Oral Fosfomycin for the Treatment of Acute and Chronic Bacterial Prostatitis Caused by Multidrug-Resistant Escherichia coli

Acute and chronic bacterial prostatitis in outpatients is commonly treated with oral fluoroquinolones; however, the worldwide dissemination of multidrug-resistant (MDR) Escherichia coli has resulted in therapeutic failures with fluoroquinolones. We reviewed the literature regarding the use of oral fosfomycin in the treatment of acute and chronic prostatitis caused by MDR E. coli. All English-language references on PubMed from 1986 to June 2017, inclusive, were reviewed from the search “fosfomycin prostatitis.” Fosfomycin demonstrates potent in vitro activity against a variety of antimicrobial-resistant E. coli genotypes/phenotypes including ciprofloxacin-resistant, trimethoprim-sulfamethoxazole-resistant, extended-spectrum β-lactamase- (ESBL-) producing, and MDR isolates. Fosfomycin attains therapeutic concentrations (≥4 μg/g) in uninflamed prostatic tissue and maintains a high prostate/plasma ratio up to 17 hours after oral administration. Oral fosfomycin's clinical cure rates in the treatment of bacterial prostatitis caused by antimicrobial-resistant E. coli ranged from 50 to 77% with microbiological eradication rates of >50%. An oral regimen of fosfomycin tromethamine of 3 g·q 24 h for one week followed by 3 g·q 48 h for a total treatment duration of 6–12 weeks appeared to be effective. Oral fosfomycin may represent an efficacious and safe treatment for acute and chronic prostatitis caused by MDR E. coli.


Introduction
Acute and chronic bacterial prostatitis is di cult to treat as few antimicrobials attain therapeutic concentrations in the prostate [1,2]. In terms of orally available antimicrobials, the β-lactams demonstrate limited penetration into the prostate [1,2]. e tetracyclines achieve su cient concentrations in the prostate, but extensive resistance limits their use [1,2]. Trimethoprim-sulfamethoxazole (TMP-SMX) has been used successfully to treat bacterial prostatitis, due to su cient prostate penetration, but resistance also has limited its use. e pharmacokinetic (PK) and pharmacodynamic (PD) properties of orally administered uoroquinolones, including their broad-spectrum bactericidal activity covering common pathogens associated with prostatitis and good prostate penetration, have made them the agents of choice for the management of acute and chronic bacterial prostatitis for the past 25 years [1,2].
Escherichia coli continues to be the most common cause of uncomplicated and complicated urinary tract infections as well as acute and chronic bacterial prostatitis, although other organisms including enterococci species are increasing [1][2][3][4][5][6]. Since 2000, progressive increases in uoroquinolone resistance among clinical isolates of E. coli have been reported; more recently, the emergence and proliferation of a dominant multidrug-resistant (MDR) subclone of sequence type 131 (ST131) has contributed to increasing uoroquinolone resistance [3,4]. ST131 is also associated with the spread of extended spectrum β-lactamase-(ESBL-) producing E. coli, primarily carrying CTX-M-14 and CTX-M-15 which confer resistance to cephalosporins, as well as resistance determinants for TMP-SMX and tetracyclines [3][4][5][6]. We have recently reported that 76.3% of uoroquinolone-resistant and 56.1% of ESBL-producing isolates of E. coli collected across Canada were ST131 [3,4]. As these ESBL-producing MDR E. coli continue to spread not only within Canada but around the globe, clinicians and researchers worry that more uoroquinolone treatment failures will be reported in patients with bacterial prostatitis [7]. Disturbingly, some of the MDR ESBLproducing E. coli (and Klebsiella spp.) are growing becoming resistant to the carbapenems, even further complicating the treatment of acute and chronic prostatitis [3].
Fosfomycin has been available to physicians in many European countries as well as Japan, South Africa, and Brazil, in both oral and parenteral formulations, for up to four decades [8][9][10][11]. Oral fosfomycin rst entered the Canadian and US markets in 1997 but was withdrawn in Canada several years later due to lack of use [8]. It was recently reintroduced in Canada and is indicated for the treatment of acute uncomplicated cystitis in adult women infected with susceptible isolates of E. coli and Enterococcus faecalis [8]. Our research group and others have recently reported that fosfomycin demonstrates potent in vitro activity versus antimicrobial-resistant E. coli including ESBLproducing, AmpC-producing, and MDR isolates [6,[9][10][11]. In addition, its ability to attain therapeutic concentrations in prostatic uids or secretions along with a favourable safety pro le has resulted in clinicians asking about its potential role for the treatment of acute and chronic bacterial prostatitis in the setting of MDR E. coli isolates when uoroquinolones cannot be used [6,[9][10][11]. is review seeks to provide an overview of the potential role of oral fosfomycin in the treatment of acute and chronic bacterial prostatitis caused by MDR E. coli, which includes a comprehensive review of available clinical data.

