Trends in the activity of mold-active azole agents against Aspergillus fumigatus clinical isolates with and without cyp51 alterations from Europe and North America (2017-2021).

Azole resistance in Aspergillus fumigatus (AFM) is increasing and often associated with cyp51 alterations. We evaluated the activity of isavuconazole and other mold-active azoles against 731 AFM isolates causing invasive aspergillosis collected in Europe (EU; n = 449) and North America (NA; n = 282). Isolates were submitted to CLSI susceptibility testing and epidemiological cutoff value (ECV) criteria. A posaconazole ECV of 0.5 mg/L was used as no CLSI ECV was determined. Azole non-wild-type (NWT) isolates were submitted for cyp51 sequencing by whole genome sequencing. Overall, isavuconazole activity (92.7%/94.0% WT in EU/NA) was comparable to other azoles (WT rate range, 90.9%-96.4%/91.8%-98.6%, respectively), regardless of the region. A total of 79 (10.8%) azole NWT isolates were detected, and similar rates of these isolates were noted in EU (10.7%) and NA (11.0%). Although most AFM were WT to azoles, increasing azole NWT rates were observed in NA (from 6.0% in 2017 to 29.3% in 2021). Azole NWT rates varied from 4.9% (2019) to 20.6% (2018) in EU without an observed trend. cyp51 alterations occurred in 56.3%/54.8% of azole NWT from EU/NA, respectively. The cyp51A TR34/L98H alteration was observed only in EU isolates (72.0% of EU isolates), while cyp51A I242V occurred only in NA isolates (58.3%). Isavuconazole remained active (MIC, ≤1 mg/L) against 18.5/47.1% of azole NWT AFM exhibiting cyp51 alterations in EU/NA, along with voriconazole (29.6/82.4%; MIC, ≤1 mg/L) and posaconazole (48.1/88.2%; MIC, ≤0.5 mg/L). Fourteen different cyp51 alterations were detected in 44 of 79 NWT isolates. The in vitro activity of the azoles varied in AFM that displayed cyp51 alterations. IMPORTANCE A few microbiology laboratories perform antifungal susceptibility testing locally for systemically active antifungal agents. The identification of emerging azole-resistant Aspergillus fumigatus is worrisome. As such, there is a critical role for antifungal surveillance in tracking emerging resistance among both common and uncommon opportunistic fungi. Differences in the regional prevalence and antifungal resistance of these fungi render local epidemiological knowledge essential for the care of patients with a suspected invasive fungal infection.

Activities of Manogepix and Comparators against 1,435 Recent Fungal Isolates Collected during an International Surveillance Program (2020).

We evaluated the in vitro activity of manogepix and comparator agents against 1,435 contemporary fungal isolates collected worldwide from 73 medical centers in North America, Europe, the Asia-Pacific region, and Latin America during 2020. Of the isolates tested, 74.7% were Candida spp.; 3.7% were non-Candida yeasts, including 27 Cryptococcus neoformans var. grubii (1.9%); 17.1% were Aspergillus spp.; and 4.5% were other molds. All fungal isolates were tested by reference broth microdilution according to CLSI methods. Based on MIC90 values, manogepix (MIC50/MIC90, 0.008/0.06 mg/liter) was 16- to 64-fold more active than anidulafungin, micafungin, and fluconazole against Candida spp. isolates and the most active agent tested. Similarly, manogepix (MIC50/MIC90, 0.5/1 mg/liter) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii. Based on minimum effective concentration for 90% of the isolates tested (MEC90) and MIC90 values, manogepix (MEC90, 0.03 mg/liter) was 16- to 64-fold more potent than itraconazole, posaconazole, and voriconazole (MIC90s, 0.5 to 2 mg/liter) against 246 Aspergillus spp. isolates. Aspergillus fumigatus isolates exhibited a wild-type (WT) phenotype for the mold-active triazoles, including itraconazole (87.0% WT) and voriconazole (96.4% WT). Manogepix was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Candida auris (MIC50/MIC90, 0.004/0.015 mg/liter) and 12 isolates of Scedosporium spp. (MEC50/MEC90, 0.06/0.12 mg/liter). Additional studies are in progress to evaluate the clinical utility of the manogepix prodrug fosmanogepix in difficult-to-treat resistant fungal infections.

