Infectious Diseases

Infectious Diseases
Curtis L. Smith, Pharm.D., BCPS
Ferris State University
Lansing, Michigan

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Learning Objectives: 3. A study is designed to assess the risk of pneu-

mococcal pneumonia in elderly patients 10 years
1. Describe appropriate treatment of patients with or more after their pneumococcal vaccination,
pneumonia, urinary tract infections, central ner- compared with elderly patients who have never
vous system infections, skin and soft tissue infec- received the vaccination. Which one of the follow-
tions, osteomyelitis, intra-abdominal infections, ing study designs is best?
and endocarditis. A. Case series.
2. Identify appropriate preventive therapy for pneu- B. Case-control study.
monia, central nervous system infections, endo- C. Prospective cohort study.
carditis, and surgical wound infections. D. Randomized clinical trial.

4. N.R. is a 28-year-old woman who presents to the

clinic with a 2-day history of dysuria, frequency,
Self-Assessment Questions: and urgency. She has no significant medical his-
Answers to these questions may be found at the tory, and the only drug she takes is oral contra-
end of this chapter. ceptives. Which one of the following is the best
empiric therapy for N.R.?
1. P.E. is a 56-year-old man who comes to the clinic A. Oral amoxicillin 3 g in a single dose.
with a 3-day history of fever, chills, pleuritic chest B. Oral ciprofloxacin 500 mg 2 times/day for 7
pain, malaise, and cough productive of sputum. In days.
the clinic, his temperature is 102.1ºF (38.9ºC) (all C. Oral TMP/SMZ double strength 2 times/day
other vital signs are normal). His chest radiograph for 3 days.
shows consolidation in the right lower lobe. His D. Oral cephalexin 500 mg 4 times/day for 3
white blood cell count (WBC) is 14.4/mm3, but all days.
other laboratory values are normal. He is given a
diagnosis of community-acquired pneumonia. He 5. B.Y. is an 85-year-old woman who is bedridden and
has not received any antibiotics in 5 years and has lives in a nursing home. She is chronically cathe-
no chronic disease states. Which one of the follow- terized, and her urinary catheter was last changed
ing is the best empiric therapy for P.E.? 3 weeks ago. Today, her urine is cloudy, and a uri-
A. Doxycycline 100 mg orally 2 times/day. nalysis shows many bacteria. B.Y. is not noticing
B. Cefuroxime axetil 250 mg orally 2 times/day. any symptoms. A urine culture is obtained. Which
C. Levofloxacin 750 mg/day orally. one of the following therapies should B.Y. receive?
D. Trimethoprim/sulfamethoxazole (TMZ/ A. No therapy because she is chronically
SMZ) double strength orally 2 times/day. catheterized and has no symptoms.
B. No antibiotic therapy, but the catheter should
2. H.W. is a 38-year-old woman who presents with be changed.
high temperature, malaise, dry cough, nasal con- C. Oral ciprofloxacin 500 mg 2 times/day for 7
gestion, and severe headaches. Her symptoms days and a new catheter.
began suddenly 3 days ago, and she has been in D. Oral ciprofloxacin 500 mg 2 times/day for
bed since then. She reports no other illness in her 14–21 days without a change in catheter.
family, but several people have recently called in
sick at work. Which one of the following is best for 6. A patient with poor renal function is given a diag-
H.W.? nosis of methicillin-resistant Staphylococcus au-
A. Azithromycin 500 mg, followed by 250 mg/ reus (MRSA) endocarditis. An initial 1-g dose of
day orally, for 4 more days. vancomycin is given. The patient has the follow-
B. Amoxicillin/clavulanic acid 875 mg orally 2 ing characteristics: height 5′10″; weight 72 kg (158
times/day. lb); and creatinine 4.2 mg/dL. The vancomycin
C. Oseltamivir 75 mg 2 times/day orally for 5 half-life in this patient is 35 hours, and its volume
days. of distribution is 0.7 L/kg. Which one of the fol-
D. Symptomatic treatment only. lowing is correct in determining when the patient
will reach a concentration of 10 mcg/L and require
another dose?

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A. About 18 hours from the time of the first dose. 9. L.G. is a 49-year-old woman with a history of
B. About 35 hours from the time of the first dose. mitral valve prolapse. She presents to her physi-
C. About 70 hours from the time of the first dose. cian’s office with malaise and a low-grade fever.
D. Initial dose inadequate to achieve a Her physician notes that her murmur is louder than
concentration of 10 mcg/mL. normal and orders blood cultures and an echocar-
diogram. A large vegetation is observed on L.G.’s
7. V.E. is a 44-year-old man who presents to the mitral valve, and her blood cultures are growing
emergency department with a warm, erythema- Enterococcus faecalis (susceptible to all antibiot-
tous, and painful right lower extremity. There is ics). Which one of the following is the best therapy
no raised border at the edge of the infection. Three for L.G.?
days ago, he scratched his leg on a barbed wire A. Penicillin G plus gentamicin for 2 weeks.
fence on his property. He has had a temperature as B. Vancomycin plus gentamicin for 2 weeks.
high as 101.8°F (38°C) with chills. Doppler studies C. Ampicillin plus gentamicin for 4–6 weeks.
of his lower extremity are negative. Blood cultures D. Cefazolin plus gentamicin for 4–6 weeks.
were drawn, and they are negative to date. Which
one of the following is the best empiric therapy for 10. N.L. is a 28-year-old woman with no significant
V.E.? medical history. She reports to the emergency de-
A. Nafcillin 2 g intravenously every 6 hours. partment with fever and severe right lower quad-
The infection may worsen, and necrotizing rant pain. She has had a dull pain for the past few
fasciitis needs to be ruled out. days, but it suddenly became severe during the
B. Penicillin G, 2 million units intravenously past 8 hours. Her temperature is 103.5°F (39.7°C),
every 4 hours. This is probably erysipelas. and she has rebound tenderness on abdominal ex-
C. Piperacillin/tazobactam 3.375 g amination. She is taken to surgery immediately,
intravenously every 6 hours. Surgical and a perforated appendix is diagnosed and re-
debridement is vitally important. paired. Which one of the following is an appropri-
D. Enoxaparin 80 mg subcutaneously 2 times/ ate follow-up antibiotic regimen?
day and warfarin 5 mg/day orally. A. Vancomycin 1000 mg intravenously every
12 hours plus metronidazole 500 mg
8. R.K. is a 36-year-old woman who presents to the intravenously every 8 hours.
emergency department with a severe headache B. Ceftriaxone 1 g/day intravenously plus
and neck stiffness. Her temperature is 99.5°F ciprofloxacin 400 mg intravenously every
(37.5°C). After a negative computed tomographic 12 hours.
scan of the head, a lumbar puncture is performed, C. Ertapenem 1 g/day intravenously.
showing the following: glucose 54 mg/dL (pe- D. No antibiotics needed after surgical repair of
ripheral, 104), protein 88 mg/dL, and WBC 220/ a perforated appendix.
mm3 (100% lymphocytes). The Gram stain shows
no organisms. Which one of the following options
describes the best therapy for R.K.?
A. This is an aseptic (probably viral) meningitis,
and no antibiotics are necessary.
B. Administer ceftriaxone 2 g intravenously
every 12 hours until the cerebrospinal fluid
(CSF) cultures are negative for bacteria.
C. Administer ceftriaxone 2 g intravenously
every 12 hours and vancomycin 1000 mg
intravenously every 12 hours until the CSF
cultures are negative for bacteria.
D. Administer acyclovir 500 mg intravenously
every 8 hours until the CSF culture results
are complete.

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I. PNEUMONIA

A. Introduction
1. Pneumonia is the most common cause of death attributable to infectious diseases (very high
rates in the elderly) and the seventh most common cause of death in the United States.
2. Hospital-acquired pneumonia is the second most common nosocomial infection (0.6%–1.1%
of all hospitalized patients)—there is an increased incidence in patients in the intensive care
unit recovering from thoracic or upper abdominal surgery and in the elderly.
3. Mortality rates
a. Community-acquired pneumonia without hospitalization: less than 1%
b. Community-acquired pneumonia with hospitalization: about 14%
c. Nosocomial: about 33%–50%

B. Community-Acquired Pneumonia
1. Definition: Acute infection of the pulmonary parenchyma, accompanied by the presence of
an acute infiltrate consistent with pneumonia on chest radiograph or auscultatory findings.
Patients must also NOT have any of the following characteristics: hospitalization 2 days
or more in the past 90 days; residence in a long-term care facility; receipt of intravenous
antibiotic therapy, chemotherapy, or wound care in the past 30 days; or attendance at a
hospital or hemodialysis clinic.
2. Symptoms of community-acquired pneumonia are listed below (must have any two). Elderly
patients often have fewer and less severe findings (mental status changes are common).
a. Fever or hypothermia
b. Rigors
c. Sweats
d. New cough with or without sputum (90%)
e. Chest discomfort (50%)
f. Onset of dyspnea (66%)
g. Fatigue, myalgias, abdominal pain, anorexia, and headache
3. Predictors of a complicated course of community-acquired pneumonia are listed below.
Hospitalization should be based on the severity of illness scores (e.g., CURB-65, PSI
[pneumonia severity index]).
a. Age older than 65 years
b. Comorbid illness (diabetes mellitus, congestive heart failure, lung disease, renal failure,
liver disease)
c. High temperature: more than 101°F (38°C)
d. Bacteremia
e. Altered mental status
f. Immunosuppression (e.g., steroid use, cancer)
g. High-risk etiology (S. aureus, Legionella, gram-negative bacilli, anaerobic aspiration)
h. Multilobe involvement or pleural effusions

C. Hospital-Acquired Pneumonia
1. Hospital-acquired pneumonia—pneumonia that occurs 48 hours or more after admission and
is not incubating at the time of admission
2. Ventilator-associated pneumonia—pneumonia that arises more than 48–72 hours after
endotracheal intubation

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3. Health care–associated pneumonia—pneumonia developing in a patient who was hospitalized

in an acute care hospital for 2 or more days within 90 days of the infection; who resided in a
nursing home or long-term care facility; who received recent intravenous antibiotic therapy,
chemotherapy, or wound care within the past 30 days of the current infection; or who attended a
hospital or hemodialysis clinic. Risk factors for hospital-acquired pneumonia:
a. Intubation and mechanical ventilation
b. Supine patient position
c. Enteral feeding
d. Oropharyngeal colonization
e. Stress bleeding prophylaxis
f. Blood transfusion
g. Hyperglycemia
h. Immunosuppression/corticosteroids
i. Surgical procedures: thoracoabdominal, upper abdominal, thoracic
j. Immobilization
k. Nasogastric tubes
l. Prior antibiotic therapy
m. Admission to the intensive care unit
n. Elderly
o. Underlying chronic lung disease

D. Table 1. Microbiology

Table 1. Incidence of Pneumonia by Organism

Community Acquired (%) Hospital Acquired (%)
Unidentifiable 40–60 Unidentifiable 50
• M. pneumoniae 13–37 • S. aureus 10
• S. pneumoniae 9–20 • Pseudomonas aeruginosa 8
• H. influenzae 3–10 • Enterobacter sp. 5
• C. pneumoniae 1–17 • Klebsiella pneumoniae 4
• Legionella pneumophila 0.7–13 • Candida 3
• Viruses Common • Acinetobacter sp. 2
Others: Uncommon • Serratia marcescens 2
• S. aureus • Escherichia coli 2
• Moraxella catarrhalis • S. pneumoniae 1
• Pneumocystis pneumonia
• Anaerobes
• Gram-negative bacilli (e.g., K. pneumoniae)
Specific populations in community-acquired pneumonia: Issues in hospital-acquired pneumonia:
• Alcoholics: S. pneumoniae, oral anaerobes, gram- • P. aeruginosa is transmitted by health care workers’
negative bacilli (i.e., Klebsiella) hands or respiratory equipment
• Nursing home: S. pneumoniae, H. influenzae, gram- • S. aureus is transmitted by health care workers’ hands
negative bacilli, S. aureus • Enterobacteriaceae endogenously colonize hospitalized
• COPD: S. pneumoniae, H. influenzae, M. catarrhalis patients’ airways (healthy people seldom have gram-
• Postinfluenza: H. influenzae, S. aureus, S. negative upper airway colonization)
pneumoniae • Stress changes respiratory epithelial cells so that gram-
• Exposure to water: Legionella negative organisms can adhere
• Poor oral hygiene: oral anaerobes • Up to 70% of patients in the intensive care unit have
• HIV infection: P. jiroveci, S. pneumoniae, M. gram-negative upper airway colonization, and 25% of
pneumoniae, Mycobacterium them will become infected through aspiration
COPD = chronic obstructive pulmonary disease; HIV = human immunodeficiency virus

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Patient Case
1. R.L. is a 68-year-old man who presents to the emergency department with coughing and shortness of
breath. His symptoms, which began 4 days ago, have worsened during the past 24 hours. He is coughing up
yellow-green sputum, and he has chills with a temperature of 102.4°F (39°C). His medical history includes
coronary artery disease with a myocardial infarction 5 years ago, congestive heart failure, hypertension,
and osteoarthritis. He rarely drinks alcohol and has not smoked since his myocardial infarction. His medi-
cations on admission include lisinopril 10 mg/day, hydrochlorothiazide 25 mg/day, and acetaminophen 650 mg
4 times/day. On physical examination, he is alert and oriented, with the following vital signs: temperature
101.8°F (38°C); heart rate 100 beats/minute; respiratory rate 24 breaths/minute; and blood pressure 142/94
mm Hg. His laboratory results were normal except for blood urea nitrogen (BUN) 32 mg/dL (serum creati-
nine 1.23 mg/dL). Blood gases were pH 7.44; pCO2 35; pO2 82; and O2 sat 90%. A sputum specimen is not
available. If R.L. were hospitalized, which one of the following would be the best empiric therapy for him?
A. Ampicillin/sulbactam 1.5 g intravenously every 6 hours.
B. Piperacillin/tazobactam 4.5 g intravenously every 6 hours plus gentamicin 180 mg intravenously
every 12 hours.
C. Ceftriaxone 1 g intravenously every 24 hours plus azithromycin 500 mg/day intravenously.
D. Doxycycline 100 mg intravenously every 12 hours.

E. Therapy
1. Community-acquired pneumonia (duration, at least 5 days)
a. Empiric treatment of nonhospitalized patients
i. Previously healthy and no antibiotic therapy in the past 3 months
(a) Macrolide (macrolide: clarithromycin or azithromycin if H. influenzae is
suspected)
(b) Doxycycline
ii. Comorbidities (chronic obstructive pulmonary disease, diabetes mellitus,
chronic renal or liver failure, congestive heart failure, malignancy, asplenia, or
immunosuppression) OR recent antibiotic therapy (within the past 3 months)
(a) Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750
mg])
(b) Macrolide (or doxycycline) with high-dose amoxicillin (1 g 3 times/day) or
amoxicillin/clavulanate (2 g 2 times/day) or a cephalosporin (ceftriaxone,
cefuroxime, or cefpodoxime)
b. Empiric treatment of hospitalized patients with moderately severe pneumonia
i. Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
ii. Ampicillin, ceftriaxone, or cefotaxime (ertapenem in select patients) plus a macrolide
(or doxycycline)
c. Empiric treatment of hospitalized patients with severe pneumonia requiring intensive care
unit treatment
i. Ampicillin/sulbactam, ceftriaxone, or cefotaxime plus either a respiratory
fluoroquinolone or azithromycin (may need to add other antibiotics if P. aeruginosa
or MRSA is suspected)
d. Treatment duration—at least 5 days, with 48–72 hours afebrile and no more than one
sign of clinical instability (elevated temperature, heart rate, or respiratory rate; decreased
systolic blood pressure; or arterial oxygen saturation) before therapy discontinuation

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Patient Case
2. B.P. is a 66-year-old woman who underwent a two-vessel coronary artery bypass graft 8 days ago and has
been on a ventilator in the surgical intensive care unit since then. Her temperature is now rising, and a
tracheal aspirate shows many WBC and gram-negative rods. Her medical history includes coronary artery
disease with a myocardial infarction 2 years ago, chronic obstructive pulmonary disease, and hypertension.
Which one of the following is the best empiric therapy for B.P.?
A. Ceftriaxone 1 g/day intravenously plus gentamicin 140 mg intravenously every 12 hours plus
linezolid 600 mg intravenously every 12 hours.
B. Piperacillin/tazobactam 4.5 g intravenously every 6 hours.
C. Levofloxacin 750 mg/day intravenously plus linezolid 600 mg intravenously every 12 hours.
D. Cefepime 2 g intravenously every 12 hours plus tobramycin 140 mg intravenously every 12 hours plus
vancomycin 15 mg/kg intravenously every 12 hours.

2. Hospital-acquired pneumonia
a. Early onset (less than 5 days) and no risk factors for multidrug-resistant (MDR)*
organisms. Common organisms include S. pneumoniae, Haemophilus influenzae,
methicillin-sensitive S. aureus (MSSA), Escherichia coli, Klebsiella pneumoniae,
Enterobacter species, and Proteus species
i. Third-generation cephalosporin (cefotaxime or ceftriaxone)
ii. Fluoroquinolone (levofloxacin, moxifloxacin, ciprofloxacin)
iii. Ampicillin/sulbactam
iv. Ertapenem
b. Late onset (5 days or longer) or risk factors for MDR organisms. Common organisms
include those listed above for early onset plus Pseudomonas aeruginosa, K. pneumoniae
(extended-spectrum β-lactamase positive), Acinetobacter species, MRSA, and Legionella
pneumophila
i. Ceftazidime or cefepime plus aminoglycoside or fluoroquinolone (cipro-, levo-)
ii. Imipenem, meropenem, or doripenem plus aminoglycoside or fluoroquinolone
(ciprofloxacin, levofloxacin)
iii. Piperacillin/tazobactam plus aminoglycoside or fluoroquinolone (ciprofloxacin,
levofloxacin)
iv. Vancomycin or linezolid should be used only if MRSA risk factors (e.g., history of
MRSA infection/colonization, recent hospitalization or antibiotic use, presence of
invasive health care devices) are present or there is a high incidence locally (greater
than 10%–15%).
c. Treatment duration—Efforts should be made to decrease therapy duration to as short as 7
or 8 days (14 days for pneumonia secondary to P. aeruginosa).

Risk factors for MDR organisms

i. Antibiotic therapy within the past 90 days
ii. Hospitalization of 5 days or more
iii. High resistance in community or hospital unit
iv. Risk factors for health care–associated pneumonia
v. Immunosuppressive disease and/or therapy

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Patient Case
3. B.P., who eventually improves, is transferred to a regular floor. She cannot remember receiving any recent
vaccinations. Which one of the following vaccinations do you recommend for this patient?
A. B.P. does not need any vaccinations.
B. B.P. should receive the pneumococcal vaccine now and the influenza vaccine in the fall.
C. B.P. should receive the influenza vaccine in the fall, but because of her current infection, the
pneumococcal vaccine is unnecessary.
D. B.P. should receive the pneumococcal vaccine now, but she is not in a group in which the influenza
vaccine is recommended.

F. Influenza
1. Characteristics of influenza infection
a. Epidemic with significant mortality
b. Epidemics begin abruptly → peak in 2–3 weeks → resolve in 5–6 weeks
c. Occurs almost exclusively in the winter months (December–April)
d. Average overall attack rates of 10%–20%
e. Mortality greatest in those older than 65 years (especially with heart and lung disease):
more than 80% of deaths caused by influenza are from this age group (20,000 deaths/year
in the United States)
2. Is it a cold or the flu? (Table 2)

Table 2. Differentiating the Symptoms of Cold and Influenza

Signs and Symptoms Influenza Cold
Onset Sudden Gradual
Temperature Characteristic, high (> 101°F [38°C]) Occasional
of 3–4 days’ duration
Cough Dry; can become severe Hacking
Headache Prominent Occasional
Myalgia (muscle aches/pains) Usual; often severe Slight
Tiredness and weakness Can last up to 2–3 weeks Very mild
Extreme exhaustion Early and prominent Never
Chest discomfort Common Mild to moderate
Stuffy nose Sometimes Common
Sneezing Sometimes Usual
Sore throat Sometimes Common

3. Pathophysiology
a. Type A
i. Influenza further grouped by variations in hemagglutinin and neuraminidase
(e.g., H1N1, H1N2)
ii. Changes through antigenic drift or shift
(a) Annual, gradual change caused by mutations, substitutions, and deletions, in
response to the development of human antibodies
(b) Less common dramatic change leading to pandemics
iii. Causes epidemics every 1–3 years

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b. Type B
i. Type B influenza carries one form of hemagglutinin and one form of neuraminidase,
both of which are less likely to mutate than the hemagglutinin and neuraminidase of
type A influenza.
ii. Changes through antigenic drift (minor mutations from year to year); when enough
drifts occur, an epidemic is likely
iii. Causes epidemics every 5 years
4. Prevention
a. Amantadine, rimantadine
i. Prevents about 50% of infections and 70%–90% of illnesses (similar to the influenza
vaccine)
ii. Dose/recommendations: short term (5–7 weeks or the duration of the epidemic);
prophylaxis during a presumed outbreak of influenza A in patients who cannot
receive vaccine (or 2 weeks only if the vaccine is given at the same time)
iii. Not recommended unless testing shows increased susceptibility
b. Neuraminidase inhibitors
i. Oseltamivir (Tamiflu)
(a) Oseltamivir administered 75–150 mg/day orally for 6 weeks during peak
influenza season showed 74% protective efficacy.
(b) Begin oseltamivir 75 mg/day orally for at least 7 days within 2 days of close
contact with an infected individual.
ii. Zanamivir (Relenza)
− Zanamivir 10 mg/day through inhalation for 4 weeks during peak influenza season
showed 67% protective efficacy.
5. Therapy
a. Treat only if patient has severe symptoms (clinical deterioration or lower respiratory tract
infection) or is at higher risk of complications—use only the neuraminidase inhibitors.
b. Amantadine (Symmetrel); rimantadine (Flumadine)
i. Inhibits viral uncoating and release of viral nucleic acid by inhibiting M2 protein
(a) Effective only against influenza A virus
(b) Decreases the duration of signs and symptoms by 1 day
ii. Adverse effects
(a) Central nervous system
(b) Gastrointestinal system—nausea, vomiting, diarrhea
(c) Peripheral edema
(d) Orthostatic hypotension
iii. Dose
(a) 100 mg orally 2 times/day
(b) Elderly patients should not receive more than 100 mg/day.
(c) Adjust for renal disease (amantadine > rimantadine).
(d) Therapy duration is 3–7 days.
(e) Initiate treatment within 1–2 days of symptoms.
(f) Not recommended unless testing shows increased susceptibility
c. Oseltamivir (Tamiflu)
i. Inhibits neuraminidase; symptoms disappear 1–1.5 days sooner
ii. Adverse effects: gastrointestinal (nausea and vomiting)

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iii. Dose
(a) A total of 75 mg orally 2 times/day for 5 days; decrease dose to 75 mg/day orally
in patients with creatinine clearance less than 30 mL/minute
(b) Initiate within 48 hours of symptom onset.
d. Zanamivir (Relenza)
i. Inhibits neuraminidase; symptoms disappear 1–1.5 days sooner
ii. Adverse effects: bronchospasm, cough
iii. Dose
(a) Two inhalations (5 mg/inhalation) 2 times/day for 5 days
(b) Initiate within 48 hours of symptom onset.

G. Pneumonia Immunizations
1. Pneumococcal vaccine
a. Characteristics
i. Pneumococcal vaccine contains 23 purified capsular polysaccharide antigens of
S. pneumoniae.
ii. The 23 capsular types account for 85%–90% of invasive S. pneumoniae infection.
iii. All six serotypes that commonly cause drug-resistant S. pneumoniae (DRSP)
infection are in the vaccine.
iv. Antibody levels remain elevated for at least 5 years.
b. Recommendations (Table 3)

Table 3. Pneumococcal Vaccine Recommendations

Vaccination-Recommended Group Revaccination
Immunocompetent People
- People ≥ 65 years - Second dose of vaccine if patient received
vaccine ≥ 5 years previously and was
< 65 years at the time of vaccination
- People 2–64 years with chronic cardiovascular disease, chronic - Not recommended
pulmonary disease, diabetes mellitus, alcoholism, chronic liver
disease, or CSF leaks; adult asthmatics or adult smokers
- People 2–64 years with functional or anatomic asplenia - Single revaccination recommended after
5 years (for anyone ≥ 2 years)
- People 2–64 years living in special environments or social settings - Not recommended
Immunocompromised People
- Immunocompromised people - Single revaccination recommended after
≥ 2 years, including those with HIV infection, leukemia, lymphoma, 5 years (for anyone ≥ 2 years)
Hodgkin disease, multiple myeloma, generalized malignancy,
chronic renal failure, or nephrotic syndrome; those receiving
immunosuppressive chemotherapy (including corticosteroids); and
those who have received an organ or bone marrow transplant
CSF = cerebrospinal fluid; HIV = human immunodeficiency virus.

2. Influenza vaccine
a. Characteristics
i. Each year’s vaccine contains two strains of type A and one strain of type B—selected
by worldwide surveillance and antigenic characterization.

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ii. Prevents illness in 70%–90% of healthy people younger than 65 years

iii. Prevents illness in 53%, hospitalization in 50%, and death in 68% of the elderly
iv. Administer yearly in September or October.
b. Recommendations
i. Everyone older than 6 months should receive the vaccine annually.
ii. Patients with human immunodeficiency virus (HIV)
(a) No risk to the patient and should be given to anyone receiving antiretrovirals
(b) Studies show a decreased antibody response (less than 60% have adequate response).
(c) Intranasal live-attenuated vaccine (FluMist)
(1) Indicated for people 2–49 years without underlying illnesses (including
health care workers)
(2) Use of inactivated vaccine is preferred for vaccinating household
members, health care workers, and others who have close contact with
immunosuppressed people.

