ONW08 Therapeutics - Infections in Immunocompromised Patients - Disease Template 2012(2)

8/2/2019 ONW08 Therapeutics - Infections in Immunocompromised Patients - Disease Template 2012(2)

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PHCY 471

QUALITY USE OF MEDICINES B

Module 1: Oncology and the Immunocompromised

Workshop 8: TherapeuticsInfections in Immunocompromised Patients

Disease Templates

1. List the bodys natural defence mechanisms (non-specific and specific) and give examples of howthey might be compromised.

Non-specific

Physical barriers normally keep invaders outo May be broken physically, allowing entry

Non-specific phagocytosis via neutrophils and other phagocytic cells

o Immunocompromised individuals will have reduced neutrophils Activation of the specific immune response via antigen processing in dendritic cellsSpecific

CD4 T helper cells recruited via dendritic cell activation Causes CD8 T cytotoxic cell response or a B cell antibody response to remove infection Memory cells are kept alive for a long time

Systemic fungal infection

i) Definition of the disease/condition.Systemic fungal infections are invasions of living tissues by fungi, which can spread throughout

internal organs.

ii) The incidence, pathophysiology, and signs and symptoms (includingwarning signs) of the disease/condition.

Primay invasive fungi:

Normally the host is infected from inhaling spores from dirt. The body will react by forming

granulomas to prevent it from spreading past the lungs, but if the load is too high, or if the host is

immunocompromised, then the fungus can spread throughout the body, which can be fatal.

Histoplasma capsulatuma Coccidioides immitisa Blastomyces dermatitidisaHowever, for immunocompromised patients, the fungal infection may arise due to an opportunistic

attack by a commensal organism. These are due to (just some of the common ones):

Candida


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Cryptococcus neformanso Note: can be isolated from CSF with India ink blotting for a rapid diagnosis

Pneumocystis jiroveci AspergillusSigns

Diffuse nodes within lungs (primary invasive fungi) Increased antigen titres Increased intrathecal pressure if CNS is involvedSymptoms

Respiratory distress (severe cases of primary invasive fungi) Patient history of prolonged infectious symptomsStart serious IV-drug treatment:

Hypoxia Hypotension Anemia Leukopenia Coagulopathy Weight loss Meningitis (note: symptoms are more subtle compared to bacterial infections, but can still be

picked up)

Being in a high-risk area/Carrying out activities which can disturb spores in a high risk area is

considered to be significant in making a diagnosis

Another risk factor might be the use of inhaled corticosteroids? Causes local immunosuppression?

iii) What is the prognosis and overall treatment goal?If localized to the lung, the prognosis is good. However, if it has become systemic, especially with

CNS involvement, the prognosis becomes poor.

Overall treatment goal is to cure by removing all the invading fungi, while preventing toxicity against

the patient.

iv) What are the main pharmacological treatment options of the disease/condition?v) Outline the choice of dosage frequency/dosage forms suitable for these patients.vi) Outline the mode of action, common side effects, drug interactions, precautions and

monitoring requirements of each pharmacological treatment option.

vii) For each pharmacological treatment option discussed above, whatpoints would you raise during patient counseling?

Empirical treatments:

Not severe (non-neutropenic)

Itraconazole or Fluconazole orally daily for 6-12 weeks Both are triazole antifungals

o Targets ergosterol production in fungal cell walls Intraconazole


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o Stomach pH should be acidic (avoid milk and antacids or proton pump inhibitors)o Inhibits CYP3A4 and p-gp (efflux pump)

Warning: HAART therapy drugs tend to involve CYP3A4 Avoid grapefruit

o Avoid breastfeeding and pregnancy Fluconazole

o Inhibits CYP2C9 (severe) CYP3A4 (not so much) Avoid grapefruit

o Avoids breastfeeding and pregnancy For both:

o Watch for rash or jaundiceo Photosensitivity: avoid sunlighto Monitor liver function

Severe (immunocompromised, presents with neutropenic fever)

Candidao IV Amphotericin B, or IV azole antifungals for 14 days or until stable (or dead)

Cryptoccus (meningitis)o Amphotericin B IV for consolidation for 14 dayso Fluconazole for 10 weeks

For Amphotericin Bo Monitor renal function (nephrotoxicity)o Be careful for people with renal deficiencies

Keep patients well hydrated IV saline for sodium loading to keep renal perfusion high

Prophylaxis

Recommended for immunocompromised patients in high-risk areas Either of the azole antifungals daily by mouthNote: This is just for empirical treatment while the fungus is being isolated to check for susceptibility

against anti-fungal treatments.

viii) Discuss the non-pharmacological treatment options of the disease/condition.Not applicable?

Febrile neutropenia

i) Definition of the disease/condition.A common side effect from cancer chemotherapy is neutropenia. This leads to the patient beingimmunocompromised, and they become susceptible to infection. Febrile neutropenia results if the

patient develops fever and other signs/symptoms of infection.

ii) The incidence, pathophysiology, and signs and symptoms (including warning signs)of the disease/condition.

