Title : Management of Uncomplicated UTI Version Control No. : 3 Release Date : 05 03 2021

Title : Management of Uncomplicated UTI Version Control No . : 3 Release Date : 05 03 2021.

Management of Uncomplicated Urinary Tract Infections (UTI).

Contents. UTI – Introduction UTI – Epidemiology Recurrent UTI Microbial spectrum of UTI Symptoms and diagnosis of UTI Drug therapy and limitations of antibiotics used in UTI Nitrofurantoin – The uro -specific antibiotic with least resistance Guidelines recommendations Martifur – The preferred medicament for uncomplicated lower UTI.

An inflammatory response of urothelium to micro-organisms in the urinary tract, resulting in clinical symptoms like dysuria, frequency, urgency, hematuria, and suprapubic or costo -vertebral angle discomfort self-reported by patient or later elicited on physical examination. Most common infections diagnosed in in- and outpatients as well as hospitalized patients..

Acute uncomplicated UTI - Occurs in patients who have normal structure and function of the genitourinary tract. 10% of women experience at least one episode in a year, and 60% have at least one episode during their lifetime. Complicated UTI – Occurs in a patient with an anatomically abnormal urinary tract or significant medical or surgical comorbidities such as diabetes mellitus, polycystic kidney disease (PCKD), nephrolithiasis, immunosuppression, etc..

Affects patients in all age groups and sexes, with females accounting for 87.5% of the cases compared with males (71.3%) Adult women are 30 times more likely than men to develop a UTI. It is due to short urethral tube of women and normal vaginal flora that colonize the external urethra In men older than 50 years, the incidence of UTI rises dramatically (range, 20-50% prevalence) Half of all women have recurrent episodes of acute cystitis during adult life.

Approximately 2% to 15% of pregnant patients have asymptomatic bacteriuria . If left untreated, up to 30% of mothers will develop acute pyelonephritis. Asymptomatic bacteriuria has been associated with low birthweight and preterm birth..

UTI is one of the most common bacterial infections among children and is a significant source of morbidity. Approximately, 2% of boys and 8% of girls are affected at the age of seven years. Factors predisposing children to UTI include congenital and functional abnormalities Risk of renal damage from UTI is the greatest in children younger than five years.

Defined as having at least three UTI episodes in 12 months or at least two episodes in six months due to incomplete treatment or reinfection Postmenopausal women, pregnant women, immunocompromised patients, and patients with catheters are more susceptible to recurrent urinary tract infections ( rUTIs ). Older adults with rUTIs and other concurrent illnesses have an elevated risk of mortality.

Types of Recurrent UTI. Reinfection. A new episode of infection with the same or different organism, which normally occurs 2 weeks after the treatment has ended (with a sterile urine report in between two infections).

PATHOGENS FREQUENCY E. coli 80-85% Staphylococcus saprophyticus 10-15% Klebsiella spp Enterobacter spp , Citrobacter sp. Proteus Mirabilis Pseudomonas aeruginosa Serratia spp 5-10%.

Symptoms occurring due to cystitis Frequency - Needing to urinate more often than usual Urgency - Sudden, compelling urge to urinate, along with discomfort in the bladder Nocturia - Excessive urination at night Supra-pubic pain – Pain in the area of bladder region Urinary incontinence - Inability to control urination Symptoms occurring due to urethritis Dysuria - Painful urination Burning micturition - Burning sensation while urination Symptoms occurring due to pyelonephritis Hematuria - Presence of blood in the urine.

UTI pathogenesis is a complex process that is influenced by various host biological and behavioral factors, and by properties of the infecting pathogen, including virulence factors (VFs). The consequences of complex host–pathogen interactions ultimately determine whether uropathogens are successful in colonization of uroepithelium or eliminated. Factors known to be important in the pathogenesis of UTI are host defense mechanism and bacterial virulence factors.

Uncomplicated urinary tract infections (UTIs) begin when : Uropathogens that reside in the gut contaminate the periurethral area and are able to colonize the urethra. Subsequent migration to the bladder and expression of pili and adhesins results in colonization and invasion of the superficial umbrella cells Host inflammatory responses, including neutrophil infiltration begin to clear extracellular bacteria. Some bacteria evade the immune system, either through host cell invasion or through morphological changes that result in resistance to neutrophils, These bacteria undergo multiplication and biofilm formation These bacteria produce toxins and proteases that induce host cell damage, releasing essential nutrients that promote bacterial survival and ascension to the kidneys. Kidney colonization results in bacterial toxin production and host tissue damage. If left untreated, UTIs can ultimately progress to bacteraemia if the pathogen crosses the tubular epithelial barrier in the kidneys..

