1.1

Definition

Infected urolithiasis refers to a concomitant or superimposed urinary tract infection (UTI) in the setting of a ureteral stone and is considered a type of complicated UTI [ ]. A positive urine culture (>100,000 colony forming units) with a single uropathogen in a patient with a ureteral stone is generally accepted as the definition of infected urolithiasis, though no universally accepted criteria exist [ ]. However, in the ED setting, features such as positive nitrites and pyuria on urinalysis along with clinical features to include fever and costovertebral angle (CVA) tenderness are more helpful in the diagnosis of infected urolithiasis, as urinary culture data are not immediately available. Infected urolithiasis may also cause near-complete or complete obstruction which can be identified radiographically, and this may progress to obstructive pyelonephritis (renal infection and systemic illness) and pyonephrosis (purulence within the collecting system) [ ]. Though most patients with uncomplicated urolithiasis can be treated conservatively, those with ureteral stone infections, to include those with and without complete obstruction, obstructive pyelonephritis, and pyonephrosis, must be treated aggressively given the significant risk of sepsis and mortality [ ]. In this article, infected ureterolithiasis, infected urolithiasis, ureteral stone infection, and infected ureteral stone are used interchangeably.

1.2

Pathophysiology

The formation of a ureteral stone is multifactorial and may involve increased urinary calcium, urate, and oxalate; decreased citrate excretion; disturbances in urinary pH and volume; anatomic abnormalities; suboptimal nutrition; and warm working environment with associated dehydration [ ]. Ureteral stone formation and UTIs are likely risk factors for each other, as patients with a higher urinary pH and bacterial colonization (particularly with urease-producing organisms) both precipitate and propagate new and existing stones [ , ]. Specifically, these bacteria promote the breakdown of urea into ammonia, which further reacts to create an alkaline environment suitable for kidney stone formation and superimposed infection [ ]. Additional theories for the pathophysiology of secondary infections in the setting of urolithiasis include biofilm formation on pre-existing stones, especially when the urothelial barrier is disrupted [ ]. If left untreated, complications in addition to non-infected stones (i.e., obstructive uropathy) include ascending infection, progression to bacteremia, and sepsis/septic shock.

1.3

Epidemiology

Ureteral stones are a relatively common disease process, with a 12-month incidence of 2.1%, of which 54.1% are males [ ]. Furthermore, the lifetime risk of ureteral stones approaches 15% [ ]. Infections in the setting of ureteral stones occur in 4% to 34% of patients based on positive urine cultures, and patients who have a history of ureteral stones are also at a higher lifetime risk of developing a UTI compared to the general population (18.7% versus 14.1%) [ , ]. In patients with a ureteral stone infection and sepsis or septic shock, the mortality rate ranges from 8.8% to 27.3%, which depends on the degree of obstruction and timing of surgical intervention [ , ]. In a study of 209 patients with septic shock secondary to a urinary source, approximately 11% had an anatomic obstruction, with this cohort demonstrating a 27.3% hospital mortality, compared to 11.2% of patients without an obstruction [ ]. Thus, infected urolithiasis imposes a significantly higher mortality rate compared with the overall mortality rate of 0.2% in all patients with ureteral stones [ ].

2.1

Presentation

Patients with infected ureteral stones present with a variety of signs and symptoms, many of which overlap with non-infected stones and pyelonephritis. The classic presentation is fever, chills, dysuria, urinary frequency, malodorous urine, and flank pain [ ]. This is often associated with nausea and vomiting in a patient with a prior history of kidney stones and recurrent UTIs [ ]. Pain is often episodic in nature and may progress from the flank to the lower abdomen as the stone progresses distally [ ]. Physical examination may demonstrate fever, dehydration, and costovertebral angle (CVA) tenderness [ ]. If left untreated, or if arriving in a delayed fashion, patients may appear ill and present with sepsis and shock.

