# Antibiotic Prophylaxis in the Management of  Vesicoureteral Reflux

Authors: Marc Cendron
Journal: Advances in Urology
 (2008)

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## Abstract

Antibiotic prophylaxis has been, since 1960s, one of the management options in treating vesicoureteral reflux. The purpose of this review article is to provide a concise overview of the rational for antiobiotic prophylaxis and to discuss the various agents used. Some of the current controversies regarding use of antibiotics for reflux will also be presented.


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## Body

## 1. Introduction

Once vesicoureteral reflux (VUR) has been diagnosed, the basic premise in management
is to prevent further ascending urinary tract infections (UTI) which may, if
left untreated, lead to pyelonephritis. Pyelonephritis,
in turn, would lead to potential renal damage [1]. Based on the work of Jean Smellie et al. in 1960s, use of antibiotic prophylaxis was found to
be helpful in reducing the recurrence rate of urinary tract infection in children
with VUR [2]. Subsequently, several long-term studies have demonstrated the
validity of the concept [3–7]. The basis for the antibiotic
prophylaxis in patients with VUR was the fact that, ultimately, reflux in low
grades (I through III) was recognized to resolve over time and thus maintenance
on low-dose antibiotic would prevent or reduce the risk of urinary tract
infection until such time that the reflux would disappear [8]. The goal of this
article is, therefore, to review the management of VUR using antibiotic
prophylaxis, its advantages and disadvantages based on a review of the
literature. The various antibiotic used
for prophylaxis in VUR will be discussed.


## 2. The Evolution of Antibiotic Prophylaxis in the Management of Patients with VUR

Regurgitation
of urine from the bladder up into the ureter and renal collecting system has
been recognized since early times [9]. VUR became identified as an etiologic
factor for pyelonephritis from the classic studies carried out by Hutch, who in
1952, studied a group of paraplegic patients diagnosed with neurogenic
dysfunction of the bladder and VUR.
Reflux of infected urine into the upper urinary tract was postulated to
be the cause of chronic and progressive renal damage [10]. Later, in 1959,
Hodson observed that reflux seemed to be more common in children with urinary
tract infections and that there was a correlation between reflux and chronic
pyelonephritis as documented by VCUG (voiding cystourethrogram) and IVU
(intravenous urogram) [11]. As the association between VUR and urinary tract
infection became more established, additional experimental studies demonstrated
the role of bacterial infection in causing renal damage in patients found to
have  VUR [12–14].Historically,
the initial approach to treating patients with reflux was observational without
continuous antibiotic. Treatment was offered only as infections occurred.
Unfortunately this approach demonstrated that renal damage could occur in
patients who had had only one infection and that further renal damage was more
likely to occur in kidneys that were noted to have parenchymal lesions but
could also occur in normal kidneys. Lenaghan reported that most infections
occurred within the first five years after the initial diagnosis [15].  In light
of the high rate of new kidney damage noted in children treated with
intermittent antibiotic therapy, it was suggested that prophylactic antibiotic
be used. Lenaghan's conclusions were
confirmed by the  international reflux study in children which also demonstrated
a high rate of new scar formation in children who were observed off continuous
antibiotic prophylaxis but with known reflux [16]. This study found that new
renal damage occurred in 12.5% of children with normal kidneys, whereas 62% of
scarred kidneys showed progression of the damage as infections were treated.  A number of subsequent studies showed that progression of scarring in
patients with reflux could occur in the face of recurrent urinary tract
infection [17, 18]. N. P. Goldraich and I. H. Goldraich, in 1992, showed that, in a large
prospective study children with VUR of grades I through V treated with
antibiotic prophylaxis, a relatively low rate of new scar formation (3%) was
found and this was seen only in cases where urinary tract
infection occurred [19].  The Southwest Pediatric Nephrology Study Group
demonstrated that in a relatively small group of patients with grade 1–3 reflux followed
for five years, 12 patients (10.7%) developed new scars on Intravenous Urogram
intravenous urogram (IVU) in the face of breakthrough infections [20]. Skoog et al. observed a
large cohort of patients (545) on continuous  low-dose antibiotic prophylactic
for up to ten years. A relatively low
rate of progressive scarring in the kidneys was noted (0.5%) mostly occurring
in children with breakthrough infection [21].
Current recommendations for antibiotic prophylaxis in children have been
formalized by the AUA guideline panel on the management of primary VUR in
children [22]. Recommendations from the
guidelines were that children with VUR grade I through IV could be initially managed
medically with continuous antibiotic prophylaxis because of fewer risks, in the
short term, and that surgery would be recommended for children who experienced
breakthrough infections.More
recently the concept of stopping antibiotic prophylaxis after a certain age has
been evaluated as parents have increasingly become weary of long-term
medication intake and concerns have been raised about side effects and
bacterial resistance. Based on the findings that, by age 4, renal scarring was unlikely
to occur in the face of urinary tract infection, cessation of antibiotic
prophylaxis was felt to be reasonable in children beyond the age of 5 [23, 24].
Cooper et al. evaluated a group of 51 patients with reflux with a mean age of
8.6 years who were not treated with prophylactic antibiotic [25]. Despite the
fact that reflux persisted in the majority of these patients, only a small
number of patients (11%) developed a subsequent urinary tract infection. No new renal scars were noted as documented by
ultrasound, which, however, may not be the most accurate modality to ascertain
for renal lesions. Unfortunately, no
long-term double blinded randomized study has been carried out to compare the
efficacy of antibiotic prophylaxis versus no antibiotic prophylaxis in patients
diagnosed with VUR based on the degree of reflux. In addition, the data is still not entirely
clear with regard to the comparison between surgical therapy and antibiotic
prophylaxis. The International Reflux
Study in Children (IRSC) failed to demonstrate a clear advantage of any of
these two forms of management [26]. The
major limitations of the study were that not all grades of reflux were managed
by either modality, since higher grades of VUR were treated surgically thus
introducing a serious selection bias. Currently, medical management of VUR
still remains commonly practiced for younger patients with lower grades of VUR
as the randomized studies are being set up.


