Evidence Based Management of Urinary Tract Infections

Evidence Based Management of Urinary Tract Infections Urinary tract infection (UTI) is the most common bacterial infection in humans. They account for more than 8.6 million physician visits (84% by women) and over 1 million hospital admissions in the United States each year. It remains one of the most common indications for prescribing antimicrobials to otherwise healthy women, 1 and up to 60% of women have at least one symptomatic UTI during their lifetime. Young, sexually active women aged between 18 24 years have the highest incidence of UTIs. About 25% of these women have spontaneous resolution of symptoms, and an equal number become infected. The prevalence of UTI in men is significantly lower than in women, occurring primarily in men with urologic structural abnormalities. 2 Pathogenesis In healthy woman, bacterial urinary infections usually spread to the urinary tract through an ascending route of fecal flora, from the fecal reservoir through the urethra into the bladder. Also, colonization of the mucosa of the vaginal introitus is an essential step in the pathogenesis of UTI. Once the introitus is colonized, sexual intercourse or urethral manipulation can force bacteria into the female bladder. 1 In pregnant woman, increased bladder volume and decreased bladder tone, contribute to increased urinary stasis and ureterovesical reflux. Additionally, up to 70 percent of pregnant women develop glycosuria, which encourages bacterial growth in the urine. Also increases in urinary progestins and estrogens may lead to a decreased ability of the lower urinary tract to resist invading bacteria. All these factors may contribute to the development of UTIs during pregnancy. 9 In patients with indwelling catheters, bacteria may enter the bladder through contamination of the tip during insertion with the flora of the distal urethra or from bacteria ascending outside or inside of the catheter. 10 Another possible route to the development of UTI is hematogenous dissemination secondary to organisms in the bloodstream (specifically pyelonephritis). Direct extension from adjacent organs via the lymphatic system, as in the case of retroperitoneal abscesses or severe bowel obstruction, has been proposed as another mechanism for UTI pathogenesis. 1 Urinary Pathogens Escherichia coli is the most common infecting organism in patients with UTI. It causes around 85% of medical newsletter I as a service to the medical profession I 09

Table 2.1 : Clinical Presentation of Cystitis, Pyelonephritis, and Urosepsis and Grading of Severity 11 Acronym Clinical diagnosis Clinical symptoms Grade of severity CY-1 Cystitis Dysuria, frequency, urgency and suprapubic pain 1 PN-2 Mild and moderate pyelonephritis Fever, flank pain, Costovertebral-angle tenderness with or without symptoms of CY 2 PN-3 Severe pyelonephritis As PN-2, but in addition, nausea and vomiting with or without symptoms of CY 3 US-4 Urosepsis (simple) Temperature >38 0 C or <36 0 C; heart rate >90 beats/min; respiratory rate >20 breaths/min or PaCO 2 <32mm Hg (<4.3kPa); WBC>12 000 cells/mm 3 or <4000 cells/mm 3 or 10% immature (band) forms; with or without symptoms of CY or PN 4 US-5 Severe urosepsis As US-4, but in addition, associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria, or an acute alteration of mental status. 5 US-6 Uroseptic shock As US-4 or US-5, but in addition, with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured. 6 CY = cystitis; PN = pyelonephritis; US = urosepsis; WBC = white blood cells. Adapted with permission from the European Association of Urology community-acquired infections and approximately 50% of nosocomial infections. In Bangladesh the major pathogens causing UTI are E.coli, Pseudomonas spp, Proteus spp, Klebsiella spp. etc. Recently one study in Bangladesh showed that women are the usual victims of the urinary pathogens and E.coli is the predominant causative organism which accounts for around 66% followed by Proteus spp (11%), Klebsiella spp (5%) and Pseudomonas spp (4%). 8 The vast majority of recurrent episodes of cystitis in women are thought to be reinfections. Two-thirds of such episodes involve the same strain of bacteria as uropathogenic strains can persist in the fecal flora for years after elimination from the urinary tract. 