Imipenem-cilastatin Research Articles

The role of β-lactam/β-lactamase inhibitors in the management of mixed infections

Microbiological studies show that the in vitro antimicrobial activity of sulbactam–ampicillin encompasses not only Gram-positive and Gram-negative aerobes, but also anaerobes. Such a broad spectrum of activity suggests its suitability as monotherapy for the empiric management of polymicrobial infections. Typical mixed infections, which are frequently life-threatening, include those occurring in the abdomen or pelvis, diabetic foot infections, and brain abscess. Numerous comparative clinical studies have revealed the clinical and bacteriological efficacy of sulbactam–ampicillin to be comparable to that of imipenem–cilastatin and the second-generation cephalosporins cefoxitin and cefotetan. In addition, other studies have demonstrated that sulbactam–ampicillin monotherapy is cost-beneficial. A reduction in the duration of hospitalization, the lack of potentially toxic side-effects, and lower drug costs associated with monotherapy all contribute to the cost-effectiveness of sulbactam–ampicillin.

Conclusion: Fourth-generation cephalosporins: new hopes and new duties.

Conclusion: Fourth-generation cephalosporins: new hopes and new duties.

イミペネム／シラスタチンナトリウムとバルプロ酸ナトリウム同時投与における薬物動態の変化

The plasma sodium valproate (VPA) concentration was significantly lower than the control 0.5, 1, 2 hours after the simultaneous administration of VPA with imipenem/cilastatin (IPM/CS), but the blood cell VPA/plasma VPA concentration was significantly higher at 2 hours after VPA administration. When we injected IPM instead of IPM/CS into rats, the plasma VPA concentration demonstarated similar low levels. The pharmacokinetic parameters of plasma VPA, the volume of distribution (Vd) and clearance (CL) were significantly higher at 1.6 and 1.7 times basal levels white the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve up to 3 hours (AUC0→3) significantly decreased by 0.7 and 0.6 times the basal level after the simultaneous administration of VPA and IPM/CS. The rate of VPA unbound protein was 30.3% before injecting the IPM vein. Although, when IPM was injected inside the vein, it increased by 37.3% at 1 minute and significantly increased by 49.9% at 15 minutes after the administration of IPM. The liver and brain VPA tissue concentration significantly decreased after the simul taneous administration of VPA with IPM/CS.Based on these finding a large amount of unbound type VPA which was produced by competition with a protein binding part of VPA depending on IPM was distributed in the tissue. VPA was especially distributed to blood cells and the kidney. The VPA that had been distributed in the liver later metabolized and was excreted. Therefore, the VPA concentration in plasma, liver and brain was observed to significantly decrease.

Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates.

L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.

Treatment of diabetic foot infection: an open randomised comparison of imipenem/cilastatin and piperacillin/clindamycin combination therapy

Objective: To compare the clinical outcome and bacteriological response in diabetic patients with a foot infection treated with imipenem/cilastatin or a combination of piperacillin/clindamycin. Methods: Patients hospitalised for diabetic foot lesions Wagner Stages II, III or IV were randomly assigned to receive either imipenem/cilastatin 500 mg QID or piperacillin 3000 mg QID in combination with clindamycin 600 mg TID. Cultures were obtained and clinical observations were made. Results: Forty-six patients (mean age 71.4 ± 9.8 years) entered the study, 22 received imipenem/cilastatin (IC) and 24 received piperacillin/clindamycin (PCL) combination therapy. In the IC group 22.2% was considered to be clinically cured, 76.2% improved. In the PCL group this was 25.0% and 50.0%, respectively. In the IC treatment group 45.0% of baseline pathogens was eradicated compared to 70.0% in the PCL group. Adverse events were more often reported in PCL treated patients (50.0% vs. 19.0% P < 0.05). Conclusions: Impipenem/cilastatin and piperacillin/clindamycin combination therapy were equally effective in the treatment of patients with diabetic foot lesions. The imipenem/cilastatin regimen caused less side effects.

Therapeutic Efficacies of Penicillin G, Cefotaxime, and Imipenem/Cilastatin against Penicillin-Resistant Pneumococcal Pneumonia in CBA/J Mice

