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Mammen, M. P., Armas, D., Hughes, F. H., Hopkins, A. M., Fisher, C. L., Resch, P. A., Rusalov, D., Sullivan, S. M., Smith, L. R.
VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal in vitro activity, and potent in vivo activity against Aspergillus fumigatus, including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (IV) doses of VL-2397. All dosing cohorts were fully enrolled; all subjects completed the safety follow-up. A safety committee reviewed the safety data for each dosing cohort prior to recommending the initiation of each subsequent cohort. No serious adverse events (SAEs) occurred; the majority of treatment-emergent adverse events (TEAEs) were mild and self-limited. The most common drug-related TEAEs were infusion site reactions. No clinically-concerning trends were noted in vital signs, electrocardiograms, physical examinations or safety laboratory results. Following single infusions of VL-2397 the overall and maximum exposures rose less than proportionally with increasing doses from 3 mg to 1200 mg as indicated by AUC24 and Cmax. No signs of VL-2397 accumulation were observed following IV infusions of 300, 600 and 1200 mg Q24H for 7 days. Renal elimination plays a major role in total body clearance with up to 47% of unmetabolized drug in urine 24 hours after administration at single doses > 30 mg. Overall, VL-2397 dosing in the study appeared to be safe and well tolerated in the healthy subjects. The safety profile, consistent PK and lack of drug accumulation support further development of VL-2397 in patients with invasive aspergillosis.
Gupta, S., Thakur, J., Pal, S., Gupta, R., Mishra, D., Kumar, S., Yadav, K., Saini, A., Yavvari, P. S., Vedantham, M., Singh, A., Srivastava, A., Prasad, R., Bajaj, A.
Interkingdom polymicrobial biofilms formed by gram-positive Staphylococcus aureus and Candida albicans pose serious threats of chronic systemic infections due to absence of any common therapeutic target for their elimination. Herein, we present the structure-activity relationship (SAR) of membrane-targeting Cholic Acid Peptide conjugates (CAPs) against gram-positive bacterial and fungal strains. Structure-activity investigations validated by mechanistic studies witnessed that valine-glycine dipeptide-derived CAP 3 is most effective broad-spectrum antimicrobial against S. aureus and C. albicans. CAP 3 was able to degrade the pre-formed single species and polymicrobial biofilms formed by S. aureus and C. albicans, and CAP 3-coated materials could prevent the formation of biofilms. Murine wound and catheter infection models further confirmed the equally potent bactericidal and fungicidal effect of CAP 3 against bacterial, fungal and polymicrobial infections. Taken together, these results demonstrate that CAPs, as potential broad-spectrum antimicrobials, can effectively clear the frequently encountered polymicrobial infections and can be fine-tuned further for future applications.
Truelove S, Keegan L, Moss W, et al.
AbstractMethodsWe conducted nine distinct systematic reviews on PubMed and Scopus (March to May 2018). We pooled and analyzed extracted data to fill in these key knowledge gaps.ResultsWe identified 6,934 articles, reviewed 781 full texts, and included 266. From this, we estimate the median incubation period is 1.4 days. On average, untreated cases are colonized for 18.5 days (95% CI, 17.7-19.4), and 95% clear Corynebacterium diphtheriae within 48 days (95% CI, 46-51). Asymptomatic carriers cause 76% (95% CI, 59-87%) fewer cases over the course of infection than symptomatic cases. The basic reproductive number is 1.7-4.3. Three doses of diphtheria toxoid vaccine are 87% (95% CI, 68-97%) effective against symptomatic disease and reduce transmission by 60% (95% CI, 51-68%). Vaccinated individuals can become colonized and transmit; consequently, vaccination alone can only interrupt transmission in 28% of outbreak settings, making isolation and antibiotics essential. While antibiotics reduce the duration of infection, they must be paired with diphtheria antitoxin to limit morbidity.ConclusionAppropriate tools to confront diphtheria exist; however, accurate understanding of the unique characteristics is crucial and lifesaving treatments must be made widely available. This comprehensive update provides clinical and public health guidance for diphtheria-specific preparedness and response.
Nys, C., Cherabuddi, K., Venugopalan, V., Klinker, K. P.
Stenotrophomonas maltophilia is an opportunistic pathogen observed in nosocomial infections. Due to biofilm production and resistance to numerous antimicrobials, eradication is difficult. This study evaluated outcomes for monomicrobial S. maltophilia infections. Seventy-six patients were included; 45 on trimethoprim-sulfamethoxazole, 31 on levofloxacin. Overall clinical cure, microbiological eradication, 28-day mortality was observed in 79%, 82%, 14%, respectively. Use of trimethoprim-sulfamethoxazole or levofloxacin resulted in high cure rates, however, a trend towards resistance selection with levofloxacin was identified.
