Dr. NK Hase in the second part of his exclusive masterclass series on urinary tract infections writes on various presentations in patients- AEB, recurrent and uncomplicated cystitis, and acute complicated infections and treatment approach to be followed for each.

 

Asymptomatic bacteriuria (ABU)

Asymptomatic bacteriuria is defined as positive urine culture in a patient who has no symptoms or signs referable to urinary tract infection.

Diagnostic criteria

• Women: Two consecutive (preferably 2 weeks apart) voided urine sample with isolation of the same bacterial strain with quantitative count of ≥10⁵ CFU/ml
• Men: A single clean catch midstream urine sample with isolation of single bacterial strain with quantitative count of ≥10⁵ CFU/ml
• Single catheterised urine sample with isolation of single bacterial strain with a quantitative count of ≥10² CFU/ml in men and women

ABU is a common and generally benign condition probably with low virulence bacteria. The common organism is E.coli. Pregnant women with ABU have a significant increased risk of pyelonephritis premature delivery, and low birth weight infants. Patients with ABU undergoing urological intervention associated with mucosal bleeding have a high rate of bacteremia and sepsis. As per the Infectious Disease Society of America (IDSA) and EAU Guidelines only pregnant women and patients undergoing urological interventions associated bleeding should be screened and if positive, should be treated.

Pregnant women: They should be screened at 12 to 16 weeks of gestation with mid-stream urine culture. If positive, it should be repeated in 7 days. If two consecutive cultures come positive, they should be treated with appropriate antibiotics according to susceptibility reports.

Potential options are:

1. Nitrofurantoin 100 mg orally, 12 hourly for 5 to 7days (avoid use during first trimester and at term)
2. Amoxicillin 500 mg orally, 8 hourly.(OR) Amoxicillin + clavulanate 625 mg 8 hourly
3. Cephalexin 500 mg orally, 6 hourly
4. Fosfomycin 3 g orally as a single dose
5. Trimethoprim-sulfamethaxazole 160/800 mg every 12 hourly

Duration of therapy should be 5 to 7 days. Follow up culture should be done 7 days after completion of therapy to confirm the sterilisation of urine.

• If repeat culture shows no growth, there is no indication for further testing for bacteriuria in the absence of symptoms suggestive of UTI
• If repeat culture is positive for bacterial growth (≥10⁵ CFU/ml), repeat the course of antimicrobial as per susceptibility pattern

EUA (European Urological Association) Guidelines strongly recommend not to screen and treat ABU in the following conditions:

Women without risk factors

• Patients with well-controlled diabetes
• Post-menopausal women
• Elderly institutionalised patients
• Patients with renal transplant
• Patients prior to arthroplasty, and non-urologic surgery
• Patients with recurrent UTI
• Patients on chronic urethral catheters

---

Uncomplicated lower urinary tract infections: Acute cystitis in women

Uncomplicated cystitis is defined as acute sporadic or recurrent cystitis limited to non-pregnant women with no relevant anatomical and functional abnormalities within the urinary tract or comorbidities. This is the most common syndrome of UTI encounter in clinical practice. Fifty to sixty percent of women experience at least one episode of cystitis in their lifetime. Nearly one in three women will have at least one episode of cystitis by age of 24 years. The incidence of cystitis in young, sexually-active women is 0.5 episode/person/year.

Microbiology

• E.coli is the most common organism in 75-95% of cases
• Staphylococcus saprophyticus is the 2nd most common organism in young sexually-active women
• Occasionally, infections are caused by Klebsiella pnumoniae and Proteus mirabilis
• Pseudomonas enterococci and staphylococci are usually seen in healthcare and post urosurgical procedures
• There is an increasing trend of E.coli, Klebsiella MDR and ESBL producer strains

Clinical features

1. The classical manifestations consist of dysuria, frequency, urgency, strangery, suprapubic pain, and haematuria. Foul-smelling odour and cloudy urine may be present.
2. Elderly women can have non-specific symptoms such as lack of wellbeing, nocturia, new or worsening of urinary frequency, urgency, incontinence, falls, and change in functional and mental status.
3. Fever, chills, rigor, and other symptoms, sign of systemic illness are not compatible with the diagnosis of acute simple cystitis.
4. Usually there are no physical signs except mild suprapubic tenderness.

