Urinary tract infections in children: treatment

Urol Clin N Am 31 (2004) 527–534

Urinary tract infections in children: treatment Sameer M. Malhotra, MD, William A. Kennedy II, MD* Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Room S-287, Stanford, CA 94305, USA

Urinary tract infections (UTIs) are among the most common reasons for referral of a pediatric patient to the urologist. Identification of an anatomic or physiologic predisposition to urinary infections is an integral part of the comprehensive management of pediatric UTIs. (Please see the article by Shortliffe appearing elsewhere in this issue for a discussion of the etiology and epidemiology of urinary tract infections in children.) The objectives in treatment of UTIs include eradication of infection, symptomatic relief, and prevention of renal damage. Prevention of renal parenchymal scarring is the most important goal, and is possible with early, aggressive treatment of acute pyelonephritic episodes in children, as well as prompt management of acute and recurrent lower UTIs. This article outlines the therapeutic options for treatment of upper and lower UTIs of various etiologies in children.

Lower urinary tract infections Acute bacterial cystitis Multiple options are available to the practitioner to treat uncomplicated lower UTIs. These options include sulfonamides, trimethoprim/ sulfamethoxazole (TMP/SFX), nitrofurantoin, cephalosporins, and trimethoprim alone. Fluoroquinolones are effective against various microbes, including most gram-positive and -negative organisms. Fluoroquinolones provide excellent coverage against Pseudomonas aeruginosa and Proteus species. Previously, concerns regarding * Corresponding author. E-mail address: [email protected] (W.A. Kennedy II).

arthrotoxic effects, including cartilage toxicity, had discouraged the use of quinolones in children. Clinical evidence has not supported these concerns, however, and multiple trials [1,2] examining ciprofloxacin in children initially have shown it to be safe in children with cystic fibrosis. One of the largest studies [1] involved 1795 patients receiving intravenous or oral ciprofloxacin courses. Treatment-associated events were reported in 11% of children receiving oral ciprofloxacin compared with 19% among intravenous recipients. Overall arthralgia occurred during 1.5% of treatment courses. Most events were of mild to moderate severity and self-resolving. This adverse event pattern was similar to that observed in adults. A multicenter clinical trial is underway to evaluate the use of ciprofloxacin in children with complicated UTIs. Data from this study also will address the safety profile of ciprofloxacin when used to treat UTIs. Before selecting from the antibiotic arsenal, the practitioner considers the susceptibility pattern of the offending organism, and determines whether adding an intramuscular dose of antibiotic to an oral course of therapy is beneficial. A study that investigated 287 children with febrile UTIs over multiple years showed that the susceptibility pattern of Escherichia coli (the most frequently isolated organism) to nitrofurantoin and nalidixic acid remained excellent over time, but resistance to TMP/SFX was significantly higher [3]. Baker and colleagues [4] performed a prospective randomized trial in which 69 children 6 months to 12 years of age with febrile UTIs received either a dose of intramuscular ceftriaxone in addition to a 10-day course of TMP/SFX or oral therapy alone. They found no difference at 48 hours in the urine sterilization rate, clinical improvement, or

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subsequent hospital admission rate of the patients. Oral cefixime (8 mg/kg/d) also has been explored as a first-line therapy with encouraging results and efficacy comparable to intravenous cefotaxime or oral TMP/SFX [5,6]. The optimal duration of treatment in pediatric, uncomplicated, acute lower UTIs is controversial. Multiple studies have examined the relative merits of short-course (one dose or up to 4 days) versus longer-course (1–2 weeks) antibiotic treatment. In multiple studies [7–11] results were better with long duration, with an attributable improvement in outcome of 5% to 21%. A recent review and statistical analysis by Michael and colleagues [12], however, was published examining 10 trials covering 652 patients 3 months to 18 years of age. There was no significant difference in the frequency of positive cultures between the short- (2–4 days) and longer-duration (7–14 days) antibiotic therapy at either 0 to 10 days after treatment or 1 to 15 months after treatment. Furthermore, there was no significant difference in the development of resistant organisms after therapy. Another study conducted by Helin [13] prospectively examined a 3-day course of TMP/SFX versus a 10-day course and surprisingly found a higher rate of recurrence over 11 months in the 10-day therapy cohort. Based on available data and current practice, a short-course of antibiotic therapy consisting of 3 days of treatment in a clinically stable older child is probably sufficient [12]. In children 2 months to 2 years of age, the longer course of treatment should be considered strongly. If an infant is 3 months of age or younger, or a young child with a suspected UTI is dehydrated, toxic, or unable to retain oral intake, initial antimicrobial therapy should be administered parenterally and hospitalization should be advised [14]. Nelson, Gurr, and Schunk [15] demonstrated that children presenting with a UTI and a temperature greater than 40(C had a higher rate of outpatient-treatment failure and warrant consideration for hospitalization. Eradication of the infection should be documented with repeat urine cultures. After urinary sterilization in children, prophylactic doses of antibiotics are recommended as clinically indicated until further work-up with imaging studies is completed [14]. Treatment of underlying voiding dysfunction and constipation is essential to successfully managing pediatric UTIs. Radiologic studies have documented an association between fecal loading seen on abdominal radiographs and recurrent

