A quantitative systems pharmacology (QSP) model for  Pneumocystis  treatment in mice

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Abstract

Background

The yeast-like fungi Pneumocystis, resides in lung alveoli and can cause a lethal infection known as Pneumocystis pneumonia (PCP) in hosts with impaired immune systems. Current therapies for PCP, such as trimethoprim-sulfamethoxazole (TMP-SMX), suffer from significant treatment failures and a multitude of serious side effects. Novel therapeutic approaches (i.e. newly developed drugs or novel combinations of available drugs) are needed to treat this potentially lethal opportunistic infection. Quantitative Systems Pharmacological (QSP) models promise to aid in the development of novel therapies by integrating available pharmacokinetic (PK) and pharmacodynamic (PD) knowledge to predict the effects of new treatment regimens.

Results

In this work, we constructed and independently validated PK modules of a number of drugs with available pharmacokinetic data. Characterized by simple structures and well constrained parameters, these PK modules could serve as a convenient tool to summarize and predict pharmacokinetic profiles. With the currently accepted hypotheses on the life stages of Pneumocystis, we also constructed a PD module to describe the proliferation, transformation, and death of Pneumocystis. By integrating the PK module and the PD module, the QSP model was constrained with observed levels of asci and trophic forms following treatments with multiple drugs. Furthermore, the temporal dynamics of the QSP model were validated with corresponding data.

Conclusions

We developed and validated a QSP model that integrates available data and promises to facilitate the design of future therapies against PCP.

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Most cited references 34

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Sulfonamide resistance: mechanisms and trends.

O Sköld (2000)

Sulfonamides were the first drugs acting selectively on bacteria which could be used systemically. Today they are infrequently used, in part due to widespread resistance. The target of sulfonamides, and the basis for their selectivity, is the enzyme dihydropteroate synthase (DHPS) in the folic acid pathway. Mammalian cells are not dependent on endogenous synthesis of folic acid and generally lack DHPS. Instead, they have a folate uptake system which most prokaryotes lack. Laboratory mutants in the dhps (folP) gene can be easily isolated and show a trade off between sulfonamide resistance and DHPS enzyme performance. Clinical resistant mutants, however, have additional compensatory mutations in DHPS that allow it to function normally. In many pathogenic bacteria sulfonamide resistance is mediated by the horizontal transfer of foreign folP or parts of it. Clinical resistance in gram-negative enteric bacteria is plasmid-borne and is effected by genes encoding alternative drug-resistance variants of the DHPS enzymes. Two such genes, sul1 and sul2, have been sequenced and are found at roughly the same frequency among clinical isolates. Remarkably, the corresponding DHPS enzymes show pronounced insensitivity to sulfonamides but normal binding to the p -aminobenzoic acid substrate, despite the close structural similarity between substrate and inhibitor. Copyright 2000 Harcourt Publishers Ltd.

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Early predictors of mortality from Pneumocystis jirovecii pneumonia in HIV-infected patients: 1985-2006.

Simon Edwards, Alison D. Grant, Jeff Miller … (2008)

