Principles of
Infectious Diseases
S.A. ZIAI
Pharm D., PhD.
Associate Professor at Pharmacology Dept.
Case

R.G., a 63-year-old, 70-kg man in the intensive care unit, underwent
emergency resection of his large bowel. He has been mechanically
ventilated throughout his postoperative course. On day 20 of his hospital
stay, R.G. suddenly becomes confused; his blood pressure (BP) drops to
70/30 mm Hg, with a heart rate of 130 beats/minute. His extremities are
cold to the touch, and he presents with circumoral pallor. His temperature
increases to 40◦C (axillary), and his respiratory rate is 24 breaths/minute.
Copious amounts of yellow-green secretions are suctioned from his
endotracheal tube.
…

Physical examination reveals sinus tachycardia with no rubs or murmurs.
Rhonchi with decreased breath sounds are observed on auscultation. The
abdomen is distended, and R.G. complains of new abdominal pain. No bowel
sounds can be heard, and the stool is guaiac positive. Urine output from the
Foley catheter has been 10 mL/hour for the past 2 hours. Erythema is noted
around the central venous catheter. A chest radiograph demonstrates bilateral
lower lobe infiltrates, and urinalysis reveals >50 white blood cells/highpower
field (WBC/HPF), few casts, and a specific gravity of 1.015. Blood,
endotracheal aspirate, and urine cultures are pending.
Laboratory values
Sodium (Na), 131 mEq/L (normal, 135 to 147)
Hemoglobin (Hgb), 10.3 g/dL
Potassium (K), 4.1 mEq/L (normal, 3.5 to 5)
Hematocrit (Hct), 33% (normal, 39%–49% [male
patients])
Chloride (Cl), 110 mEq/L (normal, 95–105)
WBC count, 15,600/μL with bands present (normal,
4,500–10,000 μL)
CO , 16 mEq/L (normal, 20–29 mEq/L)
Platelets, 40,000/μL (normal, 130,000–400,000)
Blood urea nitrogen (BUN), 58 mg/dL (normal, 8–18)
Prothrombin time (PT), 18 seconds (normal, 10–12)
Serum creatinine (SCr), 3.8 mg/dL (increased from
0.9 mg/dL at admission; normal, 0.6–1.2)
Erythrocyte sedimentation rate (ESR), 65 mm/hour
(normal, 0–20)
Glucose, 320 mg/dL (normal, 70–110)
Procalcitonin, 1 mcg/L (normal <0.25mcg/L)
2
Serum albumin, 2.1 g/dL (normal, 4–6)
What signs and symptoms manifested by R.G.
are consistent with a serious systemic infection?
Hemodynamic Changes

Critically ill patients often have central intravenous (IV) lines in place
for measuring cardiac output and systemic vascular resistance
(SVR).

Normal SVR of 800 to 1,200 dyne ・ s ・ cm–5 may fall to 500 to 600
dyne ・ s ・ cm–5 in septic shock

The heart reflexively increases cardiac output from a normal 4 to 6
L/minute to up to 11 to 12 L/minute

The combination of decreased cardiac output and decreased SVR
results in hypotension often unresponsive to pressors and IV fluids.

R.G. has hemodynamic evidence of septic shock. He is hypotensive
(BP, 70/30 mm Hg) and tachycardic (130 beats/minute)
Hemodynamic Changes

In sepsis, blood generally is shunted away from the kidneys,
mesentery, and extremities.

Normal urine output of approximately 0.5 to 1.0 mL/kg/hour (30–70
mL/hour for a 70-kg patient) can decrease to less than 20 mL/hour in
sepsis (R.G’s urine output is 10 mL/hour)

Decreased blood flow to the kidney as well as mediator induced
microvascular failure can cause acute-tubular necrosis (ATN)

R.G.’s uremia (BUN, 58 mg/dL) and increased serum creatinine
concentration (3.8 mg/dL) are consistent with decreased renal
perfusion secondary to sepsis.
Hemodynamic Changes

Decreased blood flow to the liver may result in “shock
liver,” in which liver function tests, including ALT, AST, ALP,
become elevated.

R.G. serum albumin concentration is low (2.1 g/dL) and
his PT of 18 seconds is prolonged.

R.G. is confused, his extremities are cold, and the area
around his mouth appears pale.

All these signs and symptoms provide strong evidence
that he is in septic shock.
Cellular Changes

Glucose intolerance commonly is observed in sepsis
(RG’s 320 mg/dL)

ESR, C-reactive protein, and procalcitonin, nonspecific
tests that are commonly elevated in various
inflammatory states, including infection (R.G.’s ESR is 65
mm/hour).

Procalcitonin is a marker that is a more specific indicator
for infection than ESR or C-reactive protein (R.G.’s
procalcitonin is 1.0 mcg/L).
Respiratory Changes





Production of organic acids (lactate), glycolysis , fractional extraction
of oxygen, and abnormal delivery-dependent oxygen consumption are
observed in sepsis
R.G.’s acid-base status is consistent with sepsis-associated metabolic
acidosis (chloride 110 meq/L) and compensatory respiratory alkalosis
(CO2, 16 mEq/L) (respiratory rate, 24 breaths/minute).
The chronic phase of ARDS (10–14 days after development of the
syndrome) is associated with significant lung destruction.
Severe ARDS is associated with ratios of arterial oxygen level to fraction
of inspired oxygen (Pao2/Fio2) of less than 100, low lung compliance, a
need for high positive end-expiratory pressure (PEEP), and other
respiratory maneuvers.
Although R.G. currently does not have ARDS, the severity of his sepsis
strongly suggests he may develop this complication.
Hematologic Changes

Disseminated intravascular coagulation (DIC) is a well
recognized sequel of sepsis.