1 Classification of UTI based on Clinical Features In 2010 The European Section of Infection in Urology (ESIU) in collaboration with the International Consultation on Urological Diseases (ICUD) launched an initiative to improve the diagnostics and management of urologic diseases worldwide. As part of this initiative, a new classification of UTI based on clinical presentation was introduced. Symptomatic UTIs are classified as cystitis, pyelonephritis, and urosepsis, with urethritis and male accessory gland infections (prostatitis) considered separately, given the great diversity of clinical presentations. A severity scale was suggested considering that the urosepsis syndrome is the most severe form, and pyelonephritis is more severe than cystitis. The relevant clinical presentations when a UTI is suspected were grouped into five main categories (Table 2.1). 11 Diagnosis Urinary tract infection is assessed by urinalysis or microscopic examination of urine. It is most commonly done in laboratories in primary care for the diagnosis of UTI. Assessment for pyuria and bacteriuria is also performed with the use of commercially available dipsticks. However, results of the dipstick test provide little useful information when the history is strongly suggestive of urinary tract infection. A urine culture is performed to confirm the presence of bacteriuria and the antimicrobial susceptibility of the infecting uropathogen. This test is indicated in all women with suspected pyelonephritis but is not necessary for the diagnosis of cystitis, given the reliability of the patient s history in establishing the diagnosis and the delayed availability of culture results. 3 Management Urinary tract infections is a benign condition, with early resolution of symptoms observed in 25 to 42% of women 10 I medical newsletter I as a service to the medical profession

Patient Population Premenopausal women of any age Table 2.2 : Predisposing Risk Factors for UTI 2 Risk Factors Diabetes Diaphragm use, especially those with spermicide History of UTI or UTI during childhood Mother or female relatives with history of UTIs Sexual intercourse Postmenopausal and older adult women Men and women with structural abnormalities Estrogen deficiency Functional or mental impairment History of UTI before menopause Urinary catheterization Urinary incontinence Extrarenal obstruction associated with congenital anomalies of the ureter or urethra, calculi, extrinsic ureteral compression, or benign prostate hypertrophy Intrarenal obstruction associated with nephrocalcinosis, uric acid nephropathy, polycystic kidney disease, hypokalemic or analgesic nephropathy, renal lesions from sickle cell disease with only rare cases of progression to pyelonephritis. However, it is associated with considerable morbidity and antimicrobial drugs are routinely prescribed, the primary goal being the rapid resolution of symptoms. The choice of regimen has become more complicated as antimicrobial resistance among the uropathogenic strains of E. coli has increased worldwide. A study that was conducted in a private medical college of Dhaka in the year 2015 investigated in vitro susceptibility of E. coli strains that cause urinary tract infection and revealed rates of resistance to cefuroxime 82%, azithromycin 56%, cefixime 47%, cotrimoxazole 43%, ceftriaxone 41%, ciprofloxacin 38%, amoxicillin-clavulanic acid 31%, cefepime 30%, and low resistance which ranges from 9 to 1% included gentamycin 9%, meropenem 3%, nitrofurantoin 2% and amikacin 1%. 8 Moreover, UTI caused by extended-spectrum -lactamase producing ( -lactam resistant) strains of E. coli are increasingly being reported worldwide. 3 This increased emergence of bacterial resistance and the limited options of novel antimicrobial agents have necessitated the reintroduction of some old antimicrobial agents. One such drug is fosfomycin. 