Piperacillin/Tazobactam-Induced Seizure
Rapidly Reversed by High Flux Hemodialysis
in a Patient on Peritoneal Dialysis
CHIN-SHENG LIN, MD; CHIH-JEN CHENG, MD; CHUNG-HSING CHOU, MD;
SHIH-HUA LIN, MD

ABSTRACT: Despite popular use of piperacillin, the dire
neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage
renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech,
tremor, bizarre behavior, progressive mental confusion,
and 2 episodes of generalized tonic-clonic seizure
(GTCS) after 5 doses of piperacillin/tazobactam (2 g/250
mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic
examinations showed dysarthria and bilateral Babinski
sign. Computed tomography of brain and electroen-

cephalogram were unremarkable. Despite the use of
antiepileptic agents, another GTCS episode recurred
after the sixth dose of piperacillin/tazobactam. Brain
magnetic resonance imaging did not demonstrate acute
infarction and organic brain lesions. Initiation of highflux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with
unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis
can rapidly terminate the piperacillin-induced encephalopathy. KEY INDEXING TERMS: Hemodialysis; Neurotoxicity; Piperacillin; Seizure; Uremia. [Am J Med Sci
2007;333(3):181–184.]

N

alopathy (PIPE) can still occur in susceptible groups of
patients. To date, 4 patients with PIPE have been
reported without early recognition.3– 6 Here, we describe a uremic patient receiving continuous ambulatory peritoneal dialysis (CAPD) who developed initially unrecognized PIPE that was rapidly reversed by
high-flux hemodialysis.

eurotoxicity induced by penicillin and other ␤-lactam antibiotics is a well-documented side effect. It
occurs in several vulnerable subgroups, including patients with impaired renal function, elderly patients,
those receiving an excess dosage, those with blood-brain
barrier injury, those with preexisting diseases of the
central nervous system, and those concurrently using
neurotoxic drugs.1 Patients with penicillin-induced
neurotoxicity usually present with confusion, disorientation, twitching, somnolence, myoclonus, convulsions,
and nonconvulsive status epilepticus.
Piperacillin/tazobactam contains of ␤-lactam ureidopenicillins and ␤-lactamase inhibitor and is widely
used for sepsis patients infected by ␤-lactamase producing pathogens. Piperacillin is less neurotoxic than
penicillin.2 Nevertheless, piperacillin-induced enceph-

From the Division of Nephrology, Department of Medicine (CSL,
CJC, SHL), and the Department of Neurology (CHC), Tri-Service
General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Submitted July 25, 2006; accepted in revised form September 6,
2006.
Correspondence: Shih-Hua Lin, MD, Division of Nephrology,
Department of Medicine, Tri-Service General Hospital, Number
325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan
(E-mail: shihhualin@yahoo.com).
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

Case Report
A 57-year-old woman with end-stage renal disease receiving
CAPD for 5 years was admitted due to cough, right pleuritic pain,
and fever for 3 days. She had no residual renal function (anuria).
Her medical history included type 2 diabetes mellitus, bronchiectasis, and hypertensive cardiovascular disease. Her current
medications were rosiglitazone, calcium citrate, amlodipine, and
procaterol.
The patient was alert and well oriented with blood pressure of
142/84 mmHg, pulse rate of 79/minute, and body temperature of
37.8°C. Crackle breathing sounds were heard over the bilateral
lower lung fields. Pertinent laboratory data showed a white blood
cell count of 13.7 ⫻ 103/mm3, hemoglobin of 9.7 g/dL, platelet
count of 323 ⫻ 103/mm3, C-reactive protein level of 5.71 mg/L, and
alanine aminotransferase level of 26 U/L. Chest radiography
revealed bronchial wall thickening and peribronchial infiltration
on both lower lung fields. Bronchiectasis with secondary infection
was diagnosed.
Intravenous piperacillin/tazobactam was administered at a
dosage of 2 g/250 mg every 6 hours. The patient continued CAPD
with 4 2 L exchanges per day. After the fifth dose of piperacillin/
tazobactam, she began to present with slurred speech, tremor,
bizarre behavior, and progressive mental confusion. Two episodes

181

182

CAPD, continuous ambulatory peritoneal dialysis; CCr, creatinine clearance; CNS, central nervous system; F, female; GTCS, generalized tonic clonic seizure; HD, hemodialysis;
M, male; NA, not available; PIPE, piperacillin-induced encephalopathy; RRF, residual renal function; WP, withdrawal of piperacillin.
Patient underwent lumbar puncture to exclude CNS infection.