Huge quantities of clotting factors and platelets are
consumed in DIC

Decreased fibrinogen levels and increased fibrin split
products generally are diagnostic for DIC.

The PT of 18 seconds and the decreased platelet count
of 40,000/μL in R.G. are consistent with sepsis-induced
DIC.
Neurologic Changes

Central nervous system (CNS) changes, including
lethargy, disorientation, confusion, and psychosis, are
commonly observed in septic patients.

R.G.’s confused state is consistent with that expected
with septic shock.
PROBLEMS IN THE DIAGNOSIS OF
AN INFECTION
 R.G.’s
medical history includes temporal
arteritis and seizures chronically treated
with corticosteroids and phenytoin.
Perioperative “stress doses” of
hydrocortisone recently were
administered because of his surgical
procedure. What medications or disease
states confuse the diagnosis of infection?
Confabulating Variables

Various factors, including major surgery, acute
myocardial infarction, and initiation of corticosteroid
therapy, are associated with an increased WBC count.

Unlike infection, however, a shift to the left does not
occur with these disease states or drugs.
Drug Effects

Corticosteroids are associated with an increased WBC count and
glucose intolerance with the initiation of therapy or when doses are
increased.

Furthermore, some patients experience corticosteroid-induced mental
status changes that may mimic those associated with sepsis.

Corticosteroids can reduce and sometimes ablate the febrile response.

When the dexamethasone dose is decreased after neurosurgery, the
patient subsequently may experience classic meningismus, including
stiff neck, photophobia, and headache.

The lumbar puncture may demonstrate cloudy cerebrospinal fluid
(CSF), an elevated WBC count, high CSF protein, and low CSF glucose.

Certain drugs may cause aseptic meningitis, including OKT3, NSAIDs,
sulfonamides, and certain antiepileptics.
Fever







Fever also is a common finding with autoimmune diseases, such as
systemic lupus erythematosus and temporal arteritis.
25% incidence of FUO caused by cancer
Other diseases associated with fever include sarcoidosis, chronic liver
disease, and familial Mediterranean fever
Acute myocardial infarction, pulmonary embolism, and postoperative
pulmonary atelectasis also are commonly associated with fever
After infection, autoimmune disease, and malignancy have been ruled
out, drug fever should be considered.
Drug fever generally occurs after 7 to10 days of therapy and resolves
within 48 hours of the drug’s discontinuation
A rechallenge with the offending agent usually results in recurrence of
fever within hours of administration
In summary

R.G. has an autoimmune disease, temporal arteritis,
which is known to be associated with fever.

Similarly, his corticosteroid administration and phenytoin
use may confound the diagnosis of infection.

His other signs and symptoms, however, strongly suggest
that R.G.’s problems are of an infectious origin.
ESTABLISHING THE SITE OF THE
INFECTION

What are the most likely sources of R.G.’s infection?

After blood culture sampling, a thorough physical examination often
documents the source of infection.

Urosepsis, the most common cause of nosocomial infection, may be
associated with dysuria, flank pain, and abnormal urinalysis

Tachypnea, increased sputum production, altered chest
radiograph, and hypoxemia may direct the clinician toward a
pulmonary source

Evidence for an infected IV line might include pain, erythema, and
purulent discharge around the IV catheter

Other potential sites of infection include the peritoneum, pelvis,
bone, and CNS
R.G. has several possible sites of
infection

The copious production of yellow-green sputum,
tachypnea, and the altered chest radiograph suggest
the presence of pneumonia.

The abdominal pain, absent bowel sounds, and recent
surgical procedure, however, suggest an intraabdominal source.

Lastly, the abnormal urinalysis (>50 WBC/HPF) and the
erythema around the central venous catheter suggest
urinary tract and catheter infections, respectively.
DETERMINING LIKELY PATHOGENS

