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Enteroviruses (EVs) are the most common circulating viruses and cause of viral meningoencephalitis in the United States. In the general population, enteroviral infection is usually a self-limited disease. However, in patients with humoral immunodeficiency, infections can be fatal. The present case is that of a woman with Evans syndrome treated with splenectomy and rituximab who developed hypogammaglobulinemia and, despite antibody replacement, a fatal Coxsackie B3 virus meningoencephalitis. Enteroviruses are positive-sense single-stranded RNA viruses with a capsid composed of 4 structural proteins (VP1eVP4).1,2 Although EV meningoencephalitis (EM) is typically self-limited, in patients with humoral immunodeficiency, chronic EM has been reported often with fatal outcome.3,4 The use of intravenous immunoglobulin (IVIG) has dramatically decreased the incidence of chronic EM in congenital agammaglobulinemic conditions. Unfortunately, there are limited pharmaceutical treatment options available once chronic EM develops, all with varying degrees of success, including pleconaril (a picornavirus capsid protein inhibitor), high-dose IVIG, intrathecal immunoglobulin, and use of immunoglobulin preparations selected to contain high titers of enteroviral antibody. A 28-year-old white woman presented to the University of Virginia Hospital. At 15 years of age, she was diagnosed with Evans syndrome (autoimmune hemolytic anemia) and idiopathic thrombocytopenic purpura.5 Workup at that time was negative for immunodeficiency (Table 1). She was initially treated with danazol and corticosteroids. Then, she received high-dose (1 mg/kg) IVIG and a total of 8 doses of 375 mg/m2 of rituximab during a 10-month period for severe idiopathic thrombocytopenic purpura. At 23 years, she received pneumococcal and meningococcal vaccines and underwent splenectomy for refractory idiopathic thrombocytopenic purpura. Table 1 Laboratory results before and after rituximab treatment She did well until 27 years of age, when she was hospitalized for aseptic meningitis (Table 1, lumbar puncture [LP] 1). She subsequently developed idiopathic bilateral sensorineural hearing loss. At 28 years, she was hospitalized for influenza A (H3) with concurrent facial Pseudomonas cellulitis and again for Streptococcus pneumoniae sepsis. Then, she was found to have marked hypogammaglobulinemia with impaired antibody response and profound B-cell lymphopenia (Table 1). She was started on replacement IVIG (Privigen, CSL Behring, King of Prussia, Pennsylvania) at a dose of 400 mg/kg every 4 weeks. One month later, she developed a steady decline in neurocognitive function. The following month, she developed persistent fever. Brain magnetic resonance imaging displayed white matter changes concerning for encephalitis, but no focal lesions. Cerebrospinal fluid (CSF) from an LP was remarkable for an elevated opening pressure with slight lymphocytic pleocytosis and elevated protein. Flow cytometry of the CSF demonstrated a paucity of B cells but no aberrancy in the T-cell population. CSF infectious workup was negative (Table 1, LP 2). Stereotactic brain biopsies were performed. Histopathology on all specimens demonstrated meningoencephalitis with no evidence for granulomatous inflammation, but extensive CD68+ macrophages and CD5+ T-cell reaction and minimal to no CD20+ B cells. Viral inclusions and micro-organisms were not present. Computed tomography of the head showed no evidence of intracerebral hemorrhage. Her cognitive function continued