UTIs [16]. Additionally, breastfeeding offers significant protection against UTIs in infants [17]. Human breast milk contains several factors with anti-infectious potential, including immunoglobulins (especially secretory IgA), oligosaccharides and glycoproteins with antiadhesive capacity, and cytokines. Some of the protective effects may derive from an altered mucosal colonization pattern in the breast-fed infant. Viral cystitis Viral infections of the bladder, although irritative and at times impressive in their scope, are selflimited. Supportive care with anti-inflammatory medications and adequate hydration are often all that are required. Ultrasound imaging may reveal global or focal thickening of the bladder wall (Fig. 1). In immunocompromised patients with acute adenovirus hemmorhagic cystitis, the use of ribavirin has been suggested [18]. Schistosomiasis Various treatments are available for the treatment of schistosomiasis, a parasitic infection. Unfortunately, most of the available medications carry significant side effects. The current drug of choice is praziquantel, which, unlike some other medications used to treat schistisomal infections, is effective against all species of the organism. It is administered orally as a single or divided dose of 40 to 60 mg/kg/d [19]. Surgical intervention in schistosomiasis should be reserved until the results of medication and conservative management can be assessed. Long-term infection may lead to significant fibrosis and bladder contracture. Augmentation cystoplasty, autoaugmentation, or bladder replacement may be needed. Bilharzial infection also can lead to distal ureteral strictures and subsequent obstructive uropathy. Unfortunately, the concomitant fibrosis of the ureteral and bladder walls usually precludes ureteroneocystotomy by way of submucosal tunneling as an option. Partial-flap ureteroneocystotomy has been described [20] to alleviate such distal obstruction. Enterobiasis Pinworm infestation, although a disease of the gastrointestinal tract, has been implicated as a factor in acute and chronic UTIs. Medical therapy is indicated for affected individuals. One dose of pyrantel pamoate (11 mg/kg, with a maximum of 1 g), repeated in 2 weeks’ time, is the

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Fig. 1. (A) Ultrasonograph of the bladder in child with adenovirus cystitis. Crosshatches reflect global thickening of bladder wall. (B) Pretreatment ultrasonograph of the bladder in 5-year-old boy with adenovirus cystitis. Crosshatches reflect focal thickening of bladder wall at the dome. (C) Pretreatment MRI of the bladder in 5-year-old boy with adenovirus cystitis. Arrow demonstrates focal thickening of bladder wall at the dome. (D) Posttreatment ultrasonograph of the bladder in 5-year-old boy with previous adenovirus cystitis. Arrow demonstrates resolution of focal thickening of bladder wall at the dome.

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Fig. 1 (continued )

treatment of choice. Mebendazole, 100 mg, with a repeat dose at 2 weeks is an alternative treatment. Neither drug is approved by the US Food and Drug Administration in children under 2 years of age. Chlamydia Chlamydial infections in children generally fall into two categories: perinatally transmitted cases, and sexually transmitted cases in older children. In younger children the physician must be vigilant for evidence of sexual abuse; if suspected, appropriate hospital and social service guidelines should be followed. Possible treatment agents include sulfonamides, erythromycin, and tetracyclines, usually given for a 10- to 14-day course. Tetracyclines should not be administered to children under 8 years of age because they can stain permanent teeth [21]. Epididymitis The treatment of acute epididymitis includes scrotal elevation and support, and analgesic/antiinflammatory medications. If a bacterial source is suspected, an antibiotic can be started after obtaining a urine culture. For gonococcal epididymitis, intramuscular ceftriaxone can be administered. Chlamydial infections can be treated with sulfonamides, tetracyclines (in patients older than 8 years of age), and erythromycin. Enteric bacterial infections should be treated with broad-spectrum antibiotics. Once the infection is treated, ageappropriate studies should be performed to determine the etiology of the epididymitis. There seem to be distinct causal agents of epididymitis; in the infant group, an anatomic anomaly is more

likely to be the cause. Work-up may include ultrasound, voiding cystourethrogram, or CT scan. In early pubertal boys functional voiding problems can play a leading role. Dysfunctional voiding and postponement of urination theoretically can produce high pressures in the prostatic urethra as well as the bladder. The patency of the ejaculatory duct valves may be overcome by attempts to maintain continence and allow for urethrovasal reflux and a ‘‘chemical’’ epididymitis [22]. Behavior modification with timed voiding and relaxation during voiding may be needed in such cases. Further evaluation in the office can include renal/bladder ultrasound and a uroflow study with post-void residual check (Fig. 2).

