IDSA GUIDELINESInternational Clinical Practice Guidelines for theTreatment of Acute Uncomplicated Cystitis andPyelonephrit...
Woman with acute uncomplicated cystitis                          Consider alternate diagnosis (such                       ...
each of the recommendations can be found in the full text of the     6. b-Lactam agents, including amoxicillin-clavulanate...
11. Oral trimethoprim-sulfamethoxazole (160/800 mg [1               reporting in vitro susceptibility of E. coli causing u...
data, use of individual-level predictors of resistance can be         that affect the normal fecal flora more significantly,...
Table 1. Strength of Recommendations and Quality of EvidenceCategory/grade                                                ...
provided IDSA’s conflict of interest disclosure statement and were     33]. Thus, there was insufficient new literature to s...
resistance and propensity for collateral damage, but it may have               Four randomized clinical trials compared tr...
Table 2. Results from Included Studies of Trimethoprim-Sulfamethoxazole for Treatment of Acute Uncomplicated CystitisStudy...
were significantly higher among women with a trimethoprim-                           Resistance impacts both clinical and b...
macrocrystals (100 mg twice daily for 7 days) has similar                               regimen, rather than the tradition...
included only 50% of the original study population. Intent–to-       25% (54 of 227 women) and a bacteriologic cure rate o...
efficacy rates in the studies are consistently high, although they     ciprofloxacin (P , .001) [52]. Vaginal colonization w...
initial empirical therapy should be tailored appropriately on         without ampicillin; an extended-spectrum cephalospor...
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women
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International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women

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International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women

  1. 1. IDSA GUIDELINESInternational Clinical Practice Guidelines for theTreatment of Acute Uncomplicated Cystitis andPyelonephritis in Women: A 2010 Update by theInfectious Diseases Society of America and theEuropean Society for Microbiology andInfectious DiseasesKalpana Gupta,1 Thomas M. Hooton,2 Kurt G. Naber,9 Bjorn Wullt,10 Richard Colgan,3 Loren G. Miller,4 ¨ Downloaded from cid.oxfordjournals.org by guest on February 6, 2011Gregory J. Moran,5 Lindsay E. Nicolle,8 Raul Raz,11 Anthony J. Schaeffer,6 and David E. Soper71Department of Medicine, Veterans Affairs Boston Health Care System and Boston University School of Medicine, Boston, Massachusetts; 2Department ofMedicine, University of Miami Miller School of Medicine, University of Miami, Miami Florida; 3Department of Family and Community Medicine, Universityof Maryland, Baltimore, Maryland, 4Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, and 5Department of Emergency Medicine andDivision of Infectious Diseases Olive View-UCLA Medical Center, Slymar, California; 6Deptartment of urology, Northwestern University, Chicago, Illinois; and7Departments of Obstetrics and Gynecology and Medicine, Medical University of South Carolina, Charleston, South Carolina; 8Department of InternalMedicine and Department of Medical Mirobiology University of Manitoba, Winnipeg, Canada; 9Technical University of Munich, Munich, Germany; 10LundUniversity Hospital, Lund, Sweden; and 11Infectious Diseases Unit, HaEmek Medical Center, Afula, and Rappaport Faculty of Medicine, Technion, Haifa, IsraelA Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) incollaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include theAmerican Congress of Obstetricians and Gynecologists, American Urological Association, Association ofMedical Microbiology and Infectious Diseases–Canada, and the Society for Academic Emergency Medicine.The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoseslimited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalitiesor co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects ofantimicrobial therapy (collateral damage) were considered as important factors in making optimal treatmentchoices and thus are reflected in the rankings of recommendations. EXECUTIVE SUMMARY Received 10 December 2010; accepted 17 December 2010. BACKGROUND The process for evaluating the evidence was based on the IDSA Handbook on Acute uncomplicated cystitis remains one of the mostClinical Practice Guideline Development and involved a systematic weighting of common indications for prescribing of antimicrobials tothe quality of the evidence and the grade of recommendation (Table 1) [31] It is important to realize that guidelines cannot always account for individual otherwise healthy community-dwelling women. Despitevariation among patients. They are not intended to supplant physician judgment published guidelines for the optimal selection of anwith respect to particular patients or special clinical situations. The IDSA considersadherence to these guidelines to be voluntary, with the ultimate determination antimicrobial agent and duration of therapy, studiesregarding their application to be made by the physician in the light of each demonstrate a wide variation in prescribing practicespatients individual circumstances. Correspondence: Kalpana Gupta, MD, VA Boston HCS, 1400 VFW Pkwy, 111 [1–6]. The Infectious Diseases Society of America (ID-Med, West Roxbury, MA 02132 (kalpana.gupta@va.gov). SA) published a clinical practice guideline on theClinical Infectious Diseases 2011;52(5):e103–e120 treatment of women with acute uncomplicated cystitisÓ The Author 2011. Published by Oxford University Press on behalf of theInfectious Diseases Society of America. All rights reserved. For Permissions, and pyelonephritis in 1999 [1]. Since then, antimicrobialplease e-mail: journals.permissions@oup.com. resistance among uropathogens causing uncomplicated1058-4838/2011/525-0001$37.00DOI: 10.1093/cid/ciq257 cystitis has increased, appreciation of the importance of Clinical Practice Guidelines d CID 2011:52 (1 March) d e103
  2. 2. Woman with acute uncomplicated cystitis Consider alternate diagnosis (such Absence of fever, flank pain, or other No as pyelonephritis or complicated suspicion for pyelonephritis UTI) & treat accordingly Able to take oral medication (see text) Yes Fluoroquinolones Can one of the recommended antimicrobials* (resistance prevalence high in No below be used considering: some areas) Availability Allergy history OR Tolerance -lactams Nitrofurantoin monohydrate/macrocrystals 100 (avoid ampicillin or amoxicillin mg bid X 5 days alone; lower efficacy than other (avoid if early pyelonephritis suspected) available agents; requires close follow-up) OR Trimethoprim-sulfamethoxazole 160/800 mg (one DS tablet) bid X 3 days (avoid if resistance prevalence is known to exceed 20 or if used for UTI in previous 3 months) Downloaded from cid.oxfordjournals.org by guest on February 6, 2011 OR Fosfomycin trometamol 3 gm single dose (lower efficacy than some other recommended agents; avoid if early pyelonephritis suspected) *The choice between these agents should be individualized and based on patient allergy and OR compliance history, local practice patterns, local community resistance prevalence, availability, cost, and Pivmecillinam 400 mg bid x 5 days patient and provider threshold for failure (see Table 4) (lower efficacy than some other recommended agents; avoid if early pyelonephritis suspected) Yes Prescribe a recommended antimicrobialFigure 1. Approach to choosing an optimal antimicrobial agent for empirical treatment of acute uncomplicated cystitis. DS, double-strength; UTI,urinary tract infection.the ecological adverse effects of antimicrobial therapy (collateral considered by some experts to have uncomplicated urinarydamage) has increased, newer agents and different durations of tract infection (UTI), but a discussion of specific managementtherapy have been studied, and clinical outcomes have in- of these groups is outside the scope of this guideline. In ad-creasingly been reported. In addition, women with uropath- dition, management of recurrent cystitis and of UTI inogens resistant to the treatment drug have been included in pregnant women, prevention of UTI, and diagnosis of UTI aresome studies, allowing for estimations of expected response rates all important issues that are not addressed in this guideline.in a ‘‘real-life’’ clinical setting in which empirical therapy is The issues of in vitro resistance prevalence and the potentialprescribed either without a urine culture and susceptibility for collateral damage were considered as important factors intesting or before such results are known. In light of these de- making optimal treatment choices and thus are reflected invelopments, an update of the guidelines was warranted. the rankings of recommendations. The focus of this guideline is treatment of women with acute Summarized below are the recommendations made in theuncomplicated cystitis and pyelonephritis, diagnoses limited 2010 guideline update. The Panel followed a process used in thein these guidelines to premenopausal, nonpregnant women development of other IDSA guidelines which included a sys-with no known urological abnormalities or comorbidities. It tematic weighting of the quality of the evidence and the grade ofshould be noted that women who are postmenopausal or have recommendation [32] (Table 1). A detailed description of thewell-controlled diabetes without urological sequelae may be methods, background, and evidence summaries that supporte104 d CID 2011:52 (1 March) d Gupta et al