to deteriorate despite empiric treatment with broad-spectrum antibiotics. LP was remarkable for an elevated opening pressure, and repeat CSF studies, including EV polymerase chain reaction (PCR), were negative except for persistent lymphocytic pleocytosis and elevated protein (Table 1, LP 3 and LP 4). Repeat brain magnetic resonance imaging showed no intracranial abscess, but there was slight progression of the symmetric abnormal white matter signal. Given the lack of clinical improvement despite appropriate medical therapy, a repeat brain biopsy examination was performed. In addition, tissues from the first brain biopsy and CSF were sent to the Centers for Disease Control and Prevention for immunohistochemistry and PCR for Toxoplasma species, Mycoplasma species, EV, Japanese encephalitis, and flaviviruses. Results were positive for EV by immunohistochemistry and PCR. Unfortunately, the patient had a left middle cerebral artery ischemic stroke several days after her second brain biopsy examination. She was transitioned to hospice and expired a few days later. Postmortem brain uncal and parietal tissue for PCR testing were positive for human Coxsackie virus B3, with positive VP2, VP4, and 5′ untranslated region. The VP2 and VP4 sequences showed 93% nucleotide identity with the human Coxsackie virus B3. Thus, her final cause of death was determined to be diffuse meningoencephalitis secondary to human Coxsackie virus B3 owing to an immunocompromised state.1 We hypothesize that this patient’s previous treatment with rituximab for Evans syndrome caused persistent profound B-cell lymphopenia and secondary hypogammaglobulinemia, predisposing her to EM. Although she also had a splenectomy, asplenia is not considered a high-risk condition for EM. The present case adds to an increasingly recognized, but incompletely understood, association between rituximab therapy and EM. Rituximab is a chimeric monoclonal antibody targeting CD20, which is expressed on B cells from the late pro–B-cell to memory B-cell stage.6 Given the absence of CD20 expression on plasmablasts and plasma cells, most patients treated with rituximab develop only transient, mild hypogammaglobulinemia and naive B-cell recovery occurs by12 months,7 with memory B-cell recovery after recapitulating normal B-cell ontogeny. Increased susceptibility to enteroviral infections has been observed in primary immunodeficiencies associated with defective B- and T-lymphocyte interactions such as X-linked agammaglobulinemia, hyper-IgM syndrome, and major histocompatibility class II deficiency.8 In X-linked agammaglobulinemia, congenital absence of B lymphocytes is associated with defective antigen presentation and decreased ability of B lymphocytes to sequester and destroy circulating virus.4 In contrast, patients with common variable immunodeficiency typically retain circulating B cells and are at lower risk for EM.9,10 Therefore, in patients with persistent marked B lymphopenia after rituximab, we would predict an increased risk of EM similar to patients with X-linked agammaglobulinemia. Routinely obtaining immunoglobulin levels and peripheral B-cell numbers before and after rituximab treatment should be considered to monitor for pre-existing and secondary immunodeficiency. Prompt immunoglobulin replacement intravenously or intrathecally should be initiated in patients with persistent B-cell absence because this might avert severe EM infections in these high-risk patients. As the present case illustrates, immunoglobulin replacement might be inadequate salvage therapy in established EM.

