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Keywords:

  • urinary tract infection;
  • antibiotics;
  • nitrofurantoin;
  • resistance;
  • Escherichia coli

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

OBJECTIVE

To re-evaluate the first- and second-line therapies for treating uncomplicated urinary tract infection (UTI), as although fluoroquinolones are commonly used for this purpose, its level of use is thought to be inappropriately excessive and will eventually have a detrimental impact; thus we hypothesise that nitrofurantoin might be the best choice for this indication, due to its low frequency of use and its high susceptibility rate in common UTI pathogens.

MATERIALS AND METHODS

We retrospectively analysed antimicrobial susceptibility patterns of urinary isolates from 2003 to 2007, taken from a community-based institutional hospital in Brooklyn, NY, USA.

RESULTS

In all, 10 417 cultures grew Escherichia coli from 2003 to 2007. Overall, from 2003 to 2007, 95.6% of E. coli urine isolates were 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. Co-trimoxazole (trimethoprim/sulfamethoxazole; ‘TMP/SMX’) had a mean 29% resistance rate to E. coli over the same 5-year period.

CONCLUSIONS

We consider that nitrofurantoin is a good fluoroquinolone-sparing alternative to co-trimoxazole; this study shows that nitrofurantoin is bactericidal to a mean of 95% of E. coli UTIs. Nitrofurantoin also has a resistance rate of 2.3%, by contrast to the quinolones (ciprofloxacin and levofloxacin), with resistant rates of ≈24%, and Co-trimoxazole, with a resistant rate of 29%. Nitrofurantoin is an acceptable treatment for uncomplicated UTIs and should now be considered the first-line treatment. A reconsideration of UTI treatment guidelines might now be appropriate.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Arguably the most profound advance in the management of UTIs has been the introduction of antimicrobial agents. Since the discovery of sulfanilamide in the 1930s for treating cystitis, antibiotics have been the mainstay of treatment for cystitis and pyelonephritis [1]. Over the past 70 years, the use of antimicrobials for treating UTI has developed, during which various antibiotics have come in and out of favour. For instance, due to the severity of side-effects associated with sulfanilamide, its medicinal practicality was rightly limited [2]. It was not until 1953 that a truly safe and effective treatment for uncomplicated UTI was introduced, i.e. nitrofurantoin, followed by the use of quinolones in the 1960s, then β-lactams and trimethoprim/sulfamethoxazole (‘TMP/SMX’, co-trimoxazole) in the 1970s [1].

In the 1970s and 1980s amoxicillin was regarded as empirical treatment for UTI. Unfortunately, the pervasive use of amoxicillin for this indication during that time rendered it useless, due to increasing resistance [1]. In the 1990s the Infectious Disease Society of America affirmed the use of co-trimoxazole as the first-line agent for treating of acute cystitis in women, where the resistance is <10–20%[3]. Since then, the increased use of co-trimoxazole in the 1990s led to high levels of resistance in many parts of the USA and worldwide [1,4,5]. This more recent wave of widespread resistance to co-trimoxazole and amoxicillin has led to the use of fluoroquinolones for the empirical treatment of UTI.

This recent shift in antibiotic treatment has alarmed many physicians. In a survey of physicians nationwide, most felt that the level of fluoroquinolone use in treatment of cystitis is inappropriately excessive and will eventually have a detrimental impact on society [6]. A major concern to physicians is the possibility of rapid cross-resistance between quinolones. In a multi-continent study there was a 25% increase in resistance of UTI pathogens to norfloxacin in the brief period that it was available [5].

Similarly, there was 15% and 18% resistance of Escherichia coli to ciprofloxacin in Europe and in Latin America, respectively [7]. Although resistance to ciprofloxacin is higher in both Europe and Latin America, the resistance rates reported in the USA are alarming. While certain drugs continue to be used as first-line empirical treatment for uncomplicated UTI, it is only a matter of time before the rates in the USA reach those in rest of the world. It is for this reason that there is a need to re-evaluate the first- and second-line therapies for treating uncomplicated UTI.

