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

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


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

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Unfacility urinary tract infections (UTIs) are one ofthe most prevalent reasons for antibiotic usage among otherwise healthywomales.1 In 2011, the Infectious Diseases Society of America(IDSA) published an upday to its clinical practice guidelines for thetherapy of unfacility UTIs (i.e., cystitis).1 Twelveyears had actually passed since the original guidelines were publimelted, and also notsurprisingly, there have been a variety of changes in treatmentreferrals. Such a transition in present exercise warrants testimonial of thecorrect diagnosis and also therapy of this common women’s healthworry.

Pathophysiology

UTIs build by either ascending or descending bacterialinvasion right into the urinary tract. The even more widespread mode of infection isthe ascfinishing pathway, wright here fecal flora get accessibility to the urinarytract via emigration of the urethra. Rarely, a UTI occurs by way ofthe descfinishing pathmeans. Descfinishing infections are the outcome ofhematogenous spcheck out of bacteria from a main resource situated elsewherein the body.2 By much, the most widespread uropathogen identified in uncomplex UTIs is Escherichia coli, audit for around 85% of all instances. The staying 15% are resulted in generally by Staphylococcus saprophyticus and also Klebsiella and also Proteus species.1

Signs and also symptoms of a UTI differ depending on the extentof the infection. Lower UTIs deserve to involve the urethra, bladder, and/orprostate (in men), and also tfinish to present with localized symptoms such asdysuria, urinary frequency, urgency, and also suprapubic pain or heaviness.3A UTI extending to the ureter or kidneys (i.e., pyelonephritis) oftenrequires more systemic signs and symptoms, such as leukocytosis, fever before,chills, abdominal pain, flank pain, and nausea/vomiting. Certain patientpopulaces may current acommonly. For instance, elderly patients aremuch less likely to have urinary symptoms and even more most likely to present withtransformed mental condition, changes in eating actions, and also gastrointestinalcomplaints.2

Diagnosis

Tbelow are a number of diagnostic devices that deserve to bemade use of to confirm a diagnosis of UTI. In the outpatient setting, themany convenient tool is the urine dipstick, which provides two importantmarkers for UTI detection—leukocyte esterase and also nitrite. Leukocyteesterase is indicative of white blood cells in the urine (pyuria).Nitrite suggests bacteriuria and also has a higher specificity for UTI thandoes leukocyte esterase (95%-98% versus 59%-96%).4 However, the sensitivity is limited by bacteria that do not alleviate nitrate, such as S saprophyticus and also Enterococcus and also Pseudomonasspecies. The most trustworthy strategy for confirming UTI is the urinesociety. The wanted method for collection is the midstream cleancapture, as it is the leastern invasive. The traditional cut-off forsignificant bacteriuria in this situation is 105 CFU/mL, though some resources mention 102 CFU/mL as diagnostic for a symptomatic patient.2,3

UTIs are classified as either facility oruncompli-cated. What distinguishes a facility UTI is the presence of astructural or useful abnormality in the urinary tract. By default,infections in males, youngsters, and also pregnant women are consideredfacility, as most of these cases involve some kind of urologicabnormality. Other features that signify a complicated infectionincorporate immunosuppressive conditions, diabetes, catheterization, renaltransplantation, and also neurogenic bladder.1-3 Consequently, unfacility UTIs occur in otherwise healthy and balanced, adult, nonpregnant females.

Lower UTI Treatment

In the original IDSA guidelines from 1999, the recommendedtreatment for unfacility reduced UTI in the USA wasprimarily trimethoprim-sulfamethoxazole (TMP-SMX).5 Sincethat time, new clinical data and a better focus on the potential forantibiotics to propagate antimicrobial resistance (i.e., “collateraldamage”) has actually brought about a variety of transforms in the therapy recommendationswithin the reminder update (TABLE 1).1 In additionto TMP-SMX, nitrofurantoin and also fosfomycin are currently additionally consideredcorrect empiric treatment choices because of their reasonable efficacyand low hazard for collateral damages.1 Fluoroquinolones andbeta-lactams remain alternate treatment options due to pertains to forantimicrobial resistance and inferior efficacy, respectively.

