Urinary Tract Infection Lecture Notes PDF

College of Pharmacy ‫صيدلة سريرية‬ Fourth year. Clinical Pharmacy ‫ ضياء جبار‬.‫د‬ Urinary Tract Infection (UTI) Definitions (1-5 ) 1-Urinary tract infection (UTI): is defined as the presence of micro...

College of Pharmacy ‫صيدلة سريرية‬ Fourth year. Clinical Pharmacy ‫ ضياء جبار‬.‫د‬ Urinary Tract Infection (UTI) Definitions (1-5 ) 1-Urinary tract infection (UTI): is defined as the presence of microorganisms in the urine that is not due to contamination. 2-Lower UTI: includes Cystitis (Bladder), Urethritis (urethra), Prostatitis (prostate gland), and Epididymitis. 3-Upper UTI: involves the kidney and referred to as Pyelonephritis. 4-Uncomplicated UTI: refers to cystitis and pyelonephritis that occurs in patients who have an anatomically and functionally normal urinary tract (i.e. Not associated with structural or neurological abnormalities that interfere with normal flow of urine or urination mechanism). 5-Complicated UTI: refers to UTIs that occur in patients who have an associated risk for infection in the urinary tract (stone, congenital abnormalities, obstruction, prostate hypertrophy,……….or neurological deficit that interferes with normal flow of urine). 6-Recurrent UTIs: three or more UTIs occurring within 1 year. These infections are due to reinfection or to relapse. 7-Reinfections are caused by a different organism and account for the majority of recurrent UTIs. 8-Relapse represents the development of repeated infections caused by the same initial organism. 9-Symptomatic abacteriuria (or acute urethral syndrome) is a condition in which patients present with symptoms of a lower UTI but have insignificant amounts of bacteria in the urine (the urine culture reveals less than 105 bacteria/mL of urine). 10-Asymptomatic bacteriuria: is the finding of significant amounts of bacteria in the urine in the absence of urinary symptoms. 1 Epidemiology 1-Urinary tract infections are the most common bacterial infections in humans. 2-UTI is predominantly a disease of females. The overall likelihood of developing a UTI is approximately 30 times higher in women than in men (6). 3- After the age of 50, men are affected because of prostate problems (7). Pathogenesis : There are two possible routes by which organism can reach the urinary tract: A-Hematogenous pathway B-Ascending pathway A-Hematogenous Pathway : The hematogenous route occurs through the seeding of the urinary tract with pathogens carried by the blood supply (8). B-Ascending Pathway In the majority of UTIs, bacteria establish infection by ascending from the urethra to the bladder (10). Figure 2 Pathogenesis of UTI (Fig. 2). 1-The female urethra is relatively short and allows bacteria easy access to the bladder. In contrast, males are partly protected because the urethra is longer [and antimicrobial substances are secreted by the prostate] (6). 2-In female the urethra is near the perirectal area (1) [that is colonized by pathogens (mostly E.coli) ---------these M.O. then ascend into urethra---------then into the bladder (9). Once in the bladder, the M.O. multiple quickly and can ascend the ureter to the kidney (1). Furthermore, sexual intercourse appears to be important in forcing the bacteria into female bladder (the association of cystitis in women with intercourse called honeymoon cystitis) (9). Any structural abnormality leading to the obstruction of urinary low increases the likelihood of infection. Such abnormalities include congenital anomalies of the ureter or urethra, renal stones and, in men, enlargement of the prostate (9). Risk Factors and Host defense mechanisms The ability to urinate is a normal defense mechanism that allows the bladder to wash away harmful pathogens. Any breakdown in these mechanisms can increase the likelihood of a UTI (4). (See table 1) 2  Table 1 Host defense mechanisms Host defense mechanisms 1-Urine Antiseptic, wash away bacteria 2-Ureters Design to prevent urine from backing up to the kidney 3-Immune Defense and bactericidal substances present in the mucous lining of system the bladder 4-Lactobacilli -help to maintain low PH, which is hostile to bacteria -produce H2O2, which eliminate bacteria and reduce the ability of E.coli to adhere to vaginal cells. The predisposing factors are: (7) 1. Age 2. Female sex 3. Diabetes mellitus 4. Pregnancy 5. Immunosuppression 6. Urinary tract instrumentation (e.g. catheterization) 7. Urinary tract obstruction 9. Neurologic dysfunction Notes 1-Ureteral peristalsis is decreased by pregnancy [allow bacteria easier access to the kidneys during the later stages of pregnancy] (3). 