2.2

ED evaluation

As previously mentioned, there are no universally accepted criteria for the diagnosis of infected urolithiasis. However, a combination of laboratory findings may assist in their identification. Patients should at the minimum undergo a urinalysis with culture, with pyuria, positive nitrites, positive leukocyte esterase, and large blood suggesting an infected stone [ , , , ]. A complete blood cell count and C-reactive protein (CRP) may demonstrate inflammatory changes (i.e., elevated white blood cell count [WBC]), and renal function assessment may reveal acute kidney injury (AKI) (i.e., elevated creatinine from baseline), which, if present, is likely multifactorial to include nausea and vomiting, obstructive uropathy, and end-organ dysfunction in the setting of sepsis and shock [ , ]. Specifically, in the evaluation for infected urolithiasis, the positive likelihood ratio (LR+) and negative likelihood ratio (LR-) for leukocytosis are 2 and 0.6 respectively; the LR+ for elevated CRP and positive nitrites are 2 and 36, respectively; and the LR+ for a urinalysis with >5 WBCs/high power field (hpf) is 4 [ , ]. AKI has a LR+ and LR- of 2 and 0.8, respectively [ ]. In addition to laboratory studies, computed tomography (CT) should be obtained to help confirm the presence and location of the stone and to facilitate surgical planning [ ]. Guidelines for specific CT protocols are controversial but may include CT abdomen and pelvis with intravenous (IV) contrast, without contrast, and urography (with and without contrast) [ ]. However, CT protocols should be tailored to the patient, and IV contrast should be used when there is concern for a perinephric abscess or alternative intra-abdominal process such as appendicitis or cholecystitis [ ]. Additionally, ‘low-dose’ or ‘stone-protocol’ CTs are less helpful in the identification of a stone and its complications in larger patients (body mass index >30) [ ].

2.3

ED management

Patients with infected urolithiasis are at high risk for progression to sepsis and have a significantly increased risk of mortality [ , , ]. These patients should receive broad-spectrum antibiotics covering gram negative and urease-producing organisms, especially if there is obstruction [ , ]. Additional coverage for methicillin-resistant Staphylococcus aureus (MRSA) should be considered in patients with risk factors (i.e., recent hospitalization, known carrier, recent instrumentation of the urinary tract, immunocompromised status, etc.) or those who are critically ill. Early urologic consultation is recommended for evaluation for surgical intervention including decompression [ , ]. While CT imaging will assist with operative planning, it should not delay urologic consultation. Additional supportive and symptomatic measures to include fluid resuscitation, analgesia, and anti-emetic therapies are recommended.

3.1

What are significant risk factors for infected urolithiasis?

The presence or history of ureteral stones is an independent risk factor for the development of a UTI, with a large retrospective study demonstrating a hazard ratio (HR) of 5.67 (95% confidence interval [CI] 4.52–7.18) [ ]. Furthermore, a single-center prospective observational study of 360 patients with acute nephrolithiasis found the prevalence of concomitant UTI to be 7.8% [ ]. The highest reported association of UTIs and urolithiasis was 34.1% in a 10-year Taiwanese study [ ]. However, patients with a history of UTIs, especially if recurrent, also have an increased risk of kidney stone formation [ ]. The true causality (i.e., stone causing infection or infection causing stone) is controversial [ , ]. Though all stone types are at risk for concomitant UTI, literature suggests concomitant infections are more common in females (31.6% versus 15.6% in males), large (>5 mm) stones, multiple stones (41.4% versus 16.1% for a single stone), and staghorn stones (48.4% versus 19.8% in non-staghorn stones) [ , ]. In particular, staghorn stones are associated with urease-producing bacteria that further promote the crystallization and branching of the stone [ ]. With respect to stone composition, patients who form urate and calcium oxalate stones have a much higher risk of developing an infection, with a HR of 6.87 (95% CI 2.82–16.72) and 6.36 (95% CI 4.82–8.40), respectively [ ]. In addition to stone quantity, size, and composition, patients aged <40 or > 60 years old are more likely to develop an infection, though the reason for this bimodal pattern is unclear [ ]. Other typical risks factors for UTI remain even in the presence of a ureteral stone, including diabetes, urinary catheterization, hypertension, and solitary kidney [ , , ] .

3.2

What are the signs and symptoms associated with infected urolithiasis?

