Simultaneous determination of meropenem and imipenem in rat plasma by LC-MS/MS and its application to a pharmacokinetic study.

An efficient and reliable method using LC-MS/MS was established and validated for the simultaneous quantification of meropenem and imipenem in rat plasma. An electronic spray ion source in the positive multiple reaction monitoring mode was used for the detection and the transitions were m/z 384.6 → m/z 141.2 for meropenem, m/z 300.1 → m/z 141.8 for imipenem and m/z 423.4 → m/z 207.1 for matrine (IS). The calibration curves of meropenem and imipenem were linear in the range of 0.50-200 µg/mL. Satisfactory separation was achieved with a total run time of 3.0 min, the injection volume was 3 µl. The retention times of meropenem, imipenem and IS were 1.19, 1.14 and 1.13 min, respectively. Meropenem and imipenem are easily hydrolyzed in plasma. HEPES was used as a stabilizer and added to the plasma samples immediately after centrifugation. Extractions of meropenem, imipenem and IS were carried out by protein precipitation with acetonitrile. The specificity, precision and accuracy, stability, recovery and matrix effects were within acceptance limits. This method was successfully applied to investigate the pharmacokinetics of intravenous injection of meropenem and imipenem single administration or combined with sulbactam in rats. We found that sulbactam has no influence on the pharmacokinetics behavior of meropenem or imipenem.

Determination of Total and Unbound Meropenem, Imipenem/Cilastatin, and Cefoperazone/Sulbactam in Human Plasma: Application for Therapeutic Drug Monitoring in Critically Ill Patients.

BACKGROUND: Critically ill patients show several pathophysiological alterations that can complicate antibiotic dosing. Hence, there is a strong rationale to individualize anti-infective dosing in these patients by using therapeutic drug monitoring (TDM). The current study aimed to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound plasma concentrations of 3 commonly used antibiotics (meropenem, imipenem/cilastatin, and cefoperazone/sulbactam) in the treatment of infections in critically ill patients in China, which could be suitable for routine TDM in hospital laboratories. METHODS: The unbound drug was separated from the bound drug by ultrafiltration. Simple protein precipitation was used for sample preparation. Meropenem, imipenem/cilastatin, cefoperazone/sulbactam, and their corresponding internal standards were then resolved using the Waters CORTECS C18 column. All the compounds were detected using electrospray ionization in the positive/negative ion-switching mode. RESULTS: The calibration curves were linear for all compounds, with correlation coefficients (R) above 0.99 for total concentrations in human plasma and unbound concentrations in the plasma ultrafiltrate. For both total and unbound drugs, the relative errors and intra-assay/interassay relative standard deviations were below 15%. The limit of quantification was 0.05 mcg/mL for both total plasma concentrations and plasma ultrafiltrate concentrations of all compounds. CONCLUSIONS: The method was simple, rapid, and reliable and is currently being used to provide a TDM service to enhance the efficacious use of the 3 antibiotics.

Preliminary physiologically based pharmacokinetic modeling of renally cleared drugs in Chinese pregnant women.

AIM: The aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs. METHOD: Based on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug-specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non-pregnant, Caucasian pregnant and Chinese non-pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug-specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature. RESULTS: The preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2-fold of observed data. CONCLUSIONS: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women.

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid.

AIMS: Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. METHODS: A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. RESULTS: A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1) , 9.37 l, 6.41 l, 13.7 l h(-1) , respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). CONCLUSION: The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups.

Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.

