Antibacterial activity of a new carbapenem antibiotic panipenem (PAPM), an active component of panipenem/betamipron (PAPM/BP) for parenteral use, was compared with that of imipenem (IPM), cefotaxime (CTX), ceftazidime (CAZ) cefuzonam (CZON) and flomoxef (FMOX) Resultsare summarized as follows.
1) PAPM possessed broad antibacterial spectra together with potent antibacterial activity against both Gram-positive and Gram-negative bacteria. The activity of PAPM against these pathogens was comparable to that of IPM, and was superior to that of CTX, CAZ, CZON, and FMOX except for the activity against several species of Gram-negative bacteria.
2) PAPM showed stronger time-kill activity after drug addition, as compared to CAZ and FMOX.
3) PAPM was highly stable to various types of β-lactamase other than a certain β-lactamase classified as cefuroximase, and had potent antibacterial activity comparable to or greater than IPM against β-lactamase producing strains as well.
4) PAPM was more effective than CTX and CAZ on systemic mice infections.

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Fifty percent minimum inhibitory concentraions (MIC₅₀) of panipenem (PAPM) that is the active carbapenem in panipenem/betamipron (PAPM/BP) were 0.05, 6.25, 0.2, ≤0.013, ≤0.013, ≤0.013, 1.56, >100, 0.2, 0.1, 0.39, 0.78, 1.56, 1.56, 0.2, 0.39, 0.2, 6.25, 12.5, 0.2, >100, 0.39, and 0.78μg/ml against 15 to 50 clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), coagulase-negative staphylococci (CNS), Streptococcus pyogenes, fl-streptococci, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, Pseudomonas cepacia, Acinetobacter calcoaceticus, Xanthomonas maltophilia, ampicillin-resistant Haemophilus influenzae, and Bacteroides fragilis, respectively
PAPM manifested strong binding affinities to penicillin-binding protein (PBP) 1 and 3 of S. aureus, PBP 2s of E. coli, S. marcescens, and of P. aeruginosa, those are considered as the initiation enzyme of new murein-synthesis.
PAPM inactivated types Ic, IIb, and V of β-lactamases at the same level as imipenem (IPM), although manifested weaker inactivation to other types of the enzyme than IPM.
PAPM showed little synergy in bactericidal effect with the complement. PAPM, however, manifested a good synergy with mouse cultured macrophages. Living cells of E. coli NIHJ JC2 were well engulfed and rapidly digested by the macrophages in the presence of higher than 1/8 MIC of PAPM.
PAPM was more stable to swine and human dehydropeptidase-I than IPM.

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The in vitro and in vivo antibacterial activities of panipenem/betamipron (PAPM/BP)(panipenem (PAPM)), a parenterally active new carbapenem antibiotic, were compared with those of imipenemicilastatin (IPM/CS)(imipenem (IPM)), latamoxef (LMOX), cefuzonam (CZON) or ceftazidime (CAZ).
PAPM had a broad antibacterial spectrum against gram-positive and gram-negative organisms. The antibacterial activities of PAPM against Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus spp. and Enterococcus faecalis were as potent as those of 1PM and were higher than those of the third-generation cephems.
PAPM was stable to hydrolysis by various types of β-lactamase.
The therapeutic effects of PAPM/BP on single and mixed infection models in mice were slightly better than or almost equal to those of IPM/CS.
The therapeutic efficacies of PAPM/BP against intra-nasal lung or urinary infections in mice were almost equal to those of IPM/CS or CAZ.

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Antibacterial activity of panipenem (PAPM), a new carbapenem, against more than 411 anaerobic bacteria of reference and clinical isolates was determined by agar dilution method. The stability of this compound against representative β-lactamases derived from 4 strains of Bacteroides fragilis was also determined using a spectrophotometric assay.
PAPM inhibited the growth of almost all anaerobic bacterial spesies tested with the concentration of 0.78μg/ml, except Clostridium difficile. Especially, it was very active to the β-lactamase producing strains of Bacteroides, Prevotella. This compound was not hydrolyzed by the β-lactamases from 3 strains of B. fragilis, but readily hydrolized by a metallo-β-lactamase from GAI-30144.
When panipenem/betamipron was given subcutaneously to mice at a dose of 100mg/100mg/kg for 5 days, growth of C. difficile was observed on 7 days after withdrawal of the drug with a concentration of 10²-10³CFU/g.

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The in vitro activity of panipenem (PAPM), a new carbapenem, and the in vivo activity of panipenem/betamipron (PAPM/BP) which is the combination of PAPM and betamipron (BP), an organic anion transport inhibitor, on experimental infections in mice were compared with those of imipenem (IPM), ceftazidime (CAZ), flomoxef (FM0X), cefuzonam (CZON), cefotiam (CTM), gentamicin (GM) and piperacillin (PIPC).
PAPM had broad-spectrum activity against gram-positive and gram-negative aerobes and anaerobes. The MICs of PAPM against clinical isolates were almost equal to those of IPM. The MIC90s of PAPM against the strains of methicillin-sensitive Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Haemophilus influenzae, Acinetobacter calcoaceticus, and Branhamella catarrhalis were 1.56, βg/ml. The MIC₅₀ of PAPM against methicillinresistant S. aureus was 1.56βg/ml and superior to the reference antibiotics. The MIC₅₀ and MIC₉₀ of PAPM against Pseudomonas aeruginosa were 6.25 and 12.5βg/ml, respectively, and were fourfold less active than those of IPM.
The antibacterial activity of PAPM was not affected by the pH of the medium, inoculum size and the addition of horse serum or BP.
Killing kinetic study of PAPM against exponentially growing bacteria showed that the bactericidal action which were dependent on the concentration of the drug occurred above MIC and the activity was similar to that of IPM. The bactericidal activity of PAPM also remained against slowly growing bacteria in early stationary phase. PAPM had a high affinity for penicillin-binding proteins 2, lA and 1 Bs of E. coli. In morphological observation of five strains by the differential interference contrast microscope, the exposure to PAPM resulted in the formation of spherical cells and the bacteriolysis was observed above twofold or fourfold MIC.
The therapeutic efficacy of PAPM/BP was superior to the reference antibiotics against the experimental systemic infections of gram-positive bacteria in mice and was almost equal to imipenem/cilastatin (IPM/CS) against those of the gram-negative bacteria including P. aeruginosa.

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Viable cell counts of Staphylococcus aureus (1 strain) and Pseudomonas aeruginosa (2 strains) were compared in in vitro pharmacokinetic model simulated 30 minutes drip infusion of 500mg of panipenem (PAPM) with that of imipenem (IPM).
PAPM and IPM demonstrated almost the same killing curves of S. aureus which has the same MICs for both drugs. One strain of P. aeruginosa (MIC. PAPM; 12.5μg/ml, IPM; 3.13μg/ml) showed similar viable cell curves. Another strain of P. aeruginosa (MIC. PAPM: 25μg/ml, IPM; 6.25μg/ml) showed more marked decrease in viable cell counts with IPM than with PAPM.

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In vitro and in vivo postantibiotic effects (PAEs) of panipenem/betamipron (PAPM/BP), a combination drug of panipenem (PAPM) and amino acid derivertive, were investigated.
In vitro PAEs of PAPM at 2 and 4 MIC levels after 2-hour incubation were respectively deter-mined to be 2.1 hours on Staphylococcus aureus at both levels, 0.7 and 1.0 hour on Escherichia coli, and 1.0 and 1.7 hours on Klebsiella pneumoniae. Those of imipenem (IPM) at the same MIC levels were respectiviely determined to be 2.1 and 2.4 hours on S. aureus, 0.9 hours on E. coli at both MIC levels, and 1.0 and 1.7 hours on K. pneumoniae. PAEs on Pseudomonas aeruginosa at 4 MIC level after 1-and 2-hour incubation were respectively determined to be 1.45 and 1.7 hours for PAPM, 1.7 and 1.85 hours for IPM, and 0.05 and 0 hour for ceftazidime (CAZ).
When an antibiotic was given at 50 mg/kg to thigh infection model of mice with leukocytopenia, in vivo PAE on K. pneumoniae was determined to be 1.4 hours for PAPM, 1.1 hours for PAPM/BP, 2.0 hours for PAPM/cilastatin (CS), 0.8 hour for IPM, and 1.8 hours for IPM/CS. The PAE at 50mg/kg on P. aeruginosa was determined to be-0.9 hour for PAPM, -1.1 hours for IPM, and-1.2 hours for CAZ; that at 100mg/kg was also determined to be-0.3 hour for PAPM, 0.1 hour for PAPM/BP, 0.5 hour for PAPM/CS, 0.3 hour for IPM, and 1.0 hour for IPM/CS.

