We investigated cefpirome sulfate (CPR), a new cephem antibiotic, to clarify its physicochemical properties and stability.
The chemical structure was confirmed by IR, NMR, MS and elemental analysis. The physicochemical properties were clarified by studying solubility, partition coefficients and hygroscopicity. Degradation products formed under severe conditions were isolated and identified.
The stability of CPR for injection was investigated in the solid state and aqueous solution. CPR for injection was stable for 6 hours at room temperature after it was dissolved with distilled water or saline solution etc. In solid state, CPR for injection was stable at room temperature for 27 months.

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Eighty percent minimal inhibitory concentrations (MICs) of cefpirome (CPR) to 24-59 clinical isolates of Staphylococcus aureus, methicillin-and cephem-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CNS), Streptococcus pyogenes, Streptococcus pneumaniae, Escherichia coli, Klebsiella spp., Proteus mirabilis, Proteus vulgaris, Mo-rgartella morganii, Providencia rettgeri, Providencia stuartii and Providencia alcalifaciens, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomanas aeruginosa, Xanthomcmas maltophilia, Acinetobacter calcoaceticus, ampicillin-resistant Haemophilus influenzae, and Bacteraides fragilis were 3.13, 6.25, 1.56, 0.05, 0.025, 0.05, 0.1, 0.2, 0.2, 0.1, 0.39, 0.1, 0.39, 0.78, 0.2, 6.25, >100, 3.13, 0.1, and >100μg/ml, respectively. The antibacterial activity of CPR was superior to those of other reference antibiotics against Gram-positive bacteria including MRSA. It was, however, somewhat weaker than that of ceftazidime to P. aeruginosa. CPR manifested stronger affinity to PBP3 in S. aureus than cefotaxime (CTX), but weaker to the PBPs of E. coli, S. marcescens, and P.aeruginosa than the latter. CPR, however, caused greater morphological change of the cells of P.aeruginosa than did CTX. CPR manifested good synergy of bactericidal effect with not only serum complement but also mouse cultured macrophages up to 1/8 MIC. We consider CPR to be more potent against Gram-positive bacteria because of its high affinity to the PBPs, and against Gram-negative bacteria because of its good permeation through the outer membrane. CPR is a super-broad cephem antibiotic.

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The in vitro activity of cefpirome (CPR), a new cephalosporin, was evaluated and compared with those of5cephalosporins against 1, 489 clinical isolates including aerobic and anaerobic bacteria. CPR showed a broad spectrum ofantibacterial activity against Gram-positive and Gram-negative bacteria. Especially against staphylococci other than methicillin-resistant strains, Enterococcus faecalis, Enterobacter cloacae, Citrobacter freundii, Acinetobacter calcoaceticus var. anitratus and Pseudomonas aeruginosa, the MICs of CPR were lower than the values for the other antibiotics.

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We compared the antibacterial activity of cefpirome sulfate (CPR) with those of the following antibiotics: in vitro, cephazolin, cefotaxime, cefmenoxime, latamoxef, ampicillin, and methicillin; in vivo, 4-6 drugs for each bacterial strain of cefoperazone, ceftizoxime, cefsulodin, ceftazidime (CAZ), and gentamicin, in addition to the above listed drugs examined in vitro.
CPR showed broad-spectrum antibacterial activity against clinically isolated strains of Gram-positive and -negative bacteria. It was markedly more active than any other antibiotic tested against staphylococci, including methicillin-resistant Staphylococcus aureus and Enterobacteriaceae. Furthermore, CPR tended to be superior to all other third-generation cephems tested, except CAZ, against nonfermentative Gram-negative bacilli, including Pseudomonas aeruginosa, CAZ being slightly more potent than CPR.
CPR was stable to β-lactamases (CSase-, CXase-and PCase-types) produced by various species of bacteria.
CPR was also more effective than any of the other drugs examined in improving the condition of mice systemically infected singly with two strains each of S. aureus and Escherichia coli and one strain each of Klebsiella pneumoniae, Citrobacter freundii, and P. aeruginosa, and with a combination of E. coli and P. aeruginosa.

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We determined the antibacterial activity of cefpirome (CPR), a new cephalosporin, against 33 anaerobic bacteria of reference and clinical isolates, using the agar dilution method. CPR inhibited the growth of almost all anaerobic species tested with a concentration of 6.25μg/ml, except several species including B. fragilis, B. thetaiotaomicrcm, B. ovatus, B. uniformis, F. varium, C. botulinum, and C. difficile. CPR was very active against strains of Prevotella, Porphyromonas and peptostreptococci. The stability of this compound against β-lactamases derived from three Bacteraides fragilis isolates was also determined. CPR was hydrolysed to some extent by the β-lactamases from three isolates of B. fragilis. It was more stable than cefotaxime, cefpiramide and cefotiam and less stable than ceftazidime.

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We compared the in vitro and in vivo antibacterial activity of cefpirome (CPR), a new parenteral cephem antibiotic, with those of cefotiam (CTM), ceftazidime (CAZ) and cefotaxime (CTX) and obtained the following results.
CPR had a broad antimicrobial spectrum against Gram-positive and -negative bacteria, and its antibacterial activity was almost equal to that of CTM agianst Staphylococcus aureus and Staphylococcus epidermidis of Gram-positive bacteria and similar to that of CTX against Streptococcus spp.
On the other hand, its activity against Gram-negative bacteria, like that of CTX, was very potent Against Pseudamonas aeruginosa it was slightly inferior to that of CAZ and superior to that of cefoperazone (CPZ)
In the sensitivity distribution of clinically isolated strains, the MIC₅₀ values (μg/ml) of CPR were 0.39 for S. aureus. 0.006 for Streptococcus pyogenes, 0.05 for Escherichia coli, 0.05 for Klebsiella pneumoniae, 0.1 for Proteus vulgans, 0.1 for Morganella morganii, 0.05 for Enterobacler aerogenes, 0.39 for Serratia tnarcescens, 3.13 for Acinetobacter calcoaceticus, 0.05 for Haemophilus influenzae and 3.13 for P. aeruginosa.
CPR showed bactericidal action against S. aureus, E. coli, K. pneumoniae and P. aeruginosa at concentrations close to the MIC. In a morphological examination by phase-contrast microscope, CPR produced swelling and lysis of S. aureus cells and also induced the formation of filamentous cells, spheroplast-like structures and lysis of E. coli and P. aeruginosa. CPR showed high affinity against penicillin-binding proteins (PBPs) 3 of E. coli and P. aeruginosa and decreased in the order lBs, 1A.
These observations were consistent with the morphological alterations of E. coli and P. aeruginosa exposed to CPR. The therapeutic efficacy of CPR against experimental intraperitoneal infections in mice was comparable to that of CTM against S. aureus and superior to those of CTM, CTX and CAZ against E. coli, K pneumoniae, S. ma rcescens and M. marganii of Gram-negative bacteria. In P. aeruginosa infection in mice, CPR demonstrated therapeutic efficacy inferior to that of CAZ but superior to that of CPZ.

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We investigated the antibacterial action of cefpirome (CPR), a new cephem, against Pseudomonas aeruginosa KM 338, Escherichia coli K 12 and Serratia marcescens IFO 12648, and compared it with those of cefoperazonc (CPZ), cefazolin (LEZ) and benzylpenicillin (PCG).
The minimum inhibitory concentrations (MICs) of CPR against these organisms were 3 13, 0.012 and 0.2μg/ml. respectively. The addition of a subinhibitory concentration (1/2MIC) of ethylenediaminetetraacetic acid (EDTA). which damages the permeability barrier of the outer membrane, caused little change in the MICs of CPR against all these organisms. whereas a marked reduction in the MICs of CEZ and PCG was observed in the presence of EDTA. CPR was stable to β-lactamase activities from these organisms, whereas CEZ and PCG were hydrolyzed rapidly by the enzyr-ric The croislinking reaction of peptidoglycan synthesis catalyzed by the ether-treated cells from these organisms was inhibited by a markedly lower concentration of CPR than of CEZ.
We consider the potent activity of CPR against these organisms to be due to its high permeability of the outer membrane. stability to hydrolysis by β-lactamase and/or its high sensitivity to the target enzyme (transpeptidase) of these organisms.

