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The efficacy and safety of ciprofloxacin and ofloxacin in chronic Pseudomonas aeruginosa infection in cystic fibrosis.

The clinical efficacy and safety of ciprofloxacin and ofloxacin were compared in a prospective, randomized double blind, placebo combined cross-over study in 26 adult cystic fibrosis patients with chronic broncho-pulmonary Pseudomonas aeruginosa infection. Active treatment consisted of ciprofloxacin 750 mg orally twice daily or ofloxacin 400 mg orally twice daily; both treatments were given for 14 days, with three months between treatment periods; 21 patients completed both treatment periods. Treatment with both ciprofloxacin and ofloxacin was associated with a good clinical response as judged by clinical score, lung function tests and inflammatory parameters; no difference between ciprofloxacin and ofloxacin was found. Adverse reactions were seen in nine of 24 patients who received ciprofloxacin and in six of 23 who received ofloxacin. The majority were dyspeptic reactions or photosensitivity. No serious adverse reactions occurred. Three cases of treatment failure were found, one of which was associated with development of resistant P. aeruginosa during ofloxacin treatment. The mean MIC of both drugs increased during treatment but returned to pretreatment values within three months. Ciprofloxacin and ofloxacin seem to be valuable agents for intermittent treatment of chronic P. aeruginosa lung infection in adult cystic fibrosis patients.

Adolescent↗

The role of pyocyanin in Pseudomonas aeruginosa infection.

Pyocyanin (PCN) is a blue redox-active secondary metabolite that is produced by Pseudomonas aeruginosa. PCN is readily recovered in large quantities in sputum from patients with cystic fibrosis who are infected by P. aeruginosa. Despite in vitro studies demonstrating that PCN interferes with multiple cellular functions, its importance during clinical infection is uncertain. This is partially caused by the difficulty in defining the contribution of PCN among the numerous virulence factors produced by P. aeruginosa during infection. In addition, few cellular pathways that are affected by PCN are known. This review briefly highlights recent advances that might clarify the role of PCN in P. aeruginosa pathogenesis.

Animals↗

Chimeric influenza viruses incorporating epitopes of outer membrane protein F as a vaccine against pulmonary infection with Pseudomonas aeruginosa.

Peptide 10 (NATAEGRAINRRVE, residues 305-318 of mature protein F) is one of two linear B-cell epitopes within outer membrane protein F of Pseudomonas aeruginosa both of which have been shown to elicit whole cell-reactive antibodies and to afford protection in animal models against P. aeruginosa infection. Influenza A virus was chosen as a vector to present this epitope in a human-compatible vaccine. Various lengths of the peptide 10 epitope ranging from a 5-mer (GRAIN), 7-mer (AINRRVE), 8-mer (TAEGRAIN), 9-mer (GRAINRRVE), 11-mer (AEGRAINRRVE) to a 12-mer (TAEGRAINRRVE) were attempted to be presented into the antigenic B-site of the hemagglutinin (HA) of live recombinant influenza virus. Using PCR, DNA sequences encoding these various peptide 10 lengths were inserted into the HA gene of influenza A/WSN/33 virus. By using a reverse-genetics transfection system, RNA transcribed in vitro from these chimeric HA genes was reassorted into infectious virus. To date chimeric viruses have been rescued and purified containing the peptide 10 5-mer, 7-mer, 8-mer, and 11-mer. RT-PCR and sequencing have confirmed the presence of P. aeruginosa sequences in the HA RNA segment of each chimeric virus. Each of the four chimeric viruses produced to date was used to immunize mice to determine the ability of each chimeric virus to elicit antibodies reactive with whole cells of P. aeruginosa. The immunization protocol consisted of a series of three intranasal inoculations, followed by two intramuscular injections of the chimeric virus. The chimeric virus incorporating the 11-mer elicited IgG antibodies that reacted with various immunotype strains of P. aeruginosa in a whole cell ELISA at titers of 80 to 2,560, whereas the chimeric virus incorporating the 8-mer elicited whole cell-reactive IgG antibodies at titers of 320 to 2,560. These data suggest that these two chimeric viruses may have vaccine efficacy against P. aeruginosa infection. These studies may result in the development of a chimeric influenza virus-protein F vaccine which would prove to be suitable for use in children with cystic fibrosis for the prevention of pulmonary colonization of these children with P. aeruginosa.

