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Case Report

Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations

Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS, Garibaldi Hospital, University of Catania, 95123 Catania, Italy
Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(1), 49;
Received: 7 December 2022 / Revised: 22 December 2022 / Accepted: 24 December 2022 / Published: 28 December 2022


Multidrug resistant Gram-negative bacteremia represents a therapeutic challenge clinicians have to deal with. This concern becomes more difficult when causing germs are represented by carbapenem resistant Acinetobacter baumannii or difficult-to-treat Pseudomonas aeruginosa. Few antibiotics are available against these cumbersome bacteria, although literature data are not conclusive, especially for Acinetobacter. Cefiderocol could represent a valid antibiotic choice, being a molecule with an innovative mechanism of action capable of overcoming common resistance pathways, whereas intravenous fosfomycin may be an appropriate partner either enhancing cefiderocol activity or avoiding resistance development. Here we report two patients with MDR Gram negative bacteremia who were successfully treated with a cefiderocol/fosfomycin combination.

1. Introduction

Worldwide, bacterial bloodstream infections (BSI) are associated with substantial morbidity and mortality [1,2,3], becoming devastating when BSI are caused by multidrug-resistant (MDR) organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), and MDR Gram-negative bacteria (MDR-GNB), especially difficult-to-treat Pseudomonas aeruginosa (DTT-Pa) and carbapenem-resistant Acinetobacter baumannii (CRAB) [4,5,6,7,8].
Suspecting MDR-GNB BSI, empiric combination therapy rather than monotherapy is a common option allowing an increase of the spectrum of antibiotic activity, to achieve faster bacterial clearance, to assure possible synergistic effect and to avoid—or at least to reduce—the onset of bacterial resistance [9,10,11,12]. Marking this point, Schmid et al. reported reduced mortality rates in patients with infections caused by carbapenemase-producing Enterobacterales (especially BSI) treated with combination regimens, when compared with those treated with monotherapy [9].
Recently, both new antibiotics—such as ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam [13,14] and cefiderocol—and old molecules—such as intravenous (IV) fosfomycin [15,16] and colistin—provided efficient treatment options to counteract severe infections caused by MDR organisms. Furthermore, ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol [17] and intravenous (IV) fosfomycin [18] represent potential carbapenem sparing alternatives as shown by Xie et al. by determining the number of carbapenem-days saved using the aforementioned options [19].
Cefiderocol is an injectable cephalosporin acting with “Trojan horse”-like mechanism by using active iron transporters. This siderophore antibiotic has a potent broad-spectrum activity against aerobic GNB, including MDR Enterobacterales, as well as CRAB and DTT-Pa [20,21]. Cefiderocol is considered resistant to several β-lactamases, also thank to its novel mechanism of cell-entry as siderophore molecules mimicking. In addition, cefiderocol overcomes other common mechanisms of β-lactam resistance among Gram-negative bacteria, including porin deficiency and efflux pump up-regulation [11].
On the other hand, fosfomycin, the sole antibiotic of the epoxide group, which acts by inhibition of bacterial wall formation [22], is a broad-spectrum bactericidal antibiotic available in three forms: fosfomycin tromethamine (a soluble salt), fosfomycin calcium for oral use [23] and fosfomycin disodium for intravenous use [15]. Fosfomycin is effective against several resistant Gram-positive and Gram-negative bacteria, especially as “partner-drug” of other active molecules. Despite the general belief regarding A. baumannii intrinsic fosfomycin resistance, limited information is available in scientific literature concerning the involved mechanisms [24,25]. Recently, the activity of IV fosfomycin-based combination regimen (together with antibiotics, such as aminoglycosides, colistin and minocycline) against MDR A. baumannii has renewed interest in fosfomycin as an attractive treatment partner [12,26,27].
As far as we know, only few reports described data about cefiderocol and IV fosfomycin combination for the treatment of GNB infections (including BSI) [11,28,29,30], whereas there is important scientific literature data about fosfomycin and other antibiotics association [12,26,31,32,33].
Herein, we describe two cases of MDR GNB BSI treated with a combination of cefiderocol and IV fosfomycin. We also discussed our choice in light of literature evidence about IV fosfomycin combination with cefiderocol.

2. Case Presentation

2.1. Case 1

A 75-year-old woman with a medical history of radical cystectomy and right nephrectomy due to urothelial tumor, unilateral cutaneous ureterostomy and chronic renal failure. She was brought to the emergency department seven days after the substitution of ureterostomies’ tutor due to the onset of high fever (up to 39 °C) and chills associated with hematuria. At admission, blood pressure was 110/60 mmHg; respiratory rate was 18/min; and GCS was 13 (qSOFA score was 1).
Two sets of blood cultures and urine cultures were performed, and empiric antibiotic therapy was started with piperacillin/tazobactam, dosed accordingly to patient’s impaired renal function.
Blood tests showed high white blood cell count along with mild anemia and reduced platelet levels (Table 1). Inflammatory markers were elevated, as well as procalcitonin levels. Urinalysis revealed bacteriuria and leukocyturia. Abdomen ultrasound and urinary CT did not show any focal sign of infection.
All sets of blood cultures and urine cultures resulted positive for Pseudomonas aeruginosa carbapenem resistant (resistance pattern was assessed with BD Phoenix with exception of fosfomycin, colistin and cefiderocol. See Table 2 for the full antibiogram). Fosfomycin susceptibility was confirmed by commercial AD fosfomycin agar dilution test (cat. no. 77061, Liofilchem, Italy), giving a minimum inhibitory concentration (MIC) value of 16 mg/L. The strain was susceptible to colistin—tested by broth microdilution (colistin sulfate salt, cat. no. C4461, Sigma-Aldrich, St. Louis, MO, USA). After cefiderocol susceptibility testing performed through disk diffusion (cat. no. 9266, Liofilchem, Italy) [34], antibiotic therapy was switched to IV cefiderocol 1 g three times daily plus IV fosfomycin 4 g two times daily, based on her renal clearance (eGFR of 26.2 mL/min, serum creatinine 1.85 mg/dL). Furthermore, the patient’s ureterostomy was substituted.
Within 72 h following targeted antibiotic treatment, the fever disappeared; inflammatory markers started decreasing; and blood cultures taken 48 h apart tested negative.
Antibiotic regimen was administered for 10 days, achieving clinical cure and microbiological eradication, assessed with two negative blood cultures at the end of therapy. The patient was successfully discharged after seven days after the end of the therapy, and no infection relapse occurred during this follow-up.

