Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria.

Drugs (2013) 73:1951–1966 DOI 10.1007/s40265-013-0143-y

ADIS DRUG EVALUATION

Fosfomycin Trometamol: A Review of Its Use as a Single-Dose Oral Treatment for Patients with Acute Lower Urinary Tract Infections and Pregnant Women with Asymptomatic Bacteriuria Gillian M. Keating

Published online: 8 November 2013 Ó Springer International Publishing Switzerland 2013

Abstract Fosfomycin trometamol (fosfomycin tromethamine) [MonurilÒ, MonurolÒ, MonuralÒ] is approved in numerous countries worldwide, mainly for the treatment of uncomplicated urinary tract infections (UTIs). Fosfomycin has good in vitro activity against common uropathogens, such as Escherichia coli (including extended-spectrum blactamase-producing E. coli), Proteus mirabilis, Klebsiella pneumoniae and Staphylococcus saprophyticus, and the susceptibility of uropathogens to fosfomycin has remained relatively stable over time. A single oral dose of fosfomycin trometamol 3 g (the approved dosage) achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol had similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or nitrofurantoin in women with uncomplicated lower UTIs. In addition, single-dose fosfomycin trometamol had similar bacteriological efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in pregnant women with asymptomatic bacteriuria, and similar clinical and/or bacteriological efficacy to a 5-day course of cefuroxime axetil or amoxicillin/clavulanic acid The manuscript was reviewed by: R. Colgan, University of Maryland, Department of Family and Community Medicine, Baltimore, MD, USA; A. P. MacGowan, Department of Microbiology, Bristol Centre for Antimicrobial Research & Evaluation, Southmead Health Services NHS Trust, Bristol, UK; K. G. Naber, Technical University Munich, Munich, Germany; O. R. Sipahi, Department of Infectious Diseases and Clinical Microbiology, Ege University Faculty of Medicine, Bornova Izmir, Turkey. G. M. Keating (&) Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

or a 3-day course of ceftibuten in pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with gastrointestinal adverse events (e.g. diarrhoea, nausea) reported most commonly. In conclusion, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs.

Fosfomycin trometamol in patients with acute lower urinary tract infections (UTIs) and pregnant women with asymptomatic bacteriuria: a summary Good in vitro activity against common uropathogens, with resistance rates remaining relatively stable over time Single oral dose achieves high concentrations in urine Single dose effective in the treatment of uncomplicated lower UTIs, asymptomatic bacteriuria during pregnancy and lower UTIs in pregnant women Generally well tolerated, with gastrointestinal adverse events reported most commonly Single-dose regimen has potential for reduced costs and improved compliance, and limits the development of bacterial resistance

1 Introduction Urinary tract infections (UTIs) are the most commonly occurring bacterial infections in women [1]. An uncomplicated lower UTI is usually defined as acute cystitis occurring in a healthy, premenopausal, nonpregnant woman with no known abnormalities of the urological

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tract, and is characterized by symptoms such as dysuria, urgency, frequency, suprapubic pain and/or haematuria [1, 2]. Escherichia coli is the leading uropathogen responsible for uncomplicated UTIs, with other Enterobacteriaceae (e.g. Proteus mirabilis, Klebsiella pneumoniae), Staphylococcus saprophyticus and Enterococcus faecalis also commonly implicated [3, 4]. The antibacterial agent fosfomycin was discovered in the late 1960s [5]. The original oral fosfomycin formulation was a calcium salt, which is poorly absorbed, and a derivative with greater bioavailability, fosfomycin trometamol (fosfomycin tromethamine), was subsequently developed [6, 7]. Fosfomycin trometamol (MonurilÒ, MonurolÒ, MonurÒ al ) is approved in numerous countries worldwide, including various European countries and the USA, mainly for the treatment of uncomplicated UTIs [8–11] (Sect. 6). Indeed, there has recently been a resurgence of interest in fosfomycin trometamol, given increasing levels of resistance to other antibacterial agents (e.g. cotrimoxazole and particularly fluoroquinolones), and the increased reporting of UTIs caused by extended-spectrum b-lactamase (ESBL)-producing E. coli [2–4, 12, 13]. This article reviews the clinical efficacy and tolerability of fosfomycin trometamol in patients with uncomplicated lower UTIs, pregnant women with asymptomatic bacteriuria and pregnant women with lower UTIs, as well as discussing its pharmacological properties.

2 Pharmacodynamic Properties This section summarizes the mechanism of action and in vitro antibacterial activity of fosfomycin, and the mechanisms of fosfomycin resistance. Several studies discussed in this section are only available as abstracts [14–18] and/or posters [17]. 2.1 Mechanism of Action Fosfomycin is a phosphonic acid derivative that acts as a bacterial cell wall inhibitor, interfering with the first committed step in peptidoglycan biosynthesis [5, 19]. Specifically, fosfomycin inactivates the enzyme enolpyruvyl transferase, irreversibly inhibiting the formation of the peptidoglycan precursor N-acetylmuramic acid from N-acetylglucosamine and phosphoenolpyruvate [5, 20]. 2.2 Antibacterial Activity Fosfomycin trometamol is indicated for use against susceptible organisms in the treatment of uncomplicated UTIs

G. M. Keating

(see Sect. 6) [8–11]. In the USA, it is specifically indicated for use against susceptible strains of E. coli and E. faecalis [11]. Studies in various countries have examined the in vitro antibacterial activity of fosfomycin against urinary isolates; only studies collecting urinary isolates from 2002 onwards are discussed in this section. Results of fosfomycin susceptibility testing are dependent on the method used [21], with disk diffusion or agar dilution methods usually recommended [11]. Glucose-6-phosphate should be added to fosfomycin disks or to the test media when testing for fosfomycin susceptibility [22]. Where specified, studies included in this section tested fosfomycin using disk diffusion [14, 23–31] or agar dilution [4, 18, 32–34] methods, and fosfomycin susceptibility was determined using Clinical Laboratory and Standards Institute [4, 14, 18, 23–26, 28, 30–36], British Society for Antimicrobial Chemotherapy [29] or Swedish Reference Group for Antibiotics [27] breakpoints. Fosfomycin has a broad spectrum of antibacterial activity, demonstrating good in vitro activity against Gramnegative and Gram-positive organisms commonly isolated in UTIs [19]. For example, fosfomycin was associated with susceptibility rates of 97.2–100 % against E. coli (Table 1) [4, 18, 24, 26, 31, 32, 34, 35]. Lower susceptibility rates were seen with comparator antibacterials such as cotrimoxazole (trimethoprim/sulfamethoxazole), ciprofloxacin, norfloxacin, amoxicillin/clavulanic acid and cefuroxime, although susceptibility rates of [90 % were generally seen with nitrofurantoin [4, 18, 24, 34, 35], apart from in one Spanish study in which the nitrofurantoin susceptibility rate was 66.6 % [32] (Table 1). Across various studies, E. coli resistance rates against fosfomycin were 0.1–2 % [4, 27, 30–34, 36], with a minimum concentration required to inhibit 90 % of isolates (MIC90) of 2–32 lg/mL [18, 33, 36]. Fosfomycin also had good in vitro activity against K. pneumoniae (with susceptibility rates of 69.8–84.6 %) [26, 31, 35], although higher susceptibility rates were seen with cotrimoxazole, ciprofloxacin, amoxicillin/clavulanic acid and cefuroxime in a Spanish study [35] (Table 1). Fosfomycin also demonstrated good in vitro activity against P. mirabilis, with susceptibility rates of 80.2–96.7 % [26, 31, 35] (Table 1). In terms of other Gram-negative organisms, Pseudomonas aeruginosa (40 isolates), Enterobacter spp. (16 isolates), and Acinetobacter baumannii (11 isolates) had fosfomycin susceptibility rates of 85, 75 and 9 %, respectively, in a Greek study [26], and Enterobacter spp. (45 isolates), Pseudomonas spp. (75 isolates) and A. baumannii (37 isolates) had fosfomycin susceptibility rates of 93, 44 and 35 %, respectively, in a Turkish study [31]. Fosfomycin had good in vitro activity against ESBLproducing Enterobacteriaceae [14, 23, 25, 26, 29–31]. For

