Comparison of factor VIII-related antigen and erythrocyte sedimentation rate in outpatient management of vasculitis.

Electroimmunodiffusion (Laurell rocket) determinations of factor VIII-related antigen in plasma were ordered to determine the cost/benefit ratio for factor VIII-related antigen as a putative test for endothelial damage in suspected vasculitis. Twenty-seven consecutive patients referred for vasculitis or suspected vasculitis were identified and followed up for an average of 9.1 +/- months (range: one to thirty-three months) in a prospective, unblinded study performed in a clinic, associated with a 1054-bed inner-city university hospital. There was no difference in Westergren erythrocyte sedimentation rate (WESR) in patients with final diagnosis of systemic vasculitis (SV) (38 +/- 12 mm/hour) compared to those without vasculitis (NV) (27 +/- 7) as the final diagnosis. The mean plasma concentration of factor VIII-related antigen was significantly elevated in SV (344 +/- 100%) when compared with NV (147 +/- 39%) (P < 0.016). The factor VIII-related antigen test in this study was 2.56 times more likely (crude odds ratio) than the WESR to contribute to a change in diagnosis or therapy (P = 0.016). Positive and negative predictive values (PPV and NPV) for factor VIII-related antigen (abnormal at greater than 220% of the normal value) were both 70%. PPV and NPV for WESR were 56% and 86%, respectively. The factor VIII-related test was less cost-effective than the WESR in the follow-up period unless it was important to define complete remission or differentiate vasculitis flare from infection. The authors conclude that factor VIII-related antigen is a useful test in the initial diagnosis of vasculitis.

Synovial fluid levels of complement SC5b-9 and fragment Bb are elevated in patients with rheumatoid arthritis.

To determine whether complement turnover in synovial fluids of patients with rheumatoid arthritis (RA) reflects activation by the classical or alternative pathway, we used novel immunoassays to measure products of complement activation (the membrane attack complex SC5b-9 and the cleavage fragments Bb and C4d). Mean synovial fluid levels of SC5b-9 were more than 8 times higher in RA than in crystal-induced arthritis (gout and pseudogout) and over 16 times higher than in degenerative joint disease (DJD). Similarly, Bb levels were more than 3 times higher in RA synovial fluids than in crystal-induced arthritis and over 7 times higher than in DJD. Levels of C4d did not differ among the groups. SC5b-9 levels correlated with synovial fluid C3 anaphylatoxin (C3a), Bb, and C4d levels (r = 0.81, 0.62, and 0.51, respectively). In patients with RA, synovial fluid SC5b-9 levels correlated with C3a and Bb (r = 0.6 and 0.56, respectively) but not with C4d. Therefore, novel assays for complement activation indicate that both classical and alternative pathways are involved in complement turnover and that the alternative pathway contributes more to complement activation in RA than in DJD or crystal-induced arthritis.

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus.

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Comparative evaluation of aztreonam in therapy for experimental bacterial meningitis and cerebritis.

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with several frequently used antibiotics in therapy for three types of experimental meningitis in rabbits and for experimental Escherichia coli cerebritis in rats. Aztreonam was highly active against common gram-negative meningeal pathogens in vitro (all minimal bactericidal concentrations less than or equal to 0.125 microgram/ml), including ampicillin-sensitive and ampicillin-resistant strains of Haemophilus influenzae, E. coli, and meningococci. In both rabbits and rats, serum concentrations of all antibiotics evaluated closely approximated concentrations found in humans receiving standard parenteral regimens. The percent penetration of aztreonam into purulent rabbit cerebrospinal fluid was 23%. In experimental meningitis, aztreonam was more rapidly bactericidal than ampicillin in meningitis due to ampicillin-sensitive H. influenzae, than ampicillin or chloramphenicol in meningitis due to ampicillin-resistant H. influenzae, and than gentamicin in meningitis due to E. coli. Aztreonam also reduced concentrations of E. coli in rat brain as rapidly as did gentamicin during therapy for experimental cerebritis, the early stage of brain abscess formation.

Evaluation of aztreonam in experimental bacterial meningitis and cerebritis.

