n-benzoylalanine and panipenem

Carbapenems are beta-lactam antibiotics with a broad antibacterial spectrum and a potent bactericidal activity against both aerobic and anaerobic Gram-positive and Gram-negative organisms. They have been widely investigated in the past, and imipenem/cilastatin (IPM/CS), panipenem/betamipron (PAPM/BP), meropenem (MEPM) and biapenem (BIPM) are presently in clinical use or under trial. Of the carbapenems, imipenem is not readily hydrolysed by microbial beta-lactamase but is hydrolysed to open the beta-lactam ring by DHP-I from kidney and other tissues. In order to achieve greater stability to the enzyme and to prolong the action of the carbapenem in vivo, the co-administration of CS with IPM or the attainment of the chemical construction of the 1-beta methylcarbapenem derivatives in the case of MEPM and BIPM have been performed. However, some difference was found in the DHP-I activity with these carbapenems, but there was no significant difference in the pharmacokinetic parameters: AUC, CLtot, t1/2 and MRT except urinary clearance after administration of these compounds to humans. Considering that MRT as the amount of the antibiotics retained in the body is a clinically important parameter, the structural susceptibility of the carbapenems to the decomposition by DHP-I was suggested to have no clinically meaningful correlation with the pharmacokinetics of these compounds.

Topics: Alanine; Animals; Carbapenems; Dogs; Half-Life; Humans; In Vitro Techniques; Kidney; Macaca fascicularis; Rats; Rats, Wistar; Species Specificity; Thienamycins

Topics: Alanine; Cerebrospinal Fluid; Corpus Callosum; Dexamethasone; Drainage; Humans; Liver Abscess; Magnetic Resonance Imaging; Male; Meningitis, Pneumococcal; Middle Aged; Streptococcus pneumoniae; Thienamycins; Tomography, X-Ray Computed; Treatment Outcome

Panipenem/betamipron (PAPM/BP) may be highly effective for life-threatening Streptococcus pneumoniae infection. However, the efficacy of PAPM/BP for S. pneumoniae infections has not been compared with that of other antimicrobial agents. We retrospectively compared PAPM/BP with other carbapenems for treatment of life-threatening infections in newly hospitalized adults with pneumococcal bacteremia. Clinical information for cases of pneumococcal bacteremia was collected from three teaching hospitals in Japan from January 2003 to December 2010. In total, 17 patients who received PAPM/BP therapy and 34 treated with other carbapenems (27 with meropenem, 4 with imipenem/cilastatin, and 3 with biapenem) were identified. The mean age (71 vs. 70 years old), sex distribution (women, 29 vs. 21 %), Charlson comorbidity index (CCI) (1.5 vs. 1.6), and rates of septic shock (29 vs. 38 %), and meningitis (5.9 vs. 8.8 %) did not differ significantly between the two groups. The inpatient mortality rates were lower in the PAPM/BP group (12 vs. 44 %, p = 0.03). Multiple logistic regression analysis adjusted for age, sex, CCI, and severe sepsis/septic shock showed that use of other carbapenems was associated with higher in-hospital mortality, with an odds ratio of 6.922 (95 % CI, 1.171-40.92) compared to PAPM/BP therapy. Initial PAPM/BP therapy might have a therapeutic advantage over other carbapenems in treatment of severe Streptococcus pneumoniae infections.

Topics: Aged; Aged, 80 and over; Alanine; Anti-Bacterial Agents; Bacteremia; Female; Hospitals, Teaching; Humans; Japan; Logistic Models; Male; Middle Aged; Pneumococcal Infections; Retrospective Studies; Streptococcus pneumoniae; Thienamycins; Treatment Outcome

beta-Lactam antibiotics have been suggested to have some degree of convulsive activity and neurotoxicity in experimental animals as well as in clinical situations. We examined the convulsive activities of a new carbapenem antibiotic, (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxic acid monohydrate (doripenem) using several animals and compared them with beta-lactam antibiotics. In intravenous (IV) injection studies, imipenem/cilastatin, at 400/400mg/kg produced seizure discharges on electroencephalogram (EEG) accompanied with clonic convulsions in rats. Meropenem showed only wet dog shaking behavior at 200 and 400mg/kg. Doripenem caused no changes in the EEG and behavior in rats at 400mg/kg. Imipenem/cilastatin IV potentiated the pentylenetetrazol (PTZ)-induced convulsions in mice at 250/250 mg/kg, while meropenem, panipenem/betamipron, cefazolin or doripenem did not cause any marked effects at up to 500 mg/kg. In mouse intracerebroventricular (ICV) injection studies, imipenem, panipenem and cefazolin induced clonic convulsions in a dose-dependent manner in mice. Doripenem and meropenem did not induce convulsions at up to 100 microg/mouse. In dog ICV injection studies, imipenem produced generalized seizure discharge with clonic convulsions at 100 microg/dog. Meropenem also produced spikes or seizure discharges at 100, 300 and 1,000 microg/dog. However, doripenem had no effects on the EEG and behavior in dogs at any doses. In in vitro binding studies, imipenem, panipenem, cefazolin and meropenem inhibited [(3)H]muscimol binding to the GABA(A) receptor in mouse brain homogenates while doripenem did not cause any inhibition at up to 10mM. In addition, doripenem had no influence on the anti-convulsant actions of valproic acid in the PTZ- or bicuculine-induced convulsive model. These results clearly indicate that doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.

