Resistance in UTI: A focus on Nitrofurantoin

Introduction

Bacterial urinary tract infections (UTIs) are amongst the most common infectious diseases (Figure 1), and with its diverse clinical symptoms, remains one of the widely misunderstood and challenging infectious diseases encountered in clinical practice.^3-6Drekonja DM, Johnson JRPrim Care. 2008;35(2):345-67, vii.
Benoit SR, Nsa W, Richards CL, et al. J Am Geriatr Soc. 2008 Nov;56(11):2039-44.
Available at: http://www.cdc.gov/getsmart/healthcare/learn-from-others/factsheets/longterm-care.html
Mahesh E, Medha Y, Indumathi V A, et al. BJMP 2011;4(1):a406.   Together, resistance rates of uropathogens are also significantly increasing, and a dramatic and clinically significant increase has been noted in the antimicrobial resistance of uropathogens over the past few years.⁷Wagenlehner FM, Weidner W, Perletti G, et al. Expert Opin Emerg Drugs. 2010;15(3):375-97.   Indeed, rising resistance rates have been observed with Escherichia coli (E. coli), the most notable uropathogen responsible for UTIs (Figure 2).⁸Kashanian J, Hakimian P, Blute M Jr, et al. BJU Int. 2008;102(11):1634-7.  

Figure 1. Common infections treated with antibiotics	Figure 2. Resistance rates of E. coli isolates

Accordingly, this highlights the need for new and/or revised concepts in the treatment of UTIs; regarding rapid diagnosis of UTI, accurate presumptive identification of patients with resistant pathogens, and development and identification of new antimicrobials for drug-resistant UTI. In effect, efforts should be made not to detect or treat asymptomatic bacteriuria; to ensure an appropriate duration of therapy for symptomatic infections; and to limit the use of broad-spectrum agents, especially fluoroquinolones, if narrower spectrum agents are available.³Drekonja DM, Johnson JRPrim Care. 2008;35(2):345-67, vii.  ^,7Wagenlehner FM, Weidner W, Perletti G, et al. Expert Opin Emerg Drugs. 2010;15(3):375-97.  

Prevalence patterns

Prevalence of antibiotic resistance in UTI is not limited to any particular setting, and encompasses both the community acquired and hospital infections. In a prospective study, Kurtaran et al aimed to identify the agents causing community-acquired UTIs and their resistance patterns, and to investigate risk factors for extended spectrum ß-lactamse (ESBL) production.⁹Kurtaran B, Candevir A, Tasova Y, et al. Med Sci Monit. 2010 May;16(5):CR246-51.   The authors recorded patient data amongst a total of 146 patients with community-acquired UTIs, 109 women and 37 men (mean age: 50.9±18.44 years), and evaluated the microorganisms and their sensitivity patterns. Results showed that the most common infectious agents were E. coli (76.9%), Klebsiella pneumoniae (K. pneumoniae) (9.2%), Proteus mirabilis (P. mirabilis) (4.1%), and Enterococcus spp. (1.6%) (In a different regional study on community-acquired UTIs, Abu-Taha et al found that of the total Gram-positive bacterial isolates, 58.3% were Staphylococcus saprophyticus (S. saprophyticus¹⁰Abu-Taha AS, Sweileh WM. Curr Clin Pharmacol. 2011;6(4):304-7.  ) (Figure 3).

Using univariate analysis, Kurtaran et al identified a history of a UTI within the last 6 months (p=0.029) and a history of frequent UTI (p=0.028) to be significant risk factors for ESBL production. Together, the multivariate regression analysis found a history of urinary system infection in the past 6 months (p=0.025) as the only independent risk factor. Thus, these high resistance rates to antimicrobials and particularly the extremely high rate of ESBL production in community-acquired UTIs should be carefully considered.

Likewise, in a hospital based retrospective study, Szász et al aimed to identify prevalence and antimicrobial resistance of uropathogens in different inpatient wards, and documented E. coli as predominant causative agent of UTI in both children and adults.¹¹Szász M, Lehotkai N, Kristóf K, Szabó D, Nagy K. Acta Microbiol Immunol Hung. 2009 Dec;56(4):375-87.   Nonetheless, antibiotic resistance rates might be different in children and in adult care units due to many factors. Further, the authors found the following three types of antimicrobial agents with decreasing susceptibility (rising resistance) rates: trimethoprim/sulfamethoxasole (TMP/SMX), cephalosporins and quinolones; and there were differences in resistance among the eight investigated inpatient wards.