We compared the therapeutic efficacies of penicillin G (PCG), cefotaxime (CTX), and imipenem/cilastatin (IPM/CS) against penicillin-resistant<i>Streptococcus pneumoniae</i> pneumonia in CBA/J mice. In pneumonia induced by strain TUH39 (PCG MIC; 0.063μg/mL), eight 2.5mg/kg doses of PCG administered at 1.5 hour intervals beginning 36 hours after infection reduced the number of bacteria in the lungs below the limit of detection. In contrast, a similar regimen failed to lower the number of organisms following infection with strain TUM741 (PCG MIC; 1μg/mL); however, PCG doses of 8 × 10 and 8 × 40mg/kg reduced bacterial numbers in a dose-dependent manner. CTX (MIC; 0.5μg/mL) and IPM/CS (MIC; 0.125μg/mL) at 6 × 40mg/kg were more effective than PCG at the same dose against strain TUM741 pneumonia; these antibiotics eradicated bacteria in lungs of 2 out of 5 and 5 out of 5 mice, respectively. In accord with the pulmonary clearance results, survival of mice treated with PCG (6 × 40 and 6 × 160mg/kg), CTX (6 × 40mg/kg) and IPM/CS (6 × 40mg/kg) were 30%, 80%, 40% and 100%, respectively. Pharmacokinetic analysis in lungs revealed that IPM/CS was superior to CTX and PCG in several parameters. These results demonstrate therapeutic responses to CTX, IPM/CS and high-dose PCG in a CBA/J mouse model of penicillin-resistant pneumococcal pneumonia. Results with IPM/CS were particularly favorable, suggesting this antibiotic combination as a potential first-line treatment for penicillin-resistant<i>S. pneumoniae</i> pneumonia.

Ticarcillin–clavulanate as an alternative to imipenem–cilastatin

Ticarcillin–clavulanate as an alternative to imipenem–cilastatin

Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies.

The incidence of emergent resistance and clinical factors affecting its development were evaluated by retrospective review of 173 studies encompassing over 14,000 patients. Eight antibiotic classes and 225 individual treatment regimens were evaluated. Emergent resistance occurred among 4.0% of all organisms and 5.6% of all infections treated. It appeared to be significantly more frequent with penicillin and aminoglycoside monotherapy, with significantly lower rates associated with imipenem-cilastatin, aztreonam, and combination therapy. Clinical failure also appeared to be significantly more likely to occur after emergence of resistance among organisms treated with fluoroquinolones or aminoglycosides. Infections associated with higher resistance rates were cystic fibrosis, osteomyelitis, and lower respiratory tract infections. Resistance was most common in patients in intensive care units or receiving mechanical ventilation. It was also significantly frequent among studies performed in university or teaching hospitals. Organisms associated with high resistance rates were Pseudomonas aeruginosa, Serratia, Enterobacter, and Acinetobacter sp. Factors such as infection type, underlying diseases, type of institution, and specific pathogens warrant consideration when examining emergent resistance.

Evaluation and Financial Impact of Imipenem/Cilastatin Dosing in Elderly Patients Based on Renal Function and Body Weight

Objective To evaluate the financial impact of adjusting imipenem/cilastatin (IC) dosages in elderly patients based on estimated creatinine clearance (Clcr) and body weight. Design Retrospective cost-savings analysis. Setting A 500-bed, university-affiliated, tertiary-care hospital. Main Outcome Measures All courses of IC administered to patients over age 60 during a four-month period were retrospectively assessed for appropriateness based on both dosing interval and dosage. Manufacturer's guidelines for adjusting the IC dosage based on estimated Clcr and body weight were used to define appropriate dosing. The cost savings that could have been realized by appropriately adjusting IC dosage was calculated for the study period and extrapolated to project an annual cost savings. Results Only 37 percent of patient days of therapy and 32 percent of therapy courses were judged as appropriate based on both dose amount and interval. The projected annual cost savings that could have been realized by appropriately adjusting IC dosage based on estimated Clcr and body weight was $11,550. Conclusions Adjustment of IC dosages in elderly patients based on estimated Clcr and body weight can result in significant cost savings.

Erratum to: The Study of Apparent Bacterial Disappearance and Slow-Growing Bacteria in Urine Culture by the Dip-Slide Method in Evaluating the Efficacy of Antimicrobial Drugs

15 patients with complicated urinary tract infections were treated with 500mg/500mg of imipenem/cilastatin (IPM/CS) twice a day for 5 days by intravenous infusion. Urine samples collected from the patients were cultured on dip-slides every day. The effect of the antibiotics in the urine and the problems of slow-growing bacteria were evaluated by comparing the results of untreated urine samples spread on dip-slides with those of urine samples treated by washing.

Chemotherapy with imipenem/cilastatin for severe infections accompanied by malignant hematological disorders

The clinical and bacteriological efficacy of imipenem/cilastatin (IPM/CS) was evaluated in 30 cases of serious infections associated with hematological malignancies. 1. Among 28 evaluable cases, excellent efficacy was obtained in 6 cases and good effectiveness in 10 cases, resulting in a high clinical efficacy rate (57.1%). The clinical effectiveness of IPM/CS was not dependent on neutrophil count in peripheral blood. A 53.8% efficacy rate was observed in 26 cases which had received pretreatment with other antibiotics. 2. Antibacterial activities of IPM/CS have so far been evaluated against organisms isolated in 20 of 28 cases: 2 strains of coagulase-negative Staphylococcus, 2 strains of methicillin-resistant Staphylococcus aureus, 2 strains of Enterococcus faecalis, 9 strains of Enterobacter cloacae, and 8 other strains. 3. Among 3 evaluable cases treated with IPM/CS alone, response was good in 1 case. Among 25 patients receiving IPM/CS in combination with an aminoglycoside or a penicillin, the efficacy rate was 60%. 4. Five patients had IPM/CS-related adverse events; nausea and vomiting in 2 cases, seizures in 1 case, small increases in GOT and GPT in 2 cases, and the appearance of casts in urine sediment in 1 case. These patients, however, tolerated the complete course of therapy with IPM/CS except the 2 cases with nausea and vomiting. These results indicate that chemotherapy with IPM/CS is effective for the treatment of severe infectious diseases accompanied by hematological disorders.

