The Use of Intravenous Fosfomycin in Clinical Practice: A 5-Year Retrospective Study in a Tertiary Hospital in Italy
by
,
Antonio Anastasia
1,2,
Silvia Bonura
2,3,
Raffaella Rubino
2,3,
Giovanni Maurizio Giammanco
1,3,4,
Irene Miccichè
3,5,
Maria Rita Di Pace
1,
Claudia Colomba
1 and
Antonio Cascio
1,2,3,*
1
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G D’Alessandro”, University of Palermo, 90127 Palermo, Italy
2
Infectious and Tropical Disease Unit and Sicilian Regional Reference Center for the Fight against AIDS, AOU Policlinico “P. Giaccone”, 90127 Palermo, Italy
3
Antimicrobial Stewardship Team, AOU Policlinico “P. Giaccone”, 90127 Palermo, Italy
4
Microbiology and Virology Unit, AOU Policlinico “P. Giaccone”, 90127 Palermo, Italy
5
UOC Farmacia, AOU Policlinico “P. Giaccone”, 90127 Palermo, Italy
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(6), 971; https://doi.org/10.3390/antibiotics12060971
Submission received: 13 April 2023
/
Revised: 21 May 2023
/
Accepted: 22 May 2023
/
Published: 27 May 2023
(This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship)
Abstract
:Fosfomycin in intravenous (IV) formulation has re-emerged as a valuable tool in the treatment of multi-drug resistant (MDR) and extensively drug-resistant (XDR) infections because of its broad spectrum of antibacterial action and pharmacokinetic characteristics. This retrospective study aimed to evaluate how fosfomycin was used in patients admitted to the Polyclinic of Palermo between January 2017 and July 2022. Clinical indications, therapeutic associations, clinical outcomes, and any side effects were analyzed. Intravenous fosfomycin was used in 343 patients, 63% male, with a mean age of 68 years (range 15–95). Urinary tract infections (UTIs) and hospital-acquired pneumonia (HAP) were the main indications for treatment (19% and 18% of the total cases, respectively), followed by skin and soft tissue infections and sepsis. IV fosfomycin was administered in combination with other antibacterial agents, the most common of which were ceftazidime/avibactam (35%), meropenem (17%), and colistin (14%). Nineteen patients received it as monotherapy for UTIs. About 66% had resolution of the infectious process with clinical remission (cure or discharge). Electrolyte disturbances occurred in 2.6% and gastrointestinal symptoms occurred in 2.9%. The data showed that IV fosfomycin is a safe and effective therapeutic option in the treatment of infections with multidrug-resistant microorganisms.
1. Introduction
The substantial decrease in the effective number of antibiotics and the slowdown in the development of new molecules have left few therapeutic tools for patients with multi-drug-resistant (MDR) or extensively drug-resistant (XDR) pathogen infections. From this point of view, the rediscovery of old antibiotics appeared to be one of the few viable therapeutic routes: fosfomycin proved useful due to its unique chemical structure and mechanism of action that does not exhibit cross-resistance with other antibiotics. Fosfomycin is a bactericidal antibiotic that interferes with cell wall synthesis, inhibiting UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), an enzyme responsible for catalyzing the formation of N-acetylmuramic acid [1]. Gram-positive and Gram-negative bacteria require the formation of N-acetylmuramic acid for peptidoglycan synthesis, which means that fosfomycin’s spectrum of action is very broad [2,3]. 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 [4,5,6]. Specifically, it has been found to be highly active against Staphylococcus aureus and Enterococcus spp., and it exhibits considerable activity against Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae including extended-spectrum beta-lactamases (ESBL) and carbapenemase producers [7,8,9]. Fosfomycin is generally used as part of a combination regimen and has been prescribed for various infections, such as complicated urinary tract infections (UTIs), osteomyelitis, skin and soft tissue infections, nosocomial lower respiratory tract infections, bacterial meningitis, and bacteremia/sepsis, in various countries [10,11]. This study aims to analyze the efficacy and safety of intravenous fosfomycin in the treatment of difficult-to-treat infections in a real-life setting.
2. Materials and Methods
This is a retrospective study conducted in the Hospital Paolo Giaccone in Palermo, Sicily, Italy. The records of all adult patients (> 18 years old) admitted to the infectious diseases ward or the different wards of the entire hospital, evaluated in consultancy, for whom fosfomycin in an intravenous formulation was administered for at least 24 h and each type of infection was analyzed. The period considered was between 1 January 2017 and 31 July 2022. Informed consent could not be obtained due to the study’s retrospective nature.
