by author Francisco López Medrano MD PhD Madrid, April 23 rd 2018

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1 Stubborn infections in transplant patients from recurrence to resistance Recurrent urinary tract infections in kidney transplant recipients Francisco López Medrano MD PhD Unit of Infectious Diseases University Hospital 12 de Octubre School of Medicine Universidad Complutense Madrid, Spain Madrid, April 23 rd 2018

2 Agenda Epidemiology of Recurrent Urinary Tract Infection (UTI) Treatment of recurrent UTI as for the general population Treatment of recurrent UTI in Kidney Transplant Recipients (KTR) Should we treat asymptomatic bacteriuria in KTR? Prevention of UTI in KTR An idea for the future... Conflict of interest disclosure: none

3 Epidemiology 2 UTI in 6m or 3 in 1y Clinical Syndrome (%) Cystitis 24% Pyelonephritis 10% CMV viral syndrome 17% Surgical site infection 10% Catheter-related bloodstream infection 3% Pneumonia 7% Other Considering the anatomical location of the urethral meatus, it is surprising that urine is normally sterile M Zasloff. J Am Soc Nephrol 2007; 18: Kidney Transplant Recipients 346 episodes of infection First 12 months after transplantation Fernández-Ruiz et al. Am J Transplant 2012; 12:

4 Epidemiology Britt NS et al. Nephrol Dial Transplant 2017; 32: UTI in 6m or 3 in 1y St. Louis, MO, USA 2469 Kidney Transplant Recipients Type of UTI (%) No UTI 75% Non-recurrent UTI 18% Recurrent UTI 7% 100% Graft Survival (%) 40% Gram negative resistance pattern Multidrug R ( 3 classes) Nonrecurrent UTI Recurrent UTI N UTI NR UTI R UTI p-value 49% 80% < rd g Cepha 17% 31% Co-Trimoxazole 53% 77% <0.001 Fluorquinolone 21% 50% <0.001 ESBL 16% 34% <0.001 Carbapenem 2.5% 3.7% 0.5 Aminoglycosides 12% 21% Months posttransplant 10 years

5 As for the general population... yes or no? Measure Adequate fluid intake Voiding frequency / clothes Cranberry juice */ pills (proanthocyanidins) Oral vaccine (OM-89) for E coli Topical vaginal estrogen Lactobacillus (other probiotics) Antibiotic prophylaxis Of course! Recommendation Many small trials Try it... Await for a higher level of evidence Postmenopausal women... if prophylactic antibiotics fail Low level of evidence Avoid in immunosuppressed patients YES (see next slide) * Pagonas N et al. Transplant Proc 2012; 44:

Antibiotic prophylaxis Continous Antibiotic Fosfomycin trometamol Trimethoprimsulfamethoxazole Cefalexin Ciprofloxacin Nitrofurantoin Dosage (oral) 3 g every 7-10 days 40/200 mg qd 250 mg qd 100 mg

6 Antibiotic prophylaxis Continous Antibiotic Fosfomycin trometamol Trimethoprimsulfamethoxazole Cefalexin Ciprofloxacin Nitrofurantoin Dosage (oral) 3 g every 7-10 days 40/200 mg qd 250 mg qd 100 mg qd [Consider the result of the most recent urine culture] * mg qd (Non authorized in Spain) Albert X et al. Cochrane Database Syst Rev. 2004;(3):CD * Rudenko N et al. Arzneimittelforschung 2005; 55: Ruxer J et al. Wiad Lek 2007; 60: Pre/Post-coital Intermitent self-treatment

Akiki A et al. J Urol 2015; 193: 225-9 Duty BD et al.

