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The intravenous form is not as widely available as the oral form, and it is still not approved in the United States. In Europe, it is available in countries such as Germany, Greece, France, Spain, the Netherlands, Austria, the United Kingdom and, since August 2019, also in Poland.
At present, the greatest challenge is the assessment of susceptibility to fosfomycin, for which a quantitative agar dilution method is recommended [12]. Because it is labor- and time-consuming, this method is practically never used in laboratories routinely performing microbiological tests. The undoubted advantages of this method, such as simple interpretation and high reproducibility of results [13], are outweighed by a number of drawbacks accompanying its implementation (e.g., possibility of inaccurate drug dilutions, antibiotic inactivation due to high temperature of agar, etc.). The solution could be readily available, easy-to-use, and certified commercial kits (such as AD Fosfomycin 0.25-256 Liofilchem, Waltham, MA, USA), if not for their high price [14]. Therefore, the evaluation of the sensitivity to IVFOS is carried out using automatic systems such as BD Phoenix or by gradient diffusion method E-tests (bioMérieux, M.I.C.E–OXOID) which, according to data from the literature, may lead to false results for fosfomycin. The lack of a simple and reliable method is also the reason behind the lack of cumulative data on the frequency of isolation of strains susceptible or resistant to IVFOS in individual hospitals, countries, or regions of the world, with such reports being crucial for the determination of empirical therapy regimens. This problem is exacerbated by the fact that there are no clear rules for the interpretation of results based on the currently known breakpoints (BPs). In May 2022, EUCAST presented proposals for new IVFOS BPs for discussion (consultation from 14 May to (extension) 15 July 2022). According to the announced proposals, criteria for the interpretation of susceptibility to IVFOS will be available only for E. coli and S. aureus, because there are insufficient data—including on minimum inhibitory concentration (MIC) values—for such interpretation criteria to be determined for other bacteria [15]. Unfortunately, if the new EUCAST proposals are accepted, laboratories will discontinue assessments of sensitivity to fosfomycin for most bacterial strains, including Klebsiella pneumoniae and P. aeruginosa. The lack of information on microbiological results may lead to withdrawal of IVFOS from therapy in situations where its use could be clinically beneficial.With the above in mind, in this study we performed IVFOS susceptibility assessments for 997 different clinical strains using the reference agar dilution method. The tested strains included both sensitive and resistant Gram-positive cocci and Gram-negative rods. In MIC value analysis, susceptibility differences, the type and origin of strains, and resistance mechanisms were taken into consideration.
3. ResultsThe susceptibility of 997 bacterial strains to IVFOS was determined, including the genus Acinetobacter and Enterococcus spp., for which there are no interpretation criteria (i.e., BPs) in the current EUCAST recommendations [12]. Therefore, for these two, only the analysis of MIC values was performed. In Table 1, the resistance mechanisms of the tested strains are presented. In the group of Enterobacterales, the dominant resistance mechanism was ESBL production (175 strains, including 26 Klebsiella strains that were additionally characterized by production of carbapenemases). The K. pneumoniae strains dominated in the group of carbapenemase producers, of which 71 were found to be metallo-β-lactamases (NDM), 4 were metallo-β-lactamases (VIM), and 7 were serine-β-lactamases (OXA-48). In addition, carbapenemases were found in 12 strains of P. aeruginosa (mainly VIM) and in individual strains of E. coli and Enterobacter spp. Among multidrug-resistant strains of Acinetobacter spp., only one strain produced metallo-β-lactamases, whereas in the case of other strains no mechanisms were identified with the use of phenotypic methods.Among all of the tested strains, 83% were susceptible to IVFOS, excluding Acinetobacter and Enterococcus species (Table 2). The largest