Tuesday, July 19, 2016

Meropenem and valproate

Inspired by a recent patient, an adolescent female with intractable epilepsy, whose valproate levels plummeted after meropenem.was started.

Wu CC, Pai TY, Hsiao FY, Shen LJ, Lin Wu FL. The effect of different
carbapenem antibiotics (ertapenem, imipenem/cilastatin and meropenem) on serum
valproic acid concentrations. Ther Drug Monit. 2016 Jun 15. [Epub ahead of print]

Carbapenem antibiotics (CBPMs) may significantly reduce the serum concentration of valproic acid (VPA), but the extent of this effect among various CBPMs is unknown. This study compared the extent and onset of the interactions among ertapenem, imipenem/cilastatin, and meropenem.
A five-year retrospective study was performed. Hospitalized patients over 18 years old who received VPA and a CBPM concurrently were enrolled via the pharmacy computer system. Patients who lacked VPA serum concentration measurements before or during CBPMs' use, had concurrent medication(s) that might interfere with VPA metabolism, or had a history of liver cirrhosis were excluded. Total VPA serum concentrations before and during CBPMs' use and after its discontinuation were recorded; and differences among various CBPMs were analyzed.
Fifty-two patients were included in this analysis. Irrespective of the route of administration, VPA serum concentrations were sub-therapeutic in 90% of the subjects during CBPMs' use. There was a significant decrease (p < 0.001) in VPA serum concentrations during the use of CBPMs: 72±17%, 42±22%, and 67±19% in the ertapenem (N=9), imipenem/cilastatin (N=17) and meropenem (N=26) groups, respectively. The effect of ertapenem and meropenem on VPA was significantly more expressed than that of imipenem/cilastatin (p < 0.005). The onset of this drug interaction occurred within 24 hours of CBPMs' administration, and VPA serum concentrations returned to 90% of baseline within seven days of CBPMs' discontinuation along with a 20% increase in VPA dose. Increasing VPA dose during the use of ertapenem or meropenem did not result in elevating VPA serum concentrations to therapeutic levels during the combined therapy period.
CBPMs reduced VPA serum concentration within 24 hours of administration by approximately 60%. Ertapenem and meropenem had a greater effect on VPA serum concentration than imipenem/cilastatin. Because of the dramatic reduction of VPA serum concentration during CBPMs' use, concomitant use of VPA and CBPMs should be avoided.

Miranda Herrero MC, Alcaraz Romero AJ, Escudero Vilaplana V, Fernández Lafever
SN, Fernández-Llamazares CM, Barredo Valderrama E, Vázquez López M, de Castro P.
Pharmacological interaction between valproic acid and carbapenem: what about
levels in pediatrics? Eur J Paediatr Neurol. 2015 Mar;19(2):155-61.

Valproic acid (VPA) is the most commonly used antiepileptic drug in pediatric patients, but its major drawback is its multiple pharmacological interactions.
To study children who had been simultaneously treated with carbapenems and valproic acid, considering drug levels, pharmacological interactions and clinical follow-up.
Retrospective study of children who simultaneously received treatment with VPA and carbapenems between January 2003 and December 2011. Demographic variables, indication of treatment, dose, VPA plasma levels, interactions, clinical manifestations and medical management were analyzed.
28 children with concomitant treatment with both drugs were included in the study. 64.3% were males. 78.6% of the interactions were observed in the Intensive Care Unit. 60.7% of children had been previously treated VPA and its major indication were generalized seizures. Basal plasma levels of VPA were recorded in 53% and at 24 h after admittance in 60%. "40% of basal VPA levels were below therapeutic range prior to the administration of carbapenem. After the introduction of carbapenem 88% of level determinations were below therapeutic range". 54.5% of the patients that were chronically receiving VPA and had good control of epilepsy before admission had seizures during the coadministration. One patient that was on VPA before admission but with bad control of epilepsy worsened, and one patient that acutely received VPA did not achieve seizure freedom. In these cases it was necessary to either increase VPA dose or change to a different antiepileptic drug.

Little is known about the mechanism of pharmacologic interactions between carbapenems and VPA, but it leads to a reduction in plasma levels that may cause a loss of seizure control, so simultaneous use of both drugs should be avoided when possible. If not, VPA levels should be monitored.