A standardized Excel spreadsheet was used to collect and categorize information regarding the patients’ age, gender, clinical characteristics (comorbidities and type of infection), data related to fosfomycin use (empiric vs. target therapy and side effects), and outcomes. The dose of fosfomycin and the duration of treatment was decided by the specialist based on the type and severity of the infection and renal function, according to the manufacturer’s instructions. For patients with an estimated creatinine clearance (CrCl) of > 40 mL/min, a daily dose of 16–24 g/day divided into 3–4 doses was used. The daily dose was reduced by 20%, 40%, 60%, and 70% of the full dose in patients with CrCl of 31–40, 21–30, 11–20, and ≤ 10 mL/min, respectively. Fosfomycin susceptibility of the pathogens analyzed was interpreted using EUCAST cut-off points. The primary outcome was clinical response at the end of therapy. When the data were available, the patients were subdivided according to the resolution of the infectious process indicated as recovery if they achieved complete clinical success with resolution of signs/symptoms of infection, as relapse if after an initial improvement it was necessary to add an additional line of treatment, and as death if the subject died. As a secondary outcome, the occurrence of clinical- or laboratory-based adverse effects was assessed. Isolates and susceptibility testing were identified with the Vitek 2 system (bioMérieux, Lyon, France) or the broth microdilution method (BMD). The antibiotics used in the susceptibility testing for Gram-positive bacteria were glycopeptides, cephalosporins, penicillins, daptomycin, linezolid, aminoglycosides, fluoroquinolones, trimethoprim/sulfamethoxazole (TPM/SMX), clindamycin, and tetracyclines; the antibiotics used in the susceptibility testing for-Gram negative bacteria were penicillins, cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, TPM/SMX, tetracyclines, and colistin. We obtained minimum inhibitory concentrations (MICs) for fosfomycin using the agar dilution method. The data were analyzed by descriptive statistics. Continuous variables were presented by the mean value and standard deviation (SD). Categorical variables were described by numbers and percentages.
3. Results
The population analyzed included 343 adult patients who received intravenous fosfomycin therapy for at least 24 h. The age of the patients ranged from 19 to 95 years, with a mean age of 68 years. Two-thirds were men (62.9%). As shown in Table 1, the background medical conditions included solid neoplasms (9.1%), cardiovascular disease (16.6%), pulmonary disease (16.6%), and diabetes mellitus (13.9%). Fifty-seven (16.6%) patients were admitted to a high-intensity care unit (ICU) at the time of starting IV fosfomycin therapy. In order of frequency, the main indications for fosfomycin administration were complicated and uncomplicated infections of the urinary tract (UTIs) (18.7%), lung infections (HAP) (18.4%), and skin and soft tissue infections (SSTI) including those involving surgical wound infections (15.5%) and bacteremia associated or not with signs and symptoms of sepsis (BSIs) (15.2%). IV fosfomycin has also been found to be indicated in the treatment of infectious diseases of the osteoarticular system and prosthesis, in the treatment of complicated endocarditis, infections of the central nervous system (CNS), and infections of various intrathoracic (mediastinitis, pleurisy, laryngeal fistulae, etc.) and intra-abdominal (IAIs) (cholecystitis, intra-abscesses, post-surgical intestinal infections, etc.) sites. All remaining infections that could not be categorized into the macro areas described above were designated as “other infections” (Figure 1). The indication for the use of fosfomycin was mostly based on the microbiological isolation of susceptible pathogens according to the EUCAST guidelines before the June 2022 amendment. Most of the infections detected involved only one pathogen (192) compared to polymicrobial infections (151).
In 57 patients (16.6%), no pathogen or other cause of infection was found, so empirical treatment was administered. Most of the bacteria isolated were Gram-negative (316 isolations), while Gram-positive bacteria were revealed in 60 cases. The most frequently encountered pathogens were in the order of frequency Klebsiella pneumoniae (193, 56.2%), Pseudomonas aeruginosa (42, 12.2%), Acinetobacter baumannii (36, 10.2%), Staphylococcus aureus (16, 4.6%), and Enterococcus spp. (28, 8.2%). The main microbiological isolates are shown in Figure 2 and completely described in Table S1.
A sub-analysis of all Klebsiella pneumoniae isolates was also conducted aimed at analyzing the antibiotic resistance profile. Figure 3 shows the prevalence (%) of K. pneumoniae strains sensitive to the respective antibiotic classes over a total of 193 isolates. These data showed a high percentage of susceptibility of K.pneumoniae isolates to fosfomycin (92.2%) and colistin (75.6%). Figure 3, moreover, depicts the susceptibility of K.pneumoniae to ceftazidime/avibactam, ceftolozane/tazobactam, and meropenem/vaborbactam concerning the isolates assayed for the aforementioned antibiotics, which were subsequently introduced commercially. Figure 4 shows the prevalence (%) of A. baumannii strains sensitive to the respective classes of antibiotics in a total of 36 isolates, highlighting a total resistance to fluoroquinolones (levofloxacin and ciprofloxacin) and carbapenems and a high percentage of resistance to aminoglycosides (amikacin) and trimethoprim-sulfamethoxazole. The methods used for identification did not include the possibility of assessing the resistance profile of A.baumannii for fosfomycin and ceftazidime/avibactam, the latter often used because of the concomitant presence of infection with K. pneumoniae strains. Table 2 summarizes the number of recoveries, relapses, and deaths divided by the type of infections with their respective cases in ICUs and the main microbiological isolates.
In the majority (324, 94.4%), IV fosfomycin was used in combination with other antimicrobial agents. The main therapeutic partners were ceftazidime/avibactam (35,5%), meropenem (16.6%), colistin (14.1%), vancomycin (8.1%), and daptomycin (11.4%).
