Prevention of recurrent bacterial UTI by intravesical instillation of Hyaluronic Acid(HA) (Cystistat) Martin Imhof Department for Obstetrics and Gynaecology Medical University of Vienna
Prevention of recurrent bacterial UTI by intravesical instillation of
Hyaluronic Acid(HA)(Cystistat)
Martin Imhof
Department for Obstetrics and Gynaecology
Medical University of Vienna
Urinary Tract Infection
= presence of infectious pathogens
Belong to the most frequent bacterial illnesses, which concern female
Foxman B. Epidemiology of urinary tractinfections: Incidence, morbidity and economic costs. Am J Med 2002;113(Suppl. 1A): 5S–13S
Frequency in female
• 8% girls before puberty
• 0,5 episodes/woman´s year with beginning of sexual activity („honeymoon cystitis“)
• Later 0,1 episodes/year
• Recurrence rate 25-35% in the first 3-6 months after AB Therapy
Ronald A.:The etiology of urinary tract infection: Traditional and emerging pathogens. Am J Med 2002;113: 14S–19S
Frequency in female
• 12% recurrence after first infection
• 48% recurrence after second infection
e.g. Austria
• 50.000 women with 1 recurrence/year• 25.000 woman 2 and more recurrences/year
Ronald A.:The etiology of urinary tract infection: Traditional and emerging pathogens. Am J Med 2002;113: 14S–19S
Spectrum of causative organisms
• Over 90% caused by E. coli.
• Staphylococcus saprophyticus• Enterococcus• Soor. • Pseudomonas, Klebsiella, other gram-negative
Germs and Staphylococcus aureus
• Chlamydia, Gonococcus, Mycobakteria (Tuberkulosis!), Adeno- und Herpesvirus.
Glycocalix
• Covers the epithelia of the bladder
• Protects the bladder against toxic urine components.
• Blocks the adhaesion of bacteria to the epithelia
Poggi MM, Johnstone PAS, Conner RJ. Glycosaminoglycan content of human bladders: a method of analysis using coldcup
biopsies. Urol Oncol 2000;5: 234–7
Damage of the GAG-Layer
e.g. metabolites of E.coli
interstitial cystitis
conventional UTI
Idea: Reduction of symptoms by reconstitution of GAG-Layers
Daha LK, Riedl CR, Hohlbrugger G, Knoll M, Engelhardt PF, Pflüger H.: Comparative assessment of maximal bladder capacity, 0.9% NaCl versus
0.2 MKCl, for diagnosis of interstitial cystitis: prospective controlled study. J Urol 2003;170: 807–9
Reconstitution of GAG-Layers
through „Epithelial coating“ techniques by means of intravesical instillation of
– Hyaluronic acid
– Pentosan Polysulfat– Heparin
Morales A, Emerson L, Nickel JC, Lundie M. Intravesical hyaluronic acid in the treatment of refractory interstitial
cystitis. J Urol 1996; 156: 45–8
Constantinidis et al: Prevention of recurrent bacterial cystitisby intravesical administration of hyaluronic acid: a pilot study.
BJU Int. 2004 Jun;93(9):1262-6
Aim of the study
Evaluation of the effect of intravesical instillation of Hyaluronacid on the rateof recurrence of uncomplicated urinary
tract infections
Study designNumber of Patients: 20
Inclusion criteria:
• Age 18 – 40• Documented recurrent UTI´s including date of the infection, Germ spectrum, antibiotic therapy. • Cystography• No current UTI at the beginning of the therapy
Exclusion criteria:
• Urogenital congenital and acquired defects (e.g.: ureterduplication, ureterocele, neurogene dysfunction, bladder cancer, ureter divertikel, uretero vaginal fistula, etc..) • Existence of a interstitial cystitis • Use of spermizide substances • Intra Uterin Device • Pregnancy
Documentation
• Retrospective: preceding UTI
germ spectrum
antibiotics
• Prospective: urine cultures
UTI
Treatment routine• Intravesical instillation of 40mg Hyaluronic acid
(Cystistat©) solved in 50ml PBS by means of sterile single use catheter once per week for one month
• Instillation once per month for five months
• Urine culture at– the beginning of the therapy – after 4 weeks and– after 3, 6, 9 and 12 months within the study period .
• After-treatment observation period: 6 months
• UTI during the treatment: antibiotic treatment until urine culture is again negatively .
