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BackgroundAmong members of Cryptococcus neoformans- Cryptococcus gattii species complex, C. neoformans is distributed worldwide whereas C. gattii is considered to be more prevalent in the subtropics and tropics including Taiwan. This nationwide study was undertaken to determine the distribution of genotypes, clinical characteristics and outcomes of 219 patients with proven cryptococcosis at 20 hospitals representative of all geographic areas in Taiwan during 1997–2010.Methods and FindingsOf 219 isolates analyzed, C. neoformans accounted for 210 isolates (95.9%); nine isolates were C. gattii (4.1%). The predominant genotype was VNI (206 isolates). The other genotypes included VNII (4 isolates), VGI (3 isolates) and VGII (6 isolates). Antifungal minimal inhibition concentrations higher than epidemiologic cutoff values (ECVs) were found in nine VNI isolates (7 for amphotericin B). HIV infection was the most common underlying condition (54/219, 24.6%). Among HIV-negative patients, liver diseases (HBV carrier or cirrhosis) were common (30.2%) and 15.4% did not have any underlying condition. Meningoencephalitis was the most common presentation (58.9%), followed by pulmonary infection (19.6%) and “others” (predominantly cryptococcemia) (18.7%). The independent risk factors for 10-week mortality, by multivariate analysis, were cirrhosis of liver (P = 0.014) and CSF cryptococcal antigen titer ≥512 (P = 0.020). All except one of 54 HIV-infected patients were infected by VNI genotype (98.1%). Of the 13 isolates of genotypes other than VNI, 12 (92.3%) were isolated from HIV-negative patients. HIV-infected patients compared to HIV-negative patients were more likely to have meningoencephalitis and serum cryptococcal antigen ≥1∶512. Patients infected with C. gattii compared to C. neoformans were younger, more likely to have meningoencephalitis (100% vs. 57%), reside in Central Taiwan (56% vs. 31%), and higher 10-week crude mortality (44.4% vs. 22.2%).ConclusionsCryptococcus neoformans in Taiwan, more prevalent than C. gatii, has a predominant VNI genotype. Isolates with antifungal MIC higher than ECVs were rare.

The objective of this study was to investigate the role of sulbactam in the treatment of pan-drug resistant Acinetobacter baumannii (PDRAB). We studied 89 patients with PDRAB infection treated with different antibiotic regimens. Group A (n = 39) were treated with carbapenem with sulbactam and group B (n = 30) with second and third generation cephalosporins, antipseudomonas penicillins, or fluoroquinolones with aminoglycosides. We also studied the MICs for 48 PDRAB strains by using antimicrobial agents with and without sulbactam. The clinical outcomes of the 2 groups did not differ significantly, either in terms of resolution of infection (25/59, 42% in group A vs 12/30, 40% in group B) or survival (35/59, 59% vs 17/30, 57%). However, the MICs indicated that 16 of the 48 strains were sensitive to imipenem/sulbactam, compared with only 2 of the 48 to imipenem alone. The addition of sulbactam thus reversed the response in 30% (14/46) of strains initially resistant or only intermediate sensitive to imipenem. The MICs for meropenem/sulbactam were in the sensitive range for 8 of 48 strains compared to only 3 of the meropenem alone, indicating an 11% (5/45) reversal rate when sulbactam was added to meropenem. For the 38 isolates initially resistant to both carbapenems alone, imipenem/sulbactam reversed the resistance in 16% (6/38), while meropenem/sulbactam did so in only 3% (1/38). Thus, the carbapenem-sulbactam combinations did not clearly improve clinical outcome, but they did demonstrate lower MICs for the PDRAB strains tested. It may be that aggressive, early treatment of A. baumannii infections with these agents might prevent the emergence of PDRAB strains.

Influenza infection in adults is associated with increased risk of complications, bacteremia, and mortality compared with that in children. Bacteremia in adults with influenza is associated with increased complications and mortality; thrombocytopenia and elevated CRP levels could identify those at risk.

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BackgroundA mouse brain transmigration assessment (MBTA) was created to investigate the central nervous system (CNS) pathogenesis of cryptococcal meningoencephalitis.Methodology/Principal FindingsTwo cryptococcal mutants were identified from a pool of 109 pre-selected mutants that were signature-tagged with the nourseothricin acetyltransferase (NAT) resistance cassette. These two mutants displayed abnormal transmigration into the central nervous system. One mutant displaying decreased transmigration contains a null mutation in the putative FNX1 gene, whereas the other mutant possessing a null mutation in the putative RUB1 gene exhibited increased transmigration into the brain. Two macrophage adhesion-defective mutants in the pool, 12F1 and 3C9, showed reduced phagocytosis by macrophages, but displayed no defects in CNS entry suggesting that transit within macrophages (the “Trojan horse” model of CNS entry) is not the primary mechanism for C. neoformans migration into the CNS in this MBTA.Conclusions/SignificanceThis research design provides a new strategy for genetic impact studies on how Cryptococcus passes through the blood-brain barrier (BBB), and the specific isolated mutants in this assay support a transcellular mechanism of CNS entry.

Cryptococcus demonstrates predilection for invasion of the brain, but the mechanism by which Cryptococcus crosses the blood-brain barrier (BBB) to cause brain invasion is largely unknown. In order for Cryptococcus to cross the BBB, there must be a way to either cross human brain microvascular endothelial cells, which are the main constitute of the BBB, or go in between tight junctions. Recent evidence of human brain microvascular endothelial cell responses to transcellular brain invasions includes membrane rearrangements, intracellular signaling pathways and cytoskeletal activations. Several Cryptococcal genes related to the traversal of BBB have been identified, including CPS1, ITR1a, ITR3c, PLB1, MPR1, FNX1 and RUB1. In addition, Cryptococcus neoformans-derived microvesicles may contribute to cryptococcal brain invasion. Paracellularly, Cryptococcus may traverse across BBB using either routes utilizing plasmin, ammonia or macrophages in a Trojan horse mechanism.

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