Antimicrobial Activity of Ceftolozane-Tazobactam, Ceftazidime-Avibactam, and Cefiderocol against Multidrug-Resistant Pseudomonas aeruginosa Recovered at a German University Hospital.

Multidrug-resistant (MDR) Pseudomonas aeruginosa increasingly causes health care-associated infections. In this study, we determined the activity of ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against 223 MDR P. aeruginosa clinical isolates recovered from 2013 to 2017 at the University Hospital Frankfurt by using MIC test strips. Furthermore, we evaluated the presence of genes encoding major ß-lactamases, such as VIM, IMP, NDM, GIM, SPM, and KPC; the extended spectrum ß-lactamase (ESBL)-carbapenemase GES; and the virulence-associated traits ExoS and ExoU, as in particular ExoU is thought to be associated with poor clinical outcome. For MDR P. aeruginosa isolates, the MIC50/MIC90 values of ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol were 8/>256 mg/L, 16/>256 mg/L, and 0.25/1 mg/L, respectively. Cefiderocol showed the highest susceptibility rate (97.3%) followed by ceftazidime-avibactam (48.4%) and ceftolozane-tazobactam (46.6%). In 81 (36.3%) isolates, carbapenemase gene blaVIM was detected, and in 5 (2.2%) isolates, blaGES was detected (with a positive association of exoU and blaVIM). More than half of the isolates belong to the so-called international P. aeruginosa "high-risk" clones, with sequence type 235 (ST235) (24.7%) being the most prevalent. This study underlines that ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol are important options for the treatment of infections due to MDR P. aeruginosa, with cefiderocol currently being the most active available antipseudomonal ß-lactam agent. According to our clinical experience, the outcome of cefiderocol therapy (8 patients) was favorable especially in cases of MDR P. aeruginosa-associated complicated urinary tract infections. IMPORTANCE After testing ceftolozane-tazobactam, ceftazidime-avibactam, and cefiderocol against a collection of 233 multidrug-resistant (MDR) Pseudomonas aeruginosa, we showed that cefiderocol is the most active antipseudomonal ß-lactam agent (susceptibility rates were 46.6%, 48.4%, and 97.4%, respectively). The most prevalent one was sequence type 235 (ST235) (24.7%), followed by ST244, ST175, and ST233, with all belonging to the top 10 P. aeruginosa high-risk clones with worldwide distribution. Our data indicate that during surveillance studies special attention should be paid to the MDR and highly virulent VIM- and ExoU-producing variant of ST235. Furthermore, in the case of infections caused by carbapenemase-producing MDR P. aeruginosa, cefiderocol is the preferred treatment option, while outcomes of complicated urinary tract infections and hospital-acquired pneumonia with cefiderocol were favorable.

Effect of immunosuppressive treatment on biomarkers in adult atopic dermatitis patients.

BACKGROUND: Biomarkers to objectively measure disease severity and predict therapeutic responses are needed in atopic dermatitis (AD). OBJECTIVE: Primary aim: To identify biomarkers reflecting therapeutic response in patients with AD treated systemically. Secondary aims: (i) To identify a biomarker pattern predicting responsiveness to systemic treatment. (ii) To identify differences in expression of biomarker in filaggrin gene (FLG) mutation carriers vs. non-FLG mutations carriers. METHODS: Thirty-eight severe AD patients treated with methotrexate or azathioprine participated. Serum levels of a proliferation-inducing ligand, B-cell activating factor of the TNF family, thymus and activation-regulated chemokine (chemokine (C-C motif) ligand 17) (TARC (CCl-17)), interleukin-1 receptor antagonist (IL-1RA), interleukin-1 bèta, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-18, IL-31, interferon gamma, tumour necrosis factor alpha, vascular endothelial growth factor (VEGF), monokine induced by interferon gamma (chemokine (C-X-C motif) ligand 9), interferon gamma-induced protein 10 (C-X-C motif chemokine Ligand 10), monocyte chemoattractant protein-1 (chemokine (C-C Motif) ligand 2), macrophage inflammatory protein-1 beta (chemokine (C-C motif) ligand 4), regulated on activation, normal T cell expressed and secreted (chemokine (C-C motif) ligand 5), Cutaneous T-cell-attracting chemokine (chemokine (C-C motif) ligand 27) (CTACK (CCL-27)), thymic stromal lymphopoietin, IL-5, interleukin-1 alpha and granulocyte-colony stimulating factor were analysed by ELISA and Luminex. The primary outcomes were differences in mean absolute change of SCORing Atopic Dermatitis (SCORAD) between groups after 12 weeks compared with baseline. Responders to treatment were defined by a SCORAD reduction in ≥50%. Buccal mucosa swabs were collected to determine FLG genotype status. RESULTS: Thymus and activation-regulated chemokine, CTACK, IL-13 and VEGF showed a significant decrease after treatment with methotrexate or azathioprine. However, no decrease in individual cytokine levels was significantly correlated with a change in any of the outcome parameters. In addition, baseline biomarker levels were not significantly different between responders and non-responders, and FLG and non-FLG mutants showed similar biomarker profiles. CONCLUSION: Thymus and activation-regulated chemokine and CTACK were confirmed as potential biomarkers. VEGF and IL-13 have a potential value as well. Biomarkers could not be used to discriminate at baseline between responders and non-responders, or FLG genotype status.