Diagnosis of clinically significant UTI requires both clinical assessment of symptoms and bacteriological evaluation. Urine culture for bacteriuria - ≥ 10 5 CFU/ml in asymptomatic patients - ≤ 10 2 CFU/ml in symptomatic patients. Sensitivity testing of a freshly voided MSSU (mid stream specimen of urine) In patients with indwelling urinary catheters, a catheter specimen of urine (CSU) is taken and evaluated..

It consists of Elimination of infection – Antimicrobial therapy i.e Nitrofurantoin ( urospecific and preferred), quinolones, etc. Early relief of symptoms – By urospecific spasmolytics i.e Flavoxate (most commonly used).

Agent Dosage Adverse Effects and Cautions Fluoroquinolones 200-400 mg/day BID (depending upon the type of fluoroquinolone used) Drowsiness, avoid antacids containing magnesium, high emerging resistance so risk of treatment failure. Pregnancy category C drug ( There is a chance of fetal harm if the drug is administered during pregnancy. Thus should be avoided) Trimethoprim- sulphamethoxazole 1 double-strength tablet twice a day for 5-7 days Nausea; rash; High resistance so risk of treatment failure Pregnancy category C drug (There is a chance of fetal harm if the drug is administered during pregnancy. Thus should be avoided).

Agent Normal Dosage Adverse Effects and Cautions Nitrofurantoin (MARTIFUR) Standard dose- 50 –100mg QID for 7 days Prophylactic dose – 100mg Once daily at night for 6-12 months May cause nausea and vomiting if not taken along with meals. Avoid antacid containing magnesium. Pregnancy category B* drug ( studies in pregnant women have not shown risk of fetal abnormalities) . Avoid use 38-42 weeks of gestation. Is contraindicated in neonates below 1 month. Nitrofurantoin (MARTIFUR MR) Standard dose- 100mg BD for 7 days Prophylaxis- 100mg OD at night for 6-12 months Modified release pattern leads to superior GI tolerability. Avoid antacid containing magnesium. Pregnancy category B* drug ( studies in pregnant women have not shown risk of fetal abnormalities) . Avoid use 38-42 weeks of gestation. Is contraindicated in neonates below 1 month..

Resistance to this medication has become widespread and detected in up to 20-25% of pathogens cultured from patients with UTI. Can cause bloody or watery diarrhea Can not be given to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or severe asthma May worsen thyroid disorders May cause hypoglycemia (in both diabetics and non-diabetics) Pregnancy category C drug ( There is a chance of fetal harm if the drug is administered during pregnancy. Thus should be avoided).

Quinolones are used indiscriminately in many indications and therefore, resistance is reported to be 5 – 25% to E. Coli . Pregnancy category C drug (There is a chance of fetal harm if the drug is administered during pregnancy. Thus should be avoided) Prior exposure to fluoroquinolones and recurrent UTIs are risk factors for community acquired UTIs due to Ciprofloxacin-resistant E. Coli . They are associated with the risk of tendon rupture in pediatric patients as well as adults. Quinolones are often misused in hospitals and outpatient settings..

U.S. FOOD & DRUG Fluoroquinolone Antibiotics: FDA Requires Labeling Changes Due to Low Blood Sugar Levels and Mental Health Side Effects.

Well absorbed orally Rapidly excreted in the urine so that drug levels in urine are high while serum levels are minimal Is active against more than 80% quinolone-resistant uro -pathogens Is bacteriostatic at values near MIC while bactericidal at higher urine concentrations Does not significantly affect bowel flora . Have high sensitivity to E.coli (resistance rate was only 1-2%) and also towards multi drug resistant organisms Recommended as the first choice therapy for uncomplicated cystitis and pyelonephritis in women.

Nitrofurantoin Pharmacological Profile ( Multimodal action).

Cont …. Unique Multiple Mode of action of NITROFURANTOIN: The unique multiple mode of action on various sites explain the lack of bacterial resistance to Nitrofurantoin ..

