Biomedical subjects

R F Jacobs

Publications and source records attributed to R F Jacobs.

At least 109 records · Page 6Linked to original sources

PubMed1986

Cellular uptake and cell-associated activity of third generation cephalosporins.

The ability of the third generation cephalosporins to penetrate human polymorphonuclear leukocytes (PMNs) and their antibacterial activity against cell-associated Staphylococcus aureus (SA) and Haemophilus influenzae, type b (Hib) were studied. Utilizing radioactive uptake experiments, the cellular to extracellular concentration ratios were determined to be less than one for all cephalosporins at 10 and 120 min: cefotaxime (0.08 +/- 0.02, 0.34 +/- 0.08), ceftizoxime (0.21 +/- 0.11, 0.52 +/- 0.18), ceftriaxone (0.12 +/- 0.04, 0.38 +/- 0.23), and N-formimidoyl thienamycin (0.18 +/- 0.09, 0.33 +/- 0.14). Third generation cephalosporins were similar to penicillin in their exclusion from PMNs. The killing of cell-associated SA and Hib were evaluated in a preopsonized cell-associated bacterial assay with radiolabelled SA/Hib (cfu/cpm) comparing activity of PMNs + antibiotics to the PMN cell control (no antibiotics) at 0.5, 2, and 4 h. PMNs alone killed less than or equal to 0.5 log SA/Hib over 4 h. Clindamycin killed significantly more SA (p less than 0.01) than all other antibiotics; nafcillin killed significantly fewer SA (p less than 0.05) than all other antibiotics. Although each third generation cephalosporin showed good activity against cell-associated Hib, chloramphenicol had a significantly greater effect (p less than 0.05). N-formimidoyl thienamycin demonstrated good activity only after the concentration was increased in vitro to 8 micrograms/ml. Although cellular penetration of antibiotics may be important in the eradication of cell-associated pathogens, the overall cellular activity would appear to be multifactorial.

Adult↗

PubMed1985

Timentin therapy for bone, joint, and deep soft tissue infections in children.

Timentin, a combination of clavulanic acid (0.1 g) and ticarcillin (3.0 g), has proved effective in vitro against bacterial pathogens that produce beta-lactamases. The usual etiologic bacteria of osteochondritis of the foot (Pseudomonas species) and osteomyelitis/septic arthritis (Staphylococcus aureus) are commonly resistant to penicillins. To date, we have used Timentin to treat 30 children with bone, joint, and deep soft tissue infections. Timentin was administered intravenously at an average dosage of 207 mg/kg per day for mild to moderate infection and 310 mg/kg per day for bone and joint infections with systemic signs (sepsis). The lower dose was used in 24 patients and the other six patients, who had signs of sepsis, received the higher dose. All patients received Timentin intravenously over 30 minutes every four to six hours for a minimum of five days (mean 6.6 +/- 2.6 days, range five to 14 days). The mean time to defervescence and/or reduction in clinical symptoms was 1.6 +/- 1.3 days (range zero to four days). Osteochondritis due to P. aeruginosa was diagnosed in six patients, and septic bursitis, osteomyelitis, or septic arthritis due to S. aureus (13 patients) or Staphylococcus species and group A streptococci (four patients) was diagnosed in 17 patients. All isolates were susceptible to Timentin in vitro by disk-diffusion analysis. All patients showed a response to therapy with Timentin, with or without surgical intervention. All patients had clinical and microbiologic cures; no adverse reactions or side effects were observed. There have been no clinical or microbiologic relapses to date. Timentin may prove to be useful in specific bone and joint infections in children.

Arthritis, Infectious↗

PubMed1985

Ticarcillin/clavulanic acid pharmacokinetics in children and young adults with cystic fibrosis.