The signs and symptoms of infected urolithiasis often overlap with those of pyelonephritis and uncomplicated urolithiasis. However, reported fever (relative risk [RR] 6.6, 95% CI 3.1–13, LR+ 5), dysuria (RR 4.4, 95% CI 1.8–11, LR+ 2), chills (RR 3.0, 95% CI 1.3–6.7, LR +3), urinary frequency (RR 2.5, 95% CI 1.1–5.5, LR+ 2), and malodorous urine (RR 2.7, 95% CI 0.5–8.4, LR+ 3) are symptoms most strongly associated with infected urolithiasis [ ]. Though common on presentation, other symptoms such as urinary urgency, hesitancy, hematuria, nausea, and vomiting are not associated with a significantly higher risk of infected urolithiasis [ ]. Elevated temperature (>37.9 °C) is the strongest sign associated with infected urolithiasis, with a LR+ of 15 and odds ratio (OR) of 3.1 (95% CI 1.8–13.6) [ , ]. CVA tenderness possesses a RR of 2.7 (95% CI 1.0–8.1) though the LR+ is only 1 [ ]. Other examination findings including suprapubic tenderness are less helpful in predicting infected urolithiasis [ ] .

3.3

What laboratory testing can assist in the diagnosis, and what are the keys to the urinalysis?

A urinalysis with urine culture is essential in the diagnosis of an infected kidney stone. Given their importance, patients should be given instruction for providing a clean-catch or catheterized urine sample if unable to provide a clean-catch sample to prevent contamination, which can occur in up to 54.9% of samples [ ]. Particular attention should be given to female, pregnant, and obese patients who are at the highest risk for providing a contaminated urine sample [ ] .

The American Urological Association (AUA) does not provide specific guidance on the interpretation of a urinalysis in patients with urolithiasis but does have a strong recommendation based on a Grade B level of evidence to obtain a urine culture if there are concerns for superimposed infection based on clinical or laboratory findings [ ]. Due to its importance, clinicians should ensure that urine cultures are obtained in patients with suspected infected urolithiasis rather than relying on institutional automated reflex protocols. Pyuria and positive leukocyte esterase suggest the presence of a concomitant infection, though individually, these markers have only moderate sensitivities and specificities. For the identification of a single organism with 100,000 colony forming units on urine culture, literature suggests positive leukocyte esterase has both a sensitivity and specificity of 86% and a LR+ and LR- of 6 and 0.2, respectively [ ]. Specificity and LR+ increase to 98% and 24, respectively, with the presence of large leukocyte esterase [ ]. Pyuria, defined as >5 WBCs/hpf, demonstrates a sensitivity and specificity of 86% and 79%, respectively [ ]. This correlates with a LR+ and LR- of 4 and 0.2, respectively [ ]. Increasing pyuria, with cutoffs of >10 WBCs/hpf, >15 WBCs/hpf, and > 20 WBCs/hpf are associated with increasing specificities of 87%, 91%, and 93%, respectively [ ]. At these cutoffs, the LR+ is 6, 8, and 9, respectively, although the LR- are minimally affected (0.2, 0.3, and 0.3, respectively) [ ]. Positive nitrites demonstrate a sensitivity and specificity of 43% and 99%, respectively, correlating with a LR+ of 36 and LR- of 0.6; subsequently, a urine specimen with positive nitrites has an exceedingly strong probability of resulting in a positive urine culture in the setting of urolithiasis [ , ] .

Serum inflammatory markers including WBC count above 10–11.3 × 10 ⁹ /L and CRP above 3.5 mg/L are also non-specific indicators that may predict infected urolithiasis [ , ]. Specifically, one study demonstrated that leukocytosis above 10.9 × 10 ⁹ /L has a LR+ and LR- of 2 and 0.6, respectively, and another study found that 70% of patients with obstructive and infected urolithiasis had CRP elevations above 3.5 mg/L [ , ]. These studies, however, should be used in conjunction with urinalysis findings and clinical presentation such as fever [ , ]. Other laboratory studies including creatinine elevation are less helpful [ ]. Ultimately, a urine culture is essential for diagnosing infected urolithiasis and should be obtained and followed closely regardless of patient disposition and the initial urinalysis results. Subsequently, ED physicians are encouraged to ensure that the primary care physician, admitting physician, and/or urologist are aware of pending culture results.