II. URINARY TRACT INFECTIONS

A. Introduction
1. Most common bacterial infection in humans: 7 million office visits per year; 1 million
hospitalizations
2. Many women (15%–20%) will have a urinary tract infection (UTI) during their lifetime.
3. From age 1–50, UTIs predominantly occur in women; after 50, men are affected because of
prostate problems.

B. Microbiology (Table 4)

Table 4. Incidence of Urinary Tract Infections by Organism

Community Acquired (%) Nosocomial (%)
E. coli 73 E. coli 31
S. saprophyticus 13 P. aeruginosa 10
P. mirabilis 5 Other gram-negative bacilli 10
K. pneumoniae 4 K. pneumoniae 9
Enterococcus 2 S. aureus 6
P. mirabilis 5
Enterococcus 2
Fungal 14

C. Predisposing Factors
1. Age
2. Female sex
3. Diabetes mellitus
4. Pregnancy
5. Immunosuppression
6. Urinary tract instrumentation
7. Urinary tract obstruction
8. Renal disease; renal transplantation
9. Neurologic dysfunction

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Patient Case
4. G.N. is a 62-year-old woman who presents to the clinic with a 3-day history of urinary frequency and dys-
uria. During the past 24 hours, she has had nausea, vomiting, and flank pain. One month before this visit,
the patient received 3 days of cefpodoxime for an E. coli UTI. Six weeks before the E. coli UTI, the patient
received a single 3-g dose of amoxicillin for UTI-like symptoms. This is her third UTI in 3 months. G.N. has
a history of type 2 diabetes mellitus, which is poorly controlled with some diabetic-related complications.
G.N. also has hypertension and a history of several episodes of deep venous thrombosis. Her medications
include glyburide 5 mg/day orally, enalapril 10 mg orally 2 times/day, warfarin 3 mg/day orally, and meto-
clopramide 10 mg 4 times/day. On physical examination, she is alert and oriented, with the following vital
signs: temperature 102.8°F (39°C); heart rate 120 beats/minute; respiratory rate 16 breaths/minute; blood
pressure (supine): 140/75 mm Hg; and blood pressure (standing) 110/60 mm Hg. Her laboratory values are
within normal limits except for increased international normalized ratio 2.7; BUN 26 mg/dL; serum creati-
nine 1.88 mg/dL; and WBC 12,000 (78 polymorphonuclear leukocytes, 7 band neutrophils, 10 lymphocytes,
and 5 monocytes). Her urinalysis shows turbidity, 2+ glucose; pH 7.0; protein 100 mg/dL; 50–100 WBC; +
nitrites; 3–5 red blood cells; and many bacteria and + casts. Which one of the following is the best empiric
therapy for G.N.?
A. TMP/SMZ double strength orally 2 times/day—duration of antibiotics: 7 days.
B. Ciprofloxacin 400 mg intravenously 2 times/day and then 500 mg orally 2 times/day—duration of
antibiotics: 10 days.
C. Gentamicin 140 mg intravenously every 24 hours—duration of antibiotics: 3 days.
D. Ampicillin/sulbactam 3 g intravenously every 6 hours and then amoxicillin/clavulanate 875 mg orally
2 times/day—duration of antibiotics: 10 days.

D. Clinical Presentation
1. Lower UTI—cystitis (elderly patients may have only nonspecific symptoms, such as mental
status changes, abdominal pain, and decreased eating or drinking)
a. Dysuria
b. Frequent urination
c. Urgency
d. Occasionally, gross hematuria
e. Occasionally, foul-smelling urine
2. Upper UTI—pyelonephritis (elderly patients may have only nonspecific symptoms, such as
mental status changes, abdominal pain, and decreased eating or drinking)
a. Frequency, dysuria, hematuria
b. Suprapubic pain
c. Costovertebral angle tenderness—flank pain
d. Fever, chills
e. Increased WBC
f. Nausea, vomiting
3. Factors associated with or used to define complicated UTI
a. Male sex
b. Hospital acquired
c. Pregnancy
d. Anatomic abnormality of the urinary tract
e. Childhood UTIs
f. Recent antimicrobial use
g. Diabetes mellitus

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h. Indwelling urinary catheter

i. Recent urinary tract instrumentation
j. Immunosuppression
4. Recurrent cystitis
a. Relapse: infection with the same organism within 14 days of discontinuing antibiotics for
the preceding UTI
b. Reinfection: infection with a completely different organism—most common cause of
recurrent cystitis

E. Diagnosis
1. Urinalysis (blood cultures will be positive in 20% of patients with upper UTIs)
a. Pyuria (WBC greater than 5–10/mm3)
b. Bacteriuria (greater than 102 CFU [colony-forming units]/mL is diagnostic)
c. Red blood cells
d. Cloudiness
e. Nitrite positive
f. Leukocyte esterase positive
g. Casts (if pyelonephritis)

F. Therapy
1. Uncomplicated cystitis
a. Three-day treatment regimen (vs. 5–10 days: equal in symptomatic but not
bacteriologic cure)
i. TMP/SMZ
ii. Trimethoprim
iii. Fluoroquinolone
b. Alternatives
i. Nitrofurantoin (7-day course)
ii. Fosfomycin (single dose)
c. Single-dose therapy
i. Improved adherence; fewer adverse effects; cheaper
ii. Reduced cure rates compared with a 3- or 7-day regimen
iii. Inappropriate for patients with occult upper tract involvement
iv. First-line antibiotics as listed above
2. Pregnancy (pregnant women should be screened for bacteriuria and treated, even
if asymptomatic)
a. Seven-day treatment regimen
i. Amoxicillin
ii. Nitrofurantoin
iii. Cephalexin
iii. TMP/SMZ
b. Antibiotics to avoid
i. Fluoroquinolones
ii. Tetracyclines
iii. Aminoglycosides
iv. TMP/SMZ (used frequently but avoidance recommended, especially during the
late third trimester)

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3. Recurrent cystitis
a. Relapse
i. Assess for pharmacologic reason for treatment failure.
ii. Longer treatment (for 2–6 weeks, depending on length of initial course)
b. Reinfection (reassess need for continuous prophylactic antibiotics every 6–12 months)
i. If patient has two or fewer UTIs in 1 year, use patient-initiated therapy for
symptomatic episodes (3-day treatment regimens).
ii. If patient has three or more UTIs in 1 year and they are temporally related to sexual
activity, use post-intercourse prophylaxis with TMP/SMZ SS, cephalexin 250 mg, or
nitrofurantoin 50–100 mg.
iii. If patient has three or more UTIs in 1 year that are not related to sexual activity,
use daily or 3 times/week prophylaxis with trimethoprim 100 mg, TMP/SMZ SS,
cephalexin 250 mg, norfloxacin 200 mg, or nitrofurantoin 50–100 mg.
4. Uncomplicated pyelonephritis
a. Outpatient therapy (if patient is not immunocompromised or does not have nausea
and vomiting)
i. TMP/SMZ
ii. Fluoroquinolone
b. Therapy duration: Five to 14 days (5 days with levofloxacin, 14 days with TMP/SMZ)
5. Complicated UTIs
a. Inpatient therapy
i. Fluoroquinolone
ii. Aminoglycoside
iii. Extended-spectrum β-lactam
b. Therapy duration: Five to 14 days (5 days with levofloxacin)
6. Catheter-related UTIs
a. Short-term indwelling catheters
i. About 5% of patients will develop a UTI per each day of catheterization; by 30 days,
75%–95% of patients with an indwelling catheter will have bacteriuria.
ii. Preventive antimicrobial therapy is not recommended—it only increases the chance
of selecting out resistant organisms.
iii. Asymptomatic patients with bacteriuria should not be treated.
iv. Symptomatic patients with bacteriuria should be treated with 7–10 days of antibiotics and
catheter removal; a shorter course of therapy (5–7 days) should be used if the catheter
cannot be removed.
v. The most common organisms are E. coli (21.4%), Candida species (21.0%),
Enterococcus species (14.9%), P. aeruginosa (10.0%), K. pneumoniae (7.7%), and
Enterobacter species (4.1%).
b. Long-term indwelling catheters
i. Virtually all patients will be bacteriuric with two to five organisms.
ii. Asymptomatic patients should not be treated.
iii. Symptomatic patients should be treated for a short period (7 days) to prevent
resistance, and catheter replacement may be indicated.
7. Prostatitis and epididymitis
a. Acute bacterial prostatitis
i. Primarily gram-negative organisms
ii. Therapy duration, 4 weeks

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(a) TMP/SMZ
(b) Cephalosporins
(c) Fluoroquinolones
b. Chronic bacterial prostatitis
i. Difficult to treat
ii. Therapy duration, 1–4 months
(a) TMP/SMZ
(b) Fluoroquinolones
8. Epididymitis
a. Older than 35 years; most likely caused by enteric organisms
i. Therapy duration: 10 days to 4 weeks
ii. Antibiotics: TMP/SMZ or fluoroquinolones
b. Younger than 35 years; most likely gonococcal or chlamydial infection
i. Therapy duration: 10 days
ii. Antibiotics: ceftriaxone 250 mg intramuscularly once plus doxycycline 100 mg 2
times/day

III. SKIN AND SOFT TISSUE INFECTIONS

A. Cellulitis
1. Description
a. Acute spreading skin infection that primarily involves the deep dermis and subcutaneous fat
b. Non-elevated and poorly defined margins
c. Warmth, pain, erythema and edema, and tender lymphadenopathy
d. Malaise, fever, and chills
e. Usually, patient has had previous minor trauma, abrasions, ulcers, or surgery (could be as
little as tinea infections, psoriasis, or eczema).
f. Often, patients have impaired lymphatic drainage.
2. Microorganism—usually S. pyogenes and occasionally S. aureus (rarely other organisms)
3. Treatment: 5–10 days (infection may worsen when treatment begins—must differentiate from
necrotizing fasciitis)
a. Anti-staphylococcal penicillin (nafcillin, oxacillin, or dicloxacillin)
b. Penicillin G if definitively streptococcal
c. Alternatives
i. Clindamycin
ii. β-Lactamase inhibitor combinations
iii. First-generation cephalosporin
iv. Vancomycin or linezolid for MRSA cellulitis

B. Erysipelas
1. Description
a. Acute spreading skin infection that primarily involves the superficial dermis
b. Spreads rapidly through the lymphatic system in the skin (patients may have impaired
lymphatic drainage)
c. Usually occurs in infants and the elderly
d. Most commonly occurs on the legs and feet (Facial erysipelas can occur, but they are
less common.)

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e. Warmth, erythema, and pain

f. Edge of infection is elevated and sharply demarcated from the surrounding tissue.
g. Systemic signs of infection are common, but blood cultures are positive only 5% of the time.
2. Microorganism: group A streptococcus (S. pyogenes), but occasionally, groups G, C,
and B are seen
3. Treatment: 7–10 days (infections may worsen when treatment begins)
i. Penicillin G
ii. Clindamycin

C. Necrotizing Fasciitis
1. Description
a. Acute, necrotizing cellulites that involve the subcutaneous fat and superficial fascia
b. Infection extensively alters surrounding tissue, leading to cutaneous anesthesia or gangrene.
c. Very painful
d. Streptococcal infection: either spontaneous or attributable to varicella, minor trauma
(cuts, burns, and splinters), surgical procedures, or muscle strain; mixed infection
generally secondary to abdominal surgery or trauma
e. Significant systemic symptoms, including shock and organ failure
2. Microorganisms
a. S. pyogenes
b. Mixed infection with facultative and anaerobic bacteria
3. Treatment
a. Surgical debridement: most important therapy and often requires repeated debridement
b. Antibiotics are not curative; given in addition to surgery (if used early, may be effective alone)
c. Empiric therapy: β-lactamase inhibitor combinations plus clindamycin plus ciprofloxacin,
carbapenems, cefotaxime plus clindamycin or metronidazole
d. Streptococcal necrotizing fasciitis: high-dose intravenous penicillin plus clindamycin

D. Varicella-Zoster Virus Immunization

1. Shingles vaccine (Zostavax)
a. Characteristics
i. Zoster vaccine is a live, attenuated vaccine, identical to the chicken pox vaccine
(Varivax) but with significantly more plaque-forming units of virus per vaccination.
ii. Significantly decreases the number of cases and the burden of illness in vaccinated
patients (50% effective, but decreases with age). In addition, significantly decreases
the incidence and persistence of post-herpetic neuralgia (40% effective)
b. Recommendations
i. One dose—all adults 60 years and older (regardless of chicken pox or zoster history)
ii. Not indicated for treatment of active herpes zoster infections or post-herpetic neuralgia

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Patient Case
5. G.N. returns to the clinic in 6 months with no urinary symptoms, but her chief concern is now an ulcer on her
right foot. She recently returned from a vacation in Florida and thinks she might have stepped on something while
walking barefoot on the beach. Her foot is not sore but is red and swollen around the ulcer. The ulcer is deep, and
the infection may involve the underlying bone. Her medications are the same as before, except that now, she also
takes trimethoprim 100 mg 3 times/week for UTI. Vital signs are stable, and there is nothing significant on physical
examination except the right foot ulcer. Laboratory values are within normal limits (serum creatinine 0.86 mg/dL).
Which one of the following best describes the organism(s) likely responsible for G.N.’s foot ulcer?
A. Multiple anaerobic organisms.
B. P. aeruginosa.
C. S. aureus.
D. Polymicrobial with gram-positive, gram-negative, and anaerobic organisms.

IV. DIABETIC FOOT INFECTIONS

A. A diabetes complication that most often leads to hospitalization

B. Twenty-five percent of people with diabetes develop foot infections; 1 in 15 requires amputation.

C. Etiology
1. Neuropathy: motor and autonomic
a. Mechanical or thermal injuries lead to ulcerations without patient knowledge.
b. Gait disturbances and foot deformities; maldistribution of weight on the foot
c. Diminished sweating, causing dry, cracked skin
2. Vasculopathy: decreased lower limb perfusion
3. Immunologic defects (cellular and humoral)

D. Causative Organisms - In general, polymicrobial (average, 2.1–5.8 microorganisms)

1. S. aureus
2. Streptococcus
3. Enterococcus
4. Proteus
5. E. coli
6. Klebsiella
7. Enterobacter
8. P. aeruginosa
9. Bacteroides fragilis\
10. Peptococcus

E. Therapy
1. Preventive therapy
a. Examine feet daily for calluses, blisters, trauma, etc.
b. Wear properly fitting shoes.
c. No barefoot walking
d. Keep feet clean and dry.
e. Have toenails cut properly.

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Patient Case
6. Which one of the following is the best empiric therapy for G.N.?
A. Nafcillin 2 g intravenously every 6 hours—duration of antibiotics: 6–12 weeks.
B. Tobramycin 120 mg intravenously every 12 hours plus levofloxacin 750 mg/day intravenously—
duration of antibiotics: 1–2 weeks.
C. Piperacillin/tazobactam 4.5 g intravenously every 8 hours—duration of antibiotics: 1–2 weeks.
D. Below-the-knee amputation followed by ceftriaxone 1 g intravenously every 24 hours—duration of
antibiotics: 1 week.

2. Antimicrobial therapy
a. Shallow, non–limb-threatening infections can be treated like cellulitis (penicillinase-
resistant penicillin, first-generation cephalosporin, etc.).
b. Deep, limb-threatening infections require more broad-spectrum agents.
i. Ampicillin/sulbactam
ii. Ticarcillin/clavulanate or piperacillin/tazobactam
iii. Ertapenem
iv. Fluoroquinolone plus clindamycin/metronidazole
v. Cefoxitin
vi. Third-generation cephalosporin plus clindamycin or metronidazole
c. Treatment duration: 1–2 weeks if it is only a skin/soft tissue infection or 6–12 weeks if
osteomyelitis

F. Topical Therapy - Becaplermin (Regranex)

1. A 0.01% gel of recombinant human platelet–derived growth factor
2. Increases production of cells that repair wounds and form granulation tissue
3. Improves complete healing from 35% to 50%
4. May increase cancer mortality (but not cancer incidence)

G. Surgical Therapy
1. Drainage and debridement are very important.
2. Amputation: often required; if discovered early, can maintain structural integrity of the foot

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V. OSTEOMYELITIS

Patient Case
7. W.A. is a 55-year-old man who presents with weight loss, malaise, and severe back pain and spasms that
have progressed during the past 2 months. He has also experienced loss of sensation in his lower extremi-
ties. Four months before this admission, he had surgery for a fractured tibia, followed by an infection treat-
ed with unknown antibiotics. W.A. has hypertension and diverticulitis. On physical examination, he is alert
and oriented, with the following vital signs: temperature 99.4°F (37.4°C); heart rate 88 beats/minute; respi-
ratory rate 14 breaths/minute; and blood pressure 130/85 mm Hg. His laboratory values are within normal
limits, except for WBC 14,300, erythrocyte sedimentation rate 89 mm/hour, and C-reactive protein 12 mg/
dL. Magnetic resonance imaging shows bony destruction of lumbar vertebrae 1 and 2, which is confirmed
by a bone scan. A computed tomography–guided bone biopsy shows gram-positive cocci in clusters. Which
one of the following is the best initial therapy for W.A.?
A. Vancomycin 15 mg/kg intravenously every 12 hours—duration of antibiotics: 6 weeks.
B. Nafcillin 2 g intravenously every 6 hours—duration of antibiotics: 2 weeks.
C. Levofloxacin 750 mg/day orally—duration of antibiotics: 6 weeks.
D. Ampicillin/sulbactam 3 g intravenously every 6 hours—duration of antibiotics: 2 weeks.

A. Introduction
1. Infection of the bone with subsequent bone destruction
2. Around 20 cases per 100,000 population

B. Characteristics (Table 5)

Table 5. Characteristics of Osteomyelitis

Hematogenous Spread Contiguous Spread Vascular Insufficiency
Definition Spread of bacteria through the bloodstream Spread of bacteria from an Infection results from
from a distant site adjacent tissue infection or by insufficient blood supply
direct inoculation to fight the bacteria
Patient Children (< 16 years) Adults (25–50 years) Adults (> 50 years)
population - Femur, tibia, humerus - Femur, tibia, skull
Adult
- Vertebrae
Predisposing 1. Bacteremia (IV catheters, IVDU, 1. Open reduction of fractures 1. Diabetes
factors skin infections, URI, etc.) 2. Gunshot wound 2. PVD
2. Sickle cell anemia 3. Dental/sinus infections 3. Post-CABG (sternum)
4. Soft tissue infections
Common Usually monomicrobial Usually mixed infection Usually polymicrobial
pathogens 1. Children - S. aureus (60%–90%) S. S. aureus (60%) S. aureus
epidermidis, S. pyogenes, S. pneu- S. epidermidis S. epidermidis
moniae, H. influenzae, P. aeruginosa, Streptococcus Streptococcus
Enterobacter, E. coli (all < 5%) Gram-negative bacilli Gram-negative bacilli
2. Adult - S. aureus and P. aeruginosa (foot Anaerobic (Bacteroides
gram-negative bacilli punctures), Proteus, fragilis group)
3. Sickle cell anemia - Salmonella (67%) Klebsiella, E. coli Infected prosthesis:
S. pneumoniae Anaerobic (human bites, S. aureus
4. IV drug users - P. aeruginosa decubitus ulcers) S. epidermidis
CABG = coronary artery bypass graft; IV = intravenous; IVDU = intravenous drug use; PVD = pulmonary vascular disease; URI
= upper respiratory infection.

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C. Clinical Presentation
1. Signs and symptoms
a. Fever and chills
b. Localized pain, tenderness, and swelling
c. Neurologic symptoms if spinal cord compression
2. Laboratory tests
a. Elevated WBC
b. Elevated erythrocyte sedimentation rate
c. Elevated C-reactive protein
3. Diagnostic tests
a. Radiographic tests: Positive results lag behind infectious process.
b. Computed tomography and magnetic resonance imaging scans
c. Radionuclide imaging: positive as soon as 24–48 hours after infectious process begins

D. Empiric Therapy
1. Neonates younger than 1 month
a. Nafcillin plus cefotaxime OR
b. Nafcillin plus an aminoglycoside
2. Infants (1–36 months)
a. Cefuroxime
b. Ceftriaxone
c. Nafcillin plus cefotaxime
3. Pediatrics (older than 3 years)
a. Nafcillin
b. Cefazolin
c. Clindamycin
4. Adults
a. Nafcillin or cefazolin or vancomycin
b. Choose additional antibiotics on the basis of patient-specific characteristics.
5. Patients with sickle cell anemia - Nafcillin plus ampicillin
6. Prosthetic joint infections
a. Vancomycin plus rifampin
b. Nafcillin plus rifampin

E. Therapy Length
1. Acute osteomyelitis: 4–6 weeks
2. Chronic osteomyelitis: 6–8 weeks of parenteral therapy and 3–12 months of oral therapy

F. Criteria for Effective Oral Therapy for Osteomyelitis

1. Adherence
2. Identified organism that is highly susceptible to the oral antibiotic used
3. C-reactive protein less than 2.0 mg/dL
4. Adequate surgical debridement
5. Resolving clinical course

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VI. CENTRAL NERVOUS SYSTEM INFECTIONS

A. Meningitis: Introduction
1. Incidence: about 8.6 cases per 100,000 population
2. More males than females
3. More common in children

B. Microbiology (Table 6)
1. Bacterial (septic meningitis)

Table 6. Bacterial Etiology of Meningitis, Based on Age

Age Most Likely Organisms Less Common Organisms
< 1 month (newborns) S. agalactiae Listeria monocytogenes
E. coli Herpes simplex, type 2
Klebsiella sp.
Enterobacter sp.
1 month to 2 years S. pneumoniae Viruses
N. meningitidis E. coli
S. agalactiae
H. influenzae
2–50 years N. meningitidis Viruses
S. pneumoniae
> 50 years S. pneumoniae L. monocytogenes; aerobic
N. meningitidis gram-negative bacilli; viruses

2. Other causes (aseptic meningitis)

a. Viral
b. Fungal
c. Parasitic
d. Tubercular
e. Syphilis
f. Drugs (e.g., TMZ/SMZ, ibuprofen)

C. Predisposing Factors
1. Head trauma
2. Immunosuppression
3. Central nervous system shunts
4. Cerebrospinal fluid fistula/leak
5. Neurosurgical patients
6. Alcoholism
7. Local infections
a. Sinusitis
b. Otitis media
c. Pharyngitis
d. Bacterial pneumonia
8. Splenectomized patients
9. Sickle cell disease
10. Congenital defects

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D. Clinical Presentation
1. Symptoms
a. Fever, chills
b. Headache, backache, nuchal rigidity, mental status changes, photophobia
c. Nausea, vomiting, anorexia, poor feeding habits (infants)
d. Petechiae/purpura (N. meningitidis meningitis)
2. Physical signs
a. Brudzinski sign
b. Kernig sign
c. Bulging fontanel
E. Diagnosis
1. History and physical examination
2. Lumbar puncture
a. Increased opening pressure
b. Composition in bacterial meningitis (Table 7)

Table 7. CSF Changes in Bacterial Meningitis

Component Normal CSF Bacterial Meningitis
Glucose 30–70 mg/dL < 50 mg/dL
(2/3 peripheral) (≤ 0.4 CSF:blood)
Protein < 50 mg/dL > 150 mg/dL
WBC < 5/mm3 > 1200/mm3
pH 7.3 7.1
Lactic acid < 14 mg/dL > 35 mg/dL
CSF = cerebrospinal fluid; WBC = white blood cell count.

c. Cerebrospinal fluid stains/studies

i. Gram stain (microorganisms): helps identify organism in 60%–90% of cases
ii. Latex agglutination: high sensitivity, 50%–100%, for common organisms
(a) Not recommended routinely
(b) Most useful in patients pretreated with antibiotics with subsequent negative CSF
Gram stains and cultures
iii. Acid-fast staining (tubercular meningitis)
iv. India ink test (Cryptococcus)
v. Cryptococcal antigen
vi. Herpes simplex virus-polymerase chain reaction
3. Laboratory findings
a. Increased WBC with a left shift
b. Cerebrospinal fluid Gram stain
c. Cerebrospinal fluid cultures (positive in 75%–80% of bacterial meningitis cases)
d. Blood cultures (±)
e. C-reactive protein concentrations: high negative predictive value

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Patient Case
8. D.M. is a 21-year-old university student who presents to the emergency department with the worst headache
of his life. During the past few days, he has felt slightly ill but has been able to go to class regularly and eat
and drink adequately. This morning, he awoke with a terrible headache and pain whenever he moved his
neck. He has no significant medical history and takes no medications. He cannot remember the last time he
received a vaccination. On physical examination, he is in extreme pain (10/10) with the following vital signs:
temperature 102.4°F (39.1°C); heart rate 110 beats/minute; respiratory rate 18 breaths/minute; and blood
pressure 130/75 mm Hg. His laboratory values are within normal limits, except for WBC 22,500 (82 polymor-
phonuclear leukocytes, 11 band neutrophils, 5 lymphocytes, and 2 monocytes). A computed tomography scan
of the head was normal, so a lumbar puncture was performed with the following results: glucose 44 mg/dL
(peripheral, 110); protein 220 mg/dL; and WBC 800/mm3 (85% neutrophils, 15% lymphocytes). Gram stain-
ing shows abundant gram-negative cocci. Which one of the following is the best empiric therapy for D.M.?
A. Penicillin G 4 million units intravenously every 4 hours plus dexamethasone 4 mg intravenously
every 6 hours.
B. Ceftriaxone 2 g intravenously every 12 hours.
C. Ceftriaxone 2 g intravenously every 12 hours plus dexamethasone 4 mg intravenously every 6 hours.
D. Ceftriaxone 2 g intravenously every 12 hours plus vancomycin 1000 mg intravenously every 12 hours.