Until the introduction of antibiotics in the 1930s and 1940s, acute bacterial meningitis was fatal in most cases. Since then it has become curable with a variable mortality and morbidity rate for individual pathogens and patients. Neuropathological and clinical studies have shown that a fatal outcome of the disease is often due to central nervous system (CNS) complications including cerebrovascular involvement, brain oedema formation, and hydrocephalus resulting in increased intracranial pressure and seizure activity. During recent years, experimental studies with animal models have substantially increased our knowledge of the interactions of bacterial pathogens with mammalian cells and their entry into the CNS, and the complex pathophysiological mechanisms of brain dysfunction during acute bacterial meningitis. There is now a substantial body of evidence that cytokines, chemokines, proteolytic enzymes, and oxidants are involved in the inflammatory cascade that leads to tissue destruction in bacterial meningitis. Genetic targeting and/or pharmacological blockade of these pathways was beneficial in experimental bacterial meningitis. Apart from dexamethasone, these treatment strategies hold major promise for the adjunctive therapy of acute bacterial meningitis in clinical practice.

We have investigated the possible role of nitric oxide (NO) in the pathophysiology of bacterial meningitis (BM) by using the rat model of experimental BM. The nitrite concentration in cerebrospinal fluid (CSF) was used as a measure of NO production in vivo since NO rapidly degrades to nitrite and nitrate. Rats were inoculated intracisternally with live bacteria (5 x 10(6) CFU of Haemophilus influenzae type b strain DL42 or Rd-/b+/O2), with bacterial endotoxin (20 ng of DL42 lipooligosaccharide [LOS] or 200 ng of Escherichia coli lipopolysaccharide), or with a saline control vehicle. CSF samples were collected preinoculation and at the time of maximal alteration in blood-brain barrier permeability (BBBP). CSF [nitrite] was quantified by measuring A550 after addition of the Greiss reagent and comparison to a standard curve of sodium nitrite. Rats inoculated with either DL42, Rd-/b+/O2, LOS, or lipopolysaccharide demonstrated a significantly elevated mean peak CSF [nitrite] (8.34, 15.62, 10.75, and 10.44 mM, respectively) versus the concentration prior to treatment and/or those in saline-treated animals (5.29 and 5.33 mM, respectively; P < 0.05 for each comparison). We then determined if there was a correlation between CSF [nitrite] and percent BBBP (%BBBP) at various time points postinoculation with Rd-/b+/O2. %BBBP was defined as the concentration of systemically administered 125I-labeled bovine serum albumin in the CSF divided by the level of 125I-labeled bovine serum albumin in serum multiplied by 100. The mean %BBBP increased in tandem with the mean CSF [nitrite] (R = 0.84, P = 0.018), which peaked at 18 h in the absence of a change in the serum [nitrite]. Systemic administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester demonstrated a significant reduction of mean CSF nitrite production (0.95 versus 6.0 mM in controls; P = 0.02) when administered intravenously to animals which had been inoculated intracisternally with 20 ng of LOS. Suppression of mean leukocyte pleocytosis (3,117 versus 11,590 leukocytes per mm3 in control LOS-challenged rats; P = 0.03) and mean alterations of BBBP (2.11 versus 6.49% in control LOS-challenged rats; P = 0.009) was observed concomitantly with decreased CSF [nitrite]. These results support the hypothesis that NO contributes to increased %BBBP in experimental BM.

Under certain circumstances, soluble antigens, particulate antigens, and/or microorganisms have been shown to bind to primate erythrocytes via complement receptor 1 (CR1) in the presence of specific antibodies and complement. This immune adherence reaction, specific for CR1, can lead to neutralization of antigens in the circulation and their subsequent clearance from the blood. The present experiments utilized cross-linked monoclonal antibody complexes (heteropolymers) with specificity for both CR1 and either 35S-labeled herpes simplex virus capsid or Haemophilus influenzae as prototype viral and bacterial particulate antigens, respectively. In each case, the respective specific heteropolymers facilitated binding of the target antigens (> or = 70 to 90%) in vitro to erythrocytes in the absence of complement. Several experimental protocols were employed to demonstrate that heteropolymers mediate specific, rapid (> or = 30 s), and quantitative binding of prototypical particulate pathogens to human and monkey erythrocytes but not to sheep erythrocytes, which lack CR1. These results extend the potential use of the erythrocyte-heteropolymer system to the neutralization and clearance of particulate viral and bacterial pathogens from the blood.

Research into the pathophysiology of bacterial meningitis has suggested a role for various endogenous inflammatory mediators, such as platelet-activating factor (PAF). In the present study, rats were inoculated intracisternally with various doses of PAF, with Haemophilus influenzae lipooligosaccharide (LOS) in high doses (20 ng) alone, and with a low dose of LOS (200 pg) with or without low doses of PAF (25 ng to 2.5 micrograms). Values for cerebrospinal fluid leukocytosis and percent blood-brain barrier permeability to systemically administered 125I-labeled albumin observed after inoculation of low-dose LOS with PAF were greater (P < 0.05) than those observed after inoculation of low-dose LOS alone and not statistically different from those observed after inoculation of high-dose LOS. PAF alone elicited an inflammatory response only at high doses (25 micrograms). These results support the hypothesis that low cerebrospinal fluid PAF concentrations, such as those observed in children with bacterial meningitis, may augment the inflammatory response to the presence of bacteria in the subarachnoid space.

Few diseases ignite the fear that develops when bacterial meningitis strikes a community. Its potential for communicability and fatality scares families and health care workers alike. Physicians, particularly pediatricians, recognize it as a disease with potentially subtle presentation but devastating consequences if misdiagnosed. Over the last decade, advances in the understanding of pathophysiological aspects of the disease and in vaccine development have provided opportunities to improve outcome but have simultaneously generated controversies regarding therapy because of the rapidly changing epidemiological factors involved. In this review, we highlight the changing perspectives on bacterial meningitis that have evolved as a result of experimental models, clinical intervention trials, and epidemiological trends.

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.

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.

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.