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TMP-SMX: Overall, clinical trials forUTIs evaluate two major outcomes, the resolution of bacteriuria(microorganic cure) and also the resolution of symptoms (clinical cure).Several researches assistance the efficacy of TMP-SMX in uncomplicatedcystitis, via an estimated clinical cure price of 93%.1Furthermore, TMP-SMX maintains reasonable efficacy at resistance prices of14% to 15%. In one trial, TMP-SMX was noninferior to ciprofloxacindespite a resistance price of 15%, with a clinical cure price of 86%.6 Anvarious other trial comparing TMP-SMX to nitrofurantoin had actually comparable resistance and a clinical cure rate for TMP-SMX of 79%.7Not surprisingly, patients treated via TMP-SMX with a uropathogensensitive to the antibiotic had a much higher clinical cure price thanthose with a resistant organism. However before, it is worth noting that theclinical cure rate was still 41% in those patients with a TMP-SMXresistant pathogen, likely showing spontaneous resolution using hostdefense mechanisms.

One advantage that TMP-SMX has actually over other antibiotics isadequate proof from clinical, in vitro, and also mathematical modelingdata to assistance a thresorganize of 20% resistance listed below which the antibioticis still considered appropriate for empiric use.1 Thisreferral might be even more helpful to implement in the hospitalestablishing, as neighborhood antibiograms (antibiotic sensitivity reports) arefrequently not available, and the IDSA guidelines caution againstextrapolating hospital antibiograms to resistance patterns in thecommunity. However before, one study studying E coli antimicrobialresistance among outpatient urinary isolates revealed numerous U.S.areas where resistance to TMP-SMX exceeded 20%,8 which calls into question the appropriateness of this antibiotic for empiric therapy in the outpatient establishing.

Tbelow are numerous pitfalls to making use of TMP-SMX. Intoleranceto sulfa medications is reasonably prevalent, with about 3% of hospitalinpatients enduring a drug rash.9 Less widespread but stillof worry is drug hypersensitivity syndrome, which deserve to involvehematologic abnormalities, renal dysfunction, and life-threatening skinreactions such as Stevens-Johnboy syndrome. Renal insufficiency isanother worry that might prohibit the usage of this agent, mostly due toproblem for bring about hyperkalemia. For patients on warfarin, TMP-SMXposes a far-reaching interactivity via both modification in protein bindingand also inhibition of warfarin metabolism, and also avoidance of even short-termuse may be advisable to stop perhaps dramatic prolongation of theworldwide normalized proportion (INR).

Nitrofurantoin: In the previous IDSAguidelines, nitrofurantoin had scant proof to assistance its use inuncomplicated cystitis. Over the previous decade, yet, a number ofclinical trials have actually revealed fantastic microbiological and also clinicalcure prices via this agent, via an overall estimated clinical cure rateof 93%.1 Traditionally, nitrofurantoin has actually been used for acomplete of 7 days, however recent literature shows a 5-day course to benoninferior to TMP-SMX, via a clinical cure rate of 84%.7 Though clinical benefit information are lacking at varying levels of resistance, U.S. surveillance data suggest E coli resistance to nitrofurantoin at 0% to 5%.8

Pitfalls connected with nitrofurantoin usage are mostlypertained to loss of efficacy in the establishing of renal dysattribute. Ascreatinine clearance (CrCl) declines, urinary excretion ofnitrofurantoin is lessened, through little to no excretion arising whenthe CrCl drops listed below 20 mL/min.10 However before, there is minimalevidence to delineate the level of renal dysfunction that neentrances thedrug’s clinical efficacy. Several recommendations recommfinish avoidingnitrofurantoin in patients via a CrCl much less than 50 to 60 mL/min due toan enhanced danger of neurotoxicity and pulmonary toxicity.11,12Whether or not this is a pertinent problem for the brief courses provided inUTIs is very debatable, as these rare toxicities are typically seenafter build-up from chronic use.13

Fosfomycin: Fosfomycin is aphosphonic acid derivative and also currently the just antibiotic in itscourse. A small amount of proof suggests it has equivalent clinicalefficacy to nitrofurantoin (90% vs. 95%), although with a lowermicrobiological cure price (78% vs. 86%).14 Its convenience asa single-dose regiguys provides it a specifically attrenergetic treatmentoption from a medication adherence perspective.