F. Empiric Therapy
1. Neonates younger than 1 month
a. Ampicillin plus aminoglycoside or
b. Ampicillin plus cefotaxime
2. Infants (1–23 months)
− Third-generation cephalosporin (cefotaxime or ceftriaxone) plus vancomycin
3. Pediatrics and adults (2–50 years)
− Third-generation cephalosporin (cefotaxime or ceftriaxone) plus vancomycin
4. The elderly (50 years and older)
− Third-generation cephalosporin (cefotaxime or ceftriaxone) plus ampicillin plus
vancomycin
5. Penetrating head trauma, post-neurosurgery, or CSF shunt
− Vancomycin plus cefepime, ceftazidime, or meropenem

G. Therapy for Common Pathogens

1. S. pneumoniae
a. A minimum inhibitory concentration (MIC) equal to 0.1 mcg/mL or less
i. Penicillin G 4 million units intravenously every 4 hours
ii. Ampicillin 2 g intravenously every 4 hours
iii. Alternative: third-generation cephalosporin or chloramphenicol
b. An MIC 0.1–1.0 mcg/mL
i. Third-generation cephalosporin
ii. Alternative: cefepime or meropenem
c. An MIC 2.0 mcg/mL or greater
i. Vancomycin plus a third-generation cephalosporin
ii. Alternative: moxifloxacin

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2. Neisseria meningitidis
a. An MIC less than 0.1 mcg/mL
i. Penicillin G 4 million units intravenously every 4 hours
ii. Ampicillin 2 g intravenously every 4 hours
iii. Alternative: third-generation cephalosporin or chloramphenicol
b. An MIC 0.1–1.0 mcg/mL
i. Third-generation cephalosporin
ii. Alternative: chloramphenicol, fluoroquinolone, or meropenem
3. H. influenzae
a. β-Lactamase negative
i. Ampicillin 2 g intravenously every 4 hours
ii. Alternative: third-generation cephalosporin, cefepime, chloramphenicol, or
fluoroquinolone
b. β-Lactamase positive
i. Third-generation cephalosporin
ii. Alternative: cefepime, chloramphenicol, or fluoroquinolone
4. S. agalactiae
a. Penicillin G 4 million units intravenously every 4 hours
b. Ampicillin 2 g intravenously every 4 hours
c. Alternative: third-generation cephalosporin
5. Listeria monocytogenes
a. Penicillin G 4 million units intravenously every 4 hours
b. Ampicillin 2 g intravenously every 4 hours
c. Alternative: TMZ/SMZ or meropenem

H. Therapy Length: Based on Clinical Experience, Not on Clinical Data

1. N. meningitidis: 7 days
2. H. influenzae: 7 days
3. S. pneumoniae: 10–14 days

I. Adjunctive Corticosteroid Therapy

1. Risks versus benefits
a. Significantly less hearing loss and other neurologic sequelae in children receiving
dexamethasone for H. influenzae meningitis
b. Significantly improved outcomes, including decreased mortality, in adults receiving
dexamethasone for S. pneumoniae meningitis
c. May decrease antibiotic penetration
d. Decreased penetration of vancomycin in animals after dexamethasone
2. Dose and administration
a. Give corticosteroids 10–20 minutes before or at same time as antibiotics.
b. Dexamethasone 0.15 mg/kg every 6 hours for 2–4 days
c. Use in children with H. influenzae meningitis or in adults with pneumococcal meningitis;
however, may need to initiate before knowing specific causative bacteria

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Patient Case
9. After D.M.’s diagnosis, there is concern about prophylaxis. Which one of the following is the best recom-
mendation for meningitis prophylaxis?
A. The health care providers in close contact with D.M. should receive rifampin 600 mg every 12 hours
for four doses.
B. Everyone in D.M.’s dormitory and in all his classes should receive rifampin 600 mg/day for 4 days.
C. Everyone in the emergency department at the time of D.M.’s presentation should receive the
meningococcal polysaccharide vaccine.
D. Everyone in the emergency department at the time of D.M.’s presentation should receive rifampin 600
mg every 12 hours for four doses.

J. Prophylaxis
1. S. pneumoniae
a. Pneumococcal conjugate vaccine: 13 valent
i. All children younger than 23 months
ii. Children 24–59 months with high-risk status
(a) Certain chronic diseases
(b) Alaska Native or American Indian
(c) African American
(d) Day care attendees
b. Pneumococcal polysaccharide vaccine: 23 valent - give to those at risk (see patient
groups in pneumonia section above).
2. N. meningitidis
a. Chemoprophylaxis: for close contacts (household or day care) and exposure to oral
secretions of index case
i. Rifampin:
(a) Adults: 600 mg every 12 hours × 4 doses
(b) Children: 10 mg/kg every 12 hours × 4 doses
(c) Infants (younger than 1 month): 5 mg/kg every 12 hours × 4 doses
ii. Ciprofloxacin 500 mg orally × 1 (adults only)
iii. Ceftriaxone 125–250 mg intramuscularly × 1
b. Meningococcal polysaccharide vaccine (Menomune) and meningococcal conjugate
vaccine (Menactra) (both lack serogroup B)
i. Indications (use Menactra unless patient is older than 55 years)
(a) Young adolescents (11–12 years)
(b) College freshmen living in dormitories (4 cases per 100,000 per year, especially
freshmen living in dormitories)
(c) Military recruits
(d) Travel to “meningitis belt” of Africa and Asia, Saudi Arabia for Islamic Hajj
pilgrimage
(e) People with asplenia (anatomic or functional)
(f) People with terminal complement component deficiencies
(g) Outbreaks of meningococcal disease
ii. Booster dose – recommended for adolescents at 16 years of age if they received a
first dose at age 11-12 years, or 5 years after the first dose – up to age 21 years — to
those who first received the vaccine at age 13-15 years.

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3. H. influenzae
a. Chemoprophylaxis: for everyone in households with unvaccinated children
i. Adults: rifampin 600 mg/day for 4 days
ii. Children (1 month to 12 years): rifampin 20 mg/kg/day for 4 days
iii. Infants younger than 1 month: rifampin 10 mg/kg/day for 4 days
b. H. influenzae type B polysaccharide vaccine
i. All children
ii. Indications regardless of age
(a) Asplenia (anatomic or functional)
(b) Sickle cell disease
(c) Hodgkin disease
(d) Hematologic neoplasms
(e) Solid-organ transplantation
(f) Severely immunocompromised (non-HIV related)
iii. Consider for people with HIV infection

K. Brain Abscess
1. Pathophysiology
a. Direct extension or retrograde septic phlebitis from otitis media, mastoiditis, sinusitis, and
facial cellulitis
b. Hematogenous: particularly lung abscess or infective endocarditis: 3%–20% have no
detectable focus
2. Signs and symptoms
a. Expanding intracranial mass lesion: focal neurologic deficits
b. Headache
c. Fever
d. Seizures
e. Mortality is about 50%.
3. Microbiology
a. Usually polymicrobial
b. Streptococcus in 50%–60%
c. Anaerobes in about 40%
4. Therapy
a. Incision and drainage: by craniotomy or stereotaxic needle aspiration
b. Suggested empiric regimens based on source of infection
i. Otitis media or mastoiditis: metronidazole plus third-generation cephalosporin
ii. Sinusitis: metronidazole plus third-generation cephalosporin
iii. Dental sepsis: penicillin plus metronidazole
iv. Trauma or post-neurosurgery: vancomycin plus third-generation cephalosporin
v. Lung abscess, empyema: penicillin plus metronidazole plus sulfonamide
vi. Unknown: vancomycin plus metronidazole plus third-generation cephalosporin
c. Corticosteroids if increased intracranial pressure

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VII. ENDOCARDITIS

Patient Case
10. T.S. is a 48-year-old man who presents to the emergency department complaining of fever, chills, nausea/
vomiting, anorexia, lymphangitis in his right hand, and lower back pain. He has no significant medical history
except for kidney stones 4 years ago. He has no known drug allergies. He is homeless and was an intravenous
drug abuser (heroin) for the past year but quit 2 weeks ago. On physical examination, he is alert and oriented,
with the following vital signs: temperature 100.8°F (38°C); heart rate 114 beats/minute; respiratory rate 12
breaths/minute; and blood pressure 127/78 mm Hg. He has a faint systolic ejection murmur, and his right hand
is erythematous and swollen. His laboratory values were all within normal limits. He had an HIV test 1 year
ago, which was negative. One blood culture was obtained that later grew MSSA. Two more cultures were
obtained that are now growing gram-positive cocci in clusters. A transesophageal echocardiogram shows
vegetation on the mitral valve. Which one of the following therapeutic regimens is appropriate for T.S.?
A. Nafcillin intravenous therapy—antibiotic duration: 2 weeks.
B. Nafcillin intravenously plus rifampin therapy—antibiotic duration: 6 weeks or longer.
C. Nafcillin intravenously plus gentamicin intravenous therapy—antibiotic duration: 2 weeks of both
antibiotics.
D. Nafcillin intravenously plus gentamicin—antibiotic duration: 6 weeks (nafcillin) with first 3–5 days
of gentamicin.

A. Introduction
1. Infection of the heart valves or other endocardial tissue
2. Platelet-fibrin complex becomes infected with microorganisms—vegetation
3. Main risk factors include mitral valve prolapse, prosthetic valves, and intravenous drug abuse.
4. Three or 4 cases per 100,000 population per year

B. Presentation/Clinical Findings
1. Signs and symptoms
a. Fever: low grade and remittent
b. Cutaneous manifestations (50% of patients): petechiae (including conjunctival), Janeway
lesions, splinter hemorrhage
c. Cardiac murmur (90% of patients)
d. Arthralgias, myalgias, low back pain, arthritis
e. Fatigue, anorexia, weight loss, night sweats
2. Laboratory findings
a. Anemia: normochromic, normocytic
b. Leukocytosis
c. Elevated erythrocyte sedimentation rate and C-reactive protein
d. Positive blood culture in 78%–95% of patients
3. Complications
a. Congestive heart failure: 38%–60% of patients
b. Emboli: 22%–43% of patients
c. Mycotic aneurysm: 5%–10% of patients

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C. Microbiology (Table 8)
1. Three to five blood cultures of at least 10 mL each should be drawn during the first 24–48 hours.
2. Empiric therapy should be initiated only in acutely ill patients. In these patients, three blood
samples should be drawn during a 15- to 20-minute period before initiating antibiotics.

Table 8. Incidence of Microorganisms in Endocarditis

Organism Incidence (%)
Streptococcus 50
S. aureus 25
Enterococcus 8
Coagulase-negative Staphylococcus 7
Gram-negative bacilli 6
Candida albicans 2

D. Treatment (Table 9)
Table 9. Treatment Recommendation for Endocarditis
Length of Therapy (weeks)
Organism Recommended Therapy Native Valve Prosthetic Valve
Streptococcus viridans Penicillin G 4 —
(with penicillin MIC ≤ Penicillin G + gentamicin 2 6a
0.12 mcg/mL)
Ceftriaxone 4 —
Ceftriaxone + gentamicin 2 6a
Vancomycin 4 6
Streptococcus viridans Penicillin G + gentamicin 4b 6
(with penicillin MIC > Ceftriaxone + gentamicin 4b 6
0.12 mcg/mL)
Vancomycin 4 6
Staphylococcus— Oxacillin or nafcillin 6 ≥ 6b
methicillin sensitive - ± Gentamicin for 3–5 days
- Plus rifampin in prosthetic valves
Cefazolin 6 ≥ 6b
- ± Gentamicin for 3–5 days
- Plus rifampin in prosthetic valves
Vancomycin (only if severe PCN allergy) 6 ≥ 6b
- Plus rifampin in prosthetic valves
Staphylococcus— Vancomycin 6 ≥ 6b
methicillin resistant - Plus rifampin in prosthetic valves
Enterococcus Penicillin G or ampicillin + gentamicin or streptomycin 4–6 6
Vancomycin + gentamicin or streptomycin 6 6
Enterococcus— Ampicillin/sulbactam or vancomycin + gentamicin 6 6
penicillin resistant
E. faecium—penicillin, Linezolid ≥8 ≥8
aminoglycoside, and Quinupristin/dalfopristin ≥8 ≥8
vancomycin resistant
E. faecalis—penicillin, Imipenem/cilastatin + ampicillin ≥8 ≥8
aminoglycoside, and Ceftriaxone + ampicillin ≥8 ≥8
vancomycin resistant
HACEK group Ceftriaxone 4 6
Ampicillin/sulbactam 4 6
Fluoroquinolone (cipro-, levo-, gati-, moxi-) 4 6
a
Gentamicin can be added for 2 weeks if creatinine clearance is greater than 30 mL/minute.
b
Gentamicin for 2 weeks.
HACEK = [Haemophilus, Actinobacillus Cardiobacterium, Eikenella, Kingella]
group; MIC = minimum inhibitory concentration; PCN = penicillin.

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E. Prophylaxis (Table 10)

Table 10. Endocarditis Prophylaxis

Conditions in Which Prophylaxis Is Necessary Dental Procedures That Require Prophylaxis
- Prosthetic cardiac valves including bioprosthetic and - Any dental procedure that involves the
homograft valves gingival tissues or periapical region of a
- Previous bacterial endocarditis tooth and for procedures that perforate the
- Congenital heart disease oral mucosa
- Unrepaired cyanotic congenital heart disease
- Completely repaired congenital heart defect with Other Procedures That Require Prophylaxis
prosthetic material or device, during the first 6 months Respiratory tract
after the procedure - Tonsillectomy and/or adenoidectomy
- Repaired congenital heart disease with residual defects - Surgical operations that involve an incision
adjacent to or at the site of a prosthetic patch or device or biopsy of the respiratory mucosa
- Cardiac transplant recipients who develop cardiac
valvulopathy

F. Recommended Prophylaxis for Dental or Respiratory Tract Procedures (Table 11)

Table 11. Prophylaxis for Dental or Respiratory Tract Procedures

Situation Agent Regimen
Standard general prophylaxis Amoxicillin Adults: 2 g; children: 50 mg/kg 1 hour before procedure
Unable to take oral medications Ampicillin Adults: 2 g IM/IV; children: 50 mg/kg IM/IV within 30
minutes before procedure
Cefazolin or Adults: 1 g IM/IV; children: 50 mg/kg IM/IV within 30
ceftriaxone minutes before procedure
Allergic to penicillin Clindamycin Adults: 600 mg; children: 20 mg/kg 1 hour before
procedure
Cephalexin Adults: 2 g; children: 50 mg/kg 1 hour before procedure
Azithromycin or Adults: 500 mg; children: 15 mg/kg 1 hour before
clarithromycin procedure
Allergic to penicillin and Clindamycin Adults: 600 mg; children: 20 mg/kg IV within
unable to take oral medications 30 minutes before procedure
Cefazolin or Adults: 1 g IM/IV; children: 50 mg/kg IM/IV within 30
ceftriaxone minutes before procedure
IM = intramuscularly; IV = intravenously.

Patient Case
11. Six months after treatment of his endocarditis, T.S. is visiting his dentist for a tooth extraction. Which one
of the following antibiotics is best for prophylaxis?
A. Tooth extractions do not require endocarditis prophylaxis.
B. Administer amoxicillin 2 g 1 hour before the extraction.
C. Administer amoxicillin 3 g 1 hour before the extraction and 1.5 g 6 hours after the extraction.
D. T.S. is not at increased risk of endocarditis and does not need prophylactic antibiotics.

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VIII. PERITONITIS/INTRA-ABDOMINAL INFECTIONS

A. Introduction
1. Definition: inflammation of the peritoneum (serous membrane lining the abdominal cavity)
2. Types
a. Primary: spontaneous/idiopathic—no primary focus of infection
b. Secondary: occurs secondary to an abdominal process

B. Primary Peritonitis
1. Etiology
a. Alcoholic cirrhosis and ascites (peritonitis occurs in 10% of these patients)
b. Other: postnecrotic cirrhosis, chronic active hepatitis, acute viral hepatitis, congestive
heart failure, systemic lupus erythematous, metastatic malignancy (common underlying
problem is ascites)
2. Microbiology
a. E. coli
b. K. pneumoniae
c. S. pneumoniae
d. Group A streptococcus
3. Pathogenesis
a. Hematogenous: Portosystemic shunting increases bacteria in the blood, infecting ascitic
collection.
b. Lymphogenous
c. Transmural through the intact gut wall from the lumen
d. Vaginally through the fallopian tubes
4. Clinical manifestations/diagnosis
a. Fever
b. Abdominal pain
c. Nausea, vomiting, diarrhea
d. Diffuse abdominal tenderness, rebound tenderness, hypoactive or no bowel sounds
e. Ascitic fluid
i. Protein: low because of hypoalbuminemia or dilution with transudate fluid from the
portal system
ii. White blood cell count: more than 300/mm3 (85% have more than 1000/mm3)—
primarily granulocytes
iii. pH: less than 7.35
iv. Lactic acid: more than 25 mg/dL
v. Gram stain: 60%–80% are negative, but diagnostic if it is positive

C. Secondary Peritonitis
1. Etiology
a. Injuries to the gastrointestinal tract, including
i. Peptic ulcer perforation
ii. Perforation of a gastrointestinal organ
iii. Appendicitis
iv. Endometritis secondary to intrauterine device
v. Bile peritonitis
vi. Pancreatitis

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vii. Operative contamination

viii. Diverticulitis
ix. Intestinal neoplasms
x. Secondary to peritoneal dialysis
2. Microbiology of intra-abdominal infections
a. Stomach/proximal small intestine: aerobic and facultative gram-positive and gram-
negative organisms
b. Ileum: E. coli, Enterococcus, anaerobes
c. Large intestine: obligate anaerobes (i.e., Bacteroides, Clostridium perfringens), aerobic
and facultative gram-positive and gram-negative organisms (i.e., E. coli, Streptococcus,
Enterococcus, Klebsiella, Proteus, Enterobacter)
3. Clinical manifestations/diagnosis
a. Fever, tachycardia
b. Increased WBC
c. Abdominal pain aggravated by motion, rebound tenderness
d. Bowel paralysis
e. Pain with breathing
f. Decreased renal perfusion
g. Ascitic fluid
i. Protein: high (more than 3 g/dL)—exudate fluid
ii. White blood cell count: many, primarily granulocytes

D. Therapy
1. Therapy or prophylaxis should be limited in:
a. Bowel injuries caused by trauma that are repaired within 12 hours (treat for less than 24
hours)
b. Intraoperative contamination by enteric contents (treat for less than 24 hours)
c. Perforations of the stomach, duodenum, and proximal jejunum (unless patient is on
antacid therapy or has malignancy) (prophylactic antibiotics for less than 24 hours)
d. Acute appendicitis without evidence of perforation, abscess, or peritonitis (treat for less
than 24 hours)
2. Mild to moderate community-acquired infection
a. Cefoxitin
b. Cefazolin, cefuroxime, ceftriaxone or cefotaxime plus metronidazole
c. Ticarcillin/clavulanate
d. Ertapenem
e. Moxifloxacin
f. Ciprofloxacin or levofloxacin plus metronidazole
g. Tigecycline
3. High-risk or severe community-acquired or health care–acquired infection
a. Piperacillin/tazobactam
b. Ceftazidime or cefepime plus metronidazole
c. Imipenem/cilastatin or meropenem or doripenem
d. Ciprofloxacin or levofloxacin plus metronidazole (not for health care–acquired infections)
4. Therapy duration: 4–7 days (unless source control is difficult)

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IX. Clostridium difficile Infection

A. Introduction
1. Clostridium difficile is transmitted by the fecal-oral route.
2. Overgrowth in the gastrointestinal tract occurs after antibiotic therapy.
3. Risk factors: hospital stays, medical comorbidities, extremes of age, immunodeficiency states,
advancing age, use of broad-spectrum antibiotics for extended periods
4. Production of endotoxins A and B causes pathogenesis.
5. Symptoms: watery diarrhea, abdominal pain, leukocytosis, gastrointestinal tract
complications
6. New strain (BI/NAP1) produces more enterotoxin, produces binary toxin, has increased
sporulation capacity, and is resistant to fluoroquinolones. Increased risk of metronidazole
failure, morbidity, and mortality

B. Therapy
1. Initial episode and first recurrence
a. Metronidazole 500 mg orally or intravenously 3 times/day for 10–14 days
b. Vancomycin 125 mg orally 4 times/day for 10–14 days
2. Second and third recurrences
a. Can consider higher doses of vancomycin (500 mg orally 4 times/day)
b. Taper therapy: vancomycin 125 mg orally 4 times/day for 14 days, 2 times/day for 7
days, and daily for 7 days
c. Pulse therapy: recommended vancomycin course of therapy for initial episode (for 10–14
days), followed by vancomycin every other day for 8 days, and then every 3 days for 15 days
d. Consider rifaximin 400 mg 2 times/day for 14 days or nitazoxanide 500 mg 2 times/day
for 10 days.

X. MEDICAL/SURGICAL PROPHYLAXIS

A. Introduction
1. Prophylaxis: administration of the putative agent before bacterial contamination occurs
2. Early therapy: immediate or prompt institution of therapy as soon as the patient presents; usually
contamination or infection will have preceded the initiation of therapy (e.g., dirty wounds)

Patient Case
12. You are a pharmacist who works closely with the surgery department to optimize therapy for patients
undergoing surgical procedures at your institution. The surgeons provide you with principles of surgical
prophylaxis that they believe are appropriate. Which one of the following provided principles is acceptable?
A. Antibiotics should be redosed for extended surgical procedures; redose if the surgery lasts longer than
4 hours or involves considerable blood loss.
B. All patients should be given antibiotics for 24 hours after the procedure; this will optimize
prophylaxis.
C. Preoperative antibiotics can be given up to 4 hours before the incision; this will make giving the
antibiotics logistically easier.
D. Vancomycin should be the antibiotic of choice for surgical wound prophylaxis because of its long
half-life and activity against MRSA.

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B. Classification of Surgical Procedures (Table 12)

Table 12. Classification of Surgical Procedures

Surgical Procedure Infection Rate (%)
Clean: No entry is made in the respiratory, gastrointestinal, or genitourinary tracts or 1–4
in the oropharyngeal cavity. In general, it is elective with no break in technique and no
inflammation encountered
Clean contaminated: Entry in the respiratory, gastrointestinal, genitourinary, or 5–15
biliary tracts or oropharyngeal cavity without unusual contamination. Includes clean
procedures with a minor break in technique
Contaminated: Includes fresh traumatic wounds, gross spillage from the 16–25
gastrointestinal tract (without a mechanical bowel preparation), a major break in
technique, or incisions encountering acute, nonpurulent inflammation
Dirty: Includes procedures involving old traumatic wounds, perforated viscera, or 30–45
clinically evident infection

C. Risk Factors for Postoperative Wound Infections

1. Bacterial contamination
a. Exogenous sources – flaw in aseptic technique
b. Endogenous sources
i. Most important except in clean procedures
ii. Patient flora causes infection
2. Host resistance
a. Extremes of age
b. Nutrition (i.e., malnourished patients)
c. Obesity
d. Diabetes mellitus (decreased wound healing and increased risk of infection)
e. Immunocompromised
f. Hypoxemia
g. Remote infection
h. Presence of foreign body
i. Healthy person tolerates inoculum of 105
ii. In presence of foreign body, need only 102

D. Indications for Surgical Prophylaxis

1. Common postoperative infection with low morbidity
2. Uncommon postoperative infection with significant morbidity and mortality

E. Principles of Prophylaxis (Figure 1; Tables 13 and 14)

1. Timing: Antibiotics must be present in the tissues at the time of bacterial contamination
(incision) and throughout the operative period; “on-call” dosing is not acceptable.
a. Conclusions
i. Administering antibiotics any sooner than immediately preoperatively (within 60
minutes before incision) is unnecessary.
ii. Initiating antibiotics postoperatively is no more effective than administering no
prophylaxis.

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b. Conclusions
i. Antibiotics should be redosed for extended surgical procedures.
ii. Redose if the surgery lasts longer than 4 hours (or more than 2 half-lives of the
antibiotic) or involves considerable blood loss.

5
Infection Rate (%)

0
< -2 -2 -1 1 2 3 4 5 6 7 8 9 10 >
Hours before Hours after incision 10
incision

Figure 1. Principles of prophylaxis.

Information from Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing
of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med
1992;326:281–6.

Table 13. Temporal Relation Between the Administration of Prophylactic Antibiotics and Rates of
Surgical Wound Infection
Time of No. of Patients No. (%) of Infections Relative Risk Odds Ratio
Administrationa (95% CI) (95% CI)
Early 369 14 (3.8) 6.7 (2.9–14.7) 4.3 (1.8–10.4)
Preoperative 1708 10 (0.59) 1.0
Perioperative 282 4 (1.4) 2.4 (0.9–7.9) 2.1 (0.6–7.4)
Postoperative 488 16 (3.3) 5.8 (2.6–12.3) 5.8 (2.4–13.8)
All 2847 44 (1.5) — —
a
For the administration of antibiotics; “early” denotes 2–24 hours before the incision; “preoperative” 0–2 hours before the
incision; “perioperative” within 3 hours after the incision; and “postoperative” more than 3 hours after the incision.
CI = confidence interval.