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In vitro antibacterial activities of a new carbapenem antibiotic panipenem (PAPM), an active component of parenterally effective panipenem/betamipron (PAPM/BP), were investigated, as compared to those of imipenem and other β-lactam antibiotics.
1) PAPM possessed broad antibacterial spectrum together with potent antibacterial activity against both Gram-positive and Gram-negative bacteria.
2) PAPM showed potent antibacterial activity, comparable to imipenem (IPM) against most of clinical isolates as well as greater than cefotaxime (CTX), latamoxef (LMOX), ceftazidime (CAZ), cefuzonam (CZON), flomoxef (FMOX), and piperacillin (PIPC) except for a few species of Gramnegative bacteria.
3) PAPM, furthermore, was more active than CTX, LMOX, CAZ, CZON, FMOX, and PIPC against methicillin-resistant Staphylococcus aureus and/or cephem-resistant Gram-negative rods as well.
4) PAPM was not affected by several media, medium pH, addition of horse serum into medium, and inoculum size in the expression of antibacterial activity.
5) PAPM exerted stronger bactericidal activity with the addition of drug, as compared to cefoperazone (CPZ), LMOX, CAZ, and PIPC.
6) PAPM induced acquisition of resistance in test bacteria to smaller extent than 1PM, CPZ, LMOX, CAZ, CZON, and PIPC did even by 15 times subculture repeatedly.

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Mechanism of antibacterial activity of panipenem (PAPM), a new carbapenem antibiotic, was studied. PAPM showed a high stability against hydrolysis by β-lactamases of various classes, including penicillinases, cephalosporinases and cefuroximases. This antibiotic strongly inhibited cephalosporinases and cefuroximases of gram-negative species. It also inhibited penicillinases of gram negative species, whereas it did not inhibit a penicillinase of gram-positive origanisms. It showed a high affinity for penicillin-binding protein (PBP) 1A, 1B, 2, 4, 5, and 6 of Escherichia coli. It induced spherical cells from E. coli treated with 1/8 MIC or higher concentrations, and at the MIC or higher concentrations it immediately lysed cells. Affinity for PBPs and influence on the morphology of PAPM in Pseudomonas aeruginosa was similar to those of E. coli. PAPM showed postanti-biotic effect not only against gram-positive organisms but also against gram-negative organisms. PAPM showed a cooperative bactericidal activity with human serum and white blood cells on E. coli.

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The in vivo antibacterial activities of panipenem/betamipron (PAPM/BP) and panipenem (PAPM) were evaluated against various experimental infections in mice or rats and compared with those of imipenem (IPM), imipenem/cilastatin (IPM/CS), cefazolin, cefotaxime, latamoxef, etc. Serum and organ levels of PAPM in mice and rats were also investigated.
The fact that PAPM/BP showed almost the same antibacterial activities as PAPM in mice intraperitoneal infections indicates that BP has no influence on the antibacterial activity of PAPM.
In mice, PAPM showed good therapeutic efficacy against intraperitoneal infections induced by 35 strains of 16 species of Gram-positive and Gram-negative bacteria including Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa. Especially, the in vivo anti-P. aeruginosa activities of PAPM were found to be almost equal to or better than those of IPM in mice systemic infections coused by 10 strains of P. aeruginosa.
In leukopenic mice, PAPM showed good therapeutic effects on intraperitoneal infections.
In rats, the efficacies of PAPM against intrapouch infections caused by S. aureus, Escherichia coli or P. aeruginosa were almost equal to those of imipenem.
Against a tissue cage infection model in rats caused by S. aureus, PAPM/BP showed better efficacy than IPM/CS.
In rat experimental infective endocarditis caused by P. aeruginosa, the efficacy of PAPM/BP was almost equal to that of IPM/CS.

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Antipseudomonal activity of panipenem (PAPM), a new carbapenem antibiotic, was investigated and compared with that of imipenem (IPM). In vitro bactericidal activity of PAPM against Pseudomonas aeruginosa No.1872 was 2 to 4 times less than that of IPM. PAPM, however, showed better efficacy for experimental systemic infection with this strain in mice. We investigated the reasons and concluded that at least three factors were responsible.(i) PAPM had higher Cmax and larger AUC than IPM when it was administered subcutaneously in mice.(ii) PAPM showed longer postantibiotic effect (PAE) against this strain than IPM, especially at the lower concentrations.(iii) PAPM showed stronger cooperative antibacterial activity with mouse serum against this strain than IPM did. In vitro bactericidal activities of PAPM and IPM were compared considering their PAE and pharmacokinetics in mice using automatic drug-concentration simulator. PAPM showed a bactericidal activity stronger than IPM against P. aeruginosa No.1872 when they were evaluated for their simulated ascites concentrations with 50% mouse serum. Hence, we conclude that the combination of these three factors can give PAPM an efficacy for systemic infection in mice better than that of IPM.

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In vitro susceptibilities of Pseudomonas aeruginosa PAO1 to PAPM were influenced by various concentrations of basic amino acids i.e., L-lysine, L-histidine, and L-arginine, in agar media. P.aeruginosa PA01 showed higher susceptibility to PAPM in minimal medium than it did in rich media, such as Mueller-Hinton agar. The susceptibility was decreased by the addition of a basic amino acid to the minimal medium, whereas it was influenced less by other amino acids. The susceptibilities of PA01 to cephalosporins, piperacillin, quinolones, and gentamicin were not influenced by the addition of a basic amino acid to the minimal medium. A significant change in susceptibility to PAPM by the addition of a basic amino acid was not observed with D2 protein-deficient mutants of PAOl. Clinical isolates of P. aeruginosa also showed an increase in susceptibility in minimal medium. L-Lysine in minimal medium did not have any influence on the production of D2 protein, β-lactamase, or penicillin-binding proteins of PA01 or on the chemical degradation of PAPM. These results strongly indicate that the increase in susceptibility of P. aeruginosa to carbapenems relates to less competition with basic amino acids for permeation through the D2 protein channel of P. aeruginosa.

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The acute toxicity of panipenem (PAPM), a new carbapenem antibiotic, betamipron (BP), an anionic transport inhibitor, and the combination (panipenem/betamipron (PAPM/BP)) of the two was investigated in rats.
1) The intravenous LD₅₀ values of the PAPM/BP was estimated at 1629mg/kg for males and at 1759mg/kg for females.
2) The major changes in general conditions observed after intravenous administration of the PAPM/BP were irregular respiration, cyanosis, staggering gait and inability of gait.
3) The intravenous approximate LD50 values of PAPM alone was estimated at between 1700 and 2200mg/kg for males and at between 1300 and 1700mg/kg for females. The intravenous LD50 values of BP alone was estimated at 3496mg/kg for males and at 3666mg/kg for females.
4) The acute toxicity induced by the drugs in PAPM/BP was considered to be related to thetoxicity of PAPM, judging from the lethal dose level.

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Newly developed carbapenem, panipenem (PAPM), was intravenously administered to rats for 90 days in order to clarify its subacute toxicity, followed by a 28-day recovery period.
Male and female F344 rats, 7 weeks of age, were used in this study. They were given saline (control), and 900, 300, 100 and 30mg/kg of PAPM.
Male and female F344 rats, 7 weeks of age, were used in this study. They were given saline (control), and 900, 300, 100 and 30mg/kg of PAPM.
In the 900mg/kg female group, only 1 of 15 animals died on the 5th day during the study period. In the survivors of the 900mg/kg group, erythema, abnormal breathing, decrease in spontaneous motor activities, tremor and suppression of weight gain were found. Slight increase of corpuscular constants in females given 100mg/kg or more, and slight decrease of alkaline phosphatase activity in females receiving 300mg/kg or more were observed at the end of administration. On the other hand, pathological examination revealed no toxic findings in all organs. In the recovery period, no abnormal findings were found in all examinations, and suppression of weight gain in the 900mg/kg group gradually disappeared.
In conclusion, the toxic target organ of PAPM could not be demonstrated in the present study, although 1 female from the highest dose group died.

