- Email: [email protected]
Ciprofloxacin-induced renal insufficiency in cystic fibrosis
Journal of Cystic Fibrosis 2 (2003) 152–154
Case report
Ciprofloxacin-induced renal insufficiency in cystic fibrosis Brady S. Moffetta,1, Beryl J. Rosensteinb, Peter J. Mogayzel Jr.b,* a
Department of Pharmacy, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Park 316, Baltimore, MD 21287, USA Eudowood Division of Pediatric Respiratory Sciences, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Park 316, Baltimore, MD 21287, USA
b
Received 17 March 2003; accepted 14 May 2003
Abstract Acute renal insufficiency is known to occur in patients who are taking ciprofloxacin, particularly the elderly. We report two young patients with cystic fibrosis who presented with acute renal insufficiency after 2–3 weeks of oral ciprofloxacin therapy. The incidence of this adverse effect in children and young adults who have cystic fibrosis is unknown. Multiple mechanisms for ciprofloxacin-induced nephrotoxicity have been proposed. 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: Ciprofloxacin; Cystic fibrosis; Nephrotoxicity; Renal insufficiency
1. Introduction
2. Case 1
Ciprofloxacin is commonly associated with acute renal insufficiency (ARI), but the majority of cases reported are in older adult patients w1x. Ciprofloxacin is a useful antibiotic in the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF), and many children and young adult patients receive this drug w2x. Although the side effect profile of ciprofloxacin is well known, there is very little data on the incidence of side effects in younger patients who have CF w3x. Only two cases of ARI in patients with CF have previously been reported w4,5x. Typically, adolescent or young adult patients without CF who have been reported to have ARI during ciprofloxacin therapy have been overdosed or been treated with multiple nephrotoxic medication w1x. We report two younger patients with CF who presented with ARI after a short course of ciprofloxacin therapy.
A 23-year-old white female with CF due to DF508 and R117H mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was being treated for a pulmonary mycobacterium avium intracellulare complex (MAI) infection. In addition to MAI, her sputum cultures grew Pseudomonas aeruginosa and Stenotrophomonas maltophilia. She received isoniazid, pyridoxine, ethambutol, clarithromycin and ciprofloxacin for approximately 3 months. The ciprofloxacin and isoniazid were discontinued because of significant nausea and anorexia. Laboratory testing at that time revealed a creatinine of 0.8 mgydL and blood urea nitrogen of 10 mgydL. She last received an intravenous aminoglycoside antibiotic 3 months earlier, at which time her creatinine was 1.1 mgydL. Three weeks later she was switched to a new drug regimen consisting of rifabutin 150 mg bid, ethambutol 250 mg tid and ciprofloxacin 750 mg bid (32 mg kgy1 dayy1) based on MAI antibiotic susceptibility testing. There was no change in her pulmonary status, but she developed vomiting while taking this combination of medications and had significant weight loss. At this time, she was also taking constant doses of theophylline, nortriptyline, vitamins and albuterol. Three weeks after
*Corresponding author. Tel.: q1-410-955-2035; fax: q1-410-9551030. E-mail address: [email protected] (P.J. Mogayzel Jr.). 1 Current Address: Texas Children’s Hospital, Department of Pharmacy, 6621 Fannin Street MC 2-2510, Houston, TX 77030, USA
1569-1993/03/$ - see front matter 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S1569-1993Ž03.00059-6
B.S. Moffett et al. / Journal of Cystic Fibrosis 2 (2003) 152–154
starting the new triple antibiotic regimen, laboratory testing demonstrated a creatinine of 5.1 mgydL and blood urea nitrogen of 44 mgydL. Urinalysis demonstrated 5–10 white blood cells and occasional red blood cells; no other abnormalities were present in the urine sediment. Ciprofloxacin was discontinued and her renal function improved rapidly without further therapy. She continued to take rifabutin and ethambutol. Nine days later her creatinine was 1.3 mgydL and blood urea nitrogen was 21 mgydL. Her creatinine returned to a baseline of 0.8 mgydL within 3 weeks. 3. Case 2 A 16-year-old white female with CF who was homozygous for the DF508 mutation in the CFTR gene developed symptoms of sinusitis, including headaches and post-nasal drip. She was prescribed oral ciprofloxacin 750 mg bid (38 mg kgy1 dayy1). After 10 days of therapy, she developed severe flank pain. At that time, laboratory studies revealed a creatinine of 3.2 mgydL and blood urea nitrogen of 29 mgydL. A renal ultrasound demonstrated slightly increased echogenicity of both kidneys but no other abnormalities were observed. Urinalysis was unremarkable. The patient’s other medications included pancreatic enzymes, omeprazole, azithromycin, trimethoprim-sulfamethoxazole, dornase-alfa, inhaled tobramycin and a salmeterol-fluticasone diskus. She last received an intravenous aminoglycoside antibiotic 3 months prior to this episode; at that time her creatinine was 0.5 mgydL. Ciprofloxacin was discontinued and her creatinine fell to 1.2 mgydL in 3 days and returned to 0.5 mgydL within 3 weeks. 4. Discussion The adverse effects of ciprofloxacin have been well described w3x. It has been shown that the incidence of adverse effects of ciprofloxacin in pediatric patients without CF is similar to that reported in adults w6,7x. Central nervous system effects of ciprofloxacin can be serious, resulting in seizures, depression, anxiety, euphoria, somnolence and insomnia, but do not occur with great frequency w3x. Phototoxicity has been described in both adult and pediatric patients; while nausea, vomiting and diarrhea account for the majority of gastrointestinal effects w3x. Joint toxicity was initially a greater concern in children than adults based on data from immature animals w3x. However, data have shown that the prevalence of joint toxicity in adults and children is similar w7,8x. The only reported adverse event exclusive to children is stained teeth in very young patients w9x. The renal toxicities associated with ciprofloxacin have been well described and depending upon the insult can have multiple presentations including occult hematuria, decreased renal function, increased renal weight, crys-
153
talluria and acute interstitial nephritis leading to acute renal failure w1,3x. Acute renal insufficiency due to ciprofloxacin has been primarily documented in adults during the past 15 years w1x. The true incidence of ciprofloxacin-induced ARI is difficult to determine since many patients are taking other medications that may affect renal function. There are a few reports of ARI in patients who have taken only ciprofloxacin, but these patients often have diseases that affect renal function w10x. Although the actual incidence of adverse renal effects attributable to ciprofloxacin is difficult to determine, there are common risk factors among those patients who develop ARI. One characteristic is that ARI tends to occur in older adult patients. Concomitant disease states including cardiac transplant, oncologic disease, congestive heart failure and aortic stenosis, jejunoileal bypass, hematuria, disseminated intravascular coagulation and septic shock, rheumatoid arthritis, continent urinary diversion and cranial trauma have been proposed as precipitating factors for toxicity w1x. Several patients in these case reports were also taking other medications that may have renal toxicity. Differences in drug metabolism in patients with CF may predispose them to ciprofloxacin-induced ARI. However, decreased renal clearance of ciprofloxacin seems unlikely, as many patients with CF have received multiple courses of this drug and only a very small proportion have had significant renal toxicity. Higher doses of ciprofloxacin could possibly result in an increased incidence of adverse effects, which may be significant when treating pulmonary exacerbations in patients with CF w11x. The mechanism of action for quinolone nephrotoxicity has never been clearly elucidated. Allergic interstitial nephritis (AIN) is often cited as a common cause of ciprofloxacin nephrotoxicity. The mechanism of injury is attributed to a type III hypersensitivity reaction w4x. Allergic interstitial nephritis is usually not related to the dose of offending agent and renal biopsy must be performed to obtain a definitive diagnosis. Crystallization of ciprofloxacin, most commonly associated with alkaline urine in animal models, has been suggested as a cause of ARI w12x. This is thought to be dose dependent and associated with mild renal disease. However, since urine pH is rarely alkaline in humans, crystallization is not a likely cause of ciprofloxacin toxicity in humans. The formation of urinary complexes containing drug metabolites, protein and magnesium due to impaired ability to excrete sodium or to dilute or concentrate urine has also been proposed as a cause of quinolone-induced renal toxicity in patients with CF w12x. In a report of recurrent interstitial nephritis due to beta-lactam antibiotics in a 13-year-old patient with CF, the authors postulated that the nephritis was immunemediated through humoral or cell-mediated mechanisms
