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Biomedical subjects

G R Donowitz

Publications and source records attributed to G R Donowitz.

At least 19 recordsLinked to original sources
PubMed1996

Fever in the compromised host.

Fever in the compromised host remains a significant clinical problem. Multiple potential pathogens, subtle physical findings, and a variety of noninfectious problems that may masquerade as infection contribute to this clinical challenge. A review of host defense defects along with a careful physical examination will begin to narrow the etiologic possibilities for fever. Recognizing that the majority of infections will represent as fevers of unknown etiology, a consistent approach to the patient who responds to empiric antibiotic therapy as well as to the patient who fails to respond should be developed.

Fever↗
PubMed1995

Risk factors for infection of adult patients with cancer who have tunnelled central venous catheters.

BACKGROUND: Long-dwelling tunnelled central venous catheters provide reliable access for infusion therapy of patients with cancer, but can result in serious bloodstream infections. The incidence of such infections has been documented, but few studies have assessed potential risk factors, and to the authors' knowledge, none have measured the effect of neutropenia upon the incidence of these infections. METHODS: A cohort of 71 adult patients with cancer with long-dwelling tunnelled central venous catheters was followed for a total of 12,410 catheter days until catheter removal, death, or end of study for the occurrence of catheter-related infection or sepsis of unknown origin. Fifteen factors were assessed for association with these infections. RESULTS: Thirteen patients (18%) experienced a catheter-related infection (1.0/1000 catheter days), and 23 (32%) experienced sepsis of unknown origin. Neutropenia was associated significantly with risk for catheter-related infection (relative risk [RR] = 15.1, 95% confidence interval [CI] 2.7-86.9) and sepsis of unknown origin (RR = 10.3, 95% CI 4.0-26.8). Inpatient status, acute leukemia, and cytosine arabinoside therapy also were associated with sepsis of unknown origin, but not when adjusted for neutropenia. CONCLUSION: Of the 15 potential risk factors studied, neutropenia was the only independent risk factor for infection related to long-dwelling tunnelled central venous catheters and for sepsis of unknown origin.

Adult↗
PubMed1994

Tissue-directed antibiotics and intracellular parasites: complex interaction of phagocytes, pathogens, and drugs.

Antibiotics with significant tissue penetration and intracellular accumulation may have an important role in the treatment of intracellular infections. However, clinically relevant evaluation of these antibiotics in vitro remains a challenge. Measurement of serum drug concentrations or serum bactericidal levels may not be relevant. Measurement of intracellular drug concentrations may be simplistic, given the complex interaction of drug, microbe, and phagocyte. The effect of an antibiotic on an intracellular organism depends on the drug's penetration into the cell, its intracellular location, its metabolism within the cell, and its antimicrobial activity within the organism's specific intracellular microenvironment. Legionella micdadei, an intracellular parasite that grows within monocytes, has been used for the evaluation of drugs like azithromycin that are concentrated intracellularly.

Animals↗
PubMed1993

Azithromycin inhibition of intracellular Legionella micdadei.

Legionella micdadei is an intracellular parasite that is ingested, but not killed, by leukocytes. Within monocytes, the organism has been shown to grow 1.0 to 2.0 log10 units over 48 h (D. L. Weinbaum, R. R. Benner, J. N. Dowling, A. Alpern, A. W. Pasculle, and G. R. Donowitz, Infect. Immun. 46:68-73, 1984). Intracellular L. micdadei would appear to be a useful model in which to study the effect of antibiotics which accumulate intracellularly. Azithromycin, a newly introduced azalide, is highly concentrated within leukocytes and was therefore studied to determine its effect on a single strain of L. micdadei that had been ingested by human monocytes. Peripheral blood monocytes were allowed to ingest L. micdadei and extracellular, nonadherent organisms were subsequently removed by washing. Cells and cell-associated bacteria were then incubated at 0, 24, and 48 h in media with serial concentrations of azithromycin at sub-MIC levels (less than 1.0 microgram/ml). L. micdadei in cells not exposed to azithromycin grew 0.8 +/- 0.1 log10 units (mean +/- standard deviation) at 24 h and 1.7 +/- 0.4 log10 units at 48 h. At both 24 and 48 h, the lowest concentrations of azithromycin tested (0.02 microgram/ml) significantly inhibited bacterial growth in monocytes (P = 0.02). A stepwise inhibition of L. micdadei CFUs was noted with increasing azithromycin concentrations. In contrast, when cells were exposed to antibiotic before ingesting L. micdadei, a less effective antibacterial effect was noted. Under certain in vitro conditions, azithromycin is a potent agent against intracellular L. micdadei.