percentage of susceptible strains was found among S. aureus and E. coli. The smallest percentage of sensitive strains (66%) was found in the Klebsiella spp. group. It should be noted that in Klebsiella spp. and among E. coli strains, MDR strains were identified (68.8% and 19.3%, respectively). In the group of S. aureus, 38.5% were MRSA strains, which is relevant for data analysis (Table 1). Significant statistical differences in strain susceptibility (p-value Klebsiella spp. (KL) vs. E. coli (EC), KL vs. Proteus spp. (P), KL vs. other, KL vs. Pseudomonas spp. (PS), KL. vs. S. aureus spp. (SA), E. coli vs. Enterobacter spp. (E), E. coli vs. CNS, E vs. other, E vs. PS., E vs. SA, P. vs. SA, other vs. CNS, PS. vs. SA, PS. vs. CNS, and SA vs. CNS.The susceptibility analysis of strains according to the site of isolation indicated significant statistical differences (p-value Table 3). Strains isolated from blood were the least sensitive (77.8%). Only three strains were isolated from cerebrospinal fluid (one E. cloacae ESBL+, one MRCNS, and one MSCNS), but because of the clinical significance of this material it was included in the investigation. All of these three strains were susceptible to IVFOS.IVFOS is recommended primarily for the treatment of infections caused by MDR strains. Therefore, susceptibility to this antibiotic was also determined in the group of ESBL+, carbapenemase-positive strains producing at least one of MBL enzymes (e.g., NDM-1, VIM), KPC, or OXA-48, as well as in the group of MDR Gram-negative strains that did not produce the abovementioned β-lactamases and in the group of MRS strains. The results are shown in Table 4. Statistically significant differences (p-value According to the obtained results, strains that were sensitive to other antibiotics were also fosfomycin-susceptible. IVFOS showed the lowest sensitivity in the group of Gram-negative carbapenemase-positive strains and those that additionally produced ESBL enzymes—55.6% and 61.6%, respectively. Among ESBL+ strains, 75% susceptibility to IVFOS was found (Table 4).MIC evaluation indicated that the lowest MIC50 and MIC90 values were found for S. aureus and E. coli (0.5 mg/L and 1 mg/L; 4 mg/L and 32 mg/L, respectively) (Table 5). Conversely, the highest MIC50 values were found for Acinetobacter spp. (256 mg/L), while the highest MIC90 values were found for Acinetobacter spp. and Klebsiella spp. (256 mg/L and 512 mg/L, respectively).The distribution of MIC values was also analyzed separately for susceptible strains and for strains with different antibiotic resistance mechanisms. The results are shown in Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5. The tested strains displayed a wide range of MIC values—especially Enterobacterales rods—regardless of the presence or absence of resistance mechanisms (≤0.25 mg/L–≥512 mg/L).Acinetobacter spp strains displayed a narrow range of MIC values, from 32 mg/L for one sensitive strain to more than 512 mg/L for resistant strains. For Enterococcus spp., the MIC values ranged from 32 mg/L to 64 mg/L.
The lowest MIC values were exhibited by S. aureus strains—both MSSA and MRSA. IVFOS MIC values of no more than 0.25 mg/L (21/64 MSSA and 23/40 MRSA) predominated in both groups.
Analysis of the MIC values for Enterobacterales provided no clear conclusions. However, in the largest group of the tested strains—namely, Klebsiella spp.—it was noted that the majority of both sensitive and resistant rods showed MIC values in the range from 8 mg/L to 64 mg/L, accounting for 76.9% (60/78) and 69.8% (120/172), respectively. In the range from 8 mg/L to 32 mg/L (the BP for susceptible strains according to EUCAST v.12), the respective values were 65.4% and 52.9%.
However, more strains with MICs > 32 mg/L and ≥ 512 mg/L were observed among resistant versus sensitive strains—41.3% vs. 24.1% and 12.2 vs. 7.7%, respectively. It should be noted that strains with the highest MIC values of at least 512 mg/L were found not only in groups of drug-resistant bacteria, but also in sensitive bacteria: Enterobacterales (seven strains) and P. aeruginosa (two strains). Compared to other species tested, in the case of P. aeruginosa, more strains with a low IVFOS MIC ≤ 32 mg/L were observed in the resistant group than in the sensitive group—64.8% (35 strains/54) vs. 40.4% (40/99).
