Shaoqing Shen,Qiongshi Wu,Xingjun Cai,Hua Wu,Yamei ZhengMin Wang,

1 Hainan General Hospital(Hainan Affiliated Hospital of Hainan Medical University),a.Department of Pharmacy,b.Department of respiratory and critical care medicine,c.Clinical Laboratory Haikou,Hainan Province,570311,China;

2 Department of Pharmacy,Hainan Hospital of PLA General Hospital,Sanya,Hainan Province,572013,China.

Abstract Objective:To provide reference of pharmaceutical care for the clinical treatment of a severe patient with antibiotic-associated encephalopathy.Methods:Clinical pharmacists participated in the clinical treatment of the patient with antibiotic-associated encephalopathy,provided pharmaceutical care for clinicians,including the evaluation of adverse drug events and the prevention of adverse drug interaction and development of anti-infection programs by using Pharmacokinetics/pharmacodynamics theory and therapeutic drug monitoring technique.Results:Through active clinical treatment and pharmaceutical care,the symptoms of patients with encephalopathy were relieved,and the infection was effectively controlled.Conclusion:Clinical pharmacists play a positive role in the treatment for the case with antibiotic associated encephalopathy.

Keywords:Antibiotic-associated encephalopathy,Epilepsy,Cefoperazone tazobactam,Pharmaceutical care

Background

Encephalopathy is a common and costly complication during hospitalization.About 80% of hospitalized patients may develop encephalopathy,which increases the rishs of adverse events such as prolonged hospital stays,increased complications,long-term after-hospital care,re-hospitalization,and one-year death risk[1,2].Although drugs are the known causes of encephalopathy,antibiotic-associated encephalopathy(AAE)is not well understood[1,2].In this paper,the pharmaceutical care process of a case of cefoperazone tazobactam-associated encephalopathy was analyzed,and the clinical characteristics,pathogenesis,prevention,and treatment process of AAE were briefly discussed to provide references for rational use of drugs in the clinic.

Case data

A 73-year-old male patient with a chief complaint of cough,expectoration,and shortness of breath for more than 10 days received treatment in a local hospital on November 16th,2020.He was diagnosed in another hospital with 1)suspected parapneumonic effusion based on the check for pleural effusion,2)pulmonary infection,3)chronic kidney disease(stage 5)and diabetic nephropathy,and 4)lacunar cerebral infarction.He was injected with cefoperazone tazobactam(2 g,ivgtt,q8h)for anti-infection,and received ambroxol hydrochloride injection(30 mg,ivgtt,q12h)and acetylcysteine effervescent tablets(0.6 g,po,bid)for eliminating expectoration.The patient suddenly had obnubilation,no response to the call,upturning of both eyes,trismus,and tremor of mouth corner and limb on November 28th.Due to the frequent onset of the above symptoms,the patient was transferred to the Department of Pulmonary and Critical Care Medicine of our hospital on November 30th,2020.

At the time of admission,the patient had obnubilation,repeated epileptic seizures,and cyanosis of the lips.The results of the physical examination showed that the body temperature(T)was 36.3℃,respiration(R)was 24 times/min,heart rate(HR)was 92 beats/min,and blood pressure(BP)was 150/72 mmHg.Based on the results of the blood routine test,the white blood cells(WBC)were 8.69×109/L,and the percentage of neutrophils(NEUT)was 79.2%.As the biochemical test results show,the alanine aminotransferase(ALT),aspartate aminotransferase(AST),serum creatinine(Scr),and estimated glomerular filtration rate(eGFR)were 3.8 U/L,9.2 U/L,373 μmol/L and 14.73 mL/(min·1.73 m2),respectively.C-reactive protein(CRP)and procalcitonin(PCT),the content of inflammatory indexes,was 18.84 mg/L and 0.14 ng/mL,respectively.According to the chest CT on November 16thin another hospital,there were multiple infectious lesions in lobes of two lungs,with moderate pleural effusion in both sides.The patient was diagnosed with 1)pulmonary infection,2)chronic kidney disease(stage 5)and diabetic nephropathy,3)metabolic encephalopathy,and 4)secondary epilepsy in Hainan General Hospital(Hainan Affiliated Hospital of Hainan Medical University).

Hospitalization and pharmaceutical care process

After admission on November 30th,the administration of cefoperazone tazobactam was suspended.Sodium valproate oral solution(0.3 g,injected via a gastric tube,bid)was given for anti-epilepsy,dexmedetomidine(0.2 mg,intravenously pumped,temporary)for sedation,nifedipine controlled-release tablets(30 mg,nasal feeding,qd)for blood pressure control,and linagliptin tablets(5 mg,nasal feeding,qd)for blood glucose control.The patient also received oxygen inhalation with a nasal catheter,and bedside continuous renal replacement therapy(CRRT),as shown in Figure 1.

Figure 1.Process of treatment and pharmaceutical care for a patient with cefoperazone tazobactam associated encephalopathy

Opinion on clinical pharmacists

According to the medicine specification andNational Guidelines for Antimicrobial Treatment(2nd Edition)[3],clinical pharmacists believed that the dose of cefoperazone tazobactam should be adjusted(cefoperazone:1-2 g,q12h-24h;tazobactam:not more than 0.5 g per 12 h)in the case of creatinine clearance rate(Ccr)＜30 mL/min in patients.This patient suffered severe renal insufficiency,and the estimated Ccr was 11.03 mL/min.He was given cefoperazone tazobactam(4:1,2 g,q8h)in another hospital for 2 consecutive weeks without a reduction in dosage.Therefore,AAE caused by drug overdose could not be ruled out.Subsequently,the clinical use of the suspected drug was terminated and reasonable treatment(anti-epilepsy,sedation,and CRRT)was performed.

Advices of clinical pharmacists

1)Monitoring blood concentration of sodium valproate 3 days after administration to ensure its safety and efficacy.2)The patient suffered from disturbance of consciousness and repeated epileptic seizures,and there was a risk of worsening pulmonary infection due to aspiration.Hence,close monitoring of changes in infection indexes and active sputum drainage was recommended.3)Nifedipine controlled-release tablets broken off or crushed for nasal feeding will destroy the controlled-release matrix,resulting in drug release burst,further leading to increased blood concentration.Therefore,it was recommended that amlodipine besylate tablets,a long-acting non-slow,and controlled-release preparation,should be applied,and the blood pressure should be monitored.The above recommendations were adopted by the doctors.

On December 6th,the consciousness of the patient became clear,and he was able to respond to the call by opening his eyes and making some simple motion,without obvious convulsion,fever,and intolerance of cold,but he occasionally coughed and expectorated.The blood pressure was 130/73 mmHg.Physical examination found that there was a percussive dullness in both lower lungs,the breath sound(auscultation)was rough in both upper lungs,the moist rale could be heard in both lungs,and the gurgling with sputum was obvious.The results of auxiliary examinations showed that the WBC was 10.16×109/L,NEUT was 79.5%,CRP was 92.88 mg/L,and sodium valproate blood concentration was 72.4 μg/mL.Based on the above results,the patient was clinically considered to have increased infection markers.However,since the patient had metabolic encephalopathy currently,a bedside chest radiography was conducted first to assess the pulmonary infection,and intensive hemodialysis was performed to eliminate toxins.No antibiotics were given for the time being.

Clinical pharmacists’ suggestion

Paying close attention to the changes of symptoms,signs,and infection indicators of patients.Once infection occurs,anti-infective therapy should be given immediately.

On December 8th,the patient had a fever(Tmax38.7°C)and clear consciousness.He was able to respond to the call by opening his eyes and making some simple motion,without convulsion,but both cough and expectoration were enhanced.The results of lung auscultation were the same as before.The WBC was 19.42×109/L,NEUT was 85%,CRP was 102.36 mg/L,and PCT was 9.82 ng/mL.The results of the chest DR displayed scattered exudative lesions in both lungs.Based on the above results,clinically diagnosed patients with pulmonary infection aggravated,the patient had a risk of aspiration pneumonia,and Gbacteria and anaerobic bacteria were dominated in pathogenic bacteria.Meropenem should be applied for anti-infection.

Advices of clinical pharmacists

1)Sputum and blood samples should be detected for etiology before administration to guide the use of antibiotics.2)The incidence rate of meropeneminduced epilepsy is lower than that caused by other βlactam antibiotics[4].3)The anti-infective drug was selected reasonably,but the patient had renal insufficiency(Scr:276 μmol/L;converted to Ccr:14.9 mL/min).According toSanford Guide to Antimicrobial Therapy[5],the recommended dosage of meropenem for patients with renal insufficiency should be 0.5 g,q12h,and the duration of infusion should be extended for 3 hours each time to raise %T ＞ MIC.Moreover,the blood concentration was monitored 3 days after meropenem administration.4)Since sodium valproate can reduce the blood concentration of meropenem,the two should not be used jointly.At present,there were no epileptic seizures for 3 days,thus,sodium valproate could be withdrawn or replaced with other antiepileptic drugs,and this patient was observed for epilepsy and mind changes at the same time.The doctor applied meropenem additionally as the recommended dose and discontinued sodium valproate.

On December 11th,the patient had stable vital signs and clear consciousness.He could respond to the call by opening his eyes and making some simple motion,without convulsion,cold intolerance,or shortness of breath.The body temperature returned to normal,both cough and expectoration were decreased,the breath sound(auscultation)was rough in both upper lungs,and a little moist rale could be still heard.The WBC was 12.89×109/L,NEUT was 67.5%,CRP was 81.52 mg/L,PCT was 2.96 ng/mL,Ccr was 15.44 mL/min,and urine volume was 750 mL.Carbapenem-resistantPseudomonas aeruginosawas confirmed in blood culture and sputum culture(MIC of meropenem:4 μg/mL,MIC of imipenem ≥ 8 μg/mL).The valley value of the meropenem blood concentration was 21.83 μg/mL.

Opinion on clinical pharmacists

100% T ＞ MIC can be determined when the valley value of the meropenem blood concentration is higher than the MIC ofPseudomonas aeruginosa.After treatment,the clinical symptoms and infection indexes of this patient were improved,indicating that the dose of meropenem was sufficient and the anti-infective therapy is effective.A study of the correlation between meropenem blood concentration and adverse reactions in patients with severe infection showed that the trough concentration threshold of meropenem-related neurotoxicity was Cmin＞ 27.4 mg/L and Cmin＞ 27.1 mg/L for nephrotoxicity[6].Therefore,the current administration dose was relatively safe,and the current regimen could be maintained.Clinical pharmacists recommend close monitoring of patients' renal function and psychological changes.Due to low intake,poor nutritional status,and diabetes mellitus,appropriate supplementation with enteral nutrition emulsion(TPFD)was recommended.The doctor took the advice and gave 1500 mL intestinal TPF-D,qd,through nasal feeding.

On December 12th,the patient stabilized and was transferred to the general ward,where he continued to receive anti-infection,enteral nutrition,and regular dialysis.On December 20th,the patient had no fever,cold resistance,cough,expectoration,and shortness of breath.He had clear consciousness and stuck to the point.Breath sounds in both lungs were clear,and dry and moist rales were not heard.Blood routine and inflammatory indexes were as follows:WBC 6.82×109/L,NEUT 63.4%,CRP 12.13 mg/L,PCT 0.067 ng/mL.The renal function indexes were as follows:Scr 253 μmol/L,and eGFR 23.14 mL/(min·1.73 m2).The infection had been under control,chest CT showed that the lesions and pleural effusion were obviously absorbed(as is shown in Figure 2),and the condition was stable,so the patient was smoothly discharged.

Figure 2.Radiological comparison before and after treatment Chest CT scan in other hospitals showed multiple infectious lesions in each lobe of both lungs,especially in the lower lobe of both lungs,with moderate pleural effusion on both sides(A).Bedside X-ray showed diffuse exudative lesions in both lungs(B).When transferred to the general ward,X-ray showed that exudative lesions in both lungs were more absorbed than before(C).At the end of treatment and discharge,chest CT showed that the lesions and pleural effusion were obviously absorbed(D).

Discussion

Clinical features,mechanism and risk factors of AAE

Antibiotic drugs such as penicillins,cephalosporins,carbapenems,and quinolones may induce AAE in patients,whose main manifestations are psychosis,myoclonus,epilepsy,and speech/behavior disorders.The clinical manifestations of AAE are varied.Current researches mainly divide AAE into the following three categories according to the specific antibacterial drugs,unique neurotoxic manifestation,and pathophysiological mechanism[1,2,7]:

Type 1 AAE usually occurs within 1-10 days after the administration of antibacterial drugs,and is often accompanied by myoclonus or epileptic seizures,accounting for about 29% of AAE.The magnetic resonance imaging(MRI)results of these patients are normal,but the electroencephalogram(EEG)results are abnormal,with a wide range of periodic triphasic waves.The symptoms can be alleviated 2-7 days after drug withdrawal.Type 1 AAE is a common clinical type of penicillin-(about 38-71%)and cephalosporin(about 35-41%)-induced encephalopathy is the most frequently reported clinical phenotype of cephalosporin-induced encephalopathy in the context of renal insufficiency(about 72%).The possible pathogenesis is that endogenous GABA,an inhibitory neurotransmitter,activates GABAAreceptors,resulting in massive chloride ions flowing into cells,and then leads to the increase of neural excitation action potential threshold.β-lactams have varying degrees of affinity with GABAAreceptors,which can prevent GABA from binding to receptors through a variety of mechanisms,thereby causing central excitotoxicity.

Type 2 AAE occurs within a few days after antibiotic use(median:around 5 days)and is often accompanied by the symptoms of insanity(such as delusions or hallucinations),accounting for approximately 47% of AAE.Epileptic seizures and EEG abnormalities(usually nonspecific rather than epileptic changes)are rare,and MRI results are normal.Symptoms are relieved a few days after drug withdrawal(median:about 5 days).Clinically,the common causes of type 2 AAE were procaine benzylpenicillin(about 68%),sulfonamide(about 68%),quinolone(about 67%),and macrolide(about 63%).At present,procaine,which is pharmacologically similar to cocaine,has been shown to partially block the function of the presynaptic D2 dopamine transporter and increase the level of dopamine in the synapse,resulting in excitotoxicity[1,2].The results of animal experiments indicated that quinolone-induced AAE may be related to the excessive activation of the N-methyl-D-aspartic acid(NMDA)sodium glutamate receptor[1,2].The mechanism of macrolides induced AAE remains unclear.

Type 3 AAE mainly refers to metronidazole-induced encephalopathy,which usually occurs 3 weeks after administration and is often accompanied by cerebellar dysfunction(such as ataxia or dyskinesia).The majority of patients showed extensive abnormalities on MRI,with rare epileptic seizures and abnormal EEG.The median time to remission after drug withdrawal is about 13 days.Metronidazole toxicity can lead to characteristic reversible MRI abnormalities in the cerebellar dentate nuclei,dorsal brainstem,or splenium of the corpus callosum,indicating angiogenic and cytotoxic edema.The pathogenesis of type 3 AAE may be related to the changes in the formation of free radicals(nitrogen anion free radicals,peroxide free radicals,and hydrogen peroxide)and thiamine metabolism.