Early thrombosis prophylaxis with enoxaparin is not associated with hematoma expansion in patients with spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Early pharmacological deep vein thrombosis (DVT) prophylaxis is recommended by guidelines, but rarely started within 48 h. We aimed to analyze the effect of early (within 48 h) versus late (>48 h) DVT prophylaxis on hematoma expansion (HE) and outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: We analyzed 134 consecutive patients admitted to a tertiary neurointensive care unit with diagnosed spontaneous ICH, without previous anticoagulation, severe coagulopathy, hematoma evacuation, early withdrawal of therapy or ineligibility for DVT prophylaxis according to our institutional protocol. Significant late HE was defined as ≥6 mL increase of hematoma volume between neuroimaging within 48 h and day 3-6. Multivariate analysis was performed to identify risk factors for late HE, poor 3-month outcome (modified Rankin Scale score ≥ 4) and mortality. RESULTS: Patients had a median Glasgow Coma Scale score of 14 [interquartile range (IQR), 10-15], ICH volume of 11 (IQR, 5-24) mL and were 71 (IQR, 61-76) years old. A total of 56% (n = 76) received early DVT prophylaxis, 37% (n = 50) received late DVT prophylaxis and 8 (6%) had unknown bleeding onset. Patients with early DVT prophylaxis had smaller ICH volume [9.5 (IQR, 4-18.5) vs. 17.5 (IQR, 8-29) mL, P = 0.038] and were more often comatose (26% vs. 10%, P = 0.025). Significant late HE [n = 5/134 (3.7%)] was associated with larger initial ICH volume (P = 0.02) and lower thrombocyte count (P = 0.03) but not with early DVT prophylaxis (P = 0.36). Early DVT prophylaxis was not associated with worse outcome. CONCLUSION: Significant late HE is uncommon and DVT prophylaxis within 48 h of symptom onset may be safe in selected patients with ICH.

Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014).

Omadacycline is an aminomethylcycline with in vitro activity against many gram-negative pathogens. Omadacycline and comparators were tested against Enterobacteriaceae from urinary tract infections (UTIs) selected from a 2014 global surveillance program and compared to results of isolates from 2010 surveillance. The omadacycline MIC50/90 for Enterobacteriaceae collected during 2014 was 2/≥8 µg/mL (1/4 µg/mL minus Proteus, Providencia, and Morganella spp.). The MIC50/90 for E. coli was 1/2 µg/mL, similar to that in 2010 (MIC50/90, 0.5/2 µg/mL). The MICs for 91.7% of Klebsiella spp. isolates in 2014 (89.7%, 2010) were ≤4 µg/mL. In 2010 and 2014, a total of 100.0% and 95.8% of ESBL screen-positive (SP) phenotype E. coli and 73.9% and 75.0% of ESBL SP Klebsiella spp., respectively, exhibited MIC values at ≤4 µg/mL. Omadacycline was active against UTI-causing Enterobacteriaceae isolates from NA and EU. Further study of omadacycline to treat UTIs caused by Enterobacteriaceae may be indicated.

Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014).

The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC50/90 for S. pneumoniae (2014) was 0.06/0.06µg/mL, similar to 2010 (MIC50/90, 0.06/0.12µg/mL). The omadacycline MIC90 (0.06-0.12µg/mL) was similar for the penicillin-susceptible, -intermediate, -resistant, multidrug-resistance (MDR; ≥3 classes), and ceftriaxone nonsusceptible subgroups. Omadacycline MIC90 values were 0.06-0.12µg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern.

In Vitro Activity of the Novel Lactone Ketolide Nafithromycin (WCK 4873) against Contemporary Clinical Bacteria from a Global Surveillance Program.

