Infectious Diseases I: Eric W. Mueller, Pharm.D., FCCP, FCCM

Infectious Diseases I
Eric W. Mueller, Pharm.D., FCCP, FCCM

University of Cincinnati Medical Center
Cincinnati, Ohio
Eric W. Mueller, Pharm.D., FCCP, FCCM
University of Cincinnati Medical Center
Cincinnati, Ohio
2018 ACCP/SCCM Critical Care Pharmacy Preparatory Review and Recertification Course
635
Learning Objectives SIRS Systemic inflammatory response syndrome

SJS Stevens-Johnson syndrome
1. Develop risk factor–based empiric antibiotic regi- TBSA Total body surface area
mens for patients with suspected ventilator-associated TEN Toxic epidermal necrolysis
pneumonia. UTI Urinary tract infection
2. Identify a definitive management strategy for central VAP Ventilator-associated pneumonia
line–associated bloodstream infections.
3. Describe definitive and supportive care pharmaco-
therapeutic interventions for patients with severe Self-Assessment Questions
influenza. Answers and explanations to these questions may be
4. Develop empiric and definitive antimicrobial therapy found at the end of this chapter.
plans for patients with catheter-related urinary tract
infection. Questions 1 and 2 pertain to the following case.
5. Differentiate between location of intra-abdominal K.P., a 38-year-old otherwise healthy woman, was
infection and respective empiric antimicrobial involved in a motor vehicle collision, sustaining a trau-
therapy. matic brain injury and severe chest injuries requiring
6. Describe the role of antibiotic therapy in patients endotracheal intubation and mechanical ventilation.
with acute pancreatitis. After being in the trauma intensive care unit (ICU) for
7. Develop a definitive management strategy for 96 hours, a new infiltrate is noted on her chest radio-
critically ill patients with severe Clostridium difficile graph, as well as a temperature of 101.9°F (38.8°C), a
infection. white blood cell count (WBC) of 15 x 103 cells/mm3, and
8. Recommend definitive antibiotic therapy for macroscopically purulent sputum. K.P. is hemodynami-
patients with postoperative wound infection. cally stable. Accordingly, your team decides to obtain
9. Describe the role of pharmacotherapy in the man- a bronchoscopic bronchoalveolar lavage (BAL) of the
agement of severe cutaneous reactions. affected lung field to assess for ventilator-associated
pneumonia (VAP).
Abbreviations in This Chapter 1. Which is the most likely causative pathogen of

K.P.’s suspected VAP?
ARDS Acute respiratory distress syndrome A. Acinetobacter spp.
BAL Bronchoalveolar lavage B. Methicillin-resistant Staphylococcus aureus
CAUTI Catheter-associated urinary tract infection (MRSA)
CDI Clostridium difficile infection C. Multidrug-resistant Pseudomonas aeruginosa
CLABSI
Central line–associated bloodstream D. Streptococcus pneumoniae
infection
CVC Central venous catheter 2. Based on the 2016 IDSA guidelines, which empiric
ED Emergency department antibiotic regimen is best for the likely causative
ICU Intensive care unit pathogen(s) of K.P.’s suspected VAP?
IDSA Infectious Diseases Society of America
A. Azithromycin plus moxifloxacin
IVIG Intravenous immunoglobulin
B. Cefepime
MDRO Multidrug-resistant organism
C. Ceftriaxone
MICU Medical intensive care unit
D. Ceftriaxone plus vancomycin
MRSA Methicillin-resistant Staphylococcus aureus
MRSE Methicillin-resistant Staphylococcus
3. T.D. is a 57-year-old man admitted to the medical
epidermatitis
intensive care unit (MICU) with severe hyperosmo-
MSSA Methicillin-sensitive Staphylococcus aureus
lar hyperglycemic syndrome. A subclavian central
NHSN National Healthcare Safety Network
venous catheter (CVC) is placed on his arrival at the
SICU Surgical intensive care unit
MICU. On ICU day 4, T.D. has a temperature of
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102.7°F (39.2°C) and a WBC of 17 x 103 cells/mm3. disease. During the operation, significant peritoneal
The nurse notes new-onset erythema at the catheter contamination with evidence of gross peritonitis
site. After an appropriate diagnostic workup, it is was noted together with persistent hypotension and
decided to initiate empiric antibiotic therapy for need for vasopressors. K.D. received perioperative
a suspected central line–associated bloodstream cefazolin and metronidazole. Which empiric antibi-
infection (CLABSI). Which agent is best for empiric otic regimen would be most appropriate for K.D.?
therapy? A. Ceftriaxone and vancomycin
A. Cefazolin B. Ciprofloxacin and metronidazole
B. Linezolid C. Ertapenem
C. Piperacillin/tazobactam D. Piperacillin/tazobactam
D. Vancomycin
7. T.M. is a 42-year-old man with chronic alcoholism
4. D.G., a 31-year-old woman, presents to the MICU who presents to the ED with severe epigastric pain
with severe respiratory failure and acute respiratory and serum lipase greater than 10 times the upper
distress syndrome (ARDS) requiring intubation after limit of normal. The resident orders a computed
48 hours of malaise, fever, and myalgias. The nasal tomography (CT) scan, which reveals necrosis
washing sent by the emergency department (ED) for affecting almost 40% of the pancreas but no abnor-
rapid diagnostic testing is positive for influenza A. mal fluid collections or evidence of abscess. T.M. is
The local prevalence of subtype 2009 H1N1 is high. febrile and tachycardic, and his WBC is elevated.
Which agent would be most appropriate for initial T.M.’s urine output is less than 0.5 mL/kg/hour, sug-
treatment of D.G.’s severe influenza? gestive of hypovolemia. Which best describes the
A. Amantadine role of antibiotic therapy for T.M. at this time?
B. Inhaled zanamivir A. Antibiotic therapy is not indicated.
C. Intravenous zanamivir B. Initiate empiric antibiotic therapy for presumed
D. Oseltamivir sepsis and likely pancreatic infection.
C. Initiate perioperative antibiotic therapy in prep-
5. T.S. is a 79-year-old woman admitted to the MICU aration for pancreatic debridement.
for respiratory failure and severe community- D. Initiate prophylactic antibiotic therapy to pre-
acquired pneumonia. T.S. has had a urethral catheter vent infection of necrotic tissue.
in place for 6 days while mechanically ventilated
on fentanyl infusion and intermittent haloperidol 8. J.E. is a 67-year-old woman admitted to the MICU
as needed for pain and delirium, respectively. This for severe metabolic acidosis secondary to uninten-
morning, T.S. had a temperature of 101.6°F (38.7°C) tional metformin overdosage. Her ICU stay has been
and an elevation in WBC to 16 x 103 cells/mm3; she complicated by a femoral vein CLABSI and related
is hemodynamically stable. Blood and urine cul- severe sepsis caused by pan-sensitive E. coli. J.E.
tures are sent. Urinalysis reveals significant pyuria. received a 3-day course of empiric piperacillin/tazo-
Which pathogen is most likely to cause a catheter- bactam, removal of her central line, and 11 days of
associated urinary tract infection (CAUTI) in T.S.? ceftriaxone as definitive therapy with resolution of
A. Enterococcus faecalis sepsis. Starting yesterday, it was noted that J.E. had
B. Escherichia coli nine loose bowel movements and new leukocytosis
C. P. aeruginosa of 14,500 cells/mm3, which suggests Clostridium
D. S. aureus difficile infection (CDI). J.E. continues to tolerate
enteral nutrition. Which is the most appropriate
6. K.D. is a 59-year-old man admitted to the surgi- regimen for J.E.’s suspected CDI?
cal intensive care unit (SICU) after an emergency A. Fidaxomicin 200 mg per feeding tube every 12
operation and partial bowel resection with primary hours
anastomosis for mid-small bowel necrosis and perfo- B. Metronidazole 500 mg per feeding tube every
ration likely secondary to severe peripheral vascular 8 hours
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C. Metronidazole 500 mg intravenously every 8

