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Urinary tract infections in females

Approximately 10 per cent of females are diagnosed with a urinary tract infection (UTI) annually and over 50 per cent of females will have at least one UTI during their lifetime. Typically, uncomplicated UTIs occur in late ad­olescence and during the second and fourth decades, with up to 30-to-40 per cent of females aged 20-to-40 years having a history of UTIs. Risk factors for UTIs include sexual inter­course, the use of spermicides and as­cending bowel flora. After the initial infection, many patients tend to have recurrence, with 25-to-50 per cent of patients having another infection within one year.

In females, UTIs are among the most common conditions requir­ing medical treatment and occur because of interactions between a uropathogen and host. The patho­genesis of UTIs within the urinary tract involves several processes. In­itially, the uropathogen attaches to the epithelial surface; it subsequently colonises and disseminates through­out the mucosa, causing tissue dam­age. After the initial colonisation pe­riod, pathogens can ascend into the urinary bladder, resulting in sympto­matic or asymptomatic bacteriuria. Further progression may lead to py­elonephritis and renal impairment. Specific virulence factors residing on the uropathogen’s membrane are re­sponsible for bacterial resistance to the normally effective defence mech­anisms of the host. Many bacterial adhesins with epithelial binding sites have been identified. Understand­ing both pathogenic and anti-adher­ence bacterial mechanisms will allow healthcare professionals to consider appropriate methods for prevention and management of UTIs.

Routes of infection

In healthy females, most uropatho­gens originate from rectal flora and en­ter the urinary tract through the ure­thra into the bladder (see Figure 1). This is known as the ascending route and uropathogens initially adhere to and colonise urothelium of the dis­tal urethra. In patients with an estab­lished UTI, up to 50 per cent of infec­tions may ascend into the upper uri­nary tracts and most episodes of pye­lonephritis are caused by ascension of bacteria from the bladder through the ureter and into the renal pelvis. Bac­terial ascent is enhanced in pregnan­cy and ureteral obstruction, as these medical conditions inhibit ureteral peristalsis. Bacteria that reach the re­nal pelvis can penetrate the renal pa­renchyma through the collecting ducts and disrupt renal tubules.

In healthy individuals, infection of the kidney through the haematoge­nous route is uncommon. Occasion­ally, the renal parenchyma may be breached in patients with Staphylo­coccus aureus bacteraemia or Can­dida fungaemia that originate from oral sources in immunosuppressed patients. On rare occasions, bacteria from adjacent organs may penetrate the urinary tract via the lymphatics. Conditions associated with the lym­phatic route are retroperitoneal ab­scesses and severe bowel infections.

Clinical presentation

Typically, a UTI presents with symptoms that include dysuria, py­rexia, frequency, urgency and su­prapubic pain. Foul-smelling urine and haematuria may also develop. The likelihood of a UTI in female pa­tients presenting with these symp­toms ranges from 50-to-90 per cent. Differential diagnosis includes vag­initis, sexually-transmitted infec­tions (STIs) and urethral patholo­gy. Specific features within the pa­tient’s history, physical examina­tion and voided urine may differen­tiate between vaginitis, urethral in­fections caused by STIs and other miscellaneous conditions associat­ed with dysuria. Characteristic fea­tures of vaginitis include irritative voiding with vaginal irritation and an insidious onset. Urinary symp­toms such as frequency, suprapu­bic pain and haematuria are usual­ly absent. The patient may also give a history of vaginal discharge and multiple sexual partners. Common causes of STIs are herpes simplex virus (HSV), gonorrhoea and chla­mydia. Urethritis also causes sub-acute dysuria and is associated with a history of urethral discharge and multiple sexual partners.