Neurotoxicity of panipenem/betamipron, a new carbapenem, in rabbits: correlation to concentration in central nervous system.

The neurotoxic potential of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, was compared with that of imipenem/cilastatin (IPM/CS). The drug concentration in cerebrospinal fluid (CSF) at the onset of epileptogenic electroencephalographic (EEG)-activity and the drug distribution into the central nervous system (CNS) were evaluated. Epileptogenic reactions correlated well with drug levels in CSF, but not with drug levels in circulating plasma. The concentration of PAPM in CSF at the onset of epileptogenic EEG-activity was almost twice that of IPM, suggesting that neurotoxic activity of PAPM is about half that of IPM. In addition, in terms of incidence percent for the epileptogenic EEG-activity, PAPM/BP was found to be less toxic than IPM/CS within the dose of 1.0-1.2 g/kg. Concentrations of PAPM in CSF and brain extracellular fluid after PAPM/BP i.v. infusion were comparable with those of IPM after IPM/CS infusion, indicating the similar characteristics of distribution into the CNS for the two antibiotics. From these results of pharmacologic effects and drug distributions, it is suggested that the neurotoxicity of PAPM/BP is less than half that of IPM/CS.

Clinical efficacy of imipenem/cilastatin sodium in patients with respiratory tract infections caused by Pseudomonas aeruginosa

The clinical utility of imipenem/cilastatin sodium (IPM/CS, Tienam) was studied in 9 patients with respiratory tract infections from whom Pseudomonas aeruginosa was isolated using transtracheal aspiration. The patients treated were 6 males and 3 females, with ages between 42 and 78 years. The infections diagnosed were chronic bronchitis in 5 patients, diffuse panbronchiolitis in 2 and bronchopneumonia in 2. P. aeruginosa alone was isolated from 6 patients and concomitantly with other organisms from 3. Clinical efficacy was good in 6 patients, fairly good in 1 and poor in 2. No side effects or abnormal laboratory test values were observed, except for a slight elevation of LDH in 1 patient. From these results, it appears that IPM/CS is a clinically useful antibiotic for the treatment of respiratory tract infections caused by P. aeruginosa.

チエナムによる神経毒性について

チエナムによる神経毒性について

Imipenem-cilastatin in the treatment of respiratory infections in patients with chronic airways obstruction.

Chest infections with organisms resistant to conventional antibiotics are common in patients with chronic lung disease. We have studied the use of imipenem in 40 (28 M 12 F) patients admitted for treatment of chest infections. Patients were treated with imipenem 0.5 g four times daily by intravenous infusion for 6.3 +/- 1.6 (S.D.) days. Forty-six respiratory pathogens were cultured from 36 patients including 18 Haemophilus influenzae, 6 H. parainfluenzae, 6 Streptococcus pneumoniae, 8 Pseudomonas aeruginosa, and 6 Branhamella catarrhalis. Forty-three of the 46 isolates were sensitive to imipenem, 28 to ampicillin, 33 to tetracycline and 35 to cotrimoxazole. Thirty-eight of the 40 patients improved clinically, and 34 of the 36 patients with positive sputum culture had no pathogens in their sputum after treatment. Twenty patients developed minor phlebitis at the infusion site but there were few other side effects. Imipenem may prove useful in the treatment of chest infections, particularly when the organism is resistant to conventional antibiotics.

Compressed Pellet X-ray Diffraction Monitoring for Optimization of Crystallinity in Lyophilized Solids:Imipenem:Cilastatin Sodium Case

A rapid, quantitative X-ray diffraction method to monitor the relative degree of crystallinity of lyophilized materials is described. The method was applied to determine the degree of crystallinity of imipenem [(5R,6S)-3-[[2(formimidoylamino)ethyl]thio]-6-[(R)-1-hydroxy-ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid] in 60 process related samples of the combination product of imipenem and amorphous cilastatin sodium (sodium (Z)-7-[[(R)-2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxxmido]-2-heptenoate). This assured optimizing process conditions which affect the improvement of crystallinity.

Pharmacokinetics of imipenem-cilastatin in serum and tissue.

Pharmacokinetics of imipenem-cilastatin in serum and tissue.