Ahearn, C. P., Kirkham, C., Chaves, L. D., Kong, Y., Pettigrew, M. M., Murphy, T. F.
Nontypeable Haemophilus influenzae (NTHi) is the primary cause of bacterially induced acute exacerbations of chronic obstructive pulmonary disease (COPD). NTHi adheres to and invades host respiratory epithelial cells as a means to persist in the lower airways of adults with COPD. Therefore, we mined the genomes of NTHi strains isolated from the airways of adults with COPD to identify novel proteins to investigate their role in adherence and invasion of human respiratory epithelial cells. An isogenic knockout mutant of the open reading frame NTHI1441 showed a 76.6 ± 5.5% reduction in invasion of human bronchial and alveolar epithelial cells at 1, 3, and 6 hours post infection. Decreased invasion of the NTHI1441 mutant was independent of either intracellular survival or adherence to cells. NTHI1441 is conserved among NTHi genomes. Results of whole bacterial cell ELISA and flow cytometry experiments support that NTHI1441 has epitopes expressed on the bacterial cell surface. Adults with COPD develop increased serum IgG against NTHI1441 after experiencing an exacerbation with NTHi. This study reveals NTHI1441 as a novel NTHi virulence factor expressed during infection of the COPD lower airways that contributes to invasion of host respiratory epithelial cells. The role in host cell invasion, conservation among strains, and expression of surface exposed epitopes suggest that NTHI1441 is a potential target for preventative and therapeutic interventions for disease caused by NTHi.
Wiederhold, N. P., Najvar, L. K., Shaw, K. J., Jaramillo, R., Patterson, H., Olivo, M., Catano, G., Patterson, T. F.
The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris. Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole resistant clinical isolate of C. auris. Twenty-four hours post-inoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg by intraperitoneal injection three times daily, or 260 mg/kg intraperitoneally twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (10 mg/kg intraperitoneally once daily) and continued for seven days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm, and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm, and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole resistant C. auris even when therapy is delayed.
Ledbetter, L., Cherla, R., Chambers, C., Zhang, Y., Zhang, G.
Coxiella burnetii is an obligate intracellular Gram-negative bacterium which causes human Q fever. An acidified citrate cysteine medium (ACCM-2) has been developed which mimics the intracellular replicative niche of C. burnetii and allows axenic growth of the bacteria. To determine if C. burnetii cultured in ACCM-2 retains immunogenicity, we compared the protective efficacy of formalin-inactivated C. burnetii Nine Mile phase I (PIV) and phase II (PIIV) vaccines derived from axenic culture 7, 14, and 28 days post-vaccination. PIV conferred significant protection against virulent C. burnetii as early as 7 days post-vaccination, which suggests ACCM-2-derived PIV retains immunogenicity and protectivity. We analyzed the cellular immune response in spleens from PIV- and PIIV-vaccinated mice by flow cytometry 7 and 14 days post-vaccination and found significantly more granulocytes in PIV-vaccinated mice compared to PIIV-vaccinated mice. Interestingly, we found these infiltrating granulocytes to be SSChighCD11b+CD125+Siglec-F+ eosinophils. There was no change in the number of eosinophils in PIV-vaccinated CD4-deficient mice compared to controls, which suggests that eosinophil accumulation is CD4+ T cell-dependent. To evaluate the importance of eosinophils in PIV-mediated protection, we vaccinated and challenged eosinophil-deficient dblGATA mice. dblGATA mice had significantly worse disease than their wild-type counterparts when challenged 7 days post-vaccination, while no significant difference was seen 28 days post-vaccination. Nevertheless, dblGATA mice had elevated serum IgM with decreased IgG1 and IgG2a whether mice were challenged 7 or 28 days post-vaccination. These results suggest that eosinophils may play a role in early vaccine protection against C. burnetii and contribute to antibody isotype switching.
Malin, J. J., Winter, S., van Gumpel, E., Plum, G., Rybniker, J.
Mycobacterium abscessus, a rapidly growing non-tuberculous mycobacterium (NTM), is increasingly recognized as an important pathogen causing soft tissue and lung infections as well as severe disseminated infections in immunocompromised patients (1, 2)....
