1. PHARMACOTHERAPY III PHCY 510
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
PHARMACOTHERAPY III
PHCY 510
Lecture 2 Infectious Diseases “Infections in Immunocompromised Patients” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy, CPN University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
describe the general concepts and treatment approach toward empiric therapy of infection in the immunocompromised host,
explain the pathogens associated with specific types of immune deficits in patients.

3. Immunosuppression
Infection is the result of a negative balance between the capacity of host immune defenses and the virulence of invading microorganisms.
An immunocompromised state arises when these protective barriers are breached and/or essential immune cells are absent or functionally impaired.
The most common factors leading to defective immune cell responses include
inherited or acquired diseases of the immune system,
cancer and its treatment,
infection,
poor nutritional status or metabolic disturbances,
immunosuppressive drug therapy.

4. Components of Immune Dysfunction and Infection
Mucocutaneous Barriers to Infection
Skin, respiratory tract, ears, conjunctiva, alimentary and genitourinary tracts are in constant contact with the environment.
Serve as the first line of defense against microbial invasion.
This defense is accomplished through
colonization with commensal bacteria and fungi that compete for nutrients and space with more virulent organisms (colonization resistance);
maintenance of an acidic environment in the stomach, vagina, and outer skin layers;

5. production of saliva, mucus, digestive enzymes, bile salts, and secreted immunoglobulins (IgA) that increase trapping, killing, and removal of organisms from mucocutaneous barriers
continuous mechanical measures (mucociliary clearance, sneezing, coughing, peristalsis, micturition) that aid in elimination of unattached microorganisms.
Breaches (openings) of the mucocutaneous barriers are often iatrogenic due to medical devices (central venous catheters, Foley catheters, and endotracheal tubes), procedures (surgery), and therapies (chemotherapy and radiation) that damage mucosal barriers.

6. Neutropenia
Neutrophils form the major type of leukocytes in peripheral blood, with counts ranging between 40% to 70% of leukocytes.
Also called polymorphonuclear (PMN) leukocytes or granulocytes, includes neutrophilic granulocytes (neutrophils), eosinophilic granulocytes (eosinophils), and basophilic granulocytes (basophils).
Neutrophils protect the human body from bacterial and fungal infections.
For neutrophils to be effective, they must be generated and released from the bone marrow in adequate numbers, migrate to the site of infection, and efficiently phagocytose and kill invading organisms.

7. Neutropenia (1,000 cells/mm3) due to underlying disease or the myelotoxic effects of chemotherapy is one of the most common forms of immunosuppression that affects patients to infection.
A rapid drop in neutrophil counts is frequently associated with life-threatening bacterial or fungal infection.
As the duration of neutropenia increases (i.e., ANC100 cells/mm3 for 10 days), the spectrum and severity of infections also increase.

8. Prolonged episodes of drug-induced myelosuppression (neutropenia lasting >27 days) are most commonly seen in patients receiving chemotherapy for either relapsed or refractory cancer.
These patients are at a high risk for death due to bacterial or fungal infection.
During the second and third weeks of neutropenia (phase II), yeasts appear as a noticeable cause of infection in patients who are not receiving fluconazole prophylaxis.
As neutropenia extends beyond the third week (phase III), opportunistic mold infections such as invasive aspergillosis, invasive fusariosis, or zygomycosis become more noticeable.

9. Defects In Cell-mediated Immunity
Thymus-derived lymphocytes (T lymphocytes)
Cells of the mononuclear phagocytic system (monocytes, macrophages, and dendritic cells)
Defects in the interaction of these cells can affect patients to severe and recurrent infections with viruses, intracellular bacteria, fungi, and certain Parasites.

