Seizure Activity with Imipenem Therapy: Incidence and Risk Factors

Job, Martin L.; Dretler, Robin

doi:10.1177/106002809002400504

Cited by 26 publications

(14 citation statements)

References 9 publications

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“…Cefoxitin, a cephalosporin imposes a deterioration of human colonial microbiota by reducing the population of anaerobic and enterobacteria, which ultimately leads to colonization of other pathogenic bacteria [107], [108]. Administration of imipenem (first carbapenem antibiotic) causes several side effects, including nausea, vomiting, and seizures in both adult and children under medication for various bacterial infections [109]–[111]. Resolvable abdominal pain, ENT infections, diarrhea, headache, and vomiting are the adverse effects frequently reported in cystic fibrosis patients associated with the azithromycin treatment regimens [112].…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach

Shanmugham

Pan

2013

PLoS ONE

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Mycobacterium abscessus, a non-tuberculous rapidly growing mycobacterium, is recognized as an emerging human pathogen causing a variety of infections ranging from skin and soft tissue infections to severe pulmonary infections. Lack of an optimal treatment regimen and emergence of multi-drug resistance in clinical isolates necessitate the development of better/new drugs against this pathogen. The present study aims at identification and qualitative characterization of promising drug targets in M. abscessus using a novel hierarchical in silico approach, encompassing three phases of analyses. In phase I, five sets of proteins were mined through chokepoint, plasmid, pathway, virulence factors, and resistance genes and protein network analysis. These were filtered in phase II, in order to find out promising drug target candidates through subtractive channel of analysis. The analysis resulted in 40 therapeutic candidates which are likely to be essential for the survival of the pathogen and non-homologous to host, human anti-targets, and gut flora. Many of the identified targets were found to be involved in different metabolisms (viz., amino acid, energy, carbohydrate, fatty acid, and nucleotide), xenobiotics degradation, and bacterial pathogenicity. Finally, in phase III, the candidate targets were qualitatively characterized through cellular localization, broad spectrum, interactome, functionality, and druggability analysis. The study explained their subcellular location identifying drug/vaccine targets, possibility of being broad spectrum target candidate, functional association with metabolically interacting proteins, cellular function (if hypothetical), and finally, druggable property. Outcome of the present study could facilitate the identification of novel antibacterial agents for better treatment of M. abscesses infections.

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Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach

Shanmugham

Pan

2013

PLoS ONE

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“…No data yet exist to define carbapenem exposure and the toxicity concentration threshold. However, carbapenem toxicity has been well documented with higher carbapenem doses (4 g/day) or in patients with severe renal insufficiency . Thus, optimal dosing regimens were defined as those achieving ≥90% PTA with the smallest daily dose to minimize the risk of toxicity.…”

Section: Methodsmentioning

confidence: 99%

“…However, carbapenem toxicity has been well documented with higher carbapenem doses (4 g/day) or in patients with severe renal insufficiency. 55,56 Thus, optimal dosing regimens were defined as those achieving ࣙ90% PTA with the smallest daily dose to minimize the risk of toxicity. In addition, sensitivity analyses were performed to investigate the influence of different PIRRT regimens on carbapenem dosing in PIRRT.…”

Section: Prediction Of Probability Of Target Attainmentmentioning

confidence: 99%

Use of Monte Carlo Simulations to Determine Optimal Carbapenem Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Lewis

Kays

Mueller

2016

The Journal of Clinical Pharma

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Pharmacokinetic/pharmacodynamic analyses with Monte Carlo simulations (MCSs) can be used to integrate prior information on model parameters into a new renal replacement therapy (RRT) to develop optimal drug dosing when pharmacokinetic trials are not feasible. This study used MCSs to determine initial doripenem, imipenem, meropenem, and ertapenem dosing regimens for critically ill patients receiving prolonged intermittent RRT (PIRRT). Published body weights and pharmacokinetic parameter estimates (nonrenal clearance, free fraction, volume of distribution, extraction coefficients) with variability were used to develop a pharmacokinetic model. MCS of 5000 patients evaluated multiple regimens in 4 different PIRRT effluent/duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis or hemofiltration) occurring at the beginning or 14-16 hours after drug infusion. The probability of target attainment (PTA) was calculated using ≥40% free serum concentrations above 4 times the minimum inhibitory concentration (MIC) for the first 48 hours. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA in all PIRRT combinations. At the MIC of 2 mg/L for Pseudomonas aeruginosa, optimal doses were doripenem 750 mg every 8 hours, imipenem 1 g every 8 hours or 750 mg every 6 hours, and meropenem 1 g every 12 hours or 1 g pre- and post-PIRRT. Ertapenem 500 mg followed by 500 mg post-PIRRT was optimal at the MIC of 1 mg/L for Streptococcus pneumoniae. Incorporating data from critically ill patients receiving RRT into MCS resulted in markedly different carbapenem dosing regimens in PIRRT from those recommended for conventional RRTs because of the unique drug clearance characteristics of PIRRT. These results warrant clinical validation.

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“…Fourteen published reports representing 37 individual patients were identified for review (an appendix with full details is available on request from the corresponding author). [56][57][58][59][60][61][62][63][64][65][66][67][68][69] Nearly all patients had at least one documented risk factor, with renal insufficiency being the most common. In eight cases, dosages greater than 30 mg/kg/day were reported.…”

Section: Imipenem-cilastatinmentioning

confidence: 99%

Epileptogenic Potential of Carbapenem Agents: Mechanism of Action, Seizure Rates, and Clinical Considerations

et al. 2011

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Antimicrobials are the most frequently implicated class of drugs in drug-induced seizure, with β-lactams being the class of antimicrobials most often implicated. The seizure-inducing potential of the carbapenem subclass may be directly related to their β-lactam ring structure. Data on individual carbapenems and seizure activity are scarce. To evaluate the available evidence on the association between carbapenem agents and seizure activity, we conducted a literature search of the MEDLINE (1966-May 2010), EMBASE (1974-May 2010), and International Pharmaceutical Abstracts (1970-May 2010) databases. Reference citations from the retrieved articles were also reviewed. Mechanistically, seizure propensity of the β-lactams is related to their binding to γ-aminobutyric acid (GABA) receptors. There are numerous reports of seizure activity associated with imipenem-cilastatin, with seizure rates ranging from 3-33%. For meropenem, doripenem, and ertapenem, the seizure rate for each agent is reported as less than 1%. However, as their use increases and expands into new patient populations, the rate of seizures with these agents may increase. High-dose therapy, especially in patients with renal dysfunction, preexisting central nervous system abnormalities, or a seizure history increases the likelihood of seizure activity. Although specific studies have not been conducted, data indicate that carbapenem-associated seizure is best managed with benzodiazepines, followed by other agents that enhance GABA transmission. Due to the drug interaction between carbapenems and valproic acid, resulting in clinically significant declines in valproic acid serum concentrations, the combination should be avoided whenever possible. Clinicians should be vigilant regarding the possibility of carbapenem-induced seizures when selecting and dosing antimicrobial therapy.

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Seizure Activity with Imipenem Therapy: Incidence and Risk Factors

Cited by 26 publications

References 9 publications

Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach

Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach

Use of Monte Carlo Simulations to Determine Optimal Carbapenem Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Epileptogenic Potential of Carbapenem Agents: Mechanism of Action, Seizure Rates, and Clinical Considerations

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