It has been reported[1,2,7]that renal insufficiency occurs in 25% of AAE patients,and baseline renal insufficiency is particularly common in cephalosporininduced encephalopathy.Renal insufficiency will not only raise the serum antibiotic concentration,but also lead to a decrease in serum protein level and an increase in antibiotic bioavailability due to proteinuria,thereby increasing the risk of antibiotic neurotoxicity.Meanwhile,both protein glycosylation and carbamylation will decline due to the decrease in serum protein level,leading to changes in the integrity of the blood-brain barrier.As a result,antibiotics are more likely to enter the central nervous system.According to another study[8],risk factors for AAE also include a history of central nervous system disease,advanced age,low birth weight,and drug overdose,and metronidazole-induced encephalopathy is associated with long-term medication.

Relevance evaluation of adverse drug events in this case

More than 40% of cefoperazone is excreted through bile,about 20% through the kidneys,and about 50-60%of tazobactam is excreted through the kidneys.According to the medicine specification and the

Sanford Guide to Antimicrobial Therapy[5],the dose of cefoperazone tazobactam in patients with renal insufficiency should be adjusted.This case is an elderly male patient with severe renal insufficiency and risk factors for AAE.He continued to use cefoperazone tazobactam for several days without reduction of dosage,which was the main cause of AAE.

The adverse drug events in this case were evaluated according to China's adverse drug reaction/event relevance evaluation standard,and the results were as follows:1)Consciousness changes and epileptic seizures occurred after application of cefoperazone tazobactam for 12 days,which was a reasonable temporal relation.2)The clinical manifestations of the patient were consistent with the clinical symptoms of AAE,especially the adverse reactions of cefoperazone reported at home and abroad[9,10],suggesting that the patient suffered from AAE suspected to be caused by cefoperazone-tazobactam.3)The suspected drug cefoperazone tazobactam was withdrawn,and 8 days after symptomatic supportive treatment,the patient regained consciousness and the encephalopathy symptoms disappeared.4)The patient did not use the suspected drug again.5)There were confounding factors such as cerebral infarction,infection,anoxia,and metabolic dysfunction,which could not be completely excluded.To sum up,the adverse events of AAE in this case might be related to the suspected use of cefoperazone tazobactam.

Prevention and treatment of AAE

Encephalopathy is not a common adverse reaction of antibacterial drugs,but the conditions are often serious once it occurs,which can raise the risks of complications and death.Therefore,clinicians and pharmacists should be fullly aware of the risk and hazards of AAE when using antibacterial drugs.To prevent and treat AAE in a reasonable way,the following suggestions were proposed based on the clinical treatment and pharmaceutical care process of this case of AAE,as well as related literature reports[11]:1)Before using antibacterial drugs,patients should be fully assessed for risk factors of AAE(renal insufficiency,a history of central nervous system disease,advanced age,and children).2)The patient with the above risk factors should be carefully inquired about the history of adverse reactions of drugs(especially antibacterial drugs),and potentially neurotoxic drugs should be avoided.Besides,the dosage of antibacterial drugs should be appropriately adjusted according to the pathophysiological characteristics and therapeutic drug monitoring(TDM)results of the patient.3)Pharmaceutical care should be given during the use of antibacterial drugs to detect AAE as early as possible.Once the central nervous system symptoms are found,the suspected antibacterial drugs should be withdrawn immediately,and EEG monitoring should be performed.Other types of nonneurotoxic or less neurotoxic antibacterial drugs can be applied when symptoms are relieved or there is no specific change in the EEG.4)If convulsions,nonconvulsive status epilepticus(NCSE),or specific EEG changes occur,sodium valproate or phenytoin sodium should be used as an antiepileptic,moreover,sedation and oxygen therapy should be given when necessary to improve the patient’s oxygenation state.5)Hemodialysis or hemofiltration should be conducted for patients with kidney failure or persistent symptoms of encephalopathy,thereby facilitating the elimination of neurotoxic substancesin vivo.

During the clinical treatment of this AAE patient,clinical pharmacists actively participated in the whole process of pharmaceutical care,including the evaluation of adverse drug events and the review of a drug interaction.Clinical pharmacists assisted clinicians in developing anti-infection programs by using antibacterial drug PK/PD theory and TDM technique,which achieved satisfactory therapeutic effects and effectively avoided the occurrence of adverse reactions.