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We examined the general pharmacological profile of cefpirome sulfate (CPR).
1. CPR caused a slight decrease in spontaneous motility (s. c.), mild potentiation of hexobarbital.induced hypnosis (i. p.) and slight analgesic action (i. v.) in mice, but had no other influence on the central nervous system in mice, rats or rabbits (i. v. p. s. c.).
2. Transient fall of the blood pressure accompanied by the decrease in dp/dt max and respiratory excitation were observed after CPR administration (i. v.) in a dose dependent manner in dogs and cats, while increase in the blood pressure and heart rate were observed in monkeys following CPR administration (i. v.) at 200mg/kg. These changes disappeared at 5 to 30 min after injection.
3. A slight increase in gastric juice secretion in Shay rats was observed after CPR administration (i. p.), but there was no other influence on the autonomic nervous system, motor nerves or digestive system in mice, rats, guinea pigs or cats (in vitro i. v., i. p.).
4. CPR (i. v.) had no influence on blood glucose levels in rats or rabbits, renal function in rats, or blood coagulation system in dogs. The compound showed no hemolytic effect (dog erythrocytes, in vitro) or anti-inflammatory effect in rats (i. v.).
5. When examined in vitro with rat brain synaptosome, CPR was less potent than cephaloridine but a little more potent than ceftazidime and cephalexin both in inhibiting GABA-receptor binding and in decreasing B_max.
We infer from these results that CPR has almost no general pharmacological effect, except for its antibacterial activity.

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A new cephalosporin derivative antibacterial agent, cefpirome (CPR), was administered parenterally by drip infusion to six healthy adult male volunteers for five days, and changes in fecal microflora and their correlation to fecal drug concentration were investigated.
1. The total viable count remained constant. This was due to the fact that there were no changes in the total Bacteroidaceae, which are the dominant organism in human fecal flora.
2. Eubacteria were eliminated and bifidobacteria, Enterobacteriaceae, and Veillonella were decreased drastically in almost all the volunteers.
3. Lecithinase-negative clostridia increased in some volunteers. Neither Clostridium difficile nor its toxin D-1 was detected in the fecal specimens of any of the volunteers.
4. No CPR was detected in the feces.
5. No diarrhoea or other side-effects were recognized in any of the volunteers.

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We established microbiological assay (bioassay) and HPLC methods for determinat on of cefpirome sulfate (CPR) in body fluid and tissue samples.
When the bioassay was carried out by the paper-disc method, using Bacillus subtilis ATCC 6633 as the test organism and sodium citrate agar (pH 6.4) as the test medium, CPR could be determined in plasma (serum), urine, bile and tissues. Human plasma or Consera ^® were used to prepare the standard solutions for determination of the human plasma level, and 0.1 M phosphate buffer (pH 6.0) was used for the assay of urine, bile and tissue levels. The detection limits of CPR in plasma and phosphate buffer were 0.39 and 0.2 μg/ml, respectively. By the disc-plate method, using Escherichia coli ATCC 39188 as the test organism and nutrient agar (Difco) as the test medium, the CPR level at lower concentrations (detection limit, 0.05 μg/ml) was assayed.
Plasma (serum) and urine levels of CPR were determined by HPLC with detection limits of 0.1 and 5.0 μg/ml. CPR concentrations measured by HPLC were in good agreement with those of the bioassay.
CPR was stable at -20°C in serum and urine for at least 12 weeks and in tissues for 8 weeks.

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Cefpirome sulfate (CPR) was administered at 20 mg/kg intravenously to rats with experimentally induced renal or hepatic injury, and the pharmacokinetic behavior of the compound was examined in relation to the mechanism of its excretion. Theplasma compound levels were determined by bioassay.
In normal rats, the plasma CPR levels after administration with probenecid were not different from those after administration of the compound alone, as were the results with the reference drug, ceftazidime (CAZ). This suggests that CPR is eliminated from the body mainly by glomerular filtration.
Accordingly, the pharmacokinetic parameters of CPR were examined in rats with antiglomerular basement membrane antibody-induced nephritis (showing selective glomerular lesions) and the following findings were obtained: increased Co (about 2.1 times), prolonged T_1/2 (about 1.8 times), and increased AUC (about 3.8 times) as compared with the values in normal rats. Similar changes in these parameters were observed after CAZ administration. In animals with CCI₄-induced hepatic injury, no significant delay in elimination was noted after CPR administration. As related to the mechanism of excretion of CPR, these results suggest that its pharmacokinetics may be affected by nephritis accompanied by decreased glomerular filtration.

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Using stop-flow analysis, we examined the mechanism of renal excretion of cefpirome sulfate (CPR) in mongrel dogs of bothsexes weighing 10 kg. CPR was administered by means of a constant infusion pump.
There was no CPR peak corresponding to the peak of p-amino-hippurate (PAH) secretion or to the peak of Na ⁺/K⁺reabsorption in the stop-flow pattern. After probenecid administration, the PAH peak disappeared, while the stop-flowpattern of CPR remained unchanged.
These results suggest that in dogs, CPR may be eliminated in the urine mainly b glomerular filtration.

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We compared the in vitro and in vivo binding of cefpirome sulfate (CPR) with rat, mouse, or human serum/plasma protein with that of other antibiotics. Its displacing effect on bilirubin bound to human serum albumin was also examined.
The in vitro binding of CPR with rat serum protein was not affected by the compound concentration added (25-100μg/ml) or by the incubation time (15-60 min). Therefore, the rat and mouse serum protein binding of the compound added at 50μg/ml was compared after 30-min incubation, with that of ceftazidime (CAZ), latamoxef (LMOX), cefoperazone sodium (CPZ), cefotaxime sodium (CTX), and cefazolin sodium (CEZ). CPR showed 7.7% and 11.3% binding with rat and mouse serumproteins, which were lower than the values of the reference antibiotics.
When the in vivo plasma protein binding of CPR was examined at 15 min to 4 h after administration (1 g. i. v.) to humansubjects, only 8.2-11.7% of the compound was bound to the protein at any time.
The displacing effect of CPR on bilirubin bound to human serum albumin was examined in vitro. CPZ and CTX, used as thereference substances, displaced bilirubin, and the amount or free bilirubin increased in a concentration-dependent manner. Bycontrast, even when a high concentration (800 μg/ml) of CPR was added, no significant liberation of bilirubin was observed.reflecting the low protein binding of the compound.

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We investigated the antibacterial activity, pharmacokinetics and clinical efficacyof cefpirome (CPR, HR 810), a new parenteral cephem antibiotic, and obtained the following results.
The susceptibility to CPR of 180 clinical isolates of seven species was tested using a plate dilution method with an inoculumsize of 10⁶ cells/ml. CPR showed antibacterial activity greater than that of ceftazidime (CAZ) and similar to those ofcefuzoname (CZON) and cefmetazole (CMZ) against 27 strains of Staphylococcus aureus. The antibacterial activity of CPRagainst Escherichia coli, Klebsiella spp., Morganella morganii and Proteus mirabilis was very strong, and against M. morganii itwas greatly superior to those of CZON, CAZ and CMZ. Against Pseudomonas aeruginosaCPR was slightly inferior to CAZ, butsuperior to CZON and CMZ.
The pharmacokinetics of CPR in six healthy male volunteers was investigated and compared to the results using CAZ in across-over test.
After intravenous administration of the drug at 1 g, the mean peak plasma concentration obtained by the bioassay methodwas 91.5μg/ml for CPR and 107.3 μg/ml for CAZ after 5 min. The mean values of T_1/2βin plasma were 1.7 and 1.6 h, and the AUCs were 137 and 172 μg h/ml. The urinary excretion rates within 8 h were 81%of CPR and 87% of CAZ.
Seventeen patients with bacterial infections (9 with respiratory tract infections, 7 with urinary tract infections and 1 withcholecystitis) were treated with CPR by 1 g b.i.d. drip infusion for 5-14 days. The clinical response was excellent in 8 andgood in 9 cases, the efficacy rate being 100%. No side effects or laboratory findings were observed.