  3. 3. each of the recommendations can be found in the full text of the 6. b-Lactam agents, including amoxicillin-clavulanate,guideline. cefdinir, cefaclor, and cefpodoxime-proxetil, in 3–7-day regimens are appropriate choices for therapy when other recommended agents cannot be used (B-I). Other b-lactams,I.What Is the Optimal Treatment for Acute UncomplicatedCystitis? such as cephalexin, are less well studied but may also beRecommendations (Figure 1). appropriate in certain settings (B-III). The b-lactams generally1. Nitrofurantoin monohydrate/macrocrystals (100 mg twice have inferior efficacy and more adverse effects, compared withdaily for 5 days) is an appropriate choice for therapy due to other UTI antimicrobials (B-I). For these reasons, b-lactamsminimal resistance and propensity for collateral damage other than pivmecillinam should be used with caution for(defined above) and efficacy comparable to 3 days of uncomplicated cystitis.trimethoprim-sulfamethoxazole (A-I). 7. Amoxicillin or ampicillin should not be used for 2. Trimethoprim-sulfamethoxazole (160/800 mg [1 double- empirical treatment given the relatively poor efficacy, asstrength tablet] twice-daily for 3 days) is an appropriate choice discussed in the 1999 guidelines [1] and the very highfor therapy, given its efficacy as assessed in numerous clinical prevalence of antimicrobial resistance to these agentstrials, if local resistance rates of uropathogens causing acute worldwide [8–11] (A-III).uncomplicated cystitis do not exceed 20% or if the infectingstrain is known to be susceptible (A-I). II.What Is the Treatment for Acute Pyelonephritis? Downloaded from cid.oxfordjournals.org by guest on February 6, 2011 i. The threshold of 20% as the resistance prevalence at which Recommendationsthe agent is no longer recommended for empirical treatment of 8. In patients suspected of having pyelonephritis, a urineacute cystitis is based on expert opinion derived from clinical, culture and susceptibility test should always be performed, andin vitro, and mathematical modeling studies (B-III). initial empirical therapy should be tailored appropriately on ii. In some countries and regions, trimethoprim (100 mg twice the basis of the infecting uropathogen (A-III).daily for 3 days) is the preferred agent and is considered 9. Oral ciprofloxacin (500 mg twice daily) for 7 days, with orequivalent to trimethoprim-sulfamethoxazole on the basis of without an initial 400-mg dose of intravenous ciprofloxacin, isdata presented in the original guideline (A-III) [1]. an appropriate choice for therapy in patients not requiring iii. Data are insufficient to make a recommendation for hospitalization where the prevalence of resistance of communityother cystitis antimicrobials as to what resistance prevalence uropathogens to fluoroquinolones is not known to exceed 10%should be used to preclude their use for empirical treatment of (A-I). If an initial one-time intravenous agent is used, a long-acute cystitis. acting antimicrobial, such as 1 g of ceftriaxone or a consolidated 3. Fosfomycin trometamol (3 g in a single dose) is an 24-h dose of an aminoglycoside, could be used in lieu of anappropriate choice for therapy where it is available due to intravenous fluoroquinolone (B-III). If the prevalence ofminimal resistance and propensity for collateral damage, but it fluoroquinolone resistance is thought to exceed 10%, anappears to have inferior efficacy compared with standard short- initial 1-time intravenous dose of a long-acting parenteralcourse regimens according to data submitted to the US Food antimicrobial, such as 1 g of ceftriaxone (B-III) orand Drug Administration (FDA) and summarized in the a consolidated 24-h dose of an aminoglycoside, isMedical Letter (A-I) [7]. recommended (B-III). i. Data are insufficient to make a recommendation about 4. Pivmecillinam (400 mg bid for 3–7 days) is an what fluoroquinolone resistance level requires an alternativeappropriate choice for therapy in regions where it is available agent in conjunction with or to replace a fluoroquinolone(availability limited to some European countries; not licensed for treatment of pyelonephritis.and/or available for use in North America), because ofminimal resistance and propensity for collateral damage, but 10. A once-daily oral fluoroquinolone, includingit may have inferior efficacy compared with other available ciprofloxacin (1000 mg extended release for 7 days)ortherapies (A-I). levofloxacin (750 mg for 5 days), is an appropriate choice for therapy in patients not requiring hospitalization where 5. The fluoroquinolones, ofloxacin, ciprofloxacin, and the prevalence of resistance of community uropathogens islevofloxacin, are highly efficacious in 3-day regimens (A-I) not known to exceed 10% (B-II). If the prevalence ofbut have a propensity for collateral damage and should be fluoroquinolone resistance is thought to exceed 10%, an initialreserved for important uses other than acute cystitis and thus intravenous dose of a long-acting parenteral antimicrobial, suchshould be considered alternative antimicrobials for acute as 1 g of ceftriaxone (B-III) or a consolidated 24-h dose of ancystitis (A-III). aminoglycoside, is recommended (B-III). Clinical Practice Guidelines d CID 2011:52 (1 March) d e105
  4. 4. 11. Oral trimethoprim-sulfamethoxazole (160/800 mg [1 reporting in vitro susceptibility of E. coli causing un-double-strength tablet] twice-daily for 14 days) is an complicated UTI in North America and Europe were reviewedappropriate choice for therapy if the uropathogen is known [8–11]. All of these demonstrate considerable geographic var-to be susceptible (A-I). If trimethoprim-sulfamethoxazole is iability in susceptibility. For example, resistance rates for allused when the susceptibility is not known, an initial antimicrobials were higher in US medical centers than inintravenous dose of a long-acting parenteral antimicrobial, Canadian medical centers and were usually higher in Portugalsuch as 1 g of ceftriaxone (B-II) or a consolidated 24-h dose of and Spain than other European countries. In general, resistancean aminoglycoside, is recommended (B-III). rates .20% were reported in all regions for ampicillin, and in 12. Oral b-lactam agents are less effective than other many countries and regions for trimethoprim with or withoutavailable agents for treatment of pyelonephritis (B-III). If an sulfamethoxazole. Fluoroquinolone resistance rates were stilloral b-lactam agent is used, an initial intravenous dose of a ,10% in most parts of North America and Europe, but therelong-acting parenteral antimicrobial, such as 1 g of ceftriaxone was a clear trend for increasing resistance compared with(B-II) or a consolidated 24-h dose of an aminoglycoside, is previous years. Moreover, the resistance data for nalidixic acidrecommended (B-III). in these studies suggest that .10% (in some countries, .20%)i. Data are insufficient to modify the previous guideline of the E. coli strains have acquired resistance genes for quino-recommendation for a duration of therapy of 10–14 days for lones [10, 11]. First- and second-generation oral cepha-treatment of pyelonephritis with a b-lactam agent. losporins and amoxicillin-clavulanic acid also show regional variability, but the resistance rates were generally ,10%. De- Downloaded from cid.oxfordjournals.org by guest on February 6, 2011 13. Women with pyelonephritis requiring hospitalization spite wide variability in antimicrobial susceptibility among theshould be initially treated with an intravenous antimicrobial different countries studied, nitrofurantoin, fosfomycin, andregimen, such as a fluoroquinolone; an aminoglycoside, with mecillinam (the latter 2 not tested in the Canadian study) hador without ampicillin; an extended-spectrum cephalosporin good in vitro activity in all the countries investigated. Thus,or extended-spectrum penicillin, with or without an these 3 antimicrobials could be considered appropriate anti-aminoglycoside; or a carbapenem. The choice between these microbials for empirical therapy in most regions [8–11]. Givenagents should be based on local resistance data, and the a trend toward increasing resistance, compared with previousregimen should be tailored on the basis of susceptibility results years, for most antimicrobials, continued monitoring of this(B-III). data to evaluate rates over time is necessary for sustained op- timization of empirical therapy [12].INTRODUCTION Because local in vitro resistance rates are not always known,The focus of this guideline is management of women with acute and change over