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G R Donowitz

Publications and source records attributed to G R Donowitz.

34 records · Page 2Linked to original sources
PubMed1984

Interaction of Legionella micdadei with human monocytes.

We have recently shown that Legionella micdadei is ingested, but not killed, by human neutrophils. Herein we investigate the role of human monocytes in defense against this organism. Serum and monocytes from normal donors having no detectable antibody to L. micdadei were used. Egg-passaged L. micdadei organisms multiplied inside these monocytes with a peak growth of 2 log units within 12 h. No growth occurred when monocytes were omitted or when sonicated monocytes were used. Electron microscopy 18 h after infection revealed these organisms to be intracellular in normal-appearing phagosomes. When the input multiplicity of L. micdadei was greater than 1 CFU per monocyte, no intracellular growth occurred. When egg-passaged Legionella pneumophila organisms were used, intracellular organisms were found in phagosomes studded with ribosomes at the same time period. Peak intracellular growth of L. pneumophilia occurred by 48 h. L. micdadei activated the complement system and was opsonized by C3. However the use of complement-depleted (heat-inactivated) serum as the opsonic source had no effect on the bacterium's ingestion or growth in the monocyte. Thus, L. micdadei multiples in human monocytes. This entry and growth is independent of antibody or complement. The intracellular locations of L. micdadei and L. pneumophila differ, suggesting different mechanisms for the survival of these two organisms in the monocyte.

Complement C3↗
PubMed1984

Interrelationships of polymorphonuclear neutrophil membrane-bound calcium, membrane potential, and chemiluminescence: studies in single living cells.

Stimulated neutrophils show ionic fluxes that may function as "transducers" between stimuli and effector functions. Using fluorescent probes, patterns of membrane-associated calcium (chlortetracycline, CTC) and membrane potential (3-3'-dipentyloxacarbocyanine, di-O-C5 (3)) in single living human neutrophils were observed with a fluorescence microscope fitted with an image intensifier and photometer. Fluorescence changes were related to chemiluminescence. In unstimulated neutrophils, CTC and di-O-C5 (3) fluorescence was brightest in the perinuclear region. Di-O-C5 (3) fluorescence was also seen in mitochondria. Neutrophil stimulation with zymosan, phorbol myristate acetate (PMA) or calcium ionophore (A23187) resulted in loss of di-O-C5 (3) and CTC fluorescence and chemiluminescence proportional to the strength of the stimulus. Experiments demonstrated the independence of these processes. (1) Digitonin stimulation caused chemiluminescence and di-O-C5 (3) darkening without loss of CTC fluorescence. (2) Depolarization of neutrophils did not induce CTC darkening or chemiluminescence. (3) Calcium ionophore (A23187) stimulation of neutrophils in calcium-free medium resulted in normal di-O-C5 (3) and CTC darkening, but a blunted chemiluminescence peak. (4) Calcium ionophore (A23187) stimulated the loss of di-O-C5 (3) and CTC fluorescence from chronic granulomatous disease neutrophils, but did not trigger an oxidative burst. Although neutrophil depolarization, calcium release from membranes, and oxidative activity are linked, these processes can clearly be separated.

Animals↗
PubMed1983

Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies.

In a double blind study, oral prophylactic trimethoprim/sulfamethoxazole was evaluated for its utility in preventing serious infections in patients with hematologic malignancy. Of 58 evaluated granulocytopenic episodes in 47 patients, acute leukemia was the underlying malignancy in 46 episodes. Trimethoprim/sulfamethoxazole prophylaxis resulted in fewer microbiologically documented infections (seven versus 15; p = 0.029). This was primarily the result of a reduction in episodes of bacteremia in the trimethoprim/sulfamethoxazole-treated group as compared with the placebo-treated group (three versus nine episodes; p = 0.05). The combined frequency of disseminated candidiasis, candidemia, and esophagitis of presumed fungal etiology was greater in the trimethoprim/sulfamethoxazole-treated group (six) than in the placebo-treated group (two) but not significantly so (p = 0.13). Similarly, there were no significant differences between groups in the overall incidence of infectious complications, number of febrile days, use of parenteral antibiotics, or number of days following randomization to first infectious episode. Throat and rectal surveillance cultures more frequently revealed trimethoprim/sulfamethoxazole-resistant gram-negative bacilli and yeasts in the trimethoprim/sulfamethoxazole-treated group. More frequent emergence of yeast isolates from previously culture-negative patients was documented (p = 0.033). Thus, in this study, trimethoprim/sulfamethoxazole prophylaxis during granulocytopenia reduced the incidence of microbiologically documented infections. However, the emergence of resistant bacteria and of fungi may limit the potential usefulness of this approach.

