The in vitro and in vivo antibacterial activity of carumonam (CRMN) against both Gram-positive and Gram-negative clinical isolates was studied in comparison with that of aztreonam and cefotaxime. CRMN showed potent antibacterial activity against Gram-negative bacteria, particularly strains of Enterobacteriaceae. It also inhibited strains of Pseudomonas at low concentrations, but showed less activity against Gram-positive bacteria. It was highly resistant to hydrolysis by both chromosomal and plasmid-mediated β-lactamases. On the other hand, the 50% effective dose (ED₅₀) in experimental murine mice infections was 0.098 mg/kg against Escherichia coli ML4707, 2.64 mg/kg against Serratia marcescens GN7577 and 0.43mg/kg against Klebsiella pneumoniae GN6445.

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In a study of the in vitro and in vivo antibacterial activity of a new monocyclic β-lactam antibiotic, carumonam, the drug proved to have potent antibacterial activity against a number of Gram-negative bacteria, especially Escherichia coli, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Providencia stuartii, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa.
Carumonam further proved to be as stable to β-lactamase as is aztreonam.
The therapeutic response in mice with experimental infections induced by various Gram-negative rods (given as ED₅₀) correlated well with the in vitro MIC's for the respective rods

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Carumonam (CRMN) showed MIC₈₀ to 24-52 clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus, E. coli-carrying R plasmids, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Acinetobacter calcoaceticus, Pseudomonas aeruginosa, Xanthomonas maltophilia, Haemophilus influenzae resistant to ampicillin, and Bacteroides fragilis as >100, >100, 0.1, 0.1, 0.025, 0.025, 0.39, 0.025, 0.39, 3.13, 0.39, 0.39, 6.25, 100, 0.39 and >100μg/ml., respectively. CRMN bound strongly to PBP 3, 1A and 1B of E. coli in that order. High binding-affinities of CRMN were also demonstrated to PBP 3, 1B, and 1C of S. marcescens, to PBP 3, 1A and 1B of P. aeruginosa and PBP 3 and 1A of A. calcoaceticus, in that order, although CRMN did not bind at all to the PBP's of S. aureus, even at a dose of 100μg/ml.
Synergy of bactericidal activity between CRMN and the serum complement was prominent in the cells of E. coli NIHJ JC-2. Furthermore, these were engulfed and rapidly digested by cultured macrophages derived from the peritoneal cavity of ICR mice in the presence of sub-MIC's of CRMN as low as 1/8 MIC, whereas in the absence of the drug the same microbes multiplied intracellularly and destroyed the leucocytes.

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Carumonam is a novel synthetic monocyclic β-lactam antibiotic.
It has excellent antibacterial activity against aerobic Gram-negative organisms, but poor or little activity against anaerobes and aerobic Gram-positive organisms. We determined the in vitro antibacterial activity of carumonam against 1289 strains of recent clinical isolates, and compared it with those of aztreonam (AZT), ceftazidime (CAZ), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX), latamoxef (LMOX), cefoperazone (CPZ), cefotiam (CTM), cefmetazole (CMZ), cefoxitin (CFX), cefazolin (CEZ), ampicillin (ABPC) and minocycline (MINO).
The results were as follows.
1. Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, and Enterococcus avium were resistant to carumonam and AZT with MIC's of more than 200 μg/ml.
2. The antibacterial activity of carumonam against β-streptococci (groups A, C and G) was similar to that of AZT, being generally lower than those of cephalosporin antibiotics.
3, Carumonam showed high activity against Haemophilus influenzae (including β-lactamaseproducing strains). It was also superior to those of CTM and ABPC, but inferior to CTX, LMOX and AZT. Against Neisseria gonorrhoeae, its MIC's ranged from 0.78 to 50 μg/ml, thus proving inferior to the control drugs.
4. Against Enterobacter cloacae and Enterobacter aerogenes, its MIC's were distributed over a wide range, as were those of the control drugs.
5. Against Pseudomonas aeruginosa, its activity was generally equal or superior to those of AZT and CPZ, but inferior to those of CFS and CAZ.
6. Against glucose non-fermentative Gram-negative bacilli (except P. aeruginosa), its activity was poor and MIC's were higher than 6.25 μg/ml.
7. Against Bacteroides melaninogenicus, Bacteroides fragilis, Bacteroides distasonis and Bacteroides vulgatus, its activity was relatively high, but poor against Bacteroides ovatus and Bacteroides thetaiotaomicron.

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The in vitro activity of carumonam, a new monobactam, was compared with that of aztreonam, cefmenoxime, latamoxef, cefoxitin, and ceftazidime against reference and clinical strains of anaerobic bacteria.
Carumonam was similar to aztreonam in its activity and spectrum.
Carumonam was active only against bile-sensitive Bacteroides spp. and Fusobacterium spp., such as B. ureolyticus, B. melaninogenicus, F. nucleatum, F. gonidiaformans etc. It was not active against the B. fragilis group, especially B. fragilis, although it proved stable to the β-lactamase derived from it. The bactericidal action of carumonam against B. fragilis GAI-6221 at the concentration of two times the MIC was almost equal to that of aztreonam. Carumonam was shown synergistic with cefoxitin against many strains of B. fragilis, but was not synergistic with clindamycin.
Administration of carumonam (1 mg/mouse, b. i. d) increased the bacterial counts of Clostridium difficile in only one of five mice, but cefoxitin (2 mg/mouse, b. i. d) increased the counts in all mice tested.

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We compared the in vitro and in vivo antibacterial activities of carumonam (CRMN, AMA-1080), a new semi-synthetic monobactam antibiotic, with those of aztreonam (AZT), ceftazidime (CAZ) and cefmenoxime (CMX). The following results were obtained. CRMN had good antibacterial activity against Gram-negative bacteria, but poor activity against Gram-positive.
Its activity against the latter was similar to that of AZT, CAZ and CMX. In the sensitivity distribution of clinical isolates, its activity against Gram-negative bacteria, including Pseudomonas aeruginosa, was also similar to that of AZT.
The antibacterial activity of CRMN was not affected by the addition of horse serum or inoculum size, but was influenced by the pH of the medium; i. e., was enhanced in an alkaline medium.
CRMN showed dose-related bactericidal activity against Escherichia coli, Klebsiella pneumoniae and P.aeruginosa.
We investigated the morphological response of E. coli and P.aeruginosa to CRMN by phasecontrast microscopy. CRMN caused the formation of filaments at a wide range of concentrations and showed very high affinity for PBP 3 of both organisms.
Against experimental intraperitoneal infections caused by E. coli, K. pneumoniae, Serratia marcescens, P. aeruginosa and experimental UTI caused by S. marcescens in mice, its therapeutic efficacy was comparable to that of AZT.

