Introduction

You might have submitted a urine sample to be analysed using different tests in a laboratory or hospital at some point in your life. This urinalysis test could be used to check for urinary tract infections, liver and kidney problems, and diabetes. However, urinalysis can also be used to detect the presence of pus cells in urine. An elevated number of pus cells in the urine, which is a condition called pyuria, could indicate an underlying problem. 

Pus is composed of dead white blood cells that accumulate in a wound or infection, and it actively shows that your immune system is fighting an infection. Although the most common cause of pyuria is urinary tract infections (UTIs), viral infections and even chronic use of certain medications can lead to the onset of this condition. Thus, this article takes you through the medications that can cause white blood cells in the urine.  

What is Pyuria?

Pyuria is a condition characterised by the presence of 10 or more white blood cells or pus per cubic millimetre of a urine sample.¹ A positive Gram stain result and the presence of leukocyte esterase after a urinary dipstick test are also indicative of pyuria.¹ Generally, pyuria can occur in two forms: with the presence of bacteria in pus cells (infectious pyuria) and non-infectious or sterile pyuria. Sterile pyuria is described by the chronic presence of white blood cells in the urine in the absence of a detectable bacterial infection. Sterile pyuria is a common condition and can be found in 13.9 % of women and 2.6 % of men.² Fever that occurs with pyuria is considered a urinary tract infection, and administration of antibiotics is started soon after the urinalysis.¹ 

The most common infectious causes of pyuria are urinary tract infections, sexually transmitted diseases, and viral and fungal infections. Notably, 30-80% of patients with Kawasaki disease (KD) experience pyuria as one of the renal manifestations.³ Sterile pyuria can be a misleading condition because the most common underlying finding is usually an infection of some sort. This could be an incompletely treated urinary tract infection, a recently treated UTI, or a sexually transmitted infection, especially chlamydia in an asymptomatic sexually active individual.⁴ Non-infectious causes of pyuria also include systemic diseases such as systemic lupus erythematosus, malignant hypertension, and certain drugs which can trigger the onset of pyuria. ⁴ 

Symptoms of Pyuria 

Besides the presence of white blood cells in urine, other symptoms of pyuria include: 

• Frequent urge to urinate
• Hematuria
• Urinary incontinence
• Dysuria
• Fever
• Nausea and vomiting 
• Cloudy and foul-smelling urine 
• Abdominal pain

Most of these urinary symptoms appear as a result of an underlying UTI. Thus, effective diagnosis is paramount before starting treatment. 

Medications that can cause Pyuria

Drugs are one of the most common but disregarded causes of non-infectious or sterile pyuria. Thus, the medications that can cause white blood cells in the urine include: 

• Olsalazine: This is an anti-inflammatory agent that liberates the active drug mesalamine (5-aminosalicylic acid; 5-ASA) in the gastrointestinal tract when ingested. It is used to treat anti-inflammatory conditions, including inflammatory bowel disease and ulcerative colitis. This medication causes sterile pyuria and proteinuria secondary to chronic interstitial nephritis⁵
• Nitrofurantoin: This is an antibiotic medication used to treat uncomplicated lower urinary tract infections. Nitrofurantoin is a synthetic antimicrobial made from furan and an added nitro group and a side chain containing hydantoin⁶ Nitrofurantoin has been associated with pyuria and interstitial nephritis⁵
• Non-steroidal Anti-inflammatory Drugs (NSAIDs): These medications are used for antipyretic, pain relief, and anti-inflammatory purposes. However, despite their renowned therapeutic benefits, these drugs have been linked to severe kidney-related complications. This is particularly when these medications are taken long-term, in high doses, or by patients who have underlying kidney issues⁷
• Steroids: According to the Annals of Clinical Trials and Vaccines Research, steroids, also known as corticosteroids, are synthetic drugs that mimic the function of naturally occurring steroid hormones in the body. Due to their potent anti-inflammatory, immunosuppressive, and metabolic properties, these drugs have been used in clinical practice for various purposes. Steroids themselves don't directly cause pyuria; however, they can sometimes be associated with an increased risk of UTIs and, in some cases, can lead to sterile pyuria. Moreover, corticosteroids, such as prednisone, can suppress the immune system, increasing susceptibility to infections that can trigger pyuria⁵
• Vancomycin: This is a glycopeptide antibiotic usually prescribed for treating methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermis infection. The adverse effects of administering vancomycin intravenously include low blood pressure, dizziness, muscle spasms, shortness of breath, phlebitis, and toxicity to the kidneys
• Proton Pump Inhibitors: This is a class of medication used to treat or relieve conditions related to excessive acid production. Proton pump inhibitors are widely prescribed for the management of gastroesophageal reflux disease (GERD) and peptic ulcers. Sterile pyuria is one of the infrequent side effects of proton pump inhibitors.⁹ These groups of drugs are potent inhibitors of a group of enzymes that catalyse the secretion of gastric acid in the stomach called H⁺/K⁺–adenosine triphosphatase (ATPase) enzyme.⁹ Examples of these drugs include omeprazole, pantoprazole, esomeprazole, lansoprazole, etc.⁹

How do these drugs cause Pyuria?

