We can do better: a fresh look at echinocandin dosing

Bader, Justin C; Bhavnani, Sujata M; Andes, David R; Ambrose, Paul G

doi:10.1093/jac/dkx448

Cited by 46Antifungal resistance and susceptibilityAntibiotics Pharmacokinetics and EfficacyPharmaceutical studies and practices

We can do better: a fresh look at echinocandin dosing

Open access

Bader, Justin C, Bhavnani, Sujata M, Andes, David R, Ambrose, Paul G·2018·Journal of Antimicrobial Chemotherapy

DOI 10.1093/jac/dkx448

Open this paper in CoChat — free account Open PDF

Abstract

First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally. This review presents pharmacokinetic/pharmacodynamic (PK/PD) evaluations for approved echinocandins (anidulafungin, caspofungin and micafungin) and rezafungin (previously CD101), an investigational agent. PK/PD-optimized regimens were evaluated to extend the utility of approved echinocandins when treating patients with resistant isolates. Although the benefits of these regimens were apparent, it was also clear that anidulafungin and micafungin, regardless of dosing adjustments, are unlikely to provide therapeutic exposures sufficient to treat highly resistant isolates. Day 1 probabilities of PK/PD target attainment of 5.2% and 85.1%, respectively, were achieved at the C. glabrata MIC90 (0.12 mg/L) and MIC97 (0.06 mg/L) values, respectively, for these agents. However, evaluations of rezafungin demonstrated high probabilities of target attainment over 4 weeks of therapy (100%) after administration of a single-dose regimen at the MIC90 of 0.06 mg/L. This signals that although existing therapies are not optimal to treat resistant organisms, more potent new echinocandins (relative to achievable drug exposures) may be on the horizon.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1093/jac/dkx448

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Rezafungin has a prolonged half-life of around 133 h that allows extended-interval dosing and provides high plasma drug concentrations early in therapy.
“Rezafungin has a prolonged half-life (around 133 h) that allows extended-interval dosing and provides high plasma drug concentrations early in therapy.”
From Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial (2023) · cites this paper as [11]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