Current Antimicrobial Treatment for Acute Bacterial Prostatitis
Most patients (∼85%) diagnosed with acute bacterial prostatitis (ABP-National Institutes of Health type I) can be successfully treated as outpatients with oral antimicrobials [12]. Hospitalization and intravenous antimicrobial therapy may be warranted in patients with ABP who have failed outpatient management are systemically ill, are unable to tolerate oral intake, or present with urinary retention [12]. Empiric outpatient antimicrobial therapy should commence immediately after clinical diagnosis with subsequent optimization of treatment based on urine and blood culture pathogen/susceptibility results [2]. Clinicians should consider local antimicrobial resistance trends prior to empiric treatment, especially with the increasing proliferation of ESBL-producing MDR E. coli, and the increasing role of other organisms including enterococci species [1,3]. Oral antimicrobial treatment courses of 2-4 weeks duration are generally su cient to provide microbiological and clinical cure [13]. A urine culture one week following completion of antimicrobial therapy indicating bacterial eradication is suggested to con rm microbiological cure [13]. Empiric oral antimicrobial treatment regimens for ABP vary depending on age and sexual activity of patients [12]. Fluoroquinolones, including cipro oxacin and levo oxacin, are the preferred oral agents for the treatment of ABP [1]. Due to resistance, some clinicians prefer to use combination treatment [1,2]. Alternative oral agents may also be e ective if they can penetrate acutely in amed prostatic tissue and attain therapeutic concentrations at the site of infection [2]. If hospitalization is required, a wide range of intravenous agents can be used including uoroquinolones, third-and fourth-generation cephalosporins, piperacillin-tazobactam, carbapenems, and aminoglycosides [12]. In patients where the risk of a sexually transmitted infectious pathogen is low, oral cipro oxacin 500 mg BID (twice daily) for 10-14 days or oral levo oxacin 500-750 mg OD (once daily) for 10-14 days is recommended [12]. TMP-SMX 160/800 mg BID × 10-14 days is an oral alternative to uoroquinolones [2]. Regimens covering Neisseria gonorrhoeae and Chlamydia trachomatis are recommended in sexually active men under 35 years of age and men over 35 years of age exhibiting high-risk sexual behaviour [12]. For patients satisfying these criteria, intramuscular ceftriaxone or oral ce xime, followed by doxycycline is recommended [12].

Current Antimicrobial Treatment for Chronic Bacterial Prostatitis
Approximately 10% of patients diagnosed with ABP will develop chronic bacterial prostatitis (CBP-National Institutes of Health type II) [13]. CBP is characterized by recurrent urinary tract infections (UTIs) due to persistence of the same causative pathogen resulting in unresolved urogenital symptoms [13]. Similar symptoms are reported in cases of acute and chronic bacterial prostatitis including dysuria, urgency, and perineal pain; however, patients with CBP are generally afebrile unlike patients with ABP [2,13]. Individuals with CBP typically cycle between symptomatic and asymptomatic periods for a prolonged period of time (>3 months) despite ongoing infection [1]. Treatment for CBP is often much more problematic than ABP as re ected in high rates of recurrence (25-50%) [13]. Achieving therapeutic concentrations of antimicrobial agents at the site of infection is a major limitation to the e ective treatment of CBP with oral antimicrobial agents [1]. Unlike ABP, prostatic tissue in patients with CBP may be inconsistently in amed despite persistent infection. Only agents with suitable pharmacological properties can cross prostatic capillary endothelium and attain therapeutic concentrations in prostatic epithelium [13]. Agents possessing small molecular size, high lipid solubility, a low degree of ionization, high pK a values, and low protein binding are generally favourable for penetration into prostatic uids or secretions [1]. Fluoroquinolones, sulfonamides, macrolides, and tetracyclines generally exhibit these pharmacological properties and have demonstrated clinical e cacy in the treatment of CBP [13]. Oral antimicrobial courses of ≥4 weeks are considered optimal for CBP; oral therapy of up to 6 weeks in duration is sometimes used [13]. Treatment should commence after obtaining urine/blood culture results and ideally be tailored to pathogen/susceptibility data [1]. Repeat courses of antimicrobials are discouraged for fear of generating antimicrobial-resistant strains, although some evidence suggests that long-term low-dose courses of antimicrobials may minimize symptomatic recurrences and be of particular bene t to patients with abnormal genitourinary pathology including prostatic calculi [1,13].
