RECURRENT UTI (RUTI) IN FEMALES BY PROFESSOR DR. Shereen Ragy
Epidemiology of Recurrent UTI in females (1) Urinary tract infections (UTIs) are the most common bacterial infections Additionally, UTI is the most common cause of nosocomial infection. Women make up a significant proportion of UTI sufferers with annual incidence of 12.1%. Peak incidence of UTI in women occurs between the ages of 20 to 24 years. 20-30% of women who have a UTI will have a Recurrent UTI. McLaughlin et al., 2004
Epidemiology of Recurrent UTI in females (2) Recurrent UTIs result in significant discomfort for women and have a high impact on ambulatory health care costs as a result of outpatient visits, diagnostic tests and prescriptions. RUTI is more common in post-menopausal females due to residual urine after voiding, which is often associated with bladder or uterine prolapse. In addition, the lack of estrogen causes marked changes in the vaginal microflora, including a loss of lactobacilli and increased colonization by E. coli .
Definition of Recurrent UTI in females● UTI is diagnosed in women by presence of at least 100,000 colony forming units (cfu)/mL in a pure culture of voided clean-catch urine.● Recurrent UTIs are caused by either re-emergence of bacteria from a site within the urinary tract (bacterial persistence) or new infections from bacteria outside the urinary tract (reinfection). Recurrent urinary tract infection (RUTI) is defined as three episodes of culture-confirmed UTI in the last 12 months or two episodes in the last 6 months. EAU Guidelines 2009
Pathogenesis of UTI The interaction between bacterial virulence and host defense factors can ultimately result in UTI. More virulent bacteria are necessary to infect healthy hosts with a normal urinary tract, whereas less virulent bacteria may easily infect compromised hosts. The cause of UTIs in women is usually colonization of the vagina and then the urethra with bacteria from the intestinal tract. Anderson et al., 2003
1- Bacterial Virulence in pathogenesis of UTI The initial step in pathogenesis of UTI is bacterial adherence to the urothelium by pilli. Pili are ﬁlamentous adhesive organelles produced by all UPEC (uropathogenic strains of Escherichia coli ) that present signiﬁcant virulence factors . Bacterial colonization follows and causes a host inﬂammatory response, which includes neutrophil inﬂux followed by apoptosis and exfoliation of the bladder’s epithelial cells in an effort to rid the bladder of bacteria. Anderson et al., 2003
Bacterial adherenceAdhesins on pili (fimbriae) attach to specific epithelial cell receptors (Wein et al., 2007)
2- Host Risk Factors in pathogenesis of UTI Host factors include genetic, anatomic, functional, and behavioral factors that affect the host’s susceptibility to uropathogens and its ability to overcome them. Host Risk Factors in pathogenesis of UTI Anderson et al., 2003
Risk factors of RUTI differ in pre- and post- menopausal In sexually active pre-menopausal risk factors are: frequency of sexual intercourse. spermicide use. age of first UTI (less than 15 years of age indicates a greater risk of RUTI). history of UTI in the mother (due to genetic factors and/or long-term environmental exposures). In post-menopausal risk factors are: vesical prolapse. incontinence. post-voiding residual urine. Raz et al., 2000
Management of recurrent UTI (Wein et al., 2007)
Initial Evaluation of females with RUTIs Most women with recurrent UTI’s do not have anatomic abnormalities and do not need X-rays. Assesment should include: History and physical examination that includes a pelvic examination. pelvic ultrasound for retained urine. Urine culture documenting that UTI is the cause of symptoms (typically, frequency, dysuria & hematuria). Howes DS, 2009
Specialized Evaluation of females with RUTIs Women with RUTI who should undergo further evaluation include women who also have: 1) Congenital abnormalities –either a CT scan or IVP should be done. 2) Prior pelvic surgery – a renal US should be done to check for kidney obstruction (hydronephrosis) caused by a ureter caught in scarring, a stitch or clip during prior surgery. cystoscopy to check the bladder for stitches which can form a nidus for stone or infection. (continued)
Specialized Evaluation of females with RUTIs (continued) 3) UTI’s with Klebsiella, Pseudomonas or Proteus bacteria – a KUB is done. These bacteria have urease splitting enzymes that alkalinize urine & may cause formation of struvite (infection) stones. 4) History of kidney stones – check non-contrast CT for stones, evidence of urinary obstruction. 5) Pyelonephritis – diagnosed by positive urine culture, back pain and high fever. Howes DS, 2009