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Pamipenem/betamipron (PAPM/BP) is a combination of newly developed carbapenem (panipenem (PAPM)) and betamipron (BP). The combination ratio is 1:1. PAPM/BP was intravenously administered to rats for 90 days in order to clarify its subacute toxicity.
Male and female F344 rats, 7 weeks of age, were given 400, 200 and 100mg/kg of PAPM/BP (PAPM/BP 400/400, 200/200, and 100/100mg/kg, respectively), 400 and 200mg/kg of BP, and saline.
No abnormalities in general conditions were observed without soft stool which was found in a few animals from all groups, including control, and no animals died during study period. Although a slight suppression of weight gain was observed in males given 400mg/kg of PAPM/BP, urinalysis and ophthalmology revealed no abnormalities in all treated groups. Moreover, food intake levels did not varied significantly in all treated groups.
At the end of administration, hematological and serum biochemical examination showed slight changes in PAPM/BP treated groups, e.g., decrease of RBC count and increase of mean corpuscular hemoglobin in males given 100 and 400mg/kg, decrease of hematocrit value in males of 400mg/kg group, reduction of sodium level in females receiving 200 and 400mg/kg. In BP treated groups, decrease of RBC count and hematocrit value in females of 200 and 400mg/kg groups, and reduction of sodium level in females receiving 200 and 400mg/kg were observed. However, pathological examination revealed no toxic findings in all organs examined.
In conclusion, any specific findings which indicated the toxicity of PAPM/BP or BP were not detected in the present study.

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Nephroprotective effect of betamipron (BP) and its mechanism were investigated in view of renal transport of panipenem (PAPM), a new carbapenem antibiotic, in rabbits. Concomitant intravenous dose of BP (0.5-2 folds to PAPM) decreased dose-dependently the frequency of renal tubular necrosis caused by more than 150mg/kg of antibiotic administration. The decrement of nephrotoxicity was well correlated with the inhibitory activity of the renal cortical accumulation of PAPM. The optimal dose ratio of BP was equivalent to PAPM as weight. Such nephroprotective effect of BP was also observed in rabbits with acute glomerular nephritis. Both of BP and probenecid, an organic anion transport inhibitor, were practically prevented the (147C) PAPM uptake in isolated renal tubule. BP hardly inhibited the rat renal dehydropeptidase-I activity unlike cilastatin. Nontoxic and nephroselective properties of BP might be full of promise to clinical use as a desirable nephroprotective agent for PAPM.

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Renal excretion mechanisms of panipenem (PAPM) and betamipron (BP) in rabbit were investigated by clearance techniques in vivo. The renal clearance (CLr) of PAPM under steady state exhibited 1 to 1.5-fold of glomerular filtration rate (GFR) and significantly decreased by the concomitant dose of BP. Similar decrement of CLr was found after treatment of some organic anions, probenecid or iodopyracet, but not p-aminohippuric acid. Organic cations such as N₁-methylnicotinamide and tetraethylammonium did not affect on the renal excretion of PAPM. BP and probenecid remarkably inhibited their CLr each other. Stop-flow analysis confirmed that both PAPM and BP were predominately secreted from renal proximal tubule. Concomitant intravenous dose of BP decreased the urinary excretion rate constant of cephaloridine (CER) and cephalexin (CEX) without any change of other pharmacokinetic parameters.

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Microbiological assay method was developed for the quantitative determination of a new carbapenem, panipenem (PAPM) in body fluids and tissues.
Bioassay was performed by agar-diffusion method using Bacillus subtilis SANK 76959 as the test organism and heart infusion agar as the media. Assay methods of cup-plate methods and paper-disk method were available with these conditions. However, the paper-disk method will be used in usual because of simple treatments. Minimum detectable concentrations of this method were about 0.02μg/ml for plasma, urine and other body fluids, and about 0.08μg/g for tissue samples.
Standard solution prepared with the mixture of plasma and 1M MOPS [3-(N-morpholino)-propanesulfonic acid] solution was used for the assay of plasma, and that of 0.5M MOPS for other body fluids. And the standard solution of 0.5M MOPS containing 5mM K₃Fe (CN)₆ was used for the assay of tissue samples.
PAPM in assay samples of plasma and urine was stable in biological activity for two weeks under the storage at-80°C.

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High-performance liquid chromatography (HPLC) was developed for the determination of concentrations of panipenem/betamipron (PAPM/BP), combination of a new carbapenem antibiotics, panipenem (PAPM), and an anionic transport inhibitor, betamipron (BP), and R976-2, main metabolite of PAPM. And also, stabilities of PAPM and BP in samples prepared by mixing body fluids and 1M MOPS solution (3-(N-morpholino)-propanesulfonic acid, pH 7.0) equivalently, were studied.
1) PAPM concentrations in human plasma and urine were determined by HPLC method with simple pretreatment of assay samples. Recoveries from plasma or urine were more than 97% and C. V. values were less than 5.3%, suggesting good accuracy of this method. Determination limits were about 0.3μg/ml for plasma and about 1.0μg/ml for urine.
2) R976-2 concentrations in plasma and urine were determined by column switching HPLC method. Recoveries from plasma and urine were approximately 100% and C.V. values were less than 4.7%, suggesting good accuracy of the method. Determination limits were about 1μg/ml for plasma and about 5μg/ml for urine.
3) BP in human plasma and urine were determined by HPLC method after extraction or dilution. Recoveries were approximately 95% and C.V. values were less than 1.7%, suggesting good accuracy of this method. Detemination limits were about 0.2μg/ml for plasma, about 0.5μg/ml for urine and about 0.4μg/g for tissues.
4) PAPM in plasma sample was stable for 5 days at-20°C and 28 days at-80°C, and also that in urine sample was stable for 7 days at-20°C and 42 days at-80°C. And BP in plasma and urine samples was stable for 42 days at both temperatures of-20°C and-80°C.

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Drug metabolism and disposition studies on panipenem/betamipron (PAPM/BP) were performed by using ¹⁴C-labeled panipenem ([¹⁴C] PAPM) and betamipron ([¹⁴C]BP).
Drugs were administered intravenously as [14C] PAPM/BP, PAPM/[¹⁴C] BP, [¹⁴C] PAPM or [¹⁴C] BP in rats and dogs.[¹⁴C] PAPM and [¹⁴C] BP were mainly excreted to the urine after being distributed to the kidney, liver, lung or blood. Plasma concentration, excretion rate or tissue distribution of radioactivity in rats between [¹⁴C] PAPM/BP and [¹⁴C] PAPM alone and between PAPM/[¹⁴C] BP and [¹⁴C] BP alone gave almost no differences except in the kidney distribution.
In the kidney, the maximum distribution time of [¹⁴C] PAPM was delayed by combination dose with BP.

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Panipenem/betamipron (PAPM/BP) is a combination drug of panipenem (PAPM), a new carbapenem antibiotic, and betamipron (BP), an inhibitor of organic ion transport. The pharmacokinetic parameter of this drug was compared with that of imipenem/cilastatin sodium (IPM/CS).
A cross-over study was carried out to compare blood concentrations and urinary excretion rates between these drugs using 6 healthy male adults, who were given one of the 2 drugs at 500mg/500mg by intravenous drip infusion over a period of 30 minutes.
The blood concentration (C_max) of PAPM (45.6μg/ml) at the termination of drip infusion was found to be higher than that of imipenem (IPM)(34.5μg/ml), but there was no difference in blood half-life time (T_1/2β) in the elimination phase between the 2 drugs; namely, about 1 hour for both drugs. However, IPM showed a higher cumulative urinary recovery rate up to 6 hours after the administration (65.6%) in terms of intact compound than PAPM (37.3%).
There were marked differences in pharmacokinetics between BP and cilastatin (CS) namely, C_max values of BP and CS were respectively found to be 19.6 and 54.6μg/ml, and T_1/2β values were respectively found to be 0.59 and 0.86 hour. Furthermore, cumulative urinary recovery rates up to 6 hours after the administration also differed between BP (100%) and CS (52.2%). In other words, the recovery rate of CS was only 1/2 that of BP.
In this study, side effects or abnormal laboratory findings thought to be related to the treatment with the drug were observed in none of the subjects.

