Microbial Resistance Caused by Antibiotic Prophylaxis with Amoxicillin in a Male Infant with Vesicoureteral Reflux

Vesicoureteral reflux is a common condition in infants with urinary tract infection. Although antibiotic prophylaxis to prevent recurrent urinary tract infection is widely performed, its effectiveness remains controversial. Herein we report a sevenmonth-old boy with vesicoureteral reflux. Antibiotic prophylaxis with amoxicillin caused microbial resistance accompanied by recurrent urinary tract infection. Subsequent antibiotic prophylaxis with sulfamethoxazole-trimethoprim was effective until spontaneous remission of vesicoureteral reflux occurred. Sulfamethoxazole-trimethoprim, but not amoxicillin, should be considered as an agent for antibiotic prophylaxis in infants with vesicoureteral reflux.


INTRODUCTION
U rinary tract infections are common in infants, 1 and can refl ect underlying abnormalities like vesicoureteral refl ux (VUR). 1,2 Although antibiotic prophylaxis to prevent recurrent urinary tract infection is widely performed, its eff ectiveness remains controversial. 1,[3][4][5][6][7][8][9] Herein we report a seven months old boy who was diagnosed with urinary tract infection and VUR. Antibiotic prophylaxis with amoxicillin caused microbial resistance accompanied by recurrent urinary tract infection. Subsequent antibiotic prophylaxis with sulfamethoxazole-trimethoprim (ST) was eff ective until spontaneous remission of VUR occurred.

Case Report
A seven months old infant presented with high fever. Urinary tract infection was diagnosed on the basis of both leukocyturia and a single uropathogenic organism in the urine. Microscopic examination revealed gram-positive bacteria. A culture examination revealed Enterococcus faecalis at 1 × 105 /mL in catheterised urine. He received intravenous administration of ampicillin (50 mg/kg, three times a day) for eight days, followed by oral administration of amoxicillin (10 mg/kg, three times a day) for six days. The treatment was eff ective for fever reduction. Radiological examinations were performed to investigate certain underlying conditions. Ultrasonography revealed hydronephrosis (Figure 1a). Voiding cysto-urethrography showed grade III bilateral VUR (Figure 2a). Other anomalies including posterior urethral valve, ureteropelvic junction stricture, and renal atrophy were not detected. Subsequently, he received antibiotic prophylaxis with amoxicillin (5 mg/kg, once a day) to reduce the risk of recurrent urinary tract infection.
He suff ered recurrence of urinary tract infection at one year of age. A culture examination revealed Klebsiella oxytosa at 1 × 10 5 /mL in catheterised urine. He received intravenous administration of ceftriaxone (60 mg/kg, once a day) for one day, followed by oral administration of amoxicillin (10 mg/kg, three times a day) for seven days. The treatment was eff ective and he became asymptomatic. Subsequently, he received antibiotic prophylaxis with ST (10 mg/kg sulfamethoxazole plus 2 mg/kg trimethoprim, once a day).
Technetium 99m dimercaptosuccinic acid (99mTc-DMSA) scintigraphy detected no abnormalities (data not shown). Voiding cystourethrography revealed grade II right VUR (Figure 2b) at 21 months of age. Antibiotic prophylaxis was stopped after improved VUR was confi rmed. Ultrasonography demonstrated that hydronephrosis was improved at 22 months of age ( Figure 1b) and had disappeared at 25 months of age ( Figure 1c). No side eff ects of ST treatment were noted. He has not suff ered from recurrence for > 30 months since stopping antibiotic prophylaxis.  We observed two important clinical issues in our patient: antibiotic prophylaxis with amoxicillin caused microbial resistance in an infant with VUR, and antibiotic prophylaxis with ST was eff ective in preventing recurrent urinary tract infection until spontaneous remission of VUR occurred.

Discussion
Regarding the fi rst issue, antibiotic prophylaxis with amoxicillin caused microbial resistance in our patient. Amoxicillin is often chosen as an agent for antibiotic prophylaxis to prevent recurrent urinary tract infection in infants with VUR in Japan. We chose amoxicillin because it allowed our patient to recover favorably from the urinary tract infection. Although amoxicillin covered E. faecalis in our patient, it did not cover K. oxytosa, another major microbial pathogen for urinary tract infections in infants. 1 Although amoxicillin was adequate for treatment of the urinary tract infection in the acute phase, it was inadequate for antibiotic prophylaxis in our patient. Thus, an agent for antibiotic prophylaxis should cover K. oxytosa as well as E. faecalis.
For the second issue, ST was useful as an agent for antibiotic prophylaxis until spontaneous remission of VUR occurred. ST did not allow E. faecalis and K. oxytosa, or Escherichia coli as the principal microbial pathogen for urinary tract infection, to cause recurrence. Previous reports on antibiotic prophylaxis described oral administration of ST to prevent recurrent urinary tract infection in children. [3][4][5][6][7][8][9][10] Selection of ST, rather than amoxicillin, after the initial urinary tract infection would have been preferable in our patient.
The American Academy of Paediatrics previously recommended antibiotic prophylaxis for VUR in infants and young children aged two months to two years, until completion of imaging studies like ultrasonography, voiding cystourethrography, and 99mTc-DMSA scintigraphy.10 Recently, however, there has been intense discussion on the eff ectiveness of continuous antibiotic prophylaxis in children with VUR. Some groups do not support antibiotic prophylaxis, 3-6 as summarised in Table 1. Furthermore, Conway et al. 4 indicated that antibiotic prophylaxis was associated with an increased risk of resistant infection. Meanwhile, other groups support antibiotic prophylaxis, 7-9 as also summarised in Table 1. Roussey-Kesler et al. 7 investigated 225 patients aged one month to three years with grade I-III VUR, and reported that antibiotic prophylaxis may be eff ective in boys with grade III VUR. Craig et al. 8 investigated 576 patients aged < 18 years with grade I-III VUR, as well as patients without VUR, and reported that antibiotic prophylaxis was associated with a 6% decrease in frequency of recurrence. The RIVUR Trial Investigators 9 examined 607 patients aged two to 71 months of age with grade I-IV VUR, and reported that antibiotic prophylaxis substantially reduced the risk of recurrence by 50%. Consequently, the optimal strategy remains unclear. Further accumulation of cases like the current patient is essential to clarify this point.

Conclusions
ST is useful for antibiotic prophylaxis to prevent recurrent urinary tract infection in infants with VUR, while amoxicillin is associated with a risk of microbial resistance. ST should be initially considered as an agent for antibiotic prophylaxis in infants until spontaneous remission of VUR occurs.