Infections and Inflammatory Conditions

Urinary tract infection: definitions and epidemiology

Definitions

Urinary tract infection (UTI)

UTI is currently defined as the inflammatory response of the urothelium to bacterial invasion. This inflammatory response causes a constellation of symptoms. Bladder infection (cystitis) causes frequent small volume voids, urgency, suprapubic pain or discomfort, and urethral ‘burning’ on voiding (dysuria). Acute kidney infection (acute pyelonephritis) causes symptoms of fever, chills, malaise, and loin pain, often with associated LUTS of frequency, urgency, and urethral pain on voiding. The strict requirement for >10⁵ bacteria/mL of MSU specimen is no longer required to make a diagnosis of UTI. In symptomatic patients, many clinicians will now make a diagnosis of UTI with bacterial counts of >10²/mL. Current recommendations for diagnosing UTI from MSU culture is shown in Table 6.2.

Bacteriuria: is the presence of bacteria in the urine. Bacteriuria may be asymptomatic or symptomatic. Bacteriuria without pyuria indicates the presence of bacterial colonization of the urine rather than the presence of active infection.

Pyuria: is the presence of white blood cells in the urine (implying an inflammatory response of the urothelium to bacterial infection or in the absence of bacteriuria (sterile pyuria), some other pathology such as carcinoma in situ, TB infection, bladder stones, or other inflammatory conditions.

An uncomplicated UTI: is one occurring in a patient with a structurally and functionally normal urinary tract. The majority of such patients are women who respond quickly to a short course of antibiotics.

A complicated UTI: is one occurring in the presence of an underlying anatomical or functional abnormality (e.g. incomplete bladder emptying secondary to BOO or DSD in SCI), renal or bladder stones, colovesical fistula, etc. Other factors suggesting a potential complicated UTI are diabetes mellitus, immunosuppression, hospital-acquired infection, indwelling catheter, recent urinary tract intervention, and a failure of response to appropriate treatment. Most UTIs in men occur in association with a structural or functional abnormality and are, therefore, defined as complicated UTIs. Complicated UTIs take longer to respond to antibiotic treatment than uncomplicated UTIs and if there is an untreated underlying abnormality, they will usually recur within days, weeks, or months.

UTIs may be isolated, recurrent, or unresolved.

Isolated UTI: an interval of at least 6 months between infections.
Recurrent UTI: >2 infections in 6 months or 3 within 12 months. Recurrent UTI may be due to re-infection (i.e. infection by different bacteria) or bacterial persistence (infection by the same organism originating from a focus within the urinary tract). Bacterial persistence is caused by the presence of bacteria within calculi (e.g. struvite stone), within a chronically infected prostate (chronic bacterial prostatitis), within an obstructed or atrophic infected kidney, or occurs as a result of a bladder fistula (with bowel or vagina) or UD.
Unresolved infection: implies inadequate therapy and is caused by natural or acquired bacterial resistance to treatment, infection by (multiple) different organisms, or rapid re-infection.

Table 6.1 Prevalence of bacteriuria

Age	Female	Male
Infants (<1y)	1%	3%
School (<15y)	1-3%	<1%
Reproductive	4%	<1%
Elderly	20-30%	10%

General risk factors for bacteriuria

Female sex.
Increasing age.
Low oestrogen states (menopause).
Pregnancy.
Diabetes mellitus.
Previous UTI.
Institutionalized elderly patients.
Indwelling catheters.
Stone disease (kidney, bladder).
Genitourinary tract malformation.
Voiding dysfunction (including obstruction).

Table 6.2 Recommended criteria for diagnosing UTI 1

Type of UTI	Urine culture (cfu/mL )
Acute uncomplicated UTI /cystitis in women	>10³
Acute uncomplicated pyelonephritis	>10⁴
Complicated UTI	>10⁵ in women; >10⁴ in men
Asymptomatic bacteriuria	>10⁵ in two consecutive MSU cultures >24h apart
Recurrent UTI	<10³
cfu/mL = colony forming units/mL ; MSU = midstream urine.

1 Grabe M, Bjerklund-Jphansen TE, Botto H, et al. Guidelines on Urological Infections. European Association of Urology Guidelines 2011 edition.

Urinary tract infection: microbiology

Most UTIs are caused by faecal-derived bacteria that are facultative anaerobes (i.e. they can grow under both anaerobic and non-anaerobic conditions) (see Table 6.3).

