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NYP: Final Year Project – UTI

This is another report from my dear friend! Its great, so enjoy! Oh, and i learnt something, do not, i repeat DO NOT MAKE POSTERS AT BRAS BASAH, the one near raffles hotel and the national library, major scam, i do not know which store exactly, but why go all the way and risk it right?

If you got any printing stuff need done, do it at botaksign.com.sg @ highland centre, its quality and cheap. Bras Basah = $40, botaksign= $11.50. Us broke ass students shouldn’t need to pay so much, actually no one should.

POSTER:

POS 1POS 2

 

WORD:

1. Background on Urinary Tract Infection
1.1 Overview
Urinary tract Infection (UTI) is an infection affecting parts of the renal system which includes the kidneys, the ureters, the urinary bladder, and the urethra. These structures are involved in the excretion of urine. It can occur at different stages in life, from childhood to advanced age. UTI is more common in females than males. [1]

1.2 Pathophysiology
Bacteria that cause UTI usually exist around the anus and the urethra opening. [1] The bacteria enter through the urethra and to the bladder which aids their growth. [2] The infection may spread further as the bacteria travel up to other parts of the urinary system. [2] Infection may also occur via the blood or lymphatic system. [12, 13] Improper wiping and sexual intercourse are the most prevalent causes of UTI. [2] The most common organism that causes UTI is Escherichia coli (E.coli). [1, 2] Females have a shorter urethra and it is closer to the anus, thus, women are more prone to UTI than men. The elderly are more prone to UTI due to weaker immune system and postmenopausal changes. [1]

There are two main classification of UTI that is the lower and upper UTIs categories. There are three types of UTIs in the lower category which include cystitis (infection or inflammation confined to the bladder), urethritis (infection or inflammation of the urethra) and prostatitis (infection or inflammation of the prostate gland). There are also three types of UTIs in the upper category that include pyelonephritis (infection or inflammation of the kidney and renal pelvis), intrarenal abscess (collection of pus in the kidney) and perinephric abscess (collection of pus in soft tissue surrounding of the kidney). In the two classification of UTI, each category is separated by uncomplicated and complicated UTI. Uncomplicated UTI is an infection happened with the absence of structural or functional abnormalities of the urinary tract. Complicated UTI is an infection happened with factors such as structural abnormalities, stones and exposure of catheters in the bladder which predispose patient to UTI or make UTI more difficult to treat. [1]

1.3 Symptoms
 Dysuria (painful urination) [1]
 Increased frequency of urination [1]
 Urgency (need to urinate without delay) [1]
 Cloudy, bad-smelling, or bloody urine [34]
 Suprapubic tenderness [1]
 Increased number of white blood cells [1]
 Additional symptoms for pyelonephritis (upper urinary tract infection): fever, back pain, nausea and vomiting. [1]

1.4 Diagnosis
Prior to physical examination and lab tests to confirm the diagnosis, there are some common questions (e.g. do you have any medical or surgical history, what are your habits, and what is your lifestyle) that will be asked to determine the probable diagnosis. [3] A urine dipstick test (leukocyte esterase; test for presence of white blood cells and nitrite tests; test for presence of nitrites) may be performed and results can be obtained rapidly. [3, 11] A urinalysis is conducted to test for signs of infection (e.g. presence of pyuria, bacteriuria and haematuria). [11] Urine sample can be obtained by clean-catch, midstream method, catheter, or needle aspiration, which method is preferred depends on the ability and age of the patient. [3] Urine culture is only required for the following cases: diagnosis is unclear (presence of 100,100 CFU/mL of organism indicates infection), patient has recurrent infections (identification of a single organism at lower CFU/mL likely also represents infection, in the presence of appropriate symptoms), or resistance is suspected (suspect a contaminated specimen when culture shows multiple types of bacteria). [11] Blood tests are usually performed for complicated conditions, such as pyelonephritis or kidney failure, is suspected. [3] Imaging tests (e.g. ultrasound examination, fluoroscopic study, intravenous pyelogram, cystoscopy and CT scan) can be performed to detect any underlying problem in the urinary tract that can cause an infection. It is only necessary for recurrent infections or rare cases (e.g. anatomic abnormalities). Other circumstances where imaging tests are conducted include children with UTI and people who have blood in urine. [3]