Amino Acid Sequence↗

Primary Pseudomonas maltophilia infection of the lung.

To our knowledge, this is the first reported case of primary Pseudomonas maltophilia pneumonia. Presenting symptoms were fever and chills of two days' duration and a density in the right upper lobe. Sputum culture showed normal flora, and multiple blood cultures were negative. Antibiotic therapy initially with penicillin and then with carbenicillin was unsuccessful. Selective bronchial aspiration yielded pure cultures of P maltophilia. When an appropriate antibiotic, chloramphenicol, was given, a prompt therapeutic response followed.

Aged↗

Ciprofloxacin therapy of infections caused by Pseudomonas aeruginosa and other resistant bacteria.

Ciprofloxacin was administered orally to 48 patients with 24 Pseudomonas aeruginosa infections and 13 other infections caused by cephalothin-resistant gram-negative bacilli. The types of infections treated included those of skin or skin structure, bone, urinary tract, and respiratory tract. In 83% of P. aeruginosa infections, a favorable clinical outcome occurred, compared with 85% for all infections. Failure to achieve a cure correlated with the emergence of resistant P. aeruginosa and Acinetobacter calcoaceticus strains in four instances and superinfection with Candida (two cases) and Streptococcus (two cases) species. Therapy was discontinued in three patients because of the development of nausea. Ciprofloxacin appears to be safe and effective in the therapy of infections caused by resistant gram-negative bacilli.

Administration, Oral↗

A study of bronchus-associated lymphoid tissue in a rat model of chronic pulmonary infection with Pseudomonas aeruginosa.

The immunologic pathogenesis of conditions characterized by chronic pulmonary infections, such as diffuse panbronchiolitis and those associated with cystic fibrosis, had not been fully clarified. Organized lymphoid tissue along the airway has been termed bronchus-associated lymphoid tissue (BALT), and hyperplasia of BALT is frequently observed in chronic pulmonary infections in humans. To investigate the role of BALT, we intratracheally inoculated rats with Pseudomonas aeruginosa (PA) enmeshed in agar beads according to the method of Cash et al., thereby establishing a chronic pulmonary infection model. Histopathological examination of tissue from this rat model revealed the accumulation of lymphocytes and foamy cells around bronchioles. This finding corresponds to chronic bronchiolitis in humans. Hyperplasia of BALT was also observed. Immunohistochemical examination demonstrated that Ia+ cells, helper T cells, surface IgM-positive (sIgM+) cells and sIgA+ cells had gradually increased in BALT and the walls of peripheral airways during the period from day 4 to 7. The anti-PA IgA antibody titer in bronchoalveolar lavage fluid (BALF) was also elevated during this period. After day 21, non-helper T cells became predominant in tissue sections, and the numbers of various immunoglobulin-positive cells as well as the anti-PA IgA antibody titer in BALF were reduced. Histological examination revealed that the inflammatory findings had also diminished. The time course of changes in the various immune cells in BALT and the walls of peripheral airways, paralleled the reductions in anti-PA IgA antibody titers in BALF. Our findings suggest that hyperplastic BALT may be one source of the Ig producing cells which play an important role in the local immune response characteristic of chronic pulmonary infections.

Animals↗

Combination therapy for chronic Pseudomonas aeruginosa respiratory infection associated with biofilm formation.

There had been no reports of investigations into biofilms in chronic respiratory infection in vivo. Recently, we established a new murine model of chronic respiratory infection with Pseudomonas aeruginosa. In the present study, we examined the bacteriological effect of combined clarithromycin and levofloxacin against chronic respiratory infection with P. aeruginosa. Scanning electron micrograph of the surface of the catheter intubated in mouse bronchus for 7 days demonstrated in vivo formation of a biofilm containing blood cells, complex fibrous structures and bacteria. Treatment with either clarithromycin alone or levofloxacin alone had no statistical effect on the number of viable bacteria in lung. The combined use of both drugs resulted in a significant decrease in the number of viable bacteria. The present experiment demonstrates that the newly established murine model was useful to investigate the treatment of biofilm-associated chronic respiratory infection with P. aeruginosa, and combination therapy with clarithromycin and levofloxacin was effective in biofilm-associated chronic respiratory infection.

