Q. A 45-year-old woman has been referred by the GP with a history of recurrent UTIs. How will you approach this case?
A. I would first take a thorough history. In my history I would try to establish whether this is a case of an isolated or recurrent UTI, cystitis or pyelonephritis and whether there are any features which make this a complicated infection. I would also like to exclude symptoms which may be attributable to a sexually transmitted infection such as itching, vaginal discharge or any symptoms in the partner. I would make sure that all the midstream specimen of urine (MSU) results from GP are available so that it is possible to ascertain which organism caused the infection or whether there is a non-infective process, i.e. interstitial cystitis, stones, Carcinoma in situ (CIS). The MSU results would also allow me to differentiate re-infection from persistence and the number of confirmed UTIs in 1 year.
I would then ask about their past medical history (diabetes, stones, constipation, neurological illness or previous UTIs as a child). This would help differentiation between a complicated and uncomplicated UTI. It is important to establish whether there is a family history of UTIs (UTIs associated with ABO blood group antigen non-secretors, Lewis non- secretor or P blood group secretors). The pregnancy status of the patient should always be established and whether they are on an oral contraceptive pill (possible interactions with antibiotics).
Q. What will you look for on clinical examination?
A. On physical examination (with a chaperone), I would aim to identify any underlying anatomical predisposing factors such as a palpable kidney or a palpable bladder (incomplete emptying) and whether there is any loin tenderness. On vaginal examination (PV) (again with a chaperone) I would ascertain the state of tissue oestrogenisation, the presence or absence of genital prolapse (cystocele) and/or urethral diverticulum. I would also perform a focussed neurological examination.
Q. Which investigations will you request in this case?
A. I would in general request urine dipstick followed by an MSU for urine microscopy and C and S, an x-ray kidney, ureter and bladder (KUB) and a renal tract ultrasound (USS) with a post-void residual (PVR) measurement.
Q. What findings on urinalysis suggest the presence of an infection?
A. The presence of blood, leucocytes and nitrites. I would also note the urinary pH.
Q. Can you explain how urinary dipstick analysis works?
A. Blood: the chromogen indicator on the dipstick, orthotolidine, is a peroxidase substrate.
When haemoglobin, which contains peroxidase activity, comes in contact with orthotolidine, an oxidation reaction takes place resulting in colour change (blue colour) of the indicator. False-positives (oxidising agents) can result from exercise, dehydration, menstrual blood, povidone iodine and hypochlorite solutions (bleach). False-negatives (reducing agents) can be due to vitamin C, gentisic acid and poorly mixed urine. Dipstick positive but microscopy negative indicates dilute urine (low specific gravity).
Leucocytes: Neutrophils (present in infected urine) produce the enzyme leucocyte esterase. This enzyme causes hydrolysis of an indoxyl carbonic acid ester (substrate on dipstick) to indoxyl, which in turn oxidizes a diazonium salt chromogen on dipstick to produce the colour change. False-positives are contamination from vaginal discharge and presence of formalin. False-negatives include high specific gravity of urine, dehydration, glycosuria, presence of urobilinogen, ingestion of large amounts of vitamin C and also if the test is read too soon (<2 min) or the sample has been left standing for too long (lysis of WBCs).
However, not all patients with bacteria in their urine (bacteriuria) have significant pyuria. The sensitivity of this dipstick test for the detection of infection is 70%-95%, meaning 5%-30% of patients with an infection will have a dipstick negative for leucocyte esterase.
Nitrites: Most gram-negative bacteria, the most common uropathogens, convert nitrates (present in urine) to nitrites (not normally present in the urine). Nitrites then react with the aromatic amine reagent on the dipstick, to form a diazonium salt. Then the diazonium salt interacts with hydroxybenzoquinolone to form a pink-coloured azo dye (Griess reaction). It usually takes 4 hours to make the Griess reaction. False-positives occur due to contamination. False-negatives include non-nitrite converting bacteria (gram-positive organisms and Pseudomonas), urine present in the bladder <4 hours, absent dietary nitrates, ascorbic acid and dilute urine (low specific gravity).