What are the most likely pathogens associated with R.G.’s
infection(s)?
Site of Infection: Suspected
Organisms
Site/Type of Infection
Suspected Organisms
1. Respiratory
Pharyngitis
Viral, group A streptococci
Bronchitis, otitis
Viral, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella
catarrhalis
Acute sinusitis
Viral, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis
Chronic sinusitis
Anaerobes, Staphylococcus aureus (as well as suspected organisms
associated with acute sinusitis)
Epiglottitis
Viral, Haemophilus influenzae
Site of Infection: Suspected Organisms
Site/Type of Infection
Suspected Organisms
1. Respiratory
Pneumonia
Community -acquired
Normal host
Streptococcus pneumoniae, viral, mycoplasma
Aspiration
Normal aerobic and anaerobic mouth flora
Pediatrics
Streptococcus pneumoniae, Haemophilus influenzae
COPD
Streptococcus pneumoniae, Haemophilus influenzae, Legionella,
Chlamydia, Mycoplasma
Alcoholic
Streptococcus pneumoniae, Klebsiella
Hospital-acquired
Aspiration
Mouth anaerobes, aerobic gram-negative rods, Staphylococcus aureus
Neutropenic
Fungi, aerobic gram-negative rods, Staphylococcus aureus
HIV
Fungi, Pneumocystis, Legionella, Nocardia, Streptococcus pneumoniae,
Pseudomonas
Site of Infection: Suspected Organisms
Site/Type of Infection
Suspected Organisms
2. Urinary Tract
Community-acquired
Escherichia coli, other gram-negative rods, Staphylococcus aureus,
Staphylococcus epidermidis,
enterococci
Hospital-acquired
Resistant aerobic gram-negative rods, enterococci
3. Skin and Soft Tissue
Cellulitis
Group A streptococci, Staphylococcus aureus
IV catheter infection
Staphylococcus aureus, Staphylococcus epidermidis
Surgical wound
Staphylococcus aureus, gram-negative rods
Diabetic ulcer
Staphylococcus aureus, gram-negative aerobic rods, anaerobes
Furuncle
Staphylococcus aureus
Site of Infection: Suspected Organisms
Site/Type of Infection
Suspected Organisms
4. Intra-Abdominal
Bacteroides fragilis, Escherichia coli, other aerobic gram-negative rods,
enterococci
5. Gastroenteritis
Salmonella, Shigella, Helicobacter, Campylobacter, Clostridium difficile,
amoeba, Giardia, viral,
enterotoxigenic-hemorrhagic Escherichia coli
6. Endocarditis
Pre-existing valvular
disease
Viridans streptococci
IV drug user
Staphylococcus aureus, aerobic gram-negative rods, enterococci,
fungi
Prosthetic valve
Staphylococcus epidermidis, Staphylocccus aureus
7. Osteomyelitis and
Septic Arthritis
Staphylococcus aureus, aerobic gram-negative rods
Site of Infection: Suspected Organisms
Site/Type of Infection
Suspected Organisms
8. Meningitis
<2 months
Escherichia coli, group B streptococci, Listeria
2 months–12 years
Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus
influenzae
Adults
Streptococcus pneumoniae, Neisseria meningitidis
Hospital-acquired
Streptococcus pneumoniae, Neisseria meningitidis, aerobic gramnegative rods
Postneurosurgery
Staphylococcus aureus, aerobic gram-negative rods
In R.G.

Intra-abdominal infection is likely caused by aerobic gram-negative
enteric bacteria, Bacteroides fragilis, and possibly enterococcus

Nosocomial urinary tract infection is usually caused by aerobic
gram-negative bacteria.

Pneumonia could be attributable to gram-negative bacilli and
staphylococci, as well as other organisms.

His long-term use of corticosteroids may predispose him to infection
caused by more opportunistic organisms, including Legionella, P.
jiroveci, and fungi

His IV catheter infection suggests infection caused by
staphylococci, including Staphylococcus epidermidis and S. aureus.
MICROBIOLOGIC TESTS AND
SUSCEPTIBILITY OF ORGANISMS




If the Gram stain of the tracheal aspirate demonstrates
gram-positive cocci in clusters, empirical anti
staphylococcal therapy is indicated
The India ink and potassium hydroxide (KOH) stains are
helpful in the identification of certain fungi.
The acid-fast bacilli (AFB) stain is critical in the diagnosis
of infection caused by Mycobacterium tuberculosis or
atypical mycobacteria.
In R.G.’s case, the Gram stain suggests that
antimicrobials active against gram-negative bacilli
should be used
Culture and Susceptibility Testing

Although these tests provide more information than the Gram stain,
they generally require 18 to 24 hours to complete.

DISK DIFFUSION


Based on guidelines provided by the Clinical and Laboratory Standards
Institute (CLSI), the diameter of inhibition is reported as susceptible,
intermediate, or resistant
BROTH DILUTION

As an example, if bacterial growth is observed with S. aureus at 0.5
mcg/mL of nafcillin but not at 1.0 mcg/mL, then 1.0 mcg/mL would be
considered the minimum inhibitory concentration (MIC) for nafcillin
against S. aureus.
…

Similar to the disk diffusion method, the CLSI provides
guidelines that also take into account the
pharmacokinetic characteristics of an antimicrobial

For example, ciprofloxacin achieves serum
concentrations of only 1 to 4 mcg/mL, whereas the
fourth-generation cephalosporin, cefepime, achieves
peak serum concentrations of 75 to mcg/mL;
consequently an MIC of 4.0 mcg/mL for E. coli would be
interpreted by CLSI as resistant to ciprofloxacin, but
susceptible to cefepime.
…

E test, which uses an antibiotic-laden plastic strip with increasing
concentrations of a specific antimicrobial from one end to the
other.

Several automated antimicrobial susceptibility systems are available

In some disease states (e.g., endocarditis), bactericidal therapy is
necessary. The minimum bactericidal concentration (MBC) is the
test that can be used to determine the killing activity associated
with an antimicrobial.