Fosfomycin Trometamol: A Review

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Table 1 In vitro antibacterial activity of fosfomycin against common uropathogens. Urinary isolates were collected in various countries from 2002 onwardsa Species (no. of isolates)b

Susceptibility ratec (%)

References

FT

NIT

SXT

CIP

NOR

AMC

CXM

Escherichia coli (9,389)

97.2–100.0

66.6–99.2

69.2–81.5

73.5–91.6

80.7–90.2

81.8–94.3

81.0–95.5

ESBL E. coli (522)

86–100.0

79.1–95

22.4–26

24–29.1

Gram-negative bacteria [4, 18, 24, 26, 31, 32, 34, 35] [23, 25, 26]

Klebsiella pneumoniae (490)

69.8–84.6

67.7

90.7

96.0

ESBL K. pneumoniae (249)

57.6–100.0

13.6–29

18.2–19

37.9–41

93.8

94.4

[26, 31, 35]

Proteus mirabilis (300)

80.2–96.7

2.1

63.6

87.3

98.0

99.5

[26, 31, 35]

20.6–100.0

100

97.3

93.5

92.9

86.4

[26, 35]

[23, 25, 26]

Gram-positive bacteria Staphylococcus saprophyticus (55)

AMC amoxicillin-clavulanic acid, CIP ciprofloxacin, CXM cefuroxime, ESBL extended-spectrum b-lactamase producing, FT fosfomycin, NIT nitrofurantoin, NOR norfloxacin, SXT cotrimoxazole a Urinary isolates were collected in Italy [34], Spain [32, 35], Brazil and Europe (Austria, France, Germany, Hungary, Italy, Poland, Russia, Spain, the Netherlands) [4], Greece [26], Taiwan [23], Turkey [31], Brazil [24], Lebanon [25] and Canada [18] in 2002 [34], 2003–2004 [32], 2003–2006 [4], 2004 [35], 2008 [26], 2008–2009 [23], 2008–2012 [31], 2009 [24], 2010 [25] and 2010–2013 [18] b All isolates were tested against FT. Studies also tested isolates against NIT [4, 18, 23–25, 32, 34, 35], SXT [4, 18, 23, 25, 32, 34, 35], CIP [4, 18, 23, 25, 32, 34, 35], NOR [32, 34], AMC [4, 18, 24, 32, 34, 35] and CXM [4, 32, 35] c Susceptibility to FT was tested using disk diffusion [23–26, 31] or agar dilution [4, 18, 32, 34] methods using Clinical Laboratory and Standards Institute breakpoints [4, 18, 23–26, 31, 32, 34, 35]

example, against ESBL-producing E. coli, fosfomycin had susceptibility rates of 86–100 % [23, 25, 26], which were generally higher than those seen with nitrofurantoin, cotrimoxazole or ciprofloxacin [23, 25] (Table 1). ESBLproducing E. coli resistance rates against fosfomycin were 0–2.2 % [30, 33], with an MIC90 of 32 lg/mL [33]. Against ESBL-producing K. pneumoniae, fosfomycin demonstrated higher susceptibility rates than nitrofurantoin, ciprofloxacin or cotrimoxazole [23, 25] (Table 1). The susceptibility of S. saprophyticus to fosfomycin varied by region, with a susceptibility rate of 100.0 % seen in a Greek study [26], compared with only 20.6 % in a Spanish study [35] (Table 1). Susceptibility rates for comparator antibacterials are shown in Table 1 [35]. In terms of other Gram-positive organisms, E. faecalis had a fosfomycin susceptibility rate of 91.8 % (74 isolates) [26], and a resistance rate of 2.3 % (67 isolates) [28]. Susceptibility of Enterococcus faecium to fosfomycin varied by region with a susceptibility rate of 0 % in a Greek study (12 isolates) [26] and a resistance rate of 0 % in a Turkish study (33 isolates) [28]. 2.3 Bactericidal Activity, Post-Antibiotic Effect and Effects on the Adhesive Properties of Uropathogens and Biofilms Therapeutic doses of fosfomycin achieve bactericidal concentrations in urine [12, 37]. In vitro, fosfomycin had

concentration-dependent bactericidal activity against E. coli and P. mirabilis [38]. For E. coli, a 3–4 log reduction in bacterial count, compared with control, was seen within 2 h and sterilization was seen at 6–8 h at fosfomycin concentrations of C49 the minimum inhibitory concentration (MIC). For P. mirabilis, a C3 log reduction in bacterial count, compared with control, was seen within 2 h and sterilization was seen within 6–8 h at fosfomycin concentrations of C89 MIC [38]. Against E. coli, fosfomycin had a post-antibiotic effect of 3.4, 3.4 and 4.2 h at 0.259 MIC, MIC and 89 MIC, respectively [38]. Similarly, against P. mirabilis, fosfomycin had a post-antibiotic effect of 3.2, 3.2 and 4.7 h at 0.259 MIC, MIC and 89 MIC, respectively [38]. Fosfomycin affects the adhesive properties of various uropathogens [39]. In vitro, fosfomycin decreased the adherence of E. coli [40], P. mirabilis [40] or P. aeruginosa [37] to human uroepithelial cells. Uropathogens may be associated with biofilm formation in UTIs [41]. Biofilms represent a surface accumulation of bacteria embedded in a matrix of organic polymers of microbial origin bound to a natural or artificial surface [41, 42]. Bacteria in biofilms are protected from host immune defences and have greater resistance to antibacterials [42, 43]. Synergistic activity between fosfomycin and ofloxacin [41] or acetylcysteine [44] against P. aeruginosa [41] or E. coli [44] biofilms was seen in vitro. Moreover, synergistic activity was seen between fosfomycin and

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fluoroquinolones (prulifloxacin, ciprofloxacin or levofloxacin) [45] and between fosfomycin and the aminoglycoside isepamicin [43] in rat models of P. aeruginosa biofilms. 2.4 Potential Mechanisms of Resistance A summary of the main issues pertaining to fosfomycin resistance is shown in Table 2. Several chromosomal or plasmid-mediated mechanisms of fosfomycin resistance have been described, including decreased drug uptake, target site modification and inactivation [20, 46–48]. Decreased drug uptake arises from mutations affecting the fosfomycin membrane transport systems [20, 46]. For example, mutations in the transporters responsible for the uptake of fosfomycin into E. coli (a glycerol-3-phosphate transporter and a hexose phosphate transporter) may lead to fosfomycin resistance [20, 46]. Expression of these transporters may also be down-regulated by mutations at other sites [20]. Resistance may also arise from mutations that change the structure of the fosfomycin target enolpyruvyl transferase [20], and the presence of enzymes that inactivate fosfomycin (e.g. glutathione S-transferase, L-cysteine thio transferase, epoxide hydrolase) or fosfomycin kinases that degrade fosfomycin [20, 48]. Rapid development of mutants resistant to fosfomycin is generally seen in vitro [16, 20, 46]. However, the development of mutational resistance to fosfomycin may be associated with a biological cost [20, 42, 46]. For example, mutations conferring fosfomycin resistance in E. coli may result in attenuated virulence associated with decreased growth and a reduced ability to adhere to epithelial cells [20, 42, 46, 49]. Moreover, despite the rapid development of fosfomycinresistant mutants in vitro, resistance rates among urinary isolates have remained relatively stable over time, and emergence of resistance when single-dose fosfomycin trometamol is used for the treatment of UTIs appears infrequent [20]. Indeed, a number of studies demonstrated stable fosfomycin susceptibility rates over time among urinary E. coli isolates [50–55]. However, there have been reports in Spain of increases over time in resistance of urinary ESBL-producing E. coli isolates to fosfomycin