2.2. Case 2

A 45-year-old man with Wilson disease complicated by cirrhosis and esophageal varices along with chronic renal failure was admitted to the emergency department due to hematemesis, treated with endoscopic variceal ligation combined along with terlipressin administration.
On the 5th day from the time of admission, due to the onset of fever (up to 38.5 °C), two sets of blood cultures were performed, and empiric antibiotic therapy with piperacillin/tazobactam was started. His blood pressure was 120/70 mmHg; respiratory rate was 20/min; and GCS was 15 Patient’s (qSOFA was 0).
Blood tests showed elevated white blood cell count along with higher CRP, ESR and procalcitonin levels (Table 1).
Acinetobacter baumannii only susceptible to colistin—tested by broth microdilution (colistin sulfate salt, cat. no. C4461, Sigma-Aldrich, St. Louis, MO, USA)—and cefiderocol—tested by disk diffusion (cat. no. 9266, Liofilchem, Italy)—[34] (resistance pattern was assessed with BD Phoenix with exception of fosfomycin, colistin and cefiderocol. See Table 3 for the full antibiogram) was recovered from blood cultures. Fosfomycin MIC was evaluated as aforementioned and resulted 64 mg/L. Based on his renal clearance, antibiotic therapy was switched to IV cefiderocol 1.5 g 3 times daily plus IV fosfomycin 4 g 3 times daily.
Within 72 h following cefiderocol based regimen, the fever disappeared; inflammatory markers decreased; and blood cultures taken 48 and 72 h apart tested negative.
Antibiotic therapy was administered for 7 days. After 5 days, the patient was successfully transferred to the hepatology unit for liver follow-up.

