Pseudomonas aeruginosa holds a very important position in the nosocomial and opportunistic infections, because of its resistance to most broad-spectrum antibiotics. Newly developed β-lactam antibiotics, for example piperacillin (PIPC), cefsulodin (CFS), cefoperazone (CPZ), ceftazidime (CAZ) and azthreonam possess good permeabilities through the outer membrane of this microbe and stabilities to β-lactamases produced by it.
However, some clinical isolates of P. aeruginosa are found to be resistant to these antibiotics. Interrelationships between the types of β-lactamases and resistances to these antibiotics are discussed.
1. In 144 P. aeruginosa strains, 8 (5.6%), 23 (16%), 33 (22.9%), 38 (26.4%) and 51 (35.4%) strains were resistant to higher than 12.5 μg/ml of CAZ CFS, azthreonam, PIPC and CPZ respectively.
2. In CFS resistant (M: C≥12.5μg/ml) 37 P.aeruginosa strains, 17 (45.9%), 24 (64.9%), 27 (73%), 35 (94.5%) strains were resistant to higher than 12.5μg/ml of CAZ, azthreonam, PIPC and CPZ respectively. Fourteen (37.8%) strains were resistant to all antibiotics.
3. Chromosome mediated cephalosporinase (CEPase) s were detected in 18 out of 20 strains examined.Most strains, whose CEPase activities were higher than 1μg/mg prot., were resistant to all these antibiotics.
4. Plasmid-mediated penicillinase (PCase) s, that is, TEM-1 (2 strains), PSE-4 and OXA-2, were detected in 4 out of 20 strains examined. These strains were resistant to CFS, PIPC and CPZ.
5. Two strains, each of which produced highly active chromosome mediated CEPase and plasmid mediated PCase, that is, TEM-1 or OXA-2, were resistant to all of five antibiotics.

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Minimal inhibitory concentrations of ampicillin (ABPC), carbenicillin (CBPC), piperacillin (PIPC), cefazolin (CEZ), ceftizoxime (CZX), latamoxef (LMOX), gentamicin (GM), amikacin (AMK), fradiomycin (FRM), polymixin-B (PL-B), nalidixic acid (NA), pipemidic acid (PPA) and minocycline (MINO) against 50 clinical isolates of S. marcescens and P. aeruginosa were compared between the microdilution method using Dynatec 2000 system with Mueller Hinton broth and the agar dilution method with Mueller Hinton agar (standerdized method of Japan Society of Chemotherapy).
Above or below the range of a double dilution, major discrepancy between the results of the two methods was found frequently for LMOX and MINO against S. marcescens, and more frequently for GM, AMK, FRM, PL-B and PPA against P. aeruginosa. For LMOX and MINO against S. marcescens, and PPA and MINO against P. aeruginosa, the frequency of the discrepancy was markedly decreased by increasing the final concentration of inoculated organisms from 10⁴CFU/ml to 10⁵CFU/ml in the microdilution method. For aminoglycosides and PL-B against P. aeruginosa, the frequency of the discrepancy was not decreased by increasing the final concentration, and decreased markedly by supplementation of calcium and magnesium into the broth to the level of the agar.

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Ten nephrectomy patients were intravenously given a bolus shot of 1.0 g cefmenoxime simultaneously with beginning of operation. The peripheral blood was sampled at the ligation of the renal vessels. Tissue cefmenoxime levels (μg/g) in the excised kidneys varied from 5.56 to 197 at 24 to 145 minutes after administration. The ratio of the tissue/serum cefmenoxime levels also varied from 0.262 to 4.79 with mean value of 1.33. The variations were presumed to be due to the difference in degree of the impairment of the renal functions.

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Two grams of cefoperazone-sulbactam combination (1:1) were given intravenously to a total of 11 patients prior to suprapubic prostatectomy for benign prostatic hypertrophy.
Prostatic tissue levels attained the peak of 63.6±24.9 μg/g (cefopera, one 36.7±9.5 μg/g, sulbactam 27±16.2 μg/g), 15 minutes after administration, with the P/S ratio of 0.39±0.17.
The concentration ratio of cefoperazone/sulbactam in prostatic tissue was between 1.61±0.47 and 5.39±3.19, Thus the combination effects seems to be maintained in the tissue.
Judging from the favorable transfer into the prostatic tissue and MICs against clinically isolated S. pyogenes, S. aureus, S. epidermidis, E. coli, P. vulgaris, M. morganii, P. mirabilis, Acinetobacter, cefoperazone-sulbactam combination (1:1) seems to be clinically useful for the treatment of prostatic infections.