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with ampicillin, ampicillin plus chloramphenicol, and gentamicin in rabbits with experimental meningitis induced by, respectively, ampicillin-susceptible Haemophilus influenzae, ampicillin-resistant H. influenzae, and Escherichia coli. Aztreonam was also compared with gentamicin in experimentally induced E. coli cerebritis in rats. Doses of the various agents were delivered that produced near-peak concentrations in serum comparable to those attained in humans on standard parenteral regimens. The percent penetration [( concentration in cerebrospinal fluid/concentration in serum] X 100) of aztreonam into purulent rabbit cerebrospinal fluid was 23% (versus 12, 27, and 21%, respectively, for ampicillin, chloramphenicol, and gentamicin). In experimental meningitis in vivo, aztreonam was more rapidly bactericidal than was ampicillin in ampicillin-susceptible H. influenzae meningitis, ampicillin or chloramphenicol in ampicillin-resistant H. influenzae meningitis, or gentamicin in E. coli meningitis. In the therapy of experimental cerebritis, the early stage of brain abscess formation, aztreonam reduced the numbers of E. coli in rat brain as rapidly as did gentamicin. Aztreonam deserves further evaluation in acute gram-negative bacterial infections of the central nervous system in both experimental animals and in humans.

Influence of preformed antibody on the pathogenesis of experimental Candida albicans endocarditis.

The influence of preformed antibody on the induction of experimental Candida albicans endocarditis was investigated by both in vitro and in vivo techniques. Preincubation of C. albicans with immune serum (raised in rabbits by intravenous injection of Formalin-killed yeast cells) decreased adhesion to the constituents of nonbacterial thrombotic endocarditis, e.g., fibrin plus platelets, in vitro. Two different methods, with radiolabeled or viable yeast cells, were confirmatory and demonstrated decreased adhesion of immune serum-treated C. albicans cells to 0 to 7.8% of control values (P less than 0.001). These results correlated with protection from the development of C. albicans endocarditis in the immunized rabbits. The mean (+/- standard deviation) infectious dose for 50% of the animals was 10(5.29) +/- 10(0.07) in 48 control animals versus 10(7.11) +/- 10(0.22) in 37 immunized rabbits (P less than 0.001). These studies suggest that humoral antibody may protect against C. albicans endocarditis, perhaps through inhibition of adhesion, a crucial early step in the pathogenesis of endocarditis.

Effect of methylprednisolone on entry of ampicillin and gentamicin into cerebrospinal fluid in experimental pneumococcal and Escherichia coli meningitis.

The influence of methylprednisolone on the passage of ampicillin and gentamicin into and activity within cerebrospinal fluid was examined in two models of experimental meningitis. Steroid pretreatment reduced the concentrations of these drugs in purulent cerebrospinal fluid of rabbits with experimental pneumococcal and Escherichia coli meningitis (P less than 0.05). However, the resultant mean concentrations of these antibiotics in cerebrospinal fluid still exceeded the minimal bactericidal concentrations of the infecting organisms. The rate of bactericidal effect in vivo was unaffected by steroid therapy in each model. Methylprednisolone did not have deleterious effects on the course of treated experimental meningitis under these short-term (24-h) experiments.

Comparison of cefoperazone with penicillin, ampicillin, gentamicin, and chloramphenicol in the therapy of experimental meningitis.

Cefoperazone was compared with penicillin against Streptococcus pneumoniae, gentamicin against Escherichia coli, and ampicillin and chloramphenicol against Haemophilus influenzae in the therapy of experimental meningitis in rabbits. Meningitis was produced by intracisternal inoculation into cerebrospinal fluid, and all antibiotics were administered intravenously over 8 h in dosages that would achieve serum levels comparable to those found in humans. The mean percent penetration into purulent cerebrospinal fluid, expressed as (cerebrospinal fluid concentration/serum concentration) x 100%, was 2.6% for penicillin, 22.0% for gentamicin, 12.1% for ampicillin, 23.8% for chloramphenicol, and 6.4% for cefoperazone. The mean cerebrospinal fluid antibiotic concentrations exceeded the minimum bactericidal concentration for the test strain in each experimental model, except for ampicillin in experimental meningitis due to the beta-lactamase-producing H. influenzae. Cefoperazone produced a significantly faster bactericidal effect after 4 h of treatment when compared with penicillin (P = 0.037) and ampicillin (P = 0.01) in meningitis caused by S. pneumoniae and H. influenzae (ampicillin susceptible), respectively. In meningitis caused by E. coli, cefoperazone was significantly (P = 0.006) more rapidly bactericidal after 8 h of treatment when compared to gentamicin. In addition, cefoperazone was significantly more rapidly bactericidal than either ampicillin or chloramphenicol in experimental meningitis due to beta-lactamase-producing H. influenzae. Cefoperazone deserves further evaluation in the therapy of bacterial meningitis in humans.