Fluoroquinolones are the most commonly used rst-line oral antimicrobials for the treatment of CBP due to their superior penetration into unin amed prostatic uids or secretions (10-50% of serum concentrations) [2,14,15]. A comparative study published by Perletti et al. indicated that cipro oxacin, levo oxacin, lome oxacin, o oxacin, and pruli oxacin all demonstrated comparable clinical and microbiological e cacy in the treatment of CBP [16]. Cipro oxacin at a dose of 500 mg BID for 4-6 weeks or levo oxacin at a dose of 500 mg OD for 4-6 weeks are commonly cited oral regimens for the treatment of CBP [2,14]. TMP-SMX is also a commonly used oral agent for the treatment of CBP; however, it is widely recognized to be less e ective than uoroquinolone therapy due to diminished penetration into prostatic uids or secretions and higher rates of resistance [1,14]. Doxycycline is an alternative secondline agent; however, extensive tetracycline resistance has greatly diminished its e cacy in the treatment of CBP in the last decade [1,2,14]. Macrolides such as azithromycin or clarithromycin are recommended in cases of CBP caused by atypical bacterial pathogens such as Chlamydia trachomatis [16].
We have recently reported a signi cant increase in the proportion ESBL-producing E. coli in Canadian hospitals [3,4]. Our research group and others have identi ed that the proliferation of ESBL-producing E. coli in Canada has been largely associated with the spread of a pandemic clone, E. coli O25b:H4 ST131 [3,17]. Our data further demonstrated that >75% of ESBL-producing E. coli exhibited a MDR phenotype, hence, establishing a strong association between the ESBL genotype and the MDR phenotype [3]. We reported an increase in the proportion of ESBL-producing E. coli from 3.4% to 7.1% and an increase in the frequency of MDR among ESBL-producing E. coli of 77.4% to 82.6% over a 5-year period [3]. Concomitant resistance to uoroquinolones, TMP-SMX, tetracyclines, and amoxicillin-clavulanate is common in ST131 E. coli, particularly in association with the ESBL genes CTX-M-14 and CTX-M-15 [3,18,19]. e increasing prevalence of antimicrobial-resistant phenotypes among E. coli in Canada has led to growing concern about the e cacy of empirical treatments for urinary tract infections including acute cystitis, pyelonephritis, and more recently, acute and CBP [8,20]. e di culty in treating bacterial prostatitis, especially chronic cases, can be in part attributed to the high rates of resistance to empirical agents [21]. High rates of uoroquinolone resistance, TMP-SMX resistance, and MDR E. coli have played an increasing role in the poor prognosis of patients with bacterial prostatitis [3][4][5][6]21]. Recent in vitro data from our national CANWARD surveillance study from 2007 to 2015, which included 1,207 E. coli isolates across 15 hospitals in Canada, indicated cipro oxacin and TMP-SMX resistance rates of 18.9% and 25.0%, respectively, as shown in Table 1 [4]. Our group concluded that current uoroquinolone and TMP-SMX resistance rates in E. coli exceed limits that, in some cases, no longer support their empirical use in therapy [6].
Fosfomycin has growingly received attention for the treatment of bacterial prostatitis after demonstrating clinical e cacy in the treatment of acute uncomplicated cystitis and promising in vitro activity against ESBL-producing MDR E. coli [6,8]. Fosfomycin demonstrates potent in vitro activity against a variety of resistant phenotypes including ESBLproducing, cipro oxacin-resistant, TMP-SMX-resistant, and MDR isolates of E. coli (Table 1). Overall, E. coli susceptibility to fosfomycin was reported to be 99.2% with susceptibility rates of 99.7%, 96.1%, 95.1%, and 100% for TMP-SMXresistant, cipro oxacin-resistant, ESBL-producing, and MDR isolates (Table 1) [4]. Zhanel et al. [8] and Mezzatesta et al. [20] reported similar data and corroborated our conclusion that fosfomycin's in vitro activity indicates that it may be a viable empirical therapy for uncomplicated UTIs, in the setting of extensive uoroquinolone and TMP-SMX resistance in E. coli . ese promising in vitro data, however, need to be assessed along with fosfomycin's pharmacological properties to determine its true potential for the treatment of acute and chronic prostatitis caused by MDR E. coli.

