Studies of the paradoxical effect of caspofungin at high drug concentrations

ABSTRACT Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare. We noted paradoxical turbid growth of Candida albicans isolates in broth in some high (supra-MIC) concentrations. Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 μg/ml, the frequency was 16%. Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls. Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series. Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent. Among a selected series of isolates tested at concentrations up to 50 μg/ml, an additional 53% showed a “mini-paradoxical effect”: no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration). These effects were reproducible; medium dependent in extent; noted in macro- and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other Candida species; and not due to destruction of drug in tubes showing the effect. Cooperative enhancement of inhibition by a second drug could eradicate the effect. We postulate that high drug concentrations derepress or activate resistance mechanisms. The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences.

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The Paradoxical Effect of Echinocandins in Aspergillus fumigatus Relies on Recovery of the β-1,3-Glucan Synthase Fks1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01690-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 17

Author(s):

Veronika Loiko ◽

Johannes Wagener

Keyword(s):

Cell Wall ◽

Aspergillus Fumigatus ◽

Minor Importance ◽

Initial Growth ◽

Paradoxical Effect ◽

Fungal Cell ◽

Glucan Synthase ◽

Content Type ◽

Drug Concentrations ◽

Very High

ABSTRACT Echinocandins target the fungal cell wall by inhibiting biosynthesis of the cell wall carbohydrate β-1,3-glucan. This antifungal drug class exhibits a paradoxical effect that is characterized by the resumption of growth of otherwise susceptible strains at higher drug concentrations (approximately 4 to 32 μg/ml). The nature of this phenomenon is still unknown. In this study, we analyzed the paradoxical effect of the echinocandin caspofungin on the pathogenic mold Aspergillus fumigatus. Using a conditional fks1 mutant, we show that very high caspofungin concentrations exert an additional antifungal activity besides inhibition of the β-1,3-glucan synthase. This activity could explain the suppression of paradoxical growth at very high caspofungin concentrations. Additionally, we found that exposure to inhibitory caspofungin concentrations always causes initial growth deprivation independently of the capability of the drug concentration to induce the paradoxical effect. Paradoxically growing hyphae emerge from microcolonies essentially devoid of β-1,3-glucan. However, these hyphae expose β-1,3-glucan again, suggesting that β-1,3-glucan synthesis is restored. In agreement with this hypothesis, we found that expression of the β-1,3-glucan synthase Fks1 is an essential requirement for the paradoxical effect. Surprisingly, overexpression of fks1 renders A. fumigatus more susceptible, whereas reduced expression leads to hyphae that are more resistant to the growth-inhibitory and limited fungicidal activity of caspofungin. Upregulation of chitin synthesis appears to be of minor importance for the paradoxical effect, since paradoxically growing hyphae exhibit significantly less chitin than the growth-deprived parental microcolonies. Our results argue for a model where the paradoxical effect primarily relies on recovery of β-1,3-glucan synthase activity.

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Novel Inhibitor of Plasmodium Histone Deacetylase That Cures P. berghei-Infected Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00729-08 ◽

2009 ◽

Vol 53 (5) ◽

pp. 1727-1734 ◽

Cited By ~ 29

Author(s):

S. Agbor-Enoh ◽

C. Seudieu ◽

E. Davidson ◽

A. Dritschilo ◽

M. Jung

Keyword(s):

Histone Deacetylases ◽

Mammalian Cells ◽

Malaria Parasite ◽

Antimalarial Activity ◽

Hdac Inhibitors ◽

High Drug ◽

Lead Compounds ◽

Drug Concentrations

ABSTRACT Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrations are required for effective antimalarial activity. Here, we report on HDAC inhibitors that are potent against P. falciparum at subnanomolar concentrations and that have high selectivities; the lead compounds have mean 50% inhibitory concentrations for the killing of the malaria parasite up to 950 times lower than those for the killing of mammalian cells. These potential drugs improved survival and completely and irreversibly suppressed parasitemia in P. berghei-infected mice.

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Reprocessing of Microcrystalline Cellulose Spheres with High Drug Concentrations

Drug Development and Industrial Pharmacy ◽

10.3109/03639049509065895 ◽

1995 ◽

Vol 21 (18) ◽

pp. 2121-2128

Author(s):

S. E. Lambert ◽

W. J. Reilly ◽

J. B. Schwartz

Keyword(s):

Microcrystalline Cellulose ◽

High Drug ◽

Drug Concentrations

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Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02831-15 ◽

2016 ◽

Vol 60 (7) ◽

pp. 3913-3920 ◽

Cited By ~ 25

Author(s):

Brian T. Tsuji ◽

Cornelia B. Landersdorfer ◽

Justin R. Lenhard ◽

Soon-Ee Cheah ◽

Visanu Thamlikitkul ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Drug Exposure ◽

Dose Intensity ◽

Polymyxin B ◽

Loading Dose ◽

Paradoxical Effect ◽

Bacterial Killing ◽

Unbound Fraction ◽

Content Type ◽

High Drug

ABSTRACTAdministering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains ofAcinetobacter baumanniiin the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (t1/2= 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against bothA. baumanniiisolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log10CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was anfAUC0–24(area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-densityA. baumanniiinfections.