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We measured the in vitro antimicrobial activity of cefpirome (CPR), a new semisynthetic cephalosporin agent for parenteral use, and evaluated its therapeutic efficacy in respiratory infections. The minimum inhibitory concentrations (MICs) of CPR, ceftazidime (CAZ) and latamoxef (LMOX=moxalactam) against 20 strains each of Staphylococcus aureus, Escherichta 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 the MICs, CPR was the most active against S. aureus and Enterobacteriaceae of the three agents tested, but it was somewhat less active than CAZ against P. aeruginosa. A daily dose of 2g of CPR was given intravenously for 6-36 days (mean: 20.0 days) to 5 patients: 3 with acute pneumonia, 1 with empyema and 1 with pulmonary tuberculosis. The clinical efficacy was good in three and fair in one. One case of pulmonary tuberculosis had to be excluded from clinical evaluation. Two strains of S. aureus were identified as causative organisms and both were eradicated by the administration of CPR. Drug-induced fever and an elevated GOT and GPT were observed in two patients. Elevated BUN and thrombocytepenia were found, respectively, in one patient each. These adverse reactions disappeared after completion of the therapy. From the above results, we conclude that CPR is one of the most useful cephalosporin agents for parenteral use as a first choice in the treatment of respiratory infections.

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We studied a new cephalosporin antibiotic, cefpirome (CPR), and obtained the following results.
1. Serum and urine levels of CPR were determined after intravenous drip infusion of 1.0 g to six patients with various degrees of renal function. In the patients with severely impaired renal function, the serum concentration decreased more slowly than in those in whom it was slightly or moderately impaired, and high serum levels were maintained over a long period. Excretion of CPR in urine diminished in relation to the degree of renal failure.
2. CPR was used to treat 16 patients with respiratory tract infection. Clinical response was good in 15 and poor in 1. Fever was observed as an adverse reaction in one case. Laboratory tests revealed eosinophilia, elevated transaminase (GOT, GPT) and alkaline phosphatase (Al-P) in one case, and eosinophilia in another. However, these symptoms were mild, and no severe side-effects caused by the drug were observed

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We evaluated the bile excretion and clinical efficacy of cefpirome (CPR), a new parenteral cephalosporin, in elderly patients.
Serial bile samples were collected after 1 g i. v. 60-min infusion or an i.v bolus injection of CPR to patients undergoing PTCD. Peak bile concentrations were 2.65-18.1 μg/ml in two patients with obstructive jaundice.
A clinical evaluation was carried out in 8 patients (pneumonia 3 cases, bronchopneumonia 1, acute bronchitis 1, peritonitis 1, cholangitis 1, pyelonephritis 1). Clinical response was excellent in 2, good in 2, fair in 1 and poor in 2 cases Satisfactory response was obtained in 3 of 5 patients with respiratory tract infection.
No adverse reactions or abnormal laboratory findings were observed except minor leukopenia in one patient.

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We performed basic and clinical studies on cefpirome (CPR), a new parenteral cephalosporine, and obtained the following results.
1. Five healthy adult male volunteers were given a bolus injection of 1 g of both CPR and ceftazidime (CAZ), and their blood levels and urine excretion were compared by the cross-over method. The renal excretory mechanism was investigated by dosing with CPR in combination with probenecid. The blood level of CPR at 5 min after administration of 1 g was 91.9 μg/ml. It decreased with a half-life (β-phase) of 1.64 h and was 1.63 μg/ml after 8 h. On the other hand, the blood level of the equivalent dose of CAZ was 112.4 μg/ml at 5 min and decreased with a half-life of 1.44 h. The cumulative recovery rate in urine over 8 h was 90.4% for CPR and 85.1% for CAZ. After dosing with CPR in combination with probenecid, the half-life. AUC and urinary cumulative recovery rate were 1.67 h, 132.1 μg.h/ml and 86.5%. The above results suggest that renal excretion of CPR is mainly due to glomerular filtration.
2. CPR was administered in daily doses of 1-2 g for 6-15 days to 8 patients: 3 with pneumonia, 3 with bronchitis, 1 with infected endocarditis and 1 with pyelonephritis. Clinical efficacy was excellent in 4, good in 2 and fair in 2 cases. Skin eruption was observed in one patient. Abnormal laboratory findings were observed in three patients including eosinophilia in one, increased uric acid in another and increased GOT and GPT in the third.

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We performed laboratory and clinical studies on a new cephem antibiotic, cefpirome (CPR).
The antibacterial activity of CPR in vitro against the clinically isolated strains was determined and compared with that of cefoperazone (CPZ), ceftazidime (CAZ), carumonam (CRMN) and imipenem (IPM).
Against Staphylococcus aureus, CPR was inferior to IPM, but superior to other reference drugs, and against Escherichia coli, it was the most active of all. Against Klebsiella pneumoniae all MICs of CPR were 12.5 μg/ml or less, which was second only to IPM. Against Pseudomonas aeruginosa, it was more active than CPZ.
CPR was administered to 10 patients (2 with sepsis, 5 with pneumonia, 1 with secondary bacterial infection of pulmonary fibrosis, 2 with urinary tract infection) at 0.5-1 g twice daily by drip infusion for 3-16 days. The results were excellent in 3. good in 2, fair in 1. poor in 1 and unevaluable in 3 cases. The causative organisms were eradicated in 2 cases, persisted in 1. were replaced in 1, and unevaluable in 6 cases.
In three cases hepatic dysfunction was observed. They were, however, mild and improved after cessation of administration.

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We determined sputum levels and performed a clinical study on cefpirome (CPR), a new cephalosporin antibiotic, to investigate the drug's clinical application in respiratory tract infections.
The sputum level after intravenous administration of 1 g CPR was 1.86 μg/ml after 2 h in one case, and 1.07 μg/ml after 3 h in another. Sputum transfer of CPR therefore proved satisfactory.
In a clinical study, 10 patients with respiratory tract infections were treated with CPR. The efficacy rate was 90.0%(9/10). Bacteriologically, 3 isolated strains of Haemophilus influenzae, 2 of Staphylococcus aureus and 1 of Proteus vulgaris were eradicated, but 2 strains of Pseutiomonas aeruginosa persisted.
As to side-effects, a slight feeling of warmth was observed in one patient. Abnormal laboratory findings were observed in two cases, but were transient.
From the above results, we consider CPR to be a useful antibiotic in respirator tract infections.

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We conducted basic and clinical investigations on cefpirome (CPR), a newly developed cephem drug for injection, which yielded the following results.
1. When 0.5 g of CPR was intravenously administered in a 1-h drip infusion to three elderly patients (mean age 85 years), the mean blood concentration reached a peak of 45.2 μg/ml 1 h after administration, and the mean half-life was 3.6 h.
2. The mean urinary recovery rate until 24 h after administration was 72.1%.
3. The clinical response in 28 cases (22 of pneumonia, 1 of lower respiratory tract infection, 4 of urinary tract infection, and 1 fever of unknown origin), excluding 1 unassessable case of lung cancer, was excellent in 2, good in 15, fair in 5 and poor in 6, with an efficacy rate of 60.7%.
4. As to bacteriological effect, 11 of 17 strains were eliminated (64.7%) and 5 replaced, including one strain of Staphylococcus aureus and two strains each of Enterococcus faecalis and Pseudomcmas aeniginosa.
5. Side effects were noted in one case of consciousness disorder accompanying electrolyte anomalies. As abnormal laboratory findings, there were two cases of elevated GOT and GPT, one of elevatedeosinophils, and one of elevated GOT, GPT, Al-P and anemia. But all symptoms improved upon discontinuation or end of drug administration.
The above results suggest that CPR is cl useful drug against infections in the elderly, especially those involving the respiratory tract.