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Table 14. Duration of Surgical Procedure and Risk of Infection

Duration of Surgical Infections/Standard Infections/Cefoxitin
Procedures Infections/Total Patients (%) Regimen Patients (%) Regimen Patients (%)
< 3 hours 0/46 0/29 0/17
≥ 3 hours to ≤ 4 hours 4/46 (8.7) 2/21 (9.5) 2/25 (8.0)
> 4 hours 5/27 (18.5) 0/13 5/14 (35.7)
Information from Kaiser AB, Herrington JL Jr, Jacobs JK, Mulherin JL Jr, Roach AC, Sawyers JL. Cefoxitin versus erythromycin,
neomycin, and cefazolin in colorectal operations. Importance of the duration of the surgical procedure. Ann Surg 1983;98:525–30.

2. Duration
a. Most procedures, including gastrointestinal, orthopedic, and gynecologic procedures,
require only antibiotics while the patient is in the operating room.
b. Cardiac procedures may require 24 hours of antibiotics postsurgery.
3. Spectrum
a. Need only activity against skin flora unless the operation violates a hollow viscus mucosa
b. Gastrointestinal, genitourinary, hepatobiliary, and some pulmonary operations require
additional antibiotics.
c. Colorectal surgery is one procedure in which broad-spectrum aerobic and anaerobic
coverage has been shown to be most effective.
d. Attempt to avoid a drug that may be needed for therapy.
4. Adverse reactions/bacterial resistance
a. Antibiotic prophylaxis should not cause greater morbidity than the infection it prevents.
b. Overuse may lead to resistance, which could prevent further use of the antibiotic for
surgical prophylaxis or other infections (duration of administration is an important factor).
5. Cost
a. Prophylaxis can account for a significant portion of the antibiotic budget.
b. Must be weighed against the cost of treating one person with a postoperative infection

F. Antibiotic Prophylaxis in Specific Surgical Procedures

1. Gastrointestinal
a. Gastric/duodenal
i. Because of acidity, relatively little normal flora
ii. Intragastric organisms and postoperative infections are increased with an increasing pH.
iii. Indicated for morbid obesity, esophageal obstruction, decreased gastric acidity, or
decreased gastrointestinal motility
iv. Recommendation: cefazolin 1–2 g preinduction
b. Biliary
i. Biliary tract normally has no organisms.
ii. Indicated for high-risk patients. (Often, intraoperative cholangiography shows
unexpected common duct stones, so some studies recommend using antibiotics in
all biliary surgery. In addition, studies have shown an increase in rates of infection
without risk factors.)
iii. Acute cholecystitis
iv. Obstructive jaundice
v. Common duct stones
vi. Age older than 70 years
vii. Recommendation: cefazolin (or cefoxitin) 1–2 g preinduction

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c. Appendectomy
i. Acutely inflamed or normal appendix: less than 10% risk
ii. Evidence of perforation: more than 50% risk (treatment required)
iii. If perforated appendix, treat for 3–7 days
iv. Recommendation: cefoxitin 1–2 g (or cefazolin plus metronidazole or ampicillin/
sulbactam) preinduction
d. Colorectal
i. A 30%–77% infection rate without antibiotics
ii. One of the few surgical procedures in which coverage for aerobes and anaerobes has
proved most effective
iii. Preoperative antibiotics
(a) Combined oral and parenteral regimens may be better than parenteral regimens alone.
(b) Oral regimens are inexpensive; however, some data suggest they are less effective
when used alone (without parenteral agents), have greater toxicity, and may increase
the risk of C. difficile infections.
(c) Recommendation: cefoxitin 1–2 g (or cefazolin plus metronidazole or ampicillin/
sulbactam or ertapenem) preinduction OR gentamicin/tobramycin 1.5 mg/kg
and clindamycin 600 mg–metronidazole 0.5–1 g preinduction with or without
neomycin 1 g and erythromycin 1 g at 19, 18, and 9 hours before surgery or
neomycin 2 g and metronidazole 2 g at 13 and 9 hours before surgery
(d) Note: Mechanical bowel preparation is not recommended and may be harmful.
2. Obstetrics/gynecology
a. Vaginal/abdominal hysterectomy
i. Antibiotics have been found to be most effective in vaginal hysterectomies but
generally are given for both procedures.
ii. Recommendation: cefazolin or cefoxitin 1–2 g (or ampicillin/sulbactam) preinduction
b. Cesarean section
− Recommendation: cefazolin 1–2 g after the cord is clamped
3. Cardiothoracic
a. Cardiac surgery
i. Antibiotics decrease risk of mediastinitis.
ii. Recommendation: cefazolin or cefuroxime 1–2 g preinduction (plus intraoperative
doses), if MRSA is probable or patient has been hospitalized, and then vancomycin
b. Pulmonary resection (i.e., lobectomy and pneumonectomy)
− Recommendation: cefazolin or cefuroxime 1–2 g preinduction (or vancomycin)
c. Vascular surgery
i. High mortality with infected grafts
ii. Recommendation: cefazolin 1 g preinduction and every 8 hours for three doses; if
MRSA is probable, then use vancomycin
4. Orthopedic
a. Prophylaxis is indicated when surgery involves prosthetic materials (i.e., total hip/knee, nail,
or plate).
b. Recommendation: cefazolin 1–2 g preinduction (or cefuroxime or vancomycin)
5. Head and neck
a. Indicated for major surgical procedures when an incision is made through the oral or
pharyngeal mucosa
b. Recommendation: cefazolin 1–2 g or ampicillin/sulbactam 1.5–3 g preinduction or
gentamicin 1.5 mg/kg and clindamycin 600–900 mg preinduction

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6. Urologic
a. In general, not recommended
b. Indicated if patient has a positive urine culture before surgery (should treat and then operate)
c. If therapy is unsuccessful, cover for the infecting organism and operate.

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Urinary Tract Infections
the Surgical Infection Society and the Infectious
1. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Diseases Society of America. Clin Infect Dis
Schaeffer AJ, Stamm WE. Guidelines for antimi- 2010;50:133–64.
crobial treatment of uncomplicated acute bacterial
2. Cohen SH, Gerding DN, Johnson S, et al. Clini-
cystitis and acute pyelonephritis in women. Clin
cal practice guidelines for Clostridium difficile
Infect Dis 1999;29:745–58.
infection in adults: 2010 update by the Soci-
2. Treatment of urinary tract infections in nonpregnant ety for Healthcare Epidemiology of American
women. ACOG Practice Bulletin No. 91. American (SHEA) and the Infectious Diseases Society of
College of Obstetricians and Gynecologists. Obstet America (IDSA). Infect Control Hosp Epidemiol
Gynecol 2008;111:785–94. 2010;31:431–55.

Skin and Soft Tissue Infections Medical/Surgical Prophylaxis

1. Swartz MN. Cellulitis. N Engl J Med 2004;350: 1. American Society of Health-System Pharmacists.
904–12. Therapeutic guidelines on antimicrobial prophylax-
2. Stevens DL, Bisno AL, Chambers HF, et al. Prac- is in surgery. Am J Hosp Pharm 1999;56:1839–88.
tice guidelines for the diagnosis and management 2. American Society of Health-System Pharma-
of skin and soft-tissue infections. Clin Infect Dis cists. Therapeutic guidelines for nonsurgical
2005;41:1373–406. antimicrobial prophylaxis. Am J Hosp Pharm
3. Lipsky BA, Berendt AR, Deery HG, et al. Diagno- 1999;56:1201–50.
sis and treatment of diabetic foot infections. Clin 3. Bratzler DW, Houck PM; Surgical Infection Pre-
Infect Dis 2004;39:885–910. vention Guidelines Writers Workgroup. Antimicro-
bial prophylaxis for surgery: an advisory statement
Osteomyelitis from the National Surgical Infection Prevention
Project. Clin Infect Dis 2004;38:1706–15.
1. Lew DP, Waldvogel FA. Osteomyelitis. Lancet
2004;364:369–79.

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 Infectious Diseases

Answers and Explanations to Patient Cases

1. Answer c or influenza vaccine immediately after an episode of

Although ampicillin/sulbactam has good activity against pneumonia. It is best to vaccinate whenever patients
H. influenza, Moraxella catarrhalis, and S. pneumoniae are available. B.P.’s age and medical history put her
(but not DRSP), it has no activity against atypical organ- at risk of both pneumococcal disease and influenza.
isms (L. pneumophila, M. pneumoniae, C. pneumoniae). Therefore, administration of pneumococcal and influ-
Current recommendations are to include a macrolide enza vaccines is indicated (if it is during the middle of
with a β-lactam antibiotic for hospitalized patients with influenza season and she was not vaccinated in the fall,
community-acquired pneumonia. Piperacillin/tazobac- she can receive the influenza vaccine now). B.P.’s age
tam has good activity against H. influenza, M. catarrha- places her in a group needing the pneumococcal vac-
lis, and S. pneumoniae (but not DRSP) and, with genta- cine, and everyone should receive the influenza vac-
micin, is excellent for pneumonia caused by most gram- cine. The causative agent for her current infection does
negative organisms. However, this increased activity is not affect the recommendation for vaccination.
not necessary for community-acquired pneumonia, and
the combination has no activity against atypical organ- 4. Answer B
isms. Ceftriaxone plus azithromycin is the best initial Although the treatment duration is correct for G.N.’s
choice. It has excellent activity against atypical organ- diagnosis (7 days), oral TMP/SMZ is inappropriate for
isms (because of azithromycin), H. influenzae, M. ca- complicated pyelonephritis. It will also interact with
tarrhalis, and S. pneumoniae (even intermediate DRSP). warfarin, increasing the risk of bleeding. Ciprofloxa-
Although doxycycline has activity against atypical or- cin 400 mg intravenously 2 times/day and then 500 mg
ganisms and most of the typical organisms that cause orally 2 times/day for 10 days is an appropriate choice
community-acquired pneumonia, it is not recommended and duration (7–14 days) for this complicated pyelo-
as monotherapy in hospitalized patients. In addition, its nephritis (it may also interact with warfarin, but to a
activity against S. pneumoniae may be limited (if R.L. lesser extent than TMP/SMZ). It would be expected to
lives in an area with extensive DRSP). Doxycycline have activity against the common organisms causing
would not be the best initial choice. complicated pyelonephritis. Gentamicin for 3 days is
too short a treatment duration, and ampicillin/sulbac-
2. Answer D tam, followed by amoxicillin/clavulanate, is not rec-
Ceftriaxone plus gentamicin plus linezolid is not good ommended for complicated pyelonephritis.
empiric therapy because ceftriaxone has limited activity
against P. aeruginosa, and gentamicin has variable activ- 5. Answer d
ity against P. aeruginosa, depending on the institution. Diabetic foot infections are generally polymicrobial
Because B.P. has been on a ventilator and in an intensive (average organisms, 2.5–5.8).
care unit for 8 days, she is at increased risk of nosocomial
pneumonia, specifically caused by P. aeruginosa (and 6. Answer c
possibly MRSA, depending on the institution). Although Nafcillin has excellent activity against gram-positive
piperacillin/tazobactam has good activity against most of organisms, but it would miss the gram-negative organ-
the common causes of nosocomial pneumonia (including isms and anaerobes often involved in moderate to se-
P. aeruginosa), the most recent guidelines recommend vere diabetic foot infections. Tobramycin and levoflox-
two antibiotics with activity against P. aeruginosa for pa- acin would be good against aerobic organisms, but le-
tients with severe nosocomial pneumonia, and she may vofloxacin has only limited activity against anaerobes.
require an antibiotic with MRSA activity. Levofloxacin Tobramycin may also not be a good choice for a pa-
has only moderate activity against P. aeruginosa, and tient with diabetes mellitus with long-term complica-
two drugs should be used. Cefepime plus tobramycin tions (because of the increased risk of nephrotoxicity).
plus vancomycin is the best empiric therapy because it β-Lactamase inhibitor combinations are good agents
includes two antibiotics with excellent activity against P. because they have activity against the organisms that
aeruginosa and another agent for MRSA. are often involved. Treatment duration may need to be
extended if the bone is involved. Aggressive antibiotic
3. Answer b treatment often prevents the need for an amputation.
B.P. should receive vaccinations now. There are no
contraindications to receiving either pneumococcal

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 Infectious Diseases

7. Answer A too short for S. aureus endocarditis. Nafcillin intrave-

Because sensitivities of the gram-positive organism nously × 6 weeks with gentamicin for the first 3–5 days
are still unknown, vancomycin is the best choice. In is the recommended treatment for MSSA endocarditis.
addition, the therapy duration for osteomyelitis is 4–6 Gentamicin needs to be added for only 3–5 days to de-
weeks. Therefore, the 2-week duration with nafcillin is crease the duration of bacteremia.
too short. Although levofloxacin is advantageous be-
cause it can be given orally, it will probably not achieve 11. Answer b
adequate bone concentrations to eradicate S. aureus T.S. is at increased risk of endocarditis because of his
(the most likely organism). Ampicillin/sulbactam is ef- history of the disease. Tooth extractions require pro-
fective against S. aureus (except for MRSA); its broad phylaxis for those at risk. Amoxicillin 2 g, 1 hour be-
spectrum of activity is not necessary in this situation, fore the tooth extraction, is the current recommended
and the duration is too short. dose. The 2-g dose is adequate for protection, and a
follow-up dose is not needed. Amoxicillin 3 g, 1 hour
8. Answer D before the extraction, and 1.5 g, 6 hours after the extrac-
Based on his presentation and laboratory values, D.M. tion, is the older recommended dose. A follow-up dose
has bacterial meningitis. The gram-negative cocci on is not needed.
Gram stain are most likely N. meningitidis. Penicil-
lin is effective against N. meningitidis; however, some 12. Answer a
strains are resistant, and until culture results are re- Redosing antibiotics for surgical prophylaxis is very
ceived, it is unwise to use this agent alone. Ceftriaxone important—especially for antibiotics with short half-
alone is effective for meningococcal meningitis, but lives, for extended surgical procedures, or for when
until the cultures actually grow N. meningitidis, it is there is extensive blood loss. Antibiotics given beyond
wise to maintain broader antibiotic activity. Dexameth- the surgical procedure are generally unnecessary and
asone is beneficial only in adults with pneumococcal only increase the potential for adverse drug reactions
meningitis (not meningococcal meningitis). Ceftriax- and resistant bacteria. Although preoperative antibiot-
one is the appropriate empiric antibiotic therapy in this ics given up to 4 hours before the incision may improve
situation. Vancomycin is generally used empirically the logistics of administering surgical prophylaxis,
because of its activity against highly penicillin-resis- study results show that antibiotics need to be given as
tant S. pneumoniae. After pneumococcal meningitis is close to the time of the incision as possible (definitely
ruled out on the basis of culture results, vancomycin within 2 hours). Vancomycin should not be used rou-
can be discontinued. tinely for surgical prophylaxis. The Centers for Disease
Control and Prevention does not recommend the use
9. Answer A of vancomycin for “routine surgical prophylaxis other
Only people in close contact to a patient with menin- than in a patient with life-threatening allergy to b-lac-
gococcal meningitis require prophylaxis (primarily tam antibiotics.”
those who live closely with the patient and those who
are exposed to oral secretions). The correct regimen is
rifampin 600 mg every 12 hours for four doses. Al-
though the vaccine is a good idea for those at future
risk of acquiring this infection (e.g., college students
living in dormitories), its use during an outbreak is
very limited.

10. Answer d
The treatment duration is too short (nafcillin intrave-
nously × 2 weeks) for S. aureus endocarditis. Only
streptococcal endocarditis can be treated for 2 weeks.
Although nafcillin intravenously plus rifampin ther-
apy for 6 weeks or longer is an appropriate duration
for MSSA, the rifampin does not need to be added in
patients with native valve endocarditis. Nafcillin intra-
venously plus gentamicin intravenously × 2 weeks is

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 Infectious Diseases

Answers and Explanations to Self-Assessment Questions

1. Answer A 4. Answer C
The patient has community-acquired pneumonia that Single-dose therapy is not recommended because of
does not require hospitalization (CURB-65 score is 1 decreased cure rates and inadequate treatment of po-
at most [no mention of mental status]). Because he has tential upper UTIs. Ciprofloxacin is an appropriate
not received any antibiotics in the past 3 months and choice, but 7 days of therapy is not necessary. The best
has no comorbidities, he is at low risk of DRSP. There- choice for this patient is TMP/SMZ double strength
fore, the drug of choice is either a macrolide or doxy- 2 times/day orally for 3 days. The patient should be
cycline. Cefuroxime is not recommended for treatment counseled about the potential interaction between an-
of community-acquired pneumonia. Fluoroquinolones tibiotics and oral contraceptives. β-Lactams are not as
are only recommended if the patient has had recent effective as TMP/SMZ or fluoroquinolones, and data
antibiotics or has comorbidities. Trimethoprim/sul- are limited on their use for 3 days.
famethoxazole is not used for community-acquired
pneumonia. 5. Answer A
For the asymptomatic patient who is bedridden and
2. Answer D chronically catheterized, with cloudy urine and bacte-
The symptoms in this patient (high temperature, mal- ria shown by urinalysis, no therapy is indicated. All
aise, dry cough, nasal congestion, and severe head- patients with chronic urinary catheters will be bacteri-
aches) are most consistent with influenza; therefore, an uric. Because this patient is asymptomatic, the catheter
antibacterial agent would not affect recovery. Oselta- does not need to be replaced. If she were symptomatic,
mivir should be initiated within 48 hours of symptom catheter replacement might be indicated. Antibiotics
onset, and because this patient is more than 3 days out are not indicated; however, a 7-day course would be
from symptom onset, oseltamivir will not affect re- appropriate if treatment were instituted. A long course
covery. Because of the viral etiology and time since of treatment only increases the risk of acquiring resis-
symptom onset, symptomatic treatment is all that is tant organisms.
indicated.
6. Answer B
3. Answer B Using the equation Cp = dose/Vd, where Vd = volume
A case-control study would be the most appropriate of distribution, the concentration after the first dose
study design because it is the most ethical, cost-effec- can be calculated. The concentration is 19.8 mcg/mL.
tive, timely methodology. A stronger study design— Therefore, it will take about 1 half-life to decrease to a
for instance, a prospective cohort study or a random- concentration of 10 mcg/mL (i.e., 35 hours).
ized, controlled trial—has many disadvantages if used
to answer this question. In a prospective cohort study, 7. Answer A
too many patients would need to be observed because Because cellulitis (which the patient appears to have)
of the relatively low incidence of confirmed pneumo- is most commonly caused by Streptococcus or Staphy-
coccal pneumonia. This study would therefore be too lococcus, nafcillin is the drug of choice (vancomycin
costly and take too long to complete. Randomized, con- could be initiated empirically if MRSA were a con-
trolled trials also have many disadvantages in this situ- cern in this patient). Necrotizing fasciitis needs to be
ation. First, patients would need to be vaccinated and ruled out because other organisms may be involved,
then observed for at least 10 years. Second, too many and surgery is crucial. Although penicillin is the treat-
patients would need to be observed because of the ment of choice for erysipelas, the patient probably has
relatively low incidence of confirmed pneumococcal acute cellulitis (there is no raised border at the edge
pneumonia. Third, it would be unethical to randomize of the infection, which is indicative of erysipelas). Al-
half of the patients to no vaccination. This study would though piperacillin/tazobactam has activity against
therefore be too costly, unethical, and time-consuming. both Streptococcus and Staphylococcus, this treatment
A case series would evaluate only a few patients given is too broad spectrum for an acute cellulitis. Because
a diagnosis of pneumococcal pneumonia 10 or more Doppler studies are negative, there is a low likelihood
years after vaccination. It would not provide compara- of a deep venous thrombosis.
tive data, nor would it provide a strong study design.

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8. Answer C
Even if a patient is believed to have aseptic meningitis
after analysis of the CSF, antibiotics need to be given
until CSF cultures are negative. In empiric therapy
for bacterial meningitis in adults (i.e., when the CSF
Gram stain is negative), ceftriaxone should be used
in combination with vancomycin. The vancomycin is
required for activity against resistant S. pneumoniae.
Although the symptoms and CSF results are similar to
what is expected for herpes simplex encephalitis, the
use of acyclovir alone in this patient is inappropriate.
Antibacterials must be used as well. Viral meningitis
is generally caused by coxsackie virus, echovirus, and
enterovirus, which are not treated with acyclovir.

9. Answer C
Enterococcal endocarditis should be treated for 4–6
weeks. The 2-week treatment regimen is indicated
only for S. endocarditis. There is also no indication
that the patient is penicillin allergic; thus, vancomycin
should not be used as first-line treatment. Ampicillin
plus gentamicin for 4–6 weeks is the regimen of choice
for penicillin-susceptible enterococcal endocarditis.
Cephalosporins have no activity against Enterococcus;
therefore, the regimen with cefazolin is inappropriate.

10. Answer C
A perforated appendix requires antibiotics after sur-
gery for an intra-abdominal infection. The combination
of vancomycin and metronidazole does not have ad-
equate activity against aerobic, gram-negative organ-
isms (e.g., E. coli). The combination of ceftriaxone and
ciprofloxacin does not have adequate activity against
anaerobic organisms (e.g., B. fragilis group). Ertape-
nem is a good choice for intra-abdominal infections,
although it has limited activity against Enterococcus.

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 HIV/Infectious Diseases

HIV/Infectious Diseases
Curtis L. Smith, Pharm.D., BCPS
Ferris State University
Lansing, Michigan

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 HIV/Infectious Diseases

Learning Objectives: A. Watch for jaundice because atazanavir can

cause hyperbilirubinemia.
1. Formulate an appropriate regimen to prevent B. If you think you are having a drug-related
or treat human immunodeficiency virus in- adverse effect, simply cut the dose of all of
your drugs in half.
fections, including initiation and monitoring
C. Talk to your pharmacist about drug
therapy. interactions because both atazanavir and
2. Discuss appropriate treatment of the various tenofovir inhibit cytochrome P450 (CYP) 3A4.
acquired immunodeficiency syndrome op- D. Tenofovir and emtricitabine cause additive
portunistic infections, including primary and peripheral neuropathy, so let your pharmacist
secondary prophylaxis. know if you experience tingling in your
3. Describe appropriate treatment and preven- extremities.
tive therapy for tuberculosis, including infec-
tions with drug-resistant organisms. 3. One year later, R.E. is concerned that his antiretro-
4. Classify the various antifungal agents and ex- viral therapy is not working and asks if he should
plain their role in common fungal infections. make some changes. Which one of the following
statements best represents what to tell him?
A. His therapy should be changed only if he is
Self-Assessment Questions: deteriorating clinically (e.g., having more
Answers to these questions may be found at the opportunistic infections).
B. His therapy should be changed if his viral
end of this chapter.
load is detectable after an initial suppression
to undetectable concentrations.
1. K.E. is a 29-year-old asymptomatic patient who is
C. If he is concerned about his regimen not
human immunodeficiency virus (HIV) positive.
being effective, then atazanavir/ritonavir
She recently found out she is pregnant and is es-
should be changed to fosamprenavir/
timated to be early in her first trimester. Her most
ritonavir.
recent CD4 count was 170/mm3, and her viral load
D. Resistance most commonly occurs with
was 100,000 copies/mL by reverse transcriptase–
emtricitabine, so this should be changed to
polymerase chain reaction. Which one of the fol-
lamivudine.
lowing is the best therapy for K.E. to prevent HIV
transmission to her child?
4. F.V. is a 42-year-old man who has been HIV posi-
A. No drug therapy is needed—the risks to the
tive for 10 years. He has been receiving potent
fetus outweigh any benefits.
combination antiretroviral therapy for the past 3
B. Administer zidovudine 300 mg 2 times/day
years, including zidovudine, lamivudine, and lopi-
orally throughout the pregnancy, followed by
navir/ritonavir. He is now experiencing hypergly-
zidovudine during labor and consequently to
cemia, fat redistribution, and lipid abnormalities.
the baby for 6 weeks.
Which one of the following represents how F.V.’s
C. No drug therapy is required now, but
drug-related symptoms should be managed?
administer a single dose of nevirapine at the
onset of labor. A. Add simvastatin for the lipid abnormalities
D. Administer a potent combination and treat according to the recommendations
antiretroviral therapy regimen that includes from the National Cholesterol Education
zidovudine throughout the pregnancy. Program.
B. Add pioglitazone for the glucose
abnormalities and treat according to the
2. R.E. is a 33-year-old man who has been HIV posi-
recommendations from the American
tive since 2005. Recently, his CD4 counts started to
Diabetes Association.
decrease significantly, and his viral load started to
C. Change zidovudine to tenofovir.
increase. He is initiated on tenofovir, emtricitabine,
D. Change lopinavir/ritonavir to efavirenz.
and atazanavir/ritonavir. Which one of the follow-
ing statements represents what R.E. should be told
about his therapy?