Table 6 and Table 7 present the susceptibility of the tested strains to antibiotics other than IVFOS. Among Enterobacterales and P. aeruginosa strains suceptible to IVFOS, 100% susceptibility to other antibiotics was not found. Simultaneously, full sensitivity to no other antibiotics was demonstrated. Most of the abovementioned strains were susceptible to both IVFOS and amikacin (91.4% and 83.5%, respectively), to imipenem and meropenem (more than 85% among Enterobacterales), and to meropenem and piperacillin with tazobactam (around 75% among P. aeruginosa). Only 6% of Acinetobacter spp. strains were sensitive to all antibiotics.In the group of S. aureus, 100% fosfomycin-susceptible strains were observed, and 38% were MRSA strains. All strains tested were susceptible to vancomycin and linezolid. One fosfomycin-resistant strain was also resistant to methicillin, gentamicin, ciprofloxacin, and trimethoprim–sulfamethoxazole.
Among fosfomycin-susceptible CNS, about 65% were MRCNS and, at the same time, more than 90% were susceptible to vancomycin and linezolid. Fosfomycin-resistant strains also remained susceptible to vancomycin (100%) and to linezolid (about 85%). All of the studied Enterococcus spp. strains were susceptible to tigecycline, and 98% were susceptible to linezolid.
4. DiscussionIn the current decade, the treatment of bacterial infections poses a serious clinical problem. In order to achieve therapeutic success, a number of conditions related to the drug, pathogen, and interactions in the patient’s body must be fulfilled at the same time. Changes in patients’ pharmacokinetic parameters impede the penetration of antibiotics to the site of infection and the achievement of therapeutic concentrations. Good penetration into various organs and systems is a crucial feature required of antibiotics. Therefore, antibiotics such as β-lactams—including penicillin, cephalosporins (especially high-generation ones), carbapenems, and fluoroquinolones—have become some of the most commonly used in treatment. However, good drug pharmacokinetics is not sufficient for effective therapy. Moreover, susceptibility of pathogens to the selected antibiotic is essential. Here, bacteria have been setting the bar higher and higher. Selection of strains resistant not only to a group, but to several groups or even to all available antibiotics, is taking place more frequently and rapidly. According to the WHO and ECDC’s 2020 data, worldwide—and in Europe in particular—Gram-negative rods are the most resistant to antibiotics. In 21 European countries, including Russia, Belarus, Ukraine, and Turkey, more than 50% of Acinetobacter spp. strains are resistant to carbapenems [20]. The ECDC’s detailed data indicate that in countries such as Croatia, Romania, and Lithuania this percentage exceeds 90%, while in Italy, Poland, and Bulgaria it is about 80% [21]. Unfortunately, Acinetobacter species have been reported to show resistance to colistin, which is regarded as the antibiotic of last resort [22,23,24]. Research from Saudi Arabia has shown close to 9% prevalence of such strains, and research from Greece has shown 42% prevalence of colistin-resistant strains in the group of 31 Acinetobacter spp. strains responsible for sepsis [22,23]. Serious concerns are caused by reports on the identification of strains that are resistant to the newest antibiotic—cefiderocol, which has been regarded as an option in cases where the pathogen is resistant to all other antibiotics [25,26,27].Resistance to at least three groups of antibiotics observed in more than 50% of Acinetobacter spp. was recorded in 8 EU countries, reaching the highest values in Greece (90.8%). K. pneumoniae strains—more than 50% of which were resistant to the third generation of cephalosporins in 18 European countries, and similar percentages of which were resistant to carbapenems in 6 countries (Belarus, Georgia, Greece, Moldova, Russia, and Ukraine)—are also a huge problem [20]. European data provided by the ECDC indicated that simultaneous resistance of Klebsiella spp. to three groups of antibiotics—i.e., third-generation cephalosporins, fluoroquinolones, and