Factors related to survival and treatment success in invasive candidiasis or candidemia: a pooled analysis of two large, prospective, micafungin trials.

Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remain unacceptably high. It is important to reach a more complete understanding of the risk factors underlying poor outcomes in patients with invasive Candida infections. Micafungin therapy has been assessed in two phase 3 trials compared to either liposomal amphotericin B or caspofungin. The availability of this large dataset allows the analyses of non-drug factors associated with survival and treatment success. A multivariate regression analysis was performed on data from the two trials separately and as a pooled analysis (N = 1,070). Analysis outcomes were survival at 42 days post-initiation of therapy and treatment success. For the pooled analysis, treatment success was significantly more likely for candidemia than invasive candidiasis. Both survival and treatment success were significantly less likely for the non-removal of catheter versus removal, Asian-Indians versus Caucasians, APACHE II score >20 to 30 versus or=70 years versus <50 years, baseline corticosteroids, and persistent neutropenia. Survival was also significantly less likely for treatment in other regions versus North America and for patients with renal failure at baseline. These findings help to define non-antifungal drug factors that may impact survival and treatment success in invasive candidiasis or candidemia.

Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS.

BACKGROUND: Cryptococcus neoformans is an important pathogen of immunocompromised hosts. Manifestations of cryptococcal infection have not been compared between populations based on the nature of the underlying immune deficiencies. METHODS: The Prospective Antifungal Therapy Alliance (PATH) is a registry that collects clinical data from patients with invasive fungal infections from medical centers in North America. Univariate analyses and group comparisons were conducted from the PATH registry for cases of infection due to Cryptococcus species occurring between March 2004 and April 2008. RESULTS: A total 235 cases of proven infection due to Cryptococcus species were documented, all of which were due to C. neoformans (52 in solid organ transplant [SOT] recipients, 107 in patients infected with the human immunodeficiency virus [HIV], and 76 with neither HIV nor organ transplantation). A total of 140 cases manifested as meningitis (25 in SOT recipients, 88 in HIV-positive patients, and 27 in those with neither risk factor). Of individuals with cryptococcal infection, 44.2% of SOT recipients had central nervous system (CNS) disease, while 84.1% of those with HIV infection presented with CNS involvement (P=0.0265). SOT recipients receiving calcineurin inhibitors (CNIs) were less likely to have CNS involvement in cryptococcal infection (40.1% versus 66.7%). Overall, 12-week mortality for patients with cryptococcal infection in the PATH Alliance registry was 22.6% (21.2% for SOT, 15.9% for HIV-infected patients, and 32.9% for patients with risk factors other than HIV infection or organ transplantation). CONCLUSIONS: In a prospectively assembled cohort of individuals with proven infection due to C. neoformans, CNS involvement was more common in individuals with HIV infection than in SOT recipients. The role of CNIs in the reduction of risk for CNS cryptococcosis remains to be defined. Overall survival of patients with cryptococcal infection in immunocompromised hosts has improved over time. Observed differences in the context of various host immune deficits provide a basis for further investigation of cryptococcosis and other opportunistic infections.

Development of visual attention skills in prelingually deaf children who use cochlear implants.

OBJECTIVE: To determine the effects of length of cochlear implant use and other demographic factors on the development of sustained visual attention in prelingually deaf children and to examine the relations between performance on a test of sustained visual attention and audiological outcome measures in this population. DESIGN: A retrospective analysis of data collected before cochlear implantation and over several years after implantation. Two groups of prelingually deaf children, one >6 years old (N = 41) and one <6 years old (N = 47) at testing, were given an age-appropriate Continuous Performance Task (CPT). In both groups, children monitored visually presented numbers for several minutes and responded whenever a designated number appeared. Hit rate, false alarm rate, and signal detection parameters were dependent measures of sustained visual attention. We tested for effects of a number of patient variables on CPT performance. Multiple regression analyses were conducted to determine if CPT scores were related to performance on several audiological outcome measures. RESULTS: In both groups of children, mean CPT performance was low compared with published norms for normal-hearing children, and performance improved as a function of length of cochlear implant use and chronological age. The improvement in performance was manifested as an increase in hit rate and perceptual sensitivity over time. In the younger age group, a greater number of active electrodes predicted better CPT performance. Results from regression analyses indicated a relationship between CPT response criterion and receptive language in the younger age group. However, we failed to uncover any other relations between CPT performance and speech and language outcome measures. CONCLUSIONS: Our findings suggest that cochlear implantation in prelingually deaf children leads to improved performance on a test of sustained visual processing of numbers over 2 or more years of cochlear implant use. In preschool-age children who use cochlear implants, individuals who are more conservative responders on the CPT show higher receptive language scores than do individuals with more impulsive response patterns. Theoretical accounts of these findings are discussed, including cross-modal reorganization of visual attention and enhanced phonological encoding of visually presented numbers.

