Deciphering pharmacokinetics and pharmacodynamics of fosfomycin.

Fosfomycin, a low molecular weight and hydrophilic drug with negligible protein binding, is eliminated almost exclusively by glomerular filtration, whose clearance is subject to patient renal function. The volume of distribution approximates to the extracellular body water (about 0.3 L/Kg) in healthy volunteers, but it is increased in critically ill patients with bacterial infections. Fosfomycin presents a high ability to distribute into many tissues, including inflamed tissues and abscess fluids. Based on PK/PD analysis and Monte Carlo simulations, we have evaluated different fosfomycin dosing regimen to optimize the treatment of septic patients due to Enterobacterales and Pseudomonas aeruginosa. As PK/PD targets, we selected %T>MIC > 70% for all pathogens, and AUC24/MIC > 24 and AUC24/MIC > 15 for net stasis of Enterobacterales and P. aeruginosa, respectively. Pharmacokinetic parameters in critically ill patients were obtained from the literature. Several dosing regimens were studied in patients with normal renal function: fosfomycin 2-8 g given every 6-12 hours, infused over 30 minutes- 24 hours. At the susceptibility EUCAST breakpoint for Enterobacterales and Staphylococcus spp. (MIC ≤ 32 mg/L), fosfomycin 4 g/8h or higher infused over 30 minutes achieved a probability of target attainment (PTA) > 90%, based in both %T>MIC and AUC24/MIC. For MIC of 64 mg/L, fosfomycin 6 g/6h in 30-minute infusion and 8 g/ 8h in 30-minute and 6 hours infusions also achieved PTA values higher than 90%. No fosfomycin monotherapy regimen was able to achieve PK/PD targets related to antimicrobial efficacy for P. aeruginosa with MICs of 256-512 mg/L.

PHARMACOKINETICS

Fosfomycin, currently produced by a synthetic method, is a low-molecular weight (138 g/mol), highly polar phosphonic acid derivative (cis-1,2-epoxypropyl phosphonic acid) that represents its own class of antibiotics [1,2]. Fosfomycin was initially marketed as both a calcium salt formulation (fosfomycin calcium) for oral administration and a more hydrophilic salt (fosfomycin disodium) for parenteral administration. Fosfomycin tromethamine, which provides a higher bioavailability (30-40%) [3], was later marketed and has become the standard formulation for oral administration [4].

The pharmacokinetics of fosfomycin, as in general of any antibiotic, is conditioned by pathophysiological changes that occur in the critically ill patient. These changes can impact the concentrations at the site of infection, which may potentially reduce the bactericidal activity [5]. Actually, after intravenous injection, variable peak, mean and trough concentrations have been reported in humans [6]. Table 1 shows the main pharmacokinetic parameters of fosfomycin in critically ill patients [7].

Table 1

Pharmacokinetic parameter of fosfomycin in septic patients [7].

Study population	No. of patients	Fosfomycin dose	Pharmacokinetic parameter
			Vd (L)	t1/2 (h)	Cl (L/h)	Cmax (mg/L)	AUC0-4 (mg h/L)
Sepsis	12	8 g i.v.	31.5±4.5	3.9±0.9	7.2±1.3	357±28	721±66

Distribution and tissue penetration. Fosfomycin, a hydrophilic drug with low molecular weight and negligible protein binding (ca. 0%) [8], is highly distributed throughout body tissues, including inflamed tissues and abscess fluids [2]. The volume of distribution (Vd) is consistent with extracellular body water (approximately 0.3 L/Kg) in healthy volunteers [7]. The Vd in critically ill patients with bacterial infections is increased (by as much as 50% in comparison to healthy subjects) probably due to alterations of the vascular endothelium, turning in an increase of capillary permeability [9].