Uncomplicated UTI

Infection in a subject with a normal functional and anatomical urinary tract. Most UTIs are bacterial in origin. The most common cause is Escherichia coli (E. coli), a Gram-negative bacillus, which accounts for 85% of community-acquired and 50% of hospital-acquired infections. Other common causative organisms include Staphylococcus saprophyticus, Proteus mirabilis, and Klebsiella.

Complicated UTI

Infection in a subject with a functional or anatomical abnormality of the urinary tract, underlying risk factors, or failure to respond to therapy. E. coli is responsible for up to 50% of cases. Other causes include Enterococci, Staphylococci, Pseudomonas, Proteus, Klebsiella, and other enterobacteria.

Route of infection

Ascending

The vast majority of UTIs result from infection ascending retrogradely up the urethra. Bacteria, derived from the large bowel, colonize the perineum, vagina, and distal urethra. They ascend along the urethra to the bladder (increased risk in females as urethra shorter), causing cystitis. From the bladder, they may ascend via the ureters to involve the kidneys (pyelonephritis). Reflux is not necessary for infection to ascend to the kidneys, but it will encourage ascending infection as will any process that impairs ureteric peristalsis (e.g. ureteric obstruction, Gram-negative organisms and endotoxins, pregnancy). Infection that ascends to involve the kidneys is also more likely where the infecting organism has P pili (filamentous protein appendages, also known as fimbriae, which allow binding of bacteria to the surface of epithelial cells).

Haematogenous: uncommon, but is seen with Staphylococcus (S.) aureus, Candida fungaemia, and Mycobacterium (M.) tuberculosis (causing TB).

Infection via lymphatics: seen rarely in inflammatory bowel disease and from retroperitoneal abscess.

Table 6.3 Classification of bacteria and other organisms associated with the urinary tract and UTI

Cocci	Gram +ve Aerobes	Streptococcus	Non-haemolytic: Enterococcus (E. faecalis)
			α -haemolytic: S. viridians; β -haemolytic streptococcus
		Staphylococcus	S. saprophyticus (causes ∽10% of symptomatic lower UTIs in young, sexually active women)
			S. aureus
			S. epidermidis
	Gram -ve Aerobes	Neisseria	N. gonorrhoeae
Bacilli (rods)	Gram +ve Aerobes	Corynebacteria	C. urealyticium
	Acid-fast	Mycobacteria	M. tuberculosis
	Gram +ve Anaerobes^*	Lactobacillus	(i.e. L . crispatis, L . Jensenii are common vaginal commensal organisms)
			Clostridium perfringens
	Gram -ve Aerobes	Enterobacteriacaeae	Escherichia coli, Proteus mirabilis, Klebsiella sp.
		Non-fermenters	Pseudomonas aeruginosa
	Gram -ve Anaerobes^*	Bacteroides	Bacteroides fragilis
Other organisms		Chlamydia	C. trachomatis
		Mycoplasma	M. hominus
		Ureaplasma	U . urealyticum (cause UTI in patients with indwelling catheters
		Candida	C. albicans
^* Anaerobic infections of the bladder and kidney are uncommon—anaerobes are normal commensals of the perineum, vagina, and distal urethra. However, infections of the urinary system that produce pus (e.g. scrotal, prostatic, or perinephric abscesses) can be caused by anaerobic organisms (e.g. Bacteroides sp. such as Bacteroides fragilis, Fusobacterium sp., anaerobic cocci, and Clostridium perfringens).

Factors increasing bacterial virulence

Adhesion mechanisms

Many Gram-negative bacteria have pili (also known as fimbriae) on their cell surface, which aid attachment to urothelial cells of the host. A typical piliated cell may contain 100-400 pili. Pili are 5-10nm in diameter and up to 2µm long. E. coli produces a number of antigenically and functionally different types of pili on the same cell; other strains may produce only a single type and in some isolates, no pili are seen (such as Dr adhesin associated with UTI in pregnant women and children). Pili are defined functionally by their ability to mediate haemagglutination (clumping of red blood cells) of specific types of erythrocytes. Mannose-sensitive (type 1) pili are produced by all strains of E. coli and are associated with cystitis. Certain pathogenic types of E. coli also produce mannose-resistant P pili and are associated with pyelonephritis. S pili are associated with infection of both the bladder and kidneys.

