This document discusses principles of infectious disease pharmacotherapy through a case study of a patient named R.G. It summarizes R.G.'s presentation and clinical signs consistent with infection. Potential infection sites are identified as pneumonia, intra-abdominal, and urinary tract/catheter-related. Likely pathogens are discussed. Antimicrobial selection, dosing, and administration route are considered based on the patient's condition, infection severity, susceptibility testing results, and pharmacokinetic and safety factors. Empirical therapy with ciprofloxacin, cefotaxime, and gentamicin is evaluated.

1. Principles of Infectious Diseases
Anas Bahnassi PhD
Pharmacotherapy of Infectious Diseases
Anas Bahnassi 2014
A Case-Based Approach

2. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

3. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

4. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

5. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

6. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

7. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

8. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
Establishing Infection:
Laboratory Results
Anas Bahnassi 2014

9. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

10. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
Establishing Infection Severity:
Sepsis Cascade
Anas Bahnassi 2014

11. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

12. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

13. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

14. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

15. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
Susceptibility of the organism:
In Vitro Antimicrobial Susceptibility: Aerobic Gram-
Positive Cocci
Anas Bahnassi 2014

16. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
Susceptibility of the organism:
Anas Bahnassi 2014

17. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

18. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

19. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

20. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

21. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

22. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

23. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

24. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

25. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

26. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
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

27. PharmacotherapyofInfectiousDiseasesACase-BasedApproach
Pharmacotherapy:
Infectious Diseases:
Anas Bahnassi PhD
abahnassi@gmail.com
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Anas Bahnassi 2014