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The influence of dehydropeptidase-I (DHP-I) activity on the elimination of panipenem (PAPM) in vivo was studied by examining glycyldehydrophenylalanine (GDPA) and PAPM hydrolytic activities in several tissues in animal species.
Renal GDPA hydrolytic activity was the highest in mice followed with rabbits, dogs, monkeys and humans, while in rats, it was the highest in the lung.
Tissues with high DHP-I activities have mostly high PAPM hydrolytic activity, which suggests DHP-I is strongly associated with the hydrolytic metabolism of PAPM. On the other hand, since the high DHP-I activity of human kidney has rather low PAPM hydrolytic activity, there exist species differences in substrate specificity of the DHP-I.
In rats, the plasma elimination of PAPM was the fastest accompanying with high plasma concentration of the hydrolytic product among animal species tested.
These results indicate the metabolic disposition of PAPM is deeply dependent on DHP-I activity especially in the lung and the kidney.

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The tolerability and pharmacokinetics of panipenem/betamipron (PAPM/BP), a new injectable carbapenem derivative, were examined in 31 healthy male volunteers in single-dose study. In the single-dose study of betamipron (BP), 9 subjects were given a dose of 250, 500 or 1000mg of BP and 22 subjects were given a dose of 125/125, 250/250, 500/500, 750/750 or 1000mg/1000mg of PAPM/BP in a fastings state. Both BP and PAPM/BP were well tolerated by all subjects. Adverse effect was not observed. The maximun plasma levels of panipenem (PAPM) were observed at the end of the injection and their levels showed dose-dependence. The half-life was about 70 min. Urinary recovery of PAPM was approximately 30%. On the other hand, BP was 100%.

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Nine healthy male volunteers received 500mg/500mg or 1000mg/1000mg panipenem/betamipron (PAPM/BP) by constant intravenous infusion for 60 min every 12h for 5 days. Maximum plasma levels of panipenem (PAPM) were observed at the end of the infusion, and their levels showed dose-dependence. The half-life was about 1 hour. Mean maximal plasma concentration, as PAPM, at the end of infusion of 500mg/500mg PAPM/BP (day 1) was 23.32±2.90μg/ml, with a decrease to 2.04±0.74μg/ml after 4 h. Urinary recovery durmg this period was 27.5±8.3% of dosage. The serum protem binding of PAPM and betamipron (BP) were 6 to 7% and 73%, respectively. The saliva concentration of PAPM was less than 2% of plasma concentration. No changes in the pharmacokinetic parameters were observed durmg the two 5-day study.
No drug-related side effects were observed. In laboratory findmgs transient elevation of GPT (18IU→40IU) was observed in 500mg/500mg study. No consistent changes in renal function indices were noted. Urinalysis showed no change in renal function in either the 500mg/500mg or 1000mg/1000mg studies. We conclude that daily 2000mg/2000mg PAPM/BP were well tolerated and safe.

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Panipenem/betamipron (PAPM/BP) has a broader spectrum and greater potency as well as Tienam^®. The safety and tolerability of 1000mg/1000mg PAPM/BP dissolved in Solita T3^® given every 12 hours for 5 days were evaluated in 5 healthy male volunteers. No side effects related to the drug were observed. The maximum plasma level of panipenem was observed at the end of the infusion and its level was 41.14±6.95μg/ml. Urinary recovery during first 12 hours was 23.1±6.5% as unchanged.

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The influence of repeated intravenous infusions of panipenem/betamipron (PAPM/BP)(PAPM: BP=1:1) on the fecal microflora of healthy volunteers was studied. PAPM/BP (500mg of PAPM and 500mg of BP) was administered to 5 male healthy volunteers twice a day for 4.5 days. The feces were sampled and subjected for studying of microflora on the days 2, 5, 8, 15, 22, 30, and 36, and 6 days before the administrations. The influence of the administration on the fecal microflora was minimum. Neither Clostridium difficile nor C. difficile D-1 antigen was detected in any of the samples. The change in susceptibilities of dominant isolates to PAPM was also minimum.

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The antibacterial activity and clinical efficacy of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, were investigated.
MICs of this drug against 179 clinical isolates of 7 species were measured at an inoculum size of 10⁶ cells/ml. MIC₉₀ values against Staphylococcus aureus, Escherichia coli, Klebsiella spp., Proteus mirabilis, Morganella morganii, Serratia marcescens, and Pseudomonas aeruginosa were respectively determined to be 1.56, 0.10, 0.20, 0.78, 1.56, 1.56 and 25μg/ml. These values were almost equal to those of imipenem and superior to those of ceftazidime.
The clinical efficacy was studied in 19 patients with infections (2 with sepsis, 5 with respiratory tract infection, and 12 with urinary tract infection) by administering the drug mainly at 0.5g/0.5 g×2/day. Clinical response was excellent and good in 9 patients each, showing a 94.7% efficacy rate. No side effects were noted, but decreases of RBC, Hb and Ht in laboratory findings were observed in 1 patient.

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The in vitroantimicrobial activity of panipenem/betamipron (PAPM/BP), a new carbapenem agent for parenteral use, was measured and its therapeutic efficacy in respiratory infections was evaluated. The minimum inhibitory concentrations (MICs) of PAPM/BP, imipenem (IPM) and ceftazidime (CAZ) against 20 strains each of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined by a micro-broth dilution method using the Dynatech MIC 2000 system. As shown by MICs, PAPM/BP was as active as IPM and strongly more active than CAZ against MSSA and MRSA. Against H. influenzae and Enterobacteriaceae, PAPM/BP was somewhat more active than IPM, but somewhat less active than CAZ. On the other hand, PAPM/BP was less active against P. aeruginosa than IPM and CAZ.
A daily dose of 1g/1g of PAPM/BP was given intravenously for 7-22 days (mean: 12.9 days) to 8 patients: 5 with acute pneumonia, 2 with lung abscess and 1 with the infection supervening on lung cancer. The clinical effects were excellent in 1 and good in 7. Two each strains of Streptococcus pneumoniae and H. influenzae were indentified as causative organism and 3 of them were eradicated by an administration of PAPM/BP. An elevation of the values of GOT and GPT was observed in 1 patient, but this adverse reaction disappeared after completion of the therapy.
From the above results, we conclude that PAPM/BP is one of the most useful carbapenem agents for parenteral use in the treatment of respiratory infections.

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We tested the in vitro antibacterial activity of 5 antimicrobial agents, i. e., panipenem (PAPM), imipenem (IPM), cefmetazole (CMZ), norfloxacin (NFLX) and tobramycin (TOB), against 100 strains of clinically isolated Staphylococcus aureus. Sixty-one of the strains (61%) showed multi-drug resistance. Against those S. aureus, PAPM showed a 50% MIC of 0.78μg/ml and a 90% MIC of 50μg/ml (range:≤from 0.25 to >100μg/ml). The other carbapenern, IPM, showed cross resistance in methicillin-resistant S. aureus (MRSA).
Clinical evaluation of panipenem/betamipron (PAPM/BP) was performed in 8 patients with respiratory tract infections. They consisted of 6 males and 2 females, 64-82 years of age. PAPM/BP was adiministered by drip infusion in a dose of 0.5g/0.5g (4 cases) or 0.75g/0.75g (4 cases) twice a day.
A total of 3 strains, comprising 1 S. aureus strain and 2 Pseudomonas aeruginosa strains were isolated from the sputum of patients. One strain each of S. aureus and P. aeruginosa was eradicated, and 1 P. aeruginosa strain was decreased after the treatment.
The clinical efficacy rate was 100%: excellent in 1 and good in 7 cases. No side effects were seen.
Based on the above results, we consider PAPM/BP to be an effective, safe and useful for respiratory tract infection.