G. M. Keating

[56–58]. For example, fosfomycin resistance in ESBLproducing E. coli increased from 4.4 % in 2005 to 11.4 % in 2009 in one study; this study also demonstrated a 340 % increase in the community use of fosfomycin between 1997 and 2008 [58]. However, it should be noted that in this study [58], the increase in hospital use of parenteral fosfomycin disodium was not reported for the same time period. Rates of fosfomycin susceptibility or resistance against urinary isolates of P. mirabilis [52, 53], P. aeruginosa [53] and E. faecalis [53] also remained relatively stable over time. The susceptibility of K. pneumoniae to fosfomycin remained relatively stable in one study [52], but decreased in another [53]. In keeping with the unique mechanism of action of fosfomycin (Sect. 2.1), cross-resistance between fosfomycin trometamol and other antibacterials agents is generally not seen [19]. For example, fosfomycin retained good in vitro activity among quinolone-resistant urinary isolates of E. coli [15, 17, 18, 33, 59], with all of the quinoloneresistant E. coli isolates not producing ESBL (n = 62) showing in vitro susceptibility to fosfomycin, and only 2 of the 63 (3.2 %) quinolone-resistant E. coli isolates producing ESBL showing in vitro resistance to fosfomycin in one study [17]. In another study, 100 % of E. coli isolates that were non-susceptible to cotrimoxazole (n = 85) were susceptible to fosfomycin [18]. Fosfomycin also demonstrated good in vitro activity against multidrug-resistant [18, 60–62] and extensively drug-resistant [60] Enterobacteriaceae. For example, among 152 multidrug-resistant Enterobacteriaceae clinical isolates (the majority of which were collected from urine), susceptibility rates were 92.8, 12.5 and 10.5 % for fosfomycin, cotrimoxazole and ciprofloxacin, respectively [60]. Among 85 extensively drug-resistant Enterobacteriaceae clinical isolates, susceptibility rates were 91.8, 1.2 and 2.4 % for fosfomycin, cotrimoxazole and ciprofloxacin, respectively [60]. In a recent US study, fosfomycin had in vitro activity against urinary isolates of carbapenem-resistant Klebsiella spp. (n = 29) and Enterobacter spp. (n = 5), with susceptibility rates of 57 and 80 %, respectively, and

Table 2 Fosfomycin: summary of resistance Chromosomal or plasmid-mediated mechanisms of fosfomycin resistance include decreased drug uptake, target site modification and inactivation [20, 46–48] Fosfomycin resistance rates among clinical isolates of uropathogens such as Escherichia coli, Proteus mirabilis and Enterococcus faecalis have remained relatively stable over time [50–55], despite rapid development of mutational resistance to fosfomycin being seen in vitro (which may be associated with a biological cost) [16, 20, 42, 46] Cross-resistance between fosfomycin and other antibacterials agents is generally not seen [15, 17–19, 33, 59] Fosfomycin retains good in vitro activity against multidrug-resistant [18, 60–62] and extensively drug-resistant [60] Enterobacteriaceae, carbapenem-resistant Klebsiella spp. and Enterobacter spp., and vancomycin-resistant Enterococcus faecium and E. faecalis [63]


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vancomycin-resistant E. faecium (n = 28) and E. faecalis (n = 24), with susceptibility rates of 60 and 100 %, respectively [63].

3 Pharmacokinetic Properties This section focuses on the results of studies examining the pharmacokinetics of a single dose of fosfomycin trometamol 3 g (the approved dosage; see Sect. 6) [64–67], or 50 mg/kg (i.e. a dosage of &3 g in adults) [7, 68–71], supplemented by data obtained from review articles [72, 73] and the US prescribing information [11]. 3.1 Absorption and Distribution Fosfomycin trometamol has an absolute oral bioavailability, under fasting conditions, of 33–41 % [7, 64, 70]. This is reduced to &30 % under fed conditions [11]. Oral fosfomycin trometamol is rapidly absorbed and converted to fosfomycin [11]. A mean Cmax of 21.8–32.1 lg/mL was reached within &2 h following administration of a single dose of fosfomycin trometamol 3 g [64] or 50 mg/kg [7, 68–71] under fasting conditions, and the mean AUC was 144.9–227.9 lg h/mL [7, 64, 68– 71] (Table 3). In the fed state, a mean Cmax of 12.7 lg/mL was reached within 4 h following a single dose of fosfomycin trometamol 50 mg/kg [68]. Oral fosfomycin trometamol has a mean apparent steady-state volume of distribution of 136.1 L [11]. Fosfomycin is distributed to various tissues, including the kidneys, bladder, prostate and seminal vesicles [11, 65, 66, 72]. For example, mean fosfomycin concentrations in the bladder mucosa were 17.2 lg/g of tissue 6 h after administration of a single dose of fosfomycin trometamol 3 g to patients undergoing urological surgery for bladder or prostatic cancer (bladder mucosa samples were obtained from healthy tissue) [65]. Fosfomycin also penetrates the cerebrospinal fluid and crosses the placental barrier [72, 73]. Table 3 Pharmacokinetics of a single dose of fosfomycin trometamol 3 g [64] or 50 mg/kg [7, 68–71] administered to healthy volunteers (n = 8–12) under fasting conditions Parameter

Mean values

Bioavailability (%)

33–41

Cmax (lg/mL)

21.8–32.1

tmax (h)

2.0–2.5

AUC (lg h/mL)

144.9–227.9

t (h)

2.4–7.3

AUC area under the serum concentration-time curve, Cmax peak serum concentration, t elimination half-life, tmax time to Cmax