Nafithromycin (WCK 4873), a novel antimicrobial agent of the lactone ketolide class, is currently in phase 2 development for treatment of community-acquired bacterial pneumonia (CABP). A total of 4,739 nonduplicate isolates were selected from a 2014 global surveillance program at medical institutions located in 43 countries within the United States, Europe, Latin America, and the Asia-Pacific region. Nafithromycin and comparator agents were used for susceptibility testing by reference broth microdilution methods. Nafithromycin was active against Staphylococcus aureus (MIC50/90, 0.06/>2 µg/ml), including erythromycin-resistant strains exhibiting an inducible clindamycin resistance phenotype (MIC50/90, 0.06/0.06 µg/ml) and telithromycin-susceptible strains (MIC50/90, 0.06/0.06 µg/ml), but it exhibited limited activity against most telithromycin-resistant and clindamycin-resistant isolates that were constitutively resistant to macrolides (MIC50/90, >2/>2 µg/ml). Nafithromycin was very active (MIC50/90, 0.015/0.06 µg/ml) against 1,911 Streptococcus pneumoniae strains, inhibiting all strains, with MIC values of ≤0.25 µg/ml. Telithromycin susceptibility was 99.9% for Streptococcus pneumoniae strains, and nafithromycin was up to 8-fold more potent than telithromycin. Overall, 37.9% of S. pneumoniae strains were resistant to erythromycin, and 19.7% were resistant to clindamycin. Nafithromycin was highly active against 606 Streptococcus pyogenes strains (MIC50/90, 0.015/0.015 µg/ml), inhibiting 100.0% of isolates at ≤0.5 µg/ml, and MIC50/90 values (0.015/0.015 to 0.03 µg/ml) were similar for the 4 geographic regions. Nafithromycin and telithromycin demonstrated comparable in vitro activities against 1,002 Haemophilus influenzae isolates and 504 Moraxella catarrhalis isolates. Overall, nafithromycin showed potent in vitro activity against a broad range of contemporary (2014) global pathogens. These results support the continued clinical development of nafithromycin for treatment of CABP.

Gepotidacin (GSK2140944) In Vitro Activity against Gram-Positive and Gram-Negative Bacteria.

Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the MICs and minimum bactericidal concentrations (MBCs) of gepotidacin and comparator agents for Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli Gepotidacin in vitro activity was also evaluated by using time-kill kinetics and broth microdilution checkerboard methods for synergy testing and for postantibiotic and subinhibitory effects. The MIC90 of gepotidacin for 50 S. aureus (including methicillin-resistant S. aureus [MRSA]) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates was 0.5 µg/ml, and for E. coli (n = 25 isolates), it was 4 µg/ml. Gepotidacin was bactericidal against S. aureus, S. pneumoniae, and E. coli, with MBC/MIC ratios of ≤4 against 98, 98, and 88% of the isolates tested, respectively. Time-kill curves indicated that the bactericidal activity of gepotidacin was observed at 4× or 10× MIC at 24 h for all of the isolates. S. aureus regrowth was observed in the presence of gepotidacin, and the resulting gepotidacin MICs were 2- to 128-fold higher than the baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index of >0.5 to ≤4; 82.7% for Gram-positive isolates and 82.6% for Gram-negative isolates). The postantibiotic effect (PAE) of gepotidacin was short when it was tested against S. aureus (≤0.6 h against MRSA and MSSA), and the PAE-sub-MIC effect (SME) was extended (>8 h; three isolates at 0.5× MIC). The PAE of levofloxacin was modest (0.0 to 2.4 h), and the PAE-SME observed varied from 1.2 to >9 h at 0.5× MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME against Gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens.

In Vitro Activity of Delafloxacin against Contemporary Bacterial Pathogens from the United States and Europe, 2014.