Upper urinary tract infections Pyelonephritis Treating a child with suspected pyelonephritis rapidly and successfully is of utmost importance because the timeliness of effective therapy can influence the amount of renal scarring and loss of function. Conventional thinking had placed infants and children under 5 years of age in the highest risk category for renal scarring and sequelae. Studies have shown, however, that there is no evidence of attenuated risk with older children and all patients must be treated and monitored carefully [23]. There is considerable ambiguity and controversy regarding which patients require hospitalization and parenteral antibiotics, and which may be treated effectively as outpatients. Older children who tolerate oral intake and who do not

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Fig. 2. (A) Office uroflow study from a 9-year-old boy presenting with epididymal inflammation. Tracing demonstrates the staccato flow pattern and prolonged voiding interval of a child with dysfunctional voiding. (B) Office uroflow study from same boy after appropriate interventions to treat dysfunctional voiding. Tracing demonstrates the laminar flow pattern of a child with healthy voiding hygiene.

appear septic can be treated with oral therapy. Options include TMP/SFX, nitrofurantoin, or cephalosporins. Alternatively, patients with clinical pyelonephritis can receive an intramuscular injection of a third-generation cephalosporin (eg, ceftriaxone) until culture-specific oral agents are identified. This injection should be followed by 10 to 14 days of appropriate oral therapy. Antibiotic sensitivities need to be followed on culture and may require a change in agent. If a child appears clinically toxic or septic, however, initiation of therapy with hospitalization and parenteral therapy will be necessary. In addition, neonates warrant strong consideration

for treatment as inpatients. In these patients, rehydration and initiation of broad-spectrum antibiotics (traditionally ampicillin and gentamicin) is appropriate until culture results and sensitivities are available. Alternatively, a third-generation cephalosporin may be used, but this will not cover enterococci. In neonates, intravenous antibiotics should be continued for 7 to 10 days. Culturespecific treatment doses of oral therapy should continue to complete 14 days of treatment. In patients older than 2 months of age, once they have been afebrile for 24 to 48 hours and serum markers of infection (ie, elevated white blood cell count or C-reactive protein) have normalized,

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substitution of oral medication to complete a long (10–14 day) course of total therapy is reasonable. Follow-up urine cultures are important to document eradication of infection. Prophylaxis should be administered until evaluation of the urinary tract is completed. Renal abscess Appropriate antibiotic therapy is the first step in guiding treatment. Classically, this therapy has been combined with surgical drainage to address the infection properly. More recently, percutaneous CT– or ultrasound-guided drainage can be used to obtain a culture and drain the collection. Drainage can be a solitary aspiration or continual drainage with the placement of a percutaneous pigtail catheter. Follow-up imaging is necessary to confirm resolution. Many cases can be managed without surgical intervention. If the abscess fails to resolve with a conservative approach, surgical drainage is the definitive treatment. Focal bacterial nephritis (acute lobar nephronia) is a focal form of acute bacterial nephritis, affecting one or more renal lobules. The most common causative organism is E coli, although infections also occur with Staphylococcus aureus, Pseudomonas aureginosa, Klebsiella species, and other organisms. Ultrasound is a helpful screening tool for hyperechoic or hypoechoic lesions, and CT is accurate in diagnosis (Fig. 3). Timely diagnosis and treatment is crucial because a significant percentage of these patients can progress to renal abscess. Klar and colleagues [24] treated 16 patients diagnosed with acute lobar nephronia, 25% of which evolved to renal abcess. Antibiotic treatment should last for 4 weeks, with resolution of abscess confirmed radiographically. If a staphylococcus infection is suspected because of hematogenous spread, the antibiotic of choice is penicillinase-resistant penicillin. If a patient is penicillin-allergic, treatment with vancomycin or cephalosporin is indicated. Tuberculosis According to recommendations of the American Academy of Pediatrics [25], treatment of genitourinary tuberculosis consists of 9 months of isoniazid and rifampin. For the first 2 months of therapy, a third medication should be added, such as streptomycin, pyrazinamide, ethambutol, or others. Ethambutol should not be used in young children because it has the possible side effect of optic neuritis, and such children may not be able to cooperate with a detailed eye examina-

