began to note nausea without vomiting. One day later she developed left flank pain, fevers, and chills and noted increased urinary frequency. She noted foul-smelling urine on the day prior to admission. She presented with a temperature of 38.8°C, and physical examination showed left costovertebral angle tenderness. Urinalysis of a clean-catch urine sample was notable for >50 white blood cells per high-power field, 3 to 10 red blood cells per high-power field, and 3+ bacteria. Urine culture was subsequently positive for >105 CFU of an organism per ml (seen growing on culture in Fig. 1.1 [sheep blood agar] and Fig. 1.2 [MacConkey agar]). Note that the organism is beta-hemolytic.
1 1. What do the urinalysis findings indicate? Explain your answer.
2 2. Why were the numbers of organisms in her urine quantitated on culture? How would you interpret the culture results in this case?
3 3. Which Gram-negative rods are lactose fermenters? Which one is also often beta-hemolytic?
4 4. This bacterium was resistant to ampicillin. What in this patient’s history might explain this observation? Multidrug-resistant strains of this organism are beginning to be seen as an important cause of UTI. Describe the mechanism of resistance that these organisms most likely will have.
5 5. UTIs are more frequent in women than men. Why?
6 6. Did this woman have cystitis or pyelonephritis? Why is it important to differentiate between the two?
7 7. Briefly explain the evolution of the organism causing this infection in terms of its ability to infect the urinary tract. What virulence factors have been shown to play a pathogenic role in this infection?
CASE 1 CASE DISCUSSION
1. Urine from normal individuals usually has <10 white blood cells per high-power field. Pyuria (the presence of >10 white blood cells per high-power field in urine) and hematuria (the presence of red blood cells in urine), as seen in this patient, are reasonably sensitive but not always specific indicators of UTI. The presence of bacteriuria (bacteria in urine) in this patient further supports this diagnosis. However, the presence of bacteriuria on urinalysis should always be interpreted with caution. Clean-catch urine, which is obtained by having the patient cleanse her external genitalia, begin a flow of urine, and then “catch” the flow of urine in “midstream,” is rarely sterile because the distal urethra is colonized with bacteria. Urine is an excellent growth medium. Therefore, if urine is not analyzed fairly quickly (within 1 hour), the organisms colonizing the urethra can divide (two to three generations per hour) if the urine specimen is left at room temperature rather than refrigerated or immediately planted on culture media. Organisms colonizing the urethra may be present in sufficient numbers to be visualized during urinalysis even when the patient is not infected.
2. In a normal individual, urine within the bladder is sterile. As it passes through the urethra, which has a resident microflora, it almost always becomes contaminated with a small number (<103 CFU/ml) of organisms. As a result of urethral contamination, essentially all clean-catch urine samples will contain a small number of organisms, so culturing urine nonquantitatively will not allow differentiation between colonization of the urethra and infection of the bladder. It should be noted that only a small number of clinical specimens other than urine are cultured quantitatively.
Patients in whom the bladder is infected tend to have very large numbers of bacteria in their urine. These organisms usually, but not always, are of a single species. Studies have shown that most individuals with true UTIs have >105 CFU/ml in clean-catch urine specimens. There are exceptions to this generalization. In a woman with symptoms consistent with UTIs, bacterial counts as low as 102 CFU/ml of a uropathogen—e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Proteus spp., or Staphylococcus saprophyticus—may indicate that she has a UTI. Colony counts of 102 CFU/ml of a uropathogen are highly sensitive for diagnosing UTIs but are of low specificity; colony counts of >105 CFU/ml are highly specific, but the sensitivity in the setting of acute, uncomplicated cystitis in women is only ~50%.
3. The lactose-fermenting, Gram-negative bacilli that are most commonly isolated from urine are the “KEE” organisms (Klebsiella spp., E. coli, and Enterobacter spp.). E. coli is recovered from ~80 to 85% of outpatients and ~40 to 50% of inpatients with UTI. The observation that the organism is beta-hemolytic indicates that, in all likelihood, the organism is E. coli. Approximately 55% of E. coli isolates recovered from urine of patients with pyelonephritis are beta-hemolytic, whereas K. pneumoniae and Enterobacter spp. are rarely, if ever, beta-hemolytic. Another common Gram-negative rod that is frequently beta-hemolytic is Pseudomonas aeruginosa, which is very unlikely to be the cause of community-acquired cystitis or pyelonephritis in an otherwise healthy woman. This organism is incapable of fermenting carbohydrates and should not be confused with lactose-fermenting isolates of E. coli. A spot indole test was done on the patient’s isolate and was positive, confirming the identity of this organism as E. coli.
4. The patient had a previous UTI, at which time she received oral ampicillin. One of the deleterious effects associated with the use of antimicrobial agents is the selection of antibiotic-resistant bacteria. This occurs with some degree of frequency in gut flora, where plasmids coding for resistance may be mobilized in response to antimicrobial pressure, leading to the transfer of resistance to previously susceptible organisms, such as in this E. coli isolate. Not only may resistance to the agent supplying the selective pressure result, but also the plasmid may contain genes that code for resistance to other antimicrobial agents, the end result being a multidrug-resistant organism.
During the past 10 years, the emergence of multidrug-resistant E. coli causing both community-acquired as well as health care-associated UTIs has made the selection of empiric antimicrobial therapy much more difficult. Globally, ~20% of E. coli strains causing UTIs produce extended-spectrum β-lactamases (ESBLs). Mutations in the active site of the β-lactam “extend” the activity of the β-lactamases so that they are active against all penicillins and cephalosporins. ESBLs are carried on plasmids that frequently also encode resistance to trimethoprim-sulfamethoxazole, fluoroquinolones, and aminoglycosides. Both fluoroquinolones and trimethoprim-sulfamethoxazole are widely used as empiric therapy for cystitis in women. The increasing resistance being seen in E. coli, due in part to ESBL-producing strains, greatly limits the choice of oral agents to treat uncomplicated cases of UTI. For now, ESBL-producing E. coli isolates remain susceptible to the oral agents fosfomycin and to a lesser degree nitrofurantoin, but how long this will continue to be true is difficult to predict. ESBL-producing organisms remain susceptible to carbapenems such as ertapenem and imipenem. These parenterally administered antimicrobials are widely used to treat systemic infections such as pylonephritis due to ESBL-producing organisms. However, carbapenemases have also emerged and can be encoded on plasmids that carry resistance genes similar to those found on ESBL-encoding plasmids. These carbapenemase-encoding plasmids have been found in E. coli. Nitrofurantoin is not active against carbapenemase-producing strains, while fosfomycin has some degree of activity and may be useful in treating cystitis. However, fosfomycin