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Carumonam, a new synthetic monobactam, has more potent antibacterial activity than other β-lactam antibiotic against a wide variety of Gram-negative organisms.
The antibacterial mechanisms of carumonam were investigated, comparing with those of sulfazecin against Pseudomonas aeruginosa KM338, Escherichia coli K12 and Serratia marcescens IFO 12648.
The minimum inhibitory concentrations (MIC's) of carumonam for these organisms were 12.5, 0.05 and 0.1μg/ml, whereas those of sulfazecin were 3, 200, 12.5 and 100μg/ml, respectively.
The potent antibacterial activity of carumonam, compared with that of sulfazecin, is considered to be due to its higher permeability of the outer membrane, the stability to hydrolysis by μ-lactamase and the higher sensitivity of the target enzymes of these organisms.

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The in vitro and in vivo activities of carumonam were compared with those of aztreonam and thirdgeneration cephalosporins such as cefoperazone, cefmenoxime, and cefsulodin. Carumonam was highly active in vitro against Enterobacteriaceae, Pseudomonas aeruginosa, and Haemophilus influenzae strains and weakly active against Streptococcus pneumoniae and anaerobic bacteria, but it was not active against Staphylococcus aureus. Itsminimum inhibitory concentrations (MIC's) for 80% of 1, 156 clinical Enterobacteriaceae isolates (MIC₈₀) were between 0.013 and 6.25μg/ml, the lowest MIC's of the antibiotics tested. The MIC₈₀ of carumonam for Klebsiella oxytoca was 0.1 μg/ml, whereas that of aztreonam was 25 μg/ml. The superiority of carumonam to aztreonam and reference cephalosporins was also demonstrated by their activities against cefazolin-sensitive Escherichia coli and Klebsiella pneumoniae, cefazolin-resistant K. pneumoniae, K. oxytoca, gentamicin-sensitive Serratia marcescens, Proteus spp., Providencia spp., and Morganella morganii, against which the MIC₈₀ of carumonam was less than 0.78μg/ml. The MIC₈₀ of carumonam for sulbenicillin-sensitive and-resistant P. aeruginosa was 3.13 and 12.5μg/ml, respectively, and comparable to the MIC's of aztreonam. The minimumbactericidal concentration values were mostly equal to the respective MIC values. Variation in pH, addition of horse serum, and type of growth medium had no definite effects on the activity of carumonam, but inoculum size had the usual inverse effect against several bacteria.
Carumonam protected well against lethal intraperitoneal infection caused by a variety of Gramnegative bacteria in mice. In general, the protective effects (ED⁵⁰) of carumonam and reference antibiotics correlated with the in vitro activities (MIC); carumonam showed excellent protective activity against most aerobic bacteria including K.oxytoca TN 1711 against which aztreonam was weakly active.

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The in vitro antibacterial activity of carumonam, a new N-sulfonated monocyclic β-lactam antibiotic, was evaluated by comparing its affinities for penicillin-binding proteins (PBPs), bactericidal and bacteriolytic activities, and effect on bacterial morphology with those of aztreonam and cephalosporins such as cefoperazone, cefmenoxime and cefsulodin.
Carumonam showed high affinities specifically for PBP 3 of Enterobacteriaceae and Pseudomonas aeruginosa, but affinities for PBPs of Staphylococcus aureus and Bacteroides fragilis were low. Carumonam and aztreonam, at their MIC levels, were strongly bactericidal against Enterobacteriaceae, but weakly bactericidal against P. aeruginosa. The bacteriolytic activity of carumonam as well as of aztreonam was limited to enteric bacterial species like Escherichia coli. Filamentation was the major morphological change in Gram-negative bacilli after exposure to carumonam. E. coli and Serratia marcescens were converted to ghosts after prolonged incubation with carumonam but P. aeruginosa was not.

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Escherichia coli 1U591 developed resistance to aztreonam (AZT), but not to carumonam (CRMN), by more than 2, 000 times by five transfers through a medium containing a sublethal concentration of AZT. A concomitant increase in β-lactamase activity was observed. The subsequent transfer of AZT-resistant E. coli 1U591 to an antibiotic-free medium showed no reduction in the MIC of β-lactamase activity. Furthermore, the, β-lactamase purified from the strain hydrolyzed AZT but not CRMN, suggesting a major role of the β-lactamase in the development of resistance. The substrate profile of this β-lactamase indicated that it differs from those of Proteus vulgaris and Klebsiella oxytoca.

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Carumonam (CRMN) was very resistant to hydrolysis by seven chromosomal and twelve plasmidmediated β-lactamases (including those from Klebsiella oxytoca, Proteus vulgaris, and Bacteroides fragilis that hydrolyzed aztreonam and several third-generation cephalosporins) and consequently was as effective against most, β-lactamase-producing bacteria as against β-lactamase-nonproducers. CRMN was 16-512 times as active as aztreonam against K. oxytoca strains which produce a large amount of β-lactamase. CRMN showed low affinity for penicillinases and oxyimino-cephalosporinase of P. vulgaris, but relatively high affinity for cephalosporinases from several species of Enterobacteriaceae. The β-lactamase-inducing activity of CRMN was weak; little induction was observed at 10μg/ml, the concentration that inhibits the growth of most bacteria.

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The therapeutic effect of carumonam on experimental respiratory and urinary tract infections in mice was compared with that of aztreonam.
Carumonam was as effective as aztreonam against respiratory tract infection caused by Klebsiella pneumoniae DT-S and urinary tract infections caused by Proteus mirabilis IFO 3849 and Pseudomonas aeruginosa P 9.
Taking into consideration that carumonam possesses nearly the same antibacterial activity as aztreonam against these test organisms, these results suggest that carumonam penetrates as effectively as aztreonam to infectious foci in respiratory and urinary tracts.

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Assay methods for pharmacokinetic studies of carumonam and its metabolites were developed. For microbiological determination of carumonam, an agar-well method, using Escherichia coli NIHJ as the test organism and antibiotic medium No.4 (DAIGO) as the test medium, was established. The sensitivity of the method for carumonam was about 0.1μg (potency)/ml. A method with higher sensitivity was also elaborated by using Providencia rettgeri ATCC 9250 and DST agar supplemented with 0.15% bile salts and 0.2mg% crystal violet; the sensitivity of this method was about 0.02μg (potency)/ml. A bioautographic method using the same Providencia strain, was devised for detection of antibacterially active metabolites.
Carumonam and its open, β-lactam ring hydrolysis product, Related Compound I, was quantitatively determined by an HPLC method on a Nucleosil 5C₁₈ column using 0.005M tetrabutylammonium hydrogen sulfate (pH 3.0)-acetonitrile (85:15v/v) as a mobile phase.