Background To increase access to antiretroviral therapy in resource-limited settings, several experts recommend "task shifting" from doctors to clinical officers, nurses and midwives. This study sought to identify task shifting that has already occurred and assess the antiretroviral therapy training needs among clinicians to whom tasks have shifted. Methods The Infectious Diseases Institute, in collaboration with the Ugandan Ministry of Health, surveyed health professionals and heads of antiretroviral therapy clinics at a stratified random sample of 44 health facilities accredited to provide this therapy. A sample of 265 doctors, clinical officers, nurses and midwives reported on tasks they performed, previous human immunodeficiency virus training, and self-assessment of knowledge of human immunodeficiency virus and antiretroviral therapy. Heads of the antiretroviral therapy clinics reported on clinic characteristics. Results Thirty of 33 doctors (91%), 24 of 40 clinical officers (60%), 16 of 114 nurses (14%) and 13 of 54 midwives (24%) who worked in accredited antiretroviral therapy clinics reported that they prescribed this therapy (p < 0.001). Sixty-four percent of the people who prescribed antiretroviral therapy were not doctors. Among professionals who prescribed it, 76% of doctors, 62% of clinical officers, 62% of nurses and 51% of midwives were trained in initiating patients on antiretroviral therapy (p = 0.457); 73%, 46%, 50% and 23%, respectively, were trained in monitoring patients on the therapy (p = 0.017). Seven percent of doctors, 42% of clinical officers, 35% of nurses and 77% of midwives assessed that their overall knowledge of antiretroviral therapy was lower than good (p = 0.001). Conclusion Training initiatives should be an integral part of the support for task shifting and ensure that antiretroviral therapy is used correctly and that toxicity or drug resistance do not reverse accomplishments to date.

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.

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.

Bacterial meningitis continues to be an important cause of morbidity and mortality despite the availability of effective bactericidal antibiotics. Penicillin or ampicillin remains the drug of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third generation cephalosporins have revolutionized the treatment of gram-negative meningitis. Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease.

Advances in the understanding of the pathogenesis and pathophysiology of meningitis have occurred primarily through the use of experimental animal models. These models have proven to be particularly valuable in experimental bacterial meningitis, focusing on the bacterial virulence factors responsible for the initiation of infections, CNS invasion, and induction of SAS inflammation. Recent studies have examined the formation of host inflammatory cytokines in response to these virulence factors. These cytokines may be responsible for many of the pathophysiologic consequences of bacterial meningitis (eg. increased BBB permeability, cerebral edema, and increased intracranial pressure). Meningitis due to C. neoformans occurs most commonly in patients with defects in cell-mediated immunity (eg, AIDS), and the depletion of T helper cells in AIDS patients may allow unrestricted cryptococcal growth. Viral meningitis is an illness of low prevalence when compared with the overall occurrence of viral infections at other sites. CNS infection usually occurs by means of traversal across barriers that normally exclude viral invasion of the CNS, primarily through hematogenous dissemination from initial sites of infection. These advances in the pathogenesis and pathophysiology of bacterial, fungal, and viral meningitis may lead to the development of innovative treatment strategies for these disorders.

Aztreonam, the first commercially available monobactam, has a wide range of activity against aerobic gram-negative bacilli. It can be administered two to three hours daily because its half-life is 1.6 to 2 hours. Excellent blood and tissue concentrations are attained. The MIC of aztreonam against most Enterobacteriaceae is less than or equal to 2 micrograms/ml and against P aeruginosa less than or equal to 16 micrograms g/ml. Aztreonam has been used in a wide array of infections of the urinary tract and respiratory tract, blood, intra-abdominal and gynecologic infections and infections of the skin, bones and joints. As empiric therapy, aztreonam is usually combined with another antimicrobial agent active against anaerobes and/or aerobic gram-positive cocci until culture results are available. One exception is empiric therapy for gram-negative urinary tract infections in which aztreonam can be used initially as monotherapy against susceptible gram-negative pathogens. In general, the efficacy of aztreonam is equal or superior to that of the aminoglycosides. Adverse reactions to aztreonam are unusual, and it as been shown to be a poor hapten, permitting its administration to patients with proven allergy to the penicillins and cephalosporins. Aztreonam is a useful addition to the available antibiotics for treatment of gram-negative infections.