Popovich K, Snitkin E, Zawitz C, et al.
AbstractBackgroundJails may facilitate spread of MRSA in urban areas. We examined MRSA colonization at entrance to a large urban jail to determine if there are community transmission networks for MRSA that precede incarceration.MethodsIncarcerated males at the Cook County Jail were enrolled—with enrichment for HIV-positive subjects—within 72hours of intake. Surveillance cultures were collected to determine prevalence of MRSA colonization. Genomic analysis and epidemiologic data were used to identify community transmission networks.ResultsThere were 800 incarcerations (718 individuals) enrolled; 58% were HIV-infected. The prevalence of MRSA colonization at intake was 19%. In multivariate analysis, methamphetamine use, unstable housing, current/recent skin infection, and recent injection drug use were predictors of MRSA. Among HIV patients, recent injection drug use, current skin infection, and HIV care at outpatient Clinic A that emphasizes comprehensive care to the LGBTQ community were predictors of MRSA. 14(45%) of 31 detainees with care at Clinic A had colonization. WGS revealed that the high prevalence of MRSA in Clinic A was not due to clonal spread in the clinic but rather an intermingling of distinct community transmission networks. In contrast, genomic analysis supported spread of USA500 strains within a community network. Members of this USA500 network were more likely to be HIV-infected (p
Pulido-Ortega, J., Talamas-Rohana, P., Munoz-Ortega, M. H., Aldaba-Muruato, L. R., Martinez-Hernandez, S. L., Campos-Esparza, M. d. R., Cervantes-Garcia, D., Leon-Coria, A., Moreau, F., Chadee, K., Ventura-Juarez, J.
Entamoeba histolytica (Eh) is an anaerobic parasitic protozoan and the causative agent of amoebiasis. Eh expresses proteins that are structurally homologous to humans and use them as virulence factors. We have previously shown that Eh binds exogenous interferon gamma (IFN-) on its surface and in this study, we explored whether exogenous IFN- could modulate parasite virulence. We identified an IFN--like receptor on the surface of Eh using IFN- R1 antibody by immunofluorescence, Western blot, protein sequencing and in silico analysis. Coupling of human IFN- to the IFN--like receptor on live Eh significantly up regulated the expression of Eh Cysteine proteinase A1 (EhCP-A1), EhCP-A2, EhCP-A4, EhCP-A5, Amebapore A (AP-A), Cyclooxygenase 1 (Cox-1), Gal-lectin (Hgl) and peroxiredoxin (Prx) expression in a time-dependent fashion. IFN- signaling via the IFN--like receptor enhanced Eh erythrophagocytosis of human red blood cells that was abrogated with the STAT1 inhibitor, fludarabine. Exogenous IFN- enhanced Eh chemotaxis and killing of Caco-2 colonic and Hep G2 liver cells and amebic liver abscess in hamsters. These results demonstrate that Eh expresses a surface IFN--like receptor that is functional and may play a role in disease pathogenesis and/or immune evasion.
Zhao, N., Ming, S., Lu, Y., Wang, F., Li, H., Zhang, X., Zhao, X.
Eimeria tenella microneme-1 protein (EtMIC1) has been proposed to be a transmembrane protein, but this characteristic has not yet been confirmed experimentally. Furthermore, despite EtMIC1 being an important candidate antigen, its key epitope has not been reported. Here, two linear B-cell epitopes of EtMIC1, 91LITFATRSK99 and 698ESLISAGE705, were identified by western blotting using specific monoclonal antibodies (mAbs) and were named epitope I (located in the I-domain) and epitope CTR (located in the CTR domain), respectively. Sequence comparative analyses of these epitopes among Eimeria species that infect chickens showed that epitope I varies greatly across species, whereas epitope CTR is relatively conserved. Point mutation assay results indicate that all the amino acid residues of the epitopes recognized by mAb 1-A1 or 1-H2 are key amino acids involved in recognition. Comparative analyses of indirect immunofluorescence assay (IFA) results for mAbs 1-A1 and 1-H2 under both non-permeabilization and permeabilization conditions indicate that epitope I is located on the outside of the sporozoite surface membrane whereas epitope CTR is located on the inside, together providing experimental evidence that EtMIC1 is a transmembrane protein. IFA also labeled the EtMIC1 protein on the parasitophorous vacuole membrane and on the surface of schizonts, which suggests that the EtMIC1 protein may play an important role in parasitophorous vacuole formation and E. tenella development. Immunoprotective efficacy experiments revealed that epitope I has good immunogenicity, as evidenced by its induction of high serum antibody levels, blood lymphocyte proliferation, and CD4+ blood lymphocyte percentage.
