File, Thomas M. Jr MD
From the Northeastern Ohio Universities College of Medicine and Pharmacy, Rootstown and Summa Health System, Akron, OH.
Correspondence to: Thomas M. File Jr, MD, 75 Arch St, Suite 506 (Main Office; Suite 105 for Research), Akron, OH 44304. E-mail: firstname.lastname@example.org.
The author discloses that he has received recent research funding from Cerexa/Forest, Pfizer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, and Tibotec; and he is a consultant for Cerexa/Forest, Merck, Nabriva, Pfizer, and Tetraphase.
Acute uncomplicated urinary tract infections (UTIs) are among the most common infections of otherwise healthy women. The Infectious Diseases Society of America initially published guidelines for the treatment of uncomplicated UTIs in 1999,1 but since then there have been many new developments including the emergence of significant antimicrobial resistance. This new update reflects many of the changes since the 1999 guideline.2 Organizations that cosponsored this guideline include: the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine.
Summarized below are several of the recommendations in this update (specific recommendations are graded as to the strength of recommendation, with A being the strongest and the level of evidence, with I being the highest. My comments are in italics):
I. WHAT IS THE OPTIMAL TREATMENT FOR ACUTE UNCOMPLICATED CYSTITIS?
Recommendations for empirical therapy:
* Nitrofurantoin (100 mg twice daily for 5 days) (A-1).
* Trimethoprim-sulfamethoxazole (160/800 mg [one double-strength table] twice daily for 3 days) if local resistance rates of uropathogens causing acute uncomplicated cystitis do not exceed 20% or the infecting strain is known to be susceptible (A-1). The threshold of 20% is based on expert opinion (B-III).
* Fosfomycin (3 g in single dose) (A-I)
* Pivmecillinam (400 mg twice daily for 3-7 days)
* The fluoroquinolones (ofloxacin, ciprofloxacin, and levofloxacin are effective in 3-day regimens (A-I), but they have propensity for collateral damage (eg, tendonitis, Clostridium difficile infection, selection for resistance of gram-negative bacilli) and should be reserved for uses other than acute cystitis; therefore, these should be considered alternative agents for acute cystitis (A-III)
* β-lactams, including amoxicillin-clavulanate, cefdinir, cefaclor, and cepodoxime, in 3- to 7-day regimens, are appropriate choices when other agents cannot be used (B-I).
Comment: The new recommendations for first-line agents for cystitis represent a change from the 1999 guideline in which trimethoprim-sulfamethoxazole was the primary preferred option with a fluoroquinolone listed as appropriate in communities with high rates of resistance (ie, 10%-20%). In the prior guideline, nitrofurantoin and fosfomycin were listed as possibly useful as resistance to trimethoprim-sulfamethoxazole and trimethoprim increase (B-I). The panel for the new guideline indicated that the optimal agent for cystitis depends on a variety of factors and each of the 4 agents listed as first-line options have pros and cons based on resistance rates, tolerance, cost, adverse events, convenience, and collateral effects (eg, potential for selection of resistance or for C. difficile infection). In an extensive review of clinical trials, the panel summarized the clinical efficacy of the various agents for uncomplicated cystitis as: nitrofurantoin, 93%; trimethoprim-sulfamethoxazole, 93%; fosfomycin, 91%; pivmecillinam, 73%; fluoroquinolones, 90%; and β-lactams, 89%. Regarding the β-lactams, amoxicillin and ampicillin are specifically not recommended for empirical therapy given the relatively poor efficacy and the very high rate of antimicrobial resistance. Pivmecillinam is not available in North America, and its availability is limited to some European countries. Fosfomycin is a new addition as a first-line agent in part because of its antimicrobial activity against many strains resistant to the other options. Activity of fosfomycin includes vancomycin-resistant enteroccoci, methicillin-resistant Staphylococcus aureus, and extended-spectrum β-lactamase-producing gram-negative bacilli. In addition, the convenience of a single-dose regimen and minimal propensity for collateral damage make this a useful choice. In one multicenter study of the susceptibility of uropathogens associated with uncomplicated UTIs in women, susceptibility of Escherichia coli isolates were: fosfomycin, 97%; nitrofurantoin, 94%; ciprofloxacin, 88%; cotrimoxazole, 66%; amoxicillin/clavulanate, 75%; and amoxicillin, 45%.3 Of significance, the fluoroquinolones are not included as first-line choices for acute cystitis. A major concern is the potential for promotion of fluoroquinolone resistance, not only among uropathogens but also other organisms causing more serious and difficult-to-treat infections at other sites.
