cilastatin--imipenem-drug-combination and Seizures

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

Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that in patients with severe pneumonia, monotherapy with ciprofloxacin is at least equivalent to monotherapy with imipenem in terms of bacteriological eradication and clinical response. For both treatment groups, the presence of P. aeruginosa had a negative impact on treatment success. Seizures were more common with imipenem than with ciprofloxacin. Monotherapy for severe pneumonia is a safe and effective initial strategy but may need to be modified if P. aeruginosa is suspected or recovered from pat

Topics: Adult; Aged; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Double-Blind Method; Drug Combinations; Drug Resistance, Microbial; Female; Hospitalization; Humans; Imipenem; Injections, Intravenous; Male; Middle Aged; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Regression Analysis; Seizures

The safety and efficacy of imipenem/cilastatin were evaluated in 21 children, ages 3 to 48 months, with bacterial meningitis. Eradication of bacteria from the cerebrospinal fluid was demonstrated within 24 hours of antibiotic therapy in all but 2 patients who had Haemophilus influenzae type b meningitis and ultimately achieved bacteriologic cure after 2 to 3 days of imipenem/cilastatin therapy. Cerebrospinal fluid penetrations of imipenem and cilastatin were determined at various times after drug administration with mean cerebrospinal fluid: serum ratios of 14 and 10% for imipenem and cilastatin, respectively. The study was terminated when 7 (33%) patients developed seizure activity after antibiotic therapy was administered. The usefulness of imipenem/cilastatin for the treatment of bacterial meningitis in children may be limited by a possible increased incidence of drug-related seizure activity.

Topics: Anti-Bacterial Agents; Bacterial Infections; Child, Preschool; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Infant; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Retrospective Studies; Seizures

Observations on 1,754 patients treated with imipenem/cilastatin in phase III dose-ranging studies in the United States were reviewed to determine risk factors for seizures. The patients were moderately to severely ill with numerous background disorders known to be associated with an increased risk of seizures. Fifty-two patients (3 percent) had seizures and in 16 (0.9 percent) of them the seizures were judged by the investigators to be possibly, probably, or definitely related to imipenem/cilastatin. An incidence of seizure of 2 to 3 percent was noted among patients treated with other antibiotics (usually including a beta-lactam in the regimen) at times when imipenem/cilastatin was not being given. The average time of onset of seizures for patients receiving imipenem/cilastatin was seven days after start of therapy. As with other beta-lactam antibiotics, central nervous system lesions and disorders including seizures and renal insufficiency were found to be strong risk factors for seizures. Imipenem/cilastatin dosages in excess of those currently recommended by the manufacturer, particularly in patients with renal insufficiency, were also associated with an increased risk of seizures. There was an association with Pseudomonas aeruginosa infection that remained statistically significant even after controlling for imipenem/cilastatin dosage as well as for the other factors indicated. A high background incidence of seizures in general in a group of severely ill patients makes it both difficult to assess the etiology of a seizure and important to consider the risk factors when choosing the appropriate dose of an antibiotic. Guidelines are presented for appropriate dosing of imipenem/cilastatin in relation to renal function, body weight, and infecting pathogen.

Topics: Anti-Bacterial Agents; Bacterial Infections; Body Weight; Central Nervous System Diseases; Cilastatin; Cilastatin, Imipenem Drug Combination; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Female; Humans; Imipenem; Kidney Function Tests; Male; Regression Analysis; Retrospective Studies; Risk Factors; Seizures; Thienamycins; Time Factors; United States

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

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

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

Tebipenem pivoxil (TBPM-PI), the first oral carbapenem antibiotic both in Japan and abroad, was examined on its convulsive liability. We used ICR male mice and Sprague-Dawley male rats to examine the pro-convulsive effect and anticonvulsive effect of TBPM-PI and its active metabolite, TBPM. (1) When mice were treated with TBPM-PI (30-1000 mg/kg, p.o.) or TBPM (10-300 mg/kg, i.v.), no convulsion was noted at any dose level. When rats were treated with TBPM (300 mg/kg, i.v.), no convulsant effects were noted in electroencephalography or behavioral observation. In intraventricular injection of TBPM in mice, clonic convulsion was observed in 7/10 animals at 100 microg but no effect at 30 microg. On the other hand, the administration of 10/10 microg imipenem/cilastatin (IPM/CS) resulted in clonic convulsion in all animals and tonic convulsion in 3/10 animals, and 4/10 animals died. The administration of 100 microg meropenem did not cause any effects. (2) When mice were co-administered with pentylenetetrazole (45 mg/kg: maximum dose level at which no convulsion is induced) and TBPM-PI (30-300 mg/kg, p.o.) or TBPM (300 mg/kg, i.v.), convulsion enhancing effect was not noted. On the other hand, the co-administration of pentylenetetrazole with IPM/CS (300/300 mg/kg, i.v.) enhanced a convulsive effect of pentylenetetrazole. (3) When mice were treated with TBPM-PI (30-300 mg/kg, p.o.) or TBPM (100 mg/kg, i.v.), inhibitory effect was not noted on convulsions induced by electrostimulation, pentylenetetrazole or strychinine. In conclusion, there were no pro-convulsive effects or anticonvulsive effect in the oral administration of TBPM-PI or intravenous administration of TBPM. Pro-convulsive effect was observed in the intraventricular injection of TBPM as in the case of other carbapenem antibiotics, but such action was weaker than that in IPM/CS administration. Accordingly, the risk of occurrence of convulsion related to TBPM-PI administration was low compared to IPM/CS administration, and TBPM-PI was considered to be less potential to induce convulsions in clinical use.