Behavioral inhibition and clinical outcomes in children with cochlear implants.

OBJECTIVES/HYPOTHESIS: Individual speech and language outcomes of deaf children with cochlear implants (CIs) are quite varied. Individual differences in underlying cognitive functions may explain some of this variance. The current study investigated whether behavioral inhibition skills of deaf children were related to performance on a range of audiologic outcome measures. DESIGN: Retrospective analysis of longitudinal data collected from prelingually and profoundly deaf children who used CIs. METHODS: Behavioral inhibition skills were measured using a visual response delay task that did not require hearing. Speech and language measures were obtained from behavioral tests administered at 1-year intervals of CI use. RESULTS: Female subjects showed higher response delay scores than males. Performance increased with length of CI use. Younger children showed greater improvement in performance as a function of device use than older children. No other subject variable had a significant effect on response delay score. A series of multiple regression analyses revealed several significant relations between delay task performance and open set word recognition, vocabulary, receptive language, and expressive language scores. CONCLUSIONS: The present results suggest that CI experience affects visual information processing skills of prelingually deaf children. Furthermore, the observed pattern of relations suggests that speech and language processing skills are closely related to the development of response delay skills in prelingually deaf children with CIs. These relations may reflect underlying verbal encoding skills, subvocal rehearsal skills, and verbally mediated self-regulatory skills. Clinically, visual response delay tasks may be useful in assessing behavioral and cognitive development in deaf children after implantation.

Chemotactic activity of CXC chemokines interleukin-8, growth-related oncogene-alpha, and epithelial cell-derived neutrophil-activating protein-78 in urine of patients with urosepsis.

CXC chemokines are chemotactic cytokines that specifically act on neutrophils. To obtain insight into the extent of local production of CXC chemokines during acute pyelonephritis, interleukin (IL)-8, growth-related oncogene (GRO)-alpha, and epithelial cell-derived neutrophil-activating protein (ENA)-78 were measured in urine and plasma samples from patients with culture-proven urosepsis (n=33), healthy human control subjects with sterile urine (n=31), and human volunteers intravenously injected with endotoxin (n=11). Patients had profoundly elevated urine concentrations of chemokines with no (GRO-alpha and ENA-78) or little (IL-8) elevation in plasma. Endotoxin-challenged subjects demonstrated transient increases in plasma chemokine concentrations, with no (GRO-alpha) or little (IL-8 and ENA-78) elevation in urine. Urine from patients exerted chemotactic activity toward neutrophils, which was partially inhibited by neutralizing antibodies against IL-8, GRO-alpha, or ENA-78. During urosepsis, CXC chemokines are predominantly produced within the urinary tract, where they are involved in the recruitment of neutrophils to the urinary compartment.

What are the microbial components implicated in the pathogenesis of sepsis? Report on a symposium.

Despite considerable efforts in the past quarter century to improve therapy for sepsis, mortality rates remain unacceptably high. Microbe-derived constituents can induce the host to produce many mediators that can contribute to immune dysregulation, tissue damage, and death. Although endotoxin-mediated events are clearly important in gram-negative infections, gram-positive bacteria can also play a dominant role. Understanding the interplay of microbial constituents and host immune or inflammatory responses prompted a meeting at Rockefeller University in May 1998. Participants discussed the relative merits of a "2-hit" hypothesis to explain the course of lethal septic shock and a "multihit" synergistic threshold hypothesis. Recommendations include the following: (1) developing animal models that closely mimic human sepsis; (2) further investigating antibiotic effects on bacteria; (3) assessing the relationships between endotoxin, prokaryotic DNA, and peptidoglycan (i.e., independent, additive, or synergistic) in inducing host responses; and (4) developing new strategies to improve outcomes. Studies are needed to better define which and how different microbial constituents lead to sepsis and to provide critical leads for therapeutic intervention.

Differential host inflammatory responses to viable versus antibiotic-killed bacteria in experimental microbial sepsis.

Staphylococcus aureus killed during imipenem or ceftazidime chemotherapy in mice elicited an early release of tumor necrosis factor alpha (TNF-alpha) into the systemic circulation. This response was coincident in time with an increase in leukocyte-endothelium adhesive interactions in the microvasculature. Equivalent responses were not observed without the antibiotic treatment (imipenem or ceftazidime). Protective efficacy of the same antibiotic treatment was markedly diminished in D-galactosamine-treated mice compared to controls; e.g., it dropped from 2,000-fold to 70-fold with 4 mg of imipenem per kg given at the time of challenge. Nevertheless, protection was quantitatively restored upon concurrent administration of neutralizing anti-TNF-alpha antibody or 4 mg of dexamethasone per kg to these TNF-alpha-hypersensitive mice. Importantly, protection afforded by dexamethasone was not seen when the animals were challenged with viable organisms but without the concurrent administration of antibiotic. An early TNF-alpha response could also be demonstrated upon challenge with Escherichia coli, but in this instance, neither the timing nor the magnitude of that response was influenced by treatment with these antibiotics. We conclude from these studies that the inflammatory response to viable versus killed bacteria may differ markedly depending on the particular bacterium, host sensitivity to TNF-alpha, and possibly the Gram stain classification.

Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: examination of 301 strains isolated in the United States between 1994 and 1997.

BACKGROUND: Because of continuing reports from many countries of increasing resistance of group A streptococci to macrolide antibiotics, we determined the antibiotic susceptibility of recent group A streptococcal isolates from the United States. METHODS: We evaluated 301 Streptococcus pyogenes isolates (245 from patients with uncomplicated pharyngitis and 56 isolates from patients with invasive systemic infections) for susceptibility using the Etest technique. The isolates came from 24 states and the District of Columbia during the years 1994 through 1997. Thirteen antibiotics (azithromycin, ceftriaxone, cephalothin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, imipenem, levofloxacin, oxacillin, penicillin G, tetracycline and trimethoprim-sulfamethoxazole) were studied. RESULTS: The MIC90 for penicillin was 0.016 microg/ml, which is not significantly different from previous reports. Of the 301 isolates only 2.6% were resistant to a macrolide antibiotic and only 4% were resistant to tetracycline. CONCLUSIONS: These data indicate that antibiotic resistance among recent isolates of group A streptococci (including those from patients with severe infections) currently is not a clinically significant problem in the United States.

Cutting edge: bacterial DNA and LPS act in synergy in inducing nitric oxide production in RAW 264.7 macrophages.

LPS is well recognized for its potent capacity to activate mouse macrophages to produce NO, an important inflammatory mediator in innate host defense. We demonstrate here that, although inducing little NO alone, DNA from both Gram-negative and Gram-positive bacteria synergizes with subthreshold concentrations of LPS (0.3 ng/ml) to induce NO in cultures of RAW 264.7 macrophages. The effects of the DNA are mimicked by synthetic CpG-containing oligodeoxynucleotides but not by non-CpG-containing oligodeoxynucleotides. This synergistic activity is not inhibited by neutralizing Abs against IFN. Preincubation of macrophages with DNA for 8-24 h suppresses subsequent synergistic macrophage responses to DNA/LPS, whereas prolonged pretreatment with LPS enhances synergy. RT-PCR analysis indicates that the mRNA levels of the inducible NO synthase gene are also coordinately suppressed or induced. These findings indicate that temporally controlled, synergistic interactions exist between microbial DNA and LPS in the induction of macrophage NO via enhanced inducible NO synthase gene expression.

Protease inhibitor coinfusion with amyloid beta-protein results in enhanced deposition and toxicity in rat brain.

Amyloid beta-protein, Abeta, is normally produced in brain and is cleared by unknown mechanisms. In Alzheimer's disease (AD), Abeta accumulates in plaque-like deposits and is implicated genetically in neurodegeneration. Here we investigate mechanisms for Abeta degradation and Abeta toxicity in vivo, focusing on the effects of Abeta40, which is the peptide that accumulates in apolipoprotein E4-associated AD. Chronic intraventricular infusion of Abeta40 into rat brain resulted in limited deposition and toxicity. Coinfusion of Abeta40 with the cysteine protease inhibitor leupeptin resulted in increased extracellular and intracellular Abeta immunoreactivity. Analysis of gliosis and TUNEL in neuron layers of the frontal and entorhinal cortex suggested that leupeptin exacerbated Abeta40 toxicity. This was supported further by the neuronal staining of cathepsin B in endosomes or lysosomes, colocalizing with intracellular Abeta immunoreactivity in pyknotic cells. Leupeptin plus Abeta40 caused limited but significant neuronal phospho-tau immunostaining in the entorhinal cortex. Intriguingly, Abeta40 plus leupeptin induced intracellular accumulation of the more toxic Abeta, Abeta42, in a small group of septal neurons. Leupeptin infusion previously has been reported to interfere with lysosomal proteolysis and to result in the accumulation of lipofuscin, dystrophic neurites, tau- and ubiquitin-positive inclusions, and structures resembling paired helical filaments. Coinfusion of Abeta40 with the serine protease inhibitor aprotinin also increased diffuse extracellular deposition but reduced astrocytosis and TUNEL and was not associated with intracellular Abeta staining. Collectively, these data suggest that an age or Alzheimer's-related defect in lysosomal/endosomal function could promote Abeta deposition and DNA fragmentation in neurons and glia similar to that found in Alzheimer's disease.

Why have group A streptococci remained susceptible to penicillin? Report on a symposium.

