Complicated UTIs  due to Urological Disorders

Definitions and Classification

               A complicated UTI is an infection associated with a condition, such as structural or functional abnormalities of the genitourinary tract or the presence of an underlying disease, which increases the risks of acquiring an infection or of failing therapy. Two criteria are mandatory to define a complicated UTI: a positive urine culture and one or more of the factors listed in Table: Factors That Suggest a Potential Complicated UTI.

               Complicated UTI can arise in a heterogeneous group of patients. But neither patient age nor gender per se are part of the definition of a complicated UTI. With regard to prognosis and clinical studies, it is advisable to stratify complicated UTIs due to urological disorders into at least two groups:

1. Patients in whom the complicating factors could be eliminated by therapy, e.g. stone extraction, removal of an indwelling catheter.

2. Patients in whom the complicating factor could not be or is not removed satisfactorily during therapy, e.g. permanent indwelling catheter, stone residuals after treatment or neurogenic bladder.

Table . Factors That Suggest A Potential Complicated UTI

• The presence of an indwelling catheter, stent or splint (urethral, ureteral, renal) or the use of intermittent bladder  catheterization • A post-void residual urine of > 100 mL • An obstructive uropathy of any aetiology, e.g. bladder outlet obstruction (including neurogenic urinary bladder), stones and tumour • Vesicoureteric reflux or other functional abnormalities • Urinary tract modifications, such as an ileal loop or pouch • Chemical or radiation injuries of the uroepithelium • Peri- and post-operative UTI • Renal insufficiency and transplantation, diabetes mellitus and immunodeficiency

Clinical Presentation

               A complicated UTI may or may not be associated with clinical symptoms (e.g. dysuria, urgency, frequency, flank pain, costovertebral angle tenderness, suprapubic pain and fever). Clinical presentation may vary from severe obstructive acute pyelonephritis with imminent urosepsis to a catheter-associated post-operative UTI, which might disappear spontaneously as soon as the catheter is removed. It also has to be recognized that symptoms, especially lower urinary tract sympoms (LUTS), are not only caused by UTIs but also by other urological disorders, such as benign prostatic hyperplasia (BPH), TURP, etc.

               Apart from urological abnormalities, concomitant medical conditions, such as diabetes mellitus (10%) and renal failure, which can be related to urological abnormalities, are often present in a complicated UTI.

Urine Cultures

               Significant bacteriuria in a complicated UTI is defined by counts of ≥ 10⁵ cfu/mL and ≥ 10⁴ cfu/mL, in the mid-stream sample of urine of women and men, respectively. If a straight catheter urine sample is taken, ≥ 10⁴ cfu/mL can be considered relevant. For an asymptomatic patient, two consecutive urine cultures (at least 24 hours apart) yielding ≥ 10⁵ cfu/mL of the same micro-organism are required. The requirement for pyuria is ≥ 10 WBC per high-power field (x 400) in the resuspended sediment of a centrifuged aliquot of urine or per mm³ in unspun urine. A dipstick method can also be used for routine assessment, including a leucocyte esterase test, haemoglobin and probably a nitrite reaction. Sterile pyuria is commonplace in patients with indwelling bladder catheters.

Microbiology

Spectrum and Antibiotic Resistance

               Patients with a complicated UTI, both community and hospital-acquired, tend to show a diversity of microorganisms with a higher prevalence of resistance against antimicrobials, and higher rates of treatment failure if the underlying abnormality cannot be corrected. However, the presence of a resistant strain on its own is not enough to define a complicated UTI. Urinary abnormality (anatomical or functional) or the presence of an underlying disease predisposing to a UTI is also necessary.

               A broad range of bacteria can cause a complicated UTI. The spectrum is much larger than with an uncomplicated UTI and the bacteria are more likely to be antibiotic-resistant (especially in a treatment-related complicated UTI) than those isolated in an uncomplicated UTI. Escherichia coli, Proteus, Klebsiella, Pseudomonas, Serratia spp. and enterococci are the usual strains found in cultures. Enterobacteriaceae predominate (60-75%), with E. coli as the most common pathogen, particularly if the UTI is a first infection. Otherwise, the bacterial spectrum may vary from time to time and from one hospital to another.