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The pharmacokinetic properties of carumonam (CRMN) were studied in mice, rats, rabbits, dogs, and cynomolgus monkeys and compared with those of aztreonam (AZT). CRMN administered subcutaneously in mice or intramuscularly in other animals at a dose of 20mg/kg was readily absorbed and distributed at high concentrations in the plasma, kidney, liver (except in rabbits), and lung as was AZT. The peak plasma levels of CRMN were (μg/ml): mouse 41, rat 38, rabbit 45, dog 36 and monkey 67. The areas under the plasma concentration-time curve were (μg·h/ml): mouse 20, rat 24, rabbit 67, dog 61 and monkey 80. The plasma half-lives were (h): mouse 0.24, rat 0.28, rabbit 0.73, dog 1.10 and monkey 0.89. All these ranges were comparable to respective values for AZT. The kidney levels of CRMN in all species were much higher, and the liver levels in mice, rats, and dogs were comparatively higher than the respective plasma levels; the levels in other tissues were less than the plasma levels. The kidney level of CRMN was usually higher than that of AZT, whereas the liver level of CRMN was usually lower.
CRMN was excreted mainly in urine; the recovery ranged from 51% in dogs to 73% in rabbits. Urinary recovery of CRMN in mice, rats, and monkeys was higher, but in rabbits and dogs lower than that of AZT. Biliary excretion of CRMN, 4.1% in rats and less than 0.2% in rabbits and dogs, was lower than that of AZT, namely, 19.1% in rats and c. 1% in rabbits and dogs.
The extent of protein binding of CRMN in sera of animals and humans, which ranged from 11% in dogs to 36% in rats, was lower than that of AZT, which ranged from 55% in rabbits to 85% in rats.

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The mechanism of renal excretion of carumonam (CRMN) was investigated by stop-flow analysis in dogs and rabbits.
In dogs, there was no specific CRMN peak corresponding to the peak of p-aminohippuric acid (PAH) secretion nor of Na⁺/K⁺ reabsorption in the stop-flow pattern. Though the PAH peak disappeared when probenecid was administered, the CRMN stop-flow pattern showed no change.
In the stop-flow pattern in rabbits, the peak CRMN concentration corresponded to that of PAH and disappeared when probenecid was administered.
These results suggest that the renal excretion of CRMN in dogs takes place exclusively through glomerular filtration. In rabbits, however, CRMN is excreted through glomerular filtration (c. 60%) and renal tubular secretion (c. 40%).

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Pharmacological studies on carumonam sodium (CRMN) produced the following results.
1. CRMN, even at high doses of 300 or 1, 000mg/kg i.v. in mice or rats, did not affect gross behavior, skeletal muscle coordination or body temperature, and had no hypnosis-potentiating or analgesic activities. Nor was there any effect on the spontaneous EEG in gallamine-immobilized cats (300mg/kg, i.v.), on the spinal reflex potentials in anesthetized cats (300 mg/kg, i.v.), or on the neuromuscular junction in the isolated phrenic nerve-diaphragm preparation of the rat (10^-4-10^-3g/ml). CRMN had no local anesthetic activity on the guinea-pig cornea (10% solution).
2. CRMN had little effect on respiration, heart rate, blood pressure, peripheral blood flow or EKG at i. v. doses of 100 and 300mg/kg in anesthetized cats or dogs.
3. In isolated guinea-pig heart preparations, CRMN, at an infusion rate of 0.3-10.0mg/min for 2 min (final concentrations, a 3×10^-5-10^-3g/ml), had no effect on contractile force or beating rate; though it caused a very slight increase in the coronary flow in a dose-dependent manner at 3 and 10mg/min for 2 min.
4. CRMN had no effect on the autonomic nervous system of the anesthetized cats (300mg/kg, i. v.).
5. No significant effect on urinary volume or excretion of sodium and potassium in rats was observed up to 300mg/kg i. v. of CRMN.
6. CRMN had no effect on the intestinal transport of charcoal meal in mice or gastric secretion in pylorus-ligated rats at i. v. doses of 100 and 300mg/kg.
7. In isolated smooth muscle preparations, CRMN even at a high concentration of 10^-3g/ml, had no effect on the spontaneous motility of rabbit ileum and non-pregnant rat uterus, acetylcholine-, histamine-and Ba⁺⁺-induced contractions of guinea-pig ileum or basal tone of guinea-pig tracheal muscle.

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A clinical phase-I study of carumonam (CRMN, AMA-1080/Ro 17-2301) was carried out in 27 healthy male adult volunteers to study the safety and pharmacokinetics of the drug.
Administration of CRMN was performed in the following order: in single-dose studies, starting from 500mg intravenous drip infusion (i.v.d.), 1, 000mg i.v.d., 1, 000mg intramuscular injection (i.m.), 1, 000mg i. v. injection and 2, 000mg i.v.d., and in the repeated-dose studies, two i.v. doses of 2, 000mg in 1 day, five i.v. doses of 2, 000mg in 3 days and eleven i.v. doses of 2, 000mg in 6 days. The results were as follows:
1) In the couse of the first injection, in the 5 i.v. dose study, 1 of 3 subjects complained of nausea, which disappeared immediately after termination of the injection. This subject showed no abnormalities after the second injection.
No abnormalities attributable to CRMN were observed in subjective or objective symptoms, or in the physical tests.
2) No abnormalities attributable to CRMN were observed in the laboratory tests, except for a slight elevation of GPT in 1 of 6 subjects given 11 i.v. doses of 2, 000mg.
3) As to fecal bacterial flora, a reversible change in aerobes, i.e. decrease in Enterobacteriaceae and increase in enterococci, was observed, while anaerobes were less affected. C. dificile, thought to be a cause of antibiotic-associated colitis, was not detected in any of the subjects.
4) The half-life of CRMN was 1.4-1.6 hrs by i. v. administration. Its serum level reached a peak 0.7h after i.m. administration and reduced with a half-life of 2.0h. The 24h urinary recovery rate of CRMN was 63% to 76% of the doses, most of which was excreted unmodified within 7.5h after administration. The half-life of CRMN when administered at 2, 000mg as a series of 11 i.v. doses was 1.5h at the first dose and 1.4h at the final dose, suggesting no influence by the serial administration.
5) No active metabolites were detected in urine, although a small amount of open β-lactam ring metabolite without antibiotic activity was detected in urine.
From the above findings, we conclude that CRMN is well tolerated in healthy subjects and applicable for further clinical evaluation in patients.

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The pharmacokinetics of carumonam were studied, following i.v. administration of 1g of the drug singly and in combination with probenecid.
The combined administration of carumonam with probenecid, as compared with its single administration, caused no changes in the blood concentration of the former at 2min, but prolonged its half-life in the β-phase by c. 15% and decreased the urinary recovery rate of the former in the 0-1h stage by c. 6%.
Carumonam is excreted renally, chiefly by glomerular filtration.
Blood concentration of AMA-1294, a metabolite of carumonam, reached a peak of 3μg/ml imme-diately after i. v. administration.

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Pharmacokinetics of carumonam, a new injectable monobactam antibiotic, were studied. Serum concentration and urinary excretion were determined after a single i.v. administration of lg of carumonam to healthy volunteers and to patients with renal insufficiency of various kinds. The drug concentration was determined by agar-well method using Escherichia coli NIHJ as the test organism. Pharmacokinetic analysis was performed with a two-compartment model, and 24 h endogenous creatinine clearance (Ccr) was used as a renal function index.
In all cases the peak serum levels were detected immediately after administration, and similar values were noted regardless of the subject's renal function. However, serum clearance during the β-phase tended to be prolonged parallel with the degree of renal insufficiency, so that t_1/2β, which was 1.20h in healthy volunteers, was prolonged to 4.22 h in patients with Ccr less than 30ml/min.
The mean cumulative urinary recovery rate of carumonam within 24 h in healthy volunteers was 98%. Excretion of carumonam into urine was prolonged and cumulative urinary recovery tended to decrease parallel to a decrease in Ccr. However, in patients with Ccr of less than 30ml/min the mean cumulative urinary recovery rate was relatively high (66%).

