Urethritis and cystitis

Cystitis and urethritis

I. What every physician needs to know.

Cystitis (aka bladder infection) and urethritis are lower urinary tract infections. They develop secondary to inflammation of the bladder and urethra, and they may be either complicated or non-complicated. The majority of cases are related to bacterial infections. In cystitis, the colonization of the urinary bladder occurs after organisms from the perineum ascend into the bladder. Failure of adequate emptying of the urinary bladder increases the risk of colonization, and organisms will grow and lead to inflammation in the bladder.

Urethritis occurs mainly after exposure to a sexually transmitted disease; less commonly it can be related to a structural problem with the urethra.

II. Diagnostic Confirmation: Are you sure your patient has cystitis or urethritis?

Both cystitis and urethritis may present with pain or difficulty on urination (dysuria), frequency, urgency, and/or suprapubic pain or heaviness. A careful history may help differentiate between the two diseases. Urethritis may be associated with urethral discharge or meatal pruritus. Fever and lower back pain are unusual and may indicate upper urinary tract infection. Cystitis is much more common in women than in men; young adult men with dysuria should be evaluated for signs of urethritis prior to considering cystitis.

A. History Part I: Pattern Recognition:

Patients with cystitis report pain or burning on urination, frequency of urination, hematuria, and suprapubic heaviness. They may comment that there has been a change in their urine. Patients may report feeling warm, but associated fever or chills are rare, so the latter report should trigger evaluation for upper urinary tract infection. Urethral discharge, which is not common in cystitis, may be a manifestation of urethritis. Urethritis symptoms also include urethral and vaginal discharge or morning penile crusting. The discharge is usually less evident after urination.

B. History Part 2: Prevalence:

Cystitis accounts for up to 8 million office visits per year in the United States. Understanding the prevalence of the disease in different populations or groups may help in evaluating the chances that a patient has cystitis. For example, men rarely develop cystitis unless they are of advanced age, while up to half of young adult women who are sexually active may develop cystitis each year.

Risk factors for cystitis include host factors, such as neurogenic bladder, urinary tract obstruction, diabetes, pregnancy, immunocompromised conditions, low socioeconomic status, and a history of urinary tract infection in a first-degree female relative. Modifiable factors include urethral catheterization, sexual intercourse, and the use of spermicidal contraceptive agents and diaphragms. Escherichia coli is implicated in cystitis in 75-95 percent of the cases, in addition to other gram-negative bacilli, Enterococcus species, and Staphylococcus saprophyticus. It is uncommon to isolate more than one organism in the urine culture unless structural abnormalities in the urinary tract are present.

Three to four million cases of urethritis occur in the United States every year, three-quarters of which are related to non-gonococcal organisms. Ages 15-24 years have the highest incidence, and African Americans and Hispanics have a higher incidence of disease than Caucasians do.

The microbiology of urethritis includes Neisseria gonorrhea, Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis,and Ureaplasma urealyticum.The main risk factor for urethritis is sexual exposure. A young adult with dysuria should always be asked about his or her sexual history and evaluated for the risk of having been exposed to a sexually transmitted disease. Patients with multiple sexual partners and those who have been exposed to someone with a sexually transmitted disease are at higher risk for developing urethritis. A detailed sexual history is needed to help identify risk factors.

C. History Part 3: Competing diagnoses that can mimic cystitis or urethritis.

Differentiating cystitis from urethritis is important. In addition, upper urinary tract infection, which is associated with systemic symptoms (e.g., fever, chills) and signs of kidney involvement (e.g., flank pain) should be excluded. Non-infectious causes include interstitial cystitis (a.k.a. painful bladder syndrome), which is a chronic disease associated with frequency, urgency, pelvic pain, and dyspareunia. The symptoms are often mistaken for recurrent bladder infections. The symptoms are progressive, and workup commonly results in negative urine cultures.

Hemorrhagic cystitis, a disease that occurs in oncology patients and bone marrow transplant recipients, may be related to medications (cyclophosphamide) or viral etiology (adenoviruses, polyomaviruses).

Mechanical trauma to the urethra, as well as chemical irritation (e.g., exposure to spermicides), may result in symptoms that mimic urethritis. Symptoms suggestive of recurrent urethritis with treatment should trigger an evaluation for either prostatitis or epididymitis.