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Nanobody-displaying porous silicon nanoparticles for the co-delivery of siRNA and doxorubicin

Biomaterials Science ◽

10.1039/d0bm01335h ◽

2021 ◽

Vol 9 (1) ◽

pp. 133-147

Author(s):

Terence Tieu ◽

Marcin Wojnilowicz ◽

Pie Huda ◽

Kristofer J. Thurecht ◽

Helmut Thissen ◽

...

Keyword(s):

Side Effects ◽

Porous Silicon ◽

Cancer Cells ◽

Targeted Delivery ◽

Silicon Nanoparticles ◽

High Drug ◽

Drug Concentrations ◽

Porous Silicon Nanoparticles

Targeted delivery of chemotherapeutics to cancer cells has the potential to yield high drug concentrations in cancer cells while minimizing any unwanted side effects.

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Paradoxical growth effect of caspofungin on Candida spp. sessile cells not only at high drug concentrations

The Journal of Antibiotics ◽

10.1038/s41429-018-0123-2 ◽

2018 ◽

Vol 72 (2) ◽

pp. 86-92

Author(s):

Małgorzata Prażyńska ◽

Eugenia Gospodarek-Komkowska

Keyword(s):

Growth Effect ◽

Candida Spp ◽

High Drug ◽

Drug Concentrations ◽

Paradoxical Growth ◽

Sessile Cells ◽

Paradoxical Growth Effect

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Lon Protease Is Essential for Paradoxical Survival of Escherichia coli Exposed to High Concentrations of Quinolone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00019-09 ◽

2009 ◽

Vol 53 (7) ◽

pp. 3103-3105 ◽

Cited By ~ 15

Author(s):

Muhammad Malik ◽

Joseph Capecci ◽

Karl Drlica

Keyword(s):

Escherichia Coli ◽

Dna Lesions ◽

Lon Protease ◽

High Drug ◽

Cell Lysate ◽

Drug Concentrations ◽

Parallel Increase ◽

High Concentrations ◽

Dna Size ◽

Very High

ABSTRACT A deficiency of the Escherichia coli Lon protease blocked paradoxical survival occurring at very high nalidixic acid concentrations. The absence of Lon also blocked a parallel increase in cell lysate viscosity likely to reflect DNA size. Thus, Lon may participate in repairing quinolone-mediated DNA lesions formed at high drug concentrations.

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Critical Drug Loss Induced by Silicone and Polyurethane Implantable Catheters in a Simulated Infusion Setup with Three Model Drugs

Pharmaceutics ◽

10.3390/pharmaceutics13101709 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1709

Author(s):

Nicolas Tokhadzé ◽

Philip Chennell ◽

Bruno Pereira ◽

Bénédicte Mailhot-Jensen ◽

Valérie Sautou

Keyword(s):

Liquid Chromatography ◽

Ir Spectroscopy ◽

High Drug ◽

Drug Concentrations ◽

Drug Loss ◽

Surface Potential Measurements ◽

Clinical Consequences ◽

Polyurethane Catheter ◽

Materials Used ◽

Polyurethane Catheters

Silicone and polyurethane are biocompatible materials used for the manufacture of implantable catheters, but are known to induce drug loss by sorption, causing potentially important clinical consequences. Despite this, their impact on the drugs infused through them is rarely studied, or they are studied individually and not part of a complete infusion setup. The aim of this work was to experimentally investigate the drug loss that these devices can cause, on their own and within a complete infusion setup. Paracetamol, diazepam, and insulin were chosen as models to assess drug sorption. Four commonly used silicone and polyurethane catheters were studied independently and as part of two different setups composed of a syringe, an extension set, and silicone or polyurethane implantable catheter. Simulated infusion through the catheter alone or through the complete setup were tested, at flowrates of 1 mL/h and 10 mL/h. Drug concentrations were monitored by liquid chromatography, and the silicone and polyurethane materials were characterized by ATR-IR spectroscopy and Zeta surface potential measurements. The losses observed with the complete setups followed the same trend as the losses induced individually by the most sorptive device of the setup. With the complete setups, no loss of paracetamol was observed, but diazepam and insulin maximum losses were respectively of 96.4 ± 0.9% and 54.0 ± 5.6%, when using a polyurethane catheter. Overall, catheters were shown to be the cause of some extremely high drug losses that could not be countered by optimizing the extension set in the setup.

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