Antibiotics E.Coli (%) Coag. Neg. Staph. (%) Klebsiella (%) Proteus (%) S.Aureus (%) Nitrofurantoin 90.7 90.4 78 -- 88.9 TMP/SMX 59.3 50 56.1 34.6 44.4 Ampicillin 36.4 40.4 24.4 26.9 33.3 Norfloxacin 64.1 62.8 68.3 73.1 66.7 Ciprofloxacin 64.9 62.8 65.9 61.5 66.7 Gentamicin 72.3 79.8 58.5 65.4 77.8 Amikacin 89 62.8 78 88.5 66.7 Cefotaxime 75.7 75.5 58.5 80.5 77.8.

Sensitivity of different antibiotics to bacteria causing UTI.

Nitrofurantoin should be Empiric treatment for urinary tract infections, (when culture results are awaited) The Nitrofurantoin demonstrated better activity against E. coli isolates probably Due to low resistance rate to Nitrofurantoin , this drug can be a good choice for UTI treatment in pregnancies In children cystitis can be treated with nitrofurantoin or amoxycillin for duration of 5-7 days.

Most uropathogens still display good sensitivity to nitrofurantoin while resistance is increasing to fluoroquinolones , beta-lactams, and trimethoprim- sulfamethoxazole . First-line treatments for UTI include nitrofurantoin , fosfomycin , and trimethoprim- sulfamethoxazole (when resistance levels are <20%). In pregnancy, nitrofurantoin , β -lactams , fosfomycin , and trimethoprim- sulfamethoxazole can be appropriate treatments..

Of late, several major guidelines have declared nitrofurantoin as the first-line therapy for treatment of uncomplicated lower urinary tract infections. Growing resistance to newer antibiotics coinciding with rising prevalence of extended-spectrum beta-lactamase (ESBL) producing bacteria has led to a resurgence in use of nitrofurantoin . Nitrofurantoin retained excellent sensitivity to the most common uropathogens across India.

Guidelines Recommendations of Nitrofurantoin in UTI.

Nitrofurantoin should be Empiric treatment for urinary tract infections, (when culture results are awaited) In children cystitis can be treated with nitrofurantoin or amoxycillin for duration of 5-7 days Children with a Vesicoureteric reflux may be treated with antibiotic prophylaxis as a single nighttime dose. Co- trimoxazole or Nitrofurantoin is preferred in children beyond three months of age Standard doses of antimicrobial agents: 1. Nitrofurantoin 100mg BD for 5 days 2. Nitrofurantoin 1.25-1.75 mg/kg oral 6 hourly (Dose in children).

Recommended fosfomycin trometamol , pivmecillinam or nitrofurantoin as first-line treatment for uncomplicated cystitis in women Standar dose: Nitrofurantoin monohydrate/ macrocrystals 100 mg twice daily for 5 days In prevention of recurrent UTI, nitrofurantoin 50 mg or 100 mg once daily, fosfomycin trometamol 3 g every ten days were recommended..

E. coli isolates continue to demonstrate high in vitro susceptibility to nitrofurantoin , fosfomycin , and mecillinam These antimicrobials have minimal effects on the normal fecal microbiota Clinicians should use first-line therapy (i.e., nitrofurantoin , TMP-SMX, fosfomycin ) dependent on the local antibiogram for the treatment of symptomatic UTIs in women.

Nice Guideline: Nitrofurantoin (if eGFR ≥45 ml/minute) 100 mg modified-release twice a day for 3 days are recommended in women with UTI In pregnant women, Nitrofurantoin (if eGFR ≥45 ml/minute) 100 mg modified-release twice a day for 7 days are recommended.

Ensure history is appropriate for recurrent UTI Confirm bacteriological evidence of infection Exclude underlying anatomical or functional abnormality using appropriate imaging and endoscopic evaluation Advise on prophylactic lifestyle changes Consider a prophylactic antibiotic regimen preferably Nitrofurantoin Consider alternative strategies.

