Cystitis Treatment in Women, Circa 2011: New Role for an Old Drug

Abstract

Paradigm shifts in patient care all too frequently result in recommendations for more costly medications, procedures, or devices. Clinicians rarely encounter newer therapies that improve outcomes at a lower cost—such as the “rediscovery” of metformin therapy for type 2 diabetes.1UKPDS Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7469) Google Scholar The article by McKinnell et al2McKinnell JA Stollenwerk NS Jung CW Miller LG Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis.Mayo Clin Proc. 2011; 86: 480-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar in this issue of Mayo Clinic Proceedings, coupled with 2011 practice guidelines from the Infectious Diseases Society of America (IDSA) and European Society for Microbiology and Infectious Diseases,3Gupta 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. 2011; 52: e103-e120Crossref PubMed Scopus (1811) Google Scholar provides important and welcome changes in recommendations for cost-effective management of uncomplicated lower urinary tract infection (UTI) in women. Escherichia coli and other common uropathogens possess unique surface adhesins on fimbriae and other adhesive organelles. These attachment systems promote bacterial adherence to the epithelial cell membrane and subsequent colonization of the vagina, perineum, and periurethral region with colonic bacteria. Bacteria ascend to the bladder from this colonized reservoir, commonly after sexual intercourse. Bladder invasion by bacteria may or may not lead to a symptomatic UTI, depending on the complex interplay of host genetic, behavioral, and biological factors.4Finer G Landau D Pathogenesis of urinary tract infections with normal female anatomy.Lancet Infect Dis. 2004; 4: 631-635Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Women with symptomatic cystitis present with abrupt onset of dysuria, urinary frequency, and urinary urgency. Historical factors that increase the likelihood of UTI include the following: hematuria, suprapubic pain, malodorous or turbid urine, incontinence, prior UTIs, recent sexual intercourse, spermicidal contraception, and recent antibiotic administration.5Schmiemann G Kniehl E Gebhardt K Matejczyk MM Hummers-Pradier E The diagnosis of urinary tract infection: a systematic review.Dtsch Arztebl Int. 2010; 107: 361-367Google Scholar Although office urine dipstick or laboratory urinalysis demonstrating nitrites (from the bacterial breakdown of urinary nitrates), leukocytes, or blood helps confirm a clinical diagnosis of UTI, these markers are not sufficiently sensitive to exclude the diagnosis in patients with a high pretest probability of infection,6Bent S Nallamothu BK Simel DL et al.Does this woman have an acute uncomplicated urinary tract infection?.JAMA. 2002; 287: 2701-2710Crossref PubMed Scopus (375) Google Scholar in part due to the common practice of “pushing fluids” (with resultant dilution of the urine sample) before seeking medical care. In 1999, the IDSA recommended empirical therapy for acute cystitis in select patients7Warren JW Abrutyn E Hebel JR Johnson JR Schaeffer AJ Stamm WE Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women.Clin Infect Dis. 1999; 29: 745-758Crossref PubMed Scopus (989) Google Scholar without ordering a pretreatment urine culture because the clinical outcome (resolution or persistence of symptoms) would be apparent by the time the urine culture results were available 48 to 72 hours after initiation of therapy. Appropriate empirical treatment reduces costs and increases patient convenience.8Saint S Scholes D Fihn SD Farrell RG Stamm WE The effectiveness of a clinical practice guideline for the management of presumed uncomplicated urinary tract infection in women.Am J Med. 1999; 106: 636-641Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Urine cultures with susceptibility data can be reserved for patients who are pregnant, have symptoms of upper tract disease, have risk factors for a resistant organism, or experience therapeutic failure or early relapse. Clinical algorithms that triage selected patients with cystitis to empirical treatment result in outcomes that compare favorably with office-based therapy (ie, therapy based on the results of urine dipstick testing, urinalysis, or urine culture and sensitivity).9Barry HC Hickner J Ebell MH Ettenhofer T A randomized controlled trial of telephone management of suspected urinary tract infections in women.J Fam Pract. 2001; 50: 589-594PubMed Google Scholar The combination of dysuria and urinary frequency without vaginal discharge or irritation has a 96% positive predictive value in diagnosing UTI, eliminating the need for urinalysis or culture.6Bent S Nallamothu BK Simel DL et al.Does this woman have an acute uncomplicated urinary tract infection?.JAMA. 2002; 287: 2701-2710Crossref PubMed Scopus (375) Google Scholar Patients without dysuria, with vaginal symptoms, or with atypical or upper tract symptoms require an office visit and examination for alternative diagnoses such as sexually transmitted diseases, vaginitis, and pyelonephritis. Because cystitis is a mucosal infection and most antibiotics achieve high urinary concentrations, administration of an appropriate antibiotic for only a few days results in resolution of symptoms and bacteriuria in 90% to 95% of patients.10Nicolle LE Empirical treatment of acute cystitis in women.Int J Antimicrob Agents. 