3. Discussion

The treatment of MDR-GNB infections represents a clinical and therapeutic challenge [7,13,35,36,37], with several obstacles to overcome: rapid diagnostic testing, infection control measures and prompt starting of an effective treatment following appropriate empirical coverage.
Moreover, to wisely guide the choice and management of antibiotic regimen, it is mandatory to obtain the latest information about local microbiological epidemiology [38]. The patients we presented were affected by multiple severe comorbidities complicated by BSI due to MDR-GNB, i.e., DTT-Pa and CRAB. Therapeutic options were limited due to both antimicrobial resistance patterns and patients’ characteristics, especially renal clearance.
On the basis of antibiotic susceptibility tests along with patients’ challenging clinical conditions, both our patients were treated with cefiderocol plus IV fosfomycin, achieving microbiological eradication and clinical cure.
In detail, as regarding the first case, we chose to administer cefiderocol-based therapy due to the shortage of ceftolozane/tazobactam provisions in our center and due to ceftazidime/avibactam high MIC (8 mg/L), which was near to the clinical breakpoint, in order to avoid either bacterial resistance or treatment failure, which are common features of severe infections involving fragile patients. Due to its high rate of nephrotoxicity (20–60% in different studies), colistin based therapy was not taken into consideration.
Considering the second case, due to both the limited antibiotic choice because of Acinetobacter resistance profile and the patient’s comorbidity, especially renal impairment, we decided again to avoid colistin regimen switching to cefiderocol plus fosfomycin.
Although it has no antimicrobial activity against Gram-positive and anaerobic germs, cefiderocol, the newest siderophore antibiotic, revealed significant antibacterial activity towards MDR GNB, including non-fermenting bacilli—such as Acinetobacter or Stenotrophomonas—and Enterobacterales—such as Klebsiella [39,40,41] thanks to its unique pharmacodynamic which assure bypassing common bacterial resistance mechanisms.
Although the use of a β-lactam/β-lactamases-inhibitor combination (BLIC) could represent a valid alternative for the treatment of DTT-Pa and CRAB, the choice should be done on the basis of molecular resistance mechanisms, not always investigated in hospital settings. Cefiderocol has the benefit to overcome the known β-lactamases-based mechanism of resistance—especially against metallo β-lactamases (MBL)—and, thus, could be a feasible option. Moreover, there are not randomized studies investigating the different efficacy of cefiderocol compared to ceftazidime-avibactam, ceftolozane-tazobactam or imipenem-cilastatin-relebactam in the treatment of DTT-Pa or Acinetobacter. Eventually, fosfomycin addition showed a significant efficacy even against A. baumannii strains, as its peculiar mechanism of action seems to evoke a stress, even in resistant strains as usually are Acinetobacter baumannii isolates [42], that make bacteria more susceptible to other molecules.
Indeed, cefiderocol, a catechol-type siderophore with a cephalosporin core and side chains similar to cefepime and ceftazidime, is able to overcome cumbersome bacterial resistance mechanisms, including the production of β-lactamases, even metallo-beta-lactamases (MBL), up-regulation of efflux pump expression and porin deficiency.
CREDIBLE-CR and APEKS-NP studies demonstrated cefiderocol non-inferiority when compared to the best available therapy to treat either cUTIs or nosocomial Gram-negative pneumonia [39,43].
In a recent retrospective study, Pascale et al. assessed cefiderocol monotherapy efficacy in MDR A. baumannii infections compared to colistin, showing no differences in all-cause mortality rate [44]. Similar results were obtained by Falcone et al. analyzing a population, including MBL producing Enterobacterales and non-fermenting bacteria such as A. baumannii and S. maltophilia [28].
Some authors suggest adding a second agent to cefiderocol in order to avoid resistance development and therapeutic failure, especially considering critically ill patients and those with limited therapeutic options [45,46]. A recent sectional survey by Lupia et al. [47] reported that most clinicians use IV fosfomycin as a common cefiderocol partner drug in the treatment of both Pseudomonas and Acinetobacter infections.
Fosfomycin, thanks to its favorable PK/PD profile, has been recognized as a good antibiotic option for the treatment of systemic and deep-seated infections. Indeed, after intravenous administration, fosfomycin results in a sufficient drug concentration at different body sites [48]. Recently, Antonello et al. performed a systematic review about fosfomycin’s synergistic properties, underlying the suitable features of this molecule as partner drug alongside the nearly total absence of antagonisms towards other drugs. Furthermore, authors showed that fosfomycin-based regimens are characterized by stronger bactericidal effect toward P. aeruginosa with significant synergistic interactions when associated with chloramphenicol, aminoglycosides or cephalosporins, as well as against Acinetobacter spp. especially together with sulbactam and penicillins [31].
Although there is not conclusive evidence about combination therapy over monotherapy, there are scientific reports which state that monotherapy represents an independent predictor of 28-day mortality (as was absence of infectious diseases specialist consultation) compared with combination therapy based mostly on fosfomycin [49].
Moreover, Bavaro et al. reported cefiderocol combination regimen to treat DTT P. aeruginosa, choosing fosfomycin as second agent due to its ability to reduce cefiderocol MIC [30].
However, it is not clear if fosfomycin exhibits a time- or a concentration-dependent bactericidal effect [50,51]; therefore, some authors assert that it might depend on the microorganism [52].
Furthermore, the new interest behind the use of IV fosfomycin in the treatment of infections due to GNB implies the need of adequate susceptibility testing of this antibiotic. Despite agar dilution (AD) is the reference method recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for the detection of fosfomycin susceptibility in GNB; it is not suitable for every hospital setting because it is a laborious and time-consuming process. In the last years, various commercial automated systems have been developed to detect antibiotic susceptibility faster and practically. Studies have shown high categorical agreement of these methods with AD determining the susceptibility of fosfomycin [53,54], but as reported by EUCAST, the accuracy of the results depend on the method used for the isolation’s microorganisms and on adherence to the manufacturers’ instructions [55,56].
Likewise, cefiderocol susceptibility testing is cumbersome due to the need of iron depleted broth, the area of technical uncertainty (ATU) of the disk diffusion method and the lack of validate e-test strips suitable for the main MDR GNB, except for P. aeruginosa. Furthermore, cefiderocol in vitro activity against A. baumannii is still under a magnifier [41,57].
Due to recent introduction of cefiderocol in the clinical practice, to date only few data have been published about the best combination therapy for the management of MDR infections, and both its use as monotherapy and its clinical impact are still debated. Nonetheless, fosfomycin—thanks to its peculiar mechanism of action—is recognized as one of the best companions for combination therapy [22,58,59,60,61,62,63,64,65,66,67]; indeed, Gatti and colleagues have already proposed an algorithm for targeted therapy of infection caused by P. aeruginosa, suggesting the association of cefiderocol and fosfomycin, especially for patients in intensive care units [68].
The fosfomycin definition shifted from “intrinsically inactive” to a “miscellaneous agent” to treat CRAB infections [27], as described clinically by Bavaro et al. [30] and in vitro by Nwabor et al. [27]; the latter demonstrated the potency of fosfomycin combination with other antibiotics against CRAB, in terms of MIC reduction and restitution of efficacy. Although we reported only one patient with CRAB infection and currently available data are insufficient for substantial conclusions, we administered fosfomycin as partner drug even if Acinetobacter was resistant, achieving successful clinical outcome.

4. Conclusions

Our experience suggests that a combination of intravenous fosfomycin and cefiderocol may represent a valid therapeutic option to treat GNB BSI, both as a carbapenem sparing strategy and as a treatment option in difficult to treat infections. Indeed, this combination should be carefully evaluated in larger studies and prudently compared to other available options to better assess its clinical efficacy, microbiological eradication rate and its ability to prevent antibiotic resistance development.
Intravenous fosfomycin as a partner drug in an antibiotic regimen containing new available molecules seems to be a reasonable option in view of its favorable PK/PD and its synergistic effects with several drugs. Further and stronger studies are needed both to assess whether monotherapy would be more effective and safer than combination therapy and to evaluate if a partner drug, such as fosfomycin, could “protect” newer antibiotics, such as cefiderocol, against bacterial resistance development. Therapeutic drug monitoring (TDM) may be a possible solution to assess antibiotic efficacy in frail patients, such as those with impaired renal clearance [69].

