A General Iridium-Catalyzed Reductive Dienamine Synthesis Allows a Five-Step Synthesis of Catharanthine via the Elusive Dehydrosecodine.

A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed. Pivoting on the chemoselective iridium(I)-catalyzed reductive activation of ß,γ-unsaturated δ-lactams, the efficiently produced reactive dienamine intermediates readily undergo [4 + 2] cycloaddition reactions with a wide range of dienophiles, resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (five-step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine.

General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides and Lactams.

An iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3 + 2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using 1 mol% Vaska's complex [IrCl(CO)(PPh3)2] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent regio- and diastereoselective, inter- and intramolecular dipolar cycloaddition reactions with variously substituted electron-deficient alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures, which ultimately control the unusual selectivities observed in certain cases.

Iridium-Catalyzed Aza-Spirocyclization of Indole-Tethered Amides: An Interrupted Pictet-Spengler Reaction.

A mild, reductive spirocyclization of indole-linked amides and lactams for the efficient and selective synthesis of aza-spirocyclic indoline products is described. The catalytic reductive activation of tertiary amides or lactams by Vaska's complex with tetramethyldisiloxane as the terminal reductant allowed iminium ion formation, before a diastereoselective 5-endo-trig spirocyclization of the tethered indole moiety was triggered. Terminal reduction affords the aza-spiroindoline products in an overall highly chemoselective and diastereoselective one-pot process.

Molecular epidemiology of gram-negative bacilli from infected neonates and health care workers' hands in neonatal intensive care units.

We sought to characterize the molecular epidemiology of gram-negative bacilli (GNB) causing infections in infants and associated with carriage on nurses' hands after hand hygiene was performed. From March 2001 to January 2003, GNB caused 192 (34%) of 562 hospital-acquired infections in the 2 participating neonatal intensive care units (NICUs) and were isolated from the hands of 45 (38%) of 119 nurses. Five species--Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens and Enterobacter cloacae, all of which were typed by pulsed-field gel electrophoresis--caused 169 (88%) of 192 of GNB infections. Overall, 58% of infections were caused by unique strains not cultured from other infants or nurses, and 31% of infections were part of unrecognized molecular clusters. In contrast, only 9% of strains that caused infections were cultured from nurses' hands. These data suggest that practices in addition to hand hygiene are needed to prevent horizontal transmission of GNB in the NICU.

Validation of a multicenter computer-based surveillance system for hospital-acquired bloodstream infections in neonatal intensive care departments.

Automated systems can facilitate surveillance for health care-associated infections. The New York Antimicrobial Resistance Project (NYARP) electronically monitors trends in bloodstream infections from 6 medical centers in New York, NY. To validate NYARP's data, episodes of health care-associated bloodstream infections detected by this system were compared with those obtained by an infection control practitioner performing an unrelated study in 2 participating neonatal intensive care departments. The sensitivity (84%), specificity (99%), and positive (84%) and negative (99%) predictive values of NYARP were excellent when coagulase-negative staphylococcal bloodstream infections were removed.

Outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit linked to artificial nails.

BACKGROUND: From April to June 2001, an outbreak of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae infections was investigated in our neonatal intensive care unit. METHODS: Cultures of the gastrointestinal tracts of patients, the hands of healthcare workers (HCWs), and the environment were performed to detect potential reservoirs for ESBL-producing K. pneumoniae. Strains of K. pneumoniae were typed by pulsed-field gel electrophoresis using XbaI. A case-control study was performed to determine risk factors for acquisition of the outbreak clone (clone A); cases were infants infected or colonized with clone A and controls (3 per case) were infants with negative surveillance cultures. RESULTS: During the study period, 19 case-infants, of whom 13 were detected by surveillance cultures, harbored clone A. The overall attack rate for the outbreak strain was 45%; 9 of 19 infants presented with invasive disease (n = 6) or developed invasive disease (n = 3) after colonization was detected. Clone A was found on the hands of 2 HCWs, 1 of whom wore artificial nails, and on the designated stethoscope of a case-infant. Multiple logistic regression analysis revealed that length of stay per day (odds ratio [OR], 1.05; 95% confidence interval [CI95], 1.02 to 1.09) and exposure to the HCW wearing artificial fingernails (OR, 7.87; CI95, 1.75 to 35.36) were associated with infection or colonization with clone A. CONCLUSION: Short, well-groomed, natural nails should be mandatory for HCWs with direct patient contact

