case report Wien Klin Wochenschr (2014) 126:549–552 DOI 10.1007/s00508-014-0577-6
Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature Matej Štuhec
Received: 13 December 2013 / Accepted: 22 July 2014 / Published online: 15 August 2014 © Springer-Verlag Wien 2014
Summary Objective In this case report, we present an 83-year-old Caucasian immune-competent woman with Alzheimer’s disease and organic personality disorder who developed auditory hallucinations when treated with two nitrofurantoin (NF) tablets (100 mg) every 12 h because of acute cystitis due to extended-spectrum-β-lactamase-positive Escherichia coli. Case summary An 83-year-old Caucasian woman with Alzheimer’s disease developed auditory hallucinations 2 days after intake of two NF tablets (100 mg) daily. After thorough discussion, it was decided not to rechallenge with NF because of the serious adverse effect. After NF discontinuation suggested by clinical pharmacist and switching to imipenem 500 mg and cilastatin 500 mg three times daily for 7 days, symptoms significantly improved the next day. No other drugs known to interact with NF were administered. Discussion NF-induced adverse effects have been reported frequently, but NF-induced auditory hallucinations with early onset in an immune-competent geriatric patient, without previous reported hallucinations or seizures, have not been reported in the literature. Scoring according to the Naranjo adverse drug reaction scale revealed a probable relationship between auditory hallucinations and NF use in our patient (6 points). The exact mechanism for the central nervous system (CNS) toxicity of NF in this patient is not known, but we believe that the CNS penetration of NF may result in the accumulation of toxic drug levels in CNS.
M. Štuhec, PharmD () Department for Clinical Pharmacy, Psychiatric Hospital Ormoz, Ptujska Cesta 33, Ormoz, Slovenia e-mail: [email protected]
13
Conclusion This case report can be used to remind clinicians and clinical pharmacists of keeping in mind the potential of NF associated with auditory hallucinations, which can be easily confused with more serious conditions. Keywords Nitrofurantoin · Hallucinations · Adverse effect · Clinical pharmacist · Imipenem
Akustische Halluzinationen im Zusammenhang mit dem Einsatz von Nitrofurantoin: Fallbericht und Literaturüberblick Zusammenfassung Ziel Wir stellen im vorliegenden Fallbericht eine 83-jährige kaukasische immunkompetente Frau mit Alzheimer’scher Erkrankung und organischer Persönlichkeitsstörung vor, die akustische Halluzinationen unter einer Therapie mit Nitrofurantoin (2 × 100 mg Tabletten/Tag), das sie wegen einer durch „Extended spectrum-β-Lactamase positiver Escherichia coli“ ausgelösten akuten Zystitis einnahm, entwickelte. Fallzusammenfassung Eine 83-jährige Patientin mit Alzheimer’scher Erkrankung entwickelte akustische Halluzinationen 2 Tage nach Einnahme von 2 Tabletten 100 mg Nitrofurantoin (NF) täglich. Nach ausführlicher Diskussion wurde beschlossen, NF wegen dieser schwerwiegenden Nebenwirkung nicht nochmals zu geben. Nach dem vom klinischen Pharmazeuten empfohlenen Absetzen von NF und Umsteigen auf 500 mg Imipemen und 500 mg Cilastatin 3 × täglich für 7 Tage besserten sich die Symptome bereits am 1. Tag nach Absetzen von NF. Es wurden keine anderen Medikamente mit bekannter Interaktion mit NF verabreicht. Diskussion Nebenwirkungen von NF wurden häufig beschrieben. Literaturberichte über rasch einsetzende NF-induzierte akustische Halluzinationen bei immun
Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
549
case report
kompetenten geriatrischen Patienten ohne anamnestisch bekannten Halluzinationen oder Krämpfen liegen allerdings keine vor. Ein Abschätzen der Wahrscheinlichkeit nach der Naranjo Nebenwirkungs Skala ergab bei unserer Patientin einen wahrscheinlichen Zusammenhang zwischen den Halluzinationen und dem Einsatz von NF (6 Punkte). Der exakte Mechanismus der für das Zentralnevensystem (ZNS) unserer Patientin toxischen Wirkung von NF ist nicht bekannt. Wir glauben aber, dass das Eindringen von NF in das ZNS in einer Akkumulation von toxischen Mengen des Medikaments im ZNS führen kann. Schlussfolgerung Dieser Fallbericht sollte Kliniker und klinische Pharmazeuten daran erinnern, dass NF mit akustischen Halluzinationen, die leicht mit ernsteren Situationen verwechselt werden können, assoziiert sein kann. Schlüsselwörter Nitrofurantoin · Halluzinationen · Nebenwirkungen · Klinische Pharmazeuten · Imipimen
Introduction Nitrofurantoin (NF) is a widely used antibiotic because of its low cost, easy availability, and efficacy predominantly against Escherichia coli (EC). One possible explanation for the increase in NF use is associated with increasing resistance of common urinary tract pathogens such as EC to common antibiotics [1]. NF is a relatively safe drug, with common adverse effects on the gastrointestinal tract. NF also has some severe adverse effects, such as causing pulmonary fibrosis. A 51-year-old woman with a history of recurrent urinary tract infections and treated with NF for many years has been described. She was referred to the hospital for screening for lung transplantation because of severe pulmonary restriction and dyspnea. Unfortunately, she died as a result of progressive respiratory insufficiency [2]. All these side effects are much more common in the elderly, and hence according to 2012 American Geriatrics Society Beers Criteria, this antibiotic is strongly not recommended for older adults [3]. In a paper published in 2010, 261 patients (204 women; median age, 52 years) with autoimmune hepatitis and drug-induced autoimmune hepatitis were identified, and 24 (9.2 %) were drug-induced autoimmune hepatitis cases. Two drugs, NF (n = 11) and minocycline (n = 11), were the main causes. Of the 11 NF patients, 8 (73 %) had abnormalities on hepatic imaging (mainly liver atrophy) [4]. NF-induced hepatotoxicity in the elderly is four times more common than that in younger adults and may simulate almost all known liver disorders [5]. A PubMed/Medline search was conducted using the terms nitrofurantoin, hallucinations, side effect, and adverse effect to identify randomized controlled trials and case reports that evaluated the adverse effect for this patient population. In this article, auditory hallucinations induced by NF in an 83-year-old Caucasian
immune-competent woman with Alzheimer’s disease and organic personality disorder are presented. On discontinuation of NF suggested by clinical pharmacy service, the patient recovered progressively.
Case report An 83-year-old Slovenian woman was admitted in 2013 to a psychogeriatric department because of Alzheimer’s disease and its treatment. In her medical history, she denied alcohol use, herbal product use, and smoking. The patient reported no known drug allergies and also reported adherence to her medications and exercise two times per week. She had reported no previous hallucinations or seizures. Her score on the Mini-Mental State Exam was 16/30, and she was started on memantine 5 mg daily. Her medications before hospitalization included venlafaxine 75 mg, mirtazapine 30 mg, losartan 50 mg, acetylsalicylic acid 100 mg, carvedilol 12.5 mg, and simvastatin 20 mg daily. Laboratory results collected on admission included a normal complete blood cell count, normal electrolytes, normal liver enzymes, and normal liver functions tests. After 6 days in hospital, the patient was afebrile, and serum C-reactive protein (S-CRP) level was 18 mg/L. The patient reported symptoms and signs of infection with EC; laboratory results, except S-CRP and nitrites, were normal, and therefore the patient was treated with two NF tablets (100 mg) every 12 h (two tablets daily) because of acute cystitis due to extendedspectrum-β-lactamase-positive EC (EC-ESBL), which was chosen according to her antibiogram. The day after the admission, the patient was active and quiet, and the pain in the bladder area when urinating was no longer reported. On the second day with NF in the afternoon, uncontrolled behavior and auditory hallucinations were reported, and the patient reported disorientation. She had a vivid hallucination of people who want to hurt her, and insomnia was also reported despite therapy with 10 mg zolpidem daily. In the next morning, auditory hallucinations were also reported, and therefore the patient was sent to the clinical pharmacist. After discussing the benefits and risks with the patient, we advised discontinuation of NF and switching to imipenem 500 mg and cilastatin 500 mg three times daily for 7 days. The physician accepted our recommendations, and the symptoms disappeared completely in 1 day after NF discontinuation. This adverse effect was associated with the use of NF. The day after switching, the patient was active and quiet, and the insomnia was not longer reported. The patient was discharged 7 days later with no symptoms of EC-ESBL urinary infection confirmed with antibiogram and psychical status normalized.