## 3. Antibiotics Used for Prophylactic Treatment in Patients with VUR

A
relatively small number of antimicrobials are used to treat urologic conditions
in children, the most common ones being used for antibiotic prophylaxis in the
face of VUR are trimethoprim-sulphamethoxasole (TMP/SMX), nitrofurantoin, and
penicillin derivatives amoxicillin. The advantage of these antibiotics is that
their active form or metabolites are excreted in the urine thus keeping the
urine free of bacteria. Guidelines for administrations will not be reviewed but
it should be kept in mind that only penicillin derivatives are used in younger
children under 2 months of age because the immaturity of the newborn liver and
kidneys results in a slower metabolism and excretion of these medications [27].
Allergic reactions to antimicrobials should always be a concern. A family history is helpful in determining
which child may actually be allergic to a medication. Allergic reactions manifest themselves as
either urticaria, diffuse skin rash, or, more rarely, anaphylaxis. Subcutaneous skin testing may resolve the
question of an allergic reaction to medication but since the testing itself may
be associated with some risk of allergic reaction this should be performed
under controlled conditions by an allergist. A 5% cross allergenicity between penicillin and cephalosporin should
also be recognized [28]. In general, however, children who have mild or delayed
allergic reaction to one of these classes of antimicrobials are usually able to
tolerate agents in other classes.Bacterial
drug resistance is a growing problem worldwide. In 1980s, widespread recognition
of the issue came about with the widely reported vancomycin resistant
staphylococcal aureus infection found in cases of community acquired infection
[29]. The incidence of drug resistance has clearly increased over the last 20
years and has become a major health issue. Control of antimicrobial resistance
is clearly a multifaceted task involving hospital policy, individual provider
practice, and patient compliance. Guidelines that have been developed by the
Joint Committee on Antimicrobial Resistance to help decrease the emergence of
drug resistance organism include a careful use of broad spectrum antibiotic,
the tailoring of therapy to sensitivity profiles, and the avoidance of
unnecessary prolonged therapy [30].We
will review the specific antimicrobials used in patients with VUR for
prophylaxis of infections. These include penicillins, TMP-SMX, and nitrofurantoin.The
penicillin class of antimicrobials includes natural penicillins (V and K), amino penicillins
(ampicillin and amoxicillin), the beta-lactamase resistant penicillins
(methicilin, nafcilin, oxacillin, dicloxacillin), and the antipseudomonal
penicillins (carbenicillin, ticarcillin,  azlocilin, and mezlocillin). The natural penicillins are used to prevent and
treat infections caused by group A streptococci and S pneumonia. These medications are now rarely used for
prophylaxis because of their limited commercial availability and because
resistance patterns have increased.
Amino penicillins have become the most commonly used penicillins. They are the drug of choice in treating
enterococcal urinary tract infection and can be used for prophylaxis in infants
under age 2 months. These agents are usually effective against most bacteria
susceptible to Penicillin G as well as some Penicillin G resistant gram
negative bacilli [31]. Amino penicillins are excreted primarily by the
kidney. Ampicillin is available both in
oral and intravenous formulation but Amoxicillin is only available as an oral
agent. Amoxicillin has better
bioavailability than ampicillin because more of it is absorbed from the
digestive tract. A higher percentage of
unabsorbed oral ampicillin remaining in the gut alters gut flora frequently
leading to GI upset and diarrhea which may be a concern in younger
children. A higher rate yeast infections
has also been noted.
Beta-lactamase-resistant penicillins are usually not used for prophylaxis
as are the antipseudomonal penicillins. Reactions to penicillins are relatively
rare and include hypersensitive reactions, neurotoxicity, nephrotoxicity, and
hematologic toxicity [32].Trimethoprim/sulfamethoxazole is a
combination agent that inhibits the production of bacterial folic acid, thereby
blocking DNA synthesis. It is the most
widely used outpatient antibiotic agent used for prophylaxis in children with
vesicoureteral reflux. While trimethoprim
(Primsol) alone has a similar antibacterial activity to sulfamethoxazole, the