Topics: Administration, Oral; Animals; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Imipenem; Infusions, Intravenous; Injections, Intraventricular; Male; Mice; Pentylenetetrazole; Rats; Seizures

Epileptic seizures have been reported in patients on imipenem/cilastatin (Imi/Cil) therapy. To investigate contribution of N-methyl-D-aspartate (NMDA) receptors in inducing imipenem/cilastatin (Imi/Cil) seizures, the effects of competitive NMDA antagonist, APV [(+/-)-2-amino-5-phosphonovaleric acid], non-competitive NMDA antagonist remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamidel, and glycine receptor partial agonist HA-966 [(+/-)-(3-amino-1-hydroxypyrrolid-2-one)] on electroencephalographic (EEG) activity and behaviour were studied in rats.. Adult male Wistar albino rats were implanted with electrodes and cannulae were placed into the right lateral ventricle. Animals were divided into five groups: (i) saline (icv)+Imi/Cil (ii) APV (0.2 micromol)+Imi/Cil, (iii) APV (0.4 micromol)+Imi/Cil, (iv) remacemide (100 mg/kg, ip)+Imi/Cil, and (v) HA-966 (200 microg, icv)+Imi/Cil. The drugs were administered 30 min before icv injection of Imi/Cil (100/100 microg), and their effects on incidence of seizures, latencies to EEG changes and convulsions, severity, lethality and time to lethal outcome were studied.. Imi/Cil provoked complete seizure response in all rats and all animals died within 10-18 min after the injection. EEG epileptiform activity preceded behavioral seizures. Clonic-tonic seizures were characterized by continuous bursts of high frequency high amplitude spikes in the EEG. The dose of 0.2 micromol of APV prolonged only the latency to the first EEG changes, while 0.4 micromol dose significantly influenced all seizure parameters. HA-966 increased only the latency to Imi/Cil-induced convulsions, while remacemide had no significant effect on seizure parameters.. The results suggested that excitatory neurotransmission contributed to the generation and/or propagation of Imi/Cil-induced seizures in rats, and that the effects of NMDA antagonists depended on a particular binding site within the NMDA receptor complex, and affinity to that site.

Topics: Acetamides; Animals; Binding Sites; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Electroencephalography; Imipenem; Male; Pyrrolidinones; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Valine

Convulsant activity of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, in combination with nonsteroidal anti-inflammatory drug (NSAID) was investigated in mice after intravenous or intracerebroventricular administration. Following results were obtained. 1. In combination with 4-biphenylacetic acid (BPAA) at an oral dose of 100 mg/kg, PZFX mesilate did not induce any convulsions at intravenous doses up to 200 mg/kg. Reference quinolones induced convulsions at the following intravenous doses: Enoxacin (ENX), 3.13 mg/kg or more; norfloxacin (NFLX) and lomefloxacin (LFLX), 6.25 mg/kg or more; ciprofloxacin (CPFX), 50 mg/kg or more; sparfloxacin (SPFX) and temafloxacin (TMFX), 100 mg/kg or more; fleroxacin (FLRX), 200 mg/kg. 2. PZFX mesilate at an intravenous dose of 50 mg/kg did not induce convulsions in mice after oral administration of any of 14 kinds of NSAIDs. It induced convulsions at 200 mg/kg in combination with aspirin at an oral dose of 600 mg/kg, while it did not with the other 13 kinds of NSAIDs. 3. Convulsion-inducing dose of PZFX mesilate after intracerebroventricular administration was 100 mg/body, which was higher than those of reference quinolones (NFLX, CPFX, ENX, LFLX, TMFX, levofloxacin, ofloxacin, FLRX and SPFX) and beta-lactam antibiotics (penicillin G, cefazoline, imipenem/cilastatin and panipenem/betamipron). In addition, concurrent dosing of BPAA (1 microgram/body) did not reduce the convulsion-inducing dose of PZFX mesilate. These results suggest that PZFX mesilate has remarkably weak convulsant activity.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; beta-Alanine; Biphenyl Compounds; Cefazolin; Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Convulsants; Drug Combinations; Drug Interactions; Enoxacin; Fleroxacin; Fluoroquinolones; Imipenem; Injections, Intravenous; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Norfloxacin; Oxazines; Penicillin G; Quinolones; Seizures; Thienamycins

Topics: Adult; Aged; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Therapy, Combination; Humans; Imipenem; Male; Middle Aged; Risk Factors; Seizures

Topics: Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Delivery Systems; Drug Monitoring; Drug Therapy, Combination; Humans; Imipenem; Risk Factors; Seizures