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The concentration of carumonam (CRMN) in the urological organs and sera of eleven patients was measured. Six patients had renal and upper ureter stone and five had benign prostatic hypertrophy. One gram of CRMN was injected i.v. prior to operation. One, two and three hours after administration, mean serum levels of CRMN were 62.0μg/ml, 43.1μg/ml and 30.2μg/ml respectively.
Renal tissue levels attained a maximal value of 51.7μg/g at 23 min, vesical tissue levels were 131μg/g at 20 min and prostatic tissue levels were 70.0μg/g at 36 min after i. v. administration.
Judging from the minimal inhibitory concentration of CRMN, it seemed to be clinically effective in cases of urological infection.

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The antibacterial activity of carumonam, a new monobactam antibiotic, was examined against 138 clinical isolates using the plate-dilution method with an inoculum size of 10⁶ cells/ml. The peak MIC's of the drug were 0.025μg/ml for Escherichia coli, Proteus mirabilis and Serratia marcescens, 0.05μg/ml for Morganella morganii, and 1.56-3.13μg/ml for Pseudomonas aeruginosa. The MIC's for two strains of Proteus vulgaris were 0.025 and 0.05μg/ml.
Pharmacokinetics of carumonam in six healthy male volunteers were investigated. One gram i.v. dose of the drug yielded a peak serum level of 118.2 μg/ml at 15 min., T_1/2 of 1.10 h, AUC of 122μg·h/ml and urinary excretion of 72.8% within 6h.
Twelve patients with Gram-negative bacterial infections were administered by carumonam i. v. drip infusion at 1g b. i. d. for 3-13 days. Response was excellent in seven patients and good in five. All pathogens were eradicated, and no side effects or abnormal laboratory findings were observed.
Carumonam was found to be an effective and safe drug in the treatment of these respiratory and urinary infections.

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Carumonam, a new monobactam antibiotic obtained by chemical modification of a monocyclic Β-lactam sulfazecin, shows high antibacterial activity against a broad range of Gram-negative bacilli.
It is very stable against various bacterial β-lactamases and shows low inducer activity of βlactamase production.
This agent was administered in two divided doses of 2-4g to seven patients with chronic bronchitis to evaluate its safety and efficacy.
Clinical efficacy was good in six patients and poor in one. The efficacy rate was 85.7%.
The time-course of serum and sputum concentrations of carumonam was determined after 1 g i.v. drip infusion, and high transfer efficiency into sputum was proved.
No side effects were observed, except for temporary and slight elevation of GOT in one patient.
From the above results, we conclude that carumonam is an effective and useful antimicrobial agent in the therapy of chronic bronchitis.

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In vitro antimicrobial activity of carumonam (CRMN), a new monocyclic β-lactam antibiotic, was examined by the broth-dilution method using the MIC 2, 000 system. The minimum inhibitory concentrations (WC's) of CRMN against 160 clinical isolates were compared with those of aztreonam (AZT) and cefoperazone (CPZ). Against Staphylococcus aureus, CRMN and AZT were shown to be less active than CPZ. But against all other isolates tested (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Morganella morganii and Pseudomonas aeruginosa), CRMN and AZT were more active than CPZ.
CRMN was administered by drip infusion for 1 h to one patient with diffuse panbronchiolitis at a dose of 1g, and its serum and sputum levels were assayed microbiologically. The peak serum level was 67.0μg/ml and the peak sputum level was 1.52μg/ml.
CRMN was also administered to three patients with respiratory tract infections. Clinical response was excellent in one and good in two cases. No adverse reactions or abnormalitiesin laboratory findings were observed.

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The in vitro antibacterial activities of carumonam (CRMN, AMA-1080) against 20 strains each of various clinical isolates (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Haemophilus influenzae, Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris, and Serratia marcescens) were meaured, using aztreonam, cefotetam, cefoperazone, ceftazidime, cefsulodin, piperacillin and mezlocillin as standard drugs.
The MIC₈₀'s of CRMN for the Gram-negative species were E. coli 0.05 μg/ml, K. pneumoniae<0.025, ug/ml, K. oxytoca < 0.025 μg/ml, H. influenzae < 0.1 μg/ml, E. cloaca 0.1 μg/ml, C. freundii < 25 μ g/ml, P. aeruginosa 3. 12 μg/ml, P. mirabilis < 0.025 μg/ml, P. vulgaris<0.025 μg/ml and S. marcescens<0.1 μg/ml, respectively. The drug proved to have potent antibacterial activity against all the species, and also to have the highest potency against K. oxytoca, E. cloacae and S. marcescens of the drugs tested.
The antibacterial activity of CRMN against E. coli, K. pneumoniae, P. mirabilis and P. vulgaris was comparable to that of aztreonam, and more potent than that of other cephem derivatives.
Seven patients, (one with respiratory tract infection and six with urinary tract infections), were clinically treated with 1-2 g of CRMN daily in equal divided doses, by i. v. or i. v. drip infusion, for 6-15 days.
The response to the treatment was good in 1 patient with chronic bronchitis ; good in 2, fair in 2, and poor in 1 of 5 patients with cystitis, and fair in 1 patient with pyelonephritis. Neither adverse reactions nor abnormalities in any laboratory parameters presumably due to the administration of CRMN were observed.

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We performed preclinical and clinical studies of a new monocyclic β-lactam antibiotic carumonam (CRMN, AMA-1080) and obtained the following results:
Antibacterial activity: The antibacterial activity of carumonam on 50 clinical isolates ofPseudomonas aeruginosa and 25 isolates of indole-positiveProteus spp. was compared with that of aztreonam (AZT) and of latamoxef (LMOX). The MIC's of CRMN against the isolates ofP. aeruginosa, when tested with 100-fold diluted inocula, were distributed in the range from 0.78-25 μg/ml, which were similar to those of AZT, but superior by 2-3 steps of concentration to those of LMOX. The MIC's of CRMN against indole-positiveProteus spp. were in the range from≤0. 05-1. 56 μg/ml, similar to those of both AZT and LMOX.
Absorption and excretion: Five healthy male adult volunteers were injected i. v. with 1 g each of CRMN and cefoperazone (CPZ) on a cross-over schedule. Serum concentration of CRMN reached a mean of 118 μg/ml at 5 min, and then decreased with a serum half-life of 1. 21 h. Serum concentration of CPZ reached a mean of 135 μg/ml at 5 min, and then decreased with a serum half-life of 1. 50 h. The 8-h cumulative urinary recovery rate of CRMN was 61. 3%, and that of CPZ only 16. 4%. The results of a study of the renal excretory mechanism of CRMN following probenecid pretreatment suggest that CRMN is excreted through the renal tubules.
Clinical findings: Eight patients with various internal infections were medicated with 2 g daily of CRMN for 3-20 days, and satisfactory clinical response to the treatment was achieved in four. No subjective side-symptoms were recorded in any of the patients. Laboratory studies revealed that S-GOT, S-GPT, ALP and BUN were elevated in one patient each, but no causal relation to the medication was determined.

