Tsutomu Une

Enhancement of non-specific resistance to Pseudomonas pneumonia by a synthetic derivative of muramoyl dipeptide in immunosuppressed guinea pigs.

A synthetic derivative of muramoyl dipeptide, 6-O-stearoyl-N-acetylmuramoyl-L-alanyl-D-isoglutamine [L18-MDP(A)], showed a protective effect against bacteraemic and non-bacteraemic pneumonia caused by Pseudomonas aeruginosa in immunosuppressed guinea pigs. In about half of the animals treated with the compound before infection, death from bacteraemic pneumonia produced by intratracheal inoculation of P. aeruginosa was delayed for 7 d, although all of the animals infected without prior treatment with the compound died within 4 d of infection. Multiplication of the organisms in the lung was also suppressed for at least 10 d by treatment with the compound when the animals inhaled an aerosol of P. aeruginosa. In contrast, in untreated animals the numbers of bacteria in the lung gradually increased from 10(6) to 10(9) c.f.u. g-1, and a few animals in which the organism increased to 10(9) c.f.u. g-1 had died by 6 and 10 d after infection. In both healthy and immunosuppressed animals, the accumulation of polymorphonuclear leukocytes (PMNs) in a subcutaneous air-pouch injected with heat-killed organisms was augmented by subcutaneous treatment with L18-MDP(A) 1 d before bacterial injection. The phagocytic activity of peritoneal PMNs was also increased by treatment with this compound. The augmentation of protective mechanisms against pseudomonas pneumonia by L18-MDP(A) may be attributed at least partly to the increased chemotactic and phagocytic activity of PMNs.

Influences of Cephem Antibiotics on the Immune Response in Mice

The effects of six cephem antibiotics, including ceftezole, cefmetazole, cefoxitin, cefotiam, cefoperazone, and cefotaxime, on murine humoral immunity were examined. In female BDF1 mice each cephem antibiotic was administered at a dose of 800 mg/kg/day i.v. for 7 consecutive days. Among the antibiotics tested, only ceftezole and cefoperazone induced a significant increase in serum total IgM, but not in serum total IgG. Especially in case of ceftezole, the mice developed splenomegaly due to the proliferation of IgM-producing cells in the germinal centers. The proliferation of splenic IgM-producing cells was also observed in female thymus-deficient Balb/c-nu/nu mice receiving intravenous ceftezole. Thus, the drug was indicated to enhance the polyclonal IgM production in mice by acting as a B cell mitogen. This is consistent with the in vitro finding that ceftezole exhibited a mitogenic effect on whole spleen cells from BDF1 mice, but not on B cell depleted spleen cells.

Restoration by MDP-Lys(L18) of Resistance to Pseudomonas Pneumonia in Immunosuppressed Guinea Pigs

Infections caused by gram-negative bacteria are quite frequent in patients with marginal or defective host defenses caused by antineoplastic chemotherapy or various forms of immunosuppressive treatment (12, 13). One of the most common infection sites in these patients is the lower respiratory tract including the lungs (2), and these infections are usually difficult to treat in spite of the development of potent antibiotics (14). In particular, pneumonia induced by Pseudomonas aeruginosa has attracted a great deal of attention because of the high rate of mortality involved

Protective Role of Complement in the Development of Experimental Pneumococcal Pneumonia in Mice

To evaluate the role of complement in the lung defense against Streptococcus pneumoniae, mice decomplemented with multiple injections of cobra venom factor were challenged with type 3 pneumococci by inhalation. Without injection of cobra venom factor, the organisms were eliminated rapidly from the lungs in the majority of mice, accompanied by a significant but transient decrease in the serum C3 level. Focal pneumonia developed occasionally in some mice retaining the organisms in the lungs. By decomplementation with cobra venom factor, on the other hand, pneumococci were not eliminated completely from the lungs during the early stage of infection and afterward proliferated extensively. Consequently, the mice developed typical pneumococcal pneumonia with attendant bacteremia, while the serum C3 level has recovered compensatory during the course of infection. Thus, the complement was indicated to play an important role in the lung defense against pneumococci in mice, especially during the early stage of infection.

Nonbacteremic Pseudomonas Pneumonia in Immunosuppressed Guinea Pigs

An experimental model of nonbacteremic pneumonia with a virulent strain of Pseudomonas aeruginosa was successfully established in guinea pigs immunosuppressed with cortisone acetate although the organisms were eliminated rapidly from the lungs without cortisone treatment. Using a pocket nebulizer, almost all the animals which received 106 organisms/g‐lung developed bronchopneumonia without any septic findings as long as 10 days after challenge. The lesions produced in such animals were characterized by dissemination of multiple purulogranulomatous changes. In the early stage of infection, infiltration of polymorphonuclear cells (PMNs) in the bronchiolar and alveolar spaces was diffuse, later showing multifocal accumulation with the formation of central spherical grains enclosing bacterial colonies. In the later stage, granulation tissue consisting of large mononuclear cells, fibroblasts and collagen fibers developed around the PMN accumulation. The animals which received 107 organisms/g‐lung, on the other hand, developed severe pulmonary hemorrhages and necrosis followed by septic death.

Antichlamydial Activity of Ofloxacin

The in vitro activity of ofloxacin, a new pyridone‐carboxylic acid, against 11 strains of Chlamydia trachomatis and six strains of Chlamydia psittaci was determined. All test strains of both species were inhibited by 0.39 μg of ofloxacin per ml. The antichlamydial activity of ofloxacin was comparable to that of doxycycline and four‐ to eightfold less than that of minocycline. The results of this susceptibility test, coupled with those of previous pharmacokinetic analyses of ofloxacin, warrant further evaluation of its clinical usefulness against chlamydial infections.

Ascending pyelonephritis with Pseudomonas aeruginosa in mice.

Elastase‐ and protease‐ producing strain of Pseudomonas aeruginosa induced ascending pyelonephritis in mice by intracystic challenge. The pelvis was the site of primary foci development and necrotic, purulent lesions spread from the pelvis to the perihilar area and to the cortex. Severe necrosis was a characteristic of the present infection and caused systemic infection and host death without the development of chronic lesions. In animals challenged with inocula great enough to destroy the cystic mucosa, immediate hematogenous systemic infection without cellular responses led to host death.

EXPERIMENTAL PYELONEPHRITIS IN MICE FOLLOWING ASCENDING INFECTION WITH E. COLI

Adhesive and invasive strains of Escherichia coli induced chronic pyelonephritis in mice following the acute phase. The pathological features of the induced chronic pyelonephritis were different between the groups of mice infected with these strains. In piliated adhesive strain (E77156)‐infection, the kidneys with viable bacilli showed pyonephrosis with incomplete obstruction or atrophy with coarse scar. Mice with these renal lesions showed high serum antibody levels, but histologically recurrent infection was frequent. On the other hand, in non‐piliated invasive strain (633–65)‐infection, sterile pyelonephritis developed. This chronic lesion was characterized by the migration of antigen‐bearing macrophages and lymphocytes and by a negative serum antibody response. In infections with either strain the predominant lymphocytes in the renal lesions were smooth‐surfaced T‐lymphocytes.