The major drawbacks through fosfomycin are regarded price andavailcapacity. Despite its being the shortest therapy for UTI, it isthe many expensive at approximately $40 to $50 for a solitary dose. Additionally,via UTI as its just indication in the U.S. and also the exceptionally recentendorsement of its use by the IDSA, the availability of fosfomycin atneighborhood pharmacies is variable. Lastly, susceptibility experimentation of thisantibiotic is not consistently performed, which renders surveillance ofresistance prices a challenge. However, E coli resistance to fosfomycin in Europe has remained low despite regular use of this agent,15 suggesting that routine testing might not be required.

Fluoroquinolones: Several trials havedemonstrated the efficacy of fluoroquinolones at producing bothmicrobiological and also clinical cure in the therapy of uncomplicatedlower UTI.1 With ciprofloxacin and also levofloxacin botheasily accessible as generic formulations, this antibiotic class represents anefficacious and also inexpensive therapy alternative. Despite these benefits,the IDSA has actually recommfinished reserving use of these agents as an alternativequite than a wanted treatment alternative due to their high propensityfor collateral damages. Fluoroquinolone usage is directly correlated withfluoroquinolone resistance, and hospital resistance rates are on theincrease. One study examining hospital resistance prices across 10 yearsfound an all at once 25% relative decrease in Pseudomonas aeruginosa susceptibility and a 7% decrease in E coli susceptibility to fluoroquinolones.16 In the community establishing, U.S. surveillance information show that as a whole E coli resistance to fluoroquinolones is sensibly low (~5%).8However, caution is warranted in interpreting nationwide resistance ratesdue to substantial regional variation. In fact, the exact same surveillancestudy uncovered fluoroquinolone resistance prices at 11% and also 20% in themid-Atlantic and west south-main regions, respectively.

Tbelow is also a problem for emerging resistance tononquinolone antibiotic classes. For instance, fluoroquinolone exposureis an independent hazard element for extended-spectrum beta-lactamase(ESBL)–creating E coli,17 and also it has likewise been associated via methicillin-resistant Staphylococcus aureus (MRSA) isolation.18As a result, it is recommended to reserve the use of this class foreven more significant infections for which broad-spectrum coverage is warranted.

Beta-lactams: There is a absence ofhigh-top quality evidence via beta-lactams in the therapy ofuncomplex lower UTI. Many trials are either underpowered or use anincorrect comparator arm. Studies to day of reasonable qualityindicate inferiority of beta-lactams to fluoroquinolones.1 Though a little trial comparing cefpodoxime to TMP-SMX said comparable cure prices,19 a much more current trial through this cephalosporin brought about inferior clinical cure prices compared to ciprofloxacin (82% vs. 93%).20Furthermore, tright here are equivalent pertains to for collateral damage with thethird-generation cephalosporins as for fluoroquinolones, particularlywith regard to ESBL resistance.17 First-generationcephalosporins, on the other hand, might have actually a reduced propensity forcollateral damages, and also clinical trials to explore their efficacy inuncomplex UTI are needed.

Pyelonephritis Treatment

The IDSA guidelines segregate antibiotic recommendations for pyelonephritis into outpatient and inpatient treatment (TABLES 2 and also 3).Regardmuch less of the area of therapy, a urine culture should alwaysbe sent out to evaluate the appropriateness of empiric treatment and also allow forstreamlining when feasible. For outpatient treatment, thefluoroquinolones have the most data to support empiric use.1This antibiotic course is the just one endorsed by the guidelines forempiric outpatient therapy. Tright here is a paucity of literature withregard to alternative agents.

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One study discovered TMP-SMX to be inferior to ciprofloxacin (clinical cure of 83% vs. 95%).21However before, the cure rate for TMP-SMX especially in patients withsusceptible isolates was cshed to that of ciprofloxacin (92%),indicating TMP-SMX as an acceptable treatment option once the pathogenis recognized to be sensitive. TMP-SMX–resistant isolates were much lessmost likely to be properly treated with TMP-SMX, through a clinical cure rateof only 35%. However before, patients in the TMP-SMX arm who obtained one doseof ceftriaxone at the begin of treatment had actually significantly highermicrobiological cure rates, and also so it is recommfinished to give a one-timedose of an IV antibiotic once TMP-SMX is supplied empirically.21Similarly, it is recommended to administer one IV antibiotic dose inaddition to treatment with an dental fluoroquinolone once local resistancerates exceed 10%, though this recommendation is based solely on expertopinion.