Differential Diagnosis of Recurrent UTI Not all women with the symptoms of frequency, dysuria & hematuria have UTI. In the case of Recurrent UTI, especially with negative culture; a urological and gynaecological evaluation should be performed in order to exclude a bladder cancer, obstructive problems, detrusor failure, vaginal infections, genital infection, interstitial cystitis or neurological disease. Howes DS, 2009
Complications of Recurrent UTI Serious complications of recurrent UTI include the following: Acute papillary necrosis with potential ureteric obstruction. Overwhelming sepsis syndrome with septic shock due to loss of vasomotor tone, capillary leak, and impaired myocardial performance. Perinephric abscess. Howes DS, 2009
Treatment of recurrent UTI Primary treatment for recurrent UTI should be tailored according to the culture and senstivity results. Commonly used antimicrobials that act on gram negative uropathic organisms include: Trimethoprim (TMP) and Co-trimoxazole (TMP-SMX). Fluroquinolones (ciprofloxacin, enoxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin). Nitrofurantoin. Beta-lactams penicillins (amoxycillin, ampicillin-like compounds, cefadroxil, cefuroxime, cefpodoxime).● Duration of treatment of 7 to 10 days increases rate of eradication and minimize resistance to drugs. EAU Guidelines 2009
Doses of recommended drugs for treatment of RUTI EAU Guidelines 2009
Prevention of Recurrent UTI Approaches proposed for the prevention of RUTI, include: Non-pharmacological therapies. Local Estrogen for post-menopausal females. Antimicrobial prophylaxis therapy: given regularly or postcoital prophylaxis in sexually active women. Immunoactive prophylaxis.
I- Non-pharmacological prophylactic therapy Non-pharmacological therapy for prophylaxis against recurrent UTI has doubtful role & include: Adequate fluid intake. Voiding after sexual intercourse. Ingestion of cranberry juice. Eating yogurt (contain active lactobacillus cultures). Vaginal application of lactobacilli. Avoiding constipation. Osset et al., 2001
II- Prophylactic antimicrobial therapy Women with recurrent UTI’s may be treated with, Continous prophylactic antimicrobial therapy OR Post-coital antimicrobial therapy OR Self-start antimicrobial therapy.
A- Continous prophylactic antimicrobial therapy One effective approach for the management of recurrent UTI is the prevention of infection through the use of long-term, prophylactic antimicrobials taken on a regular basis at bedtime. With respect to antibiotic prophylaxis, it is not known which antibiotic schedule is best or the optimal duration of prophylaxis, the incidence of adverse events, or the recurrence of infections after stopped prophylaxis or treatment compliance. Albert et al., 2004
EAU Guidelines 2009 onAntimicrobial prophylaxis of RUTI in females EAU Guidelines 2009
Choice of antibiotic Trimethoprim, co-trimoxazole or nitrofurantoin can still be considered as the standard regimen. In cases of ‘breakthrough’ infection due to resistant pathogens, low doses of fluoroquinolones may also be used. During pregnancy, an oral first-generation cephalosporin is recommended.
B- Post-intercourse antimicrobial therapy Post-intercourse therapy: is an alternative prophylactic approach for women in whom episodes of infection are associated with sexual intercourse. The same antimicrobials can be used in the same doses as recommended for continuous prophylaxis. Self-start therapy: may be suitable for management in well-informed, young women, in whom the rate of recurrent episodes is not too common. This is, however, strictly speaking, not prophylaxis but early treatment. Gupta et al., 2001
C- Self-start antimicrobial therapy ‘‘Self-start’’ therapy had emerged in an effort to decrease overall antibiotic usage. It relies on the patient to make the clinical diagnosis of UTI, which is not difficult for these patients. It presumes past episodes had been confirmed to be infections by culture. Patients are given a prescription for an appropriate urinary antibiotic (nitrofurantoins, TMP-SMX or cephalexin), which they take for 2 or 3 days at the first symptom of infection. Wein et al., 2007
Efficacy & Side effects of Prophylactic therapy (1) Generally, the number of patients with recurrent UTIs decreased by eightfold after prophylaxis. The UTI episodes per patient-year is reduced by 95% during antimicrobial prophylaxis. However, Prophylaxis does not appear to modify the natural history of a recurrent UTI or exert a long- term effect on the baseline infection rate.
