meropenem and Seizures

Encephalopathy is reported to have affected 250,000 people in the United States over the last decade, with considerable morbidity and mortality. Baclofen, a gamma-aminobutyric acid-B agonist that acts on the central nervous system, is the drug most widely used to treat spasticity. Baclofen overdose is a potentially deadly condition that can cause encephalopathy and can result from multiple etiologies. Renal disease can contribute to baclofen overdose and encephalopathy, and there are currently no dosing recommendations for patient's on baclofen with renal impairment.. We report an unusual case of a man aged 35 years who presented with persistent fevers, seizures, and normal mentation. The patient presented with intrathecal baclofen use and prior exposure to West Nile Virus. He developed acute kidney injury at hospital secondary to vancomycin use, and mental status declined.. This case highlights that patients with baclofen overdose can initially appear to have serious brain injury, however, full patient recovery can occur in <72 hours. This case provides additional insight into the guidelines for the treatment and management for unknown cause encephalopathy. This case also highlights the link between renal disease, baclofen, and encephalopathy through a review of the literature.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Baclofen; Brain Diseases; Electroencephalography; Fever; GABA-B Receptor Agonists; Humans; Infusion Pumps, Implantable; Infusions, Spinal; Male; Meropenem; Paraplegia; Seizures; Spasm; Spinal Cord Injuries; Vancomycin

A consensus exists among clinicians that imipenem/cilastatin is the most epileptogenic carbapenem, despite inconsistencies in the literature.. We conducted a meta-analysis of all randomized controlled trials comparing carbapenems with each other or with non-carbapenem antibiotics to assess the risk of seizures for imipenem, meropenem, ertapenem and doripenem.. In the risk difference (RD) analysis, there were increased patients with seizure (2 per 1000 persons, 95% CI 0.001, 0.004) among recipients of carbapenems versus non-carbapenem antibiotics. This difference was largely attributed to imipenem as its use was associated with an additional 4 patients per 1000 with seizure (95% CI 0.002, 0.007) compared with non-carbapenem antibiotics, whereas none of the other carbapenems was associated with increased seizure. Similarly, in the pooled OR analysis, carbapenems were associated with a significant increase in the risk of seizures relative to non-carbapenem comparator antibiotics (OR 1.87, 95% CI 1.35, 2.59). The ORs for risk of seizures from imipenem, meropenem, ertapenem and doripenem compared with other antibiotics were 3.50 (95% CI 2.23, 5.49), 1.04 (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74) and 0.44 (95% CI 0.13, 1.53), respectively. In studies directly comparing imipenem and meropenem, there was no difference in epileptogenicity in either RD or pooled OR analyses.. The absolute risk of seizures with carbapenems was low, albeit higher than with non-carbapenem antibiotics. Although imipenem was more epileptogenic than non-carbapenem antibiotics, there was no statistically significant difference in the imipenem versus meropenem head-to-head comparison.

Topics: Adult; Anti-Bacterial Agents; beta-Lactams; Carbapenems; Child; Cilastatin; Cilastatin, Imipenem Drug Combination; Doripenem; Drug Combinations; Ertapenem; Humans; Imipenem; Meropenem; Risk; Seizures; Thienamycins

The tolerability of the 2 most frequently used carbapenems, imipenem/cilastatin and meropenem, is reviewed. Both of these drugs, but especially imipenem, are potentially neurotoxic and may cause seizures if overdosed relative to renal function and/or bodyweight. The therapeutic margin is considerably narrower with imipenem/cilastatin which cannot be given at doses required for treatment of bacterial meningitis. Meropenem on the other hand, is considerably less prone to cause seizures and its tolerability and efficacy are well documented in 3 relatively large, controlled studies in adults and children with meningitis. They showed that meropenem was as effective and well tolerated as cefotaxime or ceftriaxone. Another potential advantage of meropenem over imipenem/cilastatin is that it can be given intravenously at a high rate without increased risk of nausea or vomiting. An obvious reason for using a carbapenem instead of a cephalosporin for empirical treatment of life-threatening infections is that both imipenem/cilastatin and meropenem have a broader spectrum of activity. They are also more resistant to hydrolysis by the most common beta-lactamases, including the class I cephalosporinase frequently produced by Enterobacter spp. and Pseudomonas spp. and the extended spectrum enzymes, now commonly found in Escherichia coli and Klebsiella spp.