1.5 Prognosis

There will still be good prognosis even when the patients developed the symptoms rapidly. Early pyelonephritis can also have a good prognosis if it is immediately and effectively treated. However, the prognosis declines when the UTI is not quickly identified or treated. For the elderly and immunosuppressed patients, they may not have the UTI identified early hence their prognosis may range from fair to poor, depending on the extent of damage or impairment to the urinary tract and/or the occurrence of complications such as sepsis (a whole body inflammatory response to an infection[6]). For most adults and children, if sufficiently treated, they will have a good prognosis. However, for adults and children with recurrent UTI, they may develop complications and a worse prognosis as recurrent UTI may be due to an underlying problem in the structure of urinary tract. [4]

1.6 Complication
There should not be complications if patients are treated early, with appropriate medications, UTIs can be resolved in a few days’ time. If the UTI deteriorates rapidly or becomes chronic, a number of complications may follow. Rapid deterioration of UTIs can cause dehydration, kidney failure, sepsis and death. Chronic infections may cause problems in the urinary structures; abscesses, fistulas (a permanent abnormal passageway between two organs in the body or between an organ and the exterior of the body) [7], kidney stones, and in rare cases, kidney damage or bladder cancer. Pregnant women with untreated UTIs may deliver prematurely. [5]

1.7 Special Needs/care for special group
Children with UTI, especially those who are less than 1 year of age, should be advised to go for diagnostic examination for urinary tract anomalies. [10] If ureteral dilatation is detected in infants and children, voiding cystourethrogram or isotope cystogram will be obtained to check for reflux. [11] Pregnant women with UTI always require culture or sensitivity and usually require a 7-14 day treatment. Following the treatment of acute infection, pregnant females will have their urine cultures checked every trimester. They may receive prophylactic antibiotics for the remainder of their pregnancy to prevent recurrent or upper tract disease. [10] Elderly patients are more likely to have underlying urinary tract abnormality. Acute UTI may be associated with incontinence or mental status changes in the elderly. [11]

2. Medication

2.1 Current medication for urinary tract infection and its pros and cons

Type of Medication(s) Pros Cons
Cephalosporins [1]

 

First line therapy (1st & 2nd Gen.) for acute cystitis in women, cystitis in pregnancy and complicated UTI mild illness[1]

 

Alternative medication for recurrent cystitis in women (cephalexin), (1st & 2nd Gen.) for complicated pyelonephritis mild to moderate severity, outpatient [1]

-More resistant than penicillin to B-Lactamase enzymes [13]

 

-If allergic to penicillins, cannot take cephalosporins.

-Cephalexin and cefuroxime (1st Gen.) are less effective in acute cystitis cf. SMX/TMP or fluoroquinolones [13]

Nitrofurantoin [1]

 

Alternative medication for acute cystitis in women, recurrent cystitis in women, cystitis in pregnancy and complicated UTI mild illness [1]

-Little change in E.coli resistance to nitrofurantoin [15]

 

-May be less effective than SMX/TMP  in acute uncomplicated UTI [13]

-Contraindicated in renal failure [13]

-Side Effect(s): Brown urine [13], acute pneumonitis if prolonged use [13]

Fluoroquinolones [1]

 

First line therapy for complicated pyelonephritis mild to moderate severity, outpatient [1]

 

Alternative medication for acute cystitis in women [1]

-Good oral absorption [13]

-Ciprofloxacin and Ofloxacin injections availability [13]

-Drug resistance [9]

-Side effect(s): Photosensitivity [9]

-Precautions: Not for pregnant and lactating women [9], G6PD deficient patients [9]

-Drug Interaction(s): Ciprofloxacin, ofloxacin inhibit CYP450 leads to an increase in theophylline, warfarin, cyclosporine, caffeine [13], and cimetidine interferes with fluoroquinolones [13]

-Ciprofloxacin contraindicated in children under 18 because it damages developing articular cartilage [13]

Trimethoprim- sulphamethoxazole (SMX/TMP) [1]

 

First line therapy for recurrent cystitis in women [1]

 

Alternative medication for acute cystitis in women, cystitis in pregnancy, complicated UTI mild illness and complicated pyelonephritis mild to moderate severity, outpatient [1]

-Relatively inexpensive [12]

-Effective for acute uncomplicated UTI [13]

-Synergistic effect [13]

-Wider spectrum of activity than trimethoprim [14]

 