time is anticipated, identification of individualuncomplicated cystitis and pyelonephritis who are not pregnant predictors of resistance can also be useful to informing empiricaland have no known urological abnormalities or co-morbidities. antimicrobial choice. In 2 studies evaluating epidemiologicalAn optimal approach to therapy includes consideration of an- predictors of resistance, the use of trimethoprim-sulfamethox-timicrobial resistance and collateral damage. azole in the preceding 3–6 months was an independent risk factor for trimethoprim-sulfamethoxazole resistance in womenConsideration of Antimicrobial Resistance with acute uncomplicated cystitis [13, 14]. In addition, 2 US-The microbial spectrum of uncomplicated cystitis and pyelo- based studies demonstrated that travel outside the United Statesnephritis consists mainly of Escherichia coli (75%–95%), with in the preceding 3–6 months was independently associated withoccasional other species of Enterobacteriaceae, such as Proteus trimethoprim-sulfamethoxazole resistance [15, 16]. Predictorsmirabilis and Klebsiella pneumoniae, and Staphylococcus sapro- of resistance to other cystitis antimicrobials are not as wellphyticus. Other gram-negative and gram-positive species are studied but in general support the findings that exposure to therarely isolated in uncomplicated UTIs. Therefore, local antimi- drug or to an area with endemic resistance are important factorscrobial susceptibility patterns of E. coli in particular should be to consider [17, 18]. Local resistance rates reported in hospitalconsidered in empirical antimicrobial selection for un- antibiograms are often skewed by cultures of samples obtainedcomplicated UTIs. Since the resistance patterns of E. coli strains from inpatients or those with complicated infection and maycausing uncomplicated UTI varies considerably between regions not predict susceptibilities in women with uncomplicatedand countries, a specific treatment recommendation may not be community-acquired infection, in whom resistance rates tend touniversally suitable for all regions or countries. be lower [18, 19]. Prospective and unbiased resistance sur- Active surveillance studies of in vitro susceptibility of ur- veillance of uncomplicated uropathogens at the local practiceopathogens in women with uncomplicated cystitis are helpful and/or health care system levels is critical for informingin making decisions about empirical therapy. Four large studies empirical antimicrobial decisions. In the absence of suche106 d CID 2011:52 (1 March) d Gupta et al
  5. 5. data, use of individual-level predictors of resistance can be that affect the normal fecal flora more significantly, such ashelpful. trimethoprim, trimethoprim-sulfamethoxazole, quinolones, Because treatment of acute uncomplicated cystitis is usually and ampicillin [26, 27].empirical, it is likely that some women will be treated with a drug For uncomplicated cystitis, there are 2 reasons why collateralthat does not have in vitro activity against the uropathogen. As damage merits consideration. First, there is minimal risk ofthe population resistance prevalence of a specific agent increases, progression to tissue invasion or sepsis. Moreover, studies ofthe likelihood of failure outweighs the benefits of using the drug placebo for treatment of uncomplicated cystitis demonstrateempirically. For most agents, clinical and bacterial outcomes are that clinical cure can be achieved in 25%–42% of women whonot well studied for varying levels of resistance; thus, recom- are not treated or are treated with a drug without in vitro activitymended thresholds for using alternative agents are based on against the uropathogen [28, 29]. Thus, spontaneous resolutionexpert opinion or secondary analyses of studies that include may attenuate differences in clinical outcomes when a drug withpatients with isolates resistant to the study drugs. The most ev- 80% efficacy is compared with one with 95% efficacy. Of note,idence in this regard is available for trimethoprim-sulfame- placebo therapy is associated with prolongation of symptoms asthoxazole, for which clinical, in vitro, and mathematical well as a small risk of progression to pyelonephritis, as dem-modeling studies consistently suggest a 20% resistance preva- onstrated by the 1 woman out of 38 women treated with placebolence for the threshold at which the agent is no longer recom- in the study by Christiaens et al [28]. Thus, these data do notmended for treatment of acute cystitis [20, 21]. There are justify withholding antimicrobial therapy for treatment of acuteinsufficient data for other cystitis antimicrobials to recommend cystitis. Secondly, uncomplicated UTI is one of the most com- Downloaded from cid.oxfordjournals.org by guest on February 6, 2011resistance levels at which the likelihood of failure outweighs the mon indications for antimicrobial exposure in an otherwisepotential benefits, and the decision will vary by individual healthy population; very small increments in collateral damagepractitioner discretion. For pyelonephritis, timely use of an agent repeated many times may in aggregate magnify the impact ofwith in vitro activity is essential to treat the infection and min- collateral damage when it occurs. Although reducing in-imize progression. Thus, thresholds at which a broad-spectrum appropriate use of fluoroquinolones for respiratory infectionsagent would be selected empirically followed by directed therapy could have a greater impact on fluoroquinolone resistance,or for avoiding selected agents because of anticipated in vitro limiting use for UTIs may also mitigate increasing fluo-resistance are set at a relatively low resistance prevalence. The roquinolone resistance [30].recommendation of a 10% fluoroquinolone resistance preva- Clinical Questions Addressed for the 2010 Updatelence as the threshold for using an alternative agent in con- The Expert Panel addressed the following clinical questions injunction with or in place of a fluoroquinolone for pyelonephritis the 2010 update:is primarily based on expert opinion, because there are limiteddata to provide evidence-based guidance. I. What is the optimal treatment for acute uncomplicated cystitis in adult nonpregnant, premenopausal women?Consideration of Collateral Damage II. What is the optimal treatment for acute uncomplicatedCollateral damage, a term describing ecological adverse effects of pyelonephritis in adult nonpregnant, premenopausal women?antimicrobial therapy, such as the selection of drug-resistantorganisms and colonization or infection with multidrug- PRACTICE GUIDELINESresistant organisms, has been associated with use of broad-spectrum cephalosporins and fluoroquinolones [22, 23]. Use of ‘‘Practice guidelines are systematically developed statements tobroad spectrum cephalosporins has been linked to subsequent assist practitioners and patients in making decisions about ap-infection with vancomycin-resistant enterococci, extended- propriate health care for specific clinical circumstances’’ [31].spectrum b-lactamase–producing Klebsiella pneumoniae, b- High quality guidelines are clear, reliable and reproducible,lactam-resistant Acinetobacter species, and Clostridium difficile flexible, and based on a multidisciplinary review of evidence[22]. Use of fluoroquinolones has been linked to infection with [31]. They should improve quality of care and serve as educa-methicillin-resistant S. aureus and with increasing fluo- tional tools.roquinolone resistance in gram-negative bacilli, such as Pseu-domonas aeruginosa [22]. The preserved in vitro susceptibility of METHODOLOGYE. coli to nitrofurantoin, fosfomycin, and mecillinam over manyyears of use suggests these antimicrobials cause only minor Panel Compositioncollateral damage [8, 10], perhaps because of minimal effects on The IDSA Standards and Practice Guidelines Committeenormal fecal flora [24–26]. In contrast, increased rates of anti- (SPGC) in collaboration with European Society for Microbiol-microbial resistance have been demonstrated for antimicrobials ogy and Infectious Diseases (ESCMID) convened experts in the Clinical Practice Guidelines d CID 2011:52 (1 March) d e107
