Biomedical subjects
Publications and source records attributed to W M Scheld.
Fulminant meningitis requires aggressive management in an intensive care unit setting. The pathophysiology of the various factors that damage the central nervous system in this disease have been reviewed, as well as the management of the many complications of this serious, often devastating, infection. The etiologic agents according to age group have been discussed, and recommendations for empiric therapy have been made.
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The influence of leukocytes and Haemophilus influenzae type b (Hib) capsule on blood brain barrier permeability (BBBP) to circulating 125I-albumin in normal and leukopenic rats was assessed after intracisternal inoculation of encapsulated (Rd-/b+/02) or unencapsulated (Rd-/b-/02) isogenic strains of Hib. Both normal and leukopenic animals had increased BBBP 18 h after inoculation, with normal rats demonstrating significantly increased BBBP after challenge with the encapsulated strain. Despite cerebrospinal fluid (CSF) pleocytosis in normal rats, CSF bacterial concentrations were not lower. Normal rats cleared unencapsulated Rd-/b-/02 more effectively than leukopenic rats, with BBBP correlating with CSF bacterial density and not leukocyte concentrations. Challenge with heat-killed Rd-/b+/02 resulted in increased BBBP in both normal and leukopenic rats, with greater BBBP at higher bacterial concentrations. The data suggest: (a) significant increases in BBBP occur in the near absence of CSF leukocytes; (b) CSF leukocytes can augment changes in BBBP; (c) type b capsule inhibits host clearance mechanisms within the CSF; and (d) BBBP appears to correlate with bacterial concentrations within the CSF.
The factors responsible for blood-brain barrier (BBB) injury during bacterial meningitis are incompletely defined. We evaluated the role of Haemophilus influenzae type b (Hib) lipopolysaccharide (LPS) in the alteration of blood-brain barrier permeability (BBBP) in an adult, normal and leukopenic, rat model of meningitis. Intracisternal inoculation of Hib LPS resulted in (a) dose-dependent increases in BBBP from 2 pg to 20 ng, with significant attenuation in the peak response after challenge with 500 ng and 1 microgram; (b) time-dependent increases in BBBP, with a delayed onset of at least 2 h, maximum alteration at 4 h, and complete reversal at 18 h; (c) greater BBBP than after challenge with the live parent strain; (d) and a close correlation (r = 0.86) between CSF pleocytosis and BBBP at 4 h. The LPS effect was significantly inhibited by preincubation with Polymyxin B and neutrophil acyloxyacyl hydrolase, however two different oligosaccharide-specific monoclonal antibodies did not inhibit activity. No change in BBBP after inoculation with Hib LPS occurred in leukopenic rats. Hib LPS, in the setting of an intact leukocyte response, exerts profound effects on BBBP.
Fulminant meningitis requires aggressive management in an intensive care unit setting. The pathophysiology of the various factors that damage the central nervous system in this disease have been reviewed, as well as the management of the many complications of this serious, often devastating, infection. The etiologic agents according to age group have been discussed, and recommendations for empiric therapy have been made.
Gram-negative osteomyelitis frequently responds poorly to conventional therapy. Ciprofloxacin displays excellent in vitro activity against gram-negative bacilli and offers the potential for outpatient therapy. In this ongoing study, ciprofloxacin therapy is being evaluated for the treatment of gram-negative osteomyelitis. Twenty-three patients (16 men and seven women) have been treated under the protocol (750 mg orally twice daily for 1.5 to six months), and 14 patients have completed therapy. All patients had either growth on bone cultures from an open or percutaneous biopsy, or an arthrocentesis to confirm the diagnosis. Involved sites included ankle or tibia (seven patients), vertebra (four patients), hip (five patients), metatarsal (four patients), phalanx (two patients), and metacarpal (one patient); 16 patients had chronic disease, and seven patients had acute disease. Patients had a total of 28 gram-negative bacilli, 12 gram-positive cocci, and one anaerobic gram-negative rod, for an average of 1.8 pathogens per patient. Eighteen of the 28 gram-negative bacilli were Pseudomonas species. The geometric mean minimal inhibitory concentration for all the gram-negative bacilli was 0.15 microgram/ml. The geometric mean minimal inhibitory concentration for the gram-positive isolates was 0.41 microgram/ml. All patients who completed therapy experienced a cure, with a mean follow-up of 6.1 months. Infections in all patients, except for two who are still taking ciprofloxacin, are resolving, both clinically and radiologically. One patient who was not eligible for the protocol experienced a superinfection with methicillin-resistant Staphylococcus aureus. Side effects have included urticaria, lethargy, nausea, and transient elevations of liver and renal function test results. Overall, ciprofloxacin therapy was well tolerated. This study suggests that ciprofloxacin holds promise for the outpatient treatment of gram-negative osteomyelitis.
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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.