Avoidance of host defence mechanisms

General: an extracellular capsule reduces immunogenicity and resists phagocytosis (E. coli). M. tuberculosis resists phagocytosis by preventing phagolysosome fusion.
Toxins: E. coli species have haemolysin activity which has a direct pathogenic effect on host erythrocytes.
Enzyme production: Proteus species produce ureases which cause the breakdown of urea in urine to ammonia, which then contributes to disease processes (struvite stone formation).

Antimicrobial resistance

Enzyme inactivation: S. aureus, N. gonorrhoeae, and enterobacteria can produce β-lactamase which hydrolyzes the β-lactam bond within the structure of some antibiotics so inactivating them. The β-lactam antibiotics are penicillins, cephalosporins, and carbapenems.
Altered permeability: access of the antibiotic to the bacteria is prevented by alterations in receptor activity or transport mechanisms.
Alteration of binding site: genetic variations may alter the antibiotic target, leading to drug resistance.

Host defences: factors that protect against UTI include the following.

General

Commensal flora: protect by competing for nutrients, bacteriocin production, stimulation of immune system, and altering pH.
Mechanical integrity of mucous membranes.
Mucosal secretions: lysozymes split muramic acid links in cell walls of Gram-positive organisms; lactoferrin disrupts normal metabolism of bacteria.
Urinary immunoglobulin A (IgA) inhibits bacterial adherence.

Specific

Mechanical flushing effect of urine through the urinary tract (i.e. antegrade flow of urine).
A mucopolysaccharide coating of bladder (Tamm-Horsfall protein) helps prevent bacterial attachment.
Bladder surface mucin: glycosaminoglycan (GAG) layer is an anti-adherent factor, preventing bacterial attachment to mucosa.
Low urine pH and high osmolarity reduces bacterial growth.
Female commensal flora: Lactobacillus acidophilus metabolizes glycogen into lactic acid, causing a drop in pH.
Increased rates of bladder mucosal cell exfoliation are seen during infection, which accelerates cell removal with adherent bacteria.

Lower urinary tract infection: cystitis and investigation of UTI

Cystitis: is infection and/or inflammation of the bladder.

Presentation: frequent voiding of small volumes, dysuria, urgency, offensive urine, suprapubic pain, haematuria, fever ± incontinence.

General investigation of UTI

Dipstick of MSU specimen

White blood cells (indirect testing for pyuria)

Leukocyte esterase activity detects the presence of white blood cells (WBC) in the urine. Leukocyte esterase is produced by neutrophils and causes a colour change in a chromogen salt on the dipstick. Not all patients with bacteriuria have significant pyuria (sensitivity of 75-95% for detection of infection, i.e. 5-25% of patients with infection will have a negative leukocyte esterase test, erroneously suggesting that they have no infection).

False positives (pyuria present, negative dipstick test)—concentrated urine, glycosuria, presence of urobilinogen, consumption of large amounts of ascorbic acid.
False negatives (pyuria absent, positive dipstick test)—contamination.

Remember, there are many causes for pyuria (and, therefore, a positive leukocyte esterase test occurring in the absence of bacteria on urine microscopy). This is so-called sterile pyuria and it occurs with TB infection, renal calculi, bladder calculi, glomerulonephritis, interstitial cystitis, and carcinoma in situ. Thus, the leukocyte esterase dipstick test may be truly positive in the absence of infection.

Nitrite testing (indirect testing for bacteriuria)

Nitrites are not normally found in urine and their presence suggests the possibility of bacteriuria. Many species of Gram-negative bacteria can convert nitrates to nitrites and these are detected in the urine by a reaction with the reagents on the dipstick which form a red azo dye. The specificity of the nitrite dipstick for detecting bacteriuria is >90% (false positive nitrite testing can occur with contamination). The sensitivity is 35-85% (i.e. false negatives are common—a negative dipstick in the presence of active infection) and is less accurate in urine containing <10⁵ organisms/mL. Hence, if the nitrite dipstick test is positive, the patient probably has a UTI, but a negative test often occurs in the presence of infection.

Cloudy urine, which is positive for WBCs on dipstick and is nitritepositive, is very likely to be infected.

Blood

Haemoglobin has a peroxidase-like activity, causing oxidation of a chromogen indicator on the dipstick, which changes colour when oxidized. False positives are seen with menstrual blood and dehydration.

