Antibiotics Prophylaxis in Patients with CAKUT, Does It Actually Prevent UTI? A Single Center Experience at South Africa

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are a well-documented risk factor for the development of urinary tract infection (UTI) in children. Prevention of UTI in this group of patients is advocated due to their increased risk of renal scarring, hypertension and end stage kidney failure. Methods: A 10-year retrospective review of CAKUT patients at the Johannesburg Academic Hospital, who were placed on prophylactic antibiotics over a certain period was done. The rate of UTI, the types of causative organisms isolated and the efficacy of prophylactic antibiotics in preventing UTI were documented. Results: Thirty-six (36) out of 134 patients had been started on prophylactic antibiotics after the diagnosis of CAKUT was made. There was a statistically significant association between the use of prophylactic antibiotics and the rate of UTI (p < 0.001). Patients who were not on a prophylactic antibiotic were five times more likely to have a UTI than those who were on a prophylactic antibiotic (OR = 5.21, P = 0.001, 95% CI: 1.9906 - 13.6277). There was a statistically significant association between the type of bacteria isolated and the use of antibiotic prophylaxis (p = 0.031). Conclusion: Antibiotic prophylaxis was very effective in decreasing the rate of UTI in our cohort of patients with CAKUT.

Open Journal of Nephrology nital anomalies of the kidney and urinary tract (CAKUT) than in the general paediatric population [2] [3] [4]. Among other mechanisms, CAKUT alters the natural free unidirectional flow of urine causing stasis and thereby enhancing the growth of pathogenic micro-organisms [5] [6].
The incidence of CAKUT among patients with urinary tract infection (UTI) ranges from 25% -55% [6]. Ring and Zobel found CAKUT in 42% of infants with UTI, with obstructive uropathy and vesicoureteral reflux (VUR) accounting for 37% and 59% of all the anomalies respectively [7]. Also, in that study 61% of infants with CAKUT had UTI [7].
Recurrent UTI as a result of CAKUT may predispose children to renal scarring, hypertension and CKD, which carries the risk of progression to ESRD requiring renal replacement therapy [2] [8] [9] [10].
Prevention of UTI in this group of patients is advocated due to their increased risk of renal scarring, hypertension and end stage kidney failure [2] [8] [9] [10].
In addition to enhancing personal hygiene and prevention of constipation, some clinicians place a selected group of CAKUT patients onto continuous antibiotic prophylaxis. Indications for continuous antibiotic prophylaxis include children less than 5 years with VUR, or other structural anomalies, and those who have had three documented UTIs in one year [2] [8] [9] [11].
The use of antimicrobial prophylaxis in patients with CAKUT and recurrent UTI is still controversial [10] [12] [13] [14]. Those opposing the use of prophylactic antibiotics voice the concern that this practice may breed resistant strains of pathogens, increase the risk of breakthrough infections, and encourage adverse drug reactions. They also argue that the effectiveness of antibiotic prophylaxis is questionable, and that many patients will need to be treated to benefit one child. Finally, they fear that any benefiting from this practice may be interrupted by low adherence of patients to the prescribed medication [10] [12] [13] [14].
All the aforementioned concerns are due to the fact that previous studies on the use of prophylactic antibiotics were rife with contradictory results and divergent conclusions. However, some well controlled and randomized studies, including the RIVUR and PREVENT trials, have documented some benefits of antibiotic prophylaxis use in select groups of patients [8] [13] [15] [16].
Although prophylactic antibiotics have been recommended for children with grades IV and V VUR and other significant urological anomalies, the current recommendation is to discourage prophylactic antibiotic use in children with recurrent UTI who do not have CAKUT. Rather, they should be treated promptly and adequately whenever they get UTI [14] [17].
This study was therefore set to determine the efficacy of antimicrobial prophylaxis in preventing UTI among patients with CAKUT at a paediatric nephrology setting in South Africa.

Materials and Methods
The study was a retrospective review of the medical records of all patients be- The total number of all the patients that attended the division between January 2005 and December 2014 were retrieved from the file data. Those that had CAKUT were selected. We went further to identify CAKUT patients that had at least one episode of UTI within the study period. These patients with UTI were divided into two groups; those that were placed on prophylactic antibiotics after the diagnosis of CAKUT was made and those that were not placed on any prophylactic antibiotics after the diagnosis of CAKUT was made. Finally, we compared the rate of UTIs between these two groups, over the study period.
During data collection, CAKUT was documented according to the exact diagnosis on the patients' files. It was later classified into anomalies of the kidney, anomalies of the collecting system, anomalies of the bladder, and Posterior Urethral Valves (PUV) as suggested by Song and Yosypiv [12]. The presence of a After data collation and cleaning, analysis was done using Stata 13 statistical package [21]. A confidence interval of 95% was used, and for all analyses a p-value < 0.05 was taken as statistically significant.

