Development of breakpoints of carbapenems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in peritoneal fluid

Ikawa, Kazuro; Morikawa, Norifumi; Ikeda, Kayo; Ohge, Hiroki; Sueda, Taijiro

doi:10.1007/s10156-008-0624-1

Cited by 21 publications

(20 citation statements)

References 9 publications

(7 reference statements)

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“…The penetration of meropenem into peritoneal fluid was rapid, the exposures were roughly comparable to those in plasma, and the between-patient variability of F PF was relatively small (Table 2). The estimated extent of penetration into peritoneal fluid (F PF ) in our study was in good agreement with previously reported estimates that ranged from 0.74 to 1.0 (32,33).…”

Section: Discussionsupporting

confidence: 92%

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery

Wittau

Scheele

Kurlbaum

et al. 2015

Antimicrob Agents Chemother

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c Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m 2 ). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27. W hile antimicrobial resistance is one of the greatest threats to human health, the number of new antibiotics against multidrug-resistant bacteria declined drastically over the last 3 decades (1-3). Meropenem continues to serve as an important component of our antibiotic armamentarium and covers a large range of clinically relevant pathogens for antibiotic therapy, including those causing intra-abdominal infections or infections of the subcutaneous tissue. Meropenem is a potent, broad-spectrum ␤-lactam antibiotic that yields relatively rapid bacterial killing and is among the first antibiotic options for treatment of severe infections; it covers most of the pathogens relevant for intra-abdominal infections (4). Meropenem is a hydrophilic molecule, and it is unknown whether meropenem penetrates well into the subcutaneous tissue and peritoneal fluid of obese patients.Obese patients are at a high risk of postoperative and hospitalrelated infections (5), and optimal management of these infections is crucial to improve the outcome of obese patients with severe infections. The selection of the antibiotic and dose are critical to manage those infections (5, 6). Recommended daily doses are based on pharmacokinetic/pharmacodynamic (PK/PD) studies usually conducted in nonobese healthy volunteers (5). However, PK variables may differ in obese and nonobese patients, potentially resulting in inadequate antibiotic plasma and tissue concentrations. Thus, PK studies in obese, noninfected individuals are essential to avoid the risk of over-or underdosing.Only a few studies have assessed the PK of meropenem in obese patients (4-8), and some of these studies found considerably different clearances and volumes of distribution in obese and nonobese patients. These studies did not perform population pharmacokinetic modeling and did not assess the peritoneal fluid and subcutaneous tissue penetration of meropenem in obese patients.As meropenem is a hydrophilic molecule, it is important to determine whether its PK is...

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Section: Discussionsupporting

confidence: 92%

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery

Wittau

Scheele

Kurlbaum

et al. 2015

Antimicrob Agents Chemother

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“…Combination therapy was found to prevent colistin resistance of certain isolates and appeared to limit the regrowth at the end of 24 hours. 94 Ikawa et al 95 determined the bacteriostatic and bactericidal break points of doripenem for intraabdominal infections. Doripenem drug regimens with a minimal value of 0.25/0.5 h BID and a maximal value of 0.5 g/0.5 h TID were postulated to attain bacteriostatic break points of 2 and 8 µg/mL (the highest MIC value at which the probability of attaining the bacteriostatic target [20% T .…”

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

“…In comparing doripenem and other carbapenems, it was also determined that the dosing interval and infusion time were more critical than the daily dose for maximizing the pharmacodynamics of time-dependent carbapenem activity. 95 Empirical studies showed that a 500-mg doripenem dose q8h was indicated to provide sufficient bactericidal exposure in the abdominal cavity of abdominal surgery patients and that doripenem penetrated into the peritoneal exudate rapidly and extensively-to an extent greater than or equal to that estimated from serum data. 96 To attain a clinically acceptable probability of target attainment (PTA) in peritoneal fluid, it was estimated that doripenem 0.25 and 0.5 g TID (0.5-hour infusions) should be sufficient against pathogens, including E. coli, Klebsiella spp., and E. cloacae, but that doripenem 1 g TID (0.5-hour infusion) or extended infusion regimens (4-hour) would result in increased PTAs in peritoneal fluid against P. aeruginosa isolates.…”

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

A Review of Doripenem for the Treatment of Serious Bacterial Infections

Redman

Flamm²,

Cirillo³

2010

Clinical Medicine Reviews in Therapeutics

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Doripenem is a carbapenem bactericidal agent that demonstrates in vitro activity against a wide variety of Gram-negative and Gram-positive pathogens. In vitro data show that doripenem combines the intrinsic activity of meropenem against Gram-negative pathogens with the intrinsic activity of imipenem against Gram-positive pathogens. The availability of doripenem is particularly welcome in the current setting of increased resistance among Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter species, and extended-spectrum β-lactamase-producing Enterobacteriaceae. Characteristic of doripenem is its potent activity against P. aeruginosa with a minimum inhibitory concentration (MIC) necessary for the inhibition of 90% of all isolates (MIC 90 ) of 4 µg/mL, a value that is 2 to 4 times lower than the corresponding MIC 90 values of meropenem and imipenem. Doripenem was shown to be noninferior to other commonly used antibiotics in phase 3 clinical trials and is currently approved for the treatment of complicated intra-abdominal infection and complicated urinary tract infection, and in some countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. Intravenous (IV) infusions of doripenem can be either 1 hour or for longer durations of 4 hours. Overall, IV doripenem is safe and well tolerated, with a limited propensity to induce seizures compared with other carbapenems. Doripenem may represent a valuable option when carbapenem therapy is warranted for the treatment of serious infection, particularly in cases in which the etiology is a drug-resistant, Gram-negative pathogen.