  6. 6. Table 1. Strength of Recommendations and Quality of EvidenceCategory/grade DefinitionStrength of recommendationA Good evidence to support a recommendation for or against useB Moderate evidence to support a recommendation for or against useC Poor evidence to support a recommendationQuality of evidenceI Evidence from >1 properly randomized, controlled trialII Evidence from >1 well-designed clinical trial, without randomization; from cohort or case- controlled analytic studies (preferably from .1 center); from multiple time-series; or from dramatic results from uncontrolled experimentsIII Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees NOTE. Data are from the periodic health examination. Canadian Task Force on the Periodic Health Examination. Health Canada, 1979. Adapted and Reproducedwith the permission of the Minister of Public Works and Government Services Canada, 2009 [32].management of patients with cystitis and pyelonephritis. A It should be emphasized that, as is true with any treatmentspecific effort was made to include representatives from diverse guideline, an assessment of the literature for a given agent’sgeographic areas and a wide breadth of specialties, including clinical efficacy is limited by the comparators studied. For ex- Downloaded from cid.oxfordjournals.org by guest on February 6, 2011urology, obstetrics and gynecology, emergency medicine, family ample, amoxicillin-clavulanate has been shown to be statisticallymedicine, internal medicine, and infectious diseases, with a goal significantly inferior to ciprofloxacin in a randomized trial re-of improving the generalizability and acceptance of the recom- cently published. On the other hand, in the only publishedmendations and subsequent incorporation into clinical practice. randomized study of cefpodoxime, its clinical efficacy appears toProcess Overview be comparable to that of trimethoprim-sulfamethoxazole. It isThe evaluation of evidence for each antimicrobial class used in not clear how amoxicillin-clavulanate would compare withtreatment of cystitis and pyelonephritis was performed by 2 cefpodoxime or to trimethoprim-sulfamethoxazole.members of the panel. Each member was assigned at least one Literature Review and Analysisantimicrobial class to review. The process for evaluating the For the update, the Expert Panel completed a review and analysisevidence was based on the IDSA Handbook on Clinical Practice of data published since 1998. Computerized literature searchesGuideline Development and involved a systematic weighting of of the Pubmed database were performed. The searches of thethe quality of the evidence and the grade of recommendation English-language literature from 1998 thru 2008, using the(Table 1) [32]. This scale had been modified from the one used terms, cystitis or pyelonephritis with MESH terms of ‘‘acutein the 1999 guideline. uncomplicated UTI,’’ ‘‘women,’’ and specific antimicrobials and The level of evidence rating (I, II, or III) for recommendations or classes of antimicrobials. To be included, the study had to bein this guideline refers to evidence of the antimicrobial’s efficacy an open-label or randomized, clinical trial of treatment ofin randomized clinical trials. The strength of the recommen- women with symptoms of acute uncomplicated cystitis or py-dation (A, B, or C) refers to the panel’s level of comfort in elonephritis. At least 1 follow-up visit assessing microbiologicalrecommending the antimicrobial for the treatment of un- or clinical response was required. Studies including .10% mencomplicated UTI and is based on the drug’s efficacy in clinical or patients with complicated UTI were excluded. Non–English-trials, rates of in vitro resistance among urinary pathogens, and language studies were excluded because they could not be re-the drug’s propensity to cause collateral damage and adverse liably reviewed by panel members.effects. For example, the panel felt that fosfomycin and piv- Outcomes of interest included early (first visit after treatment,mecillinam should be listed as agents recommended for treat- typically occurring at 0–7 days after the last dose of the anti-ment of uncomplicated cystitis, along with nitrofurantoin and microbial) clinical and microbiological cure, late (last visit aftertrimethoprim-sulfamethoxazole, even though they appear to be treatment, typically occurring 30–45 days after the last dose ofless efficacious clinically, because they do not appear to cause the antimicrobial) clinical cure, and adverse effects.collateral damage. On the other hand, the panel was less en-thusiastic about strongly recommending fluoroquinolones for Guidelines and Conflict of Interestacute cystitis, even though they have high clinical efficacy, be- All members of the Expert Panel complied with the IDSA policycause of concerns about collateral damage and the subsequent on conflicts of interest, which requires disclosure of any financialthreat to the usefulness of fluoroquinolones for the treatment of or other interest that might be construed as constituting an actual,other more serious infections, including pyelonephritis. potential, or apparent conflict. Members of the Expert Panel weree108 d CID 2011:52 (1 March) d Gupta et al
  7. 7. provided IDSA’s conflict of interest disclosure statement and were 33]. Thus, there was insufficient new literature to support fur-asked to identify ties to companies developing products that ther analyses of single-dose or 3-day therapy versus longermight be affected by promulgation of the guideline. Information therapy included in the previous guideline.was requested regarding employment, consultancies, stock own- The criteria used to define clinical and microbiological cureership, honoraria, research funding, expert testimony, and and the duration of follow-up and timing of follow-up visitsmembership on company advisory committees. The panel made were not uniform across studies. Many studies did not performdecisions on a case-by-case basis as to whether an individual’s or report intent to treat analyses; this may inflate the late clinicalrole should be limited as a result of a conflict. Potential conflicts and microbiological success rates. Major differences in defi-are listed in the Acknowledgements section. nitions of study outcomes are highlighted in the text.Consensus Development Based on EvidenceThe Panel met on 7 occasions via teleconference and once in GUIDELINE RECOMMENDATIONS FOR THEperson to complete the work of the guideline. The purpose of the TREATMENT OF ACUTE UNCOMPLICATEDteleconferences was to discuss the questions to be addressed, make CYSTITIS AND PYELONEPHRITISwriting assignments and discuss recommendations. Most of thework was done with e-mail correspondence. All members of the I. What Is the Optimal Treatment for Acute Uncomplicatedpanel participated in the preparation and review of the draft Cystitis?guideline. Feedback from external peer reviews was obtained. All Recommendations (Figure 1).collaborating organizations were also asked to provide feedback Downloaded from cid.oxfordjournals.org by guest on February 6, 2011 1. Nitrofurantoin monohydrate/macrocrystals (100 mg twiceand endorse the guidelines. The following organizations endorsed daily for 5 days) is an appropriate choice for therapy due tothe guidelines: American Congress of Obstetricians and Gyne- minimal resistance and propensity for collateral damagecologists, American Urological Association, Association of Med- (defined above) and efficacy comparable to 3 days ofical Microbiology and Infectious Diseases–Canada), and the trimethoprim-sulfamethoxazole (A-I).Society for Academic Emergency Medicine. The guideline was 2. Trimethoprim-sulfamethoxazole (160/800 mg [1 double-reviewed and approved by the IDSA SPGC, the IDSA Board of strength tablet] twice-daily for 3 days) is an appropriate choiceDirectors, and the ESCMID Board prior to dissemination. for therapy, given its efficacy as assessed in numerous clinicalRevision Dates trials, if local resistance rates of uropathogens causing acuteAt annual intervals, the Panel Chair, the SPGC liaison advisor, uncomplicated cystitis do not exceed 20% or if the infectingand the Chair of the SPGC will determine the need for revisions strain is known to be susceptible (A-I).to the guideline based on an examination of current literature. If i. The threshold of 20% as the resistance prevalence at whichnecessary, the entire Panel will be reconvened to discuss po- the agent is no longer recommended for empirical treatment oftential changes. When appropriate, the panel will recommend acute cystitis is based on expert opinion derived from clinical,revision of the guideline to the IDSA SPGC and Board and other in vitro, and mathematical modeling studies (B-III).collaborating organizations for review and approval. ii. In some countries and regions, trimethoprim (100 mg twiceRESULTS daily for 3 days) is the preferred agent and is considered equivalent to trimethoprim-sulfamethoxazole on the basis ofLiterature Search data presented in the original guideline (A-III) [1].The literature search identified 295 potential articles for review, iii. Data are insufficient to make a recommendation for otherof which 28 met criteria for inclusion in the analyses. The types cystitis antimicrobials as to what resistance prevalence should beof studies included randomized clinical trials and open label used to preclude their use for empirical treatment of acute cystitis.clinical trials. Expert reviews were also incorporated into the 3. Fosfomycin trometamol (3 g in a single dose) is anfinal grade recommendation. Two panel members were assigned appropriate choice for therapy where it is available due toeach antimicrobial class included in the guideline and in- minimal resistance and propensity for collateral damage, but itdependently reviewed the relevant literature. These 2 reviewers appears to have inferior efficacy compared with standard short-compared their results and reached consensus on their findings course regimens according to data submitted to the US Foodfor the antimicrobial class and then presented them to the panel. and Drug Administration (FDA) and summarized in theDiscrepancies were discussed by the panel and final adjudication Medical Letter (A-I) [7].was based on review by the chairperson and majority vote. 4. Pivmecillinam (400 mg bid for 3–7 days) is anLimitations in the Literature appropriate choice for therapy in regions where it is availableThere were a limited number of publications directly comparing (availability limited to some European countries; not licensedthe same drug given for different durations of therapy [29, and/or available for use in North America), because of minimal Clinical Practice Guidelines d CID 2011:52 (1 March) d e109
