Pharmacokinetics of imipenem in sheep with special reference to its hepato-renal effects.

BACKGROUND: Imipenem is a carbapenem antibiotic with a broad spectrum of activity. The aim of this study was to determine the pharmacokinetics of imipenem after single intravenous and intramuscular injections and the effect of repeated intramuscular injections on hepato-renal functions in sheep. METHODS: Imipenem concentrations in plasma and urine were determined by a microbiological agar plate assay. RESULTS: Following intramuscular injection, imipenem was rapidly absorbed and the peak plasma concentration was 9.99 microg ml(-1) and the systemic bioavailability was 65.97%. Urine concentrations of imipenem were much higher than in plasma. Light and electron microscopy evidenced little changes in the kidney and liver. CONCLUSION: Imipenem is likely to be efficacious in most urinary tract infections and has no adverse effects on hepato-renal structures and functions.

Spectrophotometric and chemometric methods for determination of imipenem, ciprofloxacin hydrochloride, dexamethasone sodium phosphate, paracetamol and cilastatin sodium in human urine.

New accurate, sensitive and selective spectrophotometric and chemometric methods were developed and subsequently validated for determination of Imipenem (IMP), ciprofloxacin hydrochloride (CIPRO), dexamethasone sodium phosphate (DEX), paracetamol (PAR) and cilastatin sodium (CIL) in human urine. These methods include a new derivative ratio method, namely extended derivative ratio (EDR), principal component regression (PCR) and partial least-squares (PLS) methods. A novel EDR method was developed for the determination of these drugs, where each component in the mixture was determined by using a mixture of the other four components as divisor. Peak amplitudes were recorded at 293.0 nm, 284.0 nm, 276.0 nm, 257.0 nm and 221.0 nm within linear concentration ranges 3.00-45.00, 1.00-15.00, 4.00-40.00, 1.50-25.00 and 4.00-50.00 µg mL(-1) for IMP, CIPRO, DEX, PAR and CIL, respectively. PCR and PLS-2 models were established for simultaneous determination of the studied drugs in the range of 3.00-15.00, 1.00-13.00, 4.00-12.00, 1.50-9.50, and 4.00-12.00 µg mL(-1) for IMP, CIPRO, DEX, PAR and CIL, respectively, by using eighteen mixtures as calibration set and seven mixtures as validation set. The suggested methods were validated according to the International Conference of Harmonization (ICH) guidelines and the results revealed that they were accurate, precise and reproducible. The obtained results were statistically compared with those of the published methods and there was no significant difference.

Electrochemical study of imipenem's primary metabolite at the mercury electrode. Voltammetric determination in urine.

Imipenem shows a fast chemical conversion to the more stable imin form (identical to that from biochemical dehydropeptidase degradation) in aqueous solutions that shows a wave at lower cathodic potential than the imipenem one. The aim of this work is the study of the electrochemical behaviour of the primary metabolite of imipenem (M1) and the proposal of electrochemical methods for the determination of M1 in human urine samples. Electrochemical studies were realized in phosphate buffer solutions over pH range 2.0-8.0 using differential pulse polarography, dc-tast polarography, cyclic voltammetry and linear sweep voltammetry (staircase). In acidic media, a non-reversible diffusion-controlled reduction involving two electrons and two protons occurs and the mechanism for the reduction was suggested. A differential pulse polarographic method for the determination of M1 in the concentration range 10(-6) to 10(-4)M with a detection limit of 4.5 x 10(-7)M was proposed. Also, a method based on controlled adsorptive pre-concentration of M1 on the hanging mercury drop electrode (HMDE) followed by linear sweep voltammetry allows its determination in the concentration range 2 x 10(-9) to 4 x 10(-8)M with a detection limit of 1.05 x 10(-9)M. The proposed methods have been used for the direct determination of M1 in spiked human urine and real human-derived urine with good results and should be appropriate for monitoring purposes.

Pharmacokinetic interactions of ceftazidime, imipenem and aztreonam with amikacin in healthy volunteers.

The common usage of extended spectrum beta-lactams co-administered with amikacin in everyday clinical practice for infections by multidrug-resistant isolates has created the need to search for pharmacokinetic interaction. Eighteen healthy volunteers were enrolled in the study; six were administered 1g of ceftazidime singly intravenously or combined with 0.5 g of amikacin; six received 0.5 g of imipenem singly or combined with 0.5 g of amikacin and six 1g of aztreonam singly or combined with 0.5 g of amikacin. Blood and urine samples were collected at regular time intervals and apparent serum levels were determined by a microbiological assay. Co-administration of ceftazidime and amikacin resulted in higher C(max) and AUC for amikacin than when administered alone. Co-administration of imipenem and amikacin resulted in higher C(max) for imipenem than when administered alone. The tested interactions did not affect plasma half-life (t(1/2)) and clearance rate of any antimicrobial compared with its single administration. All tested drugs were mainly eliminated by glomerular filtration. It is concluded that co-administration of ceftazidime, imipenem or aztreonam with amikacin in healthy volunteers might affect C(max) and AUC without influencing any other pharmacokinetic parameter. The probable clinical endpoint is that giving ceftazidime, imipenem or aztreonam with amikacin might result in a transient elevation of beta-lactam serum levels without further affecting the complete pharmacokinetic profile of each drug as obtained after administration of the drug alone.