aminoglycosides—was demonstrated in Greece and Bulgaria (more than 50%), as well as in Slovakia, Poland and Romania (around 44–48%).Resistance to antibiotics has also been on the rise among P. aeruginosa strains. In 2020, more than 50% of these rods were resistant to carbapenems in 6 countries, and over 25% resistance was found in 14 countries. Resistance of more than 25% of P. aeruginosa strains to ceftazidime, or to at least three groups of antibiotics among such drugs as piperacillin with tazobactam, fluoroquinolones, ceftazidime, aminoglycosides, and carbapenems, was found in four EU countries. Regardless of the genus or species of Gram-negative rods, the phenomenon of rapidly increasing resistance to fluoroquinolones is also well known. More than 50% prevalence of resistant Acinetobacter spp. strains was found in nine EU countries, in the case of Klebsiella spp. in seven countries, and for P. aeruginosa in one country [21].The abovementioned data, along with the experience of physicians who review antibiogram results on a daily basis, leave no doubt that the treatment of infections with beta-lactams or fluoroquinolones is becoming less feasible. Other antibiotics are therefore needed to replace the most commonly used ones.
Cephalosporins, carbapenems, and fluoroquinolones possess a broad spectrum of antimicrobial activity and good penetration into organs—a vital feature in empirical therapy. Therefore, the loss of these antibiotics due to increasing bacterial resistance is also a huge loss for modern medicine. It is not easy to find comparable substitutes for these antibiotics. In the age of multidrug resistance, colistin is being used again, despite poor organ penetration and a narrow spectrum of antimicrobial activity. Tigecycline has a broad spectrum of antimicrobial activity (excluding P. aeruginosa) and achieves effective concentrations in tissues, but unfortunately not in blood. Treatment of general infections with this antibiotic is therefore not advisable.
IVFOS has a broad spectrum of antimicrobial activity and very good penetration into many systems and tissues. It is also recommended for the treatment of many severe infections in both children and adults, as confirmed by many publications. In a prospective multicenter study of 209 adult patients from 20 ICU units in Germany and Austria, Putensen et al. evaluated the clinical efficacy of intravenous fosfomycin. Its use in combination therapy in various infections—including lung, CNS, urinary tract, skin and soft tissue, intra-abdominal, and other infections—brought clinical success in 81.3% of cases and a success rate of 84.8% in the case of infections caused by MDR strains [28]. In another cohort study from India, the authors obtained an overall clinical efficacy of 55% when IVFOS was used in ICU patients, but significantly better results (i.e., success rate of 79.24%) were noted in the case of UTI treatment [29]. Pontikis et al. observed the efficacy of fosfomycin in 54.2% of ICU patients, mainly with bloodstream infections (BSIs) and ventilator-associated pneumonia (VAP) [30]. In turn, Tsegka et al. analyzed the available reports on the efficacy of IVFOS in the treatment of central nervous system infections mainly caused by Staphylococcus spp. strains, Streptococcus pneumoniae, Neisseria meningitidis, and others [31]. The authors evaluated the antibiotic’s efficacy at nearly 94%. In another article, Tsegka et al. also highlighted the significance of IVFOS in therapy for bone and joint infections [32].In infections of orthopedic implants and devices, the formation of bacterial biofilm and survival of bacteria within osteoblasts are of crucial importance [33]. Stracquadanio S. et al. pointed to the fact that S. aureus has a special ability of internalization in non-professional phagocytes, while in S. epidermidis or S. lugdunensis this ability is much lower [33]. Through internalization in osteoblasts, bacteria become inaccessible to immune system cells and to most antibiotics [33]. In such cases, fosfomycin’s particle size and its ability to penetrate into bacterial biofilms and osteoblasts have a significant impact on its antimicrobial effectiveness [34,35,36]. An analysis of data from 19 papers conducted by Tsegka et al. showed 82.2% efficacy of IV fosfomycin in the treatment of bone and joint infections, most of which were caused by S. aureus (38.9%) [32]. Although IVFOS is authorized for the treatment of children and neonates, there are only a few reports about its efficacy in these age groups. Li at al. analyzed five studies on the use of IVFOS in neonatal sepsis. The effectiveness of treatment in combination therapy was between 88% and 100% [37].Another author, Williams, also looked at the use of fosfomycin in children and, in addition to the five studies mentioned above, he also included two additional studies conducted by Baquero et al. and Corti et al. [10,38,39]. In the first study, from 1977, the authors used fosfomycin in the treatment of infections caused by Serratia marcescens. Clinical efficacy was achieved in only 50% of cases when the antibiotic was used in monotherapy, and in 90% of cases when it was used in combination with gentamicin or carbenicillin [38]. In the second study, 23 children with acute hematogenic osteomyelitis were given IVFOS as monotherapy, and full clinical success was achieved [39]. However, it should be stressed that due to rapid selection of resistant subpopulations of strains, IVFOS is not recommended for monotherapy.As indicated above, fosfomycin is suitable for the treatment of many infections caused by Gram-positive and Gram-negative bacteria, both in children and adults.
In this study, we analyzed the in vitro IVFOS susceptibility of clinical strains isolated from various types of infections (the age of the patients was not taken into consideration). Except for Acinetobacter spp. and Enterococcus spp., the tested strains were isolated from urine (240), pus and wound swabs (238), and blood (203). Susceptibility to IVFOS was shown in 89% of strains isolated from skin and soft tissue infections, while the figure for strains isolated from lower respiratory tract and intra-abdominal infections was approximately 85%. The lowest level of susceptibility (78–79%) was displayed by strains isolated from urine and blood, with no statistical significant differences between these groups. In 2009–2010, scientists from Beijing assessed the sensitivity of E. coli isolates and concluded, based on then-current interpretation criteria (EUCAST v.12), that strains isolated from urine were the most sensitive to fosfomycin (94.7%), followed by strains isolated from blood (92.4%) and from purulent lesions (91.3%), with strains isolated from sputum being the least susceptible (85.6%) [40]. In our study, these rates were slightly lower, probably because the results concerned total strains of different types, including the much more resistant Klebsiella spp. and P. aeruginosa strains. In addition, in the study of Li et al., the strains tested were ESBL+, while the strains in our investigation also showed the presence of carbapenemases [40]. Another study from India, performed on 2229 strains, confirmed 95% fosfomycin susceptibility in strains isolated from urine, although MDR and carbapenemase-positive bacteria were already included in this study [41].In our study, irrespective of the strains’ origin, 83% were susceptible to IVFOS, of which 43.3% possessed at least one resistance mechanism. The highest sensitivity (over 90%) was determined for S. aureus, E. coli, and P. aeruginosa, while Klebsiella spp. were the least susceptible strains (66%). A high proportion of susceptibility to IVFOS in E. coli and S. aureus populations is widely reported in the global literature. The aforementioned study by Li et al. found 91.1% sensitivity among E. coli strains isolated from various infections [40]. Czech and Italian scientists described IVFOS susceptibility among strains isolated from urine (97% and 96.9%, respectively) [42,43]. Similarly, in the case of S. aureus, more than 90% susceptibility to IVFOS is usually observed [44,45,46].Additional properties of fosfomycin—such as activity against intracellular pathogens, antimicrobial potential against Panton–Valentine leucocidin (PVL) produced by staphylococci, and the possibility