UNIT 1

Pharmacotherapy of
Infectious Diseases
A. Bacterial, respiratory (Tuberculosis)
B. Bacterial, GIT (Typhoid fever)
C. Viral, sexually transmitted (HIV/AIDS)
D. Viral, vector-borne (Dengue)
E. Prion disease (Creutzfeldt-Jakob disease)
F. Sepsis and septic shock
 Infectious diseases can be caused by many pathogens, including bacteria, viruses, fungi, and parasites that may cause
illness and disease. For humans, the transmission of pathogens may occur in various ways: spread from person-to-person by direct
contact, water or foodborne illness, or aerosolization of infected particles in the environment and through insects such as mosquitos
and ticks. Signs and symptoms and treatment of infectious diseases depend on the host and the pathogen.

At the end of this lesson, you should be able to:

1. Explain the pathophysiology, risk factors, clinical presentation, diagnostic and laboratory tests for a particular infectious
disease.
2. Search and provide drug information for a specific infectious disease.
3. Formulate pharmacotherapy interventions and care plans to deliver the highest quality of patient-centered care to
manage infectious diseases.
4. Monitor drug therapies and evaluate therapeutic outcomes for a particular infectious disease.

Read the following overview of infectious diseases (https://my.clevelandclinic.org/health/diseases/17724-infectious-

 diseases).

What are infectious diseases?

Infectious diseases can be caused by many pathogens, including bacteria, viruses, fungi, and parasites that may cause illness and
disease. For humans, transmission of pathogens may occur in a variety of ways: spread from person-to-person by direct contact,
water or foodborne illness or aerosolization of infected particles in the environment and through insects (mosquitoes) and ticks.
Signs and symptoms and treatment of infectious diseases depend on the host and the pathogen.

Who is most at risk for getting infectious diseases?

Anyone can get an infectious disease. People with a compromised immune system have a greater risk for certain types of infections.
Those at higher risk include:
 People with suppressed immune systems, such as those going through cancer treatment or who have recently had an organ
transplant
 Those who are unvaccinated against common infectious diseases
 Healthcare workers
 People traveling to at-risk areas may be exposed to mosquitoes that carry pathogens such as malaria, dengue virus,
and Zika viruses.
How common are infectious diseases?
Infectious diseases are prevalent worldwide. Some infectious diseases strike more often than others. For instance, in the United States,
1 out of every 5 people is infected with the influenza (flu) virus each year.

What complications are associated with infectious diseases?

Many infectious diseases cause complications. These can range from mild to severe. For some conditions, complications may
include wheezing, skin rash, or extreme fatigue. Mild complications usually disappear as the infection resolves. Certain infectious
diseases may cause cancer. These include hepatitis B and C (liver cancer), and human papillomavirus (HPV) (cervical cancer).

What are the symptoms of infectious diseases?

Symptoms of infectious disease are particular to the type of disease. For example, symptoms of influenza include:
 Fever
 Chills
 Congestion
 Fatigue
 Muscle aches and headache
Other infectious diseases, such as Shigella, cause more serious symptoms, including:
 Bloody diarrhea
 Vomiting
 Fever
 Dehydration (lack of fluid)
 Shock
A patient may experience one or several symptoms of infectious disease. It is essential to see a doctor if one has any chronic
symptoms or symptoms that worsen over time.

What causes infectious diseases?

Infectious diseases in humans are caused by microorganisms, including:
 Viruses that invade and multiply inside healthy cells
 Bacteria, or small, single-celled organisms capable of causing disease
 Fungi, which include many different kinds of fungus
 Parasites, which are organisms that live inside host bodies causing sickness

Infectious diseases spread in multiple ways. In many cases, direct contact with a sick individual, either by skin-to-skin contact
(including sexual contact) or touching something another person touches, transmits the disease into a new host. Contact with body
fluids, such as blood and saliva, also spreads infectious diseases.

Some diseases spread through droplets discharged from a sick person’s body when they cough or sneeze. These droplets linger in
the air for a short period, landing on a healthy person’s skin or inhaled into their lungs.
In some cases, infectious diseases travel through the air for long periods in small particles. Healthy people inhale these particles and
later become sick. Only certain diseases spread with airborne transmission, including tuberculosis and the rubella virus.
Principles of Infectious Diseases (Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drug, 10th ed.)

 Although acute infection generally is associated with an increased white blood cell count, fever, and localizing signs, these
symptoms may be absent in less severe disease. More severe infection, including sepsis, may be associated with hypotension,
disseminated intravascular coagulation, and end-organ dysfunction.

 Other disease states, particularly autoimmune disease and malignancy, may mimic infectious diseases. Although it should be
considered a diagnosis of exclusion, drug-induced fever should be ruled out, particularly in patients without other classic signs
and symptoms of infection.

 Site-specific signs and symptoms and host factors generally predict the most likely pathogens, and empirical antimicrobial
therapy should be directed against these organisms.

 Isolation of an organism may reflect infection; however, colonization and contamination must be ruled out to avoid unnecessary
antimicrobial exposure. Once a pathogen is identified, susceptibility tests, particularly disk diffusion or broth dilution, can
demonstrate the most active antimicrobial agents.

 Once the infection site is confirmed, and the likely pathogens are identified, antimicrobial toxicity and side effects, costs, site of
infection, drug distribution, and route of administration must be considered before selection of therapy.

 Antimicrobial dosing should reflect the site of infection, route of elimination, and pharmacokinetics, and pharmacodynamics.

 Antimicrobial failure may be related to pharmacologic factors (inadequate dosing, insufficient penetration to the site of
infection, and inadequate duration) and host factors (presence of prosthetic material, undrained focus of infection, and immune
status).
Pharmacotherapy (Modern Pharmacology with Clinical Applications, 5th ed.)

Chemotherapy, initially referring to anti-parasitic therapy, now refers more broadly to the use of any chemical compound that
selectively acts on microbes or cancer.

Selective toxicity: To be clinically useful, a chemotherapeutic drug

must have selective toxicity against pathogens and favorable
pharmacokinetics. The search for safe, effective chemotherapeutic
drugs is hindered by the common evolutionary legacy humans
share with all living organisms; success requires exploitation of
metabolic or structural differences between normal human cells
and disease-producing cells. The more closely related the
undesirable cells are to normal human cells, the more difficult the
task of finding a magic bullet. For example, it is easier to cure malaria
than cancer. Since viruses commandeer human cells to provide the
necessary structural and metabolic apparatus for their functioning,
they also are difficult to kill; transformed virus-infected human cells
are only slightly altered normal human cells.

Antibiotic resistance: Exposure to very low antibiotic concentrations

in meat or milk may have provided a path whereby human
pathogens could eventually evolve high-level antibiotic drug
resistance. Recently some strains of Enterococcus and tuberculosis
have developed resistance to all known antibiotic drugs.
Inappropriate use of antibiotics is widespread, and it accelerates the development of resistance in pathogens.

Pharmacokinetics: The concentration of drugs in a patient’s body as a

function of time is determined by the dose administered and the drug’s
pharmacokinetics in the patient. The concentrations of
chemotherapeutic drugs in blood plasma, cerebrospinal fluid, urine, or
ascites fluid can be measured to determine whether sufficient drug is
present to inhibit or kill a given pathogen and to ensure
that the concentration is not so high as to be toxic to the patient.

In severe bacterial infections that are difficult to eradicate, such as

endocarditis or osteomyelitis, it may be important to ensure that the
patient’s serum remains bactericidal at the lowest, or trough,
concentration in the dosing interval. A drug’s pharmacokinetic properties
are an important source of variation in the clinical response of patients to
chemotherapy.

Further, individualization of dosing of chemotherapeutic drugs with a low

therapeutic index is essential to effective, safe chemotherapy.

Pharmacokinetic factors affecting chemotherapy

Absorption from the GIT can be affected by other drugs and by food. Aluminum, calcium, and magnesium ions in antacids or dairy
products form insoluble chelates with all tetracyclines and inhibit their absorption. Food inhibits tetracycline absorption but enhances
doxycycline absorption; food delays but does not diminish metronidazole absorption; fatty food enhances griseofulvin absorption.

The chemical structure of a drug determines which enzymes metabolize it; a drug that fails to cross the cell membrane because of
its polarity or size will be unmetabolized even if biochemically active degradative enzymes are present in the cytosol.

Systemic use of drugs that are poorly absorbed or are destroyed by the gastrointestinal environment requires parenteral
administration. However, if the goal is to attack pathogens in the gastrointestinal tract, then poor gastrointestinal absorption may be
advantageous.

An antibiotic drug that is itself nontoxic may have metabolites that are toxic, diminishing its usefulness. For example, imipenem is
hydrolyzed by renal dipeptidase to a metabolite that is inactive against bacteria but is toxic to humans. Co-administration of cilastatin
inhibits the renal dipeptidase, which both prevents the formation of the toxic metabolite and decreases imipenem clearance,
prolonging the half-life of the drug.

Partitioning of some drugs into cells occurs. Red blood cells parasitized by malaria selectively take up chloroquine, which accounts
in part for the efficacy of this antimalarial against intracellular malarial forms. The intrahepatocellular concentration of chloroquine is
500 times that of the blood plasma concentration. Macrolides and fluoroquinolones are also selectively partitioned into cells, which
accounts in part for their efficacy against mycoplasma and chlamydia, both intracellular pathogens.
Extensive protein binding of a drug decreases its free level and decreases the compound’s glomerular filtration. Because protein
binding is reversible, bound drug and free drug are in dynamic equilibrium; thus protein binding determines the optimal dose and
dosing interval of the drug.

Pharmacodynamics

In the case of antibiotic chemotherapy, the ideal pharmacodynamic response is usually no pharmacodynamic response; the
pharmacological target is not normal human cells but rather a parasite, a virus-infected human cell, or a cancerous cell. The less
selective the chemotherapeutic drug, the greater the severity of adverse effects. Cancer chemotherapy is often severely toxic, even
life threatening. Suppression of a viral infection, such as occurs in the treatment of HIV with antiviral drugs, is often complicated by
serious drug-associated toxicity, such as hepatotoxicity or bone marrow suppression.

Compared with other pharmacological agents, antibacterial chemotherapeutic drugs are remarkably safe. Toxicity is common
mainly in patients who are given inappropriately high doses or who develop high drug levels because of decreased drug clearance.
Most antibiotics are renally cleared, so renal failure is a common cause of diminished antibiotic drug clearance.

The adverse reactions associated with the use of antibacterial chemotherapy include allergic reactions, toxic reactions resulting
from inappropriately high drug doses, interactions with other drugs, reactions related to alterations in normal body flora, and
idiosyncratic reactions. Several types of allergic responses occur, including immediate hypersensitivity reactions (hives, anaphylaxis),
delayed sensitivity reactions (interstitial nephritis), and hapten-mediated serum sickness. Allergic cross-reactions to structurally related
antibiotics can occur. Although an alternative non–cross-reacting antibiotic is generally preferred, desensitization protocols are
available for situations in which there is no reasonable alternative.

There is heterogeneity in human populations for the hepatic microsomal cytochrome P450 enzyme. Possession of an unfavorable
phenotype may place a patient at risk for drug toxicity. For example, some patients who are slow acetylators of isoniazid may
develop peripheral neuropathy with standard-dose isoniazid therapy.

Toxicity is most likely in tissues that interact with the drug. For example, gentamicin is polycationic and binds to anionic phospholipids
in the cell membranes of renal proximal tubular cells, where it inhibits phospholipases and damages intracellular organelles.

Some adverse reactions are unrelated to either allergy or overdose; these are termed idiosyncratic. For instance, sulfonamides may
precipitate acute hemolysis in some people having a glucose-6-phosphate dehydrogenase deficiency.