2003; 22: 1-6Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar For the past several decades, 3 days of treatment with twice-daily trimethoprim-sulfamethoxazole (TMP-SMZ) or trimethoprim (TMP) alone has been the accepted first-line therapy for acute uncomplicated cystitis.7Warren JW Abrutyn E Hebel JR Johnson JR Schaeffer AJ Stamm WE Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women.Clin Infect Dis. 1999; 29: 745-758Crossref PubMed Scopus (989) Google Scholar Trimethoprim-sulfamethoxazole achieves very high urinary concentrations and eliminates bacteria from the vaginal-perineal reservoir due to “ionic trapping” of TMP in the acidic vaginal secretions.11Stamey TA Condy M Mihara G Prophylactic efficacy of nitrofurantoin macrocrystals and trimethoprim-sulfamethoxazole in urinary infections: biologic effects on the vaginal and rectal flora.N Engl J Med. 1977; 296: 780-783Crossref PubMed Scopus (104) Google Scholar Single-dose TMP-SMZ therapy has largely been abandoned because of a higher rate of treatment failure, whereas more prolonged courses of therapy increase the frequency of adverse effects without increasing the cure rate.12Schultz HJ McCaffrey LA Keys TF Nobrega FT Acute cystitis: a prospective study of laboratory tests and duration of therapy.Mayo Clin Proc. 1984; 59: 391-397Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar However, as the use of TMP-SMZ has increased substantially, uropathogens have shown increasing drug resistance.13Karlowsky JA Kelly LJ Thornsberry C Jones ME Sahm DF Trends in antimicrobial resistance among urinary tract infection isolates of Escherichia coli from female outpatients in the United States.Antimicrob Agents Chemother. 2002; 46: 2540-2545Crossref PubMed Scopus (283) Google Scholar Outpatient isolates of E coli in the United States show resistance rates ranging from 15% in the upper midwest to greater than 40% in the southwest and south-central United States.14Zhanel GG Hisanaga TL Laing NM et al.Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA).Int J Antimicrob Agents. 2006; 27: 468-475Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Sulfonamide administration can also be associated with a variety of serious adverse reactions, including the Stevens-Johnson syndrome.15Fritsch PO Sidoroff A Drug-induced Stevens-Johnson syndrome/toxic epidermal necrosis.Am J Clin Dermatol. 2000; 1: 349-360Crossref PubMed Scopus (152) Google Scholar Because of these limitations, many clinicians now prescribe a 3-day course of a fluoroquinolone (FQ) as first-line empirical therapy for uncomplicated cystitis, rather than reserving FQs for treatment failures, resistant organisms, or patients with medication allergies.16Kallen AJ Welch HG Sirovich BE Current antibiotic therapy for isolated urinary tract infections in women.Arch Intern Med. 2006; 166: 635-639Crossref PubMed Scopus (77) Google Scholar However, increasing FQ resistance among E coli isolates has complicated the management of UTIs.17Johnson L Sabel A Burman WJ et al.Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates.Am J Med. 2008; 121: 876-884Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar In addition, severe Clostridium difficile colitis has increasingly been attributed to FQ use.18Loo VG Poirier L Miller MA et al.A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.N Engl J Med. 2005; 353: 2442-2449Crossref PubMed Scopus (1679) Google Scholar In the setting of increased TMP-SMZ resistance and the need to limit the use of FQs, investigators have reevaluated the role of nitrofurantoin—a nearly forgotten drug—in the treatment of uncomplicated UTIs. A recent large clinical trial demonstrated that a 5-day course of twice-daily nitrofurantoin macrocrystals was equivalent or superior to a standard 3-day course of TMP-SMZ.19Gupta K Hooton TM Roberts PL Stamm WE Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women.Arch Intern Med. 2007; 167: 2207-2212Crossref PubMed Scopus (126) Google Scholar Most urinary isolates have remained sensitive to nitrofurantoin (97.7% sensitivity among E coli in one study20Kashanian J Hakimian Blute M et al.Nitrofurantoin: the return of an old friend in the wake of growing resistance.BJU Int. 2008; 102: 1634-1637Crossref PubMed Scopus (62) Google Scholar), despite decades of clinical use, presumably because of minimal gastrointestinal excretion of the drug (ie, minimal contact with enteric bacteria) and because nitrofurantoin is used almost exclusively to treat UTIs. However, nitrofurantoin has poor activity against Proteus, Serratia, and Pseudomonas species and should not be used to treat UTIs due to these organisms. Nitrofurantoin is inexpensive, safe in early pregnancy, and rarely causes C difficile colitis. Although long-term use is associated with pulmonary fibrosis, the only common adverse effects with short-term use are nausea and headache. Hemolytic anemia can be seen in patients with glucose-6-phosphate dehydrogenase deficiency. Rare serious adverse effects include drug-induced hepatitis, hypersensitivity pneumonitis, and peripheral neuropathy (especially in patients with renal insufficiency). In March 2011, the IDSA and the European Society for Microbiology and Infectious Diseases published joint updated guidelines for treatment of uncomplicated cystitis.3Gupta 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. 