-Increase change in E.coli resistance to TMP/SMX [15]

-Side Effect(s): Stomatitis [13], hemopoietic (avoid in G6PD deficient patients) [9], photosensitivity [9] and skin (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) [9]

-Drug Interaction(s):Inhibit metabolism of phenytoin [13]

 

Trimethoprim [1]

 

Alternative medication for acute cystitis in women, recurrent cystitis in women and complicated UTI mild illness [1]

-Broad spectrum of activity [14] -Negative bacterial resistance [13]

-Folate deficiency [13]

Nalidixic acid (non-fluorinated quinolone) [1]

 

Alternative medication for acute cystitis in women and complicated UTI mild illness [1]

-Not affected by urine pH [13] -Side effect(s): Photosensitivity [13]

-If used for > 2 weeks, it will affect the liver [13]

Penicillins [1]

 

Alternative medication for complicated UTI mild illness (amoxicillin) and complicated pyelonephritis mild to moderate severity, outpatient (amoxicillin-clavulanic acid as an example of β-lactam β lactamase inhibitor combinations) [1]

-Amoxicillin: effective against gram positive bacteria [8]

-Amoxicillin-clavulanic acid: effective against gram positive bacteria [8] and superior efficacy for amoxicillin-resistant organisms [16]

-Less effective than SMX/TMP in uncomplicated UTIs [13]

-Amoxicillin:

+High resistance of E.coli to amoxicillin [13]

+Side effect(s):

Suprainfection [8]

 

2.2 Current development of urinary tract infection
2.2.1 Gene modification
NBTI 5463 is a novel bacterial type II topoisomerase inhibitor with improved activity over other NBTIs against gram-negative bacteria. It has also showed efficacy in vivo activity. Bacterial type II topoisomerases mediate transient double-strand DNA breaks and take part in DNA replication. In the process of DNA replication, topoisomerases separate the DNA of daughter chromosomes (decatenation) while DNA gyrase can introduce and controls the level of negative supercoiling in the bacterial chromosomal DNA. NBTIs are bind to the DNA-bound form of gyrase and topoisomerase IV which is the most efficient in decatenation reactions. The formation of these complexes blocks the progression of the DNA replication. NBTI 5463 bind to the gyrase-DNA complex and prevents formation of double-strand breaks. [21]

2.2.2 New biological compound
Flavonoid compounds were tested as β-ketoacyl acyl carrier protein synthase I (KAS I) inhibitors of Escherichia coli (E.coli) in docking studies. KAS I is a key catalyst in bacterial fatty acid synthesis that is vital for bacterial viability and growth. Flavonoids are natural polyphenolic compounds and were reported to have many useful properties, including enzyme inhibition and anti-microbial activity. Results of the docking study of E.coli (KAS I) and 50 flavonoids showed that out of the 50 flavonoids, two compounds, genistein and isorhamnetin, had superior binding energy and satisfied the condition of drug likeliness. The binding energy of genistein and isorhamnetin is more favourable than that of known drugs thiolactomicin and cerulein. iGemdock (a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis[20]) was used as docking with the selected E. coli (KAS I-PDB ID-1FJ4) . iGemdock also followed the Lipinski’s rule of five, and hence demonstrated the drug likeliness and bioavailability of flavonoid compounds. [19]

2.2.3 New chemical compound
RX-P873 is a novel protein synthesis inhibitor and has new broad spectrum antibiotic properties. It is a novel antibiotic in preclinical development and is from the pyrrolocytosine series which exhibit high binding affinity for the bacterial ribosome. [17, 18] Pyrrolocytosine compounds are directly synthesized from 5-iodocytosine[29] and they work against multidrug-resistant gram-negative and positive strains of bacteria that cause complicated UTI, skin, lung infections and also include sepsis in vitro activity.[17] The purpose of the study was determine if RX-P873 had the ability to accumulate in eukaryotic cells and act against intracellular and extracellular forms infections by Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa). The lab test results showed that RX-P873 was more potent than antibiotics to which the strains (moxifloxacin, vancomycin, daptomycin for S. aureus; ciprofloxacin, ceftazidime for P. aeruginosa) were resistant to. Kill curves in broth showed that RX-P873 was more rapidly bactericidal against P. aeruginosa than against S. aureus. To conclude, these data suggested that RX-P873 may be a useful alternative for infections involving intracellular bacteria, especially gram-negative species. [18]