II. WHAT IS THE TREATMENT FOR ACUTE PYELONEPHRITIS?
* In patients suspected of having pyelonephritis, a urine culture and susceptibility test should always be performed, and initial empirical therapy should be tailored appropriately on the basis of the infecting uropathogen (A-III).
* Oral ciprofloxacin (500 mg twice daily) for 7 days, with or without an initial 400-mg dose of intravenous ciprofloxacin, is an appropriate choice for therapy in patients not requiring hospitalization where the prevalence of resistance of community uropathogens to fluoroquinolones is not known to exceed 10% (A-I). If an initial one-time intravenous agent is used, a long-acting antimicrobial, such as 1 g of ceftriaxone or a consolidated 24-hour dose of an aminoglycoside, could be used in lieu of an intravenous fluoroquinolone (B-III). If the prevalence of fluoroquinolone resistance is thought to exceed 10%, an initial one-time intravenous dose of a long-acting parenteral antimicrobial, such as 1 g of ceftriaxone (B-III) or a consolidated 24-hour dose of an aminoglycoside, is recommended (B-III).
* A once-daily oral fluoroquinolone, including ciprofloxacin (1000-mg extended release for 7 days) or levofloxacin (750 mg for 5 days), is an appropriate choice for therapy in patients not requiring hospitalization where the prevalence of resistance of community uropathogens is not known to exceed 10% (B-II). If the prevalence of fluoroquinolone resistance is thought to exceed 10%, an initial intravenous dose of a long-acting parenteral antimicrobial, such as 1 g of ceftriaxone (B-III) or a consolidated 24-hour dose of an aminoglycoside, is recommended (B-III).
* The recommendation for duration of therapy is 10 to 14 days for treatment of pyelonephritis with a β-lactam agent.
* Women with pyelonephritis requiring hospitalization should be initially treated with an intravenous antimicrobial regimen, such as a fluoroquinolone; an aminoglycoside, with or without ampicillin; an extended-spectrum cephalosporin or extended-spectrum penicillin, with or without an aminoglycoside; or a carbapenem. The choice between these agents should be based on local resistance data, and the regimen should be tailored on the basis of susceptibility results (B-III).
Comments: The panel identified 6 treatment studies for uncomplicated pyelonephritis; only one met their inclusion criteria ("an open-label or randomized clinical trial of treatment of women with symptoms of acute uncomplicated pyelonephritis").4 In this study, ciprofloxacin had significantly higher microbiological (99% vs 89%, respectively) and clinical (96% vs 83%, respectively) cure rates at the early posttherapy compared to trimethoprim-sulfamethoxazole. Two additional studies demonstrated that a 5- to 7-day regimen of a once-daily fluoroquinolone (ciprofloxacin, 1000 mg extended release, and levofloxacin, 750 mg, respectively) were effective for acute pyelonephritis, but both of these studies included a mixed population of men and women.5,6
Thus, although the panel has not included the fluoroquinolones as first-line options for uncomplicated cystitis, they do recommend them as first-line options for pyelonephritis depending on the relative rate of local resistance patterns. I interpret this as an indication by the panel that this is justified owing to the more serious nature of pyelonephritis. However, it is important to be aware of local resistant patterns of uncomplicated pyelonephritis to be confident of optimal empirical therapy of this potentially serious infection.
1. Warren JW, Abrutyn E, Hebel JR, et al. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin Infect Dis
2. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis
3. Palou J, Pigrau C, Molina I, et al. [Etiology and sensitivity of uropathogens identified in uncomplicated lower urinary tract infections in women (ARESC Study): implications on empiric therapy]. Med Clin (Barc)
4. Talan DA, Stamm WE, Hooton TM, et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis in women: a randomized trial. JAMA
5. Peterson J, Kaul S, Khashab M, et al. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology
6. Talan DA, Klimberg IW, Nicolle LE, et al. Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis. J Urol
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