D. Physical Examination Findings.

The exam in patients with cystitis may reveal suprapubic tenderness. Fever is infrequent and, if present, is low-grade. The presence of costovertebral angle tenderness and/or fever may indicate upper urinary tract involvement. The presence of urinary discharge may indicate urethritis. In cases where urethritis is suspected, a detailed exam of the genitalia is done for skin lesions, lymphadenopathy, and epididymal or testicular tenderness and swelling. Epididymal tenderness and induration are present if the patient has epididymitis. The meatus is also inspected for crusting or discharge. A prostate exam is also helpful to evaluate for prostatitis (swollen, tender prostate).

E. What diagnostic tests should be performed?

For cystitis: Check for presence of suprapubic or lower abdominal tenderness, no costovertebral angle tenderness, no epididymal tenderness or prostatic tenderness on exam.

For urethritis: Check for penile discharge, meatal crusts, no costovertebral angle tenderness, no epididymal tenderness or prostatic tenderness on exam. The triad of oligoarthritis, conjunctivitis, and evidence of preceding urethritis on exam is consistent with reactive arthritis.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Urine analysis, microscopy, and urine culture have been used for the diagnosis of cystitis. Most uncomplicated patients (e.g., symptomatic young women on initial presentation) with cystitis are treated based on their clinical symptoms. A urine dipstick with a negative test for nitrates and leukocyte esterase makes the diagnosis of cystitis unlikely. Positive nitrites suggest the presence of gram-negative bacteria such as Escherichia coli, Klebsiella, Proteus,and Enterobacterbecause these organisms convert urinary nitrates to nitrites. Note that S. saprophyticusand Enterococcusspecies do not reduce nitrates to nitrites.

Leukocyte esterase, an enzyme contained in white blood cells (WBCs), is released with cell lysis.

The majority of patients with cystitis will have pyuria (≥10 WBCs per mm3) on microscopy; however, pyuria without symptoms and signs is not sufficient to make the diagnosis. The presence of microscopic or gross hematuria should trigger evaluation for other possible causes, including urinary pathology (malignancy or urolithiasis) or vasculitis.

Although not required for the initial management of cystitis in women, urine cultures are helpful in identifying the organism and its susceptibility, especially in hospitalized patients where the rate of resistance increases. The urine culture should be a clean-catch midstream collection. A culture growing more than 10³ colony-forming units of organism per mm³ is considered significant in the presence of symptoms. A positive urine culture does not indicate cystitis unless accompanying symptoms consistent with cystitis are present.

Young adult men rarely develop cystitis, and microbiologic confirmation is recommended. A significant minority of women and elderly men have asymptomatic bacteriuria and should not receive antibiotics. For urethritis diagnosis, a urethral specimen examined under oil-immersion microscopy with at least ≥2 WBCs is suggestive of urethritis. The presence of gram-negative diplococci intracellularly is indicative of gonococcal urethritis.

Morning first-void urine specimens with at least 10 WBCs per high power field are consistent with the diagnosis of urethritis. Morning urine specimens may increase the yield of detecting Trichomonas vaginalis using cultures. Trichomonas vaginalis diagnosis is by microscopic evaluation of wet preparations of genital secretions. An antigen-detection rapid test using immunochromatographic capillary flow dipstick technology is also available to detect Trichomonas vaginalis, Gardenella vaginalis,and Candida albicans from vaginal secretions. Chlamydia trachomatis is diagnosed using non-culture methods. Mycoplasma genitalium may be diagnosed using polymerase chain reaction. Nucleic acid amplification tests (NAATs) are also available for Ureaplasma urealyticum. NAATs are used frequently for the diagnosis of both gonococcal and chlamydia urethritis.

Annual screening for N. gonorrhoeaeand Chlamydia trachomatis infection is recommended for all sexually active women aged <25 years and for older women at increased risk for infection.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiographic studies are not recommended for cystitis unless they are used to evaluate for an alternative diagnosis or in those with recurrent cystitis. For example, intravenous pyelogram may help identify renal calculi or ureteral strictures. A voiding cystourethrogram identifies obstructive symptoms (either prostatic hypertrophy or urethral stricture in men) or neurogenic bladder. Ultrasound of kidneys, which is often used to evaluate for hydronephrosis or obstruction, eliminates the risk associated with intravenous contrast.

Urethral stricture may be suspected in patients with symptoms of recurrent urethritis, and cystourethrogram may show obstruction.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Urine cultures are over-used in evaluating patients with cystitis; for young woman with symptoms who are presenting with an initial presentation consistent with cystitis and without concern for complications, empiric antibiotic treatment can be done without urine cultures. The prevalence of asymptomatic bacteriuria increases with age and is especially common in the elderly population.