The sensitivity of nitrite dipstick detection is 35%-85% while the specificity is 92%-100%. This means that if the nitrite test is positive the patient is likely to have a UTI but a negative test often occurs although an infection is present. The combination of the nitrite test with leukocyte esterase with a positive result on either is more specific but less sensitive than either test alone (sensitivity 75%-84%, specificity 82%-98%).
Q. Why is the urinary pH important?
A. The average urine pH varies between 5.5 and 6.5. A consistently alkaline pH >7.5 in the presence of a UTI suggests the possibility of stones. Certain organisms (Proteus, Klebsiella, Staphylococcus, Pseudomonas, Providencia, Serratia) produce the enzyme urease, which catalyses hydrolysis of urea into carbon dioxide and ammonia. Ammonia raises the pH of urine causing precipitation of calcium magnesium ammonium phosphate to form staghorn stones.
Q. How would you ask a patient to take a urine sample which is to be sent for microscopy and culture?
A. In female patients, I would ask for an MSU sample to be collected by asking them to spread the labia, wash and cleanse the periurethral area with a moist gauze from front to back, void the first 100-150 mL of urine in the toilet and then place a wide-mouthed sterile container to collect the next 10-15 mL.
In circumcised men, no special preparation is required. I would ask uncircumcised men to retract their foreskin, wash their glans penis with soap and rinse with water, keep the foreskin retracted and then collect 10-15 mL of midstream urine as previously described.
The collected sample should be cultured within a couple of hours and if that is not possible, refrigerated immediately and then cultured within 24 hours.
For microscopy, sediment is obtained by centrifuging 5-10 mL of the sample for 5 minutes at 2000 rpm and this is then examined for the presence of bacteria and white blood cells.
For culture, 0.1 mL of urine is delivered onto each half of a split-agar plate, which contains blood agar on one half for gram-positive organisms and eosin-methylene blue (EMB) on the other half for gram-negative organisms. The number of colonies is then estimated after an overnight incubation.
Q. How is Gram staining performed?
A. Gram staining is performed in the following manner: The bacterial smear is stained on a slide with crystal violet for 1-2 minutes. This is then poured off and Gram’s iodine is added for 1-2 minutes. After this time, the iodine is poured off and the stain is then decolourised by washing the slide with acetone for 2-3 seconds. The slide is washed with water and safranin counterstain added for 2 minutes. Finally, the slide is washed with water and dried.
Q. What is the basis behind the Gram stain?
A. The cell wall of Gram-positive bacteria retains the purple colour of crystal violet, whereas that of Gram-negative bacteria takes up the pink safranin counterstain.
Q. What is the microbiological definition of significant bacteriuria?
A. Kass was the first person to introduce the concept of quantitative microbiology in the diagnosis of urinary infections. In the context of pyelonephritis in pregnant women, he proposed 105 cfu/mL pure growth as a cut-off for significant bacteriuria [2]. This remained an essential criterion for the diagnosis of a UTI for many years. However, it is now known that 20%-40% of women with symptomatic UTIs present with bacteria counts of 102-104 cfu/mL of urine (pure growth) [3]. The following bacterial counts are currently considered significant in the relevant groups of patients (all pure growth) [1]:
>103 cfu/mL of MSU in acute uncomplicated cystitis in women
>104 cfu/mL of MSU in acute uncomplicated pyelonephritis in women
>104 cfu/mL of straight catheter urine sample in a complicated UTI in women
>104 cfu/mL of MSU in men (all UTIs considered complicated in men)
>105 cfu/mL of MSU in a complicated UTI in women
Q. Despite your investigations, no causes for the infections have been identified. Can you please explain to the patient why she may be getting UTIs?
A. I would explain to the patient that in the absence of an identifiable cause, recurrent UTIs are a function of the individual’s susceptibility, the virulence of the organism and the host defence mechanisms.