  8. 8. resistance and propensity for collateral damage, but it may have Four randomized clinical trials compared trimethoprim-inferior efficacy compared with other available therapies (A-I). sulfamethoxazole with another agent, including ciprofloxacin, 5. The fluoroquinolones, ofloxacin, ciprofloxacin, and norfloxacin, nitrofurantoin, and cefpodoxime proxetil, andlevofloxacin, are highly efficacious in 3-day regimens (A-I) but evaluated microbiological and clinical outcomes amonghave a propensity for collateral damage and should be reserved for women with acute cystitis (Table 2) [35–38]. The 2 studiesimportant uses other than acute cystitis and thus should be including a fluoroquinolone had findings consistent with theconsidered alternative antimicrobials for acute cystitis (A-III). 1999 guideline, reporting that trimethoprim-sulfamethoxazole 6. b-Lactam agents, including amoxicillin-clavulanate, was noninferior (95% confidence interval of difference atcefdinir, cefaclor, and cefpodoxime-proxetil, in 3–7-day 610%) to ciprofloxacin for early clinical and bacterialregimens are appropriate choices for therapy when other cure rates [35, 37]. Both studies used a longer than standardrecommended agents cannot be used (B-I). Other b-lactams, (7 days rather than 3 days) course of trimethoprim-such as cephalexin, are less well studied but may also be sulfamethoxazole versus a 3-day course of ciprofloxacin. In theappropriate in certain settings (B-III). The b-lactams generally study by Iravani et al [37], 7 days of 160/800 mg twice-dailyhave inferior efficacy and more adverse effects, compared with trimethoprim-sulfamethoxazole in 174 women had similarother UTI antimicrobials (B-I). For these reasons, b-lactams rates of early and late clinical cure as 3 days of 100 mg cipro-other than pivmecillinam should be used with caution for floxacin given twice daily to 168 women (95% early anduncomplicated cystitis. 90% late for each drug). The late bacterial cure rate (4-6 weeks 7. Amoxicillin or ampicillin should not be used for empirical after therapy) was lower with trimethoprim-sulfamethoxazole Downloaded from cid.oxfordjournals.org by guest on February 6, 2011treatment given the relatively poor efficacy, as discussed in the than for ciprofloxacin (79% vs 91%, respectively), whereas1999 guidelines [1] and the very high prevalence of antimicrobial the early bacterial cure rate was higher with trimethoprim-resistance to these agents worldwide [8–11] (A-III). sulfamethoxazole (93% vs 88%, respectively). Arredondo-GarciaEvidence Summary et al [35] reported that 7 days of trimethoprim-sulfamethoxazoleThe optimal agent for therapy of a patient with acute un- (160/800 mg twice daily) in 81 women resulted in early clinicalcomplicated cystitis depends on a number of factors (Figure 2). and bacterial cure rates of 86% and 85%, respectively, non-Each agent has pros and cons related to its use and the choice of inferior to the 89% and 92% cure rates, respectively, achieved intherapy is made on an individual basis. 97 women treated with 3 days of ciprofloxacin (250 mg twice Trimethoprim-sulfamethoxazole. The traditional first-line daily). Of note, these similar outcomes were demonstratedagent in the United States and recommended in the original despite 15% of women in the trimethoprim-sulfamethoxazoleIDSA guidelines was trimethoprim-sulfamethoxazole (tri- arm having a pretherapy isolate resistant to the treatment drug,methoprim was considered comparable) [1]. However, rising compared with only 1% of women in the ciprofloxacin arm.rates of trimethoprim-sulfamethoxazole resistance among ur- Results stratified by susceptibility of the infecting organism toopathogens, especially outside of the United States, and con- the treatment regimen were not reported. Each study includedsistent evidence that in vitro resistance correlates with bacterial a third treatment arm; results of these comparisons are discussedand clinical failures, necessitates revising this recommendation. below for the relevant antimicrobial class.Indeed, the guidelines of the European Association of Urology A small study compared a 3-day course of trimethoprim-do not recommend this agent as first choice treatment of un- sulfamethoxazole (160/800 mg twice daily) with a 3-daycomplicated cystitis [34]. course of cefpodoxime-proxetil (100 mg twice daily) [38].Figure 2. Meta-analysis of studies comparing trimethoprim-sulfamethoxazole (TMP-SMX) with nitrofurantoin (NTF) for acute uncomplicated cystitis. CI,confidence interval.e110 d CID 2011:52 (1 March) d Gupta et al
  9. 9. Table 2. Results from Included Studies of Trimethoprim-Sulfamethoxazole for Treatment of Acute Uncomplicated CystitisStudy (year) [reference] Treatment regimen Iravani et al (1999) [37] TMP-SMX, Nitrofurantoin Ciprofloxacin, 100 mg twice 160/800 mg monohydrate/ daily for 3 days twice daily macrocrystals, for 7 days 100 mg twice daily for 7 daysEarly clinical cure 165/174 (95) 166/179 (93) 160/168 (95)Early bacterial cure 161/174 (93) 153/177 (86) 148/168 (88)Late clinical cure 137/153 (90) 135/151 (89) 132/147 (90)Adverse events, % 38 34 28 Arredondo-Garcia et al TMP-SMX, Norfloxacin, Ciprofloxacin, 250 mg (2004) [35] 160/800 mg 400 mgtwice twice daily for 3 days twice daily x 7 days daily for 7 daysEarly clinical cure 70/81 (86) 90/107 (84) 86/97 (89)Early bacterial cure 69/81 (85) 93/107 (87) 89/97 (92)Late clinical cure 66/81 (82) 88/107 (82) 81/97 (84)Adverse events, % 8.7 3.9 4.0 Kavatha et al TMP-SMX, Cefpodoxime (2003) [38] 160/800 mgtwice proxetil, 100 Downloaded from cid.oxfordjournals.org by guest on February 6, 2011 daily for 3 days mg twice daily for 3 daysEarly clinical cure 70/70 (100) 62/63 (98.4)Early bacterial cure 70/70 (100) 62/63 (98.4)Late clinical cure 51/60 (85) 42/50 (84)Adverse events, % 1.4 1.6 Gupta et al TMP-SMX, 160/800 Nitrofurantoin (2007) [36] mgtwice daily monohydrate/ for 3 days macrocrystals, 100 mg twice daily for 5 daysEarly clinical cure 133/148 (90) 144/160 (90)Early bacterial cure 131/144 (91) 141/154 (92)Late clinical cure 117/148 (79) 134/160 (84)Adverse events, % 31 28% NOTE. Data are proportion of subjects (%), unless otherwise indicated. Efficacy rates refer to cure rates on the visit closest to a 5–9-day period followingtreatment. NA, not available; TMP-SMX, trimethoprim-sulfamethoxazole.Women with an uropathogen resistant to either study drug women in the nitrofurantoin arm, with a nonsignificant dif-(4 of 82 women in the trimethoprim-sulfamethoxazole arm ference of -5%. Rates were also equivalent (predefined asand 0 of 81 women in the cefpodoxime arm) were excluded. a 610% difference between agents) at 5-9 days after therapy,Clinical cure was achieved in 100% of the 70 women in the with clinical cure of 90% in each arm and bacterial cure of 91%trimethoprim-sulfamethoxazole arm, compared with 62 in the trimethoprim-sulfamethoxazole arm and 92% in the ni-(98%) of 63 women in the cefpodoxime arm. The microbio- trofurantoin arm. There was a significantly higher clinical curelogical cure rates were the same as the clinical cure rates in rate among women in the trimethoprim-sulfamethoxazoleeach arm. Adverse effects were reported in 1 patient in the arm who had a trimethoprim-sulfamethoxazole–susceptibletrimethoprim-sulfamethoxazole arm and 2 patients in the uropathogen, compared with those who had a trimethoprim-cefpodoxime arm. sulfamethoxazole–resistant uropathogen (84% vs 41%, The fourth study compared a 3-day course of trimethoprim- respectively;1 P , .001).sulfamethoxazole (160/800 mg twice daily) with a 5-day The fifth study used a prospective observational trial designcourse of nitrofurantoin monohydrate–macrocrystals (100 mg to compare clinical and bacterial outcomes among womentwice daily) and included women with uropathogens resistant with acute cystitis with a trimethoprim-sulfamethoxazole–to the study drugs [36]. The primary end point, overall clinical susceptible or –resistant uropathogen [21]. All women werecure rate at 30 days, was 79% among the 148 women in the treated with a 5-day course of trimethoprim-sulfamethox-trimethoprim-sulfamethoxazole arm and 84% among the 160 azole (160/800 mg twice daily). The microbiological cure rates Clinical Practice Guidelines d CID 2011:52 (1 March) d e111
