Treating Outpatient Cystitis in the Era of Antimicrobial Resistance

Urinary tract infections (UTIs) are one of the most common bacterial infections in the world. In the United States alone, there were an estimated 8.6 million office visits for UTI symptoms in 2007.¹ Additionally, a large, nationwide, retrospective study reported a 52% increase in hospital admissions related to UTI in the United States between 1998 and 2011.² Here we describe the oral treatment options for outpatient cystitis in an era of increasing antimicrobial resistance.

Risk Factors for Resistance

Although UTIs can be caused by several different pathogens, Escherichia coli remains the most common^3,4; however, the prevalence of multidrug-resistant (MDR) isolates among outpatients is increasing.⁵ Cystitis classification (uncomplicated vs complicated) can be important in determining the risk for an MDR organism. Patients typically considered to have uncomplicated infection include nonpregnant premenopausal women without significant comorbidities or urologic abnormalities.³ These patients are generally at lower risk for MDR organisms. Structural and functional abnormalities of the genitourinary tract (such as urethral catheterization, ureteral stent, neurogenic bladder, and benign prostatic hypertrophy) are considered to be complicating factors of a UTI and generally put the patient at higher risk for MDR pathogens.^6,7 Additional risk factors for MDR cystitis include prior antimicrobial use, recurrent UTIs, recent hospitalization, nursing home or long-term care facility residence, regular hemodialysis clinic visits, urologic procedures within the past 3 months, chronic conditions (such as diabetes mellitus), and older age.^7,8

Oral Antibiotic Treament Options

The selection of antimicrobial treatment for outpatient cystitis requires assessment of risk factors for resistance as well as allergy history, adverse effect profile, drug interaction potential, and previous urine culture data, if available.

Fluoroquinolones (FQs) and trimethoprim/sulfamethoxazole (TMP/SMX) are among the most commonly prescribed antibiotics for UTIs.^9,10 These antibiotics continue to be highly effective for UTIs caused by susceptible pathogens³; however, resistance rates to UTI pathogens have increased within the past 10 years. For example, approximately 30% and 26% of more than 200,000 urinary E coli isolates collected from adult Veterans Affairs (VA) outpatients between 2009 and 2013 were resistant to FQs and TMP/SMX, respectively.¹¹ MDR pathogens often carry concurrent resistance genes to these and other antibiotics. This is demonstrated by the high rates of resistance to FQs and TMP/ SMX among MDR urinary Enterobacteriaceae in several studies, ranging from 57% to 98% for TMP/SMX and 48% to 98% for FQs.^5,7,12 Therefore, these antibiotics are not recommended for empiric treatment of UTIs in patients with risk factors for resistance. They remain excellent choices for definitive therapy, even in MDR strains when susceptibility is detected, though most UTIs are treated empirically.

Oral β-lactams (such as amoxicillin-clavulanate and cefpodoxime) generally have inferior efficacy compared with first-line agents for cystitis; however, they may be used as alternative agents when first-line agents are not available.³ Years of use of this class of antibiotics has also produced increased resistance rates for E coli and other UTI pathogens. For example, resistance rates of urinary E coli isolates among adult VA outpatients were 37% for amoxicillin-clavulanate or ampicillin-sulbactam but only 5.4% for extended-spectrum cephalosporins.¹¹ Oral cephalosporins may be active against some MDR isolates with resistance profiles not involving extended-spectrum β-lactamases (ESBLs), such as resistance to ampicillin, early-generation cephalosporins, TMP/SMX, FQs, and/or aminoglycosides. It is important to note that the Clinical and Laboratory Standards Institute (CLSI) M100 document indicates that cefazolin susceptibilities should be used to predict susceptibility to oral cephalosporins, not intravenous third-generation cephalosporins.¹³ If an isolate is resistant to cefazolin but susceptible to intravenous third-generation cephalosporins (such as ceftriaxone), it may be appropriate to test the oral cephalosporin agents individually if needed for treatment, as some agents may remain susceptible.