For our laboratory's investigation into the role of the endothelial cells in vasospasm following subarachnoid hemorrhage and in inflammatory diseases, we found it necessary to devise a modified method of cell culture, which would be appropriate for studying human endothelial cells from lobectomized brain. We report our techniques to increase cell harvest and ensure reproducibility, our method of culturing endothelial cells from bovine major cerebral arteries, and our morphologic and immunocytochemical characterization of these cells. To increase the harvest of endothelial cells, the blood cells were washed from the lumen of the major cerebral arteries at the slaughterhouse and a modified reversed vessel technique was employed. The monolayer of cultured endothelial cells displayed a cobblestone appearance when it reached confluency and transmission electron microscopy revealed junctional complexes and interdigitation of cytoplasm at Passages 10 and 17. The cells stained positively for Factor VIII-related antigen at Passages 3, 5, 7, 10, and 15. Also the cells metabolized acetylated low-density lipoprotein at Passage 8. To determine the purify of the cultured endothelial cells, an immunocytochemical study of the cytoskeleton was performed on Passage 5 cells using either rhodamine-phalloidin or antibodies against smooth muscle myosin, desmin, and vimentin.

Over the last two decades, an alarming rise in infections caused by antibiotic-resistant microbes has been paralleled by an equally alarming decline in the development of new antibiotics to deal with the threat. In response to this brewing “perfect storm” of infectious diseases, the Infectious Diseases Society of America (IDSA) has released a white paper that proposes incentives to stimulate critically needed antibiotic development by pharmaceutical companies. A cornerstone of the recommendations is establishment of a “wild-card patent extension” program. This program would allow a company receiving United States (US) Food and Drug Administration (FDA) approval for a new anti-infective agent targeting a drug-resistant pathogen to extend the patent on a drug within their active portfolio. However, wild-card patent extension legislation is highly controversial due to concerns regarding its societal cost. We performed a systematic literature review to estimate the societal cost of wild-card patent extension compared to the savings resulting from the availability of one new antibiotic to treat multi-drug-resistant Pseudomonas aeruginosa. We conservatively estimate that wild-card patent extension applied to one new antibiotic would cost $7.7 billion over the first 2 years, and $3.9 billion over the next 18 years. Thus, even if the new antibiotic abrogated only 50% of the annual societal cost of multidrug-resistant P. aeruginosa (estimated $2.7 billion), wild-card patent extension would be cost neutral by 10 years after approval of the new antibiotic, and would save society approximately $4.6 billion by 20 years after approval. Wild-card patent extension appears to be a cost-effective strategy to spur anti-infective development. Although our analysis is limited by the precision of published data, our model employed conservative assumptions.

Novel 2-propynylcyclohexyl-5'-N:-ehtylcarboxamidoadenosines, trans-substituted in the 4-position of the cyclohexyl ring, were evaluated in binding assays to the four subtypes of adenosine receptors (ARs). Two esters, 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL146e) and acetic acid 4-(3-[6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl] -prop-2-ynyl)-cyclohexylmethyl ester (ATL193) were50 x more potent than 2-[4-(2-carboxyethyl)phenethylamino]-5'-N:-ethylcarboxamidoadenosine (CGS21680) for human A(2A) AR binding. Human A(2A) AR affinity for substituted cyclohexyl-propynyladenosine analogues was inversely correlated with the polarity of the cyclohexyl side chain. There was a comparable order of potency for A(2A) AR agonist stimulation of human neutrophil [cyclic AMP](i), and inhibition of the neutrophil oxidative burst. ATL146e and CGS21680 were approximately equipotent agonists of human A(3) ARs. We measured the effects of selective AR antagonists on agonist stimulated neutrophil [cyclic AMP](i) and the effect of PKA inhibition on A(2A) AR agonist activity. ATL193-stimulated neutrophil [cyclic AMP](i) was blocked by antagonists with the potency order: ZM241385 (A(2A)-selective)MRS1220 (A(3)-selective)N-(4-Cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]-acetamide (MRS1754; A(2B)-selective) approximately 8-(N-methylisopropyl)amino-N(6)-(5'-endohydroxy-endonorbornyl)-9-methyladenine (WRC0571; A(1)-selective). The type IV phosphodiesterase inhibitor, rolipram (100 nM) potentiated ATL193 inhibition of the oxidative burst, and inhibition by ATL193 was counteracted by the PKA inhibitor H-89. The data indicate that activation of A(2A)ARs inhibits neutrophil oxidative activity by activating [cyclic AMP](i)/PKA.