Fosfomycin does not bind to plasma proteins [11, 73]. 3.2 Metabolism and Elimination Fosfomycin is excreted unchanged in the urine and faeces and achieves high urinary concentrations [11]. Following administration of a single dose of fosfomycin trometamol 3 g in the fasting state, mean urinary fosfomycin concentrations were 706 lg/mL at 2–4 h and 10 lg/mL at 72–84 h [11]. Mean concentrations of fosfomycin in urine were reported to stay above 128 lg/mL for C36 h [64, 72] (128 lg/mL was chosen as the breakpoint between full and intermediate susceptibility [64]) and above 100 lg/mL for 48 h [69]. Indeed, bacteriostatic activity was seen in urine for 48 h after administration of oral fosfomycin trometamol 50 mg/kg, with the growth of E. coli and P. mirabilis inhibited [7]. Following administration of a single dose of fosfomycin trometamol 3 g with a high-fat meal, mean urinary fosfomycin concentrations were 537 lg/mL at 6–8 h, with a urinary concentration of C100 lg/mL maintained for 26 h [11]. The cumulative amount of fosfomycin excreted in the urine was 1,140 mg in the fasting state and 1,118 mg in the fed state [11]. Mean renal clearance of fosfomycin was 6.3 L/h and mean total body clearance was 16.9 L/h following oral administration of fosfomycin trometamol [11]. With oral administration of fosfomycin trometamol 3 g, &38 % of the dose was recovered in urine and &18 % of the dose was recovered in faeces [11]. Fosfomycin had a mean half-life (t) of 2.4–7.3 h [7, 64, 68–71] (Table 3). The pharmacokinetics of fosfomycin are not affected by gender [11]. 3.3 Special Patient Populations The t of fosfomycin increased from 11 to 50 h and the percentage of the dose recovered in urine decreased from 32 to 11 % in patients with varying degrees of renal impairment (creatinine clearance [CLCR] ranging from 54 to 7 mL/min) [11]. In addition, the t of fosfomycin was 40 h in five anuric patients undergoing haemodialysis [11]. The urinary excretion of fosfomycin did not appear to be altered in the elderly and no dosage adjustment is necessary [11]. Moreover, in seven elderly women (aged 71–90 years) with impaired renal function (CLCR of 21–72 mL/min) who received a single dose of fosfomycin trometamol 3 g, a mean 37 % of the dose was excreted unchanged in the urine, with mean urinary concentrations of 1,383 lg/mL at 0–12 h and 143 lg/mL at 72–84 h [67]. Results of this study suggest that even in patients with severe renal insufficiency (CLCR of 20–30 mL/min),

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urinary fosfomycin concentrations following a single 3 g dose of oral fosfomycin trometamol should be sufficiently high to eliminate susceptible uropathogens [74]. 3.4 Potential Drug Interactions Serum concentrations and urinary excretion of fosfomycin were reduced when fosfomycin trometamol was coadministered with metoclopramide [70]. The pharmacokinetics of fosfomycin trometamol were not affected by the coadministration of cimetidine [70].

4 Therapeutic Efficacy This main focus of this section is recent trials examining the efficacy of a single dose of fosfomycin trometamol in the treatment of uncomplicated lower UTIs [34, 75–78], asymptomatic bacteriuria during pregnancy [79, 80] or pregnant women with a lower UTI [81, 82]. A number of studies conducted in the late 1980s and in the 1990s demonstrated the efficacy of fosfomycin trometamol in the treatment of UTIs or asymptomatic bacteriuria during pregnancy [83–101]. However, these studies are not discussed further, given the changes in bacterial resistance patterns that have occurred (affecting comparator antibacterials such as fluoroquinolones) since they were published. A recent meta-analysis of 27 trials (including several older studies, as well as more recent data), found that a single dose of fosfomycin trometamol was effective in the treatment of lower UTIs both in nonpregnant women and in mixed populations [102]. 4.1 Uncomplicated Lower Urinary Tract Infection (UTI) Four recent randomized trials examined the efficacy of fosfomycin trometamol in adult women with uncomplicated lower UTIs [75–78]. Where specified, studies were of single-blind [75] and/or single-centre [75, 77] design. For three of the trials [75, 76, 78], key inclusion and exclusion criteria and definitions for clinical success and bacteriological eradication are described in Table 4. Results of a large noncomparative study in patients with uncomplicated UTIs are also briefly discussed [34] (Sect. 4.1.3). 4.1.1 Comparisons with a Fluoroquinolone or Nitrofurantoin Three trials compared the efficacy of single-dose fosfomycin trometamol with that of 3-day [76, 77] or 5-day [75] courses of ciprofloxacin [75, 77] or norfloxacin [76] in the treatment of women with uncomplicated lower UTIs; one

G. M. Keating

of these trials also included a treatment arm in which patients received a 7-day course of nitrofurantoin [77]. One study was conducted in Turkey [75], one study (which is available as an abstract) was conducted in a region of Russia in which the level of resistance of uropathogenic E. coli to fluoroquinolones was [10 % [76] and the third study was conducted in the USA [77]. A single dose of fosfomycin trometamol 3 g had similar efficacy to a 5-day course of ciprofloxacin 500 mg twice daily or a 3-day course of norfloxacin 400 mg twice daily in the treatment of women with uncomplicated lower UTIs. Clinical success rates did not significantly differ between fosfomycin trometamol and ciprofloxacin [75] or norfloxacin [76] recipients (Table 4). In the Turkish study, the mean time between initiation of treatment and substantial improvement in symptoms was 3.5 and 1.9 days with fosfomycin trometamol and ciprofloxacin, respectively [75]. Improvement of urinary findings (defined as the disappearance of pyuria in the urine sample) occurred in 80.5 % of fosfomycin trometamol recipients and in 80.0 % of ciprofloxacin recipients by day 7–10 [75]. In the Russian study, rates of clinical improvement (98.0 vs. 98.1 %) or failure (2.0 vs. 1.9 %) [assessed 5–7 days after the first dose of study medication] and rates of clinical relapse (0 vs. 2.7 %) [assessed 9–11 or 26–29 days after the first dose of study medication] also did not significantly differ between fosfomycin trometamol and norfloxacin recipients [76]. Bacteriological eradication rates did not significantly differ between fosfomycin trometamol recipients and ciprofloxacin [75] or norfloxacin [76] recipients (Table 4). In the Russian study, rates of bacteriological persistence (4.2 vs. 0 %) [assessed 5–7 days after the first dose of study medication] and rates of bacteriological reinfection (0 vs. 4.8 %) or relapse (0 vs. 4.8 %) [assessed 9–11 or 26–29 days after the first dose of study medication] also did not significantly differ between fosfomycin trometamol and norfloxacin recipients [76]. E. coli was isolated in 82 % of cases in both studies [75, 76], with other uropathogens including Enterobacter spp. (8.4 %) [75], E. faecalis (5.9 %) [76], Proteus spp. (2.8 %) [75], and S. saprophyticus (2.1 % [75] and 3.9 % [76]). Only limited results pertaining to overall clinical success and bacteriological eradication are available from the US study, which included nonpregnant women aged 18–45 years with acute uncomplicated cystitis, pyuria and a positive urine culture [77]. The women received a single dose of fosfomycin trometamol 3 g (n = 20), ciprofloxacin 250 mg twice daily for 3 days (n = 25) or nitrofurantoin 100 mg twice daily for 7 days (n = 17), and clinical success rates and bacteriological eradication rates were[90 % in all three treatment groups [77].