Antimicrobial susceptibility and synergy studies of Stenotrophomonas maltophilia isolates from patients with cystic fibrosis.

Stenotrophomonas maltophilia is a newly emerging pathogen being detected with increasing frequency in patients with cystic fibrosis (CF). The impact of this multidrug-resistant organism on lung function is uncertain. The optimal treatment for S. maltophilia in CF patients is unknown. We studied the in vitro activity of ten antimicrobial agents, and conducted synergy studies by using checkerboard dilutions of eight pairs of antimicrobial agents against strains isolated from 673 CF patients from 1996 to 2001. This represents approximately 7 to 23% of the CF patients in the United States who harbor S. maltophilia annually. Doxycycline was the most active agent and inhibited 80% of 673 initial patient isolates, while trimethoprim-sulfamethoxazole inhibited only 16%. High concentrations of colistin proved more active than high concentrations of tobramycin and gentamicin. Serial isolates (n = 151) from individual patients over time (median, 290 days) showed minimal changes in resistance. Synergistic or additive activity was demonstrated by trimethoprim-sulfamethoxazole paired with ticarcillin-clavulanate (65% of strains), ciprofloxacin paired with ticarcillin-clavulanate (64% of strains), ciprofloxacin paired with piperacillin-tazobactam (59% of strains), trimethoprim-sulfamethoxazole paired with piperacillin-tazobactam (55% of strains), and doxycycline paired with ticarcillin-clavulanate (49% of strains). In all, 522 (78%) isolates were multidrug resistant (i.e., resistant to all agents in two or more antimicrobial classes) but 473 (91%) of these were inhibited by at least one antimicrobial combination (median, four; range, one to eight). To determine appropriate treatment for patients with CF, it is important to monitor the prevalence, antimicrobial susceptibility, and clinical impact of S. maltophilia in this patient population.

A survey of latent tuberculosis infection among laboratory healthcare workers in New York City.

OBJECTIVE: To determine the prevalence of positive tuberculin skin tests (TSTs), incidence of TST conversion, risk factors for positive TSTs, and history of active TB among HCWs in microbiology laboratories in New York City. DESIGN: Two-year survey from May 1999 to June 2001. SETTING: Nineteen microbiology laboratories. RESULTS: During the first year, interviews were conducted with 345 laboratory HCWs (mean, 18 HCWs per site; range, 2 to 51) to assess the prevalence of positive TSTs, but 3 (1%) could not recall their result and were excluded from further analyses. The mean age of the remaining 342 HCWs was 48 years; 68% (n = 233) were female, 54% (n = 183) received bacille Calmette-Guerin (BCG) vaccination, and 71% (n = 244) were foreign born. The prevalence of a positive TST was 57% (n = 196), but only 20% (n = 39) of the HCWs received isoniazid. The incidence of TST conversion in the second year of the study was 1% (1 of 108). Multivariate analysis identified age (odds ratio [OR] per year, 1.05; 95% confidence interval [CI95], 1.02-1.08), foreign birth (OR, 3.80; CI95, 1.98-7.28), BCG immunization (OR, 4.89; CI95, 2.72-8.80), and employment in a mycobacteriology laboratory (OR, 2.14; CI95, 1.25-3.68) as risk factors for a positive TST. Only one HCW had been treated for active TB. CONCLUSIONS: The prevalence of positive TSTs was high among laboratory HCWs, but the TST conversion rate was low. Higher rates of treatment for latent TB infection are desirable.