A leading cause of morbidity from bacterial meningitis is an irreversible, usually profound sensorineural hearing loss, with an incidence as high as 30% in some studies. Bacterial meningitis remains the most common cause of acquired postnatal sensorineural deafness. Although several clinical studies have examined the long-term outcome of hearing in meningitis, few studies have examined the time course of hearing loss during the acute course of the disease. We have developed an animal model of meningogenic hearing loss in the rat and have plotted the time course of that hearing loss. Serial auditory brain stem responses (ABRs) were measured in rats inoculated in the cisterna magna (subarachnoid space) with Streptococcus pneumoniae (10(5) to 10(7) colony-forming units). All rats injected developed meningitis as evidenced by increased cerebrospinal fluid (CSF) white cell counts and positive CSF cultures. Serial ABR measurements taken 6, 12, 15, 18, 21, and 24 hours after inoculation demonstrated significant threshold shifts and eventual loss of the ABR waveform as compared with measurements in control rats injected with sterile culture medium. Hearing loss began approximately 12 to 15 hours after inoculation and progressed to complete loss by 24 hours (17 of 18 animals). No correlation was found between the magnitude of hearing loss and CSF white cell count or bacterial titer. Temporal bone histology of rats with meningitis shows a dense inflammatory cell infiltrate throughout the subarachnoid space. Labyrinthine inflammatory cells were confined to the scala tympani. The cochlear aqueduct is the proposed route of infection from the meninges to the labyrinth (scala tympani). Endolymphatic hydrops was also noted throughout the cochlea. These experiments both establish a reproducible animal model of meningogenic hearing loss and support the hypothesis that this hearing loss is progressive rather than abrupt in onset and is related to the duration of untreated infection. CSF inflammatory cells appear to enter the cochlea through the cochlear aqueduct. This reliable animal model will enable future studies directed toward further understanding the pathogenesis and pathophysiology of this hearing loss.

Acute bacterial meningitis is associated with significant morbidity and mortality despite the availability of effective antimicrobial therapy. The emergence of antibiotic-resistant bacterial strains in recent years has necessitated the development of new strategies for empiric antimicrobial therapy for bacterial meningitis. Specifically, the emergence of strains of Streptococcus pneumoniae that are resistant to penicillin and the cephalosporins have led to empiric therapy for patients with pneumococcal meningitis consisting of vancomycin plus a third-generation cephalosporin pending susceptibility testing. Third-generation cephalosporins are also effective as empiric therapy against other pathogens that cause community-acquired bacterial meningitis, with the exception of Listeria monocytogenes, for which ampicillin or penicillin G is the antimicrobial agent of choice. Adjunctive dexamethasone should be administered to infants and children with suspected or proven Haemophilus influenzae type b meningitis to reduce audiologic and neurologic sequelae; administration concomitant with or just before the first dose of the antimicrobial agent is optimal for best results.

Cefdinir is an extended-spectrum oral cephalosporin that is active against pathogens commonly seen in acute community-acquired bacterial sinusitis (ACABS), including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Two randomized, investigator-blind, multicenter trials (one in the United States and one in Europe) compared two dosage regimens of cefdinir (600 mg once a day for 10 days and 300 mg twice a day for 10 days) to amoxicillin-clavulanate (A-C) (500 mg three times a day for 10 days) for adult and adolescent patients with ACABS. Twelve hundred twenty-nine patients entered the U.S. study, 698 with antral puncture; 569 patients entered the European study, all with antral puncture. Clinical response (cure or improvement) was determined 7 to 14 days and 3 to 5 weeks posttherapy. Microbiologic eradication rates were determined 10 to 30 days posttherapy in a subset of patients who underwent pre- and posttherapy sinus aspirate culture. Rates of adverse events and treatment discontinuations due to adverse events were examined. Cefdinir, given once or twice daily, was as effective clinically (approximately 90% cure rate) as amoxicillin-clavulanate given three times daily in the treatment of ACABS. Microbiologic eradication rates were also similar in the three groups. The major side effect was mild diarrhea, occurring in approximately 20% of each group. Cefdinir caused fewer adverse events requiring treatment discontinuation.