The MBC is determined by taking an aliquot from each clear MIC
tube for subculture onto agar plates. The concentration at which no
significant bacterial growth (i.e., 99.9% of the original inoculum) is
observed on these plates is considered the MBC.
Gram-positive cocci
Organism
Drug of choice
Alternatives
Comments
Streptococcus pyogenes
(group A streptococci)
Penicillin
Clindamycin,
macrolide,
cephalosporin
Clindamycin is the most reliable
alternative for penicillin-allergic patients.
Streptococcus
pneumoniae
Ceftriaxone,
ampicillin, oral
amoxicillin
Macrolide,
cephalosporin,
doxycycline
• Although the incidence of penicillinnonsusceptible pneumococci is 20%–
30%, high-dose penicillin or amoxicillin
is active against most of these isolates.
• Penicillin-resistant pneumococci
commonly demonstrate resistance to
other agents, including erythromycin,
tetracyclines, and cephalosporins.
• Antipneumococcal quinolones
(gemifloxacin, levofloxacin,
moxifloxacin), ceftriaxone, and
cefotaxime are options for treatment
of high-level penicillin-resistant
isolates.
Gram-positive cocci
Organism
Drug of choice
Alternatives
Comments
Enterococcus faecalis
Ampicillin ±
gentamicin
Piperacillintazobactam;
vancomycin ±
gentamicin;
daptomycin,
linezolid,
tigecycline
 Most commonly isolated enterococcus
(80%–85%).
 Most reliable antienterococcal agents
are ampicillin (penicillin, piperacillintazobactam), vancomycin, and linezolid.
 Monotherapy generally inhibits but does
not kill the enterococcus.
 Daptomycin is unique in its bactericidal
activity against enterococci.
 Aminoglycosides must be added to
ampicillin or vancomycin to provide
bactericidal activity.
 High-level aminoglycoside resistance
should be determined for endocarditis.
Gram-positive cocci
Organism
Drug of choice
Alternatives
Comments
Enterococcus faecium
Vancomycin ±
gentamicin
Linezolid,
daptomycin,
dalfopristin/
quinupristin
(D/Q),
tigecycline
 Second most common enterococcal
organism (10%–20%) and is more likely
than E. faecalis to be resistant to multiple
antimicrobials.
 Most reliable agents are daptomycin,
D/Q, and linezolid.
 Monotherapy generally inhibits but does
not kill the enterococcus.
 Aminoglycosides must be added to cell
wall–active agents to provide
bactericidal activity.
 Ampicillin and vancomycin resistance is
common.
 Daptomycin, D/Q, and linezolid are drugs
of choice for vancomycin-resistant
isolates.
Gram-positive cocci
Organism
Drug of choice
Alternatives
Comments
Staphylococcus aureus
Nafcillin
Cefazolin,
vancomycin,
clindamycin,
trimethoprimsulfa
methoxazole
linezolid,
 10%–15% of isolates inhibited by
penicillin.
 Most isolates susceptible to nafcillin,
cephalosporins, trimethoprimsulfamethoxazole, and clindamycin.
 First-generation cephalosporins are
equal to nafcillin.
 Most second- and third-generation
cephalosporins adequate in the
treatment of infection (exceptions
include ceftazidime and cefonicid)
(nafcillin-resistant)
Vancomycin
Trimethoprimsulfamethoxazole,
minocycline,
daptomycin,
tigecycline,
televancin
Methicillin-resistant S. aureus must
be treated with vancomycin; however,
trimethoprim-sulfamethoxazole,
daptomycin, D/Q, linezolid, or
minocycline can be used.
Gram-positive cocci
Organism
Drug of choice
Alternatives
Comments
Staphylococcus
epidermidis
Nafcillin
Cefazolin,
vancomycin,
clindamycin
 Most isolates are β-lactam-,
clindamycin-, and trimethoprimsulfamethoxazole–resistant.
 Most reliable agents are vancomycin,
daptomycin, D/Q, and linezolid.
 Rifampin is active and can be used in
conjunction with other agents;
however, monotherapy with rifampin
is associated with development of
resistance.
(nafcillin-resistant)
Vancomycin
Daptomycin,
linezolid, D/Q
Gram-positive Bacilli
Organism
Drug of choice
Alternatives
Diphtheroids
Penicillin
Cephalosporin
Listeria monocytogenes
Penicillin,
ampicillin
Trimethoprimsulfamethoxazole
Corynebacterium jeikeium
Vancomycin
Erythromycin, quinolone
Comments
Gram-negative Cocci