hours
D. Vancomycin 125 mg per feeding tube every 6
hours
9. J.S. is a 42-year-old man admitted to the SICU after

an open total colectomy with ileostomy for ischemic
colitis. On postoperative day 4, the surgery resident
on your interdisciplinary ICU team notes moderate
erythema (3 cm) and purulent drainage from the
wound. The resident subsequently opens the skin
portion of the wound and finds infected material just
above the unaffected fascia. No systemic signs and
symptoms are noted. Which intervention is most
appropriate?
A. Continue dressing changes and patient
assessment.
B. Initiate empiric vancomycin for postoperative
wound infection.
C. Initiate empiric antibiotic therapy targeted
against skin and colonic flora.
D. Initiate broad-spectrum antibiotic therapy for
suspected necrotizing fasciitis.
10. A.C. is a 27-year-old man with human immunode-

ficiency virus (HIV) on active antiretroviral therapy
who presents to the burn ICU from an outside
hospital with 30% total body surface area (TBSA)
epidermolysis of his back and upper arms sugges-
tive of toxic epidermal necrolysis (TEN), likely
from sulfamethoxazole/trimethoprim. Reportedly,
A.C. arrived at the outside hospital about 6 hours
ago with less than 10% TBSA involvement. Vital
signs include heart rate 142 beats/minute, respira-
tory rate 30 breaths/minute, and blood pressure
100/50 mm Hg. Which would be the best initial
pharmacotherapeutic intervention?
A. Administer high-dose corticosteroids to halt the
progression of TEN.
B. Initiate crystalloid resuscitation for
hypovolemia.
C. Place a nasogastric tube to administer antiretro-
viral medications.
D. Initiate broad-spectrum antibiotic prophylaxis
for wound infection.
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I. VENTILATOR-ASSOCIATED PNEUMONIA
A. Epidemiology
1. About 90% of hospital-acquired pneumonia episodes in critically ill patients occur during mechanical
ventilation. Mechanical ventilation is an independent risk factor for pneumonia.
2. The incidence of pneumonia increases with the duration of mechanical ventilation. From 9% to 27%
of mechanically ventilated patients develop pneumonia. In 2012 – the most recent report that includes
3. pneumonia –the National Healthcare Safety Network (NHSN) reported mean VAP rates across the adult
critically ill populations as 0.7–4.4 episodes per 1000 mechanical ventilator-days.
4. The risk of developing VAP is highest during the first 5 days of mechanical ventilation. Individual risk
factors for VAP include underlying chronic lung disease, acute lung injury, aspiration, coma, trauma
(e.g., chest trauma; traumatic brain injury), burns, reintubation, and overall severity of illness.
5. VAP accounts for more than 50% of antibiotic use in critically ill patients and has an attributable cost of
more than $40,000 per episode.
6. VAP has an estimated attributable mortality of 10%–50%, which varies among critically ill populations.
B. Classification and Etiology

1. VAP is a distinct type of hospital-acquired pneumonia that occurs more than 48 hours after endotracheal
intubation. VAP is further classified by the Centers for Disease Control and Prevention (CDC) as a
ventilator-associated event and infection-related ventilator-associated complication. Updated guidelines
from the IDSA for the diagnosis and management of VAP were published in 2016. Please see Table 2 at
the end of this section for summary and comparison with 2005 guidelines.
2. VAP is usually caused by bacterial pathogens; may be monomicrobial or polymicrobial, but is rarely
caused by viral or fungal pathogens.
3. The prevalence of specific bacterial pathogens varies between critically ill patient populations, geographic
region, and local antibiotic usage patterns. Risk factors for multidrug-resistant organisms (MDROs) are
summarized in Box 1.
4. Classification of VAP as early onset (within the first 2–4 days of hospitalization) or late onset (after 5
days or more of hospitalization) to differentiate between suspected pathogens is no longer recommended.
However, longer duration (e.g., 5 days) of hospitalization before the onset of VAP is associated with
nosocomial and MDRO pathogens.
Box 1. Risk Factors for MDROs Causing VAP

Prior intravenous antibiotic therapy in preceding 90 days
Acute renal replacement therapy before VAP onset
5 or more days of hospitalization before to the occurrence of VAP
Septic shock at the time of VAP
ARDS preceding VAP
MDRO = multidrug-resistant organism.
C. Prevention
1. VAP is considered a reportable and preventable complication of endotracheal intubation and mechanical
ventilation.
2. Data are emerging on effective prevention strategies.
3. Recommended best practices for preventing VAP include:
a. Avoid or limit the duration of endotracheal intubation.
b. Minimize duration and deep levels of sedation to promote assessment of readiness to extubate.
639
c. Maintain and improve physical conditioning while mechanically ventilated.