  10. 10. were significantly higher among women with a trimethoprim- Resistance impacts both clinical and bacterial outcomes, sosulfamethoxazole–susceptible uropathogen than for women known or expected resistance should be considered in antimi-with a –resistant uropathogen (86% vs 42%, respectively; P , crobial choice. In this regard, resistance to trimethoprim-.001). The clinical cure rate at 5-9 days after completion of sulfamethoxazole is high in many regions of the world.therapy was also higher in the trimethoprim-sulfamethox- However, in settings with a 10% - 15% prevalence of resistanceazole–susceptible group (88% of 333 women) than in the to trimethoprim-sulfamethoxazole, cure rates with trimethoprim-trimethoprim-sulfamethoxazole–resistant group (54% of 151 sulfamethoxazole were equivalent to those with comparatorwomen; P , .001). The clinical and microbiological differ- drugs (ie, ciprofloxacin and nitrofurantoin) to which almostences remained significant at the 28–42-day follow-up visit. all isolates were probably susceptible (data on susceptibilityBecause this was not a randomized treatment trial, the data to comparators were not uniformly provided in the studies) [35–were not included in the efficacy analyses but are reported as 37]. Trimethoprim-sulfamethoxazole use is associated withthey provide insight into expected outcomes in patients with increased resistance, but, even though it has a significant impactresistant uropathogens. on intestinal flora, it is generally not thought to have a propensity Overall findings from these studies demonstrate that for ‘‘collateral damage’’ as observed with broad-spectrumtrimethoprim-sulfamethoxazole remains a highly effective cephalosporins or fluoroquinolones.treatment for acute uncomplicated cystitis in women when the Nitrofurantoin. There is additional evidence in supportrate of resistance is known or expected to be , 20%, supporting of nitrofurantoin monohydrate/macrocrystals, for which dataa strong recommendation for use in such settings. Early clinical were previously limited. There were 4 randomized trials of Downloaded from cid.oxfordjournals.org by guest on February 6, 2011and microbiological cure rates are in the 90% - 100% range nitrofurantoin versus a comparator published since the pre-(Table 2). Late outcomes are harder to compare across studies, vious guideline (Table 3) [28, 36, 37, 39]. These studiesbut when calculated using intent to treat criteria, are 80% - 90%. demonstrate that (1) nitrofurantoin monohydrate/Table 3. Results from Included Studies of Nitrofurantoin for Treatment of Acute Uncomplicated CystitisStudy RegimenIravani et al (1999) [37] Nitrofurantoin monohydrate/ TMP-SMX, 160/800 Ciprofloxacin, 100 mg macrocrystals, 100 mg twice mg twice daily for 7 days twice daily for 3 days daily for 7 daysEarly clinical cure 166/179 (93) 165/174 (95) 160/168 (95)Early bacterial cure 153/177 (86) 161/174 (93) 148/168 (88)Late clinical cure 135/151 (89) 137/153 (90) 132/147 (90)Adverse events, % 34 38 28Stein et al (1999) [39] Nitrofurantoin monohydrate/ Fosfomycin trometamol, macrocrystals, 100 mg twice single 3-gdose daily for 7 daysEarly clinical cure 232/245 (95) 240/263 (90)Early bacterial cure 189/219 (86) 192/246 (78)Late clinical cure 168/180 (93) 189/202 (94)Adverse events, % 5.6 5.3Christiaens et al (2002) [28] Nitrofurantoin macrocrystals, Placebo, 4 times 100 mg 4 times daily for 3 days daily for 3 daysEarly clinical cure 21/24 (88) 13/23 (54)Early bacterial cure 17/23 (74) 9/22 (41)Late clinical cure NA NAAdverse events, % 23 26Gupta et al (2007) [36] Nitrofurantoin monohydrate/ TMP-SMX, 160/800 macrocrystals, 100 mg twice mg twice daily for 3 days daily for 5 daysEarly clinical cure 144/160 (90) 133/148 (90)Early bacterial cure 141/154 (92) 131/144 (91)Late clinical cure 134/160 (84) 117/148 (79)Adverse events, % 28 31 NOTE. Data are proportion of subjects (%), unless otherwise indicated. Efficacy rates refer to cure rates on the visit closest to a 5–9-day period followingtreatment. NA, not available; TMP-SMX, trimethoprim-sulfamethoxazole.e112 d CID 2011:52 (1 March) d Gupta et al
  11. 11. macrocrystals (100 mg twice daily for 7 days) has similar regimen, rather than the traditional 7-day course, can be con-clinical cure rates (based on the small differences in early sidered as an effective duration of treatment based on a recentclinical cure and confidence intervals that are small enough to randomized clinical trial [36].suggest no difference in efficacy) to ciprofloxacin (100 mg Fosfomycin trometamol. There are also new data in supporttwice daily for 3 days; 93% vs 95%), trimethoprim-sulfame- of fosfomycin trometamol, a phosphonic acid derivative availablethoxazole (160/800 mg twice daily for 7 days; 93% vs 95%), in the United States and some European countries for treatmentand 3-g single-dose fosfomycin trometamol (89% vs 90%); of UTI. A 3-g single-dose of fosfomycin trometamol was com-(2) nitrofurantoin monohydrate/macrocrystals (100 mg twice pared with a 7–day course of nitrofurantoin monohydrate/daily in a 5-day regimen) is equivalent in clinical and mi- macrocrystals 100 mg twice daily in one study and with a 5-daycrobiological cure rates to trimethoprim-sulfamethoxazole course of trimethoprim 100 mg twice daily in another [39, 40].(160/800 mg twice daily in a 3-day regimen); and (3) nitro- The latter study only evaluated the microbiologic outcome andfurantoin macrocrystals (100 mg 4 times daily for 3 days) is reported that single-dose fosfomycin trometamol and 5 days ofsuperior to placebo treatment of women with acute cystitis. twice-daily trimethoprim each had an 83% bacterial cure rateTaken together, the studies demonstrate a clinical cure rate (147 of 177 fosfomycin and 70 of 84 trimethoprim-treatedwith nitrofurantoin of 88% - 93% and a bacterial cure rate of women, respectively) at the early follow-up visit [34]. The study81% - 92%. A meta-analysis of studies comparing early clin- by Stein [39] demonstrated that the early clinical response (cureical cure rates with nitrofurantoin and trimethoprim-sulfa- or improvement at 5-11 days after starting therapy) rates weremethoxazole is shown in Figure 2 and demonstrates not significantly different, at 91% (240 of 263 women) for 3-g Downloaded from cid.oxfordjournals.org by guest on February 6, 2011equivalence between the 2 agents. Of note, resistance to ni- single-dose fosfomycin trometamol treatment and 95% (232 oftrofurantoin remains low and it is well tolerated and effica- 245 women) for 100 mg of nitrofurantoin monohydrate/mac-cious in a 5-day regimen (Table 4). rocrystals given twice daily. The late clinical response rates re- Thus, current randomized clinical trial data provide strong mained high for both drugs (93%–94%). However, thesupport for consideration of nitrofurantoin as an effective agent microbiologic cure rate was significantly higher with nitro-for treatment of acute cystitis. Demonstration of efficacy, with furantoin (86%), compared with fosfomycin (78%), at the firstminimal drug resistance or propensity for collateral damage, follow-up visit (P 5 .02). Microbiologic cure rates 4-6 weeks aftermakes nitrofurantoin an attractive agent for cystitis. A 5-day therapy were 96% for fosfomycin and 91% for nitrofurantoin butTable 4. Treatment Regimens and Expected Early Efficacy Rates for Acute Uncomplicated Cystitis Mean percentage (range) Estimated Estimated clinical microbiologicalDrug (dosage) efficacyab efficacyb Common side effects ReferencesNitrofurantoin monohydrate/ 93 (84–95) 88 (86–92) Nausea,headache [36, 37, 39] macrocrystals (100 mg twice daily for 5–7 days)Trimethoprim-sulfamethoxazole 93 (90–100) 94 (91–100) Rash, urticaria,nausea, [36, 37] (160/800 mg twice daily for 3 days) vomiting, hematologicFosfomycin trometamol (3 g 91 80 (78–83) Diarrhea, nausea,headache [39, 40] single-dose sachet)Pivmecillinam (400 mg twice 73 (55–82) 79 (74–84) Nausea, vomiting, diarrhea [29, 43] daily for 3–7 days)Fluoroquinolones (dose varies 90 (85–98) 91 (81–98) Nausea/vomiting, [35, 43, 44, 46–52] by agent; 3–day regimen)c diarrhea, headache, drowsiness, insomniab-lactams (dose varies by 89 (79–98) 82 (74–98) Diarrhea, nausea, [38, 52, 54] agent; 3–5 day regimen)d vomiting, rash, urticaria a Efficacy rates refer to cure rates on the visit closest to a 5–9-day period following treatment, and are averages or ranges calculated from clinical trials discussedin the text. b Estimated clinical efficacy and microbiological efficacy rates should not necessarily be compared across agents, because study design, efficacy definition,therapy duration, and other factors are heterogeneous. Studies represent clinical trials published since publication of the 1999 Infectious Disease Society of Americaguidelines so as to represent efficacy rates that account for contemporary prevalence of antibiotic-resistant uropathogens. Note that efficacy rates may varygeographically depending on local patterns of antimicrobial resistance among uropathogens. See text for details. c Data on fluoroquinolones are compiled from regimens of ofloxacin, norfloxacin, and ciprofloxacin from the referenced clinical trials and not otherfluoroquinolones that are no longer commercially available. See text for details. d Data on blactams data cited are derived from clinical trials examining second and third generation cephalosporins and amoxicillin-clavulanate. See text for details. Clinical Practice Guidelines d CID 2011:52 (1 March) d e113