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Carumonam is a new monobactam antibiotic with antibacterial activity against Gram-negative bacilli.
The antibacterial activity in vitro of carumonam was determined against 128 strains of clinical isolates, comparing it with those of cefoperazone and another monobactam antibiotic; aztreonam. Carumonam was more active than cefoperazone and as active as aztreonam against Escherichia coli and Klebsiella, with MIC's lower than 0.1 μg/ml.
Against Pseudomonas aeruginosa it was more active than cefoperazone and as active as aztreonam.
Carumonam was administered to five patients with urinary tract infection 0.5-1g twice a day by drip infusion for 6-9 days.
The clinical effects were good in three patients, fair in one patient, and unevaluable in one. As to bacteriological effects, organisms were replaced by Gram-positive cocci in three patients, persisted in one patient, and were eradicated in one patient.
No side effects nor abnormal laboratory findings were found.

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Carumonam, a monobactum antibiotic, was studied to determine clinical efficacy and safety by intravenous route in nine patients with respiratory infections (3 pneumonia, 5 bronchiectasis, 1 diffuse panbronchiol kis).
Clinical response was good in five patients, fair in two, poor in one patient and unevaluable in one. The total efficacy rate was 87. 5%.
No adverse reactions were noted, but in the laboratory examinations transient eosinophilia was observed in one case.
From our results, we considere carumonum suitable for the treatment of respiratory infections caused by Gram-negative bacilli.

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Clinical evaluation of carumonam was performed on three patients with Gram-negative urosepsis, four with pyelonephritis, one with liver abscess and one with cholecystitis. All patients responded satisfactorily. The causative organisms were determined in three patients with bacteremia and in two with pyelonephritis. Eradication of the bacteria was noted in all five patients who were studied bacteriologically. Superinfection with Enterococcus and Staphylococcus was observed in urine of one patient with urosepsis and two with pyelonephritis. A mild degree of leukopenia was also noted in one patient after cessation of treatment with carumonam.

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Clinical and adverse effects of carumonam, a new monobactam antimicrobial agent, were studied in 20 patients with respiratory infections receiving 1-4 g b. i. d. by drip infusion.
Among them were 17 cases of respiratory tract infections, 2 of pneumonia and one of empyema.
Clinical effects were excellent in 1 patient, good in 5 patients, fair in 8, poor in 4 and unevaluable in 2 because of exacerbation of atypical mycobacteriosis. The efficacy rate was 33%.
As to causative organisms, the results were as follows: of 3 strains of H. influenzae 1 was eradicated and 2 persisted in likewise, of 3 strains of P. aeruginosa 2 were eradicated and 1 persisted; all 3 strains of GNF-GNR persisted; 2 strains of X. maltophilia decreased; and of 2 strains of K.pneumoniae 1 was eradicated, and 1 decreased.
As to adverse effects, fever and diarrhea were observed in one patient each, both improving promptly on withdrawal of the drug.
Laboratory findings revealed one case each of eosinophilia, slight leukopenia and elevation of ALP.

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Carumonam, a new monocyclic β-lactam antibiotic, was administered to 12 patients with pneumonia once daily at 2g by i.v. drip infusion.
Therapeutic response was good in 5 cases, fair in 3 cases, poor in 1 case and unevaluable in 3 cases.
Anemia was observed in one case but returned to normal after the therapy.

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Antibacterial activity of carumonam (CRMN) was examined against 25 strains of clinical isolates of Staphylococcus aureus, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis and Pseudomonas aeruginosa and compared with those of aztreonam (AZT), another monocyclic fl-lactam slightly different in structure, using an inoculum size of 10⁶CFU/ml. Neither drug proved active against S. aureus, while both exerted excellent antibacterial effects on other Gram-negative bacteria, though their effects on all species were not comparable.
CRMN was generally administered in a dosage of 1g twice daily by i. v. drip infusion to 16 patients: 13 with respiratory tract infection (8 with pneumonia, 4 with secondary infection of the bronchiectasis and another with DPB) and 3 patients with urinary tract infections. The clinical response was good in 10, fair in 1 and poor in 2 of the 13 patients with respiratory tract infections, and good in 2 and poor in 1 of the patients another with chronic urinary tract infection. The bacteriological response was eradicated in 2, unchanged in 4, replaced in 2, and unknown in 8: i. e., slightly disappointing, as compared with the clinical response.
No clinical adverse reactions were observed. Abnormalities in laboratory findings were observed in one patient, namely, elevation of BUN, S-GOT, S-GPT.
These results suggest that CRMN is a useful antibiotic in treating infections caused by Gramnegative bacteria, accompanied by a low incidence of side effects.

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Eight patients with bacterial infections admitted to Kawasaki Municipal Hospital were given carumonam, a newly developed monocyclic β-lactam antibiotic, intravenously.
A 59 year-old female patient with suspected bacterial pneumonia was successfully treated with 2g daily for 12 days.
Out of seven patients with urinary tract infections, four had chronic pyelonephritis and three had acute pyelonephritis. The organisms responsible in the four patients with chronic pyelonephritis were Enterobacter aerogenes, Proteus mirabilis, Klebsiella pneumoniae with Staphylococcus aureus and Pseudomonas sp., respectively.
Of these four, three were successfully treated with 2 g daily and one cured with 3g daily. Three patients with acute pyelonephritis due to Pseudomonas spp. with Enterobacter spp., due to Micrococcus spp. with Enterococcus, and due to Klebsiella spp., respectively, were successfully treated with 2g daily. The duration of therapy for the seven patients with pyelonephritis was 7 days. Enterococcus was cultured from the urine of two out of the seven patients after carumonam treatment.
One patient with pneumonia developed a rash during the treatment, but no other adverse effects or abnormal changes in laboratory data were observed.

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Carumonam, a new monobactam antibiotic, was administrated to 2 patients with bacteremia, 14 with respiratory tract infection, 2 with urinary tract infection, 2 with liver and biliary tract infection, and 1 with fever of unknown origin. The patients received the drug for 2 to 40 days in a dose of 0.5-6.0g/day.
Clinical effects were excellent in 2 cases, good in 10, fair in 3, poor in 2, and undetermined in 4, showing an efficacy rate of 70.6%.
As to abnormal laboratory findings possibly related to this drug, slight abnormality in liver function tests was observed in two cases, and slight leukopenia and eosinophilia in one. No side effects were found.

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Carumonam was administered to 15 patients with various infections. Excellent effects were observed in 3 patients with pyelonephritis. In 5 cases of acute pyelonephritis, 3 of acute exacerbation of chronic pyelonephritis (including one patient with bacteraemia) and 2 of cholecystitis, good clinical effects were observed. In one case of pneumonia associated pleuritis, the clinical effect was poor. No clinical response was observed in one case of acute pyelonephritis associated with severe controlled diabetes mellitus.
Drug fever was observed in two patients. Leucocyte migration inhibition tests were positive against carumonam in both these cases. Abnormal laboratory findings were elevation of ALP in one case, and elevation of GOT and GPT in 2 cases. MIC's of carumonam against 9 causative organisms isolated from urine and blood in 8 patients with pyelonephritis were 0.025-0.1μg/ml in 5 strains of Escherichia coli, 0.025-0.05μg/ml in 2 strains of Klebsiella pneumoniae, 0.025 and less than 0.0125μg/ml in one strain each of Klebsiella oxytoca and Proteus mirabilis.

