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Biomedical subjects

J E Pennington

Publications and source records attributed to J E Pennington.

At least 19 recordsLinked to original sources
PubMed1992

Immunological perspectives in prevention and treatment of nosocomial pneumonia.

The high mortality associated with current therapeutic approaches to nosocomial pneumonia has motivated consideration of newer immunologic approaches to prevention or therapy of this infection. Serotype specific vaccines, hyperimmune immunoglobulins, and monoclonal antibodies have been developed for certain problematic pathogens. Pseudomonas aeruginosa has been the major focus of this approach, and trials of hyperimmune anti-Ps. aeruginosa globulins for treatment of pneumonia are underway. Broad-spectrum, anti-lipopolysaccharide antibody preparations have also been employed for prophylaxis of nosocomial pneumonia, but to date these trials have not been successful. Finally, anticytokine antibody therapy to reduce infection-initiated inflammatory lung damage is under consideration.

Antibodies, Monoclonal↗
PubMed1991

Safety, pharmacokinetics, and functional activity of human anti-Pseudomonas aeruginosa monoclonal antibodies in septic and nonseptic patients.

A mixture of five IgM human monoclonal antibodies (MAbs) against lipopolysaccharide antigens of Pseudomonas aeruginosa, plus a human IgG1 MAb against exotoxin A, were studied in 12 noninfected patients and 8 patients with P. aeruginosa bacteremia or pneumonia (or both). The preparation was well tolerated over a dose range of 0.3-1.2 ml/kg (0.75-3.0 mg/kg IgM protein). After a single infusion of 1.2 ml/kg (3.0 mg/kg IgM protein), serum antibody titers were boosted into therapeutic range, with serum half-lives ranging from 34 to 99 h. Also, opsonophagocytic activity in serum rose more than 1 log10 for all but one antibody. In no patient was an immunologic response against the MAb preparation detected.

Adult↗
PubMed1990

Pseudomonas hyperimmune globulin passive immunotherapy for pulmonary exacerbations in cystic fibrosis.

We studied the effect of an intravenously administered gamma globulin [Ps-ivIG] enriched fivefold over conventional ivIG for Pseudomonas aeruginosa lipopolysaccharide [PA LPS] antibodies on ten patients with cystic fibrosis [CF] aged 19-32 years during hospitalization for pulmonary deterioration. All were colonized with greater than or equal to 1 PA phenotype resistant to all antibiotics at the time of admission and they received 500 mg/kg Ps-ivIG intravenously as a single dose in addition to conventional treatment, including antibiotics and chest physiotherapy. No adverse effects occurred. Circulating immune complexes and complement levels remained unchanged from baseline. Serum levels of anti-PA LPS IgG, as measured by ELISA for eight PA LPS immunotypes, increased to 244 +/- 65% (mean +/- SE) of baseline levels 1 hour post-infusion (P less than 0.01), remained significantly elevated during a mean hospital stay of 17 days, and returned to near baseline by follow-up 4 weeks after hospital discharge. Plasma half-life and clearance values were similar to those of other subjects receiving conventional ivIG. Sputum PA density declined from 3.0 to 1.2 x 10(8) cfu/mL 1 week post-infusion (P approximately equal to 0.05), and returned to baseline at follow-up. Serum anti-PA opsonic activity increased after infusion (P less than 0.01), but returned to baseline by 72 hours. Clinical scores improved from admission to discharge (P less than 0.005) without decline at follow-up. Forced vital capacity [FVC] and forced expiratory volume in one second [FEV1] increased from admission to discharge (P less than 0.01 and P less than 0.05, respectively) without decline at follow-up. Using autologous historical control data, standard hospital therapy without Ps-ivIG resulted in no improvement in FVC or FEV1, and a subsequent decline in these parameters (P less than 0.05 for each) during a similar follow-up period. This occurred despite the fact that half the patients did not have antibiotic-resistant PA on the control admission. We conclude that Ps-ivIG is a safe adjunctive therapy for pulmonary exacerbations in moderately ill cystic fibrosis patients colonized with resistant PA, and may be associated with both greater and more prolonged improvement in pulmonary function than standard therapy alone.

Adult↗
PubMed1990

Immunotherapy for infectious diseases.

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Homer A. Boushey, MD, Professor of Medicine, and Nathan M. Bass, MD, PhD, Associate Professor of Medicine, under the direction of Lloyd H. Smith, Jr, MD, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Pseudomonas aeruginosa. Vaccines and immunotherapy.