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We performed laboratory and clinical studies on cefpirome (CPR), a new injectable cephem, with the following results.
1. Antibacterial activity
The antibacterial activity against 394 clinically isolated strains of 10 species was compared with those of cefoperazone (CPZ), cefmenoxime (CMX) and ceftizoxime (CZX). The antibacterial activity of CPR against Gram-negative bacilli was higher or equal to those of CMX and CZX. Especially against Staphylococcus aureus, CPR showed the highest activity among the antibiotics tested, and was far superior to CMX and CZX and more active than CPZ against Pseudomonas aeruginosa.
2. Clinical efficacy
CPR was administered to 17 patients with respiratory tract infections. The clinical efficacy rate was 68.7%(excellent 1, good 10, fair 2, poor 3 and unevaluable 1). The overall bacteriological response rate was 85.7%.
As adverse reactions, a transient rise in transaminase levels was noticed in 5 cases, of eosinophils in 4 cases, and drug fever and rash in 1 case each.

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We carried out bacteriological and clinical studies on cefpirome (CPR).
The MICs of CPR against 445 clinically-isolated strains of 30 species were measured, using an inoculum size of 10⁶ CFU/ml, and compared with those of cefazolin (CEZ), cefotiam (CTM), cefotaxime (CTX) and ceftazidime (CAZ). Gram-positive cocci: against Staphylococcus aureus and coagulase-negative staphylococci, CEZ showed the highest activity. Against Streptococcus pneumoniae and other streptococci, CPR and CTX showed higher activity than the other drugs. Against Enterococcus spp. the activity of CTX was superior to those of the other drugs.
Gram-negative rods: CPR showed potent antimicrobial activity against strains subject to Enterobacteriaceae in general, but against Proteus spp. its activity was somewhat inferior to that of CTX. The antimicrobial activity of CAZ was equal or slightly inferior to those of CPR and CTX except against Proteus vulgaris. Against Haemophilus influenzae and Vibrio fluvialis, CTX was most potent, as was CPR against Flavobacterium spp. Against Pseudomonas aeruginosa CPR's activity was almost the same as that of CAZ, and superior to that of CTX. Against Flavobacterium spp. CPR's activity was superior to those of the other drugs. The antimicrobial acivity of CEZ and CTM was generally inferior to those of the other cephems.
Seven patients with pneumonia, 3 with septicemia and one with fever of undetermined origin (FUO) were treated with CPR at a dose of 0.5-2.0 g b.i.d. by drip infusion for 4-20 days. The clinical response was excellent in 1 case of septicemia and 2 of pneumonia, good in 5 cases of pneumonia and fair or poor in 2 cases of septicemia, 1 of pneumonia and 1 of FUO. As to isolated strains, Escherichia coli from blood, and H. influenzae and S. pneumoniae from sputum were eradicated.
Side effect was not observed in all cases.

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We performed laboratory and clinical studies on cefpirome (CPR), a new broad-spectrum cephalosporin, in respiratoryinfections, with the following results.
1. The MICs of CPR for causative organisms were measured using the agar dilution method with an inoculum size of 10⁶ CFU/ml
The MICs for 18 strains of Haemophilus influenzae were under 0.2 μg/ml; for 18 strains of Streptococcus pneumoniae, under 0.1 μg/ml; for 16 strains of Branhamella catarrhalis, 0.1-1.56 μg/ml; for 14 strains of Staphylococcus aureus, 0.39-12.5 μg/ml; and for 15 strains of Pseudomonas aeruginosa, 0.2-100 μg/ml.
2. Clinical evaluation of CPR in 9 patients with respiratory infections was good in 6, fair in 1, poor in 1 and unknown 1, the efficacy rate being 75%. Mild elevation of TSH was observed in two patients and decrease of T₃ in one.

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We performed laboratory and clinical studies on cefpirome (CPR), a new injectable cephem antibiotic, with the following results.
1. Antibacterial activity
The MICs of CPR against various clinical isolates were determined with an inoculum size of 10⁶cells/ml. The MIC₈₀ was 3.13μg/ml for Staphylococcus aureus, 25μg/ml for Enterococcus faecalis, 0.10μg/ml for Escherichia coli, Kiebsiella pneumortiae, Enterobacter aerogenes and Proteus mirabills, 0.39μg/ml for Serratia marcescens, 0.78μg/ml for Enterobacter cloacae and Proteus vulgaris, 1.56μg/ml for Citrobacter spp. and 50μg/ml for Pseudomonas aeruginosa. It was also found that, compared with the control drugs, cefotaxime, ceftazidime and cefoperazone, CPR showed superior activity against many kinds of bacteria.
2. Clinical results
A total of 11 patients (5 with pneumonia, 2 with acute bronchitis, 1 with chronic bronchitis, 1 with pyelonephritis and 1 with fever of unknown origin) were treated with CPR at a daily dose of 2 g for 5-20 days. Clinical response was excellent in 1 patient, good in 7, fair in 2 and poor in 1.
No side-effects were observed, but eosinophilia was noted in three patients.
From the above results, we consider that CPR is one of the most useful antibiotics for the treatment of infectious diseases.

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We performed laboratory and clinical studies on cefpirome (CPR), a new cephem antibiotic, with the following results.
We investigated the pharmacokinetics of the drug in nine patients with renal failure after intravenous administration of 1g. The mean plasma concentration of CPR, administered over 5 min, with and without hemodialysis, was 101.6 and 103.9μg/ml. The mean values of T_1/2 (β) in plasma were 4.5 and 19.8 h, and tht. AUCs were 287 and 1762μgh/ml.
The clinical efficacy of CPR was studied in 10 patients: 7 with pneumonia, and 1 each with chronic bronchitis, acute pyelitis and acute pyelonephritis, 2 with mycoplasma pneumonia and 1 with rheumatic pneumonia having been excluded as unevaluable.
The clinical response was excellent in 5 cases, good in 4 and fair in 1, with an overall efficacy rate of 90.0%.
Bacteriologically, all causative pathogens were eradicated.
No side-effects were noted, though abnormal laboratory findings were observed in two patients.

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Cefpirome (CPR), a new cephem antibiotic was basically and clinically evaluated to provide the following results.
1. Antimicrobial activity: CPR showed excellent activity against not only Gram-negative rods but also Gram-positive cocci, especially methicillin-resistant Staphylococcus aureus. Its activity against Streptococcus pneumoniae, Streptococcus pyogenes, S. aureus, Enterococcus faecalis, Haemophilus influenzae, Klebsiella pneumoniae, Eschenchia coli, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Serratis marcescens, Pseudomonas aeruginosa, Acinetobacter calcoaceticus and Citrobacter freundii was in general equal or superior to that of ceftazidime (CAZ), cefoperazone (CPZ), cefotaxime (CTX), piperacillin (PIPC) and gentamicin (GM).
2. CPR levels in serum and sputum: 1g of CPR was drip infused for 1 h to two patients with diffuse panbronchiolitis to measure its serum and sputum levels by bioassay. Peak serum levels were 48μg/ml and 74μg/ml at the end of drip infusion. Peak sputum levels were 1.46μg/ml and 6μg/ml at 1-2 h after infusion.
3. Clinical evaluation and adverse reactions: 34 patients (33 with respiratory infection and 1 with sepsis) were treated with 2-3g daily of CPR for 3-20 days. The clinical efficacy rate was 88.2%(acute pneumonia 87.5%, chronic respiratory tract infection 88.9%). The bacteriological efficacy rate was 89.5%. Skin eruption and fever developed in one patient each. Mild elevation of S-GOT and GPT was noted in eight and eosinophilia in five patients (and both in two patients). Most of these abnormalities disappeared after cessation of the treatment. We therefore consider CPR a useful antibiotic agent for bacterial respiratory infections.