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 HIV/Infectious Diseases

5. P.P., a 43-year-old man who is HIV positive, pres- C. Pyrimethamine plus sulfadiazine for 6 weeks.
ents to the clinic with a headache that has gradu- D. Pyrimethamine plus clindamycin and
ally worsened during the past 2 weeks. He does leucovorin for 6 weeks.
not feel very sick and has not experienced any fo-
cal seizures. His most recent CD4 count was 35/ 8. R.K., a 39-year-old man who is HIV positive, re-
mm3. He has a laboratory profile performed with ceives a diagnosis of cryptococcal meningitis and
the following results: Gram stain = negative; white begins taking amphotericin B and flucytosine. You
blood cell count = 2 mg; protein = 35 mg/dL; glu- want to keep flucytosine peak concentrations be-
cose = 75 mg/dL (peripheral = 110 mg/dL); India tween 50 and 100 mcg/mL. Assuming a trough
ink = positive; and cryptococcal antigen = 1:1024. concentration of 25 mcg/mL, every-6-hour dosing,
Which one of the following therapies should be and 100% bioavailability, which one of the fol-
used to treat P.P.? lowing doses would achieve a peak concentration
within the desired range (flucytosine volume of
A. Fluconazole 200 mg/day orally.
distribution = 0.7 L/kg and half-life = 3 hours)?
B. Amphotericin B deoxycholate 0.3 mg/kg/day
alone. A. 12.5 mg/kg.
C. Amphotericin B deoxycholate 0.3 mg/kg/day B. 37.5 mg/kg.
plus flucytosine 37.5 mg/kg every 6 hours. C. 75 mg/kg.
D. Amphotericin B deoxycholate 0.7 mg/kg/day D. 150 mg/kg.
plus flucytosine 25 mg/kg every 6 hours for 2
weeks, followed by fluconazole 400 mg/day. 9. P.I. is a 35-year-old woman who presents to the
clinic with a 2-week history of night sweats, fa-
6. A study is performed to compare the incidence of tigue, weight loss, and a persistent cough. A puri-
active tuberculosis (TB) infection in patients re- fied protein derivative (PPD) is placed, and a spu-
ceiving isoniazid (INH) versus rifampin (RIF) for tum sample is taken; then, P.I. is sent home with
latent TB infection. After completion of therapy a prescription for levofloxacin 750 mg/day orally.
Two days later, her PPD is measured at 20-mm
(6 months for INH and 4 months for RIF), 0.3% in
induration, and her sputum sample is positive for
the INH group and 0.8% in the RIF group prog-
acid-fast bacilli. P.I., who has no pertinent medical
ress to active disease. Which one of the following
history, has never been outside the United States.
represents how many patients would need to be
She lives in an area with an extremely low inci-
treated with INH over RIF to prevent one progres-
dence of multidrug-resistant TB. Which one of the
sion to active disease?
following regimens is the best therapy for P.I.?
A. 5.
A. INH 300 mg/day orally for 6 months.
B. 50.
B. INH, RIF, pyrazinamide (PZA), and
C. 200.
ethambutol (EMB) for 2 months, followed by
D. Insufficient information to calculate INH and RIF for 4 more months.
this number. C. INH and RIF for 6 months.
D. Levofloxacin 750 mg/day orally for both TB
7. G.T. is a 34-year-old woman positive for HIV who and other bacterial causes of pneumonia.
is brought to the emergency department by her
boyfriend after experiencing headaches, a change in 10. A prospective, double-blind study compared the ef-
mental status, and loss of feeling on her right side. A fects of two therapies—a potent combination anti-
computed tomographic scan shows two large ring- retroviral therapy with a ritonavir-boosted protease
enhancing lesions in her brain. Her most recent inhibitor and a potent combination antiretroviral
CD4 count was 85/mm3, but that was 4 months ago. therapy with efavirenz—in 350 patients with HIV.
She currently takes no antiretroviral agents but Which one of the following statistical tests should
takes dapsone for Pneumocystis pneumonia (PCP) be used to compare end points such as the mean
prophylaxis. Which one of the following therapies change in viral load or mean change in CD4 counts?
should be used to treat G.T.?
A. Analysis of variance.
A. Atovaquone for 4–6 weeks. B. Chi-square test.
B. High-dose trimethoprim/sulfamethoxazole C. Student t-test.
(TMP/SMX) plus clindamycin for 6 weeks. D. Wilcoxon rank sum test.

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 HIV/Infectious Diseases

I. HUMAN IMMUNODEFICIENCY VIRUS

A. Transmission of HIV
1. Sexual transmission
a. Homosexual or heterosexual
b. Increases with increased number of sexual partners
c. Prevention: Latex condom
2. Parenteral exposure to blood or blood products
a. Intravenous drug abuser: Increased with increased needle sharing
b. Hemophiliacs/blood transfusions: Decreased since 1985
3. Universal precautions (Table 1)
a. Purpose is prevention of parenteral, mucous membrane, and non-intact skin exposures to
bloodborne pathogens
b. Body fluids

Table 1. Universal Precautions

Universal Precautions Apply to: Universal Precautions Do Not Apply to:
Blood Feces
Body fluids containing visible blood Nasal secretions
Semen and vaginal secretions Sputum
Tissue Sweat
Cerebrospinal fluid Tears
Synovial fluid Urine
Pleural fluid Vomitus
Peritoneal fluid Breast milk
Pericardial fluid Saliva (precautions recommended for dentistry)
Amniotic fluid

c. General guidelines
i. Take care when using and disposing of needles, scalpels, and other sharp instruments.
ii. Use protective barriers (i.e., gloves, masks, and protective eyewear).
iii. Wash hands and skin immediately if they are contaminated with body fluids to which
universal precautions apply.
4. Perinatal transmission
a. Antepartum—Through maternal circulation
b. During delivery
c. Postpartum—Breastfeeding
d. Zidovudine therapy decreases risk of transmission from 23% to 3%–4% (less than 2%
with combination therapy).

B. Diagnosis
1. Enzyme-linked immunosorbent assay (ELISA)
a. For ELISA: Expose patient sera to HIV antigen and check for antibodies to HIV.
b. Positive: 1–6 months after the infection
c. Sensitivity and specificity: 97%–100%

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 HIV/Infectious Diseases

2. Western blot
a. Confirms ELISA
b. False-positive: 1 in 20,000
c. False-negative: 1 in 250,000
3. Rapid HIV tests
a. OraQuick Advance: Fingerstick, whole blood, or oral fluid
b. Uni-Gold Recombigen: Fingerstick or whole blood
c. Reveal G2, Multispot HIV-1/HIV-2: Serum or plasma
4. Test for HIV RNA
a. Detects HIV RNA in serum (tests for the virus, not for antibodies)
b. Branched-chain DNA, VERSANT, and Quantiplex (Bayer)
i. Signal amplification
ii. Sensitive to 75 copies/mL of HIV RNA
c. Reverse transcriptase–polymerase chain reaction, Amplicor HIV-1 Monitor (Roche):
Sensitive to 50 copies/mL of HIV RNA
d. Nucleic acid sequence–based amplification (NASBA), NucliSens (Organon Teknika):
Sensitive to 40 copies/mL of HIV RNA
e. Values expressed as copies of HIV RNA per milliliter or the log of copies of HIV RNA
per milliliter
f. Changes greater than 3-fold (about 0.5 log) are clinically significant.
5. Use of HIV RNA testing
a. Acute HIV infection (diagnosis is received sooner than with older tests)
b. Newly diagnosed HIV infection (for baseline value to follow)
c. Every 3–4 months without therapy
d. From 2 to 4 (no more than 8) weeks after starting or changing therapy (should detect a
significant decrease)
e. From 3 to 4 months after starting therapy (change therapy if decrease is limited)
f. Every 3–4 months while on therapy (checking for increase—therapy failure)
g. Whenever there is a clinical event or decrease in CD4 count
6. Who should be screened for HIV?
a. All patients aged 13–64 years (in all health care settings)
b. Adults and adolescents at increased risk of HIV infection should be checked annually
(intravenous drug users, those who have unprotected sex with several partners, men
who have sex with men, men or women who have sex for money or drugs, people
being treated for sexually transmitted diseases, recipients of several blood transfusions
1975–1985)
c. Pregnant women

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7. Case definition for HIV—2008 (Table 2)

Table 2. Case Definition for HIV—2008

Stage Laboratory Evidencea Clinical Evidence
Stage 1 Laboratory confirmation of HIV infection AND None required
CD4 count of ≥ 500/µL OR (but no AIDS-defining condition)
CD4 percentage of ≥ 29
Stage 2 Laboratory confirmation of HIV infection AND None required
CD4 count of 200–499/µL OR (but no AIDS-defining condition)
CD4 percentage of ≥ 14–28
Stage 3 Laboratory confirmation of HIV infection AND OR documentation of an AIDS-defining condition
(AIDS) CD4 count of < 200/µL OR (with laboratory confirmation of HIV infection)
CD4 percentage of < 14
Stage Laboratory confirmation of HIV infection AND AND no information on presence of AIDS-
unknown No information on CD4 count or percentage defining conditions
a
Laboratory confirmation: Positive result from an HIV antibody screening test (e.g., reactive enzyme immunoassay) confirmed
by a positive result from a supplemental HIV antibody test (e.g., Western blot or indirect immunofluorescence assay test) OR
positive result or report of a detectable quantity (i.e., within the established limits of the laboratory test) from any of the following
HIV virologic (i.e., non-antibody) tests.
AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.

8. Acquired immunodeficiency syndrome (AIDS)-defining conditions (Table 3)

Table 3. AIDS-Defining Conditions

Bacterial infections, multiple/recurrent (<13 years of age) Lymphoid interstitial pneumonia or pulmonary
Candidiasis: bronchi, trachea, or lungs lymphoid hyperp≥lasia complex (< 13 years of age)
Candidiasis: esophageal Lymphoma: Burkitt (or equivalent term)
Cervical cancer: invasive Lymphoma: immunoblastic (or equivalent term)
Coccidioidomycosis: disseminated or extrapulmonary Lymphoma: primary or brain
Cryptococcosis: extrapulmonary Mycobacterium avium complex or
Cryptosporidiosis: chronic intestinal (> 1 month in duration) M. kansasii: disseminated or extrapulmonary
Cytomegalovirus disease M. tuberculosis: any site
(other than liver, spleen, or nodes) (pulmonary or extrapulmonary)
Cytomegalovirus retinitis (with loss of vision) Mycobacterium: other species or unidentified species;
Encephalopathy: HIV related disseminated or extrapulmonary
Herpes simplex: chronic ulcer(s) (> 1 month in duration); Pneumocystis jiroveci pneumonia
bronchitis, pneumonitis, or esophagitis Pneumonia: recurrent
Histoplasmosis: disseminated or extrapulmonary Progressive multifocal leukoencephalopathy
Isosporiasis: chronic intestinal (> 1 month in duration) Salmonella septicemia (recurrent)
Kaposi sarcoma Toxoplasmosis of brain
Wasting syndrome caused by HIV
AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.

C. Primary HIV Infection

1. Characteristics of the primary HIV infection
a. About 40%–60% develop symptoms from the primary infection.
b. Abrupt onset: Duration = 3–14 days

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 HIV/Infectious Diseases

c. Occurs 5 days to 3 months after HIV exposure (generally within 2–4 weeks)
d. Fevers, sweats, lethargy, malaise, myalgias, arthralgias, headache, photophobia, diarrhea,
sore throat, lymphadenopathy
e. Treatment of an acute HIV infection is generally not recommended.
2. Progression of HIV
a. Human immunodeficiency virus replicates actively at all stages of the infection.
b. From 109 to 1010 virions are produced every day.
c. Half-life of virions is about 6 hours.
3. Immunization of patients with HIV (no live virus vaccines if CD4 count is less than 200/mm3)
a. Influenza virus vaccine: Annually before the influenza season
b. Pneumococcal vaccine: Once (ideally, before CD4 count is less than 200/mm3)
c. Hepatitis B vaccine: For all susceptible patients
d. Hepatitis A vaccine: For all at-risk patients

D. Treatment of HIV
1. Reverse transcriptase inhibitors (RTIs) (nucleoside [NRTI], nucleotide, and nonnucleoside
[NNRTI])
a. Reverse transcriptase: Enzyme required to copy viral RNA to DNA
b. Dideoxynucleoside analogs: Inserted in growing DNA chain, terminating elongation
c. See Tables 4 and 5 for RTI characteristics.
d. Nonnucleoside NRTIs and nucleotide RTIs do not require phosphorylation.
2. Protease inhibitors (see Table 6)
3. Entry inhibitors
a. Fusion inhibitors: Enfuvirtide (Fuzeon); a.k.a.: T-20 and pentafuside
i. Mechanism of action: HIV envelope protein gp120 binds to the cell’s CD4 receptor,
resulting in exposure of chemokine coreceptors on the cell; attachment of gp120 to
CD4 receptor and coreceptors CCR5 or CXCR4 results in exposure of specific peptide
sequence of gp41; enfuvirtide binds to this gp41 peptide sequence, preventing fusion.
ii. Indications—Treatment-experienced patients with HIV infection
iii. Adverse effects—Hypersensitivity reactions; local injection-site reactions (98%);
pneumonia
iv. Drug interactions—None
v. Dosing—90 mg (1 mL) 2 times/day subcutaneously (reconstitution required)
b. CCR5 antagonist: Maraviroc (Selzentry)
i. Mechanism of action: Binds to the CCR5 receptor of the CD4 T cell
ii. Indications—Treatment-experienced patients with HIV infected solely with R5 strains
iii. Adverse effects—Abdominal pain, cough, dizziness, musculoskeletal symptoms,
pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension
iv. Drug interactions—CYP3A substrate (watch CYP3A inducers and inhibitors)
v. Dosing—150–600 mg 2 times/day orally (depending on concomitant drug
interactions)
4. Integrase inhibitors: Raltegravir (Isentress)
a. Mechanism of action: Inhibits strand transfer of viral DNA to host cell DNA
b. Indications—Treatment-naïve or treatment-experienced patients with HIV infection
c. Adverse effects—Nausea, headache, diarrhea, pyrexia, creatine kinase elevation
d. Drug interactions—Metabolized by hepatic glucuronidation by uridine 5′-diphospho
(UDP)-glucuronosyltransferases (UGTs); inducers of UGT1A1: RIF, efavirenz,
tipranavir/ritonavir, and rifabutin
e. Dosing—400 mg 2 times/day orally

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 Table 4. Nucleoside Reverse Transcriptase Inhibitors
Zidovudine Lamivudine Emtricitabine Abacavir
(AZT, ZDV, Retrovir, Didanosine Stavudine (3TC, Epivir, Combivir, (FTC, Emtriva, (ABC, Ziagen, Epzicom,
Combivir, Trizivir) (ddI, Videx) (d4T, Zerit) Epzicom, Trizivir) Truvada, Atripla) Trizivir)
Form 100-mg capsules, 125-, 200-, 250-, 400-mg 15-, 20-, 30-, 150-, 300-mg tablets 200-mg capsules 300-mg tablets
300-mg tablets; enteric-coated capsules 40-mg capsules 10 mg/mL of liquid 10 mg/mL liquid 20 mg/mL liquid
50 mg/5 mL of liquid; 1 mg/mL solution Combivir: 150 mg of Truvada: 200 mg of Trizivir: 300 mg of
10 mg/mL injection 3TC/300 mg of ZDV FTC/300 mg of TDF ABC/150 mg of 3TC/300
Epzicom: 300 mg of Atripla (see Efavirenz)
mg of ZDV
3TC/600 mg of ABC Epzicom (see
Trizivir (see Abacavir) Lamivudine)
Dosing 200 mg TID or 300 > 60 kg: 200 mg BID or > 60 kg: 40 mg BID 150 mg BID or 300 mg/ 200 mg/day or 240 mg 300 mg BID or
mg BID 400 mg/day ≤ 60 kg: 30 mg BID day liquid/day 600 mg/day
≤ 60 kg: 125 mg BID or < 50 kg: 2 mg/kg BID
250 mg/day
Oral 60% 40% 86% 86% 93% 83%
bioavailability Empty stomach
Serum half-life 1.1 hours 1.6 hours 1 hour 3–6 hours 10 hours 1.5 hours
Intracellular 7 hours > 20 hours 7.5 hours 18-22 hours 39 hours 12-26 hours
half-life
Elimination Metabolized to ZDV Renal excretion 50% Renal excretion Renally excreted Renal excretion (86%) Metabolized by alcohol

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glucuronide (GZDV) 50% unchanged (70%) dehydrogenase and
Renal excretion of glucuronyl transferase
GZDV Metabolites—renal
Major toxicity Bone marrow Pancreatitis (5%) Peripheral Diarrhea, nausea, Diarrhea, nausea, Hypersensitivity, fever,
HIV/Infectious Diseases

*All may cause suppression, GI Peripheral neuropathy neuropathy abdominal pain, headache, rash, and rash, GI symptoms,
lactic acidosis intolerance, headache, (35%) (20%–30%) insomnia, and headaches hyperpigmentation malaise, fatigue, anorexia,
with hepatic insomnia, asthenia, Nausea, diarrhea Elevated liver (minimal toxicity) and myocardial infarction
steatosis nail pigmentation, and enzymes
myalgia Pancreatitis
Drug Myelosuppressive Fluoroquinolones, TMP/SMX may increase Ethanol may increase
interactions agents tetracycline; 3TC concentrations ABC concentrations
Rifampin ketoconazole, dapsone;
tenofovir
Miscellaneous Activity in activated Activity in Resistance develops Activity in resting Hypersensitivity reaction
information lymphocytes activated quickly with macrophages may be fatal—discontinue
lymphocytes monotherapy drug immediately
Activity in resting Screen for HLA-B*

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macrophages 5701 before initiation;
cross-resistance with ddI
and 3TC
BID = 2 times/day; EFV= efavirenz; GI = gastrointestinal; TID = 3 times/day; TMP/SMX = trimethoprim/sulfamethoxazole.
 Table 5. Nonnucleoside and Nucleotide Reverse Transcriptase Inhibitors
Tenofovir DF
Delavirdine Efavirenz (TDF, Viread, Truvada,
Nevirapine (Viramune) (Rescriptor) (Sustiva, Atripla) Etravirine (Intelence) Atripla)
RTI type Nonnucleoside Nonnucleoside Nonnucleoside Nonnucleoside Nucleotide
Form 200-mg tablets 100-, 200-mg tablets 50-, 200-mg capsules 100-mg tablets 300-mg tablets
50-mg/5-mL suspension 600-mg tablets Truvada: 200 mg of FTC/300
Atripla: 200 mg of mg of TDF
FTC/300 mg of TDF/ Atripla (see Efavirenz)
efavirenz 600 mg
Dosing 200 mg/day for 14 days; then 400 mg PO TID 600 mg PO qHS 200 mg PO BID 300 mg/day PO
200 mg PO BID

Oral > 90% 85% 42% Take with food 40%

bioavailability Avoid antacids Avoid with high-fat meal Take with food
Serum half-life 25-30 hours 5.8 hours 40–55 hours 20–60 hours 10-14 hours
Elimination Metabolized by CYP3A4; Metabolized by Metabolized by CYP3A4, Metabolized by CYP 3A4, 2C9, Eliminated by renal filtration
80% excreted in urine (< 5% CYP3A4, 51% excreted 14%–34% excreted in 2C19 and active secretion
unchanged), 10% in feces in urine urine,
(< 5% unchanged), 16%–61% in feces

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44% in feces
Major toxicity Rash Rash (less than Rash (less than Rash GI toxicity
GI toxicity nevirapine) delavirdine) Nausea Headache
Increased LFTs- Headache CNS symptoms (insomnia, Hypersensitivity reaction May cause lactic acidosis with
HIV/Infectious Diseases

hepatotoxicity impaired concentration, hepatic steatosis (mitochondrial

nightmares, mania) toxicity may be less)
Increased LFTs
Drug Induces CYP3A4 Inhibits CYP3A4 Induces CYP3A4 Induces CYP3A4 Increases ddI concentration—
interactions Watch rifampin, rifabutin, Separate administration Inhibits CYP 2C9 and 2C19 separate administration
OCs, protease inhibitors, with antacids and ddI
triazolam, midazolam
Miscellaneous Extensive cross-resistance Extensive cross- Extensive cross-resistance Can dissolve in water for patients May be effective against HIV
information in class resistance in class in class who cannot swallow strains resistant to other RTIs
Do not initiate in women Avoid in first trimester of May be effective against HIV
with CD4+ counts > 250 pregnancy; strains resistant to efavirenz or
cells/mm3 or in men with do not use Atripla if CrCl < nevirapine
50 mL/minute

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CD4+ counts > 400 cells/
mm3 (liver toxicity)
BID = 2 times/day; CNS = central nervous system; CrCl = creatinine clearance; CYP = cytochrome P450; ddI = didanosine; DM = diabetes mellitus; GI = gastrointestinal; HIV
= human immunodeficiency virus; LFT = liver function test; OC = oral contraceptive; PO = orally; qHS = every night; RTI = reverse transcriptase inhibitor; TID = 3 times/day.
 Table 6. Protease Inhibitors
Indinavir Saquinavir Darunavir
[IDV] Nelfinavir Ritonavir [RTV] [SQV] Fosamprenavir Lopinavir/ Atazanavir [ATV] Tipranavir [DRV]
(Crixivan) (Viracept) (Norvir) (Invirase) [f-APV] (Lexiva) Ritonavir (Kaletra) (Reyataz) [TPV] (Aptivus) (Prezista)
Form 200-, 333-, 250-, 625- 100-mg capsules; 200-mg capsules, 700 mg tablets; 100/25, 200/50 mg 100-, 150-, 200- 250-mg capsules; 75-, 150-,
400-mg mg tablets; 80 mg/mL liquid; 500-mg tablets 50 mg/mL liquid; tablets; 80/20 mg/ 300-mg capsules 100-mg/ 400-, 600-mg
capsules 50 mg/g oral refrigerate capsules prodrug of mL solution mL solution; tablets
powder amprenavir refrigerate
capsules
Dosing 800 mg q8h 750 mg TID or “Boosting dose” = 1000 mg BID 1400 mg BID, (or 400/100 mg BID or 400 mg/day 500 mg BID with 800 mg daily
800 mg + RTV 1250 mg BID 100–400 mg divided 1-2 with ritonavir 1400 mg + RTV 800/200 mg/day If taken with RTV with RTV 100
100 mg-, times/day 100 mg; take 100-200 mg/day; with food efavirenz: RTV 200 mg BID mg daily or
200 mg q12h within 2 hours of or 700 mg + RTV If on efavirenz or 100 mg + ATV 400 600 mg BID
a meal 100 mg BID). With nevirapine: mg daily with RTV
efavirenz: 700 mg + 500 mg/125 mg BID If taken without 100 mg BID
RTV 100 mg BID efavirenz: RTV
100 mg + ATV 300
mg daily
Oral 65%; 20%-80%; 65%-75%; Invirase: 4% Fosamprenavir: Tmax Solution take with Food increases Food
bioavailability 1 hour before take with meal take with food of amprenavir occurs food; absorption and increases
or 2 hours after or snack in 1.5-4 hours; take tablets without bioavailability; absorption
meals take without respect respect to food take with food and
(may take with to food bioavailability

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low-fat meal) Take with
food
Serum half-life 1.5-2 hours 3.5-5 hours 3-5 hours 1-2 hours 7-11 hours 5-6 hours 7 hours 6 hours 15 hours
Elimination CYP3A4; CYP3A4 CYP 3A4 > 2D6 > CYP3A4 CYP3A4 CYP3A4 CYP3A4 CYP3A4 CYP3A4
HIV/Infectious Diseases

renal—20% 2C9/10
Major toxicity Nephrolithiasis Diarrhea GI intolerance; GI intolerance GI intolerance; rash; GI intolerance; Indirect Hepatotoxicity; Rash (sulfa);
GI intolerance; (mild); paresthesias (circumoral (mild); oral paresthesias; fatigue; hyperbiliru- rash (sulfa); endocrine
alopecia, endocrine and extremities); taste endocrine increased LFTs; asthenia; binemia, prolonged intracranial disturbancesa
dry skin and disturbancesa disturbances; asthenia; disturbancesa endocrine pancreatitis; QT interval/heart hemorrhage;
lips; endocrine disturbancesa disturbancesa QTc prolongation; block, endocrine endocrine
endocrine endocrine disturbancesa disturbancesa
disturbancesa disturbancesa
Drug Inhibits Inhibits Inhibits CYP 3A4, 2D6 Inhibits CYP3A4 Inhibits CYP3A4 Inhibits CYP 3A4, Inhibits CYP3A4, Inhibits CYP Inhibits
interactions CYP3A4 CYP3A4 (potent) (< RTV) (< RTV) 2D6 PPIs, H2 blockers, 3A4, 2D6 CYP3A4
(< RTV); (< RTV) ddI decreases absorption antacids
ddI decreases Induces glucuronyl
absorption transferases
Miscellaneous Cross-resistance with Do not use with Less lipid effects Good for PI- Good for PI-

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information IDV IDV resistant virus resistant virus
a
Endocrine disturbances include insulin resistance (type 2 diabetes mellitus in 8%–10%), peripheral fat loss/central fat accumulation (in 50%), and lipid abnormalities (in 70%).
BID = 2 times/day; CYP = cytochrome P450; ddI = didanosine; GI = gastrointestinal; PI = protease inhibitor; q8h = every 8 hours; q12h = every 12 hours; TID = 3 times/day.
 HIV/Infectious Diseases

5. Prevention of maternal-fetal transmission

a. Pregnant women with HIV receiving no antiretroviral therapy
i. Women who meet the criteria for beginning HIV therapy in adults should receive
potent combination antiretroviral therapy (to prevent resistance); initiate therapy as
soon as possible, even in the first trimester.
ii. Women who do not meet the criteria for beginning HIV therapy should still receive
potent combination antiretroviral therapy (to prevent transmission); delay therapy
until after first trimester, but no later than 28 weeks gestation
iii. Use zidovudine as a component of therapy unless there is severe toxicity or
resistance, or unless the woman is already on a fully suppressive regimen.
iv. Avoid efavirenz in the first trimester.
v. Women who have received antiretroviral therapy in the past but are currently on
no therapy should have HIV antiretroviral resistance testing completed before
initiating therapy.
vi. Continue combination regimen through intrapartum period (with zidovudine infusion
added), and treat baby for 6 weeks.
b. Pregnant women with HIV receiving potent combination antiretroviral therapy
i. Continue current combination regimens (preferably with zidovudine) if already
receiving therapy. Avoid efavirenz in the first trimester.
ii. Continue combination regimen through intrapartum period (with zidovudine infusion
added), and treat baby for 6 weeks.
c. Pregnant women with HIV in labor (with or without therapy during pregnancy)
i. At labor, zidovudine 2 mg/kg intravenously for 1 hour followed by a 1-mg/kg/hour
infusion until cord is clamped. Discontinue oral zidovudine but continue any other
oral antiretrovirals (except stavudine).
ii. Continue antiretroviral therapy as much as possible during labor.
iii. For women who have not received antiretrovirals during pregnancy, consider single-
dose nevirapine to mother at labor onset and to baby at 48 hours (consider also
adding zidovudine/lamivudine to mother for 7 days any time single-dose nevirapine
is used, to prevent resistance).
d. Infants born to mothers who are HIV positive
i. Zidovudine 2 mg/kg every 6 hours for 6 weeks
ii. Consider additional antiretroviral agents in certain situations.
6. Prevention of postexposure infection
a. Use universal precautions.
b. Occupational exposures: needle sticks or cuts (1 in 300 risk) and mucous membrane
exposure (1 in 1000 risk)
c. Nonoccupational exposures: Treat if exposure of vagina, rectum, eye, mouth, mucous
membrane, or non-intact skin with blood, semen, vaginal secretions, or breast milk of an
individual with known HIV infection
d. Recommended therapy for occupational exposure is outlined in Table 7.
e. Recommended therapy for nonoccupational exposure is potent combination
antiretroviral therapy.
f. Postexposure prophylaxis can reduce HIV infection by about 80%.
g. Occupational exposures: Begin treatment within 1–2 hours; most effective if begun within
24–36 hours
h. Nonoccupational exposures: Begin within 72 hours.
i. Treatment should be administered for 4 weeks.