Urinary pH usually lies between 5.5 and 6.5 (range 4.5-8). A persistent alkaline pH associated with UTI indicates a risk of stones. Urease-producing bacteria (such as Proteus mirabilis) hydrolyze urea to ammonia and carbon dioxide, leading to the formation of magnesium, calcium, ammonium phosphate stones (triple phosphate or struvite calculi).

Microscopy of MSU

False negative: low bacterial counts may make it very difficult to identify bacteria and the specimen of urine may, therefore, be deemed to be negative for bacteriuria when, in fact, there is active infection.
False positive: bacteria may be seen in the MSU in the absence of infection. This is most often due to contamination with commensals from the distal urethra and perineum (urine from a woman may contain thousands of lactobacilli and corynebacteria derived from the vagina). These bacteria are readily seen under the microscope and although they are Gram-positive, they often appear Gram-negative (Gram-variable) if stained.

If the urine specimen contains large numbers of squamous epithelial cells (cells which are derived from the foreskin, vaginal, or distal urethral epithelium), this suggests contamination of the specimen and the presence of bacteria in this situation may indicate a false positive result. The finding of pyuria and red blood cells suggests the presence of active infection.

Further investigation

Determined by the clinical scenario. If this is a one-off infection in an otherwise healthy individual, no further investigations are required. However, further investigations are required if:

The patient develops symptoms and signs of upper tract infection (loin pain, malaise, fever) and, therefore, acute pyelonephritis, a pyonephrosis or perinephric abscess is suspected.
Recurrent UTIs develop (see p. 186).
The patient is pregnant.
Unusual infecting organism (e.g. Proteus), suggesting the possibility of an infection stone.

These further investigations will include a KUB X-ray ± IVU (looking for infection stones in the kidney; avoid in pregnant women), renal USS ± cystoscopy.

Non-infective cystitis

Symptoms of cystitis can also be caused by:

Pelvic radiotherapy (radiation cystitis—bladder capacity is reduced and multiple areas of mucosal telangiectasia are seen cystoscopically).
Drug-induced cystitis (e.g. cyclophosphamide, ketamine).
Urinary tract infection: general treatment guidelines

Urinary tract infection: general treatment guidelines

Antimicrobial drug therapy

The aim is to eliminate bacterial growth from the urine. Empirical treatment involves the administration of antibiotics according to the clinical presentation and most likely causative organism before culture sensitivities are available (Table 6.4). Men are often affected by complicated UTI and may require longer treatments as may patients with uncorrectable structural or functional abnormalities (e.g. indwelling catheters, neuropathic bladders).

Bacterial resistance to drug therapy

Organisms susceptible to concentrations of an antibiotic in the urine (or serum) after the recommended clinical dosing are termed ‘sensitive’ and those that do not respond are ‘resistant’. Bacterial resistance may be intrinsic (e.g. Proteus is intrinsically resistant to nitrofurantoin) via selection of a resistant mutant during initial treatment or genetically transferred between bacteria by R plasmids. Antibiotic-resistant organisms that cause complicated UTI include Gram-negative bacteria that produce AmpC enzymes or extended spectrum β-lactamases (ESBLs) (which are often multidrug resistant) and Gram-positive cocci such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCoNS), and vancomycin-resistant enterococci (VRE). To avoid increasing resistance, it is not advisable to commence antibiotics without clinical evidence of a UTI (exceptions include asymptomatic bacteriuria in pregnancy) and local microbiology guidelines should be followed.

General preventative advice

Encourage a good fluid intake, cranberry juice, double voiding, avoid constipation. In women—voiding before and after intercourse; wiping perineum from ‘front to back’ after voiding; avoid using bubble bath or washing hair in the bath (as this affects the protective commensal organisms, the lactobacilli).