Treatment

Stratification of UTIs into uncomplicated and complicated has proven to be clinically useful, and would help treatment decisions. Here, bacterial virulence factors on the one side and the integrity of the host defense mechanisms on the other side determine the course of the infection. While in uncomplicated UTIs E. coli is the leading organism, in complicated UTIs the bacterial spectrum is much broader including Gram-negative and Grampositive and often multi-resistant organisms. In consequence, the therapy of uncomplicated UTIs is almost exclusively antibacterial, whereas in complicated UTIs the complicating factors have to be treated as well.

Essentially, there are two predominant aims in the antimicrobial treatment of both uncomplicated and complicated UTIs:

• Rapid and effective response to therapy and prevention of recurrence of the individual patient treated
• Prevention of emergence of resistance to antimicrobial chemotherapy in the microbial environment.

Generally, since the main drawback of current antibiotic therapies is the emergence and rapid increase of antibiotic resistance, to combat this development several strategies can be followed (Figure 4).

Nitrofurantoin: An answer to rising bacterial resistance

Re-evaluating the 1^st- and 2^nd-line therapies for treating uncomplicated UTIs, as although fluoroquinolones are commonly used for this purpose, its level of use may considered to be inappropriately excessive and will eventually have a detrimental impact; consequently, Kashanian et al hypothesized that nitrofurantoin might be the best choice for this indication, owing to its relatively low frequency of use and its high susceptibility rate in common UTI pathogens.⁸Kashanian J, Hakimian P, Blute M Jr, et al. BJU Int. 2008;102(11):1634-7.   The authors retrospectively analyzed antimicrobial susceptibility patterns of urinary isolates from 2003 to 2007, taken from a community-based institutional hospital; in total, 10,417 cultures grew E. coli during this period.

Overall, 95.6% of E. coli urine isolates were found susceptible to nitrofurantoin, with an average 2.3% resistance rate. By contrast, E. coli uropathogens had a mean 75.6% and 75.9% susceptibility and 24.2% and 24% resistance rate to both ciprofloxacin and levofloxacin, respectively (Figure 2 and 5). Furthermore, Co-trimoxazole (trimethoprim/sulfamethoxazole; TMP/SMX) was found to have a mean 29% resistance rate to E. coli over the same 5-year period.

Thus, it clearly shows that nitrofurantoin may be considered a good fluoroquinolone-sparing alternative to co-trimoxazole in treatment of UTIs; the study showed that nitrofurantoin is bactericidal to a mean of 95% of E. coli UTIs.

Nitrofurantoin is, thus, an acceptable treatment for uncomplicated UTIs, and should now be considered the first-line treatment; incidentally, the results appear validating a reconsideration of the UTI treatment guidelines.

Global experience with nitrofurantoin

Nitrofurantion applicability appears to be evident globally, with similar trend in the east and the west. The below two experiences potentiate the outlook.

Multiple-resistant urinary tract isolates of E. coli: US Demographics

Concurrent resistance to antimicrobials of different structural classes may complicate the therapeutic management of infections, including those of the urinary tract. Daniel et al analyzed pertinent results in The Surveillance Network Database-USA to assess multidrug resistance among urinary isolates of E. coli, the most prevalent pathogen contributing to these infections.¹²Daniel F et al. Antimicrob. Agents Chemother 2001; 45(5): 1402.   Results were available for 38,835 urinary isolates of E. coli that had been tested against various antimicrobials i.e. ampicillin, nitrofurantoin, cephalothin, ciprofloxacin, and TMP/SMX. Of these isolates, 7.1% (2,763/38,835) were resistant to ≥ 3 agents and considered multidrug resistant. Further analysis showed that among the multidrug-resistant isolates, 97.8% were resistant to ampicillin, 92.8% were resistant to TMP/SMX, 86.6% were resistant to cephalothin, 38.8% were resistant to ciprofloxacin, and 7.7% were resistant to nitrofurantoin; thus nitrofurantoin showed less resistance (Figure 6).

Incidentally, the predominant phenotype among multidrug-resistant isolates (57.9%; 1,600/2,793) included resistance to ampicillin, cephalothin, and TMP/SMX – this was the most common phenotype irrespective of patient age, gender, or inpatient-outpatient status and in 8/9 nine U.S. Bureau of the Census regions. Table 1 shows rates of multidrug resistance in relation to age and gender. Indeed, these rates of multidrug resistance warrant continued surveillance.

