hr-810 and Critical-Illness

Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.. We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.. A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.. The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefepime; Cefpirome; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Infections; Meropenem; Piperacillin; Thienamycins

To develop a population pharmacokinetics model for cefpirome in ICU patients, to assess pharmacokinetic-pharmacodynamic profiles vs. MIC distribution of likely ICU pathogens, and to assess their expected cumulative fraction of response (CFR).. Prospective observational study in a multidisciplinary ICU.. Twelve patients received 2g cefpirome intravenously over 12h. Thirteen blood samples were taken on two occasions. Demographic and creatinine clearance data were collected. Based on the final covariate model obtained using NONMEM, Monte Carlo simulations were undertaken to simulate free-drug concentrations for two administration methods: intermittent bolus administration (IBA) and continuous infusion (CI) with a loading dose of 0.5 g. Concentration-time profiles were evaluated by the probability of achieving free-drug concentrations above the MIC for more than 65% of dosing interval. Using MIC distributions from the EUCAST programme the CFR for each method was evaluated. A three-compartment model with zero-order input best described the concentration-time data. The CFR for Escherichia coli and Klebsiella spp. was greater than 97% in all IBA and CI doses but for Pseudomonas aeruginosa, and Acinetobacter spp. achieved target concentrations of 56% and 46%, respectively. High-dose CI cefpirome (6g/day) for P. aeruginosa and Acinetobacter spp. was required to achieve CFR of 89%.. Measured creatinine clearance appears to be a good marker of cefpirome clearance and potentially could be used to individualise cefpirome therapy. When given as IBA or CI for E. coli and Klebsiella spp., cefpirome should be successful. Cefpirome fails to achieve the bactericidal target even when administered at high-doses such as 6g/day for P. aeruginosa and Acinetobacter spp. Prospective clinical studies are needed to conclusively validate these findings.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefpirome; Cephalosporins; Creatinine; Critical Illness; Dose-Response Relationship, Drug; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Intensive Care Units; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Monte Carlo Method

To measure plasma levels and pharmacokinetics of cefpirome in critically ill septic patients with normal renal function. To use the pharmacokinetic model to simulate alternate dosing regimens and identify those that predict sustained levels.. A prospective, open-label, descriptive study in a 22-bed, multidisciplinary, adult ICU in a university-affiliated, tertiary referral hospital.. Twelve adults with normal renal function on enrollment and with suspected or documented sepsis in whom cefpirome was judged to be the appropriate therapy by the managing clinician.. Cefpirome 2 g was infused intravenously over 3 min every 12 h. Timed blood samples were taken prior to and during two dosing intervals. Urine was collected for creatinine clearance determination.. Two patients were non-evaluable due to renal dysfunction post-enrollment. The median cefpirome trough level was 1.1 mg/l (range 0.5-8.1 mg/l) after the initial dose and 1.4 mg/l (range < 0.5-15.9 mg/l) at 'steady state'. The volumes of distribution and elimination half-lives were greater and more variable than in healthy volunteers. Pharmacokinetic simulation predicted that more frequent bolus dosing, increased doses and continuous infusions would result in concentrations greater than 4 mg/l for over 60% of the dosing interval for all patients.. Cefpirome 2 g twice daily produced low plasma troughs in a number of patients. Our data suggest that this drug regimen may be inadequate for successful treatment of difficult-to-treat infections in critically ill patients with normal renal function.

Topics: Adult; Aged; APACHE; Area Under Curve; Cefpirome; Cephalosporins; Critical Illness; Female; Half-Life; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Prospective Studies; Sepsis; Treatment Outcome

The physico-chemical properties of cefpirome (low protein binding, high water solubility and low molecular weight) suggest that it may be lost readily from the extracorporeal circulation of intensive care unit patients during continuous renal replacement therapy.. In order to make informed dosage recommendations for patients receiving artificial renal support, cefpirome loss from human blood has been quantified using in vitro models of continuous haemofiltration and haemodiafiltration. Cefpirome clearance was measured using three membrane types at varying ultrafiltrate (UFR) and dialysis flow rates (Qd).. During haemofiltration cefpirome was found to cross hollow fibre polyamide (PA) and polyacrylonitrile (PAN) membranes with equal efficiency. The mean sieving coefficients (S) of both PA and PAN membranes were consistently high (> 0.7) when two different ultrafiltration rates were used. Changing the ultrafiltration rate or membrane type had no significant effect on the sieving coefficient of cefpirome but did result in an increase in cefpirome filter clearance (Fcl). Using the haemodiafiltration model, cefpirome penetrated PAN membranes (flat plate AN69S) more efficiently than hollow fibre PA membranes (FH66D). In each case, increasing the dialysis flow rate reduced the S-value. However, although increasing Qd was associated with a greater Fcl of cefpirome when PAN membranes were employed, no such relationship was found for the PA hollow fibre membrane.. The information generated can be used to estimate a dosing regimen for intensive care patients prescribed cefpirome and receiving continuous renal replacement therapy.

Topics: Cefpirome; Cephalosporins; Chromatography, High Pressure Liquid; Critical Illness; Hemodiafiltration; Hemofiltration; Humans; In Vitro Techniques; Membranes, Artificial; Models, Biological; Renal Replacement Therapy