Risk factors

The most notable risk factors for UTIs in females are prior UTIs and frequent or recent sexual activi­ty. The relative odds for a UTI dur­ing the first 48 hours after sexual in­tercourse are increased by 60-fold and spermicidal agents increase the risk of infection from E.coli or S.saprophyticus by two- to three-fold. Females that frequently devel­op recurrent UTIs are more likely to have a maternal history of the condi­tion and to have developed their first episode at an early age. In healthy postmenopausal females, sexual ac­tivity is a less important predictor of UTI and oestrogen deficiency is be­lieved to play a greater role. Recur­rent UTIs in postmenopausal fe­males are more common in patients with cystoceles, urinary inconti­nence and a previous history of gen­itourinary surgery. Female patients with diabetes mellitus (DM) are twice as likely to develop a UTI com­pared to non-diabetic females. The risk of UTI also increases in elderly females residing in institutionalised settings, with the risk of infection showing a direct correlation with in­creasing age and physical disability.

Laboratory diagnosis

A laboratory diagnosis is based on microscopic urinalysis that in­dicates the presence of pyuria, bac­teriuria and haematuria. Pyuria on microscopy has a sensitivity of 95 per cent and a specificity of 70 per cent. The presence of bacteriu­ria has a sensitivity of 40-to-70 per cent and a specificity of 85-to-90 per cent, depending on the number of bacteria identified. Dipstick anal­yses for bacteria (nitrite) or pyuria (leukocyte esterase) are useful but remain less sensitive than micro­scopic assessment of urine. The ac­curacy of the findings on a culture of mid-stream urine (MSU) depends on how a positive urine culture is defined. Traditionally, ≥105cfu/ml is applied to a voided urine sam­ple. Although the specificity is high, the sensitivity is approximately 50 per cent. Lowering the threshold to ≥102cfu/mL in young females with suspected UTI raises the sen­sitivity without affecting the speci­ficity. Therefore, urine culture re­mains the definitive diagnostic in­vestigation for UTI and the pres­ence of ≥102cfu/mL of urine indi­cates active infection. E.coli is the responsible uropathogen in 75-to- 90 per cent of female patients and S.saprophyticus accounts for 10-20 per cent of cases. Less common or­ganisms are Klebsiella, Proteus and Enterococci.

Management

A three-day course of oral trimeth­oprim-sulfamethoxazole (TMP-SMX) results in eradication of path­ogens within seven days after com­mencing treatment in approximate­ly 94 per cent of females. Single-dose treatment is less efficacious than the three-day course, with eradication rates approaching 87 per cent. How­ever, single-dose treatment is as­sociated with fewer side-effects (11 per cent versus 18 per cent). TMP-SMX is effective and inexpensive for empirical therapy. Therefore, TMP-SMX is recommended in are­as where the prevalence of resistance to these drugs among E.coli strains causing UTI is <20 per cent. When used alone, TMP is as efficacious as TMP-SMX and is associated with few­er side-effects, probably because of the absence of the sulfa component. It can be prescribed to patients who are allergic to sulfa. Many recent studies have demonstrated that resistance to TMP-SMX is increasing globally (see Table 1). One study from Israel dem­onstrated that 29 per cent of cultures grew TMP-SMX-resistant organisms in UTI patients. In this study, micro­biological cure was achieved in 86 per cent of patients with TMP-SMX susceptible micro-organisms but in only 42 per cent of those with TMP-SMX-resistant organisms. Another prospective study from the UK dem­onstrated resistance to TMP in 13.9 per cent of isolates, and patients with resistant isolates had a longer medi­an time to symptom resolution (sev­en versus four days; p=0.0002), more frequent revisits to their at­tending physician (39 per cent ver­sus 6 per cent in the first week, p<0.0001), more subsequent antibi­otics (36 per cent versus 4 per cent in the first week, p<0.0001) and high­er rates of subsequent bacteria at one month (42 per cent versus 20 per cent with susceptible isolates). Stud­ies from the US have demonstrated TMP-SMX resistance rates of 15-to- 23 per cent in isolates from patients with acute uncomplicated UTIs. In a study from Japan, 17 per cent of iso­lates from patients with UTIs showed resistance to TMP-SMX, and aban­donment of TMP-SMX as first-line therapy for acute uncomplicated cys­titis is currently under consideration in this region.