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We carried out basic and clinical studies on panipenem/betamipron (PAPM/BP), a new carbapenem, and obtained the following results.
The in vitro antibacterial activity of panipenem (PAPM) was examined against 422 strains of clinical isolates of 22 species and compared with those of ceftazidime, cefuzonam, latamoxef, piperacillin, imipenem (IPM), cefoperazone and aztreonam. Both PAPM and IPM were very active against almost all gram-positive and gram-negative bacteria tested. The MIC against methicillinresistant Staphylococcus aureus (MRSA) was much lower in PAPM/BP than in IPM.
PAPM/BP was administered to 14 patients with respiratory infection, 1 with sepsis and 1 with urinary tract infection at a dose 1.0g/1.0g-1.5g/1.5g daily for 5-20 days. The clinical response was excellent in 9, good in 5, fair in 1 and poor in 1 case. Eight of 16 cases, in which pathogenic organisms, such as Staphylococcus aureus, Streptococcus pneumoniae, Enterobacter cloacae, Haemophilus influenzae, Klebsiella pneumoniae and Pseudomonas aeruginosa were isolated, had good responses to PAPM/BP. Side effects were seen neither subjectively nor objectively. There were only slight increases in hepatic and renal function tests in 4 patients.

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Panipenem/betamipron (PAPM/BP) is a new antibiotic for injection, in which panipenem (PAPM), a carbapenem antibiotic, is combined with betamipron (BP), N-benzoyl-β-alanine, at a ratio of 1: 1.
he antibacterial activity of PAPM against clinical isolates as well as its clinical efficacy was determined.
MICs of PAPM against methicillin-resistant Staphylococcus aureus (MRSA) ranged from 6.25 to≥100μg/ml. These figures were 2 times and several times lower than MICs of imipenem (IPM) and ceftazidime (CAZ), respectively, but were several times higher than those of vancomycin (1.56-3.13μg/ml). MICs of PAPM against Pseudomonas aeruginosa were distributed over 1.56-50μg/ml, which were 2 or 4 times higher than those of IPM and CAZ. MICs of PAPM against Acinetobacter calcoaceticus ranged from 0.1 to 6.25μgml, which were equal to those of IPM and several times lower than those of CAZ.
When PAPM/BP was given to 5 aged patients with pneumonia at 0.5g/0.5g through drip intravenous infusion 2 or 3 times a day for 9-11 days, clinical response was excellent in 1, good in 3 and poor in 1. As for bacteriological efficacy, causative organisms were eradicated in one patient, from whom methicillin-sensitive Staphylococcus aureus (MSSA) and Citrobacter were isolated, and in another, from whom Streptococcus pneumoniae and Haemophilus influenzae were isolated. The other patient, from whom MRSA was isolated, was bacteriologically evaluated to be unchanged, but clinically showed a good response. Causative organisms could not be identified in the remaining 2.
Side effects were observed in none of the patients. As to abnormal laboratory findings, a slight increase in BUN was seen in 1 patient.
From these results, PAPM/BP was thought to be highly useful for the treatment of aged patients with nosocomial pneumonia.

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Minimum inhibitory concentrations (MICs) of panipenem/betamipron, a new carbapenem antibiotic, against blood-derived enterococci and the clinical efficacy and side effects of this drug given to 16 elderly patients with infection were determined. As for MICs against 43 strains of enterococci isolated from blood, MICs against 28 strains of Enterococcus faecalis, 3 of Enterococcus casseliflavus, and 2 of Enterococcus durans were all found to be in a range from ≤0.05 to 6.3, μg/ml, while MICs against 5 strains of Enterococcus faeciumwere>100μg/ml, and those against 3 of 5 strains of Enterococcus avium were > 100μg/ml. These results were equal to those of imipenem (IPM).
As for clinical efficacy, 2 and 1 of 3 patients with sepsis respectively showed excellent and good responses, 2, 5 and 2 of 9 patients with respiratory tract infection respectively showed excellent, good and fair responses, 1 patient with pyelonephritis showed excellent response, and 1 patient with infected atheroma showed good response, disclosing an 85.7% efficacy rate. As for subjective and objective side effects, Clostridium difficile-induced colitis occurred in 2 patients. Abnormal changes in laboratory findings were slight increases in GOT and GPT in 1 and transient reduce in Na and Cl in 1 patient. Although abnormally high urinary urobilinogen and coloring of pooled urine were observed during the clinical course, these findings were determined to be artificial false positive due to coloration during urine strage, which was also observed in IPM treatment, and was assumed to caused by degradation of both drugs.

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Fundamental and clinical studies on panipenem/betamipron (PAPM/BP), a newly-developed carbapenem antibiotic, were performed, and the following results were obtained:
1) When PAPM/BP was administered to 6 healthy male volunteers at 0.5g/0.5g through intravenous drip infusion over a period of 30 minutes, plasma concentrations of panipenem (PAPM) and betamipron (BP) were respectively measured to be 31.88 and 18.30μg/ml at the termination of administration, and were gradually eliminated from the blood thereafter. Their blood half-life times (T_1/2, β) were respectively determined to be 1.03 and 0.75 hours. Urinary recovery ratios up to 6 hours after the administration were found to be 21.5% and 69.4% in the forms of intact PAPM andmetabolites (R976-2) of PAPM, respectively, and 91.5% as for BP.
When PAPM/BP was administered in combination with probenecid, PAPM showed the same changing pattern of plasma concentration as that seen in the single administration of PAPM/BP. On the other hand, BP always showed the same changing pattern and urinary excretion without any influence of probenecid, regardless of the administration of BP alone, in the form of PAPM/BP, or in combination with probenecid.
There were no differences in pharmacodynamics of piperacillin (PIPC) at the time of intravenous drip infusion at 1g over a period of 30 minutes between the single administration of PIPC and the combionation with BP.
2) The clinical study was carried out using the total of 8 patients (6 with pneumonia 1 with chronic respiratory tract infection and 1 with fever of undetermined origin), who were given PAPM/BP in a dose of 1g/1g-2g/2g/day for 5-28 days. The clinical efficacy was evaluated to be excellent in 1 patient, good in 4, fair in 2, and poor in 1.
The bacteriological efficacy was assessed to be eradicated and decreased in 1 each of 2 patients infected with Pseudomonas aeruginosa alone, respectively, and to be unchanged in one patient infected with Klebsiella pneumoniae and another with multiple infection. Side effects or abnormal laboratory findings were observed in none of the patients.

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We studied a newly developed carbapenem, panipenem/betamipron (PAPM/BP), and obtained the following results.
1) Clinical pharmacological studies of PAPM/BP were conducted in 16 patients with renal dysfunction. The drug was injected intravenously, in a dose of 0.5g/0.5g by drip infusion for 60 minutes, and serum and urine levels of panipenem (PAPM) and betamipron (BP) were determined by bioassay and high-performance liquid chromatography (HPLC). The patients were classified according to creatinine clearance (Ccr) values into group I (n=5, Ccr ≥ 60ml/min), group II (n=5, 30 ≤ Ccr≤60ml/min), group III (n=6, Ccr≤30ml/min). The peak of serum levels of PAPM and BP did not differ greatly among the three groups. T_1/2β of PAPM was 1.42 hour in the group I, 1.78 hour in the group II, and 3.94 hour in the group III, and that of BP was 0.71 hour in I, 1.31 hour in II, and 5.77 hour in III. Thus, in the patients with severe renal dysfunction, serum concentration decreased more slowly than in those with moderate renal dysfunction. Urinary elimination rate of PAPM was 35.46% in the group I, 28.04% in the group II, and 11.86% in the group III, indicating the renal function-related decrease in the elimination rate.
2) PAPM/BP was used to treat 33 patients with respiratory tract infections. Clinical response was excellent in 1, good in 28, fair in 1, and poor in 3 patients. Adverse reactions were elevations of GOT and GPT in 2, elevations of GOT in 2, an elevation of AL-P, γ-GTP and LAP in 1, an elevation of GOT and eosinophilia in 1, an elevation of AL-P and a decline in prothrombin activity in 1, and an elevation of AL-P and LDH in 1. However, these findings were slight and no severe side effects caused by the drug were observed.

