Use of Intravesicular Amikacin Irrigations for the Treatment and Prophylaxis of Urinary Tract Infections in a Patient with Spina Bifida and Neurogenic Bladder: A Case Report

Abstract

This case report describes the use of intravesicular amikacin irrigations to treat and prevent urinary tract infections (UTIs) in a pediatric patient with spina bifida and neurogenic bladder. A 15 year old Hispanic female was admitted for a UTI caused by Enterobacter cloacae and multiple-drug resistant Pseudomonas aeruginosa. A 7 day course of daily intravenous amikacin and ceftazidime was initiated along with twice daily intravesicular amikacin irrigations (15 mg/30 mL) with a dwell time of 2 hours. The patient improved and was discharged on prophylactic Bactrim SS (sulfamethoxazole/trimethoprim) 1 tablet daily and intravesicular amikacin irrigations (15 mg/30 mL) once every other day. Approximately 2 months after discharge, the patient developed another UTI from multidrug resistant Escherichia coli and was treated with a 14 day course of daily intravenous ciprofloxacin accompanied by daily intravesicular amikacin irrigations. Adjunctive therapy with either once daily or twice daily intravesicular amikacin irrigations successfully treated the patient's UTI. However, prophylactic treatment with intravesicular amikacin failed to prevent future UTIs in this patient.

INTRODUCTION

Children with spina bifida have a high risk for urinary tract infections (UTIs) due to sphincter dysfunction, hyper-reflexic bladder and urinary incontinence and retention.¹ Measures used to prevent or treat UTIs in these children include clean intermittent catheterization, antimuscarinics and antibiotics.^1,2 Although most spina bifida clinics in the United States recommend antibiotic bladder irrigations for UTI prophylaxis in pediatric patients with spina bifida and neurogenic bladder,¹ there is limited literature to help guide intravesicular antibiotic therapy in this population.² This case report describes the use of intravesicular amikacin irrigations to treat and prevent UTI in a pediatric patient with spina bifida and neurogenic bladder.

CASE REPORT

A 15-year-old Hispanic female was admitted to the general pediatric service for increased cloudiness and presence of foul smelling odor in her urine. At the time of admission she weighed 43 kg, was 118 cm tall, and had an estimated creatinine clearance of 15 mL/min. Her past medical history was significant for spina bifida, neurogenic bladder, end-stage renal disease status post living donor transplant and anemia. She also underwent the Mitrofanoff procedure to facilitate clean intermittent catheterization. Within the past 3 months, she had 3 episodes of UTIs and pyelonephritis with multidrug resistant organisms requiring hospitalizations and intravenous antibiotics. At home, she was receiving 1 tablet of sulfamethoxazole/trimethoprim (Bactrim SS, Interpharm Inc, Hauppauge, NY) orally each day (2 mg of trimethoprim/kg/day) for UTI prophylaxis. Her other home medications were given orally and include: Prednisone 5 mg every other day (Roxane Laboratories, Columbus, OH); Tacrolimus 1.5 mg twice a day (Prograf, Astellas Pharma US, Deerfield, IL); Mycophenolate 500 mg twice daily (CellCept, Genentech, San Francisco, CA); Calcitriol 0.5 mcg daily (Rocaltrol, Teva Pharmaceutical, North Wales, PA); Ranitidine 37.5 mg twice daily (Zantac, McKesson, Concord, NC); Bicitra 30 mL twice daily (Sodium citrate 500 mg and citric acid 334 mg per 5 mL, Pharmaceutical Associates, Greenville, SC); Oxybutynin ER 5 mg twice daily (Ditropan XL, Mylan Pharmaceutical, Morgantown, W.Va); Enalapril 5 mg daily (Vasotec, Mylan Pharmaceutical); Magnesium oxide 400 mg twice daily (Mag-Ox 400, McKesson) and Polysaccharide Iron Complex 150 mg twice daily (Niferex, Ther-Rx Corporation, St. Louis, MO).The patient also received Epoetin Alfa 10,000 units subcutaneous every week (Epogen, Amgen Inc, Thousand Oaks, CA) and was on a low salt diet. She is allergic to latex, penicillin and vancomycin and develops a rash when exposed to these agents.

On admission, the physical examination was within normal limits. The patient was afebrile (36°C) with normal vital signs. Her basic metabolic panel was normal except for a low serum sodium (135 mEq/L) and elevated blood urea nitrogen (51 mg/dL), serum creatinine (2.49 mg/dL), and glucose (117 mg/dL). Her complete blood count revealed a normal white blood cell (WBC) and platelet count, but low hemoglobin (11.2 g/dL) and hematocrit (34.5%). Her urine analysis was significant for a pH of 7.5, 3+ leukocyte esterase, >50 WBC count, and the presence of nitrates. Her tacrolimus trough serum concentration was 7.3 ng/mL, which was within the target range of 4 to 11 ng/mL. Throughout the hospitalization, her tacrolimus concentration ranged from 3 ng/mL to 10.9 ng/mL, but her dose did not change. Urine cultures were positive for Enterobacter cloacae and multiple-drug resistant Pseudomonas aeruginosa sensitive to only amikacin (MIC = 16 mg/L) and ceftazidime (MIC = 8 mcg/L). She was started on a 7 day course of amikacin 225 mg IV every 24 hours (Amikin, Hospira, Lake Forest, IL) and ceftazidime 1 gram IV every 24 hours (Fortaz, Sagent Pharmaceuticals, Schaumburg, IL). Peak and trough serum amikacin concentrations were 21 mg/L and 3.3 mg/L, respectively. Twice daily intravesicular amikacin irrigations (15 mg/30 mL) were initiated with a dwell time of 2 hours. Clean intermittent catheterization was continued. Her serum creatinine improved from 2.46 mg/dL to 1.32 mg/dL and her blood urea nitrogen improved from 51 mg/dL to 24 mg/dL (Figure). A subsequent urine culture was negative and the patient was discharged on prophylactic Bactrim SS 1 tablet daily (sulfamethoxazole/trimethoprim, Interpharm INC, Hauppauge, NY) and intravesicular amikacin irrigations (15 mg/30 mL) once every other day. All other home medications were continued throughout her hospitalization and upon discharge except for magnesium oxide which was discontinued at discharge.

Approximately 2 months after discharge, the patient (wt = 40.1 kg) developed another UTI. In addition to her previous discharge medications, she was now receiving clotrimazole troche 10 mg twice daily (Mycelex, Raddock Laboratories, Minneapolis, MN) and multivitamin 1 tablet daily (Thera Tabs, Major Pharmaceuticals, Livonia, MI). On admission, the physical examination was within normal limits except for some trace bilateral lower extremities edema. She was afebrile (37.1°C) with normal vital signs. Her basic serum metabolic panel was normal except for a low bicarbonate (20 mEq/L) and elevated potassium (6.4 mEq/L), magnesium (3.1 mg/dL), blood urea nitrogen (47 mg/dL), serum creatinine (3.79 mg/dL), and glucose (112 mg/dL). Her complete blood count revealed a normal white blood cell count (7.7 k/mcL), elevated platelets (399 k/mcL) and low hemoglobin (8 g/dL) and hematocrit (26.4%). Liver function tests were within normal limits. Her urine analysis was significant for a pH of 7, 3+ leukocyte esterase, WBC that were too numerous to count and moderate bacteria. Her serum tacrolimus trough concentration was 4.3 ng/mL (4-11 ng/mL). During hospitalization, her tacrolimus concentration ranged from 3.4 ng/mL to 11.8 ng/mL, but her dose was not adjusted. An EKG was performed and hyperkalemia was treated with sodium polystyrene sulfonate 15 grams orally (Kayexalate, Carolina Medical Products, Farmville, NC) and an intravenous bolus of normal saline. Her serum potassium returned to normal.

The urine culture grew Escherichia coli resistant to ampicillin, gentamicin, ceftriaxone and bactrim. She was treated for 14 days with intravenous ciprofloxacin 400 mg (10 mg/kg/day; Cipro I.V., Hospira, Lake Forest, IL) and daily intravesicular amikacin irrigations (25 mg/50 mL). The serum amikacin concentration on the third day of therapy was 0.8 mg/L. After 5 days of intravesicular therapy, the volume of the amikacin irrigation was increased to 100 mL to allow for more through washing of her bladder and concerns for bladder irritation. Amikacin irrigation (25 mg/100 mL) with a 2 hour dwell time was continued for another 14 days. At discharge, her urine culture was negative and serum creatinine improved to 2.03 mg/dL (Figure). Following discharge, the patient received another 7 day course of oral ciprofloxacin (400 mg daily) and daily amikacin intravesicular irrigation (25 mg/100 mL) with 2 hour dwell time.

DISCUSSION

Efficacy of Intravesicular Aminoglycoside Irrigations

Most of the data supporting the use of intravesicular aminoglycoside irrigations to treat UTIs are from case reports and observational studies. Wood and colleagues reported the use of continuous tobramycin bladder irrigations for 4 days as adjunctive treatment for an UTI caused by E cloacae in a critically ill 69 year old woman.³ The patient had also received a single dose of intravenous tobramycin 2 days prior to initiation of intravesicular irrigations. Gonzalez and colleagues also reported the use of continuous amikacin bladder irrigations for 3 days in the treatment of cystitis emphysematous cause by E coli in a 60 year old woman. She was also receiving intravenous amikacin and ceftriaxone. In both of the above cases, the authors suggested that bladder irrigations contributed to the eradication of the bacteria from the patient's urine.^3,4 Since both patients were receiving intravenous antibiotics concurrently, it is difficult to ascertain the impact of the intravesicular irrigations on their infectious process. Waites and colleagues conducted a randomized double-blinded study comparing the efficacy of twice daily bladder irrigations with sterile saline, 0.25% acetic acid, or neomycin-polymyxin B (40 mg/mL; 200,000 units/mL) to treat bacteriuria in adults with neurogenic bladder using indwelling catheters.⁵ After an 8 week study period, no significant reduction in bacterial colony counts were found between the three treatment groups.⁵ As such, there is currently insufficient evidence to support the use of intravesicular aminoglycoside irrigations as monotherapy in the treatment of UTIs; hence, it should not be routine practice. Our patient had a history of recurrent UTIs with multidrug resistant organisms which tend to require adjunctive therapy. It is uncertain whether our patient would have responded to intravenous antibiotic therapy alone since she also received intravesicular amikacin irrigations during both admissions.

Our patient also received amikacin bladder irrigations every other day for UTI prophylaxis between her two hospitalizations. This treatment regimen was not effective in preventing a second UTI since she had a reoccurrence within 2 months of her last UTI. However no resistant organisms developed since the causative organism of her second UTI was sensitive to amikacin. Defoor and colleagues completed a retrospective study of 80 children receiving gentamicin bladder irrigations once daily for prophylaxis.⁶ Twenty-one (26%) patients receiving once daily prophylactic gentamicin bladder irrigation had a symptomatic breakthrough UTI.⁶ Five of the 21 patients developed UTI from gentamicin resistant organisms.⁶ It is unknown whether once daily administration of aminoglycoside bladder irrigations would have prevented future UTIs in our patient. However, our patient case does suggest that the use of every other day aminoglycoside bladder irrigations may be ineffective for UTI prophylaxis.

Toxicities of Intravesicular Aminoglycoside Irrigations

Common toxicities of aminoglycosides include nephrotoxicity and ototoxicity. Our patient's serum creatinine decreased during the administration of amikacin bladder irrigations (Figure). Immediately after removal of amikacin solution from the bladder, the amikacin serum concentration was well below the toxic range, which suggests that there is minimal absorption of amikacin from the bladder. Although our patient was taking other nephrotoxic medications, her serum concentration for all of them were within the accepted reference range. Furthermore, none of the previous case reports described nephrotoxicity from bladder irrigations with aminoglycosides in adults or children.^3–6 We did not assess for ototoxicity, because none of the amikacin serum concentrations in our patient were in the range associated with producing ototoxicity. de Jong and colleagues used neomycin bladder irrigation 3 times a week for 6 weeks in a 5 year old patient with end stage renal disease on hemodialysis.⁷ The patient developed perception deafness after 6 weeks of neomycin. At that time, the serum neomycin concentration was 16 mcg/mL and remained elevated for 1 week after the neomycin bladder irrigation was discontinued. Gerharz and colleagues report that 3 adult patients, ages 51 to 71 with end stage renal disease also developed complete perception deafness after 3, 4 and 10 months of neomycin bladder irrigations.⁸ Tinnitus was the first sign of hearing loss in these 3 patients.⁸ Serum neomycin concentrations were not reported in these patients. Due to the potential for accumulation of aminoglycosides in patients with renal insufficiency, we recommend monitoring serum concentration of an aminoglycoside to minimize the risk of ototoxicity. A monitoring protocol based on patient's risk factors was developed by Defoor and colleagues.⁶

There has also been one report of bladder irritation with the use of intravesicular aminoglycoside irrigations.⁵ In an adult study 3 out of the 50 patients reported bladder spasms from twice daily neomycin/polymyxin B and acetic acid bladder irrigations.⁵ Conversely, no discomfort was reported by Defoor and colleagues in pediatric patients using gentamicin bladder irrigations.⁶ Similarly, no bladder discomfort was reported by our patient while receiving amikacin bladder irrigations.

