In Vitro Activity and Interaction of Clindamycin Combined with Dihydroartemisinin against Plasmodium falciparum

ABSTRACT Combination regimens are considered a valuable tool for the fight against drug-resistant falciparum malaria. This study was conducted to evaluate the antimalarial potential of clindamycin in combination with dihydroartemisinin in continuously cultured and in freshly isolated Plasmodium falciparum parasites, measuring the inhibition of Plasmodium falciparum histidine-rich protein II synthesis. Interaction analysis revealed a synergistic or additive mode of interaction at various concentration ratios in all continuously cultured parasites at the 50% effective concentration (EC50) level. Antagonism was not found for any of the culture-adapted parasites. In fresh P. falciparum isolates, a fixed clindamycin-dihydroartemisinin combination exhibited additive activity at the EC50 and EC90 levels. The drug mixture showed no significant activity correlation to other commonly used antimalarials. The clindamycin-dihydroartemisinin combination appears to be a promising candidate for clinical investigation.

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Baseline and multinormal distribution of ex vivo susceptibilities of Plasmodium falciparum to methylene blue in Africa, 2013–18

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa174 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mathieu Gendrot ◽

Marylin Madamet ◽

Joel Mosnier ◽

Isabelle Fonta ◽

Rémy Amalvict ◽

...

Keyword(s):

Methylene Blue ◽

Plasmodium Falciparum ◽

Ex Vivo ◽

Geometric Mean ◽

Threshold Value ◽

Effective Concentration ◽

In Vitro Activity ◽

Potential Partner ◽

Median Effective Concentration

Abstract Background Plasmodium falciparum resistance to most antimalarial compounds has emerged in Southeast Asia and spread to Africa. In this context, the development of new antimalarial drugs is urgent. Objectives To determine the baseline in vitro activity of methylene blue (Proveblue®) on African isolates and to determine whether parasites have different phenotypes of susceptibility to methylene blue. Methods Ex vivo susceptibility to methylene blue was measured for 609 P. falciparum isolates of patients hospitalized in France for malaria imported from Africa. A Bayesian statistical analysis was designed to describe the distribution of median effective concentration (EC50) estimates. Results The EC50 ranged from 0.16 to 87.2 nM with a geometric mean of 7.17 nM (95% CI = 6.21–8.13). The 609 EC50 values were categorized into four components: A (mean = 2.5 nM; 95% CI = 2.28–2.72), B (mean = 7.44 nM; 95% CI = 7.07–7.81), C (mean = 16.29 nM; 95% CI = 15.40–17.18) and D (mean = 38.49 nM; 95% CI = 34.14–42.84). The threshold value for in vitro reduced susceptibility to methylene blue was estimated at 35 nM using the geometric mean of EC50 plus 2 SDs of the 609 isolates. This cut-off also corresponds to the lower limit of the 95% CI of the methylene blue EC50 of component D. Thirty-five isolates (5.7%) displayed EC50 values above this threshold. Conclusions Methylene blue exerts a promising efficacy against P. falciparum and is a potential partner for triple combinations.

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Lovastatin Has Significant Activity against Zygomycetes and Interacts Synergistically with Voriconazole

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.1.96-103.2006 ◽

2006 ◽

Vol 50 (1) ◽

pp. 96-103 ◽

Cited By ~ 77

Author(s):

Georgios Chamilos ◽

Russell E. Lewis ◽

Dimitrios P. Kontoyiannis

Keyword(s):

Fungicidal Activity ◽

Inhibitory Concentration ◽

Effective Concentration ◽

Significant Activity ◽

In Vitro Activity ◽

Testing Methods ◽

Disk Diffusion Testing ◽

Dye Staining

ABSTRACT Zygomycetes are emerging opportunistic molds resistant to most conventional antifungals. We evaluated the in vitro activity of lovastatin (LOV), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, against seven clinical isolates of Zygomycetes by using standard microdilution methods in three different media, disk diffusion testing, and viability dye staining. To further study the in vivo efficacy of LOV against zygomycetes, we developed a Drosophila melanogaster model of zygomycosis. In different experiments, groups of Toll-deficient (Tl) flies fed LOV-containing food were subsequently injected with two representative Zygomycetes isolates (Mucor and Rhizopus spp.). Finally, we examined the effects of LOV on voriconazole (VRC) activity against zygomycetes in vitro by checkerboard dilution, Epsilometer test-based methods, and bis-(1,3-dibutylbarbituric acid) trimethine oxonol staining and in vivo in Tl flies fed food containing LOV plus VRC and infected with zygomycetes. LOV exhibited significant, medium, and strain-independent fungicidal activity against all Zygomycetes isolates in vitro by all testing methods (MIC50, 48.0 μg/ml; 50% minimal fungicidal concentration, 56.0 μg/ml; 50% effective concentration, 29.4 μg/ml [6.6 to 38.9 μg/ml]). Tl flies fed LOV-containing food and infected with Mucor had a significantly better 6-day survival rate than did infected Tl flies fed regular food (P = 0.0005). LOV displayed in vitro synergy with VRC against all Zygomycetes isolates (fractional inhibitory concentration index, 0.104 to 0.290) by all methods used. LOV also displayed synergy with VRC in the Drosophila model of zygomycosis (P < 0.01). LOV is significantly active against zygomycetes and synergizes with triazoles inherently resistant to them, such as VRC. The clinical significance of these findings needs to be further explored.