Pneumocystis jirovecii pneumonia (PCP) remains the leading cause of opportunistic infection among human immunodeficiency virus (HIV)-infected persons. Previous studies of PCP that identified case-fatality risk factors involved small numbers of patients, were performed over few years, and often focused on patients who were admitted to the intensive care unit. The objective of this study was to identify case-fatality risk factors present at or soon after hospitalization among adult HIV-infected patients admitted to University College London Hospitals (London, United Kingdom) from June 1985 through June 2006. We performed a review of case notes for 494 consecutive patients with 547 episodes of laboratory-confirmed PCP. Overall mortality was 13.5%. Mortality was 10.1% for the period from 1985 through 1989, 16.9% for the period from 1990 through June 1996, and 9.7% for the period from July 1996 through 2006 (P = .142). Multivariate analysis identified factors associated with risk of death, including increasing patient age (adjusted odds ratio [AOR], 1.54; 95% confidence interval [CI], 1.11-2.23; P = .011), subsequent episode of PCP (AOR, 2.27; 95% CI, 1.14-4.52; P = .019), low hemoglobin level at hospital admission (AOR, 0.70; 95% CI, 0.60-0.83; P < .001), low partial pressure of oxygen breathing room air at hospital admission (AOR, 0.70; 95% CI, 0.60-0.81; P < .001), presence of medical comorbidity (AOR, 3.93; 95% CI, 1.77-8.72; P = .001), and pulmonary Kaposi sarcoma (AOR, 6.95; 95% CI, 2.26-21.37; P = .001). Patients with a first episode of PCP were sicker (mean partial pressure of oxygen at admission +/- standard deviation, 9.3+/-2.0 kPa) than those with a second or third episode of PCP (mean partial pressure of oxygen at admission +/- standard deviation, 9.9+/-1.9 kPa; P = .008), but mortality among patients with a first episode of PCP (12.5%) was lower than mortality among patients with subsequent episodes of PCP (22.5%) (P = .019). No patient was receiving highly active antiretroviral therapy before presentation with PCP, and none began highly active antiretroviral therapy during treatment of PCP. Mortality risk factors for PCP were identifiable at or soon after hospitalization. The trend towards improved outcome after June 1996 occurred in the absence of highly active antiretroviral therapy.

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Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

Melanie Cushion, Michael J. Linke, Alan Ashbaugh … (2010)

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

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Author and article information

Contributors

Guan-Sheng Liu: liugn@ucmail.uc.edu

Richard Ballweg: ballwera@mail.uc.edu

Alan Ashbaugh: ashbauad@ucmail.uc.edu

Yin Zhang: Yin.zhang@CCHMC.org

Joseph Facciolo: facciojm@mail.uc.edu

Melanie T. Cushion: cushiomt@ucmail.uc.edu

Tongli Zhang:

ORCID: http://orcid.org/0000-0003-1773-6279

(513) 558-6156 , zhangtl@ucmail.uc.edu , Tongli.zhang@uc.edu

Journal

Journal ID (nlm-ta): BMC Syst Biol

Journal ID (iso-abbrev): BMC Syst Biol

Title: BMC Systems Biology

Publisher: BioMed Central (London )

ISSN (Electronic): 1752-0509

Publication date (Electronic): 17 July 2018

Publication date PMC-release: 17 July 2018

Publication date Collection: 2018

Volume: 12

Electronic Location Identifier: 77

Affiliations

[1 ]ISNI 0000 0001 2179 9593, GRID grid.24827.3b, Department of Pharmacology and Systems Physiology, College of Medicine, , University of Cincinnati, ; 231 Albert Sabin Way, Cincinnati, OH 45267-0576 USA

[2 ]ISNI 0000 0001 2179 9593, GRID grid.24827.3b, Department of Internal Medicine, College of Medicine, , University of Cincinnati, ; Cincinnati, OH USA

[3 ]ISNI 0000 0000 9025 8099, GRID grid.239573.9, Division of Biostatistics and Epidemiology, , Cincinnati Children’s Hospital Medical Center, ; Cincinnati, OH USA

Author information

Tongli Zhang http://orcid.org/0000-0003-1773-6279

Article

Publisher ID: 603

DOI: 10.1186/s12918-018-0603-9

PMC ID: 6050661

PubMed ID: 30016951

SO-VID: 665b45b0-2086-4762-8ee9-54d4eae5c4d0

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 February 2018

Date accepted : 9 July 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;

Award ID: I01BX000523

Award Recipient : Melanie T. Cushion

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ScienceOpen disciplines: Quantitative & Systems biology

Keywords: pneumocystis - systems biology - quantitative systems pharmacology,infectious disease

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ScienceOpen disciplines: Quantitative & Systems biology

Keywords: pneumocystis - systems biology - quantitative systems pharmacology, infectious disease

A quantitative systems pharmacology (QSP) model for Pneumocystis treatment in mice

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Most cited references 34

Sulfonamide resistance: mechanisms and trends.

Early predictors of mortality from Pneumocystis jirovecii pneumonia in HIV-infected patients: 1985-2006.

Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

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