Completeness of pediatric TB reporting in New York City.

OBJECTIVE: Accurate surveillance of tuberculosis (TB) in children is critical because such cases represent recent transmission, but surveillance is difficult as only 10% to 50% of cases are culture-confirmed. Hospital-based sources were used to develop alternative surveillance to assess completeness of reporting for pediatric TB in northern Manhattan and Harlem from 1993 through 1995. METHODS: Alternative surveillance sources included ICD-9-CM hospital discharge codes for active TB and gastric aspirate reports. Cases identified by alternative surveillance were compared with cases previously reported to the New York City Department of Health (NYC DOH). RESULTS: Alternative surveillance detected 25 cases of possible pediatric TB, of which four (16%) had never been reported to the NYC DOH and three (12%) had been reported as suspect cases, but had not fulfilled the criteria for a reportable case of pediatric TB. Of these seven newly counted cases, three were detected by ICD-9-CM codes, three by a gastric aspirate log book, and one by both. In contrast, 13 other cases had been reported to the NYC DOH, but were undetected by our alternative surveillance; eight of these could be verified with available medical records. Thus, the demographic and clinical characteristics of the 25 detected and the eight undetected cases with available medical records were evaluated in this study. CONCLUSION: Alternative surveillance proved effective, was complementary to the NYC DOH surveillance efforts, and increased the number of pediatric TB cases identified during the study period by 21%.

Synergistic activities of macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans isolated from patients with cystic fibrosis.

Azithromycin and clarithromycin were paired with other antibiotics to test synergistic activity against 300 multidrug-resistant pathogens isolated from cystic fibrosis (CF) patients. Clarithromycin-tobramycin was most active against Pseudomonas aeruginosa and inhibited 58% of strains. Azithromycin-trimethoprim-sulfamethoxazole, azithromycin-ceftazidime, and azithromycin-doxycycline or azithromycin-trimethoprim-sulfamethoxazole inhibited 40, 20, and 22% of Stenotrophomonas maltophilia, Burkholderia cepacia complex, and Achromobacter (Alcaligenes) xylosoxidans strains, respectively.

Evaluating acceptability and completeness of overseas immunization records of internationally adopted children.

BACKGROUND: Increasing numbers of families in the United States are adopting children who were born in other countries. Appropriate immunization of internationally adopted children provides a challenge to pediatricians who must evaluate documentation of vaccines administered overseas and fulfill the recommended US childhood immunization schedule. The acceptability of vaccinations received outside the United States was addressed by the Advisory Committee on Immunization Practices in 1994, but few population-based studies assessing these vaccinations have been reported. METHODS: We performed a retrospective cohort study of 504 children who were adopted from other countries and evaluated in 1997 and 1998. Our goal was to determine the acceptability of overseas vaccinations for meeting US immunization requirements. We assessed immunization records for both valid documentation of receipt of vaccine and comparability with the recommended US schedule. We also determined the number of children who were up to date (UTD) for diphtheria-tetanus-pertussis, polio, hepatitis B, and measles-mumps-rubella vaccines under the US schedule. RESULTS: The children's mean age at initial US evaluation was 19 months; 71% were girls, and most (88%) had resided in orphanages. They were adopted from 16 countries, most frequently from China (48%) and Russia (31%). Thirty-five percent (178) of children had overseas immunization records, 167 (94%) of which were considered valid. Most children with valid records (112 [67%] of 167) were UTD for 1 or more vaccine series under the US schedule. CONCLUSION: The majority (65%) of internationally adopted children had no written records of overseas immunizations. Among the 178 children with documented overseas immunizations, 167 (94%) had valid records and some vaccine doses that were acceptable and UTD under the US schedule. Additional research and more specific guidance in the most cost-effective approaches to evaluation of overseas vaccinations are needed to ensure appropriate state-side vaccination and to improve the health of these children and their communities.