Flamm, R. K., Shortridge, D., Castanheira, M., Sader, H. S., Pfaller, M. A.
We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) collected during 2014 through 2018 from 87 U.S. medical centers spanning all nine census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against A. baumannii-A. calcoaceticus species complex, colistin was the most active agent exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptible. Minocycline ranked second in activity with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility >90%) against S. maltophilia: minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against B. cepacia complex: trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0%), meropenem (MIC50/90, 2/8 μg/ml; 89.1%) and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.
Tanner, L., Evans, J. C., Seldon, R., Jordaan, A., Warner, D. F., Haynes, R. K., Parkinson, C. J., Wiesner, L.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a leading infectious killer globally, demanding the urgent development of faster-acting drugs with novel mechanisms of action. Riminophenazines such as clofazimine are clinically efficacious against both drug-susceptible and drug-resistant strains of Mtb. We determined the in vitro anti-Mtb activities; absorption, distribution, metabolism, and excretion properties; and in vivo mouse pharmacokinetics of a series of structurally related phenoxazines. One of these, PhX1, displayed promising drug-like properties and potent in vitro efficacy, supporting its further investigation in an Mtb-infected animal model.
Lahmer, T., Batres Baires, G., Heilmaier, M., Schmid, R. M., Sörgel, F., Kinzig, M., Huber, W., Mayr, U., Rasch, S.
Isavuconazole plasma concentrations were measured before and after Sustained Low-Efficiency Dialysis (SLED) treatment in 22 adult critically ill patients with probabale invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 μg/ml vs. 3.36 μg/ml; p
Maciel, M., Bauer, D., Baudier, R. L., Bitoun, J., Clements, J. D., Poole, S. T., Smith, M. A., Kaminski, R. W., Savarino, S. J., Norton, E. B.
Enterotoxigenic Escherichia coli (ETEC) is a major cause of infectious diarrhea in children, travelers and deployed military personnel. As such, development of a vaccine would be advantageous for public health. One strategy is to use subunits of colonization factors combined with antigen/adjuvant toxoids as an ETEC vaccine. Here, we investigated intradermal (ID) or sublingual (SL) delivery of CFA/I fimbrial antigens, including CfaEB and CfaE-LTB chimera admixed with dmLT (or double mutant heat-labile toxin LT-R192G/L211A). In addition, we compared dmLT with other LT proteins to better understand the generation of adjuvanted fimbrial and toxoid immunity as well as influence on any local skin reactogenicity. We demonstrated that immunization with dmLT admixed with CfaEB induces robust serum and fecal antibody responses to CFA/I fimbriae and LT toxin, but ID formulations are not optimal for SL delivery. Improved SL vaccination outcomes were observed when higher doses of dmLT (1-5μg) were admixed with CfaEB, or even better, when a CfaE-LTB chimera antigen was used instead. Serum anti-CFA/I total antibodies analyzed by ELISA were the best predictor of functional antibodies, based on the inhibition of red blood cell agglutination by ETEC. Immunization with other LT proteins or formulations with altered B-subunit binding during ID immunization (e.g., by addition of 5% lactose, LTA1, or LT-G33D) minimally altered development of antibody responses and cytokine recall responses, but reduced skin reactogenicity at the injection site. These results reveal how formulations and delivery parameters shape the adaptive immune responses to a toxoid and fimbria-derived subunit vaccine against ETEC.
Barde, F., Billaud, E., Goldwirt, L., Horodyckid, C., Jullien, V., Lanternier, F., Lesprit, P., Limousin, L., Cohen, J. F., Lortholary, O.
Posaconazole diffusion has been documented in various organs, contrasting with scarce data available for the human central nervous system (CNS). We analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample to plasma ratio between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycosis, even those caused by posaconazole-susceptible black fungi.
Matrevi, S. A., Opoku-Agyeman, P., Quashie, N. B., Bruku, S., Abuaku, B., Koram, K. A., Fox, A., Letizia, A., Duah-Quashie, N. O.