Azithromycin↗
PubMed1992

Candidal endophthalmitis after lithotripsy of renal calculi.

Candidal endophthalmitis is most commonly due to hematogenous seeding of the eye by Candida albicans. Although it is most often seen as a manifestation of disseminated candidiasis in patients who are seriously ill, other patients may have candidal endophthalmitis as the only evidence of fungal infection. We have presented a case of endophthalmitis due to C albicans in a patient who had bilateral renal calculi and who had received multiple antibiotics and extracorporeal shock wave lithotripsy.

Candidiasis↗
PubMed1991

The role of the chest roentgenogram in febrile neutropenic patients.

In a retrospective review of patients with neutropenia and fever, we sought to determine how often roentgenograms detected pulmonary disease, especially pneumonia, not suggested by signs and symptoms. Further, we sought to determine how often therapy was changed as a result of roentgenographic findings. Overall, 41 (22%) of 187 chest roentgenograms obtained during initial febrile episodes, recurrent fevers, or persistent fevers were abnormal. While most patients had signs and symptoms suggesting the presence of pulmonary disease, 17% had roentgenographic abnormalities detected in the absence of such findings. During initial febrile episodes, therapy was not changed in response to findings on the chest roentgenogram. However, during episodes of persistent or recurrent fever, findings on chest roentgenograms led to changes in therapy in eight (61%) of 13 episodes of which six (40%) resulted in clinical improvement. Chest roentgenograms were therefore found to be an important diagnostic tool in evaluating recurrent or persistent fever in the neutropenic patient but of little use during initial febrile episodes.

Bone Marrow Transplantation↗
PubMed1990

Ingestion of Legionella micdadei inhibits human neutrophil function.

Legionella micdadei is a human pathogen which survives within leukocytes. To determine how this organism escapes intracellular destruction, we examined its effect on human neutrophil activity. Neutrophils were allowed to ingest L. micdadei prior to evaluation of functional activity. Compared with control cells which did not ingest organisms, cells ingesting L. micdadei showed significantly depressed production of superoxide anion (24.5 +/- 9.0 nmol/10(6) cells per 15 min versus 6.9 +/- 3.2 nmol/10(6) cells per 15 min, respectively; P = 0.002), chemotaxis (43.9 +/- 0.8 mm versus 0.9 +/- 1.3 mm of directed migration, respectively; P = 0.001) and bactericidal activity against Staphylococcus aureus (97.9% versus 37.6% of ingested organisms killed, respectively; P = 0.001). Similar degrees of inhibition could not be demonstrated when either Staphylococcus aureus or Escherichia coli was ingested by cells prior to evaluation. Inhibition of neutrophil function did not occur when phagocytosis of L. micdadei was prevented. However, inhibition occurred with heat-killed as well as with viable organisms. The inhibition of neutrophil function by ingested L. micdadei may help explain the bacterium's ability to survive intracellularly and may begin to explain the pathogenesis of this disease.

Chemotaxis, Leukocyte↗
PubMed1990

Cunninghamella bertholletiae: an unusual agent of zygomycosis.

Cunninghamella bertholletiae shares many of the features typical of the other agents causing zygomycoses. Those who are immunocompromised constitute the major patient population at risk; the agents as a group are aggressive, the disease is often disseminated, and the pathologic picture of vascular invasion and tissue infarction is common. Unlike other agents of zygomycoses, Cunninghamella bertholletiae infection remains difficult to treat successfully even after early diagnosis and appropriate therapy.

Humans↗
PubMed1989

Third generation cephalosporins.

The third generation cephalosporins demonstrate greater potency, broader antibacterial spectrum, and more favorable pharmacologic characteristics than other cephalosporins. The majority of strains of E. coli, Klebsiella pneumoniae, and Proteus are susceptible, including strains resistant to aminoglycosides, anti-Pseudomonas penicillins, and other cephalosporins. Pseudomonas aeruginosa is susceptible to a subgroup of third generation agents including ceftazidime, cefoperazone, and the experimental agents cefpirome and cefpiramide. Penetration into the cerebrospinal fluid is excellent especially for cefotaxime, ceftazidime, ceftriaxone, and ceftizoxime. These agents are safe, sharing most of the known toxicities of other beta-lactam compounds. Their greatest use is in the therapy of difficult to treat gram-negative bacterial infections, including meningitis, nosocomial infections, and infections caused by Pseudomonas aeruginosa.

Bacteria↗
PubMed1987

Human nasal mucosal responses to topically applied recombinant leukocyte A interferon.

