The in vitro Susceptibility of Macrophages Infected with Amastigotes of Leishmania spp. to Pentavalent Antimonial Drugs and Other Compounds with Special Relevance to Cutaneous Isolates

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

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In vitro susceptibility of T lymphocytes from chimpanzees (Pan troglodytes) to human herpesvirus 6 (HHV-6): a potential animal model to study the interaction between HHV-6 and human immunodeficiency virus type 1 in vivo.

Journal of Virology ◽

10.1128/jvi.64.6.2751-2758.1990 ◽

1990 ◽

Vol 64 (6) ◽

pp. 2751-2758 ◽

Cited By ~ 26

Author(s):

P Lusso ◽

P D Markham ◽

S E DeRocco ◽

R C Gallo

Keyword(s):

Human Immunodeficiency Virus ◽

Animal Model ◽

Pan Troglodytes ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

In Vitro Susceptibility ◽

Immunodeficiency Virus

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In-vitro susceptibility of anaerobic bacteria to gar-936, a new glycylcycline

Clinical Microbiology and Infection ◽

10.1046/j.1469-0691.2000.00034-6.x ◽

2000 ◽

Vol 6 (3) ◽

pp. 159-163 ◽

Cited By ~ 46

Author(s):

C. Edlund ◽

C. E. Nord

Keyword(s):

Anaerobic Bacteria ◽

In Vitro Susceptibility

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In VitroActivities of Hexaazatrinaphthylenes against Leishmania spp.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00226-15 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2867-2874 ◽

Cited By ~ 13

Author(s):

Atteneri López-Arencibia ◽

Daniel García-Velázquez ◽

Carmen M. Martín-Navarro ◽

Ines Sifaoui ◽

María Reyes-Batlle ◽

...

Keyword(s):

Therapeutic Agents ◽

Content Type ◽

Inhibition Effect ◽

Intracellular Amastigotes ◽

Dependent Inhibition ◽

Leishmania Spp ◽

Dose Dependent Inhibition ◽

Dose Dependent ◽

Potential Use

ABSTRACTThein vitroactivity of a novel group of compounds, hexaazatrinaphthylene derivatives, against two species ofLeishmaniais described in this study. These compounds showed a significant dose-dependent inhibition effect on the proliferation of the parasites, with 50% inhibitory concentrations (IC50s) ranging from 1.23 to 25.05 μM against the promastigote stage and 0.5 to 0.7 μM against intracellular amastigotes. Also, a cytotoxicity assay was carried out to in order to evaluate the possible toxic effects of these compounds. Moreover, different assays were performed to determine the type of cell death induced after incubation with these compounds. The obtained results highlight the potential use of hexaazatrinaphthylene derivatives againstLeishmaniaspecies, and further studies should be undertaken to establish them as novel leishmanicidal therapeutic agents.

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146. antifungal Susceptibility Patterns of candida Parapsilosis Bloodstream Isolates in the US, 2008–2018

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.456 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S203-S203

Author(s):

Brenda L Tesini ◽

Meghan Lyman ◽

Brendan R Jackson ◽

Anita Gellert ◽

William Schaffner ◽

...

Keyword(s):

Candida Species ◽

Regional Variation ◽

Antifungal Susceptibility ◽

Bloodstream Infections ◽

Emerging Infections ◽

In Vitro Susceptibility ◽

Fluconazole Resistance ◽

The Us ◽

Susceptibility Patterns

Abstract Background Multidrug resistant Candida is an increasing concern. C. parapsilosis in particular has decreased in vitro susceptibility to echinocandins. As a result, fluconazole had been favored for C. parapsilosis treatment. However, there is growing concern about increasing azole resistance among Candida species. We report on antifungal susceptibility patterns of C. parapsilosis in the US from 2008 through 2018. Methods Active, population-based surveillance for candidemia through the Centers for Disease Control and Prevention’s (CDC) Emerging Infections Program was conducted between 2008–2018, eventually encompassing 9 states (GA, MD,OR, TN, NY, CA, CO, MN, NM). Each incident isolate was sent to the CDC for species confirmation and antifungal susceptibility testing (AFST). Frequency of resistance was calculated and stratified by year and state using SAS 9.4 Results Of the 8,704 incident candidemia isolates identified, 1,471 (15%) were C. parapsilosis; the third most common species after C. albicans and C. glabrata. AFST results were available for 1,340 C. parapsilosis isolates. No resistance was detected to caspofungin (MIC50 0.25) or micafungin (MIC50 1.00) with only one (< 1%) isolate resistant to anidulafungin (MIC50 1.00). In contrast, 84 (6.3%) isolates were resistant to fluconazole and another 44 (3.3%) isolates had dose-dependent susceptibility to fluconazole (MIC50 1.00). Fluconazole resistance increased sharply from an average of 4% during 2008–2014 to a peak of 14% in 2016 with a subsequent decline to 6% in 2018 (see figure). Regional variation is also observed with fluconazole resistance ranging from 0% (CO, MN, NM) to 42% (NY) of isolates by site. Conclusion The recent marked increase in fluconazole resistance among C. parapsilosis highlights this pathogen as an emerging drug resistant pathogen of concern and the need for ongoing antifungal resistance surveillance among Candida species. Our data support the empiric use of echinocandins for C. parapsilosis bloodstream infections and underscore the need to obtain AFST prior to fluconazole treatment. Furthermore, regional variation in fluconazole resistance emphasizes the importance of understanding local Candida susceptibility patterns. Disclosures Lee Harrison, MD, GSK (Consultant)Merck (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)