In Intensive Care Unit (ICU) patients with soft tissue infections, fosfomycin has shown to exhibit good penetration into muscle [7], and also into subcutaneous tissues regardless of the presence of inflammation [10]; however, the penetration into abscesses seems to depend on morphological characteristics, such as the permeability of the outer wall or the vascularity of the surrounding tissues [11]. Fosfomycin administered by intravenous route seems also to exhibit good penetration into infected lung tissue, reaching adequate levels in pleural fluid [12,13]. Severe lung inflammation during bacterial pneumonia seems not impair fosfomycin penetration, which supports its use in severe pulmonary infections [13]. Different studies confirm that fosfomycin presents also a favorable penetration into tissue sites traditionally considered to be associated with low penetration, which supports its potential for use in many difficult-to-treat infection sites [5, 14]. Thus, fosfomycin has the ability to cross the blood-brain barrier, and in case of meningeal inflammation, the concentration in cerebrospinal fluid increases [15]. Fosfomycin is also able to penetrate in both cortical and cancellous bone [16], and in aqueous humor [17].

Clearance. Glomerular filtration is almost the only elimination route of fosfomycin, with total clearance being highly correlated with the glomerular filtration rate, measured as creatinine clearance [8]. Actually, variations in renal function among patients justifies pharmacokinetic variability of fosfomycin in critically ill patients [18]. In spite that fosfomycin is almost entirely eliminated unchanged by the kidney, limited information exists on the clearance of fosfomycin in renally-impaired patients. By intravenous route, dose adjustment is recommended in patients with CrCl < 50 mL/min [19]. A recent study including 2 patients undergoing intermittent hemodialysis and extended dialysis showed that, in spite of the efficient tissue penetration of fosfomycin, the extracorporeal elimination can lead to a dramatic decrease of the fosfomycin serum levels [20]. Another study with 12 anuric ICU patients treated with continuous venovenous haemofiltration (CVVH) and receiving 8 g of fosfomycin every 12 h showed a longer mean half-life than found in ICU patients without renal therapy; additionally, the plasma area under the concentration-time curve (AUC) was higher in patients undergoing CVVH than in critically ill patients without CVVH. After a 12 h haemofiltration process, about 77% of fosfomycin was removed. Fosfomycin concentrations in blood resulted to be enough to eradicate relevant pathogens [21]. In any case, additional pharmacokinetic studies regarding dosing in critically ill patients undergoing different dialysis modalities are needed.

PHARMACODYNAMICS

Fosfomycin exerts bactericidal antimicrobial activity against susceptible pathogens by blocking the early stage of bacterial cell wall synthesis [22]. It has a broad spectrum of in vitro activity against a variety Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), and drug-resistant Enterobacterales and Pseudomonas aeruginosa varieties, including extended-spectrum-β-lactamase (ESBL)-producing and carbapenem-resistant (CR) organisms [19, 23]. Given that there are few available therapeutic options, fosfomycin seems an attractive alternative for the treatment of serious systemic infections caused by multidrug-resistant (MDR) bacteria.

Mutation frequency studies indicated the presence of an inherently fosfomycin resistant Escherichia coli subpopulation (agar MIC = 32-64 mg/L) within the standard starting inoculum of a susceptibility test. Given that the inherently fosfomycin-resistant subpopulation has a frequency of 3.5 x 105 and >1.2 x 109 at 5 times and 256 times the baseline fosfomycin MIC, respectively, the administration at high dose should be recommended, especially in monotherapy [24]. A recent meta-analysis showed that resistance emerged during fosfomycin monotherapy at rates ranging from < 3% to 17.9% (pooled estimate 3.4%). The authors confirm the generally noted discrepancy between high rates of in vitro emergence of resistance and its evidently low clinical relevance [25].

The EUCAST [26] defines the susceptibility breakpoint as ≤ 32 mg/L for Enterobacterales and Staphylococcus spp. for intravenous formulation. Fosfomycin has exhibited a prolonged post-antibiotic effect (PAE) in vitro against strains of E. coli and Proteus mirabilis, varying between 3.4-4.7 h, and shorter against isolates of P. aeruginosa (0.3-5.5 h) and S. aureus (0.5-1.4 h) [27, 28].

PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS

Pharmacokinetic/pharmacodynamic (PK/PD) analysis in combination with Monte Carlo simulation is a very useful tool to optimize the dosing regimens of antibiotics in order to conserve their therapeutic value. The quantitative relationship between a pharmacokinetic parameter and a microbiological parameter (MIC, minimum inhibitory concentration) is known as a PK/PD index. The three main PK/PD indices associated with the effect of the antibiotics are: %T>MIC, that is the percent of the dosing interval in which the drug concentration remains above the MIC; Cmax/MIC, which is the peak concentration divided by the MIC; and AUC24/MIC, which is the area under the concentration-time curve measured over a 24-h period divided by the MIC [29].

There is confusion in the literature about whether fosfomycin displays time- or concentration-dependent bactericidal activity. Roussos et al [28] refer that the type of activity may be organism dependent. Fosfomycin exhibits concentration-dependent killing activity against strains of E. coli, P. mirabilis and Streptococcus pneumonie and time-dependent bactericidal activity against S. aureus and P. aeruginosa [27,28].

PK/PD analysis and Monte Carlo simulation allow estimating the probability that a certain PK/PD index reaches the value required for antimicrobial efficacy. In this analysis, two different estimations of the clinical outcome can be done. On the one hand, the probability of target attainment (PTA) is defined as the percentage of simulated patients with an estimated PK/PD index equal to or higher than the value related to the efficacy of the antibiotic against a pathogen with a certain MIC. This cut-off value is known as the parmacodynamic target (PDT). As an example, the PK/PD indexes and the PDTs associated with the efficacy of fosfomycin against Enterobacterales are %T>MIC > 70% [30] and AUC24/MIC > 23 (for net stasis) [31].

On the other hand, the cumulative fraction of response (CFR) is defined as the expected probability of success of a dosing regimen against bacteria in the absence of the specific value of MIC, and thus, the population distribution of MICs of country, sanitary area or health center is used. As an example, for the MIC distribution of non-MDR P. aeruginosa reported by Asuphon et al. in Bangkok, Thailand, fosfomycin 16 g continuous infusion combined with prolonged infusion of meropenem (1-2 g infusion over 3 hours every 8 hours) achieved CFR > 88% [30]. PTA and CFR ≥ 90% are considered optimal against a bacterial population, whereas a CFR between 80% and 90% are associated with moderate probabilities of success [29].

Based on PK/PD analysis and Monte Carlo simulations, we have evaluated different fosfomycin dosing regimen to optimize the treatment of septic patients due to Enterobacterales and P. aeruginosa. As PK/PD targets, we selected %T>MIC > 70% for all pathogens, and AUC24/MIC > 24 and AUC24/MIC > 15 for net stasis of Enterobacterales and P. aeruginosa, respectively. These targets were selected based on the study by Lepak et al. [31] who demonstrated, in a neutropenic murine thigh infection model, that maximal animal survival was observed at AUC24/MIC ratio exposures comparable to the stasis targets observed in the same infection model. Pharmacokinetic parameters were obtained from a study carried out Joukhadar et al. in critically ill patients [7]. Several dosing regimens were studied in simulated patients with normal renal function: fosfomycin 2-8 g given every 6-12 hours, infused over 30 minutes- 24 hours. Ten-thousand subject Monte Carlo simulations were conducted for each dosing regimen using Oracle® Crystall Ball Fusion Edition v.11.1.1.1.00 (Oracle USA Inc., Redwood City, CA). A log-normal distribution was assumed for CI and Vd, according to statistical criteria.