Topics: Adult; Cephalosporins; Child; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Tolerance; Humans; Imipenem; Meningitis, Bacterial; Meropenem; Risk Assessment; Seizures; Thienamycins

Meropenem is a parenteral carbapenem that has been used clinically since 1994. Since the first review of its safety profile in 1995, the patient database has increased substantially. This new safety analysis includes data from 46 clinical trials in hospitalized patients with serious bacterial infections. The additional data comprise patients with lower respiratory tract and intra-abdominal infections, septicaemia and meningitis, and cancer patients with febrile neutropenia, and represents a group of more severely ill patients compared with the earlier review. In total, 4872 patients with 5026 meropenem treatment exposures were compared with 4642 patients treated with comparator agents (4752 exposures). Meropenem was administered most often by intravenous injection at 1g or 500 mg every 8 h. Meropenem-related adverse events most frequently reported were diarrhoea (2.3%), rash (1.4%), nausea/vomiting (1.4%) and injection site inflammation (1.1%). The most commonly reported meropenem-related laboratory adverse events were thrombocytosis (1.6%) and increased hepatic enzymes (1.5-4.3%). In meropenem-treated patients with meningitis, the incidence of seizures was low and none were drug related. In patients with infections other than meningitis, the incidence of seizures considered by the investigators to be related to meropenem was 0.08%. In general, the safety profile of meropenem was similar to that of the comparator agents. Withdrawals and deaths were similarly infrequent in the meropenem, cephalosporin and imipenem-cilastatin groups. Increased doses of meropenem were not associated with an increased incidence of adverse events. Meropenem was well tolerated in all patients, including children and patients with neutropenia. This new analysis supports the previous findings that meropenem has a favourable and acceptable safety profile.

Topics: Adult; Anti-Bacterial Agents; Cephalosporins; Child; Child, Preschool; Clindamycin; Diarrhea; Drug Eruptions; Humans; Imipenem; Meningitis; Meropenem; Nausea; Seizures; Thienamycins; Thrombocytosis

The safety profile of meropenem in the elderly (aged > 65 years, n=843) and/or renally impaired (creatinine clearance < 51 ml/min, n=436) was assessed by evaluating data from 26 phase III studies which compared the use of meropenem (0.5 or 1.0 g, i.v. every 8 h) with other antimicrobial agents in patients with bacterial infections. The overall pattern and frequency of adverse events following meropenem therapy in the elderly and/or renally impaired were similar to those in younger and/or non-renally impaired cohorts and to imipenem/cilastatin and injectable third generation cephalosporins. Both dosages of meropenem (0.5 and 1.0 g, i.v. every 8 h) were generally well tolerated. There was no clinically significant mean change in indicators of renal flux between baseline and the end of treatment in any patient sub-group. Importantly, meropenem-related seizures were rare (0.1%), even in patients with renal impairment. In summary, meropenem has an excellent safety profile and is therefore suitable for use in elderly and/or renally impaired patients.

Topics: Aged; Bacterial Infections; Humans; Kidney Failure, Chronic; Meropenem; Seizures; Thienamycins

Similar to other beta-lactam antibacterials, carbapenems have a neurotoxic potential that seems to be higher than that of the penicillins and cephalosporins. Seizures have been reported in several large studies of patients treated with imipenem/cilastatin. However, it seems clear that the main factor increasing the risk of neurotoxicity with imipenem/cilastatin is administration of excessive dosages relative to bodyweight and/or renal function. If the manufacturer's dosage recommendations are followed, the risk of seizures in patients receiving this combination is minimal. With meropenem, a newly registered carbapenem, the safety margin with respect to neurotoxic reactions has been increased compared with imipenem and meropenem can be used at higher doses than imipenem/cilastatin. Since the neurotoxicity of beta-lactam antibacterials seems to be caused by an interaction with gamma-aminobutyric acid (GABA) receptors, other drugs with a similar mechanism of action, such as fluoroquinolone antibacterials, should be used with caution when combined with carbapenems.

Topics: Animals; Carbapenems; Child; Cilastatin; Humans; Imipenem; Meropenem; Receptors, GABA; Seizures; Thienamycins

