Introduction

The worrying increase of antimicrobial resistance, both in inpatients and outpatients, prompts clinicians to find new therapeutic options. Fosfomycin (FOS), administered intravenously, has been recently re-evaluated for the treatment of systemic infections caused by multidrug-resistant (MDR) bacteria. FOS acts with a unique mechanism of action on the bacterial wall. It is active against many aerobic Gram-negative and -positive bacterial strains (Table 1) [2], and it should be administered with (at least) another active drug to prevent the emergence of resistance [3, 4].

Table 1 Aerobic Gram-positive and Gram-negative strains susceptible to fosfomycin [1].
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FOS is marketed both as oral (fosfomycin trometamol, fosfomycin calcium) and intravenous (fosfomycin disodium) formulation. Both time- and concentration-dependent activity have been suggested according to the bacteria evaluated, but due to its short half-life and rapid bactericidal action a time-dependent approach is more often employed [3, 5, 6]. FOS serum half-life is 4–5.7 h for oral formulation [7, 8] and approximately halved when administered intravenously [8, 9]. Although literature data on FOS volume of distribution are controversial (ranging from 40 to 136 L [6, 10]), an excellent tissue penetration is reported, including the central nervous system, soft tissues and bone tissues [6] (AUC0–4 ratio for muscle over plasma was 0.71 for patients with soft tissue infections [11]). FOS is an appealing therapeutic option also for lower respiratory tract infections, biliary tract infections and abscesses [12,13,14,15]. FOS is cleared non-metabolized by the kidney and reaches in urine concentrations higher than the minimum inhibitory concentrations (MICs) [8, 16, 17]. Urinary concentrations are higher when FOS is administered intravenously [8]. Its pharmacokinetic properties suggest a time-dependent dosing schedule, with potential clinical benefits deriving from prolonged (PI) or continuous infusion (CI) compared with intermittent infusion (II), the dosing schedule most frequently used to-date. Despite this, guidelines on the best dosing regimen for FOS are lacking. Therefore, we revised literature concerning FOS CI or PI to hypothesize the best dosing regimen based on the actual evidence.

Materials and methods

We performed a MEDLINE/PubMed search and the complete search string was as follows: “(fosfomycin[Text Word]) AND (continuous[Text Word] OR prolonged[Text Word] OR extended[Text Word]) AND (infusion[Text Word] OR intravenous[Text Word] OR pharmacodynamics[Text Word]OR pharmacokinetics[Text Word] OR “opat”[Text Word] OR outpatient[Text Word] OR elastomeric[Text Word] OR pump[Text Word])”. Ninety-one papers from inception to 4 November 2020 were identified and underwent title, abstract and full text screening. Papers written in languages other than English were excluded. Seventy-six papers were excluded for the aforementioned reasons. In addition, pertinent references of included papers and abstracts from international congresses (from 2016 to 2020) were reviewed and discussed. A total of seventeen papers were included in the present review.

Results

Seventeen papers (14 original articles, 4 of which clinical trials, 2 abstracts from international congress and 1 review) were reviewed and discussed. Preclinical and clinical studies evaluated in the present review are briefly listed in Table 2 and Table 3, respectively.

Table 2 Review of literature concerning FOS in continuous or prolonged infusion (preclinical studies).
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Table 3 Review of literature concerning FOS in continuous or prolonged infusion (clinical studies).
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Fourteen studies investigated FOS dosing regimens in the setting of Gram-negative bacteria (2 in vivo studies, 8 simulation studies, 4 clinical trials, 1 review [4, 20,21,22,23,24,25,26,27,28,29,30,31,32]), while FOS dosing regimens against Gram-positive bacteria were evaluated in 5 studies (2 in vitro studies, 2 clinical trials, 1 review [18, 19, 27, 31, 32]). One study [33] did not evaluate the activity of FOS administered in CI since its objective was to report PK/PD parameters in healthy volunteers. Six studies [19, 20, 22,23,24, 26] evaluated FOS in combination with cefotaxime, ciprofloxacin, pefloxacin, meropenem, doripenem and polymyxin B.

With regard to CI, the daily dosing regimens in the setting of FOS monotherapy were 12 g [4, 22], 18 g [4] and 24 g [30, 33], while FOS in combination with carbapenems was evaluated at daily dose of 16 g [23], resulting active against Pseudomonas aeruginosa in two studies [23, 30] and Escherichia coli extended-spectrum beta-lactamase (ESBL)-producing, but not against carbapenem-resistant P. aeruginosa.

With regard to PI, seven different dosing regimens were evaluated. A schedule of 12 g per day (4g q8hr PI) was evaluated in two studies against non-MDR isolates, administered as monotherapy [23] or combination therapy [22]. FOS monotherapy 16 g per day, administered either as 4 g q6hr PI [28, 29] or 8 g q12hr PI [28], resulted active against non-MDR isolates in two studies. Administration of 18 g per day (6 g q8hr PI) was evaluated in a PK model simulation [25] and in the ZEUS trial [31, 32]. Finally, dosing regimens of 24 g per day, either as 4 g q4hr PI [23], 6 g q6hr PI [24, 26, 27], or 8 g q8hr PI [24, 27,28,29], resulted active also against MDR isolates.