spectrum of activity expands when the drugs are combined. In addition, resistance develops less quickly
in the combined formulation than with either drug alone [33]. Sulfamethoxazole
and trimethoprim are both absorbed rapidly after all administration. The majority of sulfamethoxazole undergoes
hepatic metabolism to inactive metabolites, while approximately half of the
absorbed trimethoprim is converted hepatically into inactive metabolites. Most of the active and inactive drug is then
excreted by the kidney into the urine [34].The
adverse reactions associated with this combination of drug are most often
caused by the sulfa component. These
reactions include hypersensitivity reaction (ranging from a mild rash to severe
Stevens-Johnson exfoliative reaction which may be severe and life threatening),
severe photosensitivity reaction, and hematologic toxicity that presents as
agranulocytosis or hemolytic anemia, prompting the recommendation that a
complete blood count be obtained in children who are taking sulfa medications
for extended periods of time. Sulfonamides are contraindicated in children
younger than 2 months of age because the sulfa moiety from the drug can
displace bilirubin from its natural albumin binding site, predisposing infants
to hyperbilirubinemia [35].Nitrofurantoin
is an agent widely used for the prophylactic management of VUR. While it is most commonly administered in an
oral formulation, a parenteral form is also available. It is well absorbed orally and undergoes
significant hepatic degradation to inactive metabolites. Because of its extended metabolism and relatively poor tissue penetration, nitrofurantoin is used solely as a urinary tract desinfectant since it will achieve bacteriocidal concentration only in urine. [33]. Although its exact mechanism of action is unknown, nitrofurantoin
is thought to inhibit bacterial acetyl coenzyme A, thereby interfering with
carbohydrate metabolism. It may also disrupt bacterial cell wall synthesis.
Nitrofurantoin is usually effective in treating staphylococci, streptococci and
most community acquired gram negative uropathogens. Despite its widespread use, bacteria rarely
develop resistance to nitrofurantoin. This is most probably due to the fact
that the drug does not achieve significant levels in intestinal or vaginal
tissues and does not alter the normal flora in these areas [36]. The most common
side effect associated with nitrofurantoin is GI upset with nausea, vomiting,
or diarrhea. Use of the microcrystalline formula and administration with meals
usually eliminates these side effects. A rare, more severe side effect is
pulmonary fibrosis, which is most likely to occur after long-term therapy
(months to years) and can present acutely with episodic coughing and/or dyspnea
which would warrant a full evaluation. Hemolytic anemia can occur in patients
with glucose-six-phosphate dehydrogenase deficiency as well as in infants under
one month of age.Cephalosporins
are rarely used for antibiotic prophylaxis unless patients have shown resistance
to TMP/SMX. Because of their broad
activity against community acquired pathogen, this class of antimicrobial is
usually used for surgical prophylaxis or for acute treatment of urinary tract
infection. Cephalosporins provide a reasonable antimicrobial activity against
most gram positive and gram negative bacteria. Use of prophylaxis is usually
not recommended as the medications tend to be expensive. However, some cephalosporins including
Cephalexin have prolonged urinary concentration and may be helpful for
short-term antibiotic prophylaxis.Fluoroquinolones
inhibit action of the essential bacterial enzyme DNA gyrase which consequently
prohibits maintenance of the superhelical twist in the double stranded DNA
causing rapid cell death [37]. One important clinical aspect of the
antibacterial spectrum of fluoroquinolones is their effectiveness in treating
hospital acquired organisms. These antimicrobials have good pharmacokinetic
qualities which include rapid absorption from the intestinal tract, good tissue
penetration, and good intracellular diffusion. Long-term use of fluoroquinolones
in a pediatric population has been reported to be effective and safe in
patients with cystic fibrosis [38]. Ciprofloxacin in children seems to be well
tolerated with no significant evidence of arthropathy, bone abnormalities, and
no serious adverse side effects [39]. However, fluoroquinolones have not become
an acceptable form of antibiotic prophylaxis given their expense and given the
risk for possible emergence of resistant organism to this class of
antimicrobials [40].