A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) affects children of all skin types. Most research has focused on light skin types. Studies investigating biomarkers in people with AD with dark skin types are lacking. OBJECTIVES: To explore skin barrier and immune response biomarkers in stratum corneum (SC) tape strips from children with AD with different skin types. METHODS: Tape strips were collected from lesional and nonlesional forearm skin of 53 children with AD and 50 controls. We analysed 28 immunomodulatory mediators, and natural moisturizing factors (NMF) and corneocyte morphology. RESULTS: Interleukin (IL)-1ß, IL-18, C-X-C motif chemokine (CXCL) 8 (CXCL8), C-C motif chemokine ligand (CCL) 22 (CCL22), CCL17, CXCL10 and CCL2 were significantly higher (P < 0·05) in lesional AD skin compared with nonlesional AD skin; the opposite trend was seen for IL-1α. CXCL8, CCL2 and CCL17 showed an association with objective SCORing Atopic Dermatitis score. NMF levels showed a gradual decrease from healthy skin to nonlesional and lesional AD skin. This gradual decreasing pattern was observed in skin type II but not in skin type VI. Skin type VI showed higher NMF levels in both nonlesional and lesional AD skin than skin type II. Corneocyte morphology was significantly different in lesional AD skin compared with nonlesional AD and healthy skin. CONCLUSIONS: Minimally invasive tape-stripping is suitable for the determination of many inflammatory mediators and skin barrier biomarkers in children with AD. This study shows differences between children with AD with skin type II and skin type VI in NMF levels, suggesting that some aspects of pathophysiological mechanisms may differ in AD children with light versus dark skin types.

Development of an enantioselective amine-silver co-catalyzed Conia-ene reaction.

The development of a novel cooperative catalytic system for an amine-silver co-catalyzed Conia-ene reaction of alkyne-tethered C-H-acidic compounds is reported. By using a cost-effective silver salt and a small diamine for the 5-exo-dig-cyclization the cyclopentane products are obtained in very good yields. The enantioselectivity of the reaction could be controlled by exchanging the diamine co-catalyst with a cinchona-derived primary amine.

Prognostic impact of systemic inflammatory diseases in elderly patients with congestive heart failure.

BACKGROUND AND AIMS: Inflammation is part of the pathophysiology of congestive heart failure (CHF). However, little is known about the impact of the presence of systemic inflammatory disease (SID), defined as inflammatory syndrome with constitutional symptoms and involvement of at least two organs as co-morbidity on the clinical course and prognosis of patients with CHF. METHODS AND RESULTS: This is an analysis of all 622 patients included in TIME-CHF. After an 18 months follow-up, outcomes of patients with and without SID were compared. Primary endpoint was all-cause hospitalization free survival. Secondary endpoints were overall survival and CHF hospitalization free survival. At baseline, 38 patients had history of SID (6.1%). These patients had higher N-terminal pro brain natriuretic peptide and worse renal function than patients without SID. SID was a risk factor for adverse outcome [primary endpoint: hazard ratio (HR) = 1.73 (95% confidence interval: 1.18-2.55, P = 0.005); survival: HR = 2.60 (1.49-4.55, P = 0.001); CHF hospitalization free survival: HR = 2.3 (1.45-3.65, P < 0.001)]. In multivariate models, SID remained the strongest independent risk factor for survival and CHF hospitalization free survival. CONCLUSION: In elderly patients with CHF, SID is independently accompanied with adverse outcome. Given the increasing prevalence of SID in the elderly population, these findings are clinically important for both risk stratification and patient management.