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Synergism between Amodiaquine and Its Major Metabolite, Desethylamodiaquine, against Plasmodium falciparum In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.11.4089-4096.2004 ◽

2004 ◽

Vol 48 (11) ◽

pp. 4089-4096 ◽

Cited By ~ 15

Author(s):

S. T. Mariga ◽

J. P. Gil ◽

C. Sisowath ◽

W. H. Wernsdorfer ◽

A. Björkman

Keyword(s):

Plasmodium Falciparum ◽

Major Metabolite ◽

Vitro Activity ◽

Synergistic Activity ◽

Significant Activity ◽

In Vitro Activity ◽

Interaction Studies

ABSTRACT The in vitro activity of the prodrug amodiaquine and its metabolite monodesethyl-amodiaquine has been studied for three strains of Plasmodium falciparum: LS-2, LS-3, and LS-1. Both compounds showed significant activity against all three strains; the activity of amodiaquine was slightly higher than that of the metabolite. By use of a checkerboard design, interaction studies with both compounds yielded evidence of significant synergism; means of the sums of the fractional inhibitory concentrations were 0.0392 to 0.0746 for strain LS-2, 0.1567 to 0.3102 for strain LS-3, and 0.025 to 0.3369 for strain LS-1. In further investigations, the interaction of amodiaquine with monodesethyl-amodiaquine was tested at clinically relevant concentrations of both compounds. In these studies, involving amodiaquine at picomolar and femtomolar concentrations, the compound was found to exert high potentiating activity on monodesethyl-amodiaquine. This interaction produced mean ratios of observed to expected activity of 0.0505 to 0.0642 for strain LS-2, 0.0882 to 0.3820 for strain LS-3, and 0.0752 to 0.2924 for strain LS-1. The synergistic activity was most marked at monodesethyl-amodiaquine/amodiaquine ratios up to 100,000:1 but was still evident at higher ratios.

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In vitro activity of eravacycline and comparators in Gram-negative organisms, including drug-resistant phenotypes, isolated from respiratory sources in Europe

10.26226/morressier.56d6be7ad462b80296c97c85 ◽

2016 ◽

Author(s):

Hina Patel

Keyword(s):

Vitro Activity ◽

Drug Resistant ◽

In Vitro Activity ◽

Gram Negative ◽

Gram Negative Organisms

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In vitro activity of sulbactam-durlobactam against extensive-drug-resistant Acinetobacter baumannii isolates belonging to South America major clones

Journal of Global Antimicrobial Resistance ◽

10.1016/j.jgar.2021.05.001 ◽

2021 ◽

Author(s):

Carolina S. Nodari ◽

Fernanda F. Santos ◽

Mariana N.L. Kurihara ◽

Tiago B. Valiatti ◽

Rodrigo Cayô ◽

...

Keyword(s):

South America ◽

Acinetobacter Baumannii ◽

Vitro Activity ◽

Drug Resistant ◽

In Vitro Activity

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1375. In vitro Activity of Cefiderocol and Comparator Agents against Gram-Negative Isolates from Cancer Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1206 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S421-S422 ◽

Cited By ~ 2

Author(s):

Kenneth V I Rolston ◽

Bahgat Gerges ◽

Issam Raad ◽

Samuel L Aitken ◽

Ruth Reitzel ◽

...

Keyword(s):