Organism
Drug of choice
Alternatives
Moraxella catarrhalis
Trimethoprim-sulfamethoxazole
Amoxicillin-clavulanic acid,
erythromycin, doxycycline,
second- or third-generation
cephalosporin
Neisseria gonorrhoeae Cefixime
Ceftriaxone
Neisseria meningitidis
Third-generation cephalosporin
Penicillin
Comments
Gram-negative bacilli
Organism
Drug of choice
Alternatives
Comments
Campylobacter jejuni
Quinolone,
erythromycin
A tetracycline, amoxicillinclavulanic acid
Enterobacter
Trimethoprimsulfamethoxazole
Quinolone, carbapenem,
aminoglycoside
Escherichia coli
Third-generation
cephalosporin
First- or second-generation Extended-spectrum βcephalosporin, gentamicin lactamase (ESBL) –producers
should be treated with a
carbapenem
 Not predictably inhibited by
third-generation
cephalosporins.
 Carbapenems, quinolones,
trimethoprimsulfamethoxazole,
cefepime, and
aminoglycosides are
most active agents.
Gram-negative bacilli
Organism
Drug of choice
Alternatives
Haemophilus influenzae
Third-generation
cephalosporin
β-Lactamase inhibitor combinations,
second-generation cephalosporin,
trimethoprim-sulfamethoxazole
Helicobacter pylori
Amoxicillin +
clarithromycin +
omeprazole
Tetracycline + metronidazole +
bismuth subsalicylate
Klebsiella pneumoniae
Third-generation
cephalosporin
First- or second-generation
cephalosporin, gentamicin,
trimethoprim-sulfamethoxazole
Legionella
Fluoroquinolone
Erythromycin ± rifampin, doxycycline
Comments
Extended-spectrum
β-lactamase (ESBL)
–producers should
be treated with a
carbapenem.
Gram-negative bacilli
Organism
Drug of choice
Alternatives
Proteus mirabilis
Ampicillin
First-generation cephalosporin,
trimethoprim-sulfamethoxazole
Other Proteus
Third-generation
cephalosporin
β-Lactamase inhibitor
combination, aminoglycoside,
trimethoprim-sulfamethoxazole
Pseudomonas
aeruginosa
Antipseudomonal
penicillin (or
ceftazidime)±
aminoglycoside
(or quinolone)
Quinolone or imipenem ±
aminoglycoside
Salmonella typhi
Quinolone
Ceftriaxone
Comments
 Most active agents include
aminoglycosides,
doripenem, imipenem,
meropenem, ceftazidime,
cefepime, aztreonam and
the extended-spectrum
penicillins.
 Monotherapy is adequate
for most pseudomonal
infections.
Gram-negative bacilli
Organism
Drug of choice
Alternatives
Serratia marcescens
Third-generation cephalosporin
Trimethoprim-sulfamethoxazole,
aminoglycoside
Shigella
Quinolone
Trimethoprim-sulfamethoxazole,
ampicillin
Stenotrophomonas
maltophilia
Trimethoprim-sulfamethoxazole
Ceftazidime, minocycline, βlactamase inhibitor combination
(Timentin)
Comments
Anaerobes
Organism
Drug of choice
Alternatives
Comments
Bacteroides fragilis
Metronidazole
β-Lactamase inhibitor
combinations, penems
 Most active agents (95%–100%)
include metronidazole, the βlactamase inhibitor combinations
(ampicillin-sulbactam,
piperacillin-tazobactam,
ticarcillin-clavulanic acid), and
penems.
 Clindamycin, cefoxitin,
cefotetan, cefmetazole,
ceftizoxime have good activity
but not to the degree of
metronidazole.
 Aminoglycosides and aztreonam
are inactive.
Clostridia difficile
Metronidazole
Vancomycin
Oral vancomycin is the drug of
choice for severe infection.
Fusobacterium
Penicillin
Metronidazole, clindamycin
Other Oropharyngeal
Organism
Drug of choice
Alternatives
Prevotella
β-Lactamase inhibitor
combination
Metronidazole,
clindamycin
Peptostreptococcus
Penicillin
Clindamycin,
cephalosporin
Comments
Most β-lactams active (exceptions
include aztreonam, nafcillin,
ceftazidime).
Other
Organism
Drug of choice
Alternatives
Actinomyces israelii
Penicillin
Tetracyclines
Nocardia
Trimethoprim-sulfamethoxazole Amikacin, minocycline,
imipenem
Chlamydia trachomatis
Doxycycline
Azithromycin
Chlamydia pneumoniae
Doxycycline
Azithromycin, clarithromycin
Mycoplasma
pneumoniae
Doxycycline
Azithromycin, clarithromycin
Borrelia burgdorferi
Doxycycline
Ampicillin, second- or thirdgeneration cephalosporin
Treponema pallidum
Penicillin
Doxycycline
Comments
DETERMINATION OF ISOLATE
PATHOGENICITY