of immunomodulation of the antimicrobial activity of neutrophils—are also desirable and can enhance its activity in the treatment of severe infections [35,47,48,49,50,51]. Although fosfomycin is not the first choice for treating infections caused by MSSA or MRSA strains, these additional properties should be taken into account, especially considering that almost 100% sensitivity to this antibiotic is observed (Table 7).Valour et al. conducted an evaluation of the intra-osteoblastic activity of various antibiotics. Survival of S. aureus in osteoblasts is known to be one of the factors leading to the recurrence of bone and joint infections [33,35]. The authors demonstrated that fosfomycin shows an intracellular bactericidal effect similar to those of linezolid, ofloxacin, rifampicin, oxacillin, and clindamycin. Vancomycin and daptomycin do not display such properties, while ceftaroline and teicoplanin have only bacteriostatic effects [35]. Fosfomycin may also limit the amount of small-colony variants (SCVs) of S. aureus, although maximal antibiotic doses are required for this effect, and far better results have been achieved using ofloxacin [35]. Zelmer et al., on the other hand, pointed to the low activity of fosfomycin against extracellular small-colony variants (SCVs) of S. aureus and, consequently, to its limited usefulness in the treatment of chronic bone infections [34].Susceptibility to fosfomycin is slightly different in the case of P. aeruginosa. Firstly, unlike most bacteria, the disodium salt of fosfomycin enters the cell by means of active transport using only one transporter—glycerol-3-phosphate—due to the lack of glucose-6-phosphate (UhpT), as demonstrated by Castaneda-Garcia et al. [52]. Secondly, no BPs have been established to allow clinical interpretation of the MIC values obtained for fosfomycin and P. aeruginosa. At the same time, EUCAST has provided the BP for wild-type (WT) P. aeruginosa. A WT is a strain that does not have an acquired antibiotic resistance mechanism detected by phenotypic methods. It has been characterized by an MIC that does not exceed the defined cutoff point known as the ECOFF (epidemiological cutoff value) for the pathogen and antibiotic [53]. Therefore, the ECOFF value for fosfomycin (MIC ≤ 128 mg/L) presented on the EUCAST website has become the basis for many authors’ assessment of the susceptibility or resistance of P. aeruginosa strains [12]. However, in view of the consultations announced by EUCAST, it is not certain whether the ECOFF value for P. aeruginosa will be maintained [15].The withdrawal of the ECOFF value from EUCAST guidelines would mean that fosfomycin would not be included in antibiograms. This might be unfavorable in the case of infections caused by P. aeruginosa, as fosfomycin—in combination with other antibiotics—is one of the important therapeutic options for MDR strains [54,55,56,57,58]. In combination therapy, antibiotics are selected mainly based on the sensitivity of the strains causing infections. Therefore, susceptibility assessment is important for such a treatment. Our research found that among Pseudomonas spp., almost 91% of strains displayed sensitivity. Considering the ECOFF, Walsh et al. reported 76.6% sensitivity among P. aeruginosa strains isolated from 64 patients—mainly from cystic fibrosis [59]. Zhanel et al. did not precisely specify the sensitivity percentage but gave the MIC90 for fosfomycin as 128 mg/L [4]. It was concluded that at least 90% of P. aeruginosa strains were susceptible to IVFOS. In studies published in 2021, 86.6% of tested strains were sensitive, while 96% susceptibility of strains isolated from children with sepsis was reported by Williams et al. [10,60]. In a multicenter study performed in 2013, researchers reported 86.4% susceptibility among the tested strains, while the results of an Indian study performed in 2019 reported only 50% susceptibility of the tested stains [61,62].Klebsiella spp. Strains—especially K. pneumoniae—are currently considered to be the most resistant bacteria in the world [63,64]. Therefore, fosfomycin is mentioned as a potential therapeutic option against pathogens that