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The antibacterial and clinical effects of carumonam (CRMN, AMA-1080), a monobactam antibiotic, were investigated.
1) Bacteriological evaluation:
The antibacterial activity of CRMN was determined using 239 clinical strains of Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Serratia spp., Pseudomonas aeruginosa, etc., and the results were compared with those of cefotetan (CTT), cefpimizole (CPIZ), ceftizoxime (CZX) and cefoperazone (CPZ). Against S. aureus and E. faecalis, CRMN failed to exhibit activity. CRMN was highly active against E. coli, K pneumoniae, P. mirabilis, P. vulgaris, and M. morganii, the peak MIC's being 0.05μg/ml or less.
Thus, against these species, CRMN was equivalent or superior by c. 3 steps of concentration to CZX and about 1-4 steps superior to CTT. Against Serratia spp., CRMN was superior by c. 1 step of concentration to CZX. Against P. aeruginosa, CRMN was superior by 1 step to CPZ and c. 2 steps to CPIZ.
2) Clinical evaluation:
CRMN was administered to 9 patients: 4 with pneumonia, 2 with pulmonary suppuration and 3 with acute exacerbation of chronic respiratory infection. Clinical evaluation was: markedly effective in 1 case, effective in 5 cases, slightly effective in 1 case and ineffective in 2 cases; the efficacy rate being 66.7%. Bacteriologically, the strains of Xanthomonas maltophilia isolated in the cases of pneumonia, and the E. coli and P. aeruginosa strains in the cases of acute exacerbation of chronic respiratory infection, were eradicated. During treatment with CRMN, diarrhea occurred in one case but was mild and transient. Its relation to CRMN was undetermined. There were no abnormal laboratory findings.

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Carumonam, a new monobactam antibiotic, was administered to 25 elderly patients with infections and its clinical efficacy and side effects were investigated. The diagnoses were respiratory tract infection in 22 patients (pneumonia, 16; lower respiratory infection, 6), urinary tract infection in 2 patients, and fever of unknown origin in 1 patient. The treatment was “effective” in 11 cases, “slightly effective” in 10, and “ineffective” in 4; the efficacy rate (including “slightly effective” and “effective”) being 84%. Bacteriologically, out of 4 strains of Pseudomonas aeruginosa, two were eradicated, one decreased and one remained unchanged. Two strains of Klebsiella pneumoniae and one strain each of Proteus mirabilis, Serratia marcescens, and Escherichia coli were also eradicated, one strain of Pseudomonas cepacia was substituted by Enterococcus faecalis, and two strains of Staphylococcus aureus emerged after treatment. As to side effects, exanthema was found in one patient. Abnormal laboratory findings were leukocytopenia in 2 cases, an increase in eosinophils in 1 case, and elevated GPT and ALP in 1 case. Remission and recovery were, however, invariably obtained after discontinuation of treatment. We, therefore, think that if used in infections caused by susceptible bacteria, carumonam is also a useful antibiotic for adminisration to elderly patients.

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Carumonam, a newly developed monobactam antibiotic, was examined for its antibacterial activity in vitro, serum level after drip infusion in a patient, and for its clinical availability. The results obtained were as follows:
1) Antibacterial activity in vitro: MIC's of carumonam against Gram-negative bacilli isolated from clinical infection foci were estimated and compared with those of aztreonam, cefmenoxime, ceftazidime, cefoperazone, and ceftizoxime. In general, the antibacterial spectrum of carumonam was similar to that of aztreonam, while its activity against strains of Klebsiella pneumoniae and Proteus vulgaris was somewhat superior to that of aztreonam. Proteus mirabilis strains showed a sharp peak in the MIC distribution curve for carumonam, i. e. 0.01-0.05μg/ml.
2) Blood level: The serum peak level of carumonam at the end of a 1 h drip infusion of 1g was 50μg/ml in a case of cholangioma.
3) Clinical trials: Fourteen patients (16 episodes of infections) were treated with carumonam; the dosages being 0.5-4.0g/day for 4-16 days.
In two septicemia cases, the bacteria (Escherichia coli, Serratia marcescens) were eradicated from the blood by the treatment. The therapy was also effective in 3/4 cases of RTI, 4/4 of UTI, and 2/6 of biliary tract infections.
No side effects or laboratory abnormalities attributable to the therapy could be found in any of the cases.
These findings suggest that carumonam is a promising antibiotic against infections of Gramnegative bacilli with an availability comparable, at least, to aztreonam.

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Carumonam, a new monobactam antibiotic, was administered by i.v. drip infusion to 7 patients with respiratory tract infection (pneumonia: 3 cases, bronchiectasis with infection: 3 cases, and chronic bronchitis: 1 case), at a dose of 1 g twice a day for 6-23 days to study its clinical efficacy and safety.
Clinical effects were classified into four grades (excellent, good, fair, and poor); and the effect was excellent in 1 case, good in 3 cases, and poor in 3. The efficacy rate was 57.1%.
A slight increase of transaminase was observed in one case.

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Bacteriological and clinical studies on carumonam (CRMN), a new injectable monobactam monocyclic β-lactam) antibiotic, were carried out, and the following results were obtained.
1) Sensitivities of clinically isolated strains to CRMN were tested and compared with those of cefotiam (CTM), ceftizoxime (CZX) and aztreonam (AZT). Though CRMN and AZT were found to have no effect on Staphylococcus aureus, the activity of CRMN against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Proteus spp. was superior to AZT, peaking at 0.05 μg/ml for the MIC distribution-curve.
Activity against Pseudomonas aeruginosa ranged between 0.39-50 μg/ml of the MIC and was superior to AZT.
2) CRMN was administered to 6 patients with respiratory tract infection, at a dose of 1-2g twice a day for 3-9 days. The clinical effects were good in 2 cases, fair in 1 and poor in 3. The overall efficacy rate was 33.3%. No adverse reactions or abnormal findings in laboratory data were observed.

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Carumonam was administered to 5 patients diagnosed as having diffuse panbronchiolitis (2 cases), pneumonia (1 case), lung abscess associated with lung cancer (1 case) and chronic bronchitis associated with emphysema. The clinical response rate was 80%.
A moderate decrease in the number of platelets was documented for one patient. However, the relation of this abnormality to the test drug was indeterminate. There were no other abnormalities in laboratory tests nor any adverse reactions.
From these results, we conclude that carumonam is an effective and well-tolerated antibiotic for the treatment of respiratory tract infections.

