Pharmacokinetic and Pharmacodynamic Analysis of Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Imipenem

PurposeThis study explores factors that affect behavior in critically ill patients receiving continuous renal replacement therapy (CRRT) with imipenem and provides dosing regimens for these patients.MethodsA prospective, open-label study was conducted in a clinical setting. Both blood and effluent samples were collected pairwise at the scheduled time points. Plasma and effluent imipenem concentrations were determined by HPLC-UV. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method. The final model was evaluated by a bootstrap and visual predictive check. A population pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulations was performed to explore the effects of empirically used dosing regimens (0.5 g q6h, 0.5 g q8h, 0.5 g q12h, 1 g q6h, 1 g q8h, and 1 g q12h) on the probability of target attainment.FindingsThirty patients were included in the population model analysis. Imipenem concentration data were best described by a 3-compartment model (central, peripheral, and dialysis compartments). The clearance of the dialysis compartment (CL_d) was used to characterize drug elimination from the dialyzer. Creatinine clearance (CrCl) was the covariate that influenced the central clearance (CLc), and the effects of dialysate flow (Qd) was significant for CLd. Model validation revealed that the final model had qualified stability and acceptable predictive properties. A pharmacokinetic and pharmacodynamic analysis was conducted by Monte Carlo simulation, and patients were categorized into 12 subgroups based on different CrCl values (<30, 31–60, 61–90, and >90 mL/min) and Qd values (300, 500, and 1000 mL/h). Under the same MIC value and administration regimen, probability of target attainment values decreased with an increase of CrCl and Qd.ImplicationsCrCl and Qd had significant effects on CL_c and CL_d, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.     

Imipenem-Cilastatin-Relebactam: A Novel β-Lactam–β-Lactamase Inhibitor Combination for the Treatment of Multidrug-Resistant Gram-Negative Infections

Imipenem-cilastatin-relebactam (IMI-REL) is a novel β-lactam–β-lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β-lactamase inhibitor with the ability to inhibit a broad spectrum of β-lactamases such as class A and class C β-lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem-resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI-REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem-resistant bacteria. In a phase III trial comparing IMI-REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30-minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI-REL represents another important step in the ongoing fight against multidrug-resistant gram-negative pathogens.     

A retrospective study of methicillin-resistantStaphylococcus aureus clinical strains in Tokyo university hospital

Staphylococcus aureus clinical strains isolated in 1982 and 1992 at Tokyo University Hospital were studied for their carriage ofmecA gene, antibiotic susceptibility patterns, toxin production, coagulase isotypes, and ribotyping patterns. ThemecA-carrying strains in 1982 were mostly producers of type-4 coagulase (21 out of 31;68%), but producers of other coagulase types (type-1,-2,-7) were also found. The degree of methicillin resistance varied but was moderate with these strains (MIC₅₀=16; range, 0.5–512 μg/ml at 32°C with 2% NaCl), and some strains were even judged to be susceptible to methicillin in spite of their carriage ofmecA gene. In comparison,mecA-carrying strains in 1992 were mostly of single type in terms of production of type 2 coagulase (26 out of 27;96%), and high-level methicillin resistance (MIC₅₀>-512). Clonal expansion of the coagulase type-2 strain was implicated under selective pressure of antibiotic usage during the last decade.     

Risk-factors for the acquisition of imipenem-resistant Acinetobacter baumannii in Spain: a nationwide study

Potential risk-factors for the acquisition of imipenem-resistant Acinetobacter baumannii were investigated in a cohort study in 25 Spanish hospitals. The clonal relationship among isolates was determined by pulsed-field gel electrophoresis (PFGE). In total, A. baumannii was isolated from 203 patients, with imipenem-resistant (MIC(90) 128 mg/L) isolates being obtained from 88 patients (43%), and imipenem-susceptible isolates from 115 patients (57%). A wide clonal distribution was observed among the imipenem-resistant isolates, but spread of the same clone among centres was not demonstrated. The results indicated that imipenem-resistant A. baumannii is a widely distributed nosocomial pathogen in Spain and reaches an alarming frequency in some centres. Independent risk-factors for the acquisition of imipenem-resistant A. baumannii were a hospital size of >500 beds (multivariate OR, 6.5; 95% CI, 1.8--23), previous antimicrobial treatment (multivariate OR, 4.3; 95% CI, 1.6--11), a urinary catheter (multivariate OR, 2.7; 95% CI, 1.1--6.7) and surgery (multivariate OR, 2; 95% CI, 1.07--3.8).     

Piperacillin‐tazobactam vs. imipenem‐cilastatin as empirical therapy in hematopoietic stem cell transplantation recipients with febrile neutropenia

This randomized, dual‐center study compared the efficacy and safety of piperacillin‐tazobactam (PTZ) and imipenem‐cilastatin (IMP) in hematopoietic stem cell transplantation (HSCT) recipients with febrile neutropenia. HSCT recipients with febrile neutropenia were randomized into two groups receiving either PTZ or IMP as initial empiric antibiotic. Endpoints were defervescence rate after empiric antibiotic for 48 h, success at end of therapy, and side effects. Defervescence within 48 h after empiric antibiotic was observed in 46 patients with PTZ (75.4%) and 59 patients with IMP (95.2%) (p = 0.002). Ten patients (10/46) in the PTZ group and two patients (2/59) in the IMP group switched empiric antibiotics due to recurrent fever (p = 0.005). Success of initial antibiotic with modification was achieved in 34 patients with PTZ (55.7%) and 53 patients with IMP (85.5%) at the end of therapy (p = 0.001). To treat the bacteremia, seven of 10 patients in the PTZ group and one of eight patients in the IMP group needed to switch the empiric antibiotic (p = 0.025). Compared with PTZ, IMP had more gastrointestinal adverse events (p = 0.045). This study demonstrates that IMP had better efficacy than PTZ as an empiric antibiotic for febrile neutropenia in the HSCT setting, but with more gastrointestinal side reactions.     

Treatment of septicemia with imipenem/cilastatin sodium in very-low birth weight infants

Fifty-four very-low birth weight (VLBW) infants with proved or suspected septicemia hospitalized in the neonatal intensive care unit in Asahikawa Kosei Hospital were treated empirically with imipenem/cilastatin sodium (IPM/CS). IPM/CS was infused over a 30-minute period at a mean dose of 20.1±1.1 mg/kg (range, 17.4 to 23.4 mg/kg) and given every 12 hours for a period of 6.1±3.1 days (range, 3 to 16 days). The gestational age of the infants was 26.6±2.1 weeks (range, 24.0 to 31.0 weeks) and their birth weight was 860±234 g (range, 536 to 1478 g). At the time of initial administration of IPM/CS, the age was 30.5±2.9 days (range, 2 to 77 days), and the body weight was 799±289 g (range, 422 to 1748 g). Though 29 patients were administered IPM/CS on suspicion of septicemia, the causative organism could not be isolated. Causative organisms were isolated from the blood in 25 of the 54 patients, and includedAcinetobacter calcoaceticus (n=7),Enterobacter cloacae (n=5), methicillin-resistantStaphylococcus aureus (MRSA; n=5), other gram-negative bacilli (n=5),Staphylococcus epidermidis (n=2), MRSA andKlebsiella pneumoniae (n=1). A clinical cure was achieved in 17 of 25 infants and improvement was noted in an additional 3 infants, while 5 infants were evaluated as treatment failures. The 5 treatment failure patients were all diagnosed with MRSA infections. No adverse effects or abnormal laboratory values due to IPM/CS therapy were observed in these infants.     

Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis—a single-center randomized study

Pancreatic infection is the main indication for surgery and the principal determinant of prognosis in acute necrotizing pancreatitis. Previous studies on the effects of antibiotics have not, however, uniformly demonstrated any reduction in the need for surgery or any decrease in mortality among these patients, although the incidence of pancreatic infections was significantly reduced. This single-center randomized study was designed to compare early vs. delayed imipenem treatment for acute necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis (C-reactive protein >150 mg/L, necrosis on CT) were randomized within 48 hours either to a group receiving imipenem (1.0 g plus cilastatin intravenously 3 times a day) or a control group. Not included were those who had been started on antibiotics at the referring clinic, those who were taken directly to the intensive care unit for multiorgan failure, and those who refused antibiotics or might have had adverse reactions. Thirty-two patients were excluded because they were over 70 years of age (not potentionally operable) or for any study violation. There were 25 patients in the imipenem group and 33 patients in the control group. The main end point was the indication for necrosectomy due to infection (i.e., after the initial increase and decrease, there was a second continuous increase in temperature, white blood cell count [>30%] and C-reactive protein [>30%], with other infections ruled out, or bacteria were found on Gram stain of the pancreatic fine-needle aspirate). In the control group, imipenem was started when the operative indication was fulfilled. Conservative treatment was continued for at least 5 days before necrosectomy. The study groups did not differ from each other with regard to sex distribution, patient age, etiology, C-reactive protein concentration, and extent of pancreatic necrosis on CT. Two (8%) of 25 patients in the imipenem group compared to 14 (42%) of 33 in the control group fulfilled the operative indications (P = 0.003). Nine patients in the control group responded to delayed antibiotics but five had to undergo surgery. Of those receiving antibiotics, 2 (8%) of 25 in the early antibiotic (imipenem) group needed surgery compared to 5 (36%) of 14 in the delayed antibiotic (control) group (P = 0.04). Two (8%) of 25 patients in the imipenem group and 5(15%) of 13 patients in the control group died (P = NS [no significant difference]). Seven (28%) of 25 in the imipenem group and 25 (76%) of 33 in the control group had major organ complications (P = 0.0003). Based on the preceding criteria, early imipenem-cilastatin therapy appears to significantly reduce the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis, and reduces by half the mortality rate; this is not, however, statistically significant in a series of this size. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

Carbapenems in the USA: focus on doripenem

The threat of antibacterial resistance continues to increase globally, and therapeutic options for the treatment of some serious infectious diseases are diminishing. The carbapenems are a potent class of broad-spectrum drugs, and their stability against hydrolysis by many important β-lactamases make them an important weapon in the treatment of β-lactamase-producing bacterial pathogens. This review focuses on four carbapenems of clinical importance in the USA: imipenem, meropenem, ertapenem and doripenem. After a historical review of carbapenem development, these four carbapenems are evaluated based on their mechanism of action, spectrum of activity, potency, pharmacodynamics, clinical pharmacokinetics, clinical profiles and toxicity issues.     

肺炎克雷伯菌对亚胺培南耐药性与其使用量的相关性研究

目的探讨肺炎克雷伯菌对亚胺培南的耐药性与亚胺培南消耗量的关系。方法统计2008-2012年某院所有住院患者标本分离的肺炎克雷伯菌对亚胺培南的耐药情况,以及同期亚胺培南的消耗量（以亚胺培南使用密度表示),分析两者相关性。结果2008-2012年临床分离的肺炎克雷伯菌分别为174、187、363、290和625株,其占总病原菌检出数的构成比分别为6.88%、7.86%、10.01%、8.07%和11.05%,差异有统计学意义（χ2=16.516,P＜0.001）。2008-2012年肺炎克雷伯菌对亚胺培南的耐药率分别为0.00%、0.00%、4.13%、10.34%和25.44%,经Cochran Armitage趋势检验,差异有统计学意义（Z=12.563,P＜0.001）,即肺炎克雷伯菌对亚胺培南的耐药率呈逐年增加趋势;2008-2012年亚胺培南的消耗量分别为1.24、1.60、2.14、2.78、3.71 DDDs/（1 000住院日),呈上升趋势;亚胺培南消耗量与肺炎克雷伯菌对亚胺培南的耐药率变化呈正相关（R=0.966,P=0.007）。结论2008-2012年肺炎克雷伯菌对亚胺培南的耐药性逐年升高,与亚胺培南的消耗量密切相关,应加强对肺炎克雷伯菌的耐药性监测,并合理使用亚胺培南等碳青霉烯类抗生素。