When to Treat
Acute treatment of UTI aims to relieve symptoms and prevent complications and renal scarring. Despite the existence of studies that have suggested that early treatment of acute pyelonephritis in infants and young children had no significant effect on subsequent renal scarring,[43,44] treatment should not be delayed especially for sick infants,[45,46] as other complications such as sepsis and abscess might occur with treatment delays.[10,46] Empiric therapy should therefore be initiated after appropriate urine specimen for culture has been obtained.
Which UTI to Treat
Disease severity cannot be defined on clinical grounds alone.[47,48] The gold standard for diagnosis of renal parenchymal involvement remains the technetium-99m–dimercaptosuccinic acid (DMSA) scan. Its routine use is, however, discouraged by current guidelines, as it is doubtful whether DMSA findings would affect clinical management.[12,101] Among inflammatory indexes, C-reactive protein (CRP) and procalcitonin (PCT) have been found to be useful in identification or exclusion of pyelonephritis.[30,49] The diversity of studies has not allowed for predictive cutoffs, but a serum CRP level of <20 mg/l makes the diagnosis of pyelonephritis very unlikely.[49,50] A serum level of PCT ≥0.5 ng/ml has been found to be highly predictive for both acute renal parenchymal involvement and subsequent scarring.[49–52] All existing guidelines warrant blood tests only in severely ill children.[12,13,101,102] The measurement of local inflammatory products in the urine, such as IL-6 and IL-8, is simple and noninvasive and has given promising results, but the clinical usefulness of these tests is yet to be established.[53–58] Until definite conclusions for more accurate localization of infection are available, children <24 months of age suspected to have UTI should be treated as having pyelonephritis.
Route of Antibiotic Application
The decision for oral or parenteral therapy depends on disease severity, age and availability of potent oral agents. Well-designed, randomized comparative studies of oral to intravenous antibiotics showed no significant differences in time of clinical improvement and in prevention of scarring,[59,60] and a recent meta-analysis confirmed the efficacy of oral antibiotic regimens. Indications for hospitalization include toxic presentation, intolerance to oral intake, uncertain compliance, nonresponse to oral therapy and infants up to 2–3 months of age or up to 6 months of age according to RCH Melbourne guidelines.[10,13,46,102] Neonates have a risk of bacteremia exceeding 10% and require an initial inpatient management with full septic work-up and parenteral antibiotics for at least 4 days.[62,63] For young infants up to 3 months of age, who commonly present with fever without a source and are of high risk for bacteremia, initial parenteral treatment is advisable too.[10,46] The duration of parenteral antibiotic application seems to be inconsequential. Long-term (≥4 days) and short-term (≤3 days) intravenous therapy in infants <6 months did not differ in UTI recurrence rates within the following month. Thus, switching to oral therapy is advised after confirmation of diagnosis and clinical improvement.[12,101]
It should be stressed that studies comparing oral to parenteral therapy have usually excluded children at risk for a complicated course, such as those with known urinary tract anomalies.[10,46] Children with severe pyelonephritis, including acute lobar nephronia, may benefit from prolonged intravenous treatment. Although acute imaging is not proposed routinely by current guidelines, for children who are sick enough to be hospitalized an ultrasound of the urinary tract to exclude major abnormalities and severe forms of infection should be considered before discharge. Most of the children with UTI, however, will have a noncomplicated infection and will be aged between 3 months and 3 years and can be safely treated with an oral agent.
Treatment Duration & Response
A total course of 7–14 days is recommended for pyelonephritis. Shorter, 1–3-day antibiotic courses were proved to be inferior to the standard range. Because 7–10- and 10–14-day regimens were of equal efficacy, a 10-day course is recommended by the NICE guideline. More severe infections, such as complicated pyelonephritis due to unusual pathogens, acute lobar nephronia, renal abscess and sepsis, occur mostly in children with risk factors and require longer antibiotic courses of 3–4 weeks, individualized imaging and possibly surgical involvement.[10,46] Current guidelines do not specifically refer to more severe forms of UTI, probably because they are considered exceptional and have not been adequately described yet.
For treatment of acute bacterial cystitis, short antibiotic courses of 2–5 days have been shown to be equivalent to standard regimens for symptom relief and eradication of infection and can be applied in older, nonfebrile children. Single doses or 1-day therapies are associated with higher rates of recurrences. A re-evaluation of the child with cystitis who is still symptomatic after 24–48 h is recommended by NICE guidelines.
Children with ABU have a low possibility of developing pyelonephritis. ABU is commonly caused by low-virulence uropathogens, represents colonization rather than true infection and needs no treatment at all in children with normal urinary tracts.[8,10,12,46] Therapeutic decisions, however, can be difficult when children with ABU have a urinary tract abnormality or present with fever of a different etiology. The former do not represent a distinct category of patients, thus treatment decisions should be individualized. For the latter, if a true infection cannot be excluded on safe grounds, the best decision would be to treat and follow as in febrile UTIs (Table 5).
