Bacterial meningitis: pathogenesis, pathophysiology, and progress.
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Humans↗
Biomedical subjects
W M Scheld
Publications and source records attributed to W M Scheld.
The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies.
Pretreatment sinus puncture was performed on 339 patients with acute community-acquired sinusitis (ACAS) between 1975 and 1990. Bacterial species recovered in titers of greater than or equal to 10(4) colony-forming units per milliliter (CFU/ml) from 383 sinus aspirates included Streptococcus pneumoniae, 92 (41%); Haemophilus influenzae, 79 (35%); anaerobes, 17 (7%); streptococcal species, 16 (7%); Moraxella catarrhalis, 8 (4%); Staphylococcus aureus, 7 (33%); and other, 8 (4%). Viruses (rhinovirus, parainfluenza virus, and influenza virus) and fungi (Aspergillus, zygomycoses, Phaeohyphomycis, Pseudallescheria, and Hyalohyphomycis) have also been reported to cause ACAS. Posttreatment sinus puncture was performed on 220 of the 339 patients in six studies to evaluate efficacy of selected antimicrobial agents in producing bacteriologic cure. Ampicillin, 500 mg four times daily; amoxicillin, 500 mg three times daily; trimethoprim-sulfamethoxazole, twice a day; cefaclor, 500 mg four times daily; bacampicillin, 800 mg twice a day; cyclacillin, 500 mg three times a day; cefuroxime axetil, 250 mg twice daily; amoxicillin-clavulanate, 500/125 three times daily; and loracarbef 400 mg twice daily, given in 10-day courses, produced bacteriologic cure in more than 90% of patients. Early studies were done before beta-lactamase-producing strains of H. influenzae were a frequent cause of ACAS in Charlottesville. Management of therapeutic failures is a difficult problem for which diagnostic and therapeutic sinus puncture and lavage, prolonged antimicrobial therapy, steroid therapy, and evaluation of allergy, immunodeficiency, and surgically correctable lesions of the osteomeatal complex are recommended.
Acute Disease↗
Evaluation of new anti-infective drugs for the treatment of acute bacterial meningitis. Infectious Diseases Society of America and the Food and Drug Administration.
Predisposing conditions for acute bacterial meningitis include prematurity, young age, management in an intensive care setting, low socioeconomic background, and crowded living conditions. Clinical findings vary with age and may be nonspecific (altered feeding behavior) or specific (Kernig and Brudzinski signs). Examination and culture of cerebrospinal fluid (CSF) are essential for diagnosis. Antigen identification in CSF, serum, or urine by latex agglutination or other techniques can be useful in the identification of the pathogen. Randomized, controlled studies with a single-, double-, or evaluator-blinded design are encouraged. Among neonates, infants, and children, CSF should be examined again 24-36 hours after initiation of therapy. Outcomes should be judged by both clinical and microbiological criteria. Assessment of microbiological outcome is paramount.
Acute Disease↗
Evaluation of new anti-infective drugs for the treatment of cryptococcal meningitis. Infectious Diseases Society of America and the Food and Drug Administration.
Cryptococcus neoformans may infect persons with intact or compromised host defenses. Clinical manifestations generally correlate directly with the degree of immunosuppression. Treatment is prescribed on the basis of the severity of disease and the degree of immunosuppression. Cryptococcal meningitis is the most common clinical form of cryptococcal infection and the most amenable to study in clinical trials. The current standard of care for cryptococcal meningitis is therapy with amphotericin B. Despite clinical improvement and microbiological suppression of the organism at the completion of therapy, the microbiological outcome will be identified as presumptive persistence if treatment is continued. Patients should be observed for 1 year after completion of therapy before a final assessment is made.
Anti-Infective Agents↗
Evaluation of new anti-infective drugs for the treatment of viral encephalitis. Infectious Diseases Society of America and the Food and Drug Administration.