Application
• Depletion of the bladder• Desinfection of the introitus • Slow instillation of cystistat (used volume 50ml) with
sterile single use catheter lubricated with instillation gel
• No urination for at least 2 hours
Side effects: - mild to modest pain during application of the catheter
(92%)- Mild to moderate crampy discomfort or burning up to
2 days after treatment (34%)
Time table Treatment/Bacteriology
Treat.1/ Bac. Treat. 2 Treat. 3 Treat.4/Bac. Treat. 5 Treat. 6/Bac. Treat. 7 Treat. 8 Treat.9/ Bac. Bac. Bac
30.09.2004 08.10.2004 14.10.2004 21.10.2004 16.11.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2004 03.06.2005 29.08.2005
30.09.2004 08.10.2004 14.10.2004 21.10.2004 16.11.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2004 03.06.2005 29.08.2005
30.09.2004 08.10.2004 14.10.2004 21.10.2004 16.11.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2004 03.06.2005 29.08.2005
07.10.2004 14.10.2004 21.10.2004 29.10.2004 25.11.2004 21.12.2004 20.01.2005 17.02.2005 16.03.2004 09.06.2005 06.09.2005
07.10.2004 14.10.2004 21.10.2004 29.10.2004 25.11.2004 21.12.2004 20.01.2005 17.02.2005 16.03.2004 09.06.2005 06.09.2005
07.10.2004 14.10.2004 21.10.2004 29.10.2004 25.11.2004 21.12.2004 20.01.2005 17.02.2005 16.03.2004 09.06.2005 06.09.2005
07.10.2004 14.10.2004 21.10.2004 29.10.2004 25.11.2004 21.12.2004 20.01.2005 17.02.2005 16.03.2004 09.06.2005 06.09.2005
14.10.2004 21.10.2004 29.10.2004 04.11.2004 07.12.2004 10.01.2005 03.02.2005 03.03.2005 30.03.2005 23.06.2005 15.09.2005
14.10.2004 21.10.2004 29.10.2004 04.11.2004 07.12.2004 10.01.2005 03.02.2005 03.03.2005 30.03.2005 23.06.2005 15.09.2005
14.10.2004 21.10.2004 29.10.2004 04.11.2004 07.12.2004 10.01.2005 03.02.2005 03.03.2005 30.03.2005 23.06.2005 15.09.2005
14.10.2004 21.10.2004 29.10.2004 04.11.2004 07.12.2004 10.01.2005 03.02.2005 03.03.2005 30.03.2005 23.06.2005 15.09.2005
26.10.2004 02.11.2004 09.11.2004 16.11.2004 14.12.2004 11.01.2005 08.02.2005 08.03.2005 04.04.2005 02.07.2005 25.09.2005
26.10.2004 02.11.2004 09.11.2004 16.11.2004 14.12.2004 11.01.2005 08.02.2005 08.03.2005 04.04.2005 02.07.2005 25.09.2005
26.10.2004 02.11.2004 09.11.2004 16.11.2004 14.12.2004 11.01.2005 08.02.2005 08.03.2005 04.04.2005 02.07.2005 25.09.2005
25.11.2004 02.12.2004 09.12.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2005 04.04.2005 03.05.2005 25.07.2005 21.10.2005
25.11.2004 02.12.2004 09.12.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2005 04.04.2005 03.05.2005 25.07.2005 21.10.2005
25.11.2004 02.12.2004 09.12.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2005 04.04.2005 03.05.2005 25.07.2005 21.10.2005
25.11.2004 02.12.2004 09.12.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2005 04.04.2005 03.05.2005 25.07.2005 21.10.2005
25.11.2004 02.12.2004 09.12.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2005 04.04.2005 03.05.2005 25.07.2005 21.10.2005
25.11.2004 02.12.2004 09.12.2004 17.12.2004 13.01.2005 08.02.2005 10.03.2005 04.04.2005 03.05.2005 25.07.2005 21.10.2005
Patients
• Number of patients: 22
• Mean age: 31,6 years
• Number of instillations: 191no serious side effects
Drop out 9%
Results• Before treatment:
– 3 to 5 UTI´s a year treated with antibiotics (positive culture)
– Number of infections (mean): 3,35/12 months(min. 3, max. 5)
• Study period:– 1 to 2 UTI´s a year treated with antibiotics (positive
culture)– Number of infections (mean): 0,5/12 months
(min. 1, max. 2)
– Mean time to recurrence: 30,4 weeks (7 pat.)
Results
• Recurrence rate: 35% - 7 patients out of 20• 3 pat. with 2 UTI in observation period• 3 pat. with 1 UTI in observation period• 1 pat. with 1 UTI in treatment period
• Drop-out rate : 9%
- Interstitial cystitis during treatment
- Lost in follow up
Results
0
20
40
60
80
before
after
Total
Enterobact.
mixed ProteusEnteroc.
Klebsiella
E.coli
before after
E. coli 41 3
Klebsiella 4 1
Enterococcus 7 1
Proteus m. 4 2
Enterobacter 7 1
Mixed infect. 4 2
Total 67 10
Recurrence rate: 35% (7 patients out of 20)
Recurrence of UTI after Cystistat
0 1 2 3 4 5 6 7 8 9 10 11 12
123456789
1011121314151617181920
No UTI
Recurrence
Conclusion
• Good results in female with chronic UTI
• Reduced acceptance due to method of application
• Good acceptance in ongoing treatment
Antibiotic therapy of UTI
Simple UTI: 3 day regimen
• First line antibiotics:– Trimethoprimsulfat-Sulfat 2x960 mg– Nitrofurantoin 3x50mg– Fosfomycin 1x3g Singleshot
• Second line antibiotics:– Fluorchinolone (Norfloxacin 2x400 mg, Ofloxacin 2x200 mg
and Ciprofloxacin 2x250 mg)– Amoxicillin 2x2g– Cephalosporin 2x1g
Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of
uncomplicated acute bacterial cystitis and acute pyeonephritis in women. Infectious Diseases Society of
America (IDSA). Clin Infect Dis 1999;29:745–58.