Since the previous guidelines, no new clinical literaturehas been publiburned examining the function of beta-lactams in pyelonephritis.Therefore, present recommendations are based on limited and outdatedliterature, mostly via aminopenicillins (e.g., amoxicillin). Becausethese information have demonstrated inferior efficacy and higher relapse ratesthan typical therapy, beta-lactams reprimary an different treatmentoption.1

Inpatient treatment is reserved for those patients withserious pyelonephritis and/or the incapacity to toleprice dental medicines.Due to the absence of clinical literature, recommendations forinpatient therapy are mainly based upon experienced opinion, and also incorporate awide array of broad-spectrum IV antimicrobials (TABLE 3). Inthis instance, neighborhood resistance prices and individual patient danger factorsfor drug-resistant pathogens must be taken right into account whendetermining an proper empiric agent.1

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Conclusion

While the arrival of brand-new IDSA guidelines has broadened thetherapy choices available for reduced UTI in women, each antibiotic hasits own advantages and also pitfalls, requiring therapy tailored to theindividual patient. When possible, fluoroquinolones have to be avoided tominimize the potential for collateral damages. Evidence-based treatmentoptions for pyelonephritis reprimary limited, underscoring the importanceof utilizing a hospital or neighborhood antibiogram, as soon as easily accessible, toguide empiric treatment.

REFERENCES

1. Gupta K, Hooton TM, Naber KG, et al. Internationalclinical exercise guidelines for the therapy of acute uncomplicatedcystitis and also pyelonephritis in women: a 2010 upday by the InfectiousDiseases Society of America and the European Society for Microbiologyand also Infectious Diseases. Clin Infect 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. Lane DR, Takhar SS. Diagnosis and also administration of urinary tract infection and pyelonephritis. Emerg Med Clin N Am. 2011;29:539-552.4. Pappas PG. Laboratory in the diagnosis and also monitoring of urinary tract infections. Med Clin North Am. 1991;75:313-325.5. Warren JW, Abrutyn E, Hebel JR, et al. Guidelines forantimicrobial therapy of uncomplicated acute bacterial cystitis andacute pyelonephritis in womales. Clin Infect Dis.

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1999;29:745-758.6. Arredondo-Garcia JL, Figueroa-Damian R, Rosas A, et al.Comparichild of momentary treatment regimales of ciprofloxacin versuslong-term therapy regimens of trimethoprim/sulfamethoxazole ornorfloxacin for uncomplex reduced 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 for the treatment of acute uncomplex cystitis inwoguys. 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 outcomes from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents. 2006;27:468-475.9. Ho JM, Juurlink DN. Considerations as soon as 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 nitrofurantoin in patients withlessened renal feature. J Urol. 1968;99:371-375.11. Hanlon JT, Aspinall S, Semla T, et al. Consensusguidelines for dental dosing of mainly renally cleared medications inolder adults. J Am Geriatr Soc. 2009;57:335-340.12. Bennett WM, Aronoff GR, Golper TA, et al. Drug Prescribing in Renal Failure. Philadelphia, PA: Amerihave the right to College of Physicians; 1987.13. Goemaere NN, Grijm K, van Hal PT, den Bakker MA. Nitrofurantoin-induced pulmonary fibrosis: a situation report. J Med Case Reports. 2008;2:169-173.14. Stein GE. Comparison of single-dose fosfomycin and a7-day course of nitrofurantoin in female patients with uncomplicatedurinary tract 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 on clinical facets andantimicrobial resistance public health in females with cystitis (ARESC):ramifications for empiric therapy. Eur Urol. 2008;54:1164-1175.16. Zervos MJ, Hershberger E, Nicolau DP, et al.Relationship in between fluoroquinolone usage and also transforms in susceptibilitiesto fluoroquinolones of selected pathogens in 10 USA teachinghospitals, 1991-2000. Clin Infect Dis. 2003;37:1643-1648.17. Rodriguez-Bano J, Alcala JC, Cisneros JM, et al. Community infections caused by extended-spectrum β-lactamase-creating 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 Infect Dis. 2003;9:1415-1422.19. Kavatha D, Giamarellou H, Alexiou Z, et al.Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-termtreatment of unfacility acute cystitis in woguys. 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. Comparichild ofciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) foracute uncomplicated pyelonephritis in women: a randomized trial. JAMA. 2000;283:1583-1590.