Recent in-vitro studies have improved our understanding of how bacteria interact with cerebral endothelial cells and cross the blood-brain barrier. Several animal studies using rat and rabbit models of bacterial meningitis have revealed mediators of inflammation that are believed to play a key role in secondary brain damage, including reactive oxygen species, nitric oxide, and excitatory amino acids. Treatment with free-radical scavengers, nitric oxide synthase inhibitors, excitatory amino acid antagonists, as well as the anti-inflammatory cytokine interleukin-10 was beneficial in experimental bacterial meningitis. Apart from dexamethasone these agents hold major promise for the adjunctive therapy of bacterial meningitis in clinical practice.

With the development of nosocomial pathogens that are resistant to multiple antimicrobial agents, reasonable restriction of antibiotic use has become a priority.During an outbreak of vancomycin-resistant enterococcal infections, an audit of vancomycin hydrochloride use was conducted during October 3 through 21, 1994, and January 24 through February 2, 1995. During these periods, all orders for vancomycin were reviewed by clinical pharmacists. Use was classified as either appropriate or inappropriate based on recommendations by the Hospital Infection Control Practice Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention, Atlanta, Ga. A policy restricting the use of vancomycin was adopted in November 1994.During the first audit in October 1994, 61% of vancomycin orders were considered inappropriate according to HICPAC criteria. At the time of this audit, the first cases of an outbreak of nosocomial vancomycin-resistant Enterococcus faecium had been detected. The follow-up audit showed that 30% of vancomycin orders were inappropriate by HICPAC criteria (P.001). Overall use of vancomycin decreased by 50% and remained at this lower level for the following year.The institution of a vancomycin restriction policy was associated with a reduction of both inappropriate drug orders and total use.

Rhabdomyolysis can be precipitated by trauma, ischemia, metabolic defects, electrolyte abnormalities, drugs, and a wide variety of infectious diseases. At our institution, recent cases of rhabdomyolysis induced by influenza prompted us to review the infectious etiologies of this entity. In addition, a thorough literature search revealed numerous case reports but no general review on this subject. This study describes representative recent cases from our institution and details the wide variety of infections that can cause muscle damage. The pathophysiological mechanisms, muscle histology, and correlation with renal dysfunction are also discussed.

We have previously demonstrated that cross-linked bispecific monoclonal antibodies (mAb) heteropolymers (HP), specific for primate erythrocyte (E) complement receptor type 1 (CR1) and target antigen (Ag), facilitate the binding of these target Ag to human and non-human primate E. Once bound in vitro to rhesus monkey E, upon re-infusion these HP/Ag complexes are recognized in vivo by cells of the reticuloendothelial system (RES) and removed from the circulation without loss of the E. We now show, in squirrel monkeys, that an HP specific for E CR1 and human IgM (anti-CR1 x anti-IgM) can be used to facilitate in vivo E binding and clearance from the circulation of a previously injected and circulating model protein pathogen, human IgM. Approximately 70-80% of 125I-labeled human IgM is cleared from the circulation of each of five squirrel monkeys via the HP system. We observe, in experiments analogous to previous studies on immune complex (IC) clearance, that subsequent to HP/Ag clearance there is a decrease in the number of CR1 epitopes per E which is manifested when we use both monoclonal and polyclonal anti-CR1 probes. Our results indicate that the primary organs responsible for uptake of the complexes are the liver and spleen. This work strongly suggests that the HP/Ag complexes, bound to E, function as IC prototypes and are recognized and processed as such in vivo. Thus, the HP-E system may eventually serve as a viable immunotherapy for the clearance of blood-borne pathogens from the circulation.

Morbidity and mortality associated with bacterial meningitis remain high, although antibiotic therapy has improved during recent decades. The major intracranial complications of bacterial meningitis are cerebrovascular arterial and venous involvement, brain edema, and hydrocephalus with a subsequent increase of intracranial pressure. Experiments in animal models and cell culture systems have focused on the pathogenesis and pathophysiology of bacterial meningitis in an attempt to identify the bacterial and/or host factors responsible for brain injury during the course of infection. An international workshop entitled "Bacterial Meningitis: Mechanisms of Brain Injury" was organized by the Department of Neurology at the University of Munich and was held in Eibsee, Germany, in June 1993. This conference provided a forum for the exchange of current information on bacterial meningitis, including data on the clinical spectrum of complications, the associated morphological alterations, the role of soluble inflammatory mediators (in particular cytokines) and of leukocyte-endothelial cell interactions in tissue injury, and the molecular mechanisms of neuronal injury, with potential mediators such as reactive oxygen species, reactive nitrogen species, and excitatory amino acids. It is hoped that a better understanding of the pathophysiological events that take place during bacterial meningitis will lead to the development of new therapeutic regimens.