10. Defects in Humoral Immunity
Immunoglobulins play a critical role in fighting infections.
They fight against encapsulated bacteria such as Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenzae by binding to organisms and adaptating them prone to phagocytosis

11. Solid Organ Transplantation
Infection following solid organ transplantation depends on
type of organ transplanted,
technical or surgical complexity of the transplant surgery
the need for additional antirejection therapy
Most infections in the first month after transplantation are related to surgical complications.
Second to sixth month is the time when classic opportunistic infections begins secondary to immunosuppression used to prevent organ rejection.
Opportunistic pathogens and underlying infections
viruses (CMV, hepatitis B and C, EBV, HHV-6, adenovirus)
fungi (PCP, invasive aspergillosis, endemic mycoses)
bacterial pathogens associated with T-cell dysfunction (Listeria, Nocardia, Mycobacteria)

12. Clinical Presentation and Diagnosis
Localizing clinical signs and symptoms of infection are often absent and radiographic findings are usually diminished in immunosuppressed patients.
Reduction of clinical signs and symptoms of infections is most clear in patients with neutropenia, who will have fever as the only sign of an active infection.
Fever is not a specific sign of infection.
It may arise from the underlying malignancy, blood transfusions, biologic agents, chemotherapy, contrast dyes used in radiography, or procedures.
that allow identification of source of infection (e.g., fluctuance, fissure or ulceration, exudates, pyuria)

13. Medications can cause, or in the case of antipyretics and corticosteroids, suppress fever in immunocompromised hosts.
Antibiotics are a notorious cause of drug fever, especially in patients receiving broad-spectrum empiric coverage with multiple agents.
Once a patient is receiving more than three antimicrobial agents simultaneously, the risk of fever due to antimicrobial therapy exceeds 30%.
High fevers (40.50C) are also frequently seen with Clostridium difficile colitis

14. The mouth and oropharynx should be examined for vesicles or ulcers and gingivitis.
If present, lesions are swabbed or biopsied for direct staining or culture of bacteria, viruses, or fungi.
Careful examination of the skin and nail beds, including palpation, can provide important clues to infection caused by bacterial, viral, and fungal pathogens, as the appearance of cutaneous lesions

15. Diarrhea is common in hospitalized patients, particularly patients receiving chemotherapy or broad-spectrum antibiotics, and is not necessarily indicative of infection.
Special attention must be paid to the possibility of C. difficile colitis, which may or may not be accompanied by fever.
All immunocompromised patients with diarrhea should have their stools tested for C. difficile toxin, and empiric treatment with metronidazole with or without vancomycin may be considered if diarrhea continues.
Infections of the skeletal system, particularly osteomyelitis, are often detected by plain radiography, CT or MRI scans.

16. Meningitis and encephalitis can present as focal or diffuse CNS infections.
This require CT and/or MRI scans of the brain for diagnosis.
If intracranial pressure permits, cerebrospinal fluid should be collected for Gram staining, chemistries, microscopy, serologic examination, and PCR testing of potential viral pathogens.

17. Treatment
Typically, therapy is directed at the most likely pathogens in the initial phases of neutropenia: Enterobacteriaceae and P. aeruginosa, Streptococcus, and Staphylococcus spp.
Core antibiotics used to cover these pathogens include
antipseudomonal Beta-lactam antibiotics,
third- or fourth-generation antipseudomonal cephalosporins,
carbapenems (excluding ertapenem, which lacks anti-Pseudomonas activity),
possibly in combination with vancomycin with or without an aminoglycoside.
If vancomycin has not been added, it should be empirically started in patients with 72 hours of persistent fever.

18. Prophylaxis
Effective prophylactic strategies in immunocompromised patients requires:
First, there must be a high background incidence of infection caused by the particular pathogen or group of pathogens to justify the need for prophylaxis.
Second, an effective therapy must be available for treatment of the specific pathogens.
Third, the therapy must be well tolerated with minimal to no toxicity.
Fourth, the therapy should be convenient and available as an oral therapy so prolonged administration is feasible.
Preemptive therapy is the administration of an antimicrobial at the first detection of some marker of impending infection, but before signs and symptoms of infection develop.

19. Bacterial infections, prophylaxis aimed at gram-negative organisms is common in patients with neutropenia.
Fluoroquinolones are preferred agents to reduce the frequency of serious gram-negative infections.
Although newer fluoroquinolones (gatifloxacin, moxifloxacin, gemifloxacin) also have enhanced coverage against many gram-positive pathogens and anaerobes, they may not have sufficient coverage against Viridans streptococci.
Therefore, vancomycin or occasionally penicillin is added in patients who are expected to develop severe mucositis.

20. Fluconazole 200 to 400 mg per day reduce the incidence of both superficial and invasive candidiasis.
Itraconazole solution 200 mg taken two or three times daily is an alternative to fluconazole and also an effective strategy for reducing the frequency of infections due to Aspergillus.