Among opportunistic infections with gram-negative bacilli, those caused by Pseudomonas aeruginosa are associated with particularly high mortalities. Accordingly, considerable interest exists to develop immunotherapeutic or immunoprophylactic agents for this pathogen. In vitro as well as in vivo studies in animal models have demonstrated that LPS serotype-specific antibodies against P. aeruginosa confer protection. Thus, cell wall-derived LPS P. aeruginosa vaccines have been developed for active immunization. Toxic side effects from LPS and relatively slow immune response to active immunization in patients needing rapid protection have led to the development of high-titered anti-P. aeruginosa immunoglobulin G preparations. Passive immunotherapy with these polyclonal antibody preparations has shown promising results in animal models and in clinical pilot studies. More recently, murine and human monoclonal antibodies against P. aeruginosa have been developed. These preparations offer the potential advantage over polyclonal globulin preparations of low protein dosages and virtually unlimited supply.

Bacterial Vaccines↗
PubMed1990

Approach to therapy of respiratory infections in the critical care setting.

Therapy of pneumonia in the critical care setting includes intravenous antibiotics and supportive care. Since the etiologic agent of infection may not be clear, empiric broad-spectrum antibiotic regimens are often used. Combinations of beta-lactam and aminoglycoside agents are particularly popular regimens due to the high incidence of gram-negative bacillary and Staphylococcus aureus pneumonias in the critical care unit. Several new approaches to treatment of pneumonia in the critical care setting are being evaluated, including single-agent empiric coverage using a broad-spectrum beta-lactam agent; broad-spectrum quinolones, such as ciprofloxacin; intrabronchial aminoglycoside instillation therapy; and passive immune therapy with immunoglobulins and monoclonal antibodies.

Aminoglycosides↗
PubMed1979

Influence of genetic factors on natural resistance of mice to Pseudomonas aeruginosa.

In order to determine whether genetic background influences natural resistance to Pseudomonas aeruginosa, a series of 16 different strains of inbred mice were challenged intraperitoneally with P. aeruginosa. Significantly greater natural resistance to infection was found in mice of C3H background genome than in mice of A background genome. This phenomenon was documented for two different strains of P. aeruginosa but could not be demonstrated in control studies in which mice were intraperitoneally challenged with Staphylococcus aureus or Escherichia coli. The enhanced resistance of C3H mice was independent of currently defined haplotypes at the H-2 locus. The killing activity of serum against Pseudomonas was not greater in C3H mice than in A mice. The extension of these findings to disease in humans suggests that the particular susceptibility of certain populations of patients to Pseudomonas may be partially related to genetic factors.

Animals↗
PubMed1979

Lipopolysaccharide pseudomonas vaccine: efficacy against pulmonary infection with Pseudomonas aeruginosa.

Pneumonia due to Pseudomonas aeruginosa occurs with increased frequency and high mortality in certain populations of patients. The potential of vaccination with a heptavalent lipopolysaccharide pseudomonas vaccine for specific protection of respiratory tissues from infection with Pseudomonas was evaluated with a guinea pig model of experimental pseudomonas pneumonia. Animals routinely responded to vaccination with a fourfold rise in titer of serum hemagglutinating antibody to Pseudomonas. Of 25 control animals, all but nine died after lung challenge with Pseudomonas, whereas vaccinated animals had a greater survival rate (22 of 25 animals survived; P less than 0.01). Rates of clearance of viable Pseudomonas from lung tissue were significantly greater in vaccinated animals than in controls during the first 6 hr after infection. Both gross and microscopic findings of lung tissue damage from pseudomonas pneumonia were less in vaccinated than in control animals. Thus, lipopolysaccharide pseudomonas vaccine appears to produce a local protective response in respiratory tissue against Pseudomonas.

Animals↗
PubMed1979

Comparison of antibiotic regimens for treatment of experimental pneumonia due to Pseudomonas.

The high mortality associated with pneumonia due to Pseudomonas aeruginosa prompted a comparative trial of several currently available antibiotic regimens for this infection in a guinea pig model. Normal guinea pigs receiving an intratracheal challenge of 10(8) colony-forming units of Pseudomonas routinely died within 3-48 hr when treated with saline injections. Treatment with carbenicillin or ticarcillin did not affect this uniformly fatal outcome. Groups of animals treated with gentamicin or tobramycin had survival rates of 39% and 67%, respectively. The addition of either carbenicillin or ticarcillin to an aminoglycoside failed to enhance further the survival rates or durations of survival after infection. These survival data were supported by studies showing superior clearance of viable Pseudomonas from lung tissues in aminoglycoside-treated animals chosen at random for sacrifice 3 hr after infection. Thus, in animals experimentally challenged with P. aeruginosa to cause pneumonia and in which only a single isolate of Pseudomonas was evaluated, protection from pulmonary infection was best provided by an aminoglycoside rather than by a beta-lactam antibiotic.