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Cefpirome (CPR) is a new semisynthetic cephem possessing a 2-amino-thiazolylmethoxyimino group at the 7-position as well as a cyclopentenopyridine group at the 3-position of the cephem ring.
The in vitro antibacterial activity of CPR against clinical pathogens of respiratory Infections was measured as MIC values (inoculum size: 10⁶ CFU/ml). Its MICs against 37 strains of Streptococcus pneumoniae were <0.006-0.39μg/ml, against 34 strains of Haemophilus influenzae 0.003-0.2μg/ml, against 28 strains of Branhamella catarrhalis 0.025-6.25μg/ml, and against 19 strains of Klebsiella pneumoniae 0.006-0.39μg/ml. The peak MICs were 1.56μg/ml against Staphylocorcus aureus (123 strains) and 12.5μg/ml against Pseudomonas aeruginosa (20 strains).
Serum, sputum and bronchial secretion concentrations were determined by bioassay using Bacillus subtilis ATCC 6633 as a test organism, in patients with bacterial respiratory infections receiving CPR 1g i.v. twice daily. The maximal concentrations of CPR in serum ranged from 48-68.7μg/ml (average: 57.1μg/ml) and serum half-lives from 1.3-1.6h (average: 1.4h). Maximal sputum concentrations ranged from 1.26-1.76μg/ml (average: 1.51μg/ml) and bronchial level was 3.08μg/ml. The ratios of maximal sputum to peak serum concentrations ranged from 1.83-3.67%(average: 2.81%).
The efficacy of CPR was clinically evaluated in 16 patients with respiratory infection as excellent in 6, good in 9 and poor in 1, the overall rate being a high 93.8%. Bacteriologically, 100% eradication occurred in 14 cases in which causative pathogens were identified.
Adverse drug side effects included transient slight elevation of S-GOT and S-GPT (1), decrease of RBC (1), decrease of WBC (1), eosinophilia (1) and urine protein (1), but discontinuation of treatment was not necessary in any of the patients.
On the basis of these results, it is concluded that CPR is one of the most effective and useful antibiotics for the treatment of respiratory tract infections.

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We conducted a basic study on cefpirome (CPR), a newly developed cephem antibiotic for injection, and clinically studied its application in the treatment of respiratory infections, with the following results.
1. Antibacterial activity
Against 928 strains of 27 species isolated from clinical materials (193 strains of Gram-positive cocci, 26 of Branhamella catarrhalis, 454 of enterobacteria, 232 of nonglucose-fermentable Gram-negative bacilli, and 23 of Bacteraides fragilis) the minimum growth inhibitory concentration (MIC) of CPR was measured by the criteria of the Japanese Society of Chemotherapy. Comparison was then made with the antibacterial activity of ceftazidime (CAZ), ceftizoxime (CZX) and latamoxef (LMOX). CPR proved to be active also against Staphylococcus aureus and Pseudomonas aeruginosa. Against other species of bacteria, it was equally or more powerful than CAZ, CZX, or LMOX.
2. Blood and sputum levels
After 1g CPR was given to three patients by drip infusion, serum and sputum levels were measured. The blood peak levels were 28.0-91.5μg/ml at 1 h after administration, while the maximum sputum levels were 1.62-2.35μg/ml. At 6-8 h the concentration was still greater than 1.31μg/ml in sputum.
3. Clinical study results
CPR was administered to 8 patients with respiratory infections at 2g/day b.i.d. for 4-12 days. The clinical efficacy was rated as excellent in 3 cases, good in 1, fair in 3 and poor in 1. We noted no objective or subjective side effects related to the antibiotic, though a mild elevation in GOT and GPT was observed in one case. The increased level quickly normalized after withdrawal of the drug.

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We performed basic and clinical studies on cefpirome (CPR), a new cephalosporin, with the following results.
1. Antimicrobial activity and concentrations in plasma and sputum.
The minimum inhibitory concentrations (MICs) of CPR against a total of 307 clinically isolated strains were measured and compared with those of imipenem/cilastatin, ceftazidime, cefuzonam and ceftizoxime, using the MIC-2000 System (Dynatecb Laboratories).
CPR was more potent than ceftazidime, cefuzonam and ceftizoxime against Gram-positive bacteria, and than imipenem/cilastatin against Gram-negative bacteria. CPR had wide antimicrobial activity against these clinically isolated strains except methicillin-resistant Staphylococcus aureus.
In patients with chronic bronchitis given 2.0g of CPR, the peak serum level of the drug was 84.2-91.0μg/mland the peak sputum level 0.99-1.13μg/ml.
2. Clinical efficacy
CPR (2g/day) was given to four patients with acute exacerbation of chronic bronchitis, one with pneumonia, and one with pyothorax, for 14-31 days. Clinical response was excellent in one and good in five patients, with an efficacy rate of 100%. No side effects were observed, but in clinical laboratory tests, slight and transient abnormal findings were observed in four patients.

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Antimicrobial activities and clinical studies on cefpirome (CPR), a new injectable cephalosporin, were performed and the following results were obtained.
1. Antibacterial activity of CPR
Against 45-50 strains of 11 kinds of pathogens isolated from urine, CPR's activity was compared to those of ceftazidime (CAZ), cefmetazole (CMZ), latamoxef (LMOX), ampicillin (ABPC) and ofloxacin (OFLX). Against Escherichia coli and Ktebsiella pneumoniae, CPR was superior to CAZ, and against Proteus mirabilis and indole (+) Proteus spp., it was superior to CMZ, LMOX, ABPC and OFLX. But against Serratia marcescens and Pseudomonas aeruginosa, it showed weaker activity than CAZ.
2. Clinical efficacy
CPR was administered in a daily dose of 0.5g or 1.0g for 5 or 10 consecutive days to 16 patients. In 15 cases which were in accord with the Japanese UT! Committee, excellent results were observed in 5, moderate in 9 and poor in 1 case. The overall efficacy rate in bacteriological respons was 96.3%(26 of 27 strains eradicated). There were no adverse reactions though transient abnormal laboratory changes were observed in 6 cases (37.5%).

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We used cefpirome (CPR), a new injectable cephem antibiotic, in the treatment of urinary tract infection (UTI) to investigate its therapeutic efficacy and safety.
CPR was administered to 26 patients with complicated UTI in a daily dose of 1.0-4.0g for 5 days. The overall clinical efficacy in 23 of the patients was assessed according to the criteria proposed by the Japanese UTI Committee.
According to the attendant doctor's evaluation, the efficacy rate was 72.2%. Clinical efficacy was excellent in 5 and moderate in 14 patients, with an overall efficacy rate of 82.6%.
The only adverse effect during treatment was transient diarrhea in one patient. Abnormal laboratory findings were observed in 3 of the 26 patients: transient elevation of GPT in one, and increase of NAG in two.
We consider CPR to be an effective and safe drug in the treatment of urinary tract infections.

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Cefpirome (CPR), a new injectable cephalosporin antibiotic, was studied for its antibacterial activity against 300 clinical isolates. Clinical efficacy was also investigated in patients with complicated urinary tract infections.
Antibacterial activity
The MICs of CPR were evaluated in comparison with those of CTX, CAZ and CPZ. Against Enterococcus faecalis, Enterobacter spp., Citrobacter freundii and Serratia marcescens, CPR was the strongest of the drugs tested. Against Escherichia coli, all four drugs were equally effective. CPR was lower than CAZ and equal to CPZ against Pseudomonas aeruginosa.
Clinical effect
We evaluated the clinical efficacy of CPR in eight patients with complicated urinary tract infections for 5 days at a daily dose of 1.0 g or 2.0 g by intravenous drip infusion. The overall clinical efficacy was excellent in 1 patient out of 8, good in 4, and poor in 3, with an efficacy rate of 62.5%. In laboratory findings, elevations of WBC, platelets, Al-P, γ-GTP and LAP were noted in one case, and S-GOT and S-GPT in another. No side effects were observed.

