Newer uses of intravenous immunoglobulins as anti-infective agents.
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Animals↗
Biomedical subjects
J E Pennington
Publications and source records attributed to J E Pennington.
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↗
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↗
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↗
Treatment of experimental Pseudomonas aeruginosa pneumonia with a human IgM monoclonal antibody.
A human IgM monoclonal antibody (MA-1C1) to Fisher immunotype 3 Pseudomonas aeruginosa lipopolysaccharide antigen was evaluated for in vivo activity in a guinea pig model of experimental pneumonia. Pharmacokinetics of MA-1C1 were compared in infected and noninfected animals. Intravenous bolus infusion of MA-1C1, 1 mg/kg, resulted in peak serum antibody concentrations of 3.8 +/- 0.08 and 3.7 +/- 0.05 micrograms/ml in infected and noninfected animals, respectively. Serum half-lives were 25 and 22 h in infected and noninfected groups. Treatment with a single intravenous infusion of MA-1C1 improved survival from pneumonia and was effective over a broad dose range (0.1-2.5 mg/kg). Cumulative survivals were 18 of 47 in the MA-1C1 group and 0 of 31 in controls (P less than .001). Treatment with MA-1C1 also resulted in fewer positive blood cultures 12 h after infection (P = .04). Although MA-1C1 penetrated into inflamed bronchial fluids, local concentrations were only 5% of the concentrations achieved in serum. Thus, MA-1C1 seems to provide significant therapeutic activity against experimental P. aeruginosa pneumonia by preventing dissemination of infection from the lung.
Animals↗
Different calcium and oxidative metabolic responses in human blood monocytes during exposure to various agonists.
It has become increasingly apparent that certain agonists of phagocytic cells exert their effects by using calcium as an intracellular messenger. Most studies have employed neutrophils for such analyses. We have investigated the requirement of calcium for respiratory burst activation in human blood monocytes by using three triggering agents, concanavalin A (Con A), N-formyl-methionyl-leucil-phenylalanine (FMLP), and phorbol myristate acetate (PMA). There was no overall correlation between the maximal extent of transient rise in cytosolic-free calcium (FMLP greater than Con A greater than PMA) and superoxide (O2-) release (PMA greater than Con A greater than FMLP). PMA, as the most effective agonist of respiratory burst activity, neither increased ionized cytosolic calcium [Ca2+]i nor plasma membrane 45Ca2+ permeability. FMLP evoked increments in [Ca2+]i occurred at lower concentrations than did respiratory burst activation, whereas with Con A a rise in [Ca2+]i and O2- release were parallel. Intracellular Ca2+ release into cytosol was blocked by 8-(N,N-diethylamino)octyl-3,4,5-trimethoxy benzoate, HCl (TMB-8). This caused a parallel inhibition of Con A or FMLP elicited [Ca2+]i transients and O2- release, while burst activity stimulated by PMA was unaffected. Our data thus suggest that a transient rise in [Ca2+]i is essential for Con A and FMLP activation in human blood monocytes. In addition to the calcium signal, other intracellular messengers are required for FMLP stimulation. Respiratory burst activation by PMA appears to act independently of [Ca2+]i transients.
Calcium↗
Recent experience with Pseudomonas aeruginosa immune globulin for the treatment of experimental pneumonia.
A guinea-pig model of experimental Pseudomonas aeruginosa pneumonia was used to determine what factors affect the efficacy of passive immune therapy with a hyperimmune P. aeruginosa globulin (PA-IGIV). Animals treated 2 h after infection with a single iv infusion of PA-IGIV, 500 mg kg-1, demonstrated 33% survival. Lower dosages were less effective and there were no survivors among albumin-treated controls. Treatment with PA-IGIV was effective if given 2 or 8 h after infection but not if delayed until 24 h after infection. Animals rendered neutropenic with cyclophosphamide did not survive if treated with PA-IGIV alone. However, when PA-IGIV was added to tobramycin treatment, a significant increase in survival occurred (86%) as compared with that observed with tobramycin alone (43%) (P less than 0.05). We conclude that PA-IGIV may offer a useful therapeutic option in management of P. aeruginosa pneumonia.
Animals↗
Impact of molecular biology on Pseudomonas aeruginosa immunization.