State‐of‐the‐Art Clinical Article: Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men
Craig, W. A. (1998) · Clinical Infectious Diseases · doi:10.1086/516284 · Cited by 2,908 · see citing works
Invasive candidiasis
Kullberg, B. J., & Arendrup, M. C. (2015) · New England Journal of Medicine · doi:10.1056/nejmra1315399 · Cited by 1,315 · see citing works
Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations
Alexander, B. D., Johnson, M. D., Pfeiffer, C. D., Jiménez-Ortigosa, C., Catania, J., Booker, R., Castanheira, M., Messer, S. A., Perlin, D. S., & Pfaller, M. A. (2013) · Clinical Infectious Diseases · doi:10.1093/cid/cit136 · Cited by 778 · see citing works
Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis
Pappas, P. G., Rotstein, C. M. F., Betts, R. F., Nucci, M., Talwar, D., De Waele, J. J., Vazquez, J. A., Dupont, B. F., Horn, D. L., Ostrosky-Zeichner, L., et al. (2007) · Clinical Infectious Diseases · doi:10.1086/520980 · Cited by 638 · see citing works
Amphotericin B: current understanding of mechanisms of action
Brajtburg, J., Powderly, W. G., Kobayashi, G. S., & Medoff, G. (1990) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.34.2.183 · Cited by 503 · see citing works
Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections
Corey, G. R., Kabler, H., Mehra, P., Gupta, S., Overcash, J. S., Porwal, A. D., Giordano, P., LUCASTI, C. J., Perez, A., Good, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1310422 · Cited by 305 · see citing works
In Vivo Comparison of the Pharmacodynamic Targets for Echinocandin Drugs against Candida Species
Andes, D., Diekema, D. J., Pfaller, M. A., Bohrmuller, J., Marchillo, K., & Lepak, A. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01584-09 · Cited by 226 · see citing works
Self-citation
Single-Dose Oritavancin Versus 7–10 Days of Vancomycin in the Treatment of Gram-Positive Acute Bacterial Skin and Skin Structure Infections: The SOLO II Noninferiority Study
Corey, G. R., Good, S., Jiang, H., et al. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/ciu778 · Cited by 223 · see citing works
A Multicenter, Double‐Blind Trial of a High‐Dose Caspofungin Treatment Regimen versus a Standard Caspofungin Treatment Regimen for Adult Patients with Invasive Candidiasis
Betts, R. F., Nucci, M., Talwar, D., Gareca, M., Queiroz‐Telles, F., Bedimo, R. J., Herbrecht, R., Ruiz‐Palacios, G., Young, J. H., Baddley, J. W., et al. (2009) · Clinical Infectious Diseases · doi:10.1086/598933 · Cited by 214 · see citing works
A Randomized, Double-Blind, Parallel-Group, Dose-Response Study of Micafungin Compared with Fluconazole for the Treatment of Esophageal Candidiasis in HIV-Positive Patients
Wet, N. T. E. D., Llanos‐Cuentas, A., Suleiman, J. M. A. H., Baraldi, E., Krantz, E., Negra, M. D., & Diekmann-Berndt, H. (2004) · Clinical Infectious Diseases · doi:10.1086/423377 · Cited by 203 · see citing works
Azithromycin: 3-Day Versus 5-Day Course in the Treatment of Respiratory Tract Infections in Children
Ficnar, B., Huzjak, N., Oreskovic, K., Matrapazovski, M., & Klinar, I. (1997) · Journal of Chemotherapy · doi:10.1179/joc.1997.9.1.38 · Cited by 202 · see citing works
Breakthrough invasive candidiasis in patients on micafungin.
Pfeiffer, C. D., Garcia-Effron, G., Zaas, A. K., Perfect, J. R., Perlin, D. S., & Alexander, B. D. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.02390-09 · Cited by 196 · see citing works
FKS Mutant Candida glabrata: Risk Factors and Outcomes in Patients With Candidemia
Beyda, N. D., John, J., Kilic, A., Alam, M. J., Lasco, T. M., & Garey, K. W. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/ciu407 · Cited by 174 · see citing works
Update on Antifungal Drug Resistance
Perlin, D. S., Shor, E., & Zhao, Y. (2015) · Current Clinical Microbiology Reports · doi:10.1007/s40588-015-0015-1 · Cited by 174 · see citing works
Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults
Sandison, T., Ong, V., Lee, J., & Thye, D. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01627-16 · Cited by 161 · see citing works
Drug-ResistantCandida glabrataInfection in Cancer Patients
Farmakiotis, D., Tarrand, J. J., & Kontoyiannis, D. P. (2014) · Emerging Infectious Diseases · doi:10.3201/eid2011.140685 · Cited by 152 · see citing works
Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant
Hiemenz, J., Cagnoni, P. J., Simpson, D., Devine, S. M., Chao, N. J. A., Keirns, J. J., Lau, W. M., Facklam, D., & Buell, D. N. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.4.1331-1336.2005 · Cited by 150 · see citing works
The echinocandin antifungals: an overview of the pharmacology, spectrum and clinical efficacy
Wiederhold, N. P., & Lewis, R. E. (2003) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.12.8.1313 · Cited by 144 · see citing works
In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model
Andes, D., Diekema, D. J., Pfaller, M. A., Prince, R. A., Marchillo, K., Ashbeck, J., & Hou, J. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01061-07 · Cited by 140 · see citing works
Self-citation
FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance
Zimbeck, A. J., Iqbal, N., Ahlquist, A. M., Farley, M. M., Harrison, L. H., Chiller, T., & Lockhart, S. R. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00836-10 · Cited by 136 · see citing works
The evolution of haploidy and diploidy
Otto, S. P., & Gerstein, A. C. (2008) · Current Biology · doi:10.1016/j.cub.2008.09.039 · Cited by 121 · see citing works
Pharmacokinetics and Pharmacodynamics of Antifungals
Andes, D. R. (2006) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2006.06.007 · Cited by 115 · see citing works