Viral encephalitis may develop subsequent to viremia, via neuronal spread, or by arthropod vector. Diagnosis often requires invasive studies such as lumbar puncture and brain biopsy. This guideline addresses herpes simplex, rabies, and arbovirus infections of the central nervous system. Clinical trials should be designed according to the availability of approved therapeutic agents. Study designs with an active control (herpesvirus), a placebo control (arbovirus), or no control (rabies virus) are recommended. Outcome should be assessed 4-6 weeks, 4-6 months, and 11-13 months after the completion of therapy. For newborns with encephalitis, outcome should be assessed yearly through the age of 5 years. Assessment of clinical outcome is paramount.
Anti-Infective Agents↗
Evaluation of new anti-infective drugs for the treatment of toxoplasma encephalitis. Infectious Diseases Society of America and the Food and Drug Administration.
Toxoplasma gondii is a protozoan that exists in three forms, all of which are potentially infectious for humans. After acute infection, cysts persist in the central nervous system and extraneural tissue. Human hosts with compromised immunity, particularly those with the acquired immunodeficiency syndrome, are vulnerable to reactivation and dissemination. The most common clinical expression of toxoplasma infection is encephalitis. The diagnosis is established by clinical presentation, computed tomography and/or magnetic resonance imaging, and detection of antibodies to T. gondii in serum of patients positive for human immunodeficiency virus. Brain biopsy may be performed. Protocols may be developed for the evaluation of new regimens for the treatment of acute encephalitis, the suppression of disease after treatment, or the prevention of reactivation before the onset of clinical disease. Assessment of clinical outcome is paramount.
Anti-Infective Agents↗
Pathophysiology of blood-brain barrier alterations during experimental Haemophilus influenzae meningitis.
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Animals↗
Therapy of experimental meningitis due to Salmonella enteritidis.
In many areas of the developing world, Salmonella spp. account for greater than 50% of the gram-negative enteric organisms isolated from cerebrospinal fluid (CSF). The response of Salmonella meningitis to conventional therapy (chloramphenicol and/or ampicillin) is slow, complications arise frequently, and mortality rates of 60 to 80% are common. Two newer agents, ceftriaxone and imipenem, were compared with ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP-SMX) in the therapy of experimental Salmonella meningitis beginning 14 h after intracisternal inoculation and continued by constant intravenous infusion for 8 h. Drug concentrations in serum and CSF closely approximated those achieved in the sera and CSF of humans receiving standard parenteral regimens. Penetration into purulent CSF [(concentration of drug in CSF/concentration of drug in serum) x 100] ranged from 18 to 41%. The rate of bacterial killing in CSF was significantly (P less than 0.001) more rapid during therapy with ceftriaxone and imipenem than it was during therapy with chloramphenicol or TMP-SMX. Ceftriaxone and imipenem sterilized the CSF of six of seven animals at 8 h, whereas it sterilized the CSF of three of eight animals treated with ampicillin (P = 0.18), one of eight animals treated with chloramphenicol, and none of seven animals treated with TMP-SMX (P less than or equal to 0.01; ceftriaxone or imipenem versus chloramphenicol or TMP-SMX). New beta-lactams, including ceftriaxone and imipenem, appear to be effective therapy against Salmonella spp. in this animal model and deserve further evaluation in humans.
Animals↗
Theoretical and practical considerations of antibiotic therapy for bacterial meningitis.
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Anti-Bacterial Agents↗
Enterobacter endocarditis.
Endocarditis due to Enterobacter species is very rare. We recently cared for a patient who developed E. cloacae endocarditis following mitral valve replacement with a porcine heterograft, and was successfully treated with antibiotic therapy alone. A review of the literature disclosed an additional 17 well-described cases of enterobacter endocarditis. Two-thirds of the patients had underlying cardiac disease. The mitral valve was most frequently involved (10/16 cases) with 4 of the patients having concomitant aortic valve involvement. The overall mortality rate was 44.4%. Antibiotic therapy of enterobacter endocarditis should consist of the combination of a beta-lactam antibiotic and an aminoglycoside with careful monitoring of blood cultures to assure the adequacy of therapy. Resistance of enterobacter to previously susceptible antibiotics may occur during therapy due to induction of a chromosomally-mediated beta-lactamase, necessitating a change in antimicrobial therapy. Valvular surgery is indicated for patients failing medical management.