Thus the objective of the present study was to determine the most effective and relevant method of initially treating uncomplicated UTIs. We hypothesised that nitrofurantoin might be the best choice for current first-line empirical treatment, because it has not been a traditional first-line treatment and because of its superior susceptibility in the most commonly encountered organisms implicated in uncomplicated UTI.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Inpatient and outpatient urine cultures were collected and analysed at the authors’ institution; antimicrobial susceptibility of isolates was tested using National Committee for Clinical Laboratory Standards. We retrospectively studied the susceptibility patterns of uropathogens using urine bacteria isolates collected from 2003 to 2007. The results were analysed statistically by one-way anova.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Isolates were recovered from urine samples obtained from both men and women patients from 2003 to 2007; 10 417 cultures grew E. coli. Of the 10 417 E. coli isolates from 2003 to 2007, 1509 were cultured in 2003, 1653 in 2004, 1913 in 2005, 2133 in 2006 and 3209 in 2007 (Table 1 and Fig. 1). The increasing number in cultures from 2003 to 2007 was due to an increased number of clinic openings at the hospital during that time and a decrease in the number of cultures being sent to outside laboratories for analysis.

Table 1. E. coli susceptibility patterns (as the percentage)
DrugYear of E. coli isolateMean
20032004200520062007
Number of isolates150916531913213332092083
Ciprofloxacin
 Susceptible  79.6  74.0  75.3  75.0  74.3  74.6
 Resistant  20.3  26.0  24.4  24.8  25.4  24.2
 Intermediate   0.1   0.0   0.4   0.2   0.3   0.2
Levofloxacin
 Susceptible  79.7  74.0  75.7  75.3  74.7  75.9
 Resistant  20.3  26.0  24.0  24.5  25.1  24.0
 Intermediate   0.0   0.0   0.3   0.2   0.3   0.2
Nitrofurantoin
 Susceptible  97.8  97.7  95.3  93.7  93.6  95.6
 Resistant   0.8   1.0   2.2   3.3   3.3   2.1
 Intermediate   1.4   1.3   2.5   3.0   3.1   2.3
Co-trimoxazole
 Susceptible  73.5  67.4  70.2  71.9  71.5  70.9
 Resistant  26.5  32.6  29.8  28.1  28.5  29.1
 Intermediate   0.1   0.0   0.0   0.0   0.0   0.0
image

Figure 1. Susceptibility patterns of E. coli from 2003 to 2007.

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The overall susceptibilities of E. coli to various drugs varied significantly; that to nitrofurantoin was remarkably higher than for ciprofloxacin, levofloxacin and co-trimoxazole. Overall, from 2003 to 2007, 95.18% of E. coli urine isolates were susceptible to nitrofurantoin, with only a 2.3% resistance rate (P < 0.05). In stark contrast, the susceptibility rate of E. coli to ciprofloxacin, levofloxacin and co-trimoxazole was significantly lower. E. coli uropathogens had a 75% susceptibility and a 24% resistance rate to both ciprofloxacin and levofloxacin (P < 0.05). There was an even more noticeable/appreciable difference for co-trimoxazole, showing a mean 29% resistance rate of E. coli over the same 5-year period (P < 0.05). The differences in average E. coli susceptibility among all four antibiotics were all statistically significant (P < 0.05) except between ciprofloxacin and levofloxacin (P > 0.05). Differences in susceptibilities from year to year among individual antibiotics (i.e. ciprofloxacin 2003 vs 2007) were not statistically significant (P > 0.05). The absolute and percentage susceptibility patterns are shown in Table 1 and Fig. 1. Among all drugs, nitrofurantoin had the most pronounced and consistent activity against E. coli.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

An uncomplicated UTI is an episode of cystitis that occurs in young healthy non-pregnant women with no functional or anatomical abnormalities of the urinary tract [8]. It is estimated that 3% of women in the USA visit a doctor at least once per year for UTI [9], which accounts for 3–5 million physician visits yearly [3]. Also, about half of all women have at least one UTI during their lifetime [10].