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 HIV/Infectious Diseases

Table 7. Recommended Therapy for Postexposure Infection

Exposure Type Severity HIV-Positive Classa Recommended Prophylaxisb
Percutaneous exposure Less severe Class 1 Basic 2-drug regimen
Class 2 Expanded ≥ 3-drug regimen
More severe Class 1 or 2 Expanded ≥ 3-drug regimen
Mucous membrane and Small volume Class 1 or 2 Basic 2-drug regimen
non-intact skin exposure Large volume Class 1 Basic 2-drug regimen
Class 2 Expanded ≥ 3-drug regimenc
a
Class 1: Asymptomatic HIV infection or low viral load (< 1500 copies/mL); class 2: symptomatic HIV infection or high viral load.
b
Basic two-drug regimen: ZDV/3TC or FTC; d4T/3TC or FTC; TDF/3TC or FTC.
c
Expanded three-drug regimen: add LPV/RTV, ATV, f-APV, IDV/RTV, SQV/RTV, NFV, or EFV.

Patient Case
1. F.G. is a 27-year-old man who is HIV positive but asymptomatic. One year ago, his CD4 count was 815/mm3,
and his viral load was 1500 copies/mL (by reverse transcriptase–polymerase chain reaction). F.G. continues
to be monitored; his CD4 count has decreased (most recent was 240/mm3), and his viral load has increased
(most recent was 60,000 copies/mL by reverse transcriptase–polymerase chain reaction). Which one of the
following treatments should F.G. receive?
A. Antiretroviral therapy should not be given because F.G.’s CD4 count is still above 200/mm3.
B. Initiate F.G. on zidovudine alone because his CD4 count is still above 200/mm3.
C. Initiate F.G. on combination therapy of zidovudine, lamivudine, and nevirapine.
D. Initiate F.G. on combination therapy of tenofovir, emtricitabine, and atazanavir/ritonavir.

7. Treatment of the patient who is HIV positive

a. Initiating potent combination antiretroviral therapy in an antiretroviral-naïve patient
i. Any symptomatic patient who is HIV positive (regardless of CD4 count)
ii. CD4 less than 350/mm3
iii. Initiate therapy regardless of CD4 T-cell count in pregnant women, patients with HIV-
associated nephropathy, and patients coinfected with hepatitis B virus (HBV) when
treatment for HBV infection is indicated.
iv. Recommended in patients with CD4 350–500/mm3 (lower strength of recommendation)
v. Consider in patients with CD4 greater than 500/mm3.
b. Preferred therapy: Efavirenz OR atazanavir/ritonavir OR darunavir/ritonavir OR
raltegravir PLUS tenofovir/emtricitabine
c. Alternative therapy: One protease inhibitor (atazanavir/ritonavir, fosamprenavir/ritonavir
[once or twice daily], lopinavir/ritonavir [once or twice daily], saquinavir/ritonavir)
OR one NNRTI (efavirenz, nevirapine) PLUS two NRTIs (abacavir or zidovudine or
tenofovir/emtricitabine or lamivudine)
d. Acceptable therapy
i. Efavirenz PLUS two NRTIs (didanosine/lamivudine or emtricitabine)
ii. Atazanavir PLUS two NRTIs (abacavir or zidovudine/lamivudine)
e. Regimens that need more data
i. Maraviroc PLUS zidovudine/lamivudine
ii. Raltegravir PLUS two NRTIs (abacavir or zidovudine/lamivudine)
iii. Darunavir/ritonavir or saquinavir/ritonavir PLUS two NRTIs (abacavir or
zidovudine/lamivudine)

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 HIV/Infectious Diseases

f. Regimens to be used with caution

i. Nevirapine PLUS abacavir/lamivudine
ii. Nevirapine PLUS tenofovir/emtricitabine
iii. Fosamprenavir PLUS two NRTIs (abacavir or zidovudine or tenofovir/emtricitabine
or lamivudine)
g. Not recommended regimens
i. All monotherapies
ii. Dual NRTI regimens alone
iii. Triple NRTI regimens other than abacavir/lamivudine/zidovudine

Patient Cases
2. Six months after starting appropriate therapy, F.G.’s CD4 count is 620/mm3, and his viral load is undetectable.
Two years later, his CD4 count decreases to 310/mm3, and his viral load is 15,000 copies/mL. Which one of
the following changes is best to make to F.G.’s therapy?
A. No changes should be made; wait until his viral load is again more than 50,000 copies/mL.
B. Change tenofovir to abacavir because abacavir is a more potent antiretroviral.
C. Change tenofovir and emtricitabine to abacavir and lamivudine.
D. Change the entire regimen to abacavir, lamivudine, and fosamprenavir/ritonavir.

3. Which one of the following should be monitored now that F.G. is receiving fosamprenavir/ritonavir?
A. Peripheral neuropathy.
B. Drug interactions with drugs metabolized by CYP1A2.
C. Endocrine disturbances such as hyperglycemia, fat redistribution, and lipid abnormalities.
D. Nephrolithiasis.

h. Change therapy for the following reasons:

i. Virologic failure
(a) Not achieving HIV RNA less than 400 copies/mL by 24 weeks or less than 50
copies/mL by 48 weeks of therapy (continue therapy, but assess adherence and
consider intensification)
(b) Repeated detection of virus (50–1000 copies/mL) after initial suppression to
undetectable levels
ii. Immunologic failure
(a) No specific definition
(b) Some studies have used the following:
(1) Failure to increase 50–100 cells/mm3 above the baseline CD4 cell count
during the first year of therapy
(2) Failure to increase the CD4 count above 350 cells/mm3 in 4–7 years
i. Options for treatment failure
i. Perform resistance testing (while patient is on failing regimen or within 4 weeks of
discontinuing).
ii. Prior therapy with no resistance
(a) Check adherence and address underlying causes. Consider reinitiating the
same regimen.
(b) Initiate a new regimen.
(c) Intensify one therapy or pharmacokinetically boost one therapy.

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 HIV/Infectious Diseases

iii. Prior therapy with resistance—Start a new regimen with at least two and preferably
three fully active agents.
iv. Extensive therapy with resistance—Re-suppress viral load maximally or at least
adequately to prevent clinical progression.
v. New regimen with at least two fully active agents is not possible—Continue current
regimen.
j. Resistance testing
i. Types of testing
(a) Genotypic
(1) Testing for the presence of mutations known to cause drug resistance
(2) Comparing the HIV-1 pol gene with a wild-type gene
(3) Recommend to guide therapy in patients with virologic failure while on
their first or second regimen.
(b) Phenotypic
(1) Test for inhibitory concentration needed to decrease HIV replication by
50% (IC50)
(2) Values are reported as fold changes in sensitivity.
(3) An increase of more than 4-fold in IC50 = “sensitive.”
(4) A 4- to 10-fold increase in IC50 = “intermediate.”
(5) An increase of more than 10-fold in IC50 = “resistant.”
(6) Added to genotypic testing in patients with complex drug resistance
mutation patterns
ii. Indications
(a) Recommended: Upon entrance into care
(b) Recommended: Virologic failure during potent combination antiretroviral therapy
(c) Recommended: All pregnant women with HIV
(d) Recommended: Suboptimal suppression of viral load after initiation of potent
combination antiretroviral therapy
(e) Recommended: Acute HIV infection before initiating therapy to determine
whether a drug-resistant virus was transmitted
(g) Genotypic testing recommended for treatment-naïve patients
(h) Phenotypic testing recommended for treatment-experienced patients with
complex resistance patterns
iii. Benefits
(a) Resistance testing is an independent indicator of virologic outcome (better short-
term viral load response in those who had testing completed).
(b) May also benefit patients by limiting drug exposures, toxicities, and expense
iv. Limitations
(a) The effect of resistance testing is limited in heavily treated patients.
(b) The HIV RNA value must be 500–1000 copies/mL or more.
(c) Current need for expert interpretation
(d) Difficult-to-detect small mutant populations (less than 20%)
(e) Cost: About $400–$500 per test

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 HIV/Infectious Diseases

II. OPPORTUNISTIC INFECTIONS: PATIENTS WITH HIV

Herpes Zoster
400
Kaposi's Sarcoma
350
Oral Candidiasis
300 Non-Hodgkin's Lymphoma
CD4 Count Pneumocystis carinii Pneumonia
250
(cells/mm3) Herpes simplex virus infections
200 Cryptococcal meningitis
Toxoplasmosis
150
MAI and CMV
100

50
Time

Figure 1. Relationship between CD4 count and risk of HIV-related opportunistic infections.

A. Overview of HIV-Associated Infections

1. Principle No. 1: The fungal, parasitic, and viral infections acquired by people who are
infected with HIV are rarely curable. At best, the infection is controllable during an acute
episode but usually requires long-term suppressive therapy.
2. Principle No. 2: Most HIV-associated infections represent endogenous reactivation of
previously acquired organisms and do not represent a threat to others.
3. Principle No. 3: Concurrent or consecutive infections with different organisms are a
common clinical occurrence in severely immunosuppressed people with HIV infection.
4. Principle No. 4: The observed frequency of certain parasitic and fungal infections depends on
the prevalence of asymptomatic infection with these pathogens in the local population.
5. Principle No. 5: Infections associated with HIV are severe, often disseminated and atypical,
and characterized by a high density of organisms.
6. Principle No. 6: Certain B-cell–associated infections are seen with increased frequency in
people with HIV infections (i.e., pneumococcal infection).

B. Categories of Acute Opportunistic Infections in the Setting of Potent Combination

Antiretroviral Therapy
1. Subclinical infections unmasked by immune reconstitution soon after beginning therapy
(within 12 weeks)—Continue antiretroviral therapy.
2. Infections beginning more than 12 weeks after onset of therapy; caused by either immune
reconstitution or incomplete immunity—Continue antiretroviral therapy.
3. Infections occurring because of failure of potent combination antiretroviral therapy—
Complete resistance testing and modify antiretroviral therapy.

C. Initiating Potent Combination Antiretroviral Therapy in the Setting of Acute Opportunistic Infections
1. Opportunistic infections with no effective therapy require prompt initiation of antiretroviral
therapy: Cryptosporidiosis, microsporidiosis, promyelocytic leukemia, and Kaposi sarcoma

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 HIV/Infectious Diseases

Patient Cases
4. Three years later, F.G. (from patient case questions 1–3) has not responded to any of his antiretroviral treat-
ment regimens because of resistance or intolerance. His CD4 count has decreased to 135/mm3. Against which
one of the following infections should he receive primary prophylaxis?
A. PCP.
B. Cryptococcal meningitis.
C. Cytomegalovirus (CMV).
D. Mycobacterium avium complex (MAC).

5. B.L. is a 44-year-old man positive for HIV who arrives at the emergency department severely short of
breath. He is an extremely nonadherent patient and has not seen a health care provider in more than 3 years.
A chest radiograph shows pulmonary infiltrates in both lung fields. The following laboratory profile and
tests are performed: sodium = 147 mEq/L; potassium = 4.2 mEq/L; chloride = 104 mEq/L; bicarbonate =
25.2 mEq/L; glucose = 107 mg/dL; blood urea nitrogen = 38 mg/dL; serum creatinine = 1.1 mg/dL; aspar-
tate aminotransferase = 28 IU/L; alanine aminotransferase = 32 IU/L; lactate dehydrogenase = 386 IU/L;
alkaline phosphate = 75 IU/L; pH = 7.45; partial pressure of oxygen = 63 mm Hg; partial pressure of carbon
dioxide = 32 mm Hg; and oxygen saturation = 85%. Sputum Gram stain is negative; silver stain is also nega-
tive. Which one of the following treatments should B.L. receive?
A. Pentamidine intravenously with adjuvant prednisone therapy.
B. TMP/SMX for 21 days.
C. TMP/SMX intravenously with adjuvant prednisone therapy for 21 days.
D. Atovaquone for 21 days.

2. Antiretroviral therapy should begin within 2 weeks of acute opportunistic infections, except
for TB, in which the infection should be treated first.

D. Pneumocystis jiroveci pneumonia

1. Clinical presentation
a. Fever, shortness of breath, and nonproductive cough
b. Increased lactate dehydrogenase
c. Diffuse pulmonary infiltrates
d. In general, with CD4 counts less than 200/mm3
e. Hypoxemia with increased alveolar-arterial (A-a) gradient and decreased partial
pressure of oxygen—A-a gradient = 150—partial pressure of oxygen—partial pressure
of carbon dioxide
2. Diagnosis
a. Induced sputum or bronchoalveolar lavage or transbronchial biopsy
b. Methenamine silver stain of sputum sample
3. Therapy
a. Trimethoprim/sulfamethoxazole
i. Dose = 5 mg/kg of TMP every 8 hours for 21 days (orally or intravenously)
ii. Adverse effects (80% of patients, with 20%–60% requiring discontinuation)
(a) Nausea and vomiting
(b) Rash
(c) Anemia, thrombocytopenia, leukopenia
iii. Prophylaxis dose = TMP/SMX double strength or single strength once daily or 3 times/
week (pediatric dose = 150 mg/m2 per dose of TMP and 750 mg/m2 per dose of SMX)

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b. Clindamycin and primaquine

i. Dose = 300–900 mg of clindamycin every 6–8 hours and primaquine base 15–30 mg/
day for 21 days (intravenous clindamycin may be used)
ii. Adverse effects
(a) Rash
(b) Anemia, methemoglobinemia
c. Pentamidine
i. Dose = 4 mg/kg/day for 21 days (intravenously)
ii. Adverse effects
(a) Hypotension
(b) Rash
(c) Electrolyte disturbances
(d) Hypo- or hyperglycemia
(e) Pancreatitis
iii. Prophylaxis dose = 300 mg by nebulization (Respirgard) once monthly (can predose
with β-agonist to diminish respiratory irritation)
d. Trimethoprim and dapsone
i. Dose = 5 mg/kg of TMP every 8 hours and dapsone 100 mg/day for 21 days (orally
only for mild to moderate PCP)
ii. Adverse effects
(a) Nausea and vomiting
(b) Anemia
iii. Prophylactic dose = dapsone 100 mg/day (pediatric dose = 1 mg/kg/day) or 50 mg/
week with 50–75 mg of pyrimethamine and 25 mg of leucovorin
e. Atovaquone (Mepron)
i. Dose = 750 mg 2 times/day for 21 days given with a high-fat meal (orally only for
mild to moderate PCP)
ii. Pediatric dose (less than 40 kg [88 lb]) = 40 mg/kg/day divided 2 times/day
iii. Equal to TMP/SMX for PCP but not an antibacterial
iv. Potential for decreased efficacy in patients with diarrhea (because of poor absorption)
v. Adverse effects
(a) Nausea and vomiting
(b) Rash
(c) Transient increase in liver function tests
(d) Insomnia, headache, fever
vi. Prophylactic dose = 1500 mg/day (alternative to TMP/SMX)
f. Adjuvant therapy: Corticosteroids
i. Used in patients with severe PCP (A-a gradient of 35 or more or partial pressure of
oxygen of 70 or less)—Start within 72 hours.
ii. Decreases mortality
iii. Dose = 40 mg 2 times/day of prednisone for 5 days, followed by 40 mg/day for 5 days,
and then 20 mg/day for remainder of PCP therapy (use cautiously in patients with TB)
4. Prophylaxis
a. Secondary prophylaxis in patients after PCP (may be discontinued if CD4 count is more
than 200/mm3 for 3 months or longer because of potent combination antiretroviral therapy)
b. Primary prophylaxis in patients with CD4 count less than 200/mm3 (may be discontinued if
CD4 count is more than 200/mm3 for 3 months or longer because of potent combination
antiretroviral therapy)

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E. Candida Infections
1. Oral Candida infections (thrush)
a. More than 90% of patients with AIDS sometime during their illness
b. Signs and symptoms
i. Creamy white, curdlike patches on the tongue and other oral mucosal surfaces
ii. Pain; decreased food and fluid intake
2. Candida esophagitis
a. Not always an extension of oral thrush (30% do not have oral thrush)
b Signs and symptoms: Painful swallowing, obstructed swallowing, substernal pain
3. Diagnosis
a. Signs and symptoms of infection
b. Fungal cultures/potassium hydroxide smear
c. Endoscopic evaluation
4. Therapy (oral candidiasis is easy to treat [3–14 days’ duration], but it relapses within 30 days)
a. Nystatin
i. Indicated for mucous membrane and cutaneous Candida infections
ii. Use for initial episodes in patients with CD4 count more than 50/mm3.
iii. Five milliliters (100,000 units/mL); swish and swallow 4 times/day
iv. Poor adherence
b. Clotrimazole—Alternative to nystatin
i. Use for initial episodes in patients with CD4 count more than 50/mm3.
ii. Clotrimazole (Mycelex) troches 10 mg 5 times/day
iii. Poor adherence (generally better tolerated than nystatin)
c. Fluconazole
i. Indicated for oropharyngeal and esophageal candidiasis
ii. Two percent relapse on fluconazole versus 28% on placebo
iii. Ten percent of patients develop fluconazole-resistant infections.
iv. A total of 100–200 mg/day
d. Itraconazole
i. Indicated for oropharyngeal and esophageal candidiasis
ii. Oral solution: 200 mg/day

Patient Case
6. G.H. is a 33-year-old man positive for HIV who presents to the clinic with a severe headache that has gradu-
ally worsened during the past 3 weeks. He also has memory problems and is always tired. He has refused
antiretroviral therapy in the past, and his most recent CD4 count was 75/mm3. He is given a diagnosis
of Cryptococcal meningitis and is successfully treated. Which one of the following is the best follow-up
therapy for G.H.?
A. No maintenance treatment is required.
B. Administer fluconazole 200 mg/day orally.
C. Administer amphotericin B1 mg/kg/week intravenously.
D. He is protected as long as he is also receiving PCP prophylaxis.

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F. Cryptococcosis
1. C. neoformans
2. Occurs in 6%–10% of patients with AIDS
3. In general, occurs in patients with CD4 counts less than 50/mm3
4. Acute mortality is 10%–25%, and 12-month mortality is 30%–60%.
5. Worldwide distribution
a. Found in aged pigeon droppings and nesting places (e.g., barns, window ledges)
b. Organism must be aerosolized and inhaled; it then disseminates hematogenously.
6. Signs and symptoms
a. Almost always meningitis (66%–84%)
b. Usually present for weeks or months (1 day to 4 months; average = 31 days)
c. Insidious onset
i. Low-grade fever (80%–90%)
ii. Headaches (80%–90%)
iii. Altered sensorium (20%): Irritability, somnolence, clumsiness, impaired memory and
judgment, behavioral changes
iv. Seizures may occur late in the course (less than 10%).
v. Minimal nuchal rigidity, meningismus, photophobia
7. Diagnosis
a. Cerebral spinal fluid (CSF) changes including:
i. Positive CSF cultures
ii. Cerebral spinal fluid India ink
iii. Cerebral spinal fluid cryptococcal antigen titer (91%)
iv. Elevated opening pressure greater than 20 cm of H2O
b. Serum cryptococcal antigen more than 1:8
8. Therapy
a. Amphotericin B deoxycholate: 0.7–1 mg/kg/day (or liposomal amphotericin 4–6 mg/
kg/day) PLUS flucytosine 25 mg/kg every 6 hours for at least 2 weeks, followed by
fluconazole 400 mg/day for at least 8 weeks—Commonly used in patients with AIDS
b. Amphotericin B deoxycholate: 0.7–1 mg/kg/day (or liposomal amphotericin 4–6 mg/kg/
day) for 4–6 weeks (or 1 month after negative cultures); alternative in patients with AIDS
c. Amphotericin B deoxycholate: 0.7–1 mg/kg/day PLUS fluconazole 800 mg/day for 2
weeks, followed by fluconazole 800 mg/day for at least 8 weeks
d. Fluconazole 400–800 mg/day PLUS flucytosine 25 mg/kg every 6 hours for 6 weeks
e. Fluconazole 800–2000 mg/day for 10–12 weeks
9. Outcome
a. Therapeutic response: 42%–75%
b. Length of therapy is controversial, but antifungals should probably be continued as long
as CSF and other body fluid cultures are positive and for 1 month after negative cultures.
c. Relapse: 50%–90% (with about 100% mortality)
10. Prophylaxis
a. Relapses usually occur within first year after therapy (less often with highly active
antiretroviral therapy [HAART]).
b. Secondary prophylaxis: Fluconazole 200 mg/day (may consider discontinuing if
CD4 count is more than 200/mm3 for 6 months or longer after potent combination
antiretroviral therapy; reinitiate if CD4 count decreases to less than 200/mm3)
c. Primary prophylaxis: Not indicated (decreases the incidence of cryptococcosis but does
not decrease mortality and may lead to resistance)

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Patient Cases
7. After treatment of his cryptococcal meningitis, G.H. is initiated on potent combination antiretroviral thera-
py. For 2, 6, and 8 months after starting the therapy, his CD4 counts are 212, 344, and 484/mm3, respectively.
Which one of the following is the best follow-up therapy for G.H. now?
A. Continue the fluconazole maintenance.
B. Maintenance therapy with fluconazole should be given for at least 1 year; then, it can be discontinued
because the CD4 counts have increased.
C. Maintenance therapy with fluconazole should be continued until CD4 counts are greater than 500/mm3.
D. Maintenance therapy with fluconazole can be discontinued.

8. J.C., a 36-year-old woman positive for HIV, has severe anemia. She has been tested for iron deficiency and
has been taken off zidovudine and TMP/SMX. She has also started to lose weight and to have severe diar-
rhea. A blood culture is positive for MAC. Which one of the following treatments is best for J.C.?
A. Clarithromycin plus EMB for 2 weeks, followed by maintenance with clarithromycin alone.
B. Azithromycin plus EMB for at least 12 months.
C. Clarithromycin plus INH for 2 weeks, followed by maintenance with clarithromycin alone.
D. EMB plus rifabutin indefinitely.

G. M. avium Complex
1. Organism characteristics
a. Complex is similar (main species are M. avium and M. intracellulare, which are not
differentiated microbiologically).
b. Ubiquitous in soil and water
i. Organisms gain access through the gastrointestinal tract.
ii. After access, the organism spreads hematogenously.
c. Usually occurs in patients with HIV having a CD4 count less than 50/mm3
2. Signs and symptoms (nonspecific)
a. Weight loss, intermittent fevers, chills, night sweats, abdominal pain, diarrhea, chronic
malabsorption, and progressive weakness
b. Anemia
c. Elevated alkaline phosphatase
3. Diagnosis
a. Blood culture
b. Bone marrow biopsy
c. Stool cultures (do not treat if cultured only in the stool)
4. Therapy
a. The MAC is independently associated with risk of death, and treatment prolongs survival.
b. Suggested therapeutic regimen—Macrolide plus EMB: Clarithromycin 500 mg (7.5–15
mg/kg) 2 times/day (alternative: azithromycin 500–600 mg/day 10–20 mg/kg) PLUS
EMB 15 mg/kg/day
c. Other agents:
i. Rifabutin (Mycobutin) 150–600 mg/day (added to regimen if patient has CD4
less than 50/mm3, has a high mycobacterial load, or is not currently taking
antiretrovirals; rifabutin dose chosen on the basis of other antiretrovirals because
of drug-drug interactions)
ii. Ciprofloxacin 750 mg (10–15 mg/kg) 2 times/day
iii. Amikacin 10–15 mg/kg/day intravenously

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d. Chronic maintenance therapy/secondary prophylaxis may be discontinued after 12

months of therapy if CD4 count is more than 100/mm3 for 6 months or longer because of
potent combination antiretroviral therapy and if patient is asymptomatic.
5. Primary prophylaxis in patients with CD4 counts less than 50/mm3 (may be discontinued
if CD4 count is more than 100/mm3 for 3 months or longer because of potent combination
antiretroviral therapy)
a. Clarithromycin 500 mg orally 2 times/day: 3 times lower incidence of MAC bacteremia
(vs. placebo)
b. Azithromycin 1200 mg orally once weekly
c. Rifabutin 300 mg/day (150 mg orally 2 times/day with food if there are gastrointestinal
adverse effects)
i. Two times longer until a positive MAC culture (vs. placebo)
ii. Decreased incidence of symptoms related to MAC
iii. Adverse effects: Rash, gastrointestinal disturbances, neutropenia, body fluid
discoloration
iv. DO NOT give alone to patients with active TB.

