Kimberly L. Still, PharmDPGY-2 internal Medicine Pharmacy ResidentMedStar Union Memorial HospitalBaltimore, Maryland

Daryn K. Norwood, PharmD, BCPS, BCPP, CGPProgram Director, PGY-2 interior Medicine Pharmacy ResidencyClinical Pharmacist, internal MedicineMedStar Union Memorial HospitalBaltimore, Maryland

US Pharm. 2012;37(9):56-60.

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Uncomplicated urinary tract infections (UTIs) room one ofthe most typical reasons for antibiotic use among otherwise healthywomen.1 In 2011, the contagious Diseases society of America(IDSA) published an upgrade to that clinical exercise guidelines for thetreatment the uncomplicated UTIs (i.e., cystitis).1 Twelveyears had actually passed since the initial guidelines to be published, and notsurprisingly, there have been a variety of changes in treatmentrecommendations. Such a shift in existing practice warrants evaluation of theappropriate diagnosis and treatment that this typical women’s healthissue.


UTIs construct by one of two people ascending or descending bacterialinvasion right into the urinary tract. The much more common mode of epidemic isthe ascending pathway, wherein fecal flora gain accessibility to the urinarytract via colonization of the urethra. Rarely, a UTI occurs by way ofthe to decrease pathway. Diminish infections are the result ofhematogenous spread of bacteria native a primary source located elsewherein the body.2 through far, the most typical uropathogen established in uncomplicated UTIs is Escherichia coli, accountancy for around 85% of all cases. The continuing to be 15% are resulted in primarily by Staphylococcus saprophyticus and Klebsiella and Proteus species.1

Signs and also symptoms that a UTI vary depending on the extentof the infection. Lower UTIs have the right to involve the urethra, bladder, and/orprostate (in men), and tend to existing with localized symptoms such asdysuria, urinary frequency, urgency, and also suprapubic ache or heaviness.3A UTI prolonging to the ureter or kidney (i.e., pyelonephritis) ofteninvolves much more systemic signs and symptoms, such as leukocytosis, fever,chills, abdominal pain, flank pain, and nausea/vomiting. Particular patientpopulations may existing atypically. Because that example, elderly patients areless likely to have urinary symptom and much more likely to present withaltered mental status, alters in eat habits, and also gastrointestinalcomplaints.2


There space a variety of diagnostic devices that deserve to beutilized to check a diagnosis the UTI. In the outpatient setting, themost convenient tool is the urine dipstick, which gives two importantmarkers for UTI detection—leukocyte esterase and also nitrite. Leukocyteesterase is indicative of white blood cell in the urine (pyuria).Nitrite shows bacteriuria and has a higher specificity because that UTI thandoes leukocyte esterase (95%-98% versus 59%-96%).4 However, the sensitivity is restricted by bacteria that perform not reduce nitrate, such together S saprophyticus and also Enterococcus and also Pseudomonasspecies. The most reliable method for confirming UTI is the urineculture. The preferred method for arsenal is the midstream cleancatch, together it is the the very least invasive. The traditional cut-off forsignificant bacteriuria in this instance is 105 CFU/mL, though part sources point out 102 CFU/mL together diagnostic for a symptomatic patient.2,3

UTIs room classified together either facility oruncompli-cated. What distinguishes a complex UTI is the visibility of astructural or functional abnormality in the urinary tract. Through default,infections in men, children, and pregnant women space consideredcomplicated, as most of these cases involve some type of urologicabnormality. Other attributes that signify a complicated infectioninclude immunosuppressive conditions, diabetes, catheterization, renaltransplantation, and also neurogenic bladder.1-3 Consequently, uncomplicated UTIs take place in otherwise healthy, adult, nonpregnant females.

Lower UTI Treatment

In the initial IDSA guidelines from 1999, the recommendedtreatment for uncomplicated lower UTI in the United claims wasprimarily trimethoprim-sulfamethoxazole (TMP-SMX).5 Sincethat time, new clinical data and also a greater focus on the potential forantibiotics come propagate antimicrobial resistance (i.e., “collateraldamage”) has led come a variety of changes in the therapy recommendationswithin the guideline update (TABLE 1).1 In additionto TMP-SMX, nitrofurantoin and also fosfomycin space now also consideredappropriate empiric treatment alternatives due to their reasonable efficacyand low threat for collateral damage.1 Fluoroquinolones andbeta-lactams remain alternate treatment options due to pertains to forantimicrobial resistance and inferior efficacy, respectively.