Persisting high mortalities from Pseudomonas aeruginosa infection have led to new strategies for treatment. In vitro and animal studies indicate that antibodies against P. aeruginosa antigens increase host defense against this infectious agent. The most effective immunogen is lipopolysaccharide (LPS) antigen; however, LPS vaccines are poorly tolerated. Furthermore, the LPS molecule does not lend itself well to production by genetic engineering. Pseudomonas aeruginosa protein antigens which might be amenable to recombinant DNA production are outer membrane proteins and exotoxin A, modified to decrease toxicity but maintain immunogenicity. Another strategy for immunization with anti-LPS P. aeruginosa antibodies is passive administration of either hyperimmune immunoglobulins (polyclonal) or monoclonal antibodies. Passive immunization offers the dual advantage of rapid protection or treatment and is well tolerated. Several monoclonal antibodies against LPS P. aeruginosa antigens have been described, including both murine and human types. Studies in animal models of infection indicate that P. aeruginosa monoclonal antibodies do protect, thus, the most feasible application of molecular biology to the problem of P. aeruginosa infection appears to be production of immunotype-specific monoclonal antibodies for immune therapy.
Animals↗
Recent advances in the treatment of pneumonia in the intensive care unit.
The treatment of pneumonia acquired in the intensive care unit (ICU) includes intravenous antibiotics and supportive care. In many cases, the aetiologic agent of infection is not clear and empirical broad-spectrum antibiotic regimens are commonly used. Combinations of beta-lactam and aminoglycoside agents are particularly popular due to the high incidence of Gram-negative bacillary and Staphylococcus aureus pneumonias in the hospital setting. Several new approaches to treatment of pneumonia in the ICU are currently being evaluated including single-agent empirical treatment with broad-spectrum beta-lactam agents; intrabronchial aminoglycoside instillation therapy; oral quinolone agents for treatment of Gram-negative bacillary pneumonia; and passive immune therapy. Conventional and experimental therapy are discussed in this report.
Aminoglycosides↗
Immunotherapy of infectious diseases: past, present and future.
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Animals↗
[Pseudomonas aeruginosa immunoglobulin in experimental pneumonia].
A guinea pig model of experimental Pseudomonas aeruginosa pneumonia was used to evaluate factors affecting the efficacy of passive immune therapy with Psomaglobin N, a hyperimmune P. aeruginosa globulin. Animals treated 2 h after infection with a single intravenous infusion of Psomaglobin N, 500 mg/kg, demonstrated 33% survival. Lower dosages were less effective and no survivors occurred among albumin-treated controls. Treatment with Psomaglobin N was effective if given 2 h or 8 h after infection but not if delayed until 24 h after infection. Animals rendered neutropenic with cyclophosphamide did not survive if treated with Psomaglobin N alone. However, when Psomaglobin N was added to tobramycin treatment, a significant increase in survival occurred (86%) as compared to that observed with tobramycin alone (43%) (p less than 0.05). We conclude that Psomaglobin N may offer a useful therapeutic option in management of P. aeruginosa pneumonia.
Animals↗
Familial lymphoid interstitial pneumonitis.
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Humans↗
Passive immune therapy for experimental Pseudomonas aeruginosa pneumonia in the neutropenic host.
Studies were conducted in guinea pigs, myelosuppressed by cyclophosphamide, for determination of whether passive immune therapy for Pseudomonas aeruginosa pneumonia would be useful in the setting of neutropenia. Groups of infected animals (14 per group) were treated with a single intravenous infusion of hyperimmune IgG antibody to P. aeruginosa (PA-IGIV; 500 mg/kg), tobramycin (1.7 mg/kg per 8 hr), ticarcillin (120 mg/kg per 6 hr), or combinations of these regimens. Control groups received intravenous albumin solution. Survival rates were 0% with albumin only, 0% with PA-IGIV, 43% with tobramycin (P less than .05), 86% with tobramycin plus PA-IGIV (P less than .05 vs. tobramycin alone), 7% with ticarcillin, and 43% with ticarcillin plus PA-IGIV (.05 less than P less than .10 vs. ticarcillin alone). Additive intrapulmonary killing of P. aeruginosa and prevention of bacteremia were observed in animals treated with tobramycin plus PA-IGIV compared with either treatment alone. Thus, passive immune therapy for P. aeruginosa pneumonia may be useful in the neutropenic host, but only when used in conjunction with antimicrobial agents.
Agranulocytosis↗
Comparative efficacies of ciprofloxacin, ampicillin and chloramphenicol in treatment of experimental Haemophilus influenzae pneumonia.
An experimental murine model of bacteraemic Haemophilus influenzae pneumonia was used to evaluate the therapeutic efficacy of ciprofloxacin, as compared with ampicillin and chloramphenicol. An ampicillin-sensitive (AS) and an ampicillin-resistant (AR) challenge strain were employed. Ciprofloxacin treatment produced intrapulmonary killing of H. influenzae which was superior to that achieved with ampicillin (P less than 0.001, both strains) and chloramphenicol (P less than 0.001, strain AS; P less than 0.005, strain AR). Likewise, survival from strain AS pneumonia was 61% in the ciprofloxacin-treated animals, as compared with 43% for the chloramphenicol-treated, and 22% for the ampicillin-treated groups. We conclude that ciprofloxacin may be an effective agent in treating pneumonia caused by either ampicillin-sensitive or ampicillin-resistant strains of H. influenzae.
