A case study of sodium valproate and carbapenem drug interaction
发布日期：
2024-06-14
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Patient condition:

The patient had recurrent fever without any cause, with body temperature as high as 38.8℃, which could be reduced to normal by taking medication. Before admission, he had nausea and vomiting with chest, back and right upper abdominal pain, which was persistent and aggravated by eating, and diarrhea, 4-5 times/day, with yellow loose stools, intermittent foamy, accompanied by tenesmus.




Diagnosis of illness


①Consider acute pancreatitis with peripheral exudative effusion and abdominopelvic effusion; ②Gallbladder stones; 

③Enlarged heart, widened pulmonary arteries, pulmonary arterial hypertension was not excluded; 

④Pericardial effusion, bilateral pleural effusion, and segmental atelectasis in both lungs; 

⑤ Exudative changes in both lungs;

⑥Calcified foci of hepatic S6 and 7, intrahepatic bile duct stones to be identified; 

⑦ Subcutaneous edema of the lower thoracic wall and abdominal wall.



Diagnostic and therapeutic process

Step1

He was admitted to the department of general medicine mainly for fever investigation, and was given latamoxef 0.5 g, q8h, ivgtt for anti-infection from the first day to the fourth day, and was switched to imipenem/cilastatin 1.0 g, q8h, ivgtt to continue the anti-infection on the fifth day. On the sixth day, the patient had a sudden convulsion and was transferred to the cardiothoracic ICU after being given sodium valproate and methylprednisolone for resuscitation.

Step2

Cardiothoracic Surgery ICU, imipenem/cilastatin (Junte) 1.0 g, q8h, ivgtt, anti-infection, valproate 1.2 g, qd, iv (pump) and levetiracetam tablets 0.5 g, q12h anti-seizure. Convulsions occurred again on the seventh day and were treated symptomatically. Valproic acid blood concentration was measured on the eighth day as 35.53 μg/mL, which was lower than the effective blood concentration (50-100 μg/mL).

Step3

Day9-Day21, internal ICU, cefoperazone /sulbactam 3 g, q12h, iv (pump) anti-infective was given, Day20-Day23 was changed to meropenem 1 g, q8h, iv (pump) anti-infective. Sodium valproate 1.2 g, qd, iv (pump) antiepileptic on the same day on day 12, 10 mL (0.4 g) of oral solution of sodium valproate, tid, p.o, was given on days 13 through 16, and the dose of sodium valproate was upwardly adjusted to 12 mL (0.48 g), tid, p.o from 11.20-11.23, and because of substandard blood levels, sodium valproate was changed on days 20 through 23 to 1.2 g, qd, iv (pump). Valproate blood concentrations were 57.83 μg/mL, 15.17 μg/mL, and 12.44 μg/mL on days 15, 20, and 21, respectively, and were below the effective concentration during the combination with meropenem[1].

Valproic acid in combination with carbapenems

Valproic acid (VPA) is a clinically used broad-spectrum antiepileptic drug, which is effective against various types of seizures, and its blood concentration range should be maintained at 50-100 μg/ml during its use.The combination of valproate with certain drugs may result in drug-drug interactions, leading to the failure of antiepileptic therapy, among which the effect of carbapenems (CBPMs) on the blood concentration of valproate has attracted clinical attention. The effect of carbapenems (CBPMs) on the blood concentration of sodium valproate has attracted clinical attention.In 1997, Nagia et al. reported for the first time that panipenem significantly decreased the blood concentration of sodium valproate.In 1998, De Turck BL et al. found that the combination of meropenem with sodium valproate resulted in a decrease in the blood concentration of the latter.

CBPMs induced epilepsy, the most reported is imipenem, which caused epilepsy incidence as high as 3%-33%, while other CBPMs caused epilepsy at a lower incidence, such as meropenem 0.7%-0.8%, ertapenem 0.18%, and doripenem 1.2%. Combination of carbapenem antimicrobials with VPA significantly reduces the blood concentration of VPA and induces seizures within 24h. The effects of different carbapenem antimicrobial drugs on VPA blood concentrations varied, with ertapenem and meropenem having a greater effect on VPA blood concentrations than imipenem/cilastatin. The combination of meropenem and VPA decreased VPA blood levels independent of the VPA dose. After the discontinuation of carbapenems, VPA blood concentration rises slowly and takes a long time (usually at least 7 days or more) to return to the level of blood concentration without carbapenems or even fails to return to the original level.


Pharmacy Recommendations

Due to the interaction of carbapenem antimicrobials with VPA, the combination of the two should be avoided as much as possible. Where feasible, consideration should be given to the choice of alternative antibiotics prior to the use of carbapenems. If carbapenem therapy is unavoidable, the following interventions are possible:

1, It is recommended that additional antiepileptic drugs be added during treatment with VPA, and additional antiepileptic drugs should continue to be added within 7 days of carbapenem discontinuation.

2, In some patients, switching from VPA to alternative antiepileptic drugs may be considered. The choice of an alternative antiepileptic should be based on seizure type, side effects, drug interactions, and patient-related factors, including renal and hepatic function. Levetiracetam has a lower risk of drug interactions and is an attractive alternative to VPA. Phenytoin and other enzyme-inducing antiepileptic drugs, including phenobarbital and carbamazepine, are not preferred alternatives to VPA due to their potential drug interactions. Carbapenem-related seizures are best treated with benzodiazepines, followed by other drugs that enhance the propagation of γ-aminobutyric acid [2-3].



Reference

[1] 张色华.1例丙戊酸钠联用碳青霉烯类药物致血药浓度降低并血氨升高的病例分析[J].智慧健康,2022,8(03):196-198.DOI:10.19335/j.cnki.2096-1219.2022.3.066.
[2]李爽,李新林,周敬凯,等.不同碳青霉烯类抗生素对丙戊酸血浆药物浓度的影响[J].中国感染与化疗杂志,2015,15(04):387-390.

[3]王东晓，李莉，朱曼，等．
从 1 例老年感染患者探讨碳青霉烯类药物与丙戊酸钠的药物相互作用［J］.中国药物应用与监测，2013，10( 2) : 87-90.




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