TMP-SMX: Overall, clinical trials forUTIs evaluate two major outcomes, the resolution that bacteriuria(microbiological cure) and the resolution of symptom (clinical cure).Several studies support the efficacy of TMP-SMX in uncomplicatedcystitis, through an estimated clinical cure rate of 93%.1Moreover, TMP-SMX maintains reasonable efficacy at resistance rates of14% come 15%. In one trial, TMP-SMX to be noninferior come ciprofloxacindespite a resistance rate of 15%, with a clinical cure price of 86%.6 an additional trial compare TMP-SMX to nitrofurantoin had similar resistance and also a clinical cure rate for TMP-SMX that 79%.7Not surprisingly, patient treated with TMP-SMX through a uropathogensensitive to the antibiotic had actually a much greater clinical cure price thanthose v a resistant organism. However, that is worth noting that theclinical cure price was quiet 41% in those patients through a TMP-SMXresistant pathogen, most likely reflecting voluntarily resolution via hostdefense mechanisms.

One advantage that TMP-SMX has actually over various other antibiotics issufficient evidence from clinical, in vitro, and mathematical modelingdata to support a threshold the 20% resistance listed below which the antibioticis quiet considered suitable for empiric use.1 Thisrecommendation may be much more practical to implement in the hospitalsetting, as community antibiograms (antibiotic sensitivity reports) areoften not available, and also the IDSA guidelines caution againstextrapolating hospital antibiograms to resistance fads in thecommunity. However, one study evaluating E coli antimicrobialresistance among outpatient urinary isolates revealed numerous U.S.regions wherein resistance to TMP-SMX gone beyond 20%,8 which calls into question the appropriateness that this antibiotic for empiric treatment in the outpatient setting.

There are several pitfalls to using TMP-SMX. Intoleranceto sulfa medicines is relatively common, with around 3% that hospitalinpatients suffering a drug rash.9 much less common yet stillof concern is drug hypersensitivity syndrome, which deserve to involvehematologic abnormalities, renal dysfunction, and life-threatening skinreactions such together Stevens-Johnson syndrome. Renal insufficiency isanother worry that may prohibit the usage of this agent, generally due toconcern for causing hyperkalemia. Because that patients ~ above warfarin, TMP-SMXposes a far-reaching interaction via both modification in protein bindingand inhibition that warfarin metabolism, and also avoidance of also short-termuse may be recipient to avoid perhaps dramatic prolongation that theinternational normalized proportion (INR).

Nitrofurantoin: In the previous IDSAguidelines, nitrofurantoin had scant evidence to support its use inuncomplicated cystitis. Over the past decade, however, a number ofclinical trials have revealed terrific microbiological and clinicalcure rates with this agent, with an in its entirety estimated clinical cure rateof 93%.1 Traditionally, nitrofurantoin has actually been supplied for atotal of 7 days, but recent literature shows a 5-day food to benoninferior to TMP-SMX, through a clinical cure price of 84%.7 despite clinical advantage data are doing not have at varying levels of resistance, U.S. Monitoring data indicate E coli resistance come nitrofurantoin in ~ 0% come 5%.8

Pitfalls associated with nitrofurantoin use space mostlyrelated to loss that efficacy in the setup of renal dysfunction. Ascreatinine clearance (CrCl) declines, urinary excretion ofnitrofurantoin is reduced, with tiny to no excretion developing whenthe CrCl falls below 20 mL/min.10 However, there is minimalevidence to delineate the level of renal dysfunction that negates thedrug’s clinical efficacy. Several recommendations recommend avoidingnitrofurantoin in patients v a CrCl much less than 50 come 60 mL/min early toan boosted risk of neurotoxicity and also pulmonary toxicity.11,12Whether or not this is a relevant problem for the brief courses offered inUTIs is very debatable, together these rare toxicities are commonly seenafter accumulation from chronic use.13

Fosfomycin: Fosfomycin is aphosphonic acid derivative and currently the only antibiotic in itsclass. A little amount that evidence suggests it has equivalent clinicalefficacy come nitrofurantoin (90% vs. 95%), although v a lowermicrobiological cure price (78% vs. 86%).14 that convenience asa single-dose regimen renders it a specifically attractive treatmentoption native a medication adherence perspective.

The key drawbacks v fosfomycin are connected to cost andavailability. In spite of its gift the shortest treatment for UTI, the isthe many expensive at around $40 to $50 for a solitary dose. Moreover,with UTI together its just indication in the U.S. And also the an extremely recentendorsement the its use by the IDSA, the availability of fosfomycin atcommunity pharmacies is variable. Lastly, susceptibility experimentation of thisantibiotic is not consistently performed, which provides surveillance ofresistance rates a challenge. However, E coli resistance come fosfomycin in Europe has actually remained low despite frequent usage of this agent,15 suggesting that routine trial and error may no be required.