The single-dose pharmacokinetics of ticarcillin and clavulanic acid (Timentin) were evaluated in children and young adults with cystic fibrosis after a 0.5-hour intravenous infusion of both a 3.1 and a 3.2 gm formulation (representing 3.0 gm ticarcillin combined with 100 mg and 200 mg clavulanic acid, respectively) in a crossover design. A 75 mg/kg dose of the ticarcillin component was used. Model-dependent and noncompartmental pharmacokinetic parameters were congruous. The disposition of ticarcillin and clavulanic acid was characterized adequately by a one-compartment open model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of ticarcillin from serum were 1.19 hours, 0.231 L/kg, and 0.150 L/hr/kg, respectively, for the 3.1 gm formulation and 1.21 hours, 0.211 L/kg, and 0.123 L/hr/kg, respectively, for the 3.2 gm formulation. For ticarcillin, 86% and 93% of the dose of the 3.1 and 3.2 gm formulations, respectively, were excreted unchanged in urine during the first 6 hours after infusion. Concomitant renal clearance values were 0.120 and 0.112 L/hr/kg for the 3.1 and 3.2 gm formulations, respectively. Approximately 50% of a clavulanic acid dose was excreted unchanged in urine during the 6-hour postinfusion period for both formulations. For ticarcillin, no significant differences were observed between the 3.1 and 3.2 gm formulations. For clavulanic acid, a significant difference between the two formulations was observed in comparison of the area under the serum concentration vs time curve and dose size (P less than 0.01). Linear inverse relationships were identified between demographic factors (e.g., age, weight, height, body surface area) and both the apparent volume of distribution and total body clearance of ticarcillin and clavulanic acid for both formulations. The ticarcillin/clavulanic acid combination in either the 3.1 or 3.2 gm formulation is suitable for microbiologic and clinical evaluation in patients with cystic fibrosis.

Adolescent↗

PubMed1985

A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children.

Fifty children with bacterial meningitis were prospectively randomized to receive cefotaxime (50 mg/kg/dose every 6 hours) or ampicillin and chloramphenicol in standard doses. Twenty-three patients received cefotaxime and 27 received standard therapy. Bacterial isolates included: Haemophilus influenzae (29), Streptococcus pneumoniae (eight), Neisseria meningitidis (eight), group B streptococci (three), and Salmonella enteritidis (two). Ten (34%) of the H. influenzae isolates were resistant to ampicillin, nine on the basis of beta-lactamase production. All strains were susceptible to cefotaxime. Clinical cure rates for the cefotaxime (100%) and standard therapy (96%) groups were similar; survival without detectable sequelae was similar, at 78% and 77%, respectively. The duration of therapy, 11.1 +/- 2.4 days (range 10 to 21 days) vs 11.9 +/- 3.9 days (range 10 to 21 days), and days to defervescence, 4.7 +/- 2.6 days (range 1 to 14 days) vs 5.6 +/- 2.9 days (range 2 to 17 days), were similar in the cefotaxime and standard therapy groups, respectively. No adverse drug reactions or side effects were noted in either group. Cefotaxime was found to be as safe and effective as standard therapy for the treatment of bacterial meningitis in children.

Adolescent↗

PubMed1985

Intracellular growth and phagocytosis of Blastomyces dermatitidis by monocyte-derived macrophages from previously infected and normal subjects.

Blastomyces dermatitidis evokes responses of human cellular immunity typical of other intracellular fungal pathogens. Differences in growth rates of intracellular Blastomyces yeast and the differences in amounts of yeast phagocytized by macrophages were determined for macrophages derived from peripheral blood monocytes from 11 persons with treated blastomycosis and 11 normal, healthy persons. Cellular immunity was examined by lymphocyte uptake of [3H]thymidine in response to a specific antigen of Blastomyces yeast. Yeast were more readily phagocytized by macrophages from the previously treated donors when compared with those from the normal donors; the yeast were confirmed to be intracellular by transmission electron microscopy. Likewise, a decrease in growth rates of yeast was demonstrable in cultures of macrophages from previously treated donors as compared with normal donors. This greater efficiency of phagocytosis and growth inhibition of B. dermatitidis reflects another mechanism of human cellular immunity to this fungal infection.

Blastomyces↗

PubMed1985

Phagocytosis of type III group B streptococci by neonatal monocytes: enhancement by fibronectin and gammaglobulin.

The potential of fibronectin to enhance phagocytosis of type III group B streptococci by cultured neonatal monocytes was evaluated. Fibronectin had significantly less effect on phagocytosis compared with type-specific antibody to group B streptococci; fibronectin increased the cell association of organisms to a level comparable to that of adult pooled serum and significantly more than that of serum-free controls. Microbicidal activity suggested that this cell association consisted of attachment but not ingestion, and electron micrographs showed the extracellular location of these organisms. In contrast, the effect of fibronectin on type III group B streptococci preopsonized with intravenous gammaglobulin revealed significantly greater numbers of cell-associated organisms than did addition of type-specific antibody to group B streptococci, pooled adult serum plus fibronectin, or serum-free controls. Phagocytosis was similar when assessed by microbicidal activity compared with the cultures with added type-specific antibody and significantly greater when compared with those with added pooled serum, and results were confirmed by electron microscopy. Therefore, fibronectin together with intravenous gammaglobulin enhanced ingestion of type III group B streptococci by neonatal monocytes.

Cells, Cultured↗

PubMed1985

Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis.