  1. On 11/27/12 I had written: For anyone who may not be aware of the valproate/meropenem interaction, there is one. 16 yo on valproate, along with many other antiseizure medications (this is the same patient from messages regarding probably not carbamazepine related leukopenia in the past; he is no longer on carbamazepine, however). VPA 9/11 119.7 total 51.8 free; 9/20 121.5 total 40.1 free; 11/23 after interval of abdominal pain and emesis total 64.6.

    Placed on vancomycin and meropenem for pneumonia. Despite transition to IV valproate, VPA total levels 11/25 18.8, 11/26 25.3 11/27 35.2. Meropenem discontinued 11/26.

    On 1/27/13 I wrote again: Our institution has just had another patient whose valproate levels plummeted after meropenem was coadministered. My colleague called attention to the following abstract. Note the duration of the effect.

    Haroutiunian S, Ratz Y, Rabinovich B, Adam M, Hoffman A. Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study. J Clin Pharmacol. 2009 Nov;49(11):1363-9

    Several case reports indicate that carbapenem antibiotics, especially meropenem, may decrease the plasma concentrations of vaiproic acid (VPA), thus decreasing its therapeutic activity. To investigate the onset, severity, and dose dependency of the interaction between meropenem and VPA, the authors carried out a retrospective evaluation of data collected during 24 months from patients hospitalized in a tertiary medical center.
    The analysis included 36 patients. VPA mean +/- SEM plasma concentration decreased from of 50.8 +/- 4.5 microg/mL to 9.9 +/- 2.1 microg/mL (P < .001) following meropenem administration. After discontinuation of meropenem, VPA plasma concentrations remained low for 7 days and then gradually increased after 8 to 14 days, reaching values comparable to those before meropenem initiation. Different daily VPA doses showed a similar pattern of decreased VPA concentrations. The mean decrease in individual plasma VPA concentration was 82.1%+/- 2.7%. The mean VPA plasma concentration of patients in whom samples were drawn within 24 hours of meropenem initiation was 9.9 +/- 3.2 microg/mL. In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly.

  2. Currently there are 4 proposed mechanisms by which carbapenems may cause an extensive drop in VPA concentrations:

    1. Decreased absorption of VPA secondary to inhibition of intestinal transporters by carbapenems;

    2. Decreased enterohepatic recirculation of VPA due to decreased gut bacterial beta-glucuronidase, which may be disrupted due the broad-spectrum activity of carbapenems;

    3. Increased distribution of VPA into erythrocytes; and

    4. Disruption of the normal metabolism of VPA. (However, any changes in enzymatic functioning would not justify the rapid decline in therapeutic concentrations as this is a slow process and takes time to evolve.)

    It is important for clinicians to understand the clinical significance of this interaction and how to monitor for it. Park and colleagues examined 6 cases of patients who received concomitant VPA and carbapenem antibiotic therapy for a duration ranging from 4 to 25 days. They noted that VPA concentrations fell by an average of 81.2% (range, 67%-92.8%) with the lowest concentration measured between day 4 and day 11. However, the drop may occur earlier in therapy. One patient who did experience breakthrough seizures was receiving nearly a doubled daily dose in an attempt to compensate for the drop in VPA concentrations, illustrating the fact that this interaction may not be able to be "outdosed."

    Mancl and colleagues noted that the decrease in VPA concentrations occurs within the first week of initiation of carbapenem therapy, with some patients recovering quickly after cessation of carbapenem therapy (ie, within 3 days) and others taking longer to reach therapeutic levels of VPA (ie, up to 2 weeks). Tobin and colleagues[3] retrospectively evaluated 6 cases of critically ill patients who received concurrent VPA and carbapenems. The patients had complicated admission diagnoses: 5 required mechanical ventilation, each had underlying liver disease, 1 had renal insufficiency, and 2 others required renal replacement therapy. Five of 6 cases had seizure activity while receiving dual VPA-carbapenem therapy. Estimated clearance of VPA was increased by over 190%; trough concentrations were reduced 58% from baseline. The final patient remained therapeutic but had seizure activity shortly after the initiation of carbapenem therapy.


  3. Park MK, Lim KS, Kim TE, Han HK, Yi SJ, Shin KH, Cho JY, Shin SG, Jang IJ, Yu KS. Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases. Ther Drug Monit. 2012 Oct;34(5):599-603.

    The plasma concentrations of valproic acid (VPA) are known to decrease during the concomitant administration of carbapenem antibiotics, such as meropenem, imipenem, and ertapenem. This study summarizes 6 cases of drug-drug interactions between VPA and carbapenem antibiotics.
    To investigate the onset and severity of the reductions in the concentration of VPA in patients with or without the coadministration of carbapenem antibiotics, the authors performed a retrospective evaluation of therapeutic drug monitoring (TDM) reports that described a decrease in the serum concentrations of VPA during the concomitant use of carbapenem antibiotics from January 2008 to December 2010 in the Seoul National University Hospital. The evaluated TDM reports included 6 cases. The decrement ratio of the VPA serum concentration was calculated from the TDM reports, and the change in the half-life of the VPA was also estimated.
    Six cases presented with changes in the VPA serum concentration before and after the administration of carbapenem antibiotics. (Three cases were treated with meropenem, 2 were treated with ertapenem, and 1 was treated with imipenem.) The VPA concentrations reduced by (mean ± SD) 88.7 ± 5.3% (3 cases of meropenem), 74.0 ± 9.8% (2 cases of ertapenem), and 73.3% (1 case of imipenem), respectively, and the half-life of VPA reduced by 80.1 ± 9.0%, 64.4 ± 24.2%, and 50.6%, respectively.
    The interaction between VPA and carbapenem antibiotics caused decreases in the VPA serum concentrations; the extent of this decrease was greater in the meropenem-treated patients than in the imipenem-treated or ertapenem-treated cases. Because the therapeutic effect of VPA depends on its serum concentration, it should be recognized that there may be a loss of seizure control in patients using VPA with carbapenem antibiotics.

  4. Mancl EE, Gidal BE. The effect of carbapenem antibiotics on plasma
    concentrations of valproic acid. Ann Pharmacother. 2009 Dec;43(12):2082-7.

    To critically evaluate the mechanisms of the interaction between valproic acid and carbapenem antibiotics.
    A PubMed search (January 1971-June 2009) was performed to identify literature on the interaction between valproic acid and carbapenem antibiotics. Additional references were identified through review of bibliographies of identified articles.
    Data on the mechanisms of the interaction between valproic acid and carbapenem antibiotics were extracted from identified references that were published in English.
    Valproic acid plasma concentrations fall markedly during concomitant administration with carbapenem antibiotics due to a combination of absorption, distribution, and metabolism mechanisms. Carbapenems appear to inhibit the intestinal transporter of valproic acid, thereby reducing absorption of orally administered valproic acid. In vivo experiments in rats demonstrate a 57% reduction in absorption of orally administered valproic acid in the presence of imipenem. Follow-up studies in Caco-2 cells suggest that the inhibition probably occurs at the basolateral membrane. In addition, enterohepatic recycling of valproic acid may be diminished due to carbapenem activity against gut flora producing beta-glucuronidase. When rabbits and rats were given intravenous valproic acid-glucuronide, the glucuronide metabolite of valproic acid, 50-90% of the conversion back into valproic acid was inhibited in the presence of a carbapenem. An increase in erythrocyte distribution of valproic acid has also been observed in the presence of carbapenems. After intravenous administration of a carbapenem and valproic acid, valproic acid plasma concentrations fell in the presence of a carbapenem, yet whole blood concentrations of valproic acid did not change significantly. Follow-up studies suggest that the mechanism of this distribution shift is that multidrug resistance proteins on adenosine triphosphate-binding cassette transporters on erythrocyte membranes are inhibited by carbapenems. Thus, valproic acid is not effluxed out of the erythrocytes. Finally, carbapenems may enhance glucuronidation of valproic acid by increasing UDP-glucuronic acid levels. In rats, UDP-glucuronic acid levels increased by 1.7-fold in the presence of panipenem, which was proportionate to the increase in valproic acid-glucuronide formation.
    Published data demonstrate a serious and complex interaction between valproic acid and carbapenem antibiotics. Coadministration should be avoided, but if no other antibiotic therapies exist, it is imperative to monitor valproic acid concentrations more frequently. Clinicians should anticipate higher doses of valproic acid to maintain therapeutic serum concentrations during coadministration and subsequent dose reductions upon discontinuation of the carbapenem antibiotic.