5-aminosalicylic acid (5-ASA), such as mesalamine, is primarily used to treat ulcerative colitis. However, many patients with ulcerative colitis use mesalamine for long-term maintenance and to keep ulcerative colitis in remission. However, an uncommon side effect of this medication is interstitial nephritis. Interstitial nephritis, an inflammation of the interstitium of the kidneys, can cause pyuria because the inflammation can elicit an influx of white blood cells (which form pus) into the urine. Additionally, according to the UK General Practice Research Database, the incidence of renal disease due to the use of mesalamine is 0.17 cases per 100 patients per annum. 

NSAIDs are one of the most well-known over-the-counter drugs that exert their effects by inhibiting cyclooxygenase (COX) enzymes, which are essential for the synthesis of prostaglandins.¹⁰ This results in a reduction in prostaglandin synthesis, which can elicit renal consequences. This disruption reduces blood flow to the kidneys and can potentially lead to acute renal failure.¹⁰ In addition to acute renal failure, NSAIDs are associated with acute interstitial nephritis and a condition known as NSAID-induced renal disease.¹¹ Additionally, NSAIDs can also cause damage to distal tubular cells, which impairs the ability of the kidneys to acidify the urine. This leads to a condition called distal renal tubular acidosis and, ultimately, pyuria.¹⁰

Vancomycin-associated acute kidney injury (VA-AKI) was first recognised in 1958.⁸ Vancomycin elicits a higher risk of acute kidney injury compared to other antibiotics.¹² It penetrates most tissues and has a high concentration in the kidneys. This drug exposes the tubular cells and the surrounding interstitium to potentially nephrotoxic substances.⁸ The main mechanisms of VA-AKI include high intracellular drug concentration in the renal tubules of people with risk factors for nephrotoxicity. This subsequently induces oxidative stress, activation of the complement system, inflammatory injury, and cellular apoptosis in proximal renal tubules.⁸ Cellular apoptosis and inflammatory injury can cause the presence of white blood cells in urine.⁸

Management and Prevention of Pyuria

Pyuria is usually a symptom of an underlying health condition.¹³ Thus, early diagnosis, timely treatment, and effective management are essential for maintaining the health of the urinary tract.¹³ Most importantly, treatment depends on the exact cause of pyuria. If the urine test reveals a bacterial or fungal infection, antibiotics or antifungals are prescribed, respectively. The following are the strategies for the management and prevention of pyuria:

• Lifestyle and preventive measures: Apart from medical interventions for infectious pyuria, adopting certain lifestyle habits and preventive measures can contribute to the management and prevention of pus cells in urine.¹³ These include proper hydration, maintenance of good personal hygiene, avoiding the use of irritants, and ensuring STIs or other infections are completely treated
• Cessation of medications for medication-induced pyuria cases. This will be after consulting your physician for alternative drugs if necessary¹³  
• Urinalysis: This is the hallmark indicator of white blood cells in urine. This should be done in addition to a thorough evaluation of clinical history. This is to avoid a differential diagnosis, as the symptoms of pyuria can mimic other conditions¹³

Summary

• Drug-induced pyuria is a condition characterised by the presence of white blood cells in urine due to the use of certain medications
• One of the most common causes of pyuria is urinary tract infection. However, other causes include sexually transmitted infections, pneumonia, pregnancy, tuberculosis, sepsis, drugs, etc.
• The drugs that can cause white blood cells in urine include diuretics, antibiotics (vancomycin and nitrofurantoin), steroids, and proton pump inhibitors
• These medications can cause pyuria as a side effect of their prolonged use and various renal manifestations
• Drug-induced pyuria can be prevented by lifestyle modifications such as proper hydration, proper personal hygiene, and cessation of certain medications

FAQs

How is pyuria diagnosed?

Pyuria can be diagnosed by carrying out routine urine tests. These include urinalysis, blood tests for full blood counts, and kidney and renal function. A renal ultrasound or computerised tomography can be done to diagnose renal stones or nephritis. 

How do you know if it's pyuria or UTI?

Pyuria doesn't have specific symptoms, but the underlying cause may induce urinary symptoms. Thus, urinalysis looking for elevated white blood cell count is indicative of pyuria and is the key in differentiating a UTI and pyuria. UTI can cause additional symptoms like burning and urination, which can extend to the bladder, urethra, and sometimes, kidneys. 

What are the risk factors of pyuria?

Some risk factors increase the chances of developing pyuria. The risk factors include gender, age, diabetes, and pregnancy. 

What should be the normal range of pus cells in urine? 

It is normal to have a small number of pus cells in a urine sample. However, the normal range of pus cells in urine when viewed under a microscope differs slightly in males and females. The normal count of pus cells in male urine samples is less than 4 cells/HPF (high-power field), whereas for females, the normal pus cell count is between 5–7 cells/HPF. Any increase in the number of pus cells in urine can be observed physically through the visible changes in urine and urinary symptoms.