The antibiotics most frequently used empirically in cases of infections without micro-biological findings were in the order of frequency meropenem (20 cases), daptomycin (14 cases), and vancomycin (8 cases). The use of monotherapy was chosen exclusively for the treatment of complicated and uncomplicated infections of the urinary system for a total of 19 patients. All antibiotic combinations used are described in Table S2. The mean treatment duration was 12 ± 6.2 days, strongly depending on the indications and the main combination therapies. There was a resolution of the infectious process in 65.8% of cases. Patient death occurred in 26.2% of the total cases, while recurrence was observed in 4.9%. Comparisons of the various treatment indications and the corresponding cases and clinical resolution rates for each indication showed a success rate on several occasions of above 60 percent. Table 3 shows the number of recoveries, relapses, and deaths divided by the main combination therapies and specific isolates.
The drug safety analysis showed an absence of adverse events in 94.2%. The percentage of adverse events (5.8%) showed a prevalence of gastrointestinal symptoms (nausea and diarrhea) (2.9%), followed by isolated or multiple electrolyte disturbances (2.6%), and they occurred within the first week of treatment (Table 4). The need for discontinuation of treatment occurred only in four cases, due to uncorrectable hypokalemia. No serious adverse events were observed in the entire cohort analyzed.
4. Discussion
The exponential increase in infections with MDR, XDR, or pandrug-resistant (PDR) microorganisms has rediscovered the therapeutic utility of old antibiotic molecules in monotherapy or in combination. Fosfomycin, among these, has emerged as being at the forefront of the treatment of such diseases. Our results on the use of intravenous fosfomycin in a population of 343 patients are in line with those of other studies in the literature. Fosfomycin has been classically used in UTIs but its use in other types of infections and against difficult-to-treat pathogens has gained more interest due to its unique mechanisms of action and favorable safety profile [10]. As already reported by Grabein et al. [10], the main indication for treatment in our case was a urinary tract infection (18.7%), including the use of monotherapy in that group of patients, with a rate of resolution greater than 70%.
The highest clinical success rates were observed in osteomyelitis (83.8%), SSTIs (67.3%), intra-abdominal infections (64.9%), and bacteremia/sepsis (61.5%), with success rates similar to those reported by other studies [12,13] but lower than those reported by Putensen et al. [14] (81%). On the other hand, resolution of the infectious process in the treatment of pneumonia and endocarditis appeared to be more limited in our cohort than in the literature studies [12,13], likely due to the severely compromised status of the patients and the concomitant presence of other diseases. This probably accounts for the high mortality rate shown in patients admitted to ICUs (85.9%) as shown in Table 2.
In the study of patients with documented infection, the main microbiological isolation was K.pneumoniae (56.2%). K.pneumoniae isolates were 82.3% sensitive to fosfomycin with MICs < 16 (76.6%) or equal to 32 (15.4%), and 82.4% were resistant to carbapenems. In all cases, IV fosfomycin was used in combination with other antibiotics with a resolution rate of 66.3%, which is in agreement with other studies in the literature [9,15,16,17]. These data, in addition to those we collected, seem to present IV fosfomycin as having valid therapeutic efficacy against K. pneumoniae, with various spectra of resistance proposing its use as a therapeutic alternative despite the absence of currently validated MIC breakpoints. Our use of the association of fosfomycin and ceftazidime/avibactam for K.pneumoniae and other Gram-negative bacteria obtained a clinical cure rate of 61.6%, similar to that described in other studies [18,19,20,21]. Worth reporting is the finding of K.pneumoniae isolates blaKPC resistant to ceftazidime/avibactam (10% of the isolates for which the antibiotic was assayed) and ceftolozane/tazobactam (92% of the isolates for which it was assayed), underlining the prevalence of pathogens resistive to new therapeutic molecules but sensitive to fosfomycin within our epidemiology. No resistance was observed to meropenem/vaborbactam. Regarding S.aureus and E.coli isolates, all those analyzed were sensitive to fosfomycin, confirming the finding already evaluated by Maraki et al. [22]. In our cohort, fosfomycin was used almost exclusively in combination with other antibiotics (94.4% of patients), supported by synergistic effects as recently recommended, especially if MDR Gram-negative pathogens are involved [13,23,24]. Remarkably, EUCAST stated that there are not enough data for providing any meaningful clinical breakpoint of fosfomycin against P.aeruginosa or A.baumannii, but our use in these types of infections was based on several clinical data on the efficacy of IV fosfomycin in combination with other antibiotics mainly derived from observational studies [25,26,27]. The most commonly used combination antibiotics were ceftazidime/avibactam, meropenem, and colistin with a resolution rate of 59.8% (73 of 122), 61.4% (35 of 57), and 51.1% (25 of 49), respectively. The main associations used are in line with the literature data based on both retrospective clinical trials and in vitro efficacy studies [3,10,15,26]. In agreement with Putensen et al. [14], also in our study, fosfomycin was not used as a therapeutic alternative in the perspective of a carbapenem-sparing regimen [28,29] but as a valid weapon of association with them especially in pneumonia (hospital-acquired and community-acquired pneumonia) and bacteremia/sepsis. Our use of the association of fosfomycin and colistin reported a clinical cure rate of 51.3%, similar to that described in other studies [26,30,31,32]. These studies and other studies in the literature analyzing combination therapy with ceftazidime/avibactam are described in Table 5. Although fosfomycin is not expected to be used in empirical treatment protocols, we used it in the treatment of particularly severe patients in relation to its synergistic potential and its broad spectrum of action, with a favorable outcome in 64.4% of cases. IV fosfomycin was found to be well tolerated and safe in almost all cases analyzed, with no occurrence of serious adverse effects. Only a small percentage of electrolyte disturbances (hypokalemia and/or hypernatremia) and gastrointestinal disturbances were found to be 2.6% and 2.9%, respectively, as already highlighted in other studies [10,24,33] and much less than that found in the cohort of Zirpe et al. [34]. However, this study does not remain free of limitations, ascertainable to its retrospective nature and the vast heterogeneity of the clinical setting of the patients for whom fosfomycin was used. Additionally noteworthy is the lack of a control group and the presence of co-administered antibiotics that act as confounding factors but are necessary for the treatment of infections with multidrug-resistant pathogens.