d. Minimize pooling of secretions above the endotracheal tube cuff.
e. Elevate head of bed at least 30 degrees.
f. Maintain integrity of mechanical ventilator circuit.
D. Diagnosis
1. The diagnostic approach for VAP includes (1) determining whether clinical signs and symptoms are
caused by pneumonia and (2) if pneumonia is present, identifying the causative pathogen(s), preferably
using lower respiratory tract culture.
2. About half of mechanically ventilated patients with a clinical suggestion of pneumonia will have
bacteriologically confirmed pneumonia.
3. Clinical signs and symptoms of pneumonia include new or changing infiltrate on chest radiograph and
at least two of the following:
a. a. Elevated WBC
b. b. Fever (e.g., temperature greater than 100.4°F [38°C])
c. c. Macroscopically purulent sputum production
d. d. Impaired or worsening oxygenation
4. Lower respiratory tract cultures can be obtained through noninvasive or invasive techniques and reported
as qualitative, semiquantitative, or quantitative.
a. Quantitative (expressed as colony-forming units per milliliter) and semiquantitative (expressed as
rare/few to many) cultures using recommended diagnostic growth thresholds are more specific than
qualitative cultures for identifying the causative pathogen.
b. Noninvasive techniques: Tracheal aspirate from endotracheal or tracheostomy tube – proximal to
distal sampling (depending on depth of sample) of upper airway secretions; usually semiquantitative
c. Invasive techniques
i. Blind, catheter-directed, or bronchoscopic BAL – Distal sampling of lung lobe/segment using
saline lavage; significant quantitative growth threshold above 10,000 or 100,000 CFU/mL
ii. Bronchoscopic protected specimen brush – Distal sampling of specific bronchial segment;
significant quantitative growth threshold above 1000 CFU/mL
5. The suggested diagnostic strategy for VAP includes clinical suspicion and use of noninvasive sampling
with semiquantitative cultures to diagnose VAP, rather than invasive sampling or noninvasive sampling
with quantitative cultures.
a. If an invasive strategy with quantitative cultures is used, it is suggested that antibiotics be withheld
rather than continued if quantitative culture results are below the diagnostic threshold for VAP (i.e.,
PSB < 1,000 cfu/mL; BAL < 10,000 cfu/mL).
E. Treatment
1. Antibiotic therapy for VAP is empiric or definitive.
2. Antibiotic selections should include intravenous agents able to achieve relevant lung concentrations
related to pathogen minimum inhibitory concentration (MIC) dosed optimally using evidence-based
pharmacokinetic and pharmacodynamic principles.
3. Empiric antibiotic therapy should be initiated in patients with clinical suspicion for VAP (Table 1).
Patients with septic shock should receive antibiotics within 1 hour from onset of hypotension (see Sepsis
chapter).
a. Inappropriate empiric antibiotic therapy for VAP (delay in or absence of antibiotics active against
identified causative pathogen[s]) is associated with increased mortality.
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b. To decrease the likelihood of inappropriate therapy, empiric antibiotic selections should be based on:
i. Presence of MDRO risk factor
ii. Local VAP pathogen prevalence, particularly MRSA
iii. Local antibiotic susceptibility patterns (i.e., ICU-specific antibiogram)
c. All patients with suspected VAP should receive an antibiotic active against MSSA and P. aeruginosa.
i. Suggest prescribing two antipseudomonal antibiotics from different classes in patients with any
of the following:
(a) MDRO risk factor
(b) ICU antibiogram with greater than 10% of gram-negative isolates are resistant to an agent
being considered for monotherapy (i.e., multidrug-resistant [MDR] P. aeruginosa)
(c) ICU where local antimicrobial susceptibility rates unavailable
d. Suggest including an agent active against MRSA in patients with any of the following:
i. MDRO risk factor
ii. ICU MRSA prevalence greater than 10%–20% of S. aureus
iii. Prevalence of MRSA is not known
e. Combination antibiotic therapy using agents with similar bacterial spectra but different mechanisms
of action may be necessary to increase the likelihood of appropriate empiric antibiotic therapy for
other gram-negative pathogens.
Table 1. VAP Classifications, Associated Pathogens, and Recommended Empiric Antibiotic Therapy Based on 2016
IDSA VAP Guidelines
Likely Pathogens Recommended Empiric Antibiotic(s)a
Patients without MDRO risk factor: Single antipseudomonal agent with 90% or greater empiric activity on
local ICU antibiogram, and local MRSA prevalence is less than 10-20%
P. aeruginosa
S. pneumoniae
Haemophilus influenzae
α- and β-hemolytic Streptococcus spp. Cefepime, imipenem, levofloxacin, meropenem,
Methicillin-sensitive S. aureus (MSSA) piperacillin/tazobactam
Antibiotic-sensitive enteric gram-negative bacilli (GNB)
(e.g., E. coli; Klebsiella spp.; Enterobacter spp.; Proteus
spp.; Serratia spp.)
Patient without MDRO risk factor: Single antipseudomonal agent with less than 90% empiric activity on
local ICU antibiogram and/or local MRSA prevalence greater than 10-20%b
P. aeruginosa
Antipseudomonal β-lactamc
P. aeruginosa (aztreonam, cefepime, ceftazidime, imipenem,
Methicillin-resistant S. aureus (MRSA) meropenem, piperacillin/tazobactam)
S. pneumoniae +
Haemophilus influenzae Antipseudomonal fluoroquinolone (ciprofloxacin or
α- and β-hemolytic Streptococcus spp. levofloxacin)
Methicillin-sensitive S. aureus (MSSA) OR
Antibiotic-sensitive enteric gram-negative bacilli (GNB) aminoglycosided
(e.g., E. coli; Klebsiella spp.; Enterobacter spp.; Proteus (amikacin, gentamicin, or tobramycin)
spp.; Serratia spp.)
MRSA
Linezolid or vancomycin
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Table 1. VAP Classifications, Associated Pathogens, and Recommended Empiric Antibiotic Therapy Based on 2016
IDSA VAP Guidelines (continued)
Likely Pathogens Recommended Empiric Antibiotic(s)a
Patients with MDRO risk factor
Antipseudomonal β-lactamc
(aztreonam, cefepime, ceftazidime, imipenem,
meropenem, piperacillin/tazobactam)
P. aeruginosa
+
Methicillin-resistant S. aureus (MRSA)
Antipseudomonal fluoroquinolone (ciprofloxacin or
Acinetobacter spp.
levofloxacin)
Antibiotic-resistant enteric GNB (e.g., extended-
OR
spectrum β-lactamase [ESBL]-producing organisms)
aminoglycosided
Stenotrophomonas maltophilia
(amikacin, gentamicin, or tobramycin)
AND
Linezolid or vancomycin
a
Agents/classes are listed in alphabetic order.
b
There may be situations in which a patient has no MDRO risk factors but may meet the recommendation to receive dual antipseudomonal therapy and/or MRSA
coverage.
c
Doripenem has a U.S. Food and Drug Administration (FDA) warning against use for treatment of ventilator-associated bacterial pneumonia.
d
Guidelines suggest avoiding empiric aminoglycoside if alternative agents with activity are available.
f. Lower respiratory tract cultures should be obtained before initiation of antibiotic therapy to increase
the likelihood of identifying causative pathogen(s). Inappropriate delays in initiation of antibiotic
therapy should be avoided in unstable patients (e.g., patients with septic shock).
g. Empiric antibiotic therapy should be de-escalated to definitive therapy, depending on identified
pathogen(s) and antibiotic susceptibilities.
4. Definitive antibiotic therapy should be focused on the causative pathogen(s) identified on lower respiratory
tract culture.
a. Pathogen-specific definitive antibiotic choices should be based on antibiotic susceptibilities and, if
possible, available evidence supporting efficacy and safety in patients with VAP.
i. MRSA: Vancomycin or linezolid; daptomycin is not indicated for pneumonia because of direct
inhibition by pulmonary surfactant.
ii. P. aeruginosa
(a) Monotherapy with a β-lactam listed below and found to be susceptible on final culture
results is recommended in immunocompetent patients not in septic shock and not at a
high risk of dying. Concomitant aminoglycoside or antipseudomonal fluoroquinolone is
recommended in immunocompromised patients and those in septic shock or at a high risk
of dying. Combination therapy can be de-escalated to monotherapy β-lactam once septic
shock resolves.
(b) β-Lactams: Cefepime, ceftazidime, piperacillin/tazobactam, imipenem, or meropenem
(c) Aminoglycosides: Amikacin, gentamicin, or tobramycin
(d) Fluoroquinolones: Ciprofloxacin or levofloxacin
iii. Acinetobacter spp.: Imipenem or meropenem; ampicillin/sulbactam (sulbactam is active agent)
as alternative option
iv. Stenotrophomonas maltophilia: Sulfamethoxazole/trimethoprim
v. Extended-spectrum β-lactamase (ESBL)-producing organisms: Carbapenem (e.g., ertapenem;
imipenem; meropenem)
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b. Duration of definitive antibiotic therapy is recommended to be 7 days for all patients rather than
longer durations. Pathogen-based recommendations for duration of definitive antibiotic are no longer
indicated in VAP guidelines.
i. The PneumA trial was a pivotal noninferiority study that evaluated 8 days (7 full treatment
days) versus 15 days (14 full treatment days) for duration of definitive antibiotic therapy in
patients with bacteriologically diagnosed VAP. The primary noninferiority outcome was VAP
recurrence. All patients included in the study received appropriate empiric antibiotic therapy
(JAMA 2003;290:2588-98). Major study findings were:
(a) Definitive antibiotic therapy for 8 days was noninferior to 15 days in patients with VAP not
caused by non–lactose-fermenting gram-negative bacilli (e.g., P. aeruginosa).
(b) Patients with VAP caused by non–lactose-fermenting gram-negative bacilli in the 8-day
group more often had VAP recurrence.
(c) The rate of MDR pathogens during a recurrent VAP episode was higher in patients in the
15-day group.
ii. Two meta-analyses that included the results of the PneumA trial suggest limited benefit of
prolonged duration of definitive antibiotic therapy for treating VAP. Synopsis includes:
(a) Any increase in VAP recurrence rate is small;
(b) Mortality and clinical cure do not appear to be affected by shorter durations;
(c) Evidence for recurrence from subgroup analyses has important limitations.
iii. Guidelines acknowledge that situations may exist in which shorter or longer durations of
definitive antibiotic therapy may be indicated, depending on the rate of clinical and radiologic
improvement.
5. Response to antibiotic therapy should be assessed serially using clinical signs and symptoms of infection
and status of VAP-related organ dysfunction.
a. Lack of response in signs and symptoms of VAP beyond treatment day 3 necessitates reassessment
of diagnosis, causative pathogen(s), antibiotic regimen, and presence of pneumonia-related
complications (e.g., ARDS).
b. Patients thought to have persistent VAP should undergo repeat lower respiratory tract culture and
receive empiric antibiotic therapy considering previous pathogen(s) and antibiotic exposure.
Table 2. Summary of Key Changes in 2016 IDS VAP Guidelines