3.4

What is the utility of ultrasound versus CT?

The use of ultrasound in the evaluation for urolithiasis has been advocated to avoid radiation exposure. Specifically, in younger adults with renal colic, ultrasound alone may be adequate in its diagnosis, especially if the stone is >5 mm [ ]. In these patients, hydronephrosis, especially if moderate to severe, is suggestive of urolithiasis; however, unless directly visualized, ultrasound cannot confirm the actual presence of urolithiasis [ ]. Most studies demonstrate modest accuracy in the diagnosis of urolithiasis, with a meta-analysis of nine studies demonstrating a sensitivity and specificity of 70.2% and 75.4%, respectively, correlating with a LR+ and LR- of 3 and 0.4, respectively [ ]. However, the sensitivity of ultrasound for the diagnosis of renal infections is limited at only 56.6%, with a normal appearing kidney being a common finding [ ]. Ultrasound literature regarding the identification of urolithiasis complications including superimposed infections is extremely sparse. Ultrasound, however, may be more useful in determining disease progression of an infected stone to pyonephrosis, or development of pus in the setting of a urinary obstruction [ ]. In these cases, ultrasound has a LR+ and LR- of 30 and 0.1, respectively [ ]. However, the challenges for identifying a stone as the etiology of pyonephrosis or pyelonephritis remain [ ] .

CT of the abdomen and pelvis is the imaging study of choice to identify the location and size of urolithiasis, evaluate for infectious complications, and perform operative planning. However, CT is not a functional test of urinary drainage but is rather an anatomical evaluation of the urinary tract and other abdominal organs. The AUA has a strong recommendation to obtain a non-contrast CT in patients who may need percutaneous nephrolithotomy and a conditional recommendation to obtain a non-contrast CT in patients who may benefit from shockwave lithotripsy or ureteroscopy [ ]. Generally, large stones (>10-15 mm), stones that have failed conservative management (failure to pass spontaneously within 4–6 weeks), patients with intractable pain, proximal stones, and infected stones should be evaluated for urologic intervention [ ]. Furthermore, the American College of Radiology Appropriateness Criteria suggests that CT imaging (with and/or without IV contrast) in patients with suspected renal infection and a history of stone or obstruction is usually appropriate and demonstrates a sensitivity of 97% [ ]. Though the diagnosis of infected urolithiasis can be made based on history, examination, and laboratory evaluation, clinicians should maintain a low threshold to obtain a CT in the ED to identify stone characteristics and facilitate urologic interventions [ ]. Clinicians should also consider the use of contrast when suspecting infectious complications (i.e., pyelonephritis, pyonephrosis, abscess), to exclude alternative etiologies of flank pain (i.e., appendicitis), and facilitate urologic interventions [ ] .

3.5

What antibiotics are necessary, and what are the major treatment considerations?

Generally, broad-spectrum antibiotics should be administered to patients with suspected infected stones given their risk for progression to sepsis, though neither the AUA nor IDSA make specific recommendations [ , ]. Antibiotics should target gram-negative rods and urease-producing organisms ( Table 1 ). Meta-analysis data demonstrate that the most common organisms associated with infected urolithiasis are E. coli , Klebsiella , Enterococcus species (spp), Proteus , and Pseudomonas [ , ]. In infected struvite stones, Proteus spp. are common, but additional consideration must be given to urease-forming species such as Staphylococcus , Providencia , and Serratia [ ]. Initial empiric therapies include ceftriaxone in patients without concern for Pseudomonas and cefepime or piperacillin-tazobactam for patients with Pseudomonas risk factors [ , ]. These include the use of an indwelling catheter or nephrostomy tube, immunosuppression, recurrent UTIs, and dementia [ ]. Vancomycin, daptomycin, or linezolid should be added in critically ill patients or if the etiology is suspected to be secondary to MRSA [ , ]. Alternative broad-spectrum antibiotics that may be considered include carbapenems with anti-pseudomonal activity (i.e., meropenem) and aminoglycosides [ ]. Antibiotic selection, however, should ideally be performed in conjunction with urology and based on the local antibiogram.

Table 1

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