Although less than 5 per cent of urine isolates are resistant to nitro­furantoin, it is considerably less ac­tive than TMP-SMX against aero­bic Gram-negative rods other than E.coli. Furthermore, nitrofurantoin is more expensive than TMP-SMX. It is usually well tolerated, however, it is frequently prescribed for seven days and this may cause significant gastrointestinal upset. Nitrofuran­toin is not associated with plasmid-mediated resistance and is a suitable choice for patients with recent expo­sure to other antimicrobial agents.

Fluoroquinolones offer excellent activity and are usually well tolerat­ed. Their resistance is less than 5 per cent in most regions, however, resist­ ance rates are beginning to increase worldwide. In the Mediterranean re­gion, up to one-third of strains that demonstrate reduced susceptibili­ty to fluoroquinolones belong to two clonal groups: O15:H1 and O25:H4. This implies that strains belonging to these two clonal groups play a ma­jor role in determining the increas­ing rate of flouroquinolone-resistant E.coli strains in the community. One study from Japan reported fluoro­quinolone resistance in 8 per cent of isolates from patients with acute un­complicated cystitis. Worryingly, re­sistance rates for E.coli isolated from acute uncomplicated cystitis to cip­rofloxacin increased from 15.2 per cent in 2002 to 23.4 per cent in 2006. Fluoroquinolones should be regard­ed as a second-line treatment option due to their high cost and to preserve their sensitivity against uropatho­gens. Their use for uncomplicated UTIs should be limited to patients who are allergic to less-expensive drugs, patients with previous expo­sure to antimicrobial agents caus­ing bacterial resistance, and to re­gions where resistance to TMP-SMX is greater than 20 per cent.

When TMP-SMX is contraindicat­ed, a three-day course of ciprofloxa­cin, levofloxacin, norfloxacin, lome­floxacin or gatifloxacin is an appro­priate alternative. Importantly, fluo­roquinolones are less active against S.saprophyticus and many Gram-negative uropathogens. The high in vitro resistance to ampicillin and sul­fonamide and the high cost of amox­icillin/clavulanate limit their use­fulness in the setting of an acute un­complicated UTI. More than 90 per cent of females report the absence of acute urinary symptoms within 72 hours after commencement of anti­microbial therapy.

Three days of therapy is the pre­ferred treatment regimen. One study that reviewed over 300 clinical trials of single-dose, three- or seven-day treatment with TMP-SMX, fluoro­quinolones and β-lactam antimi­crobial agents found that three-day therapy is more effective than sin­gle-dose therapy. In addition, three-day therapy with TMP-SMX, amoxi­cillin or cloxacillin is associated with cure rates that are comparable with longer courses of therapy and an in­cidence of adverse effects that are as low as single-dose therapy (see Ta­ble 2).

In general, young female patients who are asymptomatic after anti­microbial therapies do not require a follow-up visit or repeat MSU. A follow-up visit is recommended with MSU in older females and in all male patients. Urological eval­uation with ultrasound, CT or cys­toscopy is unnecessary in these fe­males. Patients who do not respond to antimicrobial therapy should un­dergo appropriate microbiological and urological evaluations.

Complicated UTIs

Complicated UTIs may occur in patients with risk factors a compro­mised urinary tract or by a very re­sistant uropathogen (see Figure 2).

The clinical spectrum of a compli­cated UTI can range from mild UTI to life-threatening urospesis. Urine cultures are mandatory to identify the invading uropathogen and its antimicrobial susceptibility in this group of patients. The following are common host-factors that predis­pose to complicated UTIs:

                  Functional and/or structural ab­normalities of the urinary tract.

                  Recent instrumentation of the urinary tract.

                  Recent usage of antimicrobial therapy.

                  Diabetes mellitus.

                  Immunosuppression.

                  Pregnancy.

                  Hospital-acquired infections.

Due to the wide range of host con­ditions and uropathogens that are associated with complicated UTIs, appropriate guidelines for empiri­cal therapy remain limited (see Ta­ble 3). Patients with mild-to-mod­erate illness can be treated on an outpatient basis with oral fluoro­quinolones. If the susceptibility pattern of the pathogen is known, TMP-SMX may also be effective.