Although antibiotics shorten the duration of symptoms and cure >90% of UTIs [11] it is critical to choose the appropriate antibiotic. In a survey of 100 patients in an emergency department who were prescribed fluoroquinolones for suspected UTI, 81% received inappropriate prescriptions [12].

With the increasing usage of quinolones as a primary treatment for UTI there has been increasing resistance worldwide. In a study involving single-dose prophylaxis with ciprofloxacin in urological procedures, the prevalence of E. coli resistance to ciprofloxacin increased from 3% to 12%[13].

The widespread use of broad-spectrum antibiotics, to which uropathogens once had little resistance, has led to resistant microorganisms. In a study using data from The Surveillance Network Database (a microbiology database from laboratories in nine geographical regions of the USA) E. coli and Staphylococcus saprophyticus were implicated in 74% of all uncomplicated UTI in females aged 15–50 years. Of those, 16–18% of E. coli were resistant to co-trimoxazole, vs 1% resistance to nitrofurantoin. In addition, 91% of all the isolates taken from females aged 15–50 years were susceptible to nitrofurantoin [4].

Similarly, in a study conducted in Turkey from 1998 to 2003, investigating 1703 uropathogen isolates, E. coli was implicated in 73.2% of UTI. Of all the E. coli isolates, 40% were resistant to co-trimoxazole. Also, the resistance of E. coli to ciprofloxacin increased from 14.7% in 1998 to 24.5% in 2003 (P < 0.05), while the resistance to nitrofurantoin remained <10%[14].

The present results showed similar findings (Table 1 and Fig. 1); the resistance of E. coli to nitrofurantoin ranged from 0.8% in 2003 to 3.3% in 2007, compared to that of ciprofloxacin and levofloxacin, which ranged from 20% in 2003 to 25% in 2007. The highest resistance among all antimicrobials studied was co-trimoxazole, which had a mean resistance of 29.1% over the same 5-year period.

We consider that nitrofurantoin is a good fluoroquinolone-sparing alternative to co-trimoxazole [8]. In a double-blinded placebo-controlled study of 78 females aged 15–54 year, 88% were cured of their UTI with a 7-day/100 mg course of nitrofurantoin [15]. Our data also confirmed that nitrofurantoin is bactericidal to a mean of 95.6% of E. coli-implicated UTIs, which according to previous reports accounts for 70–95% of all UTI [2].

Importantly, the present data, although taken from inpatient and outpatient settings, show clearly the high bactericidal rate of nitrofurantoin compared to the increasing resistance rates of ciprofloxacin, levofloxacin and co-trimoxazole.

The broad range of bactericidal action of nitrofurantoin explains the relative lack of accumulated resistance to the drug over the past 50 years. Bacterial flavoproteins reduce nitrofurantoin to highly reactive intermediates that inactivate many cellular processes. Nitrofurantoin inhibits protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis and cell-wall synthesis [16,17]. Nitrofurantoin is active against most forms of E. coli, Enterococci and S. saprophyticus. In a study from Canada, 91.8% of all uncomplicated UTI were caused by E. coli[18]. In another study of UTIs in 813 women, 93% of all urinary isolates were E. coli and S. saprophyticus[8]. In a third study, E. coli was the causative pathogen in 70–95% of uncomplicated UTI and S. saprophyticus was the pathogen in 5–10%[2].

Based on these studies and the present data, we infer that nitrofurantoin might be extremely effective in treating uncomplicated UTIs (70–95% of UTI × 95.6%E. coli susceptibility). The lower cure rates and the increasing resistance associated with ciprofloxacin and levofloxacin should no longer make quinolones the first choice for treatment.