Adolescent↗
PubMed1983

Evidence for a nonoxidative mechanism of human natural killer (NK) cell cytotoxicity by using mononuclear effector cells from healthy donors and from patients with chronic granulomatous disease.

In vitro natural killer (NK) activity expressed by blood mononuclear cells from patients with chronic granulomatous disease of childhood (CGD) was equivalent to that expressed by cells from normal, healthy volunteers. Because neutrophils and monocytes from these same donors exhibited extremely depressed oxidative functions, our data could be interpreted to show that a) NK cells derived from a unique and separate cellular lineage unaffected by the disease-related oxidative defect, or b) the in vitro cytolytic mechanism(s) of NK cells were not dependent on oxygen metabolites. These hypotheses were examined by using as NK effector cells large granular lymphocytes (LGL) from healthy donors whose monocytes and neutrophils had normal oxidative functions. Such functions were measured in the nitroblue tetrazolium dye reduction assay, which is a qualitative measurement of superoxide anion production; by reduction of ferric cytochrome c, a more specific and quantitative measurement of superoxide anion production; and in the luminol-enhanced chemiluminescence assay, an extremely sensitive measure of several reactive oxygen radicals, including superoxide anion, hydroxyl radical, and singlet oxygen. Whereas monocytes and neutrophils from healthy donors were readily stimulated with zymosan or phorbol myristate acetate (PMA) in each of these assays. LGL produced no detectable amounts of oxygen metabolites when co-incubated either with K562 erythroleukemia cells, PMA, E. coli endotoxin, or the calcium ionophore A23187. Thus, because NK cell activity is normal in CGD patients with major oxidative defects, and because no reactive oxygen metabolites could be detected in LGL that simultaneously exhibited potent NK activity, we conclude that in vitro NK activity by human mononuclear cells involves a lytic mechanism(s) independent of oxygen metabolites.

Cell Differentiation↗
PubMed1983

Differential survival of Leishmania donovani amastigotes in human monocytes.

Leishmania donovani is an important intracellular protozoal pathogen of man; it is found solely within macrophages in its amastigote stage in humans, and exists in its extracellular, flagellated promastigote stage in the sandfly, its arthropod vector. To determine if either stage of L. donovani was capable of surviving within monocytes--the oxidatively active precursors of tissue macrophages--interactions of the parasite with human monocytes were studied in vitro. Amastigotes and promastigotes were ingested to a comparable degree by monocytes; whereas 79% of promastigotes were killed within 48 hr, however, amastigotes survived and multiplied threefold over 5 days. Promastigotes, which have been shown to be sensitive to hydrogen peroxide-peroxidase-halide microbicidal mechanisms, elicited a phagocytic oxidative burst that was 49% of the response to serum-opsonized zymosan, as assessed by luminol-enhanced chemiluminescence. NBT was reduced to formazan in 71% of monocytes exposed to promastigotes. The death of promastigotes within monocytes could be attributed at least in part to oxidative microbicidal mechanisms because there was no significant decrease in the number of cell-associated parasites in monocytes from donors with chronic granulomatous disease of childhood. In contrast to promastigotes, amastigotes survived within monocytes, despite eliciting an oxidative response that was 27% of the response produced by serum-opsonized zymosan; this response was not significantly different from that produced by promastigotes. In a phagocyte-free system, amastigotes were found to be sevenfold more resistant than were promastigotes to the lethal effects of hydrogen peroxide. The survival of L. donovani in human monocytes is thus dependent on the parasite stage; promastigotes are ingested, they elicit an oxidative burst, and the majority are killed by oxidative microbicidal mechanisms, whereas amastigotes are ingested and survive to parasitize human monocytes successfully, despite eliciting a phagocytic oxidative burst.

Adult↗
PubMed1982

Pittsburgh pneumonia agent: chest film manifestations.

Pittsburgh pneumonia agent, Legionella micdadei, is a Gram-negative, weakly acid-fast bacillus, recently recognized as a cause of pulmonary infection in the immunocompromised host. The chest radiographic findings in seven patients with this disease are reported. These consist of single or multiple nodules and segmental infiltrates involving part of all of one or more lobes. A striking feature in this series was the rapid growth of the pulmonary densities.

Adult↗
PubMed1982

Monocyte function in patients with chronic granulomatous disease of childhood.

