ECCMID 2023: Antibiotic Stewardship for Urinary Tract Infections: Challenges and Opportunities
The session discusses complicated urinary tract infection (UTI) and its definition, rapid UTI diagnostics and management, recurrent UTI and urinary tract infections after urological procedures and interventions.
According to the European Association of Urology, complicated UTI is an infection that is more difficult to eradicate than an uncomplicated UTI. Complicated UTI may be associated with an underlying disease requiring broad spectrum antibiotic treatment, as usual treatment is not effective. Complicated UTI is a wide variety of infection and it is heterogeneous while uncomplicated UTI is simple and homogeneous. There are several factors associated with complicated UTIs such as anatomical factors (obstruction of urinary tract) , bacterial resistance, recent surgery and immunosuppressive conditions such as diabetes mellitus . UTIs are classified as uncomplicated (recurrent/ sporadic), complicated UTIs, recurrent UTIs which could be complicated or uncomplicated, catheter-associated UTI (complicated UTI) and urosepsis. The FDA guidelines define complicated UTI which includes pyuria, a documented pathogen in urine/blood culture, accompanied by local and systemic signs and symptoms. The risk factors for the development of complicated UTI include indwelling urinary catheter, neurogenic bladder, obstructive uropathy, azotemia due to intrinsic renal disease and urinary retention. The American Urology Association guidelines definition does not apply to men, pregnant women, immunocompromised patients, patients with catheterization and in those with anatomic abnormalities. The Infectious Disease Society of America (IDSA) guidelines define complicated UTI as developing due to structural and functional abnormalities of the genitourinary tracts or any UTI in a male patient. Collating data from these guidelines, a consensual definition of complicated UTI includes male population, presence of anatomic or functional abnormalities of the urinary tract and the presence of catheter (self-catheterization or indwelling catheter). According to the European Association of Urology, cystitis, pyelonephritis and recurrent UTI could be a complicated or an uncomplicated UTI . Catheter-associated UTI and UTI in men is always complicated. The IDSA guidelines do not have guidance for complicated UTI. In the EAU and IDSA guidelines, the first-line recommendation is Fosfomycin trometamol, followed by nitrofurantoin and pivmecillinam. For uncomplicated pyelonephritis, the drug recommendation is similar and the treatment duration is 5-14 days. The management of catheter-associated UTIs have similar recommendations by both the guidelines and the treatment duration is 3-14 days. In complicated UTI, the EAU recommends beta lactam with aminoglycoside or third generation cephalosporin with parenteral administration for a duration of 7-14 days. Clinical data has shown that seven days of antibiotic treatment for UTI among male who are not febrile is sufficient. In patients with neurogenic bladder who are febrile, the antibiotic treatment should be for 7 days and 5 days for afebrile patients. In polymicrobial cases of catheter-associated UTI, it is important to consider if the patient is febrile or not and then change the catheter. The management should be based on treating the predominant organism and not the more resistant one.
In UTI, there is increasing antimicrobial resistance among uropathogens due to empirical and broad-spectrum antibiotics. The proper diagnosis of UTI is to guide appropriate treatment and avoid the use of unnecessary antibiotics. The detection of a potential uropathogen does not mean that the patient needs treatment. E. coli is a common pathogen associated with complicated and uncomplicated UTI. the frequency of the species varies in different clinical populations. Increased clinical evidence states that counts < 105 CFU/ml are associated with UTI. Urine culture remains the Gold standard test for diagnosing UTI. This helps to identify the pathogen, quantify it and helps perform antimicrobial susceptibility testing . The department of Clinical Microbiology at Hvidovre Hospital has optimized the gold standard of urine sampling in order to achieve a less turn-around time (< 24 hours). This has been achieved through electronic requisition, prompts and barcode printers. The samples are transported on the same day of collection and there is same-day robotic processing. The primary antimicrobial susceptibility testing (AST) on urine samples is optimized for 105 CFU/ml. Post incubation, there is automatic plate imaging taken 17 hours later after biplate and 16 hours later for MH plate. All negative and positive samples are answered electronically within 24 hours to both the physician and the patient. In 10% samples, the AST is repeated due to low CFU or due to the presence of more than 1 species. The samples from primary healthcare, it has been found that since 2021, >50% of urine samples are culture negative. The future perspective for diagnostics must include a personalized diagnosis and treatment for patients, rapid AST, distinguishing UTI needing treatment to bacteriuria which does not require treatment. Rapid screening of urine samples has the potential to avoid unnecessary antibiotics, improve laboratory workflow and reduce cost. However, there is a need for different cutoffs for different patient groups and they need to be programmable on the instrument. The available screening methods include microscopy, lateral flow assay, lateral flow immunoassay, flow cytometry and light scattering. To overcome the dependency of bacterial growth in a laboratory setting, new approaches that are based on molecular and proteomic technologies have gained increased attention in order to reduce the time required for an analysis from days to hours. The identification platform MALDI-TOF is fast, sensitive and specific; but, is expensive for initial equipment and is placed in large central laboratories. It is not available for direct urine screening or testing, and performing AST. Fluorescence in situ hybridisation (FISH) has limited application and requires several probes. PCR based tests are qualitative tests and require several probes for UTI pathogens. Microfluidics is an emergent technique which has potential, both as an individual and when combined with biosensors it can form an integrated platform. In conclusion, rapid screenings need well-defined cut-offs, technologies which are approved for other applications need optimization for direct urine testing and integrated PCR-biosensor platforms have a great potential. Rapid point of care instruments can avoid unnecessary antibiotic use.