  12. 12. included only 50% of the original study population. Intent–to- 25% (54 of 227 women) and a bacteriologic cure rate of 34%,treat analyses were not reported [39]. Overall, the bacterial effi- both inferior to active drug. In another randomized trial com-cacy of fosfomycin is lower than that of other first-line agents, paring 3 days of pivmecillinam (400 mg bid) with 3 days ofbut clinical efficacy (based on a single study) was comparable norfloxacin (400 mg bid), pivmecillinam treatment resulted in(Table 4). Additional information considered by the com- lower bacterial cure rates (222 (75%) of 298 vs 276 (91%) of 302,mittee was the reference in the 1999 IDSA UTI guideline to respectively; P , .001) and lower clinical cure rates (360 (82%)unpublished data demonstrating lower bacterial eradication of 437 vs 381 (88%) of 433, respectively; P 5 .02) [43]. In vitrorates with fosfomycin than with 10 days of trimethoprim- resistance to pivmecillinam was not associated with a high ratesulfamethoxazole and with 7 days of ciprofloxacin. These of failure; 30 (88%) of 34 pivmecillinam-treated patients whostudies are still not available in the published literature except had a pivmecillinam-resistant uropathogen achieved bacterialas previously referenced in a Medical Letter report [7]. cure. Several in vitro studies examined the activity of fosfomycin Although not available in the United States or Canada, piv-against multidrug-resistant pathogens. These demonstrate that mecillinam is one of the agents of choice in many Nordicfosfomycin is active against vancomycin-resistant enterococci countries due to low resistance rates and low propagation of(VRE), methicillin-resistant S. aureus (MRSA), and extended- resistance [24]. Different doses and durations have been asso-spectrum b-lactamase (ESBL)–producing gram-negative rods ciated with varying efficacy rates, and a 5-day or 7-day regimen[41]. As resistance among uropathogens causing community- is probably superior to a 3-day regimen. Similarly, a 400-mgacquired uncomplicated cystitis increases, fosfomycin may be- dose fared better than a 200-mg dose for both bacterial and Downloaded from cid.oxfordjournals.org by guest on February 6, 2011come more useful, particularly if no other oral agents with in clinical efficacy. The efficacy rates are notably lower than othervitro activity are available [42]. Clinical outcomes are not yet recommended agents (Table 4). Of note, the rate of resistancereported from randomized, controlled studies; thus, specific among E. coli to pivmecillinam remains low despite its frequentrecommendations for the role of fosfomycin in the treatment of use in some European countries [24].multidrug-resistant uropathogens cannot be included in the Fluoroquinolones. There were 12 randomized trials ofcurrent guideline. However, observational studies are supportive fluoroquinolones for treatment of acute cystitis. The majority ofof clinical efficacy [41, 42]. these compared one fluoroquinolone with another, often in The convenience of a single-dose regimen, in vitro activity varying doses or durations. Sparfloxacin and gatifloxacin are noagainst resistant gram-negative rods, and minimal propensity longer widely available because of their adverse effects, and thus,for collateral damage make fosfomycin a useful choice in some results related to these 2 agents are not included in the analysesareas. It is recommended as a first-line agent in the guidelines of [44–47]. Two large studies compared 500 mg of extended-the European Association of Urology, although it is not uni- release once-daily ciprofloxacin to the 250-mg twice-daily for-formly available [34]. Susceptibility data are also not uniformly mulation of ciprofloxacin and demonstrated equivalent cureavailable, because testing is not routinely performed in many rates [48, 49]. Another study compared ciprofloxacin (250 mgclinical laboratories. Furthermore, the effect of fosfomycin on twice daily) in a 3-day versus a 7-day regimen and demonstratedthe intestinal flora after intake of a single 3-g dose (the standard equivalent cure rates but significantly higher adverse event ratesdosage for uncomplicated UTI) has not been well studied, but with the longer regimen [50]. A small study compared nor-the effect is probably minor [25]. This assumption is supported floxacin 400 mg twice daily with norfloxacin 800 mg once dailyby the high rate of E. coli susceptibility in regions with frequent and demonstrated similar bacterial and clinical outcomes, albeituse of fosfomycin for uncomplicated cystitis in women [10]. with limited power to detect true differences [33]. One study Pivmecillinam. Pivmecillinam, the orally bioavailable form compared single-dose ciprofloxacin with 3 days of norfloxacinof mecillinam, is distinguished from other b-lactams because of and found the agents to be equivalent, with microbiological andits specificity for the urinary tract, minimal resistance or pro- clinical cure rates in the 91% - 94% range [51].pensity for collateral damage, and reasonable treatment efficacy. Three studies compared a fluoroquinolone with a drug fromIt is an extended gram-negative spectrum penicillin used only another class. Two demonstrated better clinical and microbio-for treatment of UTI. Two studies met our inclusion criteria logical cure rates with the fluoroquinolone regimen (norfloxacin[43]. One study compared different doses of pivmecillinam with vs pivmecillinam and ciprofloxacin vs amoxicillin-clavulanate)placebo. Pivmecillinam at 200 mg 3 times daily for 7 days, [43, 52]. The third demonstrated early clinical and bacterial200 mg twice daily for 7 days, and 400 mg twice daily for 3 days cure rates to be similar with 3 days of low-dose ciprofloxacinresulted in early clinical cure rates of 62% (132 of 217 women), or a standard dose but longer duration (7 days each) of64% (136 of 220 women), and 55% (119 of 220 women), re- trimethoprim-sulfamethoxazole and nitrofurantoin [37]. Thespectively, and bacteriologic cure rates of 93%, 94%, and 84%, details for each of these studies are discussed under therespectively. Placebo therapy resulted in a clinical cure rate of respective comparator agent. Overall clinical and bacteriale114 d CID 2011:52 (1 March) d Gupta et al
  13. 13. efficacy rates in the studies are consistently high, although they ciprofloxacin (P , .001) [52]. Vaginal colonization with ur-were occasionally ,90% (Table 4). opathogens before and after therapy was also measured, and the Thus, fluoroquinolones remain very effective for the treat- higher clinical failure rate observed with amoxicillin-clavulanatement of acute cystitis, although increased fluoroquinolone re- was associated with a lower rate of eradication of vaginal ur-sistance among community uropathogens is mitigating the opathogens in the amoxicillin-clavulanate group. These findingsusefulness of this antimicrobial class. Once-daily dosing of ci- are consistent with the postulated mechanism for b-lactamprofloxacin is now available and of equal efficacy as the twice- inferiority in the treatment of UTI being, in part, related todaily formulation, albeit more expensive, since the latter is now persistence of the vaginal reservoir for infection. Another studygeneric. Single-dose fluoroquinolone therapy remains an option compared 2 b-lactam antibiotics, cefdinir (100 mg twice daily)but with possibly lower efficacy rates than with longer regimens versus ceflacor (250 mg 3 times daily), each for 5 days, and[1]. Fluoroquinolones with longer half-lives, such as pefloxacin demonstrated equivalent clinical (91% vs 93%, respectively) andand fleroxacin, may be useful for single-dose therapy, but no microbiological (85% vs 80%, respectively) cure rates [54].studies met our eligibility criteria and neither agent is available Thus, the overall evidence of the efficacy of b-lactams forin all locales, including North America and many parts of Eu- treatment of acute cystitis has not changed since the previousrope. The main concern regarding fluoroquinolone use for acute guideline [1]. Most studies demonstrate that b-lactams arecystitis is the promotion of fluoroquinolone resistance, not only generally inferior in cure rates to the fluoroquinolones [42, 52].among uropathogens but also other organisms, causing more The study by Kavatha et al [38] demonstrating that an advancedserious and difficult–to-treat infections at other sites. There is generation oral cephalosporin (cefpodoxime proxetil) resulted Downloaded from cid.oxfordjournals.org by guest on February 6, 2011also concern about the association between fluoroquinolone use in cure rates equivalent to those of trimethoprim-sulfame-and increased rates of MRSA [22]. Many experts now call for thoxazole is intriguing and needs to be confirmed in a largerrestricting use of fluoroquinolones to those episodes of un- clinical trial [38]. However, even if these observations are con-complicated cystitis when other UTI antimicrobials are not firmed, concern about emergence of gram-negative ESBL re-suitable [53]. The