Healthy adults were randomly assigned to receive intranasal sprays of recombinant leukocyte A interferon (IFN; 9 X 10(6) U per day) or placebo once daily for four or 10 days. Scrape nasal biopsy specimens stained by hematoxylin and eosin and mucosal punch biopsy specimens stained by immunoperoxidase techniques with monoclonal antibodies to lymphocyte subsets were collected before and after exposure. Blinded analysis of the punch biopsy specimens by two pathologists found increased degrees of lymphocyte infiltration compared with preexposure samples in 56% of IFN vs. 0% of placebo recipients at four days (P = .008) and 60% of IFN vs. 10% of placebo recipients at 10 days (P = .057). By immunoperoxidase staining the cellular infiltrates were primarily in the subepithelium and comprised principally (mean, greater than or equal to 84%) T lymphocytes. In the 10-day IFN recipients, subepithelial T helper (Leu-3):T suppressor (Leu-2) cell ratios ranged from 2:1 to 5:1. The number of distribution of B (Leu-14) or natural killer (Leu-7) cells did not appear affected by IFN.

Administration, Topical↗
PubMed1986

5-Fluorouracil effect on cultured murine stem cell progeny and peripheral leukocytes.

Pretreatment of mice with 5-fluorouracil (5-FU) depletes total marrow cellularity but leaves a residual population of cells with enhanced regenerative capability. Using the long-term Dexter liquid culture system, we studied the effects of 5-FU on murine marrow cells and their production of pluripotent stem cells (CFU-S) and monocyte-granulocyte precursors (CFU-C). We also examined oxidative and bactericidal activity of neutrophil progeny of marrow cells in culture to determine the effect of 5-FU on effector cell activity. As an in vivo comparison, effector cell activity of neutrophils from peritoneal exudates of 5-FU treated animals was examined. C57B1/6J mice were treated with 5-FU, 100 mg/kg or 150 mg/kg, 4-7 days prior to marrow cell harvest and culture. Total cell counts, CFU-S, and CFU-C were all reduced compared with values from saline-treated controls. Over time, cell production from 5-FU marrow increased, reaching supranormal levels by 2-3 weeks of culture. The neutrophil progeny obtained from these marrow cultures showed normal reduction of nitroblue tetrazolium dye (NBT), but abnormally low chemiluminescence. In contrast, neutrophils from peritoneal exudate of 5-FU-treated animals showed normal chemiluminescence, but abnormally low reduction of NBT. Normal bactericidal activity was exhibited by both neutrophil progeny from marrow cultures and by neutrophils from peritoneal exudates of 5-FU-treated animals. The present data indicate that mouse marrow cells surviving 5-FU have an enhanced proliferative capacity in vitro and are capable of producing neutrophil progeny that, despite some abnormalities of oxidative function, have normal bactericidal capability.

Animals↗
PubMed1985

A controlled study of ticarcillin plus clavulanic acid versus piperacillin as empiric therapy for fever in the immunocompromised host.

Clavulanic acid, a potent beta-lactamase inhibitor, was studied in fixed combination with ticarcillin and used with tobramycin as empiric therapy for fever in the immunocompromised host. Fifty febrile episodes were evaluated in patients with hematologic malignancy and/or neutropenia. Eighty-one percent of evaluable infections treated with the study regimen of ticarcillin, clavulanic acid, and tobramycin responded. Seventy-four percent of evaluable infections treated with the control regimen of piperacillin, tobramycin, and vancomycin responded (p = 0.4). Resistance to piperacillin and ticarcillin were noted in 23.8 percent of 21 isolated organisms. Resistance to ticarcillin and clavulanic acid was noted in only one (4.7 percent) of the isolated organisms (p = 0.092). Untoward reactions, including rash, nephrotoxicity, and superinfection, were unusual and occurred with equal frequency in the study and control groups. Clavulanic acid in combination with ticarcillin was effective and safe in treating fever in the immunocompromised host.

Bacterial Infections↗
PubMed1985

Positive direct antiglobulin tests due to clavulanic acid.

Clavulanic acid, a beta-lactamase inhibitor, was found to be associated with the development of a positive direct antiglobulin test. Of 23 antibiotic courses in patients treated with ticarcillin, clavulanic acid, and tobramycin, 10 (43.5%) developed positive direct antiglobulin tests versus 2 of 26 (7.7%) patients treated with piperacillin and tobramycin (P = 0.0044). In vitro immunohematological studies showed that clavulanic acid caused a nonimmunologic adsorption of plasma proteins onto the erythrocyte surface. Hemolysis was not associated with such nonimmunologic adsorption. However, the resulting positive antiglobulin test might delay cross matching of blood products for transfusions or interfere with the evaluation of true immune-mediated hemolytic anemia.

Clavulanic Acid↗
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↗