Serratia marcescens grows from a culture of R.G.’s endotracheal
aspirate. How can it be determined whether an isolate represents a
true bacterial infection versus colonization or contamination?

Colonization indicates that bacteria are present at the site;
however, they are not actively causing infection.

Poor sampling techniques or inappropriate handling of specimens
can result in contamination

If a suction catheter was used to sample R.G.’s endotracheal
aspirate, the infecting organism likely would be cultured; however,
other nonpathogenic flora would also appear in the culture
medium (colonization)
…

In summary, culture results do not solely identify true
pathogens. In R.G., the Serratia may be a pathogen,
contaminant, or colonizer. Nevertheless, considering the
severity of R.G.’s illness and his associated respiratory
symptoms, treatment directed against this pathogen is
necessary.
ANTIMICROBIAL TOXICITIES

In light of the positive culture for Serratia, his increased
respiratory secretions, and a worsening chest
radiograph, ventilator-associated pneumonia (VAP) is
likely. Pending susceptibility results, R.G. is empirically
started on imipenem and gentamicin. In review of his
patient records, R.G. has no known allergies. Are there
equally effective, less toxic options for this patient?
Adverse Effects and Toxicities

Before antimicrobial therapy is started, it is important to
elicit an accurate drug and allergy history.

When “allergy” has been reported by the patient, it is
necessary to determine whether the reaction was
intolerance, toxicity, or true allergy
β-Lactams, (penicillin, cephalosporins, monobactams, penems)
Allergic: anaphylaxis, urticaria,
serum
sickness, rash, fever
• Many patients will have “ampicillin rash” or “β-lactam
rash” with no cross-reactivity with any other penicillins/βlactams. Most commonly observed in patients with
concomitant EBV disease.
• Likelihood of IgE-mediated cross-reactivity between
penicillins and cephalosporins approximately 5%–10%.
• Most recent data strongly suggest minimal IgE crossreactivity between penicillins and imipenem/meropenem.
• No IgE cross-reactivity between aztreonam and penicillins.
Diarrhea
Particularly common with ampicillin, augmentin, ceftriaxone,
and cefoperazone.
Antibiotic-associated colitis can occur with most
antimicrobials.
β-Lactams, (penicillin, cephalosporins, monobactams, penems)
Hematologic: anemia,
thrombocytopenia,
antiplatelet activity,
hypothrombinemia
• Hemolytic anemia more common with higher doses.
• Antiplatelet activity (inhibition of platelet aggregation) most common
with the antipseudomonal penicillins and high serum levels of other βlactams.
• Hypothrombinemia more often associated with those cephalosporins
with the methyltetrazolethiol side chain (cefamandole, cefotetan).
Reaction preventable and reversible with vitamin K.
Hepatitis or biliary sludging Hepatitis most common with oxacillin. Biliary sludging and stones reported
with ceftriaxone
Phlebitis
Seizure activity
Associated with high levels of β-lactams, particularly penicillins and
imipenem.
Potassium load
Penicillin G (K+).
Nephritis
Neutropenia
Nafcillin
Disulfiram reaction
Associated with cephalosporins with methyltetrazolethiol side chain
(cefamandole, cefotetan).
Hypotension, nausea
Associated with fast infusion of imipenem
Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin)
Nephrotoxicity
Averages 10%–15% incidence. Generally reversible, usually occurs after 5–7
days of therapy.
Risk factors: dehydration, age, dose, duration, concurrent nephrotoxins,
liver disease.
Ototoxicity
1%–5% incidence, often irreversible. Both cochlear and vestibular toxicity
occur.
Neuromuscular paralysis
Rare, most common with large doses administered via intraperitoneal
instillation or in patients with myasthenia gravis.
Macrolides (erythromycin, azithromycin, clarithromycin)
Nausea, vomiting,
“burning” stomach
Oral administration. Azithromycin and clarithromycin associated with less
nausea than erythromycin.
Cholestatic jaundice
Reported for all erythromycin salts, most common with estolate.
Ototoxicity
Most common with high doses in patients with renal or hepatic failure.
Clindamycin
Diarrhea
Most common adverse effect. High association with antibiotic-associated
colitis.
Tetracyclines (including tigecycline)
Allergic
Photosensitivity
Teeth and bone deposition
and discoloration
Avoid in pediatrics (<8 years old), pregnancy, and breast-feeding
GI
Upper GI predominates
Hepatitis
Primarily in pregnancy or the elderly.
Renal (azotemia)
Tetracyclines have antianabolic effect and should be avoided in patients
with ↓ renal function. Less problematic with doxycycline.
Vestibular
Associated with minocycline, particularly high doses.
Vancomycin
Ototoxicity
Only with receipt of concomitant ototoxins such as aminoglycosides or
macrolides.
Nephrotoxicity
Nephrotoxic only with high doses or in combination with other
nephrotoxins.
Hypotension, flushing
Associated with rapid infusion of vancomycin. More common with
increased doses.
Phlebitis
Needs large volume dilution.
Linezolid
Thrombocytopenia, neutropenia, anemia, MAO inhibition, tongue discoloration
Sulfonamides
GI
Nausea, diarrhea.
Hepatic
Cholestatic hepatitis, ↑ incidence in HIV
Rash
Exfoliative dermatitis, Stevens-Johnson syndrome. More common in HIV.
Hyperkalemia
Only with trimethoprim (as a component of trimethoprim-sulfamethoxazole).
Bone marrow
Neutropenia, thrombocytopenia. More common in HIV.
Kernicterus
Caused by unbound drug in the neonate. Premature liver cannot conjugate
bilirubin. Sulfonamide displaces bilirubin from protein, resulting in excessive
free bilirubin and kernicterus.
Chloramphenicol
Anemia
Idiosyncratic irreversible aplastic anemia (rare). Reversible dose-related
anemia.
Gray syndrome
Caused by inability of neonates to conjugate chloramphenicol.
Quinolones
GI
Nausea, vomiting, diarrhea.
Prolonged QT
Moxifloxacin; possibly all quinolones as a class.
Drug interactions
↓ Oral bioavailability with multivalent cations.
CNS
Altered mental status, confusion, seizures.
Cartilage toxicity
Toxic in animal model. Despite this toxicity, appears safe in children
including patients with cystic fibrosis.
Tendonitis or tendon rupture Common in elderly, renal failure, concomitant glucocorticoids.
…

Imipenem is associated with seizures, particularly in patients with
renal failure and in doses in excess of 50 mg/kg/day.

Considering R.G.’s acute onset of renal failure and his history of
seizures, other carbapenems, such as meropenem or doripenem, or
alternative classes of antibacterials would be preferable.

Gentamicin similarly may not be a good choice in R.G. His
increased age and declining renal function predispose him to
aminoglycoside nephrotoxicity and ototoxicity (cochlear and
vestibular).

A reasonable recommendation pending susceptibility results would
be to discontinue imipenem and gentamicin and treat with
meropenem or doripenem with or without a fluoroquinolone.
ROUTE OF ADMINISTRATION

The Serratia was determined to be susceptible to
ciprofloxacin. Oral ciprofloxacin was considered for the
treatment of R.G.’s presumed Serratia pneumonia, but
the IV route was prescribed. Why is the oral
administration of ciprofloxacin reasonable (or
unreasonable) in R.G.?