panel agrees and recommends that fluo- sistance to these agents limits enthusiasm for any widespreadroquinolones be reserved as an alternative only when other UTI use. Broad-spectrum cephalosporins, in particular, have beenagents cannot be used (Figure 1). associated with collateral damage, the most concerning of which b-Lactams. Five randomized trials evaluating b-lactam is ESBL resistance among gram-negative bacteria [22]. Nar-antibiotics were identified and included in the analyses. rower-spectrum cephalosporins are often used for treatment ofOnly 1 study included a 3-day regimen of trimethoprim- UTI and may result in less collateral damage, compared withsulfamethoxazole as the standard comparator [38]. This study broad-spectrum cephalosporins; however, there is a lack of ad-demonstrated that 100 mg of cefpodoxime proxetil twice equately powered studies to make specific recommendations fordaily for 3 days was equivalent to trimethoprim-sulfame- these agents. Thus, the panel feels that currently available datathoxazole (160/800 mg twice daily for 3 days), with 100% of supports avoidance of b-lactams other than pivmecillinam for70 women treated with trimethoprim-sulfamethoxazole and empirical therapy of uncomplicated cystitis unless none of the98% of 63 women treated with cefpodoxime experiencing recommended agents are appropriate.clinical and microbiological cured at day 4–7 after completion The choice of agent should be individualized on the basis ofof therapy. Clinical cure at 28 days was somewhat lower but patient allergy and compliance history, local practice patterns,not different between the treatment arms (Table 2). However, local community resistance prevalence, availability, cost, andthe statistical power of the study to find differences between patient and provider threshold for failure. In the event of di-the drugs was limited by its small sample size. Side effects agnostic uncertainty regarding cystitis versus early pyelone-were not different between the 2 groups. In another study, phritis, use of agents such as nitrofurantoin, fosfomycin, andamoxicillin-clavulanate (500/125 mg twice daily) was com- pivmecillinam should be avoided, because they do not achievepared with ciprofloxacin (250 mg twice daily), both for 3 days, adequate renal tissue levels. Such uncertainly may exist in thewith 4 months of follow-up [52]. Clinical cure at the last setting of cystitis symptoms accompanied by subjective fever thatfollow-up visit was observed in 58% of 160 women treated with is not verified at the time of examination, a prolonged durationamoxicillin-clavulanate, compared with 77% of 162 women of cystitis symptoms (typically greater than 5–7 days), or vaguetreated with ciprofloxacin (P , .001). The differences were flank pain or tenderness which is not otherwise explained.significant even among the subgroups of women infected withstrains susceptible to the treatment drug (60% vs 77%, re- II. What Is the Treatment for Acute Pyelonephritis?spectively; P 5 .004). Microbiological cure at 2 weeks was Recommendations.observed in 76% of 156 women treated with amoxicillin- 8. In patients suspected of having pyelonephritis, a urineclavulanate, compared with 95% of 161 women treated with culture and susceptibility test should always be performed, and Clinical Practice Guidelines d CID 2011:52 (1 March) d e115
  14. 14. initial empirical therapy should be tailored appropriately on without ampicillin; an extended-spectrum cephalosporin orthe basis of the infecting uropathogen (A-III). extended-spectrum penicillin, with or without an 9. Oral ciprofloxacin (500 mg twice daily) for 7 days, with or aminoglycoside; or a carbapenem. The choice between thesewithout an initial 400-mg dose of intravenous ciprofloxacin, is agents should be based on local resistance data, and thean appropriate choice for therapy in patients not requiring regimen should be tailored on the basis of susceptibilityhospitalization where the prevalence of resistance of results (B-III).community uropathogens to fluoroquinolones is not knownto exceed 10% (A-I). If an initial one-time intravenous agent is Evidence Summaryused, a long-acting antimicrobial, such as 1 gof ceftriaxone or Optimal therapy for acute uncomplicated pyelonephritis de-a consolidated 24-h dose of an aminoglycoside, could be used pends on the severity of illness at presentation and local re-in lieu of an intravenous fluoroquinolone (B-III). If the sistance patterns as well as specific host factors (such asprevalence of fluoroquinolone resistance is thought to exceed allergies). In addition, urine culture and susceptibility testing10%, an initial 1-time intravenous dose of a long-acting should be performed, and initial empirical therapy should beparenteral antimicrobial, such as 1 g of ceftriaxone (B-III) or tailored appropriately on the basis of the infecting uropathogen.a consolidated 24-h dose of an aminoglycoside, is Strategies for optimizing empirical therapy when local resistancerecommended (B-III). patterns are not known include using an initial intravenous dose i. Data are insufficient to make a recommendation about what of a long-acting parenteral antimicrobial and starting withfluoroquinolone resistance level requires an alternative agent in a broader-spectrum agent and narrowing therapy when labo- Downloaded from cid.oxfordjournals.org by guest on February 6, 2011conjunction with or to replace a fluoroquinolone for treatment ratory results are available.of pyelonephritis. There were 6 treatment studies of acute uncomplicated py- elonephritis identified, but only 1 study met our inclusion cri- 10. A once-daily oral fluoroquinolone, including teria. This study compared a 7-day regimen of oral ciprofloxacinciprofloxacin (1000 mg extended release for 7 days)or (500 mg twice daily) with a 14-day regimen of trimethoprim-levofloxacin (750 mg for 5 days), is an appropriate choice for sulfamethoxazole (160/800 mg twice daily) for treatment oftherapy in patients not requiring hospitalization where the women presenting to emergency departments or outpatientprevalence of resistance of community uropathogens is not clinics with mild to moderate pyelonephritis [55]. An initialknown to exceed 10% (B-II). If the prevalence of fluoroquinolone intravenous 400-mg dose of ciprofloxacin in the ciprofloxacinresistance is thought to exceed 10%, an initial intravenous dose of group or a 1-g dose of ceftriaxone in the trimethoprim-a long-acting parenteral antimicrobial, such as 1 g of ceftriaxone sulfamethoxazole group was allowed in the protocol at the(B-III) or a consolidated 24-h dose of an aminoglycoside, is discretion of the clinician. Women with an uropathogen re-recommended (B-III). sistant to the study drug to which they were randomized con- 11. Oral trimethoprim-sulfamethoxazole (160/800 mg [1 tinued to receive the drug unless they experienced clinical failuredouble-strength tablet] twice-daily for 14 days) is an (14 women in the trimethoprim-sulfamethoxazole group and 1appropriate choice for therapy if the uropathogen is known woman in the ciprofloxacin group). Ciprofloxacin had signifi-to be susceptible (A-I). If trimethoprim-sulfamethoxazole is cantly higher microbiological (99% vs 89%, respectively) andused when the susceptibility is not known, an initial clinical (96% vs 83%, respectively) cure rates at the early post-intravenous dose of a long-acting parenteral antimicrobial, therapy visit. Cure rates were similar regardless of whethersuch as 1 g of ceftriaxone (B-II) or a consolidated 24-h dose of an initial intravenous dose of ciprofloxacin was given. Amongan aminoglycoside, is recommended (B-III). trimethoprim-sulfamethoxazole–treated women, those with a 12. Oral b-lactam agents are less effective than other trimethoprim-sulfamethoxazole–resistant uropathogen hadavailable agents for treatment of pyelonephritis (B-III). If an significantly lower microbiological eradication and clinical cureoral b-lactam agent is used, an initial intravenous dose of rates, compared with those with a susceptible uropathogen.a long-acting parenteral antimicrobial, such as 1 g of An initial intravenous dose of ceftriaxone significantlyceftriaxone (B-II) or a consolidated 24-h dose of an improved the microbiological eradication rate and moderatelyaminoglycoside, is recommended (B-III). improved the clinical cure rate in women with a trimethoprim- i. Data are insufficient to modify the previous guideline sulfamethoxazole–resistant uropathogen.recommendation for a duration of therapy of 10–14 days for Two additional studies also demonstrated that a 5–7-daytreatment of pyelonephritis with a b-lactam agent. regimen of a once-daily fluoroquinolone (ciprofloxacin, 1000 13. Women with pyelonephritis requiring hospitalization mg extended release, and levofloxacin, 750 mg, respectively)should be initially treated with an intravenous antimicrobial were effective for acute pyelonephritis [56, 57]. These studies didregimen, such as a fluoroquinolone; an aminoglycoside, with or not meet our inclusion criteria because they includede116 d CID 2011:52 (1 March) d Gupta et al

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