Diagnosis

Diagnosis is mainly clinical. Acute symptoms like dysuria, frequency, urgency, and suprapubic pain in the absence of vaginal discharge or irritation suggest probability of cystitis is more than 90%. Urine dipstick positivity for leukocyte esterase and nitrile, urinary microscopy showing pyuria may be useful adjunct especially in atypical symptoms.

Definitive diagnosis is made by demonstration of bacteriuria. Urine culture should be done before starting antimicrobial therapy, particularly in women who present with atypical symptoms. Considering emerging resistant pattern, we do urine culture in all patients with suspected UTI.

Urine culture is strongly recommended in pregnant women with symptoms that do not resolve with short course of antimicrobial therapy or if symptoms recur within four weeks after completion of treatment and those with suspected acute pyelonephritis.

Traditionally, urine culture showing bacterial count ≥10⁵ CFU/ml is considered diagnostic. But ≥102-10³ CFU/ml in symptomatic patients has acceptable sensitivity and specificity. No further investigations are required unless the patient’s symptoms do not resolve with treatment and recurrent infections.

Differential diagnosis

Conditions other than cystitis can cause symptoms of dysuria, urgency, frequency and suprapubic pain and need to be considered as differential diagnosis.

1. Vaginitis: The presence of vaginal discharge, odour, pruritus, dyspareunia in the absence of urgency or frequency suggests vaginitis.
2. Urethritis: Dysuria, irritation and discharge in the urethral opening is highly suggestive of urethritis. There is also pyuria but no bacteriuria. In sexually-active women with multiple sexual partners gonorrhoea, chlamydia, mycoplasma, trichomoniasis, candidiasis, and herpes simplex should be considered as a cause of urethritis.
3. Pelvic Inflammatory Disease (PID): The patient may present with dysuria, frequency, lower abdominal pain and backache. There may be fever. Lower abdominal tenderness and pelvic examination showing mucopurulent endocervical discharge or cervical motion tenderness is characteristic of PID.
4. Painful bladder syndrome: This is a chronic syndrome characterised by dysuria, frequency, urgency, pain in the lower abdomen, back, pelvis, and urethra. There may be pain during sexual intercourse. There is no infection, no pyuria or bacteriuria. It is a diagnosis of exclusion.

Management: The aim of the therapy is to get symptomatic relief, eradication of microorganisms, and prevention of recurrence.

General measures

• Liberal fluid intake(2-3 L/day)
• Frequent and timely voiding help to flush bacteria from the bladder
• Holding urine for longer time allow bacteria to multiply in bladder
• There is no evidence supporting alkalinisation
• Urinary analgesic phenazopyridine 200 mg orally three times a day after meal can reduce dysuria (should be used only for 2 days)
• Paracetamol or Ibuprofen may be used to relieve pain

Antimicrobial therapy

Antimicrobial agent should be prescribed according to local susceptibility pattern. In cystitis, antibiotics having urinary concentration will be preferred while in pyelonephritis tissue concentration is important. Because of emergence of high grade resistance and Extended Spectrum Beta Lactamase (ESBL) producing E.coli and Klebsiella, ampicillin, amoxicillin, co-trimaxazole and quinolones (ciprofloxacin and levofloxacin) is no longer the drug of choice for empirical treatment to start.

As there is a high incidence of multidrug resistant gram-negative isolates, it is recommended to obtain urine culture and susceptibility test even in uncomplicated cystitis. For empiric treatment, oral option includes Nitrofurantoin monohydrate/macrocrystals 100 mg orally, twice a day for 7 days, or Fosfomycin 3 g of powder mixed in water as single dose, or if available Pivmecillinam 400 mg orally twice daily for 5 to 7 days.