Author Contributions

Conceptualization, A.M. (Andrea Marino) and E.C.; investigation, S.S.; data curation, M.G.; writing—original draft preparation, A.M. (Antonio Munafò) and M.C.; writing—review and editing, B.C.; supervision, R.B. and G.N. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Written informed consent has been obtained from the patients to publish this paper.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Leal, H.F.; Azevedo, J.; Silva, G.E.O.; Amorim, A.M.L.; De Roma, L.R.C.; Arraes, A.C.P.; Gouveia, E.L.; Reis, M.G.; Mendes, A.V.; De Oliveira Silva, M.; et al. Bloodstream infections caused by multidrug-resistant gram-negative bacteria: Epidemiological, clinical and microbiological features. BMC Infect. Dis. 2019, 19, 609. [Google Scholar] [CrossRef] [PubMed]
  2. Marino, A.; Campanella, E.; Stracquadanio, S.; Ceccarelli, M.; Zagami, A.; Nunnari, G.; Cacopardo, B. Corynebacterium striatum Bacteremia during SARS-CoV2 Infection: Case Report, Literature Review, and Clinical Considerations. Infect. Dis. Rep. 2022, 14, 383–390. [Google Scholar] [CrossRef]
  3. El-Sokkary, R.; Erdem, H.; Kullar, R.; Pekok, A.U.; Amer, F.; Grgić, S.; Carevic, B.; El-Kholy, A.; Liskova, A.; Özdemir, M.; et al. Self-reported antibiotic stewardship and infection control measures from 57 intensive care units: An international ID-IRI survey. J. Infect. Public Health 2022, 15, 950–954. [Google Scholar] [CrossRef] [PubMed]
  4. Di Franco, S.; Alfieri, A.; Pace, M.C.; Sansone, P.; Pota, V.; Fittipaldi, C.; Fiore, M.; Passavanti, M.B. Blood stream infections from mdr bacteria. Life 2021, 11, 575. [Google Scholar] [CrossRef] [PubMed]
  5. Schroeder, M.; Weber, T.; Denker, T.; Winterland, S.; Wichmann, D.; Rohde, H.; Ozga, A.K.; Fischer, M.; Kluge, S. Epidemiology, clinical characteristics, and outcome of candidemia in critically ill patients in Germany: A single-center retrospective 10-year analysis. Ann. Intensive Care 2020, 10, 142. [Google Scholar] [CrossRef]
  6. Viscoli, C. Bloodstream Infections: The peak of the iceberg. Virulence 2016, 7, 248–251. [Google Scholar] [CrossRef][Green Version]
  7. Bassetti, M.; Peghin, M.; Vena, A.; Giacobbe, D.R. Treatment of Infections Due to MDR Gram-Negative Bacteria. Front. Med. 2019, 6, 74. [Google Scholar] [CrossRef][Green Version]
  8. Erdem, H.; Hargreaves, S.; Ankarali, H.; Caskurlu, H.; Ceviker, S.A.; Bahar-Kacmaz, A.; Meric-Koc, M.; Altindis, M.; Yildiz-Kirazaldi, Y.; Kizilates, F.; et al. Managing adult patients with infectious diseases in emergency departments: International ID-IRI study. J. Chemother. 2021, 33, 302–318. [Google Scholar] [CrossRef]
  9. Schmid, A.; Wolfensberger, A.; Nemeth, J.; Schreiber, P.W.; Sax, H.; Kuster, S.P. Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis. Sci. Rep. 2019, 9, 15290. [Google Scholar] [CrossRef][Green Version]
  10. Cebrero-Cangueiro, T.; Labrador-Herrera, G.; Pascual, Á.; Díaz, C.; Rodríguez-Baño, J.; Pachón, J.; del Palacio, J.P.; Pachón-Ibáñez, M.E.; Conejo, M.C. Efficacy of Fosfomycin and Its Combination with Aminoglycosides in an Experimental Sepsis Model by Carbapenemase-Producing Klebsiella pneumoniae Clinical Strains. Front. Med. 2021, 8, 615540. [Google Scholar] [CrossRef]
  11. Bavaro, D.F.; Belati, A.; Diella, L.; Stufano, M.; Romanelli, F.; Scalone, L.; Stolfa, S.; Ronga, L.; Maurmo, L.; Dell’aera, M.; et al. Cefiderocol-based combination therapy for “difficult-to-treat” gram-negative severe infections: Real-life case series and future perspectives. Antibiotics 2021, 10, 652. [Google Scholar] [CrossRef] [PubMed]
  12. Russo, A.; Bassetti, M.; Bellelli, V.; Bianchi, L.; Marincola Cattaneo, F.; Mazzocchetti, S.; Paciacconi, E.; Cottini, F.; Schiattarella, A.; Tufaro, G.; et al. Efficacy of a Fosfomycin-Containing Regimen for Treatment of Severe Pneumonia Caused by Multidrug-Resistant Acinetobacter baumannii: A Prospective, Observational Study. Infect. Dis. Ther. 2021, 10, 187–200. [Google Scholar] [CrossRef] [PubMed]
  13. Bassetti, M.; Vena, A.; Sepulcri, C.; Giacobbe, D.R.; Peghin, M. Treatment of bloodstream infections due to gram-negative bacteria with difficult-to-treat resistance. Antibiotics 2020, 9, 632. [Google Scholar] [CrossRef] [PubMed]
  14. Wilson, G.M.; Fitzpatrick, M.; Walding, K.; Gonzalez, B.; Schweizer, M.L.; Suda, K.J.; Evans, C.T. Meta-analysis of Clinical Outcomes Using Ceftazidime/Avibactam, Ceftolozane/Tazobactam, and Meropenem/Vaborbactam for the Treatment of Multidrug-Resistant Gram-Negative Infections. Open Forum Infect. Dis. 2021, 8, ofaa651. [Google Scholar] [CrossRef]