The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.

Cefotaxime↗

PubMed1985

Chlamydial pneumonitis induced in newborn guinea pigs.

One- to three-day-old guinea pigs were inoculated intranasally with the chlamydial agent of guinea pig inclusion conjunctivitis. Physical signs of infection included a marked increase in respiration rate on days 5 to 10 of infection and radiographic evidence of pneumonia on day 6. When animals were killed at various times after infection and lung tissue was examined by histopathology, evidence of pneumonia was found beginning on day 4 and lasting as long as day 12, with maximal pathological changes on days 6 to 8. The pneumonia was generally unilateral and consisted of an acute inflammatory component in the bronchioles with granulocytes in both the lumen and the wall of the bronchioles and an interstitial and intra-alveolar mononuclear infiltrate in the parenchyma of the lung. Chlamydial antigen was detected in the bronchial epithelial cells by immunoperoxidase staining, and the guinea pig inclusion conjunctivitis organism was isolated from lung tissue on days 6 to 9. No other significant bacteria were isolated from lung tissue or seen on gram stains of lung sections. Both immunoglobulin M and immunoglobulin G serum antibodies to the guinea pig inclusion conjunctivitis agent were detected as early as day 8 and reached peak levels on day 12. The infection was apparently self-limiting. This model presents the opportunity to investigate pathophysiological and immunological aspects of chlamydial respiratory infections in a neonatal animal.

Animals↗

PubMed1985

Factors related to the appearance of alveolar macrophages in the developing lung.

The numbers of alveolar macrophages (AM) are known to be low in utero and to increase rapidly after birth. This study analyzed factors related to the appearance of AM in the lungs of term and preterm monkeys (Macaca nemestrina). We found that the numbers of AM were greater at birth in term than in preterm monkeys (p less than 0.01) and that they increased with postnatal age in term animals (r = 0.86) and in preterm animals without hyaline membrane disease (HMD) (r = 0.79). In contrast, the numbers of AM did not increase with postnatal age in preterm animals with HMD (r = 0.17). By multivariant analysis, AM numbers correlated most strongly with a combination of 2 variables: lavage fluid phospholipid and absence of HMD (r = 0.996). Preparations of alveolar surface-active material from newborn monkeys and to a lesser degree from adult monkeys were found to stimulate migration and polarization of monkey AM and blood monocytes in vitro. The migration-stimulating factor(s) in alveolar surface-active material had an apparent molecular weight greater than 10,000 and appeared not to be a lipoxygenase product of arachidonic acid metabolism. These data indicate a correlation between factors regulating lung pressure-volume stability and AM numbers and are consistent with a potential role for components of alveolar surface-active material in regulating the perinatal increase in AM.

Aging↗

PubMed1985

Lymphocyte subpopulations of blood and alveolar lavage in blastomycosis.

Patients with blastomycosis were found to have differing lymphocyte populations depending on the extent of disease manifestations and whether or not therapy had been started. Patients with recovering pulmonary blastomycosis who had been receiving antifungal treatment for at least four weeks had lymphocyte subpopulations no different from control donors. Patients with treated extrapulmonary blastomycosis had similar T helper (TH) to T suppressor (TS) ratios compared to recovering pulmonary patients and control subjects; this ratio gives a false impression because extrapulmonary blastomycosis patients had a reduced absolute number of lymphocytes with either marker. In bronchoalveolar lavage fluid, pulmonary blastomycosis patients who were clinically improved while receiving antifungal therapy had fewer TH cells and a greater number of lymphocytes with the TS marker than did control subjects. Patients with pulmonary blastomycosis prior to therapy had a smaller TH/S ratio than the other groups in peripheral blood primarily due to a reduction in the circulating TH fraction in both absolute numbers of cells and in the percentage of total T lymphocytes. Pulmonary blastomycosis patients re-evaluated after at least four weeks of antifungal therapy had TH/S ratios that were similar to normal persons. This increase in TH lymphocytes corresponded to clinical improvement and in a temporal correlation to that described for the development of specific immunity in this illness.

Adult↗

PubMed1985

Tularemia in adults and children: a changing presentation.

Tularemia, a febrile zoonosis with six clinical types, recently has been shown to occur at an increased incidence in children compared with previous reports. Ulceroglandular and glandular tularemia are still the most common types, but pneumonic tularemia has increased in incidence. However, with these changes, an overall decline in mortality has been observed. Children exhibit fever, pharyngitis, hepatosplenomegaly, and constitutional symptoms more often than affected adults. The complication of late lymph node suppuration is found in half of the tularemia patients with lymphadenopathy. A high index of clinical suspicion and a good medical history and physical examination confirmed by specific serologic studies are the critical factors in the successful diagnosis of tularemia in children.