Patient symptoms should be relieved within 48 to 72 hours. If symptoms persist, antimicrobial therapy can be changed according to susceptibility pattern. If symptoms persist in spite of appropriate antimicrobial therapy urologic assessment and radiographic imaging will be indicated to rule out anatomical-structural abnormality.

If the above empiric options are not appropriate because of contraindication or resistance, antimicrobial therapy can be deferred until susceptibility reports become available. However, if there is concern about deffering antimicrobial therapy because of bothersome symptoms or risk factors, for more serious infection options include using one of the oral regimens for simple cystitis that was not chosen because of the possibility of resistance or using initial dose of parental agents as used in complicated UTI.

Routine follow-up urine culture should be undertaken only when infection persists or recurs within two weeks. In such a situation, the patient will require a longer course of antimicrobial therapy (10 to 14 days) based on culture susceptibility pattern.

Prevention

Women should be educated about the preventing reinfection. They should be advised to drink plenty of fluids, practice frequent and timed voiding, and void before and after sexual intercourse. Spermicidal agents should be avoided. Cranberry products and mannose D may prevent recurrences.

---

Recurrent simple cystitis in women

Recurrent UTI is defined as two or more infections occurring in 6 months or three or more infections in 1 year. Most of the recurrences are thought to represent reinfection than relapse. Reinfection is defined as new infection by the same or different organism following eradication of the prior one.

Relapse is defined as recurrence occurring within two weeks of completion of treatment for original infection and when the infecting uropathogen is same as original. Relapse suggests emergence of prior infection which was incompletely eradicated. It warrants more extensive urologic evaluation and extended (4 to 6 weeks) course of antimicrobial therapy.

Recurrent simple cystitis can occur among women even with normal, physiological urinary tract. Around 25% of women with an episode of cystitis will have a second confirmed episode within 6 months and 5% will have a third episode. In a Finnish study of women, ages 17 to 82 who had E.coli cystitis, 44% had a recurrence within one year.

Risk factors for recurrent cystitis include frequent sexual intercourse, multiple partners, use of spermicidal jelly and mechanical and physiological factors that impede bladder emptying. Women with recurrent cystitis also appear to have increased susceptibility to vaginal colonisation with uropathogen even during asymptomatic periods. Risk factors are same as simple cystitis.

Most of the cases with recurrent cystitis do not warrant imaging or urologic evaluation. Women with relapsing infection, repeated isolation of Proteus species, history of passing stones, persistent haematuria after eradication of infection, voiding issues such as incomplete voiding, incontinence, prolapsed uterus require renal ultrasound or CT, uroflow-metry, post-void residue and urogynaecologic evaluation.

Management

Patient education about characteristics of reinfection and relapse is important. Patints should be advised to drink plenty of fluids (2-3 L/day). Control of blood glucose is necessary if diabetic. Urine should not be held for a long time. Frequent voiding helps prevent adherence and multiplication of bacteria in the bladder. The patient should be told to empty the bladder fully (double voiding can be done to avoid accumulation of residual urine in the bladder which predisposes to infection). Spermicidal should be avoided. Instead, alternative form of contraception should be tried. Intrauterine contraceptive devices should be taken care off. Post-coital voiding should be practiced and the genital area should be cleaned before and after intercourse.

Vaginal creams, lotions, deodorant sprays, or soaps and bubble bath should be avoided as they would alter vaginal flora and predispose to UTI. Patients should be advised to avoid multiple unprotected sexual partners which will reduce the risk of both UTI and STD Infections. Constipation should be avoided; patient should be advised t wipe from front to back after emptying bowel which will reduce the spread of E.coli from pregenital area to urethra.