The proper route of antibiotic administration depends on
many factors, including the severity of infection,
antimicrobial oral bioavailability, and other patient
factors
…

In patients who appear “septic,” blood flow often is
shunted away from the mesentery and extremities,
resulting in unreliable bioavailability from the
gastrointestinal (GI) tract or muscles

Some drug interactions with oral agents (e.g., reduced
bioavailability associated with concomitant quinolone
and antacid administration and the decreased
absorption of itraconazole with concurrent proton-pump
inhibitor [PPI] therapy).
ANTIMICROBIAL DOSING

What dose of IV ciprofloxacin should be given to R.G.?
What factors must be taken into account in determining
a proper antimicrobial dose?

Selection of the appropriate dosage should be based
on evidence confirming the efficacy of the dosage in
the treatment of a specific infection

Patient-specific factors, including weight, site of
infection, and route of elimination, also must be
considered in dosage selection
…

The patient’s weight is important, particularly for agents with a low
therapeutic index (e.g., aminoglycosides, imipenem, flucytosine);
these drugs should be dosed on a milligram per kilogram per day
basis

Site of Infection


An uncomplicated urinary tract infection requires lower doses
considering the high urinary drug concentrations that are achieved with
most renally cleared agents
Anatomic and Physiologic Barriers

For example, penetration into cerebrospinal fluid, Vitreous humor, and
the prostate gland
…

Route of Elimination

Renal function can be estimated via 24-hour urine collection or with
equations, such as the Cockcroft and Gault equation

Aminoglycosides, vancomycin, acyclovir, and ganciclovir are cleared
primarily by the kidney. Thus, dosage adjustment is recommended for these
drugs in patients with renal failure

Azithromycin, clindamycin, and metronidazole are primarily eliminated by
the liver

Most β-lactams are eliminated by the kidney. In contrast, ceftriaxone and
most antistaphylococcal penicillins (e.g., nafcillin, oxacillin, dicloxacillin) are
eliminated both renally and nonrenally
…


R.G.’s age (63 years),weight (70 kg) and current serum creatinine (3.8
mg/dL) results in a calculated creatinine clearance of 14 mL/minute.
R.G. normally would be given an IV dosage of ciprofloxacin at 400 mg
every 12 hours.

His increasing creatinine, however, suggests that his dosage should be
decreased to 200 to 300 mg every 12 hours.

No standard liver function test (AST, ALT, alkaline phosphatase) has
been demonstrated to correlate well with hepatic drug clearance
Patient Age
…

Fever and Inoculum Effect

Fever increases and decreases blood flow to mesenteric, hepatic, and
renal organ systems and can either increase or decrease drug
clearance

As an example, piperacillin may demonstrate an MIC of 8.0 mcg/mL
against P. aeruginosa at a concentration of 105 colony-forming units/mL
(CFU/mL); however, at 109 CFU/mL, the MIC may increase to 32 to 64
mcg/mL.

This phenomenon is well recognized, particularly with β-lactamase–
producing bacteria treated with β-lactam antimicrobials

Aminoglycosides, quinolones, and imipenem appear to be less affected
by the inoculum effect than β-lactams.
PHARMACOKINETICS AND
PHARMACODYNAMICS

R.G.’s respiratory status remains unchanged; thus, the
ciprofloxacin is discontinued and cefotaxime and
gentamicin are started empirically. The use of a constant
IV infusion of cefotaxime is being considered in R.G. In
addition, the use of single daily dosing of gentamicin is
being discussed. What is the rationale for these
approaches, and would either be advantageous for
R.G.?
Concentration dependent vs Time
dependent Killing

The animal model suggests that β-lactam antimicrobials should be
dosed such that their serum levels exceed the MIC of the pathogen
as long as possible

This observation appears to be most important in the neutropenic
model, in which the use of a constant infusion more reliably inhibits
bacterial growth compared with traditional intermittent dosing

An additional benefit of the use of constant infusions of β-lactams is
that smaller daily doses appear to be as effective as higher doses
administered intermittently

The efficacy of quinolone antimicrobials appears to correlate with
the peak plasma concentration to MIC ratio or area under the
curve (AUC) to MIC ratio
…

Aminoglycosides traditionally have been administered every 8 to 12
hours to achieve peak serum gentamicin levels of 5 to 8 mcg/mL to
ensure efficacy in the treatment of serious gram-negative infection

Gentamicin troughs of greater than 2mcg/mL have been
associated with an increased risk for nephrotoxicity

Vancomycin troughs of 5 to 10 mcg/mL have been traditionally
recommended; however, more recent recommendations suggest
higher troughs (10 to 20 mcg/mL) depending on the site of infection
and severity of illness
Post Antibiotic Effect

Several antimicrobials (e.g., aminoglycosides) have been
associated with a pharmacodynamic phenomenon known as a
post antibiotic effect (PAE)

PAE is delayed regrowth of bacteria after exposure to an antibiotic
(i.e., continued suppression of normal growth in the absence of
antibiotic levels above the MIC of the organism)

As an example, if P. aeruginosa is cultured in broth, it will multiply to
a concentration of 109 CFU/mL. If piperacillin is added in a
concentration above the MIC for the organism, a reduction in the
bacterial concentration is observed. When piperacillin is removed
from the broth, immediate bacterial growth takes place.
…

If the above experiment is repeated with gentamicinif the
gentamicin is removed from the system, a lag period of 2 to 6 hours
takes place before characteristic bacterial growth occurs. This lag
period is defined as the PAE

A PAE also has been observed with quinolones and imipenem
against gram-negative organisms.