Efficacy & Side effects of Prophylactic therapy (2) When prophylactic therapy is discontinued, (even after extended periods), approximately 60% of women will become re-infected within 3-4 months. Side effects of prophylactic antimicrobials include vaginal and oral candidiasis and gastrointestinal symptoms. Howes DS, 2009
Recurrent UTI during pregnancy Women with bacteria in the urine during pregnancy should be placed on low dose prophylactic antibiotics until delivery (e.g, Keflex or amoxacillin) for prophylaxis. Other options for patients who are allergic to penicillins include nitrofurantoin or co-trimoxazole. Women with bacteria in their urine who do not have symptoms and who are not pregnant do not need to be treated with antibiotics.
Immuno-active prophylaxis (1) A- Oral administration (Uro-vaxom) Properties Uro-Vaxom is an extract of Escherichia coli, a germ responsible for the majority of urinary infections. It stimulates the immune system in order to increase the body’s natural defences against a wide spectrum of urinary pathogens. Uro-Vaxom prevents recurrent urinary tract infections, in particular cystitis. Effects Uro-Vaxom is an immunostimulating agent. In animals, a protective effect against experimental infections, a stimulation of macrophages, B-lymphocytes and immunocompetent cells in the Peyers patches, as well as an increase in IgA level in intestinal secretions have been reported. In humans, Uro-Vaxom stimulates T-lymphocytes, induces production of endogenous interferon and increases sIgA level in urine.
Immuno-active prophylaxis (2) Composition Active principle: 1 capsule contains: 6 mg of lyophilized bacterial lysates of E. coli. Mechanism of action
Immuno-active prophylaxis (3) Indications Immunotherapy. Prevention of recurrent lower urinary tract infections. Comedication in the treatment of acute urinary tract infections. Dosage and administration Preventive treatment and/or consolidation therapy: 1 capsule daily on an empty stomach, for 3 consecutive months. Treatment during acute episodes: 1 capsule daily on an empty stomach as comedication to conventional antimicrobial therapy, until disappearance of the symptoms but for at least 10 consecutive days. Shelf life Stored in its original package, Uro-Vaxom has a shelf life of 5 years.
Immuno-active prophylaxis (4) Adverseeffects The overall incidence of adverse effects in clinical trials lies around 4 %. Gastrointestinal troubles (diarrhea, nausea, abdominal pain), dermatologic reactions (pruritus, exanthema), as well as generalized problems (slight fever) are the most frequent complaints reported. Limitations for use Known hypersensitivity towards the constituents of Uro-Vaxom. The efficacy and safety of Uro-Vaxom have not been established in children below 4 years. Uro-Vaxom is presumed to be safe and unlikely to produce a sedative effect. Pregnancy and lactation Reproduction studies in animals have not demonstrated any risk to the fetus, but controlled studies in pregnant or breast-feeding women are not available.
Immuno-active prophylaxis (5) B- Injectable administration Immunoactive prophylaxis is also available as intramuscular and intravaginal immunization with heat-killed uropathogenic bacteria. EAU Guidelines 2009
Inpatient Care for RUTI The necessity for admission is based on host factors, age, risk of complicated infection, and likelihood of morbidity with failed outpatient treatment.I- All patients with complicated UTI including: Structural abnormalities (eg, calculi, tract anomalies, indwelling catheter, obstruction). Metabolic disease (eg, diabetes, renal insufficiency) Impaired host defenses (eg, HIV, current chemotherapy, underlying active cancer). Howes DS, 2009
Inpatient Care for RUTI (continued)II- Some patients with uncomplicated pyelonephritis also should be admitted: Patients unable to maintain adequate oral hydration or have evidence of vasomotor instability or unresponding fever despite antipyretic therapy. Patients with debilitating pain or dehydration that cannot be corrected promptly in the outpatient. Patients with inadequate home care or resources to fill prescriptions or comply with the medical regimen.
Take home message Recurrent UTIs are a major issue for many women because they are common, costly, and cause considerable morbidity. Patients with Recurrent UTI should be properly investigated by lab and radiological techniques to exclude complicated causes or gynecological problems. Prophylactic therapy proved efficacy with decrease rate of recurrence, minimal side effects and drug resistance but without alteration of natural history of disease.