Non-antimicrobial prophylaxis in recurrent UTI

• Topical estrogen therapy is recommended by AUA/EUA in peri- and post-menopausal women with recurrent UTI for prevention
• Estrogen use stimulates the proliferation of lactobacilli in vaginal epithelium, reduces vaginal pH, and prevents vaginal colonisation by uropathogen
• Local estrogen cream twice a week or vaginal ring (2 mg estradiol) changed every 12 weeks are effective in reducing UTI attacks but not as effective as antibiotic prophylaxis
• Cranberry juice and tablets have been shown to reduce recurrent UTI in small studies; the proposed mechanism of action is thought to be related to proanthocyanide present in cranberries which prevents adhesion of bacteria to uroepithelium; optimal dose is not known
• The other preparations like probiotics (lactobacilli), D-Mannose, methanamide, herbal therapies, and intravesical therapies have been found effective in small trials but there is no clear efficacy data; they require further clinical evaluation before recommending for use

Antimicrobial prophylaxis

Antimicrobial prophylaxis has been demonstrated to be highly effective in reducing risk of recurrent infections. Reserve the antimicrobial prophylaxis for women with two or more infections in six months. The symptoms are bothersome and affect quality of life. There are different antimicrobial prophylaxis regimens such as continuous prophylaxis, post-coital prophylaxis and acute self treatment. A continuous prophylaxis is indicated if recurrent cystitis episodes have no temporal relation to sexual activity.

The choice of antimicrobials should be based on local susceptibility patterns of uropathogen causing the patients previous cystitis. Selection should also consider availability, safety, and cost, level of renal function, pregnancy status, potential interactions and drug allergies.

Most commonly preferred drugs considering current susceptibility pattern

• Nitrofurantoin: 50-100 mg orally at bed time, or
• Trimethoprim-sulphamethoxazole 1/2 tablet (40/200 mg) once daily, or
• Cephalexin 125-250 mg orally once a day, if susceptible, or
• Fosfomycin 3 g with water orally every 7 to 10 days

The duration of prophylaxis will be 6 to 12 months. Patients should be followed up three-monthly for tolerability and side effects.

Post-coital prophylaxis: It may be a more efficient method of prevention than continuous prophylaxis in women whose cystitis episode may be temporally related to sexual intercourse. Single dose of antimicrobial (trimethoprim-sulphamethoxazole or nitrofurantoin) drug should be given post coitally. Post-coital prophylaxis usually results in receipt of smaller amount of antimicrobial dose than continuous prophylaxis.

Self-diagnosis and self-treatment: Women who have clearly documented recurrent infections, are motivated, adheherent to medical instruction and are in close contact with the treating doctor can be selected for self-diagnosis and self-treatment of cystitis. In such cases, women are given a prescription for a typical course of antimicrobial to use for symptoms suggestive of cystitis. If the symptoms do not subside within 48 to 72 hours, instructions should be given to attend the hospital. Several studies have shown that cystitis can be accurately self-diagnosed by women more than 85 to 95% of the time. Self-treatment is effective and safe.

---

Acute complicated urinary tract infections

Traditionally, UTIs are considered complicated if they occur in the setting of structurally, functionally or metabolically abnormal tract. According to current thinking, any urinary tract infection which extends beyond the bladder with systemic symptoms should be considered as complicated UTI.

Criteria includes UTI with systemic symptoms and signs like fever, chills, rigor, significant fatigue, malaise, abdominal pain, flank pain, pelvis and perineal pain in men with or without dysuria, urinary frequency, suprapubic pain and haematuria. By this definition pyelonephritis is complicated UTI regardless of patient characteristics.

Risk factors

• Obstruction or other structural abnormalities (nephrolithiasis, strictures, prostatic enlargement, pelvic and retroperitoneal malignancies –ca cervix, lymphomas, bladder divertculi, cysts, ileal conduits, fistulae, urinary diversions)
• Functionally abnormal urinary tract (neurogenic bladder, vesico ureteral reflux)
• Urologic interventions (nephrostomy tube, ureteral stents, indwelling catheters)
• Metabolic abnormality (uncontrolled diabetes, neutropenia, immunosupprression– transplant patient, recent antimicrobial exposure, infection with multidrug resistant organisms)
• Other settings (UTI in male, pregnancy, elderly, renal failure, and occurrence in children is considered as complicated)

Microbiology

E.coli is the most common cause of acute, complicated cystitis. Other pathogens include Klebsiella, Proteus, Pseudomonas, enterococci, and staphylococci (methicillin-sensitive and methicillin-resistant Staphylococci aureus). Pseudomonas is more common in patients with healthcare exposure and following urologic intervention. Staphylococcus saprophyticus is an occasional cause of pyelonephritis in young healthy women.