Table 6.4 Recommendations for antimicrobial therapy1

Infection	Bacteria	Initial empirical drug	Duration
Acute, uncomplicated cystitis	E. coli, Klebsiella, Proteus, Staphylococci	Nitrofurantoin Alternatives:	55-7 days
		Trimethoprim	55 days
		Co-trimoxazole	33 days
		Fluoroquinolone (ciproflox-acin)	33 days
Acute, uncomplicated pyelonephritis	E. coli, Proteus, Klebsiella, other Enterobacteriacae, Staphylococci	Fluoroquinolone Cephalosporin Alternatives:	7-10 days
		Aminopenicillin
		with beta-lactamase inhibitor (BLI )
		(amoxicillin/clavulanic acid)
		Aminoglycoside (gentamicin)
Complicated UTI	E. coli, Enterococcus, Pseudomonas, Staphylococci	Fluoroquinolone Aminopenicillin/BLI Cephalosporin	Continue for 3-5 days after control of infection/
Nosocomial^* UTI	Staphylococcus, Klebsiella, Proteus	Carbapenem (meropenem) ±Aminoglycoside	elimination of underlying cause. Parenteral
Acute complicated pyelonephritis	Enterobacter, Pseudomonas, (Candida)	For Candida: -Fluconazole -Amphotericin B	treatment is usually followed by oral antibiotics to complete course
^*Nosocomial = hospital acquired. These are general recommendations only, adapted from EAU guidelines, to fit with common UK antibi-otic use. You should be guided by your local microbiology department whose recommendations will be based on local and regional bacterial sensitivities and resistance.

1 Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on Urological Infections. European Association of Urology Guidelines 2011 edition.

Recurrent urinary tract infection

Recurrent UTI is defined as >2 infections in 6 months or 3 within 12 months. It may be due to re-infection (i.e. infection by different bacteria) or bacterial persistence (infection by the same organism originating from a focus within the urinary tract).

Bacterial persistence

Bacterial persistence usually leads to frequent recurrence of infection (within days or weeks) and the infecting organism is usually the same organism as that causing the previous infection(s). There is often an underlying functional or anatomical problem and infection will often not resolve until this has been corrected. Causes include kidney stones, the chronically infected prostate (chronic bacterial prostatitis), bacteria within an obstructed or atrophic infected kidney, vesicovaginal or colovesical fistula, and bacteria within a urethral diverticulum.

Re-infection

This usually occurs after a prolonged interval (months) from the previous infection and is often caused by a different organism than the previous infecting bacterium.

Women: with re-infection, do not usually have an underlying functional or anatomical abnormality. Re-infections are associated with increased vaginal mucosal receptivity for uropathogens and ascending colonization from faecal flora. These women cannot be cured of their predisposition to recurrent UTIs, but they can be managed by a variety of techniques (see

p. 176).

Men: with re-infection, may have underlying BOO (due to BPE or a urethral stricture), which makes them more likely to develop a repeat infection, but between infections, their urine is sterile (i.e. they do not have bacterial persistence between symptomatic UTIs). A flexible cystoscopy, post-void bladder USS for residual urine volume and in some cases, urodynamics or urethrography may be helpful in establishing the potential causes.

Both men and women with bacterial persistence usually have an underlying functional or anatomical abnormality and they can potentially be cured of their recurrent UTIs if this abnormality can be identified and corrected.

Management of women with recurrent UTIs due to re-infection

Imaging tests, including KUB X-ray and renal USS, and flexible cystoscopy, can be performed to check for potential sources of bacterial persistence (i.e. to confirm this is a ‘simple’ case of re-infection rather than one of bacterial persistence). In the absence of finding an underlying functional or anatomic abnormality, these patients cannot be cured of their tendency to recurrent urinary infection, but they can be managed in several ways.

Preventative and conservative management

Maintain a high fluid intake.
Avoidance of spermicides used with the diaphragm or on condoms. Spermicides containing nonoxynol-9 reduce vaginal colonization with lactobacilli and may enhance E. coli adherence to urothelial cells. Recommend an alternative form of contraception.
Cranberry juice or tablets (contains proanthocyanidins which inhibit bacterial adherence).
Oestrogen replacement. A lack of oestrogen in post-menopausal women causes loss of vaginal lactobacilli and increased colonization by E. coli. Oestrogen replacement (topical or systemic) can result in recolonization of the vagina with lactobacilli and help eliminate colonization with bacterial uropathogens.1
Natural yoghurt applied to the vulva and vagina can help restore normal flora, thereby improving the natural resistance to recurrent infections.
Alkalinization of the urine with potassium citrate or sodium bicarbonate can help alleviate symptoms of cystitis.

Low-dose antibiotic prophylaxis

Oral antimicrobial therapy with full-dose oral tetracyclines, ampicillin, sulphonamides, amoxicillin, and cefalexin causes resistant strains in the faecal flora and subsequent resistant UTIs. However, trimethoprim, nitrofurantoin, and low-dose cefalexin have minimal adverse effects on the faecal and vaginal flora.

