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RECOMMENDATIONS OF AMERICAN ACADEMY OF PEDIATRICS IN UTI

Pediatrics in review vol. 20 No. 10 October 1999
DIAGNOSIS
Recommendation 1:
- The presence of UTI should be considered in infants and young children 2 months to 2 years of age with unexplained fever

Recommendation 2:
- In infants and young children 2 months to 2 years of age with unexplained fever, the degree of toxicity, dehydration, and ability to retain oral intake must be carefully assessed

Recommendation 3:
- If an infant or young children 2 months to 2 years of age with unexplained fever is assessed as being sufficiently ill to warrant immediate antimicrobial therapy, a urine specimen should be obtained by suprapubic aspiration (SPA) or transurethral bladder catheterization: the diagnosis of UTI cannot be established by a culture of urine collected in a bag.

Recommendation 4:
- If an infant or young children 2 months to 2 years of age with unexplained fever is assessed as not being so ill as to require immediate antimicrobial therapy, there are two options:
§ Option 1: obtain and culture a urine specimen collected by SPA of transurethral catheterization.
§ Option 2: obtain urine specimen by the most convenient mean and perform a urinalysis. If the urinalysis suggests a UTI, obtain and culture a urine specimen collected by SPA of transurethral catheterization; if urinalysis does not suggest a UTI, it is reasonable to follow the clinical course without initiating antimicrobial therapy, recognizing that a negative urinalysis dose not rule out a UTI.

Recommendation 5:
- Diagnosis of UTI requires a culture of the urine.

TREATMENT

Recommendation 6:
- If the infant or young child 2 months to 2 years of age with suspected UTI is assessed as toxic, dehydrated, or unable to retain oral intake, initial antimicrobial therapy should be administered parenterally and hospitalization should be considered.

Recommendation 7:
- In the infant or young child 2 months to 2 years of age who may not appear ill but who has a culture confirming the presence of UTI, antimicrobial therapy should be initiated parenterally or orally.

Recommendation 8:
- Infant or young child 2 months to 2 years of age with UTI who have not had the expected clinical response with 2 days of antimicrobial therapy should be re-evaluated and another urine specimen should be cultured.

Recommendation 9:
- Infant or young child 2 months to 2 years of age, including those whose treatment initially was administered parenterally, should complete a 7-14 days antimicrobial course orally.

Recommendation 10:
- After a 7-14 day course of antimicrobial therapy and sterilization of the urine, Infant or young child 2 months to 2 years of age with UTI should receive antimicrobials in therapeutic or prophylactic dosages until the imaging studies are completed.





EVALUATION: IMAGING

Recommendation 11:
- Infant or young child 2 months to 2 years of age with UTI, who do not demonstrate the expected clinical response with 2 days of antimicrobial therapy, should undergo ultrasonography promptly. Voiding systourethrography (VCUG) or radionuclide cystography (RNC) is strongly encouraged to be performed at the earliest convenient time. Infants and young children who have the expected response to antimicrobials should have a sonogram performed at the earliest convenient time; a VCUG or RNC is strongly encouraged.

Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity

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Burton D Rose, MD, Dori F Zaleznik, MD
The main concerns with the use of aminoglycoside antibiotics are nephrotoxicity and ototoxicity. This card will review what is known about the pathogenesis of these complications and how the nephrotoxicity might be prevented.
NEPHROTOXICITY
Acute renal failure due to acute tubular necrosis is a relatively common complication of aminoglycoside therapy, with a rise in the plasma creatinine concentration of more than 0.5 to 1 mg/dL (44 to 88 µmol/L) occurring in 10 to 20 percent of patients [1,2]. The aminoglycosides are freely filtered; almost all of the drug is then excreted, with a small amount being taken up by, stored in, and leading to damage of the tubular cells, particularly in the proximal tubule. Acute renal failure can occur even if drug levels are closely monitored [3], although the risk is clearly greater in those patients with high levels [1,2].
Dose frequency also may be important as animal and preliminary human studies suggest that giving the total dose once a day is as effective an antimicrobial regimen and substantially less nephrotoxic than giving divided doses three times a day. The uptake mechanism in the proximal tubule is saturable; thus, a single large dose may not increase renal uptake if it exceeds reabsorptive capacity, but will be associated with less total uptake because the drug is being given less often.
Role of charge – The number of cationic amino groups (NH3+) per molecule appears to be an important determinant of nephrotoxicity [1,4]. Thus, neomycin (6 per molecule) produces the most renal injury and streptomycin (3) the least. Gentamicin, tobramycin, netilmicin (5) and amikacin (4) have intermediate toxicity [2]. Initial reports suggested that gentamicin was more nephrotoxic than tobramycin [3]. These studies, however, excluded patients with sepsis or hypotension in an attempt to exclude other potential causes of renal failure. In this limited population, gentamicin was more nephrotoxic, but the renal injury was mild with the plasma creatinine concentration remaining below 2 mg/dL (176 µmol/L) in almost all patients [3]. In comparison, there seemed to be no increase in toxic effect when all treated patients are included, which more closely simulates the real world [2,5,6].
The role of molecular charge seems to be related to binding of the cationic aminoglycoside to receptors in the luminal and subcellular membranes [1]. Recent evidence suggests the following sequence of events. At the luminal membrane of the proximal tubule, aminoglycosides are bound to anionic phospholipids; they are then delivered to an anionic protein called megalin and undergo endocytic uptake into the cell [7]. (Megalin, also called glycoprotein 330, is the antigenic target for antibodies in experimental membranous nephropathy. Within the cell, the aminoglycoside accumulates within lysosomes, an effect that may also be charge-mediated. Inhibition of lysosomal function (such as decreased synthesis or activation of the proteolytic enzymes cathepsin B and cathepsin L) may be responsible for subsequent aminoglycoside-induced cellular injury [8].
Prevention
The importance of charge may have potential therapeutic implications. Experimental studies suggest that, in addition to once-daily dosing, aminoglycoside nephrotoxicity can be diminished in several ways, each of which is related to cationic charge:
· By the administration of a cationic molecule, such as the calcium channel blockers verapamil and nitrendipine, which may compete with the aminoglycoside for binding to anionic membrane lipids [9].
· By the administration of polyaspartic acid, a polyanion that binds to the aminoglycoside, forming a nontoxic complex [1,10,11]. This binding appears to occur within the acid milieu of the lysosomes in the proximal tubular cells; thus, toxicity but not renal cortical accumulation of the aminoglycoside is prevented [11].
· By the administration of sodium bicarbonate to alkalinize the urine, since raising the pH will decrease the net positive charge on the aminoglycoside thereby diminishing its uptake by the tubular cells [12].
· By the administration of a penicillin, such as ticarcillin, which also may be effective by decreasing aminoglycoside uptake [4,13]. How this might occur is not known but these agents are anionic.

Although these findings are intriguing, their applicability to humans remains to be proven.
OTOTOXICITY
The pathogenesis of aminoglycoside-induced ototoxicity with hearing loss is less well understood. However, several studies have some light on how this might occur. One hypothesis is related to receptors for NMDA (N-methyl-D-aspartate), which are present at the synapse between cochlear hair cells and neural afferents [14]. Aminoglycosides can mimic the positive modulation of polyamines at these receptors, possibly producing excitotoxic damage. The observation that the administration of NMDA antagonists markedly attenuates hearing loss in animals is consistent with this hypothesis. Furthermore, there is a high correlation between in vitro activation of the receptor and relative cochlear toxicity in humans (gentamicin>tobramycin>amikacin>neomycin).
There also appears to be a genetic predisposition to the development of ototoxicity with aminoglycosides. Point mutations in the small (12S) ribosomal RNA gene have been described in a number of families with inherited susceptibility to ototoxicity [15,16]. The presumed mechanism is that the mutant human RNA binds aminoglycosides with high affinity; in comparison, the wild-type human RNA does not bind aminoglycosides at all [17].

References
1. Humes, HD. Aminoglycoside nephrotoxicity. Kidney Int 1988; 33:900.
2. Moore, RD, Smith, CR, Lipsky, JJ, et al. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100:352.
3. Smith, CR, Lipsky, JJ, Oetty, BG, et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 1980; 302:1106.
4. Bennett, WM, Wood, CA, Houghton, DC, Gilbert, DN. Modification of experimental aminoglycoside nephrotoxicity. Am J Kidney Dis 1986; 8:292.
5. Meyer, RD. Risk factors and comparisons of clinical nephrotoxicity of aminoglycosides. Am J Med 1986; 80(6B):119.
6. Matzke, GR, Lucarotti, RL, Shapiro, HS. Controlled comparison of gentamicin and tobramycin nephrotoxicity. Am J Nephrol 1983; 3:11.
7. Moestrup, SK, Cui, S, Vorum, H, et al. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest 1995; 96:1404.
8. Olbricht, CJ, Fink, M, Gutjahr, E. Alterations in lysosomal enzymes of the proximal tubule in gentamicin nephrotoxicity. Kidney Int 1991; 39:639.
9. Sokol, PP, Huiatt, KR, Holohan, PD, Ross, CR. Gentamicin and verapamil compete for a common transport mechanism in renal brush border membrane vesicles. J Pharmacol Exp Ther 1989; 251:937.
10. Gilbert, DN, Wood, CA, Kohlhepp, SJ, et al. Polyaspartic acid prevents experimental aminoglycoside nephrotoxicity. J Infect Dis 1989; 159:945.
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