We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.
Purified disaccharide peptide monomers obtained from Neisseria gonorrhoeae by enzymatic digestion of gonococcal peptidoglycan damaged the mucosa of human fallopian tubes in organ culture. Two peptidoglycan fragments were tested: a nonreducing, anhydromuramyl-containing monomer (the principal fragment shed by growing gonococci) and the analogous reducing, muramidase-derived monomer. The damage produced by either of these peptidoglycan monomers resulted in sloughing of ciliated cells from the mucosa and resembled the damage observed in active gonococcal infection and that produced by filter-sterilized toxic supernatant fluids from gonococcal-infected organ cultures. The minimal toxic dose of peptidoglycan monomers was 0.75 micrograms/ml. Neither lipopolysaccharide, sodium dodecyl sulfate, nor Triton X-100, possible contaminants from the monomer-purification procedures, was present in sufficient quantity to account for the damage. Both of the gonococcal peptidoglycan monomers may be present in vivo and thus may play a role in the pathogenesis of gonococcal infection.
The relative virulence of isogenic clones of colony type 1 (T1) (piliated) and colony type 4 (T4) (nonpiliated) gonococci was assessed in organ cultures of human fallopian tubes. The rate of damage to fallopian tube mucosa was determined by measurements of ciliary activity and was correlated with the sequential pathologic events observed by light and electron microscopy. During the first 24 hr of the infection, T1 gonococci attached to and damaged the mucosa more rapidly than did T4 gonococci. This damage was manifested primarily by sloughing of ciliated cells. The observation that gonococci attached almost exclusively to nonciliated cells but damaged primarily ciliated cells suggested that this damage was mediated by one or more toxic factors. After attaching, gonococci entered the nonciliated mucosal cells, increased in numbers inside them, and then invaded the subepithelial tissues. Thus, attachment of gonococci to the fallopian tube mucosa may facilitate effective delivery of one or more gonococcal toxins to target cells in the mucosa and may initiate a process by which gonococci traverse the mucosal barrier.
The mechanisms by which Neisseria meningitidis establishes a carrier state or invades mucosal surfaces of the host to cause septicemia and meningitis are unknown. An experimental model of human columnar nasopharyngeal tissue in organ culture was developed, and the interaction of encapsulated, piliated N meningitidis with this mucosal surface was studied. Electron microscopic studies showed that meningococci attached selectively to nonciliated columnar cells of the nasopharynx. After attachment, the microvilli of these nonciliated cells elongated and surrounded the organisms. Six to twelve hours after infection, endocytic vacuoles containing meningococci were seen in the apical portion of some nonciliated columnar cells. Later, diplococci were seen in the subepithelial tissues adjacent to lymphoid tissue; this observation suggested that meningococci had penetrated the epithelial layer. The interaction of meningococci with the nasopharyngeal epithelium may be an important means whereby these bacteria establish a carrier state or invade the host.
The distribution of aminoglycosides in the cerebrospinal fluid (CSF) space was examined after intralumbar, intraventricular, and systemic administration during seven episodes of gram-negative bacillary meningitis. Six episodes were associated with culture proved ventriculitis. Parenteral therapy with gentamicin or tobramycin produced low concentrations of aminoglycoside (less than 1.0 mug/ml) in the lumbar, ventricular, and cisternal CSF. Administration of 5 to 10 mg of aminoglycoside into the lumbar intrathecal space resulted in 27-81 mug/ml in the lumbar CSF, but 0-2.1 mug/ml in the ventricular CSF. In contrast, aminoglycoside administered into the cerebral ventricles produced concentrations in the lumbar CSF of 11.5-27.5 mug/ml and ventricular CSF of 12.8-40 mug/ml. All six episodes treated via the ventricular route resulted in a bacteriologic cure. Intraventricular administration of aminoglycosides offers a reliable means of achieving high aminoglycoside concentrations throughout the subarachnoid space.
The factors that determine attachment of meningococci predominantly to the mucosa of the nasopharynx rather than to other mucosal surfaces are unknown. Isolates of Neisseria meningitidis from the nasopharynx of carriers and from patients with meningococcal disease were found to be heavily piliated. Isogenic piliated and nonpiliated meningococcal clones were derived from blood and cerebrospinal fluid isolates. Meningococci with pili consistently attached to human nasopharyngeal cells in greater numbers than meningococci without pili. Meningococci treated with trypsin or mechanical shear forces lost pili and exhibited decreased attachment. Attachment of piliated meningococci differed markedly among epithelial cells from different sites. In contrast, nonpiliated meningococci attached equally but in low numbers to all cell types. These data suggest that pili are important mediators of meningococcal attachment. The number and distribution of receptor sites for pili or pili-associated meningococcal ligands differ among human cells and may determine sites of meningococcal colonization.
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