Fosfomycin Penetration into Prostatic Fluids or Secretions
Oral fosfomycin is typically administered using the fosfomycin tromethamine (FT) formulation due to superior bioavailability (∼40%) versus fosfomycin calcium (∼12%) [10]. Upon oral administration, FT is rapidly absorbed in the gut where it enters the bloodstream and dissociates, releasing fosfomycin as a free acid [8,10]. Once in the blood, fosfomycin is distributed throughout the body to a variety of tissues and biological uids including the kidneys, bladder, prostate, lungs, cerebrospinal uid, bone, abscess uid, and heart valves [8,10]. Fosfomycin has a large volume of distribution (V d of ∼2 L/kg) indicating extensive tissue/cellular penetration [22]. Fosfomycin's ability to successfully penetrate and achieve therapeutic concentrations in prostatic uids or secretions is likely due to favourable pharmacological properties including small molecular size and low protein binding [1,8,10]. In addition, the high lipid solubility of fosfomycin is favourable for penetration into the lipid-rich parenchyma of the prostate [22].
Few peer-reviewed studies have assessed fosfomycin's penetration into human prostatic uids or secretions. Gardiner et al., published the rst prospective human study measuring intraprostatic fosfomycin concentrations after administration of a single 3 g oral preoperative dose to patients undergoing transurethral resection of the prostate (TURP) [9]. Plasma, urine, and prostatic tissue biopsies from the transition and peripheral zones were obtained at single time points after commencement of TURP surgery for each of the 26 subjects (mean age, weight, and eGFR (estimated glomerular ltration rate) of 68 ± 9 years, 86.2 ± 13 kg, and 67 ± 12 mL/minute/1.73 m 2 , resp.) [9]. All 26 subjects in the study were undergoing treatment for benign prostatic hyperplasia and were otherwise healthy. Fosfomycin concentrations were measured using liquid chromatography-mass spectrometry ( Table 2). e mean fosfomycin concentration in the transition zone was determined to be 8.30 ± 6.63 μg/g (range, 0.56-26.05 μg/g) measured at a mean postdose time of 598 ± 152 min [9]. e mean concentration in the peripheral zone was determined to be 4.42 ± 4.10 μg/g (range, 0.17-18.06 μg/g) measured at a mean postdose time of 608 ± 155 min [9]. e overall mean prostate concentration was reported to be 6.50 ± 4.93 μg/g (range, 0.67-22.06 μg/g) with a mean postdose measurement time of 602.9 ± 153.36 min [9]. Seventy percent of subjects demonstrated mean fosfomycin prostatic concentrations of ≥4 μg/g at the time of measurement, indicating they achieved a concentration above the MIC 90 (≥4 μg/mL) of E. coli [8][9][10]. Average plasma concentrations were reported to be 11.42 ± 7.60 μg/mL (range, 2.29-40.38 μg/mL) measured at a mean postdose time of 565 ± 149 min [9]. Mean fosfomycin urine concentrations were 570.57 ± 418.40 μg/mL (range, 47.99-1522.05 μg/mL) measured at a mean postdose time of 581 ± 150 min. Data from each participant was used to determine the mean prostate/plasma ratio (0.67 ± 0.57; range, 0.07-2.92) as graphically represented in Figure 1 [9]. is study successfully demonstrated that fosfomycin is capable of reaching therapeutic concentrations in the prostate and maintains a high prostate/plasma ratio up to 17 hours after oral administration of a single dose [9]. For patients with acute and chronic bacterial prostatitis, in ammation of the prostate would likely enhance prostatic penetration of fosfomycin, and prostatic uid or secretion concentrations would be expected to be even greater than those reported by Gardiner et al. [9].
Rhodes et al. assessed the optimal timing of prophylactic oral fosfomycin administration prior to TURP [23]. Plasma, peripheral zone, and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing TURP following a single oral dose of 3 g of fosfomycin. Rhodes et al. reported that fosfomycin is likely to reach prostatic concentrations ≥ 4 μg/g, when administered 1-4 hours prior to surgery [23]. Rhodes et al. reported that fosfomycin transition zone prostate concentrations exceeded 4 μg/mL in 90% of the population between hours 1 and 9 after fosfomycin administration while peripheral zone prostate concentrations exceeded 4 μg/mL in 70% of the population between hours 1 and 4. e authors concluded that oral fosfomycin should be administered 1-4 hours prior to prostate biopsy in order to achieve therapeutic concentrations in the prostate to prevent postoperative infection with E. coli [22].