AIMS: Significant alterations in the pharmacokinetics (PK) of antimicrobials have been reported in critically ill patients. We describe PK parameters of imipenem in intensive care unit (ICU) patients with suspected ventilator-associated pneumonia and evaluate several dosage regimens. METHODS: This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of ventilator-associated pneumonia caused by Gram-negative bacilli, who empirically received imipenem intravenously every 8 h. Plasma imipenem concentrations were measured during the fourth imipenem infusion using six samples (trough, 0.5, 1, 2, 5 and 8 h). Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate the following six dosage regimens: 500, 750 or 1000 mg with administration every 6 or 8 h. The pharmacodynamic target was defined as the probability of achieving a fractional time above the minimal inhibitory concentration (MIC) of >40%. RESULTS: Fifty-one patients were included in the PK analysis. Imipenem concentration data were best described by a two-compartment model with three covariates (creatinine clearance, total bodyweight and serum albumin). Estimated clearance (between-subject variability) was 13.2 l h(-1) (38%) and estimated central volume 20.4 l (31%). At an MIC of 4 µg ml(-1) , the probability of achieving 40% fractional time > MIC was 91.8% for 0.5 h infusions of 750 mg every 6 h, 86.0% for 1000 mg every 8 h and 96.9% for 1000 mg every 6 h. CONCLUSIONS: This population PK model accurately estimated imipenem concentrations in ICU patients. The simulation showed that for these patients, the best dosage regimen of imipenem is 750 mg every 6 h and not 1000 mg every 8 h.

Fosfomycin-daptomycin and other fosfomycin combinations as alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.

The efficacy of daptomycin, imipenem, or rifampin with fosfomycin was evaluated and compared with that of daptomycin-rifampin in a tissue cage model infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Strain HUSA 304 was used. The study yielded the following results for MICs (in µg/ml): fosfomycin, 4; daptomycin, 1; imipenem, 0.25; and rifampin, 0.03. The study yielded the following results for minimum bactericidal concentration (MBC) (in µg/ml): fosfomycin, 8; daptomycin, 4; imipenem, 32; and rifampin, 0.5. Daptomycin-rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance.

Comparison of the pharmacokinetics of imipenem after intravenous and intrathecal administration in rabbits.

BACKGROUND: Intrathecal administration of antibiotics has potentially high effectiveness for the treatment for severe intracranial infections, particularly nosocomial meningitis. The use of intrathecal injection of antibiotics has been reported mostly in case reports. However, there is sparse data regarding the pharmacokinetics of antibiotics after intrathecal administration. AIM: This study investigated whether intrathecal injection is an effective method for the administration of imipenem. MATERIALS AND METHODS: The pharmacokinetics of imipenem after intrathecal and intravenous administration of 1:1 imipenem: cilastatin (IMI/CIL) to rabbits were compared. RESULTS: The AUC0-t in the cerebrospinal fluid for intrathecal administration was approximately twice that of an equal dose of intravenous administration at doses of 0.35, 0.7, and 1.4 mg/kg. Brain concentrations of imipenem after intrathecal injection were three times greater than observed after intravenous injection and remained high for at least 8 hours post-injection. Elimination of imipenem after administration by either route was primarily via urine, but a transient surge of imipenem in bile and intestinal tissue was observed. CONCLUSIONS: Results indicate that there is a clinical potential for intrathecally administered IMI/CIL. Further studies are warranted to investigate the potential for seizure and to assess the translatability of the rabbit model to human treatment.

Clinically relevant plasma concentrations of colistin in combination with imipenem enhance pharmacodynamic activity against multidrug-resistant Pseudomonas aeruginosa at multiple inocula.