Adolescent↗

PubMed1985

Recurrent bacterial meningitis: coronal thin-section cranial computed tomography to delineate anatomic defects.

Three patients with histories of recurrent bacterial meningitis were previously examined with skull and sinus radiographs, routine cranial computed tomography, intrathecal radioisotope tracer studies, and immunologic evaluation. None of these studies were diagnostic. Pneumococcal vaccine and prophylactic penicillin therapy were ineffective in preventing recurrent episodes in two cases. Thin-section (2-mm) direct coronal computed cranial tomography demonstrated anatomic defects in all three patients. The use of metrizamide cisternography was not necessary to diagnose the defects. All patients had basiethmoidal encephaloceles which were repaired surgically. Direct coronal computed tomography offers a relatively easy noninvasive method for delineating anatomic abnormalities in patients with recurrent meningitis.

Child↗

PubMed1984

Renal clearance of imipenem in children.

Imipenem renal clearance was studied in six children (three males, three females; 2.9-11.2 years of age) following a single intravenous dose (21.7 +/- 5.1 mg/kg) of imipenem/cilastatin (1:1). In an approximately six-hour period following drug administration, 65.3 +/- 9.7% of the imipenem dose was excreted in the urine unchanged. The renal clearance (280.03 +/- 24.34 ml/min/1.73 m2) of imipenem was found to account for 69.2% of the corresponding plasma imipenem clearance (404.89 +/- 24.83 ml/min/1.73 m2). Contrary to existing adult data, the imipenem renal clearance in our subjects was 1.95-fold greater than the estimated creatinine clearance, suggesting significant tubular secretion of imipenem in children. Examination of urinary imipenem excretion rate versus plasma concentration relationships in three of the children revealed a potential renal tubular reabsorption component for imipenem in children. Comparison of renal imipenem clearance data in these children to similar data from adults suggests that quantitatively important developmental differences may exist for the renal handling of imipenem.

Adult↗

PubMed1984

Single-dose pharmacokinetics of imipenem in children.

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin) was evaluated in 13 pediatric patients (mean age 5.2 +/- 3.5 years). Imipenem was administered in combination with cilastatin as either a 10 mg/kg or 25 mg/kg dose (not to exceed 500 mg) over 15 minutes. Plasma disposition in children was best described by a two-compartment open model. The distribution phase was rapid (t1/2 lambda 1 = 0.18 hours) and was followed by a monoexponential elimination phase (t1/2 lambda 2 = 1.2 hours). The calculated value for the apparent volume of distribution (0.66 L/kg) was similar to that of total body water. The total plasma clearance was rapid (0.36 L/hr/kg). Direct proportionality was exhibited between administered dose and either resultant plasma concentration or area under the plasma concentration versus time curve. Comparison of imipenem plasma pharmacokinetic data derived from these children with data reported from adult subjects revealed disparities for both the apparent volume of distribution and plasma clearance. Based on preliminary pharmacokinetic simulations using parameters generated from our study, a 25.0 mg/kg dose of imipenem administered every 6 hours appears adequate for initiation of therapy in children.

Anti-Bacterial Agents↗

PubMed1984

Cefotaxime therapy of bacterial meningitis in children.

Thirty children with bacterial meningitis were randomized to receive either ampicillin and chloramphenicol in standard doses or cefotaxime (50 mg/kg/dose every 6 h) for 10 to 14 days. Eighteen patients received ampicillin and chloramphenicol and 12 patients received cefotaxime. Cerebrospinal fluid isolated included: Haemophilus influenzae (20), Streptococcus pneumoniae (4), Neisseria meningitidis (3), Group B streptococcus (2), and Salmonella enteritidis (1). Five of the H. influenzae isolates were ampicillin resistant but no isolates were resistant to cefotaxime. The minimum inhibitory concentrations of cefotaxime for 30 isolates ranged from 0.0004 to 0.06 mg/l, while the minimum bactericidal concentrations ranged from 0.007 to 0.12 mg/l. The cerebrospinal fluid bactericidal titres for the cefotaxime-treated group ranged from 1:64 to 1:1024. On the second day of therapy the mean cefotaxime serum concentrations were 56.9 +/- 28.7 mg/l at 1 h and 3.66 +/- 5.65 mg/l at 6 h after administration of the drug whilst mean desacetyl-cefotaxime serum concentrations were 12.31 +/- 7.56 mg/l at one hour and 7.96 +/- 8.26 mg/l at 6 h respectively. Cerebrospinal fluid concentrations of cefotaxime and desacetylcefotaxime measured one hour after drug administration were 3.72 +/- 5.57 mg/l and 4.35 +/- 7.12 mg/l, respectively. No adverse drug reactions were noted in either treatment group. Cefotaxime proved to be both as safe and as efficacious as standard therapy for the treatment of bacterial meningitis in children.