Broad-spectrum cephalosporins are drugs of choice for the treatment of meningitis in communities which can afford them. The emergence of cephalosporin-resistant pneumococci demands the clinical trial of alternate agents. Carbapenems are active against the bacteria causing meningitis, but the use of imipenem-cilastatin was frustrated by drug-associated seizures. The safety and efficacy of meropenem, a new carbapenem, were compared to those of cefotaxime in a prospective randomized trial of 190 children with bacterial meningitis. Seizures occurred within 24 h before antibiotic therapy in 16 of 98 patients (16%) randomized to receive meropenem and in 6 of 92 patients (7%) randomized to receive cefotaxime. In patients without seizures before therapy, seizures occurred during therapy in 5 of 82 patients (6%) receiving meropenem and in 1 of 86 patients (1%) receiving cefotaxime (95% confidence interval: -0.7%, 10.6%). None were thought to be drug related. Twenty-four meropenem-treated patients (24%) and 11 cefotaxime-treated patients (12%) had neurological abnormalities before therapy. In patients without pretherapy neurological abnormalities, these abnormalities were present after treatment in 4 of 74 meropenem-treated patients (5%) and in 2 of 81 cefotaxime-treated patients (2%) (95% confidence interval: -3.2%, 9.1%). Of 75 meropenem-treated and 64 cefotaxime-treated patients with pretherapy positive cerebrospinal-fluid cultures, 68 and 59, respectively, had repeat lumbar punctures. Bacterial eradication was found to be 100% in both groups. Our data suggest that meropenem may be a carbapenem agent that is well tolerated and effective in the treatment of bacterial meningitis.

Topics: Adolescent; Cefotaxime; Child; Child, Preschool; Dexamethasone; Female; Hearing Tests; Humans; Infant; Male; Meningitis, Bacterial; Meropenem; Nervous System Diseases; Prospective Studies; Seizures; Thienamycins; Treatment Outcome

Clinical experience suggests higher occurrence of carbapenem-associated seizures in the elderly than what is reported in the available literature (range between 0.2% and 0.7%). An audit of 1345 patients with age 60 years or older, who received imipenem, ertapenem or meropenem during their acute hospitalisation found 32 (2.4%) subjects developed seizures. Subjects with more than one central nervous system disorders were 11.6 times more likely to develop seizures (odds ratio 11.61, P < 0.001) and subjects with prior history of seizures is associated with four times greater risks (odds ratio 4.02, P = 0.005). Physicians should exercise caution when prescribing carbapenems in elderly, especially those with known epilepsy and a high number of intracranial pathologies.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactams; Carbapenems; Ertapenem; Female; Hospitalization; Humans; Imipenem; Logistic Models; Male; Meropenem; Seizures; Singapore

Seizures caused by beta-lactam antibiotics are relatively rare. However, they represent a clinically significant phenomenon and have been widely reported in all age groups. Here we describe two infants presenting subtle multifocal seizures with a migrating aspect on EEG during beta-lactam antibiotic treatment with agents from the carbapenem group (meropenem) and the cephalosporin group (ceftazidime).

Topics: Anti-Bacterial Agents; Carbapenems; Humans; Infant; Meropenem; Seizures

The antibiotics cefepime and meropenem are recommended for the treatment of neutropenia. However, cefepime has been found to be associated with both peripheral and central adverse events such as renal impairment and seizures, respectively. Previous studies showed that cefepime exacerbated convulsions in corneal kindled mouse models of epilepsy. However, its involvement in chemotherapy-induced side effects is unknown.. In this study, we examined the convulsive potential of cefepime (500 mg/kg) and meropenem (500 mg/kg) in pentylenetetrazol (PTZ)-kindled mice using an electroconvulsive shock test with low-intensity stimulus currents. Then, the effects of 5-fluorouracil (5-FU, 200 and 400 mg/kg, i.p.) treatment, a model of chemotherapy-induced side effects, were investigated in the PTZ-kindled mouse model.. In fully PTZ-kindled mice, intravenous administration of cefepime (500 mg/kg) or meropenem (500 mg/kg) did not elicit any convulsions in the electroconvulsive shock test with low-intensity stimulus currents. In the PTZ-kindled mice treated with 5-FU (200 mg/kg), intravenous administration of cefepime (500 mg/kg) exacerbated the convulsions that occurred within 1 min in the electroconvulsive shock test, and the mice subsequently developed convulsive status epilepticus. However, intravenous administration of meropenem (500 mg/kg) did not produce such effects.. These findings suggest that the combination of 5-FU and cefepime exacerbates early-onset convulsive seizures and elicits delayed-onset convulsive status epilepticus. Additionally, 5-FU treatment increases the risk of induction of neurotoxic side effects by cefepime.

Topics: Animals; Anti-Bacterial Agents; Cefepime; Convulsants; Disease Models, Animal; Fluorouracil; Kindling, Neurologic; Male; Meropenem; Mice; Mice, Inbred ICR; Pentylenetetrazole; Seizures

Topics: Aged; Anti-Bacterial Agents; Craniotomy; Drug Resistance, Multiple, Bacterial; Empyema; Enterobacteriaceae Infections; Humans; Male; Meningeal Neoplasms; Meropenem; Piperacillin, Tazobactam Drug Combination; Postoperative Complications; Seizures; Spinal Puncture; Staphylococcal Infections; Surgical Wound Infection; Treatment Outcome; Vancomycin

Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).