2.3 New products that are on clinical trial
Finafloxacin is a treatment for complicated UTI and acute pyelonephritis. The results from the randomized, parallel and double-blind phase 2 clinical study [22] showed that finafloxacin was more effective and safer than ciprofloxacin. 225 participants have either received 800 mg (i.v. or oral) finafloxacin once daily for a total of 5 or 10 days, or 400 mg (oral)/500 mg (i.v.) ciprofloxacin twice daily for 10 days. [22, 23] The data had shown that patients who were assigned to take finafloxacin for five days had a higher, more rapid and sustained level of pathogen eradication and improved clinical outcomes than those treated with ciprofloxacin for 10 days. This was proven by an interim evaluation done on the day 3 of the study which revealed that finafloxacin eradicated pathogens more quickly than ciprofloxacin (89% vs. 79%). The short 5 -day treatment course with finafloxacin did not cause an increased incidence of relapses when compared to the both 10-day treatment courses in the study. Efficacy of finafloxacin is equivalent in both 5 and 10 days treatment regimens as it was proved in a combined evaluation of the clinical and microbiological response with efficacy rates of 70% and 68% on the day 17 of the study. Both finafloxacin dosing courses were more efficient than the treatment with ciprofloxacin for 10 days. The rapid antibacterial activity and antimicrobial effect of finafloxacin showed that it was unaffected by urine pH, with comparable activity at acidic, neutral and basic conditions, and is effective against ciprofloxacin-resistant pathogens and ESBL (extended-spectrum beta-lactamases) producing bacteria. [23]

Plazomicin is also a treatment for complicated UTI and acute pyelonephritis. The randomized, parallel and double-blind phase 2 clinical study [24] of plazomicin that was compared to levofloxacin, has demonstrated a comparable efficacy and acceptable safety to levofloxacin. [25] 145 participants have received either 10mg/kg or 15mg/kg (i.v.) plazomicin once daily for 5 days, or 750mg (i.v.) levofloxacin once daily for 5 days [24]. In non-clinical studies, plazomicin had shown good potency in vitro activity and in vivo efficacy against multidrug-resistant (MDR) Enterobacteriaceae. It has the potential to demonstrate clinical efficacy in patients with complicated UTI infections. In MDR Enterobacteriaceae, plazomicin remains active with comparison to most other antibiotics, including the marketed aminoglycosides which have limited potency due to resistance. [25] Plazomicin has proceeded to phase 3, but has yet to recruit participants. The arms consist of plazomicin (i.v.) and meropenem (i.v.) in phase 3 and after completion of the study drug, both arms will be followed by an optional levofloxacin (oral) therapy when clinically appropriate. [26]

Lactin-V is a prophylaxis treatment for recurrent UTI. Lactin-V is a randomized, single group and double-blind phase 2 clinical study. [27] The lack of the normal protective lactobacilli in the vagina is often associated with women with recurrent UTIs hence the researchers have designed this trial to evaluate if restoration of the lactobacilli will reduce the rate of recurrent UTI in UTI-prone women. [35] 100 participants have received either a vaginal capsule containing Lactobacillus crispatus in high concentration or a placebo vaginal capsule. Subjects of both arms were required to self-administered once daily for 5 days during the 1st week, and self-administered once weekly for 10 weeks. [27] The results showed that the recurrent UTI had occurred in 15% (7 out of 48) of women receiving Lactin-V group compared with 27% (13 out of 48) of women receiving placebo group[27, 28], thus, compared to placebo, Lactin-V had reduced the incidence of UTI by approximately 50%. Safety and tolerability were confirmed in this study. A high level of Lactin-V colonization was achieved, and had a significant decrease in recurrent UTI to only those who took Lactin-V. As for women who took placebo have no such decrease, regardless of colonization pattern. [28]

2.4 Suggest a potential direction which is not cover by the current trial
There is an ongoing trial to determine if cranberry-lingonberry juice should be started during acute UTI to effectively prevent recurrence of UTIs in children. [30] My suggestion would be that the trial could mention about the water intake. As drinking plenty of water will help to flush out the bacteria from the urethra during urination. [31] Thus, the level of water intake should be controlled in both arms. The trial would require the participants of both arms to drink the recommended daily water intake for different gender and age groups. This is to ensure that the water intake will not interfere with the results of the study and this creates an opportunity to discover of the extent of this combined therapy of water intake and cranberry-lingonberry juice can be more effective than drinking water alone in preventing recurrence of UTIs. If this is implemented into the trial study, ensure that the participants are willing and have the capacity to consume the recommended daily water intake as accordingly. In addition to the current trial, I would also suggest that the trial should exclude participants that meet the following exclusion criteria: allergy to cranberries and/or lingonberries, unwillingness of consumption of cranberry-lingonberry juice and have drug interactions with cranberry and lingonberry.