Q. What is meant by susceptibility to infections?
A. Studies have demonstrated that women who suffer with recurrent UTIs may be inherently more susceptible due to their increased epithelial cell receptivity for uropathogens. Pathogenic bacteria adhere more readily to the vaginal, urethral and buccal epithelial cells of susceptible women due to the presence of an increased number of receptor sites. This trait (of increased susceptibility to UTI) is associated with HLA-A3 phenotype, Lewis blood group status Le(a-b-) and Le(a+b-), P blood group secretors and ABO blood group antigen non-secretors.
Q. What is pathogenicity?
A. It is defined as the ability of an organism to cause disease.
Q. What is virulence?
A. It is the degree of pathogenicity.
Q. What are bacterial virulence factors?
A. ttey are the characteristics of uropathogens which allow them to colonise and flourish within the host. ttey can be divided into factors directed against external agents or those against the host.
1. Factors which are directed against external agents, e.g. antimicrobial resistance, can be inherited chromosomally (Proteus’ intrinsic resistance to nitrofurantoin), acquired chromosomally (mutations) or extra-chromosomally mediated (via plasmids).
2. Factors which are directed against the host include:
a. Toxin production, e.g. haemolysin.
b. Enzyme production, e.g. urease.
c. Production of antihumoral substances, e.g. IgA inactivating protein by gonorrhoea and proteus.
d. General mechanisms, e.g. penetration of host by Schistosoma spine, phage variation by organisms to change from a fimbriated to a non-fimbriated form to evade phagocytosis.
e. Adherence mechanisms - Bacterial adherence to vaginal and urothelial epithelium is a pre-requisite for the initiation of a UTI. To facilitate this process, certain uropathogens express a number of antigenically and functionally active proteins called adhesins on their cell surface. These adhesins may take the form of fimbriae or pili or may be afimbrial. The most well-known afimbrial adhesin is the Dr adhesin, associated with UTIs in children and pregnant women. The most well-described pili, found on Escherichia coli, are as follows:
i. Type 1 - Associated with E. coli causing cystitis. Also known as mannose sensitive pili, as the haemagglutination of guinea pig erythrocytes mediated by these pili is inhibited by mannose.
ii. p pili - Found strains of E. coli causing pyelonephritis. Also called mannose resistant pili, as the haemagglutination reaction is not inhibited by mannose.
iii. s pili - Associated with both bladder and kidney infection.
Q. What are the normal host defence mechanisms against UTIs?
A. A number of host defence mechanisms exist to reduce the incidence and propensity to acquire and develop urinary tract infections. These defences normally work in parallel and include:
1. The normal commensal flora of the vaginal introitus and periurethral area, e.g. lactobacilli reduce the ability of uropathogens to colonise by lowering the vaginal pH by converting glycogen to lactic acid.
2. The normal antegrade flow of urine.
3. The vaginal environment related to oestrogen and cervical IgA.
4. The physical and chemical characteristics of urine (osmolality, pH, urea and organic acid concentration).
5. The normal exfoliation of urothelial cells.
6. Tamm-Horsfall protein (secreted by cells of ascending limb of loop of Henle) - binds the type 1 pili of E. coli and thus prevents adherence.
7. The presence of an intact GAG layer.
Q. Are you aware of any risk factors for the development of recurrent UTIs?
A. There are certain factors which increase the propensity to develop recurrent urinary tract infections. These may be divided into general and specific factors.