Animals↗

Enhanced protection of cyclophosphamide-treated mice against infection with Pseudomonas aeruginosa after treatment with Z-100, a polysaccharide-rich extract from Mycobacterium tuberculosis Aoyama B.

We investigated the effect of Z-100, a polysaccharide-rich extract from Mycobacterium tuberculosis strain Aoyama B, on the protection of immunocompromised mice against infection with Pseudomonas aeruginosa. Mice were given cyclophosphamide and then treated with varying doses of Z-100 for 5 days or left untreated. One day after the completion of the treatment, they were challenged with P. aeruginosa and the mortality was scored. A significantly enhanced protection was observed in the treated group and bacterial number in organs was significantly lower compared with non-treated group. Though the activity of phagocytes did not appear to be activated since there was no difference in chemiluminescence response of peritoneal phagocytes between control and Z-100-treated groups, an enhanced accumulation of phagocytes was observed after bacterial challenge in Z-100-treated group. It was suggested that Z-100 is effective in the restoration of impaired resistance of immuno-compromised mice to bacterial infection possibly through a stimulation of phagocyte accumulation into the site of infection.

Adjuvants, Immunologic↗

Prediction and diagnosis of early Pseudomonas aeruginosa infection in cystic fibrosis: a follow-up study.

Immunoglobulin G (IgG) antibodies to Pseudomonas aeruginosa surface antigens in serum were estimated by enzyme-linked immunosorbent assay for all patients from whom P. aeruginosa was isolated for the first time during a study period of 3 years (33 patients). The titer of IgG antibodies was greater than control values at or up to 24 months before the first isolation of P. aeruginosa in 24 patients. Another five patients had titers that were within the control range before isolation of P. aeruginosa but increased to above the control range within the following 2 months. In these 29 patients, continuing intermittent isolations of P. aeruginosa were accompanied by further increases in titer. The presence of a systemic immune response above the control range indicates tissue invasion and hence infection. Four patients were deemed to have no infection: one or two isolations of P. aeruginosa were accompanied by no increase in specific antibodies to above the control range throughout the entire study period. Fifteen patients received intravenous antipseudomonal chemotherapy. Eradication of the organism and a return of titer to control values, suggesting complete removal of the organisms, occurred in 5 patients, while continued isolations and only a partial decrease in titer occurred in 10 patients. The 15 patients who received treatment improved clinically, in contrast to untreated patients, whose clinical state worsened during the study period. Continuous steroid treatment, given to two patients, was accompanied by a dramatic decrease in both serum IgG concentration and titer, despite continuing intermittent isolations of P. aeruginosa. These results confirm and extend our earlier finding that this assay appears to detect P. aeruginosa infection at a very early stage and helps in differentiating between early infection and harmless colonization. It also appears to be a useful monitor of the progress of infection and the response to intravenous antibiotic treatment in these early stages of infection, before any clinical changes are sufficiently large to be detected, in patients who were not on continuous steroid therapy. The effect of steroid treatment on the immunological response and clinical outcome of patients with early P. aeruginosa infection requires further investigation.

Adolescent↗

Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice.

INTRODUCTION: Antibiotics are used to treat bacterial infections by killing the bacteria or inhibiting their growth, but resistance to antibiotics can develop readily. The discovery that bacterial quorum-sensing regulates bacterial virulence as well as the formation of biofilms opens up new ways to control certain bacterial infections. Furanone compounds capable of inhibiting bacterial quorum-sensing systems have been isolated from the marine macro alga Delisea pulchra. OBJECTIVES: Two synthetic furanones were tested for their ability to attenuate bacterial virulence in the mouse models of chronic lung infection by targeting bacterial quorum-sensing without directly killing bacteria or inhibiting their growth. METHODS: Study I. Mice with Escherichia coli MT102 [luxR-PluxI-gfp(ASV)] lung infection were injected intravenously with N-acyl homoserine lactones with or without furanones to test the interference of furanones with quorum-sensing. Study II. Mice with lung infection by Pseudomonas aeruginosa PAO1 [dsred, lasR-PlasB-gfp(ASV)] were injected intravenously with furanones to evaluate their inhibiting effects on quorum-sensing. Study III. Mice with P. aeruginosa PAO1 lung infection were treated with different doses of furanones to evaluate the therapeutic effects of furanones on the lung infection. RESULTS: Furanones successfully interfered with N-acyl homoserine lactone and suppressed bacterial quorum-sensing in lungs, which resulted in decreases in expression of green fluorescent protein. Furanones accelerated lung bacterial clearance, and reduced the severity of lung pathology. In a lethal P. aeruginosa lung infection, treatment with furanone significantly prolonged the survival time of the mice. CONCLUSION: Synthetic furanone compounds inhibited bacterial quorum-sensing in P. aeruginosa and exhibited favourable therapeutic effects on P. aeruginosa lung infection.