Table 2 shows the PTA values obtained for every dosing regimen. At the susceptibility EUCAST breakpoint for Enterobacterales and Staphylococcus spp. (MIC ≤ 32 mg/L), fosfomycin 4 g/8h or higher infused over 30 minutes, achieved PTA > 90%, based in both %T>MIC and AUC24/MIC. For MIC of 64 mg/L, fosfomycin 6 g/6h in 30-minute infusion and 8 g/8h in 30-minute and 6 hours infusions also achieved PTA values higher than 90%. In this regard, it is important to bear in mind that the fosfomycin MIC90 usually reaches values of 32 mg/L in ESBL-producing E. coli, 64 mg/L in ESBL-producing K. pneumoniae and MRSA and 512 mg/L in P. aeruginosa [32-34]. No fosfomycin monotherapy regimen was able to achieve PK/PD targets related to antimicrobial efficacy for P. aeruginosa with MICs of 256-512 mg/L.

Table 2

The probability of target attainment (%PTA) of various fosfomycin monotherapy regimens.

	Probability %T>MIC>70%
	infusion 30 minutes						infusion 6 hours
CMI (mg/L)	2 g/6 h	4 g/12 h	4 g/8 h	4 g/6 h	6 g/6 h	8 g/8 h	4g/8 h	8g/8 h
0.03	100	100	100	100	100	100	100	100
0.06	100	100	100	100	100	100	100	100
0.13	100	100	100	100	100	100	100	100
0.25	100	100	100	100	100	100	100	100
0.5	100	100	100	100	100	100	100	100
1	100	100	100	100	100	100	100	100
2	100	100	100	100	100	100	100	100
4	100	100	100	100	100	100	100	100
8	100	100	100	100	100	100	100	100
16	100	97	100	100	100	100	100	100
32a	78	20	98	100	100	100	100	100
64	0	0	11	79	100	98	49	100
128	0	0	0	0	23	11	0	50
	ProbabilityAUC24/MIC > 24 (for Enterobacterales)				ProbabilityAUC24/MIC > 15 (for P. aeruginosa)
CMI (mg/L)	4 g/12 h	4 g/8 h	4 g/6 h	6g/6h 8g/8h	4 g/12 h	4 g/8 h	4 g/6 h	6g/6h 8g/8h
0.03	100	100	100	100	100	100	100	100
0.06	100	100	100	100	100	100	100	100
0.13	100	100	100	100	100	100	100	100
0.25	100	100	100	100	100	100	100	100
0.5	100	100	100	100	100	100	100	100
1	100	100	100	100	100	100	100	100
2	100	100	100	100	100	100	100	100
4	100	100	100	100	100	100	100	100
8	100	100	100	100	100	100	100	100
16	100	100	100	100	100	100	100	100
32a	98	100	100	100	100	100	100	100
64	4	71	99	100	81	100	100	100
128	0	0	4	71	0	24	82	100
256	0	0	0	0	0	0	0	24
Continuous infusion		12 g/day		16 g/day
Probability Css > 32 mg/L		100		100
Probability Css > 64 mg/L		70		98
Probability Css > 128 mg/L		0		4

In gray, values ≥90%, in bold, values ≥80 and <90%. aFosfomycin EUCAST breakpoint.

A previous study [7] in which the target site penetration properties of fosfomycin was investigated, revealed that after the administration of 8 g IV to patients with sepsis, the concentration in the interstitium and in plasma remained ≥ 70 mg/L during a 4-hours observation period. Considering that the plasma half-life of fosfomycin is <3.5 h, the target site concentrations will reach < 35 mg/L 8 hours after drug administration. Therefore for a MIC of 32 mg/L, twice-daily dosing might be insufficient, unless that fosfomycin is administered in combination with other antibiotics.

Critically ill patients have been shown higher Vd values and a high level of interpatient variability than seen in non-critically ill patients and high doses may be necessary [18]. Although 24 g/day of fosfomycin achieved the PK/PD targets, it may cause side effects, such as hypokalemia and saline overload. Provided that it has been reported that hypokalemia was more frequent when fosfomycin disodium was administered in 30- or 60-minutes infusions compared with a 4-hours infusion and the high doses of fosfomycin can produce overload of sodium, especially in elderly patients with heart failure or cirrosis or in those who are receiving haemodialysis [35, 36].