Efficacy of prophylaxis: recurrences of UTI may be reduced up to 90% when compared with placebo.2 Only small doses of antimicrobial agent are required, generally given at bedtime for 6-12 months.

Symptomatic re-infection during prophylactic therapy is managed with a full therapeutic dose with the same prophylactic antibiotic or another antibiotic. Prophylaxis can then be restarted. Symptomatic re-infection immediately after cessation of prophylactic therapy is managed by restarting nightly prophylaxis.
Trimethoprim: the gut is a reservoir for organisms that colonize the periurethral area, which may cause episodes of acute cystitis in young women. Trimethoprim eradicates Gram-negative aerobic flora from the gut and vaginal fluid (i.e. it eliminates the pathogens from the infective source). Trimethoprim is also concentrated in bactericidal concentrations in the urine following an oral dose. Adverse reactions: include gastro-intestinal (GI) disturbance, rash, purities, depression of haematopoiesis, allergic reactions. Rare side effects: erythema multiforme, toxic epidermal necrolysis, photosensitivity. Use with caution in renal impairment as it can increase creatinine by competitively inhibiting tubular secretion.
Nitrofurantoin: is completely absorbed and/or inactivated in the upper intestinal tract and, therefore, has no effect on gut flora. It is present for brief periods at high concentrations in the urine and leads to repeated elimination of bacteria from the urine. Nitrofurantoin prophylaxis, therefore, does not lead to a change in vaginal or introital colonization with Enterobacteria. The bacteria colonizing
the vagina remain susceptible to nitrofurantoin because of the lack of bacterial resistance in the faecal flora. Adverse reactions: include GI upset, chronic pulmonary reactions (pulmonary fibrosis), peripheral neuropathy, allergic reactions (angioedema, anaphylaxis, urticaria, rash, and pruritus). Rare side effects: blood dyscrasias (agranulocytosis, thrombocytopenia, aplastic anaemia), liver damage. Risk of an adverse reaction increases with age (particularly >50y old).
Cefalexin: at 250mg or less nightly is an excellent prophylactic agent because faecal resistance does not develop at this low dosage. Adverse reactions: GI upset, allergic reactions.
Fluoroquinolones (e.g. ciprofloxacin): short courses eradicate Enterobacteria from faecal and vaginal flora. The (longer term) use of ciprofloxacin is increasingly discouraged, with some hospitals not allowing its routine use in an attempt to reduce the incidence of symptomatic Clostridium difficile.
- Adverse reactions: tendon damage (including rupture) which may occur within 48h of starting treatment. The risk of tendon rupture is increased by the concomitant use of corticosteroids.
- Contraindicated: in patients with a history of tendon disorders related to quinolone use. Discontinue quinolone immediately if tendonitis suspected (elderly patients are most prone to tendonitis).
- Other adverse reactions: GI upset, Stevens-Johnson syndrome, allergic reactions.

Post-intercourse antibiotic prophylaxis

Sexual intercourse has been established as an important risk factor for acute cystitis in women and women using the diaphragm have a significantly greater risk of UTI those using other contraceptive methods.3 Postintercourse therapy with antimicrobials, such as nitrofurantoin, cefalexin, or trimethoprim, taken as a single dose effectively reduces the incidence of re-infection.

Self-start therapy

Women keep a home supply of an antibiotic (e.g. trimethoprim, nitrofurantoin, or a fluoroquinolone) and start treatment when they develop symptoms suggestive of UTI.

Management of men and women with recurrent UTIs due to bacterial persistence

Investigation

These are directed at identifying the potential causes of bacterial persistence outlined on

p. 186.

KUB X-ray to detect radio-opaque renal calculi.
Renal USS to detect hydronephrosis and renal calculi. If hydronephrosis is present, but the ureter is not dilated, consider the possibility of a radio-opaque stone obstructing the pelviureteric junction (PUJ) or a PUJ obstruction (PUJO).
Determination of PVR volume by bladder USS.
IVU or CTU where a stone is suspected, but not identified on plain X-ray or USS.
Flexible cystoscopy to identify possible causes of recurrent UTIs such as bladder stones, an underlying bladder cancer (rare), urethral or bladder neck stricture, or fistula.

1 Raz R, Stamm WE (1993) A controlled trial in intravaginal estriol in postmenopausal women with recurrent urinary tract infection. N Engl J Med 329:753.

2 Nicolle LE, Ronald AR (1987) Recurrent urinary tract infection in adult women: diagnosis and treatment. Infect Dis Clin North Am 1:793.