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We performed basic and clinical studies on cefpirome (CPR), a new cephem antibiotic, to investigate its utility in complicated urinary tract infections.
1. MICs of CPR against reference strains showed high antibacterial activity against both Gram positive and -negative bacteria. MICs for clinical isolates strains from urinary tract infections was good against Escherichia coli (MIC₉₀ 0.2μg/ml), and intermediate for Staphylococcus aureus, Staphylococcus epidermidis, Citrobacter freundii, and Enterobacter cloacae (MIC₉₀: 6.25-25μg/ml), but highly resisted strains were observed in Serratia marcescens (MIC₉₀: 50μg/ml) and Pseudomonas aeruginosa (MIC₉₀:>100μg/ml). But in comparison with the reference drugs ceftazidime (CAZ), cefoperazone (CPZ), and cefmenoxime (CMX), CPR showed equivalent or higher antimicrobial activity against most bacterial species.
2. Seven patients with complicated urinary tract infections were given 2g of CPR i.v. for 5 days, and six of these were evaluated according to the criteria proposed by the Japanese UTI Committee. The overall efficacy rate was 83%(5/6). No adverse reactions or abnormal laboratory test values were observed.
From the above findings, CPR proved to be an effective and safe drug in the treatment of complicated urinary tract infections.

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We performed pharmacokinetic and clinical studies on cefpirome (CPR), a new injectable cephem antibiotic.
1. Pharmacokinetics
CPR was administered to 10 patients with percutaneous nephrostomy in hemilateral kidney obstructed by ureteral stones. The kinetics of the drug were investigated after intravenous drip infusion of 1g for 1h.
With the diminution of total renal function, the blood concentration of the drug was prolonged and the AUC increased. The concentration and excretion of both nephrostomy and bladder urine were in parallel with the divided creatinine clearance (Ccr). Reflecting the fact that the Ccr of the nephrostomy was lower than that of the other side, both the concentration and the excretion of the drug in the former were low.
The mean excretion rate was 45.7% in patients with a total Ccr of 20-40ml/min, 54.3% in 40-60ml/min and 60.1% in >60ml/min.
2. Clinical evaluation
CPR was administered to 13 patients with complicated urinary tract infection at a single dose of 0.5g or 1g, twice daily (morning and evening) by intravenous drip infusion for 5 days. The overall clinical efficacy was excellent in 2 patients, moderate in 6 and poor in 3, and the overall efficacy rate was 73% by the criteria of the Japanese UTI Committee. The bacterial elimination rate was 88%(14/16).
As to side-effects, facial redness was observed in one patient. Slight elevation of transaminase was observed in another as an abnormal laboratory findings.

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We studied the antibacterial activity, pharmacokinetics and clinical efficacy of cefpirome (CPR), a new injectable cephalosporin, in the urological field. The results were as follows.
1. Antibacterial activity
We determined the MICs of CPR against clinical isolates (213 strains of 14 species) from urinary tract infections, and compared them with those of cefoperazone (CPZ), latamoxef (LMOX) and ceftazidime (CAZ).
CPR had strong antibacterial activity against Escherichia coil, Klebsiella, Enterobacter cloacae, Serratia, Proteus mirabilis, Proteus vulgaris and Morganella morganii. Although the activity of CPR against Pseudomonas aeruginosa was not strong, CPR had stronger activity against Staphylococcus epidennidis and Enterococcus faecalis than did CPZ, LMOX and CAZ.
2. Pharmacokinetics
The pharmacokinetics of CPR were studied in four healthy volunteers. After three single administrations of CPR 1g, CPR 0.5g and CAZ 1.0g, the peak blood concentrations were 53.0μg/ml, 24.3μg/ml and 53.7μg/ml.
The serum half-lives were 1.69 h, 1.69 h, 1.71 h and the urinary recovery rates up to 9 h were 63.3%, 69.1%, 76.8%.
3. Clinical efficacy
Of 29 cases of complicated urinary tract infection, 21 were evaluated according to the criteria of the Japanese UTI Committee.
The overall clinical efficacy rate was 76.2% and 28/32 (87.5%) strains were eradicated bacteriologically.
No side effects were observed, but mild elevation of transaminase was noted in one case.

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We clinically evaluated cefpirome (CPR), a new cephem antibiotic, in patients with complicated UTI and acute prostatitis. The concentrations of CPR in human prostatic tissue and serum obtained during transurethral resection of the prostate were also determined after intravenous infusion of 1 g of CPR. The following results were obtained.
1. As to the ratio of CPR levels in the removed prostatic tissue to serum, the average at 60 min after infusion was 0.34.
2. According to the Japanese UTI Committee's criteria, the overall clinical efficacy rate in 10 patients with complicated UTI and 6 with acute bacterial prostatitis was 90% and 100%.
3. In 20 patients who were given CPR, no subjective or objective side effects were observed, but in laboratory findings transient deterioration was detected in 4 patients.
These results indicate that CPR is a useful antimicrobial agent in acute prostatitis and also in complicated UTI.

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We evaluated a newly developed cephem antibiotic, cefpirome (CPR), for its clinical efficacy and safety in 12 cases of chronic complicated cystitis, 6 cases of chronic complicated pyelonephritis and 3 cases of post-prostatectomy infection.
The drug was administered i.v. or by d.i. in a daily dose of 1.0 g or 2.0 g for 5 days Clinical efficacy, evaluated according to the criteria proposed by the Japanese UTI Committee (3rd ed.), was excellent in 3, moderate in 11 and poor in 3 of 17 patients with chronic complicated UTI. The overall efficacy rate was 82.4%.
Bacteriologically, 27 of 31 strains (87.1%) isolated from chronic complicated UTI were eradicated after CPR treatment.
No adverse reactions occurred in any of the cases. In laboratory examinations, abnormal values were observed in I of 21 cases (slight elevation of S-creatinine).

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We investigated the antimicrobial activity and clinical efficacy of cefpirome (CPR), a new injectable cephem.
The antimicrobial activity of CPR against 300 strains isolated from patients with urinary tract infections (UTI) at an inoculum size of 10⁶ CFU/ml was measured by the agar dilution method and compared with those of ceftazidime (CAZ), cefoperazone (CPZ) and ofloxacin (OFLX).
The bacterial isolates consisted of 30 strains each of staphylococci, Enterococcus faecalis, Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Proteus vulgaris and Pseudomumas aeruginosa. The antibacterial activity of CPR against staphylococci, E. faecalis, C. freundii and E. cloacae, was 4 to 64 times as potent as that of CAZ, and equally effective against S. marcescens, but less so against P. aeruginosa.
CPR was given to 13 patients with complicated UTI at 1.0 or 2.0g per day for 5 days. According to the criteria proposed by the Japanese UTI Committee, the clinical efficacy in 12 cases of complicated UTI was excellent in 4, moderate in 7 and poor in 1, with an overall efficacy rate of 91.7%. Fifteen of 16 urinary bacterial strains were eradicated but one of GNF-GNR persisted. One patient suffered from an overall general itch after the first administration, and two patients experienced a metallic taste.
In laboratory findings, transient elevation of GPT and eosinophilia were observed each in one case, but recovered after the treatment.