Self-citation
Monitoring Antifungal Resistance in a Global Collection of Invasive Yeasts and Molds: Application of CLSI Epidemiological Cutoff Values and Whole-Genome Sequencing Analysis for Detection of Azole Resistance in Candida albicans
Castanheira, M., Deshpande, L. M., Davis, A. P., Rhomberg, P. R., & Pfaller, M. A. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00906-17 · Cited by 114 · see citing works
Once-Weekly Micafungin Therapy Is as Effective as Daily Therapy for Disseminated Candidiasis in Mice with Persistent Neutropenia
Gumbo, T., Drusano, G. L., Liu, W., Kulawy, R., Fregeau, C., Hsu, V., & Louie, A. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01337-06 · Cited by 101 · see citing works
Drug interactions of the newer oral antifungal agents
Katz (1999) · British Journal of Dermatology · doi:10.1046/j.1365-2133.1999.00011.x · Cited by 95 · see citing works
A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation
Sirohi, B., Powles, R. L., Chopra, R., Russell, N. H., Byrne, J., Prentice, H. G., Potter, M. N., & Koblinger, S. (2006) · Bone Marrow Transplantation · doi:10.1038/sj.bmt.1705398 · Cited by 93 · see citing works
Re-evaluating current antibiotic therapy
Craig, W. A. (2001) · Respiratory Medicine · doi:10.1016/s0954-6111(01)90023-x · Cited by 91 · see citing works
Echinocandin pharmacodynamics: review and clinical implications
Pound, M. W., Townsend, M. L., & Drew, R. H. (2010) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkq081 · Cited by 69 · see citing works
Rapid Development of Candida krusei Echinocandin Resistance during Caspofungin Therapy
Forastiero, A., Garcia-Gil, V., Rivero-Menéndez, O., Garcia‐Rubio, R., Monteiro, M. C., Alastruey‐Izquierdo, A., Jordán, R., Agorio, I., & Mellado, E. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01005-15 · Cited by 68 · see citing works
Characterisation of breakthrough invasive mycoses in echinocandin recipients: an evidence-based review
Sun, H., & Singh, N. (2009) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2009.09.020 · Cited by 66 · see citing works
Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial
Dunbar, L. M., Milata, J., McClure, T., Wasilewski, M. M., & the SIMPLIFI Study Team (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00029-11 · Cited by 65 · see citing works
Emergence of echinocandin-resistant Candida spp. in a hospital setting: a consequence of 10 years of increasing use of antifungal therapy?
Fekkar, A., Dannaoui, É., Meyer, I., Imbert, S., Brossas, J., Uzunov, M., Mellon, G., Nguyen‐Quoc, S., Guiller, E., Caumes, É., et al. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-014-2096-9 · Cited by 63 · see citing works
In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans
Ambrose, P. G., Drusano, G. L., & Craig, W. A. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cis001 · Cited by 61 · see citing works
Self-citation
Use of Epidemiological Cutoff Values To Examine 9-Year Trends in Susceptibility of Candida Species to Anidulafungin, Caspofungin, and Micafungin
Pfaller, M. A., Boyken, L. B., Hollis, R. J., Kroeger, J. S., Messer, S. A., Tendolkar, S., & Diekema, D. J. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.02120-10 · Cited by 59 · see citing works
Activity of a Long-Acting Echinocandin (CD101) and Seven Comparator Antifungal Agents Tested against a Global Collection of Contemporary Invasive Fungal Isolates in the SENTRY 2014 Antifungal Surveillance Program
Pfaller, M. A., Messer, S. A., Rhomberg, P. R., & Castanheira, M. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02045-16 · Cited by 53 · see citing works
Fractal Geometry and the Pharmacometrics of Micafungin in Overweight, Obese, and Extremely Obese People
Hall, R. G., Swancutt, M. A., & Gumbo, T. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.05193-11 · Cited by 52 · see citing works
Echinocandin Resistance in Candida Species Isolates from Liver Transplant Recipients
Prigent, G., Aït‐Ammar, N., Levesque, É., Fekkar, A., Costa, J., Anbassi, S. E., Foulet, F., Duvoux, C., Merle, J., Dannaoui, É., et al. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01229-16 · Cited by 44 · see citing works
Pharmacological basis of CD101 efficacy: exposure shape matters
Lakota, E. A., Bader, J. C., Ong, V., Bartizal, K., Miesel, L., Andes, D. R., Bhavnani, S. M., Rubino, C. M., Ambrose, P. G., & Lepak, A. J. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00758-17 · Cited by 40 · see citing works
Self-citation
Caspofungin-non-susceptible Candida isolates in cancer patients
Kofteridis, D. P., Lewis, R. E., & Kontoyiannis, D. P. (2009) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkp444 · Cited by 39 · see citing works
A rationale for reduced-frequency dosing of anidulafungin for antifungal prophylaxis in immunocompromised patients
Brüggemann, R. J. M., van der Velden, W. J. F. M., Knibbe, C. A. J., Colbers, A. P. H., Hol, S., Burger, D. M., Donnelly, J. P., & Blijlevens, N. M. A. (2014) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dku477 · Cited by 28 · see citing works
Development of echinocandin‐resistant C andida albicans candidemia following brief prophylactic exposure to micafungin therapy
Ruggero, M. A., & Topal, J. E. (2014) · Transplant Infectious Disease · doi:10.1111/tid.12230 · Cited by 23 · see citing works
Efficacy of Extended-Interval Dosing of Micafungin Evaluated Using a Pharmacokinetic/Pharmacodynamic Study with Humanized Doses in Mice
Lepak, A. J., Marchillo, K., VanHecker, J., Azie, N. E., & Andes, D. R. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02124-15 · Cited by 10 · see citing works
Self-citation