  15. Grabein, B.; Graninger, W.; Rodríguez Baño, J.; Dinh, A.; Liesenfeld, D.B. Intravenous fosfomycin—Back to the future. Systematic review and meta-analysis of the clinical literature. Clin. Microbiol. Infect. 2017, 23, 363–372. [Google Scholar] [CrossRef][Green Version]
  16. Losito, A.R.; Raffaelli, F.; Del Giacomo, P.; Tumbarello, M. New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review. Antibiotics 2022, 11, 579. [Google Scholar] [CrossRef]
  17. Abdul-Mutakabbir, J.C.; Alosaimy, S.; Morrisette, T.; Kebriaei, R.; Rybak, M.J. Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug-Resistant Gram-Negative Pathogens. Pharmacotherapy 2020, 40, 1228–1247. [Google Scholar] [CrossRef]
  18. Múñez Rubio, E.; Ramos Martínez, A.; Fernández Cruz, A. Fosfomycin in antimicrobial stewardship programs. Rev. Esp. Quimioter. 2019, 32, 62–66. [Google Scholar]
  19. Xie, O.; Cisera, K.; Taylor, L.; Hughes, C.; Rogers, B. Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection. Ann. Clin. Microbiol. Antimicrob. 2020, 19, 57. [Google Scholar] [CrossRef]
  20. Syed, Y.Y. Cefiderocol: A Review in Serious Gram-Negative Bacterial Infections. Drugs 2021, 81, 1559–1571. [Google Scholar] [CrossRef]
  21. Zhanel, G.G.; Golden, A.R.; Zelenitsky, S.; Wiebe, K.; Lawrence, C.K.; Adam, H.J.; Idowu, T.; Domalaon, R.; Schweizer, F.; Zhanel, M.A.; et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs 2019, 79, 271–289. [Google Scholar] [CrossRef] [PubMed]
  22. Michalopoulos, A.S.; Livaditis, I.G.; Gougoutas, V. The revival of fosfomycin. Int. J. Infect. Dis. 2011, 15, e732–e739. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Marino, A.; Stracquadanio, S.; Bellanca, C.M.; Augello, E.; Ceccarelli, M.; Cantarella, G.; Bernardini, R.; Nunnari, G.; Cacopardo, B. Oral Fosfomycin Formulation in Bacterial Prostatitis: New Role for an Old Molecule-Brief Literature Review and Clinical Considerations. Infect. Dis. Rep. 2022, 14, 621–634. [Google Scholar] [CrossRef] [PubMed]
  24. Sharma, A.; Sharma, R.; Bhattacharyya, T.; Bhando, T.; Pathania, R. Fosfomycin resistance in Acinetobacter baumannii is mediated by efflux through a major facilitator superfamily (MFS) transporter-AbaF. J. Antimicrob. Chemother. 2017, 72, 68–74. [Google Scholar] [CrossRef][Green Version]
  25. Gil-Marqués, M.L.; Moreno-Martínez, P.; Costas, C.; Pachón, J.; Blázquez, J.; McConnell, M.J. Peptidoglycan recycling contributes to intrinsic resistance to fosfomycin in Acinetobacter baumannii. J. Antimicrob. Chemother. 2018, 73, 2960–2968. [Google Scholar] [CrossRef]
  26. Ku, N.S.; Lee, S.H.; Lim, Y.S.; Choi, H.; Ahn, J.Y.; Jeong, S.J.; Shin, S.J.; Choi, J.Y.; Choi, Y.H.; Yeom, J.S.; et al. In vivo efficacy of combination of colistin with fosfomycin or minocycline in a mouse model of multidrug-resistant Acinetobacter baumannii pneumonia. Sci. Rep. 2019, 9, 17127. [Google Scholar] [CrossRef][Green Version]
  27. Nwabor, O.F.; Terbtothakun, P.; Voravuthikunchai, S.P.; Chusri, S. Evaluation of the synergistic antibacterial effects of fosfomycin in combination with selected antibiotics against carbapenem–resistant acinetobacter baumannii. Pharmaceuticals 2021, 14, 185. [Google Scholar] [CrossRef]
  28. Falcone, M.; Tiseo, G.; Leonildi, A.; Della Sala, L.; Vecchione, A.; Barnini, S.; Farcomeni, A.; Menichetti, F. Cefiderocol- Compared to Colistin-Based Regimens for the Treatment of Severe Infections Caused by Carbapenem- Resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2022, 66, e02142-21. [Google Scholar] [CrossRef]
  29. Falcone, M.; Tiseo, G.; Nicastro, M.; Leonildi, A.; Vecchione, A.; Casella, C.; Forfori, F.; Malacarne, P.; Guarracino, F.; Barnini, S.; et al. Cefiderocol as Rescue Therapy for Acinetobacter baumannii and Other Carbapenem-resistant Gram-negative Infections in Intensive Care Unit Patients. Clin. Infect. Dis. 2021, 72, 2021–2024. [Google Scholar] [CrossRef]
  30. Bavaro, D.F.; Romanelli, F.; Stolfa, S.; Belati, A.; Diella, L.; Ronga, L.; Fico, C.; Monno, L.; Mosca, A.; Saracino, A. Recurrent neurosurgical site infection by extensively drug-resistant P. aeruginosa treated with cefiderocol: A case report and literature review. Infect. Dis. 2021, 53, 206–211. [Google Scholar] [CrossRef]
  31. Antonello, R.M.; Principe, L.; Maraolo, A.E.; Viaggi, V.; Pol, R.; Fabbiani, M.; Montagnani, F.; Lovecchio, A.; Luzzati, R.; Di Bella, S. Fosfomycin as partner drug for systemic infection management. a systematic review of its synergistic properties from in vitro and in vivo studies. Antibiotics 2020, 9, 500. [Google Scholar] [CrossRef] [PubMed]