GTCS
Bronchiectesis
with secondary
infection
CAPD
57/F
Current case

Anuria

CAPD
47/M
4 (Tong, 2004)

3 mL/min

HD
46/F
3 (Bassilios, 2002)

NA

No
Normal
11/M
2 (Malanga, 1997)

a

4 hour
WP ⫹ high-flux
hemodialysis ⫻
4 hrs
Acute cerebral
infarction

3 days
WP
Acute delirium

4 g twice daily ⫻
7 days
2 g 4 times
daily ⫻ 1.5 days

CNS infectiona

2 days
WP ⫹ hemodialysis ⫻
4 hrs
GTCS
4 g twice daily ⫻
2 days

WP
CNS infectiona
GTCS
3 g 4 times
daily ⫻ 2 days

CNS infectiona

NA

1 day
WP
Confusion,
hallucinations
82/F
1 (Park-Matsumoto,
1996)

NA

No

Subacute
bacterial
endocarditis
Pseudomonas
aeruginosa
bacteremia
Hemophilus
influenzae
pneumonia
Lobar pneumonia

6 g daily ⫻ 5 days

CNS infectiona

Treatment of
PIPE
Initial
Diagnosis
Neurologic
Presentation
Piperacillin
Dosage
Infection
Dialysis
RRF
Age/
Sex

Piperacillin is primarily eliminated unchanged by
the kidneys and its elimination rate is significantly
correlated with creatinine clearance.7 The half-life
of piperacillin in individuals with creatinine clearances above 90 mL/min ranges from 1.3 to 1.5 hours.
In patients with chronic renal failure (creatinine
clearances less than 7 mL/min), its half-life extends
2- to threefold due to the accumulation of the drug.8
The generally recommended dosage of piperacillin is
4 g intravenously every 6 to 8 hours (12–16 g/day) in
patients with normal renal function and the maximum recommended dosage is 8 g/day in patients
whose creatinine clearances are less than 20 mL/
min.9 In uremic patients receiving regular dialysis,
administration of 2 g every 8 hours (6 g/day) has
been suggested to treat serious systemic or peritoneal infections.10 Because peritoneal clearance of
piperacillin is poor, with only 6% of piperacillin
being removed by peritoneum,10 no supplement dose
is required in patients receiving CAPD. Given the
structural and pharmacokinetic characteristics of
piperacillin, such as water solubility, relatively
small molecular weight (517 D), and protein binding
affinity (16 –20%),11 approximately 30% to 40% of
piperacillin could be removed by hemodialysis and
an additional 750 mg piperacillin should be administered after each hemodialysis session.
Our patient received 8 g/day piperacillin intravenously and developed GTCS after the fifth dose.
Although the neurologic symptoms were temporarily relieved by antiepileptic agents, the GTCS
recurred after the sixth dose of piperacillin and the
patient rapidly recovered after receiving high-flux
hemodialysis and the withdrawal of the drug. All of
the above pointed to the diagnosis of PIPE and
supported the effectiveness of high-flux hemodialy-