Streptococci (viridans group, Streptococcus bovis, enterococci still account for the majority of cases of infective endocarditis in the non-addict population. Experimental animal models of endocarditis have been used (primarily in rabbits) to delineate the major therapeutic principles of this disease; viz. bactericidal antimicrobial agents must be given parenterally in high dosages for prolonged period of time. Overall, there is a good correlation between results obtained by: (1) in-vitro susceptibility testing (especially killing kinetics in broth); (2) therapeutic comparisons in experimental animal models and (3) clinical trials of different antimicrobial regimens in humans with streptococcal endocarditis. This review contrasts the published results obtained in vivo with experimental animal models to those obtained with various therapeutic approaches to streptococcal endocarditis in humans. The contribution of animal models to current therapeutic recommendations in man is underscored.
The nonrecirculating isolated perfused rat liver was used to study biliary antibiotic excretion by the liver in a steady-state, controlled environment in which bile flow, bile salt output, and antibiotic delivery were maintained under constant conditions. The effects of piperacillin, ampicillin, and gentamicin on bile flow and bile salt output were analyzed; none altered bile salt output, and only high concentrations of piperacillin (100 micrograms/mL) increased bile flow. The ratio of antibiotic concentration in bile and perfusate depended on the type of antibiotic and perfusate concentration. Piperacillin infusions at perfusate concentrations of 50 or 100 micrograms/mL (in the presence of 60 microM taurocholate) yielded bile to perfusate ratios of 112 +/- 10 versus 49 +/- 3, respectively. Using similar perfusate, the concentration ratios for ampicillin (20 micrograms/mL) and gentamicin (10 micrograms/mL) were only 3.4 +/- 0.5 and 0.5 +/- 0.1, respectively. By altering the perfusate to contain either 60 microM or 240 microM taurocholate, we found variance in bile salt output from 27 +/- 1 to 115 +/- 2 mumol/h, yet this alteration had little effect on the output of ampicillin (perfusate concentration of 20 micrograms/mL), 73 +/- 7 versus 74 +/- 12 micrograms/h, or piperacillin (perfusate concentration 100 micrograms/mL), 10 +/- 1 versus 11 +/- 2 mg/h. Thus, it appears ampicillin and piperacillin are excreted into bile at high concentrations by bile salt-independent pathways. Partial biliary obstruction (6 cm H2O) results in significant decreases in bile volume. Infusion of 50 micrograms/mL of piperacillin resulted in increased biliary flow that approached nonobstructed values. Obstruction resulted in significant decreases in bile piperacillin concentration. Whether the choleretic effect of high concentrations of piperacillin has any clinical significance in nonobstructed or obstructed conditions remains to be established.
Although meningitis is the most common form of central nervous system (CNS) blastomycosis, solitary mass lesions are not an infrequent presentation. Four of our patients presented with focal neurological deficits as a result of single intracranial mass lesions. Only 1 had clearcut evidence of extraneural blastomycosis. One was a coal miner, another worked with soil samples, and one was an engineer for a wood pulp company. All were previously healthy and 2 had diabetes. Complement fixation and immunodiffusion tests were negative in all 4 patients, and white blood cell counts and erythrocyte sedimentation rates were normal. Wet mount of tissue obtained intraoperatively by aspiration demonstrated the organism in 2 cases, culture from a lung lesion made the diagnosis in 1 case, and stain and culture of ventricular fluid revealed the organisms in the fourth case. Multiple cultures of cerebrospinal fluid from lumbar puncture were negative. All 4 patients survived. Amphotericin B alone was curative in 2 cases; surgical removal alone was curative in 1. All 4 computerized tomographic scans revealed isodense or slightly hyperdense single mass lesions with homogeneous contrast enhancement and surrounding edema, and tumor was the preoperative diagnosis in 2 cases. Such scans should suggest CNS blastomycoma in patients from the endemic area, despite the lack of other systemic manifestations. Diagnosis nevertheless rests on the characteristic histopathologic appearance in tissues and/or culture. Solitary intracranial blastomycomas may be less rare than previously thought; at our institution, we observed 4 cases in 4 years.
Bacterial meningitis continues to account for worldwide morbidity and mortality despite the advent of effective bactericidal antibiotic therapy. Recent advances over the past 10 years in the development of experimental animal models as well as basic investigation into critical bacterial surface virulence factors have begun to clarify a conceptual framework for understanding the mechanism of meningitis development in humans. Basic observations regarding competing host defenses and bacterial virulence factors have supported a pathogenetic sequence of mucosal colonization with a meningeal pathogen; systemic host invasion with intravascular replication; blood brain barrier penetration and unimpeded CSF proliferation amid the impaired host defenses in the CSF milieu; and pathophysiologic sequelae including vasogenic, cytotoxic, and interstitial brain edema (and other processes) accounting for irreversible neuronal injury and death. Only through continued basic investigation into each of these pathogenetic steps will significant reductions in morbidity and mortality ensue.