Currently multi drug resistant extended-spectrum beta-lactamase (ESBL)-producing E.coli and Klebsiella are emerging as major uropathogens in complicated UTI. One of our studies showed high-grade resistance to ampicillin, amoxicillin, cotrimoxazole, cephalosporins, and quinolones.

Clinical manifestations

Symptoms and signs of pyelonephritis classically include fever with chills, flank pain, nausea, vomiting, fatigue, malaise and costo-vertebral renal angle tenderness. These may or may not be associated with dysuria, frequency, urgency, suprapubic pain, and haematuria.

The patient may present with bacteraemia, sepsis, shock, multiorgan system failure with acute kidney injury and failure. Complications are more likely to occur in patients with uncontrolled diabetes, urinary tract obstruction, recent urinary tract instrumentation, in those who are immunosuppressed, and in the elderly.

Urosepsis is the most common cause of bacteraemia and septic shock in the elderly. Patients with diabetes and urinary tract obstruction may progress to develop corticomedullary abscess, emphysematous pyelonephritis, and papillary necrosis.

Diagnostic approach

History and physical examination may give some diagnostic clues. Fever with chills, flank pain, nausea, vomiting, fatigue, malaise and costo-vertebral renal angle tenderness may be present. These may or may not be associated with dysuria, frequency, urgency, suprapubic pain, and haematuria. This history suggests it is complicated UTI. Physical examination may show a toxic, ill patient with abdominal, costovetebral and suprapubic tenderness.

1. Among sexually active young women, pelvic examination is warranted to rule out pelvic inflammatory disease.
2. Among men with symptoms of nocturia, hesitancy, sense of incomplete evacuation with pelvic or perineal pain, cautious digital rectal examination is warranted to evaluate prostatitis/prostatic abscess.

Investigations

• Urine routine, urine culture and blood culture should be sent before starting antimicrobial therapy
• Significant pyuria is present in almost all patients. Its absence suggests alternative diagnosis
• The presence of white cell cast in urine suggests pyelonephritis but sensitivity is poor
• The urine gram stain can also be helpful to narrow down the list of potential causative organism as gram positive or gram negative and helps in selecting empiric antimicrobial agents
• Complete blood count may reveal leucocytosis, anaemia, and thrombocytopenia in case of sepsis
• High CRP, procalcitonin level may predict the severity of illness
• All patients will need blood glucose estimation to rule out DM
• Renal function tests- blood urea nitrogen, serum creatinine should be done in all to detect renal impairment and selection, and adjustment of drug doses
• In young females of child-bearing age, pregnancy test should be done to rule out pregnancy
• Positive blood culture suggests bacteremia and urosepsis

Imaging

Imaging studies are indicated in patients who remain febrile and have symptoms despite 48 to 72 hours of antimicrobial therapy. Imaging studies are indicated on admission itself if the patient is- diabetic, severely ill with sepsis, or in septic shock to rule out obstruction, abscess or emphysematous pyelonephritis.

Computed Tomography (CT) scanning with or without contrast is generally the study of choice. It is more sensitive than renal ultrasound or excretory urography for detecting renal abnormalities and complications. CT without contrast has become the standard radiographic study for demonstrating calculi, cyst infection, haemorrhage, and emphysematous pyelonephritis. Contrast is needed to demonstrate alteration in perfusion.

Mild infection may not show any changes on CT. Renal ultrasound is preferred in patients in whom radiation exposure and contrast is contraindicated.

Management

Patient management will depend upon the severity of illness. A patient with mild to moderately severe illness who is haemodynamically stable, well-hydrated, having normal renal function, and likely to report any complaint can be managed on outpatient basis.

