Management of Leukocytes in Urinalysis with Negative Nitrites
Direct Answer
Do not treat with antibiotics based solely on leukocytes with negative nitrites—the presence of urinary symptoms is absolutely required before initiating antimicrobial therapy. 1, 2
Diagnostic Interpretation
The combination of positive leukocytes with negative nitrites creates diagnostic uncertainty that requires careful clinical correlation:
Leukocytes alone have poor positive predictive value for actual UTI, with specificity of only 78% (range 64-92%), meaning significant false-positive rates occur from contamination, inflammation, or asymptomatic bacteriuria 2
Negative nitrites significantly reduce the likelihood of gram-negative organisms (E. coli, Proteus, Klebsiella), which are the most common uropathogens, as these bacteria convert nitrates to nitrites 2
When both leukocyte esterase AND nitrite are positive together, specificity reaches 96%, but when only leukocytes are positive, you lose this diagnostic certainty 1, 3
The absence of nitrites does NOT rule out UTI, as sensitivity is only 19-48%, particularly in patients who void frequently (insufficient bladder dwell time) or with non-nitrate-reducing organisms like Enterococcus or Staphylococcus saprophyticus 3, 2
Clinical Decision Algorithm
Step 1: Assess for Specific Urinary Symptoms
If the patient has NO specific urinary symptoms (dysuria, frequency, urgency, fever >38.3°C, gross hematuria, suprapubic pain), do NOT proceed with treatment or further testing 1, 2
This represents asymptomatic bacteriuria with pyuria, which occurs in 15-50% of elderly patients and provides no clinical benefit when treated 2
Treatment only increases antimicrobial resistance and exposes patients to drug toxicity without improving outcomes 2
If the patient HAS acute-onset specific urinary symptoms, proceed to Step 2 1, 2
Step 2: Ensure Proper Specimen Collection
Before making treatment decisions, verify specimen quality:
High epithelial cell counts indicate contamination, which is the most common cause of false-positive leukocyte esterase results 2
If contamination is suspected, obtain a clean specimen: midstream clean-catch in cooperative patients or in-and-out catheterization in women unable to provide clean specimens 1, 2
Process specimens within 1 hour at room temperature or 4 hours if refrigerated to maintain accuracy 2
Step 3: Obtain Urine Culture Before Starting Antibiotics
Always collect urine culture with antimicrobial susceptibility testing before initiating empiric antibiotics in symptomatic patients 1, 2
Culture is mandatory because negative nitrites suggest possible non-E. coli organisms (Enterococcus, Staphylococcus saprophyticus, Streptococcus agalactiae) that may have different antibiotic sensitivities 4, 5
In one pediatric study, 59% of culture-positive UTIs with negative urinalysis were caused by non-E. coli organisms 4
Step 4: Initiate Empiric Antibiotic Therapy (If Symptomatic)
For symptomatic patients with leukocytes and negative nitrites, consider broader empiric coverage that includes non-nitrate-reducing organisms:
First-line options for uncomplicated cystitis: Nitrofurantoin 100 mg four times daily for 5 days, or Trimethoprim-sulfamethoxazole (TMP-SMX) double-strength twice daily for 3 days, depending on local resistance patterns 1, 6
TMP-SMX may be particularly appropriate when negative nitrites suggest non-E. coli organisms, as one study showed 82.2% sensitivity in the negative urinalysis group versus 71.3% in positive urinalysis 4
Avoid fluoroquinolones as first-line therapy unless complicated UTI or pyelonephritis is suspected, as they should be reserved for more serious infections 7
Step 5: Re-evaluate Clinical Response
Reassess within 48-72 hours and adjust antibiotics based on culture results and susceptibility testing 1
If no improvement, consider imaging for anatomic abnormalities or alternative diagnoses 1
Special Population Considerations
Elderly and Long-Term Care Residents
Use an algorithmic approach: assess for fever, rigors, or clear-cut delirium first 1
Only prescribe antibiotics if systemic signs are present (fever >38.3°C, hemodynamic instability) OR if urinalysis shows BOTH positive nitrite AND positive leukocyte esterase 1, 3
Non-specific symptoms like confusion or functional decline alone should NOT trigger treatment without specific urinary symptoms 2
Catheterized Patients
Only treat if symptomatic with fever, hemodynamic instability, or specific urinary symptoms 1
Change the catheter before collecting the culture specimen if urosepsis is suspected 3
Asymptomatic bacteriuria with pyuria is nearly universal in chronic catheterization and should not be treated 2
Pregnant Patients
Always obtain culture and treat even asymptomatic bacteriuria due to risk of pyelonephritis 1
Avoid fluoroquinolones and nitrofurantoin near term 1
Febrile Infants and Young Children (<2 years)
Urine culture is mandatory even with negative urinalysis, as 10-50% of culture-proven UTIs have false-negative urinalysis 3, 2
Young infants have particularly poor nitrite sensitivity due to frequent voiding and insufficient bladder dwell time 3
Common Pitfalls to Avoid
Do NOT treat asymptomatic bacteriuria (positive culture without symptoms), as this leads to unnecessary antibiotic use and resistance 3
Do NOT rely solely on dipstick results without considering clinical symptoms, as this leads to overtreatment 3, 8, 9
Do NOT assume all positive leukocytes represent infection—distinguish true UTI from asymptomatic bacteriuria, especially in elderly populations 2
Do NOT continue antibiotics beyond recommended duration (3-5 days for uncomplicated cystitis), as longer courses increase resistance risk without additional benefit 3
Do NOT order urinalysis or culture in asymptomatic individuals, as this leads to unnecessary treatment cascades 2