154
B.S. Moffett et al. / Journal of Cystic Fibrosis 2 (2003) 152–154
based on a lack of detectable immune complexes or anti-tubular basement membrane antibodies w13x. Granulomatous interstitial nephritis (GIN) is another form of cell-mediated nephritis, which has been described in patients taking penicillins and sulfa drugs and may be a mechanism by which quinolones cause ARI w1x. Both of the patients in this report received ciprofloxacin 750 mg twice daily for approximately 2–3 weeks prior to developing ARI. The renal insufficiency resolved quickly after ciprofloxacin was discontinued, suggesting its key nephrotoxic role in these two patients, and no further therapy was required. Two other cases of ARI in patients with CF have been reported. A 25-yearold patient with CF and diabetes mellitus experienced decreased renal function, an increase in serum creatinine and flank pain after three courses of ciprofloxacin. The only abnormal finding on biopsy was epithelial vacuoles in the distal tubules, a finding that is often associated with gentamicin toxicity w5x. The only other reported case of ciprofloxacin-associated ARI in a patient with CF occurred in an 18-year-old woman who was treated with 750 mg of ciprofloxacin three times daily (30 mg kgy1 dayy1), compared to twice daily in our patients. Renal biopsy revealed discrete interstitial infiltration without interstitial nephritis and flattened tubular epithelium w4x. Only two other children have been described with ciprofloxacin-induced ARI and one of them had a deliberate overdose leading to acute tubular necrosis w14x. The other patient was an 11-year-old boy who developed ARI while being treated with ciprofloxacin for typhoid fever w15x. Renal biopsy in this latter case revealed interstitial nephritis. In conclusion, the cases reported here add to the side effect profile of an important drug commonly used in the younger CF patient population. These two cases constitute half of the published cases of quinoloneassociated ARI in young CF patients. The cases described are unusual due to the young age of the patients and we propose that CF plays a role in predisposing younger patients to ciprofloxacin-induced nephrotoxicity. The mechanism by which the renal injury occurs is currently elusive and most likely multifactorial. These cases illustrate that ARI can be a significant side effect of ciprofloxacin therapy especially in younger patients with CF.
Acknowledgments Dr Mogayzel is supported by research grant from the Cystic Fibrosis Foundation. References w1x Lomaestro BM. Fluoroquinolone-induced renal failure. Drug Saf 2000;22:479 –85. w2x Richard DA, Nousia-Arvanitakis S, Sollich V, Hampel BJ, Sommerauer B, Schaad UB. Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Cystic fibrosis study group. Pediatr Infect Dis J 1997;16:572 – 8. w3x Patterson DR. Quinolone toxicity: methods of assessment. Am J Med 1991;91:35S–37S. w4x Bald M, Ratjen F, Nikolaizik W, Wingen AM. Ciprofloxacininduced acute renal failure in a patient with cystic fibrosis. Pediatr Infect Dis J 2001;20:320 –1. w5x Gerritsen WR, Peters A, Henny FC, Brouwers JR. Ciprofloxacin-induced nephrotoxicity. Nephrol Dial Transplant 1987;2:382 –3. w6x Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use–safety report. Pediatr Infect Dis J 1997;16:127 –9 (Discussion 160–122). w7x Ball P. Ciprofloxacin: an overview of adverse experiences. J Antimicrob Chemother 1986;18(Suppl. D):187 –93. w8x Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in children. Ann Pharmacother 2000;34:347 –59 (Quiz 413344). w9x Lumbiganon P, Pengsaa K, Sookpranee T. Ciprofloxacin in neonates and its possible adverse effect on the teeth. Pediatr Infect Dis J 1991;10:619 –20. w10x Bailey JR, Trott SA, Philbrick JT. Ciprofloxacin-induced acute interstitial nephritis. Am J Nephrol 1992;12:271 –3. w11x Schaefer HG, Stass H, Wedgwood J, Hampel B, Fischer C, Kuhlmann J, Schaad UB. Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients. Antimicrob Agents Chemother 1996;40:29 –34. w12x Jick S. Ciprofloxacin safety in a pediatric population. Pediatr Infect Dis J 1997;16:130 –3 (Discussion 133–134, 160–132). w13x Sakarcan A, Marcille R, Stallworth J. Antibiotic-induced recurring interstitial nephritis. Pediatr Nephrol 2002;17:50 –1. w14x Dharnidharka VR, Nadeau K, Cannon CL, Harris HW, Rosen S. Ciprofloxacin overdose: acute renal failure with prominent apoptotic changes. Am J Kidney Dis 1998;31:710 –2. w15x Simpson J, Watson AR, Mellersh A, Nelson CS, Dodd K. Typhoid fever, ciprofloxacin and renal failure. Arch Dis Child 1991;66:1083 –4.