3 Fihn SD, Latham RH, Roberts P, et al. (1985) Association between diaphragm use and urinary tract infection. JAMA 254:240.

Upper urinary tract infection: acute pyelonephritis

Definition: pyelonephritis is an inflammation of the kidney and renal pelvis.

Presentation

Clinical diagnosis is based on the presence of fever, flank pain, bacteriuria, pyuria, often with an elevated white cell count. Nausea and vomiting are common. It may affect one or both kidneys. There are usually accompanying symptoms suggestive of a lower UTI (frequency, urgency, suprapubic pain, urethral burning or pain on voiding) responsible for the subsequent ascending infection to the kidney.

Differential diagnosis: includes cholecystitis, pancreatitis, diverticulitis, appendicitis.

Risk factors: females ” class=LK href=”javascript:void(0)” target=right xpath=”/CT{06b9ee1beed594192fe83c602fef4af9a59e63f847d6df62927a64e26327cf0c46df57f267338dd5ad66fd15d0cd53c0}/ID(AB2-M1)”>> males, VUR, urinary tract obstruction, calculi, SCI (neuropathic bladder), diabetes mellitus, congenital malformation, pregnancy, indwelling catheters, urinary tract instrumentation.

Pathogenesis and microbiology: initially, there is patchy infiltration of neutrophils and bacteria in the parenchyma. Later changes include the formation of inflammatory bands extending from the renal papilla to cortex and small cortical abscesses. Eighty percent of infections are secondary to E. coli (possessing P pili virulence factors). Other infecting organisms: Enterococci (E. faecalis), Klebsiella, Proteus, Staphylococci, and Pseudomonas. Any process interfering with ureteric peristalsis (i.e. obstruction) may assist in retrograde bacterial ascent from bladder to kidney.

Investigation and treatment

For those patients who have a fever, but are not systemically unwell, outpatient management is reasonable. Culture the urine and start oral antibiotics according to your local antibiotic policy (which will be based on the likely infecting organisms and their likely antibiotic sensitivity). EAU guidelines1 give several suggestions, including fluoroquinolones (i.e. oral ciprofloxacin, 500 mg bd) for 7-10 days. Aminopenicillin with β-lactamase inhibitor (i.e. co-amoxiclav) is an alternative.
If the patient is systemically unwell, resuscitate, culture urine and blood, start intravenous (IV) fluids and IV antibiotics, again selecting the antibiotic according to your local antibiotic policy. EAU guideline1 options include IV aminopenicillin with β-lactamase inhibitor ± aminoglycoside (gentamicin) with monitoring of levels. Alternatives include cephalosporins (i.e. ceftazidime) and carbapenems (i.e. meropenem).
Arrange a KUB X-ray and renal USS to see if there is an underlying upper tract abnormality (such as a ureteric stone), unexplained
hydronephrosis, or (rarely) gas surrounding the kidney (suggesting emphysematous pyelonephritis).
If the patient does not respond within 3 days to a regimen of appropriate IV antibiotics (confirmed on sensitivities), arrange a computed tomography urogram (CTU). Failure of response to treatment suggests possible pyonephrosis (i.e. pus in the kidney which will only respond to drainage), a perinephric abscess (which again will only respond to drainage), or emphysematous pyelonephritis. The CTU may demonstrate an obstructing ureteric calculus that may have been missed on the KUB X-ray and USS may show a perinephric abscess. A pyonephrosis should be drained by insertion of a percutaneous nephrostomy tube. A perinephric abscess should also be drained by insertion of a drain percutaneously.
If the patient responds to IV antibiotics, change to an oral antibiotic of appropriate sensitivity when they become apyrexial (3-5 days after control of infection or after elimination of underlying problem) and continue this for approximately 10-14 days.

1 Grabe M, Bjerklund-Johansen TE, Botto H, et al. (2011) Guidelines on urological infections. European Association of Urology Guidelines 2011 [online]. Available from:

http://www. uroweb.org/gls/pdf/15_Urological_Infections.pdf.

Pyonephrosis and perinephric abscess

Pyonephrosis

An infected hydronephrosis where pus accumulates within the renal pelvis and calyces. It is associated with damage to the parenchyma, resulting in loss of renal function. The causes are essentially those of hydronephrosis where infection has supervened (e.g. ureteric obstruction by stone, PUJ obstruction).