Characteristic 2005 Guidelines 2016 Guidelines
GRADE criteria to identify “recommended”
Expert opinion based on level of evidence (strong) or “suggested” (weak) guidance based
Methodology
ranging from Level I (high) to III (low) on level of evidence categories “very low,” “low,”
“moderate,” and “high quality”
Suggest clinical suspicion with noninvasive
sampling and semiquantitative cultures
Diagnosis Clinical strategy or bacteriologic strategy If invasive sampling is used, suggest that
antibiotics be withheld rather than continued
if quantitative culture results are below the
diagnostic threshold for VAP
No longer differentiate VAP episodes based on
time from hospital admission
Classification Early onset or late onset Emphasis on local risk assessment for P.
aeruginosa and MRSA occurring early in
hospitalization
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Table 2. Summary of Key Changes in 2016 IDS VAP Guidelines (continued)

Characteristic 2005 Guidelines 2016 Guidelines
• Antibiotic therapy in preceding 90 days
• Chronic dialysis within 30 days
• Current hospitalization of 5 days or
• Prior intravenous antibiotic therapy in
more
preceding 90 days
• Home chronic wound care
• Acute renal replacement therapy before VAP
• Home infusion therapy
onset
MDRO Risk • Hospitalization in the preceding 90
• 5 or more days of hospitalization before the
Factors days
occurrence of VAP
• Immunosuppressive disease and/or
• Septic shock at the time of VAP
therapy
• ARDS preceding VAP
• Known contact or colonization with
MDROs
• Residence in a nursing home or
extended-care facility
Recommend coverage for MSSA, P. aeruginosa,
and other gram-negative bacilli in all empiric
regimens.
Suggest including an agent active against MRSA if
any of the following:
Categorized based on early onset or late
• MDRO risk factor for antimicrobial resistance
onset and presence of MDRO risk factor
• ICU MRSA prevalence greater than 10%-20%
• Early onset without MDRO risk
of all S. aureus
factor: no antipseudomonal or MRSA
Empiric Therapy • Prevalence of MRSA is not known
coverage
• Late onset or early onset with MDRO Suggest prescribing dual antipseudomonal antibi-
risk factor: dual antipseudomonal and otics from different classes if any of the following:
MRSA coverage • MDRO risk factor for antimicrobial resistance
• ICUs with greater than 10% of gram-negative
isolates are resistant to an agent being
considered for monotherapy
• ICU where local antimicrobial susceptibility
rates unavailable
Suggest avoiding if alternative agents with
Aminoglycosides No specific recommendation
adequate gram-negative activity are available
Suggest avoiding if alternative agents with
Colistin No specific recommendation
adequate gram-negative activity are available
In patients who received appropriate Recommend 7 days rather than longer durations
Duration of empiric antibiotic therapy: regardless of pathogen
Definitive • Non–lactose-fermenting Gram negative Suggest using procalcitonin plus clinical criteria
Therapy bacilli: 14 days to guide discontinuation of antibiotic therapy,
• All other pathogens: 7 days rather than clinical criteria alone
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Patient Cases
1. C.T. is a 48-year-old man sustaining a 40% TBSA burn to his left side with likely inhalational injury requir-
ing mechanical ventilation. C.T. has been in the ICU for 7 days. Overnight, C.T. had a temperature of 102.1°F
(38.9°C), a WBC of 18 x 103 cells/mm3, and an increase in macroscopically purulent sputum production; C.T.
is hemodynamically stable with no signs of new-onset organ dysfunction. C.T.’s chest radiograph is difficult
to assess, given his inhalational injury. The respiratory therapist was asked by the fellow to do a catheter-
directed BAL for suspected VAP. The culture was sent to the microbiology laboratory. Which would be best
to do at this point?
A. Initiate broad-spectrum empiric antibiotic therapy for suspected MDR VAP.
B. Use Gram stain results to determine empiric antibiotic regimen.
C. Await preliminary quantitative culture results before initiating empiric antibiotic therapy.
D. Send blood and urine cultures, and await their results before initiating empiric antibiotic therapy.
2. C.P. is a 67-year-old woman with a medical history significant for chronic obstructive pulmonary disease
(COPD), type 2 diabetes, and coronary artery disease. She is readmitted to the ICU with respiratory failure
requiring intubation secondary to severe COPD. C.P. had a 10-day hospitalization 12 days ago, during which
time she received intravenous azithromycin for a COPD exacerbation. On day 4 of this readmission, a wors-
ening infiltrate is in the left lower lung base with increased sputum production from admission, maximum
temperature is 101.9°F (38.8°C), and there is worsening oxygenation, despite previous improvement in initial
COPD exacerbation. The patient is thought to have clinical VAP, and a semiquantitative tracheal aspirate
is sent to identify causative pathogen(s). The local ICU prevalence of MRSA is 30%, and the most active
β-lactam antibiotic against P. aeruginosa on the antibiogram has 80% activity. Which empiric antibiotic
regimen is best for this patient?
A. Azithromycin plus moxifloxacin.
B. Cefepime plus tobramycin, and vancomycin.
C. Ceftriaxone plus azithromycin.
D. Linezolid plus tobramycin.
3. K.L., a 37-year-old man who presents after a motorcycle collision, has sustained several orthopedic and
chest injuries. K.L. has been mechanically ventilated for 8 days, during which time he was given a diagno-
sis of VAP caused by Klebsiella pneumoniae. K.L. received appropriate empiric antibiotic therapy and has
improved oxygenation, decreased WBC temperature curve. Which would be the best duration of definitive
antibiotic therapy for K.L.’s VAP?
A. 48 hours after resolution of clinical signs and symptoms.
B. 7 days.
C. 10 days.
D. 14 days.
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II. CENTRAL LINE–ASSOCIATED BLOODSTREAM INFECTIONS
A. Epidemiology
1. Critically ill patients commonly require short-term (less than 14 days per catheter) or temporary (non-
tunneled or non-implanted) placement of a CVC or central line for medication administration and
hemodynamic support and monitoring.
2. More than 40,000 bloodstream infections a year are associated with central catheter placement.
3. In 2012, the NHSN reported rates of CLABSI across adult critically ill populations of 0.8–3.4 episodes
per 1000 central line–days. Although specific rates vary, all central line types and locations of insertion
have an attributable risk of bloodstream infection.
4. Established risk factors for CLABSI include:
a. Excessive manipulation of the catheter during and after insertion
b. Internal jugular or femoral insertion site
c. Microbial colonization at the insertion site or catheter hub
d. Neutropenia
e. Prolonged duration of catheterization
f. Prolonged hospitalization before catheterization
g. Total parenteral nutrition
5. The attributable cost of a CLABSI is up to $40,000 per episode.
B. Definitions
1. Central or peripheral venous catheters are defined by the location at which the distal tip of the catheter
terminates. CVCs terminating in a great vessel are considered part of the central blood circulation.
The distal tip of a CVC usually resides in the inferior, superior, or distal vena cava, right atrium, or
pulmonary artery (e.g., pulmonary artery catheter).
2. CVCs are usually inserted into the central venous system using the internal or external jugular, subclavian,
femoral, or iliac veins. There are several types of short-term CVCs:
a. Single- and multiple-lumen (e.g., triple lumen) catheters: Most commonly used CVC
b. Catheter introducer: Used for massive resuscitation or facilitation of pulmonary artery catheter
insertion
c. Peripherally inserted central catheter (PICC): Short- or medium-term central catheter inserted in a
peripheral vein (e.g., cephalic, basilic, or brachial veins)
d. Pulmonary artery catheter: A central catheter of around 100 cm used for invasive hemodynamic
monitoring
3. Primarily for surveillance, the CDC defines CLABSI as a primary laboratory-confirmed bloodstream
infection occurring no sooner than 2 calendar days from catheter placement and no later than the day
after catheter removal. Laboratory-confirmed bloodstream infection is defined as either:
a. A recognized pathogen (i.e., not a common commensal organism) cultured from one or more blood
cultures, and the organism cultured from blood is not related to an infection at another site, or
b. A common commensal organism (e.g., diphtheroids, Bacillus spp., coagulase-negative staphylococci,
viridans streptococci) cultured from two or more blood cultures drawn on separate occasions, and
the organism cultured from blood is not related to an infection at another site, and patient has at
least one of the following signs or symptoms: fever (temperature greater than 100.4°F [38°C]), chills,