Topics: Animals; Anti-Bacterial Agents; Aztreonam; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; CHO Cells; Cricetulus; Drug Stability; Escherichia coli; Female; Humans; Meropenem; Mice; Microbial Sensitivity Tests; Molecular Structure; Monobactams; Pseudomonas aeruginosa; Receptors, GABA-A; Seizures; Structure-Activity Relationship; Thienamycins

β-lactam antibiotics may necessitate higher than licensed drug doses to achieve therapeutic exposures in critically ill patients. Therapeutic drug monitoring can be used to guide dosing so as to maximise therapeutic effect whilst reducing the likelihood of exposure-related toxicity.. A retrospective review of critically ill patients identified those that received higher than licensed doses of either meropenem (3-6 g/day) or piperacillin-tazobactam (16 g-2 g/day) (i.e. high-dose group) guided by therapeutic drug monitoring. β-lactam-associated toxicities were compared with a patient group of similar age, sex, body mass index and admission diagnosis that received licensed doses of either antibiotic.. Mean daily doses were more than 40% higher in the high-dose groups for each antibiotic. There were no significant differences between the high-dose and licensed-dose groups in terms of hepatocellular derangement (17.9% vs. 31.8%, P=0.25 for meropenem and 17.4% vs. 16.0%, P=0.90 for piperacillin-tazobactam), cholestasis (28.0% vs. 13.6%, P=0.32 for meropenem and 13.0% vs. 4.0%, P=0.26 for piperacillin-tazobactam), need for continuous renal replacement therapy (0% vs. 9.1%, P=0.10 for meropenem and 0% vs. 8.0%, P=0.16 for piperacillin-tazobactam), seizure incidence (7.1% vs. 4.5%, P=0.70 for meropenem and nil for either piperacillin-tazobactam group), thrombocytopenia (9.1% vs. 10.7%, P=0.85 for meropenem and 4.0% vs. 4.3% for piperacillin-tazobactam), or neutropenia (4.5% vs. 3.6%, P=0.95 for meropenem and 0.0% vs. 4.3% for piperacillin-tazobactam).. Higher than licensed doses of meropenem and piperacillin-tazobactam guided by therapeutic drug monitoring were not associated with additional toxicities. Larger prospective studies are required to confirm the clinical utility of higher than licensed dosing.

Topics: Adult; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Chemical and Drug Induced Liver Injury; Cholestasis; Critical Illness; Drug Monitoring; Female; Humans; Male; Meropenem; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Renal Replacement Therapy; Retrospective Studies; Seizures; Thienamycins; Thrombocytopenia

We have reported significantly higher convulsion prevalence in patients treated with cefepime than in those treated with meropenem. Additionally, cefepime-associated convulsions were found only in patients with brain disorders, not renal failure. Here, we compared the convulsive liability of cefepime and meropenem administered intravenously in normal and corneal kindled mice with low seizure thresholds. We used the proconvulsive test in normal mice following pentylenetetrazol (PTZ) injection and electroconvulsive shock at low-stimulus currents and in corneal kindled mice. We also measured electroencephalogram (EEG) activity 1 min after antibiotic injections. Intravenous injection of cefepime and meropenem at 250 or 500 mg/kg of body weight had no effect on PTZ-induced convulsions in normal mice. However, in convulsions induced by electroconvulsive shock at low-stimulus currents, mean seizure stage following cefepime administration at 500 mg/kg was significantly higher than that following saline injection. Additionally, EEG spikes were recorded for mice that were given cefepime (500 mg/kg). In corneal kindled mice following cefepime injection, mean seizure stage was significantly higher than that following meropenem injection. The convulsive liability of cefepime is significantly higher than that of meropenem in normal and corneal kindled mice. In patients with low seizure thresholds, convulsive liability of cefepime may be assumed.