Presentation

Patients with pyonephrosis are usually very unwell with a high fever, flank pain, and tenderness.

Risk factors

Stone disease, previous UTI, or surgery.

Investigation

KUB X-ray: may show an air urogram (secondary to gas produced by infecting pathogens).
USS: shows evidence of obstruction (hydronephrosis) with a dilated collecting system, fluid-debris levels or air in the collecting system.
CT: shows hydronephrosis, stranding of perinephric fat, and thickening of renal pelvis.

Perinephric abscess

Perinephric abscess develops as a consequence of extension of infection outside the parenchyma of the kidney in acute pyelonephritis, from rupture of a cortical abscess, or if obstruction in an infected kidney (i.e. pyonephrosis) is not drained quickly enough. More rarely, it is due to haematogenous spread of infection from a distant site or infection from adjacent organs (i.e. bowel). The abscess develops within Gerota’s fascia.

Risk factors

Diabetes mellitus; immunocompromise; obstructing ureteric calculus may precipitate the development of a perinephric abscess.

Causes

Perinephric abscesses are caused by S. aureus (Gram-positive), E. coli, and Proteus (Gram-negative organisms).

Presentation

Patients present with fever, unilateral flank tenderness, and ≥5 day history of milder symptoms. Failure of a seemingly straightforward case of acute pyelonephritis to respond to IV antibiotics within a few days also arouses suspicion that there is an accumulation of pus in or around the kidney or obstruction with infection.

A flank mass with overlying skin erythema and oedema may be observed. Extension of the thigh (stretching the psoas) may trigger pain and psoas spasm may cause a reactive scoliosis.

Investigation

FBC: shows raised white cell count and CRP.
Urine analysis and cultures.
Blood cultures: are required to identify organisms responsible for the haematogenous spread of infection (i.e. S. aureus).
USS or CTU: can identify size, site, and extension of retroperitoneal abscesses and allow radiographically controlled percutaneous drainage of the abscess.

Treatment

Commence broad-spectrum IV antibiotics (i.e. aminoglycoside and aminopenicillin with β-lactamase inhibitor) until culture sensitivities are available. Drainage of the collection should be performed, either radiographically or by formal open incision and drainage if the pus collection is large. IV antibiotics should be used initially and followed by a course of oral antimicrobials until clinical review and re-imaging confirms resolution of infection. Nephrectomy may be required for extensive renal involvement or a non-functioning infected kidney.

Acute pyelonephritis, pyonephrosis, perinephric abscess, and emphysematous pyelonephritis—making the diagnosis

Maintaining a degree of suspicion in all cases of presumed acute pyelonephritis is the single most important thing in allowing an early diagnosis of complicated renal infection such as a pyonephrosis, perinephric abscess, or emphysematous pyelonephritis to be made. If the patient is very unwell, is diabetic, or has a history suggestive of stones, they may have something more than just a simple acute pyelonephritis. Specifically ask about a history of sudden onset of severe flank pain a few days earlier, suggesting the possibility that a stone passed into the ureter, with later infection supervening. Arranging a KUB X-ray and renal USS in all patients with suspected renal infection will demonstrate the presence of hydronephrosis, pus, or stones.

Clinical indicators suggesting a more complex form of renal infection are length of symptoms prior to treatment and time taken to respond to treatment. Most patients with uncomplicated acute pyelonephritis have been symptomatic for <5 days. Most with, for example, a perinephric abscess have been symptomatic for >5 days prior to hospitalization. Patients with acute pyelonephritis became afebrile within 4-5 days of treatment with an appropriate antibiotic whereas those with perinephric abscesses remained pyrexial.1

1 Thorley JD, Jones SR, Sanford JP (1974) Perinephric abscess. Medicine 53:441.

Other forms of pyelonephritis

Emphysematous pyelonephritis (EPN)

A rare severe form of acute necrotizing pyelonephritis caused by gasforming organisms. It is characterized by fever and abdominal pain, with radiographic evidence of gas within and around the kidney (on plain radiography or CT) (Fig. 6.1). It usually occurs in diabetics (93% in a contemporary series)1 and, in many cases, is precipitated by urinary obstruction by, for example, ureteric stones. The high glucose levels associated with poorly controlled diabetes provides an ideal environment for fermentation by Enterobacteria, carbon dioxide being produced during this process. EPN is commonly caused by E. coli, less frequently by Klebsiella and Proteus.

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