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We examined the in vitro antibacterial activity, concentration in patient, and its clinical availability of panipenem/betamipron (PAPM/BP), a new antibiotic which is mixed a new carbapenem panipenem (PAPM) with betamipron (BP).
1) Antibacterial activity: MICs of PAPM against clinical isolates of Staphylococcus aureus and various species of Gram-negative rods were determined and compared with those of ceftazidime (CAZ), cefmenoxime (CMX) or cefuzonam (CZON). PAPM had broad antibacterial activity, which was overall similar to that of imipenem (IPM) with the exception of Pseudomonas aeruginosa. PAPM was more active in vitro than CAZ, CMX and CZON against methicillinsusceptible Staphylococcus aureus, inhibiting all that at concentration of 0.1/μg/ml. Against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Providencia rettgeri. In vitro activity of PAPM was inferior to that of CAZ, CMX and CZON. However, PAPM was superior to CMX and CZON in activity against P. aeruginosa and Serratia marcescens.
2) In 1 patient of lung suppuration, the concentration of PAPM in plasma and abscess fluid was measured after administration of PAPM/BP (0.5g/0.5g drip infusion in one hour). The maximal concentration in plasma was 27.95μg/ml at the end of administration. While in abscess fluid, the maximam concentration was 0.38μg/ml at 2 hours after start of administration.
3) Clinical trial: Ten respiratory tract infections, 1 intestinal tract infection, and 2 sepsis were treated with PAPM/BP. The dosage was 1g/1g-2g/2g per day for 5-28 days. Ten of 11 assessable cases responded well to the therapy. S. aureus and Branhamella catarrhalis isolated from respiratory tract before therapy were eradicated. As side effects, fever, diarrhea and arthralgia were found in 1 case. Elevation of serum creatinine and leukopenia were found in each 1 case.

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We made a laboratory and clinical studies on panipenem/betamipron (PAPM/BP), a new injectable carbapenem, with the following results.
1) Antibacterial activity: The antibacterial activity of 10 species (clinical isolates) was compared with those of imipenem (IPM), ceftazidime (CAZ), cefmenoxime (CMX), cefuzonam (CZON). Antibacterial activities of panipenem (PAPM) against methicillin-sensitive Staphylococcus aureus MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter calcoaceticus, Enterobacter cloacae were far superior to those of CAZ, CMX, CZON and almost equal to those of IPM. Furthermore, PAPM also showed excellent activities against Escherichia coli, Klebsiella pneumoniae and other Gram-negative bacilli, it was almost the same as IPM.
2) Clinical effects: PAPM/BP was administered to 13 patients with various infections: pneumonia 9, pyothorax 1, lower respiratory tract infection 1, diffuse panbronchiolitis 1, decubitus infection 1. The clinical efficacy rate was 69.2%(excellent 1, good 8, poor 4). As side effects, vomiting and diarrhea, and drug fever were observed in each 1 patient. Abnormal laboratory findings were transient elevation of transaminases levels in 5 cases, leukopenia in 2 cases and transient elevation of AL-P in 1 case.

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Fundamental and clinical studies were conducted using panipenem/betamipron (PAPM/BP) which is an injectable combined drug of newly developed carbapenem antibiotic, panipenem (PAPM) and N-benzoyl-β-alanine (betamipron (BP)) at a ratio of 1:1, and the results were obtained as follows.
1) The MICs of PAPM and the control drugs such as imipenem (WM), piperacillin (PIPC), cefoperazone (CPZ) and ceftazidime (CAZ) against the clinical isolates were determined in accordance with the Standard Method established by Japan Society of Chemotherapy.
The MIC₈₀s of PAPM against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Serratia marcescens, Proteus mirabilis, Proteus vulgaris, Citrobacter freundii and Pseudomonas aeruginosa were 0.10, 3.13, 0.20, 0.78, 0.78, 0.78, 3.13, 1.56, 0.39 and 50μg/ml, respectively, and the antibacterial activity of PAPM was as potent as that of IPM. In particular, the antibacterial activity of PAPM against Gram-positive cocci was far more potent than that of PIPC, CPZ and CAZ. The antibacterial activity of PAPM against P. aeruginosa was as potent as that of PIPC, CPZ and CAZ, but PAPM showed more potent antibacterial activity than the control drugs against most other Gram-negative bacilli except for Proteus spp.
2) PAPM/BP was used in the treatment of 7 patients (3 patients with pneumonia, 1 with chronic bronchitis, 1 with sepsis and 2 with cystitis). Their age ranged from 30 years to 74 years and there were 2 males and 5 females. All of these patients had one or more underlying diseases which are prone to cause infectibility. PAPM/BP was given in the daily dosage of 1.0g/1.0g-2.0g/2.0g for 3-23 days, and the clinical response was excellent in 1 case, good in 5 and unknown in 1. The identified causative bacteria included Haemophilus influenzae, Branhamella catarrhalis, P. aeruginosa, Xanthomonas maltophilia and K. pneumoniae and most of these causative bacteria became negative. But in 2 cases, the causative bacteria were replaced. Neither side effect nor abnormal laboratory test value were observed.

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Panipenem/betamipron (PAPM/BP) was administered in a single dose of 0.5g/0.5g to 7 cases with respiratory tract infection in 30 minutes by intravenous drip infusion and the drug levels in plasma were determined with time. For panipenem (PAPM), C_max immediately after termination of drip infusion was 36.79±3.04μg/ml, AUC was 57.88±5.30μg·hr/ml, and T_1/2 was 0.9 hour, while for betamipron (BP), C_max was 24.58±2.76μg/ml. AUC was 24.11±2.83μg·hr/ml, and T_1/2 was 0.4 hour. No dissociation was observed between PAPM and BP.
PAPM/BP was used in 18 cases with respiratory tract infection. Overall results indicated the effective rate of 68.8%. No difference was noted in the effective rate between bronchitis and pneumonia. The effective rate varied depending on the severity of infection.
Streptococcus pneumoniae, Branhamella catarrhalis and Haemophilus spp. were completely eradicated, but the eradication rate of Pseudomonas aeruginosa was not satisfactory. Four cases had side effects, and the administration was discontinued in two cases. A side effect, which was considered to be allergic, developed in two cases. In aged patients, a possible relationship between such side effect as nausea and vomiting and the infusion rate of the drug was suggested.
Abnormal laboratory test results attributable to PAPM/BP were detected in two cases. Mild increase in GOT and GPT levels and mild increase in LDH level were observed, but the values returned to normal immediately after discontinuance of the infusion.
On the basis of the above results, PAPM/BP was considered to be useful in the treatment of respiratory tract infections. Also, it was found that the pharmacokinetics of the drug's blood levels was ideal.

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The new developed carbapenem antibiotics panipenem/betamipron (PAPM/BP), was evaluated in vitro and in vivo. The results were as follows:
1) Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 480 clinical isolates of 15 different species were determined and compared with the other 7 kinds of drugs, imipenem (IPM), ceftizoxime (CZX), latamoxef (LMOX), ceftazidime (CAZ), cefuzonam (CZON), piperacillin (PIPC), cefaclor (CCL). PAPM/BP showed excellent antimicrobial activity against Grampositive and negative bacteria including methicillin-resistant Staphylococcus aureus. The MICs of PAPM/BP were almost the same as that of IPM except against Pseudomonas aeruginosa.
2) PAPM concentrations in serum and sputum: A patient with chronic bronchitis was given 1g/1g of PAPM/BP intravenously and its concentrations in serum and sputum were measured at intervals using HPLC. A peak concentration in serum was observed immediately after the infusion, and achieved 160 μg/ml. Whereas, a peak sputum level of 8.40μg/ml was observed 2-3 hours after the infusion. This suggests that PAPM has rapid and good penetration into the lung.
3) Clinical efficacy and adverse reaction: Thirty-two patients with respiratory tract infections were treated with PAPM/BP. An overall efficacy rate was 72.4%(excellent in 6 cases, good in 15, fair in 4, poor in 4, and not evaluable in 3). Burning sensation and diarrhea were observed in 1 case as the adverse reaction. As the laboratory abnormal findings, elevation of GOT and/or GPT in 6 cases, elevation of serum amylase in 1, eosinophilia in 7, and decrease of platelet in 1 were observed. All of these were mild and improved rapidly after completion of PAPM/BP, indicating that PAPM/BP is a quite safety agent.