Case report
Ciprofloxacin-induced renal insufficiency in cystic fibrosis Brady S. Moffetta,1, Beryl J. Rosensteinb, Peter J. Mogayzel Jr.b,* a
Department of Pharmacy, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Park 316, Baltimore, MD 21287, USA Eudowood Division of Pediatric Respiratory Sciences, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Park 316, Baltimore, MD 21287, USA
b
Received 17 March 2003; accepted 14 May 2003
Abstract Acute renal insufficiency is known to occur in patients who are taking ciprofloxacin, particularly the elderly. We report two young patients with cystic fibrosis who presented with acute renal insufficiency after 2–3 weeks of oral ciprofloxacin therapy. The incidence of this adverse effect in children and young adults who have cystic fibrosis is unknown. Multiple mechanisms for ciprofloxacin-induced nephrotoxicity have been proposed. 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: Ciprofloxacin; Cystic fibrosis; Nephrotoxicity; Renal insufficiency
1. Introduction
2. Case 1
Ciprofloxacin is commonly associated with acute renal insufficiency (ARI), but the majority of cases reported are in older adult patients w1x. Ciprofloxacin is a useful antibiotic in the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF), and many children and young adult patients receive this drug w2x. Although the side effect profile of ciprofloxacin is well known, there is very little data on the incidence of side effects in younger patients who have CF w3x. Only two cases of ARI in patients with CF have previously been reported w4,5x. Typically, adolescent or young adult patients without CF who have been reported to have ARI during ciprofloxacin therapy have been overdosed or been treated with multiple nephrotoxic medication w1x. We report two younger patients with CF who presented with ARI after a short course of ciprofloxacin therapy.
A 23-year-old white female with CF due to DF508 and R117H mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was being treated for a pulmonary mycobacterium avium intracellulare complex (MAI) infection. In addition to MAI, her sputum cultures grew Pseudomonas aeruginosa and Stenotrophomonas maltophilia. She received isoniazid, pyridoxine, ethambutol, clarithromycin and ciprofloxacin for approximately 3 months. The ciprofloxacin and isoniazid were discontinued because of significant nausea and anorexia. Laboratory testing at that time revealed a creatinine of 0.8 mgydL and blood urea nitrogen of 10 mgydL. She last received an intravenous aminoglycoside antibiotic 3 months earlier, at which time her creatinine was 1.1 mgydL. Three weeks later she was switched to a new drug regimen consisting of rifabutin 150 mg bid, ethambutol 250 mg tid and ciprofloxacin 750 mg bid (32 mg kgy1 dayy1) based on MAI antibiotic susceptibility testing. There was no change in her pulmonary status, but she developed vomiting while taking this combination of medications and had significant weight loss. At this time, she was also taking constant doses of theophylline, nortriptyline, vitamins and albuterol. Three weeks after
*Corresponding author. Tel.: q1-410-955-2035; fax: q1-410-9551030. E-mail address: [email protected] (P.J. Mogayzel Jr.). 1 Current Address: Texas Children’s Hospital, Department of Pharmacy, 6621 Fannin Street MC 2-2510, Houston, TX 77030, USA
1569-1993/03/$ - see front matter 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S1569-1993Ž03.00059-6
B.S. Moffett et al. / Journal of Cystic Fibrosis 2 (2003) 152–154
starting the new triple antibiotic regimen, laboratory testing demonstrated a creatinine of 5.1 mgydL and blood urea nitrogen of 44 mgydL. Urinalysis demonstrated 5–10 white blood cells and occasional red blood cells; no other abnormalities were present in the urine sediment. Ciprofloxacin was discontinued and her renal function improved rapidly without further therapy. She continued to take rifabutin and ethambutol. Nine days later her creatinine was 1.3 mgydL and blood urea nitrogen was 21 mgydL. Her creatinine returned to a baseline of 0.8 mgydL within 3 weeks. 3. Case 2 A 16-year-old white female with CF who was homozygous for the DF508 mutation in the CFTR gene developed symptoms of sinusitis, including headaches and post-nasal drip. She was prescribed oral ciprofloxacin 750 mg bid (38 mg kgy1 dayy1). After 10 days of therapy, she developed severe flank pain. At that time, laboratory studies revealed a creatinine of 3.2 mgydL and blood urea nitrogen of 29 mgydL. A renal ultrasound demonstrated slightly increased echogenicity of both kidneys but no other abnormalities were observed. Urinalysis was unremarkable. The patient’s other medications included pancreatic enzymes, omeprazole, azithromycin, trimethoprim-sulfamethoxazole, dornase-alfa, inhaled tobramycin and a salmeterol-fluticasone diskus. She last received an intravenous aminoglycoside antibiotic 3 months prior to this episode; at that time her creatinine was 0.5 mgydL. Ciprofloxacin was discontinued and her creatinine fell to 1.2 mgydL in 3 days and returned to 0.5 mgydL within 3 weeks. 4. Discussion The adverse effects of ciprofloxacin have been well described w3x. It has been shown that the incidence of adverse effects of ciprofloxacin in pediatric patients without CF is similar to that reported in adults w6,7x. Central nervous system effects of ciprofloxacin can be serious, resulting in seizures, depression, anxiety, euphoria, somnolence and insomnia, but do not occur with great frequency w3x. Phototoxicity has been described in both adult and pediatric patients; while nausea, vomiting and diarrhea account for the majority of gastrointestinal effects w3x. Joint toxicity was initially a greater concern in children than adults based on data from immature animals w3x. However, data have shown that the prevalence of joint toxicity in adults and children is similar w7,8x. The only reported adverse event exclusive to children is stained teeth in very young patients w9x. The renal toxicities associated with ciprofloxacin have been well described and depending upon the insult can have multiple presentations including occult hematuria, decreased renal function, increased renal weight, crys-
153
talluria and acute interstitial nephritis leading to acute renal failure w1,3x. Acute renal insufficiency due to ciprofloxacin has been primarily documented in adults during the past 15 years w1x. The true incidence of ciprofloxacin-induced ARI is difficult to determine since many patients are taking other medications that may affect renal function. There are a few reports of ARI in patients who have taken only ciprofloxacin, but these patients often have diseases that affect renal function w10x. Although the actual incidence of adverse renal effects attributable to ciprofloxacin is difficult to determine, there are common risk factors among those patients who develop ARI. One characteristic is that ARI tends to occur in older adult patients. Concomitant disease states including cardiac transplant, oncologic disease, congestive heart failure and aortic stenosis, jejunoileal bypass, hematuria, disseminated intravascular coagulation and septic shock, rheumatoid arthritis, continent urinary diversion and cranial trauma have been proposed as precipitating factors for toxicity w1x. Several patients in these case reports were also taking other medications that may have renal toxicity. Differences in drug metabolism in patients with CF may predispose them to ciprofloxacin-induced ARI. However, decreased renal clearance of ciprofloxacin seems unlikely, as many patients with CF have received multiple courses of this drug and only a very small proportion have had significant renal toxicity. Higher doses of ciprofloxacin could possibly result in an increased incidence of adverse effects, which may be significant when treating pulmonary exacerbations in patients with CF w11x. The mechanism of action for quinolone nephrotoxicity has never been clearly elucidated. Allergic interstitial nephritis (AIN) is often cited as a common cause of ciprofloxacin nephrotoxicity. The mechanism of injury is attributed to a type III hypersensitivity reaction w4x. Allergic interstitial nephritis is usually not related to the dose of offending agent and renal biopsy must be performed to obtain a definitive diagnosis. Crystallization of ciprofloxacin, most commonly associated with alkaline urine in animal models, has been suggested as a cause of ARI w12x. This is thought to be dose dependent and associated with mild renal disease. However, since urine pH is rarely alkaline in humans, crystallization is not a likely cause of ciprofloxacin toxicity in humans. The formation of urinary complexes containing drug metabolites, protein and magnesium due to impaired ability to excrete sodium or to dilute or concentrate urine has also been proposed as a cause of quinolone-induced renal toxicity in patients with CF w12x. In a report of recurrent interstitial nephritis due to beta-lactam antibiotics in a 13-year-old patient with CF, the authors postulated that the nephritis was immunemediated through humoral or cell-mediated mechanisms
154
B.S. Moffett et al. / Journal of Cystic Fibrosis 2 (2003) 152–154
based on a lack of detectable immune complexes or anti-tubular basement membrane antibodies w13x. Granulomatous interstitial nephritis (GIN) is another form of cell-mediated nephritis, which has been described in patients taking penicillins and sulfa drugs and may be a mechanism by which quinolones cause ARI w1x. Both of the patients in this report received ciprofloxacin 750 mg twice daily for approximately 2–3 weeks prior to developing ARI. The renal insufficiency resolved quickly after ciprofloxacin was discontinued, suggesting its key nephrotoxic role in these two patients, and no further therapy was required. Two other cases of ARI in patients with CF have been reported. A 25-yearold patient with CF and diabetes mellitus experienced decreased renal function, an increase in serum creatinine and flank pain after three courses of ciprofloxacin. The only abnormal finding on biopsy was epithelial vacuoles in the distal tubules, a finding that is often associated with gentamicin toxicity w5x. The only other reported case of ciprofloxacin-associated ARI in a patient with CF occurred in an 18-year-old woman who was treated with 750 mg of ciprofloxacin three times daily (30 mg kgy1 dayy1), compared to twice daily in our patients. Renal biopsy revealed discrete interstitial infiltration without interstitial nephritis and flattened tubular epithelium w4x. Only two other children have been described with ciprofloxacin-induced ARI and one of them had a deliberate overdose leading to acute tubular necrosis w14x. The other patient was an 11-year-old boy who developed ARI while being treated with ciprofloxacin for typhoid fever w15x. Renal biopsy in this latter case revealed interstitial nephritis. In conclusion, the cases reported here add to the side effect profile of an important drug commonly used in the younger CF patient population. These two cases constitute half of the published cases of quinoloneassociated ARI in young CF patients. The cases described are unusual due to the young age of the patients and we propose that CF plays a role in predisposing younger patients to ciprofloxacin-induced nephrotoxicity. The mechanism by which the renal injury occurs is currently elusive and most likely multifactorial. These cases illustrate that ARI can be a significant side effect of ciprofloxacin therapy especially in younger patients with CF.
Acknowledgments Dr Mogayzel is supported by research grant from the Cystic Fibrosis Foundation. References w1x Lomaestro BM. Fluoroquinolone-induced renal failure. Drug Saf 2000;22:479 –85. w2x Richard DA, Nousia-Arvanitakis S, Sollich V, Hampel BJ, Sommerauer B, Schaad UB. Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Cystic fibrosis study group. Pediatr Infect Dis J 1997;16:572 – 8. w3x Patterson DR. Quinolone toxicity: methods of assessment. Am J Med 1991;91:35S–37S. w4x Bald M, Ratjen F, Nikolaizik W, Wingen AM. Ciprofloxacininduced acute renal failure in a patient with cystic fibrosis. Pediatr Infect Dis J 2001;20:320 –1. w5x Gerritsen WR, Peters A, Henny FC, Brouwers JR. Ciprofloxacin-induced nephrotoxicity. Nephrol Dial Transplant 1987;2:382 –3. w6x Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use–safety report. Pediatr Infect Dis J 1997;16:127 –9 (Discussion 160–122). w7x Ball P. Ciprofloxacin: an overview of adverse experiences. J Antimicrob Chemother 1986;18(Suppl. D):187 –93. w8x Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in children. Ann Pharmacother 2000;34:347 –59 (Quiz 413344). w9x Lumbiganon P, Pengsaa K, Sookpranee T. Ciprofloxacin in neonates and its possible adverse effect on the teeth. Pediatr Infect Dis J 1991;10:619 –20. w10x Bailey JR, Trott SA, Philbrick JT. Ciprofloxacin-induced acute interstitial nephritis. Am J Nephrol 1992;12:271 –3. w11x Schaefer HG, Stass H, Wedgwood J, Hampel B, Fischer C, Kuhlmann J, Schaad UB. Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients. Antimicrob Agents Chemother 1996;40:29 –34. w12x Jick S. Ciprofloxacin safety in a pediatric population. Pediatr Infect Dis J 1997;16:130 –3 (Discussion 133–134, 160–132). w13x Sakarcan A, Marcille R, Stallworth J. Antibiotic-induced recurring interstitial nephritis. Pediatr Nephrol 2002;17:50 –1. w14x Dharnidharka VR, Nadeau K, Cannon CL, Harris HW, Rosen S. Ciprofloxacin overdose: acute renal failure with prominent apoptotic changes. Am J Kidney Dis 1998;31:710 –2. w15x Simpson J, Watson AR, Mellersh A, Nelson CS, Dodd K. Typhoid fever, ciprofloxacin and renal failure. Arch Dis Child 1991;66:1083 –4.