or hypotension
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4. The Infectious Diseases Society of America (IDSA) defines a catheter-related bloodstream infection as
minimally bacteremia or fungemia in a patient who has an intravascular device and:
a. More than one positive blood culture obtained from a peripheral vein. A definitive diagnosis requires
that the same organism(s) grow from at least one percutaneous blood culture and from the CVC tip
or that two blood cultures, one from a catheter hub and one from a peripheral vein, are positive for
the same organism(s).
b. Clinical manifestations of infection (e.g., fever, chills, and/or hypotension), and
c. No apparent source for bloodstream infection other than the catheter
C. Etiology
1. CLABSIs are usually monomicrobial. Pathogen prevalence is based on patient-specific risk factors and
underlying illness.
2. Common organisms responsible for CLABSIs include coagulase-negative staphylococci (e.g.,
Staphylococcus epidermidis), S. aureus, Candida spp., and enteric gram-negative bacilli (e.g., E. coli,
Klebsiella spp., Enterobacter spp.).
3. Risk factors for MDROs include critical illness, femoral catheter placement, immunosuppression, and
previous antibiotic exposure.
4. Candida spp. are more common in patients with the following risk factors: total parenteral nutrition,
prolonged exposure to broad-spectrum antibiotics, hematologic malignancy, stem cell or solid-organ
transplantation, femoral site of catheterization, or colonization owing to Candida spp. at several sites.
D. Prevention
1. CLABSI is considered a preventable complication. The NHSN, using CDC definitions, provides
population-specific event rates for institution surveillance and performance benchmarks.
2. The foundation for preventing CLABSI includes training and education, proper aseptic insertion
techniques, and active surveillance and performance improvement systems.
3. Recommended best practices for preventing CLABSI have been proposed and endorsed by the IDSA, the
Society for Healthcare Epidemiology of America (SHEA), and the Joint Commission. These evidence-
based recommendations are categorized as basic practices for all acute care hospitals or special practices
wherein basic practices are less than effective at reducing CLABSI rates. The entire document is available
(Infect Control Hosp Epidemiol 2014;35:753-71). Major recommendations include:
a. Basic practices
i. Minimize central venous line insertions and durations of insertion.
ii. Provide comprehensive education to and ensure competency for all involved with insertion,
care, and maintenance of CVC.
iii. Daily chlorhexidine baths for patients to reduce colonization
iv. Use of a systematic process or checklist at the time of insertion to ensure adherence to proper
insertion technique
v. Alcohol-based chlorhexidine skin cleanser for the site during insertion
vi. Handwashing during insertion, care, and maintenance of the catheter
vii. Cleanse catheter hubs before accessing.
viii. Routine post-insertion site care
ix. Limit prolonged use of intravenous tubing sets.
b. Special practices
i. Use antiseptic or antimicrobial-impregnated catheters.
ii. Chlorhexidine-containing site/catheter dressings
iii. Use antiseptic hub cover or port protector.
iv. Antimicrobial lock therapy
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E. Diagnosis
1. Clinical signs and symptoms of infection have poor sensitivity and specificity. Fever is the most sensitive
clinical finding, whereas inflammation or purulence at the insertion site is the most specific.
2. If a CLABSI is suspected, paired blood cultures drawn from the catheter (at least one hub/port) and from
a peripheral vein should be obtained. The individual bottles should be appropriately marked through the
culture-reporting period.
a. If a blood culture cannot be drawn from a peripheral vein, it is recommended that at least two blood
cultures be obtained through different catheter hubs/ports.
b. Blood cultures positive for S. aureus, coagulase-negative staphylococci, or Candida spp. that are not
attributable to another source should increase the suggestion of CLABSI.
c. Blood cultures should be obtained before initiation of antimicrobial therapy, as appropriate.
3. A definitive diagnosis of CLABSI requires positive percutaneous blood culture results with positive
culture of same pathogen from the catheter tip or catheter-drawn cultures.
F. Treatment
1. Catheter removal should be considered in all patients with a confirmed CLABSI. If a CVC is still
necessary, a different anatomic site should be used. Changing to a new catheter at the same site using a
guidewire or catheter introducer should be avoided.
2. Antimicrobial therapy for CLABSI is empiric or definitive.
3. Inappropriate empiric antimicrobial therapy is associated with increased mortality, including bacterial
and fungal etiologies.
a. Empiric antimicrobial therapy should minimally include an agent active against methicillin-resistant
coagulase-negative (e.g., methicillin-resistant S. epidermidis [MRSE]) or coagulase-positive (e.g.,
MRSA) staphylococci. Vancomycin or daptomycin are preferred; linezolid should not be used for
empiric management of CLABSI.
b. Pathogen-specific risk factors, documented colonization, and previous antimicrobial exposure
should be considered when choosing empiric antimicrobial therapy.
i. Patients at risk of MDROs should receive combination therapy against gram-negative bacilli
using agents from separate antibiotic classes.
ii. Use of an echinocandin (e.g., anidulafungin, caspofungin, or micafungin) should be considered
for patients at risk of candidemia. Fluconazole is reasonable in patients without recent exposure
to and low prevalence of nonsusceptible species.
c. Local antimicrobial activity should be considered to increase the probability of appropriate therapy.
d. Empiric antimicrobial therapy should be de-escalated, depending on the identified pathogen(s) and
related antimicrobial susceptibility. Antimicrobial therapy should be discontinued if a CLABSI is
not evident and there are no other sources of infection.
4. Definitive management and antimicrobial therapy should be based on whether the CLABSI is complicated
or uncomplicated and the identified pathogen(s). Ongoing clinical trials may provide guidance to the
optimal duration of antibiotic therapy for CLABSI and non–central line-associated bacteremia (e.g.,
BALANCE Trial. Trials 2015;16:173.).
a. The duration of antimicrobial therapy should be based on the first day of negative blood culture.
b. Complicated CLABSI
i. Endocarditis; immunosuppression (S. aureus only); diabetes (S. aureus only); chronic
intravascular hardware; osteomyelitis; positive blood cultures greater than 72 hours from
initiation of appropriate therapy; septic thrombus; thrombophlebitis
ii. Remove catheter.
iii. Treat with pathogen-targeted antimicrobial therapy for 4–6 weeks; 6–8 weeks for osteomyelitis.
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c. Uncomplicated CLABSI
i. Coagulase-negative staphylococci
(a) Consider catheter removal. If catheter is retained, consider antibiotic lock therapy in
addition to systemic antibiotic therapy.
(b) Treat with systemic antibiotic therapy for 5–7 days.
ii. S. aureus
(a) Remove catheter.
(b) Treat with systemic antibiotic therapy for a minimum of 14 days.
(1) Methicillin-sensitive S. aureus (MSSA) – Penicillinase-resistant penicillin (e.g.,
nafcillin); first-generation cephalosporin (e.g., cefazolin)
(2) MRSA – Vancomycin; daptomycin or linezolid; sulfamethoxazole/trimethoprim
(c) Patients with catheter tip bacterial growth but negative blood cultures should receive
antibiotic therapy for 5–7 days with close monitoring for signs and symptoms of ongoing
infection and consideration for repeat blood cultures.
iii. Enterococcus spp.
iv. Gram-negative bacilli
v. Candida spp.
(b) Treat with systemic antifungal therapy for at least 14 days.
Patient Cases
4. T.W. is a 47-year-old woman admitted to the MICU with respiratory failure secondary to severe 2009 H1N1
influenza infection. T.W., who requires intubation and mechanical ventilation, is given a diagnosis of septic
shock associated with influenza and a secondary MSSA pneumonia. An internal jugular vein CVC was
placed in the ED during acute resuscitation. T.W. continues to require a CVC. Although her hypotension and
fever resolved 72 hours post-admission, she has a new temperature of 101.7°F (38.7°C) with worsening leu-
kocytosis on ICU day 5; there is no change on her chest radiograph. Which action would be best to take next?
A. Initiate broad-spectrum antibiotic therapy for a new sepsis episode.
B. Perform bronchoscopic BAL for suspected VAP.
C. Remove CVC.
D. Send two sets of blood cultures, one from the catheter and one from a peripheral blood sample.
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Patient Cases (continued)
Questions 5 and 6 pertain to the following case.