For hospitalised patients, intra­venous ampicillin and gentamicin provides adequate coverage against most pathogens. Antimicrobial ther­apy can also be modified when sen­sitivity data are available. Therapy is usually continued for 10-to-14 days and switched from parenteral to oral whenever possible. Repeat urine cul­ture should be performed seven and 14 days after therapy to ensure ade­quate efficacy has been achieved.

Recurrent UTIs

Recurrent UTIs are caused by re-emergence of bacteria from a site within the urinary tract (persistence) or from new infective uropathogens outside the urinary tract (reinfec­tion). Bacterial persistence must be caused by the same uropathogen on each occasion and reinfections typ­ically occur at varying intervals and are usually caused by different spe­cies of bacteria. It is important to dif­ferentiate between persistence and reinfections, as management pro­tocols differ. Patients with bacteri­al persistence can be cured of recur­rent cystitis by identifying and surgi­cally removing/correcting the focus of infection. Patients complaining of recurrent reinfection usually require long-term medical management, as a structural defect is not usually pre­sent. Reinfections in males occasion­ally occur and are usually because of an underlying abnormality such as urethral stricture. In these situations, surgical evaluation is warranted.

Females with recurrent infections and who are exposed to vaginal sper­micides from either condoms or dia­phragms should consider alternative methods of contraception or protec­tion from STIs.

Continuous and post-coital prophylaxis with low-dose antimi­crobial agents is effective in treat­ing recurrent UTIs and prophylac­tic treatment should not be com­menced until active infection has been eradicated. Absence of infec­tion can be confirmed by negative urine cultures one-to-two weeks af­ter treatment has been discontinued.

Continuous prophylaxis is an op­tion for females who have had two or more symptomatic infections over a six-month period. Randomised, pla­cebo-controlled trials have demon­strated that continuous prophylaxis with nitrofurantoin, trimethoprim (± sulfamethoxazole), ciprofloxacin or norfloxacin decreases recurrent episodes by 95 per cent (ie, from two-to-three episodes per patient/year to 0.1-to-0.2 episodes per patient/year) and may also prevent episodes of py­elonephritis. In general, antimicro­bial prophylaxis is initiated on a trial basis for a six-month period. If good outcomes are reported, the agent may be continued for two-to-five years without the emergence of a re­sistant organism. The rate of chronic adverse effects associated with anti­microbial agents ranges from 7-to-40 per cent for trimethoprim containing regimens, from 0-to-40 per cent for nitrofurantoin, from 7-to-21 per cent for norfloxacin and up to 13 per cent for ciprofloxacin. Gastrointestinal dis­turbances, rash and yeast vaginitis are the most common adverse effects en­countered (see Figure 3).

Post-coital prophylaxis is an option for female patients who describe a di­rect association between sexual inter­course and subsequent UTI. A reduc­tion in the frequency of recurrences has been demonstrated when nitro­furantoin, TMP-SMX or fluoroqui­nolones have been administered post-coitus. Intermittent self-treatment as opposed to continuous treatment has also been recommended in some sce­narios. Many females can accurately self-diagnose an acute UTI and may be instructed to commence a three-day course of an antimicrobial agent at the onset of symptoms. However, females are advised to seek medical attention if symptoms persist 48-to- 72 hours after completing the appro­priate antimicrobial course. Several studies have demonstrated that post-coital voiding does not play a preven­tative role for recurrent cystitis. In ad­dition, it appears that poor urinary hy­giene does not predispose to recurrent UTIs.

Conclusion

It is important for healthcare pro­fessionals to be familiar with the management of UTIs because of their high prevalence. Female pa­tients who present with recurrent UTIs should be advised on avoid­ance of exposure to vaginal spermi­cides, and antimicrobial prophylax­is or methods of self-administration may be considered. Imaging studies should be reserved for patients pre­senting with complicated UTIs. The increasing incidence of antimicro­bial resistance in conjunction with the highly prevalent nature of UTIs suggests that prudent and appropri­ate use of antimicrobial agents is be­coming increasingly important.

References on request

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