Flagged first, then by citations

Research works printed but not linked: 2

Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1-10.
Hall D, Shinabarger DL, Pillar CM et al. Evaluation of the fungicidal activity of CD101, a novel echinocandin, and comparators against recent clinical iso- lates of Candida spp. In Abstracts of the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2015. Abstract M-825. American Society for Microbiology.

Sorted by citations

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial
Thompson, G. R., Soriano, A., Cornely, O. A., Kullberg, B. J., Kollef, M., Vazquez, J., Honore, P. M., Bassetti, M., Pullman, J., Chayakulkeeree, M., et al. (2023) · The Lancet · doi:10.1016/s0140-6736(22)02324-8 · Cited by 192 · see citing works
Rezafungin versus caspofungin in a phase 2, randomized, double-blind study for the treatment of candidemia and invasive candidiasis: the STRIVE Trial
Thompson, G. R., Soriano, A., Skoutelis, A., Vazquez, J. A., Honore, P. M., Horcajada, J. P., Spapen, H., Bassetti, M., Ostrosky-Zeichner, L., Das, A. F., et al. (2021) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa1380 · Cited by 163 · see citing works
Biofilms and beyond: Expanding echinocandin utility
Larkin, E. L., Dharmaiah, S., & Ghannoum, M. A. (2018) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkx451 · Cited by 31 · see citing works
Population pharmacokinetics of rezafungin in patients with fungal infections
Rubino, C. M., & Flanagan, S. (2021) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00842-21 · Cited by 22 · see citing works

Relative Frequency of Paradoxical Growth and Trailing Effect with Caspofungin, Micafungin, Anidulafungin, and the Novel Echinocandin Rezafungin against Candida Species
Tóth, Z., Forgács, L., Kardos, T., Kovács, R., Locke, J. B., Kardos, G., Nagy, F., Borman, A. M., Adnan, A., & Majoros, L. (2020) · Journal of Fungi · doi:10.3390/jof6030136 · Cited by 20 · see citing works
Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis - review of the literature
Kofla, G., & Ruhnke, M. (2011) · European Journal of Medical Research · doi:10.1186/2047-783x-16-4-159 · Cited by 153 · see citing works
Echinocandin antifungals: review and update
Morrison, V. A. (2006) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.4.2.325 · Cited by 85 · see citing works
Medical Claims and Current Applications of the Potent Echinocandin Antifungals
Smith, L., & Lu, S. (2009) · Recent Patents on Anti-Infective Drug Discovery · doi:10.2174/157489110790112563 · Cited by 2 · see citing works
Echinocandin Antifungal Drugs in Fungal Infections: A Comparison
Chen, S. C.-A., Slavin, M. A., & Sorrell, T. C. (2011) · Drugs · doi:10.2165/11585270-000000000-00000 · Cited by 371 · see citing works

Authors: Bader, J. C., Bhavnani, S. M., Andes, D. R., & Ambrose, P. G.
Affiliations: Institute for Clinical Pharmacodynamics (United States) (US)
University of Wisconsin–Madison (US)
Corresponding author: Ambrose, Paul G
ORCID: Bhavnani, Sujata M
Andes, David R
Ambrose, Paul G
Venue: Journal of Antimicrobial Chemotherapy
Publisher: Oxford University Press (OUP)
Published: 2018-01-01
Volume: 73
Issue: suppl_1
Pages: i44-i50
ISSN: 0305-7453 (ISSN-L)
1460-2091
DOI: 10.1093/jac/dkx448
OpenAlex: W2782314309
Cited by: 46
References: 42
Citations by year: 2026: 1 · 2025: 1 · 2024: 7 · 2023: 4 · 2022: 3 · 2021: 9 · 2020: 10 · 2019: 4 · 2018: 3 · 2017: 4
FWCI: 0.88
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Antimicrobial Chemotherapy (publishedVersion)
PubMed (publishedVersion)
Funders: Cidara Therapeutics
Melinta Therapeutics
Astellas Pharma
Wockhardt
Actelion Pharmaceuticals
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords: echinocandins, antifungal dosing, pharmacokinetic-pharmacodynamic modeling, probability of target attainment, anidulafungin, caspofungin, micafungin, rezafungin, Candida glabrata, echinocandin resistance, single-dose regimen, antifungal resistance
MeSH terms: Antifungal Agents, Humans, Echinocandins, Drug-Related Side Effects and Adverse Reactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

We can do better: a fresh look at echinocandin dosing

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks