Valproate Interaction With Carbapenems: Review and Recommendations

Abstract

Introduction: Valproic acid is a commonly used antiepileptic drug. Combining valproate derivatives with carbapenem antibiotics is associated with a potential drug interaction that decreases serum concentration of valproate and may expose the patient to uncontrolled seizure risk from valproate subtherapeutic concentration. Raising awareness of this drug interaction among health care providers including emergency department physicians, neurologists, and pharmacists is highly needed. The aim of this article was to review the current literature about the potential drug interaction resulting from combining valproate derivatives with carbapenem antibiotics and to establish therapeutic recommendations regarding their use together. Methods: A review of the literature was conducted using Medline (through PubMed), Ovid, Embase, Cochrane library using the following keywords: valproate, valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition, a manual search through major journals for articles referenced in PubMed was performed. Related publications from January 1998 till November 2018 were included in the initial search. Relevant publications were reviewed, and data regarding patients, type of carbapenem used, valproic acid dosing and level, interaction severity, and clinical outcome were summarized. Results and Discussion: Few clinical trials and multiple case reports have shown that carbapenem antibiotics including meropenem, ertapenem, imipenem, and doripenem can decrease the serum concentration of valproate derivatives leading to a subtherapeutic serum concentration and seizures in some patients. Valproic acid serum concentration may be significantly decreased with addition of a carbapenem antibiotic but generally return toward normal shortly after discontinuation of the carbapenem antibiotic. Conclusions: Generally, the concurrent use of carbapenem antibiotics with valproate derivatives should be avoided due to the potential of drug-drug interaction that results in subtherapeutic valproate serum concentration. Other antimicrobial agents should be considered as alternatives to carbapenems but if a concurrent carbapenem is necessary, using an additional antiepileptic agent is recommended. Therapeutic drug monitoring of valproate serum concentrations is warranted when a carbapenem-valproic acid combination therapy is unavoidable.

Introduction

Drug interactions are commonly encountered in therapeutics. A clinician’s duty is to determine the clinical significance of interactions and how to manage them. The interaction between carbapenem and valproic acid (VPA) has been reported in literature in many case reports and retrospective studies. Patients with epilepsy maintained on VPA might have a comorbid condition such as an infection, which may require treatment with a carbapenem antibiotic concomitantly. Carbapenems decrease the serum concentration of VPA significantly in a rapid fashion, predisposing patients to a high risk of seizures. This review will summarize the current literature on this topic and recommendations regarding their use together.

Valproic Acid

Valproic acid is a broad-spectrum antiepileptic drug (AED) that is highly effective both in adults and children. It is one of the first-line drugs in the treatment of epilepsy. It is also used in the treatment of migraine, bipolar disorder, and schizophrenia.^1,2 The antiepileptic effect of VPA is mediated through its weak blocking activity of sodium ion channels which produce weak inhibition of enzymes that deactivate γ-aminobutyric acid. The exact mechanism behind its psychotropic effect in treating bipolar disorder is not clear.³

Valproate has a complex pharmacokinetic profile that follows a 3-compartment model and shows nonlinear pharmacokinetic properties due to saturable protein binding.^3,4 Valproic acid is typically 90% to 95% bound to plasma protein, mainly albumin. The serum-free (unbound) fraction of VPA ranges between 6% and 10%. However, it depends on serum albumin, serum VPA concentration, age, and end-organ failure.² Other drugs that are highly protein bound can also displace valproate from albumin and precipitate toxicity (eg, aspirin).³ Therefore, interpreting the total serum concentration might be misleading sometimes.

The initial dosing is 10 to 15 mg/kg/d usually administered every 8 to 12 hours. Total daily dose can be increased weekly by 5 to 10 mg/kg/d to a maximum of 60 mg/kg/d with a target therapeutic range of 50 to 100 mg/L. Valproic acid is extensively metabolized by liver, mainly by glucuronidation (40%), β-oxidation, and ω-oxidation (20%). Less than 3% of drug is excreted unchanged via kidney. Valproic acid is an enzyme inhibitor which can increase the plasma concentration of some drugs (eg, tricyclic antidepressants, lamotrigine).^2,3 Adverse drug reactions (ADRs) of VPA include dizziness, weight gain, fatigue, and headache, whereas the most serious ADRs include hepatotoxicity and pancreatitis.¹

Carbapenem Antibiotics

Carbapenems (meropenem, doripenem, imipenem, ertapenem, and tebipenem) are a class of antibiotics that belongs to the β-lactam antibiotics, similar to penicillins and cephalosporins. They differ from the other classes in their exact chemical structure. The mechanism of action for this class is similar to penicillins; it works as a cell wall synthesis inhibitor. Carbapenems have a wide spectrum of antimicrobial coverage (gram-positive, gram-negative, and anaerobic bacteria). The use of carbapenems has increased as a result of the rising resistance to cephalosporin antibiotics in Enterobacteriaceae (Escherichia coli, Klebsiella, Enterobacter, and related genera).⁵

The spread of extended-spectrum β-lactamase–caused infections and the proven efficacy of carbapenems against these organisms have led to its wide use in practice. Unfortunately, some resistance is emerging due to the carbapenem-destroying β-lactamases (“carbapenemases”). Carbapenem-resistant Enterobacteriaceae are remarkably resistant organisms and can cause serious infections leaving providers with limited treatment options. All carbapenems are administered parenterally except tebipenem (an oral drug approved only in Japan).⁵

The pharmacokinetic properties of carbapenems are relatively similar. Meropenem and doripenem have a linear pharmacokinetics. Ertapenem has a high plasma protein binding capacity in therapeutic concentration; however, the effect on pharmacokinetics is minor and hence near-linear pharmacokinetics can be assumed. Carbapenems do not accumulate in patients with normal kidney function.⁶

VPA-Carbapenem Interaction

Carbapenems have been shown to reduce serum concentration of VPA in case reports and retrospective studies. The interaction was first reported in the Japanese literature in the late 1990s. The mechanism behind the interaction is complex and still has not been fully elucidated. The reduction in serum VPA concentration induced by carbapenems happens rapidly within 24 hours of concomitant administration and may lead to the aggravation of seizures. It is recommended to avoid the use of these 2 medications concurrently.⁷

Methods

A literature review for relevant evidence was performed by searching Medline (through PubMed), Ovid, Embase, Cochrane library using the following keywords: valproate, valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition, a manual search through major journals for articles referenced PubMed was performed. Related publications from January 1998 till November 2018 were included in the initial search. Relevant publications were reviewed and data regarding patients, type of carbapenem used, VPA dosing and level, interaction severity, and clinical outcome were summarized. Results, recommendations, and alternative options to manage this interaction were discussed.

Results and Discussion

Search Results

Using Medline search, manual search through major journals, and Cochrane Library database, clinically relevant results were identified. Many case reports, review articles, and some pharmacokinetic and retrospective clinical trials were found relevant to the valproate-carbapenem interaction. Most of these papers reported a significant reduction in valproate blood concentration in patients receiving concurrent carbapenem therapy. Cochrane Library database was reviewed, but no relevant systematic reviews were found.

Clinical Findings

The interaction between VPA and carbapenems has been investigated in clinical studies with the main focus being on the decrease in serum VPA concentration and the clinical manifestation of the interaction.^7-11 Some of these studies reported an increase in seizures during VPA-carbapenem combination therapy.^7,9

A retrospective study has looked at 28 children who received VPA either orally or intravenously concomitantly with a carbapenem. Noting that the therapeutic range of plasma VPA concentration for seizures is 50 to 100 mg/L, the study found that plasma VPA concentration was subtherapeutic in 88% of the patients after the introduction of a carbapenem leading to seizures in 54.5% (6/11) of patients who were maintained on VPA and had good control of epilepsy. The authors of the study recommended avoiding the concomitant use of carbapenem antibiotic with VPA and VPA concentration monitoring if the use is warranted.⁹

Similarly, Huang et al⁷ reported that carbapenems decrease serum VPA concentration to subtherapeutic concentration. This observational study included 54 adult patients with epilepsy treated with VPA and a carbapenem for infection. Valproic acid serum concentration was measured at baseline and after starting carbapenem therapy. The change in serum VPA concentration was calculated and a decrease in serum concentration was found since the first day of carbapenem therapy and continuously onward. Seizure was provoked in 48% (26/54) of the study sample. This percentage is higher than the rate of carbapenem or infection-related seizures. In addition, patients included in the study had at least 3 months of seizure control with VPA therapy. Study investigators have also found that renal disease and enzyme-inducing AEDs especially phenytoin are risk factors to the reduced serum concentration of VPA during the concomitant treatment with carbapenems.