5. Conclusions
Our results suggest that fosfomycin is a safe and effective option for the treatment of difficult-to-treat infections due to Gram-negative and Gram-positive pathogens. It represents a valuable aid against extensively drug-resistant (XDR) and pan-drug-resistant (PDR) infections.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/antibiotics12060971/s1. Table S1. Microbiological isolates (data from mono- and polybacterial infections); Table S2. Fosfomycin combination partners and the number of cases.
Author Contributions
Conceptualization, A.C.; methodology, A.A., A.C.; formal analysis, A.A.; investigation, A.A., S.B., R.R., G.M.G., I.M., M.R.D.P.; data curation, A.A., S.B., R.R., G.M.G., I.M.; writing—original draft preparation, A.A.; writing—review and editing, A.A., S.B., R.R., G.M.G., I.M., C.C.; visualization, M.R.D.P.; supervision, A.C.; funding acquisition, A.C. All authors have read and agreed to the published version of the manuscript.”
Funding
The publication costs of this article were covered by the Fund for VQR improvement assigned to the Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties of the University of Palermo.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee “Palermo I”, Palermo, Italy (DTR-MDR DIMUNA-Verbal n.11 22/12/2022).
Informed Consent Statement
The need for written informed consent was waived owing to the observational and retrospective nature of the study and the complete anonymization of the cases.
Data Availability Statement
The data sets are available if required.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Candel, F.J.; David, M.M.; Barberán, J. New perspectives for reassessing fosfomycin: Applicability in current clinical practice. Rev. Esp. De Quimioter. 2019, 32, 1–7. [Google Scholar]
- 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] [PubMed]
- Falagas, M.E.; Vouloumanou, E.K.; Samonis, G.; Vardakas, K.Z. Fosfomycin. Clin. Microbiol. Rev. 2016, 29, 321–347. [Google Scholar] [CrossRef] [PubMed]
- Fransen, F.; Hermans, K.; Melchers, M.J.B.; Lagarde, C.C.M.; Meletiadis, J.; Mouton, J.W. Pharmacodynamics of fosfomycin against ESBL- and/or carbapenemase-producing Enterobacteriaceae. J. Antimicrob. Chemother. 2017, 72, 3374–3381. [Google Scholar] [CrossRef] [PubMed]
- Louie, A.; Maynard, M.; Duncanson, B.; Nole, J.; Vicchiarelli, M.; Drusano, G.L. Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model. Antimicrob. Agents Chemother. 2018, 62, e02627-17. [Google Scholar] [CrossRef]
- Walsh, C.C.; McIntosh, M.P.; Peleg, A.Y.; Kirkpatrick, C.M.; Bergen, P.J. In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2015, 70, 3042–3050. [Google Scholar] [CrossRef]
- Kaase, M.; Szabados, F.; Anders, A.; Gatermann, S.G. Fosfomycin susceptibility in carbapenem-resistant enterobacteriaceae from Germany. J. Clin. Microbiol. 2014, 52, 1893–1897. [Google Scholar] [CrossRef]
- Falagas, M.E.; Maraki, S.; Karageorgopoulos, D.E.; Kastoris, A.C.; Mavromanolakis, E.; Samonis, G. Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to Fosfomycin. Int. J. Antimicrob. Agents 2010, 35, 240–243. [Google Scholar] [CrossRef]
- Michalopoulos, A.; Virtzili, S.; Rafailidis, P.; Chalevelakis, G.; Damala, M.; Falagas, M.E. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: A prospective evaluation. Clin. Microbiol. Infect. 2010, 16, 184–186. [Google Scholar] [CrossRef]
- Grabein, B.; Graninger, W.; Baño, J.R.; 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]
- Docobo-Pérez, F.; Drusano, G.L.; Johnson, A.; Goodwin, J.; Whalley, S.; Ramos-Martín, V.; Ballestero-Tellez, M.; Rodriguez-Martinez, J.M.; Conejo, M.C.; van Guilder, M.; et al. Pharmacodynamics of fosfomycin: Insights into clinical use for antimicrobial resistance. Antimicrob. Agents Chemother. 2015, 59, 5602–5610. [Google Scholar] [CrossRef]
- Dinh, A.; Salomon, J.; Bru, J.P.; Bernard, L. Fosfomycin: Efficacy against infections caused by multidrug-resistant bacteria. Scand. J. Infect. Dis. 2012, 44, 182–189. [Google Scholar] [CrossRef] [PubMed]
- Pontikis, K.; Karaiskos, I.; Bastani, S.; Dimopoulos, G.; Kalogirou, M.; Katsiari, M.; Oikonomou, A.; Poulakou, G.; Roilides, E.; Giamarellou, H. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int. J. Antimicrob. Agents 2014, 43, 52–59. [Google Scholar] [CrossRef] [PubMed]
- Putensen, C.; Ellger, B.; Sakka, S.G.; Weyland, A.; Schmidt, K.; Zoller, M.; Weiler, N.; Kindgen-Milles, D.; Jaschinski, U.; Weile, J.; et al. Current clinical use of intravenous fosfomycin in ICU patients in two European countries. Infection 2019, 47, 827–836. [Google Scholar] [CrossRef] [PubMed]
- Mikhail, S.; Singh, N.B.; Kebriaei, R.; Rice, S.A.; Stamper, K.C.; Castanheira, M.; Rybak, M.J. Evaluation of the Synergy of Ceftazidime-Avibactam in Combination with Meropenem, Amikacin, Aztreonam, Colistin or Fosfomycin against well-characterized multidrug-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2019, 63, e00779–19. [Google Scholar] [CrossRef]
- Tharavichitkul, P.B.M.; Khantawa, B.; Bousoung, V. Activity of fosfomycin against extended-spectrum-b-lactamase-producing Klebsiella pneumoniae and Escherichia coli in Maharaj Nakorn Chiang Mai Hospital. J. Infect. Dis. Antimicrob. Agents 2005, 121, 126. [Google Scholar]
- Vardakas, K.Z.; Legakis, N.J.; Triarides, N.; Falagas, M.E. Susceptibility of contemporary isolates to fosfomycin: A systematic review of the literature. Int. J. Antimicrob. Agents 2016, 47, 269–285. [Google Scholar] [CrossRef] [PubMed]
- Oliva, A.; Volpicelli, L.; Di Bari, S.; Curtolo, A.; Borrazzo, C.; Cogliati Dezza, F.; Cona, A.; Agrenzano, S.; Mularoni, A.; Trancassini, M.; et al. Effect of ceftazidime/avibactam plus fosfomycin combination on 30 day mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae: Results from a multicentre retrospective study. JAC Antimicrob. Resist. 2022, 4, dlac121. [Google Scholar] [CrossRef]
- Zheng, G.; Zhang, J.; Wang, B.; Cai, J.; Wang, L.; Hou, K.; Zhang, Y.; Zhang, L.; Yang, Z.; He, J.; et al. Ceftazidime-Avibactam in Combination with In Vitro Non-susceptible Antimicrobials Versus Ceftazidime-Avibactam in Monotherapy in Critically Ill Patients with Carbapenem-Resistant Klebsiella Pneumoniae Infection: A Retrospective Cohort Study. Infect. Dis. Ther. 2021, 10, 1699–1713, Erratum in: Infect. Dis. Ther. 2022, 11, 935–936. [Google Scholar] [CrossRef] [PubMed]
- Burastero, G.J.; Orlando, G.; Santoro, A.; Menozzi, M.; Franceschini, E.; Bedini, A.; Cervo, A.; Faltoni, M.; Bacca, E.; Biagioni, E.; et al. Ceftazidime/Avibactam in Ventilator-Associated Pneumonia Due to Difficult-to-Treat Non-Fermenter Gram-Negative Bacteria in COVID-19 Patients: A Case Series and Review of the Literature. Antibiotics 2022, 11, 1007. [Google Scholar] [CrossRef]
- Zhanel, G.; Baxter, M.; Wong, M.; Mirzanejad, Y.; Lee, A.; Dhami, R.; Kosar, J.; Werry, D.; Irfan, N.; Tessier, J.-F.; et al. Real-life experience with IV fosfomycin in Canada: Results from the Canadian LEadership on Antimicrobial Real-life usage (CLEAR) registry. J. Glob. Antimicrob. Resist. 2023, 33, 171–176. [Google Scholar] [CrossRef]
- Maraki, S.; Samonis, G.; Rafailidis, P.I.; Vouloumanou, E.K.; Mavromanolakis, E.; Falagas, M.E. Susceptibility of urinary tract bacteria to Fosfomycin. Antimicrob. Agents Chemother. 2009, 53, 4508–4510. [Google Scholar] [CrossRef] [PubMed]
- Bassetti, M.; Graziano, E.; Berruti, M.; Giacobbe, D.R. The role of fosfomycin for multidrug-resistant gram-negative infections. Curr. Opin. Infect. Dis. 2019, 32, 617–625. [Google Scholar] [CrossRef] [PubMed]
- Abdallah, T.A.K.; Elajez, R.; Ibrahim, T.B.; Alimam, A.B.; Omrani, A.S. Efficacy and safety of intravenous fosfomycin for the treatment of difficult-to-treat Gram-negative bacterial infections. J. Infect. Public Health 2021, 14, 1620–1622. [Google Scholar] [CrossRef] [PubMed]
- Falagas, M.E.; Kastoris, A.C.; Karageorgopoulos, D.; Rafailidis, P.I. Fosfomycin for the treatment of infections caused by multidrugresistant non-fermenting Gram-negative bacilli: A systematic review of microbiological, animal and clinical studies. Int. J. Antimicrob. Agents 2009, 34, 111–120. [Google Scholar] [CrossRef]