## 4. The down Sides of Antibiotic Prophylaxis in the Management of VUR

Three interrelated issues come
into play when considering prophylactic antibiotic therapy for VUR: compliance, efficacy, and long-term
side-effects of chronic antibiotic administration. Let us examine each of these
issues. A recent report indicate that long-term
administration of a daily antibiotic may not be carried out as carefully and
consistently as one would hope. Hensle et al. in a review of patterns of care
based on health insurance data showed that only 17% of patients were at least
80% compliant with prophylactic treatment [41]. In addition, as time goes by,
compliance with antibiotic intake has been shown to go down by the first year
follow-up visit [42]. Efficacy of antibiotic therapy in reducing the rate of
urinary tract infection is hard to evaluate as no long-term, randomized
placebo-controlled studies have, to date, been published. The Cochran Database
Systematic Review meta-analysis reported that there was no significant
difference in risk for urinary tract infection between daily antibiotic
prophylaxis and no prophylaxis or between intermittent (3 days per week)
prophylaxis and no prophylaxis [43]. The report also found no difference in the
risk of renal parenchymal damage between the various treatment options. In
addition the review indicated that 30 to 50% of patients on antibiotic
prophylaxis were reported to have a UTI within 5 years. In a recent
multicenter, randomized study of antibiotic prophylaxis treatment of patients
with lower grades of VUR, Garin et al. showed a similar one year urinary
infection rate between patients who were treated with or without antibiotic
prophylaxis: 23.6% of children with
grade 1 through 3 reflux received antibiotics and acquired a urinary tract
infection while 22.4% of those on no antibiotic prophylaxis acquired one. Interestingly,
those patients on antibiotic prophylaxis were found to have a higher rate of
pyelonephritis upon follow-up [44]. Recurrent infections are, therefore, a
worrisome issue in patients with VUR maintained on antibiotic prophylaxis.
Sjöström reported a rate of breakthrough urinary tract infections in patients
with reflux up to 47% of case [45]. Whether or not these infections are harmful
in the long term is unclear but this persistent ability to acquire urinary
tract infection clearly brings into question the efficacy of antibiotic
prophylaxis and the role of host susceptibility to infections. If one looks at
the ability of prophylactic antibiotic to reduce the risk for renal scarring, Reddy
et al. reported no difference in occurrence of renal damage amongst patients
with VUR randomized to receive either antibiotic prophylaxis or no antibiotics
[46]. Finally, it would appear that outcomes seem to be rather similar in
patients randomly assigned to medical or surgical management [47]. In a recent open-label, randomized
study from Italy,
antibiotic prophylaxis was not found to be effective in reducing the rate of
pelonephritis recurrence and the incidence of renal damage in young children with
VUR grades II, III, IV [48].


## 5. Conclusion

Antibiotic prophylaxis
still seems to be a reasonable management option after initial diagnosis of VUR
especially in children under age five who may be more susceptible to renal
damage if an ascending urinary tract infection occurs. Issues of noncompliance,
questionable efficacy, potential side effects and allergic reactions, and
antimicrobial resistance have now brought into question use of antibiotic
prophylaxis in the management of VUR.
Further,
uncertainty is built into the fact that prediction of reflux
resolution varies from patient to patient and may involve other factors than
anatomic ones. The complex nature of the
interaction between VUR and UTIs and their effects on the kidneys make the
identification of those patients at risk for ascending urinary tract infection
and subsequent renal damage the biggest challenge in managing VUR. Since the available data is still not
sufficient in providing objective guidelines for use of antibiotic prophylaxis
in managing VUR, further long-term, randomized placebo-controlled studies are
clearly needed to allow better insight into this form of management. In the
first year after diagnosis, consistent, low-dose administration of antibiotics
may be helpful in reducing the rate of urinary tract infection provided that
the right antibiotic is administered keeping in mind the caveat of such a
treatment, mainly the rising rate of antimicrobial resistance [48]. It should
be noted that cranberry juice may have a role in reducing the rate of UTIs [49].
Parents of children diagnosed with VUR should be apprised of the potential side effects  of the
medications used for prophylaxis of UTIs and of the other options available for
treatment. Reassurance as to the relatively
low rate of complication rate seen with antibiotic prophylaxis should be
emphasized. Until such studies show unequivocally that antibiotic prophylaxis
is ineffective in preventing urinary tract infection and renal damage,
antibiotic prophylaxis still remains a viable option in the management of VUR
[50].



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