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TOPIC: PNEUMOCYSTIS PNEUMONIA

Subject: Foundation In Biotechnology.

Code: BIOT 5120

Group 4

Venkata Satya Sai Nagasri Abhishek Chembuli

Vaibhav Kawde

Dhruvkumar Patel

Mahima Swaroopa Upputholla

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INTRODUCTION

Pneumocystis pneumonia (PCP) is an extreme infection as a result of the fungus Pneumocystis jirovecii. Most of those who get PCP have a clinical condition that weakens their immune system, like HIV/AIDS, or takes drugs (such as corticosteroids) that lower the frame's capability to fight germs and sickness.
Scientists have changed the category of this organism because it first appeared in patients with HIV in 1980. Pneumocystis jirovecii used to be categorized as a protozoan however is now considered a fungus. Pneumocystis jirovecii used to be known as Pneumocystis carinii.
In the US, humans with HIV/AIDS are less in to get PCP today than earlier than the supply of antiretroviral therapy (ART). According to a study, PCP was the most common opportunistic infection from 2008–to 2010. It was estimated that a total of 10,590 were hospitalized due to PCP in 2017.

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SYMPTOMS & RISK FACTORS

Symptoms

Progressive Exertional Dyspnea (95%)

Fever (> 80%)

Chest Discomfort

Chills

Weight Loss

Hemoptysis (rare)

Non-productive Cough (95%)

Risk factors for Pneumocystis pneumonia (2008–2012)

30-40% of people who get PCP have HIV/AIDS
20% of adults carry this fungus at any given time, and the immune system removes the fungus after several months.

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ETIOLOGY

The transmission of Pneumocystis is through the air and it is most commonly found in the lungs of a healthy individual.
The compromised cellular immunity and humoral immunity lead to the onset of Pneumocystis pneumonia.

Inhaling microorganism

Trophic form of Pneumocystis attaches to alveoli

Uncontrolled replication of the Pneumocystis

Activated alveolar macrophage without CD4+ cannot eradicate the microorganism

Immune System

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MECHANISM OF ACTION

Active Immune System

Compromised Immune System

Pneumocystis

APC

TCD4 & Tfh

B Cells

Antibodies

M2 Macrophages

Pneumocystis

APC

TCD4 & Tfh

B Cells

Antibodies

M2 Macrophages

Eliminates Pneumocystis

Activation

Eliminate

MHC II Activation

Cannot eliminate fungi

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ORGANS AFFECTED

SP-A

Inhibits the regulation of innate immune cells in the body

SP-D

SP-D binds to gpA and promotes attachment of fungi to macrophages and inhibits phagocytosis.

Inflammation and fluid buildup
Tuberculosis

Lungs

Splenomegaly

Spleen

Linear IgA
Morphea

Skin

PROTEINS MALFUNCTION

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WHY ONLY PNEUMOCYSTIS PNEUMONIA?

PCP takes advantage of your weak immune system to attack your lungs. If not treated right away, PCP can be severe and even fatal.
Due to a severely compromised immune system (HIV/AIDS, corticosteroids), we can expect a huge spike in the people suffering from Covid-19 and other lung-related issues.

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DRUGS IN DEVELOPMENT

There are no current developing drugs for pneumocystis pneumonia as most of the targets have been achieved by the former drugs. Recent studies have shown identifying novel techniques to identify the new targets.

One highly successful drug against pneumocystis pneumonia is Trimethoprim-sulfamethoxazole (TMP-SMZ) which has compromised its efficacy in recent times.

TMP-SMZ is regarded as the first-line treatment and prophylaxis for P. jirovecii infection, but the frequency of adverse reactions and newly emerged antibiotic resistance limit its use.
It has caused several side effects like fever, rash, nausea, vomiting, transaminase elevation, and more serious toxicities such as neutropenia and toxic epidermal necrolysis.