Topics: Alanine; Animals; Anti-Bacterial Agents; Anticonvulsants; Carbapenems; Convulsants; Dogs; Doripenem; Drug Interactions; Electroencephalography; Injections, Intravenous; Injections, Intraventricular; Male; Meropenem; Mice; Mice, Inbred ICR; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Thienamycins; Valproic Acid

Although plasma concentrations of panipenem were elevated and the risk of adverse events would increase in patients with renal impairment, a precise dosage regimen for patients with renal impairment has not been established.. Population pharmacokinetic analyses were performed with plasma concentrations from 26 healthy volunteers and 41 patients. Optimal dosage regimens for patients with renal impairment were determined based on the bacteriostatic index of C(20%T)>(MIC), the concentration corresponding to the time above MIC of 20% of the dosing interval.. The clearance of panipenem and betamipron was correlated with creatinine clearance and the volume of the distribution of panipenem was correlated with body weight. C(20%T)>(MIC) for a standard dosage regimen of panipenem was 4.3 microg/ml, and the optimal dosage regimen for the patients was established based on this value.. The dosage regimen of panipenem for patients with renal impairment should be reduced when creatinine clearance is lower than 60 ml/min.

Topics: Adult; Aged; Aged, 80 and over; Alanine; Area Under Curve; Chromatography, High Pressure Liquid; Creatinine; Haemophilus influenzae; Humans; Kidney Function Tests; Metabolic Clearance Rate; Middle Aged; Renal Insufficiency; Thienamycins

Panipenem/betamipron (Carbenin), a parenteral carbapenem antibiotic, is used for the treatment of severe and intractable bacterial infections caused by gram-positive and gram-negative bacteria. Because 30% of panipenem and most of the betamipron are excreted in the urine in an unchanged form, renal function is the important determinant of the dosage regimen of panipenem/betamipron. In this study, the pharmacokinetics of panipenem/betamipron were investigated in patients with end-stage renal disease (ESRD) undergoing hemodialysis treatment to establish an appropriate dose regimen. We further attempted to predict the in vivo clearance in patients undergoing hemodialysis based on the in vitro dializability. The pharmacokinetics of panipenem/betamipron were investigated in eight patients after a 1-h intravenous infusion of panipenem/betamipron (500 mg/500 mg). The in vitro extraction ratios of panipenem/betamipron through a high-flux dialyzer were obtained, and compared with those obtained in vivo. The clearances of panipenem in patients were 9.53 +/- 1.26 l/h with hemodialysis, and 2.92 +/- 0.238 l/h without hemodialysis. In contrast, those of betamipron were 4.18 +/- 0.643 l/h and 0.615 +/- 0.511 l/h, respectively. The clearance of panipenem with hemodialysis were predicted well from in vitro extraction ratios, while that of betamipron was overestimated about 1.4-fold, probably due to high plasma protein binding and the binding difference between patients and healthy subjects. After comparing the pharmacokinetic behavior of panipenem in patients with ESRD and that of a surrogate marker of efficacy, we recommend that these patients be treated with 500 mg/500 mg of panipenem/betamipron once daily, which gives a similar clinical result in a patient with normal renal function.

Topics: Adult; Aged; Alanine; Anti-Bacterial Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Thienamycins

We report here two cases of MRSA sepsis following craniotomy. In case 1, a petroclival meningioma was subtotally removed and lumbar drainage was inserted postoperatively to prevent cerebrospinal fluid leakage. Ventriculo-peritoneal shunt was performed after meningitis was treated with vancomycin and panipenem/betamipron. Two weeks after the procedure, the patient revealed continuous spiking fevers related to MRSA sepsis, which did not improve with vancomycin and arbekacin administration. The focus of infection was found by scintigraphy and CT by 67Ga to be spondylo-diskitis at the level of L2-L3. The lesion was removed and bone from the iliac crest grafted. In case 2, seven days after surgery for multiple meningioma, the patient exhibited spiking fevers and swelling in the left leg. The central venous catheter was removed from the left femoral vein and MRSA was found from blood culture. The patient was treated with arbekacin (200 mg/day). Venous thrombosis diagnosed by CT was treated with heparin. Symptoms related to the infection and laboratory data did not improve because the concentration of arbekacin in the blood did not reach an effective level. The symptoms markedly improved when the dose of arbekacin was doubled (400 mg/day).

Topics: Adult; Aged; Alanine; Aminoglycosides; Ampicillin; Anti-Bacterial Agents; Craniotomy; Dibekacin; Drug Therapy, Combination; Female; Humans; Male; Meningeal Neoplasms; Meningioma; Methicillin Resistance; Postoperative Complications; Sepsis; Staphylococcal Infections; Sulbactam; Thienamycins; Treatment Outcome; Vancomycin

To investigate the involvement of nitric oxide (NO) in childhood meningitis, we measured the concentrations of NO2- (a stable metabolite of NO) in serial samples of cerebrospinal fluid (CSF) from 11 children with septic and 7 with aseptic meningitis and 26 control patients without meningitis. The mean concentration of NO2- in samples obtained during the early stages of septic meningitis, but not aseptic meningitis, was significantly higher than in control samples. Clinical and laboratory improvement following administration of antibiotics and dexamethasone was associated with a fall in CSF [NO2-] to normal levels in these patients. CSF [NO2-] remained almost consistently within the normal range in patients with aseptic meningitis. Our findings indicate that NO production is enhanced in the CSF compartment of children with septic meningitis and support the hypothesis that NO is involved in the pathophysiology of septic meningitis.

Topics: Alanine; Anti-Bacterial Agents; Child; Child, Preschool; Dexamethasone; Female; Humans; Infant; Male; Meningitis, Aseptic; Meningitis, Haemophilus; Meningitis, Pneumococcal; Nitric Oxide; Thienamycins

A 44-year-old female admitted to our hospital because of fever, purpura and macroscopic hematuria. She had been diagnosed as having ventricular septal defect (VSD). She noticed purpura with pain on bilateral legs and macroscopic hematuria since September 18, 1994. Three weeks later she also manifested a fever. Physical examination of admission revealed numerous purpura and leg edema. Laboratory data showed macroscopic hematuria, marked anemia (Hb 3.3 g/dl), leukocytosis, azotemia (Cr 2.7 mg/dl) and positive acute phase reactants. Increased serum immune complex level and hypocomplementemia were also found. The diagnosis of allergic purpura was made initially, but positive blood culture of Streptococcus mitis and the detection of vegetation attached to the right ventricular wall near the ostium of the VSD made the definite diagnosis of infective endocarditis (IE). Chemotherapy with PCG was started for two weeks but with no effect. The chemotherapy was altered to panipenem/betamipron with a daily dose of 3 g, Then, her fever fell and purpura, macroscopic hematuria and renal failure gradually disappeared. In this case, the cause of renal manifestations was considered to be immune complex glomerulonephritis. This is the first report of IE with macroscopic hematuria due to immune complex glomerulonephritis.

Topics: Acute Kidney Injury; Adult; Alanine; Endocarditis, Bacterial; Female; Hematuria; Humans; IgA Vasculitis; Thienamycins

The preventive effect of betamipron (N-benzoyl-3-propionic acid: BP) on the renal uptake and nephrotoxicity of carbapenems (panipenem and imipenem) was studied in rabbits. Panipenem, a new carbapenem antibiotic, induced nephrotoxicity at a dose of 200 mg/kg, i.v., but this was less severe than that caused by a single dose of imipenem or cephaloridine. Along with the significant reduction of nephrotoxicity, the uptake of these carbapenems in the renal cortex was remarkably inhibited by simultaneous treatment with BP (200 mg/kg, i.v.). These results suggest that BP reduces the nephrotoxicity of carbapenems through inhibiting the active transport of carbapenems in the renal cortex. Because of the low toxicity of BP (LD50 in the rat, more than 3,000 mg/kg, i.v.), it was concluded that BP might be a good candidate for reducing the nephrotoxicity induced by panipenem or imipenem.

Topics: Alanine; Animals; Carbapenems; Glycosuria, Renal; Imipenem; In Vitro Techniques; Kidney Cortex; Kidney Diseases; Male; Necrosis; Proteinuria; Rabbits; Thienamycins

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.

Topics: Alanine; Animals; beta-Alanine; Brain; Drug Therapy, Combination; Electroencephalography; Male; Rabbits; Thienamycins