Antibiotic therapy may be prescribed without requiring a urine culture for symptomatic young women who have an uncomplicated lower urinary tract infection. If there is suspicion of a complicated infection or symptoms do not respond to initial therapy, then a culture of the urine is recommended.

No test for microbiologic cure is needed after the treatment of cystitis, and repeat urine cultures are not recommended. The two situations in which asymptomatic bacteriuria is treated are pregnancy, where a 7-day course of amoxicillin or nitrofurantoin is used, and preoperative antibiotic use to reduce the risk of sepsis for patients who are going to have a genitourinary procedure. Antibiotic use for asymptomatic bacteriuria prior to a genitourinary procedure is appropriate if there is a high risk of developing mucosal bleeding and for those who are undergoing transurethral resection of the prostate.

III. Default Management.

For bacterial cystitis, empiric treatment is based on symptoms. The recommended antibiotics include Nitrofurantoin 100 mg orally twice daily for 5 days, or trimethoprim/sulfamethoxazole 160/800 mg (one DS) orally twice for 3 days if the resistance rate to trimethoprim/sulfamethoxazole is <20%, or fosfomycin trometamol (3 g single dose). Fluoroquinolones (ofloxacin, ciprofloxacin, or levofloxacin) for 3 days provide an alternative if the patient is allergic or intolerant to the recommended antibiotics. Fluoroquinolones are highly effective, but their indiscriminate use is associated with increased antimicrobial resistance. Beta-lactams are less efficacious and may be used for three to 7 days. Amoxicillin 500 mg orally three times daily covers enterococcal infection and may be used in pregnancy if the organism is susceptible.

The increasing prevalence of antibiotic-resistant uropathogens is likely to limit the effectiveness of current oral antibiotics in individuals who suffer from recurrent or chronic cystitis due to extended spectrum beta-lactamase producing organisms.

If no available diagnostic tests are available, urethritis treatment targets both gonococcal and non-gonococcal infection. If the Gram stain microscopy reveals gram-negative diplococci consistent with gonococcal organisms, treatment should cover both gonorrhea and chlamydia. Patients with gonococcal urethritis are treated with dual therapy to slow the emergence of resistance to cephalosporins: ceftriaxone 250 mg intramuscularly (preferred) in combination with azithromycin 1 g orally. Alternatively, cefixime 400 mg in combination with azithromycin 1 g may be given orally once. Rare cases of decreased susceptibilities to cephalosporins have been reported, in addition to failures to treatment with oral cefixime.

Oral gemifloxacin 320 mg plus oral azithromycin 2 g or single doses of intramuscular gentamicin 240 mg plus oral azithromycin 2 g may be considered for those who are allergic to cephalosporins. A test of cure is not needed for persons with uncomplicated urethritis.

The treatment of chlamydia urethritis is azithromycin 1 g orally once or doxycycline 100 mg orally twice daily for one week. Patients with recurrent or persistent symptoms after treatment with doxycycline may have doxycycline-resistant M. genitaliumor Ureaplasma urealyticum. T. vaginalis,which may also cause urethritis in men, can be identified by culture or NAAT. If the patient was compliant with the initial doxycycline-based regimen, retreatment with one dose of azithromycin 1 g orally and one dose of metronidazole 2 g orally is recommended. Moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium; therefore, men who fail a regimen of azithromycin should be retreated with moxifloxacin 400 mg orally once daily for 7 days.

B. Physical Examination Tips to Guide Management.

The follow-up physical exam for cystitis shows less lower abdominal and suprapubic tenderness with treatment. For urethritis, resolution of the discharge on exam is seen.

C. Laboratory Tests to Monitor Response to and Adjustments in Management.

Repeat testing is not recommended for cystitis or urethritis as a test of cure. Patient with urethritis secondary to chlamydia, gonorrhea, or trichomonas should be offered partner services and instructed to return 3 months after treatment for repeat testing because of high rates of reinfection, If symptoms persist or recur after completion of therapy, patients should be instructed to return for re-evaluation.

D. Long-term management.

Patients who have persistent symptoms should be re-evaluated for the accuracy of diagnosis. If a patient was initially treated empirically (i.e., no urine culture sent) and symptoms persist, consider infection related to an organism resistant to the current regimen. A urine culture is recommended, and treatment should be based on the results. Recurrent cystitis is common in young adult women; the majority of the cases are thought to be related to reinfection. Relapse after treatment occurs within two weeks of treatment for cystitis. Repeated episodes may require further workup for structural or functional bladder problems.