The in vitro activities of delafloxacin and comparator antimicrobial agents against 6,485 bacterial isolates collected from medical centers in Europe and the United States in 2014 were tested. Delafloxacin was the most potent agent tested against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus, Streptococcus pneumoniae, viridans group streptococci, and beta-hemolytic streptococci and had activity similar to that of ciprofloxacin and levofloxacin against certain members of the Enterobacteriaceae Overall, the broadest coverage of the tested pathogens (Gram-positive cocci and Gram-negative bacilli) was observed with meropenem and tigecycline in both Europe and the United States. Delafloxacin was shown to be active against organisms that may be encountered in acute bacterial skin and skin structure infections, respiratory infections, and urinary tract infections.

In Vitro Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae.

Gepotidacin (formerly GSK2140944) is a novel, first-in-class, triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV via a unique mechanism and has demonstrated in vitro activity against Neisseria gonorrhoeae, including drug-resistant strains, and also targets pathogens associated with other conventional and biothreat infections. Broth microdilution was used to evaluate the MIC and minimum bactericidal concentration (MBC) activity of gepotidacin and comparators against 25 N. gonorrhoeae strains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against three N. gonorrhoeae strains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against three N. gonorrhoeae strains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against two N. gonorrhoeae strains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC50 and MIC90 for gepotidacin against the 25 N. gonorrhoeae isolates tested were 0.12 and 0.25 µg/ml, respectively. The MBC50 and MBC90 for gepotidacin were 0.25 and 0.5 µg/ml, respectively. Gepotidacin was bactericidal, and single-step resistance selection studies did not recover any mutants, indicating a low rate of spontaneous single-step resistance. For combinations of gepotidacin and comparators tested using checkerboard methods, there were no instances where antagonism occurred and only one instance of synergy (with moxifloxacin; fractional inhibitory concentration, 0.375). This was not confirmed by in vitro time-kill studies. The PAE for gepotidacin against the wild-type strain ranged from 0.5 to >2.5 h, and the PAE-SME was >2.5 h. These in vitro data indicate that further study of gepotidacin is warranted for potential use in treating infections caused by N. gonorrhoeae.

Isavuconazole, micafungin, and 8 comparator antifungal agents' susceptibility profiles for common and uncommon opportunistic fungi collected in 2013: temporal analysis of antifungal drug resistance using CLSI species-specific clinical breakpoints and proposed epidemiological cutoff values.

The in vitro activities of isavuconazole, micafungin, and 8 comparator antifungal agents were determined for 1613 clinical isolates of fungi (1320 isolates of Candida spp., 155 of Aspergillus spp., 103 of non-Candida yeasts, and 35 non-Aspergillus molds) collected during a global survey conducted in 2013. The vast majority of the isolates of the 21 different species of Candida, with the exception of Candida glabrata (MIC90, 2 µg/mL), Candida krusei (MIC90, 1 µg/mL), and Candida guilliermondii (MIC90, 8 µg/mL), were inhibited by ≤0.25 µg/mL of isavuconazole. C. glabrata and C. krusei were largely inhibited by ≤1 µg/mL of isavuconazole. Resistance to fluconazole was seen in 0.5% of Candida albicans isolates, 11.1% of C. glabrata isolates, 2.5% of Candida parapsilosis isolates, 4.5% of Candida tropicalis isolates, and 20.0% of C. guilliermondii isolates. Resistance to the echinocandins was restricted to C. glabrata (1.3-2.1%) and C. tropicalis (0.9-1.8%). All agents except for the echinocandins were active against 69 Cryptococcus neoformans isolates, and the triazoles, including isavuconazole, were active against the other yeasts. Both the mold active triazoles as well as the echinocandins were active against 155 Aspergillus spp. isolates belonging to 10 species/species complex. In general, there was low resistance levels to the available systemically active antifungal agents in a large, contemporary (2013), global collection of molecularly characterized yeasts and molds. Resistance to azoles and echinocandins was most prominent among isolates of C. glabrata, C. tropicalis, and C. guilliermondii.

In vitro activity of a Hos2 deacetylase inhibitor, MGCD290, in combination with echinocandins against echinocandin-resistant Candida species.