Studies on new dehydropeptidase inhibitors. III. Biological properties of WS1358A1.

WS1358A1, a novel inhibitor of renal dehydropeptidase (DHP), augmented the urinary recovery of a carbapenem antibiotic imipenem and improved its protective effect in experimental infections when simultaneously administered to mice with the antibiotic. WS1358A1 was a competitive DHP inhibitor with a Ki value of 1.6 x 10(-7) M.

Determination of imipenem in human plasma, urine and tissue by high-performance liquid chromatography.

A simple and reliable HPLC method is described for the new beta-lactam antibiotic imipenem; suitable extraction procedures for the drug in human plasma, urine and prostatic tissue are described. The figures of merit for the assays are reported and examples given of their application.

[Influence of urine pH and cations on antimicrobial activities of penems].

We compared the antimicrobial activities of penems in human urine with those in Mueller-Hinton broth in order to clarify the usefulness of penems for urinary tract infections. Furthermore, we also investigated the influence of urine components, such as pH, magnesium concentration and calcium concentration, on the antimicrobial activities of penems. Three penems, i.e., imipenem, panipenem and meropenem were employed. And two bacterial strains, i.e., Escherichia coli NIHJ JC-2 and Pseudomonas aeruginosa 18s, were tested. There was no significant difference in MBCs between human urine and Mueller-Hinton broth against E. coli. However, MBCs of penems in human urine was lower than those in Mueller-Hinton broth against P. aeruginosa. On the other hand, MBCs of penems against these two strains were low when urine pH was high or urine calcium concentration was low. No influence of urine magnesium concentration on MBCs of penems was seen. From these results, it was suggested that we should measure the antimicrobial activities of penems not only in Mueller-Hinton broth, but also in human urine, when we administer penems to patients with urinary tract infections. And we should foresee the clinical effects of penems against urinary tract infections paying attention to urine pH of the patients.

Population pharmacokinetic-pharmacodynamic target attainment analysis of imipenem plasma and urine data in neonates and children.

BACKGROUND: Population pharmacokinetic (PK)-pharmacodynamic target attainment analysis of imipenem was performed to elucidate the PK properties in neonates and children and to rationalize and optimize dosing regimens. METHODS: Population PK models were separately developed in neonates and children by simultaneously fitting plasma and urine data from 60 neonates and 39 children. The newly developed models were then used to estimate the probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration) against clinical isolates of common bacteria in pediatric patients. RESULTS: The data were best described by a 1-compartment model in neonates and a 2-compartment model in children, respectively. Renal clearance in children (0.187 L/h/kg) was double that of neonates (0.0783 L/h/kg), whereas the volume of distribution at steady-state was approximately 1.8-fold larger in neonates (0.466 L/kg) than in children (0.260 L/kg). Age was not a statistically significant covariate in the PK of both groups. Infusions (0.5 h) of 15 mg/kg every 8 h (45 mg/kg/day) and 25 mg/kg every 12 h (50 mg/kg/day) were shown to be sufficient against common bacterial isolates in both patient populations. However, 1.5-h infusions of 25 mg/kg every 8 h (75 mg/kg/day) in neonates and 25 mg/kg every 6 h (100 mg/kg/day) in children were required to be effective against Pseudomonas aeruginosa (minimum inhibitory concentration for 90% of the isolates=16 µg/mL). CONCLUSIONS: These results explain the changes in imipenem PK properties during the human growth process and provide guidance for tailoring dosing regimens in each pediatric age group.

Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data.

In this study, a pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis of imipenem (IPM) in patients with impaired renal function was conducted. IPM (500 mg) was administered via a 0.5-h or 1-h infusion to 27 patients with varying renal function. A population PK model was developed by simultaneously fitting plasma and urinary concentration data. A two-compartment model adequately described IPM pharmacokinetics, and creatinine clearance (CL(Cr)) was identified as the most significant covariate. A PK-PD simulation predicted the probabilities of attaining the target in plasma [40% of the time above the minimum inhibitory concentration (MIC)] and defined the PK-PD breakpoints (the highest MICs at which the probabilities were ≥90%). In a patient with a CL(Cr) of 90 mL/min, prolongation of infusion time (from 0.5 h to 1.5 h) increased the PK-PD breakpoint from 1 µg/mL to 2 µg/mL with a 500 mg dose every 8h (q8h) and from 2 µg/mL to 4 µg/mL with a 500 mg dose every 6h (q6h). Meanwhile, in a patient with a CL(Cr) of 20 mL/min, the PK-PD breakpoints for both 0.5-h and 1.5-h infusions were 1 µg/mL with a 250 mg dose every 12h (q12h), 2 µg/mL with a 250 mg dose q8h and a 500 mg dose q12h, and 4 µg/mL with a 250 mg dose q6h. These results indicate that a shorter dosing interval is beneficial in patients with impaired renal function as it results in greater PK-PD breakpoints and a reduction in excessive maximum plasma concentrations. These results help to optimise IPM regimens, particularly in patients with impaired renal function.