F.P. is a 29-year-old man admitted to the MICU from another hospital with severe, alcohol-induced, sterile acute
pancreatitis. During his 5-day stay at the outside hospital, he had multiple organ failure, including respiratory
failure requiring tracheostomy. A right internal jugular CVC was placed on the patient’s admission to the outside
hospital. On MICU day 3, F.P. has a maximum temperature of 102°F (38.9°C). Two sets of blood cultures are
obtained; the right internal jugular catheter is removed and the tip sent for culture.
5. Which regimen would be best to consider for empiric management of a suspected CLABSI?
A. Daptomycin and ceftriaxone.
B. Fluconazole.
C. Linezolid and cefepime.
D. Vancomycin, cefepime, and tobramycin.
6. F.P. is found to have K. pneumoniae CLABSI and receives appropriate empiric antibiotic therapy. He has
had a good clinical response with no persistence of bacteremia. Which represents the best duration of F.P.’s
definitive antibiotic therapy for CLABSI?
A. 5 days.
B. 14 days.
C. 21 days.
D. 4 weeks.
III. INFLUENZA
A. Epidemiology
1. Influenza is a seasonal viral illness affecting all ages and associated with significant morbidity and
mortality. Seasonal patterns in the United States vary from year to year. The 2008–2009 influenza
season started in November 2008 and waned by April 2009, but then, because of influenza A H1N1
(2009 H1N1), it resurged in May 2009, peaking in mid-October 2009 and persisting to April 2010. The
2015–2016 season spanned late November 2015 through late June 2016.
2. Up to 400,000 patients a year in the United States are hospitalized with influenza-related illness.
During the 2016–2017 season (as of 4/29/2017), the reported overall rate (per 100,000 population) of
hospitalization for laboratory-confirmed influenza was 65.2 (2.1-fold higher than the 2015–2016 season),
ranging from 20.0 for adults 18–49 years of age to 291.1 for those 65 years or older. Around 16.9% of
hospitalizations required ICU admission, which is similar to the past 5 influenza seasons (range: 2014-
2015, 15.0% to 2013–2014, 22.3%).
3. Risk factors for severe influenza requiring hospitalization include chronic respiratory or metabolic
illness, immunosuppression (disease or pharmacotherapy), pregnancy, and age older than 65 years.
In 2009, reemergence of the high-virulence strain influenza A H1N1 (pandemic 2009 H1N1) caused
significant morbidity and mortality in young adults and other groups considered at a lower risk of severe
influenza. The pandemic 2009 H1N1 strain continues to be tracked and varies significantly from year-
to-year. During the 2013–2014 season, 2009 H1N1 was implicated in up to 50% of cases, while it was
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associated with fewer than 2% of cases in 2014–2015. This strain was responsible for nearly 54% of
influenza cases in 2015–2016 and just over 2% in 2016-2017.
4. The most common complications of severe influenza include hypoxemic respiratory failure, bacterial
pneumonia, and ARDS. Concomitant sepsis, septic shock, multiple organ failure, encephalopathy, and
rhabdomyolysis also are associated with severe influenza.
5. Among all causes of deaths in the United States, pneumonia and influenza have surpassed the epidemic
threshold since 2009, with rates close to 10% during the peak of influenza seasons. Severe influenza
caused by the 2009 H1N1 strain has been associated with crude mortality rates of 15%–53%.
B. Etiology
1. Influenza is caused by the RNA viruses influenza A, B, or C, which usually spread through droplet
transmission. Influenza A and B viruses are the predominant causes of clinically significant illness.
Influenza virus subtypes are described by surface proteins hemagglutinin (H) and neuraminidase (N).
2. Influenza A has been the most prevalent cause of influenza since 2009, with 2009 H1N1 and H3 being
the most prevalent influenza A subtypes. Influenza B prevalence has varied during the same period, but
it remains an important cause of illness. Strain prevalence during the 2016–2017 season (as of June 2016)
has been 76% for influenza A H3, 22% for influenza B, 2.2% for influenza A 2009 H1N1, and less than
1% for non-specified subtypes of influenza A.
3. Influenza viruses can cause a broad range of respiratory tract infections, ranging from mild to moderate
upper respiratory tract infections to severe pneumonia. Influenza infection has been associated with
acute viremia.
C. Prevention
1. Annual vaccination remains the primary tool for influenza prevention.
2. In-hospital and ICU outbreaks of influenza can contribute to viral transmission and associated sequelae.
3. Institutions should begin implementing influenza screening and infection control measures when
influenza viruses are confirmed to be in the local community.
4. The CDC recommends the implementation of droplet precautions for hospitalized patients with suspected
or confirmed influenza; further, these precautions are recommended for 7 days after illness onset or until
24 hours after the resolution of fever and respiratory symptoms, whichever is longer.
D. Diagnosis
1. Patients with influenza may present with fever, myalgias, headache, malaise, dry cough, pharyngitis, and
rhinorrhea. Fever and myalgias generally last 3–5 days, whereas malaise and respiratory symptoms may last
2 weeks or more. Patients with severe influenza may present with hypoxemic respiratory failure and sepsis.
2. Clinical signs and symptoms of influenza are nonspecific. To confirm the diagnosis of influenza,
sampling of the upper respiratory tract using nasal washing or nasopharyngeal swab or lower respiratory
tract within 5 days of illness is preferred. Diagnostic tests obtained beyond 5 days may have false-
negative results.
3. Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase
chain reaction (PCR), and immunofluorescence assays.
a. Viral culture and reverse transcription polymerase chain reaction (RT-PCR) are the most sensitive
and are the only tests able to identify individual influenza subtypes. These tests can be performed
using nasopharyngeal swab or respiratory tract culture (e.g., sputum, BAL).
b. Rapid diagnostic tests of nasopharyngeal swab or nasal wash have high specificity (90%–95%) (i.e.,
low false-positive rate and rapid turnaround), promoting these tests as first line for general diagnosis.
Depending on the rapid diagnostic assay used, differentiation between influenza A and influenza B
is possible, although further subtype identification is not available with these tests. Because of poor
sensitivity, negative rapid diagnostic tests should be followed up with viral culture or RT-PCR.
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4. Case definitions for influenza surveillance are suspected, probable, or confirmed based on patient
presentation and laboratory assessment.
a. Suspected – Mild to severe influenzalike illness within reasonable seasonal threshold.
b. Probable – Mild to severe influenzalike illness within reasonable seasonal threshold or after recent
contact with person with probable or confirmed influenza infection and not otherwise explained.
c. Confirmed – Mild to severe influenzalike illness with confirmatory laboratory tests indicating
presence of influenza A or B.
E. Management and Treatment