Alginates↗

Pseudomonas testosteroni infections: eighteen recent cases and a review of the literature.

Pseudomonas testosteroni has been largely overlooked as a potential pathogen in humans. Ten cases of infection due to P. testosteroni were identified at a single metropolitan hospital in Texas during a three-year period. The organism was most often found in association with anatomic abnormalities of the gastrointestinal tract (six of 10 cases); perforation of the appendix was the commonest abnormality (five cases). The infections were more often polymicrobial (seven cases) than monomicrobial (three cases) and usually involved other organisms that, like P. testosteroni, are of colonic origin. Eight additional cases of infection involving P. testosteroni were reported by other hospitals in Texas during the same period. The organism was isolated from the peritoneal cavity in five of these cases. The results of these surveys suggest that infections of humans with P. testosteroni, while not common, are not as rare as might be predicted on the basis of the number of cases reported in the literature.

Adult↗

The role of Langerhans cells in Pseudomonas aeruginosa infection.

PURPOSE: Previous experimental studies have shown that extended-wear contact lens usage results in a centripetal migration of Langerhans cells from the conjunctiva into the central cornea. To test the consequences of this, Langerhans cells were induced into the cornea before Pseudomonas aeruginosa infection in BALB/c mice that are normally resistant (the cornea heals) and in C57BL/6 mice that are susceptible (the cornea perforates) to bacterial challenge. METHODS: Mean clinical scores, slit lamp examination, adenosine diphosphatase (ADPase), and acid phosphatase staining as well as immunostaining with DEC-205, B7-1, CD4, and interleukin-2 receptor (IL-2R) antibodies and histopathologic, RT-PCR, and delayed-type hypersensitivity (DTH) analyses were used to examine the effects on bacterial disease after polystyrene bead induction of Langerhans cells into the cornea before bacterial challenge. RESULTS: No difference in disease response was observed in bead- versus sham-treated C57BL/6 mice after bacterial infection; however, significant differences leading to corneal perforation were seen in BALB/c mice that included an increased number of Langerhans cells in the central cornea at 1 and 6 days after infection, an increased number of B7-1+ (mature) Langerhans cells at 6 days after infection, CD4+ and IL-2R+ T cells at 5 days after infection, enhanced DTH, and increased mRNA levels for IFN-gamma in cornea and cervical lymph nodes. Alternately, levels of IL-4 were significantly higher in the cornea and cervical lymph nodes of sham- versus bead-treated animals. CONCLUSIONS: These data provide evidence that Langerhans cells are critical in the innate immune response to P. aeruginosa and provide new information regarding the mechanisms governing resistance versus susceptibility to bacterial infection with this opportunistic pathogen.

Acid Phosphatase↗

Synergistic effect of immune gamma-globulin fraction on protection by antibiotic against corneal ulcers in experimental mice infected with Pseudomonas aeruginosa.