Aminoglycosides↗
PubMed1979

Evaluation of a new polyvalent Pseudomonas vaccine in respiratory infections.

A new polyvalent, cell wall extract, Pseudomonas aeruginosa vaccine (PEV-01), was evaluated by using a guinea pig model of experimental Pseudomonas pneumonia. Guinea pigs routinely developed fourfold rises in serum hemagglutinating Pseudomonas antibodies after four vaccine injections given over 2 weeks. Vaccinated animals survived an intratracheal Pseudomonas challenge (1 X 10(8) colony-forming units) significantly better (13 of 14 survived) than did a control group (5 of 14 survived) (P less than 0.01). Clearance of viable Pseudomonas from lung tissue was significantly better in vaccinees than controls at both 3 h (P less than 0.02) and 6 h (P less than 0.05) after infection. Both gross and histological examinations of lung tissue revealed less pulmonary tissue damage in vaccinated animals following Pseudomonas infection. Thus, PEV-01 Pseudomonas vaccine appears capable of eliciting a specific protective response in the guinea pig respiratory tract.

Animals↗
PubMed1979

Cyclophosphamide and cortisone acetate inhibit complement biosynthesis by guinea pig bronchoalveolar macrophages.

To explore mechanisms of drug-induced alterations in local host defenses in the lung, the capacity of guinea pig alveolar macrophages to synthesize the second (C2) and fourth (C4) components of complement was studied following treatment with cyclophosphamide and cortisone acetate. Administration of either drug significantly inhibited biosynthesis of C2 and C4 within 1 day. After 1 week of treatment, local complement synthesis was inhibited approximately 80%, although serum levels of the corresponding proteins were normal.

Animals↗
PubMed1978

Pathogenesis of Pseudomonas aeruginosa pneumonia during immunosuppression.

A guinea pig model of immunosuppression was utilized to study the effects of immunosuppressive chemotherapy on lung response to challenge with Pseudomonas aeruginosa. Study groups included normal guinea pigs, as well as guinea pigs that received a one-week course of cortisone acetate (CA, 100 mg/kg per day) plus 15 mg of cyclophosphamide (CTX)/kg per day (CA + LoCTX group) or 30 mg of cyclophosphamide/kg per day (CA + HiCTX group). Separate groups received CA or HiCTX alone. Intratracheal instillation of P. aeruginosa resulted in bilateral hemorrhagic pneumonia in both normal and immunosuppressed animals. Survival was 100% for normal animals and for those given CA alone, 67% in the CA + LoCTX and the HiCTX groups, and 0 in the CA + HiCTX group. Increased mortality correlated with a diminished polymorphonuclear leukocyte inflammatory response in infected lung tissues and also with the addition of CA to CTX. Clearance of viable P. aeruginosa from lung tissue was significantly reduced in animals receiving the combination CA + HiCTX. Thus, decreased lung inflammation and the addition of CA appeared to be important determinants for fatal pseudomonas pneumonia.

Animals↗
PubMed1978

Differential effects of cyclophosphamide and cortisone acetate on bronchoalveolar phagocytic cell populations.

The effects of cyclophosphamide and cortisone acetate on numbers of pulmonary alveolar macrophages (PAM) and on inflammatory response of polymorphonuclear leukocytes to bacterial infection in the lung were studied in guinea pigs. Groups of animals were treated for 7 days with each drug alone or in combination. Bronchoalveolar lavage was carried out on the day after completion of the drug regimens. Selected animals were challenged via the trachea with Pseudomonas aeruginosa 2 hours before lavage. Single-drug therapy did not significantly decrease numbers of PAM in lavage fluids, but combined therapy led to a 60 per cent (P less than 0.01) decrease in numbers of PAM. Normal animals and cortisone-treated animals responded 2 hours after Pseudomonas lung challenge with a 4-fold increase in PMN in lavage fluid, wherease animals treated with cyclophosphamide or the combined-drug regimen failed in this response. The clearance of viable Pseudomonas organisms from bronchoalveolar fluids was inhibited only in animals treated with both cyclophosphamide and cortisone. Thus, only a combined regimen of cyclophosphamide plus cortisone led to the simultaneous occurrence of decreased numbers of PAM, as well as inhibition of polymorphonuclear leukocyte inflammation in the lung. Combined immunosuppressive drug regimens may result in more severe alterations in lung host defense for the clearance of bacteria than does single-drug therapy.

Animals↗