Adults with chronic granulomatous disease of childhood (CGD) have been described who remain relatively free of infection despite markedly abnormal neutrophil function. Monocyte function in four adults with this mild or atypical CGD syndrome was examined and compared to that of normal controls and to that of two patients with the more severe or classic CGD syndrome. Monocytes from patients with atypical CGD killed 75.7% +/- 2.6% (mean +/- SEM) of ingested organisms at 30 min, while monocytes from the patients with classic CGD killed only 50.3% +/- 4.2% of bacteria (p less than 0.001). The difference in bactericidal activity between atypical CGD monocytes and normal monocytes was relatively small (75.7% +/- 2.6% versus 88.1% +/- 3.7%, respectively) but was statistically significant (p = 0.007). Monocytes from both atypical and classic CGD patients showed markedly impaired oxidative metabolism. Differences in monocyte bactericidal activity may explain why atypical CGD patients have fewer infections than classic CGD patients. The presence of nonoxidative bactericidal mechanisms in atypical CGD monocytes is suggested by the demonstration of bactericidal activity despite severe oxidative metabolic defects.

Blood Bactericidal Activity↗
PubMed1981

Moxalactam and cefazolin: comparative pharmacokinetics in normal subjects.

Moxalactam, a new beta-lactam antibiotic with a wide in vitro spectrum of activity, was compared with cefazolin after intravenous and intramuscular administration of 1.0 g in a double-blind crossover design in 21 adult male subjects with normal renal function. Serum samples were obtained at 0.5, 1, 2, 3, 4, 6, 8, and 12 h, and urine was collected at 0 to 2, 2 to 4, 4 to 6, 6 to 8, and 8 to 12 h after dosing. Intravenous kinetics were described by a linear two-compartment model. For moxalactam, the drug clearance and volume of distribution were larger (115.2 versus 75.9 ml/min per 70 kg, P = 0.001, and 0.44 versus 0.19 liter/kg, P less than 0.001, respectively), and the t1/2beta was longer (3.47 versus 2.18 h, P = 0.01), with correspondingly smaller area under the curve (151 versus 236 h x mg/ml, P = 0.003) and lower serum concentration at 30 min (62 versus 106 micrograms/ml, P = 0.003) than cefazolin. Intramuscular kinetics were similar and were well described by a single-compartment model. Urinary recovery was essentially identical for both drugs: 55 to 75% in 8 h. Consistent departures from the two-compartment model for moxalactam (not noted for cefazolin) suggested enterohepatic recirculation of moxalactam. Both drugs were well tolerated, and no adverse reactions were noted.

Adult↗
PubMed1979

Opportunistic pneumonia: a clinicopathological study of five cases caused by an unidentified acid-fast bacterium.

Five patients had opportunistic pulmonary infection caused by acid-fast bacilli, unusual clinical presentations and a unique pathological picture. Clinically, these cases mimicked septic pulmonary emboli or bacterial pneumonia. The infection was temporally related to high-dose corticosteroid therapy, given for renal-transplant rejection in four patients and for therapy of lymphocytic lymphoma in one. Histologic sections of lung-biopsy or autopsy material showed an acute suppurative pneumonia with dense alveolar infiltration by neutrophils, without granuloma formation or caseous necrosis. Predominantly intracellular acid-fast bacilli were present. The organism failed to grow in culture on routine bacterial, fungal and mycobacterial mediums. This unusual and possibly new acid-fast organism is a probable cause of suppurative pneumonia in impaired hosts receiving corticosteroid therapy.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study.