2011; 52: e103-e120Crossref PubMed Scopus (1811) Google Scholar The expert panel elevated nitrofurantoin to first-line therapy (along with TMP-SMZ) because of its efficacy, minimal resistance, and lower propensity to cause “collateral damage” (ie, selection of drug-resistant organisms and colonization/infection with multidrug-resistant organisms). When deciding between TMP-SMZ and nitrofurantoin, antibiotic resistance to TMP-SMZ is the most important identified factor for clinicians to consider. Cost factors should also be considered in the management of UTIs. In this issue of the Proceedings, McKinnell et al2McKinnell JA Stollenwerk NS Jung CW Miller LG Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis.Mayo Clin Proc. 2011; 86: 480-488Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar present the results of a sophisticated decision analysis comparing the cost-effectiveness of nitrofurantoin, TMP-SMZ, and FQs in the treatment of uncomplicated UTIs. Decision analyses help clinicians answer questions about multiple treatment alternatives that would otherwise be difficult to resolve in a clinical trial.21Le TP Miller LG Empirical therapy for uncomplicated urinary tract infections in an era of increasing antimicrobial resistance: a decision and cost analysis.Clin Infect Dis. 2001; 33: 615-621Crossref PubMed Scopus (66) Google Scholar The authors based their analysis on an extensive and detailed review of the literature on costs and clinical outcomes of UTIs. They conducted sensitivity analyses for a wide spectrum of costs (eg, for medication, office evaluation, treatment failure, and adverse reactions), antibiotic sensitivities, and treatment outcomes. To our knowledge, this is the first published decision analysis of the use of empirical therapy with nitrofurantoin and confirms its equivalence or superiority in settings in which TMP-SMZ resistance exceeds 17%. Indeed, TMP-SMZ resistance currently exceeds 15% in most of the United States.13Karlowsky JA Kelly LJ Thornsberry C Jones ME Sahm DF Trends in antimicrobial resistance among urinary tract infection isolates of Escherichia coli from female outpatients in the United States.Antimicrob Agents Chemother. 2002; 46: 2540-2545Crossref PubMed Scopus (283) Google Scholar The McKinnell et al analysis supports and reinforces the following IDSA expert recommendations:3Gupta 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. 2011; 52: e103-e120Crossref PubMed Scopus (1811) Google Scholar •Consider nitrofurantoin (nitrofurantoin monohydrate/macrocrystals, 100 mg twice daily for 5 days) as first-line therapy for women with signs and symptoms of acute uncomplicated cystitis. Avoid nitrofurantoin use in patients with symptoms of upper tract disease (fever, chills, nausea, vomiting, or flank pain).•TMP-SMZ remains a viable alternative (if local resistance is low), especially if the patient has not received recent TMP-SMZ therapy or has an infecting strain known to be susceptible.•Reserve FQ therapy for treatment failures or for patients with suspected upper tract disease.•Avoid using amoxicillin or ampicillin as empirical therapy because of high rates of antimicrobial resistance and poor efficacy.•Alternative β-lactam therapies (eg, amoxicillin-clavulanate, cefdinir, cefaclor, cefpodoxime) for 3 to 7 days are appropriate when other agents cannot be used.•Fosfomycin trometamol (administered as a single 3-g dose). Note that fosfomycin is active against most gram-positive and gram-negative bacteria, including extended spectrum β-lactamase–producing organisms and compares favorably to other antimicrobial agents.22Shrestha NK Tomford JW Fosfomycin: a review.Infect Dis Clin Pract. 2001; 10: 255-260Crossref Scopus (19) Google Scholar, 23Ceran N Mert D Kocdogan FY et al.A randomized comparative study of single-dose fosfomycin and 5-day ciprofloxacin in female patients with uncomplicated lower urinary tract infections.J Infect Chemother. 2010; 16: 424-430Crossref PubMed Scopus (34) Google Scholar However, fosfomycin trometamol is significantly more ex pen sive than nitrofurantoin, TMP-SMZ, and ciprofloxacin. Nitrofurantoin has evolved as the “metformin” of uncomplicated UTIs: an old drug rediscovered to be an effective, safe, well-tolerated, and inexpensive first-line therapeutic option for cystitis. Nitrofurantoin has maintained its antimicrobial activity against most uropathogens that cause uncomplicated cystitis, and it is unlikely to induce antibiotic resistance. Clinicians accustomed to using TMP-SMZ for uncomplicated cystitis should consider switching to nitrofurantoin because of increasing TMP-SMZ resistance and treatment failures. Clinicians using FQs in this setting should consider switching to nitrofurantoin in order to reserve FQ use for more serious infections and to further curtail the development of resistant microorganisms. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost AnalysisMayo Clinic ProceedingsVol. 86Issue 6PreviewTo analyze the costs of nitrofurantoin use compared to those of other antibiotics recommended for treatment of uncomplicated urinary tract infection (UTI). Full-Text PDF