Fig. 3. (A) Pretreatment contrast-enhanced CT scan of an 8-year-old girl with right vesicoureteral reflux presenting with pyelonephritis. Arrow demonstrates focal bacterial nephritis (lobar nephronia) affecting middle lobule. (B) Posttreatment contrast-enhanced CT scan of the same girl with focal bacterial nephritis. Arrow demonstrates resolution at middle lobule with uniform contrast enhancement in right renal unit.

tion. In children with HIV, treatment with three drugs must continue throughout therapy and may need to continue beyond 9 months. The need for surgical intervention in children with tuberculosis usually is limited to long-term complications in a small percentage of patients. These complications include repair of ureteral strictures, ureterovesical-junction reconstruction in newly incompetent ureteral orifices, or augmentation cystoplasty in small, contracted bladders. Xanthogranulomatous pyelonephritis A condition of obscure etiology, xanthogranulomatous pyelonephritis (XGP) most often affects middle-aged or elderly women, but is seen

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occasionally in children. The most common organisms isolated include Proteus mirabilis and E coli. Severe in nature, XGP can lead to widespread renal damage. Often the affected renal unit is nonfunctional. Frequently XGP is seen in association with staghorn calculi of the kidney. Nephrectomy usually is required, but partial nephrectomies have been done in focal cases (Fig. 4). Associations between XGP and renal-cell carcinoma, papillary transitional-cell carcinoma, and squamous-cell carcinoma of the renal pelvis have been documented in adults and support performing total nephrectomy in patients [26]. Candidiasis The treatment of candiduria depends on the extent of infection. In otherwise healthy children

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who develop candiduria after protracted courses of broad-spectrum antibiotics, discontinuation of the therapy should lead to spontaneous clearance of the fungal infection. Symptomatic infections limited to the bladder may be eradicated by instillation and irrigation of the bladder with a solution of amphotericin B (5% in sterile water, shielded from light). Alternatively, a patient can be treated with urinary alkalization. Upper-tract candidal infections also can be treated by irrigation with amphotericin B through an existent nephrostomy tube. Alternatively, oral 5-flucytosine may be given, but is contraindicated in children with renal azotemia or bone-marrow depression. Obstructing fungal balls in the renal pelvis may require percutaneous or surgical removal by way of pyelotomy, followed by nephrostomy-tube irrigations. Infected tubes need to be replaced and exchanged for new ones. Forced diuresis with furosemide to clear fungal balls from the renal pelvis without the use of nephrostomy tubes has been reported [27]. The nephrotoxicity of amphotericin B is well documented, and monitoring of renal function is necessary. Medications for the treatment of candiduria include ketoconazole and fluconazole (initial dose 10 mg/kg; maintenance 5 mg/kg for 1–2 weeks), with less associated nephrotoxicity. Aspergillosis After Candida species, Aspergillosis species is the second most common fungal infection in immunocompromised patients. Treatment is similar to that of candiduria, with high-dose intravenous amphotericin B as first-line therapy. As with candiduria, with fungal balls in the renal pelvis, percutaneous or open surgical removal is occasionally necessary, followed by upper-tract irrigation with amphotericin through a nephrostomy tube. Echinococcosis (hydatid cyst disease)

Fig. 4. (A) Non–contrast-enhanced CT scan of a 4-yearold girl with XGP in left kidney. Arrow demonstrates staghorn calculus in collecting system. (B) Contrastenhanced CT scan of same girl with XGP in left kidney. Arrows demonstrate nonfunctioning renal parenchyma. Complete nephrectomy was performed after period of nephrostomy tube drainage reveal no return of renal function. (Courtesy of J. Abidari, MD, Stanford, CA.)

The most common location for hydatid cyst disease in humans is in the kidneys (approximately 3% of all infections). Albendazole (15 mg/kg/ d divided into three doses for 28 days) is the preferred drug for medical management, and must be taken for 4 weeks at a time. As many as four courses can be taken with 15-day intervals between courses. Positive responses are seen in 40% to 60% of pediatric patients treated. Percutaneous management of the disease through cyst drainage with ultrasound guidance has become more successful

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in resolving the disease. There is a risk for systemic anaphylaxis reaction with the spillage of cyst fluid. Surgical intervention is also an option for solitary lesions or failed medical management. Care must be taken to avoid spillage during resection because this can seed the abdomen or lead to anaphylaxis.

