Current clinical use of intravenous fosfomycin in ICU patients in two European countries

Fosfomycin is a bactericidal broad-spectrum antibiotic active against a variety of Gram-positive (GP) and Gram-negative (GN) pathogens including ‘problem bacteria’ such as carbapenemase- or extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-resistant enterococci and multidrug-resistant (MDR) Pseudomonas aeruginosa [1‐5], supported by synergistic effects with many other antibiotics [6, 8]. Due to the unique chemical structure, cross-resistance and -allergies with other antibiotics have not been reported so far [7]. Fosfomycin exhibits advantageous pharmacokinetic properties making it particularly useful for complicated deep-seated, even biofilm-associated infections such as respiratory tract, bone or central nervous system (CNS) infections [7, 9‐14]. Fosfomycin can be used without any age limitations. However, due to the high sodium load (1 g fosfomycin contains 14 mmol (320 mg) sodium), electrolyte imbalances such as hypernatremia or hypokalemia might occur [6, 15].

Fosfomycin was included in the WHO list of essential medicines for treatment of adults and children within the RESERVE group of antibacterial medicines [16, 17]. Prospective, randomized, controlled clinical trials with fosfomycin in mono- and combination therapy, though having been initiated recently, are still ongoing. Currently, data on the efficacy and safety of intravenous (IV) fosfomycin in the daily clinical practice are still limited. In addition, fosfomycin is used for indications for which no randomized controlled trials would likely to be feasible due to constraints regarding time and study design.

Here, we present real-life efficacy and safety data on the current clinical use of IV fosfomycin in two countries with longstanding experience from the largest prospective non-interventional study conducted to date.

The statistical analysis was performed using the statistical software SPSS v. 23.0 (IBM). Continuous variables were expressed by mean ± standard deviation or median and interquartile range (IQR) as appropriate.

Overall, 209 patients were included (ITT population), for which an evaluable clinical endpoint was attained in 182 cases (cPP population) and an evaluable microbiological endpoint in 90 cases (mPP population). In detail, 172 of the patients were enrolled in 19 German study centers and 37 in one Austrian study center.

To date, this study is the largest non-interventional study focusing on the use of intravenous fosfomycin in the daily clinical practice. In total, 209 critically ill patients were enrolled, presenting with severe, life-threatening infections. Severity of illness of our patients was higher as of those reported in a previous study [39].

In our study, we found a broad use of IV fosfomycin against both GP and GN pathogens with a higher proportion of Gram-positives (54.2%). The widespread spectrum of indications ranging from infections predominantly caused by Gram-negatives such as cUTI to others most often associated with GP pathogens such as CNS infections, BJI or endocarditis, indicate that fosfomycin has been used across different sites of infection. High in vitro activity against several ‘problem bacteria’, in particular S. aureus and S. epidermidis, is clinically reflected by the large number of staphylococcal infections (36.5%) treated in NIS-FOM [21, 22]. Despite several alternative therapeutic options, fosfomycin was mostly used in MSSA infections [23, 24]. This might suggest that severe S. aureus infections with deep focus might represent entities not yet adequately covered by standard therapy [25].

In contrast to studies solely reporting on the use of IV fosfomycin as a last-resort option in infections due to MDR GN pathogens such as carbapenemase-producing Enterobacteriaceae or ESBL-producers [26, 33, 38, 39], data from this two-country study suggest that only in 24% of all patients the indication for fosfomycin use was an infection caused by MDR pathogens. More often it was used as a combination partner against other difficult-to-treat infections with limited therapeutic options or where the first-line treatment had already failed. In difficult-to-treat infections, even in those with biofilm involvement, IV fosfomycin has become a valuable combination partner supported by its advantageous pharmacokinetic properties [26‐28, 30]. Its chemical properties allow fosfomycin to penetrate deep into tissues, even into bones and the CNS, which might explain the preferred use in CNS infections (22.3%) such as brain abscesses or bacterial meningitis, BJI (14.2%), or sepsis (10.5%) [11, 13, 29].