- 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]
- Russo, A.; Bassetti, M.; Bellelli, V.; Bianchi, L.; Cattaneo, F.M.; 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]
- Fournier, D.; Chirouze, C.; Leroy, J.; Cholley, P.; Talon, D.; Plésiat, P.; Bertrand, X. Alternatives to carbapenems in ESBL-producing Escherichia coli infections. Méd. Mal. Infect. 2013, 43, 62–66. [Google Scholar] [CrossRef]
- Bouxom, H.; Fournier, D.; Bouiller, K.; Hocquet, D.; Bertrand, X. Which non-carbapenem antibiotics are active against extended-spectrum β-lactamase-producing Enterobacteriaceae? Int. J. Antimicrob. Agents 2018, 52, 100–103. [Google Scholar] [CrossRef]
- Apisarnthanarak, A.; Mundy, L.M. Carbapenem-resistant Pseudomonas aeruginosa pneumonia with intermediate minimum inhibitory concentrations to doripenem: Combination therapy with high-dose, 4-h infusion of doripenem plus fosfomycin versus intravenous colistin plus fosfomycin. Int. J. Antimicrob. Agents 2012, 39, 271–272. [Google Scholar] [CrossRef]
- Navarro-San Francisco, C.; Mora-Rillo, M.; Romero-Gómez, M.P.; Moreno-Ramos, F.; Rico-Nieto, A.; Ruiz-Carrascoso, G.; Gómez-Gil, R.; Arribas-López, J.R.; Mingorance, J.; Paño-Pardo, J.R. Bacteraemia due to OXA-48-carbapenemase-producing Enterobacteriaceae: A major clinical challenge. Clin. Microbiol. Infect. 2013, 19, E72–E79. [Google Scholar] [CrossRef]
- Thampithak A, Chaisiri K, Siangsuebchart O, Phengjaturat K, Aonjumras W, Hemapanpairoa J. Prescription Pattern of Intravenous Fosfomycin in a Provincial Hospital in Thailand. Infect Chemother. 2022, 54, 699–710. [CrossRef]
- Iarikov, D.; Wassel, R.; Farley, J.; Nambiar, S. Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database. Infect. Dis. Ther. 2015, 4, 433–458. [Google Scholar] [CrossRef] [PubMed]
- Zirpe, K.G.; Mehta, Y.; Pandit, R.; Pande, R.; Deshmukh, A.M.; Patil, S.; Bhagat, S.; Barkate, H. A real-world study on prescription pattern of fosfomycin in critical care patients. Indian J. Crit. Care Med. 2021, 25, 1055–1058. [Google Scholar] [PubMed]
- 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] [PubMed]
- Assimakopoulos, S.F.; Karamouzos, V.; Eleftheriotis, G.; Lagadinou, M.; Bartzavali, C.; Kolonitsiou, F.; Paliogianni, F.; Fligou, F.; Marangos, M. Efficacy of Fosfomycin-Containing Regimens for Treatment of Bacteremia due to Pan-Drug Resistant Acinetobacter baumannii in Critically Ill Patients: A Case Series Study. Pathogens 2023, 12, 286. [Google Scholar] [CrossRef] [PubMed]
Figure 1.
Indications for fosfomycin use. UTIs = urinary tract infections; IAIs = intra-abdominal infections; BSI = bloodstream infections; CNS inf. = central nervous system infections; SSTI = skin and soft tissue infections.
Figure 1.
Indications for fosfomycin use. UTIs = urinary tract infections; IAIs = intra-abdominal infections; BSI = bloodstream infections; CNS inf. = central nervous system infections; SSTI = skin and soft tissue infections.
Figure 2.
Main microbiological isolates.
Figure 3.
Prevalence of K.pneumoniae isolates sensitive to respective molecules in the extended antibiograms to the aforementioned antibiotics. Data shown as the percentages and number of susceptible strains/total isolates. TPM/SMX = trimethoprim–sulfamethoxazole CAZ/AVI = ceftazidime/avibactam MER/VAB = meropenem/vaborbactam CEF/TAZ = ceftolozane/tazobactam.
Figure 3.
Prevalence of K.pneumoniae isolates sensitive to respective molecules in the extended antibiograms to the aforementioned antibiotics. Data shown as the percentages and number of susceptible strains/total isolates. TPM/SMX = trimethoprim–sulfamethoxazole CAZ/AVI = ceftazidime/avibactam MER/VAB = meropenem/vaborbactam CEF/TAZ = ceftolozane/tazobactam.
Figure 4.
Prevalence of A. baumannii isolates sensitive to the respective molecules in the extended antibiograms to the aforementioned antibiotics. Data shown as the percentages and number of susceptible strains/total isolates. FQ = fluoroquinolones; AG = aminoglycoside; TPM/SMX = trimethoprim–sulfamethoxazole.
Figure 4.