In spite of 50 years of extensive use of penicillin, group A streptococci remain exquisitely susceptible to this antibiotic. This observation that continuing susceptibility has occurred despite the development of resistance to other antimicrobial agents prompted a day-long meeting at Rockefeller University (New York) in October 1996. Among the most likely explanations for this remarkable state of continued susceptibility to penicillin are that beta-lactamase may not be expressed or may be toxic to the organism and/or that low-affinity penicillin-binding proteins either are not expressed or render organisms nonviable. Other potential explanations are that circumstances favorable for the development of resistance have not yet occurred and/or that there are inefficient mechanisms for or barriers to genetic transfer. Recommended future actions include (1) additional laboratory investigations of gene transfer, penicillin-binding proteins, virulence factors, and homeologous recombination and mismatch repair; (2) increased surveillance for the development of penicillin resistance; (3) application of bioinformatics to analyze streptococcal genome sequences; and (4) development of vaccines and novel antimicrobial agents. Thus far the susceptibility of group A streptococci to penicillin has not been a major clinical or epidemiological problem. A similar observation, however, could have been made decades ago about Streptococcus pneumoniae. It is therefore vital for the scientific community to closely examine why penicillin has remained uniformly highly active against group A streptococci in order to maintain this desirable state.

Antibiotics, cytokines, and endotoxin: a complex and evolving relationship in gram-negative sepsis.

Compelling experimental evidence now exists that antimicrobial agents induce the release of endotoxin from Gram-negative bacteria during the process of bacteriolysis. Different antimicrobial classes, particularly those which act upon the outer membrane of bacteria, vary in the amount of free endotoxin released from Gram-negative organisms. Despite this in vitro evidence, clinically important consequences of antibiotic-induced endotoxin release have yet to be consistently documented. Complexities in the host-pathogen interactions during actual infection with Gram-negative bacteria may account for the difficulties in demonstrating this phenomena in vivo. This brief review analyses these interactions and defines clinical settings where antibiotic-induced endotoxin release may prove to be clinically relevant.

Evaluation of a computer program for teaching laboratory diagnosis of acid-base disorders.

A computer program was evaluated as a tool for increasing the diagnostic acumen of medical housestaff and students in identifying acid-base disorders. The participants were randomized into two groups; group A (N = 20) was encouraged to use the software, and group B (N = 19) was denied access. Pre- and post-tests were administered to delineate the groups' ability to identify correctly an acid-base disorder from laboratory data (electrolytes and arterial blood gas). During 6 weeks, group A used the computer for a mean of 2.83 h (range 1 to 6). The mean +/- SE number of correct answers out of 20 questions, prior to use of the computer program, were 5.7 +/- 0.8 (95% confidence interval 3.9 to 7.5) for group A and 5.2 +/- 0.6 (95% confidence interval 3.9 to 6.5) for group B. These results were not statistically different. Correct responses increased significantly in group A to 10.3 +/- 0.9 (P < 0.0001, 95% confidence interval 8.4 to 12.2) but did not increase significantly in group B. The data suggest that this software program was effective in increasing the diagnostic capabilities of medical housestaff and students for identifying acid-base disorders.

Antibiotics and nephrostomy tube care: preliminary observations. Part I. Bacteriuria.

The authors sought to establish whether bacteriuria or candiduria would develop in patients with a noninfected, obstructed renal collecting system after placement of a percutaneous nephrostomy tube. Tubes were placed in 27 sterile systems in 25 patients. Urine was cultured at 7-10-day intervals, and urinalysis was performed. Bacteriuria and pyuria were defined on the basis of laboratory values of greater than or equal to 10(4) colony-forming units per milliliter and greater than or equal to five white blood cells per high-powered field, respectively. Twenty-two systems were followed until all demonstrated multiple organisms. No clinical symptoms were related to bacteriuria.

Antibiotics and nephrostomy tube care: preliminary observations. Part II. Bacteremia.

Bacteriuria occurs after long-term drainage of the kidney. This study was designed to determine if the risk of bacteremia increases at the time of tube or stent change, whether bacteremia correlates with clinical infection, and if prophylactic antibiotics are effective in the prevention of bacteremia. One hundred four tube changes in 74 patients with percutaneous nephrostomy tubes and documented positive urine cultures were studied. Patients were arbitrarily divided into groups receiving and not receiving antibiotics before nephrostomy tube change. Asymptomatic bacteremia was documented in 11 of 104 tube changes (11%). Results of five blood cultures were positive in the group receiving antibiotics, and six cases of bacteremia occurred in the group not receiving antibiotics (P = .96). Routine nephrostomy/stent change can cause frequent, asymptomatic bacteremia in patients with colonization of bacteria in the urinary tract. Antibiotic prophylaxis was unsuccessful in preventing transient bacteremia, a factor that may have implications in patients with underlying valvular heart disease and other patients at risk for bacteremia.