Hemodialysis International 2014; ••:••–••
Case Report
Piperacillin/tazobactam-induced neurotoxicity in a hemodialysis patient: A case report Precil Diego M. M. NEVES1, Fernanda M. FREITAS1, Christiane A. KOJIMA2, Beatriz L. CARMELLO2, Rodrigo BAZAN3, Pasqual BARRETTI2, Luis C. MARTIN2 1
Internal Medicine Department 2Nephrology Department 3Neurology Department, University of São Paulo State, São Paulo, Brazil
Abstract Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta-lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/ tazobactam use. This report presents a case of a hypertensive and diabetic 67-year-old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/ tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta-lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients. Key words: Chronic kidney disease, hemodialysis, neurotoxicity, piperacillin/tazobactam
BACKGROUND Beyond uremic toxins, several substances potentially cause neurotoxicity in chronic kidney disease (CKD) patients, such as toxins from Averrhoa carambola or medi-
Correspondence to: Precil Diego Miranda de Menezes Neves, MD, University of São Paulo State, Distrito de Rubião Júnior, without number, Botucatu, SP 18618-970, Brazil. E-mail: [email protected] Conflict of interest: The authors report no conflicts of interest. The authors are responsible for the content and writing of the paper.
cations, which is not seen in people with normal renal function.1 In dialysis patients, infections are a major cause of morbidity and mortality, as a result, the frequent use of antibiotics is required; therefore, the knowledge on safety of these drugs is crucial. The most common cause of neurotoxicity in CKD patients are reaction to antibiotics use mainly beta-lactams as cephalosporins. Few cases of piperacillin/tazobactaminduced neurotoxicity have been described.2,3 Thereby, the purpose of this paper is to report a case of a hemodialysis patient who presented atypical neurological symptoms associated with piperacillin/tazobactam use and to review the literature.
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12194
1
Neves et al.
Figure 1 Thorax radiography showing right lower lung lobe opacity associated with a mild pleural effusion, compatible with the diagnosis of health care-associated pneumonia.
CASE PRESENTATION This case report is about a 67-year-old female patient who had been on regular hemodialysis for 11 years, whose comorbidities were hypertension, previous ischemic stroke 10 years before hospitalization, with mild left arm hemiparesis, and basal renal disease due to diabetes mellitus. At hospitalization, the patient presented clinical and radiologic manifestations of pneumonia on the right lower lung lobe, which had started 15 days before. Laboratory and complementary tests showed O2 saturation of 93% without supplementary oxygen; hemoglobin = 11.3 g/dL, white blood cells count = 23.400/mm3 with a large amount of immature neutrophils, serum C-reactive protein = 595 mg/L, Blood Urea Nitrogen: = 98 mg/dL, and serum creatinine = 4.5 mg/dL. Thorax radiography (Figure 1) showed right lower lung lobe opacity associated with a mild pleural effusion. Antibiotic therapy started with cefepime 1 g after each hemodialysis session. Two days after first cefepime dose, she was vigil, time and space oriented, without any alterations in the reflexes and sensibility tests, and had no signs of meningeal irritation; however, she presented dysarthria, hemiparesia got worst, had severe limbs ataxia, IX and X cranial nerves paresis, and left central facial paralysis.