Patients who are critically ill, haemodynamically unstable should be admitted in the hospital, preferably in the intensive care unit. Maintain SpO2 more than 90%, MAP (Mean Arterial Pressure) more than 70 mmHg, keep well-hydrated, measure urine out every hourly, order urine and blood culture before starting antibiotics. Get imaging CT abdomen done to rule out obstruction, abscess, or other complications.

Start empiric antimicrobial promptly without delay. Antimicrobial selection should be done according to local susceptibility pattern. Considering multidrug resistant (MDR) gram negative, ESBL producer strains in hospitalised critically ill patient, we prefer to start with:

• Injection Meropenem 1 g intravenously eight hourly, or
• Injection Imipenem 500 mg intravenously every six hourly, or
• Doripenem 500 mg IV eight-hourly plus Injection Vancomycin 15 mg/kg IV 12-hourly (dose adjustment as per renal function),or
• Injection Linezolid 600 mg IV every 12-hourly (OR) Injection Teicoplanin 400 mg IV every 12-hourly

If there are no risk factors for multidrug resistance for gram negative or gram positive organism, we start with broad spectrum antimicrobial regimen. Injection Ceftriaxone 1 g IV once daily or Injection Piperacillin-Tazobactum 4.5 g IV every eight-hourly.

If Pseudomonas infection is suspected, therapy is started with Cefaperazone plus sulbactum 1.5 g every twelve-hourly or aminoglycosides like Amikacin 7.5 mg/kg IV or Gentamycin 5 mg/kg IV once a day as infusion (dose adjustment as per renal function) or Cefepime 2 g IV eight-hourly.or Ceftazidime 2 g IV, every eight-hourly.

Once antimicrobial therapy is started, the patient should become afebrile within 48 to 72 hours. If the patient remains febrile, antimicrobial should be changed as per susceptibility testing report. Imaging should be done to rule out obstruction. If obstruction is found, promptly relieve the obstruction.

If the patient shows symptomatic improvement and becomes afebrile, broad spectrum empiric regimen can replaced by narrower spectrum agents (de-escalation) as per urine blood susceptibility report. Patients who were initially treated with a parental regime can be switched to oral agents once symptoms have improved and if culture and susceptibility testing permits.

Occasionally, susceptibility result precludes the use of oral regimen and parenteral agent is needed to complete the course of treatment. Options for outpatient administration of parental antimicrobial includes, use of peripherally inserted central catheter or pre-existing central catheter or intramuscular injections.

Recommended appropriate oral agents to treat acute, complicated UTI include:

• Llevofloxacin 750 mg orally once a day
• Ciprofloxacin 500 mg twice daily
• Trimethoprim+sulphamethaxazole (160/800) orally, twice daily

Word of caution in our setting- there is high grade resistance to quinolones and cotrimoxazole. Oral betalactamase and betalactamase inhibitors are less effective for acute complicated UTI, but appropriate alternatives if susceptibility is documented and other agents are not feasible.

In the outpatient setting, treatment should be initiated with injection Ertapenem 1 g IV or IM once a day until the susceptibility testing results are available. If susceptible, levofloxacin or ciprofloxacin or cotrimoxazole can be continued. If no susceptibility to oral drugs is indicated, injection Ertapenem can be continued to complete the course.

In addition to antimicrobial therapy underlying obstruction should be relieved promptly. Voiding and storage disorder may need correction. Antimicrobial therapy may not be effective unless underlying structural, functional and metabolic abnormalities are corrected.

Total duration of antimicrobial therapy generally ranges from 10 to 14 days. If there is persistent focus of infection and relapsing infection therapy needs to be extended to 4 to 6 weeks or till the focus is completely resolved. Long term follow-up is recommended in patients with complicated UTI to asses relapse, reinfection, and residual functional impairment.

---

To read the first article in the series which discusses diagnosis and classification, click here.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author Dr. NK Hase is a Director clinical Nephrology & Transplant working at Jupiter Hospital, Thane and former Professor & Head of Department of Nephrology Seth GS Medical College and KEM Hospital, Mumbai.