Topics: Animals; Anti-Bacterial Agents; Cefepime; Cephalosporins; Convulsants; Disease Susceptibility; Drug Administration Schedule; Electroencephalography; Electroshock; Injections, Intravenous; Male; Meropenem; Mice; Mice, Inbred ICR; Pentylenetetrazole; Seizures; Severity of Illness Index; Species Specificity; Thienamycins

We sought to evaluate the safety of imipenem and meropenem in the treatment of infections in neurosurgical patients.. An observational retrospective study was conducted of consecutive cases treated with imipenem from Sept. 2007 to Sept. 2009 and meropenem within 1 year from Sept. 2008 in Beijing Tiantan Hospital, China. Data including the dosage and duration of the drug use, occurrence of seizures and mortality outcome was collected from the electronic pharmacy records. The incidence of epilepsy, epileptic standardized morbidity rate (SMR) were reported. Attention was paid to the relationship between the use of imipenem/meropenem and the incidence of epilepsy.. The imipenem patients within two years amounted to 71, with mean age 45.9±20.2 years, male to female ratio 46/25. The incidence of epilepsy was 11.3% (8 cases). Among them, 1 case occurred during treatment (1/633, 1.6/1000 patient-days), and the remaining 7 cases occurred before treatment (7/2819, 2.5/1000 patient-days), with the standardized incidence rate 0.64, 95% CI (0.08-5.18).The meropenem patients within one year amounted to 92, mean age 45.1±19.4 years, male to female ratio 51/41. The incidence of epilepsy was 6.5% (6 cases). 2 occurred during treatment (2/582, 2.0/1000 patients-hospital days) and 4 before treatment (4/2047, 3.4/1000 patients-inpatient days), standardized incidence rate 1.76, 95% CI (0.32-9.63).. Despite many other epileptogenic factors, imipenem or meropenem did not increase the risk of seizures in neurosurgical patients. There was not further risk for patients with pre-existing seizures or creatinine clearance abnormalities when dosed appropriate.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Child; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Incidence; Male; Meropenem; Middle Aged; Retrospective Studies; Seizures; Thienamycins; Young Adult

Topics: Aged, 80 and over; Anti-Bacterial Agents; Anticonvulsants; Drug Interactions; Female; Humans; Meropenem; Seizures; Thienamycins; Valproic Acid

The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime).. The maximum dose of cefepime in the USA (6 g per day) is higher than that in Japan (4 g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem.. A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2 years at Ehime University Hospital. Cefepime or meropenem-associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem.. The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders.. Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime-associated convulsions.

Topics: Adult; Aged; Anti-Bacterial Agents; Brain Diseases; Cefepime; Cephalosporins; Female; Hospitals, University; Humans; Infusions, Intravenous; Japan; Male; Meropenem; Neurotoxicity Syndromes; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Renal Insufficiency; Retrospective Studies; Risk; Seizures; Staphylococcal Infections; Staphylococcus aureus; Thienamycins

Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin.. We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness.. Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days versus 40.7/1000 infant days, P < 0.001). There was no difference in seizures with meropenem versus imipenem/cilastatin (adjusted odds ratio 0.96; 95% confidence interval: 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use-odds ratio 0.68 (0.50, 0.88) and odds ratio 0.77 (0.62, 0.95), respectively.. In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.

Topics: Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Cohort Studies; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Humans; Imipenem; Incidence; Infant; Intensive Care, Neonatal; Meropenem; Retrospective Studies; Seizures; Survival Analysis; Thienamycins

The pharmacological interaction between meropenem and valproic acid is potentially serious, especially in critically ill patients, resulting in low plasmatic levels of the anticonvulsant. However, to our knowledge, this interaction between meropenem and reduced valproic acid plasma levels has not been reported in the pediatric chilean population. We present two clinical cases of chilean children, thus reporting that this interaction is present in our population, with an aim at educating physicians about the possibility of such interaction.

Topics: Anticonvulsants; beta-Lactamase Inhibitors; Child, Preschool; Drug Interactions; Epilepsy; Fatal Outcome; Female; Humans; Infant; Meropenem; Seizures; Thienamycins; Valproic Acid

Both valproic acid and levetiracetam are anti-epileptic drugs, often used either alone or in combination. The present study compares valproate (VPA) with levetiracetam (LEV) as an intravenous (i.v.) anticonvulsant treatment in intensive care patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) with a high risk of seizures.. A prospective, single-center patient registry of 35 intensive care unit (ICU) patients with onset seizure and/or high risk of seizures underwent an anticonvulsive, first-line single treatment regimen either with VPA or LEV. Plasma concentrations (pc), interactions between drugs in the ICU context, adverse effects and seizure occurrences were observed and recorded.. A significant decrease in the pc in patients treated with LEV was observed after changing from intravenous (160±51μmol/l) to enteral liquid application (113±58μmol/l), corresponding to a 70.3% bioavailability for enteral liquid applications. The pc in VPA patients decreased significantly, from (491±138μmol/l) to (141±50μmol/l), after adding meropenem to the therapy (p<0.05). Three epileptic seizures occurred during anticonvulsive therapy in the LEV group, and two in the VPA group, including one non-convulsive status epilepticus (NCSE).. Though this finding needs further verification, the enteral liquid application of levetiracetam seems to be associated with lower bioavailability than the common oral application of levetiracetam. The use of the antibiotic drug meropenem together with valproic acid leads to lower pc levels in patients treated with of valproic acid. For clinical practice, this indicates the need to monitor the levels of valproic acid in combination with meropenem.