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For the purpose of studying the safe and effective administration dose of tobramycin, intravenous drip infusion of tobramycin was made on adults and neonates.
Multiple administration on adults (16-56 years of age): Intravenous drip infusion of 40-120mg of tobramycin was made two or three times daily for 30-450min. Effective serum concentration (4 μg/ml or more) was observed in seven out of sixteen cases and in the seven cases the administration dose was 1.2mg/kg or more. No accumulation due to multiple administration was observed.
Single administration on adults (22-63 years of age): Intravenous drip infusion of 90mg of tobramycin was made for one hour. Effective serum concentration was observed in nine out of ten cases and the administration dose was 1.5mg/kg or more in all cases.
Neonates (4-49 days after birth): When intravenous drip infusion of tobramycin of 2mg/kg was made for one hour, effective serum concentration was observed in only one out of seven cases, in only one out of eleven cases when intravenous drip infusion of 3mg/kg was made for one hour, and in only two out of five cases when intravenous drip infusion of 3mg/kg was made for 30 minutes.
Biological half-life in neonates was more extended than in adults and the distribution volume and serum clearance in neonates were two or three times greater than in adults.
By intravenous drip infusion of tobramycin on neonates, a significant correlation was observed between elimination rate constant and distribution volume and between elimination rate constant and days after birth or body weight.
The biological half-life of neonates 4-7 days after birth was significantly extended when compared to that 9-29 days after birth.

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The incidence and clinical features of drug fever caused by antibiotics were investigated by analyzing the data from patients who had been treated for more than 7 days with antibiotics of parenteral use. Of a total of 390 patients analysed, 193 had malignant diseases (lung cancer in most cases) and the remaining 197 had non-malignant diseases, of which pulmonary infectious diseases such as pneumonia, lung abscess and chronic respiratory tract infections constituted the majority.
Beta-lactams were shown to be antibiotics that induced drug fever most frequnetly. Piperacillin induced drug fever in 18 of 108 (17%), cefotaxime in 11 of 72 (15%), ceftizoxime in 7 of 49 (14%) and cefoperazone in 6 of 74 (8%) patients. In contrast, the incidence of drug fever due to ampicillin (3%) and cefazolin (0%) respectively was low. The relatively higher incidence of drug fever caused by new derivatives of β-lactam antibiotics suggests that the side chains attached to their core moieties are involved in the mechanism of occurrence of drug fever. On the other hand, antimicrobial agents other than β-lactams caused drug fever only rarely.
It was found that, in patients with malignancy, respiratory infection was the most frequent cause of fever above 38°C elicited during antibiotic therapy. In contrast, in patients with non-malignant diseases, the use of antibiotic itself was the most frequent cause of the fever. The most common pattern of drug fever due to antibiotics was as follows: A low grade fever occurred on or after the 7 th day of antibiotic therapy. Then the daily highest body temperature rose gradually. Finally, intermittent fever developed and subsided promptly after cessation of the causative drug. The fever of this type accounted for 70% of all the drug fever.
It is noteworthy, in making diagnosis of drug fever due to antibiotics, that a transient elevation of serum lactate dehydrogenase (LDH) level was observed in one half (51%) of patients with drug fever.In addition, a transient decrease of slight degree in the number of neutrophils and platelets was observed in a considerable portion of patients with drug fever.

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To evaluate the clinical efficacy and safety of ofloxacin, a new synthetic antimicrobial agent of oxazine derivative, it was orally administrated to 23 patients with infectious exacerbation of diffuse panbronchiolitis, including 15 patients with P. aeruginosa infection.
Ofloxacin was given 200-300mg b. i. d.or t. i. d. for 133 days on an average, and the average total dose was 75.6g.
The clinical efficacy rate was 57% in all cases, and was 60% even in the cases with P. aeruginosa infection.
As for the bacteriological response, all cases of H. influenzae (3 cases) and S. pneumoniae (1 case) were eradicated while all 3 cases of glucose non-fermentating gram negative rods remained unchanged. The response in 16 cases of P. aeruginosa (including 1 case with polymicrobial infection) were, eradicated 3, decreased 2 and unchanged 11, giving the eradication rate of 19%.
No severe side effects were observed in spite of the long-term therapy for more than 4 weeks. Taking into account that ofloxacin is a drug for oral use, it is considered to be useful for long-term therapy of diffuse panbronchiolitis, especially for the P. aeruginosa infection.

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