Adolescent↗

PubMed1984

Human serum bactericidal activity against Haemophilus influenzae type b.

We examined bactericidal and opsonizing activity of pooled adult 'immune' serum against Haemophilus influenzae type b with and without the addition of phagocytes. Four type b strains from cerebrospinal fluid (CSF) and three such strains from the nasopharynx (NP) of healthy children were examined. Duplicate reaction mixtures contained organisms in exponential (E) or stationary phase (S) of growth, serum, a complement source (human agammaglobulinaemic serum), and culture medium (bactericidal assay); separate assays contained the above components and polymorphonuclear leucocytes (opsonization system). A decrease in bacterial density of greater than or equal to 1 log10 unit was considered significant. All four S-CSF strains, three of four E-CSF strains and one of three S-NP strains were sensitive to the bactericidal activity of pooled serum. The other E-CSF strain, two S-NP strains and all three E-NP strains were resistant to the bactericidal activity of pooled serum. Two of three E-NP strains were opsonized by pooled serum; the other strains resistant to the bactericidal activity of pooled serum were also resistant to opsonization. Bactericidal and opsonizing activity of serum from an immunized adult was greater than or equal to that of pooled serum against each strain. Assuming normal adults are immune to invasive H. influenzae type b infection, an experimental test reflecting this immunity is the bactericidal activity against CSF isolates tested in stationary phase. We conclude that protection against invasive disease due to H. influenzae type b appears more complex than the presence of bactericidal and opsonizing activity in serum.

Adult↗

PubMed1984

Adherence of Haemophilus influenzae to monkey respiratory tissue in organ culture.

We studied the adherence of Haemophilus influenzae to monkey respiratory mucosa using nasal turbinates maintained in organ culture. Adherence of capsulated and rough strains was not inhibited by monosaccharides, sucrose, human albumin, foetal calf serum or polyribophosphate. However, antisera directed against surface components decreased bacterial adherence. Although variation in adherence capacity in individual strains was observed there was no correlation with capsulation, anatomical site of strain isolation or biotype. Bacterial surface structures other than capsular material appear important in effecting upper respiratory tract colonization.

Animals↗

PubMed1984

Interaction of primate alveolar macrophages and Legionella pneumophila.

We studied the interaction between Legionella pneumophila, which is principally a pulmonary pathogen, with primate alveolar macrophages (AM), which are the primary pulmonary cellular defense mechanism. For these studies we used L. pneumophila, type I, which were grown in albumin-yeast extract broth, were greater than 80% viable, and were comparable in virulence for guinea pigs to organisms from guinea pig spleen homogenates. For comparison, avirulent agar-passed L. pneumophila, type I, and a strain of Escherichia coli were also used. In the absence of detectable antibody, AM phagocytosed similar numbers of virulent and avirulent Legionella and killed the majority of ingested Legionella in 15-30 min, as determined by two different assays. The virulent and avirulent Legionella appeared to be equally susceptible to the cidal systems of the AM and both were killed more readily than were E. coli under both assay conditions. Phagocytosis of Legionella by AM was associated with a localized respiratory burst, as indicated by nitroblue tetrazolium reduction around ingested organisms. Killing of AM-associated Legionella was inhibited by the hydroxyl radical (OH.) scavenger mannitol (but not by an equiosmolar concentration of sodium sulfate), and by a combination of superoxide dismutase and catalase (but not by either enzyme alone). These findings suggest a contribution by OH., one generated by the metal-catalyzed interaction of superoxide and hydrogen peroxide (Haber-Weiss reaction) in the anti-Legionella activity of AM. The virulent Legionella that survived intracellularly increased in number from 4 X 10(4) at 1 h to 6 X 10(6) at 96 h after infection. In contrast, avirulent Legionella replicated more slowly, increasing in number from 4 X 10(4) to 1 X 10(5) over the same period. Replication of virulent Legionella destroyed the AM monolayers by 120 h, whereas monolayers containing avirulent organisms remained intact. Thus, virulence of Legionella appears not to correlate with its ability to survive early killing by AM, but rather with the ability of the small fraction of surviving organisms to replicate within these cells.

Animals↗