The use of combination antibiotic therapy may be beneficial against rapidly emerging resistance in Pseudomonas aeruginosa. The aim of this study was to systematically investigate in vitro bacterial killing and resistance emergence with colistin alone and in combination with imipenem against multidrug-resistant (MDR) P. aeruginosa. Time-kill studies were conducted over 48 h using 5 clinical isolates and ATCC 27853 at two inocula (~10(6) and ~10(8) CFU/ml); MDR, non-MDR, and colistin-heteroresistant and -resistant strains were included. Nine colistin-imipenem combinations were investigated. Microbiological response was examined by log changes at 6, 24, and 48 h. Colistin combined with imipenem at clinically relevant concentrations increased the levels of killing of MDR and colistin-heteroresistant isolates at both inocula. Substantial improvements in activity with combinations were observed across 48 h with all colistin concentrations at the low inoculum and with colistin at 4× and 16× MIC (or 4 and 32 mg/liter) at the high inoculum. Combinations were additive or synergistic against imipenem-resistant isolates (MICs, 16 and 32 mg/liter) at the 10(6)-CFU inoculum in 9, 11, and 12 of 18 cases (i.e., 9 combinations across 2 isolates) at 6, 24, and 48 h, respectively, and against the same isolates at the 10(8)-CFU inoculum in 11, 7, and 8 cases, respectively. Against a colistin-resistant strain (MIC, 128 mg/liter), combinations were additive or synergistic in 9 and 8 of 9 cases at 24 h at the 10(6)- and 10(8)-CFU inocula, respectively, and in 5 and 7 cases at 48 h. This systematic study provides important information for optimization of colistin-imipenem combinations targeting both colistin-susceptible and colistin-resistant subpopulations.

[Assessment of efficacies of imipenem, cefoperazone-sulbactam and cefepime in rats with experimental thigh abscess model with multidrug resistant and susceptible Acinetobacter baumannii strains]. / Sefoperazon-sulbaktam, imipenem ve sefepimin antibiyoterapi etkinliklerinin çogul dirençli ve duyarli acinetobacter baumannii ile olusturulan deneysel ikili apse modelinde karsilastirilmasi.

Imipenem, cefaperazon-sulbactam and cefepime are the antibiotics of choice for the treatment of soft tissue infections due to Acinetobacter baumannii. In this study, it was aimed to determine the invivo and invitro efficacy of, these antibiotics against drug susceptible and multidrug resistant A.baumannii in an experimental abscess model. Abscess models were established in Wistar-Albino type female rats. Susceptibility tests were performed by E-test. Rats were divided randomly into four groups with eight rats in one group. Standard absorbent paper discs containing 6 log10 CFU microorganisms were used to form an abscess model. The first group was regarded as the control group and the other three groups were the study group each treated with one of the test antibiotics. Cardiac blood samples for serum antibiotic efficacy test, were obtained on the fourth day of treatment and 30 minutes after the last dose. The number of live bacteria at the area of infection was determined by colony count method. All of the three antibiotics reached sufficient concentration in sera of rats and there were no statistically important difference between the efficacies of these antibiotics (p= 0.778). In all of the antibiotic-treated groups, the weight of the abscess material were less, macroscopic views were smaller and the colony counts per gram of abscess tissue were less than the control group (p< 0.001). All antibiotics were effective against susceptible and resistant strains in vitro. No resistance was detected against imipenem, cefaperazon-sulbactam and cefepime in the course of therapy. Cefaperazone-sulbactam and cefepime were as effective as imipenem against susceptible and multi-drug resistant A.baumannii both in vivo and in vitro. Since irrational use of extended spectrum cephalosporins are frequently associated with the emergence of carbapenem resistant strains, the use of relatively narrow spectrum antibiotics should better be considered in the empirical treatment of A.baumannii infections.

Efficacy of tigecycline vs. imipenem in the treatment of experimental Acinetobacter baumannii murine pneumonia.