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Cefpirome (CPR) is a new antibiotic drug of the cephalosporin group for parenteral use, with resistance and lower binding to β-lactamases, a broad spectrum of activity against both Gram-positive and -negative bacteria and low MICs against Gram-negative bacilli. We used the drug to treat 7 in-patients and 1 out-patient: 3 with skin and soft tissue infections (including 2 advanced cancer patients), 3 with localized peritonitis due to acute appendicitis, 1 episode of acute peritonitis in a postoperative patient with early gastric cancer, and 1 patient with peritonitis due to Crohn's disease of the ascending colon. CPR in a dose of 1-2 g was administered by i.v. bolus injection or i.v. drip infusion for 30-60 min once or twice daily for 4-10 days. Clinical response was excellent in 1, good in 6, fair in 1 and poor in no cases. The efficacy rate was 87.5%. Causative organisms were isolated in 6 cases (8 strains), four being Escherichia coli, and one each of Klebsiella pneumoniae, Pseudomonas aeruginosa, Peptostreptococcus sp. and Bacteroides fragilis. All were eradicated after CPR treatment except P. aeruginosa, which decreased.
Before operating two of the above cases (acute appendicitis), CPR 1 g was administered by i.v. bolus injection. Samples of purulent ascites, the appendix and serum were taken during the operation. CPR concentrations were measured by bioassay with Bacillus subtilis ATCC 6633 as a test organism. At 1 h after i.v. injection of CPR, concentrations were: 0.68 μg/ml in purulent ascites, 30.7 μg/ml in serum and 11.7 and 23.9 μg/g in appendix. CPR concentrations in infected tissues and body fluids were higher than its MICs against isolated organisms.
No adverse effects were observed in this study. We therefore consider that CPR is a safe and useful antibiotic for intravenous administration in skin and soft tissue infections, acute peritonitis, and other infectious diseases in the surgical field.

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We carried out clinical studies on cefpirome (CPR), a new parenteral cephalosporin antibiotic, in the treatment of abdominal, pelvic dead space, postoperative, and skin and soft tissue infections in the field of surgery.
CPR was administered to 32 patients with peritonitis, cholecystitis, cholangitis, hepatic abscess, infection of pelvic dead space, subcutaneus abscess, phlegmon, postoperative wound infection, periproctal, abscess, infectious pilonidal sinus, pyothorax, infectious endocarditis and suppurative osteomyelitis.
The number of patients classified by the degree of severity of infection was 6 cases (18.8%) severe, 19 (59.4%) moderate and 7 (21.9%) mild.
The clinical efficacy assessed by the physician in charge was: 7 cases excellent, 20 good and 5 fair of the 32 cases, the overall efficacy rate being 84.4%.
The bacteriological response was excellent in 2, good in 14, and fair in 2 of18 strains of Gram-positive cocci, with an efficacy rate of 88.9%. Of 12 strains of Gram-negative rods, it was excellentin 2, good in 7 and fair in 3, with an efficacy rate of 75%. And of 11 strains of anaerobes, it was excellent in 1, good in 8 and fair in 2, with an efficacy rate 81.8%.
The bacteriological efficacy against clinically isolated 41 strains was 35 eradicated, 1 decreased, 2 persisted and 3 replaced, the eradication rate being 92.7%.
The clinical efficacy in 15 cases previously given ineffective drug-treatmentwas 13 cases excellent or good, and the efficacy rate was 86.7%.
There were no subjective or objective side effects.
In the laboratory findings, slight elevation of GOT and GPT was observed in 1of the 32 cases (3.1%).
The MICs were lower than 12.5μg/ml against 24 (80%) of 30 clinically isolated strains of 15 species.

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We performed basic and clinical studies on cefpirome (CPR), a new cephalosporin, and obtained the following results.
The antibacterial activity of CPR against clinical isolates was compared with those of ampicillin (ABPC), piperacillin (PIPC), aspoxicillin (ASPC), cefazolin (CEZ), cefuroxime (CXM), cefoperazone (CPZ), cefotiam (CTM), cefotaxime (CTX), ceftizoxime (CZX), cefpiramide (CPM), ceftazidime (CAZ), cefoxitin (CFX), cefmetazole (CMZ), cefotetan (CTT), latamoxef (LMOX), imipenem (IPM), tobramycin (TOB) and minocycline (MINO). Its activity against methicillin-resistant Staphylococcus aureus (MRSA) was also compared with those of cloxacillin (MCIPC), amoxicillin (AMPC), cephalothin (CET), cephaloridine (CER), cefamandole (CMD), flomoxef sodium (FMOX), cefepime (BMY-28142), ofloxacin (OFLX), tosufloxacin (TFLX), netilmicin (NIL), vancomycin (VCM), and fosfomycin (FOM). The MICs of CPR were studied against clinical isolates such as coagulase-positive staphylococci (CPS), coagulase-negative staphylococci (CNS), Escherichia coli, Klebsiella pneumoniae. Enterobacter cloacae, Pseudomonas aeruginosa and MRSA.
CPR showed excellent activity against E. coli and K. pneumoniae, and good activity against E. cloacae, but it was slightly less active against P. aeruginosa and MRSA.
In the clinical study, CPR was administered to nine patients with mainly intra-abdominal infections. Clinical response was fairly good in eight cases and fair in one case.
No serious side effects were noted.

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We studied the clinical efficacy of cefpirome (CPR), a cephem antibiotic for intravenous injection, in treating surgecal infections. We also studied the drug's distribution to body fluids and tissue.
The clinical efficacy was evaluated in 12 cases: localized peritonitis (5), intraperitoneal abscess (2), perirectal abscess (2), postoperative pneumonia (1), postoperative wound infection (1) and cholecystitis (1). CPR was administered by intravenous drip at a unit dose of 1-2 g twice daily for 4-18 days, the total dose being 7-36 g. The clinical efficacy was excellent in 2 patients, good in 7 and fair in 3, the efficacy rate (excellent or good) being 75.0%. The bacteriological effect was eradication or decreased in 7 strains.As to causative bacteria, 2 of 2 strains isolated from infection with Gram-positive cocci and 2 of 5 strains isolated from infection with Gram-negative rods were eradicated after CPR treatment.
We studied side effects and laboratory test values, and noted a mild prolongation of prothrombin time in one case, though no hemorrhagic tendency was clinically observable. We noted no other side effects or abnormal laboratory findings attributable to the antibiotic during treatment.
We administered 1 g of CPR to six patients scheduled to undergo cholecystectomy. Approx. 2 h after administration, the drug concentration (median) in the wall of the extracted gall bladder, in thebile juice within the gall bladder, and in the bile juice within the common bile duct, was 15.1μg/g, 7.8 and 21.8μg/ml, respectively. The concentration in the appendicular tissue in two of the patients was 6.7μg/g (2 h after administration of 2 g) or 1.7μg/g (7 h after administration of 1 g). The distribution in the pus of patients with intraperitoneal abscess was 29.1μg/ml on day 7 consecutive administration at 2g/day.

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We investigated cefpirome (CPR), a new cephalosporin, in terms of its serum level, bile and abdominal exudate distribution and clinical efficacy. The exudate was obtained from the abdominal cavity after operation. The results obtained were as follows.
CPR showed moderate distribution in bile, and its peak level (54 and 43μg/ml) occurred at 6h after 1 g administration intravenously.
In abdominal exudate, its peak level (14-20μg/ml) occured 3-6 h after administration.
Of nine patients with surgical infections treated with CPR, clinical response was good in six, poor in one No side effects were noted, although a transient slight elevation of serum GOT and GPT in one case was observed in laboratory parameters.