Prevalence of A. baumannii isolates sensitive to the respective molecules in the extended antibiograms to the aforementioned antibiotics. Data shown as the percentages and number of susceptible strains/total isolates. FQ = fluoroquinolones; AG = aminoglycoside; TPM/SMX = trimethoprim–sulfamethoxazole.
Table 1.
The number of cases, recoveries, relapses, deaths, and missing data divided by the demographic characteristics and comorbidities.
Table 1.
The number of cases, recoveries, relapses, deaths, and missing data divided by the demographic characteristics and comorbidities.
| Cases N | Recovery N (%) | Relapse N (%) | Death N (%) | Missing Data | |
|---|---|---|---|---|---|
| Total | 343 | 226 (65.8) | 17 (4.9) | 90 (26.2) | 10 (2.9) |
| Sex | |||||
| Male | 216 (62.9) | 148 (68.5) | 9 (4.2) | 54 (25) | 5 (2.3) |
| Female | 127 (37.1) | 78 (61.4) | 8 (6.2) | 36 (28.3) | 5 (3.9) |
| Age (mean ± DS) 68 ± 13.9 65.3 ± 13.9 64.1 ± 15 65.3 ± 14 | |||||
| 18–45 years | 34 | 25 (73.5) | 2 (5.9) | 6 (17.6) | 1 |
| 46–65 years | 113 | 75 (66.4) | 6 (5.3) | 26 (23) | 6 |
| 66–95 years | 195 | 126 (64.6) | 9 (4.6) | 57 (29.2) | 3 |
| Comorbidity | |||||
| Solid neoplasm Hematological diseases Cardiovascular diseases Diabetes mellitus Kidney failure Lung diseases HIV/AIDS SARS-CoV-2 Other | 31 (9.1) 29 (8.4) 57 (16.6) 48 (13.9) 29 (8.4) 57 (16.6) 11 (3.2) 18 (5.2) 59 (17.2) | 21 (67.7) 18 (62.1) 35 (61.4) 37 (77.1) 20 (68.9) 29 (50.9) 9 (81.8) 9 (50) 38 (64.4) | 3 (9.6) 1 (3.4) 3 (5.2) 1 (2.1) 2 (6.8) 4 (7) 0 2 (11.1) 3 (5.1) | 4 (12.9) 9 (31) 16 (28.1) 9 (18.8) 7 (24.1) 23 (40.4) 2 (18.2) 7 (38.9) 17 (28.8) | 3 1 3 1 - 1 - - 1 |
Table 2.
Number of cases, recoveries, relapses, and deaths divided by the type of infection and the main microbiological isolates.
Table 2.
Number of cases, recoveries, relapses, and deaths divided by the type of infection and the main microbiological isolates.
| Cases N | Recovery N (%) | Relapse N (%) | Death N (%) | |
|---|---|---|---|---|
| Type of infection and subgroups in the ICU (intensive care unit) | ||||
| UTI/Pyelonephritis UTI/Pyelonephritis in the ICU Endocarditis Endocarditis in the ICU Skin and soft tissue infections (SSTI) SSTI in the ICU Central nervous system (CNS) infections CNS infections in the ICU Osteomyelitis Bacteremia/sepsis Bacteremia/sepsis in the ICU Intrathoracic infections Intrathoracic infections in the ICU Intra-abdominal infections Intra-abdominal infections in the ICU Pneumonia Pneumonia in the ICU Other infections | 69 6 13 4 49 4 10 4 37 52 12 6 2 37 9 63 16 7 | 55 (79.7) 2 (40) 6 (46.1) - 33 (67.3) - 6 (60) - 31 (83.8) 32 (61.5) 1 (8.3) 3 (50) - 24 (64.9) - 31 (49.2) 3 (18.7) 6 (85.7) | 3 (4.3) - 2 (15.4) - 3 (6.1) - - - 2 (5.4) 1 (1.9) - 1 (10) - 1 (2.7) - 4 (6.3) - 0 | 11 (15.9) 4 (60) 5 (38.5) 3 (75) 10 (20.4) 3 (75) 3 (30) 3 (75) 2 (5.4) 18 (34.6) 11 (91.7) 2 (40) 2 (100) 12 (32.4) 9 (100) 27 (42.9) 13 (81.3) 1 (14.3) |
| Main microbiological isolates | ||||
| Klebsiella pneumoniae | 193 | 129 (66.8) | 5 (2.6) | 57 (29.5) |
| Pseudomonas aeruginosa | 42 | 28 (66.7) | 1 (2.4) | 7 (16.7) |
| Acinetobacter baumannii | 36 | 17 (47.2) | 2 (5.5) | 16 (44.4) |
| Staphylococcus aureus | 16 | 12 (75) | 1 (6.3) | 2 (12.5) |
| Enterococcus spp. | 28 | 17 (60.7) | 2 (7.1) | 9 (32.1) |
Table 3.
The number of cases, recoveries, relapses, and death divided by the main combination therapies and specific isolates.
Table 3.