Patient Case
9. P.L. is a 44-year-old man positive for HIV who receives a diagnosis of CMV retinitis. He currently receives
zidovudine, lamivudine, and efavirenz as antiretroviral agents; dapsone for PCP prophylaxis; and flucon-
azole for esophageal candidiasis. Which one of the following agents is the best empiric therapy?
A. Valganciclovir 900 mg twice daily orally and change zidovudine to tenofovir.
B. Ganciclovir 5 mg/kg intravenously twice daily and change dapsone to atovaquone.
C. Foscarnet 90 mg/kg twice daily intravenously and change efavirenz to atazanavir/ritonavir.
D. Acyclovir 10 mg/kg intravenously every 8 hours and keep his other drugs the same.

H. Cytomegalovirus
1. Characteristics of CMV infection
a. Fifty-three percent of Americans between 18 and 25 years old are CMV positive.
b. Eighty-one percent of Americans older than 35 years are CMV positive.
c. More than 95% of homosexual men are CMV positive.
d. About 90% of CMV infections are asymptomatic (if illness occurs, it resembles
mononucleosis).
e. Virus remains latent in the host after initial infection but may reactivate if patient
becomes immunocompromised (especially cell-mediated immunity).
f. Ninety percent of patients with AIDS develop CMV infections, and 25% experience
life- or sight-threatening disease (pre-HAART data: pre-1996).
2. Diagnosis of CMV infection
a. Serology (detects exposure to CMV)
b. Virus isolation
i. Tissue culture—Requires up to 6 weeks
ii. Shell vial technique—Requires only 16 hours; organism is incubated overnight and
then detected by immunofluorescence microscopy with monoclonal antibodies

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c. Cytology/histology
i. Large (cytomegalic) cell with a large, central, basophilic, intranuclear inclusion
(“owl’s eye”)
ii. Low yield
3. Manifestations of CMV
a. Gastrointestinal
i. Colitis: 5%–10% of patients with AIDS
ii. Esophagitis/gastritis uncommon
iii. Hepatitis: 33%–50% with histologic evidence but minimal clinical importance
iv. Maintenance drugs not needed
b. Pneumonia
i. Cytomegalovirus is commonly in bronchial secretions; of questionable importance
ii. Chest radiography results are similar to those seen with PCP.
iii. Symptoms: Shortness of breath; dyspnea on exertion; dry, nonproductive cough
iv. Treat if:
(a) Documented tissue infection
(b) Cytomegalovirus is only pathogen
(c) Deteriorating illness
v. About 50%–60% of patients will respond; no need for maintenance
c. Retinitis
i. Occurs in 10%–15% of patients with AIDS; is clinically most important CMV
infection
ii. In general, patients have CD4 counts less than 100/mm3.
iii. Begins unilaterally and spreads bilaterally
iv. Early complaints: “Floaters,” pain behind the eye
v. In general, progressive; no spontaneous resolution (blindness in weeks to months)
vi. Twenty-six percent progression, even with treatment; retinal detachment very common
4. Therapy for CMV infections
a. Ganciclovir (Cytovene-IV, Cytovene), valganciclovir (Valcyte)
i. Competes with deoxynucleosides, inhibiting viral DNA synthesis
ii. Must be triphosphorylated; the rate-limiting step in this process is the first
phosphorylation. Cytomegalovirus induces the production of the enzymes required to
monophosphorylate ganciclovir but not acyclovir.
iii. Valganciclovir is rapidly converted to ganciclovir in the intestinal wall and liver (F of
about 60%).
iv. Adverse effects
(a) A total of 65% have adverse effects, and 76% have moderate to severe
neutropenia (25% less than 1000/mm3, 16% less than 500/mm3).
(1) In general, after 10 days
(2) Ganciclovir plus zidovudine: 82% will have severe hematologic toxicity
(3) Patients receiving ganciclovir can tolerate only up to 300 mg/day of
zidovudine.
(b) Thrombocytopenia (9% less than 20,000/mm3)
(c) Confusion; convulsions; dizziness; headache; thinking disorders
(d) Nausea; vomiting; diarrhea; abnormal liver function tests
(e) Possible reproductive toxicity

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v. Dose
(a) Induction: Valganciclovir 900 mg orally 2 times/day for 14–21 days (alternative:
ganciclovir 5 mg/kg intravenously every 12 hours for 14–21 days)
(b) Maintenance: Valganciclovir 900 mg/day orally (alternative: ganciclovir 5 mg/
kg/day intravenously)
(c) All (100%) patients will relapse in 1–8 weeks without maintenance.
(d) Intravenous maintenance therapy requires establishment of central venous access.
vi. Local therapy
(a) Intraocular implant (Vitrasert): Designed to release 1 mcg/hour (replace after 6–8
months) plus valganciclovir 900 mg/day orally
(b) Local therapy alone is associated with an increased incidence of ocular adverse
effects, contralateral CMV retinitis, and extraocular CMV disease.
b. Foscarnet
i. Inhibits viral-induced DNA polymerase; no effect on human DNA polymerase
ii. Effective against all herpes viruses (especially CMV), HBV (±), and HIV
iii. Foscarnet and ganciclovir are equally effective against CMV, but foscarnet decreases
(by about 4 months) mortality because of its anti-HIV effects.
iv. Adverse effects
(a) Renal impairment
(1) Especially occurs if the patient is dehydrated or taking other renal toxic drugs
(2) A 2–3 times increase in serum creatinine (more than 50% had to discontinue)
(3) Usually reversible
(4) Prevented by administering 2.5 L/day of normal saline
(b) Decrease in hemoglobin and hematocrit
(c) Altered serum electrolytes (calcium, phosphorus, magnesium)
(d) Penile ulcerations
v. Preparation and dose
(a) Commercial preparation is available in 500-mL glass bottles at 24 mg/mL; 24
mg/mL should be administered centrally. For peripheral administration, use 12
mg/mL.
(b) One gram of foscarnet contains about 600 mg of sodium chloride.
(c) Induction: 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for 14–21 days
(administer for 1 hour)
(d) Maintenance: 90–120 mg/kg/day (administer for 2 hours)
(e) Decrease dose by 3.5 mg/kg for each 0.1 mL/minute/kg of creatinine clearance
below 1.6 mL/minute/kg.
(f) Maintenance therapy requires establishment of central venous access.
c. Cidofovir (Vistide)
i. Acts as a nucleoside monophosphate, inhibiting viral DNA polymerase
ii. Intracellular activation required
iii. Adverse effects
(a) Renal impairment
(b) Manifested as proteinuria and increased creatinine concentrations
(c) Decreased with concurrent probenecid (2 g, 3 hours before infusion and 1 g, 2
and 8 hours after infusion—to decrease renal secretion) and saline hydration
(d) Probenecid may cause nausea, vomiting, headache, fever, and flushing.
iv. Neutropenia (15% of patients)

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v. Dose
(a) Induction: 5 mg/kg/week for 2 weeks
(b) Maintenance: 5 mg/kg every other week
(c) Maintenance therapy does not require the establishment of central venous access.
5. Prophylaxis
a. Secondary prophylaxis is required for all patients (see individual drugs for specific
doses); it may be discontinued if the CD4 count is more than 100/mm3 for 3–6 months
or longer because of potent combination antiretroviral therapy; restart secondary
prophylaxis if the CD4 count decreases to less than 100/mm3.
b. Primary prophylaxis not recommended. In patients with CD4 counts less than 50/mm3,
regular funduscopic examinations are recommended.

I. Toxoplasmosis
1. Description
a. Toxoplasma gondii (protozoan)
b. Felines are the hosts for sporozoite production (change litter box daily, wash hands
after changing litter box or have someone else change the litter box, and, ideally, keep
the cat indoors).
c. A total of 15%–68% of adults in the United States are seropositive for T. gondii.
d. Secondary to undercooked beef, lamb, or pork (stress avoidance in patients with HIV)
e. Case-defining illness in 2.1% of patients with AIDS
2. Signs and symptoms
a. Fever, headache, altered mental status
b. Focal neurologic deficits (60%): Hemiparesis; aphasia; ataxia; visual field loss; nerve
palsies
c. Seizures (33%)
d. Cerebral spinal fluid: Mild pleocytosis, increased protein, normal glucose
3. Diagnosis
a. Brain biopsy: Only definitive diagnosis but generally not done
b. Antibodies or T. gondii isolation in serum or CSF
c. Magnetic resonance imaging scan or computerized tomographic scan: Multiple, bilateral,
hypodense, ring-enhancing mass lesions (magnetic resonance imaging scan more
sensitive than computerized tomographic scan)
4. Therapy
a. Standard therapy
i. Pyrimethamine 50–75 mg/day (loading dose = 200 mg in two doses) PLUS
ii. Sulfadiazine 1000–1500 mg every 6 hours (watch crystalluria)
(a) Bone marrow suppression: Thrombocytopenia, granulocytopenia, anemia
(b) Add folinic acid (leucovorin) 10–25 mg/day to reduce bone marrow effects
of pyrimethamine.
(c) Duration: 6 weeks or after signs and symptoms resolve
b. Alternative therapy
i. Clindamycin
(a) Dosage: 600–1200 mg intravenously every 6 hours for 6 weeks; after 3 weeks,
can change to oral 600 mg every 8 hours
(b) Used in combination with pyrimethamine/leucovorin for sulfa intolerance or by
itself when bone marrow suppression occurs

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ii. Atovaquone
(a) Dosage: 1500 mg orally 2 times/day
(b) Used in combination with pyrimethamine/leucovorin or in combination with
sulfadiazine or alone (monitor plasma concentrations if using alone)
iii. Azithromycin
(a) Dosage: 900–1200 mg/day orally
(b) Used in combination with pyrimethamine (do not use alone for acute therapy)
iv. Other alternatives: Clarithromycin plus pyrimethamine, 5-FU (fluorouracil) plus
clindamycin, dapsone plus pyrimethamine plus leucovorin, and minocycline
or doxycycline combined with pyrimethamine plus leucovorin, sulfadiazine, or
clarithromycin
5. Prophylaxis
a. Relapse rates approach 80% without maintenance therapy.
b. Toxoplasma-seropositive patients with a CD4 count of 100/mm3 or less should receive
primary prophylaxis.
c. For primary prophylaxis, use TMP/SMX double strength once daily or dapsone/
pyrimethamine/leucovorin or atovaquone with or without pyrimethamine at doses used
for PCP prophylaxis (may be discontinued if the CD4 count is more than 200/mm3 for 3
months or longer because of potent combination antiretroviral therapy).
d. For secondary prophylaxis, use the following (may be discontinued if the CD4 count is
more than 200/mm3 for 6 months or longer because of potent combination antiretroviral
therapy):
i. Pyrimethamine 25–50 mg/day plus leucovorin 10–25 mg/day with sulfadiazine
2–4 g/day
ii. Clindamycin 600 mg every 8 hours can be substituted if sulfa intolerance occurs.
iii. Atovaquone 750 mg orally every 6–12 hours with or without pyrimethamine/
leucovorin or sulfadiazine

III. TUBERCULOSIS

A. Mycobacterium tuberculosis
1. Factors associated with acquiring TB
a. Exposure to individuals with active pulmonary TB
b. Geographic location
c. Low socioeconomic status
d. Nonwhite race
e. Male sex
f. Acquired immunodeficiency syndrome
g. Foreign birth

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2. Epidemiology (Figure 2)

Number of persons with reported cases of

tuberculosis, 1986-2009

All Persons US-Born Persons Foreign-Born Persons

30000
25000
20000
Cases

15000
10000
5000
0
86

88

90

92

94

96

98

00

02

04

06

08
19

19

19

19

19

19

19

20

20

20

20

20
Year

Figure 2. Epidemiology of tuberculosis.

B. Pathophysiology (Figure 3)
1. Person-to-person transmission—Airborne droplets carrying M. tuberculosis are inhaled.
2. Infection primarily pulmonary, although can occur in other organ systems

Released bacilli attract

Remaining 10% monocytes and
Inhaled droplet Activated alveolar
multiply within the macrophages forming the
bypasses mucociliary macrophages ingest
macrophages and primary tubercle - growth
system and becomes and destroy over
are released when occurs within the
implanted in the 90% of the inhaled
the macrophage macrophages with neither
bronchioles or alveoli tubercle bacilli
dies destruction of bacilli or
macrophages occurring

In patients with diminished cell Delayed

mediated immunity the delayed In susceptible patients bacilli hypersensitivity kills the bacilli-
hypersensitivity reaction is continue to grow -- the caseous laden macrophages resulting in
greater and the caseous center center enlarges destroying formation of a tubercle with a
expands adjacent lung tissue caseous center

With continued delayed

hypersensitivity reaction
(immunocompromised patients) Patients with normal immune Bacilli die in the caseous center
the caseous center liquifies systems destroy bacilli escaping Positive PPD
which provides a viable from the caseous center leading to Asymptomatic
environment for bacillary little to no tissue destruction
growth - now growth occurs
extracellularly

Note:
This caseous liquification and Bacilli remain dormant in the caseous center
bacillary growth can occur Positive PPD
even in "normal" patients - Asymptomatic (for life?)
Erosion of bronchial
therefore antimicrobial therapy
tissue occurs and
is necessary
cavities form
Approximately 10% of those
infected develop clinical
tuberculosis

Figure 3. Pathophysiology of tuberculosis.

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C. Diagnosis (Table 8)

Table 8. Diagnosis of Tuberculosis

Nonspecific Signs and Symptoms Radiology Microbiology
Cough Chest radiograph Sputum smear for AFB
Malaise patchy or nodular Sputum culture for
Weight loss infiltrates in Mycobacterium tuberculosis
Fever, chills upper lobes;
Night sweats cavitary lesions
Pleuritic pain
AFB = acid-fast bacillus.

1. Skin test for PPD (Table 9)

a. Recommended dose is 5 tuberculin units/0.1 mL.
b. Mantoux method
i. Intradermal injection of tuberculin into forearm
ii. Measure diameter of induration after 48–72 hours.
c. False-negative tests occur in 15%–20% of people infected with M. tuberculosis, primarily
in those recently infected or anergic.
d. Two hundred fifty tuberculin units per 0.1 mL of solution can be used, but this is not
recommended by the Centers for Disease Control and Prevention.
e. Only 8% of people vaccinated with Bacille Calmette-Guérin at birth will react 15 years later.

Table 9. Recommendation for Purified Protein Derivative Skin Test

Criterion for Positive Skin Test (mm) Applicable Group
5 Patients with chest radiograph consistent with TB
Close contacts of individuals with newly diagnosed
infectious TB
Patients with HIV infection
Patients with documented defects in cellular immunity
Patients receiving prednisone ≥ 15 mg/day for ≥ 1 month
10 Recent immigrants (within the past 5 years) from
countries with a high prevalence of TB (even if they
had BCG)
Intravenous drug abusers
Residents and employees of prisons/jails, nursing homes,
hospitals, and homeless shelters
Patients with diseases known to be associated with
a higher risk of TB (diabetes mellitus, silicosis,
leukemias and lymphomas, chronic renal failure),
gastrectomy, and jejunoileal bypass
Children < 4 years
15 Patients with no identifiable risk factors
BCG = Bacille Calmette-Guérin; HIV = human immunodeficiency virus; TB = tuberculosis.

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2. Interferon-gamma release assays/targeted blood tests

a. QuantiFERON-TB Gold and T-SPOT.TB
b. Blood test that detects the release of interferon-gamma in response to M. tuberculosis
infection
c. Greater sensitivity and specificity than the PPD test
d. Most beneficial to verify a positive PPD in patients with a history of Bacille Calmette-
Guérin vaccine
3. Booster effect
a. The TB test can restimulate hypersensitivity in those exposed in the past.
b. Occurs within 1 week of the test and persists for longer than 1 year
c. Those with small TB test reactions can be retested in 1 week—If positive, it should
be attributed to boosting of a subclinical hypersensitivity; chemoprophylaxis is not
necessary.

Patient Case
10. J.M. is a 42-year-old man who has a yearly PPD skin test because he works at a long-term care facility. Forty-
eight hours after the PPD was placed, he had an 18-mm induration. This is the first time he has reacted to this
test. His chest radiograph is negative. Which one of the following is best in view of J.M.’s positive PPD?
A. No treatment is necessary, and J.M. should have another PPD skin test in 1 year.
B. Another PPD skin test should be performed in 1 week to see whether this is a booster effect.
C. J.M. should be monitored closely, but no treatment is necessary because he is older than 35 years.
D. J.M. should be initiated on INH 300 mg/day orally for 6 months.

D. Therapy
1. Treatment of latent TB infection
a. The goal is to prevent latent (asymptomatic) infection from progressing to clinical
disease.
b. The treatment of latent TB infection should be instituted in the following groups with a
positive PPD skin test:
i. Close contacts of individuals with newly diagnosed infectious TB
ii. Health care workers at facilities treating patients with TB
iii. Foreign-born people from high-prevalence countries (immigration within 5 years)
iv. Homeless people
v. People working at or living in long-term care facilities
vi. Patients with HIV infection
vii. Recent converters (within a 2-year period)
viii. People with abnormal chest radiographs that show fibrotic lesions—likely to
represent old, healed TB
ix. People with medical conditions that have been reported to increase the risk of
TB: Intravenous drug use, diabetes mellitus, silicosis, Hodgkin disease, leukemia,
immunosuppressive therapy, corticosteroids, end-stage renal disease
c. Dosing regimens
i. Patients who are not infected with HIV:
(a) Administer INH 300 mg/day or 900 mg 2 times/week for 6–9 months.
(b) Alternative: RIF ± INH for 4 months

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ii. Patients who are coinfected with HIV:

(a) Administer INH 300 mg/day for 9 months.
(b) Alternative: INH 900 mg 2 times/week for 9 months (lower strength of evidence)
iii. Areas with multidrug-resistant isolates: Two drugs with activity against the isolate for
6–12 months

Patient Case
11. R.J. is a 32-year-old man positive for HIV infection who presents to the clinic with increased weight loss
and night sweats, as well as a cough productive of sputum. He is currently receiving fosamprenavir/ritona-
vir 700 mg/100 mg 2 times/day, zidovudine 300 mg 2 times/day, lamivudine 150 mg 2 times/day, fluconazole
200 mg/day orally, and TMP/SMX double strength daily. A sputum sample is obtained, which is positive for
acid-fast bacillus. R.J. lives in an area with a low incidence of multidrug-resistant TB. Which one of the follow-
ing is the initial treatment of choice?
A. Initiate INH, RIF, and PZA with no change in HIV medications.
B. Initiate INH, RIF, and PZA; increase the dosage of fosamprenavir/ritonavir; and use a higher dosage of RIF.
C. Initiate INH, rifabutin, PZA, and EMB, with a lower dosage of rifabutin.
D. Initiate INH, rifabutin, PZA, and EMB and decrease the dosage of fosamprenavir/ritonavir.

2. Treatment of active TB infection (Table 10)

a. Principles of treatment
i. Regimens must contain many drugs to which the organisms are susceptible.
ii. Drug therapy must continue for a sufficient period.

Table 10. Pharmacotherapeutic Agents in the Treatment of Tuberculosis

First-Line Agents Second-Line Agents
Isoniazid (INH) Para-aminosalicylic acid
Rifampin (RIF) Ethionamide
Pyrazinamide (PZA) Cycloserine
Ethambutol (EMB) Kanamycin/amikacin
Streptomycin (SM) Capreomycin
Fluoroquinolones
Rifabutin
Rifapentine

b. Therapeutic options for patients without HIV infection. (Note: Any regimen administered
2, 3, or 5 times/week should be done by directly observed therapy.)
i. Option 1: INH, RIF, PZA, and EMB for 2 months (daily, 5 times/week, 3 times/week,
or 2 times/week), followed by INH and RIF for 4 months (daily, 5 times/week, 3
times/week, or 2 times/week)
ii. Option 2: INH, RIF, and EMB for 2 months (daily or 5 times/week), followed by
INH and RIF for 7 months (daily, 5 times/week, or 2 times/week)

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c. Therapeutic options for patients with HIV

i. Option 1: INH, RIF, PZA, and EMB for 2 months (daily, 5 times/week, or 3 times/
week), followed by INH and RIF for 4 months (daily, 5 times/week, or 3 times/week)
ii. Option 2: INH, RIF, and EMB for 2 months (daily or 5 times/week), followed by
INH and RIF for 7 months (daily or 5 times/week)
d. Concurrent therapy in patients with HIV
i. Protease inhibitors and NNRTIs (except for efavirenz or nevirapine) should not be
administered concurrently with RIF; NRTIs can be administered with RIF.
ii. A washout period of 1–2 weeks may be necessary once RIF is discontinued before
protease inhibitors or NNRTIs are initiated.
iii. Rifabutin can be substituted for RIF; patients may take NNRTI s with rifabutin, but
doses may need to be increased to 450–600 mg/day (see HIV guidelines).
iv. Patients may take protease inhibitors with RIF, but the rifabutin dose should be
decreased to 150 mg every day or every other day (300 mg 3 times/week may be an
option).
v. Patients taking rifabutin and protease inhibitors or NNRTIs should have HIV RNA
concentrations performed periodically.
e. Known drug resistance to INH: Administer RIF, PZA, and EMB for 6 months; rifabutin
may be substituted for RIF in patients with HIV.
f. Known drug resistance to RIF: Administer INH, PZA, and EMB for 9–12 months;
streptomycin may be added for the first 2 months to shorten the total treatment time to 9
months.

Patient Case
12. Which one of the following represents the best follow-up for R.J.?
A. Treatment with the initial drugs should continue for 6 months.
B. Treatment can be decreased to just INH and a rifamycin after 2 months for a total treatment of 18–24
months.
C. Treatment can be decreased to just INH and a rifamycin after 2 months for a total treatment of 6
months; HIV RNA concentrations should be observed closely during therapy.
D. Treatment can be decreased to INH, a rifamycin, and either PZA or EMB after 2 months for a total
treatment of 6 months; HIV RNA concentrations should be observed closely during therapy.

IV. ANTIFUNGAL THERAPY

A. Amphotericin B (Fungizone, Abelcet, Amphotec, AmBisome)

1. Mechanism of action: Binds to ergosterol in the fungal cell membrane, altering membrane
permeability and causing cell lysis
2. Spectrum of activity
a. Candida, Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans,
Paracoccidioides, Histoplasma capsulatum, Sporothrix, Aspergillus, mucormycoses
b. Clinical use
i. Cryptococcal meningitis
ii. Systemic fungal infections caused by sensitive fungi
iii. Limited use clinically with newer antifungals

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3. Adverse effects
a. Renal toxicity (glomerular and tubular)
i. Glomerular filtration rate decreases by about 40% within 2 weeks and usually
stabilizes at 20%–60% of normal.
ii. In general, reversible unless total dose is more than 4–5 g
iii. Manifestations: Renal tubular acidosis, urine casts, azotemia, oliguria, magnesium
and potassium wasting
iv. Prevention:
(a) Correct salt depletion—3 L of normal saline for 24 hours or 500 mL of normal
saline before and after amphotericin dose
(b) Avoid diuretics and liberalize salt intake—Risk/benefit with other disease states
b. Thrombophlebitis—Prevention
i. Dilute to 0.1 mg/mL and infuse for at least 4 hours; a faster infusion (i.e., 45 minutes
to 2 hours) may be tolerated.
ii. Use a central site.
iii. Adding heparin may decrease phlebitis.
c. Anemia
d. Fever/chills
i. Mechanism: Amphotericin B induces prostaglandin synthesis.
ii. Premedications:
(a) Hydrocortisone—25 mg intravenously before the dose or in the bottle
considerably decreases fever and chills (higher doses are not significantly better)
(b) Ibuprofen (10 mg/kg up to 600 mg 30 minutes before infusion)—Significantly
more fever/chills in placebo (87%) than in ibuprofen group (48%)
(c) Acetylsalicylic acid, acetaminophen, diphenhydramine—Never shown to be
effective (but not specifically studied)
e. Rigors treatment:
i. Meperidine 50 mg—Stops reaction within 30 minutes (mean = 10.8 minutes)
ii. If the patient consistently needs meperidine, then prophylactic doses may
be appropriate.
4. Dosing
a. Test dose of 1 mg (in 25–50 mL of 5% dextrose in distilled water [D5W]) or aliquot of
initial dose) for 20–30 minutes
b. If tolerated, prepare dose to a concentration of 0.1 mg/mL in D5W (amphotericin B
potency not affected by light [for 24 hours]).
c. Start therapy with 0.25 mg/kg (some suggest 5–10 mg) administered for 4–6 hours.
d. Increase gradually to desired milligram per kilogram concentration (i.e., 5- to 10-mg
increments).
e. May increase rapidly in fulminant infections or immunocompromised patients
f. Amphotericin can be given on alternate days by doubling the daily dose to a maximum
of 1.5 mg/kg.
5. Liposomal amphotericin
a. Liposomal formulations are designed to maintain therapeutic efficacy, but they diminish
renal- and infusion-related toxicity.