The immunogenicity in humans of a botulinum type F vaccine.

A purified monovalent botulinum type F toxoid vaccine was administered to 35 healthy adult volunteers in a phase I clinical trial. Serum samples from the vaccinated volunteers were evaluated for an antibody response at various time intervals over 1 year by mouse bioassay and ELISA. The antibody response was measured for varying doses of vaccine (2, 5, or 10 microg), and after single or multiple (two or three doses @ 10 microg) vaccinations. Six out of 15 (40%) individuals developed antibody titers after receiving a single dose. After two and three vaccinations, there was a 90% (18/20) and 100% (10/10) seroconversion rate, respectively. Eight months after initial injection, 57 and 63% of individuals were antibody positive following two or three vaccinations, respectively. Single vaccinations, at any of the tested dosages, elicited lower, if any, antibody response than did multiple vaccinations. After the third vaccination, ELISA titers positively correlated with mouse neutralization bioassay titers (r(2)=0.86).

Status of tuberculosis infection control programs at Texas hospitals, 1989 through 1991.

BACKGROUND: Paralleling the resurgence of tuberculosis (TB) in the United States, the reported number of persons with TB in Texas increased by 33% during 1985 through 1992, the third largest rise among all the states. This increase prompted us to survey hospitals in Texas to determine their degree of compliance with recommendations in the Centers for Disease Control and Prevention TB guidelines. METHODS: In April 1992, we mailed a voluntary questionnaire about TB infection control practices, health care worker tuberculin skin testing procedures, and Mycobacterium tuberculosis laboratory methods to a convenience sample of hospitals in Texas. RESULTS: Of 180 hospitals surveyed, 151 (83%) returned completed questionnaires. Of these, 90 (60%) were nonteaching community hospitals; 28 (19%) were teaching community hospitals; 13 (9%) were university-affiliated hospitals; and 20 (13%) were other hospitals. The number of hospitals to which patients with TB were admitted increased from 98 (65%) in 1989 to 122 (81%) in 1991. Respondent hospitals had a mean of 183 acute care beds (median 100, range 5 to 999), 6 acid-fast bacillus isolation rooms (median 2, range 0 to 57) and 7.5 admissions/year of patients with TB (median 2, range 0 to 202). Of hospitals responding to specific questions, 20% (27/137) admitted patients with multidrug-resistant TB, 18% (25/140) reported not having any acid-fast bacillus isolation rooms, and 28% (35/125) had no rooms meeting all of the Centers for Disease Control and Prevention criteria for acid-fast bacillus isolation (negative air pressure, > or = 6 air changes per hour, and air directly vented to the outside). The tuberculin skin test conversions among health care workers rose from 246 (0.6%) in 1989 to 547 (0.9%) in 1991. CONCLUSION: Although the number of Texas hospitals admitting patients with TB increased during 1989 through 1991, many facilities still did not have infection control practices consistent with the 1992 Centers for Disease Control and Prevention TB guidelines.

Simulation analysis of formycin 5'-monophosphate analog substrates in the ricin A-chain active site.

Ricin is an RNA N-glycosidase that hydrolyzes a single adenine base from a conserved loop of 28S ribosomal RNA, thus inactivating protein synthesis. Molecular-dynamics simulation methods are used to analyze the structural interactions and thermodynamics that govern the binding of formycin 5'-monophosphate (FMP) and several of its analogs to the active site of ricin A-chain. Simulations are carried out initiated from the X-ray crystal structure of the ricin-FMP complex with the ligand modeled as a dianion, monoanion and zwitterion. Relative changes in binding free energies are estimated for FMP analogs constructed from amino substitutions at the 2- and 2'-positions, and from hydroxyl substitution at the 2'-position.

Development of a live, oral, attenuated vaccine against El Tor cholera.