  32. Sirijatuphat, R.; Thamlikitkul, V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob. Agents Chemother. 2014, 58, 5598–5601. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Wang, J.; He, J.T.; Bai, Y.; Wang, R.; Cai, Y. Synergistic activity of colistin/fosfomycin combination against carbapenemase-producing Klebsiella pneumoniae in an in vitro pharmacokinetic/pharmacodynamic model. Biomed Res. Int. 2018, 2018, 5720417. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Eucast: Cefiderocol Susceptibility Testing. Available online: (accessed on 5 December 2022).
  35. Hawkey, P.M.; Warren, R.E.; Livermore, D.M.; McNulty, C.A.M.; Enoch, D.A.; Otter, J.A.; Wilson, A.P.R. Treatment of infections caused by multidrug-resistant gram-negative bacteria: Report of the British society for antimicrobial chemotherapy/healthcare infection society/british infection association joint working party. J. Antimicrob. Chemother. 2018, 73, iii2–iii78. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Kanj, S.S.; Bassetti, M.; Kiratisin, P.; Rodrigues, C.; Villegas, M.V.; Yu, Y.; van Duin, D. Clinical data from studies involving novel antibiotics to treat multidrug-resistant Gram-negative bacterial infections. Int. J. Antimicrob. Agents 2022, 60, 106633. [Google Scholar] [CrossRef]
  37. Giuffre, M.; Geraci, D.M.; Bonura, C.; Saporito, L.; Graziano, G.; Insinga, V.; Aleo, A.; Vecchio, D.; Mammina, C. The increasing challenge of multidrug-resistant gram-negative bacilli: Results of a 5-year active surveillance program in a neonatal intensive care unit. Medicine 2016, 95, e3016. [Google Scholar] [CrossRef][Green Version]
  38. Cultrera, R.; Libanore, M.; Barozzi, A.; D’anchera, E.; Romanini, L.; Fabbian, F.; De Motoli, F.; Quarta, B.; Stefanati, A.; Bolognesi, N.; et al. Ceftolozane/tazobactam and ceftazidime/avibactam for multidrug-resistant gram-negative infections in immunocompetent patients: A single-center retrospective study. Antibiotics 2020, 9, 640. [Google Scholar] [CrossRef]
  39. Bassetti, M.; Echols, R.; Matsunaga, Y.; Ariyasu, M.; Doi, Y.; Ferrer, R.; Lodise, T.P.; Naas, T.; Niki, Y.; Paterson, D.L.; et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): A randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect. Dis. 2021, 21, 226–240. [Google Scholar] [CrossRef]
  40. Paterson, D.L.; Kinoshita, M.; Baba, T.; Echols, R.; Portsmouth, S. Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies. Infect. Dis. Ther. 2022, 11, 853–870. [Google Scholar] [CrossRef]
  41. Stracquadanio, S.; Torti, E.; Longshaw, C.; Henriksen, A.S.; Stefani, S. In vitro activity of cefiderocol and comparators against isolates of Gram-negative pathogens from a range of infection sources: SIDERO-WT-2014–2018 studies in Italy. J. Glob. Antimicrob. Resist. 2021, 25, 390–398. [Google Scholar] [CrossRef]
  42. Paranos, P.; Vourli, S.; Pournaras, S.; Meletiadis, J. Assessing Clinical Potential of Old Antibiotics against Severe Infections by Multi-Drug-Resistant Gram-Negative Bacteria Using In Silico Modelling. Pharmaceuticals 2022, 15, 1501. [Google Scholar] [CrossRef] [PubMed]
  43. Wunderink, R.G.; Matsunaga, Y.; Ariyasu, M.; Clevenbergh, P.; Echols, R.; Kaye, K.S.; Kollef, M.; Menon, A.; Pogue, J.M.; Shorr, A.F.; et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): A randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect. Dis. 2021, 21, 213–225. [Google Scholar] [CrossRef] [PubMed]
  44. Pascale, R.; Pasquini, Z.; Bartoletti, M.; Caiazzo, L.; Fornaro, G.; Bussini, L.; Volpato, F.; Marchionni, E.; Rinaldi, M.; Trapani, F.; et al. Cefiderocol treatment for carbapenem-resistant Acinetobacter baumannii infection in the ICU during the COVID-19 pandemic: A multicentre cohort study. JAC-Antimicrob. Resist. 2021, 3, dlab174. [Google Scholar] [CrossRef] [PubMed]
  45. Stracquadanio, S.; Bonomo, C.; Marino, A.; Bongiorno, D.; Privitera, G.F.; Bivona, D.A.; Mirabile, A.; Bonacci, P.G.; Stefani, S. Acinetobacter baumannii and Cefiderocol, between Cidality and Adaptability. Microbiol. Spectr. 2022, 10, e02347-22. [Google Scholar] [CrossRef]
  46. McCreary, E.K.; Heil, E.L.; Tamma, P.D. New perspectives on antimicrobial agents: Cefiderocol. Antimicrob. Agents Chemother. 2021, 65, e02171-20. [Google Scholar] [CrossRef]
  47. Lupia, T.; Corcione, S.; Shbaklo, N.; Montrucchio, G.; De Benedetto, I.; Fornari, V.; Bosio, R.; Rizzello, B.; Mornese Pinna, S.; Brazzi, L.; et al. Meropenem/Vaborbactam and Cefiderocol as Combination or Monotherapy to Treat Multi-Drug Resistant Gram-Negative Infections: A Regional Cross-Sectional Survey from Piedmont Infectious Disease Unit Network (PIDUN). J. Funct. Biomater. 2022, 13, 174. [Google Scholar] [CrossRef]