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APPROVED DRUGS

Drug	Drug Class	Manufacturer	Brand Name	Approval Year
Atovaquone	Antiprotozoal agents	Glaxo Wellcome Inc.	Mepron	1999
Trimetrexate Glucuronate	Dihydrofolate reductase (DHFR) Inhibition	Medimmune Oncology Inc.	Neutrexin	1993
Pentamidine isethionate	Antiprotozoals	APP Pharmaceuticals	Nebupent	1989
Sulfamethoxazole and trimethoprim	Antibiotic	Glenmark Generics, Sun Pharm Industries	Bactrim	1973

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COST & EFFICACY OF THE APPROVED DRUGS

Drug	Cost of the Drug (USD)	Efficacy
Atovaquone	334.81 / 750mg	90%
Trimetrexate Glucuronate	300 / 10mg	76%
Pentamidine isethionate	172.49 / 300mg	65%
Sulfamethoxazole and trimethoprim	16.74 / 160mg	91%

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UNMET NEED

The fungi are becoming resistant to the first-line treatment of this disease which is trimethoprim/sulfamethoxazole which causes quite a few adverse effects like hypersensitivity (rashes) and fevers in the majority of the HIV patients
Weakening of immune system will impact the health of an individual by sudden onset of fever, often gets worse by chest discomfort
PCP has shown a significant impact on organ transplantation by long-term graft failure irrespective of rejection.
Fungi are constantly evolving in order to survive existing medications, which has resulted in the emergence of resistant strains. To eliminate such strains, new targets must be discovered.

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CASPOFUNGIN

Caspofungin (Cancidas) is the first member of the class of antifungal medications called echinocandins. It works by slowing the growth of fungi that cause infection, typically administered intravenously.
Caspofungin is discovered by James Balkovec, Regina Black, and Frances A. Bouffard.
This can be used in treating yeast infections in the blood, stomach, lungs, oesophagus and other fungal infections in all age groups.
Lower failure switch and toxicity effect of Caspofungin has replaced other first-line treatments like trimethoprim, pentamidine and clindamycin.

Brand name – Cancidas
Generic name - Caspofungin
Average weight - 1093.331
Type – Small molecule
Chemical formula - C₅₂H₈₈N₁₀O₁₅
Approval - 30 December 2016

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MECHANISM OF ACTION (DRUG)

This works by inhibiting cell wall synthesis.
It is a noncompetitive inhibition of the enzyme β-(1,3)-D-glucan synthase, which is a critical component of the synthesis of the fungal cell wall.

With Drug

Note - This enzyme is not present in mammalian cells.

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IP LANDSCAPE

Caspofungin acetate is the generic ingredient in two branded drugs marketed by Merck, Cipla, Fresenius Kabi USA, Gland, Jiangsu Pharms, Mylan Labs Ltd, UBI, and Xellia Pharms Aps
Caspofungin is included in 8 NDAs.
There is currently one patent protecting this compound.
There are six drug master file entries for caspofungin acetate
Patent Summary:-

US patents: 1
International patents: 14
Patent Applications: 1380

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DISCOVERY RESEARCH

Caspofungin is a semisynthetic derivative of pneumocandin B0, a naturally occurring, lipophilic cyclic peptide isolated from the fungus, Glarea lozoyensis.
Fermentation development was to improve the titer of pneumocandin B0 to make it commercially viable.
Properties of pneumocandin B0 were improved by Semisynthetic modification by medicinal chemistry, leading to the discovery of caspofungin.
Development of commercial semisynthesis and purification and formulation development to improve stability.
Clinical development and approval of CANCIDAS® as an antifungal drug that subsequently saved thousands of lives.

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PRECLINICAL TRIALS

Preclinical studies were perfomed by Wim van Vianen, Siem de Marie, Marian T. ten Kate , Ron A. A. Mathot and Irma A. J. M. Bakker-Woudenberg of Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Center Rotterdam.