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We investigated the penetration of a new injectable cephem antibiotic, cefpirome (CPR), into bile, gallbladder tissue, wound exudate and wound space exudate.
Bile: the serum level of CPR 1 g after intravenous injection in a postoperative choledocholithiatic patient with indwelling T-tube whose hepatic function was slightly abnormal, was 55.4μg/ml at 5 min after administration and maintained at 10μg/ml or higher for 6 h. The biliary level attained 11.1μg/ml in 2 h, and maintained at 10μg/ml or higher for 6 h.
Gallbladder tissue: the serum level of CPR 1 g at 1 h after administration in a cholecystectomy patient with normal hepatic function was 31.9±11.7 (mean±SD)μg/ml, and the CPR level in the gallbladder tissue was as high as 15.8±2.51μg/g at 1 h after administration.
Wound exudate and wound space exudate: the serum level of CPR 1 g after intravenous injection in one ventrotomy patient and four radical mastectomy patients with normal hepatic and renal function was 39.1±3.2μg/ml at 1 h and 5.1±0.7μg/ml at 5 h after administration, thus a serum level of 5μg/ml or higher was maintained. The wound exudate level of CPR 1 g after intravenous injection was 20.7±13.2 at 1 h and 7.3±3.8μg/ml at 5 h after administration in four patients, thus an exudate level of 5μg/ml or higher was maintained for 5 h. The wound space exudate level in 4 cases was 12.8±9.8μg/ml at 1 h and 4.7±0.7μg/ml at 5 h after administration. Thus the wound exudate level tended to be somewhat higher than the wound space exudate level.
Given CPR's antibacterial activity and its good penetration into bile, gallbladder tissue, wound exudate and wound space exudate, the drug's utility in surgical infections is presumably high.

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We evaluated the stability of cefpirome (CPR) in human bile in 15 cases. The bile was prepared at 100μ/ml of CPR, then sequential residual activity was calculated at 20°C, 4°C and -20°C for pH value and β-lactamase activity. It was stable at -20°C until 24 h, but remarkable inactivation was observed at 20°C -8h, and in the two cases with β-lactamase activity and a pH value of more than 8.40, the most remarkable inactivation was observed.
Penetration of CPR into exudate after radical mastectomy was calculated in four cases. A peak concentration of 20.5-76.6μg/ml was achieved after 2-4 h with a 1 g i. v. dose of CPR.
CPR therapy was basically and clinically evaluated in 10 patients: 5 with acute cholecystitis, 2 with abscess, 1 with phlegmon, 1 with intraabdominal abscess and 1 with RLQ abdominal pain of unknown origin.(This last case was excluded from evaluation). Clinical response was good (including one excellent) in all 5 cases of cholecystitis and in both cases of abscess and phlegmon, but response was poor in the case of intraabdominal abscess. As to adverse effects, mild and transient elevation of GPT was observed.

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We performed basic and clinical studies on cefpirome (CPR), a newly developed injectable cephem antibiotic, in the field of surgery. The following results were obtained.
1. Antibacterial activity
The MIC₅₀ and MIC₉₀ (MIC₅₀/MIC₉₀) of CPR against Staphylococcus aureus, Eschenchia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, isolated from surgical foci, were 1.56 (μg/ml)/25 (μg/ml), ≤0.05/0.2, ≤0.05/≤0.05 and 25/50, respectively. The results showed that CPR has excellent antibacterial activity against E. coli and K. pneumoniae, equivalent to that of ceftizoxime (CZX). Against S. aureus, CPR was inferior to minocycline (MINO) but somewhat superior to cefotiam (CTM), and against P. aeruginosa it was nearly equivalent to piperacillin (PIPC).
2. Distribution of CPR to bile
The peak concentration of CPR in bile was 140μg/ml, 60μg/ml and 189μg/ml in three cases, and ratio of the bile to the plasma concentration was 1.40μg/ml, 0.58μg/ml and 3.26μg/ml, indicating moderate migration.
3. Clinical evaluation
Fourteen patients with surgical infections were treated with CPR. Overall efficacy was excellent in 2, good in 10, fair in 1 and poor in 1, with an efficacy rate of 86%. The bacteriological response was: eradicated in 5, replaced in 2 and decreased in 2 cases. As for side effects, 38°C fever was noted in one case. Abnormal laboratory findings were observed in seven cases, representing a high incidence. But none of the abnormal fluctuations was serious or presented any particular clinical problems.

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Cefpirome (CPR), a new cephem antibiotic, is thought to have potent antibacterial activity against Gram-positive as well as -negative organisms and superior stability to β-lactamase. We examined distribution of CPR to gallbladder tissue and bile, and its clinical efficacy against infections in the surgical field.
1. The blood levels of CPR after 1 g drip infusion were 40.3±7.7μg/ml (mean±SE)(n=5) at 1 h and 22.4±3.4μg/ml (n=5) at 2 h on average.
2. The levels in gallbladder tissue after 1g infusion were 28.9±7.6μg/g (n=3) at 1 h and 10.6±5.1μg/g (n=3) at 2 h on average.
The levels in gallbladder bile were 11.4μg/ml (n=2) at 1 h on average, except in one case of cystic duct obstruction, and 17.1±6.4 μg/ml (n=3) at 2 h on average.
3. The peak biliary levels of CPR in 3 patients with T-tube drainage were 37.0-68.0μg/ml at 4-5 h after a 1g drip infusion. The recovery rates of CPR up to 6 h were 0.31-0.40%.
4. CPR was administrated to a total of 39 cases, including biliary tract infections 18, peritonitis 11, wound infections 5. intraperitoneal abscess 3, and one each of abdominal wall abscess and chest wall abscess.
The clinical efficacy was assessed in 31 of the 39 patients, and was rated as excellent in 4, good in 24, fair in 2 and poor in 1, with a clinical efficacy rate of 90.3%.
5. There were side effects in one case and abnormal laboratory findings were observed in seven cases, though these were slight.

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Between September 1988 and January 1990, we gave cefpirome (CPR) to five subjects after surgery and studied the pharmacokinetics of the drug. In the same period, we treated 20 patients with surgical infections with the same drug and evaluated its clinical effects.
1. In the basic study, 1 g was given intravenously over a 30 min. period. The peak levels in the plasma, 78.4-114 μg/ml, were at around the end of this time. The peak levels in the bile, 10.7-148 μg/ml, were at hours 2-5, depending on the patient. At hours 5 and 6, the range was 10.4-114 μg/ml.
2. In the 20 patients with surgical infection, the clinical efficacy of the drug was excellent in seven, good in nine, fair in one, and poor in two, with an efficacy rate of 84%.
3. The bacteriological response was evaluated in the 16 patients, for whom the species of the probable causative organism could be identified. The bacteria were eradicated in ten patients, decreased in one, were replaced in one, and persisted in four, with an eradication rate of 69%.
4. For the six strains of Pseudomonas aeruginosa isolated, the highest MIC was 6.25 μg/ml, so this drug should be effective toward this species. Two strains of Staphylococcus aureus were isolated, one of which was resistant to methicillin. It was not eradicated.

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Clinical studies on cefpirome (CPR), a new cephem antibiotic, were investigated in 39 cases of surgical infections.
1. Blood levels were determined by HPLC and bioassay method after intravenous administration of CPR 1 g. The mean levels were 71.7±19.9μg/ml immediately after drip infusion, and 9.0 ±4.6μg/ml after 6 h. Maximum levels in urine were 1300-3230 μg/ml at 1-2 h.
2. Maximum levels in several human tissues, such as the gallbladder, pancreas, spleen, thyroid, subcutaneous fat, peritoneum and omentum, were 44.6, 15.9, 11.4, 9.31, 14.1, 22.8 and 11.1 μg/g at about 4 h after intravenous administration of CPR 1 g, respectively.
3.As to transfer of CPR into bile in patients with an indwelling T-tube, the maximum level was dose-dependedly 27.9μg/ml and 55.3 μg/ml 2 h after administration of CPR 1 g or 2 g.
4.In two patients with gastric cancer received intravenously CPR 1 g, peak levels of CPR in ascitic fluid were 13.9 and 22.5μg/ml at 3 h after drip infusion on the first postoperative day.
5.The clinical result in 15 patients, (2 with diffuse peritonitis, 1 with abdominal abscess, 8 with cholecystitis, and 4 with cholangitis), was excellent in 1, good in 10, fair in 3 and unknown in 1, with a clinical efficacy rate being 78.6%.
As abnormal laboratory findings, elevated BUN and creatinine in only one case were noted.

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