Nitrofurantoin was approved by the US Food and Drug Administration in 1953 for the treatment of lower urinary tract infections; because of its low serum and tissue levels, however, it should not be used for the treatment of pyelonephritis, prostatitis, or complicated disease. Many studies have demonstrated that nitrofurantoin is as effective as other antibiotic options, with cure rates of approximately 79% to 92%, and could be given for a duration as short as 5 days.^3,14 Additionally, nitrofurantoin has retained high susceptibility rates despite several decades of use.¹⁵ It has even demonstrated retained activity against US outpatient MDR E coli isolates (75%-98% susceptible).⁵ In a small retrospective study completed in Turkey, a 14-day course of nitrofurantoin demonstrated clinical and microbiological success rates of 69% and 68%, respectively, in 75 patients with cystitis due to ESBL-producing E coli.¹⁶ Therefore, nitrofurantoin may represent a suitable oral option in patients with cystitis due to ESBL-producing E coli. Additional clinical data evaluating the efficacy of nitrofurantoin in the treatment of cystitis due to MDR organisms are limited. Of note, although nitrofurantoin was previously recommended only in patients with a creatinine clearance of >60 mL/min, the American Geriatrics Society Beers Criteria now support its use in patients with a creatinine clearance of >30 mL/min.¹⁷

Similar to nitrofurantoin, fosfomycin is an older antibiotic that has also retained activity against urinary pathogens.¹⁸ In addition, fosfomycin demonstrated high susceptibility rates (96%) among 95 ESBL- or AmpCproducing urinary E coli isolates at 3 Canadian hospitals from 2015 to 2016.¹⁹ Although a single-dose regimen has been well studied for uncomplicated cystitis due to antibiotic-susceptible organisms, there is less guidance available for the treatment of complicated or MDR cystitis. The most commonly used regimen for these infections is the off-label 3-dose regimen (given every 48-72 hours).^20,21 The clinical efficacy of fosfomycin for the treatment of MDR cystitis has been evaluated in several nonrandomized studies. For example, in a retrospective study of 41 patients with a UTI due to an MDR organism, 59% had microbiological cure (70% for those with ESBL-producing E coli or Klebsiella pneumoniae).²⁰ In another study, the clinical and microbiological success rates were 94% and 79%, respectively, among 52 patients with cystitis due to ESBL-producing organisms.²¹ These data suggest that fosfomycin may be an effective option for MDR UTIs. However, it should be noted that fosfomycin susceptibility rates are generally lower among Klebsiella and Pseudomonas isolates, and resistance may develop while patients are on fosfomycin for UTIs caused by Pseudomonas.^18,22 A potential barrier to the routine use of fosfomycin in the clinical setting is the lack of routine susceptibility testing in most microbiology laboratories. Therefore, providers typically need to ask their microbiology lab for specific susceptibility testing for this antibiotic. Additionally, CLSI breakpoints are established only for E coli and Enterococcus faecalis¹³; therefore, clinicians should use caution in extrapolating these breakpoints to other organisms.

Need for Intravenous Therapy

As resistance rates continue to increase among outpatient urinary pathogens, the number of patients who can be treated with oral treatment options is decreasing. In patients with risk factors for resistant organisms and recent use or previous failure of nitrofurantoin or fosfomycin, it may be reasonable to initiate therapy with parenteral antibiotics while awaiting culture and susceptibility results. Initial intravenous antibiotics may also be considered for patients with multiple risk factors for resistance or multiple antibiotic allergies or for whom there is concern about more severe or systemic infection or infection with Pseudomonas.

Conclusions

Increasing antimicrobial resistance has limited oral antibiotic selection for outpatient cystitis treatment. Therefore, risk factors for resistance, antibiotic history, previous culture data, antibiotic allergy history, concomitant medications, and severity of infection should be carefully considered when choosing an antibiotic regimen for patients presenting with cystitis symptoms. Nitrofurantoin and fosfomycin appear to retain activity and remain effective for cystitis, including infections caused by MDR organisms. Therefore, these antibiotics may be considered for some patients with cystitis who are at risk for resistance.

Camargo is originally from Brownsville, Texas. He relocated to San Antonio to pursue his pharmacy career. He completed his 2 years of undergraduate studies at the University of the Incarnate Word and is currently a student at the Feik School of Pharmacy with an expected graduation date of May 2019.Giancola is an infectious diseases clinical pharmacist and an antimicrobial stewardship program codirector at Brooke Army Medical Center. She received her PharmD from Northeastern University and completed postgraduate training at St. Mary’s Medical Center in Huntington, West Virginia (PGY-1), and the Oklahoma City VA Health Care System (PGY-2 infectious diseases) in Oklahoma. *She is an active member of the Society of Infectious Diseases Pharmacists.