2.5 Suggest a potential intervention of the selected product that is on trial
Gynofit® vaginal gel, containing lactic acid and glycogen is on a Phase 4 study and evaluate if it will reduce the incidence of recurrent of bacterial vaginosis (BV). There were studies shown that acidification helps to lower the vaginal pH and thus encourages the growth of lactobacilli. By increasing the growth of vaginal lactobacilli, it may deter the growth of other organisms by preventing them from attaching to the cells lining of the vagina. [32] BV is associated with UTIs, as a study had showed that women with BV have a greater risk of UTI. [33] With cross-reference to Lactin-V, which contains lactobacillus, the results had showed that it did reduce the recurrence rate of UTI. In my viewpoint, Gynofit® can be research as a potential prophylaxis treatment for recurrent of UTI.
4. References

1. Fung, M. (2015). Urinary Tract Infections [PDF document]. Retrieved from https://learn.nyp.edu.sg
2. Jerry R. Balentine, D. F. (2 September, 2015). Urinary Tract Infections (UTIs). Retrieved from medicinenet.com: http://www.medicinenet.com/urinary_tract_infection/page2.htm
3. Jerry R. Balentine, D. F. (2 September, 2015). Urinary Tract Infections (UTIs). Retrieved from medicinenet.com: http://www.medicinenet.com/urinary_tract_infection/page5.htm
4. Charles Patrick Davis, M. P. (23 October, 2015). Urine Infection. Retrieved from RxList: http://www.rxlist.com/urine_infection-page9/drugs-condition.htm#what_is_the_prognosis_for_a_urinary_tract_infection_uti
5. Charles Patrick Davis, M. P. (23 October, 2015). Urine Infection. Retrieved from RxList: http://www.rxlist.com/urine_infection-page9/drugs-condition.htm#what_are_possible_complications_of_a_urinary_tract_infection_uti
6. Wikipedia, t. f. (2 September, 2015). Sepsis. Retrieved from Wikipedia, the free encyclopedia: https://en.wikipedia.org/wiki/Sepsis
7. Medicine, G. E. (2008). fistula. Retrieved from THEFREEDICTIONARY: http://medical-dictionary.thefreedictionary.com/fistula
8. Leung, H. (2014). Anti-Infectives II: Penicillins & Cephalosporins (Beta-Lactams) [PDF document]. Retrieved from https://learn.nyp.edu.sg
9. Leung, H. (2014). Anti-Infectives IV: Quinolones & Sulphonamides [PDF document]. Retrieved from https://learn.nyp.edu.sg
10. (2014). URINARY TRACT INFECTION (UTI) IN FEMALES. In R. A. Frank J. Domino, The 5-Minute Clinical Consult 2014 (p. 1283). LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business.
11. Akhil Das, M. F. (2014). URINARY TRACT INFECTION (UTI) IN FEMALES. In R. A. Frank J. Domino, The 5-Minute Clinical Consult Premium 2015 (p. 1238). Wolters Kluwer Health.
12. Czarapata, B. J. (2014). Renal and Urologic Problems, Problems of Urinary Function. In S. R. Sharon L. Lewis, Medical-Surgical Nursing: Assessment and Management of Clinical Problems … (pp. 1065, 1067,1070). Mosby.
13. (2010). In M. Kruger, PEBC Syllabus Revision Guide (pp. 123-124, 131, 145-148, 181, 186-188). http://www.pebcexam.com.
14. Barr, B. S. (2011). Pharmacology. In W. V. Barr, Equine Pediatric Medicine (p. 328). Manson Publishing.
15. Guillermo V. Sanchez, R. N. (April, 2012). In Vitro Antimicrobial Resistance of Urinary Escherichia coli Isolates among U.S. Outpatients from 2000 to 2010. Retrieved from PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318377/
16. Gordon, D. (2010). Beta-Lactamase Inhibitors and Combinations. In S. M. M Lindsay Grayson, Kucers’ The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs (p. 194). CRC Press.
17. Robert K. Flamm, P. R. (2 February, 2015). In vitro activity of RX-P873 tested against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. . Retrieved from American Society for Microbiology: http://aac.asm.org/content/early/2015/01/27/AAC.04840-14