An Indian experience with Nitrofurantoin: Choice of antibiotic for empirical therapy of acute cystitis in a setting of high antimicrobial resistance

The fact that UTI is the third most common cause of hospital visits in India may perhaps compel the physicians to start antibiotics empirically. Further, a high prevalence of antimicrobial resistance among urinary isolates in diverse geographic regions within the country would make it pragmatic to identify the most appropriate antibiotic for empirical treatment of community-acquired UTIs based on local antimicrobial sensitivity profile.¹³Biswas D, Gupta P, Prasad R, et al. Indian J Med Sci 2006;60:53-8.   The study followed a prospective clinico-microbiological study design including all clinically diagnosed patients with community acquired UTI (acute cystitis) attending a tertiary care teaching hospital over a period of three years. Clean-catch midstream urine specimens, from 524 non-pregnant women with community-acquired acute cystitis, were subjected to semi-quantitative culture and antibiotic susceptibility by the Kirby-Bauer disc diffusion method. Overall, 354 (67.5%) specimens yielded significant growth of E. coli. More than 35% of the urinary E. coli isolates were resistant to the fluoroquinolones. Further, resistance was less against Nitrofurantoin (9.3%, 33), and more than 80% of the fluoroquinolone-resistant strains were sensitive to Nitrofurantoin.

In conclusion, the best in-vitro susceptibility profile in the study was shown by Nitrofurantoin. Also, it showed that a significantly high proportion of the urinary E. coli isolates had already developed resistance to the currently prescribed empirical antibiotics, viz. the fluoroquinolones. Accordingly, considering these in-vitro susceptibility patterns, a transition in empirical therapy appears imminent; with nitrofurantoin depicting a clear edge.

Nitrofurantoin in pediatric practice

As one of the common childhood infections, UTIs constitute an important part of a pediatrician’s daily routine practice. The infections not only can lead to life-threatening complications in infants, but also to renal scarring and related complications across all age groups. Therefore, in order to avoid morbidity, treatment should be started as soon as a UTI is recognized; however, since urine cultures (the goldstandard for the diagnosis of UTI) take 24-48 hour to process, initial treatment is started empirically.¹⁴Özahi Ípek I, Bozaykut A. Pediatric Health 2010;4(2):219-225.   At this moment, knowledge of the causative pathogens and local antibiotic sensitivity patterns would help to ensure appropriate treatment. In this context, studies conducted all over the world have shown high levels of resistance to ampicillin, cephalexin and TMP/SMX. Further, the prevalence of antibiotic resistance of uropathogens in complicated and recurrent UTIs was found to be even higher than that in first, uncomplicated UTIs. With low resistance rates and safety profile, nitrofurantoin is recommended for the treatment of cystitis and prophylaxis.

Long-term prophylaxis in children with recurrent UTIs: Nitrofurantoin vs. trimethoprimsulphamethoxazole

Recurrent infections may be particularly bothersome regardless of age and gender, and are potential indication for prophylaxis. Both host and pathogen factor may impact the occurrence of the recurrent infections.¹⁵Finer G, Landau D. Pathogenesis of urinary tract infections with normal female anatomy. Lancet Infect Dis 2004; 4: 631-35.   Nitrofurantoin is beneficial not only in the treatment of UTIs but also as a prophylactic agent. Falakaflaki et al compared prophylactic effect of nitrofurantoin and TMP-SMX in recurrent UTI in children, and to determine antibiotic resistance pattern while receiving prophylaxis.¹⁶Falakaflaki B , Fallah R, Jamshidi MR, et al International Journal of Pharmacology 2007; 3(2): 179-182.   Dependent on the study protocol, 132 patients in two similar groups were randomized to receive either TMP-SMX (n = 66) or nitrofurantoin (n = 66) as single night dose for six months, and data was recorded relating to age, sex, indication for prophylaxis, occurrence of UTI, culture and sensitivity results. Based on age, patients were categorized into three groups: 3-12 months, 1-5 years, 6-12 years.

Results showed that nitrofurantoin was more effective than TMP-SMX in preventing recurrent UTIs; recurrence rate was 36.2% in nitrofurantoin group compared with 63.8% in the TMP-SMX group (p = 0.029) (Figure 7). Interestingly, the protective effect was more significant in children aged 1-5 years compared to other age groups (p = 0.046). While 37.5% of the organisms causing the UTIs were resistant to nitrofurantoin, the number was comparatively higher in other group – in TMP-SMX group, 56% of the organisms were resistant to the prophylactic agent. Thus, it shows that nitrofurantoin has a lower rate of recurrence and causes fewer emergences of resistance bacteria than TMP-SMX, and is, therefore, more suitable for prevention of recurrent UTIs in children.