1. Management of critically ill patients with influenza includes treatment of primary influenza infection,
secondary bacterial infection(s), and related noninfectious complications (e.g., respiratory failure, ARDS,
prolonged mechanical ventilation, multiple organ failure). Management of common bacterial infections
and noninfectious complications is described in other chapters.
a. Diagnostic tests for influenza should be obtained and empiric antiviral treatment of influenza
initiated during seasonal outbreaks in critically ill patients presenting with acute febrile and
respiratory illness consistent with influenza. Severely ill patients with influenza may present with
hypothermia similar to other populations with sepsis. Accompanying severe hypoxemic respiratory
failure should heighten the concern for influenza.
b. Antiviral treatment (Table 3) should be initiated within 48 hours from onset of symptoms.
Hospitalized patients receiving antiviral therapy after 48 hours from symptom onset may benefit.
c. Neuraminidase inhibitors have emerged as the mainstay of antiviral therapy for recent influenza A
and B strains. These agents inhibit viral neuraminidase, decreasing the release of post-replication
viral particles (virions) from infected cells, limiting spread to additional tissues. Neuraminidase
inhibition may also suppress the initiation of infection after acute inoculation.
i. Oseltamivir phosphate is an oral (capsule, powder for suspension) ethyl ester prodrug converted
through hepatic ester hydrolysis to the active form oseltamivir carboxylate. Oseltamivir can
be administered to critically ill patients by orogastric or nasogastric tube. An intravenous
formulation of oseltamivir has been tested in early clinical trials.
ii. Zanamivir is available on the market as an orally inhaled drug delivered by a Diskhaler
device. Intravenous zanamivir is available for patients with severe influenza through clinical
trial participation or emergency investigational new drug through the manufacturer. Use of
intravenous zanamivir should be considered in patients who cannot tolerate or absorb oseltamivir
because of suspected or known gastric stasis, malabsorption, or GI bleeding.
iii. Peramivir is an intravenous neuraminidase inhibitor with activity against influenza A and B.
Peramivir was approved in December 2014 for use in patients 18 years or older with acute
uncomplicated influenza. Peramivir is administered as a single 15-minute intravenous infusion.
d. Adamantanes inhibit the replication of influenza A viruses by preventing viral assembly.
Adamantanes also interfere with the function of the transmembrane domain of the viral M2 protein,
preventing release of viral particles into host cells.
e. Susceptibility of influenza to available antiviral agents varies from year to year and between strains
and subtypes. Local surveillance of susceptibility patterns at the beginning and throughout a
respective season is imperative to provide appropriate therapy.
i. In the 2016–2017 season, 100% of tested influenza A (2009 H1N1 and H3) and B viruses were
susceptible to oseltamivir, peramivir, and zanamivir.
ii. High levels of resistance to the adamantanes (amantadine and rimantadine) persisted among
circulating influenza A viruses. The adamantanes are not effective against influenza B viruses.
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Table 3. Influenza-Specific Pharmacotherapy