Summary Timely treatment of UTIs is imperative in improving the health of children and preventing long-term sequelae. Failure to do so may lead to disseminated infections, renal scarring and hypertension, renal insufficiency, or other serious complications. A vigilant and aggressive practitioner should be able to prevent these adverse sequelae through thoughtful and appropriate therapy. Identification of an anatomic (ie, vesicoureteral reflux) or a physiologic (ie, dysfunctional voiding) predisposition to UTIs is a part of the comprehensive management of pediatric UTIs. References [1] Hampel B, Hullman R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use—safety report. Pediatr Infect Dis J 1997;16(1):127–9, 160–2. [2] Schaad UB. Use of the new quinolones in pediatrics. Isr J Med Sci 1994;30(5–6):463–8. [3] Goldraich NP, Manfroi A. Febrile urinary tract infection: Escherichia coli susceptibility to oral antimicrobials. Pediatr Nephrol 2002;17(3):173–6. [4] Baker PC, Nelson DS, Schunk JE. The addition of ceftriaxone to oral therapy does not improve outcomes in febrile children with urinary tract infections. Arch Pediatr Adolesc Med 2001;155(2):135–9. [5] Reed K, Newton W. Oral or IV antibiotics for the treatment of febrile children with UTIs? J Fam Pract Nov 1999;48(11):912–3. [6] Dagan R, et al. Once daily cefixime compared with twice daily TMP/SFX for treatment of UTI in infants and children. Ped Infect Dis J 1992;11(3): 198–203. [7] Madrigal G, et al. Single dose antibiotic therapy is not as effective as conventional regimens for the management of acute UTIs in children. Pediatr Infect Dis J 1988;7:316–9. [8] Bailey RR, Abbott GD. Treatment of UTI with a single dose of TMP/SFX. Can Med Assoc J 1978; 118:551–2. [9] Bailey RR, Abbott GD. Treatment of UTI with a single dose of amoxycillin. Nephron 1977;18: 316–20.

[10] Copenhagen Study Group of UTIs in Children. Short term treatment of UTI in girls. Scand J Infect Dis 1991;23:213–20. [11] Stahl G, et al. Single dose treatment of uncomplicated UTI in children. Ann Emerg Med 1984;13: 705–8. [12] Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute UTI in children. Cochrane Database Syst Rev2003;(1):CD003966. [13] Helin I. Short term treatment of lower UTIs in children with TMP/SFX. Infection 1981;9(5): 249–51. [14] American Academy of Pediatrics. Practice parameter: the diagnosis, treatment and evaluation of the initial UTI in febrile infants and young children. Pediatrics 1999;103(4):843–52. [15] Nelson DS, Gurr MB, Shunk JE. Management of febrile children with UTIs. Am J Emerg Med 1998; 16(7):643–7. [16] Blethyn AJ, Jenkins HR, Roberts R, Verrier Jones K. Radiological evidence of constipation in UTI. Arch Dis Child 1995;73(6):534–5. [17] Riccabona M. UTIs in children. Curr Opin Urol 2003;13(1):59–62. [18] Jurado M, Navarro JM, Hernandez J, et al. Adenovirus associated hemmorhagic cystitis after bone marrow transplant successfully treated with IV ribavirin. Bone Marrow Transplant 1995;15: 651–2. [19] King CH, Mahmoud AAF. Drugs five years later—praziquantel. Ann Intern Med 1989;110: 290–6. [20] Bazeed MA, et al. Partial flap ureteroneocystostomy for bilharzial strictures of the lower ureter. Urology 1982;20:237–41. [21] Renson CE. Tetracyclines in teeth. Br Med J 1977; 2(6091):892. [22] Bukowski T, et al. Epididymitis in older boys: dysfunctional voiding as an etiology. J Urol 1995; 154(2):762–5. [23] Benador D, Benador N, Slosman D, Mermillod B, Girardin E. Are younger children at highest risk of renal sequelae after pyelonephritis? Lancet 1997; 349(9044):17–9. [24] Klar A, et al. Focal bacterial nephritis in children. J Pediatr 1996;128(6):850–3. [25] American Academy of Pediatrics. Report of the Committee of Infectious Diseases 1988. 21st edition. Elk Grove Village (IL): American Academy of Pediatrics; 1988. [26] Schoborg TW, Saffos RO, Urdaneta L, et al. Xanthogranulomatous pyelonephritis associated with renal carcinoma. J Urol 1980;124:125. [27] Alkalay AL, et al. Noninvasive medical management of fungus ball uropathy in a premature infant. Am J Perinatol 1991;8:1330–2.