Organisms – Rats

Assay – Quantitative XTT

Infusion of the drug – 1, 2, 3, 4mg/kg/day

Duration – 10 days

100% survival rate in the group administered with 4mg/kg/day

4 times effective than the other drugs

Preclinical Studies

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CLINICAL TRIALS

Total number of subjects = 277

90% of subjects - HIV-seropositive, immunocompromised

Infusion of drug – 35mg, 50mg, 75mg

Duration – 2 weeks

2% of subjects suffered from adverse drug effects

Drug related effects – Fever, phlebitis

98% of subjects tolerated the drug without any adverse effects

Phase II/III

The clinical trials of caspofungin were performed by C A Sable, B-Y T Nguyen, J A Chodakewitz, M J DiNubile of Department of infectious disease, Merck Research laboratories, Pennsylvania, USA

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MANUFACTURING

Selectively dehydrating pneumocandin Bo to obtain a nitrile

Reducing the nitrile to primary amine

Reacting the primary amine with an arylthiol in a suitable solvent to obtain a thioether

Reacting the thioether with ethylenediamine to obtain the caspofungin acetate having a formula C₅₂H₈₈N₁₀O₁₅

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PRICE OF THE DRUG

Drug Name	Vendor	Count	Price (USD)
Cancidas 70MG	Merck Sharp & Dohme Corporation	1	229.19
Cancidas 50MG	Merck Sharp & Dohme Corporation	1	220.58

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ETHICAL ISSUES

Patients with CD4 counts of less than 50%, who develop pneumothoraces while intubated, and who spend more than 2 weeks in the ICU receiving mechanical ventilation appear to have a very poor survival rate (10%).
The cost-effectiveness of ICU care for patients with severe PCP has decreased in recent years as the survival rate has declined. It now costs approximately $200,000 (US) to save a year of life through the use of the ICU in PCP, a relatively ineffective intervention.
These issues can be resolved by focusing on cost-effective plans and keeping a track of the medical practices.

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SUMMARY

Pneumocystis Pneumonia is caused by Pneumonia jirovecii which affects the immune system and lungs of the host and severely affects the population suffering from HIV/AIDS. At least 20% of the population is exposed to the fungi but the body’s immune system eliminates them from time to time. Pneumonia jirovecii inhibits the activation of the MHC II which in turn cannot promote the formation of M2 macrophages and antibodies towards the elimination of fungi. Trimethoprim-sulfamethoxazole (TMP-SMZ) is considered the first-line treatment for this disease in spite of many other drugs being discovered. In recent times, these drugs have shown less potential for curing as fungi have developed resistance to the drug. Such strains can be eliminated by discovering new targets and therapies. Caspofungin eliminates the fungi by inhibiting the cell wall synthesis and exposing the cells to the nearby particles which burst the cell from inside. It has shown great impact in terms of efficiency and safety in its pre-clinical and clinical trials. The drug has been approved by US FDA on 30 December 2016.

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REFERENCES

Balkovec, James M., et al. “Discovery and Development of First in Class Antifungal Caspofungin (CANCIDAS®)—A Case Study.” Nat. Prod. Rep., vol. 31, no. 1, 2014, pp. 15–34. Crossref, https://doi.org/10.1039/c3np70070d.
“Caspofungin Acetate.” Deep Knowledge on Small-Molecule Drugs and the Global Patents Covering Them, 19 Apr. 2022, www.drugpatentwatch.com/p/generic-api/CASPOFUNGIN+ACETATE#patent_family.
Deep Knowledge on Small-Molecule Drugs and the Global Patents Covering Them, 19 Apr. 2022, www.drugpatentwatch.com/p/generic-api/CASPOFUNGIN+ACETATE#patent_family.
“Caspofungin: Uses, Interactions, Mechanism of Action | DrugBank Online.” DrugBank, go.drugbank.com/drugs/DB00520. Accessed 18 Apr. 2022.
Haque, Abida K., and Patrick A. Adegboyega. “Pneumocystis Jiroveci Pneumonia.” Dail and Hammar’s Pulmonary Pathology, 2008, pp. 487–514. Crossref, https://doi.org/10.1007/978-0-387-68792-6_13.

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