The in vivo activity of tigecycline was evaluated in an experimental pneumonia model (C57BL/6 mice) by Acinetobacter baumannii. Two clinical strains were used: minimum inhibitory concentrations (MICs) of imipenem and tigecycline 1 and 2 microg/mL (imipenem-susceptible, IPM-S), and 8 and 2 microg/mL (imipenem-intermediate, IPM-I), respectively. For imipenem (30 mg/Kg), T/CMI (h) were 1.04 and 0.51 for IPM-S and IPM-I, respectively. For tigecycline (5 mg/Kg), the area under the concentration-time curve (AUC)/MIC(0-24 h) (serum and lung) were 9.24 and 4.37 (for the two strains), respectively. In the efficacy experiments with the IPM-S, imipenem (log CFU/g 3.59 +/- 0.78, p = 0.006) and tigecycline (2.82 +/- 1.2, p = 0.054) decreased the bacterial counts in lungs with respect to its controls; with the IPM-I, both imipenem (1.21 +/- 0.52, p = 0.002) and tigecycline (3.21 +/- 0.28, p = 0.035) decreased the bacterial counts with respect to the controls. In the survival experiments, with the IPM-S, the mortality was the same in the control (67%) and in the tigecycline (77%) groups, and imipenem reduced it (21%, p = 0.025); with the IPM-I, the mortality was the same in the control (87%) and in the tigecycline (85%) groups, and imipenem (0%) reduced it (p < 0.001). In summary, the present study shows that tigecycline is less efficacious than imipenem in the treatment of experimental A. baumannii pneumonia caused by IPM-S and IPM-I strains.

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

PURPOSE: This 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. METHODS: A 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. FINDINGS: Thirty 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 (CLd) 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. IMPLICATIONS: CrCl and Qd had significant effects on CLc and CLd, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.

Hydrophilic interaction chromatography/tandem mass spectrometry for the simultaneous determination of three polar non-structurally related compounds, imipenem, cilastatin and an investigational beta-lactamase inhibitor, MK-4698, in biological matrices.

A method coupling hydrophilic interaction chromatography (HILIC) with tandem mass spectrometry (MS/MS) has been developed for the simultaneous determination of three polar non-structurally related compounds--a carbapenem antibiotic, imipenem (IMP), a renal dehydropeptidase inhibitor, cilastatin (CIL), and an investigational beta-lactamase inhibitor, MK-4698 (BLI), in rat plasma, monkey plasma and mouse blood. The analytes were extracted through protein precipitation, chromatographed on a Waters Atlantis HILIC column, and detected on a Sciex API4000 mass spectrometer using a Turbo-Ion Spray ion source in positive ionization mode following multiple-reaction monitoring (MRM). The assay dynamic range was 0.1-100 microg/mL for IMP, CIL and BLI, respectively, using a total of 20-25 microL biologic samples, and the total HPLC/MS/MS run time was 4 min/injection. The assay was found to be sensitive, selective and reproducible. The challenges, namely, sample stability, blood sample processing, matrix effect in monkey study samples, and dilution re-assays for the limited mouse blood samples, are resolved and discussed. This technique allowed rapid analysis of polar compounds in biologic matrixes with satisfactory chromatographic retention and increased throughput.

A novel reversed-phase high-performance liquid chromatographic assay for the simultaneous determination of imipenem and meropenem in human plasma and its application in TDM.

A rapid and specific reversed-phase high-performance liquid chromatographic (RP-HPLC) assay with UV detection has been developed and validated for the simultaneous determination of imipenem and meropenem in human plasma. The extraction process was performed through protein precipitation method using acetonitrile and dichloromethane, and the recoveries of quality controls (QCs) were > 91.5%. Isocratic elution followed by gradient elution of acetonitrile and water was employed over a C18 analytical column for separation. The detection was performed at 298 nm. This method was accurate and reproducible (coefficient of variation, CV < 8%), allowing quantification of carbapenem at the plasma-level ranges from 0.1 to 100 µg/ml without interference of any of the 30 frequently prescribed drugs. Stabilities of imipenem and meropenem were determined with or without stabilizer solutions at -80°C, -20°C, +4 °C and room temperature 20°C. These two drugs showed higher stability at the low temperatures. Addition of 3-(N-morpholino) propanesulfonic acid (MOPS) might also increase their stability. The results of therapeutic drug monitoring (TDM) in neonates and adults showed high inter- and intra- individual variabilities in the trough concentrations of imipenem and meropenem, thus confirming the importance and necessity of TDM. For neonatal patients, imipenem 20 mg/kg, q12h (40mg/kg/day) failed to produce significant therapeutic effects, and either the dose or the frequency was adjusted to achieve 60mg/kg/day or above to maintain the trough concentration required for the curative effect. The low operational cost and good separation efficiency would help implement this assay for the routine therapeutic drug monitoring of imipenem and meropenem in hospitals.