Case

Discussion

Table 1. Reported Cases of Piperacillin-Induced Encephalopathy

of generalized tonic-clonic seizure (GTCS) occurred later and
were controlled by giving intravenous lorazepam (2 mg) and
phenytoin (750 mg). On neurologic examination, the patient was
drowsy with dysarthria and a bilateral Babinski sign was
present. Pupils were symmetric and reactive to light; ocular fundi
were normal; extraocular movements were full and conjugated.
There were no meningeal signs and neither motor nor sensory
focal deficits. Deep tendon reflexes were normal. Laboratory
investigations showed normal plasma levels of sodium (138 mEq/L),
potassium (3.6 mEq/L), chloride (99 mEq/L), calcium (10.8 mg/dL),
magnesium (1.8 mg/dL), and ammonia (62 ␮g/dL) levels. Computed tomography of the brain and electroencephalogram were
unremarkable. The diagnosis of acute ischemic stroke was made
tentatively. However, the GTCS recurred after the sixth dose of
piperacillin/tazobactam. Emergency magnetic resonance imaging
(MRI) and angiography of the brain showed no evidence of acute
infarction, aneurysm, and vascular malformation.
Because no other causes could be identified for the patient’s
severe neurologic manifestations, PIPE was highly suspected. The
neurologic abnormalities were rapidly reversed after 4 hours highflux hemodialysis (synthetic polysulfone, surface area 2.1 m2) and
substituting ciprofloxacin for piperacillin/tazobactam. The patient
was discharged 4 days later without any neurologic sequelae.

Recovery
Time

Piperacillin-Induced Encephalopathy

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Lin et al

sis in removing piperacillin despite no direct measurement of serum and/or dialysate piperacillin concentrations before and after hemodialysis in this
patient.
To date, 5 patients including ours have been reported to develop PIPE (Table 1). All of them presented with diverse neurologic manifestations such
as confusion, drowsiness, hallucinations, myoclonus,
and convulsion. Furthermore, these patients were
initially misdiagnosed as having a central nervous
system infection or acute cerebral infarction, leading
to invasive lumbar puncture and unnecessary examinations. As in our case, the previous 2 uremic patients receiving dialysis therapy developed GTCS
seizure and acute delirium after the identical dosage
of piperacillin/tazobactam (8 g/1 g/day) for 7 days
and 2 days, respectively. A maximum 8 g/day of
piperacillin, recommended as the appropriate dosage for dialysis patients by some authors, appeared
to be excessive.6 The precipitating factors were old
age in the first patient and excess dosage in the
other 4 patients.10,11 The neurologic symptoms often
disappeared 1 to 3 days after the withdrawal of
piperacillin/tazobactam. Our promising finding suggests that high-flux hemodialysis can rapidly reverse the PIPE due to its higher ultrafiltration coefficient, larger pores dialyzer membrane and
higher clearance of small to middle molecular
weight molecules.

The mechanisms underlying PIPE may be similar
to those of penicillin. Epileptogenic properties of
penicillins have been related to the ␤-lactam ring,
and an enzymatic cleavage of this ring has resulted
in the loss of epileptogenic activity.12 The pathogenesis of seizure induced by ␤-lactam antibiotics involves the inhibition of ␥-aminobutyric acid (GABA)
binding to the GABAA receptors.1 It has been also
shown that penicillin can reduce the number of
benzodiazepine receptors, which might play a significant role in the development of PIPE.13 In addition
to ␤-lactam ring, thiazolidine ring (benzylpenicillin) and
substitutions of the side chain (cefazolin, cefepime) had
been demonstrated to increase the high likelihood of
neurotoxicity (Fig 1).2,12 Without any epileptogenic
side chain substitutions, piperacillin is less neurotoxic than cefazolin, cefepime, and benzylpenicillin.
Despite less neurotoxicity, the drug’s pharmacokinetic
and pharmacodynamic changes, the presence of the
comorbid conditions such as old age and preexisting
neurologic disorders, and the concomitant use of potential neurotoxic drugs may render the patients with
chronic renal failure more vulnerable to the neurotoxic
side effects of piperacillin.
In conclusion, PIPE is often either overlooked or
misinterpreted as other neurologic disorders. Clinicians need to have a higher index of suspicion for
PIPE when piperacillin is administered, especially
in patients with impaired renal function. High-flux

Figure 1. Piperacillin, benzylpenicillin, and cephalosporins. All have the ␤-lactam ring (dotted line) structure. (A) piperacillin; (B)
5-member thiazolidine ring (dotted line) in benzylpenicillin; (C, D) heterocyclic ring at position 3 and heteroaromatic nucleus at position
7 in cefazolin and cefepime, respectively.

THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

183

Piperacillin-Induced Encephalopathy

hemodialysis can rapidly terminate the life-threatening condition associated with PIPE.
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