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Amphotericin B Abelcet Amphotec AmBisome

Liposome type Multilamellar Colloidal dispersion Unilamellar
vesicle with in aqueous solution liposome
ribbonlike (disk-shaped
structure bilayer)
Dose 1 mg/kg/day 5 mg/kg/day 3–4 mg/kg/day 3–5 mg/kg/
for 2 hours for 3–4 hours day
Test dose Yes None Yes None
Chills/rigors (%) 54–56 18 77 18
Fever (%) 44–47 14 55 17
Nephrotoxicity (%) 34–47 28 8 19
Hypokalemia (%) 12–29 5 26 7
Hypomagnesemia (%) 11–26 NA 6 20

b. Mostly taken up by macrophages in the lung, liver, spleen, bone marrow, and
circulating monocytes
c. Liposomes target fungi cell membranes much more than human cell membranes.
d. Amphotericin dissociates from the liposome over time, decreasing its toxicity
(only free drug is toxic).
e. Primary use in patients with aspergillosis who cannot tolerate amphotericin B
f. Potential use for invasive candidiasis

B. Azole Antifungals
1. Mechanism of action: Inhibits the synthesis of ergosterol, a component of the fungal cell
membrane, vital for normal growth
2. Ketoconazole (Nizoral)
a. Spectrum of activity
i. Candida species, Blastomyces, histoplasmosis, Paracoccidioides, Sporothrix,
dermatophytes
ii. Clinical use: Histoplasmosis, superficial Candida and other infections, blastomycosis,
paracoccidioidomycosis
b. Adverse effects
i. Nausea, abdominal pain, headache, rash
ii. Adrenal insufficiency, decreased libido, impotence, gynecomastia, menstrual
irregularities (inhibits steroidogenesis)
iii. Increased liver function tests, potential fulminate hepatitis
c. Drug interactions (CYP3A4 substrate and inhibitor)
i. Antacids, H2-blockers, proton pump inhibitors, didanosine (gastrointestinal absorption)
ii. Rifampin (decreases ketoconazole concentrations)
iii. Cyclosporine
iv. Phenytoin
v. Warfarin
vi. Methylprednisolone, midazolam, alprazolam, simvastatin, lovastatin
vii. Protease inhibitors
d. Dosing: 200–400 mg/day

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3. Fluconazole (Diflucan)
a. Spectrum of activity
i. Candida species (poor activity against C. glabrata and no activity against C. krusei),
Cryptococcus, Blastomyces, histoplasmosis, dermatophytes
ii. Clinical use
(a) Candida infections (primarily C. albicans and C. parapsilosis)
(b) Cryptococcal meningitis
b. Pharmacokinetics
i. Well absorbed orally (F = 100%)—Also available intravenously
ii. Half-life is about 30 hours—Primarily eliminated unchanged in the urine
c. Adverse effects
i. Nausea, abdominal pain, headache
ii. Increased liver function tests
d. Drug interactions (CYP3A4 inhibitor at more than 400 mg/day and CYP2C9 inhibitor at
lower doses)
i. Cyclosporine
ii. Phenytoin
iii. Warfarin
e. Dosing
i. Oral candidiasis—100–200 mg/day
ii. Esophageal candidiasis—200 mg/day
iii. Invasive candidiasis—400–800 mg/day
iv. Acute cryptococcal meningitis—400 mg/day
v. Cryptococcal meningitis prophylaxis—200 mg/day
4. Itraconazole (Sporanox)
a. Spectrum of activity
i. Candida species (usually just C. albicans), Cryptococcus, Aspergillus, Blastomyces,
histoplasmosis, dermatophytes
ii. Clinical use
(a) Onychomycosis
(b) Histoplasmosis
(c) Aspergillus
b. Pharmacokinetics
i. Oral absorption about 55% when given with food—Also available intravenously
ii. Half-life is about 20 hours—Extensively metabolized—Hydroxyitraconazole is active.
c. Adverse effects
i. Nausea, abdominal pain, headache, rash
ii. Increased liver function tests, potential fulminate hepatitis
d. Drug interactions (CYP3A4 inhibitor at more than 400 mg/day and CYP2C9 inhibitor at
lower doses)
i. Antacids, H2-blockers, proton pump inhibitors, didanosine (gastrointestinal absorption)
ii. Cyclosporine
iii. Digoxin (decreases digoxin volume of distribution)
iv. Phenytoin
v. Warfarin
vi. Protease inhibitors
vii. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors
e. Dosing: 200 mg/day

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5. Voriconazole (Vfend)
a. Spectrum of activity
i. Candida species, Aspergillus, Fusarium, Scedosporium
ii. Clinical use
(a) Resistant Candida infections (especially C. glabrata and C. krusei)
(b) Aspergillus
b. Pharmacokinetics
i. Oral absorption about 95%—Also available intravenously
ii. Half-life is about 6 hours—Extensively metabolized—CYP (2C9, 3A4, 2C19)
c. Adverse effects
i. Abnormal vision 30% (abnormal vision, color changes, photophobia). Short-term
(20–30 minutes) effects on retina. Dose related. Not studied for more than 28 days of
therapy
ii. Increased liver function tests, rash, nausea
d. Drug interactions (CYP3A4 inhibitor and substrate; see Table 11)
e. Dosing
Aspergillosis: Loading dose = 6 mg/kg 2 times intravenously (infuse for 2 hours);
maintenance dose = 4 mg/kg every 12 hours intravenously (infuse for 2 hours)
Candida: 400 mg orally/intravenously every 12 hours for 2 doses; then 200 mg every 12
hours
i. For patients who are receiving phenytoin, increase dose to 5 mg/kg every 12 hours
intravenously or 200–400 mg every 12 hours orally.
ii. Dose reduction for moderate-severe cirrhosis: After loading dose, decrease dose by
50% in Child-Pugh class A/B—No information for patients in Child-Pugh class C
iii. No adjustment of the oral dose for renal insufficiency; patients with creatinine
clearance less than 50 mL/minute should not receive the intravenous product because
of accumulation of the intravenous vehicle sulfobutyl ether-β-cyclodextrin

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Table 11. Drug Interactions Reported with Voriconazole

Drug Effect Recommendation
Rifampin (CYP inducer) ↓ Voriconazole Coadministration contraindicated
Rifabutin (CYP inducer) ↓ Voriconazole, Coadministration contraindicated
­↑ rifabutin
Carbamazepine (CYP inducer) ↓ Voriconazole Coadministration contraindicated
Barbiturates, long acting ↓ Voriconazole Coadministration contraindicated
(CYP inducers)
Pimozide (CYP3A4 substrate) ↑­ Pimozide, Coadministration contraindicated
­↑ risk QT prolongation
Quinidine (CYP3A4 substrate) ­↑ Quinidine, Coadministration contraindicated
­↑ risk QT prolongation
Ergot alkaloids ­↑ Ergot alkaloids, Coadministration contraindicated
­↑ risk ergotism
Sirolimus (CYP3A4 substrate) ­↑ Sirolimus Coadministration contraindicated
Cyclosporine ­↑ Cyclosporine Reduce cyclosporine dose by half when
(CYP3A4 substrate) initiating voriconazole. Monitor levels closely.
Increase cyclosporine dose as necessary when
voriconazole is discontinued
Tacrolimus (CYP3A4 substrate) ­↑ Tacrolimus Reduce tacrolimus dose to one-third of initial
dose when initiating voriconazole. Monitor
levels closely. Increase tacrolimus dose as
necessary when voriconazole is discontinued
Omeprazole ↑­ Voriconazole, In patients receiving omeprazole doses ≥ 40
(CYP2C19 inhibitor, CYP2C19 and ­↑ omeprazole mg, reduce the omeprazole dose by half
CYP3A4 substrate)
Warfarin (CYP2C9 substrate) ­↑ Warfarin, ­PT Closely monitor PT/INR and adjust warfarin
dose as needed
CYP = cytochrome P450; INR = international normalized ratio; PT = prothrombin time.

6. Posaconazole (Noxafil)
a. Spectrum of activity
i. Candida species, Cryptococcus, Trichosporon, Aspergillus, Fusarium
ii. Clinical use
(a) Candida infections
(b) Aspergillosis
(c) Zygomycoses
(d) Fusariosis
b. Pharmacokinetics
i. Oral absorption enhanced by a high-fat meal—No intravenous formulation
ii. Half-life is about 24–30 hours—Primarily eliminated unchanged in the feces
c. Adverse effects
i. Nausea, vomiting, diarrhea
ii. Increased liver function tests, rash, hypokalemia, thrombocytopenia
iii. QTc-interval prolongation
d. Drug interactions—CYP3A4 inhibitor

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e. Dosing: Oropharyngeal candidiasis: 400 mg/day; refractory oropharyngeal candidiasis:

400 mg 2 times/day; prophylaxis of invasive fungal infections in neutropenic and graft-
versus-host disease patients: 200 mg 3 times/day

C. Echinocandins
1. Mechanism of action: Inhibits the synthesis of 1,3-β-d-glucan, an essential component of the
fungal cell wall
2. Caspofungin (Cancidas), micafungin (Mycamine), anidulafungin (Eraxis)
a. Spectrum of activity
i. Candida species (weak against C. parapsilosis), Aspergillus
ii. Clinical use
(a) Candida: Fungemia, intra-abdominal abscesses, peritonitis, and pleural
space infections
(b) Esophageal candidiasis
(c) Invasive aspergillosis (refractory or intolerant of other therapies)
b. Pharmacokinetics
i. Only available intravenously
ii. Half-life of about 1–2 days—Caspofungin and micafungin hepatically metabolized;
anidulafungin chemically degraded in the blood
c. Adverse effects: Infusion site–related reactions, headache, gastrointestinal symptoms
d. Drug interactions
i. Caspofungin: Avoid concomitant use with cyclosporine or tacrolimus.
ii. Micafungin: Avoid concomitant sirolimus or nifedipine.
iii. Anidulafungin: None
e. Dosing
i. Caspofungin—70 mg once intravenously, followed by 50 mg/day intravenously
ii. Micafungin—Candidemia 100 mg/day; esophageal candidiasis 150 mg/day
iii. Anidulafungin—200 mg once intravenously, followed by 100 mg/day intravenously

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References

Human Immunodeficiency Virus Society of America: treatment of tuberculosis. Am

1. Panel on Antiretroviral Guidelines for Adults and J Respir Crit Care Med 2003;167:603–62.
Adolescents. Guidelines for the use of antiretro- 2. Havlir DV, Barnes PF. Tuberculosis in patients
viral agents in HIV-1-infected adults and adoles- with human immunodeficiency virus infection. N
cents. Department of Health and Human Services. Engl J Med 1999;340:367–73.
December 1, 2009; 1–161. Available at www.aid- 3. Small PM, Fujiwara PI. Management of tu-
sinfo.nih.gov/ContentFiles/AdultandAdolescent- berculosis in the United States. N Engl J Med
GL.pdf. Accessed December 23, 2010. 2001;345:189–200.
2. Thompson MA, Aberg JA, Cahn P, et al; Interna- 4. Targeted tuberculin testing and treatment of latent
tional AIDS Society–USA. Antiretroviral treat- tuberculosis infection. Am J Respir Crit Care Med
ment of adult HIV infection: 2010 recommenda- 2000;161:S221–47.
tions of the International AIDS Society–USA
5. Jasmer RM, Nahid P, Hopewell PC. Latent tuber-
panel. JAMA 2010;304:321–33.
culosis infection. N Engl J Med 2002;347:1860–6.
3. Panel on Treatment of HIV-Infected Pregnant
Women and Prevention of Perinatal Transmission. Antifungal Therapy
Recommendations for Use of Antiretroviral Drugs
in Pregnant HIV-1-Infected Women for Mater- 1. Pappas PG, Kauffman CA, Andes D, et al. Infec-
nal Health and Interventions to Reduce Perinatal tious Diseases Society of America. Clinical prac-
HIV Transmission in the United States. May 24, tice guidelines for the management of candidiasis:
2010:1–117. Available at http://aidsinfo.nih.gov/ 2009 update by the Infectious Diseases Society of
ContentFiles/PerinatalGL.pdf. Accessed October America. Clin Infect Dis 2009;48:503–35.
1, 2010. 2. Perfect JR, Dismukes WE, Dromer F, et al. Clini-
4. Centers for Disease Control and Prevention. Up- cal practice guidelines for the management of
dated U.S. Public Health Service guidelines for the cryptococcal disease: 2010 update by the Infec-
management of occupational exposures to HIV tious Diseases Society of America. Clin Infect Dis
and recommendations for postexposure prophy- 2010;50:291–322.
laxis. MMWR 2005;54(No. RR-9):1–17.
5. See also www.medscape.com/hiv for more infor-
mation on HIV, antiretroviral therapy, and drug
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Opportunistic Infections in Patients with HIV

1. Centers for Disease Control and Prevention.
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adolescents. MMWR 2009;58(No. RR-4):1–207.
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RR-11):1–166.

Tuberculosis
1. American Thoracic Society/Centers for Dis-
ease Control and Prevention/Infectious Diseases

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Answers and Explanations to Patient Cases

1. Answer: d 4. Answer: a
The patient should be treated at this time; potent combina- When the CD4 count decreases to 135/mm3, the patient
tion antiretroviral therapy should be initiated when CD4 should receive primary prophylactic treatment against
counts fall below 350/mm3. The combination therapy PCP (CD4 count less than 200/mm3). Primary prophylax-
of tenofovir, emtricitabine, and atazanavir/ritonavir is is is necessary for MAC when the CD4 count is less than
a preferred initial therapeutic regimen. Monotherapy 50/mm3. For CMV, patients with CD4 counts less than
is not indicated for HIV. Although treatment with zi- 50/mm3 should receive regular funduscopic examina-
dovudine/lamivudine and nevirapine is an acceptable tions. In general, primary prophylaxis is not used for
alternative, it should not be first-line therapy. cryptococcal meningitis.

2. Answer: D 5. Answer: C
A change in potent combination antiretroviral therapy Although pentamidine would be an appropriate thera-
should be made when the viral load becomes detect- peutic option for a patient who is HIV positive with
able after a period of levels below detection. Some cli- PCP, the optimal empiric therapy is TMP/SMX intra-
nicians would wait and monitor the patient closely if venously with adjuvant prednisone therapy for 21 days.
the viral load increased to 10,000 copies/mL. However, Although TMP/SMX is the drug of choice for PCP,
adjuvant prednisone therapy is indicated because the
these patients generally will require changes in therapy
patient’s A-a gradient is 55, and the patient’s partial
in the future. Resistance testing should be completed to
pressure of oxygen is less than 70. Atovaquone is indi-
optimize therapy. Without knowledge of resistance pat-
cated only for patients with mild to moderate PCP who
terns, the best change is to initiate an entirely new regi-
cannot tolerate TMP/SMX. This patient does not meet
men of abacavir, lamivudine, and fosamprenavir/rito-
this criterion.
navir because changing all three agents simultaneously
limits the possibility of resistance occurring quickly to
the new regimen. In general, changes of only one drug 6. Answer: B
in a regimen should be made only for intolerance. If the Patients with cryptococcal meningitis should always
virus is resistant to the combination regimen, chang- receive secondary prophylaxis. One of the principles
ing only one drug will simply lead to resistance to the of treating AIDS-related illnesses is that the infections
new antiviral; moreover, changing only one drug is the are seldom curable, and generally, long-term prevent-
equivalent of monotherapy. Ideally, any new regimen able therapy is required. Weekly amphotericin B has
should have at least two fully active drugs. been studied for secondary prophylaxis, but flucon-
azole is the best agent for secondary prophylaxis. The
agents that are effective for PCP prophylaxis have no
3. Answer: c activity against Cryptococcus.
A patient taking fosamprenavir/ritonavir should be
monitored for endocrine disturbances (e.g., hypergly-
7. Answer: D
cemia, fat redistribution, lipid abnormalities) because
all protease inhibitors can cause endocrine distur- Maintenance therapy for cryptococcal meningitis with
bances. Because fosamprenavir/ritonavir does not fluconazole can be discontinued when the CD4 count
cause peripheral neuropathy (although didanosine, zal- increases to greater than 200/mm3 for 6 months or
citabine, and stavudine do), there is no need to monitor longer after potent combination antiretroviral therapy.
fosamprenavir/ritonavir. Drug interaction with drugs Because G.H.’s CD4 counts have been greater than 200/
metabolized by CYP1A2 is not of concern because mm3 for at least 6 months, maintenance therapy can be
fosamprenavir is an inhibitor of CYP3A4, and ritona- discontinued.
vir is an inhibitor of CYP 2D6 and 3A4. Fosamprenavir
does not cause nephrolithiasis; thus, the patient does 8. Answer: B
not need to be monitored for this (although a patient For the treatment of MAC, azithromycin plus EMB for
taking indinavir does). at least 12 months is the best therapeutic combination
and includes one of the newer macrolides and a second

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agent (EMB is usually the preferred second agent). full-dose ritonavir) or an NNRTI (except for efavi-
Therapy may be discontinued after 12 months if CD4 renz) with RIF. Patients who are HIV positive should
counts increase with potent combination antiretroviral be initiated on four drugs for TB, and fosamprenavir
therapy and if the patient is asymptomatic. Clarithro- should not be used with RIF. The best recommendation
mycin plus EMB for 2 weeks, followed by maintenance is INH, rifabutin, PZA, and EMB, with a lower dose of
with clarithromycin alone, is incorrect because there is rifabutin; it includes the four drugs for TB and a lower
no induction therapy followed by maintenance mono- dose of rifabutin (because of fosamprenavir/ritonavir
therapy for MAC. A therapeutic regimen of clarithro- inhibition). The fosamprenavir/ritonavir dose does not
mycin plus INH is not the best because INH has no need to be changed when adding rifabutin.
activity against MAC. Although EMB plus rifabutin
has activity against MAC, the current recommenda-
12. Answer: c
tions are that all therapeutic regimens include either
azithromycin or clarithromycin; therefore, the EMB For R.J., only the rifamycin and INH need to be contin-
plus rifabutin regimen is not the treatment of choice. ued after 2 months of therapy with the four drugs for TB.
The regimen can be simplified to a rifamycin and INH
after 2 months, but the recommended total treatment
9. Answer: A duration is 6 months. The concentrations of HIV RNA
This patient, who is positive for HIV infection, receives should be monitored closely because of potential altera-
a new diagnosis of CMV retinitis and should receive tions in drug concentrations of the protease inhibitor.
valganciclovir orally for treatment. In addition, his zi-
dovudine should be changed to another NRTI because
the combination of valganciclovir and zidovudine
causes considerable bone marrow depression. Foscar-
net is an option, but it generally causes more toxicity
and must be given intravenously. There would be no
need to change his efavirenz if foscarnet were initiated.
Ganciclovir intravenously is also an option but should
not be used first line unless valganciclovir cannot be
given. In addition, zidovudine and TMP/SMX would
interact with ganciclovir. Acyclovir does not have ac-
tivity against CMV.

10. Answer: d
A patient with an induration of greater than 15 mm after
a PPD skin test for TB needs to be assessed for treat-
ment. Because J.M.’s PPD skin test was negative last
year, he is considered a recent converter and needs to
be treated. He would also need to be treated if there
were patients with TB at the long-term care facility.
The booster effect is a phenomenon associated with an
initial small reaction causing immunologic stimulation,
followed by a larger reaction with a subsequent test.
J.M. had an initial large reaction (18-mm induration).
Age is not a factor to consider in treating latent TB. Ini-
tiating INH 300 mg/day orally for 6 months is the best
recommendation for managing J.M.’s positive PPD.

11. Answer: c
R.J. should have his HIV medications altered (RIF will
induce the metabolism of fosamprenavir and ritonavir).
He should not receive a protease inhibitor (except for

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Answers and Explanations to Self-Assessment Questions

1. Answer: D of therapy, and a failure to increase the CD4 count

Transmission of HIV to a child is decreased if the above 350 cells/mm3 while on therapy. If there is a
mother’s viral load is decreased. The benefits of ther- question of ineffective antiretroviral therapy, single
apy far outweigh the risk. A potent combination an- drugs should be changed only with caution (consid-
tiretroviral therapy that includes zidovudine through- er changing the entire regimen). Resistance does not
out the pregnancy is the most appropriate therapeutic occur more commonly with emtricitabine than with
regimen for an asymptomatic patient with HIV who is other antiretroviral agents.
pregnant (even in the first trimester) and has a low CD4
count and high viral load (although if the woman is on a 4. Answer: D
fully suppressed regimen without zidovudine, that regi-
A change in therapy is indicated for the patient tak-
men should be continued without changes). Although
ing potent combination antiretroviral therapy and ex-
zidovudine 300 mg 2 times/day orally throughout the
periencing hyperglycemia, fat redistribution, and lipid
pregnancy, followed by zidovudine during labor and
abnormalities. Although adding lipid-lowering agents
to the baby for 6 weeks, was the regimen originally
may be indicated to lower cardiovascular risks, simv-
studied to decrease HIV transmission, potent combina-
astatin should not be used with lopinavir or ritonavir
tion antiretroviral therapy is indicated because of the
because of the drug interaction (increased simvastatin
patient’s low CD4 count and high viral load; therefore,
concentrations lead to increased risk of myalgias).
single-drug therapy is inappropriate. A single dose of
Pravastatin is a better choice (even though it may de-
nevirapine at the onset of labor will not have the im-
crease ritonavir concentrations). Although adding an
pact on viral load and will not lower the risk of HIV
insulin-sensitizing agent may be indicated, piogli-
transmission as much as potent combination antiret-
tazone should not be used with lopinavir or ritonavir
roviral therapy throughout the pregnancy. Single-dose
because of the drug interaction (increased pioglitazone
nevirapine is indicated in women in labor who were not
concentrations and potential induction of protease in-
treated during their pregnancy.
hibitor metabolism by pioglitazone). Changing agents
is a good solution, but NRTIs do not cause endocrine
2. Answer: A abnormalities, so changing from the nucleoside RTI zi-
The patient should be told that atazanavir can cause dovudine to the nucleotide RTI tenofovir will not im-
hyperbilirubinemia. This patient should be told to talk prove the symptoms. At this time, changing agents (if
to a pharmacist about the current combination therapy possible) to an effective regimen that does not cause
because there are many drug interactions with antiret- endocrine disturbances is the best option. Because
roviral agents. However, although atazanavir inhibits protease inhibitors most commonly cause endocrine
CYP3A4, tenofovir does not (it is an NRTI, not a prote- disturbances, changing to an NNRTI-based regimen
ase inhibitor). In addition, informing the patient to cut is best.
the dose in half if there are adverse effects is incorrect
because antiretroviral drugs, especially protease in- 5. Answer: D
hibitors, should never be used below the recommended
The current recommended regimen for treating cryp-
dose. Informing the patient that tenofovir and emtric-
tococcal meningitis in patients positive for HIV is am-
itabine cause additive peripheral neuropathy is incor-
photericin B 0.7 mg/kg/day plus flucytosine 25 mg/
rect because neither of these drugs is associated with
kg every 6 hours for 2 weeks, followed by fluconazole
that adverse effect.
400 mg/day. Fluconazole alone is recommended only
for mild to moderate cryptococcal meningitis, and
3. Answer: B the dose should be 400 mg/day. Studies have shown
There are many other reasons to change antiretrovi- that early mortality is greater with fluconazole alone
ral therapy in addition to clinical deterioration. These than with amphotericin B alone. When amphotericin
include an inability to decrease viral load to undetect- B is used alone for cryptococcal meningitis, the dose
able levels, the detection of virus after initial suppres- should be 0.7 mg/kg per day, not 0.3 mg/kg per day.
sion to undetectable levels, a failure to increase the The flucytosine dose of 37.5 mg/kg every 6 hours is
CD4 count by 50–100 cells/mm3 during the first year high and is especially prone to cause bone marrow sup-
pression in patients who are HIV positive.

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6. Answer: C the best parametric test for comparing two groups. Al-
The number of patients needed to treat with INH over though an analysis of variance is a parametric test, it is
RIF to prevent one progression to active disease is 200 used to compare more than two groups. A chi-square
= 1/(0.008 − 0.003). The only information needed is the test is used to compare nominal or categorical data
absolute risk in both groups, which is provided. between two groups. The end points in this study are
continuous and, therefore, should not be compared us-
ing this statistical test. The Wilcoxon rank sum test is a
7. Answer: D nonparametric analog to the t-test.
Pyrimethamine plus clindamycin and leucovorin for 6
weeks is the correct choice for the treatment of toxo-
plasmosis in a patient who is HIV positive, not taking
antiretrovirals, and taking dapsone for PCP prophylax-
is. Atovaquone is not first-line therapy, although data
support its effectiveness in combination with sulfa-
diazine or pyrimethamine; TMP/SMX is not effective
for treatment or secondary prophylaxis of toxoplas-
mosis. Pyrimethamine and sulfadiazine are the first-
line agents for toxoplasmosis; however, leucovorin
should always be used with pyrimethamine to prevent
myelosuppression.

8. Answer: B
To achieve flucytosine peak concentrations between 50
and 100 mcg/mL (assuming a trough concentration of
25 mcg/mL, every-6-hour dosing, and 100% bioavail-
ability; flucytosine volume of distribution = 0.7 L/
kg; half-life = 3 hours), the concentration needs to be
changed by 25  75 mcg/mL. Using the equation ΔCp =
dose/Vd, a dose of 12.5 mg/kg would increase the con-
centration only 17.8 mcg/mL. A dose of 75 mg/kg would
increase the concentration by 107 mcg/mL, whereas a
dose of 150 mg/kg would increase the concentration by
214 mcg/mL. The correct dose is 37.5 mg/kg because
it would increase the concentration by 53.6 mcg/mL.

9. Answer: B
Because the patient is symptomatic and her sputum is
acid-fast bacillus positive, she should be treated for an
active TB infection. Isoniazid, RIF, PZA, and EMB
for 2 months, followed by INH and RIF for 4 more
months, is the recommended therapy for active TB.
Patients should be initiated on at least three antibiotics
for the first 2 months. Although fluoroquinolones have
some activity against TB, their use as first-line mono-
therapy is inappropriate.

10. Answer: C
Data are continuous and probably normally distributed
(given the large population of 350 patients in the study);
therefore, a parametric test is indicated. The t-test is

Updates in Therapeutics: The Pharmacotherapy Preparatory Review and Recertification Course

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Updates in Therapeutics: The Pharmacotherapy Preparatory Review and Recertification Course

448