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Table 4 Efficacy of single-dose fosfomycin trometamol in the treatment of uncomplicated lower urinary tract infection in womena Study (study design)

Treatment

No. of randomized pts

Rate (% of pts) [no. of evaluable pts] Clinical successb

Bacteriological eradicationc

Comparisons with a fluoroquinolone Ceran et al. [75]

FT 3 g SD

130

83.1 [77]

83.1 [77]

(r, sb, sc)

CIP 500 mg bid 9 5 days

130

81.5 [65]

78.5 [65]

d

Rafalskiy et al. [76]

FT 3 g SD

53

76.0 [50]

95.8 [48]

(r)

NOR 400 mg bid 9 3 days

55

68.5 [54]

100.0 [54]

FT 3 g SD SXT 160/800 mg bid 9 3 days

68e

88.2 [34] 82.1 [28]

Comparison with SXT Stapleton et al. [78]d (r)

bid twice daily, CIP ciprofloxacin, FT fosfomycin trometamol, NOR norfloxacin, pts patients, r randomized, sb single-blind, sc single-centre, SD single dose, SXT cotrimoxazole, UTI urinary tract infection a

Key inclusion criteria included: women aged 18–45 [78], 18–55 [76] or 18–65 [75] years; uncomplicated lower UTI [75, 76, 78]; and pyuria, bacteriuria, dysuria and urgency for\1 week [75]. Key exclusion criteria included: complicated UTI [75, 76], systemic infection [75], upper UTI [76], nosocomial UTI [76]; UTI duration of [7 days [76]; recurrent UTI ([3 per year) [75] or [2 UTI relapses within the past 6 months [76]; antibacterial treatment in the previous 15 [75] or 30 [76] days; invasive urological manipulation in the past 30 days [76]; pregnant or lactating [75]; and urinary system abnormalities, obstruction or renal parenchymal disease [75] b

Where specified, clinical success was defined as the resolution of symptoms and signs [75] or no further treatment for subsequent or unresolved symptoms [78], and was assessed on days 7–10 [75] or 5–7 days after the first dose of medication [76]

c

Where specified, bacteriological eradication was defined as a negative urine culture [75], and was assessed on days 7–10 [75] or 5–7 days after the first dose of medication [76] d

Available as an abstract

e

Sixty-eight women were randomized; the no. of pts randomized to each treatment arm was not specified

The main goal of this study was to evaluate the effect of treatment on rectal microbial flora [77]. At the enrolment visit, 94 % of women had rectal colonization with E. coli; the prevalence of rectal E. coli was significantly (p \ 0.001) reduced after treatment with fosfomycin trometamol and ciprofloxacin, but not nitrofurantoin. Isolation of two ciprofloxacin-resistant rectal E. coli strains from a single patient occurred &10 days after completing treatment with ciprofloxacin. Among patients receiving fosfomycin trometamol or nitrofurantoin, all isolated rectal E. coli strains were susceptible to the study drug [77]. 4.1.2 Comparison with Cotrimoxazole A pilot study conducted in the USA compared the efficacy of single-dose fosfomycin trometamol 3 g with that of a 3-day course of cotrimoxazole 160/800 mg twice daily in the treatment of women with uncomplicated lower UTIs [78]. This study is available as an abstract [78]. Clinical success rates were [80 % in patients receiving a single dose of fosfomycin trometamol 3 g or a 3-day course of cotrimoxazole 160/800 mg twice daily (Table 4) [78]. Resistance of E. coli to the study medication was seen in no fosfomycin trometamol recipients and in 20 % of cotrimoxazole recipients [78].

4.1.3 Noncomparative Study In a large noncomparative, multicentre, Italian study, women (n = 315) and men (n = 72) with uncomplicated UTIs (274 of whom had acute UTIs and 113 of whom had recurrent UTIs) received a single dose of fosfomycin trometamol 3 g [34]. A total absence of symptoms was reported in 88.9 % of fosfomycin trometamol recipients 8–9 days after treatment, with a clear improvement seen in the remaining 11.1 % of patients [34]. Bacteriological eradication occurred in 91.7 % of patients [34]. The most commonly isolated pathogens included E. coli (76.7 % of isolates), K. pneumoniae (7.5 %), P. mirabilis (4.7 %), Citrobacter freundii (4.4 %), E. faecalis (2.6 %) and S. saprophyticus (1.8 %). Eradication rates for E. coli, K. pneumoniae, P. mirabilis, C. freundii, E. faecalis and S. saprophyticus were 94.9, 89.6, 77.7, 94.1, 80.0 and 100.0 %, respectively [34]. 4.2 Asymptomatic Bacteriuria During Pregnancy Two randomized, single-centre trials compared the efficacy of a single dose of fosfomycin trometamol with a 5-day course of cefuroxime axetil [79] or a 7-day course of

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G. M. Keating

amoxicillin/clavulanic acid [80] in the treatment of pregnant women with asymptomatic bacteriuria. The trials were conducted in Turkey [79] and Spain [80]. Key inclusion and exclusion criteria and the definition for bacteriological eradication are shown in Table 5.

cefuroxime axetil 250 mg twice daily (Table 5) [79]. The most commonly isolated pathogens were E. coli (94.0 % of isolates), E. faecalis (3.6 %) and Staphylococcus spp. (2.4 %) [79]. 4.2.2 Comparison with Amoxicillin/Clavulanic Acid

4.2.1 Comparison with Cefuroxime Axetil The bacteriological eradication rate did not significantly differ between pregnant women with asymptomatic bacteriuria who received a single dose of fosfomycin trometamol 3 g and those receiving a 5-day course of

The bacteriological eradication rate (primary endpoint) did not significantly differ between pregnant women with asymptomatic bacteriuria who received a single dose of fosfomycin trometamol 3 g and those receiving a 7-day course of amoxicillin/clavulanic acid 625 mg every 8 h

Table 5 Efficacy of single-dose fosfomycin trometamol in the treatment of pregnant women with asymptomatic bacteriuria [79, 80] or lower urinary tract infection [81, 82] Study (study design)

Treatment

No of randomized pts

Rate (% of pts) [no. of evaluable pts] Bacteriological eradicationa

Reinfectionb

Recurrenceb

Persistenceb

Clinical successc

Asymptomatic bacteriuria trialsd Bayrak et al. [79] (r, sc)

FT 3 g SD

45

93.2 [44]

CXM 250 mg bid 9 5 days

45

95.0 [40]

Estebanez et al. [80] (r, nb, sc)

FT 3 g SD

65

83.0e [53]

1.9*

1.9

9.4

AMC 625 mg q8h 9 7 days

66

80.4e [56]

14.3

1.8

3.6

Lower urinary tract infection trialsf Krcmery et al. [82] (r, mc) Usta et al. [81] (r)

FT 3 g SD

21

95.2 [21]

CTB 400 mg od 9 3 days

20

90.0 [20]

FT 3 g SD

30

82.1 [28]

78.6 [28]

AMC 625 day 9 5 CXM 500 day 9 5

30

81.5 [27]

77.8 [27]

30

89.7 [29]

86.2 [29]

mg/ days mg/ days

AMC amoxicillin/clavulanic acid, bid twice daily, cfu colony-forming units, CTB ceftibuten, CXM cefuroxime axetil, FT fosfomycin trometamol, mc multicentre, nb nonblind, od once daily, pt(s) patient(s), q8h every 8 h, r randomized, sc single-centre, SD single dose, UTI urinary tract infection * p = 0.045 vs. AMC a

Bacteriological eradication was defined as a negative culture 7 days [79] or 10–14 days [80] after completing therapy or at week 2 [81], or sterile urine or growth \103 cfu per mL at days 28–42 [82] b