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Panipenem/betamipron (PAPM/BP) is a new carbapenem antibiotic, which contains panipenem (PAPM) and betamipron (BP). We performed laboratory and clinical studies on the drug to evaluate its usefulness in respiratory tract infections.
The antibacterial activity of PAPM against respiratory pathogenic bacteria was superior to those of other β-lactam antibiotics: its MIC₅₀ (the minimum concentration at which 50% of isolates were inhibited) of PAPM at 10⁶CFU/ml was 0.78μg/ml against Haemophilus influenzae, <0.003μg/ml against Streptococcus pneumoniae, 0.025μg/ml against Branhamella catarrhalis, 0.1μg/ml against Staphylococcus aureus, and 12.5μg/ml against Pseudomonas aeruginosa.
The maximal sputum levels of PAPM ranged 0.166μg/ml to 3.75μg/ml in 5 patients with respiratory tract infections and the ratios of maximal sputum levels to peak serum levels were 0.5%, 14.6% and 6.25% in 3 patients out of these 5 patients during treatment of PAPM/BP.
Twenty-one patients with respiratory infections were studied on clinical evaluation of PAPM/BP, which was administered 1.0g/1.0g or 1.5g/1.5g daily for 3 to 15days. Causative organisms were H. influenzae (10), S. pneumoniae (7), B. catarrhalis (2), and P. aeruginose (5). The bacteriological effect was 75%, and the clinical therapeutic efficacy was 85.7%.
From these results, we concluded that PAPM/BP was one of the effective and useful antibiotics for the treatment of respiratory tract infections.

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Measurement of antibacterial activities of panipenem/betamipron (PAPM/BP), a combination drug of a newly-developed carbapenem antibiotic for injection, panipenem (PAPM), and betamipron (BP) at a ratio of 1:1, and its clinical study in respiratory airway infections were carried out, and the following results were obtained:
1) Antibacterial activity: Minimum inhibitory concentrations (MICs) were measured against 927 strains of 27 species isolated from clinical specimens (193 strains of Gram-positive cocci, 26 of Branhamella catarrhalis, 453 of enterobacteria, 232 of glucose-non-fermenting Gram-negative rods, and 23 of Bacteroides fragilis) according to the standard procedure described by the Japan Society of Chemotherapy, and the obtained antibacterial activities were compared with those of imipenem (IPM), carumonam (CRMN) and ceftazidime (CAZ). As a result, PAPM/BP was found to have a broad antibacterial spectrum against Gram-positive organisms, including Staphylococcus aureus, and Gram-negative organisms, and its antibacterial activities were as strong as those of IPM.
2) Sputum levels in respiratory airway infections: Sputum concentrations of PAPM/BP weremeasured in 4 patients after the intravenous drip infusion at 0.5g/0.5g over a period of 30 minutes. The maximum sputum concentrations were 0.56-1.44μg/ml at 1-2 hours or 3-4 hours after the administration.
3) Clinical results: The clinical efficacy was determined using 5 patients with respiratory airway infection (4 with pneumonia and 1 with bronchiectasis) by administering PAPM/BP twice daily through intravenous drip infusion for 6-15 days. Daily dosages in terms of PAPM/BP were 0.5g/0.5g in 1 patient, 1.0g/1.0g in 3, and 1.5g/1.5g in 1. The overall clinical efficacy was good in 3 patients and fair in 2. No subjective or objective side effects due to the treatment with PAPM/BPwere observed. Slight elevation of GOT, which rapidly returned to normal after the termination of the treatment with this drug, and decrease of creatinine clearance were detected in each 1 patient.

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We performed laboratory and clinical evaluation of panipenem/betamipron (PAPM/BP), a new injective carbapenem, with the following results.
1) Antimicrobial activity
The minimum inhibitory concentrations (MICs) of panipenem (PAPM), an active form of PAPM/BP, against total 346 clinical isolates of 14 different species were determined and compared with those of imipenem (IPM), ceftazidime (CAZ), cefuzonam (CZON) and ceftizoxime (CZX). PAPM had wide spectrum of antimicrobial activities to those clinically isolated strains except methicillinresistant Staphylococcus aureus (MRSA), whose activities were almost equal to those of IPM. PAPM had a more effective antimicrobial activity against Enterobacter cloacae, but less against Pseudomonas aeruginosa than IPM.
2) Clinical efficacy
PAPM/BP 1.0g/1.0g/day or 1.5g/1.5g/day were given to 4 patients with bacterial pneumonia, 1 patient with acute bronchitis, and 2 patients with acute pyelonephritis. Clinical responses were excellent in 4 patients, good in 1, fair in 1, but not evaluated in 1. Distinct pathogens, Streptococcus pneumoniae, Staphylococcus aureus, and Serratia odorifera were all eliminated. Fever, supposed to be caused by the drug, was observed in 1 patient. No apparent kidney dysfunction was observed.

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Fundamental and clinical studies of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, were performed.
In the fundamental study, antibacterial activities of panipenem, imipenem (IPM), ceftazidime (CAZ), latamoxef (LMOX), and cefmetazole (CMZ) against isolates obtained from patients with urinary tract infection and stored at our department were measured using the MIC-2000 system. MIC₉₀ values of PAPM against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, indole-positive Proteus spp., and Enterobacter spp. were found to be as low as 3.13 μ/ml or less, while those against Enterococcus faecium, Proteus mirabilis, Serratia marcescens and Pseudomonas aeruginosa were 6.25 μg/ml or more, especially high against E. faecium and P. aeruginosa (namely, 100μg/ml or more). However, MIC₅₀ values of PAPM against these species were 3.13 μg/ml or less, excluding 100μg/ml against E. faecium and 25 μg/ml against P. aeruginosa. In comparison with other drugs, PAPM was confirmed to have the antibacterial activity equal to that of 1PM, and superior to those of CAZ, LMOX, and CMZ.
The clinical study was performed in the total of 6 patients, including 3 with complicated pyelonephritis, and 3 with complicated cystitis. Efficacy evaluation was perfomed according to the criteria of Japanese UTI Committee (3rd ed), and 5 patients were determined to be eligible for the evaluation. The clinical efficacy at 5th day was excellent, good and poor in 1 each of the 3 patients with complicated pyelonephritis, and the bacteriological efficacy was eradicated in 2 and replaced in 1. The clinical efficacy was good in 2 patients with complicated cystitis, and the bacteriological efficacy was eradicated in both cases. As for side effects and abnormal laboratory findings, an increase in GOT, and increases in LDH and potassium were observed in 1 patient each.

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We basically studied the antimicrobial activity of panipenem and used panipenem/betamipron (PAPM/PB) to treat patients with genitourinary tract infections with the following results.
1) The in vitro antimicrobial of panipenem (PAPM) was excellent against Staphylococcus aureus, Enterococcus faecalis, Escherichia coil, Serratia marcescens, Klebsiella pneumoniae and Pseudomonas aeruginosa clinical isolates.
2) PAPM/BP was administered to 20 patients with acute uncomplicated pyelonephritis, chronic complicated urinary tract infections and prostatitis at a dose of 0.5g/0.5g or 0.75g/0.75g twice daily. Clinical efficacy in acute uncomplicated pyelonephritis was excellent in 5 patients, and in complicated UTI, it was excellent in 2, moderate in 4 and poor in 2. Slight elevations of GOT· GPT and LDH were observed in respectively 1 patient.

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Panipenem/betamipron (PAPM/BP) is a new carbapenem antibiotic having a broad antibacterial spectrum against aerobic and anaerobic Gram-positive and Gram-negative organisms. Prior to the clinical application of this drug, its plasma concentrations were examined in 2 groups of rabbits in either dehydrated or hyperhydrated state. As a result, there were no differences between the 2 groups.
Subsequently, PAPM/BP was administered to 25 patients with genito urinary tract infections, including 17 with complicated urinary tract infections, 2 with acute uncomplicated pyelonephritis, and 6 with acute epididymitis. The clinical efficacy of PAPM/BP was evaluated according to the Japanese UTI criteria for evaluation of efficacy. Ten patients fulfilling the UTI criteria all with complicated urinary tract infection, and clinical efficacy was excellent in 6, good in 3 and poor in 1.
No adverse reactions ex or 1 shock-reaction by subcutaneous test of the drug, which was recovered with steroid therapy, were observed. Abnormal laboratory findings were found in 2 cases of slight liver dysfunction and 1 of elevation of lymphocyte. Moreover, 1 each of anaemia and decrease of erythrocyte, being not clear with the relation to the drug, was noted.

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We evaluated the clinical value of panipenem/betamipron (PAPM/BP), both bacteriologically and clinically in the treatment of urinary tract infections, and obtained the following results.
1) The antibacterial activities of panipenem (PAPM) against reference strains and various isolates from urinary tract infections were compared with those of the controls, imipenem (IPM), piperacillin (PIPC), cefmetazole (CMZ) and ceftazidime (CAZ).
Both Gram-positive and Gram-negative bacteria were sensitive to PAPM as same as IPM in the study on the standard strains.
Antibacterial activity of PAPM against clinical isolates was higher than the controls, especially for Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae and Enterobacter cloacae.
2) Seventeen patients with complicated urinary tract infections were treated with 0.5g/0.5g, 1.0g/1.0g or 1.5g/1.5g/day of PAPM/BP for 5 days. According to the Japanese UTI Committee, 15 patients were evaluable and the overall efficacy rate was 60%.
3) Clinical adverse reactions, diarrhea and vomiting were noticed in 2 patients.The pathological changes in the results of clinical examinations, elevation of GPT and LAP and eosinophilia were noticed in 3 patients. However, these reactions and changes were mild and not troublesome.
4) We concluded that PAPM/BP was effective and safe in the treatment of urinary tract infections.

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Fundamental and clinical studies on panipenem/betamipron (PAPM/BP), a new parenteral carbapenem antibiotic, were carried out, and the following results were obtained.
1) Antibacterial activity: MICs of panipenem (PAPM) against 250 strains of clinical isolates, including 9 species of Gram-positive and Gram-negative organisms, were compared with those of imipenem (IMP), ceftazidime (CAZ), cefoperazone (CPZ), and piperacillin (PIPC). Antibacterial activities of PAPM against the above-mentioned strains were found to be the same as or 2 times weaker than those of IMP, and PAPM exhibited excellent antibacterial activities against such Gram-positive organisms as Staphylococcus epidermidis and Enterococcus faecalis.
2) Pharmcokinetics: PAPM/BP was administered to 5 healthy male subjects at 0.5g/0.5g and 0.75g/0.75g through drip intravenous infusion using the cross over method to measure blood and urinary concentrations.
Mean maximum blood concentrations of PAPM were found 30 minutes after administration at 0.5g and 0.75g to be 37.2±1.8 and 61.4±4.9μg/ml, respectively. After that, blood concentrations gradually decreased, but were still detected at 0.23±0.03 and 0.43±0.08μg/ml, respectively, 6hours after administration. Urinary recovery ratios up to 6 hours after administration at 0.5g and 0.75g were respectively calculated to be 21.1±3.4% and 19.5±3.6%.
Blood concentrations of betamipron (BP) after adiministration at 0.5g and 0.75g respectively reached maximum levels of 23.8±1.4 and 39.0plusmn;3.1μg/ml after 30 minutes, rapidly decreased thereafter, and were found to be almost below the detection limit after 6 hours. Urinary recovery ratios of BP up to 6 hours after administration at 0.5g and 0.75g were respectively determined to be 91.9±5.4% and 97.9±1.4%.
3) Renal tissue transport: Transport into the human renal tissue was determined in 4 patients. PAPM concentrations at 0-105 minutes after the drip intravenous infusion of PAPM/BP at 0.5g/0.5g were measured to be 3.8-8.7μg/g in the renal pelvis, 1.0-14.4μg/g in the renal medulla, and2.1-18.9μg/g in the renal cortex. BP concentrations were measured to be 8.9-26.2μg/g in the pelvis, 29.0-113.7μg/g in the medulla, and 25.7-208.5μg/g in the cortex.
4) PAPM/BP was administered to 47 patients with urinary tract infection at 0.5g/0.5g or 0.75g/0.75g through drip intravenous infusion twice daily in the morning and evening for 5 days. According to the UTI criteria, a 74.4% efficacy rate and a 91.1% eradication rate were obtained. As for side effects, there were chest pain and pharyngeal discomfort in 1 patient, diarrhea in 1, and rash in 1, but these symptoms were diminished by discontinuation of the treatment. Abnormal changes in laboratory findings were slight increases in GOT and GPT in 1 patient, increases in GOT and total bilirubin in 1, eosinophilia in 2, eosinophilia and basocytosis in 1, and myelocytes in 1, which changes were mild and transient.
From these results, PAPM/BP was determined to be a useful parenteral antibiotic in the treatment of urinary tract infections.

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We studied the antibacterial activity and clinical efficacy of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic (lianipenem (PAPM)) combined with an anion transport inhibitor (betamipron (BP)), in the urological field.
1) Antibacterial activity: We determined the MICs of PAPM against clinical isolates (209 strains of 14 species) from urinary tract infections, and compared them with those of imipenem (IPM), ceftazidime (CAZ) and cefoperazone (CPZ). The overall antibacterial activities of PAPM were almost equal to IPM but superior to those of other control drugs.
2) Clinical efficacy: According to the criteria of Japanese UTI committee, the overall clinical efficacy rate was 52.9% (9/17) for chronic complicated UTI. Bacteriologically 20 of 26 strains (76.9%) were eradicated.
3) Side effect: No clinical side effects were observed. Concerning laboratory findings, a transient elevation of GOT and γ-GTP was noted in 1 case, a transient eosinophilia was noted in 1 case, and a mild leukopenia with eosinophilia was noted in 1 case.

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Panipenem/betamipron (PAPM/BP) was administered to 59 patients with complicated rinary tract infection and 1 with acute prostatitis, and the following results were obtained.
1) When MICs of panipenem (PAPM), imipenem (IPM) and ceftazidime (CAZ) against bacteria isolated before treatment were measured, PAPM was found to have equal and superior antibacterial activities against various bacteria to those of IPM and CAZ.
2) Fifty-one patients with complicated urinary tract infection satisfied the criteria of the Japanese UTI committee, and 20, 25 and 6 of them were respectively determined to have excellent, good and poor responeses. The overall clinical efficacy rate was 88.2%.
3) Bacteriologically, the eradication rate of Gram-positive organisms was found to be 100%, and that of Gram-negative organisms was 94.0%.
4) Side effects were observed in 2 of the 60 patients treated with PAPM/BP; they are, shock and vomiting nausea occurring in 1 each. Six incidences of abnormal laboratory finding were observed in 3 patients, and were mainly related to liver function disorders.

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Antimicrobial activity of panipenem (PAPM) to 300 strains isolated from the patients with urinary tract infections (UTI) was measured by the agar dilution method with an inoculum size of 10⁶CFU/ml. The drug was highly active against Enterococcus faecalis, Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis and Proteus vulgaris, and moderately active against Staphylococcus spp. and Pseudomonas aeruginosa. These activities were comparable to imipenem, and superior to ceftazidime against gram-positive cocci.
Panipenem/betamipron (PAPM/BP) was given to 34 patients with urogenital tract infections at 0.5g/0.5g-1.5g/1.5g for 5-7 days. According to the criteria proposed by the UTI Committee in Japan, the overall clinical effective rate was 73.9% in 23 cases of complicated UTI and 100% in 5 cases of acute bacterial prostatitis. The clinical response in 3 cases of acute epididymitis was evaluated to be 100% according to doctor's judgement. No patients had adverse reactions. A case of eosinophilia, 2 cases of elevation of GOT, and a case of elevation of GOT·EGPT were found on laboratory examinations, but these were mild and transient.

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