Moreover, in the same study, an analysis was performed to compare the interaction effect on serum VPA concentration with different agents from the carbapenem class. Meropenem and ertapenem drug interaction analysis showed a higher reduction in VPA serum concentration compared with imipenem. The mean reduction in VPA concentration was found to be 77% (range, 34%-99%), 71% (range, 38%-98%), and 52% (29%-73%), respectively.

Another retrospective study has also investigated the effect of different carbapenems on serum VPA concentration. It included 52 adult patients who were on VPA and carbapenem combination. Serum concentrations of VPA were measured before, during, and after carbapenem therapy. Serum VPA concentration was reduced to subtherapeutic concentrations in 90% of patients. This reduction was seen in both the oral and intravenous routes of VPA. Average VPA serum concentration before carbapenem use was 58.6 ± 19.2 mg/L, whereas it was 23.7 ± 16.3 mg/L during carbapenem use. The average reduction in serum VPA concentrations with the concomitant use of ertapenem (N = 9), meropenem (N = 26), and imipenem/cilastatin (N = 17) was 72% ± 17%, 67% ± 19%, and 42% ± 22%, respectively. The decrease in VPA concentrations was more significant with ertapenem and meropenem use compared with imipenem/cilastatin use (P < 0.005). Doses of carbapenems were increased in some patients, and serum VPA concentrations continued to decrease in patients receiving meropenem and ertapenem. In one patient who was receiving imipenem/cilastatin, increasing VPA dose by 17% has lead to parallel increase in serum VPA concentrations from 19 to 26.4 mg/L. Regardless, clinically this does not make imipenem/cilastatin a preferred choice as it is the most epileptogenic carbapenem and its use should be avoided in patients with seizure history.¹⁰

Furthermore, the study found that the decrease in serum VPA concentration started within the first 24 hours of carbapenem administration. Despite increasing VPA dose in 6 patients who were also on ertapenem or meropenem, their serum VPA concentration continued to decrease. Serum concentrations were also checked within 7 days after discontinuation of carbapenem in 13 patients. The study also found that it returned to 90% of baseline along with a 20% increase in VPA dose.

Haroutiunian et al⁸ have addressed several pharmacokinetic concepts such as onset, severity, and dose dependency of the interaction. This retrospective analysis included 36 patients. The decrease in plasma VPA concentrations happened rapidly, reaching 9.9 ± 3.2 μg/mL within 24 hours of meropenem initiation. Concentrations dropped significantly from 50.8 ± 4.5 μg/mL to 9.9 ± 2.1 μg/mL (P < .001). Results showed a mean decrease in 82.1% ± 2.7% following meropenem administration. The study has also stated that plasma VPA concentrations stayed low up to 7 days of meropenem discontinuation and then increased gradually to baseline concentrations after 8 to 14 days. Different daily doses of VPA showed similar pattern of VPA concentration reduction in this population.

The interaction has also been reported in several case reports and case series, describing the significant drop in VPA concentration, many times to subtherapeutic concentrations.^12-19 The drop in concentrations after carbapenem therapy initiation was noticed to be rapid and significant (up to 90%), similar to what has been reported in the above-mentioned studies. These case reports also reported that VPA concentration returned to normal rapidly in a similar manner. On the contrary, one of the case reports showed a persistent (up to 2 weeks) reduction in valproate concentrations after discontinuation of meropenem.¹⁹ Seizures occurred in some patients as a result of decreased serum VPA concentrations.

Park et al¹⁸ reported 6 cases which exhibited a drop in the serum VPA concentration before and after the administration of carbapenem antibiotics. The carbapenems that were used in these cases were meropenem (N = 3), ertapenem (N = 2), and imipenem (N = 1). The mean decrease in serum VPA concentration was 88.7% ± 5.3%, 74.0% ± 9.8%, and 73.3%, respectively. Correspondingly, half-life of VPA was reduced resulting in 80.1% ± 9.0%, 64.4% ± 24.2%, and 50.6% with concomitant use of meropenem, ertapenem, and imipenem, respectively.

Spriet et al¹¹ observed the pharmacokinetic interaction between valproate and meropenem in 39 patients. In 19 patients who had daily plasma concentration monitoring, plasma VPA concentration dropped within the first 24 hours. The overall average decrease in valproate plasma concentrations was 66%. Electroclinical deterioration was seen in 55% of patients making the interaction clinically relevant. The authors concluded that meropenem and valproate should not be administered together.

