Nitrofurantoin or Fosfomycin to treat an uncomplicated UTI?

BACKGROUND AND PURPOSE:

• Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases have recommended nitrofurantoin and fosfomycin as first-line agents
• Huttner et al. (JAMA 2018) compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis

METHODS:

• Randomized clinical controlled trial
• Participants: Women ≥18 years and older with
  • Symptoms of lower UTI | Positive urine dipstick result | No known resistance to study antibiotics
• Randomized to two arms
  • Oral nitrofurantoin (100 mg 3 times a day for 5 days)
  • Single 3-g dose of oral fosfomycin
• Primary outcomes were measured at 14 and 28 days after therapy completion
  • Clinical resolution: Complete resolution without prior failure
  • Failure: Need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy
  • Indeterminate: Persistence of symptoms without objective evidence of infection
• Secondary outcomes included
  • Bacteriologic response and incidence of adverse events

RESULTS:

• 513 patients were randomized
  • median age, 44 years
  • 475 (93%) completed the trial
  • 377 (73%) had a confirmed positive baseline culture
• Clinical resolution through day 28 was statistically significant in favor of nitrofurantoin
  • 70% of patients receiving nitrofurantoin and 58% of patients receiving fosfomycin
  • Difference of 12% (95% CI, 4%-21%; P = .004)
• Microbiologic resolution was statistically significant in favor of nitrofurantoin
  • 74% of patients receiving nitrofurantoin and 63% of patients receiving fosfomycin
  • Difference of 11% (95% CI, 1%-20%; P = .04)
• 28 day data consistent with 14 day findings

CONCLUSION:

• Clinical response chosen as primary outome as that is what is most meaningful to the patient
• There may be more baseline resistance to fosfomycin than originally thought
• Nitrofurantoin success rates were less than expected but study had higher rate of non-E coli then often seen
  • Resistance increasing faster in areas where nitrofurantoin is available over the counter
• There was a significantly greater likelihood of clinical and microbiological resolution in women with uncomplicated UTI after 5-day nitrofurantoin, compared with a single-dose fosfomycin
• The accompanying editorial raises concern regarding dosing
  • Recommendation is for nitrofurantoin twice a day
  • Authors used 3 times a day because this is the more prevalent dosing schedule in Europe
• Despite limitations, the editorial does claim that the overall design and results of this study do suggest that nitrofurantoin is more clinically effectiveness than fosfomycin for acute uncomplicated cystitis among middle-aged women

Learn More – Primary Sources:

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women A Randomized Clinical Trial

JAMA editorial: Nitrofurantoin vs Fosfomycin – Rendering a Verdict in a Trial of Acute Uncomplicated Cystitis

Uncomplicated Cystitis: When to Culture, How to Treat and Recommended Prevention Strategies

CLINICAL ACTIONS:

Acute uncomplicated cystitis is often readily recognized by patients as a routine bladder infection.  Uncomplicated cystitis rarely progresses to pyelonephritis and urosepsis even if untreated. The primary goal of treatment is to relieve symptoms. If a patient presents with pain, urgency and frequent urination

• Determine if a patient may have pyelonephritis as urine cultures are indicated in all cases of upper urinary tract infection (UTI)
  • Culture: Costo-vertebral angle tenderness | Fever | Chills | Flank pain | Nausea/ vomiting | Recurrent/ persistent symptoms despite treatment
• In the absence of signs and/or symptoms of pyelonephritis, cultures are not required
• Consider urinalysis in specific circumstances such as
  • Postmenopausal women who may have intermittent dysuria or urge incontinence without infection
  • Women without a previous history of UTI

• Women with previous history and recognize UTI symptoms can be treated empirically without urinalysis

Antibiotic Therapy

Note: The following recommendations apply to nonpregnant women | There has been concern regarding the use of nitrofurantoin and sulfonamides in the first trimester due to possible risk for birth defects

• First-line therapy 
  • Trimethoprim-Sulfamethoxazole (TMP-SMX) 160-800 mg PO BID x 3 days
  • Fosfomycin 3 gm PO single dose
  • Nitrofurantoin 100 mg PO BID x 5 days
  • Consider beta-lactam for pregnant patients
• Fluoroquinolones: Reserved for situations in which other agents are not appropriate  
  • Ciprofloxacin 250 mg BID x 3 days
  • Levofloxacin 250 mg BID x 3 days

Note: FDA recommends the following

FDA has approved label changes that reserve the use of fluoroquinolone antibacterial medicines when treating acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTI) for patients who do not have alternative treatment options

SYNOPSIS:

UTI is the most common infection encountered in the outpatient setting. By age 32, half of all women will have had at least one UTI. Recurrence rates are over 25%. Fluoroquinolones are effective, but the recommendation is to avoid as a first-line medication to prevent future resistance and maintain these medications as a second-line treatment when needed.

KEY POINTS:

• Risk factors include
  • Sexual intercourse | Use of spermicides and diaphragm | Previous UTI | New sexual partner | Increasing parity | Diabetes | Obesity | Kidney stones | indwelling catheter
  • With increasing age, consider vaginal atrophy, pelvic organ prolapse and bladder retention

• No association between
  • Pre/ postcoital voiding | Daily beverage consumption | Frequency of urination | Delayed urination | Wiping patterns | Tampon use | Douching | Hot tub use | Type of underwear

• Consider formal urologic evaluation for women with
  • Persistent hematuria | Multiple early recurrences of cystitis with the same bacteria

• Patients with pyelonephritis with severe/worsening illness or persistent fever 48 to 72 hours after initiation of antibiotics
  • Image to evaluate for stone, abscess or obstruction
• Treatment of uncomplicated cystitis should take into consideration local antimicrobial resistance patterns
  • Resistance rates higher than 15 to 20% will require a change in antibiotic class
  • Beta-lactams such as cephalosporins and amoxicillin are less effective due to increasing resistance
• Nonantimicrobial prevention of recurrent UTI
  • Change spermicides or consider other birth control option | Topical estrogen if menopausal (local may be more beneficial than oral)

• Note: Do not screen or treat asymptomatic bacteriuria in nonpregnant, premenopausal women

Learn More – Primary Sources:

CDC: Adult Outpatient Treatment Recommendations | Antibiotic Use

ACP: Appropriate Use of Short-Course Antibiotics in Common Infections

USPSTF: Screening for Asymptomatic Bacteriuria in Adults

FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects