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Simple UTIs not so simple after all
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The public awareness of multidrug resistance pathogens has risen almost as quickly as the rate of development of these pathogens. The media has played a significant role in alerting and educating the public on the emergence of the superbugs. It only took the reports of a methicillin-resistant Staphylococcus aureus outbreak among a high school wrestling team in 1993 to send the public and media into a frenzy.
Next came the alarming rise of Clostridium difficile. It was deemed the next MRSA. Shortly after, vancomycin-resistant enterococcus was thrust into the news. Now over the last year, the gram-negative bacteria have found their way into the spotlight. The extended-spectrum beta-lactamase (ESBL) gram-negative pathogens, the carbapenem-resistant Enterobacteriacea (CRE) and now the New Delhi metallo beta lactamase-1 (NDM-1) are regarded as the newest superbugs. While most of these bacteria pose a significant threat to hospitalized patients, their emergence in the community setting is alarming. The isolation of these multidrug resistant pathogens is starting to “complicate” the treatment of a simple UTI.
Treatment options
Treatment options are often limited by lack of susceptibility, adverse effects, lack of oral availability and cost. Fosfomycin (Monurol, Forest Laboratories) is an old and forgotten agent that may find its way into the spotlight for treatment of UTIs.
Bladder inflammation was described in females in the 1800s. A conservative approach was taken with bed rest and letting Mother Nature take its course, which in previous literature was noted to take 4 weeks for resolution of symptoms. In the 1900s, treatment with chemotherapeutic agents were employed to quicken resolution of symptoms. The introduction of sulfonamide in 1937 launched the era of treating cystitis or UTIs with antimicrobial therapy. In urology, UTIs are not considered serious until they become recurrent, are identified in a female who is pregnant, are complicated by abnormal anatomy, premenopausal females or resistant pathogens are isolated. UTIs account for more than 7 million physician’s office visits and more than 1 million hospital admissions in the United States annually. Overuse of antimicrobials, either with too broad spectrum or longer than necessary durations of therapy, to treat asymptomatic and even symptomatic cystitis is noted in the literature. Emergence of resistance is also clearly correlated to this overuse of antimicrobials.
Off-label usage
Fosfomycin was approved by the FDA in 1996 for uncomplicated UTI caused by Escherichia coli and Enterococcus faecalis in females. It since has had off-label use for complicated UTI’s and prostatitis in males. It has been a commonly prescribed anti-infective in Japan and Europe for several decades but is rarely used in inpatient or outpatient settings in the US. It is currently available in the US as an oral agent; 3 g in 3 to 4 oz of water as a single dose for uncomplicated UTI or 3-g dose every 2 to 3 days for 3 days for complicated UTI in males.
Fosfomycin has a broad-spectrum antimicrobial with activity against most aerobic gram-positive and gram-negative bacteria. Some of the most notable urinary pathogens, including E. coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus, Pseudomonas, Enterococcus and vancomycin-resistant enterococcus have all showed susceptibility in vitro to fosfomycin. Fosfomycin uses a L-alpha-glycerophosphate transport system as a primary entrance to bacteria but has a secondary transport system via the hexose phosphate uptake system. It irreversibly inhibits the enzyme pyruvyl transferase, which initiates the first step of peptidoglycan biosynthesis and, ultimately, inhibits cell wall synthesis. These two mechanisms make emergence of resistance to fosfomycin more difficult. The reported bacterial resistance to fosfomycin is chromosomally mediated and rare instances of some plasmid mediated resistance. If mutations are going to occur they need to overcome the two transport mechanisms previously noted.
Fosfomycin also has favorable pharmacokinetic properties. Metabolism does not occur in the body and the drug is primarily excreted unchanged in the urine. After a single 3-g dose of fosfomycin, urine levels are more than 128 mg/L, which occurs within 4 hours and is maintained for at least 36 to 48 hours. These high, sustained levels allow a single dose to be bactericidal against urinary pathogens. Therapeutic drug levels have also been noted in the kidneys, bladder wall, prostate and seminal vesicles.
Fosfomycin has very few documented adverse effects. Most notable are gastrointestinal disturbances, usually diarrhea (10%), headaches (4%) and vaginitis (6%). In 2008, the Center for Drug Evaluation and Research (CDER) required a safety labeling change to include warning of C. difficile-associated diarrhea to fosfomycin.
With the favorable pharmacokinetic profile, wide spectrum of antibacterial activity, easy administration and clean adverse effect profile, why are clinicians not using fosfomycin to treat UTIs? Bactrim and nitrofurantoin continue to be the gold standard. The studies with fosfomycin are relatively limited but the data with bactrim and nitrofurantoin are numerous. A 1999 study published in Clinical Therapeutics showed nitrofurantoin 100 mg orally twice daily for 7 days vs. fosfomycin 3 g orally once-daily had slightly more favorable early clinical cure (95% vs. 90%) and early bacterial cure (86% vs. 78%). Late clinical cure and adverse effects were similar. Even though it does not have the approved indication, the antimicrobial spectrum of activity and the pharmacokinetic profile suggest it may be useful in the treatment of more complicated UTIs.
Why should we reconsider fosfomycin for uncomplicated UTIs and possibly complicated UTIs? Since 1999, antimicrobial resistance among the normal urinary pathogens that cause uncomplicated cystitis has “complicated” treating cystitis. Fluroquinolone, beta-lactam and bactrim resistance is well noted. In practice, clinicians are starting to see patients who present with a relatively uncomplicated case of cystitis but the urinary pathogens isolated on culture are alarming: VRE, Pseudomonas, ESBL E.coli, and Carbapenemase-resistant Klebsiella, to name a few. In these cases, nitrofurantoin and bactrim will not treat these bugs. A clinician is forced to consider broader spectrum agents such as fluroquinolones, but resistance is so high they are a less viable option. It leads to a hospital admission to treat with intravenous therapy or establish home care for IV therapy. A simple UTI has now become complicated.
Re-emergence of in vitro testing of fosfomycin against pathogens such as multi drug resistant Pseudomonas, ESBL E.coli, KPCs, and VRE is promising. Microbiology laboratories have the capability to test these isolates against fosfomycin. The current treatment options for these pathogens are limited by route of administration (IV carbapenems, tigecycline or colistin), adverse effects and high costs. Linezolid is available orally but the cost is substantially higher than a single dose of fosfomycin. Whether inpatient or outpatient, physicians and pharmacists should remember that fosfomycin is a viable option. The pharmacokinetic profile is optimal for treating uncomplicated and even complicated UTIs, the single oral dose is a more reasonable alternative to hospital admission or home care for IV therapy, minimal adverse effects noted and is a very cost-effective alternative. Fosfomycin may be old but should not be forgotten. It should be an agent we add back into our arsenal to treat UTIs that are complicated by the V superbug.
For more information:
- Gupta K. Clin Infect Dis. 2011;52:103-128.
- Hooton TM. Infect Dis Clin North Am. 1997;11:551–581.
- Patton JP. Med Clin North Am. 1991;75:495-513.
- Schappert SM. Vital Health Stat. 1999;13:1-39.
- Stein G. Clin Ther. 1999;21:1864-1872.
Kimberly D. Boeser, PharmD, is an infectious disease clinical pharmacist at University of Minnesota Medical Center-Fairview. Disclosure: Boeser reports no relevant financial disclosures.
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