MGCD290, a Hos2 fungal histone deacetylase inhibitor, showed modest activity when tested alone (MIC range, 0.12-4 µg/mL; MIC50/90, 0.5/4 µg/mL) against Candida glabrata (n=15; 14 fks mutants; 5 also fluconazole resistant), Candida albicans (8 fks mutants; 2 also fluconazole resistant), Candida tropicalis (4 fks mutants), and Candida krusei (3 fks mutants). However, MGCD290 showed synergy or partial synergy for 33.3%, 30.1%, 36.7%, and 80.0% of the isolates when tested with anidulafungin, caspofungin, micafungin, and fluconazole, respectively. Favorable interactions were achieved with low concentrations of MGCD290 (0.015-0.25 µg/mL), and categorical shifts were observed in 2 of 8 (25.0%) isolates of C. albicans and 2 of 3 (66.7%) isolates of C. krusei and in 4 of the 5 (80.0%) fluconazole-resistant isolates of C. glabrata. MGCD290 exerts a distinctly favorable influence on the MICs of fluconazole and the echinocandins, resulting in conversion from resistance to susceptibility regardless of fks mutations.

Telavancin Activity against gram-positive bacteria isolated from patients with skin and skin-structure infections.

Telavancin is approved in the United States and Canada for the treatment of complicated skin and skin structure infections (cSSSI) in adults caused by susceptible Gram-positive organisms. The antimicrobial activity of telavancin and comparators was evaluated against 5,027 (2007-2008) Gram-positive bacteria responsible for SSSI in medical centers in Asia-Pacific, European, Latin American, and North American regions. Telavancin was active against Staphylococcus aureus (MIC50(/)90, 0.12/0.25 mg/l; 100.0% susceptible) and coagulase-negative staphylococci (MIC50(/)90, 0.12/0.25 mg/l). telavancin inhibited all Enterococcus faecalis, including four strains displaying a VanB phenotype, at ≤ 1 mg/L (MIC50(/)90, 0.25/0.5 mg/l), except for two isolates with a VanA phenotype (MIC, >2 mg/l). Vancomycin-susceptible and VanB vancomycin-resistant E. faecium were inhibited by telavancin at ≤ 0.25 mg/L, while this drug exhibited elevated MIC values (≥ 0.5 mg/l) against E. faecium of VanA phenotype (MIC50(/)90, 2/>2 mg/l). Telavancin was potent against ß-haemolytic streptococci (MIC50(/)90, 0.03/0.12 mg/l; 100.0% susceptible) and viridans group streptococci (MIC50(/)90, 0.03/0.06 mg/l; 100.0% susceptible). These in vitro data document the activity of telavancin against contemporary Gram-positive isolates and support its clinical use for the treatment of cSSSI caused by the indicated pathogens.

Does caffeine modulate verbal working memory processes? An fMRI study.

To assess the effect of caffeine on the functional MRI signal during a 2-back verbal working memory task, we examined blood oxygenation level-dependent regional brain activity in 15 healthy right-handed males. The subjects, all moderate caffeine consumers, underwent two scanning sessions on a 1.5-T MR-Scanner separated by a 24- to 48-h interval. Each participant received either placebo or 100 mg caffeine 20 min prior to the performance of the working memory task in blinded crossover fashion. The study was implemented as a blocked-design. Analysis was performed using SPM2. In both conditions, the characteristic working memory network of frontoparietal cortical activation including the precuneus and the anterior cingulate could be shown. In comparison to placebo, caffeine caused an increased response in the bilateral medial frontopolar cortex (BA 10), extending to the right anterior cingulate cortex (BA 32). These results suggest that caffeine modulates neuronal activity as evidenced by fMRI signal changes in a network of brain areas associated with executive and attentional functions during working memory processes.

[Functional magnetic resonance imaging before motor cortex stimulation for phantom limb pain]. / fMRT vor Motorkortexstimulation beim Phantomschmerz.