Cancer Patients ◽

Active Agent ◽

Vitro Activity ◽

Significant Activity ◽

In Vitro Activity ◽

Research Support ◽

Gram Negative ◽

E Coli ◽

Research Grant

Abstract Background Gram-negative bacilli (GNB) are now the predominant cause of bacterial infection in cancer patients (CP). Many GNB are problematic because they have become resistant to commonly used antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin, is active against a wide spectrum of GNB. We evaluated its in vitro activity and that of eleven comparator agents against GNB isolated from CP. Methods A total of 341 recent GNB blood isolates from CP were tested using CLSI approved methods for MIC determination by broth microdilution. Comparator agents were amikacin (A), aztreonam (AZ), ceftazidime (CZ), ceftazidime/avibactam (CAV), cefepime (CEF), ciprofloxacin (CIP), colistin (CL), meropenem (MR), ceftolozane/tazobactam (C/T), tigecycline (TG), and trimethoprim/sulfamethoxazole (T/S). Results CFDC MIC90s as mg/L were: S. maltophilia [50 isolates] 0.25, E. coli (ESBL−) [50 isolates] 0.5, E. coli (ESBL+) [51 isolates] 2.0, K. pneumoniae (ESBL− and +) [60 isolates] 0.5; K. pneumoniae (CRE) [22 isolates] 2.0; P. aeruginosa (MDR) [32 isolates] 1.0; E. cloacae [27 isolates] 4.0; Achromobacter spp. [15 isolates] 0.12. CFDC inhibited P. agglomerans, Burkholderia spp., Sphingomonas spp., Ochrobactrum spp. at ≤1 mg/L [23 total isolates] and Elizabethkingia spp. and R. radiobacter at ≤8 mg/L [11 total isolates]. Among comparator agents, only T/S had consistent activity against S. maltophilia. For E. coli (ESBL− and +) MR, TG, CAV, CL were most active. For K. pneumoniae (ESBL–and +) MR, CAV were most active. For K. pneumoniae (CRE) and P. aeruginosa (MDR), none of the comparators had significant activity. For E. cloacae, MR, A, CAV, TG were most active. Among the uncommon organisms, MR and TG had the greatest activity. Conclusion Although susceptibility breakpoints have yet to be determined, CFDC has significant activity (≤4 mg/L) against most problematic Gram-negative organisms causing infections in CP based on available pharmacokinetic/pharmacodynamic data. In particular, its activity against S. maltophilia was superior to the comparators. Also, it was the most active agent against P. aeruginosa (MDR) and K. pneumoniae (CRE). Based on our results, CFDC warrants clinical evaluation for the treatment of blood stream infections caused by GNB in CP. Disclosures K. V. I. Rolston, Merck: Investigator, Research grant; JMI Laboratories: Investigator, Research grant; Shionogi (Japan): Investigator, Research grant. B. Gerges, Shionogi: Collaborator, Research support. S. L. Aitken, Shionogi: Scientific Advisor, Consulting fee; Merck: Scientific Advisor, Consulting fee; Medicines Co: Scientific Advisor, Consulting fee; Achaogen: Scientific Advisor, Consulting fee; Zavante: Scientific Advisor, Consulting fee; R. Prince, Shionogi: Investigator, Research support. Merck: Investigator, Research support.

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Cefepime/sulbactam as an enhanced antimicrobial combination therapy for the treatment of MDR Gram-negative infections

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz420 ◽

2019 ◽

Cited By ~ 1

Author(s):

David W Wareham ◽

M H F Abdul Momin ◽

Lynette M Phee ◽

Michael Hornsey ◽

Joseph F Standing

Keyword(s):

Fixed Ratio ◽

Vitro Activity ◽

Definitive Treatment ◽

High Dose ◽

In Vitro Activity ◽

Gram Negative ◽

Pharmacodynamic Modelling ◽

Carbapenem Resistant ◽

Combination Regimens

Abstract Background β-Lactam (BL)/β-lactamase inhibitor (BLI) combinations are widely used for the treatment of Gram-negative infections. Cefepime has not been widely studied in combination with BLIs. Sulbactam, with dual BL/BLI activity, has been partnered with very few BLs. We investigated the potential of cefepime/sulbactam as an unorthodox BL/BLI combination against MDR Gram-negative bacteria. Methods In vitro activity of cefepime/sulbactam (1:1, 1:2 and 2:1) was assessed against 157 strains. Monte Carlo simulation was used to predict the PTA with a number of simulated cefepime combination regimens, modelled across putative cefepime/sulbactam breakpoints (≤16/≤0.25 mg/L). Results Cefepime/sulbactam was more active (MIC50/MIC90 8/8–64/128 mg/L) compared with either drug alone (MIC50/MIC90 128 to >256 mg/L). Activity was enhanced when sulbactam was added at 1:1 or 1:2 (P < 0.05). Reduction in MIC was most notable against Acinetobacter baumannii and Enterobacterales (MIC 8/8–32/64 mg/L). Pharmacokinetic/pharmacodynamic modelling highlighted that up to 48% of all isolates and 73% of carbapenem-resistant A. baumannii with a cefepime/sulbactam MIC of ≤16/≤8 mg/L may be treatable with a high-dose, fixed-ratio (1:1 or 1:2) combination of cefepime/sulbactam. Conclusions Cefepime/sulbactam (1:1 or 1:2) displays enhanced in vitro activity versus MDR Gram-negative pathogens. It could be a potential alternative to existing BL/BLI combinations for isolates with a cefepime/sulbactam MIC of 16/8 mg/L either as a definitive treatment or as a carbapenem-sparing option.

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