Treatment response is usually noted within 24–48 h. Repeat urine cultures seem not to be needed in children with clinical response. The 1999 AAP guideline recommended repeat cultures in patients without improvement after 48 h of treatment and those with infections from organisms resistant to the chosen antibiotic. Subsequent studies showed minimal utility of this practice even when fever lasted beyond 48 h.[66,67] A selective use of follow-up cultures in children with resistant or unusual uropathogens, such as Enterococci, and those who are still febrile after 72 h of treatment might be warranted.
The choice of empirical antibiotic regimen is guided by the expected pathogen and the local resistance patterns. Coverage of Escherichia coli, which is by far the leading uropathogen, and Enterococcus species in neonates and young infants are priorities in antibiotic selection. Non-E. coli Gram-negative pathogens and Pseudomonas aeruginosa should be considered in children with urinary tract abnormalities or dysfunction, under antibiotic prophylaxis or recently exposed to antibiotics.[68–70] Resistance of uropathogens to antibiotics is increasing worldwide. Traditional first-line antibiotics for UTIs in children, such as ampicillin/amoxicillin and cotrimoxazole, with resistance rates of up to 50 and 30%, respectively, have been rendered inadequate.[11,71] However, E. coli remains largely sensitive to second- and third-generation cephalosporins and nitrofurantoin, Enterococcus species to ampicillin and non-E. coli Gram-negative pathogens and P. aeruginosa to aminoglycosides.
The combination of ampicillin with a third-generation cephalospoprin or aminoglycoside is the safest choice for neonates and young infants aged <2–3 months.[10,46] Third-generation cephalosporins are appropriate for treatment of older children.[10,46] Therapeutic options should include ampicillin when enterococcal UTI is suspected (i.e., in children with major urinary tract anomalies, catheterization or manipulation of external genitalia). Aminoglycosides in one daily dose should be considered in patients suspected for non-E. coli Gram-negative or Pseudomonas UTIs and in areas with high resistance rates of uropathogens to β-lactams.[10,46,61] Adjustments according to the sensitivity of the identified pathogen should be made after culture results are available.
Second- and third-generation cephalosporins are appropriate first-line agents for oral treatment of pyelonephritis. Alternatively, amoxicillin–clavulanate can be used, in particular when enterococcal infection is suspected. Although ciprofloxacin is highly efficient against most uropathogens, its use should remain a choice of last resort, mostly for infections caused by Pseudomonas or other multidrug-resistant pathogens.[10,46] For the treatment of lower UTI, nitrofurantoin, cotrimoxazole or an oral cephalosporin can be used.[10,101] Children on prophylaxis should not be treated with therapeutic doses of the prophylactic agent in breakthrough UTI, as resistant organisms are usually expected.
Limitations of Antibiotic Use
In children with renal insufficiency a dosage adjustment to glomerular filtration rate may be required. Experience with trimethoprim and trimethoprim–sulfamethoxazole is limited in infants aged <6 weeks. Nitrofurantoin has been related to increased risk of hemolytic anemia in infants aged <3 months and should not be used for pyelonephritis as it does not achieve therapeutic concentrations in the bloodstream, nor as in children with glomerular filtration rate <50% because it is not sufficiently eliminated in the urine.[10,12] When aminoglycosides are used, drug monitoring is essential.
UTI severity and permanent renal scarring are associated with the integrity of the urinary tract, virulence of uropathogens and the host innate immune response.[4,71,72] When bacteria invade the urinary tract, the innate immune system is activated through Toll-like receptor signaling, and chemokines and cytokines are locally produced. This genetically determined inflammatory response is a major determinant of disease severity and scarring and can be estimated by the measurement of cytokines in the urine.[72,73] Alternative approaches for UTI management have emerged through research in this field. Two studies showed a beneficial effect of steroids in prevention of scarring in children with acute pyelonephritis.[73,74] In the first study, intravenous dexamethasone, which was used adjunctively to antibiotics, was associated with reduction of urinary cytokines. In the second study the beneficial effect of oral methylprednisolone was documented with significantly lower rate of scarring in follow-up DMSA scans for steroid recipients. Vitamin A, known for its anti-inflammatory properties, has been found to protect from scarring and from UTI recurrences.[75,76] In vitro studies of a probiotic that contains E. coli Nissle 1917 strain have shown bactericidal effect against several uropathogens. The clinical use of this agent might be beneficial in recurrent UTIs by eliminating the colonization with pathogenic bacteria within the bowel.
Expert Rev Anti Infect Ther. 2012;10(10):1153-1164. © 2012 Expert Reviews Ltd.