Vibrio cholerae El Tor strains from Peru, Bangladesh, and Bahrain were attenuated by deletion of a genetic element that encodes virulence factors and RS1. The B subunit of ctx (ctxB) was reintroduced into the recA gene of the deletion mutants, rendering them unable to recombine with exogenous genetic elements and generating Peru-3, Bang-3, and Bah-3. Fifteen volunteers received one dose of various vaccine strains at 4 x 10(6) to 1 x 10(8) cfu. All strains colonized the gut. A > or = 4-fold rise in vibriocidal titer was observed in 14 volunteers, with titers of > or = 1600 in 13. Peru-3 was the least reactogenic, but 2 of 6 volunteers had loose stools. Peru-14, a filamentous motility-deficient mutant of Peru-3, was well tolerated and colonized 18 of 21 volunteers at doses of 2 x 10(6) to 1 x 10(9) cfu. Also, when 8 Peru-3 or Peru-5 vaccinees, 5 Peru-14 vaccinees, and 8 controls were challenged with 2 x 10(6) cfu V. cholerae El Tor Inaba (N16961), 11 vaccinees were protected compared with no controls. Peru-14 shows promise as a safe, effective, single-dose oral vaccine against El Tor cholera.

Characterization of monoclonal antibodies against Naja naja oxiana neurotoxin I.

Seven monoclonal antibodies (mAbs) were developed against neurotoxin I (NT-1), a protein from central Asian cobra (Naja naja oxiana) venom which binds specifically to nicotinic acetylcholine receptor (AchR). All of the mAbs cross-reacted with another long-chain post-synaptic neurotoxin, Bungarus multicinctus alpha-bungarotoxin (alpha-BT), but not Naja naja kaouthia alpha-cobratoxin, in an enzyme-linked immunosorbent assay (e.l.i.s.a.). Short-chain post-synaptic neurotoxins like Naja naja atra cobrotoxin, Laticauda semifasciata erabutoxin b, or N. n. oxiana neurotoxin II did not cross-react with the NT-1 mAbs, but an antigen(s) found in Dendroaspis polylepis, Acanthophis antarcticus and Pseudechis australis venoms was immunoreactive. The e.l.i.s.a. readings for dithiothreitol-reduced NT-1 and NT-1 mAbs ranged from 13 to 27% of those for native toxin but reduced alpha-BT was not immunoreactive. Synthetic NT-1 peptides were used in epitope-mapping studies and two, non-contiguous regions (Cys15-Tyr23 and Lys25-Gly33 or Pro17-Lys25 and Asp29-Lys37) were recognized by the NT-1 mAbs. The NT-1 mAbs individually inhibited 31-71% of alpha-BT binding to AchR in vitro and afforded a slight protective effect in vivo with a toxin: antibody mole ratio of 1:1.5. This report is the first to describe mAbs which recognize and protect against a heterologous, long-chain, post-synaptic neurotoxin from snake venom.

Clinical results of transanal endoscopic microsurgery.

Using the "transanal endoscopic microsurgery" technique, 140 patients were treated at the Department of Surgery in Cologne and Mainz. Of the patients with adenomas, 68.2% had typical symptoms preoperatively. The postoperative hospital attendance was 8.7 days, with an average resection size of 14.4 cm2. The postoperative complication rate was 5%, and there were no deaths related to the technique. In a prospective controlled trial, 2.2% of the patients with adenomas treated endoscopically in Mainz showed recidivation, requiring reoperation. The follow-up rate was 100%. In 30 cases, microscopic examination revealed carcinoma. Radical reoperation in 8 pT1 tumours showed neither remaining tumour nor lymph node metastases. Twelve patients with pT1 carcinoma treated by local surgery alone were recurrence-free with an average follow-up period of 12.3 months. So far, there have been no late results.

Technique of transanal endoscopic microsurgery.

Sessile adenomas are predominantly localized in the rectum and lower sigma. Surgical removal is indicated but often implies an invasive surgical procedure. Using conventional transanal surgical techniques, only the lower rectum can be reached and there are high rates of recurrence. The new technique combines an endoscopic view of the rectum under gas insufflation via a stereoscopic telescope with conventional surgical preparation and suturing. Adenomas can be excised using the mucosectomy technique or full-thickness-excision, whereas carcinomas should be excised using full-thickness excision with a sufficient border of healthy mucosa. In carcinomas of the sacral cavity, we remove the retrorectal fat up to the fascia of Waldeyer, including the regional lymph nodes. Transanal endoscopic microsurgery is the most economical and tissue-saving surgical technique for the removal of rectal adenomas and early rectal carcinomas.