Discussion There are few reports of psychiatric adverse effects of NF. NF-induced seizures and hyponatremia were reported
550 Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
13
case report
in an 87-year-old Slovenian woman, who was admitted in May 2012 to a psychiatric department because of Alzheimer’s disease. After 3 days of treatment with NF, seizures (grand mal) and convulsions were observed for the first time, and consequently, midazolam was introduced. NF was withdrawn from the therapy and a switch to amoxicillin and clavulanic acid 1 g two times daily was chosen, and the patient recovered. The patient left the hospital 2 weeks later with no symptoms of EC urinary infection and psychical status normalized [6]. A recent longitudinal study of 1304 veterans, aged 65 years or older, residing in a community living center found that NF was in the top four suboptimally prescribed medications among 21 primarily renally cleared medications. Potentially inappropriate prescribing of primarily renally cleared medications was determined by estimating creatinine clearance using the Cockcroft–Gault and Modification of Diet in Renal Disease equations and applying explicit guidelines for contraindicated medications and dosing [7]. In our case, creatine levels were measured before treatment with NF, and Cockcroft–Gault equation was used to estimate kidney function. There were no abnormalities, and therefore renal disease was excluded. The latest guidelines of the American Society for Infectious Diseases and the European Society for Microbiology and Infectious Disease from December 2010 recommended NF as a first-line treatment where resistance to trimethoprim–sulfamethoxazole (TMP-SMX) exceeds 20 %. NF (100 mg twice daily for 5 days) is an appropriate choice for therapy of women with uncomplicated cystitis due to minimal resistance and propensity for collateral damage and efficacy comparable with 3 days of TMPSMX. The threshold of 20 % as the resistance prevalence at which the TMP-SMX is no longer recommended for empirical treatment of acute cystitis is based on expert opinion derived from clinical, in vitro, and mathematical modeling studies. Research has shown that the resistance to NF develops slowly [8]. Unfortunately, in vitro testing does not translate to NF being effective in older adults; therefore, we should use NF in elderly with great caution as this case clearly demonstrates [9]. Because of high resistance to TMP-SMX and quinolones and their interaction with psychiatric drugs, NF can be used in elderly patients with cystitis. In our report, adverse effect was determined by a clinical pharmacist using the Naranjo probability scale and was probably associated with NF use (6 points) [10]. We also do not believe that any pharmacokinetic and/or pharmacodynamic drug–drug interaction could occur, which would have led to this adverse effect. The relationship between the patient’s symptoms and the initiation and discontinuation of NF suggests that the drug had a causal effect. This case also demonstrates the importance of clinical pharmacist involvement in the psychiatric patient’s pharmacotherapy. The exact mechanism for the central nervous system (CNS) toxicity of NF in this patient is not known, but we believe that the CNS penetration of NF may result in the accumulation of toxic drug levels in CNS and contribute
13
to these complications. There were no other medication changes or medical conditions that could have explained this phenomenon. Psychiatric patients developing fever and elevated S-CRP levels especially during the first week of treatment should undergo a thorough physical examination, electrocardiogram assessment, and measurements of white blood cell count, absolute neutrophil count, S-CRP, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis, and neuroleptic malignant syndrome [11]. In addition, TMP-SMX-induced hallucinations in an immune-competent patient with switching to NF and risperidone, without associated polypharmacy, were also reported in the literature. In this case report, an 86-year-old Caucasian immune-competent woman with major depressive disorder and insomnia who developed hallucinations when treated with two TMP-SMX tablets (80 mg/400 mg) every 12 h (four tablets daily) for lower urinary infection was reported. After TMP-SMX discontinuation and switching to NF and risperidone, symptoms significantly improved [12]. This case report demonstrates successful use of NF in elderly patients with cystitis, in whom TMP-SMX was withdrawn. Because of high resistance to quinolones and TMPSMX, their interaction with psychiatric drugs, and adverse effects of NF, amoxicillin and clavulanic acid could be used in elderly patients with cystitis, in whom NF was withdrawn, and imipenem and cilastatin could be used in case of EC-ESBL in psychogeriatric patients, in whom NF is also appropriate according to the antibiogram. There is also a small possibility that the hallucinations were due to acute confusion caused by a systemic infection not adequately treated with NF, and hence the improvement when a systemically active antibiotic was commenced, which also should be considered. In general, with all the information given in this case, we do not believe that the hallucinations were due to acute confusion caused by a systemic infection situation in this case. Based on published data, we believe that NF discontinuation and switching to imipenem and cilastatin was the most appropriate approach for our patient. NF-induced adverse effects have been reported frequently, but NF-induced auditory hallucinations with early onset in immune-competent geriatric patient, without previous reported hallucinations or seizures, have not been reported in the literature. This case report can be used to remind clinicians and clinical pharmacists of keeping in mind the potential of NF associated with auditory hallucinations, which can be easily confused with more serious conditions. Conflict of interests The authors have no personal affiliations, financial relationship, or any commercial interest to disclose relative to this article. The submitted report or any essential part of it is not published or simultaneously submitted to other publications prior to its appearance in this Journal.
Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
551
case report References 1. Mendoza-Valdes A, Rosete A, Rios Bueno E, et al. Antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections in adults. Med Klin. 2010;105:698–704. 2. Goemaere NN, Grijm K, van Hal PT, et al. Nitrofurantoininduced pulmonary fibrosis: a case report. J Med Case Rep. 2008;21:169. 3. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616–31. 4. Björnsson E, Talwalkar J, Treeprasertsuk S, et al. Druginduced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51:2040–8. 5. Triantafyllou K, Vlachogiannakos J, Ladas SD. Gastrointestinal and liver side effects of drugs in elderly patients. Best Pract Res Clin Gastroenterol. 2010;24:203–15. 6. Stuhec M, Svab V. Nitrofurantoin-induced life-threatening seizures. Wien Klin Wochenschr. 2012;124:653–4.
7. Hanlon JT, Wang X, Handler SM, et al. Potentially inappropriate prescribing of primarily renally cleared medications for older veterans affairs nursing home patients. J Am Med Dir Assoc. 2011;12:37–83. 8. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52:e103–20. 9. Karlowsky JA, Thornsberry C, Jones ME, et al. Susceptibility of antimicrobial-resistant urinary Escherichia coli isolates to fluoroquinolones and nitrofurantoin. Clin Infect Dis. 2003;36:183–7. 10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. 11. Stuhec M. Clozapine-induced elevated C-reactive protein and fever mimic infection. Gen Hosp Psychiatry. 2013;35:680.e5–6. 12. Stuhec M. Trimethoprim-sulfamethoxazole-related hallucinations. Gen Hosp Psychiatry. 2014;36:230.e7–8.
552 Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
13
Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature Matej Štuhec
Received: 13 December 2013 / Accepted: 22 July 2014 / Published online: 15 August 2014 © Springer-Verlag Wien 2014
Summary Objective In this case report, we present an 83-year-old Caucasian immune-competent woman with Alzheimer’s disease and organic personality disorder who developed auditory hallucinations when treated with two nitrofurantoin (NF) tablets (100 mg) every 12 h because of acute cystitis due to extended-spectrum-β-lactamase-positive Escherichia coli. Case summary An 83-year-old Caucasian woman with Alzheimer’s disease developed auditory hallucinations 2 days after intake of two NF tablets (100 mg) daily. After thorough discussion, it was decided not to rechallenge with NF because of the serious adverse effect. After NF discontinuation suggested by clinical pharmacist and switching to imipenem 500 mg and cilastatin 500 mg three times daily for 7 days, symptoms significantly improved the next day. No other drugs known to interact with NF were administered. Discussion NF-induced adverse effects have been reported frequently, but NF-induced auditory hallucinations with early onset in an immune-competent geriatric patient, without previous reported hallucinations or seizures, have not been reported in the literature. Scoring according to the Naranjo adverse drug reaction scale revealed a probable relationship between auditory hallucinations and NF use in our patient (6 points). The exact mechanism for the central nervous system (CNS) toxicity of NF in this patient is not known, but we believe that the CNS penetration of NF may result in the accumulation of toxic drug levels in CNS.
M. Štuhec, PharmD () Department for Clinical Pharmacy, Psychiatric Hospital Ormoz, Ptujska Cesta 33, Ormoz, Slovenia e-mail: [email protected]
13
Conclusion This case report can be used to remind clinicians and clinical pharmacists of keeping in mind the potential of NF associated with auditory hallucinations, which can be easily confused with more serious conditions. Keywords Nitrofurantoin · Hallucinations · Adverse effect · Clinical pharmacist · Imipenem
Akustische Halluzinationen im Zusammenhang mit dem Einsatz von Nitrofurantoin: Fallbericht und Literaturüberblick Zusammenfassung Ziel Wir stellen im vorliegenden Fallbericht eine 83-jährige kaukasische immunkompetente Frau mit Alzheimer’scher Erkrankung und organischer Persönlichkeitsstörung vor, die akustische Halluzinationen unter einer Therapie mit Nitrofurantoin (2 × 100 mg Tabletten/Tag), das sie wegen einer durch „Extended spectrum-β-Lactamase positiver Escherichia coli“ ausgelösten akuten Zystitis einnahm, entwickelte. Fallzusammenfassung Eine 83-jährige Patientin mit Alzheimer’scher Erkrankung entwickelte akustische Halluzinationen 2 Tage nach Einnahme von 2 Tabletten 100 mg Nitrofurantoin (NF) täglich. Nach ausführlicher Diskussion wurde beschlossen, NF wegen dieser schwerwiegenden Nebenwirkung nicht nochmals zu geben. Nach dem vom klinischen Pharmazeuten empfohlenen Absetzen von NF und Umsteigen auf 500 mg Imipemen und 500 mg Cilastatin 3 × täglich für 7 Tage besserten sich die Symptome bereits am 1. Tag nach Absetzen von NF. Es wurden keine anderen Medikamente mit bekannter Interaktion mit NF verabreicht. Diskussion Nebenwirkungen von NF wurden häufig beschrieben. Literaturberichte über rasch einsetzende NF-induzierte akustische Halluzinationen bei immun
Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
549
case report
kompetenten geriatrischen Patienten ohne anamnestisch bekannten Halluzinationen oder Krämpfen liegen allerdings keine vor. Ein Abschätzen der Wahrscheinlichkeit nach der Naranjo Nebenwirkungs Skala ergab bei unserer Patientin einen wahrscheinlichen Zusammenhang zwischen den Halluzinationen und dem Einsatz von NF (6 Punkte). Der exakte Mechanismus der für das Zentralnevensystem (ZNS) unserer Patientin toxischen Wirkung von NF ist nicht bekannt. Wir glauben aber, dass das Eindringen von NF in das ZNS in einer Akkumulation von toxischen Mengen des Medikaments im ZNS führen kann. Schlussfolgerung Dieser Fallbericht sollte Kliniker und klinische Pharmazeuten daran erinnern, dass NF mit akustischen Halluzinationen, die leicht mit ernsteren Situationen verwechselt werden können, assoziiert sein kann. Schlüsselwörter Nitrofurantoin · Halluzinationen · Nebenwirkungen · Klinische Pharmazeuten · Imipimen
Introduction Nitrofurantoin (NF) is a widely used antibiotic because of its low cost, easy availability, and efficacy predominantly against Escherichia coli (EC). One possible explanation for the increase in NF use is associated with increasing resistance of common urinary tract pathogens such as EC to common antibiotics [1]. NF is a relatively safe drug, with common adverse effects on the gastrointestinal tract. NF also has some severe adverse effects, such as causing pulmonary fibrosis. A 51-year-old woman with a history of recurrent urinary tract infections and treated with NF for many years has been described. She was referred to the hospital for screening for lung transplantation because of severe pulmonary restriction and dyspnea. Unfortunately, she died as a result of progressive respiratory insufficiency [2]. All these side effects are much more common in the elderly, and hence according to 2012 American Geriatrics Society Beers Criteria, this antibiotic is strongly not recommended for older adults [3]. In a paper published in 2010, 261 patients (204 women; median age, 52 years) with autoimmune hepatitis and drug-induced autoimmune hepatitis were identified, and 24 (9.2 %) were drug-induced autoimmune hepatitis cases. Two drugs, NF (n = 11) and minocycline (n = 11), were the main causes. Of the 11 NF patients, 8 (73 %) had abnormalities on hepatic imaging (mainly liver atrophy) [4]. NF-induced hepatotoxicity in the elderly is four times more common than that in younger adults and may simulate almost all known liver disorders [5]. A PubMed/Medline search was conducted using the terms nitrofurantoin, hallucinations, side effect, and adverse effect to identify randomized controlled trials and case reports that evaluated the adverse effect for this patient population. In this article, auditory hallucinations induced by NF in an 83-year-old Caucasian
immune-competent woman with Alzheimer’s disease and organic personality disorder are presented. On discontinuation of NF suggested by clinical pharmacy service, the patient recovered progressively.