18. Julien M. Buyck, P. M. (26 May, 2015). RX-P873, a novel protein synthesis inhibitor, accumulates in human THP-1 monocytes and is active against intracellular infections by Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria. . Retrieved from American Society for Microbiology: http://aac.asm.org/content/early/2015/05/20/AAC.00428-15
19. Berakdar, G. S. (September , 2015). Docking studies of flavonoid compounds as inhibitors of β-ketoacyl acyl carrier protein synthase I (Kas I) of Escherichia coli. Retrieved from ScienceDirect: http://www.sciencedirect.com/science/article/pii/S1093326315300280
20. Hsu KC, C. Y. (15 February, 2011). iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. Retrieved from PubMed.gov: http://www.ncbi.nlm.nih.gov/pubmed/21342564
21. Thomas J. Dougherty, A. N. (May, 2014). NBTI 5463 Is a Novel Bacterial Type II Topoisomerase Inhibitor with Activity against Gram-Negative Bacteria and In Vivo Efficacy. Retrieved from PubMed Central Canada : http://pubmedcentralcanada.ca/pmcc/articles/PMC3993248/
22. GmbH, M. P. (8 April , 2015). Finafloxacin for the Treatment of cUTI and/or Acute Pyelonephritis. Retrieved from ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT01928433?term=phase+2+finafloxacin&rank=1
23. Microbiology, A. S. (21 September, 2015). Finafloxacin for the treatment of urinary tract infections. Retrieved from Medicalxpress: http://medicalxpress.com/news/2015-09-finafloxacin-treatment-urinary-tract-infections.html
24. Achaogen, I. (9 July, 2013). Study of Plazomicin (ACHN-490) Compared With Levofloxacin for the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis. Retrieved from ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT01096849?term=Phase+2+Plazomicin&rank=1
25. Achaogen, I. (n.d.). Plazomicin. Retrieved from ACHAOGEN: http://www.achaogen.com/plazomicin/
26. Achaogen, I. (29 June , 2015). A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP). Retrieved from ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02486627?term=Phase+3+Plazomicin&rank=2
27. Stapleton, A. (3 June, 2014). Intravaginal LACTIN-V for Prevention of Recurrent Urinary Tract Infection. Retrieved from ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/study/NCT00305227
28. AE, S. (2011). LACTIN-V. Retrieved from OSEL: http://oselinc.com/site/research-development/lactin-v/
29. Hudson RH, D. A. (2005). A direct synthesis of pyrrolocytosine from 5-iodocytosine. Retrieved from PubMed.gov: http://www.ncbi.nlm.nih.gov/pubmed/16247992
30. Tapiainen, T. (1 December, 2014). Cranberry-lingonberry Juice Started During Acute Infection in Prevention of Urinary Tract Infections in Children. Retrieved from ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT01861353?term=urinary+tract+infection&recr=Recruiting&rank=4
31. Roth, E. (22 August, 2013). 7 Best Remedies for Bladder Infections. Retrieved from Healthline: http://www.healthline.com/health/bladder-infection-treatments#Overview1
32. University Hospital Inselspital, B. (24 September, 2015). Treatment Comparison of Antibiotics Versus Vaginal Lactic Acid in Non-pregnant Women With Acute Symptomatic Bacterial Vaginosis. Retrieved from ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/study/NCT02042287?term=vaginosis&rank=51&show_desc=Y#desc
33. Harmanli OH, C. G. (May, 2000). Urinary tract infections in women with bacterial vaginosis. Retrieved from PubMed.gov: http://www.ncbi.nlm.nih.gov/pubmed/10775734
34. Jerry R. Balentine, D. F. (2 September, 2015). Urinary Tract Infections (UTIs). Retrieved from MedicineNet.com: http://www.medicinenet.com/urinary_tract_infection/page3.htm
35. Brooks, M. (20 April, 2011). Probiotic May Help Prevent Recurrent Urinary Tract Infection. Retrieved from Medscape: http://www.medscape.com/viewarticle/741144

 

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