Sexually active women should be advised to void after sexual intercourse and avoid the use of spermicidally lubricated contraceptives where possible. Women with recurrent UTI should be encouraged to take shower after sexual intercourse to reduce colonisation by faecal and perineal organisms. Postmenopausal women can be prescribed estrogens. This will help shift the vaginal flora from potentially pathogenic enterobacteriaceae to protective lactobacilli . Adequate daily fluid intake will encourage mechanical washout of bacteria from the bladder and make colonisation less likely..

Minimal Side effects Convenient/better Compliance Least Resistance Minimal effective dose To minimize frequency and severity of recurrent infection.

Martifur & Martifur MR (50,100 mg) An Ideal Antimicrobial Agent for UTI.

Adults Martifur MR 100 mg – 1 BD for 7-10 days Martifur 100 mg – 1 QID for 7-10 days Children (> 1 month) Martifur 100 mg - 5-7 mg/kg body weight in divided dosage for 7 days Martifur MR 50 mg [6-12 yrs (>20 kgs )] – 1 tab BID.

Adults Martifur MR 50 mg – 1 OD at bedtime (up to 12 mth ) Martifur 100 mg – 50-100 mg OD at bedtime ( upto 12 mth ) Children (> 1 month) Martifur 100 mg – 1-2 mg/kg/body weight OD bedtime Martifur MR 50 mg [6-12 yrs (>20 kgs )]– 1 tab OD at bedtime Short-time Surgical Prophylaxis Martifur 100 mg – ½ tab 4 times a day for the duration of procedure and 3 days thereafter..

Twice daily dosing offers improved patient compliance The new formulation of modified released Nitrofurantoin has improved GI tolerance Achieves required urinary level rapidly and then maintains the desired urinary concentration for longer time until next dosage. This explains the superior GI tolerability (no excessive drug release) and BID dosage (lasts for 12 hrs.) Release pattern is approved by US FDA..

A unique uro -specific spasmolytic that acts on the detrusor muscles of urinary bladder Inhibits PDE enzyme which results in increase in conc. of cAMP , thus decreases calcium conc. within the cell and causes detrusor muscle relaxation. Blocks the action of slow calcium ions channel. Also has local analgesic and anaesthetic activity equivalent to lidocaine ..

URnSPAS. Flavoxate which takes care of the symptoms of UTI.

Uro -specific Spasmolytic that Ameliorates the Symptoms of UTI After initiation of antibiotics for UTI, it takes time before irritative symptoms get relieved. It leads to patients having bothersome irritative symptoms that persist for few days. Thus, Urispas plays an important role if administered early. Urispas relieves irritative urinary symptoms like nocturia , dysuria, suprapubic pain, irritation, burning micturition, etc through its local analgesic and anaesthetic action. It brings prompt relief from irritating urinary symptoms of UTI even before antibiotic action starts as it starts acting within 1 st hour of administration..

It can be co-prescribed with Nitrofurantoin or with any antibiotics in patients with UTI. Flavoxate has minimal side effects and negligible drug-drug interaction. Pregnancy category B drug (studies in pregnant women have not shown risk of fetal abnormalities).

lo1. Healthcare-associated urinary tract infections account for approximately 40% of all infections in hospital Enterobacteriaceae represent the most common pathogens associated with hospital-wide catheter-related UTI followed by Candida species, Enterococci , and P. aeruginosa In 2006 and 2007, 21.2% of K. pneumoniae and 5.5% of E coli isolates from patients with CAUTIs were resistant to ceftriaxone or ceftazidime 15-25% hospitalized patients are catheterised.

Patient-Level Risk Factors Female sex Age >50 Severe underlying illness Diabetes mellitus Serum creatinine >2 mg/ dL Modifiable Risk Factors Duration of catheterization Non-adherence to appropriate catheter care Catheter insertion after 6th day of hospitalization Catheter insertion outside operating room.

It consists of : Prophylactic therapy with antimicrobial and flavoxate Elimination of infection – Antimicrobial (Nitrofurantoin) Relief of symptoms – By urinary antispasmodics ( Flavoxate ).

Flavoxate is a urinary antispasmodic that ameliorates the symptoms of CAUTI in following ways: Relieves irritative urinary symptoms, like nocturia , dysuria, and pain through spasmolytic action* Relieves burning sensation by exerting a local anesthetic and analgesic action*.

Improves the drainage capacity of the bladder by relaxing its muscle so the urine flows through the catheter and not along its sides. This decreases the chances of bacterial colonization.