Ampicillin↗
Comparative evaluation of enoxacin, ofloxacin, ampicillin, and chloramphenicol for treatment of experimental Haemophilus influenzae pneumonia.
A murine model of bacteremic Haemophilus influenzae type b pneumonia was used to evaluate the therapeutic efficacies of the quinolone antimicrobial agents enoxacin and ofloxacin compared with those of ampicillin and chloramphenicol. Ampicillin-susceptible (AS) and ampicillin-resistant (AR) challenge strains were employed. Treatment with enoxacin or ofloxacin produced intrapulmonary killing of H. influenzae that was superior to that achieved with ampicillin (P less than 0.01 to P less than 0.001 for both AS and AR strains). Ofloxacin and enoxacin also provided killing greater than that with chloramphenicol for the AS strain (P less than 0.01 to P less than 0.001). For the AR strain, ofloxacin provided killing greater than that obtained with chloramphenicol (P less than 0.001). Survival from AS strain pneumonia was 60% in enoxacin-treated and 78% in ofloxacin-treated animals compared with 41% for chloramphenicol-treated and 23% for ampicillin-treated groups. We conclude that enoxacin and ofloxacin may be effective antimicrobial agents in treating either AS or AR strains causing H. influenzae pneumonia.
Ampicillin↗
Ampicillin versus cefamandole as initial therapy for community-acquired pneumonia.
One hundred seven patients with community-acquired pneumonia thought to be of bacterial etiology by the admitting physician but whose initial sputum Gram stain was inadequate to direct specific therapy were randomized to receive either intravenous ampicillin or cefamandole as empiric therapy. Patients were excluded if the initial sputum Gram stain was highly suggestive of infection with Streptococcus pneumoniae, Staphylococcus aureus, or an enteric gram-negative bacillus. The two study groups had comparable demographic and presenting clinical features. The mean age of the patients evaluable for determination of clinical efficacy was 69 years, and greater than 75% had at least one serious underlying medical disorder. In the 90 evaluable patients, there were 11 therapeutic failures (12%), including 5 deaths (5%). Cefamandole, a broad-spectrum antibiotic, was not more efficacious than ampicillin in producing a satisfactory clinical response or in shortening the duration of parenteral therapy. Patients received an average of only 4 days of intravenous antibiotics before changeover to oral therapy and were hospitalized for a mean of 7 days. No patient experienced a relapse of pneumonia following successful completion of parenteral drug therapy. We conclude that cefamandole is not a more effective agent than ampicillin for empiric therapy of community-acquired bacterial pneumonia of uncertain etiology.
Administration, Oral↗
Therapeutic strategies for Pseudomonas aeruginosa pneumonia in the myelosuppressed host.
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Agranulocytosis↗
Comparative oxidative microbicidal activity of human blood monocytes and alveolar macrophages and activation by recombinant gamma interferon.
The relative oxidative and microbicidal activities of human blood monocytes compared with those of alveolar macrophages (AM) are poorly defined. Furthermore, the comparative efficiency of recombinant gamma interferon (rIFN gamma) to enhance microbicidal function of these 2 cell populations is uncertain. In this study, blood monocytes and AM were obtained concomitantly from 10 healthy, nonsmoking human subjects. Cells were adjusted to equivalent cell concentrations and assayed for respiratory burst activity (superoxide anion production) during soluble (Concanavalin A) or particulate (bacteria) stimulation. Microbicidal activity against Pseudomonas aeruginosa, Listeria monocytogenes, and Candida albicans was also determined for each cell type. Finally, the capacity of rIFN gamma treatment (200 U/ml for 24 h) to enhance these cellular activities was determined. Oxidative activity of AM was greater than that of blood monocytes (p less than 0.01, bacteria; p less than 0.02, Con A). Likewise, AM exhibited greater killing of P. aeruginosa (p less than 0.01) and L. monocytogenes (p less than 0.01) than did monocytes. Neither cell killed C. albicans. Treatment with rIFN gamma greatly enhanced both respiratory burst and microbicidal activity of blood monocytes, but had no effect on AM respiratory burst. Despite this, rIFN gamma-treated AM did exhibit some enhanced killing of L. monocytogenes (p less than 0.05). We conclude that oxidative microbicidal activity of resident AM greatly exceeds that of blood monocytes, but that blood monocytes are relatively more susceptible to activation by rIFN gamma.
Adult↗