Endocarditis, Bacterial↗
Adjunctive therapy in bacterial meningitis--what make sense?
Bacterial meningitis continues to cause morbidity and mortality despite bactericidal antibiotic therapy. Experimental studies of pathophysiology reveal the bacteria and their surface components within cerebrospinal fluid (CSF) induce the release of inflammatory cytokines that promote CSF inflammation, injure the cerebral microvasculature and cause brain edema. Adjunctive corticosteroids reduce inflammation, ameliorate the pathophysiology, and improve neurologic outcome in children. Practical recommendations are made for children and selected adults regarding current and future directions of adjunctive therapy.
Animals↗
Loracarbef (LY 163892) vs amoxicillin/clavulanate in bacterial maxillary sinusitis.
Loracarbef (LY 163892), a beta-lactam antibiotic (carbacephem), was compared with amoxicillin/clavulanate potassium in a 10-day, single-blind, randomized parallel trial in the treatment of acute bacterial maxillary sinusitis. Based on posttherapy aspirate and culture, there was a 95.2% bacteriologic cure rate in patients receiving loracarbef (400 mg twice daily) and an 86.7% cure rate in patients receiving amoxicillin/clavulanate (500/125 mg three times daily) (p = 0.359). Loracarbef was comparable in efficacy to amoxicillin/clavulanate with a more desirable safety profile.
Adolescent↗
Evaluation of quinolones in experimental animal models of infections.
Many discriminative experimental animal models of infection have been utilized in the evaluation of newer fluoroquinolones. In vivo efficacy of many of the newer agents has been shown in experimental models of meningitis, endocarditis, pneumonia, urinary tract infections, pyelonephritis, osteomyelitis, abscesses of various types, septic arthritis, gastroenteritis, salmonellosis, listeriosis, tuberculosis, syphilis, sinusitis, prostatitis and burn wound sepsis, among others. This review focuses on recent developments in a few selected areas. Although the limitations of animal model studies are well described, these results provide a rationale for the appropriate clinical usage of the newer fluoroquinolones in humans.
4-Quinolones↗
Blood-brain barrier alterations in bacterial meningitis: development of an in vitro model and observations on the effects of lipopolysaccharide.
To further examine the effects of purified Haemophilus influenzae type b lipopolysaccharide (LPS) on blood-brain barrier permeability, we have developed an in vitro model of the BBB. Microvascular endothelial cells were isolated from rat cerebral cortices by enzymatic digestion, dextran centrifugation, and separation on percoll gradients. The cells were determined to be endothelial in origin by positive fluorescent staining for Factor VIII-related antigen and the ability to take up acetylated low density lipoproteins, and their cerebral origin by the formation of junctional complexes in vitro. Cells were seeded onto semipermeable polycarbonate filters and permeability assessed by measuring traversal of radioactive albumin across the monolayer. Treatment of the cells with LPS at concentrations of 1.0 microgram/ml and 0.1 microgram/ml for 4 h led to statistically significant increases in albumin permeability of 4.6% (P = 0.001) and 5.6% (P less than 0.001), respectively, without evidence of cell death as assessed by release of lactate dehydrogenase into the media. These results indicate that LPS significantly increases albumin permeability across a monolayer of cerebral microvascular endothelial cells in the absence of host inflammatory cells. Future studies on the effects of LPS on intracellular regulation will determine the mechanisms responsible for these alterations.
Albumins↗
Ceftriaxone in treatment of serious infections. Meningitis.