2-Decreased neutrophil function, and glucosuria, which are often associated with diabetes, increase the risk of UTI (3) [Women with diabetes have a two- to threefold higher rate of UTI than women without diabetes] (10). Pathogens 1- The most common cause of uncomplicated UTIs is Escherichia coli, which accounts for 80% to 90% of community-acquired infections) (1). Staphylococcus saprophyticus for 5–15% ; and Klebsiella species, Proteus species, and other organisms for 5–10% (10). 2-In complicated UTI, E. coli remains the predominant organism, but other aerobic gram- negative rods, such as Klebsiella species, Proteus species, and Pseudomonas aeruginosa, also are frequently isolated (10). 3-Complicated infections are also more often polymicrobial in etiology (6). Clinical presentation The typical signs and symptoms of upper and lower tract infections are listed in table 2 (4). 3 Diagnosing UTIs 1-Diagnosis of UTI based on clinical findings alone is accurate in only approximately 70% of patients (6). 2-In most outpatient settings, diagnosis of a UTI is made by urinalysis. This test is a reliable method that evaluates the urine for pyuria (the presence of pus or WBC in the urine), hematuria, and bacteria (4). The urine specimen collected after initiation of the urine stream (midstream) to avoid contamination (6). 3-Culture: The gold-standard criterion for the diagnosis of UTI is the urine culture (6). The next step is to determine the susceptibility of the organism to select an appropriate agent for treatment (1). Note: 1-Bacterial susceptibility to different antimicrobial drugs is usually determined by using drug concentration that correlate with achievable serum concentrations of those drugs (6). 2-However, drugs useful in the treatment of UTI are excreted primarily by the kidney, and urine concentrations of these drugs may be 20 to 100 times greater than serum concentrations (6). 3-Therefore, infections caused by organisms that are only intermediately susceptible, or even “resistant” to the tested concentration of antibacterial drug, might still be effectively treated with the high concentration of drug achieved in the urine (6). Desired outcome (goal of treatment) (1): 1-Treat the infection and eradicate the invading M.O. 2-Prevent recurrence of infection. Treatment 1-Antimicrobial therapy is the cornerstone of treatment in UTIs (2). 2-Other products used in the management of UTI include analgesics like Phenazopyridine (Uresept ®)which is an analgesic used for the short-term management of pain symptoms (4). [It is ineffective in the actual eradication of true UTI (6). Urinary analgesics also may mask signs and symptoms of UTIs not responding to antimicrobial therapy] (1) 1-Cystitis: A-Acute Uncomplicated Cystitis Uncomplicated cystitis represents the most common of UTIs. These are frequently managed in the outpatient setting, and occur in women of childbearing age. E. coli is the most frequent (85%) of causal organisms (2). Short-course therapy (3-day therapy) with Antibiotic [e.g. TMP-SMX or a fluoroquinolone (e.g., ciprofloxacin, or levofloxacin, but not moxifloxacin ………)] or a 5-day course of nitrofurantoin, is effective (See table 3) (1). Which agent to choose empirically partly hinges on known resistance rates in the geographic Region (8). 4 B-Acute complicated Cystitis: These are usually treated with suitable antibiotic for 7- 10 days (8) (See table 3) (1) Table 3: Example of the common Antibiotics used in the Treatment of lower UTI Uncomplicated Lower tract Infections Complicated Lower tract Infections Antibiotic Dose Duration Dose Duration TMP-SMX 2 tablet BID 3 days 2 tablet BID 7-10 days Ciprofloxacin 250 mg BID 3 days 250- 500 mg BID 7-10 days Amoxicillin- 500 mg (as 5-7 days 500 mg (as amoxicillin) 7-10 days clavulanate amoxicillin) TID TID Nitrofurantoin 100 mg BID 5 days Levofloxacin 250 mg once daily 3 days 750 once daily 5 days 250 once daily 10 days Fosfomycin 3 gm single dose 1 day 2-Acute Pyelonephritis: A-Mild cases (as low-grade fever without nausea or vomiting) (8). This patient may be treated with an oral Antibiotics (usually for 2 weeks but see levofloxacin) as an outpatient as shown in table 4 (1). Table-4 :Outpatient Antimicrobial Therapy for Acute pyelonephritis Antibiotic Dose Duration (TMP-SMX) 2 tablet BID 14 days Ciprofloxacin 500 mg BID 14 days Amoxicillin-clavulanate 500 mg TID 14 days Levofloxacin 750 once daily 5 days 250 mg once daily 10 days B-In the seriously ill patient (infection is severe enough to cause vomiting, decreased food intake, and dehydration) (8). This should be hospitalized and intravenous drugs administered initially before being switched to oral therapy. Patients with pyelonephritis are traditionally given 14 days of therapy (8). The traditional initial therapy has included: A-An extended-spectrum cephalosporin (e.g. ceftriaxone)( with or without an aminoglycoside). Or: B- An I.V. fluoroquinolone (e.g. ciprofloxacin) Or : C- An I.V aminoglycoside (e.g. gentamicin) with or without ampicillin (1). Patients should be treated with parenteral antibiotics until fluids can be taken orally and the patient is symptomatically improved and afebrile for 24 to 48 hours. This should be followed with a course of oral antibiotics for a total duration of antimicrobial therapy of 14 days (6). 