Therapeutic efficacy and the treatment days for cure of imipenem/cilastatin sodium (IPM/CS) in treatmentof pulmonary infections were prospectively determined in comparison with those of β-lactams other thancarbapenems mainly ceftazidime (CAZ) or sulbactam/cefoperazone (SBT/CPZ).
The overall response rate was 84.9% (62/73) in the IPM/CS group and 74.7% (56/75) in the β-lactam group, the difference not being significant. In the subjects having underlying respiratory diseases, the response rate was91.1% (41/45) and 73.9% (34/46) in the IPM/CS and β-lactam groups, respectively. In patients with infectionssecondary to chronic respiratory disease, the rate was 91.2% (31/34) in the former group and 66.7% (24/36) inthe latter group, respectively. The differences were significant for both stratified analyses.The treatment days for cure judged by the attending physician were 12.9±0.6 days in the IPM/CS group, and 14.5±0.7 days in the β-lactam group. The difference was not, however, significant. In patients with mild tomoderate infections, the treatment days for cure was 12.0±0.6 days (n=64) in the IPM/CS group and 14.3±0.7days (n=70) in the β-lactam group. In patients with underlying respiratory disease, the treatment days for curewere 11.8±0.7 days (n=45) and 14.7±0.9 days (n=46) in the IPM/CS and β-lactam groups, respectively. In patientswith infections secondary to chronic respiratory disease, the days were 11.1±0.7 days (n=34) and14.7±1.1 days (n=36), respectively. Thus, IPM/CS therapy significantly reduced the number of treatment daysuntil cure. There was, however, no significant difference between the two therapy groups in treatment of the patientswith severe infections, those without underlying respiratory disease, or those with pneumonia and/or lungabscess.
The treatment days for cure were also assessed by the members of review committee taking into considerationof body temperature, leukocyte count, and C-reactive protein. As the result, it was 6.9±0.5 days in the IPM/CS and 10.3±0.7 days in the β-lactam groups, respectively, and the difference was significant. Time (days) untilcure was also compared between the two groups using survival time analysis, confirming a more rapid responsein the IPM/CS group. Although IPM/CS therapy was associated with a shorter response time as assessed by boththe attending physicians and the review committee, there were considerable differences between the results ofthese judgements. Thus, the duration of treatment with injectable antibiotics requires reevaluation in the future.
No significant differences were observed between the groups with respect to parameters indicating side effectsand laboratory abnormalities. There were no severe symptoms or laboratory findings, and symptoms andchanges in laboratory values, if any resolved during the course of therapy or after the withdrawal of treatment.
In conclusion, IPM/CS seems to be very useful as first-line therapy for respiratory tract infections and for shortening the duration of treatment.

View full abstract

This report describes the results on pharmacokinetics, efficacy and safety of cefozopran (CZOP) in neonatal patients.
Enrolled patients were 136 in total whose informed consents to enter this study had been given by their parents. Among them, blood samples were collected from 42 neonates to analyze concentrations of CZOP by population pharmacokinetics (PPK) methods. Based on this analysis, the average pharmacokinetic parameters of CZOP and the variabilites of them in different morbid pharmacological backgrounds and in different subjects were evaluated.
This PPK analysis showed that clearance (CL) and distribution volume (Vd) of CZOP could be estimated by the following equations;
CL=0.0452×WT^1.75 (in the case of the postnatal age of over than 1 day)
CL=0.623×0.0452WT1.75 (in the case of the postnatal age of 1 day or less)
Vd=0.455×WT
where WT indicates body weight in kg.
The coefficients of variation among individual subjects on CL and Vd were found to be 20.7% and 20.0%, respectively.
From this PPK analysis it was indicated that the elimination of CZOP is dependent on the postnatal age and is approximately 38% lower in the younger group than in the older group. Therefore, it could be concluded that, though the cases of evaluation were small in number, adjustment of dosing of CZOP is necessary, particularly in prolongation of intervals of administration, in cases of postnatal age of 1day or less.

View full abstract

An investigation was carried out to determine the therapeutic effect of panipenem/betamipron (PAPM/BP), ainjectable carbapenem antimicrobial agent, on infections in pregnant women during perinatal period. Of the 41patients enrolled in the study, 34 were subjected to the analysis, with 1 exemption because of protocol violations (regimen), 3 because of uncertain evidence symptoms of infection, and 3 because of failure to undergo laboratorytests. PAPM/BP was administered by intravenous drip infusion at doses of 0.5g twice or three times a day dailyfor periods of 3 to 14 days. The efficacy rate according to the evaluation of the Drug Efficacy Evaluation Committeeand the attending physicians was 79.4% (27/34), with 49 of the 61 clinical isolates (80.3%) being eradicated.Safety was evaluated as “safe” in 39 of the 41 assessable patients (94.1%). Mild headache and nausea wereexperienced by 1 patient (2.4%) as adverse drug reactions, but the symptoms disappeared after the completion oftreatment. Slight elevations of GOT, GPT and LDH in laboratory tests were observed in 1 patient (2.4%), but these values returned to normal after the completion of treatment. These results suggested that PAPM/BP may bea useful drug in the treatment of bacterial infections during the perinatal period. To firmly establish its safety, however, further clinical and pharmacokinetic studies are needed in larger populations.