Reinfection was defined as infection with a different pathogen [2 weeks after completion of initial therapy, recurrence as infection with the same pathogen within 2 weeks of completing treatment and persistence as presence of the same pathogen (C105 cfu per mL) with no eradication

c

Clinical success was defined as the resolution of symptoms Key inclusion criteria included: asymptomatic bacteriuria (C105 cfu/mL of the same pathogen in two consecutive cultures from a pt without fever or symptoms of UTI) [79, 80]; and second trimester of pregnancy [79]. Key exclusion criteria included: symptomatic UTI [80] or presence of leukocytosis, fever, urolithiasis or lower back pain [79]; receiving antibacterials 14 days prior to taking the culture for any reason other than having a UTI [80]; high-risk pregnancy [80]; requiring admission to hospital [80]; abnormalities in the urinary tract [79, 80] or history of previous urological surgery [79]; and infection with a pathogen resistant to either of the study antibacterials [80] d

e f

Primary endpoint

Key inclusion criteria included: symptomatic lower UTI, with significant bacteriuria and/or pyuria [81, 82] and positive urine culture [81]; and pregnancy of C12 weeks’ gestation [81]. Key exclusion criteria included: signs and symptoms of upper UTI (e.g. fever, flank pain, costovertebral tenderness, leukocytosis) [81, 82]; negative urine culture or C2 pathogens detected in urine culture [81]; asymptomatic bacteriuria [82]; urinary tract abnormalities [81, 82] or obstruction or renal parenchymal disease [81]; recurrent UTIs (C3 in the past year) [81]; and hospitalized for any cause in the past month [81]


4.3.1 Comparison with Amoxicillin/Clavulanic Acid or Cefuroxime Axetil In pregnant women with a lower UTI, the clinical success rate did not significantly differ between patients receiving a single dose of fosfomycin trometamol 3 g and those receiving a 5-day course of amoxicillin/clavulanic acid or cefuroxime axetil (Table 5) [81]. In addition, there was no significant difference between fosfomycin trometamol, amoxicillin/clavulanic acid and cefuroxime axetil recipients in the mean duration of symptoms (6.14 vs. 6.26 vs. 5.79 days) or in the mean recovery time from symptoms (3.29 vs. 3.15 vs. 2.97 days) [81]. Bacteriological eradication rates did not significantly differ between the three treatment groups (Table 5) [81]. The most commonly isolated pathogen was E. coli (71.4 %), followed by group B b-hemolytic streptococci (8.3 %), K. pneumoniae (7.2 %), Enterobacter spp. (6.0 %) and Enterococcus spp. (3.6 %) [81]. The compliance rates was significantly (p \ 0.05) higher among fosfomycin trometamol recipients than among amoxicillin/clavulanic acid or cefuroxime axetil recipients (100.0 vs. 77.8 and 82.8 %) [81].

Oral fosfomycin trometamol was generally well tolerated, according to the results of a pooled analysis reported in the US prescribing information [11]. The most commonly occurring drug-related adverse events in fosfomycin trometamol recipients included diarrhoea, vaginitis, nausea, headache, dizziness, asthenia and dyspepsia (Fig. 1). The pooled analysis included 1,233 fosfomycin trometamol recipients, 374 nitrofurantoin recipients, 428 cotrimoxazole recipients and 455 ciprofloxacin recipients, and utilized older trial data on which the approval of fosfomycin trometamol in the USA was based [11]. A similar tolerability profile was described in pooled analyses reported in the Italian, German and Irish summary of product characteristics (SPC). Adverse events were generally of limited duration and resolved spontaneously [8]. Common adverse events (incidence of C1 and \10 %) reported with oral fosfomycin trometamol included headache [8–10], dizziness [9, 10], vertigo [8], diarrhoea

Fosfomycin trometamol (n = 1,233) Nitrofurantoin (n = 374) Cotrimoxazole (n = 428) Ciprofloxacin (n = 455)

10 9 8 7 6 5 4 3 2 1

ø

pe ys D

th

en

ne As

D

iz

zi

da ea

ia

ss

e ch

a se H

au N

Va

gi

ni

oe D

ia

rrh

4.3.2 Comparison with Ceftibuten In pregnant women with a lower UTI, the bacteriological eradication rate did not significantly differ between patients receiving a single dose of fosfomycin trometamol 3 g and those receiving a 3-day course of ceftibuten 400 mg once

tis

a

0

ia

Randomized trials conducted in Turkey [81] and the Slovak Republic [82] compared the efficacy of single-dose fosfomycin trometamol with that of 5-day courses of amoxicillin/clavulanic acid or cefuroxime axetil [81] or a 3-day course of ceftibuten [82] in pregnant women with a lower UTI. Key inclusion and exclusion criteria and definitions for bacteriological eradication and clinical success are shown in Table 5.

5 Tolerability

ps

4.3 Pregnant Women with a Lower UTI

daily (Table 5) [82]. Infection persisted in one fosfomycin trometamol recipient and two ceftibuten recipients [82]. At baseline, the most commonly isolated pathogen was E. coli (76.2 % of isolates), followed by Staphylococcus spp. (16.7 %) and E. faecalis (7.1 %) [82]. The total cure rate (i.e. clinical and bacteriological cure) did not significantly differ between fosfomycin trometamol recipients and ceftibuten recipients [82].

Incidence (% of patients)

(Table 5) [80]. The pathogens isolated most commonly in the initial culture included E. coli (64.1 % of isolates), P. mirabilis (7.7 %), Streptococcus agalactiae (7.6 %), E. faecalis (6.9 %) and K. pneumoniae (6.1 %) [80]. The reinfection rate was significantly lower with fosfomycin trometamol than with amoxicillin/clavulanic acid, with no significant between-group difference in the rates of recurrence or persistence (Table 5) [80]. Noncompliance was seen in no fosfomycin trometamol recipients and in 8.9 % of amoxicillin/clavulanic acid recipients [80].

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Fig. 1 Tolerability of fosfomycin trometamol. Shown are drugrelated adverse events occurring in [1 % of fosfomycin trometamol recipients in a pooled analysis of clinical trial data [11]. ø = an incidence of 0 %

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G. M. Keating

[8–10], nausea [8–10], dyspepsia [8–10], vulvovaginitis [8, 10] and/or asthenia [9, 10]. Results of more recent clinical trials in patients with uncomplicated lower UTIs [34, 75, 76] are in agreement with the findings of these pooled analyses [8–11]. Singledose fosfomycin trometamol was generally well tolerated [34, 75, 76], with gastrointestinal (GI) adverse events reported most commonly [34, 75]. For example, GI adverse events were reported in 3.9 % of fosfomycin trometamol recipients and in 3.1 % of ciprofloxacin recipients among women with an uncomplicated lower UTI [75]. Moreover, in a large noncomparative study in 387 women and men with uncomplicated UTIs who received single-dose fosfomycin trometamol, adverse events were reported in 4.9 % of patients, with diarrhoea, nausea and vomiting occurring in 3.1, 1.3 and 0.5 % of patients, respectively [34]. The incidence of adverse events did not significantly differ between fosfomycin trometamol and norfloxacin recipients (0 vs. 1.9 % of patients) in another trial in women with an uncomplicated lower UTI [76]. Fosfomycin trometamol was better tolerated than amoxicillin/clavulanic acid among pregnant women with asymptomatic bacteriuria [80]. Adverse events (nausea, vomiting and/or diarrhoea) were reported significantly more frequently with amoxicillin/clavulanic acid than with fosfomycin trometamol (19.6 vs. 1.9 % of patients; p = 0.008) [80]. Only minor adverse events were reported among pregnant women with asymptomatic bacteriuria who received fosfomycin trometamol or cefuroxime axetil [79]. An allergic skin rash was reported in 1 of 44 (2.3 %) fosfomycin trometamol recipients and vulvovaginal monoliasis was reported in 2 of 40 (5.0 %) cefuroxime axetil recipients [79]. Among pregnant women with a lower UTI who received fosfomycin trometamol, amoxicillin/clavulanic acid or cefuroxime axetil, diarrhoea was reported in 10.7, 11.1 and 6.9 % of patients, respectively, nausea was reported in 10.7, 11.1 and 3.4 % of patients, respectively, abdominal pain was reported in 0, 14.8 and 3.4 % of patients, respectively, and vaginal pruritus was reported in 3.6, 7.4 and 13.8 % of patients, respectively [81]. There were no significant between-group differences in terms of the incidence of these adverse events [81]. Fosfomycin trometamol was well tolerated in pregnant women with a lower UTI, with adverse events (mainly nausea) being of a minor, transient nature [82].

