Setting the Beta-Lactam Therapeutic Range for Critically Ill Patients: Is There a Floor or Even a Ceiling?

Barreto, Erin F.; Webb, Andrew; Pais, Gwendolyn; Rule, Andrew D.; Jannetto, Paul J.; Scheetz, Marc H.

doi:10.1097/cce.0000000000000446

Cited by 46 publications

(46 citation statements)

References 97 publications

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“…Neurotoxicity has the strongest association with elevated beta-lactams concentrations ( 38 – 41 ), but no study of this review described any neurotoxicity case. Other previously described beta-lactams-associated adverse reactions as nephrotoxicity, hepatotoxicity and cytopenias seem to be concentration independent and they have low incidence in pediatric patients ( 42 ).…”

Section: Discussionmentioning

confidence: 88%

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

et al. 2022

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The antimicrobial therapy of sepsis and septic shock should be individualized based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to deliver effective and timely treatment of life-threatening infections. We conducted a literature scoping review to identify therapeutic targets of beta-lactam antibiotics in septic pediatric patients and the strategies that have been applied to overcome sepsis-related altered pharmacokinetics and increase target attainment against susceptible pathogens. A systematic search was conducted in the MEDLINE, EMBASE and Web of Science databases to select studies conducted since 2010 with therapeutic monitoring data of beta-lactams in septic children. Last searches were performed on 02 September 2021. Two independent authors selected the studies and extracted the data. A narrative and qualitative approach was used to summarize the findings. Out of the 118 identified articles, 21 met the eligibility criteria. Population pharmacokinetic modeling was performed in 12 studies, while nine studies reported data from bedside monitoring of beta-lactams. Most studies were conducted in the United States of America (n = 9) and France (n = 5) and reported PK/PD data of amoxicillin, ampicillin, azlocillin, aztreonam, cefazolin, cefepime, cefotaxime, ceftaroline, ceftazidime, doripenem, meropenem and piperacillin/tazobactam. Therapeutic targets ranged from to 40% fT> MIC to 100% fT> 6 × MIC. Prolonging the infusion time and frequency were most described strategies to increase target attainment. Monitoring beta-lactam serum concentrations in clinical practice may potentially maximize therapeutic target attainment. Further studies are required to define the therapeutic target associated with the best clinical outcomes.

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Section: Discussionmentioning

confidence: 88%

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

et al. 2022

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“…Initially it was thought that attaining a substantial proportion of time, e.g., 40–70%, where the free (i.e., unbound) concentration was above the MIC ( f T >MIC ) was an appropriate target [ 48 ]. Over time, the application of a target of 100% f T >MIC has become more prevalent for achievement of optimal bacterial killing and resistance suppression for difficult-to-treat pathogens and critically ill patients [ 49 , 50 ]. Recently, some studies have explored even higher targets, e.g., 100% f T >4× MIC [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against Pseudomonas aeruginosa for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model

et al. 2022

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We evaluated piperacillin-tazobactam and tobramycin regimens against Pseudomonas aeruginosa isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MICpiperacillin 4 mg/L, MICtobramycin 0.5 mg/L) and CR380 (MICpiperacillin 32 mg/L, MICtobramycin 1 mg/L), simulating the pharmacokinetics of: (A) tobramycin 7 mg/kg q24 h (0.5 h-infusions, t1/2 = 3.1 h); (B) piperacillin 4 g q4 h (0.5 h-infusions, t1/2 = 1.5 h); (C) piperacillin 24 g/day, continuous infusion; A + B; A + C. Total and less-susceptible bacteria were determined. SCTK demonstrated synergy of the combination for all isolates. In the IVM, regimens A and B provided initial killing, followed by extensive regrowth by 72 h for both isolates. C provided >4 log10 CFU/mL killing, followed by regrowth close to initial inoculum by 96 h for Pa1281, and suppressed growth to <4 log10 CFU/mL for CR380. A and A + B initially suppressed counts of both isolates to <1 log10 CFU/mL, before regrowth to control or starting inoculum and resistance emergence by 72 h. Overall, the combination including intermittent piperacillin-tazobactam did not provide a benefit over tobramycin monotherapy. A + C, the combination regimen with continuous infusion of piperacillin-tazobactam, provided synergistic killing (counts <1 log10 CFU/mL) of Pa1281 and CR380, and suppressed regrowth to <2 and <4 log10 CFU/mL, respectively, and resistance emergence over 120 h. The shape of the concentration–time curve was important for synergy of the combination.

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“…This concentration should be maintained for the entire period between doses, and after this time the minimum concentration should reach a value of 1-2x of the observed MIC of the pathogen obtained in microbiological cultures. Neurotoxicity has also been shown to be the most dose-dependent adverse event, although direct evidence is not yet available to indicate the concentration above which this complication is likely to occur [127].…”

Section: Methods Of Reducing the Frequency And Severity Of Antibiotic...mentioning

confidence: 99%

Antibiotics and the Nervous System—Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

2021

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Antibiotics as antibacterial drugs have saved many lives, but have also become a victim of their own success. Their widespread abuse reduces their anti-infective effectiveness and causes the development of bacterial resistance. Moreover, irrational antibiotic therapy contributes to gastrointestinal dysbiosis, that increases the risk of the development of many diseases, including neurological and psychiatric. One of the potential options for restoring homeostasis is the use of oral antibiotics that are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapy may exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactams and quinolones. Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus or seizures. Their pathomechanism results from the disturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similarities between the structure of the β-lactam ring and GABA molecule) and impairment of the functioning of benzodiazepine receptors (BZD). However, on the other hand, antibiotics have also been studied for their neuroprotective properties in the treatment of neurodegenerative and neuroinflammatory processes (e.g., Alzheimer’s or Parkinson’s diseases). Antibiotics may, therefore, become promising elements of multi-targeted therapy for these entities.

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Setting the Beta-Lactam Therapeutic Range for Critically Ill Patients: Is There a Floor or Even a Ceiling?

Abstract: Supplemental Digital Content is available in the text.

Cited by 46 publications

References 97 publications

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

Beta-Lactams Therapeutic Monitoring in Septic Children–What Target Are We Aiming for? A Scoping Review

Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against Pseudomonas aeruginosa for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model

Antibiotics and the Nervous System—Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

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