Principles of Infectious Diseases

Anas Bahnassi PhD

Pharmacotherapy of Infectious Diseases

Anas Bahnassi 2014

A Case-Based Approach

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Clinical Pearls

• 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.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Clinical Pearls

• Isolation of an organism may reflect infection; however, colonization and contamination must be ruled out to avoid unnecessary antimicrobial exposure.

• Once the site of infection 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 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).

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Approaching the Problem

Infection is documented

Infection site is identified

Additional Lab tests

requested

Signs and Symptoms

Organism Responsible

Antimicrobial agent

identified

Dose and Duration

Patient Size

Infection site

Route of Administra-

tion

Other factors

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection:

• R.G., a 63-year-old, 70-kg man in the ICU, underwent emergency resection of his large bowel.

• Mechanically ventilated throughout his post-op course.

• On day 20 of his hospital stay, R.G. suddenly becomes confused; BP drops to 70/30 mm Hg, HR of 130 b/min.

• His extremities are cold to the touch, and he presents with circumoral pallor.

• His temperature increases to 40◦, RR = 24/min. • Copious amounts of yellow-green secretions are

suctioned from his endotracheal tube.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection:

Physical examination reveals: • Sinus tachycardia with no rubs or murmurs. • Rhonchi with decreased breath sounds are

observed on auscultation. The abdomen is distended. R.G. complains of new abdominal pain.

• No bowel sounds can be heard, and the stool is guaiac positive.

• Urine output from the Foley catheter has been 10 mL/hour for the past 2 hours.

• Erythema is noted around the central venous catheter.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection:

• A chest radiograph demonstrates bilateral lower lobe infiltrates, and urinalysis reveals >50 white blood cells/high power field (WBC/HPF), few casts, and a specific gravity of 1.015. Blood, endotracheal aspirate,

• Urine cultures are pending.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection:

Laboratory Results

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection:

Which of R.G.’s signs and symptoms are consistent with infection?

• His WBC count (15,600/μL) is increased, and a “shift to the left” (bands, i.e., premature neutrophils) is observed on the differential.

• R.G has fever which is a common manifestation for infection.

• The bilateral lower lobe infiltrates on R.G.’s chest radiograph,

• Presence of copious amounts of yellow-green secretions from his endotracheal tube, and the erythema surrounding his central venous catheter also are compatible with one or more infectious processes.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection Severity:

Sepsis Cascade

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection Severity:

What signs and symptoms manifested by R.G. are consistent with a serious systemic infection?

• Hemodynamic Changes. • Cardiac Output. • Systemic Vascular Resistance.

• Cellular Changes. • Glucose Metabolism

• Respiratory Changes. • Hematologic Changes.

• Disseminated intravascular coagulation

• Neurologic Changes. • Lethargy…

• Fever. • Drug Effects.

• Corticosteroids mask infection. Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Establishing Infection Site:

What are the most likely sources of R.G.’s infection?

R.G. has several possible sites of infection. • The copious production of yellow-green

sputum, tachypnea, and the altered chest radiograph suggest pneumonia.

• The abdominal pain, absent bowel sounds, and recent surgical procedure, however, suggest an intra-abdominal source.

• The abnormal urinalysis (>50 WBC/HPF) and the erythema around the central venous catheter suggest urinary tract and catheter infections.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Determining the likely pathogen:

What are the most likely pathogens associated with R.G.’s infection(s)?

• Bacterial pneumonia is caused by various pathogens, including: Streptococcus pneumoniae, Enterobacteriacae, and atypical pathogens (e.g., Legionella pneumophila)

• Empirical antimicrobial therapy directed against all the above organisms is not necessary in all patients. • Community acquired pneumonia in normal hosts is

generally associated with S. pneumoniae, Haemophilus influenza, and “atypical” bacterial pathogens.

• In contrast, nosocomial (hospital, nursing home) pneumonia is associated with gram-negative bacilli (e.g., Escherichia coli, Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa) and Staphylococcus aureus.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Susceptibility of the organism:

A Gram stain of R.G.’s tracheal aspirate shows gram-negative bacilli. What tests may assist with the identification of the pathogen(s)?

• Culture and susceptibility testing (18-24h to complete) • Disk Diffusion (Agar). • Broth Dilution (Tubes).

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Susceptibility of the organism:

In Vitro Antimicrobial Susceptibility: Aerobic Gram-Positive Cocci

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Susceptibility of the organism:

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Antimicrobial Toxicities:

Serratia marcescens grows from a culture of R.G.’s endotracheal aspirate. How can it be determined whether an isolate represents a true bacterial infection versus colonization or contamination?

• Culture results do not solely identify true • pathogens. • In R.G., the Serratia may be a pathogen,

contaminant, or colonizer. • Considering the severity of R.G.’s illness

and his associated respiratory symptoms, treatment directed against this pathogen is necessary.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Antimicrobial Toxicities:

R.G. is empirically started on imipenem and gentamicin. In review of his patient records, R.G. has no known allergies. Are there equally effective, less toxic options for this patient?

• Adverse Effects and Toxicities: • Allergies…

• Concomitant Disease States: • Older patients with hearing deficits are poor

candidates for potentially ototoxic aminoglycoside therapy.

• Diabetic or kidney transplant patients with candidemia may be better treated with fluconazole or an echinocandin rather than nephrotoxic amphotericin B products

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Antimicrobial Cost of Therapy:

What factors should be included in calculating the cost of R.G.’s antimicrobial therapy?

• Determining the true cost of antimicrobial therapy is complex.

• Acquisition cost, IV bags, infusion controllers, and labor must be incorporated into the analysis.

• Although they are difficult to estimate, other costs, including antibiotic toxicity and failure of therapy, also should be included.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Antimicrobial Cost of Therapy:

What factors should be included in calculating the cost of R.G.’s antimicrobial therapy?

• Determining the true cost of antimicrobial therapy is complex.

• Acquisition cost, IV bags, infusion controllers, and labor must be incorporated into the analysis.

• Although they are difficult to estimate, other costs, including antibiotic toxicity and failure of therapy, also should be included.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Route of Administration:

Oral ciprofloxacin was considered for the treatment of R.G.’s presumed Serratia pneumonia, but the IV route was prescribed. Why is the oral administration of ciprofloxacin reasonable (or unreasonable) in R.G.?

• In septic patients,” blood flow often is shunted away from the mesentery and extremities, resulting in unreliable oral or muscular bioavailability.

• Hemodynamically unstable patients should always receive antimicrobials by the IV route to ensure therapeutic antimicrobial levels.

• Drug interactions with oral agents can result in subtherapeutic serum concentrations (e.g., reduced bioavailability associated with concomitant quinolone and antacid administration and the decreased absorption of itraconazole with[PPI] therapy).

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Antimicrobial Dosing:

What dose of IV ciprofloxacin should be given to R.G.? What factors must be taken into account in determining a proper antimicrobial dose?

• Patient Age. • Site of Infection. • Anatomic and physiologic barriers. • Fever and Inoculum effect. • Route of Elimination

• Creatinine Clearance.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h

Pharmacokinetics and Pharmacodynamics:

R.G.’s respiratory status remains unchanged; thus, the ciprofloxacin is discontinued and cefotaxime and gentamicin are started empirically. The use of a constant IV infusion of cefotaxime is being considered in R.G. In addition, the use of single daily dosing of gentamicin is being discussed. What is the rationale for these approaches, and would either be advantageous for R.G.?

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h

Pharmacokinetics and Pharmacodynamics: • β-Lactams, such as cefotaxime, are not associated with

increased bacterial killing with increasing drug concentrations but of the duration of time the AB is kept above MIC.

• The efficacy of quinolone antimicrobials appears to correlate with the peak plasma concentration to MIC ratio or (AUC) to MIC ratio.

• Gentamycin has been administered q 8 -12 hrs to achieve peak serum of 5-8 g/mL to ensure efficacy in the treatment of serious gram-ve infection.

• Gentamicin troughs >2mcg/mL have been associated with an increased risk for nephrotoxicity,

• Several antimicrobials (e.g., aminoglycosides) have been associated with a pharmacodynamic phenomenon known as a postantibiotic effect (PAE). PAE is delayed regrowth of bacteria after exposure to an antibiotic.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h

Once-Daily Dosing of Aminoglycosides: • As a result of PAE and other pharmacodynamic

factors, certain antimicrobials may be dosed less frequently.

• Higher doses less frequently should provide the same advantages.

• Single daily dosing of aminoglycosides has been investigated primarily in patients with normal renal function, and few critically ill patients have been treated with this nontraditional regimen.

• Thus, patients in septic shock are less clear candidates for once-daily dosing.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Antimicrobial Protein Binding:

Ceftriaxone (Rocephin), rather than cefotaxime (Claforan), is being considered for the treatment of R.G.’s infection. Ceftriaxone is more highly protein bound than cefotaxime. Why is protein binding important in the selection of therapy?

• Free (i.e., unbound) rather than total drug levels are best correlated with antimicrobial activity.

• Although ceftriaxone is 85% to 90% protein bound, the free concentrations probably remain far above the MIC of the Serratia.

• Therefore, protein-binding considerations are unlikely to be important in the treatment of R.G.’s infection.

Anas Bahnassi 2014

Ph

arm

aco

ther

apy

of

Infe

ctio

us

Dis

eas

es

A C

ase

-Bas

ed A

pp

roac

h Pharmacotherapy:

Infectious Diseases:

Anas Bahnassi PhD

abahnassi@gmail.com

http://www.twitter.com/abpharm

http://www.facebook.com/pharmaprof

http://www.linkedin.com/in/abahnassi Anas Bahnassi 2014