Is there any evidence for a 10-day course of nitrofurantoin (Macrobid)?

Comment by InpharmD Researcher

A comprehensive literature search did not reveal well-established evidence supporting a longer than 7-day course of nitrofurantoin based on indications, recurrence rates, or resistance patterns. The 2011 IDSA guidelines recommend a 5-day course of nitrofurantoin for acute uncomplicated cystitis. Compared to other commonly prescribed antimicrobial agents for urinary tract infections (UTIs), resistance rates to nitrofurantoin remained stable in outpatient settings when used for acute cystitis. A meta-analysis noted that most clinical trials utilizing longer durations of therapy were derived from the 1970-80s. Additionally, results from a recent national pediatric cohort found no association between duration (3-5, 7, 10, and 14 days of treatment) and recurrence of uncomplicated UTI.

Background

Per a 2020 updated review on antimicrobial agents in the treatment of urinary tract infections (UTIs), nitrofurantoin, fosfomycin, and pivmecillinam are most active against Escherichia coli (E.coli), including multidrug-resistant (MDR) isolates such as ESBL- and AmpC-beta-lactamase-producing E.coli, isolated in outpatients with acute cystitis. Compared to other antimicrobial agents, the resistance rates appeared relatively stable over time. The nitrofurantoin regimen discussed within the review was limited to a five-day course of therapy only, as recommended by 2011 Infectious Diseases Society of America (IDSA) guidelines (nitrofurantoin monohydrate/macrocrystals 100 mg BID x 5 days for acute uncomplicated cystitis). [1], [2]

A 2015 meta-analysis of controlled trials (N= 27 randomized controlled trials [RCT]; 4,807 patients) evaluated the efficacy and toxicity of nitrofurantoin in the treatment of lower urinary tract infections (UTIs). Trials with a treatment duration of ≤ 14 days were included. Courses of 5 to 7 days of nitrofurantoin generated clinical cure rates ranging between 79% and 92%, which was comparable to trimethoprim/sulfamethoxazole (TMP-SMX), ciprofloxacin and amoxicillin. Though a subgroup analysis of clinical and microbiological cure rates based on the duration of therapy was not performed, authors noted that most studies gave nitrofurantoin for 5 or 7 days, but 10- or 14-day regimens were given in studies conducted before 1983. One 2007 RCT (N= 61) comparing the efficacy of TMP-SMX, ciprofloxacin, and nitrofurantoin in women with type 2 diabetes mellitus and acute community-acquired cystitis administered nitrofurantoin (100 mg Q6H) for 10 days. Results found both ciprofloxacin and nitrofurantoin were associated with better bacteriologic eradication compared to TMP-SMX (78% vs. 78% vs. 45%; p= 0.036), and nitrofurantoin also had the lowest in vitro resistance rate. Unfortunately, the full publication of this study was not available in English and a relatively outdated trial from Mexico may not represent the US prescribing patterns and local antibiograms nowadays. [3], [4]

Although not directly evaluating the efficacy of a 10-day course of nitrofurantoin based on resistance patterns, a 2021 cohort study (N= 6,866 episodes of nitrofurantoin) compared 5-days (n= 3,247) versus 7-days (n= 3,619) of nitrofurantoin in the management of UTI among diabetic females. With more comorbidities, diabetes-related complications, and insulin uses in the 7-day group, adjusted risk differences (RD) for treatment failure within 28 days revealed an insignificant difference between the two durations (15.9% failures in the 5-day group vs. 14.4% in the 7-day group; RD 1.4%, 95% CI -0.6 to 3.4). This study supports a shorter duration of nitrofurantoin to reduce cumulative nitrofurantoin exposure in diabetic patients. [5]

References:

[1] Bader MS, Loeb M, Leto D, Brooks AA. Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents. Postgrad Med. 2020;132(3):234-250. doi:10.1080/00325481.2019.1680052
[2] Gupta K, Hooton TM, Naber KG, et al. 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
[3] 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
[4] López-Carmona JM, Salazar-López MA, Rodríguez-Moctezuma JR, López-Delgado ME, Manrique-Lizárraga JM. Cistitis aguda en mujeres con diabetes mellitus tipo 2. Comparación de tres esquemas antimicrobianos [Acute cystitis in women with type 2 diabetes. Three antimicrobial schemes]. Rev Med Inst Mex Seguro Soc. 2007;45(5):503-512.
[5] Hendriks-Spoor KD, Wille FL, Doesschate TT, Dorigo-Zetsma JW, Verheij TJM, van Werkhoven CH. Five versus seven days of nitrofurantoin for urinary tract infections in women with diabetes: a retrospective cohort study. Clin Microbiol Infect. 2022;28(3):377-382. doi:10.1016/j.cmi.2021.06.034
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is there evidence for a 10-day course of nitrofurantoin (Macrobid)?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Association of Antibiotic Treatment Duration With Recurrence of Uncomplicated Urinary Tract Infection in Pediatric Patients