Complicated UTIs Associated with Urinary Stones

               In the subset of complicated UTIs related to urinary stones, the frequency of E. coli and enterococci infection seems less important pathogens. In contrast, a greater portion of Proteus spp. and Pseudomonas is found. Of the urease-producing organisms, Proteus, Providencia, Morganella spp., and Corynebacterium urealyticum are predominant, but Klebsiella, Pseudomonas, Serratia and staphylococci are also urease producers to a certain extent. Among patients with staghorn calculus disease, 88% were found to have a UTI at the time of diagnosis, with 82% of patients infected with urease-producing organisms. The enzyme, urease, splits urea into carbon dioxide and ammonia. The resulting increase in ammonia in the urine injures the glycosaminoglycan (GAG) layer, which in turn increases bacterial adherence and enhances the formation of struvite crystals. These aggregate to form renal stones and incrustations on urinary catheters.

               The pathogenic potential of coagulase-negative staphylococci and non-group D streptococci is controversial. Under certain circumstances, such as the presence of a stone or foreign bodies, staphylococci can be relevant pathogens. Otherwise, staphylococci are not so common in complicated UTIs (0-11%).

Urine Cultures

               Significant bacteriuria in a complicated UTI is defined by counts of ≥ 10⁵ cfu/mL and ≥ 10⁴ cfu/mL, in the mid-stream sample of urine of women and men, respectively. If a straight catheter urine sample is taken, ≥ 10⁴ cfu/mL can be considered relevant. For an asymptomatic patient, two consecutive urine cultures (at least 24 hours apart) yielding ≥ 10⁵ cfu/mL of the same micro-organism are required. The requirement for pyuria is ≥ 10 WBC per high-power field (x 400) in the resuspended sediment of a centrifuged aliquot of urine or per mm³ in unspun urine. A dipstick method can also be used for routine assessment, including a leucocyte esterase test, haemoglobin and probably a nitrite reaction.

Treatment

General Principles

               Treatment strategy depends on the severity of the illness. Appropriate antimicrobial therapy and the management of the urological abnormality are mandatory. If needed, supportive care is given. Hospitalization is often necessary depending on the severity of the illness.

Choice of Antibiotics

               Empirical treatment of a symptomatic complicated UTI requires a knowledge of the spectrum of possible pathogens and local antibiotic resistance patterns, as well as assessment of the severity of the underlying urological abnormality (including the evaluation of renal function). Bacteraemia is usually reported too late to influence the choice of antibiotics. However, suspicion of bacteraemia must influence the empirical treatment. Most important for the prognosis is still the severity of the associated illness and of the underlying urological condition. Many therapeutic trials have been published on the use of specific antimicrobial therapies in complicated UTIs. Unfortunately, most reports are of limited use for the practical management of the patient in a day-to-day situation because of limitations such as:

• poor characterization of the patient populations

• unclear evaluation of the severity of the illness

• nosocomial and community-acquired infections are not accurately distinguished

• urological outcome is seldom taken into consideration.

               Intense use of any antimicrobial, especially when used on an empirical basis in this group of patients with a high likelihood of recurrent infection, will lead to the emergence of resistant micro-organisms in subsequent infections. Whenever possible, empirical therapy should be replaced by a therapy adjusted for the specific infective organism(s) identified in the urine culture. Therefore, a urine specimen for culture must be obtained prior to initiating therapy and the selection of an antimicrobial agent should be re-evaluated once culture results are available.

               So far, it has not been shown that any agent or class of agents is superior in a case where the infective organism is susceptible to the drug administered. Agents appropriate for empiric therapy of complicated UTI are shown in Tables below.