Many antibiotics alter the enteric microbial flora, particularly if high concentrations reach the colon. Antibiotic-sensitive bacteria are
suppressed or killed, thereby removing their inhibitory effects on potentially pathogenic organisms. Overgrowth of pathogenic
microbes can then occur. Unlike anaerobes, Clostridium difficile is resistant to clindamycin and some beta-lactams. Use of such
antibiotic permits the proliferation of C. difficile, which then elaborates its toxin in high concentration. This toxin can cause
pseudomembranous colitis, which can be fatal if not recognized and treated.

The effectiveness of chemotherapy is enhanced by adequate immune function; however, some antibiotics suppress immune
function. For example, tetracyclines can decrease leukocyte chemotaxis and complement activation. Rifampin decreases the
number of T lymphocytes and depresses cutaneous hypersensitivity. Antibiotics such as the sulfonamides may induce
granulocytopenia or bone marrow aplasia. These effects are not well understood but may be due to enteric bacterial metabolic
byproducts of these antibiotics.

Management

Clinical pharmacists should be able to prepare and analyze treatment plans that optimize antimicrobial use, and recommend
evidence-based approaches to manage patients requiring antimicrobial treatment.
***Prion diseases are included in this unit since prions, though unlike microbes, are infectious (some are inherited).

Prion diseases (https://www.hopkinsmedicine.org/health/conditions-and-diseases/prion-diseases)

Prion diseases comprise several conditions. Prion diseases can affect both humans and animals and are sometimes spread to humans
by infected meat products. The most common form of prion disease that affects humans is Creutzfeldt-Jakob disease (CJD).

Prion diseases occur when normal prion protein, found on the surface of many cells, becomes abnormal and clump in the brain,
causing brain damage. This abnormal accumulation of protein in the brain can cause memory impairment, personality changes,
and difficulties with movement. Experts still don't know a lot about prion diseases, but unfortunately, these disorders are generally
fatal.

Risk factors for prion disease include:

 Family history of prion disease
 Eating meat infected by “mad cow disease.”
 Infection from receiving contaminated corneas or from contaminated medical equipment

Symptoms of prion diseases include:

 Rapidly developing dementia
 Difficulty walking and changes in gait
 Hallucinations
 Muscle stiffness
 Confusion
 Fatigue
 Difficulty speaking

Prion diseases are confirmed by taking a sample of brain tissue during a biopsy or after death. However, healthcare providers can
do a number of tests before to help diagnose prion diseases such as CJD or rule out other diseases with similar symptoms. Prion
diseases should be considered in all people with rapidly progressive dementia.

The tests include:

 MRI (magnetic resonance imaging) scans of the brain
 Samples of fluid from the spinal cord (spinal tap/ lumbar puncture)
 Electroencephalogram, which analyzes brain waves; this painless test requires placing electrodes on the scalp
 Blood tests
 Neurologic and visual exams to check for nerve damage and vision loss

Prion diseases cannot be cured, but certain medicines may help slow their progress. Medical management focuses on keeping
people with these diseases as safe and comfortable as possible, despite progressive and debilitating symptoms.
 Dive into your reference materials and familiarize yourself with the following representative diseases.

Group Activity: Provide the information needed for the specific infectious diseases:

A. Bacterial, respiratory (Tuberculosis)

B. Bacterial, GIT (Typhoid fever)
C. Viral, sexually transmitted (HIV/AIDS)
D. Viral, vector borne (Dengue)
E. Prion diseases (Creutzfeldt-Jakob disease)
F. Sepsis and septic shock

 For each disease, describe the following:

A. General pathophysiology with diagram
B. Factors that induce or potentiate the disease
C. Clinical presentation (at least 5 signs and 5 symptoms)
D. Laboratory and Diagnostic test/s
E. Goals of therapy (at least 3)
F. Therapeutic options (First and Second line treatments according to the latest guidelines)
G. Drug monitoring parameters (subjective-therapeutic, objective- therapeutic, subjective-toxic, objective-toxic)
References
 TO BE ACCOMPLISHED BY THE ASSIGNED GROUP

 Group Activity: Read the following case and answer the questions. Present your answers in the form of a
PowerPoint presentation that would describe the management of this particular patient.

