Can fosfomycin be used for prostatitis? The spread of antibiotic resistance has clinicians pondering what other drug options may be available when preferred agents no longer work. Here oral fosfomycin for acute or chronic bacterial prostatitis is discussed.
Article Author: Brittany A. Williams, Pharm.D.
Article Mentor: Amber Billings, Pharm.D., MPH, BCPS, AAHIVP
[Last updated: 2 June 2019]
Bacterial prostatitis is divided into both acute and chronic conditions. According to the National Institutes of Health, acute prostatitis is defined as “an acute urinary tract infection with prostatic involvement” . In contrast, chronic prostatitis is defined as “recurrent urinary tract infections with the same organism in prostatic secretions during asymptomatic periods” . Typical uropathogens include gram-negative bacilli (GNB); however, gram positive and atypical organisms could also be pathogenic. Escherichia coli (commonly termed E. coli) is the most prominent cause of bacterial prostatitis and is estimated to cause 50-80% of infections .
Fluoroquinolones (e.g., ciprofloxacin, levofloxacin) have historically been the drugs of choice for prostatitis due to high intra-prostatic concentrations ; however, the Infectious Disease Society of America (IDSA) guidelines also recommend sulfamethoxazole-trimethoprim (TMP-SMX), tetracyclines, or macrolides as oral antimicrobial regimen options . Beta-lactams may also be considered for acute prostatitis.The duration of therapy for treatment ranges from 2 to 4 weeks with acute prostatitis and 4 to 6 weeks for chronic prostatitis . With increasing multidrug-resistant gram-negative bacteria (MDR-GNB), additional oral treatment options warrant exploration and fosfomycin may be one such option .
Some points to consider before initiating fosfomycin are discussed here. We do not discuss intravenous fosfomycin, which the FDA recently declined to approve (at least for now) in April of 2019.
1. Spectrum of Activity
Fosfomycin exhibits in vitro activity against both gram-negative and gram-positive bacteria including E. coli, Enterococcus faecalis, Enterococcus faecium, Citrobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris and Serratia marcescens [2,5]. Furthermore, current research suggests this also encompasses extended-spectrum beta-lactamase (ESBL) producing, AmpC-producing, and other types of MDR E. coli. With a broad spectrum of activity, fosfomycin covers many of the common uropathogens seen in prostatitis and may remain an option in the setting of fluoroquinolone or SMX/TMP resistance.
It is notable that many labs do not routinely perform fosfomycin sensitivity testing. A special request to the microbiology lab may be required to obtain fosfomycin susceptibilities.
2. Prostate Penetration
Fosfomycin exhibits favorable pharmacologic properties that allow for penetration into the prostate including a small molecular weight, low protein binding, and high lipid solubility [2, 6-7]. Furthermore, pharmacokinetic studies have examined fosfomycin concentrations in human prostate fluids and secretions. These studies indicate that the prostatic fosfomycin concentration is above the MIC90 (>4 mg/mL) for E. coli in 70% of cases. High concentrations are maintained up to 17 hours after administering a single dose orally. In addition, when the prostate is inflamed, the concentrations are expected to be higher.
3. Clinical Data
Karaiskos et al. published a prospective, observational study of 44 patients treated with oral fosfomycin for chronic bacterial prostatitis due to MDR pathogens . The most common organism isolated was E. coli. Patients were included if they met the National Institutes of Health (NIH) category II definition for chronic prostatitis. The primary outcome of interest was clinical and microbiologic cure at the end of treatment and was achieved in 82% of patients. The duration of treatment was 6 weeks for most patients unless calcifications were noted on imaging, in which case the duration was extended to 12 weeks. The secondary outcome was the rate of relapse at 3 and 6-month follow up appointments and was seen in 20% and 27% of patients, respectively. The most prevalent adverse reaction seen was diarrhea, which required therapy discontinuation in 1 of 8 patients and extending the interval in 4 patients. Overall, this trial highlights the potential therapeutic effect of fosfomycin with MDR pathogens in the treatment of chronic bacterial prostatitis.
Grayson et al. published two case reports of MDR-GNB prostatitis treated with oral fosfomycin . The first patient had acute prostatitis due to ESBL-producing E. coli refractory to six weeks of meropenem and ertapenem and was subsequently treated for 16 weeks with oral fosfomycin. The second patient initially presented with an ESBL-producing E. coli UTI but was subsequently diagnosed with acute prostatitis. He was treated with oral fosfomycin for 12 weeks. Clinical and microbiologic cure at the 6-month follow up visit was documented in both cases. Once again, the most common adverse reaction was gastrointestinal, including fecal urgency and diarrhea refractory to loperamide with twice daily dosing. These case reports suggest that fosfomycin can also be used in acute prostatitis.
Finally, Los-Arcos et al. conducted a retrospective study examining the efficacy of fosfomycin for refractory chronic bacterial prostatitis in 15 patients . Refractory disease was due to previous therapy failure, side effects, or resistance to both fluoroquinolones and SMX/TMP. In order to be included in the study, the patient had to have a history of chronic bacterial prostatitis, active symptoms, no genitourinary abnormalities, and laboratory evidence of infection. Patients were treated for 6 weeks and followed for at least a year. E. coli was the most prominent pathogen isolated, and the study included MDR, ESBL, and AmpC-producing organisms. At a median of 20 months, the clinical cure rate was approximately 50%. The authors postulated this low cure rate could be due to an MIC > 4 mg/mL in some isolates and prostatic calcifications in 57% of the patients. Of note, no patients exhibited gastrointestinal side effects in this study. This trial indicates that fosfomycin may be used for refractory chronic bacterial prostatitis but with a reduced the clinical cure rate compared to the study by Karaiskos and colleagues.
4. Dosing & Administration
3g PO for urinary tract infection
|1. Pour contents into 3-4 ounces of water and stir to dissolve
2. Do not use hot water
3. Take immediately without regard to food
|Karaiskos et al.||
3g PO daily x 7 days then
3g PO q48h
3g q72h with diarrhea
6-12 weeks (longer duration if calcifications in prostate)
|1. Dissolve contents of the sachet in a glass of water
2. Take immediately on an empty stomach, before bedtime and after emptying bladder
|Grayson et al.||
3g PO once daily
|Los-Arcos et al.||
3g PO q48-72h
References 4,5,8, and 9 were used to develop this table.
5. Cost and Availability
According to RED BOOK, the average wholesale price of fosfomycin is approximately $100 per 3-gram packet . Furthermore, it may not be readily stocked in many community pharmacies. Therefore, barriers to access due to cost or availability should be considered when recommending fosfomycin for an extended duration.
In conclusion, fosfomycin appears to be a viable option for treating acute or chronic prostatitis, especially in patients who have failed or do not tolerate guideline-based therapies. Fosfomycin has sufficient penetration into the prostate, an estimated in vitro activity of 99.2% against E. coli, and promising evidence supporting both clinical and microbiological eradication rates that range from 50-77% and exceed 50%, respectively . While the dosing interval varies between trials, the maximum tolerated interval may be dependent on the gastrointestinal side effects. Furthermore, the cost of fosfomycin may preclude use in some patients. Although further research is warranted, fosfomycin may be an option for the treatment of acute and chronic bacterial prostatitis in patients who are refractory or resistant to fluoroquinolone or SMX/TMP therapy.
As fosfomycin is considered for acute or chronic bacterial prostatitis, clinicians should carefully weigh the risks and benefits of therapy, including what has been discussed here and other factors beyond the scope of this article.
REFERENCES / RECOMMENDED READINGS
2. Zhanel GG, Zhanel MA, Karlowsky JA. Oral Fosfomycin for the Treatment of Acute and Chronic Bacterial Prostatitis Caused by Multidrug-Resistant Escherichia coli. Can J Infect Dis Microbiol. 2018; 2018: e1-9.
ABOUT THE AUTHORS
Brittany A. Williams, Pharm.D.
Before attending pharmacy school, Dr. Williams completed an Associate in Science degree during high school and attended College of Charleston for undergraduate education. She graduated from South Carolina College of Pharmacy, Medical University of South Carolina Campus. Currently, Dr. Williams is completing a Post-Graduate Year 1 Pharmacy Practice Residency at Spartanburg Medical Center with interest areas in pediatrics, infectious diseases, and oncology. Upon completion of the residency program, she plans to practice as a clinical pharmacist.
Amber Billings, Pharm.D., MPH, BCPS, AAHIVP
Dr. Billings (formerly Giles) received a bachelor degree in Biology from Presbyterian College (Clinton, SC), master of public health degree from University of South Carolina (Columbia, SC), and doctor of pharmacy degree from South Carolina College of Pharmacy (Charleston, SC). She then completed a Post-Graduate Year 1 Pharmacy Practice Residency at Spartanburg Medical Center (Spartanburg, SC) followed by a Post-Graduate Year 2 Infectious Diseases Pharmacy Residency at Jackson Memorial Hospital (Miami, FL). She is a board-certified pharmacotherapy specialist and AAHIVM-certified HIV pharmacist.
Dr. Billings is currently an assistant professor of pharmacy practice at Presbyterian College School of Pharmacy (Clinton, SC) and practices as an infectious diseases clinical pharmacist at Medical Group of the Carolinas- Infectious Disease (Spartanburg, SC) where she precepts 4th year pharmacy students and Post Graduate Year 1 Residents on infectious diseases ambulatory care rotations. She is an active member of SIDP, AACP, SCSHP, and the ID-EN. Her research interests include HIV, opportunistic infections, and antimicrobial stewardship.
Disclosures: The article author and article mentor report no conflicts of interests.
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