The general factors are applicable to all patient groups and include the following:
1. Factors that reduce the normal antegrade flow of urine such as bladder outflow obstruction, low fluid intake and a neurogenic bladder
2. Factors that promote bacterial colonisation such as sexual intercourse, the use of spermicides and vaginal oestrogen depletion
3. Factors that facilitate the retrograde ascent of pathogens such as female gender, the presence of an indwelling catheter, urinary/faecal incontinence and incomplete bladder emptying with ischaemia of the bladder wall
4. Factors that reduce the ability of the immune system to fight infection such as diabetes mellitus, steroid use or HIV positivity
Certain specific factors are applicable to females of different age groups such as:
1. Premenopausal women
a. Sexual intercourse
b. Use of spermicide
c. A new sexual partner
d. Previous UTIs
e. Age at first UTI
f. Maternal history of UTI
2. Pregnant women
a. UTI in non-pregnant state
b. Asymptomatic bacteriuria
c. Length of gravidity (maximum between weeks 9-17)
3. Menopausal women
a. History of UTI before menopause
b. Urinary incontinence
c. Atrophic vaginitis due to oestrogen deficiency
d. Cystocele
e. Increased post-void urine volume
f. Blood group antigen secretory status
g. Urine catheterisation and functional status
h. Deterioration in elderly institutionalised women
Q. What are opportunistic infections?
A. ttey are infections caused by non-pathogens (e.g. commensals) due to a weakened host defence mechanisms.
Q. You have found no cause for infections in this woman. How will you manage her?
A. As the investigations have revealed no reversible factors, it is unfortunately not possible to ensure her recurrent UTIs will not re-occur. I would explain to the patient that the aim of her management in her case would be to first control her symptoms and second to reduce the frequency of infections. To this effect, I would first give her general advice such as to:
1. Ensure a high fluid intake.
2. Void before and after sexual intercourse.
3. Avoid detergents in her bath.
4. Avoid spermicidal contraceptives as spermicides promote colonisation of pathogens by destroying the commensal bacterial flora.
5. Try to keep her urine acidic if possible.
6. Consider applying lactobacilli topically to the vaginal area (bioyoghurt).
7. Apply topical oestrogen to the vagina (if there is evidence of vaginal atrophy) to eliminate pathogenic colonisation by restoring normal vaginal environment and recolonisation with lactobacilli.
8. Encourage a regular daily intake of cranberry juice or cranberry tablets. It is known that the active ingredient proanthocyanidins block bacterial adherence to urothelium and reduce frequency of infections by up to 12%-20%.
More specifically, I would then counsel the patient regarding the potential use of antimicrobial therapy. ttree regimes are available depending upon the frequency of UTIs, relationship with intercourse and preference and acceptability of the patient:
1. Self-start intermittent therapy usually involves a 3-day course of a quinolone, trimethoprim or nitrofurantoin at full therapeutic dose. These may be initiated by the patient upon the onset of symptoms. The patient is asked to take an MSU sample before starting treatment and keep it in the fridge. If the antibiotics are successful then the MSU sample does not necessarily need to be cultured. However if the symptoms do not resolve then the sample can be used to assess bacterial sensitivities. The literature suggests that 3-day courses are superior to single-dose therapy and equivalent to longer courses with
fewer side effects [4]. However, 7-day courses are recommended for men and for women with symptoms for >1 week or with complicating factors.
2. Post-intercourse prophylaxis involves a single dose of a quinolone, trimethoprim, cephalexin or nitrofurantoin to be taken immediately after intercourse if UTIs are closely related to sexual activity [5].
3. Low-dose long-term antibiotic prophylaxis works by eliminating the introital and enteric reservoirs of pathogenic bacteria and does not seem to cause reinfections with resistant organisms. It is prescribed in the form of one tablet every night of trimethoprim (100 mg), cephalexin (250 mg), nitrofurantoin (50 mg) or a quinolone (e.g. ciprofloxacin 250 mg) for 6-12 months [6]. In general, breakthrough infections should be treated by therapeutic courses of a different antibiotic chosen on the basis of sensitivities (if available) and prophylaxis resumed after treatment. Recurrences may be reduced by up to 95%. However, prophylaxis does not alter the long-term baseline infection rate and ~60% women start getting infections again a few months after stopping the regime [1].
Q. You find out she is now pregnant. How common are UTIs in pregnancy?
A. Urinary infections are not uncommon in pregnancy. Approximately 4%-7% of pregnant females have asymptomatic bacteriuria (same percentage as that of normal population). However, of these, 20%-40% will develop pyelonephritis during pregnancy (usually in the third trimester). Hence, pregnancy is one condition where asymptomatic bacteriuria should be treated.