Result
Over the study period 691 new patients were seen at the clinic and, of those, 138 were diagnosed with CAKUT. Four records were excluded from analysis because they were lost to follow up after their diagnosis was made (they visited the clinic  Table 1). The median age at presentation was 8.4 months (IQR 1.9 -47.7) and the median duration of follow up was 39 months (IQR = 12.5 -81.7).
Out of the 134 patients with CAKUT, 36 patients had been started on prophylactic antibiotics after the diagnosis of CAKUT was made. Figure 1 shows the types of CAKUT on prophylactic antibiotics. The frequency of prophylactic antibiotic usage was highest among patients with urethral anomalies (35%).
Ninety-eight (98) patients were not commenced on any prophylactic antibiotic. Forty-nine (50.0%) of those without prophylactic antibiotics had at least one episode of UTI on follow up, while only seven (19.4%) of those on antibiotic prophylaxis developed a UTI. The association between UTI and prophylactic antibiotic use is shown in Table 2. There was a statistically significant association between the use of prophylactic antibiotics and the rate of UTI (p < 0.001). Patients who were not on prophylactic antibiotics were five times more likely to have a UTI (OR = 5.21, P = 0.001, 95% CI: 1.9906 -13.6277).
A more detailed breakdown of the use of prophylactic antibiotic and the rate of UTI among the different classes and sub groups of CAKUT can be seen in Table 3. There was a decreased frequency of UTI in patients on antibiotic prophylaxis in all the different classes and sub groups of CAKUT. Table 4 and Figure 2 show the effect of prophylactic antibiotics on the pattern of the bacteria isolated among the different types of CAKUT. Prophylactic      There was a statistically significant association between the type of bacteria isolated and the use of antibiotic prophylaxis (p = 0.031).

Discussion
Preventing recurrent UTIs in patients with CAKUT is one of the most effective ways of preventing progression to end stage kidney disease in this cohort of children [2] [8] [9] [10] but, due to conflicting reports on the benefits of antibi- Our results emphasize the positive role that antibiotic prophylaxis can play in the prevention of UTI in children with CAKUT. Unfortunately, due to the retrospective nature of our data collection, we could not analyze the long-term effect of antibiotic prophylaxis on renal function but we feel that just to be able to prevent the morbidity of each UTI, it is worthwhile putting at least some children with CAKUT, as suggested by Simoese, on antibiotic prophylaxis.
Currently, the division of paediatric nephrology at CMJAH does not have any antibiotic prophylaxis protocol for the management of patients with UTI and/or CAKUT. Each index patient is treated based on his/her unique clinical condition. The results of this study will help us change this policy to place more patients onto antibiotic prophylaxis.

N. C. Okoronkwo et al. Open Journal of Nephrology
As mentioned above, the extent to which antibiotic prophylaxis influenced the development of microbial resistance in this study was not explored other than to compare the group who had been on prophylaxis with the group who had not.
There was a statistically significant association between the type of bacteria isolated and the use of antibiotic prophylaxis (p = 0.031). In the group who were on antibiotic prophylaxis, Klebsiella pneumoniae was the most common organism isolated as opposed to E. coli in the group that were not on prophylactic antibiotics.
Our study findings are in keeping with other reports which have showed that children on prophylactic antibiotics are often infected with causative organisms other than E. coli [25] [26].
It is recommended that the urine bacterial profile of CAKUT patients on prophylactic antibiotics are reviewed regularly [13] [27]. This will enable physicians to remain ahead of emerging strains of atypical organisms in this cohort of patients.

Conclusion
Antibiotic prophylaxis was very effective in decreasing the rate of UTI in our cohort of patients with CAKUT. Although we could not ascertain which particular subgroup of CAKUT would benefit most from prophylactic antibiotic use, it is worthwhile putting at least some children with CAKUT on antibiotic prophylaxis.

1)
To determine which of the conditions which make up CAKUT are most suitable for antibiotic prophylaxis.
2) To determine which antibiotics are most suitable for prophylaxis in these conditions.
3) To determine the long-term effects of antibiotic prophylaxis on renal function in children with CAKUT.

4)
To study the long-term effects of antibiotic prophylaxis on UTI resistance patterns in children with CAKUT.

Recommendation
Majority of our patients that were on antibiotic prophylaxis were PUV patients.
It is recommended that more of the other types of CAKUT be placed on antibiotic prophylaxis to evaluate the effect of the later on rate of UTI for individual CAKUT types.