Leila is a 20- year old woman who went to the health center for a check-up because she noticed “painful blisters” in her genital area.
She also complains of “terrible head aches and muscle aches”. She reported that the “blisters” have been present for three days
already. She also noticed a white odorless vaginal discharge that has lasted for two weeks. Upon interview, she disclosed that she’s
sexually active and admits to vaginal and anal intercourse with two regular partners in the last two months.

SH: She lives with her boyfriend and works as a waitress. She drinks beer and smokes marijuana occasionally
Meds: Junel 21 1/20 (1 tab PO OD)
Multivitamins with iron (1 tab PO OD)
Ibuprofen 200mg (PO PRN)
Ciprofloxacin 250mg (PO OD)
All: Penicillin
ROS: (+) diarrhea and anorectal pain, last menstrual period was 6 weeks ago
Physical examination:
Gen: Thin, NAD
VS: BP 130/70, PR 78, T 37.8, RR 17, Wt. 50kg, Ht. 5’5”
Skin: normal
HEENT: PERRLA, EOMI
Neck: normal
Chest: normal
CV: normal
Abd: soft, mild tenderness to palpation in RLQ, (+) bowel sounds, no HSM
Genit/Rect: Tender inguinal adenopathy.
External exam clear for nits and lice
Several extensive shallow small painful vesicular lesions over vulva and labia, swollen and red.
Vagina red, rugated, moderate amounts of creamy white discharge.
Cervix pink, covered with above discharge, nontender, ~3 cm.
Corpus nontender, no palpable masses.
Adnexa with no palpable masses or tenderness.
Rectum with no external lesions; (+) diffuse inflammation and friability internally, no masses
Ext: normal
Neuro: alert and oriented, CN intact
Labs: Na 135 mEq/L Hgb 12.9 g/dL WBC 6.3 × 103/mm3 RPR nonreactive
K 4.0 mEq/L Hct 37.3% PMNs 64% Preg test: hCG pending
Cl 102 mEq/L Plt 255 × 103/mm3 Bands 2% HIV serology: ELISA pending
CO2 27 mEq/L Eos 1%
BUN 11 mg/dL Lymphs 24%
SCr 0.9 mg/dL Monos 9%
Glu 72 mg/dL

Other: Vaginal discharge- “whiff” test (–)

pH <4.5
wet mount Trichomonas (–)
clue cells (–)
yeast (+)
The following results were reported two days later:
Vulval swab DFA monoclonal stain: HSV-2 isolated
Vaginal and rectal swab gonorrhea NAAT (PCR): Neisseria gonorrhoeae (+)
Vaginal and rectal swab chlamydia NAAT (PCR): Chlamydia trachomatis (+)

The following results were reported 5 days later:

Viral culture at base of genital vesicular fluid: HSV-2 isolated
Rectal and cervical bacterial cultures: N. gonorrhoeae (+)
Rectal and cervical cultures: C. trachomatis (+)

Assessment: Leila may be pregnant, and has primary genital HSV-2 infection, vaginal candidiasis, and gonococcal and chlamydial
infections of the vagina, cervix, and rectum.
Questions:
1. What subjective and objective data are consistent with a primary genital herpes infection?
2. Create a list of the patient’s drug therapy problems. Could any of the patient’s problems have been caused by drug therapy?
3. What are the goals of pharmacotherapy in this case?
4. What feasible pharmacotherapeutic alternatives are available for the treatment of genital herpes, chlamydia, and gonorrhea?
5. What non-pharmacologic therapies might be useful for this patient?
6. Create a treatment plan for this patient: include the specific drugs, dosage form, dose, dosing regimen, duration of therapy
7. If the NAAT PCR test for chlamydia was not conducted, and the culture result was negative for chlamydia but positive for
gonorrhea, would a treatment for chlamydia still be warranted? Justify your answer.
8. What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic
outcome and to detect or prevent ADRs?
9. How would you counsel this patient? What information should be provided to enhance compliance, ensure successful therapy,
and minimize ADRs?