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Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production

Microorganisms ◽

10.3390/microorganisms9020320 ◽

2021 ◽

Vol 9 (2) ◽

pp. 320

Author(s):

Wilmer Alcazar ◽

Sami Alakurtti ◽

Maritza Padrón-Nieves ◽

Maija Liisa Tuononen ◽

Noris Rodríguez ◽

...

Keyword(s):

Nitric Oxide ◽

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Leishmania Amazonensis ◽

Superoxide Production ◽

In Vitro Susceptibility ◽

Intracellular Parasites ◽

Betulin Derivatives

Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

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1592. Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Against Enterobacterales and Pseudomonas aeruginosa With Overexpression of AmpC β-Lactamase From Phase 3 Clinical Trials

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1772 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S792-S793

Author(s):

Lynn-Yao Lin ◽

Dmitri Debabov ◽

William Chang ◽

Urania Rappo

Keyword(s):

Clinical Trials ◽

Active Agent ◽

Complicated Urinary Tract Infection ◽

Carbapenem Resistance ◽

Vitro Activity ◽

In Vitro Activity ◽

Control Groups ◽

In Vitro Susceptibility ◽

Intra Abdominal Infection

Abstract Background AmpC overproduction is a main mechanism of carbapenem resistance, in the absence of acquired carbapenemases. Ceftazidime-avibactam (CAZ-AVI) has potent in vitro activity against AmpC-producing P. aeruginosa and Enterobacterales that are resistant to carbapenems and other β-lactams. Methods Activity of CAZ-AVI and comparators was evaluated against AmpC-overproducing Enterobacterales (n=77) and P. aeruginosa (n=53) collected from 4 CAZ-AVI clinical trials: RECLAIM (complicated intra-abdominal infection [cIAI]), REPRISE (cIAI/complicated urinary tract infection [cUTI]), RECAPTURE (cUTI) and REPROVE (hospital-acquired pneumonia/ventilator associated pneumonia). In vitro susceptibility of CAZ-AVI and comparators was performed by broth microdilution using ThermoFisher custom panels. CLSI breakpoints were used to determine susceptibility. Quantitative PCR and microarray data were used to characterize presence and expression of AmpC. Clinical response at test of cure was assessed. Results Against 77 AmpC-overproducing Enterobacterales isolates, meropenem-vaborbactam (MVB) (98.7% susceptible [S]), CAZ-AVI (96.1% S), and meropenem (MEM) (96.1% S) had similar in vitro activity (Table), with greater in vitro activity than amikacin (AMK) (84.4% S), gentamicin (61.0% S), and ceftolozane-tazobactam (TZC) (35.1% S). Clinical cures in patients with baseline AmpC-overproducing Enterobacterales were 21/26 (81%) in CAZ-AVI group vs 17/20 (85%) in control groups. Against 53 AmpC-overproducing P. aeruginosa isolates, CAZ-AVI (73.6% S) showed greater in vitro activity than AMK (69.8% S), TZC (58.5% S), and MEM (37.7% S). Clinical cures in patients with baseline AmpC-overproducing P. aeruginosa were 12/14 (86%) in CAZ-AVI group vs 9/12 (75%) in control groups. MIC distributions against the same P aeruginosa isolates were CAZ-AVI (MIC50/90, 4/ >64 µg/mL), MVB (MIC50/90, 8/32 µg/mL), and MEM (MIC50/90, 8/32 µg/mL). Table Conclusion CAZ-AVI was the most active agent against AmpC-overproducing P. aeruginosa with higher proportion of clinical cure than controls. CAZ-AVI was also among the most active agents against AmpC-overproducing Enterobacterales, with >96% isolates susceptible. Disclosures Lynn-Yao Lin, MS, AbbVie (Employee) Dmitri Debabov, PhD, AbbVie (Employee) William Chang, BS, AbbVie (Employee) Urania Rappo, MD, MS, PharmD, Allergan (before its acquisition by AbbVie) (Employee)

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