Recurrent UTI is a side-effect and not the actual problem. The presenter, Dr. Angela Huttner presented a clinical case of a 53-year old woman with hypertension and rheumatoid arthritis with recurrent UTIs where non-antibiotic measures were not useful. The patient experienced at her home and work; her medications included oral perindopril. In cases like the one presented here, it is important to acquire a detailed history, especially the medication list. The patient was taking upadacitinib which is an immunomodulatory monoclonal antibody. The long-term effects of this medication are several and recurrent UTI is one of them. In such circumstances, it should be checked if these drugs can be discontinued or replaced with other drugs. A detailed sexual history of the patient is essential and if it is non-contributory then urologic work-up should be performed. The doctor presented another case of a 26 year old woman with no known past medical history and chief complaints of dysuria with urgency, frequency and suprapubic tenderness. She's had four UTI episodes in the last year since the start of a new relationship. which were treated with antibiotics. She had E. coli which was ESBL producing. In the current scenario, not every cystitis patient needs an antibiotic. Delayed prescription can be practiced , ibuprofen can be prescribed for symptoms. If the symptoms persist for more than 3 days, then antibiotics can be taken. The patient must be advised to drink a lot of water. A clinical trial (2015, Germany) which compared ibuprofen for symptoms and for recurrence of UTI over 28 days versus Fosfomycin in 500 women, it was found that 67% of women receiving ibuprofen recovered fully without antibiotics at the end of 1 month. Pyelonephritis occurred in only 2% patients . Delayed prescription should be avoided in patients with a history of pyelonephritis, an immunosuppressed patient including one with poorly controlled diabetes, patient with symptoms > 5 days, elderly women. In acute cases of cystitis, the first-line agents recommended by the Swiss guidelines (2019) include delayed prescription followed by Nitrofurantoin, co-Trimoxazole; Fosfomycin is considered as a 2nd line agent. Nitrofurantoin is non-inferior and E. coli does not easily become resistant to this drug. There is minimal collateral damage (resistance selection). The drug is associated with a rare incidence of serious toxicity. Ciprofloxacin co-trimoxazole are clinically superior but E. coli and other uropathogens become quickly resistant. These antibiotics should be reserved for upper UTI. Among non-antibiotic approaches, D-mannose is under study and could be a potential for managing this condition. An E. coli conjugated vaccine is under phase I trial including 18000-19000 women by Jannsen. Among antibiotic approaches, Nitrofurantoin 100mg remains to be the best option and post-coital prophylaxis works best.
The patients with UTI are exposed to antibiotic pressure, not only in hospital, but also as outpatients. These prescriptions do not come only from treatment, but mainly from prophylaxis to prevent infections. The main antibiotics used for all indications are quinolones and cephalosporins which have produced a high burden of antimicrobial resistance among these patients . The priorities for stewardship in urology should be to reduce unnecessary exposure to antibiotics of patients and reduce the overuse of fluoroquinolones. With respect to prophylaxis, the two problems are pre-procedural prophylaxis to improve management of bacteriuria and post-procedural prophylaxis which goes before 24 hours. There is discordance among guidelines regarding the procedures for which prophylaxis is indicated. While the American guidelines recommend a single-dose approach, the European guidelines propose the treatment of asymptomatic bacteriuria with a full course of antibiotics. However, the single-dose approach should be aimed for. While quinolones have been the standard of care for prophylaxis in urology for many indications, the European Commission has prohibited the use of quinolones as prophylaxis. Fosfomycin is a broad spectrum antibiotic which reaches high concentrations in urine and adequate in the prostate.; for AMS, it is a suitable option. Fosfomycin has shown superior results in transrectal prostatic procedures and non-inferior results in endoscopic procedures. Antibiotic stewardship should be led by urologists and the focus should be duration of antibiotics rather than indications. An ongoing antimicrobial stewardship program has shown a 45% reduction in global consumption of antibiotics and 90% reduction in the quinolone consumption . Febrile UTIs are frequent after urological procedures. In bacteremic infections, there is good evidence supporting the use of quinolones as a step down therapy due to their high bioavailability. But their use may be limited due to increased rates of resistance. With respect to oral therapies, penicillin has good bioavailability however needs a reduced dose in oral form. Cephalosporins have poorer bioavailability than penicillin. In observational studies in patients with gram negative infections from urinary sources where the drugs are transitioned to either oral beta lactam or oral quinolones, it has been observed that there are confronting results where recurrence risk is unclear. In these studies, the risk of recurrence is < 10% and the absolute risk difference between treatment groups is < 5%. While using oral beta lactams for treating bacteremia, high doses are needed. Around 80% experts wait till the 7th day to transition to oral antibiotic therapy. There is need for more evidence on the safety of much earlier oral treatments compared to what is done in clinical practice. In conclusion, oral step-down is safe in stable patients without a properly controlled source, clinical criteria, instead of the fixed number of days, should be used to decide the appropriate time for step down. High bioavailability agents must be prioritized in infections with source problems. High dose beta lactams such as penicillin is a reasonable step down treatment for other infections with a lower risk of recurrence. In order to define a strategy that avoids recurrence of infection after a procedure, one needs to understand the mechanism of the infection. In patients with febrile UTI, antibiotic treatment for 7 days in low-risk patients may be sufficient. In acute prostatitis where there is an increased risk of treatment failure, 14 days antibiotic treatment is advised.
European Congress of Clinical Microbiology and Infectious Disease 2023, 15th April - 18th April 2023, Copenhagen, Denmark