Fosfomycin for the Treatment of Acute and Chronic Prostatitis
To our knowledge, a total of four publications (3 papers and one poster) have reported clinical data of oral fosfomycin therapy in the treatment of acute and chronic prostatitis (  [7]. e subjects (median age of 54 years) were selected based on the following inclusion criteria: diagnosis of CBP, failure of prolonged rstline antimicrobial therapy, and no possibility of successful uoroquinolone or TMP-SMX treatment due to resistance, failure, or side e ects. CBP diagnosis was determined when all four of the following criteria were satis ed: (i) ≥1 symptomatic occurrence of prostatitis of ≥4 weeks duration or ≥2 episodes of any duration in the preceding 12 months, (ii) active symptoms of prostatitis, (iii) absence of genitourinary abnormality as determined by urologic ultrasound on more than one occasion, and (iv) evidence of infection as determined by a positive Meares-Stamey test, positive semen culture, or ≥2 urine cultures with presence of the same pathogen ≥ 1 month apart. First-line antimicrobial therapy failure was de ned by persistence of the same causative pathogen in cultures after treatment with cipro oxacin at a dose of 500 mg/12 h for ≥4 weeks or TMP-SMX at a dose of 160 mg/800 mg/12 h for ≥6 weeks. All subjects in the study ful lled the inclusion criteria and also fell within the clinical de nition of CBP. E. coli was isolated as the causative pathogen in 14/15 (93.3%) subjects in the study. MDR (resistant to at least one agent in ≥3 antimicrobial drugclasses) E. coli accounted for 5/14 (35.7%) isolates. An ESBL phenotype was identi ed in 4/14 (28.6%) E. coli isolates, and 1/14 (7.1%) E. coli isolates was identi ed as an AmpC      [24]. Subject 1, a 73-year-old diabetic man developed signs/symptoms including high fever, dysuria, and frequency shortly after undergoing a transrectal ultrasound-(TRUS-) guided biopsy of the prostate. e patient was diagnosed with acute prostatitis. After failing rst-line antimicrobial therapy, the patient was transferred to Austin Health in Melbourne, Australia, where urine culture and prostate biopsy were performed. ESBL-producing E. coli was isolated in culture that demonstrated in vitro resistance to cipro oxacin and susceptibility to meropenem, ertapenem, and fosfomycin (MIC, 1 μg/mL). e biopsy showed evidence of focal acute and chronic prostatitis. Meropenem at a dose of 1 g was administered intravenously q 8 hours for 2 weeks followed by outpatient intravenous ertapenem 1 g OD for 4 weeks. Two weeks posttreatment the patient relapsed. ESBLproducing E. coli with the same susceptibility pro le as observed previously grew in urine culture. e patient was placed back on intravenous meropenem (1 g·q 8 h) for two weeks and followed up with oral fosfomycin 3 g OD for 14 days. e fosfomycin dose was increased to 3 g BID; however, the patient displayed fecal urgency/diarrhea beginning 36 hours after the increase in dosage. e increased dose was discontinued after ve days, and the patient reverted back to a 3 g OD dosage regimen. e patient completed a total course of 16 weeks oral fosfomycin. Microbiological eradication and clinical cure were documented after a 6 month follow-up period. Subject 2, an 80-year-old man was initially treated for a urinary tract infection caused by ESBL-producing E. coli. e susceptibility pro le indicated resistance to cipro oxacin but susceptibility to fosfomycin (MIC, 1 μg/mL). e patient was treated with oral fosfomycin 3 g every 72 hours for 2 weeks. Five days posttreatment, the patient relapsed and presented with symptoms of dysuria, polyuria, and malodorous urine. A urine culture grew the same pathogen as previously identi ed. Computed tomography (CT) indicated an enlarged prostate. A clinical diagnosis of acute prostatitis was made, and the patient was placed back on oral fosfomycin 3 g OD for 12 weeks. Microbiological eradication and clinical cure were documented after a 6 month follow-up period.