To develop computerized methods to monitor and recommend dosage changes for patients treated with excessive dosages of imipenem/cilastatin (I/C) and to determine the incidence of I/C-associated seizures in our patient population.. Prospective observational and interventional study of all patients admitted to LDS Hospital and treated with I/C from May 1, 1987, through June 30, 1991.. LDS Hospital, Salt Lake City, UT, a 520-bed, tertiary care center associated with the University of Utah School of Medicine.. Using a hospital information system we developed computerized algorithms to identify and monitor patients receiving I/C. These algorithms screened the computer-stored medical records of all inpatient admissions for I/C prescription orders. Computer-decision support algorithms estimated the renal function of each I/C-treated patient and provided suggestions when dosages were determined to be excessive. Additional computer-generated alerts identified patients who were receiving anticonvulsants concomitantly with I/C or whose therapy reflected dosage changes in the previous 24 hours. A list of all I/C-treated patients with alerts was reviewed daily by a clinical pharmacist and prescribing physicians were contacted if the computer-generated suggestions were clinically relevant.. The number and characterization of I/C-associated seizures.. From May 1, 1987, through June 30, 1991, we prospectively monitored 107,600 patients of whom 1951 were treated with I/C. The following risk factors for I/C-associated seizures were observed in the I/C-treated population: CNS disease (6 percent), seizure disorders (0.6 percent), and abnormal renal function (70 percent). The observational and interventional methods employed in this study resulted in 79 percent of the patients receiving I/C dosages appropriate for their corresponding renal function. During the 50-month study period, we detected four seizures (0.20 percent) in the I/C-treated patients. All 4 patients were receiving I/C dosages that were excessive with respect to their renal function.. Our rate of seizure (0.2 percent) was lower than the 1-2 percent rate reported in the literature despite the fact that more than 70 percent of the patients who received I/C had risk factors for seizure. We believe that appropriate dosing of I/C results in a low rate of associated seizures. Computer-assisted monitoring of I/C dosages in relation to renal function resulted in a reduced incidence of seizures.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Algorithms; Child; Cilastatin; Cilastatin, Imipenem Drug Combination; Clinical Pharmacy Information Systems; Drug Combinations; Female; Hospital Bed Capacity, 500 and over; Hospitals, University; Humans; Imipenem; Incidence; Length of Stay; Male; Middle Aged; Patient Admission; Population Surveillance; Prospective Studies; Seizures; Utah

Topics: Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Colorado; Drug Combinations; Hospital Bed Capacity, 300 to 499; Humans; Imipenem; Medication Errors; Pharmacists; Pharmacy Service, Hospital; Program Evaluation; Retrospective Studies; Risk Factors; Seizures

Two patients with multiple organ systems failure developed seizures after receiving imipenem/cilastatin (I/C) despite dose adjustment for poor renal function. Neither patient had a past history of seizures, nor had experienced seizures after receiving high doses of other beta-lactam antibiotics. Simple dose adjustment of I/C based on low creatinine clearances may not be adequate to prevent seizures.

Topics: Aged; Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Male; Middle Aged; Seizures

Topics: Cilastatin; Cilastatin, Imipenem Drug Combination; Creatinine; Drug Administration Schedule; Drug Combinations; Humans; Imipenem; Seizures

We report here four patients with acute leukemia, who developed seizure or tremor following treatment with imipenem, a new broad-spectrum antibiotic. All four patients had no renal dysfunction and recovered after discontinuation of the drug. Two patients who developed seizure had a past history of cerebral hemorrhage with symptoms of meningitis in one and the other had received frequent intrathecal injections of methotrexate. Seizure also occurred in another patient who was given multiple intrathecal injections of methotrexate. The remaining old patient developed tremor after the first administration of imipenem which did not progress to convulsion. Cerebral hemorrhage or meningitis is known to predispose patients for convulsion following imipenem treatment. In addition, the present study suggests that central nervous system damage related with intrathecal injections of methotrexate may be a predisposing factor. Thus, imipenem should be given with caution to acute leukemia patients who often have risk factors for developing imipenem-related complications.

Topics: Acute Disease; Adult; Aged; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Female; Humans; Imipenem; Leukemia; Middle Aged; Seizures; Tremor

The beta-lactam antibiotics imipenem-cilastatin, BMY-26225, and cefazolin significantly lowered the convulsive threshold of pentylenetetrazole in mice. In addition, imipenem-cilastatin and cefazolin were found to inhibit 3H-labeled gamma-aminobutyric acid binding to synaptic membranes from rat brains. Our results suggest that the pentylenetetrazole convulsive model may be useful in evaluating the proconvulsive liabilities of new carbapenems and other beta-lactam antibiotics and that the mechanism of imipenem-cilastatin and cefazolin toxicity may involve interaction with gamma-aminobutyric acid receptors.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Binding, Competitive; Cefazolin; Cilastatin; Cilastatin, Imipenem Drug Combination; Cyclopropanes; Disease Models, Animal; Drug Combinations; gamma-Aminobutyric Acid; Imipenem; Lactams; Male; Mice; Pentylenetetrazole; Seizures; Thienamycins