To reduce risk patients with urethritis should be educated and counseled about sexually transmitted diseases and changes in behavior. Those with gonococcal and non-gonococcal urethritis should be offered testing for syphilis and human immunodeficiency virus (HIV). Partners of patients with non-gonococcal urethritis should be evaluated and treated if they were exposed within 60 days. For those with chlamydia urethritis, if no sexual activity occurred within the last 60 days, the most recent sexual partner should be evaluated and treated. Patients should abstain from sexual activity for 1 week after starting treatment for urethritis.

No test of cure is recommended for patients treated for cystitis with symptom resolution. Test of cure is not recommended for urethritis unless therapeutic adherence is in question, symptoms persist, or reinfection is suspected.

E. Common Pitfalls and Side-Effects of Management

Cystitis is a common disease. The initial presentation consistent with cystitis does not require extensive workup, and empiric antibiotic treatment is reasonable for women with symptoms suggestive of cystitis. Men, who rarely develop cystitis, should be evaluated for other sources for their dysuria (e.g., prostatitis epididymitis and orchitis) if the symptoms persist.

Recurrent symptoms should trigger re-evaluation of the accuracy of diagnosis and the decision to do further workup for structural urinary problems. Patients with urethritis should always be asked about any history of a new sexual partner or high-risk sexual behavior. Partner evaluation and treatment are also important.

IV. Management with Co-Morbidities

Patients with comorbidities may be on medications that interact with antibiotics used for cystitis and urethritis. For example, warfarin effect is potentiated by the use of quinolones or trimethoprim/sulfamethoxazole, so patients on warfarin may need close follow-up on their anticoagulation levels, and the dose may need to be temporarily lowered. Quinolones reduce the elimination of theophylline-based medications and may require dose adjustments. Beta-lactam agents have few drug interactions with chronic medications.

A. Renal Insufficiency

Because many of the antimicrobials to treat cystitis are renally cleared, adjustment of the antibiotic dose should be made depending on the renal function. This applies to regimens that are not a single dose. In addition, trimethoprim/sulfamethoxazole may lead to hyperkalemia, especially in the elderly and in patients with renal insufficiency.

B. Liver Insufficiency

Caution should be taken when macrolides are used in patients with severe liver failure, and quinolones with hepatic clearance (moxifloxacin) should be avoided. Metronidazole is also significantly cleared by the liver, and caution should be used when prescribing it to patients with hepatic insufficiency.

C. Systolic and Diastolic Heart Failure

Quinolones and macrolides have been associated with arrhythmias and increased risk of QT prolongation.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

Quinolones used to treat cystitis rarely may lead to dysglycemia.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

Evaluate for drug-to-drug interactions with quinolones or macrolides, especially in patients on antifungal azoles or immunosuppressive therapy.

H. Primary Lung Disease (COPD, Asthma, ILD)

Evaluate for drug-to-drug interactions with quinolones, especially if the patient is on theophylline-based treatment.

I. Gastrointestinal or Nutrition Issues

Antibiotic-associated diarrhea or Clostridium difficileinfection should be considered in patients with new-onset diarrhea or abdominal pain after initiation of antibiotics.

J. Hematologic or Coagulation Issues

Antibiotics that interact with the metabolism of warfarin (quinolones or trimethoprim/sulfamethoxazole) may lead to an increase in prothrombin time.

K. Dementia or Psychiatric Illness/Treatment

Quinolones may cause dizziness and delirium in the elderly.

V. Transitions of Care

A. Sign-out Considerations While Hospitalized.

Patients treated in the hospital for cystitis should be watched for any fever or systemic symptoms, which will indicate upper tract involvement or complicated urinary tract infection. Patients with urethritis secondary to a sexually transmitted disease may be watched for undiagnosed prostatitis or epididymitis.

B. Anticipated Length of Stay.

Cystitis and urethritis are treated in the outpatient setting and do not require hospitalization.

C. When is the Patient Ready for Discharge?

Both cystitis and urethritis are treated in the outpatient setting, and the patient is usually clinically stable. Patients who exhibit systemic symptoms should be evaluated for an alternate diagnosis.