Topics: Administration, Oral; Aged; Aneurysm, Ruptured; Anti-Bacterial Agents; Anticonvulsants; Biological Availability; Brain Ischemia; Critical Care; Drug Interactions; Enteral Nutrition; Epilepsy; Female; Humans; Intensive Care Units; Levetiracetam; Male; Meropenem; Middle Aged; Piracetam; Prospective Studies; Seizures; Subarachnoid Hemorrhage; Thienamycins; Valproic Acid

There has been a resurgence of interest in the use of colistin for the treatment of multidrug-resistant Gram-negative bacterial infections. A more favorable infection outcome is observed when colistin is used in combination with carbapenems. We present a patient with severe New Delhi metallo-β-lactamase-1 Escherichia coli infection who developed convulsions rapidly followed by acute respiratory muscle weakness and apnoea during treatment with colistin and meropenem. Chromatographic assay showed a "trough" colistin level that was approximately fourfold higher than previously reported maximum steady-state colistin plasma levels in critically ill patients. The patient's renal clearance never necessitated dose adjustments, suggesting that the observed high plasma colistin level might be due to impaired non renal elimination. Although meropenem itself has very low neurotoxic potential, its concomitant use with colistin may have elicited colistin neurotoxicity.

Topics: Anti-Bacterial Agents; Apnea; beta-Lactamases; Chromatography; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Humans; Male; Meropenem; Middle Aged; Plasma; Seizures; Thienamycins

Meropenem is a carbapenem with a broad spectrum of activity against beta-lactamase-producing organisms. Valproic acid is widely used in the treatment of generalized tonic-clonic and partial seizures. Concomitant administration of meropenem and valproic acid reportedly leads to a rapid decline in serum concentrations of valproic acid, which is sometimes associated with seizures.. This report describes an 85-year-old Chinese male inpatient who twice received concomitant administration of meropenem and valproic acid for the treatment of pneumonia and poststroke epilepsy, respectively. Rapid declines in valproic acid concentrations were observed both times after meropenem administration. No seizures occurred in the first treatment period; however, when the patient suffered pneumonia again 3 months later, the same concomitant therapy was prescribed, and seizures occurred. It is difficult to identify a single etiology of the seizures. Based on a score of 7 on the Naranjo adverse drug reaction probability scale, the seizures were considered to be probably related to the concomitant administration of meropenem and valproic acid.. Various factors make the effect of concomitant administration of meropenem and valproic acid unpredictable, even in the same patient. Caution should be used when administering meropenem and valproic acid concomitantly, especially in elderly patients with central nervous system disorders, even if the patient has had a successful prior experience with these 2 drugs. If concomitant administration is essential, very close serum concentration monitoring and clinical observation are necessary.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Anticonvulsants; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Humans; Male; Meropenem; Pneumonia; Seizures; Thienamycins; Treatment Outcome; Valproic Acid

To compare clinical outcomes of patients receiving an alternative dosage of meropenem with those of patients receiving imipenem-cilastatin or the traditional dosage of meropenem after failure of or intolerance to cefepime for treatment of febrile neutropenia.. Retrospective, single-center cohort study.. 1250-bed urban academic medical center.. One hundred twenty-seven adults with neutropenic fever who received either imipenem-cilastatin or meropenem; imipenem-cilastatin was the preferred carbapenem until September 1, 2006, after which meropenem became the formulary carbapenem.. Of the 127 patients, 40 received imipenem-cilastatin 500 mg every 6 hours between September 1, 2005, and August 31, 2006; 87 patients received meropenem between September 1, 2006, and August 31, 2007: 29 received a traditional dosage of meropenem 1 g every 8 hours, and 58 received an alternative dosage of meropenem 500 mg every 6 hours. Primary outcomes of time to defervescence (median 3 vs 2 vs 3 days), need for additional antibiotics (20% vs 17% vs 14%), and time to receipt of additional antibiotics (median 5 vs 2 vs 1 days) were not significantly different among the imipenem-cilastatin, traditionally dosed meropenem, and alternatively dosed meropenem groups, respectively. In addition, significant differences in secondary outcomes, which were treatment duration (median 10 vs 8 vs 8 days), seizure rate (0% vs 0% vs 0%), in-hospital mortality (5% vs 7% vs 7%), and 30-day mortality (13% vs 7% vs 14%), were not identified among the three groups, respectively.. The alternative meropenem dosage of 500 mg every 6 hours yielded similar patient outcomes, including time to defervescence, need for additional antibiotics, duration of therapy, and mortality, when compared with the traditional meropenem dosage and imipenem-cilastatin in adults with febrile neutropenia. In addition, no adverse effects on clinical outcomes were observed with the alternative dosage of meropenem.