Administration of Intravesicular Aminoglycoside Irrigations

No consistent standards exist regarding the optimal concentration of aminoglycoside bladder solution used for irrigation in the treatment of UTIs in pediatric patients with neurogenic bladders. The concentration used in our patient changed from 500 mg/L to 250 mg/L between her first and second hospitalization due to concerns of potential bladder irritation and for more through washing of her bladder. Concentrations of antimicrobial bladder irrigations should be guided by the minimum inhibitory concentration (MIC) of the causative organism. In our case, the MIC of the Pseudomonas aeruginosa for amikacin was 16 mg/L. To be effective, the concentration of the aminoglycoside at the infectious site should be 10 times the MIC or 160 mg/L in our case. Therefore, the concentration of the bladder irrigation (i.e., 500 mg/L) was adequate. For the second hospitalization, we did not obtain an MIC for Escherichia coli; however, the organism was sensitive to amikacin. In the literature, the MIC for Escherichia coli sensitive to amikacin is reported to be 1.5 to 2.04 mg/L.⁹ Therefore, the lower concentration of 250 mcg/mL should have provided adequate coverage. Previous reports in adults using continuous amikacin or tobramycin bladder irrigations used concentrations of 500 mg/L, and 42 mg/L, respectively.^3,4 Gentamicin bladder irrigations at a concentration of 480 mg/L have been used in pediatric patients.⁶

There is also a lack of consistency regarding the appropriate solution volume for antimicrobial bladder irrigation. In adults, volumes as little as 30 mL twice a day to a continuous infusion of 42 mL/hr have been described.^3–5 In pediatrics, the volume of gentamicin bladder irrigations were reported as 30 mL.⁶ Intermittent amphotericin B bladder irrigations of 200 to 300 mL have been reported in the literature.¹⁰ In pediatrics, normal bladder capacity can be calculated using the following equation: age +1 × 30 mL for children up to 8 years of age.¹¹ In adolescents, normal bladder capacity is approximately 220 mL.¹² However, patients with neurogenic bladders may have a larger volume capacity due to the lack of pressure.¹³ It has been reported that the bladder capacity of adolescent patients with neurogenic bladder who are continent is approximately 500 mL.¹³ In our patient, the volume of the bladder irrigations increased from 30 mL to 100 mL over the course of 2 hospitalizations. The initial recommendation of 30 mL was based on the study conducted by Defoor and colleagues.⁶ Subsequent increases in bladder irrigation volume were recommended by the nephrologist in order to wash the bladder more efficiently and to limit risk of bladder irritation. Although we did not measure the bladder volume capacity of our patient, using the available information, we estimated our patient's bladder capacity to be between 200–500 mL.^11–13 Based on a single patient, it is difficult to know if the increased volume did wash out our patient's bladder more thoroughly and provided additional benefit.

The dwell time used in our patient was 2 hours and the frequency of bladder irrigations varied from once to twice daily for treatment and every other day for prophylaxis. A variety of dwell times and frequencies have been reported in adults from as little as 20 minutes twice a day for neomycin/polymyxin B to continuous tobramycin irrigations at 42 mL/hr.^3,5 No specific dwell times have been reported for aminoglycoside bladder irrigations in the pediatric population. Defoor and colleagues used gentamicin instillations twice daily for treatment and daily for prophylaxis.⁶ The gentamicin was allowed to dwell until the next scheduled catheterization. de Jong and colleagues reported using neomycin bladder irrigations in a 12 year old for 1 year and a 5 year old patient for 6 weeks.⁷ The neomycin irrigations were administered three times a week.⁷ The dwell time was not listed for these patients. It is important to note that the 5 year old patient developed perception deafness after 6 weeks of neomycin bladder irrigations.⁷ In our patient, every other day prophylactic treatment with amikacin bladder irrigations was not effective. More information is needed in order to determine the optimal concentration and dwell time for these irrigations.

CONCLUSIONS

Adjunctive therapy with either once or twice daily intravesicular amikacin irrigations successfully treated our patient's UTI. However, prophylactic treatment with intravesicular amikacin once every other day failed to prevent future UTIs in this patient. The concentration of the intravesicular amikacin irrigations should be at least 10 times the MIC of the causative organism. More studies are needed to assess the efficacy of intravesicular antimicrobial irrigations as a sole treatment for UTIs caused by multi-drug resistant bacteria in patients with spina bifida and neurogenic bladder. Also, future studies are needed to determine the optimal dwell time for bladder irrigations in patients with neurogenic bladder and the impact of these irrigations on the development of resistant bacteria.

ABBREVIATIONS

UTI

urinary tract infection

Figure.

Antimicrobial treatment course for two hospitalizations due to urinary tract infections.

*Amikacin Intravesicular Irrigation 15 mg/30 mL with 2 hour dwell time in bladder

†Amikacin Intravesicular Irrigation 25 mg/50 mL x 5 days then 25 mg/100 mL x 7 days with 2 hour dwell time in bladder

‡Amikacin Intravesicular Irrigation 25 mg/100 mL with 2 hour dwell time in bladder