References:

1. Schappert SM, Rechtsteiner EA. Ambulatory medical care utilization estimates for 2007. Vital Health Stat. 2011;(169):1-38.
2. Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM. The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011. Open Forum Infect Dis. 2017;4(1):ofw28 . doi: 10.1093/ofid/ofw281.
3. Gupta K, Hooton TM, Naber KG, et al; Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. doi: 10.1093/cid/ciq257.
4. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284. doi: 10.1038/nrmicro3432.
5. Sanchez GV, Baird AMG, Karlowsky JA, Master RN, Bordan FM. Nitrofurantoin retains antimicrobial activity against multidrug-resistant urinary Escherichia coli from US outpatients. J Antimicrob Chemother. 2014;69(12):3259-3262. doi: 10.1093/jac/dku282.
6. Nicolle LE; AMMI Canada Guidelines Committee. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005;16(6):349-360.
7. Khawcharoenporn T, Vasoo S, Singh K. Urinary tract infection due to multidrug-resistant Enterobacteriaceae: prevalence and risk factors in a Chicago emergency department. Emerg Med Int. 2013;2013:258517. doi: 10.1155/2013/258517.
8. Tenney J, Hudon N, Alnifaidy H, Li JTC, Fung KH. Risk factors for acquiring multidrug-resistant organisms in urinary tract infections: a systematic literature review. Saudi Pharm J. 2018;26(5):678-684. doi: 10.1016/j.jsps.2018.02.023.
9. Grigoryan L, Zoorob R, Wang H, Trautner BW. Low concordance with guidelines for treatment of acute cystitis in primary care. Open Forum Infect Dis. 2015;2(4):ofv159. doi: 10.1093/ofid/ofv159.
10. Kobayashi M, Shapiro DJ, Hersh AL, Sanchez GV, Hicks LA. Outpatient antibiotic prescribing practices for uncomplicated urinary tract infection in women in the United States, 2002-2011. Open Forum Infect Dis. 2016;3(3):ofw159. doi: 10.1093/ofid/ofw159.
11. Morrill HJ, Morton JB, Caffrey AR, et al. Antimicrobial resistance of Escherichia coli urinary isolates in the Veterans Affairs health care system. Antimicrob Agents Chemother. 2017;61(5):e02236-e02216. doi: 10.1128/AAC.02236-16.
12. Hirsch EB, Zucchi PC, Chen A, et al. Susceptibility of multidrug-resistant gram-negative urine isolates to oral antibiotics. Antimicrob Agents Chemother. 2016;60(5):3138-3140. doi: 10.1128/AAC.02961-15.
13. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2018.
14. Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015;70(9):2456-2464. doi: 10.1093/jac/dkv147.
15. Ny S, Edquist P, Dumpis U, et al; NoDARS UTI study group. Antibiotic resistance of Escherichia coli from outpatient urinary tract infection in women in six European countries including Russia [published online November 14, 2018]. J Glob Antimicrob Resist. doi: 10.1016/j.jgar.2018.11.004.
16. Tasbakan MI, Pullukcu H, Sipahi OR, Yamazhan T, Ulusoy S. Nitrofurantoin in the treatment of extended-spectrum β-lactamase-producing Escherichia coli-related lower urinary tract infection. Int J Antimicrob Agents. 2012;40(6):554-556. doi: 10.1016/j.ijantimicag.2012.08.003.
17. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers criteria for potentially inappropriate medication use in older adults [published online January 29, 2019]. J Am Geriatr Soc. doi: 10.1111/jgs.15767.
18. Hirsch EB, Raux BR, Zucchi PC, et al. Activity of fosfomycin and comparison of several susceptibility testing methods against contemporary urine isolates. Int J Antimicrob Agents. 2015;46(6):642-647. doi: 10.1016/j.ijantimicag.2015.08.012.
19. Ou LB, Nadeau L. Fosfomycin susceptibility in multidrug-resistant Enterobacteriaceae species and vancomycin-resistant Enterococci urinary isolates. Can J Hosp Pharm. 2017;70(5):368-374.
20. Neuner EA, Sekers J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother. 2012;56(11):5744-5748. doi: 10.1128/AAC.00402-12.
21. Pullukcu H, Tasbakan M, Sipahi OR, Yamazhan T, Aydemir S, Ulusoy S. Fosfomycin in the treatment of extended spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents. 2007;29(1):62-65. doi: 10.1016/j.ijantimicag.2006.08.039.
22. Walsh CC, McIntosh MP, Peleg AY, Kirkpatrick CM, Bergen PJ. In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother. 2015;70(11):3042-3050. doi: 10.1093/jac/dkv221.