Although most β-lactam antibiotics, such as antipseudomonal
penicillins or cephalosporins, do not exhibit PAE with gram-negative
organisms, PAE has been demonstrated with β-lactam with grampositive pathogens such as S. aureus.
Once-Daily Dosing of
Aminoglycosides

Single daily dosing of aminoglycosides has been investigated
primarily in patients with normal renal function

Thus, patients in septic shock are less clear candidates for oncedaily dosing.

In summary, the use of a constant IV infusion of cefotaxime is
possible in R.G., but the benefit of this mode of administration is not
clear. Considering the severity of R.G.’s infection and his elevated
serum creatinine level, he is not a candidate for single daily dosing
of aminoglycosides (i.e., 5 to 6 mg/kg every 24 hours).
ANTIMICROBIAL FAILURE

Despite “appropriate” treatment, R.G. is unresponsive to
antimicrobial therapy. What antibiotic-specific factors
may contribute to “antimicrobial failure”?

Antimicrobials may fail for various reasons, including
patient specific host factors, drug or dosage selection,
and concomitant disease states

One of the most common reasons is drug resistance

Organisms that produce extended-spectrum (ESBL) or
amp C β-lactamases may be unresponsive to β-lactam
therapy despite associated in vitro susceptibility
…

Superinfection also may play a role in the unsuccessful treatment of
infection

If R.G.’s ceftriaxone-treated Serratia pneumonia subsequently
worsens and a tracheal aspirate returns positive for P. aeruginosa,
then supercolonization and, perhaps, superinfection have occurred.

Combination Therapy

Most infections can be treated with monotherapy (e.g., an E. coli
wound infection is treatable with a cephalosporin).

Some infections, however, require two-drug therapy, including most
cases of enterococcal endocarditis and perhaps certain P.
aeruginosa infections
…





Hilf et al. studied 200 consecutive patients with P. aeruginosa
bacteremia and demonstrated a 47% mortality in those receiving
monotherapy (antipseudomonal β-lactam or aminoglycoside) versus
27% in those in whom two-drug therapy was used
In contrast to the findings of the previous trial, more current
investigations do not support the use of two drugs over monotherapy in
the treatment of serious gram-negative infection, including P.
aeruginosa
An exception to this rule is bacteremia caused by P. aeruginosa in
neutropenic patients
Indifference, synergism, or antagonism
An example of antagonism is the combination of imipenem with a less
β-lactamase–stable β-lactam, such as piperacillin. If P. aeruginosa is
exposed to imipenem and piperacillin, the imipenem induces the
organism to produce increased β-lactamase
…

Pharmacologic Factors

Subtherapeutic dosing regimens are commonplace,
particularly for agents with a low therapeutic index, such as
the aminoglycosides.

For example, a serious gram-negative pneumonia may not
respond to aminoglycoside therapy if the achievable peak
gentamicin serum levels are only 3 to 4 mcg/mL. Considering
that only 20% to 30% of the aminoglycoside penetrates from
serum into bronchial secretions, only 0.5 to 1.0 mcg/mL may
exist at the site of infection level that may be inadequate to
treat pneumonia
…

Another example of dosing contributing to antimicrobial failure
centers on the use of loading doses.

Aminoglycosides or vancomycin should be initiated with a loading
dose, particularly in patients with renal failure. If the clinician
neglects to use a loading dose, it may take several days before a
therapeutic level is achieved.

Retrospective analyses have, however, demonstrated a high failure
rate associated with vancomycin in the treatment of MRSA isolates
with an MIC of 2 mcg/mL

By CLSI standards, an isolate of MRSA with an MIC of 2 mcg/mL is
considered susceptible
…

The pharmacodynamic parameter that serves as the best predictor of
vancomycin activity against S. aureus is the AUC to MIC ratio, with a
value greater than 350 independently associated with success. The
probability of attaining this value with isolates with an MIC of 2 mcg/mL
is 0%, even when achieving vancomycin trough concentrations of 15
mcg/mL

The infection site also potentially contributes to antimicrobial failure

Another potential reason for antimicrobial failure is inadequate therapy
duration

Host Factors

Infection of prosthetic material (e.g., IV catheters, orthopaedic
prostheses, mechanical cardiac valves, and vascular grafts) is difficult
to eradicate without removal of the hardware.
…

Similar to removal of prostheses, large undrained abscesses are
difficult, if not impossible, to treat with antimicrobial therapy.

Diabetic foot ulcer cellulitis may not respond adequately to
antimicrobial therapy.

Immune status, particularly neutropenia or lymphocytopenia, also
affects the outcome in the treatment of infection

Profoundly neutropenic patients with disseminated Aspergillus
infections are unlikely to respond to even the most appropriate
antifungal therapy.

Similarly, patients with AIDS who have low CD4 lymphocyte counts
cannot eradicate various infections, including those caused by
cytomegalovirus, atypical mycobacteria, and cryptococci.
Other than initiation of adequate antimicrobial
therapy, what adjunct measures can be considered
in this patient with septic shock?

Key recommended

adjuncts include administration of broad-spectrum antibiotics within
1 hour of diagnosis of septic shock, administration of either
crystalloid or colloid fluid resuscitation, and norepinephrine or
dopamine to maintain mean arterial pressure of at least 65 mm Hg.

Stress-dose steroid therapy can be given to those patients whose
blood pressure is poorly responsive to fluid resuscitation and
vasopressors

Other adjuncts include targeting lower blood glucose levels, stress
ulcer prophylaxis, and prevention of deep vein thrombosis in septic
patients.