View full abstract

Two fosfomycin-resistant strains, FRC 14 (parent strain, Escherichia coli [E.coli] c73-18) and FRK104 (parentstrain, E. coli 0124), were isolated from spleens before the bacterial disappearance, after inoculating the parentstrains intraperitoneally into mice and treating them with a single oral dose of fosfomycin. The resitant strainswere successfully isolated by a replica method from a mass of sensitive cells of respective parent. To elucidatethe pathogenesis of the resistant strains, their characteristics were investigated. The MIC of fosfomycin forFRC14 was 25μg/ml (4 times the MIC for the parent) and that for FRK 104 was 100 μg/ml (8 times the MIC forthe parent). The strain FRC14 showed a defective utilization of sn-glycerol 3-phosphate (G3P), but utilization ofother carbohydrates was similar to that of the parent strain. Thus, the strain FRC14 seemed to be a glpT mutant.The strain FRK104 did not use variety of carbohydrates including G3P, but used glucose 6-phosphate. The utilizationof G3P was recovered in the presence of cAMP. Thus, the strain FRK 104 seemed to be a ptsI mutant.These resistant strains were diminished their killing activity for mice in comparison to that of the each parentstrain when they were inoculated intraperitoneally. The cell number of FRC 14 decreased or disappeared in bloodand spleen in mice, while that of the parent increased. The strain FRK104 diminished its ability of producing keratoconjuctivitis in guinea pigs in comparison to that of the parent strain.

View full abstract

Antibiotic-induced release of endotoxin (lipopolysaccharide, LPS) from Pseudomonas aeruginosa was investigated in in vitro with different antibiotic concentrations and in the pharmacokinetic autosimulation system.We compared the effect of isepamicin (ISP) with those of 3 β-lactam antibiotics, piperacillin (PIPC), ceftazidime (CAZ) and imipenem (IPM).
ISP showed a strong bactericidal activity, but the amount of free LPS did not increase by 6 hrs (28±2 ng/mlat 1MIC). PIPC and CAZ caused a gradual killing and a large amount of LPS release at 4 hrs (515 ng/ml and493 ng/ml, respectively, at 1 MIC). At 1/4×MIC, PIPC and CAZ did not reduce colony forming counts andinduced more release of free LPS. The organism treated with IPM released less LPS, while it was killed rapidly.
The viable cell counts decreased dramatically after administration of ISP in the pharmacokineticautosimulation system.
ISP inhibited the bacterial regrowth and the following release of free LPS by 8 hrs. Great amounts of freeLPS were released 4 hrs after the administration of PIPC and CAZ in the simulation system, associated withmorphological changes; elongation, cell lysis or regrowth. IPM showed a strong bactericidal activity and lessliberation of free LPS, but the free LPS level increased at 8 hrs, accompanied by the regrowth of the organism.The total amounts of LPS released by P. aeruginosa PAO1 in 8 hours of the pharmacokinetic simulation systemwere as follows;
ISP<IPM<CAZ<PIPC.

View full abstract

Kasugamycin, a unique aminoglycoside antibiotic, has been used for many years solely for crop protections1).In general, aminoglycoside antibiotics possess broad and strong inhibitory activity against both Gram-positive and -negative bacteria, however, kasugamycin merely exhibits limited activity against phytopathogenicmicrobes such as Pyricularia oryzae and certain strains of pseudomonads.
Recently, in human and animal chemotherapy, it has been seriously concerned about the emergenceof multiply resistant bacteria by consumption of a large amount of antibiotics not only for therapy butalso for growth-promotion of farm animals.
It was believed that kasugamycin, the agricultural antibiotic, does not undergo any cross-resistancewith other clinically important aminoglycoside antibiotics because of its weak or almost no activityagainst common pathogenic microbes except for some phytopathogenic fungi and pseudomonads. However, no confirmative study on this fact has been published so far.
In this study, we compared activity of kasugamycin with those of twelve clinically usedaminoglycoside antibiotics against susceptible standard strains and well-characterized aminoglycosideresistantstrains as well as clinically isolated strains, in order to show the least potential of kasugamycin to create cross-resistant human pathogens against clinically important aminoglycoside antibiotics.

View full abstract

The therapeutic efficacy of a topical antifungal solution containing a mixture of 0.2% pyrrolnitrin and 0.4%clotrimazole (Pyroace®W) was tested in a guinea pig model of tinea pedis using a 1% newly solution formulatedpreparation of miconazole (Dermalin-L®) as a reference drug. Infected animals were treated once or twice dailywith the testing drug and once daily with the reference drug for 4 weeks. Therapeutic efficacy was evaluated onthe basis of the extent of the yield of fungal cultures from the infected skin tissues (infection intensity) relative number of culture-negative animals at the end of the treatment period.
In an animal group treated once daily with the testing drug, the infection intensity was significantly lowerthan that for untreated or vehicle-treated control group (p<0.0001) although there was no culture-negative animal.A similar extent of therapeutic efficacy was obtained with a once daily treatment with the reference drug, yielding one of ten culture-negative animal. A better efficacy was seen in animals treated twice daily with thetesting drug; the infection intensity was further decreased to a significant level and eight of ten animals becameculture-negative.
These results demonstrated that twice daily treatment with the testing drug was highly effective in guineapig model of tinea pedis, 80% of infected animals being mycologically cured. It confirms the clinical usefulness of this regimen in the treatment of patients with tinea pedis or other types of dermatophytosis.

View full abstract