Weber-Christian disease is an uncommon disorder of unclear etiology whose unifying feature is fatty tissue inflammation. Its association with alpha 1-antitrypsin deficiency produces severe clinical manifestations. Although many agents have been used to treat Weber-Christian disease, current therapy is based on the poorly documented use of corticosteroids. We have reported the case of a young man with life-threatening Weber-Christian disease associated with alpha 1-antitrypsin deficiency unresponsive to corticosteroids who responded to cyclophosphamide.
Cyclacillin, a new aminosalicylic semisynthetic penicillin, was compared with amoxicillin for the therapy of acute bacterial maxillary sinusitis in 80 patients (ages, 12 to 70 years) in a prospective, double-blind, randomized clinical trial. Direct sinus aspirations for quantitative culture were done for all patients before and after 10 days of therapy. Both drugs were administered at a dosage of 500 mg orally three times daily. Among culture-positive patients, clinical cure was achieved in 23 of 26 patients and 25 of 27 patients treated with cyclacillin and amoxicillin, respectively, for an overall cure rate of 91%. Bacteriologic failure occurred in 9% (4 of 44 patients); 3 of the 4 failures were in the cyclacillin group. There was no correlation between clinical or bacteriologic cure and the results of sinus transillumination (clear, dark) at follow-up. Initial direct sinus aspirates were positive in 57 of 80 cases (70%): 25 (44%) of these were the result of Streptococcus pneumoniae and 23 (40%) were the result of Haemophilus influenzae. All of these isolates were susceptible (MIC, less than or equal to 0.5 microgram/ml) to both study drugs; no ampicillin-resistant H. influenzae was recovered. On day 10 of therapy, mean concentrations of both drugs in serum were 2.5 to 2.7 micrograms/ml, but no antibiotic was detectable in 20 of 21 simultaneous sinus aspirates. Adverse effects (rash, diarrhea) were infrequent and similar in both groups. Cyclacillin appears equivalent to amoxicillin in the therapy of acute maxillary sinusitis.
The cerebral capillary endothelium is unique and functions as an effective blood-brain barrier (BBB) owing to its intercellular tight junctions and rare pinocytotic vesicles. To assess how bacterial meningitis alters the BBB, rats were inoculated intracisternally with three encapsulated meningeal pathogens (Escherichia coli K1+, Streptococcus pneumoniae type III, Haemophilus influenzae type b) and an unencapsulated mutant strain (H. influenzae Rd). After defined infection durations, the morphologic alterations of the cerebral capillary endothelium were quantitatively assessed by transmission electron microscopy. Results revealed a significant increase in pinocytotic vesicle formation (P less than 0.001) early after meningitis induction (4 h) that was sustained with longer infection durations (10 h, 18 h) for all encapsulated strains tested. In addition, there was a progressive increase in completely separated intercellular junctions with increasing infection duration, (P less than 0.05). 4 h after induction of meningitis with H. influenzae Rd, cerebrospinal fluid (CSF) bacterial concentrations, cerebral capillary morphologic changes, and functional BBB permeability to circulating 125I-albumin were similar to those observed with H. influenzae type b. However, prolonging the H. influenzae Rd infection to 18 h allowed for CSF clearance of the organism, thereby precluding the significant increase in separated junctions or progression of functional BBB permeability seen with the encapsulated H. influenzae type b. These data suggest a uniform morphologic explanation for altered BBB permeability in meningitis with a reproducible temporal sequence. Encapsulation does not appear essential for BBB injury, but may facilitate its progression by allowing the organism to evade host clearance.
An animal model was developed for studying the pharmacokinetics of antibiotics administered intraventricularly in hydrocephalus. Obstructive hydrocephalus was consistently produced in craniectomized adult rats by injecting kaolin into the cisterna magna. After induction of hydrocephalus, vancomycin was injected into the right lateral ventricle of each rat. Bilateral ventricular cerebrospinal fluid (CSF) and brain parenchymal samples were obtained at 0.5, 1, 2, 4, 8, and 12 hours and the concentration of vancomycin in these samples was determined. Brain tissue was also analyzed histologically. The results show: (a) vancomycin is rapidly distributed within the CSF, including the contralateral ventricle, within 30 minutes; (b) vancomycin concentrations were nearly identical in both ventricles at all time points; (c) mean peak CSF vancomycin concentrations occurred at 2 hours and were 23.8 and 21.3 micrograms/ml for the left and right lateral ventricles, respectively; (d) elimination from CSF was slow (T1/2 beta = 2.22 hours, T1/2 gamma = 19.65 hours); (e) no vancomycin was detected (less than or equal to 2 micrograms/g) in the samples of periventricular white matter; (f) histological changes observed were consistent with untreated obstructive hydrocephalus and did not seem to be related to vancomycin treatment. The clinical significance of these results and the usefulness of the experimental model are discussed.