are resistant to many other antibiotics, including beta-lactams. In its new 2022 recommendations, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) included the possibility of implementing IVFOS in combination therapy for patients with severe infections caused by carbapenem-resistant Enterobacterales that are susceptible to polymyxins, aminoglycosides, tigecycline, or fosfomycin, or in the case of unavailability of antibiotics combined with β-lactam inhibitors [55]. Furthermore, in the report of the British Society for Antimicrobial Chemotherapy, fosfomycin was noted as the last-resort drug for MDR infections [65]. The authors of these recommendations further specified IVFOS as an alternative to carbapenems for use against ESBL+ strains. In our research, only 66% of Klebsiella spp. strains were susceptible to fosfomycin. However, it is relevant that in this group, 170 out of the 250 tested strains produced β-lactamases, of which 84 were carbapenemases. All NDM-1-positive strains were of the Klebsiella genus. Resistant strains were predominant in this type, which may explain their lower susceptibility to fosfomycin compared to the other bacterial types tested. An analysis of MIC value distribution indicated that among resistant Klebsiella spp. strains, 41.3% had MIC values > 32 mg/L, whereas among sensitive strains such MIC values were observed at a rate of 24.4%.The analysis of susceptibility to IVFOS according to the type of resistance mechanism to other antibiotics indicated that strains producing only carbapenemases or ESBL enzymes (55.6–61.6%) were the least sensitive. ESBL strains were almost 76% sensitive to IVFOS, while MDR strains with unidentified resistance mechanisms were sensitive in about 82% of cases. These results indicate a high probability of infections caused by fosfomycin-sensitive Enterobacterales and potential application of fosfomycin in not only targeted but also empirical therapy. However, each empirical antibiotic administration should be verified by a microbiological test result.
Studies from Poland conducted in 2011–2020 showed practically the same susceptibility levels as those demonstrated in the present paper, both in the carbapenemase-positive (55%) and carbapenemase-negative strains (75%), as well as among Klebsiella spp. (65%) [66]. When comparing these outcomes, it could be concluded that resistance to fosfomycin does not increase. However, such thinking can be misleading, as it should be taken into account that in Poland IVFOS has been approved since Q3 of 2019. The analysis of the relationship between its use and the pace of resistant strain selection will be possible in subsequent years. Turkish researchers studied E. coli and K. pneumoniae strains producing OXA-48, NDM-1, VIM, and IMP enzymes and identified 56.3% susceptibility to fosfomycin [67]. This result is consistent with the outcomes presented in this study. Increased sensitivity rates in the group of carbapenemase-positive strains of Enterobacterales were reported for KPC and NDM strains (84.2% and 92.9%, respectively) [41]. Based on current criteria for the interpretation of MIC values (sensitive strains ≤ 32 mg/L), the SENTRY global surveillance program also reported 82.6% susceptibility among 23 E. coli and K. pneumoniae carbapenemase-positive strains tested [68].Undoubtedly, monotherapy with IVFOS accelerates the development of resistance; therefore, combination therapy is recommended [55]. Unfortunately, no advantage has been shown for the use of IVFOS in combination therapy. However, there are literature reports on the use of IVFOS in various combinations with antibiotics such as colistin, β-lactams, ceftazidime–avibactam, aminoglycoside, fluoroquinolones, tigecycline, and even rifampicin, depending on the pathogens and their susceptibility profiles [55,69,70,71,72,73,74].The level of susceptibility to any antibiotic, including to fosfomycin, is not constant over time and must be monitored on an ongoing basis, even during daily microbiological diagnostics. The recommendation of the agar dilution method certainly does not support the testing procedures, as it is difficult and time-consuming.