Case report An 83-year-old Slovenian woman was admitted in 2013 to a psychogeriatric department because of Alzheimer’s disease and its treatment. In her medical history, she denied alcohol use, herbal product use, and smoking. The patient reported no known drug allergies and also reported adherence to her medications and exercise two times per week. She had reported no previous hallucinations or seizures. Her score on the Mini-Mental State Exam was 16/30, and she was started on memantine 5 mg daily. Her medications before hospitalization included venlafaxine 75 mg, mirtazapine 30 mg, losartan 50 mg, acetylsalicylic acid 100 mg, carvedilol 12.5 mg, and simvastatin 20 mg daily. Laboratory results collected on admission included a normal complete blood cell count, normal electrolytes, normal liver enzymes, and normal liver functions tests. After 6 days in hospital, the patient was afebrile, and serum C-reactive protein (S-CRP) level was 18 mg/L. The patient reported symptoms and signs of infection with EC; laboratory results, except S-CRP and nitrites, were normal, and therefore the patient was treated with two NF tablets (100 mg) every 12 h (two tablets daily) because of acute cystitis due to extendedspectrum-β-lactamase-positive EC (EC-ESBL), which was chosen according to her antibiogram. The day after the admission, the patient was active and quiet, and the pain in the bladder area when urinating was no longer reported. On the second day with NF in the afternoon, uncontrolled behavior and auditory hallucinations were reported, and the patient reported disorientation. She had a vivid hallucination of people who want to hurt her, and insomnia was also reported despite therapy with 10 mg zolpidem daily. In the next morning, auditory hallucinations were also reported, and therefore the patient was sent to the clinical pharmacist. After discussing the benefits and risks with the patient, we advised discontinuation of NF and switching to imipenem 500 mg and cilastatin 500 mg three times daily for 7 days. The physician accepted our recommendations, and the symptoms disappeared completely in 1 day after NF discontinuation. This adverse effect was associated with the use of NF. The day after switching, the patient was active and quiet, and the insomnia was not longer reported. The patient was discharged 7 days later with no symptoms of EC-ESBL urinary infection confirmed with antibiogram and psychical status normalized.
Discussion There are few reports of psychiatric adverse effects of NF. NF-induced seizures and hyponatremia were reported
550 Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
13
case report
in an 87-year-old Slovenian woman, who was admitted in May 2012 to a psychiatric department because of Alzheimer’s disease. After 3 days of treatment with NF, seizures (grand mal) and convulsions were observed for the first time, and consequently, midazolam was introduced. NF was withdrawn from the therapy and a switch to amoxicillin and clavulanic acid 1 g two times daily was chosen, and the patient recovered. The patient left the hospital 2 weeks later with no symptoms of EC urinary infection and psychical status normalized [6]. A recent longitudinal study of 1304 veterans, aged 65 years or older, residing in a community living center found that NF was in the top four suboptimally prescribed medications among 21 primarily renally cleared medications. Potentially inappropriate prescribing of primarily renally cleared medications was determined by estimating creatinine clearance using the Cockcroft–Gault and Modification of Diet in Renal Disease equations and applying explicit guidelines for contraindicated medications and dosing [7]. In our case, creatine levels were measured before treatment with NF, and Cockcroft–Gault equation was used to estimate kidney function. There were no abnormalities, and therefore renal disease was excluded. The latest guidelines of the American Society for Infectious Diseases and the European Society for Microbiology and Infectious Disease from December 2010 recommended NF as a first-line treatment where resistance to trimethoprim–sulfamethoxazole (TMP-SMX) exceeds 20 %. NF (100 mg twice daily for 5 days) is an appropriate choice for therapy of women with uncomplicated cystitis due to minimal resistance and propensity for collateral damage and efficacy comparable with 3 days of TMPSMX. The threshold of 20 % as the resistance prevalence at which the TMP-SMX is no longer recommended for empirical treatment of acute cystitis is based on expert opinion derived from clinical, in vitro, and mathematical modeling studies. Research has shown that the resistance to NF develops slowly [8]. Unfortunately, in vitro testing does not translate to NF being effective in older adults; therefore, we should use NF in elderly with great caution as this case clearly demonstrates [9]. Because of high resistance to TMP-SMX and quinolones and their interaction with psychiatric drugs, NF can be used in elderly patients with cystitis. In our report, adverse effect was determined by a clinical pharmacist using the Naranjo probability scale and was probably associated with NF use (6 points) [10]. We also do not believe that any pharmacokinetic and/or pharmacodynamic drug–drug interaction could occur, which would have led to this adverse effect. The relationship between the patient’s symptoms and the initiation and discontinuation of NF suggests that the drug had a causal effect. This case also demonstrates the importance of clinical pharmacist involvement in the psychiatric patient’s pharmacotherapy. The exact mechanism for the central nervous system (CNS) toxicity of NF in this patient is not known, but we believe that the CNS penetration of NF may result in the accumulation of toxic drug levels in CNS and contribute