4 The antimicrobial agent fosfomycin was discovered in 1969, at a time when bacteria had not yet produced extended spectrum β lactamases (ESBL) or carbapenemases. Decades later, it is not uncommon for Gram negative organisms to be multidrug resistant and even pan resistant to available antibiotic regimens, leaving clinicians with few therapeutic alternatives. Because fosfomycin has been shown to retain activity against these virulent pathogens, there is renewed interest in its use as a therapeutic agent. The bactericidal action of fosfomycin occurs at an earlier step in cell wall synthesis than that of β lactam antibiotics. From an in vitro standpoint, fosfomycin generally has high activity against ESBL and carbapenemase producing Enterobacteriaceae. Multidrugresistant Pseudomonas aeruginosa susceptibility appears to be more dependent on the local antibiogram. Fosfomycin formulations have a large volume of distribution, penetrate biofilms, and concentrate in the urine. Both oral and intravenous fosfomycin formulations are effective for a wide range of Gram negative infections and disease severities. 5 A study of Czech Republic in the year 2014 investigated the susceptibility to fosfomycin of UTI pathogens, particularly Gram-negative rods including those producing β-lactamase. Three thousand two hundred and ninty five unique isolates of Gram-negative bacteria which had caused urinary tract infections were examined. The antibiotic susceptibility was measured by disk diffusion test. The most frequently tested bacterial isolates were Escherichia coli (51.3%, n = 1703), Klebsiella pneumoniae (19.4%, n = 643) and Proteus spp. (11.8%, n = 392). Among all isolates 29.0% (n = 963) were resistant to medical newsletter I as a service to the medical profession I 11

Severity Gradient of severity Symptoms No symptoms Local symptoms Dysuria, frequency, urgency, pain or bladder tenderness + General symptoms Fever, Flank pain Nausea, vomiting Systemic response SIRS Fever, shivering Circulatory failure Circulatory and organ failure Organ dysfunction Organ failure Diagnosis ABU CY-1 PN-2 PN-3 Febrile UTI US -4 US-5 US-6 Investigations Dipstick (MSU Culture + S as Required) Dipstick MSU Culture + S Renal ultrasound or IV Pyelogram/renal CT Dipstick MSU Culture + S and Blood culture Renal ultrasound and/or Renal and abdominal CT Uncomplicated UTI Complicated UTI Medical and Surgical Treatment NO* Empirical 3-5 d Empirical + directed 7-14 d Empirical + directed 7-14 d Consider combining 2 antibiotics Empirical + directed 10-14 d Combine 2 antibiotics Drainage/surgery as required Fig 2.1: Synoptic view of the classification of urinary tract infection as proposed by the European Association of Urology Section of Infection in Urology and including the basic principles of diagnosis and treatment. Reproduced with permission from the European Association of Urology CT= computed tomography; ABU=asymptomatic bacteriuria; CY = cystitis; IV = intravenous; MSU = midstream sample of urine; PN = pyelonephritis; US = urosepsis; UTI = urinary tract infection. * Two presently accepted exceptions: during pregnancy and prior to urological surgery. Table 2.3 : Overall in-vitro Susceptibility of the Common Gram-negative Rods to Commonly Used Per-oral Antibiotics 6 Fosfomycin Nitrofurantoin Ampicillin Cefuroxime Ciprofloxacin Co-trimoxazole E. coli (n=1703) 97.0 2.2 96.6 3.4 46.3 53.7 90.5 9.5 75.8 24.0 67.8 31.8 K. pneumoniae (n=643) 80.4 10.0 64.9 35.1 0.0 100.0 51.9 48.1 52.4 47.0 49.4 50.3 Proteus sp. (n=392) 78.3 16.6 38.8 61.2 81.6 18.4 68.9 28.8 51.3 47.7 Enterobacter sp. (n=261) 82.8 11.1 0.0 100.0 77.2 19.7 71.4 27.8 Citrobacter sp. (n=97) 100.0 0.0 0.0 100.0 90.7 9.3 76.3 23.7 E. coli- Escherichia coli, K. pneumoniae-klebsiella pneumoniae, Proteus sp.- Proteus species, Enterobacter sp.-enterobacter species, Citrobacter sp.- Citrobacter species. fluoroquinolones, 11.3% (n = 374) produced extended spectrum β-lactamase and 4.2% (n = 141) produced AmpC β-lactamase. The overall in vitro susceptibility was significantly higher for fosfomycin compared to the other tested oral antibiotics (nitrofurantoin, ampicillin, co-trimoxazole, ciprofloxacin and cefuroxime) against all tested Gram-negative rod isolates (Table 2.3). From this study, it is found that fosfomycin is a promising antibiotic for urinary tract infection. 6 Cystitis Recommended empirical treatment regimens for acute uncomplicated cystitis are shown in Table 2.4. Short-course regimens (ranging from a single dose to a 5-day regimen, depending on the antimicrobial agent) are recommended as first-line treatment, since they are as effective as longer regimens in achieving symptomatic cure and have fewer adverse effects. If a first-line 12 I medical newsletter I as a service to the medical profession

Table 2.4 : Empirical Treatment of Acute Uncomplicated Cystitis.* 3 Antimicrobial Regimen First-line therapy Nitrofurantoin monohydrate macrocrystals, 100mg twice daily for 5 days (with meals)# TMP-SMX, 160 mg and 800 mg twice daily for 3 days** Fosfomycin 3-g sachet in a single dose Second-line therapy Fluoroquinolones: ciprofloxacin, 250 mg twice daily for 3 days**; levofloxacin, 250 mg or 500 mg once daily for 3 days** -lactams (e.g., amoxicillin clavulanate, cefdinir, cefaclor, and cefpodoxime proxetil) for 3 to 7 days# Efficacy Clinical efficacy of 5-to-7-day regimen: 93% (84 to 95%); a 3-day regimen appears to be less effective than longer regimens; minimal in vitro resistance to E. coli Clinical efficacy of 3-day TMP-SMX regimen:93% (90 to 100%); similar efficacy with trimethoprim alone, 100 mg twice daily for 3 days**; avoid if resistance rate is greater than 20% or if exposure occured within prior 3 to 6 months. Clinical efficacy: 91% based on a single, randomized trial. Clinical efficacy: 90% (85 to 98%); minimal in vitro resistance, but high prevalence of in vitro resistance in some regions of the world Clinical efficacy of 3-to-5-day regimens: 89% (79 to 98%); less effective than TMP-SMX or fluoroquinolones; few efficacy data on narrow-spectrum cephalosporins (e.g., cephalexin); avoid empirical amoxicillin or ampicillin Comments Minimal ecologic adverse effects; avoid if pyelonephritis is suspected; common side effects include nausea, headache, and flatulence. Probably fewer ecologic adverse effects than seen with fluoroquinolones;common side effects include nausea, vomiting, anorexia, rash, urticaria, hematologic complications and photosensitivity. Minimal ecologic adverse effects; avoid if pyelonephritis is suspected; common side effects include diarrhea, nausea, headache, and vaginitis. Common side effects include nausea, vomiting, diarrhea, headache, drowsiness, and insomnia Probably fewer ecologic adverse effects than seen with parenteral broad-spectrum cephalosporins; common side effects include diarrhea, nausea, vomiting, rash, and urticaria * Efficacy rates and ranges and antimicrobial recommendations are based on the Infectious Diseases Society of America guidelines. Cure rates should not necessarily be compared across agents, owing to differences among trials and varying local patterns of antimicrobial resistance. TMP-SMX denotes trimethoprim sulfamethoxazole. #This regimen presents no clear risk to the fetus, on the basis of studies in animals, humans, or both (pregnancy category B). ** Studies in animals have shown an adverse effect of this regimen on the fetus (pregnancy category C); use only if the potential benefit justifies the potential risk to the fetus. antimicrobial agent is not effective, fluoroquinolones or β-lactams are reasonable alternatives, although it is preferable to minimize their use because of concerns of adverse effects and increasing resistance. 3 Recurrent Cystitis Urinary symptoms that persist or recur within a week or two of treatment for uncomplicated cystitis suggest infection with an antimicrobial-resistant strain or, rarely, relapse. In such cases, a urine culture should be performed and treatment should be initiated with a broader-spectrum antimicrobial agent, such as a fluoroquinolone. Episodes of cystitis that occur at least 1 month after successful treatment of a urinary tract infection should be treated with a first-line short-course regimen (Table 2.4). If the recurrence is within 6 months, one should consider a first-line drug other than the one that was used originally, because of the increased likelihood of resistance. 3 medical newsletter I as a service to the medical profession I 13