When FOS given as monotherapy did not result to be active, this was due to the emergence of resistant strains [4, 22, 26]. FOS resistance occurred later when FOS was administered in CI compared with intermittent infusion [23, 26]. The administration of FOS with another active antibiotic was able to overcome resistance in most cases obtaining sustained bactericidal effect [23, 26].

PI resulted in 80–90% probability of target attainment (PTA) in studies simulating the efficacy of FOS against both P. aeruginosa and Enterobacterales [23,24,25, 28]. FOS administered in CI showed even better results, reaching 100% PTA against P. aeruginosa isolates in the study by Matzneller et al. [30].

Table 4 sums up the investigated dosing regimens and their effectiveness against the tested isolates.

Table 4 FOS administered as continuous or prolonged infusion: dosing regimens evaluated in the reviewed studies. Dosing regimens active against the tested isolates are highlighted in green, while ineffective regimens are presented in red. NE, not evaluated; CI, continuous infusion; PI, prolonged infusion; LD, loading dose; REF, reference; ESBL, extended-spectrum beta-lactamase; KPC, K. pneumoniae carbapenemase; CRPA, carbapenem-resistant P. aeruginosa; CRE, carbapenem-resistant Enterobacterales. *In combination with carbapenems. **In combination with polymyxin B
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Discussion and conclusion

This is the first systematic review evaluating FOS administered as CI or PI. Actual guidelines or expert opinions indicate slightly different dosages for the administration of FOS in CI [34, 35].

Our revision suggests that FOS 8 g loading dose followed by a daily dose of 16 g or up to 24 g CI is the best approach for patients with normal renal function. This dosage should be tailored considering the site of infection and the FOS MIC of the bacteria responsible of the infection. A critical evaluation of different dosing regimens should always be performed. For instance, evaluation of FOS penetration in abscesses reported a long half-life of the molecule (32 ± 39 h) in the pus, suggesting that FOS CI would not add any advantage compared with II in this scenario [36]. This is due to the fact that CI leads to higher AUC but reduced Cmax compared with II [30, 33].

FOS administered according to dosing regimens CI or PI is an option to keep in mind to treat systemic infections caused by MDR bacteria. Although FOS turned out to be well tolerated, thrombophlebitis and circumscribed paresthesia were reported to occur especially when the antibiotic is administered according to the CI or PI regimens [30, 33]. Administration of IV Ringer’s lactate simultaneously with FOS reduced the risk of thrombophlebitis in one study [33].

Dose adjustment according to renal function is required to keep the good safety profile of the drug, as acute or chronic kidney injury can cause a reduction in the glomerular filtration and therefore in the drug elimination [37, 38].

The emergence of resistant bacterial strains resulted in a weak activity of FOS in some series [4, 22, 26]. About this critical issue, CI delayed the development of resistance to FOS compared with II [4]. FOS has excellent synergistic properties [39] and these can lead to a long-lasting bactericidal effect [23, 26]. Furthermore, taking the advantages obtained by the synergism of FOS with other antibiotics, FOS can be considered for the combination treatment of some isolates intrinsically resistant to FOS or against which FOS has only a weak activity, i.e., P. aeruginosa or Acinetobacter spp. [23, 40,41,42,43]. Indeed, FOS represents a good option for combination therapies with antibiotics active against such bacteria.

Another advantage of PI or CI is the potential decrease of electrolyte imbalance if compared with rapid infusion [44]. In fact, the intravenous formulation contains 13.5 mEq/g of sodium; therefore, caution is needed to avoid hyopokalemia, especially in patients with heart insufficiency or who are undergoing dialysis [34].

Although few clinical studies evaluating FOS in CI or PI against Gram-positive bacteria are available to-date, this review suggests potential benefits from the use of this antibiotic in this setting [18, 19, 27, 31, 32]. This is interesting if we take into consideration the anti-biofilm properties of FOS, against both Gram-positive and Gram-negative bacterial strains [45, 46].

To the best of our knowledge, no study evaluated the efficacy of FOS prescribed as CI in outpatients through elastomeric pumps. Due to its long-term stability, intravenous FOS CI might be an option also for the outpatient parenteral antimicrobial therapy (OPAT), thus shortening hospitalization and its related risks and costs.

In summary, this systematic review suggests that FOS 8 g loading dose followed by a daily dose of 16 g or up to 24 g CI is a promising therapeutic regimen in the treatment of systemic infections including those due to MDR organisms. Future studies on FOS administered according to the CI regimen should include the evaluation of dosing regimens in patients with chronic renal failure and in haemodialysed patients. The efficacy of FOS according to the site of infection requires further investigation and expert advice should always be sought. Furthermore, as evaluation of PK/PD parameters on healthy volunteers after CI showed better results compared with II [30, 33], clinical trials comparing the superiority of CI or PI to II in different settings are desirable.