Design

Retrospective cohort study (USA)

N= 7,698

Objective

To evaluate the association of antibiotic treatment duration with recurrence rates in children with new-onset cystitis or pyelonephritis.

Study Groups

7-day antibiotic regimen, for any UTI (n= 2,589 cases)

10-day antibiotic regimen, for any UTI (n= 3,401 cases)

14-day antibiotic regimen, for any UTI (n= 141 cases)

3-5 day antibiotic regimens, for only non-pyelonephritis UTIs (n= 1,567 cases)

Inclusion Criteria

Age 2-17 years, outpatient uncomplicated UTI diagnosis, UTI prescription medication claims reported to Truven Health within 3 days before to 5 days after the UTI diagnosis

Exclusion Criteria

Another infection diagnosed during the same visit (ex: otitis media, cellulitis), prior UTI within 6 months of study initiation, inpatient stay within 3 days of the UTI diagnosis, 3-5 day supply of antibiotics prescribed for pyelonephritis, prescriptions for >1 antibiotic therapy class or supply values for multiple days (ex: 1 drug for 3 days and another for 7 days), other antibiotic treatment within the prior 10 days

Methods

Retrospective data were analyzed from cohorts derived from the Truven Health MarketScan Commercial Claims and Encounters Database for 2013-2015. An uncomplicated UTI was identified via a primary diagnosis of acute pyelonephritis (ICD-9 590.1) or acute cystitis (595.0), or a primary diagnosis of fever (788.1) or dysuria (780.6) with a secondary diagnosis of acute pyelonephritis or acute cystitis. Oral medications for use in UTIs were defined as amoxicillin with or without clavulanate, ampicillin, any cephalosporin, trimethoprim-sulfamethoxazole [TMP-SMX], sulfisoxazole, ciprofloxacin, levofloxacin, or nitrofurantoin.

The 3-5-day regimen cohort was included but limited to cystitis only, to account for durations chosen based either on adult (IDSA) guidelines or on studies of short-course treatment of lower-tract UTI in pediatric samples.

Duration

Review duration: July 2013 through September 2015

Outcome Measures
  • UTI relapse (measured from the date of presumed completion of antibiotic supply through the 14 days after [relapsing patients are excluded from reinfection results])
  • UTI reinfection (measured from 15 to 30 days after the presumed completion of antibiotic supply)
  • UTI recurrence (relapse or reinfection)
  • UTI infection progression (any recurrence with a pyelonephritis diagnosis in a patient initially diagnosed with cystitis)
  • Covariates associated with increased UTI recurrence risk

Baseline Characteristics

  

Regimens of 3-5 days (acute cystitis only)

(n= 1,567)

7-day regimen (any UTI) 

(n= 2,589)

10-day regimen (any UTI) 

(n= 3,401)

14-day regimen (any UTI) 

(n= 141)

  p-Value

Age 2 years

 1.3% 2.0% 4.5% 2.8% <0.01

Age 3-5 years

 7.7% 11.6% 22.9% 10.6% <0.01

Age 6-10 years

 18.2% 21.6% 31.1% 18.4% <0.01

Age 11-17 years

 72.8% 64.9% 41.5% 68.1% <0.01

Female

96.7% 95.9% 94.2% 95.0% <0.01

Pyelonephritis

 0 (0%) 274 (10.6%) 737 (21.7%) 93 (66.0%) Not Disclosed (ND)

Fever, in any of 4 diagnosis fields on the UTI diagnosis date

 1.0% 3.7% 7.9% 14.9% <0.01

Dysuria, in any of 4 diagnosis fields on the UTI diagnosis date

 18.0% 17.1% 13.9% 11.3% <0.01

Oral or injected antibiotic use within 6 months before the studied UTI case

 41.9% 44.4% 45.1% 44.7% <0.01

Antibiotic classes used during the studied UTI

Oral monotherapies:

  1. Cephalosporin of narrower spectrum (cefaclor, cefadroxil, cefprozil, cefuroxime, or cephalexin)
  2. Cephalosporin of broader spectrum (cefdinir, cefixime, or cefpodoxime)
  3. Penicillin
  4. Sulfonamide
  5. Fluoroquinolone
  6. Urinary anti-infective (nitrofurantoin formulations)
  1. 5.3%
  2. 2.4%
  3. 3.0%
  4. 58.1%
  5. 17.2%
  6. 12.4%
  1. 10.1%
  2. 4.9%
  3. 4.4%
  4. 39.2%
  5. 9.5%
  6. 25.6%
  1. 13.2%
  2. 13.6%
  3. 11.9%
  4. 39.3%
  5. 5.0%
  6. 3.6%
  1. 11.3%
  2. 13.5%
  3. 4.3%
  4. 27.7%
  5. 10.6%
  6. 5.0%
 <0.01

Combination therapies:

  1. Injected cephalosporin + Oral cephalosporin
  2. Injected cephalosporin + Oral fluoroquinolone
  3. Injected cephalosporin + TMP-SMX
  4. Other injected and/or oral combinations
  1. 0.2%
  2. 0.3%
  3. 0.6%
  4. 0.4%
  1. 1.6%
  2. 1.5%
  3. 2.0%
  4. 1.2%
  1. 5.4%
  2. 2.0%
  3. 3.5%
  4. 2.5%
  1. 7.1%
  2. 4.3%
  3. 11.3%
  4. 5.0%
 <0.01

Results

Endpoint

Regimens of 3-5 days (acute cystitis only) 

(n= 1,567)

7-day regimen (any UTI) 

(n= 2,589)

  

10-day regimen (any UTI) 

(n= 3,401)

14-day regimen (any UTI) 

(n= 141)

p-Value

UTI Relapse

 2.7% 3.7% 4.8% 5.7% <0.01

UTI Reinfection

 1.4% 1.8% 1.5% 1.5% ND

UTI Recurrence (Relapse or Reinfection)

 4.0% 5.4% 6.3% 7.1% <0.05

UTI Infection Progression

 0.3% 0.2% 0.2% 0.0% ND

Covariates associated with increased recurrence risk:

  1. Pretreatment antibiotic use (odds ratio [OR] 1.29 [95% CI 1.06 to 1.57])
  2. Pyelonephritis on the UTI diagnosis date (OR 1.44 [95% CI 1.03 to 2.00])
  3. Follow-up visit during antibiotic treatment (OR 3.21 [95% CI 2.20 to 4.68])
  4. Parenteral antibiotic (OR 1.89 [95% CI 1.33 to 2.69])
  5. Interaction of pyelonephritis diagnosis with nitrofurantoin monotherapy (OR 3.68 [95% CI 1.20 to 11.29])

After adjustment for these covariates, the association between duration of antibiotic treatment and recurrence was not significant between 7-day and 10-day regimens (OR 1.07 [95% CI 0.85 to 1.33]), or between 7-day and 14-day regimens (OR 0.89 [95% CI 0.45 to 1.78]).

Study Author Conclusions

In commercially insured patients aged 2 to 17 years with uncomplicated UTI, rates of recurrence did not significantly differ for antibiotic regimens of 7, 10, or 14 days after statistically adjusting for measured covariates, including markers of severity. UTI recurrence within 30 days of antibiotic depletion occurred at a rate of less than 6%, and progression from cystitis to pyelonephritis was uncommon. The findings from this study provide support for shorter course UTI treatment within pediatric practices.

InpharmD Researcher Critique

Significant differences between baseline characteristics (age, fever, dysuria, prior antibiotic use within 6 months, and the current UTI antibiotic[s]) and leaving pyelonephritis data combined into certain groups confounds the initial comparisons of the treatment duration groups. However, the impact of the combined pyelonephritis data was removed in the adjusted OR analysis of 7- vs. 10- and 7- vs. 14-day regimens, supporting the shorter 7-day regimen. Despite these adjusted results, the 5-day regimen was not included in any adjusted comparison.



References:

Afolabi TM, Goodlet KJ, Fairman KA. Association of Antibiotic Treatment Duration With Recurrence of Uncomplicated Urinary Tract Infection in Pediatric Patients. Ann Pharmacother. 2020;54(8):757-766. doi:10.1177/1060028019900650