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Laboratory and clinical studies were performed on carumonam (CRMN), a new monobactam antibiotic, and results were as follows.
1) Antimicrobial activity
MIC's of CRMN against various clinical isolates were determined with an inoculum size of 10⁶ cells/ml. Most strains of Escherichia coli, Klebsiella spp., Proteus spp. were 0.10 μg/ml or less; 70-80%strains of Enterobacter spp., Serratia marcescens, Morganella morganii, and Citrobacter spp. were 3.13μg/ml or less; 85% straine of Pseudomonas aeruginosa were 12.5 μg/ml or less, and the peak was 3.13μg/ml. These activities were a little higher than those of aztreonam and cefmenoxime. There was no activity against Staphylococcus aureus and Enterococcus faecalis.
2) Clinical efficacy
Three patients with pneumonia, 2 with bronchitis, 2 with bacteremia, 1 with acute cystitis and gingivitis, and 1 with subcutaneous abscess, were treated with CRMN at a daily dose of 2-6 g for 5-6 days. Clinical response was excellent in 1, good in 6, and poor in 2 patients. Bacterial effects were good in E. coli, Klebsiella pneumoniae, Serratia marcescens, and S. pneumoniae, and fair in P. aeruginosa. Causative organisms in the patients with a good response were eradicated. Exanthema was observed in one patient, GOT, GPT elevation in two, and low-grade eosinophilia in two.

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Carumonam, a new monobactam antibiotic, was investigated for its antibacterial activity against clinical isolates and concentrations in serum and sputum. In addition, the drug was administered to patients with respiratory infection to investigate its therapeutic effect. The results were as follows.
Antibacterial activity: Using 940 strains (106 of Gram-positive bacteria, 614 Enterobacteriaceae, 189 of glucose non-fermenting Gram-negative bacilli and 31 of Bacteroides fragilis) recently isolated from various clinical materials, the minimum inhibitory concentrations (MIC's) of carumonam were determined by the methods proposed by the Japan Society of Chemotherapy, and compared with those of several control drugs; latamoxef, cefmenoxime, cefotetan and cefbuperazone. Carumonam was the most active of all the drugs tested against Klebsiella spp., Proteus spp., Serratia marcescens, Pseudomonas aeruginosa and Acinetobacter calcoaceticus and showed MIC's of>100 μg/ml against Staphylococcus aureus, Enterococcus faecalis and B. fragilis. As to other enteric bacteria and glucose non-fermenting Gram-negative bacilli, the antibacterial activity of carumonam was almost equivalent to those of the control drugs.
Concentrations in blood and sputum: In one case each of chronic bronchitis and bronchiectasis, 1 h intravenous drip infusion of 1 g produced a peak blood concentration of 52-58 μg/ml at the completion of the infusion. The blood half-life was c. 50 min. The concentration in sputum was 1.25-2.1 μg/ml (2.2-4.1% of the peak blood concentration).
Clinical results in respiratory infections: In one case of bronchiectasis, 3 of chronic bronchitis and 2 of pneumonia complicated in lung cancer (a total of 7 cases) carumonam was administered by intravenous drip infusion at a dose of 2 g daily, in two divided doses, for 7-13 days. In a global clinical evaluation based on the course of bacteria, inflammatory findings such as CRP, WBC and sedimentation rate, chest X-ray findings, etc., “good” rating was obtained in 4 cases and “poor” in 3. Administration of the drug caused rash and itching sensation in one patient on day 7 of treatment. These symptoms subsided soon after discontinuation of treatment. In one patient, slight elevations of ALP, γ-GTP and LAP were found, which had returned to pretreatment levels 1 week after completion of treatment.

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Carumonam (CRMN, AMA-1080), a novel synthetic monocyclic β-lactam antibiotic, was basically and clinically evaluated with the following results:
1) Antimicrobial activity: CRMN was specifically active against aerobic Gram-negative bacteria including Pseudomonas aeruginosa. Its activity against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Enterobacter cloacae, Enterobacter aerogenes and P. aeruginosa was in general equal or superior to that of the third-generation cephems such as ceftizoxime, cefoperazone and latamoxef.
2) Carumonam level in serum and sputum: CRMN was drip infused for 1 h to five patients with chronic respiratory infections at a dose of 1 or 2 and its serum and sputum levels were assayed microbiologically. Peak serum levels were 33.5-64.7μg/ml with the 1g dose and 88.4-146.6μg/ml with the 2g dose at the end of drip infusion. Peak sputum levels were 1.21-6.56μg/ml (2g) at 2 to 4 h after infusion. The average ratio of peak levels in sputum to those in serum was 3.7 and 5.6%, respectively.
3) Clinical results: CRMN was administered to 13 patients with various respiratory infections. Clinical response was excellent in 2, good in 6, fair in 3 and poor in 1 patient, and 1 patient was not evaluable. The overall efficacy rate was 66.7%. In one patient S-GPT and urobilinogen values were transiently elevated mildly to moderately. We therefore conclude that CRMN is a useful antibiotics in treating patients with respiratory infections due to aerobic Gram-negative bacteria.

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Carumonam is a new beta-lactam antibiotic, or so-called monobactam, with antibacterial activity against Gram-negative bacilli and high stability to a wide range of beta-lactamases. Laboratory and clinical studies were performed to evaluate its usefulness in bacterial respiratory infections.
In vitro antibacterial activity of carumonam (CRMN) against respiratory pathogens was measured as MIC's (inoculum size: 10⁶ cfu/ml). MIC's against 48 strains of Streptococcus pneumoniae were 1.56->100μg/ml (peak MIC: 12.5 μg/ml), 41 strains of Haemophilus influenzae ≤0.1μg/ml, 26 strains of Branhamella catarrhalis 1.56-6.25 μg/ml, 9 strains of Escherichia coli 0.05-0.2 μg/ml, 21 strains of Klebsiella pneumoniae 0.05-3.13 μg/ml (MICH: 0.2 μg/ml), 10 strains of Enterobacter sp. 0.05-6.25 μ g/ml (MIC₉₀: 0.2 μg/ml), and 30 strains of Pseudomonas aeruginosa 0.39-25 μg/ml (MIC₉₀: 6.25 μg/ml).
Concentrations of CRMN in sputum and serum were determined in four patients after i.v. administration of 1 g over 30-60 min. Maximum sputum levels were 1.6 μg/ml, 1.91 μg/ml, 3.04 μg/ml and 5.28 μg/ml, respectively.
Ratios of maximum sputum level to peak serum level ranged from 0.57 to 1.5%. In two of the four patients, concentrations of CRMN in bronchial secretions from different sites in the lung were investigated just after i.v. injection. In one patient, the concentrations of 3 of these specimens varied from ≤ 0.3 to 12.5μg/ml, while in the other, they ranged from ≤ 1.4 to 2.66 μg/ml.
Twenty-two patients with respiratory tract infections (bronchitis 3, chronic bronchitis 7, chronic pulmonary emphysema 1, bronchiectasis 4, chronic bronchiolitis 5, pneumonia 2) were treated. Clinical efficacy was observed in 14 of 22 cases (64%). Twenty-three strains of causative organisms were isolated. None of 1 Staphylococcus aureus (0%) but 2 strains of 2 S. pneumonia (100%), 7 strains of 7 H. influenzae (100%), 3 strains of 3 B. catarrhalis (100%), and 4 strains of 10 Pseudomonas sp.(40%) were eradicated.
One case of mild leucocytopenia and 3 cases (2 patients) of drug fever were noted, but all recovered after cessation of CRMN.
On the basis of these results, we conclude that carumonam is an effective and useful antibiotic for the treatment of respiratory tract infections due not only to Gram-negative bacilli, but also to some strains of S. pneumoniae.