Incidence is common, with a 5-10% chance of death


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Most common infectious organisms are Gram positive bacteriao But fungi (Candida and Aspergillus) should also be considered if anti-bacterial therapy

fails

Infectious organisms tend to originate from the host, instead of being acquired from someone else(so strict isolation isnt important)

o Skin and GI tractRisk factors

Duration of neutropenia Extent of neutropenia (i.e. how low the neutrophil count goes) Age (immune function degrades with age) Co-morbiditiesSigns and symptoms

Fever (duh, it is called febrile neutropenia for a reason) Catheter sites may be infected (catheter = bypass physical skin barrier) may be red and tender Blood tests

oNeutrophils are low

iii) What is the prognosis and overall treatment goal?5-10% chance of death and this comes very quickly and so the patient can degrade and die within

hours. Need to work fast to treat infections.



vii) For each pharmacological treatment option discussed above, what points would youraise during patient counseling?

Prophylactic antibiotics

Not recommended, except for AIDs patients/ bone marrow transplant patients sulfamethoxazole-trimethoprimColony stimulating factors

Little effect on the extent of neutropenia Reduces the length of neutropenia, which is why it works Most common adverse effect is bone painAnti-bacterial treatment

Low risk

Ciprofloxacin and Amoxicillin clauvinate orally 1-2 weeks Ciprofloxacin

o Fluoroquinolone antibiotico Broad-spectrum activity, good for both Gram + andveo Inhibits DNA gyrase used to unwind DNA for DNA replicationo Avoid in pregnancy and breastfeedingo Beware for people with liver or renal insufficiencies


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o Nausea and vomiting are common side effects Amoxicillin clauvinate (Augmentin)

o Beta-lactam antibiotico Prevents cell wall synthesis (cross-linking more specifically)o Beware of allergic reactions (fever is common)o Diarrhea, nausea and vomiting are common side effects

High risk

Start IV vancomycin STATo Glycopeptide antibiotico Effective against Gram positive bacteriao Prevents cell wall synthesiso Thrombophlebitis and nephrotoxicity may occuro TDM (Therapeutic Drug Monitoring) required

Can add an aminoglycoside (e.g. gentamycin)o Effective against Gram negative bacteriao Ototoxic and nephrotoxic, TDM also required

Also consider cephalosporins (e.g. Cefepime)o Pretty much the same as beta-lactamso Therefore, be careful of cross-reactivity, patients allergic to beta lactams are also allergic

to cephaosporins

viii) Discuss the non-pharmacological treatment options of the disease/condition?Hand washing is key for prophylaxis.

HIV infection/AIDS and associated opportunistic

infections

i) Definition of the disease/condition.Infection by the HIV retrovirus causes the number of CD4+ cells in the body to decline over time, as

the HIV virus targets the CCR5 or CXCR4 receptor on the surface of CD4+ cells. The disease

progresses to AIDS once the CD4+ count is low and the immune system is unable to mount effective

responses against pathogens/commensuals, as the backbone of the acquired immune response (the

CD4 helper T cells) have been eliminated.

ii) The incidence, pathophysiology, and signs and symptoms (includingwarning signs) of the disease/condition.

The overall incidence of HIV/AIDS is going up due to the newer therapies allowing people to livelonger. This means the morbidity has increased over time.

Signs and symptoms

Diagnosis is made with HIV ELISA and Western Bloto ELISA is an antibody specific assay which can detect HIV antigenso Western blot allows specific components (such as the viral glycoproteins) to be detected

HIV RNA assays can be used to detect the number of viral copies in the blood There are several steps to the disease:


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o Initial infection High viral counts and CD4 counts Manifests itself with flu-like symptoms, without any symptoms in the genitalia. Occurs over a few days Seroconversion occurs, which is when the body starts to produce antibodies

against HIV (this can now be detected)

o Latent infection Reduced viral counts, and slowly declining CD4 counts Patients are generally asymptomatic, as their CD4 counts are high enough May last years

o AIDS CD4 counts are critically low; the immune system fails Opportunistic and AIDS defining infections occur Death is not far off now

iii) What is the prognosis and overall treatment goal?As long as they can keep the viral load down, and the CD4 count up, they will have a similar life

expectancy as a normal person

But this is hard to achieve, even with perfect adherence due to the virus high mutation rate and it can

never be cured due to integration into the hosts genome.



vii) For each pharmacological treatment option discussed above, whatpoints would you raise during patient counseling?

When to start Defer treatment if CD4 counts are adequate (+500) because its not worth exposing the patient to

side effects when the immune system can still work

Consider treatment once it starts dropping past this point Definitely start after having opportunistic infectionsHAART (Highly Active Anti-Retroviral Therapy)

Need to first identify what mutations the HIV strain has picked upo Hopefully its the wild type with no mutations, its easier to treat as it has no resistanceso Allows us to use whatever drug combination (easiest to the patient)

For nave patients with wild type:o Efavirenz/tenofovir/emtricitabine

AVOID IN PREGNANCYo Ritonavir-boosted atazanavir + tenofovir/emtricitabine

Atazanavir requires an acidic stomach AVOID IN PREGNANCY

o Ritonavir-boosted darunavir + tenofovir/emtricitabine AVOID IN PREGNANCY

o Raltegravir + tenofovir/emtricitabine AVOID IN PREGNANCY


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o Zidovudine USE IN PREGNANCY

viii) Discuss the non-pharmacological treatment options of the disease/condition?Adherence is absolutely vital here, as non-adherence leads to even faster mutations and resistance, so

it can become very hard to treat. Can give a drug holiday, or be supervised in a rest home

Prevent spread by using barriers and preventing the sharing of needles for IV drug abuse

Nutrition should be looked after, as weight loss and occur (its linked to a poorer prognosis)

ONW08 Therapeutics - Infections in Immunocompromised Patients - Disease Template 2012(2)

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