13
to these complications. There were no other medication changes or medical conditions that could have explained this phenomenon. Psychiatric patients developing fever and elevated S-CRP levels especially during the first week of treatment should undergo a thorough physical examination, electrocardiogram assessment, and measurements of white blood cell count, absolute neutrophil count, S-CRP, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis, and neuroleptic malignant syndrome [11]. In addition, TMP-SMX-induced hallucinations in an immune-competent patient with switching to NF and risperidone, without associated polypharmacy, were also reported in the literature. In this case report, an 86-year-old Caucasian immune-competent woman with major depressive disorder and insomnia who developed hallucinations when treated with two TMP-SMX tablets (80 mg/400 mg) every 12 h (four tablets daily) for lower urinary infection was reported. After TMP-SMX discontinuation and switching to NF and risperidone, symptoms significantly improved [12]. This case report demonstrates successful use of NF in elderly patients with cystitis, in whom TMP-SMX was withdrawn. Because of high resistance to quinolones and TMPSMX, their interaction with psychiatric drugs, and adverse effects of NF, amoxicillin and clavulanic acid could be used in elderly patients with cystitis, in whom NF was withdrawn, and imipenem and cilastatin could be used in case of EC-ESBL in psychogeriatric patients, in whom NF is also appropriate according to the antibiogram. There is also a small possibility that the hallucinations were due to acute confusion caused by a systemic infection not adequately treated with NF, and hence the improvement when a systemically active antibiotic was commenced, which also should be considered. In general, with all the information given in this case, we do not believe that the hallucinations were due to acute confusion caused by a systemic infection situation in this case. Based on published data, we believe that NF discontinuation and switching to imipenem and cilastatin was the most appropriate approach for our patient. NF-induced adverse effects have been reported frequently, but NF-induced auditory hallucinations with early onset in immune-competent geriatric patient, without previous reported hallucinations or seizures, have not been reported in the literature. This case report can be used to remind clinicians and clinical pharmacists of keeping in mind the potential of NF associated with auditory hallucinations, which can be easily confused with more serious conditions. Conflict of interests The authors have no personal affiliations, financial relationship, or any commercial interest to disclose relative to this article. The submitted report or any essential part of it is not published or simultaneously submitted to other publications prior to its appearance in this Journal.
Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
551
case report References 1. Mendoza-Valdes A, Rosete A, Rios Bueno E, et al. Antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections in adults. Med Klin. 2010;105:698–704. 2. Goemaere NN, Grijm K, van Hal PT, et al. Nitrofurantoininduced pulmonary fibrosis: a case report. J Med Case Rep. 2008;21:169. 3. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616–31. 4. Björnsson E, Talwalkar J, Treeprasertsuk S, et al. Druginduced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology. 2010;51:2040–8. 5. Triantafyllou K, Vlachogiannakos J, Ladas SD. Gastrointestinal and liver side effects of drugs in elderly patients. Best Pract Res Clin Gastroenterol. 2010;24:203–15. 6. Stuhec M, Svab V. Nitrofurantoin-induced life-threatening seizures. Wien Klin Wochenschr. 2012;124:653–4.
7. Hanlon JT, Wang X, Handler SM, et al. Potentially inappropriate prescribing of primarily renally cleared medications for older veterans affairs nursing home patients. J Am Med Dir Assoc. 2011;12:37–83. 8. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52:e103–20. 9. Karlowsky JA, Thornsberry C, Jones ME, et al. Susceptibility of antimicrobial-resistant urinary Escherichia coli isolates to fluoroquinolones and nitrofurantoin. Clin Infect Dis. 2003;36:183–7. 10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. 11. Stuhec M. Clozapine-induced elevated C-reactive protein and fever mimic infection. Gen Hosp Psychiatry. 2013;35:680.e5–6. 12. Stuhec M. Trimethoprim-sulfamethoxazole-related hallucinations. Gen Hosp Psychiatry. 2014;36:230.e7–8.
552 Auditory hallucinations associated with nitrofurantoin use: case report and review of the literature
13