The number of cases, recoveries, relapses, and death divided by the main combination therapies and specific isolates.
| Cases N | Recovery N (%) | Relapse N (%) | Death N (%) | |
|---|---|---|---|---|
| Main combination therapies and subgroups with specific isolates | ||||
MEROPENEM
| 57 21 3 5 21 | 35 (61.4) 13 (61.9) 3 (100) 3 (60) 13 (61.9) | 1 (1.8) - - - - | 18 (31.5) 8 (38.1) - 2 (40) 8 (38.1) |
CEFTAZIDIME–AVIBACTAM
| 122 99 6 5 7 | 73 (59.8) 61 (61.6) - - 5 (71.4) | 3 (2.5) 2 (2) - - - | 42 (34.4) 35 (35.5) 6 (100) 5 (100) 2 (29.6) |
COLISTIN
| 49 23 6 17 3 | 25 (51.1) 13 (56.2) 4 (66.7) 8 (47.1) 1 (33.3) | 2 (4.1) - - 2 (11.8) - | 15 (30.6) 9 (39.1) - 7 (41.2) 2 (66.7) |
DAPTOMYCIN
| 39 4 3 21 | 30 (76.9) 4 (100) 2 (66.7) 14 (66.7) | 3 (7.7) - - 3 (14.3) | 6 (15.4) - 1 (33.1) 4 (19) |
VANCOMYCIN
| 28 2 3 9 | 20 (71.4) 1 (50) 1 (33.3) 7 (77.8) | - - - - | 6 (21.4) - 1 (33.3) 2 (22.2) |
Table 4.
Safety of fosfomycin.
| ADVERSE EVENT | N (%) |
|---|---|
| Absence of side effects Side effects
| 323 (94.2) 20 (5.8) 7 (2) 4 (1.2) 4 (1.2) 3 (0.9) 1 (0.3) 1 (0.3) |
Table 5.
Comparison of the combination therapies and the clinical cure in our study and other studies.
Table 5.
Comparison of the combination therapies and the clinical cure in our study and other studies.
| Combination Therapy with Intravenous Fosfomycin and Ceftazidime/Avibactam | ||||
|---|---|---|---|---|
| Author, year | Study | No. of cases | Pathogens | Clinical cure |
| Our study | Retrospective | 122 | K.pneumoniae (81.2 %) and other | 73/122 (59.8%) |
| Oliva et al., 2022 [18] | Retrospective, two-center | 61 | KPC-producing K.pneumoniae | 45/61 (75.4%) |
| Zheng et al., 2021 [19] | Retrospective | 6 | Carbapenem-Resistant K.pneumoniae | 4/6 (66.7%) |
| Burastero et al., 2022 [20] | Retrospective | 9 | P.aeruginosa | 6/9 (66.7%) ¹ |
| Zhanel et al., 2023 [21] | Retrospective | 16 | K.pneumoniae | 11/16 (68.7%) |
| Gatti et al., 2022 [35] | Retrospective | 2 | P.aeruginosa | 1/2 (50%) ¹ |
| Combination therapy with intravenous fosfomycin and colistin | ||||
| Author, year | Study | No. of cases | Pathogens | Clinical cure |
| Our study | Retrospective | 49 | K.pneumoniae, P.aeruginosa, A.baumannii | 25/49 (51.1%) |
| Apisarnthanarak et al., 2011 [30] | Retrospective | 24 | P.aeruginosa | 14 (58%) |
| Sirijatuphat et al., 2014 [26] | Randomized controlled | 47 | A.baumannii | 28 (59.6%) |
| Navarro et al., 2012 [31] | Prospective observational | 4 | K.penumoniae | 3 (75%) ² |
| Assimakopoulos et al., 2023 [36] | Retrospective | 7 | A.baumannii | 6/7 (85.7%) ¹ |
| Russo et al., 2020 [27] | Prospective, observational | 18 | A.baumannii | 16/18 (88.9%) ² |
| Thampithak et al., 2022 [32] | Retrospective | 82 | A.baumannii, P.aeruginosa, Enterobacterales | 36/82 (43.9%) ² |
1 The data in the study are described as “microbiological cure”; 2 the data in the study are indicated as “no death”.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Anastasia, A.; Bonura, S.; Rubino, R.; Giammanco, G.M.; Miccichè, I.; Di Pace, M.R.; Colomba, C.; Cascio, A. The Use of Intravenous Fosfomycin in Clinical Practice: A 5-Year Retrospective Study in a Tertiary Hospital in Italy. Antibiotics 2023, 12, 971. https://doi.org/10.3390/antibiotics12060971
AMA Style
Anastasia A, Bonura S, Rubino R, Giammanco GM, Miccichè I, Di Pace MR, Colomba C, Cascio A. The Use of Intravenous Fosfomycin in Clinical Practice: A 5-Year Retrospective Study in a Tertiary Hospital in Italy. Antibiotics. 2023; 12(6):971. https://doi.org/10.3390/antibiotics12060971
Chicago/Turabian StyleAnastasia, Antonio, Silvia Bonura, Raffaella Rubino, Giovanni Maurizio Giammanco, Irene Miccichè, Maria Rita Di Pace, Claudia Colomba, and Antonio Cascio. 2023. "The Use of Intravenous Fosfomycin in Clinical Practice: A 5-Year Retrospective Study in a Tertiary Hospital in Italy" Antibiotics 12, no. 6: 971. https://doi.org/10.3390/antibiotics12060971
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