2
Computed tomography (CT) revealed only residual lesions caused by the previous stroke. During this period, a 4-h session of hemodialysis was performed using lowflux polysulfone dialyzer, with ultrafiltration rate of 2000 mL, blood flow rate of 300 mL/min, and dialysate flow rate of 500 mL/min. Based on clinical manifestations, the patient was diagnosed as having probable cefepime-induced neurotoxicity; and cefepime treatment was and changed to intravenous piperacillin/tazobactam (2 g/250 mg) every 6 hour. The dialyzer was replaced by the high-flux polysulfone. After the second hemodialysis session, following the antibiotic and dialytic prescription changes, the patient presented strong improvement and neurologic base status recovery. Four days after the new treatment, she had no symptoms, when suddenly presented dysarthria, severe dysmetria, myoclonus, asterisks, left arm weakness, and cranial nerve VII central paralysis. Brain CT showed no signs of a new stroke, and electroencephalogram showed diffuse disorganization of basal activity with no epileptiform paroxysms. Echocardiogram and electrocardiogram were unchanged compared with the previous exams. Piperacillin/tazobactam-induced neurotoxicity was hypothesized and this antibiotic was discontinued. After two hemodialysis sessions, she returned to her neurological basal status. At hospital discharge, the patient presented no pneumonia signs and was completely recovered from neurological manifestations. This paper reports a case of a patient in hemodialysis for 11 years who presented neurological symptoms (dysarthria, severe dysmetria, myoclonus) after 4 days using of piperacillin/tazobactam and had a previous neurotoxicity episode due to cefepime, both drugs were used to treat pneumonia. Because of the neurological manifestations seeing, which are symptoms of stroke, image exams were performed to rule out it. Cefepime was previously withdrawn with complete remission of neurological symptoms, but only 4 days after the start of using piperacillin/tazobactam, the symptoms recurred and remitted only after this treatment was discontinued. Cephalosporin neurotoxicity is broadly reported in CKD patients and can explain the first manifestations observed,4–7 while only few reports of piperacillintazobactam-associated neurological manifestations have been described, the majority of them in patients with neutropenia and thrombocytopenia.3,9 Only five cases were reported8 until 2007; in four of them, the primary diagnosis was central nervous system infection, and in one, acute cerebral stroke was suspected. In none of these
Hemodialysis International 2014; ••:••–••
Piperacilin/tazobactam-induced neurotoxicity
cases, piperacillin/tazobactam-induced neurotoxicity was the primary hypothesis. About the pathogenesis, beta-lactam-induced neurotoxicity is attributed to the lactam ring, whose epileptogenic activity is blunted when the ring is cleaved. In addition, inhibition of the gamma-aminobutyric acid binding to its receptor may produce the neurological symptoms.2,8 Piperacillin-tazobactam has low molecular weight (517 D), but it is protein-bound transported in the blood, and theoretically is poorly depurated by low-flux dialyzers. Thus, based on a previous case report, we replaced the dialytic prescription by a high-flux hemodialysis.8 Compared with the reported case, the time to recovery was greater in the present case; we speculated that it could be explained by the patient’s previous central nervous injury. The limitation of this case report is the lack of serum/ dialysate piperacillin/tazobactam dosage; however, the temporal relationship between antibiotic usage and the neurological symptoms, the recovery of neurological baseline status after hemodialysis treatment, as well as the exclusion of structural lesions in image exams reinforce the presumed diagnosis.
CONCLUSION In conclusion, this paper alerts for the possibility of dialysis patients, in particular those with previous neurological manifestations after the use of a beta-lactam, may be more susceptible to neurotoxicity by others. The drug-induced neurotoxicity must be always in mind when CKD patients present neurological symptoms while using antibiotics because complete recovery may be reached when the drug is halted and hemodialysis is instituted.
CONSENT Written informed consent was obtained from the patient for publication of this Case report and any accompanying
Hemodialysis International 2014; ••:••–••
images. A copy of the written consent is available for review by the editor of this journal.
Manuscript received May 2014.
REFERENCES 1 Martin LC, Caramori JST, Barretti P, Soares VA. Soluço intratável desencadeado por ingestão de carambola (averrhoa carambola) em portadores de insuficiência renal crônica. J Bras Nefrol. 1993; 15:92–94. 2 Graaf P, Boer NKH, Jharap B, Mulder CJJ. Drug monitoring and toxicology. Clin Chem. 2008; 54:218–219. 3 Lambourne J, Kitchen J, Hughes C, Merry C. Piperacillin/ tazobactam-induced paresthesiae. Ann Pharmacother. 2006; 40:977–979. 4 Kim SY, Lee IS, Park SL, Lee J. Cefepime neurotoxicity in patients with renal insufficiency. Ann Rehabil Med. 2012; 36:159–162. 5 Chatelier D, Jourdain M, Mangalaboyi J, Ader F, Chopin C. Cefepime-induced neurotoxicity: An underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med. 2002; 28:214– 217. 6 Bresson J, Burtz CP, Josserand J, Bardin C, Mantz J, Pease S. Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. J Antimicrob Chemother. 2008; 10:849–850. 7 Sonck J, Laureys G, Verbeelen D. The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrol Dial Transplant. 2008; 23:966–970. 8 Lin CS, Cheng CJ, Chou CH, Lin SH. Piperacillin/ tazobactam-induced seizure rapidly reversed by high flux hemodialysis in patient on peritoneal dialysis. Am J Med Sci. 2007; 333:181–183. 9 Tong MKH, Siu YP, Yung CY, Kwan TH. Piperacillin/ tazobactam-induced acute delirium in peritoneal dialysis patient. Nephrol Dial Transplant. 2004; 19:1341.
3
Case Report
Piperacillin/tazobactam-induced neurotoxicity in a hemodialysis patient: A case report Precil Diego M. M. NEVES1, Fernanda M. FREITAS1, Christiane A. KOJIMA2, Beatriz L. CARMELLO2, Rodrigo BAZAN3, Pasqual BARRETTI2, Luis C. MARTIN2 1
Internal Medicine Department 2Nephrology Department 3Neurology Department, University of São Paulo State, São Paulo, Brazil
Abstract Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta-lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/ tazobactam use. This report presents a case of a hypertensive and diabetic 67-year-old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/ tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta-lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients. Key words: Chronic kidney disease, hemodialysis, neurotoxicity, piperacillin/tazobactam
BACKGROUND Beyond uremic toxins, several substances potentially cause neurotoxicity in chronic kidney disease (CKD) patients, such as toxins from Averrhoa carambola or medi-
Correspondence to: Precil Diego Miranda de Menezes Neves, MD, University of São Paulo State, Distrito de Rubião Júnior, without number, Botucatu, SP 18618-970, Brazil. E-mail: [email protected] Conflict of interest: The authors report no conflicts of interest. The authors are responsible for the content and writing of the paper.
cations, which is not seen in people with normal renal function.1 In dialysis patients, infections are a major cause of morbidity and mortality, as a result, the frequent use of antibiotics is required; therefore, the knowledge on safety of these drugs is crucial. The most common cause of neurotoxicity in CKD patients are reaction to antibiotics use mainly beta-lactams as cephalosporins. Few cases of piperacillin/tazobactaminduced neurotoxicity have been described.2,3 Thereby, the purpose of this paper is to report a case of a hemodialysis patient who presented atypical neurological symptoms associated with piperacillin/tazobactam use and to review the literature.
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12194
1
Neves et al.
Figure 1 Thorax radiography showing right lower lung lobe opacity associated with a mild pleural effusion, compatible with the diagnosis of health care-associated pneumonia.
CASE PRESENTATION This case report is about a 67-year-old female patient who had been on regular hemodialysis for 11 years, whose comorbidities were hypertension, previous ischemic stroke 10 years before hospitalization, with mild left arm hemiparesis, and basal renal disease due to diabetes mellitus. At hospitalization, the patient presented clinical and radiologic manifestations of pneumonia on the right lower lung lobe, which had started 15 days before. Laboratory and complementary tests showed O2 saturation of 93% without supplementary oxygen; hemoglobin = 11.3 g/dL, white blood cells count = 23.400/mm3 with a large amount of immature neutrophils, serum C-reactive protein = 595 mg/L, Blood Urea Nitrogen: = 98 mg/dL, and serum creatinine = 4.5 mg/dL. Thorax radiography (Figure 1) showed right lower lung lobe opacity associated with a mild pleural effusion. Antibiotic therapy started with cefepime 1 g after each hemodialysis session. Two days after first cefepime dose, she was vigil, time and space oriented, without any alterations in the reflexes and sensibility tests, and had no signs of meningeal irritation; however, she presented dysarthria, hemiparesia got worst, had severe limbs ataxia, IX and X cranial nerves paresis, and left central facial paralysis.