Table. Antimicrobial Treatment Options for Empiric Therapy of Complicated UTI

Antibiotics recommended for initial empirical treatment • Fluoroquinolones • Aminopenicillin plus a BLI • Cephalosporin (Groups 2 or 3a) • Aminoglycoside Antibiotics recommended for empirical treatment in case of initial failure or for severe cases • Fluoroquinolone (if not used for initial therapy) • Ureidopenicillin (piperacillin) plus BLI • Cephalosporin (Group 3b) • Carbapenem • Combination therapy: - Aminoglycoside + BLI - Aminoglycoside + fluoroquinolone Antibiotics not recommended for empirical treatment • Aminopenicillins, e.g. amoxicillin, ampicillin • Trimethoprim-sulphamethoxazole (only if susceptibility of pathogen is known) • Fosfomycin trometamol BLI = ß-lactam inhibitor

Table. Recommendations for Antimicrobial Therapy in Urology.

Diagnosis	Most frequent pathogen/species	Initial, empirical antimicrobial therapy	Therapy duration
Cystitis    acute, uncomplicated	• E. coli • Klebsiella • Proteus • Staphylococci	• Trimethoprim-sulphamethoxazole°	3 days
		• Fluoroquinolone*	(1-)3 days
		• Fosfomycin trometamol	1 day
		• Pivmecillinam	(3-)7 days
		• Nitrofurantoin	(5-)7 days
Pyelonephritis acute, uncomplicated	• E. coli • Proteus • Klebsiella • Other enterobacteria • Staphylococci	• Fluoroquinolone* • Cephalosporin (group 3a) Alternatives: • Aminopenicillin/BLI • Aminoglycoside	7-10 days
UTI with complicating factors   Nosocomial UTI    Pyelonephritis acute,  complicated	• E. coli • Enterococci • Pseudomonas • Staphylococci • Klebsiella • Proteus • Enterobacter • Other enterobacteria	• Fluoroquinolone* • Aminopenicillin/BLI • Cephalosporin (group 2) • Cephalosporin (group 3a) • Aminoglycoside In case of failure of initial therapy within 1-3 days or in clinically severe cases: Anti-Pseudomonas active: • Fluoroquinolone, if not used initially • Acylaminopenicillin/BLI • Cephalosporin (group 3b) • Carbapenem • ± Aminoglycoside	3-5 days after defeverescence or control/elimination of complicating factor
	• Candida	• Fluconazole • Amphotericin B
Prostatitis acute, chronic	• E. coli • Other enterobacteria • Pseudomonas	Fluoroquinolone* Alternative in acute bacterial prostatitis: • Cephalosporin (group 3a/b)	Acute: 2-4 weeks Chronic: 4-6 weeks or longer
Epididymitis acute	• Enterococci • Staphylococci • Chlamydia • Ureaplasma	In case of Chlamydia or Ureaplasma: • Doxycycline • Macrolide	10 days
Urosepsis	• E. coli • Other enterobacteria   After urological interventions – multi-resistant pathogens: • Pseudomonas • Proteus • Serratia • Enterobacter	• Cephalosporin (group 3a/b) • Fluoroquinolone* • Anti-Pseudomonas active acylaminopenicillin/BLI • Carbapenem • Aminoglycoside	3-5 days after defeverescence or control/elimination of complicating factor

BLI = ß-lactamase inhibitor; UTI = urinary tract infection. *Fluoroquinolone with mainly renal excretion (see text). °Only in areas with resistance rate < 20% (for E. coli).

Follow-up After Treatment

               The greater likelihood of the involvement of resistant micro-organisms in complicated UTIs is another feature of these infectious diseases. This is not a priori related to the urinary abnormality, but is related more to the fact that patients with a complicated UTI tend to have recurrent infection. For these reasons, prior to and after the completion of the antimicrobial treatment, urine cultures must be obtained for the identification of the micro-organisms and the evaluation of susceptibility testing.