Topics: Adult; Anti-Bacterial Agents; Cefepime; Cephalosporins; Cilastatin; Cilastatin, Imipenem Drug Combination; Cohort Studies; Dose-Response Relationship, Drug; Drug Combinations; Female; Fever; Hospital Mortality; Humans; Imipenem; Male; Meropenem; Middle Aged; Neutropenia; Retreatment; Seizures; Thienamycins; Time Factors

Topics: Adolescent; Anti-Bacterial Agents; Epilepsies, Myoclonic; Female; Humans; Meropenem; Seizures; Thienamycins

beta-Lactam antibiotics have been suggested to have some degree of convulsive activity and neurotoxicity in experimental animals as well as in clinical situations. We examined the convulsive activities of a new carbapenem antibiotic, (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxic acid monohydrate (doripenem) using several animals and compared them with beta-lactam antibiotics. In intravenous (IV) injection studies, imipenem/cilastatin, at 400/400mg/kg produced seizure discharges on electroencephalogram (EEG) accompanied with clonic convulsions in rats. Meropenem showed only wet dog shaking behavior at 200 and 400mg/kg. Doripenem caused no changes in the EEG and behavior in rats at 400mg/kg. Imipenem/cilastatin IV potentiated the pentylenetetrazol (PTZ)-induced convulsions in mice at 250/250 mg/kg, while meropenem, panipenem/betamipron, cefazolin or doripenem did not cause any marked effects at up to 500 mg/kg. In mouse intracerebroventricular (ICV) injection studies, imipenem, panipenem and cefazolin induced clonic convulsions in a dose-dependent manner in mice. Doripenem and meropenem did not induce convulsions at up to 100 microg/mouse. In dog ICV injection studies, imipenem produced generalized seizure discharge with clonic convulsions at 100 microg/dog. Meropenem also produced spikes or seizure discharges at 100, 300 and 1,000 microg/dog. However, doripenem had no effects on the EEG and behavior in dogs at any doses. In in vitro binding studies, imipenem, panipenem, cefazolin and meropenem inhibited [(3)H]muscimol binding to the GABA(A) receptor in mouse brain homogenates while doripenem did not cause any inhibition at up to 10mM. In addition, doripenem had no influence on the anti-convulsant actions of valproic acid in the PTZ- or bicuculine-induced convulsive model. These results clearly indicate that doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.

Topics: Alanine; Animals; Anti-Bacterial Agents; Anticonvulsants; Carbapenems; Convulsants; Dogs; Doripenem; Drug Interactions; Electroencephalography; Injections, Intravenous; Injections, Intraventricular; Male; Meropenem; Mice; Mice, Inbred ICR; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Thienamycins; Valproic Acid

To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures.. A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged.. Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient.. This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Anticonvulsants; Drug Interactions; Epilepsy; Female; Humans; Infusions, Intravenous; Meropenem; Seizures; Thienamycins; Valproic Acid

Topics: Adult; Aged; Anticonvulsants; Drug Interactions; Humans; Male; Meropenem; Seizures; Sepsis; Thienamycins; Valproic Acid

Topics: Animals; Carbapenems; Central Nervous System; Haemophilus influenzae; Humans; Meningitis, Bacterial; Meropenem; Neurotoxicity Syndromes; Randomized Controlled Trials as Topic; Seizures; Thienamycins

The safety profile of meropenem in the elderly (aged > 65 years, n = 843) and/or renally impaired (creatinine clearance < 51 ml/min, n = 436) was assessed by evaluating data from 26 phase III studies which compared the use of meropenem (0.5 or 1.0 g, i.v. every 8 h) with other antimicrobial agents in patients with bacterial infections. The overall pattern and frequency of adverse events following meropenem therapy in the elderly and/or renally impaired were similar to those in younger and/or non-renally impaired cohorts and to imipenem/cilastatin and injectable third generation cephalosporins. Both dosages of meropenem (0.5 and 1.0 g, i.v. every 8 h) were generally well tolerated. There was no clinically significant mean change in indicators of renal flux between baseline and the end of treatment in any patient sub-group. Importantly, meropenem-related seizures were rare (0.1%), even in patients with renal impairment. In summary, meropenem has an excellent safety profile and is therefore suitable for use in elderly and/or renally impaired patients.