Synergistic effects of immune gamma-globulin fraction containing antibodies of OPE, protease and elastase of Pseudomonas aeruginosa on the activities of antibiotic, dibekacin (DKB), in the cornea of mice were examined for the purpose of studying therapy for corneal ulcers due to Pseudomonal infection. In the case of the intramuscular injection, a medium effective dose (ED50) of DKB alone against corneal ulcers caused by strain IID 1210 of P. aeruginosa in experimental mice was 620 mug per mouse. When 15.6 to 18.7 mg of gamma-globulin fraction was subcutaneously given to each mouse prior to the infection with strain IID 1210, opacity instead of severe ulcers was observed only in the central area of cornea. The immune gamma-globulin fraction was far more effective in the protection of cornea from the infection than the calf serum that showed no antibody titer against OEP, protease and elastase. The ED50 values of DKB's combined with the immune gamma-globulin, Fr. 1 and Fr. 2, and the calf serum were 34 and 73, and 480 mug per mouse respectively. There was found no statistical difference in ED50 value between DKB combined with the calf serum and one without it. There was, however, significant difference in ED50 value between DKB's combined with Fr. 1 and Fr. 2, and one with the calf serum. When DKB alone is dropped in the eye of mouse for the protection, the ED50 value was 15 mug per mouse. When 1.56 to 1.87 mg of the immune gamma-globulin fraction was dropped in the eye after the infection with P. aeruginosa, there was observed no protection against corneal ulcers. the ED50 values of DKB's combined with Fr. 1, Fr. 2 and the calf serum were 0.96, 0.94 and 13 mug per mouse, respectively. There was no significant difference between the ED50 values of 0.96 and 0.94 mug, and between 15 and 18 mug. There was, however, significant difference between the former ED50 values (0.96 and 0.94 mug) and the latter ones (15 and 18 mug). The combination of DKB and the immune gamma-globulin fraction was found to be superior to the combination of DKB and the calf serum in the therapeutic effect on corneal ulcers caused by strain IID 1210 of P. aeruginosa.

Abscess↗

Characterization of arachidonic acid metabolism and the polymorphonuclear leukocyte response in mice infected intracorneally with Pseudomonas aeruginosa.

PURPOSE: To examine the activity of myeloperoxidase (MPO) and the concentrations of the proinflammatory metabolites of arachidonic acid (AA) in ocular tissue of mice that are either capable or incapable of restoring corneal clarity during an intraocular Pseudomonas aeruginosa infection. METHODS: For a period of 11 days after infection, whole eyes were enucleated and homogenized in buffer from mice given only an initial infection as well as from mice given a subsequent infection in the previously uninfected eye either 4 or 8 weeks after the initial infection. Tissue-free supernatants from the ocular homogenates were used for the determination of MPO activity by quantitating the conversion of specific substrate by spectrophotometric methods and for the quantitation of AA metabolites by ELISA: RESULTS: Overall, animals reinfected at 4 and 8 weeks had a lower inflammatory response when compared to the mice given only the initial infection. The lowest levels of LTB4 and MPO activity, indicators of PMN involvement, were observed in the the 8-week reinfected mice, which restored corneal clarity in an enhanced manner. CONCLUSIONS: These results suggest that induced ocular PMN responses may play a role, in part, in the inflammatory response leading to the tissue destruction observed during ocular P. aeruginosa infection.

Animals↗

Protective effect of saikosaponin A, saikosaponin D and saikogenin D against Pseudomonas aeruginosa infection in mice.

Effects of saikosaponins and their genins on nonspecific resistance against Pseudomonas aeruginosa and Listeria monocytogenes infections were investigated. When mice were administered intraperitoneally (i.p.) saikosaponins one day before i.p. infection with P. aeruginosa, saikosaponins a and d induced a marked enhancement of nonspecific resistance at a dose of 10 micrograms/mouse. Also, saikogenin D, a secondary metabolite of saikosaponin d, showed an enhancing effect. The most effective condition for enhancing the nonspecific resistance was i.p. administration of saikosaponin d one day before i.p. or intravenous (i.v.) infection with P. aeruginosa, when mice were treated i.p., i.v., or subcutaneously with saikosaponin d 1, 4 or 7 days previously. Effect of saikosaponin d was weaker than that of formalin-killed bacilli of Propionibacterium acnes and lipopolysaccharide. On the other hand, effect of saikosaponin d on enhancement of nonspecific resistance against L. monocytogenes was not seen. Effector cells participating in the enhanced protection induced by saikosaponin d may be macrophages, since macrophages were a major component in peritoneal cells obtained from mice administered i.p. saikosaponin d 1 day earlier and intracellular bactericidal activity of peritoneal macrophages against P. aeruginosa increased.

Animals↗