Italy, The Netherlands, Portugal, Switzerland), in which it has nationally approved labelling. For example, in Italy, fosfomycin trometamol is approved for use in the treatment of acute bacterial cystitis, acute episodes of recurrent bacterial cystitis, acute bacterial urethrovesical syndrome, aspecific bacterial urethritis, asymptomatic significant bacteriuria in pregnancy and postoperative urinary infections, and as prophylaxis of UTIs in surgical interventions and in diagnostic transurethral manoeuvres [8]. In Germany, fosfomycin trometamol is approved for use in women aged C12 years with acute uncomplicated UTIs associated with susceptible organisms (e.g. E. coli, K. pneumoniae, P. mirabilis, S. saprophyticus) [9]. In Ireland, fosfomycin trometamol is indicated for use in the treatment of adults with acute uncomplicated UTIs associated with sensitive organisms [10]. In the US, fosfomycin trometamol is indicated for use in the treatment of women with uncomplicated UTIs associated with susceptible strains of E. coli and E. faecalis [11]. Fosfomycin trometamol is not indicated for use in the treatment of pyelonephritis or perinephric abscess [11]. A single 3 g dose of fosfomycin trometamol is recommended for the treatment of uncomplicated UTIs in adults [8–11]. A single 2 g dose of fosfomycin trometamol is recommended for use in children [8]. The Italian [8] and Irish [10] SPC states that fosfomycin trometamol should be taken on an empty stomach (preferably before bedtime after bladder emptying [8]), the German SPC recommends that fosfomycin trometamol be taken &2 h before or after a meal [9], and the US prescribing information states that fosfomycin trometamol may be taken with or without food [11]. Current data do not indicate that administration of fosfomycin trometamol to pregnant women has any adverse effect on the fetus or newborn [8, 9, 11]. Fosfomycin trometamol is rated pregnancy category B in the USA [11] (i.e. it should only be used during pregnancy if clearly needed). The Italian, German and Irish SPCs generally advise caution when prescribing fosfomycin trometamol to pregnant women [8–10]. Local prescribing information should be consulted for contraindications, special warnings and precautions relating to fosfomycin trometamol.

6 Dosage and Administration

7.1 Guideline Recommendations

Fosfomycin trometamol is approved in various European countries (e.g. Austria, Belgium, France, Germany, Ireland,

An uncomplicated lower UTI is usually defined as acute cystitis occurring in a healthy, premenopausal,

7 Place of Fosfomycin Trometamol in the Treatment of Patients with Acute Lower UTIs and Pregnant Women with Asymptomatic Bacteriuria


nonpregnant woman with no known urological tract abnormalities, with all other patients considered to have complicated UTIs [2, 3]. However, use of this definition misclassifies as complicated many UTIs that can be effectively managed with a short course of antibacterial therapy (e.g. episodes of mild to moderate cystitis in healthy, ambulatory, compliant women who are pregnant, are elderly, have catheter-related UTIs or who have mild diabetes mellitus) [2]. A new classification system based on clinical presentation, risk factors and availability of appropriate antibacterial therapy has been proposed in Europe [103]. Uncomplicated lower UTIs are associated with considerable morbidity, and the primary goal of antibacterial therapy is the rapid resolution of symptoms [2]. Fosfomycin trometamol is one of the antibacterials recommended by current international guidelines for the empirical treatment of women with acute uncomplicated cystitis [3]. Other recommended empirical treatment options include nitrofurantoin, cotrimoxazole and pivmecillinam [3]. If these antibacterials cannot be used, fluoroquinolones or b-lactams are alternative options [3]. It is thought that limiting the use of fluoroquinolones in UTIs may help mitigate increasing fluoroquinolone resistance [3]. Adherence to treatment guidelines [3, 104] for uncomplicated lower UTIs could be improved. For example, a recent French study of general practitioners found that treatment guidelines for UTIs were adhered to in only 20 % of patients, with the prescribed antibacterial either one that was not recommended as a first-line treatment option or prescribed at an incorrect dosage or for an incorrect duration in the remaining 80 % of patients [105]. Over 60 % of patients with uncomplicated cystitis were prescribed a fluoroquinolone, &20 % were prescribed a furan, \10 % were prescribed fosfomycin trometamol and the remaining patients were prescribed cotrimoxazole or another antibacterial [105]. In terms of modifying prescribing behaviour, another French study found that a multimodal approach comprising dispatching guidelines concerning the prescribing of antibacterials in UTIs to general practitioners and voluntary attendance at educational sessions on antibacterial prescribing increased the prescribing of fosfomycin trometamol by 28.5 %, and decreased the prescribing of norfloxacin by 9.1 % [106]. When selecting an antibacterial for the empirical treatment of uncomplicated UTIs, local susceptibility patterns, particularly with regard to E. coli, should be considered [3]. Cotrimoxazole should not be used for the empirical treatment of UTIs if local resistance rates of uropathogens exceed 20 % [3]. Data are currently insufficient to make recommendations regarding resistance thresholds precluding empirical treatment with other antibacterials [3].

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7.2 Single-Dose Fosfomycin Trometamol an Important Option Recent data from various countries indicate that fosfomycin retains excellent in vitro activity against urinary E. coli isolates, with good in vitro activity also generally seen against urinary ESBL-producing E. coli, P. mirabilis, K. pneumoniae and S. saprophyticus isolates (Sect. 2.2). Susceptibility to fosfomycin has remained relatively stable over time in most countries, although Spanish studies have reported increases in ESBL-producing E. coli strains with resistance to fosfomycin (Sect. 2.4). These increases may be linked to rapid increases in the use of fosfomycin or the acquisition of fosfomycin resistance by a previously circulating CTX-M-15-producing E. coli O25b-ST131phylogroup B2 strain [56, 58]. In recent studies, fosfomycin demonstrated good in vitro activity against multidrugresistant and extensively drug-resistant Enterobacteriaceae isolates (Sect. 2.4). A small (n = 41) retrospective chart review found treatment with fosfomycin trometamol was associated with a bacteriological eradication rate of 59 % in hospitalized patients with UTIs associated with multidrug-resistant pathogens [62]. Additional clinical data concerning the use of fosfomycin trometamol in the treatment of multidrug-resistant infections are needed [107]. A suggested reason for the generally preserved in vitro susceptibility of E. coli to fosfomycin and antibacterials such as nitrofurantoin and mecillinam is that these agents are associated with only minor collateral damage (e.g. they have a low risk of selecting for drug-resistant pathogens) [3]. By contrast, broad-spectrum fluoroquinolones and cephalosporins tend to select for drug-resistant pathogens [3]. The minor collateral damage seen with fosfomycin may reflect its minimal effects on normal faecal flora [3, 20]. For example, all isolated rectal E. coli strains remained susceptible to fosfomycin after administration of singledose fosfomycin trometamol to women with an uncomplicated lower UTI, whereas ciprofloxacin-resistant rectal E. coli strains emerged in a recipient of ciprofloxacin (Sect. 4.1.1). The use of a single-dose regimen contributes to the low risk of resistance seen with fosfomycin trometamol, as uropathogens are exposed to the antibacterial for only a relatively short period (i.e. less intensive selective pressure) [20]. A single dose of oral fosfomycin trometamol achieves urinary concentrations that are higher than the MICs of common uropathogens and are sustained for &36–48 h (Sect. 3.2), resulting in a rapid bactericidal effect and limited opportunity for mutant selection [69, 108]. Results of recent studies indicate that single-dose fosfomycin trometamol had similar efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or

