drug preparation need to be strengthened to allow a reduction of hypernatremia cases, considering that most of our cases were related to reconstitution errors. Moreover, our results demonstrated that when tight monitoring and management of the event is performed with a close collaboration between the ID specialist and the hospital pharmacist there, is a reduction in antibiotic withdrawal. Given the clinical significance of high sodium content and its potential fatal clinical consequences, the parenteral use of fosfomycin should be carefully monitored, especially in patients with underlying heart disease.