  48. Hashemian, S.M.R.; Farhadi, Z.; Farhadi, T. Fosfomycin: The characteristics, activity, and use in critical care. Ther. Clin. Risk Manag. 2019, 15, 525–530. [Google Scholar] [CrossRef][Green Version]
  49. Khawcharoenporn, T.; Chuncharunee, A.; Maluangnon, C.; Taweesakulvashra, T.; Tiamsak, P. Active monotherapy and combination therapy for extensively drug-resistant Pseudomonas aeruginosa pneumonia. Int. J. Antimicrob. Agents 2018, 52, 828–834. [Google Scholar] [CrossRef]
  50. Rodríguez-Gascón, A.; Canut-Blasco, A. Deciphering pharmacokinetics and pharmacodynamics of fosfomycin. Rev. Esp. Quimioter. 2019, 32, 19–24. [Google Scholar]
  51. Dijkmans, A.C.; Zacarías, N.V.O.; Burggraaf, J.; Mouton, J.W.; Wilms, E.B.; van Nieuwkoop, C.; Touw, D.J.; Stevens, J.; Kamerling, I.M.C. Fosfomycin: Pharmacological, clinical and future perspectives. Antibiotics 2017, 6, 24. [Google Scholar] [CrossRef][Green Version]
  52. Roussos, N.; Karageorgopoulos, D.E.; Samonis, G.; Falagas, M.E. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections. Int. J. Antimicrob. Agents 2009, 34, 506–515. [Google Scholar] [CrossRef] [PubMed][Green Version]
  53. Akpinar, E.; Kansak, N.; Aksaray, S. Comparison of automated broth microdilution system (Vitek-2) and agar dilution method in the detection of fosfomycin susceptibility in E. coli and K. pneumoniae isolates causingrinary tract infection. Mediterr. J. Infect. Microbes Antimicrob. 2021, 10, 26. [Google Scholar] [CrossRef]
  54. Aprile, A.; Scalia, G.; Stefani, S.; Mezzatesta, M.L. In vitro fosfomycin study on concordance of susceptibility testing methods against ESBL and carbapenem-resistant Enterobacteriaceae. J. Glob. Antimicrob. Resist. 2020, 23, 286–289. [Google Scholar] [CrossRef] [PubMed]
  55. Marino, A.; Stracquadanio, S.; Ceccarelli, M.; Zagami, A.; Nunnari, G.; Cacopardo, B. Oral fosfomycin formulation for acute bacterial prostatitis; a new role for an old molecule: A case report and brief literature review. World Acad. Sci. J. 2022, 4, 26. [Google Scholar] [CrossRef]
  56. European Society of Clinical Microbiology and Infectious Diseases EUCAST: Clinical Breakpoints and Dosing of Antibiotics. Available online: (accessed on 30 November 2022).
  57. Simner, P.J.; Patel, R. Cefiderocol antimicrobial susceptibility testing considerations: The achilles’ heel of the trojan horse? J. Clin. Microbiol. 2021, 59, e00951-20. [Google Scholar] [CrossRef]
  58. Gobernado, M.A. Sociedad Española de Quimioterapia Revisión Fosfomicina. Marzo 2003, 16, 15–40. [Google Scholar]
  59. Flamm, R.K.; Rhomberg, P.R.; Lindley, J.M.; Sweeney, K.; Ellis-Grosse, E.J.; Shortridge, D. Evaluation of the bactericidal activity of fosfomycin in combination with selected antimicrobial comparison agents tested against Gram-negative bacterial strains by using time-kill curves. Antimicrob. Agents Chemother. 2019, 63, e02549-18. [Google Scholar] [CrossRef][Green Version]
  60. Papp-Wallace, K.M.; Zeiser, E.T.; Becka, S.A.; Park, S.; Wilson, B.M.; Winkler, M.L.; D’Souza, R.; Singh, I.; Sutton, G.; Fouts, D.E.; et al. Ceftazidime-Avibactam in Combination with Fosfomycin: A Novel Therapeutic Strategy against Multidrug-Resistant Pseudomonas aeruginosa. J. Infect. Dis. 2020, 221, 666–676. [Google Scholar] [CrossRef][Green Version]
  61. Cuba, G.T.; Rocha-Santos, G.; Cayô, R.; Streling, A.P.; Nodari, C.S.; Gales, A.C.; Pignatari, A.C.C.; Nicolau, D.P.; Kiffer, C.R.V. In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin or aztreonam against MDR Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2020, 75, 1874–1878. [Google Scholar] [CrossRef]
  62. Drusano, G.L.; Neely, M.N.; Yamada, W.M.; Duncanson, B.; Brown, D.; Maynard, M.; Vicchiarelli, M.; Louie, A. The Combination of fosfomycin plus meropenem is synergistic for pseudomonas aeruginosa PAO1 in a hollow-fiber infection model. Antimicrob. Agents Chemother. 2018, 62, e01682-18. [Google Scholar] [CrossRef][Green Version]
  63. Leelasupasri, S.; Santimaleeworagun, W.; Jitwasinkul, T. Antimicrobial Susceptibility among Colistin, Sulbactam, and Fosfomycin and a Synergism Study of Colistin in Combination with Sulbactam or Fosfomycin against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii. J. Pathog. 2018, 2018, 3893492. [Google Scholar] [CrossRef] [PubMed][Green Version]
  64. Zhao, B.; He, D.; Wang, L. Advances in Fusarium drug resistance research. J. Glob. Antimicrob. Resist. 2021, 24, 215–219. [Google Scholar] [CrossRef] [PubMed]