5 3-Asymptomatic Bacteriuria: i-The management of asymptomatic bacteriuria depends on the age of the patient and, if female, whether she is pregnant (1). ii-In children, treatment should consist of conventional courses of therapy, as described for symptomatic infections (1). iii-In the nonpregnant female, therapy is controversial; however, it appears that treatment has little effect on the natural course of infections (1). iv-Asymptomatic bacteriuria in older persons does not seem to have any harmful effects, and there is no evidence that treating it is beneficial, therefore, routine treatment of asymptomatic bacteriuria in older persons is not indicated (9). Treatment is recommended for asymptomatic bacteriuria in pregnancy (see later) Prophylaxis for UTI 1-In patient with infrequent infections (i.e. fewer than three infections per year), each episode should be treated a separated infection (1). 2- Surgically correctable anatomic abnormalities that predispose the patient to recurrent infections (e.g., obstruction, stones) should be ruled out (6). 3-Before chronic antimicrobial suppressive therapy is initiated, active infections must be completely eradicated with a full course of appropriate antibiotic therapy. The low doses of antimicrobials used for chronic prophylaxis suppress bacterial growth but do not eliminate active infection (6). 4-In women who associate their recurrent UTIs with sexual intercourse, voiding after intercourse may help prevent infection. Also a self-administered postcoital prophylaxis with single dose TMP-SMX is effective in these patients (1). 5-In patient with frequent infections (three or more UTIs in 1 year) that are not related to sexual activity (7), long term –prophylactic antimicrobial therapy may be used (1). [The number of symptomatic episodes per year is not absolute; decisions should take the patient's preferences into account] (10). 6-Therapy is generally given for 6 months, with urine culture followed periodically (1). [Typically, a prophylactic regimen is prescribed for 6 months and then discontinued, at which point the rate of recurrent UTI often returns to baseline. If bothersome infections recur, the prophylactic program can be reinstituted for a longer period] (10). 7-These antibiotics may be used use daily or 3 times/week (6, 7).(table 5). 6  Table 5: Antimicrobial Agents Commonly Used for Chronic Prophylaxis Against Recurrent UTIs (6) Agent Adult dose Nitrofurantoin 50–100 mg nightly Trimethoprim 100 mg nightly TMP-SMX 0.5–1 tablet nightly Or 3/wk Norfloxacin 200 mg/d Cephalexin 125–250 mg/d UTI in pregnancy: In women with bacteriuria whether symptomatic or asymptomatic there is a 30-40% chance of developing acute Pyelonephritis during pregnancy , and it also may increase the incidence of prematurity and low birth weight babies. Therefore, all pregnant women with bacteriuria should be treated with a 7 days course of an antibiotic safe in pregnancy (cephalexin, amoxicillin, and nitrofurantoin) with regular follow up during pregnancy (9). UTIs in Men If UTI occurs in men, then an abnormality (structural or functional) should be suspected and therefore treated as a probable complicated infection until proven otherwise. For this reason, men typically will receive 2 weeks of therapy, and in situations of failure may be treated up to 6 weeks (8). References 1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, 10th Edition. Copyright 2017. 2-Anita D. Patel, Management of Urinary Tract Infections in Women. US Pharm. 2007;32(9):26-33. 3-David J Quan, Richard A Helms. Textbook of Therapeutics: Drug and Disease Management. 8th edition. 4-Karla T. Foster, and Leisa Marshall. Management of Urinary Tract Infections An Overview of Treatment Considerations. U.S. Pharmacist. 2004;6:60-71 5-Anthony P. Buonanno. Review of Urinary Tract Infection. US Pharm. 2006;6:HS-26-HS- 36. 6-Mary Anne koda-kimble (ed.), Applied Therapeutics: The clinical use of drugs, 11th ed., 2018. 7-ACCP Updates in Therapeutics®. The Pharmacotherapy Preparatory Review and Recertification Course. 2018. 8-Marie A. Chisholm-Burns, Barbara G. Wells. Pharmacotherapy principles and practice. 4th edition.2016. 9-Roger Walker. Clinical pharmacy and Therapeutic. 