Despite the introduction of numerous therapeutic advances, the morbidity and mortality associated with bacterial meningitis remain significant. Research into the pathophysiology of bacterial meningitis has revealed that the inflammatory response resulting from bacterial invasion of the subarachnoid space is due in large part to the activity of host-derived mediators. This inflammatory response is ultimately responsible for the long-term neurological sequelae and death associated with bacterial meningitis. In vitro and in vivo models of bacterial meningitis have identified several points in the inflammatory cascade that may be amenable to therapeutic intervention. Numerous potential therapeutic agents that may limit inflammation of the subarachnoid space have been and are being developed, and trials in animal models and in humans are under way. The judicious use of safe and effective agents with demonstrated efficacy as adjuncts to bactericidal antimicrobial agents in the therapy for bacterial meningitis in humans may improve the prognosis of this disease.

The fluoroquinolone antibiotics are relatively new agents with long serum half lives, a high degree of bioavailability, and a broad spectrum of activity against many gram-negative and some gram-positive organisms. They are useful in a range of clinical settings but should not be considered as first-line treatment of many infections. Specific indications include chronic osteomyelitis caused by multiple-resistant gram-negative bacilli, chronic bacterial prostatitis refractory to other oral antibiotics, complicated urinary tract infections, and empiric therapy of suspected bacterial GI infections. Quinolones may also be considered when patients are allergic to a conventional agent, when infections are caused by multiple-resistant gram-negative bacilli, or when the toxicity of an alternate therapy is greater.

Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder.

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.

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.

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.

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.

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.

These data demonstrate that haemocin production and type b encapsulation, although closely associated, are encoded by independent genetic elements. Studies with the infant rat model of infection suggest that haemocin may play a role in the pathogenesis of invasive H. influenzae type b infection. The availability of the cloned hmc locus and mutants deficient in the production of haemocin will allow further analysis of the genetic basis of haemocin production.

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.

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.

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.

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.

Despite recent progress in the prevention and therapy of hospital acquired infections, nosocomial pneumonia remains an important problem in critically ill patients. Nosocomial pneumonia develops in five to ten patients per 1,000 admissions and has a mortality rate of 20 to 50 per cent. This review updates three areas that have been the subject of investigation in recent years: pathogenesis, especially the role of gastric colonization with gram-negative bacilli in retrograde pharyngeal spread; diagnosis, particularly by bronchoalveolar lavage and the protected specimen brush during bronchoscopy, and therapy with extended spectrum penicillins, third generation cephalosporins, imipenem, aztreonam and quinolones.

Advances in the understanding of the pathogenesis and pathophysiology of meningitis have occurred primarily through the use of experimental animal models. These models have proven to be particularly valuable in experimental bacterial meningitis, focusing on the bacterial virulence factors responsible for the initiation of infections, CNS invasion, and induction of SAS inflammation. Recent studies have examined the formation of host inflammatory cytokines in response to these virulence factors. These cytokines may be responsible for many of the pathophysiologic consequences of bacterial meningitis (eg. increased BBB permeability, cerebral edema, and increased intracranial pressure). Meningitis due to C. neoformans occurs most commonly in patients with defects in cell-mediated immunity (eg, AIDS), and the depletion of T helper cells in AIDS patients may allow unrestricted cryptococcal growth. Viral meningitis is an illness of low prevalence when compared with the overall occurrence of viral infections at other sites. CNS infection usually occurs by means of traversal across barriers that normally exclude viral invasion of the CNS, primarily through hematogenous dissemination from initial sites of infection. These advances in the pathogenesis and pathophysiology of bacterial, fungal, and viral meningitis may lead to the development of innovative treatment strategies for these disorders.

Bacterial meningitis continues to be an important cause of morbidity and mortality despite the availability of effective bactericidal antibiotics. Penicillin or ampicillin remains the drug of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third generation cephalosporins have revolutionized the treatment of gram-negative meningitis. Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease.