Pharmacokinetic properties and stability of continuous-infusion meropenem in adults with cystic fibrosis

BACKGROUND: Meropenem is commonly used to treat lung infections in adults with cystic fibrosis (CF). Although continuous infusion is the ideal method to maximize the pharmacodynamic properties of this betalactam antibiotic, meropenem is stable for only approximately 4 to 6 hours at room temperature, and its pharmacokinetic (PK) properties, when administered by continuous infusion to patients with CF, are largely unknown. OBJECTIVE: This study was undertaken to determine the PK properties and stability of meropenem when administered to adults with CF by a continuous ambulatory drug-delivery infusion pump stored in a cold pouch between 2 freezer packs. METHODS: This open-label, multidose, randomized, crossover PK study was conducted at the Clinical Research Center at Hartford Hospital (Hartford, Connecticut). Adults aged > or = 18 years with CF were eligible. Study participants were randomized to receive meropenem 125 mg/h or 250 mg/h (equivalent to 3 g and 6 g, respectively, over 24 hours) by continuous IV infusion for 12 hours. Serum samples were collected throughout the infusion and then for 6 hours after infusion to determine the PK properties (volume of distribution [V(d)], elimination rate constant, total body clearance [CL], terminal half-life [t 1/2], and steady-state concentration [C(ss)]). Serum meropenem concentrations were assayed using high-performance liquid chromatography, and PK profiles were determined using compartmental analysis. Meropenem stability was ascertained by sampling the drug directly from the infusion pump at prespecified time points. Meropenem tolerability was assessed throughout the study by questioning subjects on how they felt. In addition, laboratory values of serum chemistries and liver enzymes were compared with baseline values. RESULTS: Seven adult volunteers with CF (4 women, 3 men; mean [SD] age, 27 [10] years [range, 19-46 years]) participated in the study. Mean (SD) C(ss) values were 8.31 (0.68) mg/L and 18.50 (3.31) mg/L for the 125-mg/h and 250-mg/h infusion rates, respectively. V(d), CL, and t 1/2 were dose independent and similar between the 2 infusion rates. Meropenem stability was maintained over 12 and 24 hours. Meropenem by continuous infusion was well tolerated. One patient complained of a headache during the study. CONCLUSIONS: In this study of adults with CF, meropenem infusion rates of 125 mg/h and 250 mg/h provided serum drug concentrations greater than the minimum inhibitory concentration for pathogens considered meropenem susceptible (< or =4 microg/mL) and intermediately resistant (8 microg/mL), respectively.     

Prevalence of extended spectrum beta-lactamase producing Escherichia coli and Klebsiella isolates in a large community teaching hospital in Connecticut

The prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESC) and Klebsiella (KS) among consecutive non-urine isolates were evaluated. Twenty-four of 392 isolates produced ESBLs. Among these half were from respiratory sites and all were susceptible to meropenem. Pulse field-gel electrophoresis (PFGE) showed 12 clonally distinct ESBLs and iso-electric focusing (IEF) revealed that most (83%) produced multiple enzymes.     

The role of gender in the long-term prognosis of patients with myocardial infarction submitted to fibrinolytic treatment

PURPOSE: To determine the role of gender in short- and long-term survival after a thrombolytic-treated myocardial infarction. METHODS: A total of 686 consecutive patients with ST-elevation acute myocardial infarction, admitted to a single center and treated with intravenous streptokinase, were studied prospectively and consecutively. Assessment of clinical and in-hospital variables permitted comparison of baseline characteristics and both in-hospital and long-term survival between men and women. RESULTS: A significantly (odds ratio=0.48, P=0.009) lower 14-day mortality rate for males (8.5%) relative to females (16%) was noted. However, this difference became non-significant after adjustment for age (odds-ratio male/female=0.62, P=0.097) or age and other variables (odds ratio=0.71, P=0.17). At the end of the follow-up (up to 12 years), survival rates for the whole population were 59.6% and 54.4% for men and women, respectively (chi-square=1.4, P=0.24); excluding in-hospital deaths, the rates were 65.1% and 64.8%, respectively (chi-square=0.21, P=0.65). CONCLUSIONS: In the short-term follow-up, women have a significantly higher mortality relative to men in an unadjusted analysis. This difference became non-significant after adjusting for age, or age and other variables. In the long-term follow-up, sex was not correlated with prognosis.     

Pharmacodynamics of meropenem and imipenem against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa

STUDY OBJECTIVE: To compare the pharmacodynamics of meropenem and imipenem, both administered as 500 mg every 6 hours, against populations of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa. DESIGN: Ten thousand-subject Monte Carlo simulation. INTERVENTION: Variability in total body clearance (ClT), volume of distribution as calculated by the terminal elimination rate (Vdbeta), and minimum inhibitory concentration (MIC) distributions (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, A. baumannii, P. aeruginosa) were derived from the literature for both meropenem and imipenem. For the free drug concentrations, the percentage of the dosing interval that the drug concentrations remain above the MIC (%T>MIC) for each carbapenem-bacteria combination was calculated for 10,000 iterations, substituting a different ClT, Vdbeta, fraction of unbound drug, and MIC into the equation each time based on the probability distribution for each parameter. Probabilities of attaining targets of 30%, 50%, and 100% T>MIC were calculated. MEASUREMENTS AND MAIN RESULTS: Meropenem free drug %T>MIC exposure was significantly greater than that of imipenem against Enterobacteriaceae and P. aeruginosa, whereas imipenem exposure was greater for A. baumannii. For both agents, free drug %T>MIC exposure was greatest against Enterobacteriaceae and less for A. baumannii and P. aeruginosa. Probabilities of target attainment for 30% and 50% T>MIC were similar between drugs for most bacteria. At 100% T>MIC, meropenem target attainments were greater than those of imipenem against Enterobacteriaceae and P. aeruginosa, and imipenem attainment was higher for A. baumannii. CONCLUSION: The probability of attaining lower pharmacodynamic targets for most gram-negative bacteria is similar for these carbapenems; however, differences become apparent as the pharmacodynamic requirement increases. Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary.     

Inhibition of multidrug resistance by immunisation with synthetic P-glycoprotein-derived peptides

Overexpression of the membrane glycoprotein (P170) represents the most common multidrug resistance (MDR) mechanism in cancer therapy. Specific auto-antibodies to extracellular loops 1, 2 and 4 of murine P170 were elicited in mice using palmitoylated synthetic peptides reconstituted in liposomes, with or without Lipid A, and resuspended in alum. IgM antibodies were detected 14 days following the first injection and IgG1 became predominant after the third challenge. Animals did not show any auto-immune symptoms or induced toxicity up to 18 months after the immunisation. Previous immunisations of mice using liposomes with MDR1 peptides increases the efficacy of chemotherapy treatments with doxorubicin and vinblastine against P388 R cells with increase of 77% in the survival half time in the immunised group. Sera from the immunised mice were also effective in reducing cellular resistance to vinblastine and doxorubicin in vitro. Taken together, these data suggest that this immunisation approach might have potential clinical applications.     

Results of a feasibility study for a psycho-educational intervention in head and neck cancer

BACKGROUND: With survival rates for people with head and neck (H&N) cancers static during the past 30 years and the enormous burden of psychosocial impacts they suffer well documented, the testing of psychosocial interventions in this group is a priority. OBJECTIVE: To test the feasibility of providing a psycho-educational intervention for people with H&N cancer. METHODOLOGY: A prospective non-randomised design was used. Subjects were patients with H&N cancer. They were offered the Nucare coping strategies program in one of three formats: small group and one-to-one formats with therapists; and a home format, with material for home use, without a therapist. Outcomes measures (quality of life (QOL) and anxiety and depression) were collected at baseline and following the intervention. Analyses were performed using non-parametric statistics. RESULTS: Of 128 people invited to participate, 66 agreed, 59 completed the intervention and 50 had outcomes data. Following the intervention, there were significant improvements in physical and social functioning and global QOL, and reduced fatigue, sleep disturbance and depressive symptoms. CONCLUSIONS: These data suggest that the intervention is desired by the target group, feasible to deliver after cancer therapy and may have some beneficial effects, although an appropriately designed study is required to confirm this.     

Accuracy of sonography with a hydration test in differentiating between excretory renal obstruction and renal sinus cysts

PURPOSE: The aim of this prospective study was to determine whether sonography with a hydration test to induce diuresis can be used to reliably differentiate between excretory renal obstruction and renal sinus cysts. METHODS: We performed sonographic examination of all patients diagnosed with minimal or moderate obstruction of the intrarenal collecting system or renal sinus cysts on the basis of excretory urography, CT, or both between September 1, 1998, and October 31, 1999. The largest fluid-filled structures in the renal sinus were sonographically measured before and after each patient ingested 1.5 l of water. Cases in which the maximum diameters of the largest anechoic structures increased by at least 10% after hydration were diagnosed with excretory renal obstruction. The sonographic diagnoses were compared with the final diagnoses on excretory urography, CT, or both. RESULTS: Both kidneys were affected in 16 of the 36 patients examined, for a total of 52 kidneys. The sonographic diagnosis was consistent with the results of urography or CT in 48 (92%) of the 52 kidneys. The sonographic approach had a specificity of 92% and a sensitivity of 93% for the diagnosis of excretory renal obstruction, with only 1 false-negative and 3 false-positive results. CONCLUSIONS: When used with the stimulated diuresis test, sonography can reliably distinguish between excretory renal obstruction and renal sinus cysts and can be used as an alternative to other imaging techniques such as urography.     

Production and resolution of cantharidin-induced inflammatory blisters

While inflammatory blisters have long been utilized as a means of evaluating antimicrobial disposition to aid in the development of new treatments for skin and skin structure infections, sparse data are available regarding the healing of the blisters once the experiment has been completed. We report the blister induction technique and resolution time in ten volunteers enrolled in a pharmacokinetic study using the cantharidin-induced inflammatory blister technique.     

Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion

STUDY OBJECTIVE: To assess the pharmacokinetics of meropenem administered as a 3-hour infusion. DESIGN: Randomized, crossover, open-label study. SETTING: Clinical research center. SUBJECTS: Six healthy adult male volunteers. INTERVENTION: Each subject received meropenem 0.5 or 2 g every 8 hours as a 3-hour infusion for three doses and then crossed over to the other dosage regimen. MEASUREMENT AND MAIN RESULTS: Pharmacokinetic parameters of both regimens were compared, and no significant differences between 0.5- and 2-g doses for the dose-independent parameters (half-life, clearance, and volume of distribution at steady state) were observed. The regimens displayed dose proportionality and were consistent with that of a traditional 0.5-hour infusion. The 3-hour infusion optimized the pharmacodynamic profile of meropenem and worked within the constraints of stability at room temperature stability. CONCLUSION: Prolonging the percentage of time above the minimum inhibitory concentration is a feasible option with meropenem; however, further studies are needed to quantify how this increase translates to efficacy.     

Pleconaril,a novel antipicornaviral agent

Despite the availability of therapy for selected symptoms, no specific antiviral agents are available to treat or prevent infections due to the viruses of the Picornaviridae family--rhinoviruses and enteroviruses. Characterization of the three-dimensional structure of picornaviruses in the 1980s allowed development of compounds targeted at the virus itself. Pleconaril is a novel, orally available, systemically acting molecule whose pharmacokinetics are characterized by a two-compartment open model with first-order absorption and with a safety profile similar to that of placebo. It shows promising results in treatment of picornaviral respiratory tract infections, meningitis, and other life-threatening infections.