We consider that nitrofurantoin is an acceptable treatment for uncomplicated UTIs [19] and should be considered the first-line treatment. Follow-up prospective randomized trials are needed to identify the exact cure rates of uncomplicated UTI with nitrofurantoin and other antibiotics.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES
  • 1
    Nickel JC. Management of urinary tract infections: historical perspective and current strategies: Part 2 – modern management. J Urol 2005; 173: 2732
  • 2
    Hooton TM. The current management strategies for community-acquired urinary tract infection. Infect Dis Clin North Am 2003; 17: 30332
  • 3
    Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Disease Society of America (IDSA). Clin Infect Dis 1999; 29: 74558
  • 4
    Gupta K, Sahm DF, Mayfield D, Stamm WE. Antimicrobial resistance among uropathogens that cause community-acquired urinary tract infections in women: a nationwide analysis. Clin Infect Dis 2001; 33: 8994
  • 5
    Gordon KA, Jones RN, SENTRY Participant Groups (Europe, Latin America, North America). Susceptibility patterns of orally administered antimicrobials among urinary tract infection pathogens from hospitalized patients in North America: comparison report to Europe and Latin America. Results from the SENTRY Antimicrobial Surveillance Program 2000. Diagn Microbiol Infect Dis 2003; 45: 295301
  • 6
    Naber KG. Survey on antibiotic usage in the treatment of urinary tract infections. J Antimicrob Chemother 2000; 46: 4952
  • 7
    Vromen M, Van Der Ven A, Knols A, Stobberingh EE. Antimicrobial resistance patterns in urinary isolates from nursing home residents. Fifteen years of data reviewed. J Antimicrob Chemother 1999; 44: 1136
  • 8
    Hooton TM. Fluoroquinolones and resistance in the treatment of uncomplicated urinary tract infection. Int J Antimicrob Agents 2003; 22 (Suppl. 2): 6572
  • 9
    National Center for Health Statistics. National Ambulatory Medical Care Survey, United States, 1979 summary. Vital and health statistics, 13 (66). DHHS Publication no. (PHS) 82. Washington DC: Government Printing Office, 1982: 1727
  • 10
    Jones RN, Kugler KC, Pfaller MA, Winokur PL. Characteristics of pathogens causing urinary tract infections in hospitals in North America: results from the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis 1997; 35: 5563
  • 11
    Nicolle L, Anderson PA, Conly J et al. Uncomplicated urinary tract infection in women. Current practice and the effect of antibiotic resistance on empiric treatment. Can Fam Physician 2006; 52: 6128
  • 12
    Lautenbach E, Larosa LA, Kasbekar N, Peng HP, Maniglia RJ. Fluoroquinolone utilization in the emergency department of academic medical centers: prevalence of, and risk factors for, inappropriate use. Arch Intern Med 2003; 163: 6015
  • 13
    Wagenlehner F, Stower-Hoffmann J, Schneider-Brachert W, Naber KG, Lehn N. Influence of a prophylactic single dose of ciprofloxacin on the level of resistance of Escherichia coli to fluoroquinolones in urology. Int J Antimicrob Agents 2000; 15: 20711
  • 14
    Kurutepe S, Surucuoglu S, Sezgin C, Gazi H, Gulay M, Ozbakkaloglu B. Increasing antimicrobial resistance in Escherichia coli isolates from community-acquired urinary tract infections during 1998–2003 in Manisa, Turkey. Jpn J Infect Dis 2005; 58: 15961
  • 15
    Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract 2002; 52: 70810
  • 16
    McGraw-Hill. Access Medicine. Available at: http://accessmedicine.com/popup.aspx?aID=2510021. Accessed October 2007
  • 17
    McGraw-Hill. Access Medicine. Available at: http://accessmedicine.com/popup.aspx?aID=948548. Accessed October 2007
  • 18
    Mazzulli T. Antimicrobial resistance trends in common urinary pathogens. Can J Urol 2001; 8 (Suppl. 1): 25
  • 19
    Brumfitt W, Hamilton-Miller JM. Efficacy and safety profile of long-term nitrofurantoin in urinary infections: 18 years’ experience. J Antimicrob Chemother 1998; 42: 36371