6th edition.2019. 10-Dan L. Longo, et al, eds. Harrison's Principles of Internal Medicine, 20th Edition. Copyright © 2018. 7  College of Pharmacy Fourth Year. Clinical Pharmacy Selective Topics Benign prostatic hyperplasia (BPH) The prostate is a gland surrounds the 1- urethra below the bladder. It secretes fluid that is expelled with the a seminal fluid and improves the motility, prolongs the survival of sperm. It also has a bactericidal effect (1). BPH is defined as benign 2- enlargement of the prostate gland. Prevalence is estimated at one in four men over the age of 40 years and incidence increases markedly with age (1). The cause of BPH is unknown but 3- probably involves hormonal changes associated with aging (1). Clinical Manifestations In BPH, the enlarged prostate compresses the urethra, thus obstructing urine outflow (1). Symptoms of BPH are classified as obstructive or irritative. A-Obstructive symptoms: result from failure of the urinary bladder to empty urine (2) due to urethral compression from prostate gland hyperplasia (3). It include: 1-Hesitancy: hesitancy is difficulty in initiating urination. (because the bladder detrusor muscle taking a longer time to generate pressure to overcome urethral resistance) (3). 2-Decrease in urinary force. 3-Occasional midstream stoppage. Urinary stream intermittency is caused by the inability of the bladder detrusor muscle to maintain the pressure until the end of voiding. 4-Postvoiding dribbling. 5-Feeling of incomplete bladder emptying (3). B-Irritative symptoms: result from the failure of the urinary bladder to store urine (2). The patient complains of : 1-Nocturia approximately four to five times a night. 2-Daytime urinary frequency of eight to ten times a day. Incomplete emptying of the bladder results in shorter intervals between voiding, explaining the complaint of frequency (3). The symptoms of urinary frequency are more pronounced at night because cortical inhibitions are lessened and bladder sphincter tone is more relaxed during sleep (3). Treatment Tamsulosin, an alpha1-adrenergic blocker, was reclassified from POM to OTC in March 2010, for the treatment functional symptoms of BPH in men between the ages of 45 and 75 years (1). This represents the first UK OTC medicine to treat a chronic condition. This reclassification was made due to the fact that the majority of men with BPH do not consult their doctors when they experiencing BPH symptoms (4). A-Mode of action: In the prostate, bladder neck and urethra, the alpha-1A receptor is predominant. Tamsulosin is selective drug for alpha-1A receptors, so it relax smooth muscle to improve outflow and symptoms of BPH (1). B-Adverse reactions: Dizziness is the most commonly reported side effect (about 1.3% of patients) (4). C-Conditions for supply of tamsulosin without prescription 1-Tamsulosin is available as capsules containing tamsulosin hydrochloride 0.4 mg; the dose is one capsule daily (strength and dose are the same as the POM version) (1). 2-On initial request from a man for supply of the product or advice on lower urinary tract symptoms, the pharmacist assesses the severity of symptoms (1, 4). Symptoms-check questionnaire This incorporates a quality-of-life score and the International Prostate Symptom Score. Low scores on both scales suggest mild symptoms and a good quality of life, and tamsulosin would not be appropriate (4). (Figure 11-1) 3-If treatment is deemed appropriate an initial 2-week supply is made, at the end of which the situation is reviewed by the pharmacist and, if symptoms have improved and the drug is well tolerated, a further supply for four weeks is made. If his symptoms are not relieved, referral is advised (1). 4-After six weeks, tamsulosin will only be supplied if a doctor has carried out a clinical assessment of the patient to confirm that pharmacy supply continues to be suitable (1). Conditions that required referral (1). Referral must be made to a physician if a man reports any of the following: * Aged less than 45 or more than 75 years * Any age if urinary symptoms are associated with any of the following: (pain on urination, blood in urine, cloudy urine, fever and excessive thirst) * Currently receiving prescription medications for BPH * Currently receiving alpha1 blockers for the treatment of hypertension * History of orthostatic hypotension, heart, liver or kidney disease * Prostate surgery in the medical history * planned eye surgery for cataract.(Tamsulosin can cause profound loss of tone of the dilator muscle of the iris, increasing the technical difficulty of cataract surgery for patients on the drug). Figure 11-1: Quality-of-life score and the International Prostate Symptom Score