Q. Which antibiotics may be used safely in pregnancy and what other precautions are required?
A. The safe antibiotics during pregnancy are penicillins and cephalosporins. Nitrofurantoin may be used in the first and second trimesters only. The antibiotics to avoid during pregnancy are as follows:
|
Tetracyclines |
All trimesters |
|
Quinolones |
All trimesters |
|
Trimethoprim |
First trimester |
|
Aminoglycosides |
Second and third trimesters |
|
Chloramphenicol |
Third trimester |
|
Sulphonamide |
Third trimester |
|
Nitrofurantoin |
Third trimester |
It is very important that once the treatment has been completed a negative urinary culture is performed to confirm eradication of the bacteria. This is in contrast to simple uncomplicated UTIs where this is not necessary.
Q. How would you treat recurrent UTIs in pregnancy?
A. In case of recurrent UTIs in pregnancy a low dose of cephalexin, 125-250 mg daily, is usually safe and effective.
Q. Can you describe the mode of action/side effects of the common antibiotics?
A. The mode of action and the side effects of the most common antibiotics are listed in Table 9.1.
Table 9.1 The mode of action and the side effects of the most common antibiotics used in treatment of UTI
|
Agent |
Action |
Mode of action |
Common side effects and cautions |
Relevance in pregnancy |
|
Penicillins |
Bactericidal |
Interference with bacterial cell wall synthesis |
Hypersensitivity, diarrhoea |
Safe |
|
Cephalosporins |
Bactericidal |
Interference with bacterial cell wall synthesis |
Hypersensitivity, diarrhoea |
Safe |
|
Macrolides (erythromycin, etc.) |
Bacteriostatic |
Inhibition of ribosomal protein synthesis |
Safe |
|
|
Quinolones (ciprofloxacin, etc.) |
Bacteriostatic |
Prevent DNA replication by inhibiting DNA gyrase |
Tendon damage (higher risk when given with steroids), diarrhoea, contraindicated in epileptics, interaction with warfarin |
Unsafe |
|
Tetracyclines |
Bacteriostatic |
Inhibition of ribosomal protein synthesis |
Hepatotoxicity, deposition in growing bones and teeth |
Unsafe |
|
Trimethoprim |
Bacteriostatic |
Prevents DNA replication by inhibiting dihydrofolate reductase |
Unsafe in first trimester |
|
|
Aminoglycosides (gentamicin) |
Bactericidal |
Inhibition of ribosomal protein synthesis |
Nephrotoxicity, ototoxicity, impairs neuromuscular transmission, caution in elderly and those with renal impairment |
Unsafe in second and third trimesters |
|
Nitrofurantoin |
Bactericidal |
Damages bacterial DNA by inhibiting multiple enzyme systems |
Acute and chronic lung toxicity, hepatotoxicity, allergic reactions, inadequate urine concentration at GFR <50 |
Unsafe in third trimester |
Q. How do you administer therapeutic doses of gentamicin?
A. I use gentamicin at a single daily dose of 3-7 mg/kg body weight based on the Hartford protocol as long as there are no contraindications. The advantages of this regime include convenience for the patients and staff, need to check levels less frequently and lower risk of nephrotoxicity as too many peak serum levels are avoided and a more steady level is achieved. The treatment outcome is better as the ratio of peak serum concentration to minimum inhibitory concentration is higher. Subsequent interval adjustments are made by using a single concentration in serum and hospitals use their own protocols for monitoring of once- daily therapy.
An example of one such protocol is as follows:
Give the first dose when indicated
Give the second and subsequent doses at 1700 hours the next day
Check gentamicin levels after the third dose at 1200 hours
Give the next dose based on the levels:
<1 mg/L - Same dose
1-2 mg/L - Reduce dose by 25% and re-check levels before next dose
>2 mg/L - Omit that day’s dose, re-check levels next day