Vélez Díaz-Pallarés et al²⁰ conducted a 2-phase trial; retrospective observation followed by prospective period with intervention to assess the interaction and to evaluate the impact of the pharmacist intervention in the management of VPA-carbapenem interaction. The trial reported a significant reduction in the VPA concentration. The pharmacist interventions include identification and reporting of potential interactions, managing VPA-carbapenem interaction, and improving prescribing process. Table 1 summarizes the most relevant published studies regarding VPA-carbapenem interaction.

Table 1.

Summary of Published Studies On Concurrent VPA-Carbapenem Therapy

References	Study design	Population	VPA dose	Carbapenem used	Level reduction (VPA)	Outcome
Miranda Herrero et al9	Retrospective study	28 children	29.1-55.3 mg/kg/d	Meropenem	88% of levels were subtherapeutic	Seizure in 54.5% of patients
Huang et al7	Observational study	54 adults	1600 mg/d (average)	Meropenem Ertapenem Imipenem	Average level reduced to 16.9 µg/mL	Seizure in 48.1% of patients
Wu et al10	Retrospective study	52 adults	24.1 ± 10.2 mg/kg/d	Meropenem Ertapenem Imipenem	Subtherapeutic in 90% of patients, level reduced within 24 hours of administration by approximately 60%	Seizure (at least 2 patients)
Haroutiunian et al8	Retrospective study	36 patients	2040 ± 70 mg/d	Meropenem	VPA mean ± SEM plasma concentration decreased from 50.8 ± 4.5 µg/mL to 9.9 ± 2.1 µg/mL	NA
Vélez Díaz-Pallarés et al20	Retrospective followed by prospective period with intervention	26 patients	NA	Meropenem	Retrospective period: 2.14-22.76 µg/mL Prospective period: 1.63-43.87 µg/mL	Seizure in 1 patient
Spriet et al11	Retrospective study	39 patients	1600 ± 680 mg/daily (mean)	Meropenem	Average drop in VPA level of 66%	Electroclinical deterioration in 55% of patients. Increase in number of epileptic seizures in 3 patients

Note. VPA = valproic acid; N/A = not available.

Doripenem, the most recent carbapenem, was approved by the Food and Drug Administration in 2007. The product monograph²¹ addressed the interaction with VPA and the pharmacokinetic parameters of VPA were analyzed. Four doses of doripenem (500 mg every 8 hours) were administered to 23 healthy male adults who had been receiving valproate 500 mg every 12 hours for 7 days. Results showed a decrease in the mean minimum concentration (by 78%), maximum concentration (by 45%), and the area under the concentration-time curve (by 63%) relative to VPA alone. A reduction in serum concentration of VPA was observed within 12 hours after initiation of doripenem.

Valproate-doripenem interaction was also reported in 2 adult female patients who received both medications concurrently. The case report showed that VPA concentrations decreased by 69% in one patient and 62% in the other case within 2 days of doripenem-valproate coadministration.²²

Mechanism of Interaction

Valproic acid-carbapenem interaction is a pharmacokinetic interaction that results in reduction in VPA concentrations. A pharmacokinetic interaction is an alteration in the disposition of a drug at any of the following phases: absorption, distribution, metabolism, and excretion by a coadministered agent.²³ Some animal studies suggest that the interaction mechanism between VPA and carbapenem includes decreased intestinal absorption,^24,25 which simply does not explain the interaction as it is also seen with VPA administered intravenously. Other proposed mechanisms are inhibition of valproate glucuronide (VPA-G) hydrolysis,²⁶ induction of valproate hepatic glucuronidation,^25,26 increased renal clearance of VPA-G,^27,28 and increase in distribution of VPA into red blood cells.

The exact mechanism of the interaction is not known yet. However, the rapid onset of the interaction (within 24 hours) and the 7 to 14 days recovery period after stopping carbapenem suggest that the mechanism of interaction appears to be enzyme inhibition. Generally, inhibition of drug metabolism is rapid in onset (24-48 hours), whereas induction usually takes longer (7-10 days).²³ According to some references, decreased enteric hydrolysis of the VPA-G (ie, decreased enterohepatic recirculation) is thought to be principally responsible.^21,28-32 Suzuki et al³³ investigated the effect of meropenem on acylpeptide hydrolase (APEH). Acylpeptide hydrolase is an enzyme thought to be involved in hydrolyzing VPA-G metabolite back to its active VPA molecule. They found that plasma concentrations of VPA were decreased more rapidly in dogs coadministered with meropenem compared with a control group. An increase in VPA-G clearance was also seen which suggests that the hydrolysis of it to the active valproate was inhibited. In an in vitro experiment in the same study, they also observed APEH inhibition by meropenem in human and dog liver cytosol and considered it as a key process in this interaction.³³

Notably, Spriet and Willems³⁴ reported in a case report lack of interaction between valproate and meropenem in a patient with severe liver impairment. The suggested explanation is that VPA metabolism was substantially impaired owing to loss of functional hepatic cells, meaning that upregulation of glucuronidation of VPA by meropenem might not have taken place. They also mentioned that biliary drug secretion is reduced in patients with cirrhosis, which further could explain the therapeutically maintained concentration of VPA in this patient. Decreased albumin concentration in a hepatically impaired patient is common and could lead to more unbound valproate concentration and control of seizure. However, albumin concentrations were maintained at 30 to 35 g/L in this patient.

Valproic acid use should be avoided in patients with liver disease because it could be contributed to hepatic toxicity thought to be induced by some of its metabolites. If not, it would be wise to watch for adverse drug effects of valproate frequently and monitor serum concentration of the drug.⁴

Intentional Use of VPA-Carbapenem Interaction

The interaction between valproate and meropenem was used as an interventional treatment for patients in 2 case reports. A patient treated with valproate for bipolar disorder was found unresponsive due to ingestion of about 10 g of extended-release divalproex sodium. Supportive care was provided for the patient; however, initial concentration of VPA was 396.2 µg/mL and then increased to reach 415 µg/mL. A decision was made to start meropenem for treatment of possible aspiration pneumonia and to make benefit of its ability to decrease VPA concentration. Serum VPA declined significantly after the first dose of meropenem and concentrations were found to be 36.5 µg/mL after 14 hours of therapy. Patient has improved and was extubated. He received a total of 8 doses of meropenem (500 mg every 6 hours).³⁵

In another case report, VPA toxicity was treated by supportive care, 1 dose of intravenous (IV) ertapenem (1 g), activated charcoal, and levocarnitine. Ertapenem was chosen due to its long half-life among other carbapenems. The VPA concentrations were decreased by ~20% after 1 hour of ertapenem administration. Eventually, after 3 days, patient successfully recovered and VPA concentrations were 5 µg/mL without the need for dialysis.³⁶

As data are limited to these 2 case reports, the benefits of the intentional use of this interaction to manage VPA toxicity should be carefully weighed against potential risks till further evidence supported by well-designed clinical trials is available.

Management Options

Valproic acid-carbapenem interaction can be managed using several options. The selection of alternative antibiotics should be considered before the use of a carbapenem whenever feasible. Tigecycline or polymyxins can be considered in some cases as alternatives to provide coverage against gram-negative microorganisms. Fosfomycin and nitrofurantoin can be considered as potential alternatives to carbapenems for urinary tract infections.⁵

If carbapenem therapy is unavoidable, adding another adjunct AED to VPA during carbapenem therapy is an option; the added medication needs to be continued 7 days after the carbapenem discontinuation.³⁷

Moreover, switching from VPA to an alternative antiepileptic agent can be considered in some patients. The choice of the alternative antiepileptic should be based on seizure type, side effects, drug interactions, and patient-related factors including renal and hepatic functions. Having a low risk of drug interactions makes levetiracetam an attractive alternative to VPA. Phenytoin and other enzyme-inducing antiepileptic agents, including phenobarbital and carbamazepine, are not preferred alternatives to VPA due to their potential drug interactions.⁷

Finally, in patients with low risk of seizure (prolonged seizure-free period or receiving post-neurosurgery seizure prophylaxis) receiving a carbapenem antibiotic therapy for short period, therapeutic drug monitoring of the serum valproate concentration with proper clinical monitoring while receiving valproate derivative is required and may be adequate.³⁷

Conclusions

In light of the currently available clinical studies and published case reports, combination of VPA and carbapenem antibiotics should be avoided whenever possible. The reported VPA concentration reduction is significant and this pharmacokinetic interaction can be accompanied by seizure in some patients. Other antimicrobial agents should be considered as alternatives to carbapenem antibiotics. Replacing VPA with another non-interactingantiepileptic agent or prescribing additional antiepileptic medication can be an option. Therapeutic drug monitoring of valproate concentration is warranted when a carbapenem-VPA combination therapy is necessary, especially on initiating or stopping the carbapenem antibiotic.