Topics: Aged; Bacterial Infections; Humans; Kidney Failure, Chronic; Meropenem; Seizures; Thienamycins

Since carbapenems and cephalosporins have been suggested to induce convulsive side effects through an inhibitory action on the central gamma-aminobutyric acid (GABA)-mediated inhibitory transmission, the present study evaluated the convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)-1-hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4thiomorpholin ylcarbonyl)pyrrolidin-3-thio]-l-methylcarbapen-2-em-3- carboxylic acid (DK-35C) in in vitro and in vivo experiments, in comparison with cefazolin, imipenem and meropenem. In in vitro experiments, their abilities to inhibit [3H]muscimol (5 nM) binding to GABA(A) receptors were measured using crude synaptic membranes prepared from the rat cerebral cortex. The concentrations (mM) of the antibiotics which inhibit 50% of the specific binding, were 0.6 for imipenem, 1.8 for cefazolin, 15.4 for DK-35C and 27.6 for meropenem. In in vivo experiments, intracerebroventricular (i.c.v.) injections of cefazolin, imipenem and DK-35C induced convulsions in a dose-dependent manner in rats. The doses (nmol/rat) of the antibiotics which induce convulsions in 50% of rats, were 57 for imipenem, 96 for cefazolin, 377 for DK-35C and >3000 for meropenem. In the mouse pentylenetetrazole (PTZ) convulsive model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200 mg/kg) shifted the dose-response curve of PTZ (i.p.) to the left, indicating enhancement of the convulsive activity of PTZ. However, pretreatment with cefazolin, meropenem or DK-35C at a dose of 400 mg/kg did not produce any marked effects on the convulsive activity of PTZ compared with the saline vehicle-pretreated control. The results clearly demonstrate a good correlation between in vitro GABA(A) receptor binding assay and in vivo i.c.v. convulsive model using rats, and suggest that DK-35C may possess a relatively weak convulsive activity mediated through an interaction with GABA(A) receptors.

Topics: Animals; Carbapenems; Cefazolin; Cephalosporins; GABA Agonists; Imipenem; Injections, Intraventricular; Male; Meropenem; Mice; Mice, Inbred ICR; Muscimol; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Synaptic Membranes; Thienamycins

Topics: Animals; Drug Approval; Humans; Imipenem; Incidence; Meropenem; Seizures; Thienamycins; United States; United States Food and Drug Administration

The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.

Topics: Analysis of Variance; Animals; Binding, Competitive; Cilastatin; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Imipenem; Injections, Intravenous; Male; Meropenem; Mice; Muscimol; Pentylenetetrazole; Rats; Receptors, GABA-A; Seizures; Thienamycins

The neurotoxicity of meropenem was much lower than that of both imipenem and panipenem after intraventricular administration to mice. To clarify the major structural features responsible for the induction of convulsions by carbapenem antibiotics, the structure-activity relationship on convulsant activity was investigated in N-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compounds with strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gamma aminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediated inhibitory transmission. However, the in vivo convulsant activity of some of these compounds did not correlate with their in vitro inhibitory effect on GABAA receptor binding.

Topics: Animals; Imipenem; Meropenem; Mice; Mice, Inbred ICR; Receptors, GABA; Seizures; Structure-Activity Relationship; Thienamycins

Topics: Animals; Anti-Bacterial Agents; Brain; Imipenem; Incidence; Injections, Intraventricular; Meropenem; Mice; Seizures; Structure-Activity Relationship; Thienamycins

The proconvulsive tendency of the novel carbapenem, meropenem was compared to that of imipenem, alone and in combination with cilastatin. The potentiation of metrazole-induced convulsions in mice was measured. Both imipenem and imipenem/cilastatin caused significant potentiation of metrazole-induced convulsions at a dose of 200 mg/kg, i.v. In contrast, meropenem (50-400 mg/kg, iv) failed to exhibit any significant potentiation of metrazole-induced seizures.

Topics: Animals; Carbapenems; Cilastatin; Imipenem; Male; Meropenem; Mice; Seizures; Thienamycins