The distribution of the presented MIC values shows that both multidrug-resistant strains and strains that are susceptible to other antibiotics can display a wide range of MIC values, as can be seen in the case of Enterobacterales or P. aeruginosa. MDR Enterobacterales strains may show very low MIC values, such as 0.25 or 0.5 mg/L, but strains that are sensitive to other antibiotics may present a high level of resistance to fosfomycin, with MIC values as high as ≥512 mg/L. However, it was demonstrated that in the group of strains sensitive to other antibiotics, susceptibility to IVFOS was greater (90.8%) than in the group of MDR strains (72.9%). A similar observation was made with regard to the quantity of strains with low MIC values. MDR strains may have very low MIC values for fosfomycin, and in such cases the risk of rapid selection of resistant strains is delayed in time, making effective treatment more probable.
A separate discussion is required to describe the role of fosfomycin in infections caused by Enterococcus spp. and Acinetobacter spp. It is not possible to assess the sensitivity to IVFOS due to the lack of interpretation criteria. In our study, for Acinetobacter spp., we obtained high MIC values indicating resistance to fosfomycin, but such values are commonly identified [75,76]. Currently, infections caused by Acinetobacter are probably one of the biggest therapeutic challenges. New antibiotics, such as ceftazidime–avibactam, meropenem–vaborbactam, or plazomicin, are not active against Acinetobacter spp. [77]. There is also no certainty that cefiderocol—the most recent antibiotic—will be effective against MDR Acinetobacter spp., given the disturbing reports about strains that are resistant to this antibiotic [25,26,27]. The main mechanism behind the resistance of Acinetobacter spp. to cefiderocol is reduction in the expression of the siderophore receptor genes pirA and piuA [25,26,27]. Therefore, studies on fosfomycin’s activity in combination with other antibiotics are being conducted, regardless of the high MIC values reported for Acinetobacter spp. Nwabor et al. evaluated the effectiveness of fosfomycin combinations with selected antibiotics, such as carbapenems and aminoglycosides. The MIC90 of IVFOS for the tested strains was 256 mg/L, and the strains were also carbapenem-resistant [78]. This is also consistent with our results. A synergistic effect with gentamicin was identified, and an additive effect was observed for other antibiotics. A 2–16-fold reduction in the MIC values of the tested antibiotics was noted when they were combined with fosfomycin [76]. Another study proved fosfomycin’s synergism with imipenem against Acinetobacter spp. [75]. Despite the above reports, in the most recent recommendations of the ESCMID and ESICM (the European Society of Intensive Care Medicine) in December 2021, fosfomycin was not included as a therapeutic option against Acinetobacter spp.—even in combination with other antibiotics [55]. However, it was present as part of combination therapy in treatment regimens proposed by Bassetti and Garau in 2021 [79].The possibility of using fosfomycin in enterococcal infections has been triggering even more discussion. EUCAST does not recommend an assessment of enterococcal susceptibility to either oral or intravenous fosfomycin. Studies have shown its potential activity with regard to E. faecalis in particular, but also E. faecium [80,81,82]. These strains usually present MIC values in a rather narrow range of concentrations, as confirmed by the results obtained in our research. The MIC values were in the range from 32 mg/L to 64 mg/L, both for VRE/HLGR and for susceptible strains; the MIC50 and MIC90 for E. faecalis and E. faecium were 32 mg/L and 64 mg/L and 64 mg/L and 64 mg/L, respectively. Similar MIC values were obtained by other authors, although for E. faecium they were slightly higher, reaching 128 mg/L [4,68,80]. There have also been studies where the MIC reached values of >1024 mg/L. This was the case for the VRE strains tested by Guo et al. [81]. In a group of 234 VRE strains, the authors reported only 4.3% with an MIC of 32 μg/mL, 39.3% with 64 μg/mL, and 56.4% with ≥128 mg/L [81]. Usually, according to the analysis of the literature data by Vardakas et al., MIC values for Enterococcus spp. do not exceed 128 mg/L [82]. However, further research is needed on the applicability of fosfomycin in the treatment of infections caused by E. faecium, where in the case of GRE, HLAR, and linezolid-resistant strains, the therapeutic range is dramatically limited. Even new antibiotics such as eravacycline do not have indications as broad as those of fosfomycin.
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