Community-acquired pneumonia remains an important infectious disease problem, with more than 4 million cases occurring in the United States annually. Although Streptococcus pneumoniae remains the most commonly identified organism, a variety of bacterial and nonbacterial pathogens may be involved. Hospitalization is unnecessary in most cases, and oral antibiotic therapy is common. In the majority of cases, the etiology of pneumonia is unknown at the time of presentation, necessitating the use of empiric therapy. Quinolones have not been utilized in this setting in the past because of their inconsistent coverage of S pneumoniae. Sparfloxacin (RP 64206) is a broad-spectrum fluoroquinolone with excellent activity in vitro against the majority of bacteria involved in community-acquired pneumonia, including pneumococcus. We therefore studied the efficacy and safety of sparfloxacin compared with the second-generation cephalosporin cefaclor as empiric therapy for patients with community-acquired pneumonia in a double-masked, double-dummy, multicenter trial. Three hundred thirty patients aged 18 years or older with community-acquired pneumonia suspected of being bacterial in etiology were enrolled at 74 centers in the United States from June 1, 1992, to March 4, 1995. Patients meeting the inclusion criteria were randomized to receive 10 days of either sparfloxacin 400 mg orally once followed by sparfloxacin 200 mg orally daily (n = 168), or cefaclor 500 mg orally every 8 hours (n = 162). There were no significant differences between groups with regard to baseline characteristics. Patients were followed up serially at 4 +/- 1 days, 20 +/- 3 days, and 38 +/- 7 days after the beginning of therapy. Patients were evaluated for clinical response, clinical recurrence of infection, and eradication of baseline pathogens. The primary efficacy variable was the clinical response (cured or improved) in the subgroup of patients meeting the definition of clinically assessable. Responses were also evaluated in the intent-to-treat population. In the intent-to-treat population, 35.7% of patients receiving sparfloxacin were clinically cured, compared with 32.1% of patients receiving cefaclor. Clinical successes (patients clinically cured plus improved) were also comparable (72.6% of patients in the sparfloxacin group and 71.0% of patients in the cefaclor group). Similar clinical success rates were noted using only the clinically assessable population (primary efficacy variable). Forty-four percent of patients receiving sparfloxacin and 39.1% of patients receiving cefaclor were clinically cured. In the sparfloxacin group, 86.6% of patients were clinical successes, compared with 84.4% of patients in the cefaclor group. Microbiologic cures were comparable in both groups. There was no difference in the incidence of recurrence of infection or superinfection. Adverse events thought to be due to study drug occurred equally in both groups (14.3% in the sparfloxacin group vs 14.8% in the cefaclor group). Results show that sparfloxacin is a safe and effective empiric therapy for patients with community-acquired pneumonia and is comparable to cefaclor.

Adolescent↗
PubMedDate not supplied

Polymorphonuclear neutrophils: an effective antimicrobial force.

The production and deployment of polymorphonuclear neutrophils (PMNs) are under close regulation. PMNs interact through cytokines with a number of cell types, including macrophages, lymphocytes, and endothelial cells. PMNs are guided by bacterial products and cytokines to target sites, where microbes are recognized and killed. Killing occurs through oxygen-dependent and oxygen-independent mechanisms. The frequent and severe infections seen in patients with defects (either congenital or acquired) in PMN function demonstrate the importance of PMNs in host defense against infection. PMNs are potent inflammatory cells and can exacerbate disease states such as myocardial ischemia, gram-negative bacterial sepsis, and the adult respiratory distress syndrome.

Cell Adhesion↗
PubMedDate not supplied

Empiric therapy for pneumonia.

Bacterial pneumonia remains a serious infectious disease even in the modern era of antibiotics and still causes significant morbidity and mortality. Because of the large number of organisms that may cause pulmonary disease, the inexactness of commonly used diagnostic techniques, and the serious consequences of untreated disease, empiric therapy has become accepted practice. Empiric therapy should be designed for treatment of the most likely etiologic organisms while minimizing the potential adverse effects of "shotgun" therapy: drug toxicity, superinfection, and excessive cost. The recognition of common pneumonia syndromes helps narrow the spectrum of possible etiologic agents and consequently aids in the design of rational empiric antibiotic therapy.

Acute Disease↗
PubMedDate not supplied

Comparison of once-daily cephalosporin regimens for community-acquired lower respiratory tract infections in patients with chronic lung disease.

The efficacy of cefonicid and of ceftriaxone, administered once daily for the treatment of lower respiratory tract bacterial infections (pneumonia or bronchitis), was evaluated and compared in 118 patients with chronic lung disease. The patients were randomly assigned to receive 1 gm of either drug, intravenously or intramuscularly, daily for three to 11 days (mean, seven days). Pathogenic bacteria were isolated from sputum in 59% of patients; Haemophilus influenzae and Streptococcus pneumoniae predominated. Clinical cure or improvement was noted in 95% and 93% of patients treated with cefonicid and ceftriaxone, respectively, and bacteriologic cure or improvement in 69% and 81% (the differences were not significant). Side effects were infrequent and similar in the two treatment groups, except that diarrhea was more common in the ceftriaxone group (11%, versus 4.4% in the cefonicid group). It is concluded that patients with chronic lung disease who experience acute exacerbations associated with infection caused by H influenzae or S pneumoniae, or other susceptible organisms, can be effectively treated with once-daily administration of either cefonicid or ceftriaxone.

Adult↗