Nitrofurantoin and pregnancy

UTIs are the most common bacterial infections during pregnancy, characterized by presence of significant bacteria anywhere along the urinary tract.²⁰Le J, Briggs GG, McKeown A, Bustillo G. Ann Pharmacother. 2004;38(10):1692-701.   A number of studies have demonstrated the safety of nitrofurantoin in pregnancy. Indeed, case-control studies and case series involving thousands of women who received nitrofurantoin during pregnancy reportedly indicated no increase in major malformations among the newborns.²¹Lee M, Bozzo P, Einarson A, et al. Can Fam Physician. 2008; 54(6): 853-854.  

In a multicenter, double-blind, randomized, placebo controlled non-inferiority trial Lumbiganon et al evaluated whether a 1-day nitrofurantoin regimen is as effective as a 7-day regimen in eradicating asymptomatic bacteriuria during pregnancy; pregnant women were randomly allocated to receive either a 1-day or a 7-day course of 100 mg of nitrofurantoin, which was taken twice daily.²²Lumbiganon P, Villar J, Laopaiboon M, et al. Obstet Gynecol. 2009;113(2 Pt 1):339-45.   The primary outcome was bacteriologic cure on day 14 of treatment. Of 24,430 eligible women, 1,248 had asymptomatic

bacteriuria (5.1%). Of these, 778 women were successfully recruited, and 386 and 392 women were randomly allocated to 1-day and 7-day regimens, respectively. E. coli was the most common potentially pathogenic bacteria detected, with prevalence approaching 50%. Bacteriologic cure rates at treatment day 14 were 75.7% and 86.2% for 1-day and 7-day regimens, respectively (Figure 8); and the cure rate difference was -10.5%. Moreover, mean birth weight and mean gestational age at delivery were significantly lower in the 1-day regimen group. Thus, the study showed that a 7-day regimen of nitrofurantoin was significantly more effective than a 1-day regimen; accordingly, women with asymptomatic bacteriuria in pregnancy should receive the standard 7-day regimen of nitrofurantoin.

Conclusion

UTIs are amongst the frequently encountered infections in practice, and currently antibiotic resistance is one of the world’s most pressing public health threats. Particularly, the emergence of multidrug resistant clonal groups has provided urgency to develop and identify novel preventative, therapeutic, and prophylactic strategies. Nitrofurantoin, a well-known antimicrobial, exhibits rising relevance in this context as it can be used for both treatment and prophylaxis of UTIs, regardless of age and gender, i.e. in adults and children, and men and women, and even in pregnant females. Yet, local resistance patterns could affect the treatment decision.

References

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4. Benoit SR, Nsa W, Richards CL, et al. J Am Geriatr Soc. 2008 Nov;56(11):2039-44.
5. Available at: http://www.cdc.gov/getsmart/healthcare/learn-from-others/factsheets/longterm-care.html
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8. Kashanian J, Hakimian P, Blute M Jr, et al. BJU Int. 2008;102(11):1634-7.
9. Kurtaran B, Candevir A, Tasova Y, et al. Med Sci Monit. 2010 May;16(5):CR246-51.
10. Abu-Taha AS, Sweileh WM. Curr Clin Pharmacol. 2011;6(4):304-7.
11. Szász M, Lehotkai N, Kristóf K, Szabó D, Nagy K. Acta Microbiol Immunol Hung. 2009 Dec;56(4):375-87.
12. Daniel F et al. Antimicrob. Agents Chemother 2001; 45(5): 1402.
13. Biswas D, Gupta P, Prasad R, et al. Indian J Med Sci 2006;60:53-8.
14. Özahi Ípek I, Bozaykut A. Pediatric Health 2010;4(2):219-225.
15. Finer G, Landau D. Pathogenesis of urinary tract infections with normal female anatomy. Lancet Infect Dis 2004; 4: 631-35.
16. Falakaflaki B , Fallah R, Jamshidi MR, et al International Journal of Pharmacology 2007; 3(2): 179-182.
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19. Available at: http://www.who.int/selection_medicines/committees/subcommittee/2/fluoroquinolones_rev.pdf
20. Le J, Briggs GG, McKeown A, Bustillo G. Ann Pharmacother. 2004;38(10):1692-701.
21. Lee M, Bozzo P, Einarson A, et al. Can Fam Physician. 2008; 54(6): 853-854.
22. Lumbiganon P, Villar J, Laopaiboon M, et al. Obstet Gynecol. 2009;113(2 Pt 1):339-45.