The continuous surveillance of polymorphisms in the kelch propeller domain of Plasmodium falciparum from Africa is important for the discovery of the actual markers of artemisinin resistance in the region. The information on the markers is crucial for control strategies involving chemotherapy and chemoprophylaxis for residents and non-immune travellers to the country. Polymorphisms in the kelch propeller domain of Ghanaian malaria parasites from three different ecological zones at several time periods were assessed. A total of 854 archived samples (2007-2016) collected from uncomplicated malaria patients aged ≤9 years old from 10 sentinel sites were used. Eighty-four percent had wildtype sequences (PF3D7_1343700) while many of the mutants had mostly nonsynonymous mutations clustered around codons 404-650. Variants with different amino acid changes of the codons associated with ART resistance validated markers were observed in Ghanaian isolates: frequencies for I543I, I543S, I543V, R561P, R561R, C580V were 0.12% each and 0.6% for R539I. Mutations reported from African parasites, A578S (0.23%) and Q613L (0.23%) were also observed. Three persisting NS mutations, N599Y (0.005%), K607E (0.004%) and V637G (0.004%) were observed in 3 of the 5 time periods nationally. The presence of variants of the validated markers of artemisinin resistance as well as persisting polymorphisms after 14 years of artemisinin-based combination therapy use argues for continuous surveillance of the markers. The molecular markers of artemisinin resistance and the observed variants will be monitored subsequently as part of ongoing surveillance of antimalarial drug efficacy/resistance studies in the country.
Thibault, C., Lavigne, J., Litalien, C., Kassir, N., Theoret, Y., Autmizguine, J.
Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetics (PK) trial of TZP in children 2m-6y from various clinical subpopulations. Children who were on TZP per standard of care were prospectively included and assigned to receive 80 mg/kg/dose q6h infused over 2h (2-5 months) or 90 mg/kg/dose q8h infused over 4h (6 months-6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin minimal inhibitory concentration (MIC) for Enterobacteria and P. aeruginosa for ≥ 50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7y (2m-6y) and 11.4 kg (3.8-27.6). A 2-compartment model with first-order elimination best described piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on volume of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4h infused over 0.5h in infants 2-≤ 6m and 130 mg/kg/dose every 8h infused over 4h in children > 6m-6y against bacteria with a MIC up to 16 mg/L. A total of 44 children (49%) had ≥ 1 adverse event, with 3 of these (site infiltrations) considered definitely associated with extended infusions.
Xiao, S., Guo, H., Weiner, W. S., Maddox, C., Mao, C., Gunosewoyo, H., Pelly, S., White, E. L., Rasmussen, L., Schoenen, F. J., Aube, J., Bishai, W. R., Lun, S.
The sub-optimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor was found to be encouraging in an extensively drug-resistant tuberculosis case study (M.C. Payen et al, Int J Tuberc Lung Dis 2012. 16:558–60). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by the non-canonical accessory proteins that are not considered as the classical targets of β-lactams, and that small-molecule inhibitors of these accessory targets may sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for their abilities to sensitize M. tuberculosis to meropenem. We identified six hit compounds that belong to either N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mouse. Structure-activity relationship studies on both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that the oxidoreductases, the MmpL family proteins, and the 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that are capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by the β-lactams accessory proteins. β-lactam compound-compound synthetic lethality may be an alternate approach for drug-resistant tuberculosis.
Madlen Davies, Rahul Meesaraganda, Ben Stockton
Representatives of Sun Pharma and Abbott have given gifts to quack doctors, encouraging them to prescribe their antibiotics. Madlen Davies, Rahul Meesaraganda, and Ben Stockton report.
Bilal, H., Bergen, P. J., Kim, T. H., Chung, S. E., Peleg, A. Y., Oliver, A., Nation, R. L., Landersdorfer, C. B.
Exacerbations of chronic Pseudomonas aeruginosa infections are a major treatment challenge in cystic fibrosis due to biofilm formation and hypermutation. We aimed to evaluate different dosage regimens of meropenem and tobramycin in monotherapies and combination against hypermutable carbapenem-resistant P. aeruginosa. A hypermutable P. aeruginosa isolate (MICmeropenem and MICtobramycin 8 mg/L) was investigated in the dynamic CDC biofilm reactor over 120 h. Regimens were meropenem as standard (2 g 8-hourly, 30% epithelial lining fluid (ELF) penetration) and continuous infusion (CI, 6 g/day, 30% and 60% ELF penetration), and tobramycin 10 mg/kg 24-hourly (50% ELF penetration). The time-courses of total and less-susceptible bacteria and MICs were determined and antibiotic concentrations quantified by LC-MS/MS. All monotherapies failed with substantial regrowth of planktonic (>6 log10 CFU/mL) and biofilm (≥6 log10 CFU/cm2) bacteria. Except for meropenem CI (60% ELF penetration) all monotherapies amplified less-susceptible planktonic and biofilm bacteria by 120 h. The meropenem standard regimen with tobramycin caused initial killing followed by considerable regrowth with resistance (MICmeropenem 64 mg/L, MICtobramycin 32 mg/L) for planktonic and biofilm bacteria. The combination containing the meropenem CI, at both levels of ELF penetration, synergistically suppressed regrowth of total planktonic bacteria and resistance of planktonic and biofilm bacteria. The combination with meropenem CI at 60% ELF penetration in addition synergistically suppressed regrowth of total biofilm bacteria. Standard regimens of meropenem and tobramycin were ineffective against planktonic and biofilm bacteria. The combination with meropenem CI exhibited enhanced bacterial killing and resistance suppression of carbapenem-resistant hypermutable P. aeruginosa.