Fluoroquinolones: Numerous trials havedemonstrated the efficacy the fluoroquinolones at producing bothmicrobiological and also clinical cure in the therapy of uncomplicatedlower UTI.1 through ciprofloxacin and also levofloxacin bothavailable as generic formulations, this antibiotic class represents anefficacious and also inexpensive treatment option. Despite these advantages,the IDSA has recommended reserving usage of this agents together an alternativerather than a preferred treatment option due to their high propensityfor collateral damage. Fluoroquinolone use is directly correlated withfluoroquinolone resistance, and hospital resistance rates are on therise. One study assessing hospital resistance rates across 10 yearsfound an as whole 25% relative decrease in Pseudomonas aeruginosa susceptibility and also a 7% decrease in E coli susceptibility to fluoroquinolones.16 In the neighborhood setting, U.S. Monitoring data indicate that all at once E coli resistance come fluoroquinolones is relatively low (~5%).8However, fist is warranted in interpreting national resistance ratesdue to significant regional variation. In fact, the exact same surveillancestudy discovered fluoroquinolone resistance prices at 11% and also 20% in themid-Atlantic and west south-central regions, respectively.

There is likewise a concern for arising resistance tononquinolone antibiotic classes. Because that example, fluoroquinolone exposureis an independent risk variable for extended-spectrum beta-lactamase(ESBL)–producing E coli,17 and it has likewise been connected with methicillin-resistant Staphylococcus aureus (MRSA) isolation.18As a result, the is encourage to reserve the usage of this class formore severe infections for which broad-spectrum coverage is warranted.

Beta-lactams: There is a absence ofhigh-quality proof with beta-lactams in the therapy ofuncomplicated reduced UTI. Many trials room either underpowered or use aninappropriate comparator arm. Research studies to day of reasonable qualitysuggest inferiority the beta-lactams to fluoroquinolones.1 though a little trial compare cefpodoxime to TMP-SMX argued comparable cure rates,19 a much more recent trial through this cephalosporin led to inferior clinical cure rates compared to ciprofloxacin (82% vs. 93%).20Additionally, over there are comparable concerns because that collateral damages with thethird-generation cephalosporins together for fluoroquinolones, particularlywith regard to ESBL resistance.17 First-generationcephalosporins, on the various other hand, may have actually a reduced propensity forcollateral damage, and clinical trials to explore their efficacy inuncomplicated UTI room needed.

Pyelonephritis Treatment

The IDSA accuse segregate antibiotic referrals for pyelonephritis into outpatient and also inpatient therapy (TABLES 2 and 3).Regardless that the ar of treatment, a urine culture should alwaysbe sent out to evaluate the appropriateness of empiric treatment and allow forstreamlining as soon as possible. Because that outpatient treatment, thefluoroquinolones have actually the many data to support empiric use.1This antibiotic course is the just one endorsed by the indict forempiric outpatient treatment. Over there is a paucity of literature withregard to different agents.


One study discovered TMP-SMX to be worse to ciprofloxacin (clinical cure of 83% vs. 95%).21However, the cure rate for TMP-SMX especially in patients withsusceptible isolates was close to that of ciprofloxacin (92%),indicating TMP-SMX as an acceptable therapy option as soon as the pathogenis well-known to be sensitive. TMP-SMX–resistant isolates were much lesslikely come be effectively treated through TMP-SMX, v a clinical healing rateof only 35%. However, patient in the TMP-SMX eight who got one doseof ceftriaxone at the begin of therapy had substantially highermicrobiological healing rates, and also so the is encourage to offer a one-timedose of one IV antibiotic when TMP-SMX is offered empirically.21Similarly, that is encourage to carry out one IV antibiotic sheep inaddition to treatment through an dental fluoroquinolone when local resistancerates exceed 10%, despite this referral is based exclusively on expertopinion.

Since the previous guidelines, no brand-new clinical literaturehas been published evaluating the duty of beta-lactams in pyelonephritis.Thus, present recommendations are based on minimal and outdatedliterature, mainly with aminopenicillins (e.g., amoxicillin). Becausethese data have actually demonstrated worse efficacy and higher relapse ratesthan standard therapy, beta-lactams continue to be an different treatmentoption.1

Inpatient treatment is booked for those patients withsevere pyelonephritis and/or the inability to tolerate dental medications.Due to the lack of clinical literature, recommendations forinpatient treatment room largely based upon expert opinion, and include awide range of broad-spectrum IV antimicrobials (TABLE 3). Inthis case, local resistance rates and also individual patient hazard factorsfor drug-resistant pathogens should be taken right into account whendetermining an suitable empiric agent.1



While the arrival of new IDSA indict has broadened thetreatment options available for lower UTI in women, each antibiotic hasits own benefits and pitfalls, requiring treatment tailored to theindividual patient. Once possible, fluoroquinolones should be avoided tominimize the potential for collateral damage. Evidence-based treatmentoptions because that pyelonephritis stay limited, underscoring the importanceof using a hospital or community antibiogram, when available, toguide empiric treatment.


1. Gupta K, Hooton TM, Naber KG, et al. Internationalclinical exercise guidelines because that the therapy of acute uncomplicatedcystitis and pyelonephritis in women: a 2010 update by the InfectiousDiseases society of America and also the European society for Microbiologyand infectious Diseases. Clin epidemic Dis. 2011;52:e103-e120.2. Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: The McGraw-Hill Companies; 2008:1899-1910.|3. Roadway DR, Takhar SS. Diagnosis and also management the urinary tract infection and pyelonephritis. Emerg Med Clin N Am. 2011;29:539-552.4. Pappas PG. Laboratory in the diagnosis and also management of urinary street infections. Med Clin north Am. 1991;75:313-325.5. Warren JW, Abrutyn E, Hebel JR, et al. Guidelines forantimicrobial treatment of uncomplicated acute bacter cystitis andacute pyelonephritis in women. Clin epidemic Dis.

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1999;29:745-758.6. Arredondo-Garcia JL, Figueroa-Damian R, Rosas A, et al.Comparison of temporary treatment regimen the ciprofloxacin versuslong-term therapy regimens of trimethoprim/sulfamethoxazole ornorfloxacin because that uncomplicated lower urinary tract infections: arandomized, multicentre, open-label, prospective study. J Antimicrob Chemother. 2004;54:840-843.7. Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-coursenitrofurantoin because that the therapy of acute uncomplicated cystitis inwomen. Arch Intern Med. 2007;167:2207-2212.8. Zhanel GG, Hisanaga TL, Laing NM, et al. Antibiotic resistance in Escherichia coli outpatient urinary isolates: last results native the phibìc American Urinary Tract epidemic Collaborative Alliance (NAUTICA). Int J Antimicrob Agents. 2006;27:468-475.9. Ho JM, Juurlink DN. Considerations once prescribing trimethoprim-sulfamethoxazole. Can Med Assoc J. 2011;183:1851-1858.10. Goff JB, Schlegel JU, O’Dell RM. Urinary excretion ofnalidixic acid, sulfamethizole and also nitrofurantoin in patient withreduced renal function. J Urol. 1968;99:371-375.11. Hanlon JT, Aspinall S, Semla T, et al. Consensusguidelines for oral dosing of primarily renally cleared medications inolder adults. J to be Geriatr Soc. 2009;57:335-340.12. Bennett WM, Aronoff GR, Golper TA, et al. Drug Prescribing in Renal Failure. Philadelphia, PA: American college of Physicians; 1987.13. Goemaere NN, Grijm K, valve Hal PT, den Bakker MA. Nitrofurantoin-induced pulmonary fibrosis: a situation report. J Med case Reports. 2008;2:169-173.14. Stein GE. Compare of single-dose fosfomycin and also a7-day food of nitrofurantoin in female patients with uncomplicatedurinary street infection. Clin Ther. 1999;21:1864-1872.15. Naber KG, Schito G, Botto H, Palou J, et al.Surveillance examine in Europe and also Brazil top top clinical facets andantimicrobial resistance epidemiology in females through cystitis (ARESC):implications because that empiric therapy. Eur Urol. 2008;54:1164-1175.16. Zervos MJ, Hershberger E, Nicolau DP, et al.Relationship in between fluoroquinolone use and also changes in susceptibilitiesto fluoroquinolones the selected pathogens in 10 United says teachinghospitals, 1991-2000. Clin infect Dis. 2003;37:1643-1648.17. Rodriguez-Bano J, Alcala JC, Cisneros JM, et al. Neighborhood infections led to by extended-spectrum β-lactamase-producing Escherichia coli. Arch Intern Med. 2008;168:1897-1902.18. Weber SG, gold HS, Hooper DC, et al. Fluoroquinolones and also the hazard for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg epidemic Dis. 2003;9:1415-1422.19. Kavatha D, Giamarellou H, Alexiou Z, et al.Cefpodoxime-proxetil matches trimethoprim-sulfamethoxazole for short-termtherapy the uncomplicated acute cystitis in women. Antimicrob Agents Chemother. 2003;47:897-900.20. Hooton TM, Roberts PL, Stapleton AE. Cefpodoxime vsciprofloxacin for short-course treatment of acute uncomplicatedcystitis. JAMA. 2012;307:583-589.21. Talan DA, Stamm WE, Hooton TM, et al. To compare ofciprofloxacin (7 days) and also trimethoprim-sulfamethoxazole (14 days) foracute uncomplicated pyelonephritis in women: a randomized trial. JAMA. 2000;283:1583-1590.