The broad spectrum of combination partners might be due to synergistic or additive effects of fosfomycin with many other classes of antibiotics that could be explained by inhibiting the bacterial cell wall synthesis at an earlier stage than other antibiotics (e.g., beta-lactams) [2]. Interestingly, our data indicate that fosfomycin was not used as a carbapenem-sparing treatment option, evermore discussed in the literature [31, 32]. Instead, in infections like nosocomial pneumonia (HAP, VAP) or abdominal infection (Table 4) fosfomycin was most often combined with a carbapenem. This combination is supported by synergistic effects and has recently been recommended, especially if MDR GN pathogens are involved [26, 33‐36].

Although IV fosfomycin is generally considered a second-line treatment option, it was used in first-line therapy in more than a quarter of patients. Given its ability to rapidly cross the blood/brain barrier, fosfomycin may be regarded as a useful combination partner for treatment of CNS infections, e.g., when combined with a third- or fourth-generation cephalosporin [37].

The overall clinical success rate in the NIS-FOM study is the highest compared to other more recent studies on IV fosfomycin with similar design. Dinh et al. reported a favorable overall outcome in 76.8% of evaluable patients; BJI 82.6%, lung infection 67.7%, UTI 100%, endocarditis or neurological infection 83.3%, and bacteremia 57.1% [38]. According to Pontikis et al., clinical outcome at day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively [39]. However, in both studies the proportion of MDR pathogens was significantly higher, ranging between 70 and 100%. In NIS-FOM, clinical success rates ranged from 67% in patients with endocarditis to 89% in patients with CNS infection, emphasizing the role of fosfomycin in the treatment of GP pathogens [6]. Of note, all patients with endocarditis developed a bacteremia or sepsis concomitantly, hampering a favorable clinical outcome [40]. In the subgroup of infections with MDR pathogen (including MRSA), clinical and microbiological success was adequate (Table 7). The reason for comparatively low clinical and microbiological success in patients with intraabdominal infections is unknown so far and needs further investigation.

Critically ill patients with impaired organ function and intensive co-medication challenge a safe and effective antibiotic treatment [42]. Pharmacokinetic interactions are common, possibly leading to discontinuation of therapy [43]. Many antibiotics, e.g., glycopeptides or colistin, are associated with serious adverse events such as nephrotoxicity, limiting their therapeutic use [44, 45]. However, our data show that IV fosfomycin was used in a large dosing range. Reported adverse events were generally non-serious and expected, without troubling drug/drug interactions. Moreover, safety results from the NIS-FOM are in line with recent reviews corroborating the good safety profile of the substance [6, 15]. Given the sodium load of IV fosfomycin, discontinuation of the drug due to accumulating high sodium levels in six cases was reasonable to prevent potentially serious electrolyte imbalances. One limitation of our study is the lack of a control group. Thus, it remains unclear how many patients would have developed hypernatremia or hypokalemia independent of fosfomycin treatment. In general, hypokalemia is a common problem in ICU patients and medication is merely one possible explanation [41]. Therefore, clinicians should be aware of disturbances in sodium and potassium homeostasis and initiate adequate measures early to avoid further complications. Altogether, fosfomycin’s safety profile appears advantageous, since the generally non-serious and expected nature of adverse events constitutes no limiting factor in therapy.

These results suggest that IV fosfomycin is an effective and safe combination partner in the treatment of critically ill patients with severe infections due to Gram-negative and Gram-positive pathogens, even in first-line treatment. Fosfomycin was used across different indications and sites of infection, independently of the pathogen’s resistance pattern. On the other hand, IV fosfomycin is also suitable for highly specific patients and settings, when standard treatment might be inadequate due to clinical circumstances or has already failed. Thus, considering the critical medical condition of the study population and the severity of underlying infections, the high overall success rate of 81% together with an advantageous safety profile is very promising and might give rise for further prospective clinical trials.