Cunha et al. reported a single case of a 53-year-old man successfully treated for chronic prostatitis with a combination of doxycycline and oral fosfomycin [22]. e patient presented with symptoms including dysuria, frequency, and malodorous urine. Urinalysis indicated high-grade pyuria and mucous threads. Urine culture isolated ESBL-producing E. coli resistant to doxycycline (MIC, >16 μg/mL) and uoroquinolones (MIC, >8 μg/mL) but susceptible to fosfomycin (MIC, 2 μg/mL). e patient was initially treated with nitrofurantoin (100 mg·q 12 h) for one month. Nitrofurantoin treatment was unsuccessful, and the patient's symptoms persisted. Doxycycline likewise provided no improvement. e patient was then placed on oral fosfomycin 3 g·q 72 h for 1 month. Within days of initiating oral fosfomycin, the patient relapsed and symptoms returned. Urine culture grew the same pathogen as previously isolated.
e patient was then treated with a high-dose course of oral fosfomycin (6 g·q 72 h for 1 month); however, the patient again relapsed. Finally, combination therapy with oral fosfomycin 3 g·q 72 h and oral doxycycline 100 mg·q 12 hours for 2 weeks resulted in sustained microbial eradication and clinical cure.
Karaiskos et al. reported on 20 patients with chronic prostatitis treated with oral fosfomycin at Hygeia General Hospital's outpatient infectious diseases clinic in Athens, Greece [25]. Of the 20 subjects (mean age of 53.6 years), E. coli was the causative pathogen in 13 (65%) subjects. Susceptibility data indicated that 8/13 (61.5%) E. coli isolates were uoroquinolone-resistant, 7/13 (53.8%) were TMP-SMX-resistant, and 2/13 (15.4%) were ESBL producers. All isolates were susceptible to fosfomycin. Oral fosfomycin was administered at a dose of 3 g OD for one week followed by 3 g·q 48 hours for 6 weeks. e patient follow-up occurred at 3 months and 6 months posttreatment. Clinical cure was documented in 10/13 (77%) subjects. Of the three clinical treatment failures, two patients relapsed and one patient discontinued treatment due to severe diarrhea. Five of 20 subjects (25%) reported adverse e ects during treatment, most commonly diarrhea.

Place in Therapy
e rapid global spread of MDR ESBL-producing E. coli represents a growing challenge in the treatment of acute and chronic prostatitis [3,4]. High rates of resistance to empirical agents have consequently increased the likelihood of clinical treatment failures in cases of bacterial prostatitis, especially those caused by ESBL-producing MDR E. coli [7,21]. e necessity for e ective alternative oral therapies in the treatment of acute and chronic prostatitis is imperative. Fosfomycin has emerged as a potential oral therapy candidate due to superior in vitro activity (99.2% susceptibility) versus various E. coli resistant genotypes/phenotypes and adequate penetration into prostatic tissue (≥4 μg/g in 70% of patients) [8,9]. Current data suggests that oral fosfomycin demonstrates clinical cure rates in the range of 50-77% in patients with bacterial prostatitis caused by antimicrobial-resistant E. coli [7,25]. Reported microbiological eradication rates in these same patients are >50% [7]. E ective oral fosfomycin treatment doses for chronic prostatitis have ranged from 3 g OD to 3 g·q 72 hours [7,22,24,25]. Published evidence suggests that oral fosfomycin dosing frequency exceeding 3 g OD is not recommended due to the increased propensity for gastrointestinal adverse e ects [10,24]. High-dose fosfomycin (>3 g per dose) has not demonstrated improved clinical e cacy versus 3 g doses [22]. Based upon the current available evidence, an oral fosfomycin dosage of 3 g q 24 h for the rst week of treatment followed by 3 g q 48 h for the remaining duration of treatment appears e ective.
is dosage regimen has demonstrated the highest clinical cure rates while minimizing gastrointestinal adverse e ects. If gastrointestinal adverse e ects occur, the fosfomycin dosage/frequency should be adjusted appropriately. Based upon the available evidence, oral fosfomycin treatment durations of 6-16 weeks appeared to be e ective. We note that the majority of clinical cures have been documented after 6-7 weeks of treatment with oral fosfomycin. We are unaware of any data treating patients with bacterial prostatitis with oral fosfomycin for longer than 16 weeks. Clearly, additional clinical data are needed to determine optimal dosage/duration of oral fosfomycin treatment for acute and chronic prostatitis caused by antimicrobial-resistant E. coli. In addition, combination antimicrobial data with fosfomycin are required to fully assess fosfomycin's potential for treatment. In conclusion, we report that oral fosfomycin may be a reasonable treatment alternative for acute and CBP caused by antimicrobial-resistant E. coli. In addition, oral fosfomycin may also be appropriate for use when rst-line treatments fail or cannot be used due to adverse e ects.