The risk of seizures among the carbapenems: a meta-analysis

Cannon, Joan P.; Lee, Todd A.; Clark, Nina M.; Setlak, Paul; Grim, Shellee A.

doi:10.1093/jac/dku111

Cited by 90 publications

(56 citation statements)

References 74 publications

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“…While imipenem at 4 g/day clearly benefitted the predicted success rate of therapy, this dose may slightly increase the risk of seizures compared to 2 or 3 g imipenem per day (55,56). To obtain extensive synergy with tobramycin and prevent resistance, an unbound imipenem concentration of approximately 8 mg/liter was needed against our carbapenem-resistant isolates.…”

Section: Discussionmentioning

confidence: 99%

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Yadav

Landersdorfer

Nation

et al. 2015

Antimicrob Agents Chemother

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cAcinetobacter baumannii is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize ␤-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii. We studied combinations of 10 ␤-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of A. baumannii using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (<2.3 log 10 ) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other ␤-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/ liter combined with an aminoglycoside yielded synergistic killing (>5 log 10 ) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MIC, 32 mg/ liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log 10 killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.A ntimicrobial resistance in Gram-negative bacteria is one of the three greatest threats to human health (1-3). Acinetobacter baumannii is one of the three most challenging Gram-negative pathogens, especially in intensive care units. In approximately 14,000 critically ill patients, A. baumannii infections were highly associated (P Ͻ 0.001) with increased mortality (4). A. baumannii often causes bloodstream, respiratory tract (including ventilatorassociated pneumonia), and wound infections (including burns and combat wounds); these are associated with high morbidity (1, 2, 5) and up to 87% mortality (6). Multidrug-resistant A. baumannii strains have caused major outbreaks in the United States and worldwide (7,8).In the past, ␤-lactams and aminoglycosides were successfully used to treat susceptible A. baumannii (9), but unfortunately, strains have emerged that are resistant to virtually all antibiotics in monotherapy (10, 11). While carbapenems were hitherto considered the treatment of choice against severe A. baumannii infe...

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Section: Discussionmentioning

confidence: 99%

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Yadav

Landersdorfer

Nation

et al. 2015

Antimicrob Agents Chemother

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“…To our knowledge, there is no report of carbapenem-associated PRES. However, seizures are reported more frequently with carbapenems compared to other antibiotics [66]. …”

Section: Discussionmentioning

confidence: 99%

Clinical Management of Posterior Reversible Encephalopathy Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Series and Review of the Literature

et al. 2015

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Background: Posterior reversible encephalopathy syndrome (PRES) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Among others, calcineurin inhibitors (CNI) for prophylaxis of graft-versus-host disease (GvHD) may promote the development of PRES, but the pathomechanism is still controversial. Discontinuation of CNI facilitates remission of symptoms but might contribute to the unfavorable prognosis of PRES due to an elevated incidence of GvHD. Methods: This is a case series of 7 patients with PRES from a retrospective analysis of 146 consecutive patients who received alloHSCT for hematologic malignancies. Results: At the onset of PRES, all patients presented a systemic infection, while no influence was seen for underlying disease, conditioning regimen, donor type, or GvHD. Discontinuation of CNI and control of the blood pressure reversed neurological symptoms in 6 patients, while 1 patient died from septic multiorgan failure. After bridging with prednisolone and/or mycophenolic acid, replacement of CNI by the mammalian target of rapamycin (mTOR) inhibitor everolimus effectively prevented severe GvHD without recurrence of PRES. Conclusions: A systemic infection/inflammation may be an important cause of PRES. Prophylaxis of GvHD by the mTOR inhibitor everolimus in case of PRES after alloHSCT demonstrated promising results but needs to be validated in larger cohorts.

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“…Our most robust regimen, which contained imipenem at 5 g/day as a continuous infusion, was promising with regard to success rate of therapy; however, this dose may slightly increase the risk of seizures compared to that with 2 to 4 g imipenem per day (44,45). Following imipenem treatment, nausea and vomiting were observed in one patient (out of 45 patients in the study); these symptoms were considered to be probably due to rapid infusion, as they disappeared after the duration of infusion was increased (46).…”

Section: Yadav Et Al Antimicrobial Agents and Chemotherapymentioning

confidence: 99%

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

Yadav

Bulitta

Nation

et al. 2017

Antimicrob Agents Chemother

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Optimizing antibiotic combinations is promising to combat multidrugresistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 10 7.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MIC imipenem ] of 16 mg/liter and MIC tobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5ϫ MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded Ն2-log 10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by Ն0.88ϫ MIC imipenem in combination with a median of 0.75ϫ MIC tobramycin (range, 0.032ϫ to 2.0ϫ MIC tobramycin ) or 0.50ϫ MIC amikacin (range, 0.25ϫ to 0.50ϫ MIC amikacin ). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve Ͼ2.0-log 10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, Ͼ4.0 log 10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

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The risk of seizures among the carbapenems: a meta-analysis

Abstract: 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.

Cited by 90 publications

References 74 publications

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

Clinical Management of Posterior Reversible Encephalopathy Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Series and Review of the Literature

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

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