PHCY 471 QUALITY USE OF MEDICINES B Module 1: Oncology and the Immunocompromised Workshop 8: Therapeutics Infections in Immunocompromised Patients

s Disease Templates
1. List the bodys natural defence mechanisms (non-specific and specific) and give examples of how they might be compromised. Non-specific Physical barriers normally keep invaders out o 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 cells

Specific 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 (including warning 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 dermatitidisa However, 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

Cryptococcus neformans o Note: can be isolated from CSF with India ink blotting for a rapid diagnosis Pneumocystis jiroveci Aspergillus

Signs Diffuse nodes within lungs (primary invasive fungi) Increased antigen titres Increased intrathecal pressure if CNS is involved Symptoms Respiratory distress (severe cases of primary invasive fungi) Patient history of prolonged infectious symptoms Start 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) v) vi) vii) What are the main pharmacological treatment options of the disease/condition? Outline the choice of dosage frequency/dosage forms suitable for these patients. Outline the mode of action, common side effects, drug interactions, precautions and monitoring requirements of each pharmacological treatment option. For each pharmacological treatment option discussed above, what points 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

Stomach pH should be acidic (avoid milk and antacids or proton pump inhibitors) 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 jaundice o Photosensitivity: avoid sunlight o Monitor liver function

o o

Severe (immunocompromised, presents with neutropenic fever) Candida o 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 days o Fluconazole for 10 weeks For Amphotericin B o 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 mouth Note: 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 being immunocompromised, 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

Most common infectious organisms are Gram positive bacteria o 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 tract

Risk factors Duration of neutropenia Extent of neutropenia (i.e. how low the neutrophil count goes) Age (immune function degrades with age) Co-morbidities Signs 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 o Neutrophils 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. iv) v) vi) vii) What are the main pharmacological treatment options of the disease/condition? Outline the choice of dosage frequency/dosage forms suitable for these patients. Outline the mode of action, common side effects, drug interactions, precautions and monitoring requirements of each pharmacological treatment option. For each pharmacological treatment option discussed above, what points would you raise during patient counseling?

Prophylactic antibiotics Not recommended, except for AIDs patients/ bone marrow transplant patients sulfamethoxazole-trimethoprim Colony 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 pain Anti-bacterial treatment Low risk Ciprofloxacin and Amoxicillin clauvinate orally 1-2 weeks Ciprofloxacin o Fluoroquinolone antibiotic o Broad-spectrum activity, good for both Gram + and ve o Inhibits DNA gyrase used to unwind DNA for DNA replication o Avoid in pregnancy and breastfeeding o Beware for people with liver or renal insufficiencies

o Nausea and vomiting are common side effects Amoxicillin clauvinate (Augmentin) o Beta-lactam antibiotic o 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 STAT o Glycopeptide antibiotic o Effective against Gram positive bacteria o Prevents cell wall synthesis o Thrombophlebitis and nephrotoxicity may occur o TDM (Therapeutic Drug Monitoring) required Can add an aminoglycoside (e.g. gentamycin) o Effective against Gram negative bacteria o Ototoxic and nephrotoxic, TDM also required Also consider cephalosporins (e.g. Cefepime) o Pretty much the same as beta-lactams o 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 (including warning signs) of the disease/condition.

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

Signs and symptoms Diagnosis is made with HIV ELISA and Western Blot o ELISA is an antibody specific assay which can detect HIV antigens o 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:

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) Latent infection Reduced viral counts, and slowly declining CD4 counts Patients are generally asymptomatic, as their CD4 counts are high enough May last years AIDS CD4 counts are critically low; the immune system fails Opportunistic and AIDS defining infections occur Death is not far off now What is the prognosis and overall treatment goal?

iii)

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. iv) v) vi) vii) What are the main pharmacological treatment options of the disease/condition? Outline the choice of dosage frequency/dosage forms suitable for these patients. Outline the mode of action, common side effects, drug interactions, precautions and monitoring requirements of each pharmacological treatment option. For each pharmacological treatment option discussed above, what points 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 infections HAART (Highly Active Anti-Retroviral Therapy) Need to first identify what mutations the HIV strain has picked up o Hopefully its the wild type with no mutations, its easier to treat as it has no resistances o Allows us to use whatever drug combination (easiest to the patient) For nave patients with wild type: o Efavirenz/tenofovir/emtricitabine AVOID IN PREGNANCY o 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

Zidovudine USE IN PREGNANCY Discuss the non-pharmacological treatment options of the disease/condition?

viii)

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)