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Carumonam, was administered to 12 patients with surgical infections, including 5 with peritonitis, 5 with biliary tract infection, and 2 with wound infection.
Clinical results were excellent in 6, good in 4 and poor in 2 patients.
The total efficacy rate was 83% (10/12).
Bacteriological studies showed eradication of bacilli in 8 out of 10 cases.
There were no serious side effects or abnormal laboratory findings.

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Clinical effects and excretion into postoperative peritoneal exudate of carumonam (CRMN), a new N-sulfonated monocyclic β-lactam antibiotic, were studied.
CRMN was given to four patients with surgical infections, including peritonitis and postoperative wound infection. It was administered i. v. 1g × 2/day. Clinical effects were good in two cases and fair in two.
Concentration of CRMN in intraperitoneal exudate was 6.6, 6.9, and 4.4μg/ml on the 1, 2, and 3 postoperative day following gastrectomy, when CRMN was given 1g × 2/day intravenously. The concentration was higher than the MIC of CRMN against most Gram-negative pathogens.
Out of a total of 10 cases, including 6 cases of prophylactic use, no subjective or objective adverse effects were noticed.

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Basic and clinical studies on carumonam, a new monobactam antibiotic, were investigated and the following results were obtained.
Antibacterial activities of carumonam against clinical isolates were compared with aztreonam (AZT), cefotetan (CTT), ticarcillin (TIPC) and mezlocillin (MZPC).
Against clinical isolates such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa and Serratia marcescens, carumonam showed almost equal activity to AZT, but was more effective than other β-lactams against Gram-negative bacteria, including E. coli, K. pneumoniae, E. cloacae. It also demonstrated good activity against P. aeruginosa and excellent activity against S. marcescens. In clinical trials, it was administered i. v. by drip infusion to 11 patients with various surgical infections. The response was good in 5 cases, fair in 1 case and poor in 5 cases. In an evaluation of 7 cases of peritonitis, the result was good in 5 cases, fair in 1 and poor in 1 case. No serious side effects were noted.

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We performed basic and clinical studies of carumonam.
Carumonam proved to have an antibacterial spectrum similar to that of aztreonam.
The MIC's of carumonam against clinical isolates were widely distributed: ≤12.5 μg/ml for Escherichia coli, 6.25 μg/ml for Klebsiella pneumoniae, 0.05-> 100 μg/ml for Enterobacter cloacae, ≤12.5 μg/ml for Citrobacter freundii, and 0.8-25 μg/ml for Pseudomonas aeruginosa. Its antibacterial activity against E. coli was slightly inferior to that of aztreonam but comparable against other species.
Five healthy adults were injected i. v. with 0.5 or 1.0 g of carumonam, and serum and urine samples were determined by both bioassay and HPLC. The mean serum concentration after administration of 0.5 g was 54.8 μg/ml by bioassay and 53.5 μg/ml by HPLC at 5 min, and 0.4 and 0.4 μg/ml at 10 h respectively. The mean recovery rate of carumonam from urine within 10 h was 72.1% by bioassay and 77.7% by HPLC, and of metabolites was 4.0%.
The mean serum concentration after administration of 1.0 g was 118.4 μg/ml by bioassay and 125.6μg/ml by HPLC at 5 min, and 1.4 and 0.7μg/ml at 10h, respectively.
The half-life (T112) in serum was c. 1.5 h. The serum concentration of carumonam thus proved to be dose-dependent. The mean recovery rate from urine within 10 h was 74.0% by bioassay and 81.0% HPLC, and of metabolites was 3.3%.
Six postoperative cholecystectimized patients were injected i. v. with 1.0g, and bile samples were determined by bioassay. The mean biliary concentration was 10.1 μg/ml at 1 h, and 0.7 penal at 6h. When the patients were administered 1.0 g of carumonam or 1.0 g of aztreonam by single-shot i. v. administration in a cross-over study, the serum concentration of carumonam was c. 50% that of aztreonam.
Biliary concentration of carumonam reached a peak at 2h, and that of aztreonam at 5 h. The mean peak concentration of carumonam was c. 25% of the latters.
hirty-five patients with surgical infections were treated with carumonam. Response was excellent in 1, good in 29, fair in 4 and poor in 1 patient, the overall efficacy rate being 85.7% (i.e., in 30/35 response was good or excellent).
No adverse reactions were observed.

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Basic and clinical studies were carried out on carumonam, a new monobactam antibiotic, in the field of surgery and the following results were obtained.
1. Antimicrobial activity: carurnonurn, like aztreonam, had no activity against Staphylococcus aureus. Against Escherichia coli, Klebsiella and Pseudomonas aeruginosa, however, carumonam had strong antimicrobial activity, equal or stronger than that of aztreonam.
2. Secretion into bile: biliary concentrations were determined in three patients. The degree of secretion into bile was low with peak levels of 13.7, 14.3, 16.5μg/ml, respectively.
3. Clinical results: carumonam was administered to 24 patients with surgical infections. Clinical results were excellent in 7 cases, good in 13, fair in 2, poor in 1 and unknown in 1. The overall efficacy rate was 87.0%.
No side-effects due to carumonam were obsetved, but in the laboratory findings, elevations of GOT, GPT or ALP were noted in 3 cases.

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Basic and clinical studies of carumonam, a new monobactam antibiotic, were conducted on 23 patients: 20 with purulent peritonitis, 2 with traumatic peritonitis and 1 with biliary peritonitis.
1) The ascites level of carumonam 1h after start of administration was 24.9μg/ml for 1g i. v. injection, 19.7μg/ml for 1g i. v. drip and 33.4μg/ml for 2g i. v. drip. In 6 patients on abdominal drainage, when 1g was given by i. v. drip twice daily for 5 consecutive days, its mean ascites level was 20μg/ml on day 1 of treatment, 4.1μg/ml on day 3, and 2.8μg/ml on day 5. In one patient who was on a T-tube, administration of 1g and 2g yielded peak biliary levels of 17.3μg/ml and 33.3μg/ml, respectively, indicating a dose-dependent transfer of the drug into bile.
2) In a clinical trial, carumonam was administered at a single dose of 1-2 g, 2 to 4 times a day for 5-11 days. When the drug was given by i. v. injection or drip to 23 patients (14 with diffuse peritonitis, 8 with localized peritonitis, and 1 with biliary peritonitis) at a total dose of 7-36g (16.5g on average) for 6.7 days (on average), its clinical effect was rated “excellent” in 6 cases, “good” in 11, “fairly good” in 3, and “poor” in 3, the overall efficacy rate being 73.9%. No severe side effects were found in any of the cases.

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