D. Arranging for Clinic Follow-up

For cystitis, follow-up with the primary care provider for recurrent episodes is needed, in which case outpatient workup may be warranted, including evaluation for functional or structural problems with the urinary system. A referral to a urologist may be helpful when either a neurogenic bladder or obstructive symptoms is suspected.

For urethritis, follow-up with primary care provider to evaluate for resolution of symptoms is needed. If symptoms persist, consider an alternate diagnosis or an organism that was not covered initially.

1. When should clinic follow up be arranged and with whom?

For cystitis, follow-up with the primary care provider is arranged if the symptoms do not resolve within 2-3 days of treatment. Referral to a urologist may be needed if the primary care provider suspects either neurogenic or structural urinary abnormalities. For urethritis, if symptoms persist or recur after completion of therapy, patients should be instructed to return for re-evaluation with the primary care provider. Patient with urethritis secondary to chlamydia, gonorrhea, or trichomonas should be instructed to return 3 months after treatment for repeat testing because of high rates of reinfection.

2. What tests should be conducted prior to discharge to enable the best clinic first visit?

None

3. What tests should be ordered as an outpatient prior to or on the day of the clinic visit?

None

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

For cystitis, patients should be counseled on methods to reduce the risk of recurrence, including voiding after intercourse and avoiding spermicide or diaphragm use. For urethritis, patients should be counseled on low-risk sexual behaviors and partner notification.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

For urethritis, primary care providers should counsel patients on adopting low-risk sexual behavior and partner notification.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Recurrent cystitis is usually related to the same organism. Patients may be prescribed antibiotics to use when the symptoms start and advised to seek medical attention if there is no improvement. No prolonged antimicrobial prophylaxis, which may be associated with isolating more resistant organisms and an increased risk for Clostridium difficileinfection, is recommended. For urethritis, low-risk sexual behavior is key to reducing the risk for reinfection.

VI. What is the evidence?

Gupta, K, Hooton, TM, Naber, KG. “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. vol. 52. 2011. pp. e103-120.

Nicolle, LE, Bradley, S, Colgan, R, Rice, JC, Schaeffer, A, Hooton, TM. “Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults”. Clin Infect Dis. vol. 40. 2005. pp. 643-54.

Hooton, TM. “Uncomplicated Urinary Tract Infection”. New Engl J Med. vol. 366. 2012. pp. 1028-37.

Hanno, PM, Burks, DA, Clemens, JQ. “AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome”. J Urol. vol. 185. 2011. pp. 2162-70.

“Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections”. Morb Mortal Wkly Rep. vol. 61. 2010. pp. 590-94.

“Sexually Transmitted Diseases Treatment Guidelines, 2015”. MMWR Recomm Rep. 2015. pp. 64

Miller, WC, Ford, CA, Morris, M. “Prevalence of chlamydial and gonococcal infections among young adults in the United States”. JAMA. vol. 291. 2004. pp. 2229-36.

Bradshaw, CS, Tabrizi, SN, Read, TR. “Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure”. J Infect Dis. vol. 193. 2006. pp. 336-45.

Foxman, B. “Urinary tract infection syndromes occurrence, recurrence, bacteriology, risk factors, and disease burden”. Infect Dis Clin N Am. vol. 28. 2014. pp. 1-13.

Mody, L, Juthani-Mehta, M. “Urinary tract infections in older women a clinical review”. JAMA. vol. 311. 2014. pp. 844-54.

Grigoryan, L, Trautner, BW, Gupta, K. “Diagnosis and management of urinary tract infections in the outpatient setting a review”. JAMA. 2014. pp. 1677-84.

Barber, AE, Norton, P, Spivak, AM, Mulvey, MA. “Urinary tract infections: current andemerging management strategies”. Clin Infect Dis. vol. 57. 2013. pp. 719-24.

Moi, HM, Blee, K, Horner, PJ. “Management of non-gonococcal urethritis”. BMC Infect Dis. vol. 15. 2015. pp. 294

Bachmann, LH, Manhart, LE, Martin, DH, Seña, AC, Dimitrakoff, J, Jensen, JS, Gaydos, CA. “Advances in the understanding and treatment of male urethritis”. Clin Infect Dis. vol. 61. 2015. pp. S763-9.

Rietmeijer, CA, Mettenbrink, CJ. “Recalibrating the Gram stain diagnosis of male urethritis in the era of nucleic acid amplification testing”. Sex Transm Dis. vol. 39. 2012. pp. 18-20.

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