Dixon, B. R. E. A., Hossain, R., Patel, R. V., Algood, H. M. S.
Helicobacter pylori is a Gram-negative bacterium that infects the gastric epithelia of its human host. Everyone who is colonized with these pathogenic bacteria can develop gastric inflammation, termed gastritis. Additionally, a small proportion of colonized people will develop more adverse outcomes including gastric ulcer disease, gastric adenocarcinoma or gastric MALT lymphoma. The development of these adverse outcomes is dependent on the establishment of a chronic inflammatory response. The development and control of this chronic inflammatory response is significantly impacted by CD4+ T helper cell activity. Noteworthy, T helper 17 (Th17) cells, a pro-inflammatory subset of CD4+ T cells, produce several pro-inflammatory cytokines that activate innate immune cell antimicrobial activity, drive a pathogenic immune response, regulate B cell responses, and participate in wound healing. Therefore, this review was written to take an intricate look at the involvement of Th17 cells, and their affiliated cytokines (IL-17A, IL-17F, IL-21, IL-22 and IL-26) in regulating the immune response to H. pylori colonization and carcinogenesis.
Labuda, J. C., Depew, C. E., Pham, O. H., Benoun, J. M., Ramirez, N. A., McSorley, S. J.
Salmonella infection can cause gastroenteritis in healthy individuals or a serious, systemic infection in immune-compromised patients and has a global impact. CD4 Th1 cells are the main lymphocyte population that participates in bacterial clearance during both primary and secondary infection in mice of the H-2b haplotype. Previous studies have used congenic mice to examine the function of Major Histocompatibility Class (MHC) molecules in elimination of this pathogen from the host. In this study, we further characterized the ability of H-2b, H-2k, and H-2u molecules to influence adaptive immunity to Salmonella in MHC congenic mice. By depleting different cell populations during infection, we unexpectedly found that CD8 T cells in addition to CD4 T cells play a major role in accelerated bacteria clearance from H-2k congenic hosts. Our data suggest that CD8 T cells accelerate clearance in some MHC congenic mouse strains and could therefore be an unexpected contributor to the protective efficacy of Salmonella vaccines outside of the typical studies in C57BL/6 mice.
Retningslinjer til sundhedsprofessionelle vedr. håndtering af infektion med zikavirus (2019)
Antiviral behandling af hiv smittede personer (2019)
Lumbalpunktur af patienter i blodfortyndende behandling (2019)
False-negative Results of Human Immunodeficiency Virus (HIV) Rapid Testing in HIV Controllers
21.09.2019Clinical Infectious Diseases Advance Access
Resistance of Influenza Virus to Antiviral Medications
20.09.2019Clinical Infectious Diseases Advance Access
Oseltamivir resistance in severe influenza A(H1N1)pdm09 pneumonia and acute respiratory distress syndrome: a French multicenter observational cohort study
20.09.2019Clinical Infectious Diseases Advance Access
Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes
20.09.2019Clinical Infectious Diseases Advance Access
Reply to Krahn and Sebastiani
20.09.2019Clinical Infectious Diseases Advance Access
Hvorfor synes Professor Thomas Benfield, at du bør læse"Oral versus Intravenous Antibiotics for Bone and Joint Infection."?
Hvad synes Professor Niels Obel om"Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis."?
Hvorfor anbefaler Professor Thomas Benfield artiklen"Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial."?
Hvad synes Professor Morten Sodemann om"Evidence-based clinical guidelines for immigrants and refugees."?
Hvad mener Professor Niels Obel om artiklen"Use of statins and risk of AIDS-defining and non-AIDS-defining malignancies among HIV-1 infected patients on antiretroviral therapy."?
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