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“…The investigated pharmacokinetics of a dosage of 2 g daily each 6 hours are described in Table III. Additionally, drug efficacy was evaluated by the previously reported PK/ PD correlation (Zhanel et al, 2007;Ikawa et al, 2008). Free-fraction drug plasma concentrations were maintained above the MIC within the time interval (fT>MIC), expressed as a percentage, and imipenem effectiveness is guaranteed at 40%fT>MIC.…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

“…PK/PD data obtained for pediatric burn patients were estimated based on the percentage of the dose interval that the drug plasma concentration was maintained above the MIC, and the time-dependent imipenem effectiveness criterion was considered to be 40% fT>MIC, as recommended by Ikawa et al (2008). Drug effectiveness against isolated pathogens during the antimicrobial susceptibility testing reached MIC values of 2 mg/L for patients in all sets investigated.…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic correlation of imipenem in pediatric burn patients using a bioanalytical liquid chromatographic method

Santos

Sanches

Júnior

et al. 2015

Braz. J. Pharm. Sci.

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A bioanalytical method was developed and applied to quantify the free imipenem concentrations for pharmacokinetics and PK/PD correlation studies of the dose adjustments required to maintain antimicrobial effectiveness in pediatric burn patients. A reverse-phase Supelcosil LC18 column (250 x 4.6 mm 5 micra), binary mobile phase consisting of 0.01 M, pH 7.0 phosphate buffer and acetonitrile (99:1, v/v), flow rate of 0.8 mL/min, was applied. The method showed good absolute recovery (above 90%), good linearity (0.25-100.0 µg/mL, r 2 =0.999), good sensitivity (LLOQ: 0.25 µg/mL; LLOD: 0.12 µg/mL) and acceptable stability. Inter/intraday precision values were 7.3/5.9%, and mean accuracy was 92.9%. A bioanalytical method was applied to quantify free drug concentrations in children with burns. Six pediatric burn patients (median 7.0 years old, 27.5 kg), normal renal function, and 33% total burn surface area were prospectively investigated; inhalation injuries were present in 4/6 (67%) of the patients. Plasma monitoring and PK assessments were performed using a serial blood sample collection for each set, totaling 10 sets. The PK/PD target attained (40%T>MIC) for each minimum inhibitory concentration (MIC: 0.5, 1.0, 2.0, 4.0 mg/L) occurred at a percentage higher than 80% of the sets investigated and 100% after dose adjustment. In conclusion, the purification of plasma samples using an ultrafiltration technique followed by quantification of imipenem plasma measurements using the LC method is quite simple, useful, and requires small volumes for blood sampling. In addition, a small amount of plasma (0.25 mL) is needed to guarantee drug effectiveness in pediatric burn patients. There is also a low risk of neurotoxicity, which is important because pharmacokinetics are unpredictable in these critical patients with severe hospital infection. Finally, the PK/PD target was attained for imipenem in the control of sepsis in pediatric patients with burns.Uniterms: Imipenem/quantification. Antibiotics/dosage. Pediatric patients/burn/antibiotics use. High Performance Liquid Chromatography/quantitative analysis. Drug plasma monitoring. PK/PD.Desenvolveu-se e aplicou-se método bioanalítico para quantificar concentrações de imipenem livre para estudos de farmacocinética (PK) e de correlação PK/PD dos ajustes de dose requeridos para manter a efetividade antimicrobiana em pacientes pediátricos queimados. Utilizou-se coluna Supelcosil LC18 (250 x 4,6 mm 5 micra), fase móvel binária, consistindo de tampão fosfato 0,01M pH 7,0 e acetonitrila (99:1, v/v) e fluxo de 0,8 mL/min. O método mostrou boa recuperação absoluta (acima de 90%), boa linearidade (0,25-100,0 µg/mL, r 2 =0.999), boa sensibilidade (LLOQ: 0,25 µg/mL; LLOD: 0,12 µg/mL) e estabilidade aceitável. Os valores de precisão inter/intradia foram 7,3/5,9% e a exatidão média foi de 92,9%. O método bioanalítico foi aplicado para quantificar concentrações de fármaco livre em crianças com queimaduras, Seis pacientes pediátricos queimados (idade média de 7,0 anos, 27,5 kg), com função renal n...

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Development of breakpoints of carbapenems for intraabdominal infections based on pharmacokinetics and pharmacodynamics in peritoneal fluid

Cited by 21 publications

References 9 publications

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery

A Review of Doripenem for the Treatment of Serious Bacterial Infections

Pharmacokinetic-pharmacodynamic correlation of imipenem in pediatric burn patients using a bioanalytical liquid chromatographic method

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