This study deals with the diagnostic value of functional magnetic resonance imaging (fMRI) in a patient with phantom limb pain following traumatic amputation of the right arm. After failure with medication, resection of stump neurinoma, and spinal cord stimulation, fMRI with evidence of cortical reorganization was performed. Tactile stimulation of the perioral region and motor imagery with cranial, tactile stimulation of the stump led to a caudal shift in fMRI activity. Subsequent motor cortex stimulation brought relief from the pain. By detecting cortical reorganization, fMRI contributes to the indication for motor cortex stimulation for phantom pain and aids in electrode positioning.

Comparative antimicrobial potency of meropenem tested against Gram-negative bacilli: report from the MYSTIC surveillance program in the United States (2004).

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a longitudinal resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of bacterial pathogens to carbapenems and other broad-spectrum agents. In 2004 (year six), the antimicrobial activity of 12 broad-spectrum agents was assessed against 2,799 Gram-negative bacterial isolates submitted from 15 United States (USA) medical centers using Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) recommended methods. Meropenem continued to demonstrate a high potency with MIC90 values 4- to 32-fold lower than imipenem against the Enterobacteriaceae. The wide spectrum of activity for meropenem against all Gram-negative isolates was demonstrated by the overall rank order of percentage susceptibility at CLSI breakpoints: amikacin (96.5%) > meropenem (96.0%) > imipenem (95.8%) > piperacillin/tazobactam (91.5%) > tobramycin (91.4%) > cefepime (91.2%) > ceftazidime (89.0%) > gentamicin (88.0%) > aztreonam (81.5%) > levofloxacin (80.5%) > ciprofloxacin (80.2%) > ceftriaxone (69.1%). Only the aminoglycosides (84.5%) and carbapenems (76.1-83.8%) exhibited acceptable levels of susceptibility against the Acinetobacter spp. isolates as this species group became more resistant to all antimicrobial classes. A continued increase in the resistance rate for both ciprofloxacin and levofloxacin over the six years was observed, most alarming among Escherichia coli (20.2-20.7%) and indole-positive Proteus species (34.4-42.2%) isolates, some documented as clonal. Continued surveillance of these broad-spectrum antimicrobial agents appears warranted to monitor the potency and spectrum of activity against Gram-negative pathogens causing serious infections and the emergence of new or novel resistance mechanisms that could compromise carbapenem therapy.

In vitro activity of beta-lactam antimicrobial agents in combination with aztreonam tested against metallo-beta-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii.

We evaluate the antimicrobial interactions between aztreonam and selected beta-lactams when tested against metallo-beta-lactamase (MbetaL)-producing clinical strains. Ten Pseudomonsa aeruginosa strains, including nine MbetaL-producers (IMP-1, -2, -13, -16, VIM-1, -2, -7, SPM-1 and GIM-1) and five Acinetobacter baumannii strains, including three MbetaL-producers (IMP-1 and -2) were tested using time kill/bactericidal activity methods. Aztreonam at 4, 8 and 16 mg/L was combined with four other beta-lactam antimicrobials (cefepime, ceftazidime, meropenem and piperacillin/tazobactam or ampicillin/sulbactam), each tested at the recognized susceptible breakpoint concentration. Enhanced activity (synergism or additive effect) was observed with four P. aeruginosa strains (IMP-16, VIM-2, SPM-1 and GIM-1 containing strains) and four A. baumannii strains, while antagonism was observed with two P. aeruginosa (IMP-16 and SPM-1-producing strains) and one A. baumannii (non-MbetaL) strain. All other strains showed indifferent interaction (variation of +/- 1 log10 CFU/ml) with any combination evaluated.

Modulatory effects on human sensorimotor cortex by whole-hand afferent electrical stimulation.

OBJECTIVE: To investigate the effect of electrical stimulation of the nerve afferents of the hand on cortical activity elicited by whole-hand subthreshold stimulation for sensation in healthy human subjects. METHODS: Ten healthy volunteers were studied using BOLD-fMRI with 1) a test motor-task with finger-to-thumb tapping of the left hand, 2) a whole-hand afferent electrical stimulation of the left hand below the sensory level for sensation for 30 minutes, 3) a second fMRI run with the same paradigm as in the test motor-task immediately after electrical stimulation, and 4) a final identical fMRI run 2 hours post-stimulation to test the cortical changes induced by electrical stimulation. Experiments were carried out on a 1.5 T MR scanner and for fMRI echoplanar sequences were used. Data analysis was performed with SPM99. RESULTS: An increase of movement-related responses was seen within the primary motor and primary somatosensory areas of both hemispheres when comparing the test motor-task with the motor-task after electrical stimulation relative to the baseline or sham stimulation. Two hours post-stimulation the modulatory effects of mesh-glove stimulation diminished to baseline level except within the contralateral primary motor region. CONCLUSIONS: The increased BOLD response spatially localized within the sensorimotor cortex reflects an increase in neuronal activity that may provide augmented neuronal excitability.

Neisseria meningitidis with decreased susceptibility to penicillin: report from the SENTRY antimicrobial surveillance program, North America, 1998-99.

The purpose of this study was to estimate the prevalence of Neisseria meningitidis with decreased susceptibility to penicillin (MIC, >0.06 microg/mL) in North America (NA). Antimicrobial susceptibility testing by Etest (AB BIODISK, Solna, Sweden) was performed on 53 invasive clinical isolates obtained from 11 SENTRY Antimicrobial Surveillance Program participants in NA (9 states, 2 provinces) during 1998-99. All strains were markedly susceptible to ciprofloxacin (MIC(90), 0.008 microg/mL) and cefotaxime (MIC(90), < or = 0.002 microg/mL). Only 54.7% were susceptible to trimethoprim-sulfamethoxazole (TMP/SMX) at < or = 0.5/9.5 microg/mL. One strain was resistant to rifampin (MIC, > 32 microg/mL) and 16 isolates (30.2%) were relatively resistant to penicillin with MICs ranging from 0.094 to 0.25 microg/mL. No beta-lactamase production was detected. The serogroup distribution was 40% Y, 28% B, 24% C, 2% W-135, and 6% of strains were nongroupable. The prevalence of N. meningitidis with decreased susceptibility to penicillin in NA appears higher than previous reports.

Activity of BMS284756 (T-3811) tested against anaerobic bacteria, Campylobacter jejuni, Helicobacter pylori and Legionella spp.

BMS284756, a novel des-fluoro (6) quinolone (formerly T-3811), was tested for activity and spectrum using reference agar dilution (AD) and Etest (AB BIODISK, Solna, Sweden) methods. The antimicrobial activities of BMS284756, ciprofloxacin, gatifloxacin, levofloxacin, and trovafloxacin were evaluated against Campylobacter jejuni (38 strains), Helicobacter pylori (21 strains), Legionella spp. (66 strains), and 197 anaerobic isolates. BMS284756 (MIC(90), 0.008 microg/mL) was four-fold more active than gatifloxacin and trovafloxacin against H. pylori strains. Gatifloxacin and BMS284756 (MIC(50), 0.03 microg/mL) were > or = two-fold more active than levofloxacin against C. jejuni, but their spectrums were judged equivalent overall (89.4% susceptible). Against the Legionella spp., ciprofloxacin and levofloxacin (MIC(90), 0.25 microg/mL) had two-fold greater activity compared to gatifloxacin or BMS284756, but all strains were considered inhibited at clinically achievable levels. BMS284756 and trovafloxacin (MIC(90), 2 and 4 microg/mL, respectively) were four-to-eight-fold more potent than other comparators against the Gram-negative anaerobic species. Against the Gram-positive anaerobes (dominated by Clostridium difficile; 61 strains), BMS284756 activity was generally reduced, but equivalent or superior to trovafloxacin (68% inhibited at < or = 4 microg/mL). Inter-method comparisons (Etest versus AD) of BMS284756 MIC values showed a high correlation for C. jejuni and anaerobes (93.3 to 97.6% +/- two log (2) dilution steps). In conclusion, BMS284756 was very active against C. jejuni, H. pylori, Legionella spp. and most anaerobes, thus the potential role of this des-fluoro compound for treatment of infections caused by these fastidious species warrants further investigation.