Urea as new stabilizing agent for imipenem determination: electrochemical study and determination of imipenem and its primary metabolite in human urine.

Imipenem shows a fast chemical conversion to a more stable imin form (identical to that of biochemical dehydropeptidase degradation) in aqueous solutions and stabilizing agents used avoid its electrochemical study and determination. The aim of this work is the proposal of urea as stabilizing agent which allows the electrochemical study of imipenem and the proposal of electrochemical methods for the determination of imipenem and its primary metabolite (M1) in human urine samples. Electrochemical studies were realized in phosphate buffer solutions over pH range 1.5-8.0 using differential-pulse polarography, DC-tast polarography, cyclic voltammetry and adsorptive stripping voltammetry. In acidic media, a non-reversible diffusion-controlled reduction involving a two steps mechanism which involves one electron and one proton in the first step and two electrons and two protons in the second step occurs and the mechanism for the reduction was suggested. A differential-pulse polarographic method for the determination of imipenem in the concentration range 3.2x10(-6) to 2x10(-5)M (0.95-3.4 mg/L) and its primary metabolite in the concentration range 1.4x10(-6) to 10(-4)M (0.43-26.1 mg/L) with detection limits of 9.6x10(-7)M (0.28 microg/L imipenem) and 4.3x10(-7)M (0.14 microg/L M1) was proposed. Also, a method based on controlled adsorptive pre-concentration of imipenem on the hanging mercury drop electrode followed by voltammetric measure, allows imipenem determination in the concentration range 1.8x10(-8) to 1.2x10(-6)M (5.42-347 microg/L) with a detection limit of 5.4x10(-9)M (1.63 microg/L). The proposed methods have been used for the direct determination of the analytes in a pharmaceutical formulation and human urine.

A beneficial interaction between imipenem and piperacillin possibly through their renal excretory process.

In order to assess the beneficial mechanism of the concomitant use of imipenem (IPM) with piperacillin (PIPC) for the treatment of serious infectious diseases such as sepsis, the effects of PIPC on the uptake of IPM by rat renal cortical slices and on the plasma concentrations of IPM after intravenous infusion to rabbits were studied. The uptake of IPM by the rat renal cortical slices was significantly inhibited by p-aminohippurate, probenecid and PIPC whereas the uptake of PIPC by the slices was slightly decreased in the presence of IPM. When IPM was administered together with PIPC by 1-h infusion, the plasma concentrations of IPM were significantly increased during the infusion. These results imply that PIPC possibly interferes with the renal transport of IPM mediated by an organic anion transporter across the renal basolateral membranes, which leads to a longer period above the minimum inhibitory concentrations of IPM.

Comparative study of pharmacokinetics and serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin.

We compared the pharmacokinetics and the serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Fifteen healthy volunteers received 1 g of cefpirome, ceftazidime, and ceftriaxone intravenously, 500 mg of imipenem-cilastatin intravenously, and 500 mg of ciprofloxacin orally. High-performance liquid chromatographic assays were used to quantitate unchanged antibiotic in plasma and urine. Serum bactericidal activities were determined against six clinical isolates each of Staphylococcus aureus, Enterobacter cloacae, and Pseudomonas aeruginosa by using a modified microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977). Overall, cefpirome exhibited pharmacokinetics similar to those of ceftazidime: half-life (t1/2), 1.95 h; concentration at 1 h (C1h), 47 to 49 micrograms/ml for both antibiotics. Ceftriaxone displayed the longest t1/2 (7.65 h) and the highest C1h (137.8 micrograms/ml), while we observed the shortest t1/2 (1.05 h) and the lowest C1h (19.85 micrograms/ml) with imipenem. At 1 h, cefpirome and, even more so, imipenem showed significantly better serum bactericidal activities against S. aureus (1:273 and 1:80) than did the other antibiotics (P less than 0.0005; analysis of variance with randomized block design and Bonferroni correction). Against E. cloacae, we observed the highest serum bactericidal titers at 1 h with cefpirome, and this superiority vis-à-vis the other antibiotics tested was maintained for up to 8 h after dosing. Ceftazidime remained the most active agent tested against P. aeruginosa (serum bactericidal activity titers, 1:43 at 1 h) up to 8 h. In summary, the study showed that cefpirome and imipenem provide more potent serum bactericidal activities than do broad-spectrum cephalosporins against S. aureus; thus, both of these antibiotics should be adequate against serious S. aureus infections. In addition, cefpirome appears to be a promising alternative for treatment of infections caused by E. cloacae and P. aeruginosa.