Therapeutic drug monitoring of imipenem and the incidence of toxicity and failure in hospitalized patients: a retrospective cohort study.

OBJECTIVES: Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is increasingly employed to ensure adequate antibiotic exposure and slow emergence of resistance. Imipenem's therapeutic range has not been defined; we report plasma concentrations and clinical outcomes of patients receiving imipenem for bacterial infections. METHODS: All hospitalized adult patients undergoing imipenem TDM during therapy for suspected or confirmed bacterial infections between 1 January 2013 and 28 February 2017 were included in this single-centre retrospective cohort. The primary outcome was incidence of clinical toxicity; secondary outcomes included incidence of clinical failure and median imipenem concentrations in those with and without toxicity and/or failure. Total imipenem concentrations were measured via high-performance liquid chromatography with ultraviolet detection. RESULTS: A total of 403 imipenem levels were drawn from 300 patients. Fifteen (5%) patients experienced an adverse event considered at least possibly related to imipenem. Eighty-eight (29%) patients had clinical failure; augmented renal clearance appeared to emerge as a protective factor against failure (OR 0.42; 95% CI 0.20-0.89). Median first-measure trough concentration was 3.2 mg/L (IQR 1.7-6.5). Patients with suspected toxicity did not have higher concentrations. Patients whose dose was not increased after a trough level <2 mg/L was returned trended towards increased clinical failure (3/28 (11%) vs. 12/63 (19%)), though the difference was not statistically significant. CONCLUSIONS: Toxicity was rare and clinical failure frequent in this cohort of patients whose imipenem concentrations were generally low and occasionally undetectable. Larger trials are needed to define optimal imipenem exposure.

Simultaneous determination of three carbapenem antibiotics in plasma by HPLC with ultraviolet detection.

A simple, precise and accurate high-performance liquid chromatography (HPLC) method using ultraviolet (UV) detection has been developed for simultaneous determination of carbapenem antibiotics: imipenem, meropenem and ertapenem in human plasma. Samples were spiked with ceftazidime as internal standard and proteins were precipitated by acetonitrile. Separation was achieved on a C8 column with a mobile phase composed of phosphate buffer 0.1M (pH 6.8) and methanol in gradient elution mode. Detection was performed at 298 nm. Calibration curves were linear from 0.5 to 80 mg/L for each compound, with correlation coefficients over 0.997. Intra- and inter-day validation studies showed accuracy between -4.5 and 8.1% and precision below 10.4%. Mean recoveries were 82.2, 90.8 and 87.7% for imipenem, meropenem and ertapenem, respectively. This method provides a useful tool for the therapeutic drug monitoring of carbapenems.

Pharmacokinetics and pharmacodynamic assessment of imipenem in the intraperitoneal fluid of abdominal surgery patients.

BACKGROUND: Imipenem is used to treat intra-abdominal infections, however, this treatment would benefit from a better understanding of imipenem penetration into the abdominal cavity. METHODS: Imipenem 500 mg was infused to 10 laparotomy patients. The total drug concentrations in plasma and intraperitoneal fluid were analyzed noncompartmentally and 3-compartmentally (population pharmacokinetic analysis), and used for a Monte Carlo simulation with minimum inhibitory concentration data. RESULTS: The AUC(0-infinity) ratio of the intraperitoneal fluid to the plasma was 0.82 +/- 0.06 (mean +/- SD, n = 6). The pharmacodynamic exposures in the intraperitoneal fluid were higher than in the plasma. The probabilities of achieving a bacteriostatic/bactericidal target (20/40% of the time above minimum inhibitory concentration for 24 h) in the intraperitoneal fluid using a regimen of 500 mg every 8 h against the Bacteroides fragilis group, Escherichia coli and Klebsiella species were 97.3/89.1, 98.8/97.2 and 100/98.2%, respectively. However, a regimen of 1,000 mg every 8 h was needed to achieve 96.7/89.3% against Pseudomonas aeruginosa. CONCLUSION: These results may help us to understand the intraperitoneal penetration of imipenem and to determine the dosing regimen for intra-abdominal infections.

Effect of elevated imipenem/cilastatin minimum inhibitory concentrations on patient outcomes in Gram-negative bloodstream infections.

OBJECTIVES: Carbapenem minimum inhibitory concentration (MICs) are known to predict outcomes for patients with Gram-negative bacteraemia. However, limited data exist on how MICs influence such outcomes when organisms are classified as carbapenem-resistant. The purpose of this study was to evaluate the effect of increasing imipenem/cilastatin MICs on mortality in patients with Gram-negative bloodstream infection (BSI). METHODS: Patients with an imipenem/cilastatin-resistant (MIC>4mg/L) monomicrobial Gram-negative BSI were eligible for inclusion in the study and were assessed for baseline characteristics, organ function, microbiological data, timing and type of therapeutic treatment, and in-hospital mortality. RESULTS: A total of 62 patients with imipenem/cilastatin-resistant bacterial isolates (MIC>4mg/L) were retrospectively studied. Time to event analyses found no difference between patients who received carbapenem therapy and those who did not (P=0.10). After adjustment, patients receiving directed therapy were less likely to die (adjusted hazard ratio=0.35, 95% confidence interval 0.15-0.83; P<0.01), whereas higher modified Acute Physiology and Chronic Health Evaluation (APACHE) II score and days to positive culture were associated with non-survival. CONCLUSION: This study did not demonstrate a relationship between receipt of a carbapenem and mortality in patients with carbapenem-resistant Gram-negative BSI.

Activity of imipenem against VIM-1 metallo-beta-lactamase-producing Klebsiella pneumoniae in the murine thigh infection model.

The in-vivo activity of imipenem against VIM-1-producing Klebsiella pneumoniae (VPKP) was assessed in a thigh infection model in neutropenic mice. Animals were infected with three VPKP isolates (imipenem MICs 2, 4 and 32 mg/L, respectively) and a susceptible clinical isolate (MIC 0.125 mg/L) that did not produce any beta-lactamase with broad-spectrum activity. Bacterial density at the site of infection was determined after imipenem treatment (30 and 60 mg/kg every 2 h for 24 h). The log(10) reduction in CFU/thigh was greatest for the wild-type isolate, intermediate for the two imipenem-susceptible VPKP isolates, and lowest for the imipenem-resistant VPKP isolate. Whilst in-vivo imipenem activity appeared reduced against in-vitro susceptible VIM-1 producers compared with a VIM-1-negative control, an increased drug dosage could moderate this reduction.

Simultaneous determination of cefepime, vancomycin and imipenem in human plasma of burn patients by high-performance liquid chromatography.

A liquid chromatographic method with UV detection for simultaneous determination of cefepime, vancomycin and imipenem has been developed. Cefuroxime was used as internal standard. After the clean up of samples by plasma protein precipitation, 5 microl of the extract were injected into the chromatograph and peaks were eluted from the Sulpelcosil LC-18 column using a mobile phase consisting of 0.075 M acetate buffer:acetonitrile (92:8, v/v), pH 5.0 at low rate (0.8 ml/min). The detection wavelength was 230 nm. The limit of detection was 0.4 microg/ml for cefepime and 0.2 microg/ml for vancomycin and imipenem. The method was applied to plasma samples of burn patients, and only small volumes of plasma were required for the simultaneous determination of those antimicrobial agents.

Chronopharmacokinetics of imipenem in the rat.

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C(max), T(max), elimination half-life (t(1/2)), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C(max) (49%), T(max) (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.