Pyelonephritis Acute pyelonephritis should be classified clinically at the time of presentation into either uncomplicated or complicated categories. Most episodes of uncomplicated pyelonephritis are treated in the outpatient setting with either a fluoroquinolone (7-14 days) or trimethoprim/sulfamethoxazole (at least 14 days). Women should be admitted if pyelonephritis is severe, if there is hemodynamic instability or any complicating factor (e.g., diabetes, renal stone, or pregnancy), if oral medications are not tolerated, or if there is concern regarding potential non-adherence to treatment. 3 Therapy for patients with complicated pyelonephritis should include initial hospitalization, supportive therapies, administration of wide spectrum intravenous antibiotic therapy, and relief of aggravating conditions. Such maneuvers could consist of simple bladder catheterization, percutaneous nephrostomy drainage, or definitive surgery. These patients require longer duration of culture-specific antibiotic dosing, careful monitoring, long-term follow-up, and possible definitive management of their underlying condition. 7 Follow-up after Cystitis or Pyelonephritis After treatment for uncomplicated cystitis or pyelonephritis, a urine culture is unnecessary if symptoms have resolved, except in pregnant women. In women with recurrent uncomplicated cystitis or pyelonephritis, routine urologic evaluation (with the use of ultrasonography or computed tomography) has a low diagnostic yield and is not recommended. However, it should be considered in women who have persistent hematuria or multiple early recurrences of cystitis involving the same strain of bacteria. In women with pyelonephritis who have severe or worsening illness, persistent fever 48 to 72 hours after the initiation of appropriate antimicrobial treatment, or symptoms suggestive of a stone, abscess, or obstruction, urologic evaluation should be performed to rule out these latter abnormalities. It is also reasonable to perform imaging studies in women who have two or more recurrences of pyelonephritis. 3 Conclusion Urinary tract infection is the most common infection in women which require an antibiotic prescription. UTIs vary greatly by clinical presentation and classified into mainly cystitis, pyelonephritis and urosepsis. A definitive diagnosis can be made based on clinical features and laboratory tests like urinalysis and urine culture. It can be managed by empirical use of antibiotics. But as antibiotic resistance is one of the major challenge to human health, judicious antibiotic use can significantly reduce this problem. In recent years, fosfomycin has re-emerged as an alternative solution for the treatment of UTI. References 1. Juan NK, Steven G. Acute uncomplicated urinary tract infections. [Internet] Published; 2013 http://www.clevelandclinicmeded.com/medicalpubs/di seasemanagement/infectious-disease/urinary-tract-inf ection/ 2. Helen SL, Jennifer L. Urinary Tract Infection [Internet]. PSAP 2018 BOOK 1. Available from https://www.accp.com/docs/bookstore/psap/p2018b1 _sample.pdf 3. Thomas MH. Uncomplicated Urinary Tract Infection. N Engl J Med 2012; 366:1028-37 4. Vrushali P, Sarman S. Fosfomycin for the treatment of drug-resistant urinary tract infections: potential of an old drug not explores fully. Int Urol and Neph 2017:49(9): 1637-1643 5. Julia LR, Winter JS. Fosfomycin for the treatment of resistant gram-negative bacterial infections. [Internet]. Publishing; 30 April 2014 https://doi.org/10.1002/ phar.1434 6. Mirosav L, Pavla P. Lenka R, Fajfr et al. The susceptibility to fosfomycin of Gram-negative bacteria isolates from urinary tract infection in the Czech Republic: data from a unicentric study. BMC Urology 920170 17:33 7. Nickle JC. The management of acute pyelonephritis in adults. Can J Urol.2001 Jun: 8 Suppl 1:29-38 8. Siddiqua M, Alam AN, Akter S. Antibiotic resistance pattern of bacteria causing urinary tract infection in a private medical college hospital, Dhaka. Ban j Med Sci. 2017;16 (01):42-47 9. JMT Barford, ARM Coates. The pathogenesis of catheter-associated urinary tract infection. Journal of Infection Prevention.2009;9(2):50-56 10. John E. Delzell, Michael L. Lefevre. Urinary Tract Infections during Pregnancy. Am Fam Physician 2000 Feb 1;61(3):713-720. 11. Vitaly S, Kurt N, Truls EB. Improved Classification of Urinary Tract Infection: Future Considerations. European Urology Supplements 15 (2016) 71-80. 14 I medical newsletter I as a service to the medical profession