7 Refer the patient to the Gynecologist or the Urologist Pelvic floor dysfunction Prostatic hypertrophy Vesicoureteral reflux * * Akiki A et al. J Urol 2015; 193: Duty BD et al. Asian J Urol 2015; 2: Gómez-Luján et al. Transplant Proc 2018; 50:

8 Look for something hidden... Aspergillus M tuberculosis Leishmania infantum Polycystic kidney disease Encrusting cystitis C urealyticum López-Medrano F et al. Clin Infect Dis 2008: 46: Schistosoma haematobium

9 Should we treat asymptomatic bacteriuria? Fiorante S, López-Medrano F et al. Kidney International 2010; 78: Kidney Transplant Recipients Follow-up: 36 months Systematic search and treatment of AB 96 patients developed 298 episodes of AB Creatinine clearance (ml/min) p>0.05 Months after transplantation

10 Should we treat asymptomatic bacteriuria? Origüen J, López-Medrano F et al. Am J Transplant 2016; 16: All participants: AB was systematically searched and treated in the first 2 months after KT Prospective randomized (1:1 ratio) clinical trial (NCT ) Primary outcome: incidence of pyelonephritis (24 months)

11 Should we treat asymptomatic bacteriuria? Origüen J, López-Medrano F et al. Am J Transplant 2016; 16: Treatment of AB Group 53 patients Treatment of AB Group 36 patients 2/3 of the episodes of AB were treated 112 KTR ITT population Modified PP population Control Group 59 patients Treatment of AB Group 50 patients None episode of AB was treated

12 Should we treat asymptomatic bacteriuria? Origüen J, López-Medrano F et al. Am J Transplant 2016; 16: Incidence of pyelonephritis (%) AB treatment group Control group OR (95% CI) p-value ITT analysis ( ) 0.65 Modified PP analysis ( ) 1.0 AB was followed by UTI in only 3.6% of the episodes 1/3 of the pyelonephritis did not presented previous episodes of AB Recurrence of AB under treatment: 51% Resolution of AB without treatment: 32%

13 Should we treat asymptomatic bacteriuria? Coussement J et al. Nephol Dial Transplant 2018; (online) Do you treat AB in adult KTRs? (n = 240 physicians) Sabé N. NCT Coussement J. NCT

14 Search for hypogammaglobulinemia... Fernández-Ruiz M, López-Medrano F et al. Am J Transplant 2012; 12: Kidney Transplant Recipients Day +30 after Tx: 11% presented serum IgG < 500 mg/dl IgG level (mg/dl) Day +30 Months 2 to 6 > < 500 P-value Global bacterial infection 27.4% 35.4% 50% Bacteraemia 3.2% 11.4% 19.2% Pyelonephrytis 1.1% 8.9% 19.2% 0.002

15 Should we treat hypogammaglobulinemia? Poster ECCMID 2018 Kidney Transplant Recipients IgG < 500 mg/dl Day IVIg replacement vs. 47 non IVIg replacement Retrospective study Preliminary results

16 Prevention! Yahav D et al. Eur j Clin Micribiol Infect Dis 2018; 37: Patel P et al. Am J Transplant 2017; 17: Risk Ratio 95% CI Gunawansa ( ) Indu ( ) Parapiboon ( ) Taghizadeh ( ) Total (95% CI) 0.65 ( ) p=0.04 Risk Ratio 95% CI UTI rates Favors <14d Favors >14d Early stent removal (5 days) vs. Late stent removal (6 weeks) UTI 6/79 (7.6%) 31/126 (24.6%) p=0.004

17 In hospital prevention! N Engl J Med 2008; 358: e15 N Engl J Med 2006; 354: e22

18 For the future... Vitamin D Gatti D et al. Minerva Medica 2016: 107:

19 For the future... Vitamin D Kwon YE et al. Medicine 2015; 94: e594 p=0.001 Park YJ et al. Korean J Intern Med p= ; 32:

20 Enjoy Madrid!

Diagnostic approach and microorganism resistance pattern in UTI Yeva Rosana, Anis Karuniawati, Yulia Rosa, Budiman Bela

Diagnostic approach and microorganism resistance pattern in UTI Yeva Rosana, Anis Karuniawati, Yulia Rosa, Budiman Bela Microbiology Department Medical Faculty, University of Indonesia Urinary Tract Infection