  65. Lee, Y.C.; Chen, P.Y.; Wang, J.T.; Chang, S.C. A study on combination of daptomycin with selected antimicrobial agents: In vitro synergistic effect of MIC value of 1 mg/L against MRSA strains. BMC Pharmacol. Toxicol. 2019, 20, 25. [Google Scholar] [CrossRef]
  66. Mihailescu, R.; Tafin, U.F.; Corvec, S.; Oliva, A.; Betrisey, B.; Borens, O.; Trampuza, A. High activity of fosfomycin and rifampin against methicillin-resistant staphylococcus aureus biofilm in vitro and in an experimental foreign-body infection model. Antimicrob. Agents Chemother. 2014, 58, 2547–2553. [Google Scholar] [CrossRef] [PubMed][Green Version]
  67. Oliva, A.; Curtolo, A.; Volpicelli, L.; Cogliati Dezza, F.; De Angelis, M.; Cairoli, S.; Dell’utri, D.; Goffredo, B.M.; Raponi, G.; Venditti, M. Synergistic meropenem/vaborbactam plus fosfomycin treatment of kpc producing k. Pneumoniae septic thrombosis unresponsive to ceftazidime/avibactam: From the bench to the bedside. Antibiotics 2021, 10, 781. [Google Scholar] [CrossRef] [PubMed]
  68. Gatti, M.; Viaggi, B.; Rossolini, G.M.; Pea, F.; Viale, P. An Evidence-Based Multidisciplinary Approach Focused on Creating Algorithms for Targeted Therapy of Infection-Related Ventilator-Associated Complications (IVACs) Caused by Pseudomonas aeruginosa and Acinetobacter baumannii in Critically Ill Adult Patients. Antibiotics 2022, 11, 33. [Google Scholar] [CrossRef] [PubMed]
  69. Gatti, M.; Giannella, M.; Rinaldi, M.; Gaibani, P.; Viale, P.; Pea, F. Pharmacokinetic/Pharmacodynamic Analysis of Continuous-Infusion Fosfomycin in Combination with Extended-Infusion Cefiderocol or Continuous-Infusion Ceftazidime-Avibactam in a Case Series of Difficult-to-Treat Resistant Pseudomonas aeruginosa Bloodstream Infections and/or Hospital-Acquired Pneumonia. Antibiotics 2022, 11, 1739. [Google Scholar] [CrossRef]
Table 1. Laboratory findings at admission and after antibiotic treatment. WBC: White blood cells; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactic dehydrogenase; eGFR: estimated glomerular filtration rate; CRP: C-reactive protein; ESR: erythrosedimentation rate.
Table 1. Laboratory findings at admission and after antibiotic treatment. WBC: White blood cells; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactic dehydrogenase; eGFR: estimated glomerular filtration rate; CRP: C-reactive protein; ESR: erythrosedimentation rate.
Patient 1Patient 2
Laboratory findings, unit (reference range) AdmissionEnd of therapyAdmissionEnd of therapy
WBC, cells/mmc (4000–10,000) 14,500420013,2003700
Neutrophils, % (40–75) 82.348.388.258.5
Lymphocytes, % (25–50) 12.642.96.128
Monocytes, % (2–10)
Platelets, cells/mmc ×103 (150–400) 1141182446
Haemoglobin, g/dL (12–16)
AST, UI/L (15–35) 17451431
ALT, UI/L (15–35) 616945
LDH, UI/L (80–250) 174184431142
Creatinine, mg/dL (0.8–1.2) 1.981.741.780.65
CRP, mg/dL (0–0.5) 13.070.516.440.65
ESR, mm/h (0–10) 12363356
Procalcitonin, ng/mL (<0.05) 40.078.670.12
D-dimer, ng/mL (<250) 12077631715644
Table 2. Pseudomonas aeruginosa antibiotic susceptibility. MIC: minimum inhibitory concentration; S: susceptible; R: resistant.
Table 2. Pseudomonas aeruginosa antibiotic susceptibility. MIC: minimum inhibitory concentration; S: susceptible; R: resistant.
AntibioticsMIC (mg/L)S/RAST
Amikacin<8SAs given by BD Phoenix
Cefiderocol13 mmSDD
AST: antimicrobial susceptibility tests; AD: agar dilution; BMD: broth microdilution; DD: disk diffusion.
Table 3. Acinetobacter baumannii antibiotic susceptibility. MIC: minimum inhibitory concentration; S: susceptible; R: resistant.
Table 3. Acinetobacter baumannii antibiotic susceptibility. MIC: minimum inhibitory concentration; S: susceptible; R: resistant.
AntibioticsMIC (mg/L)S/RAST
Amikacin>16RAs given by BD Phoenix
Cefiderocol15 mmSDD
AST: antimicrobial susceptibility tests; AD: agar dilution; BMD: broth microdilution; DD: disk diffusion; NA: not applicable.
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MDPI and ACS Style

Marino, A.; Stracquadanio, S.; Campanella, E.; Munafò, A.; Gussio, M.; Ceccarelli, M.; Bernardini, R.; Nunnari, G.; Cacopardo, B. Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations. Antibiotics 2023, 12, 49.

AMA Style

Marino A, Stracquadanio S, Campanella E, Munafò A, Gussio M, Ceccarelli M, Bernardini R, Nunnari G, Cacopardo B. Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations. Antibiotics. 2023; 12(1):49.

Chicago/Turabian Style

Marino, Andrea, Stefano Stracquadanio, Edoardo Campanella, Antonio Munafò, Maria Gussio, Manuela Ceccarelli, Renato Bernardini, Giuseppe Nunnari, and Bruno Cacopardo. 2023. "Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations" Antibiotics 12, no. 1: 49.

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