2
Computed tomography (CT) revealed only residual lesions caused by the previous stroke. During this period, a 4-h session of hemodialysis was performed using lowflux polysulfone dialyzer, with ultrafiltration rate of 2000 mL, blood flow rate of 300 mL/min, and dialysate flow rate of 500 mL/min. Based on clinical manifestations, the patient was diagnosed as having probable cefepime-induced neurotoxicity; and cefepime treatment was and changed to intravenous piperacillin/tazobactam (2 g/250 mg) every 6 hour. The dialyzer was replaced by the high-flux polysulfone. After the second hemodialysis session, following the antibiotic and dialytic prescription changes, the patient presented strong improvement and neurologic base status recovery. Four days after the new treatment, she had no symptoms, when suddenly presented dysarthria, severe dysmetria, myoclonus, asterisks, left arm weakness, and cranial nerve VII central paralysis. Brain CT showed no signs of a new stroke, and electroencephalogram showed diffuse disorganization of basal activity with no epileptiform paroxysms. Echocardiogram and electrocardiogram were unchanged compared with the previous exams. Piperacillin/tazobactam-induced neurotoxicity was hypothesized and this antibiotic was discontinued. After two hemodialysis sessions, she returned to her neurological basal status. At hospital discharge, the patient presented no pneumonia signs and was completely recovered from neurological manifestations. This paper reports a case of a patient in hemodialysis for 11 years who presented neurological symptoms (dysarthria, severe dysmetria, myoclonus) after 4 days using of piperacillin/tazobactam and had a previous neurotoxicity episode due to cefepime, both drugs were used to treat pneumonia. Because of the neurological manifestations seeing, which are symptoms of stroke, image exams were performed to rule out it. Cefepime was previously withdrawn with complete remission of neurological symptoms, but only 4 days after the start of using piperacillin/tazobactam, the symptoms recurred and remitted only after this treatment was discontinued. Cephalosporin neurotoxicity is broadly reported in CKD patients and can explain the first manifestations observed,4–7 while only few reports of piperacillintazobactam-associated neurological manifestations have been described, the majority of them in patients with neutropenia and thrombocytopenia.3,9 Only five cases were reported8 until 2007; in four of them, the primary diagnosis was central nervous system infection, and in one, acute cerebral stroke was suspected. In none of these
Hemodialysis International 2014; ••:••–••
Piperacilin/tazobactam-induced neurotoxicity
cases, piperacillin/tazobactam-induced neurotoxicity was the primary hypothesis. About the pathogenesis, beta-lactam-induced neurotoxicity is attributed to the lactam ring, whose epileptogenic activity is blunted when the ring is cleaved. In addition, inhibition of the gamma-aminobutyric acid binding to its receptor may produce the neurological symptoms.2,8 Piperacillin-tazobactam has low molecular weight (517 D), but it is protein-bound transported in the blood, and theoretically is poorly depurated by low-flux dialyzers. Thus, based on a previous case report, we replaced the dialytic prescription by a high-flux hemodialysis.8 Compared with the reported case, the time to recovery was greater in the present case; we speculated that it could be explained by the patient’s previous central nervous injury. The limitation of this case report is the lack of serum/ dialysate piperacillin/tazobactam dosage; however, the temporal relationship between antibiotic usage and the neurological symptoms, the recovery of neurological baseline status after hemodialysis treatment, as well as the exclusion of structural lesions in image exams reinforce the presumed diagnosis.
CONCLUSION In conclusion, this paper alerts for the possibility of dialysis patients, in particular those with previous neurological manifestations after the use of a beta-lactam, may be more susceptible to neurotoxicity by others. The drug-induced neurotoxicity must be always in mind when CKD patients present neurological symptoms while using antibiotics because complete recovery may be reached when the drug is halted and hemodialysis is instituted.
CONSENT Written informed consent was obtained from the patient for publication of this Case report and any accompanying
Hemodialysis International 2014; ••:••–••
images. A copy of the written consent is available for review by the editor of this journal.
Manuscript received May 2014.
REFERENCES 1 Martin LC, Caramori JST, Barretti P, Soares VA. Soluço intratável desencadeado por ingestão de carambola (averrhoa carambola) em portadores de insuficiência renal crônica. J Bras Nefrol. 1993; 15:92–94. 2 Graaf P, Boer NKH, Jharap B, Mulder CJJ. Drug monitoring and toxicology. Clin Chem. 2008; 54:218–219. 3 Lambourne J, Kitchen J, Hughes C, Merry C. Piperacillin/ tazobactam-induced paresthesiae. Ann Pharmacother. 2006; 40:977–979. 4 Kim SY, Lee IS, Park SL, Lee J. Cefepime neurotoxicity in patients with renal insufficiency. Ann Rehabil Med. 2012; 36:159–162. 5 Chatelier D, Jourdain M, Mangalaboyi J, Ader F, Chopin C. Cefepime-induced neurotoxicity: An underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med. 2002; 28:214– 217. 6 Bresson J, Burtz CP, Josserand J, Bardin C, Mantz J, Pease S. Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. J Antimicrob Chemother. 2008; 10:849–850. 7 Sonck J, Laureys G, Verbeelen D. The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrol Dial Transplant. 2008; 23:966–970. 8 Lin CS, Cheng CJ, Chou CH, Lin SH. Piperacillin/ tazobactam-induced seizure rapidly reversed by high flux hemodialysis in patient on peritoneal dialysis. Am J Med Sci. 2007; 333:181–183. 9 Tong MKH, Siu YP, Yung CY, Kwan TH. Piperacillin/ tazobactam-induced acute delirium in peritoneal dialysis patient. Nephrol Dial Transplant. 2004; 19:1341.
3