In view of these results and in agreement with Parker et al. [5], it seems to be opportune for dosing critically ill patients, to increase the daily dosage over the first 24-48 hours (by using loading doses to counter the increased Vd) and then to continue frequent but lower doses, based on estimates of renal function. Another strategy of dosing can be the use of a loading dose and to continue using not so high doses (12-16 g/day) by continuous perfusion, which as observed in table 2, maintain the steady state concentration (Css) > 32 mg/L.

The combination of fosfomycin and meropenem is synergistic and prevents the emergence of drug resistance in severe infections caused by ESBL-producing Enterobacterales and P. aeruginosa strains. Docobo-Pérez et al. [37] examined the utility of fosfomycin alone (4 g/q8h) at the very dense inoculum of 1010 CFU/mL against ESBL-producing E. coli strain with a fosfomycin MIC of 1 mg/L. Fosfomycin as monotherapy reduced the bacterial concentration by 3 log10 CFU/mL. However, mutants able to grow at 256 mg/L appeared after 48 h of treatment and, 24 h later, the resistant mutants replaced the susceptible population. The combination of fosfomycin (4 g/q8h) and meropenem (1 g/q8h) produced a 10-log10 CFU/mL bacterial reduction and sterilization of the bacterial inoculum after 48 h of treatment. In addition, the combination completely suppressed all clones resistant to fosfomycin at a dose of 12 g/day when employed as monotherapy.

The use of intravenous fosfomycin as monotherapy for systemic infection caused by P. aeruginosa may be problematic because the bacterial killing is virtually eliminated at high inoculum, suggesting that combination with other antibiotics is required for this organism [27]. In in vitro studies, the combination of fosfomycin with carbapenems has shown good synergistic effects against P. aeruginosa isolates. Asuphon et al. [30] through synergy studies using an E-test strips of fosfomycin in combination with meropenem have reported that MIC90 for non-MDR P. aeruginosa were 512 mg/L for fosfomycin monotherapy, 128 mg/L for fosfomycin combined with meropenem, 8 mg/L for meropenem monotherapy and 3 mg/L for meropenem combined with fosfomycin. The same authors calculated the PTAs for fosfomycin and meropenem used alone or in combination. For non-MDR P. aeruginosa, fosfomycin 16 g continuous infusion combined with meropenem 1-2 g, 3-hour infusion every 8 hours achieve approximately 80% PTA for MIC90 128 mg/L of fosfomycin and 3 mg/L of meropenem. However, the loading dose of fosfomycin needed in a continuous infusion regimen will apply. Considering the carbapenem-resistant P. aeruginosa subgroup, MIC90 were >1,024 mg/L for fosfomycin monotherapy, 192 mg/L for fosfomycin combined with carbapenems, > 32 mg/L for meropenem monotherapy and 6 mg/L for meropenem combined with fosfomycin. For PTA of > 90% of meropenem in combination with fosfomycin, the dosage should be fosfomycin 8 g every 8 hours infusion over 6 hours in combination wtih meropenem 2 g every 8 hours prolonged infusion at MIC90 less than 128 mg/L of fosfomycin and less than 6 mg/L for meropenem. In this regard, Sauermann et al. [11] reported, in an in vivo study, that the average concentration at steady state of fosfomycin in the abscess fluid after the administration of 8 g every 8 hours was 184 mg/L. This concentration was higher than the MIC90 (128 mg/L) of non-MDR P. aeruginosa and carbapenem-resistant P. aeruginosa against fosfomycin combined with meropenem [30].

Synergism has been also documented between fosfomycin and glycopeptides, linezolid and daptomycin against MRSA and Enterococcus spp. [38, 39].

Until more data are available, fosfomycin should not be used as monotherapy to treat systemic infections with either high MICs or with high bacterial densities [27, 37].