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nitrofurantoin in women with uncomplicated lower UTIs (Sect. 4.1). Use of single-dose fosfomycin trometamol may also be associated with a low risk of adverse events, lower costs and better compliance [108, 109]. For example, a single dose of oral fosfomycin trometamol was generally well tolerated, with the most commonly reported adverse events including GI adverse events (Sect. 5). In addition, significantly higher compliance rates were seen with fosfomycin trometamol than with amoxicillin/clavulanic acid or cefuroxime axetil in a recent study (Sect. 4.3). Asymptomatic bacteriuria has been associated with adverse outcomes, such as pyelonephritis and premature birth, in pregnant women [110, 111]. Indeed, screening for, and treatment of, asymptomatic bacteriuria is recommended in pregnant women [110]. Single-dose fosfomycin trometamol had similar efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in the treatment of asymptomatic bacteriuria in pregnancy (Sect. 4.2), and was associated with significantly fewer adverse events than amoxicillin/clavulanic acid (Sect. 5). Single-dose fosfomycin trometamol also had similar efficacy to a 5-day course of amoxicillin/clavulanic acid or cefuroxime axetil or a 3-day course of ceftibuten in pregnant women with a lower UTI (Sect. 4.3) and was generally well tolerated, with GI adverse events reported most frequently (Sect. 5). Although fosfomycin crosses the placental barrier (Sect. 3.1), no adverse effects on the fetus or new-born child have been reported following exposure to a single dose of fosfomycin trometamol [8, 9, 11]. Similarly, no maternal safety concerns have been identified in recent [79–82] or older [84, 94, 100] studies examining the use of single-dose fosfomycin trometamol in pregnant women with asymptomatic bacteriuria or a lower UTI. Similar to a number of other antibacterials (e.g. nitrofurantoin [112], cefuroxime axetil [113]), fosfomycin trometamol is rated pregnancy category B in the USA [11]. Caution is advised when administering fosfomycin trometamol to pregnant women in the EU [8–10] (Sect. 6). In-depth discussion of the use of multiple doses of fosfomycin trometamol in the treatment of UTIs is beyond the scope of this review. Briefly, recent studies demonstrated that two [114] or three [115, 116] doses of fosfomycin trometamol were effective in postmenopausal women with uncomplicated lower UTIs [114] or in patients with ESBL-producing E. coli-related uncomplicated [116] or complicated [115, 116] lower UTIs (clinical success rates of 78–94 %). Recent studies also demonstrated the efficacy of longer-term therapy with fosfomycin trometamol in the prevention of recurrent lower UTIs in nonpregnant women [117] or postmenopausal women with type 2 diabetes [118].

G. M. Keating

A recent retrospective analysis showed that a single oral dose of fosfomycin trometamol 3 g prevented UTIs in men undergoing transrectal-ultrasound guided biopsy of the prostate [119]. Results of this analysis are in agreement with studies conducted in the late 1980s and in the 1990s demonstrating that the prophylactic use of fosfomycin trometamol prevented UTIs in patients undergoing urological investigation or surgery [120–125]. These studies were conducted exclusively or predominantly in men. Several older studies of fosfomycin trometamol in patients with UTIs also included men [87, 95, 98, 101, 126], as did a recent noncomparative study [34] (Sect. 4.1.1). Trials also demonstrated the efficacy of fosfomycin trometamol in children with lower UTIs, although data are limited [127–130].

7.3 Conclusion In conclusion, fosfomycin has good in vitro activity against common uropathogens, with resistance rates remaining relatively stable over time. A single oral dose of fosfomycin trometamol 3 g achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol has similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of comparator antibacterials (including ciprofloxacin, norfloxacin, cotrimoxazole, nitrofurantoin, cefuroxime axetil, amoxicillin/clavulanic acid and ceftibuten) in women with uncomplicated lower UTIs, pregnant women with asymptomatic bacteriuria or pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with GI adverse events (e.g. diarrhoea, nausea) reported most commonly. Thus, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs. Data selection sources: Relevant medical literature (including published and unpublished data) on fosfomycin trometamol was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 21 October 2013], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Fosfomycin trometamol, fosfomycin tromethamine, fosfomycin, urinary tract infections, asymptomatic bacteriuria Study selection: Studies in patients with urinary tract infection or asymptomatic bacteriuria who received fosfomycin trometamol. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this


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article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. 18.

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Fosfomycin trometamol versus netilmicin in children's lower urinary tract infections.

Fosfomycin trometamol versus norfloxacin in the treatment of uncomplicated lower urinary tract infections of the elderly.

Single dose fosfomycin trometamol versus multiple dose nitrofurantoin in pregnant women with bacteriuria: preliminary results.

General practitioner study: fosfomycin trometamol versus amoxycillin clavulanate in acute urinary tract infections.

Urinary tract infections and asymptomatic bacteriuria in older adults.

Fosfomycin trometamol versus amoxycillin--single-dose multicenter study of urinary tract infections.

Single-dose fosfomycin trometamol (Monuril) versus multiple-dose norfloxacin: results of a multicenter study in females with uncomplicated lower urinary tract infections.

A comparative double-blind randomised study of single dose fosfomycin trometamol with trimethoprim in the treatment of urinary tract infections in general practice.

Bacterial sensitivity to fosfomycin in pregnant women with urinary infection.

The experience of pregnant women with a diagnosis of fetal lower urinary tract obstruction (LUTO).

Correction: The Prevalence of Asymptomatic Bacteriuria in Iranian Pregnant Women: A Systematic Review and Meta-Analysis.

The Prevalence of Asymptomatic Bacteriuria in Iranian Pregnant Women: A Systematic Review and Meta-Analysis.

Single-dose fosfomycin trometamol versus multiple-dose cotrimoxazole in the treatment of lower urinary tract infections in general practice. Multicenter Group of General Practitioners.

Oral prophylaxis with fosfomycin trometamol in transurethral prostatectomy and urological maneuvers: literature review and personal experience.

Oral fosfomycin for treatment of urinary tract infection: a retrospective cohort study.

Urinary tract infections in older women: a clinical review.

Management of Asymptomatic Bacteriuria, Urinary Catheters and Symptomatic Urinary Tract Infections in Patients Undergoing Surgery for Joint Replacement: A Position Paper of the Expert Group 'Infection' of swissorthopaedics.

Fosfomycin trometamol versus pipemidic acid in the treatment of bacteriuria in pregnancy.

Psychological aspects of lower urinary tract infections in women.

Psychological aspects of lower urinary tract infections in women.

Psychological aspects of lower urinary tract infections in women.

Psychological aspects of lower urinary tract infections in women.

Bacteria causing symptomatic urinary tract infection or asymptomatic bacteriuria.

Pressure-flow nomogram for women with lower urinary tract symptoms.