In many pediatric infectious disease programs, ceftriaxone or cefotaxime is now the preferred drug for bacterial meningitis caused by H. influenzae, meningococci, and pneumococci. Ceftriaxone reaches a high bactericidal titer in the cerebrospinal fluid and persists at the site of infection longer than any other beta-lactam antibiotic. Short-course, once-daily therapy with ceftriaxone requires more study; currently, many pediatricians administer the agent twice daily for suspected or proven meningitis. Given the association of sequelae with prolongation of positive CSF cultures, ceftriaxone's rapid bactericidal activity is an advantage, which may require an adjunctive agent to block the inflammatory response due to antibiotic-induced release of endotoxin and other cell wall components. As empiric therapy, ceftriaxone is effective in infants and children three months to 18 years old. It is not yet recommended in neonates, because of concerns about bilirubin displacement. Thus, infants up to three months of age should receive ampicillin plus cefotaxime. In adults, ceftriaxone is effective therapy for presumed bacterial meningitis but must be combined with ampicillin initially, since L. monocytogenes meningitis cannot be excluded in most cases until CSF culture results are available.
Adolescent↗
Ofloxacin.
Ofloxacin is a newly licensed fluoroquinolone with an antimicrobial spectrum similar to ciprofloxacin. Compared with ciprofloxacin, the MIC90 values for ofloxacin are lower for S aureus, C trachomatis, and Ureaplasma urealyticum, but somewhat higher against gram-negative bacteria (especially P aeruginosa). Ofloxacin has favorable pharmacokinetics with almost 100% bioavailability; peak serum concentrations obtained one to two hours following oral dosing are higher than those achieved with ciprofloxacin. The oral bioavailability is decreased by the coadministration of antacids, but ofloxacin does not alter serum theophylline concentrations. Ofloxacin has demonstrated bacteriologic and clinical efficacy in the treatment of urinary tract infections, respiratory tract infections, prostatitis, and skin and soft tissue infections caused by susceptible organisms, although there are little data to recommend ofloxacin over ciprofloxacin for these indications. Ofloxacin should not be used alone to treat anaerobic or mixed aerobic/anaerobic infections, and a penicillin or cephalosporin is preferred for known or suspected streptococcal or pneumococcal infection. Ofloxacin is the only quinolone currently approved for the treatment of uncomplicated gonorrhea. It also is effective therapy for nongonococcal urethritis, although the tetracyclines are much less expensive. Ofloxacin has a good safety profile, but, as with other fluoroquinolones, it should not be used in children or in pregnant or nursing women. Further comparative trials may broaden the range of infections that can be treated with ofloxacin.
Clinical Trials as Topic↗
Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor.
The diversity of infectious agents capable of inducing meningitis and blood-brain barrier (BBB) injury suggests the potential for a common host mediator. The inflammatory polypeptides, IL-1 and TNF, were tested in an experimental rat model as candidate mediators for induction of meningitis and BBB injury. Intracisternal challenge of rIL-1 beta into rats induced neutrophil emigration into cerebrospinal fluid (CSF) and significantly increased BBB permeability to systemically administered 125I-BSA as early as 3 h later (P less than 0.05). This injury was reversible, dose dependent and significantly inhibited by prior induction of systemic neutropenia (via intraperitoneal cyclophosphamide) or preincubation of the rIL-1 beta inoculum (50 U) with an IgG monoclonal antibody to rIL-1 beta. Similar kinetics and reversibility of CSF inflammation and BSA permeability were observed using equivalent dose inocula of rIL-1 alpha. rTNF-alpha was less effective as an independent inducer of meningitis or BBB injury over an inoculum range of 10(1) U (0.0016 micrograms/kg)-10(6) U (160 micrograms/kg) when injected intracisternally, but inoculum combinations of low concentrations of rTNF alpha (10(3) U) and rIL-1 beta (0.0005-5.0 U) were synergistic in inducing both meningitis and BBB permeability to systemic 125I-BSA. These data suggest that in situ generation of interleukin-1 within CSF (with or without TNF) is capable of mediating both meningeal inflammation and BBB injury seen in various central nervous system infections.
Animals↗