Influenza Half- Treatment Adverse
Agent Bioavailability Comments
Activity life (hr) Dosage Effects
75 mg twice a Dosage adjustment
day for 5 daysa; for renal impairment
up to 150 mg may be necessary;
Orally or Nausea,
Oseltamivir twice a day patients requiring
A and B OG/NG tube: 6–10 vomiting,
carboxylate has been used continuous renal
> 75% delirium
in patients replacement therapy
with severe should receive
influenza normal dosing
Dosage adjustment
recommended
A and B;
in patients with
limited
Diarrhea, creatinine clearance
clinical trial
600 mg once hypersensitiv- below 50 mL/
Peramivir experience IV: 100% 20
for 15 minutes ity reactions, min; should be
for
delirium administered
Influenza B
after dialysis in
strains
patients receiving
hemodialysis
Not recommended in
Allergic
patients with chronic
reactions,
Inhaled: Up to lung disease or
10 mg twice a diarrhea,
Zanamivir A and B 17% 2.5–5 severe influenza; not
day for 5 daysa nausea,
IV: 100% available for delivery
headache,
through mechanical
dizziness
ventilator circuit
Nausea,
dizziness,
insomnia, High resistance to
100 mg twice
Amantadine A only 70%–100% 15–17 lower seizure current influenza A
a day
threshold, strains
anticholinergic
effects
Dizziness,
High resistance to
nausea,
100 mg twice current influenza
Rimantadine A only > 90% 24–35 vomiting;
a day A strains; limited
anticholinergic
market availability
effects
a
Longer durations of up to 14 days may be needed for severely ill patients.
IV = intravenous(ly); NG = nasogastric; OG = orogastric.
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2. Response to antiviral therapy should be assessed throughout treatment using clinical signs and symptoms
of infection. Development of oseltamivir resistance during therapy has been reported, but this is rare.
If suggested through local surveillance, therapy should be switched to zanamivir by the appropriate
administration route. Improvement in infectious and noninfectious complications may be delayed,
despite resolution of primary influenza infection. ARDS, in particular, may persist for days beyond
primary influenza.
Patient Cases
7. T.Y., a 32-year-old woman who has had flulike symptoms for the past 72 hours, presents to the ED from home
with severe fatigue, shortness of breath, and rigors. T.Y. has a heart rate of 120 beats/minute, mean arterial
pressure 70 mm Hg, respiratory rate 24 breaths/minute, temperature 102.7°F (39.3°C), and arterial oxygen
saturation (Sao2) of 85% on room air. Because it is in the middle of influenza season (high prevalence of
influenza A and B), a nasal swab is done and sent for rapid diagnostic testing for suspected influenza infec-
tion. Shortly thereafter, T.Y. is intubated for severe respiratory failure and admitted to the MICU. In addition
to antibiotic therapy for CAP, which would best be considered next?
A. None; the patient is outside the time window to effectively treat influenza.
B. Await rapid diagnostic test results before initiating influenza-specific therapy.
C. Give amantadine.
D. Give oseltamivir.
8. G.L. is a 25-year-old woman admitted to the medical ICU in late February this year with severe, acute
hypoxemic respiratory failure requiring mechanical ventilation. G.L. is hypotensive, requiring norepineph-
rine after fluid resuscitation, and has acute kidney injury. She is awaiting a renal consult for continuous renal
replacement therapy. A rapid diagnostic test of a nasal washing suggests influenza B, consistent with this
year’s local influenza epidemiology. A nasogastric feeding tube is placed when she is admitted to the ICU.
Which would be most appropriate to treat G.L.’s severe influenza?
A. Enteral amantadine.
B. Enteral oseltamivir.
C. Inhaled zanamivir.
D. Intravenous peramivir.
IV. CATHETER-ASSOCIATED URINARY TRACT INFECTIONS
A. Epidemiology
1. Urinary catheters are commonly used in critically ill patients, with documented use of 50%–80% of
adult critically ill patient-days. Urinary catheters most often used are short term (less than 30 days)
temporary indwelling or intermittent urethral catheters. Other catheters include suprapubic catheters or
external collection catheters (e.g., condom catheters). Presence of an indwelling urinary catheter is an
independent risk factor for urinary tract infection (UTI).
2. CAUTIs are the most common cause of infection in critically ill patients. In 2012, the incidence (cases
per 1000 catheter-days) of CAUTIs varied among acute care critically ill populations and ranged from
1.2 for medical/surgical patients to 4.7 for burn patients.
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3. CAUTIs account for 15%–21% of hospital-acquired bacteremias.

4. The attributable mortality for CAUTI is 0%–15%.
B. Definitions
1. CDC adult surveillance definitions
a. UTI – At least one of the following signs or symptoms: Fever (temperature greater than 100.4°F
[38°C]); suprapubic tenderness; or costovertebral angle pain or tenderness and one of the following:
i. A positive urine culture of 105 CFU/mL or more of no more than two species of microorganisms
ii. At least one of the following findings: Positive dipstick for leukocyte esterase and/or nitrite,
pyuria (urine specimen with at least 10 white blood cells/mm3 of unspun urine or greater than
5 white blood cells/high-power field of spun urine), or microorganisms seen on Gram stain of
unspun urine and a positive urine culture of 103–105 CFU/mL of no more than two species of
microorganisms
b. CAUTI – A UTI in which an indwelling urinary catheter was in place for greater than 2 days and
attributable to the catheter removed no more than 1 day before infection
2. IDSA adult definitions
a. Catheter-associated asymptomatic bacteruria – Patients with indwelling urethral, indwelling
suprapubic, or intermittent catheterization (or condom catheter in a man) is defined by the presence
of 105 CFU/mL or greater of one or more bacterial species in a single catheter urine specimen in a
patient without symptoms compatible with UTI
b. CAUTI – In patients with indwelling urethral, indwelling suprapubic, or intermittent catheterization,
CAUTI is defined by the presence of symptoms or signs compatible with a UTI with no other
identified source of infection, together with 103 CFU/mL or more of one bacterial species in a
single catheter urine specimen or in a midstream-voided urine specimen from a patient whose
urethral, suprapubic, or condom catheter has been removed within the previous 48 hours. Lower
colony counts are more likely to represent significant bacteriuria in a symptomatic person than in
an asymptomatic person.
C. Etiology
1. Most pathogens causing CAUTIs are acquired from the external environment, including the urethra, the
catheter collection system, and local skin flora. Most short-term catheter CAUTIs are monomicrobial.
Longer duration of an indwelling catheter is associated with the formation of biofilms within the catheter
and related system, which can promote polymicrobial infections.
2. E. coli is the most prevalent pathogen causing CAUTIs; however, because of a wider distribution of
pathogens compared with non–catheter-associated UTIs, E. coli accounts for only about one-third of
CAUTIs. Additional bacterial pathogens include other enteric gram-negative bacilli (e.g., Klebsiella spp.;
Proteus spp.; Enterobacter spp.), non–lactose-fermenting gram-negative bacilli (e.g., P. aeruginosa), and
gram-positive cocci (e.g., Enterococcus spp.; MSSA; MRSA; MRSE). Candida spp. may be involved in
up to one-third of CAUTIs.
3. Similar to other health care–associated infections, causative pathogens are associated with local pathogen
patterns, pathogen-specific risk factors, and patient severity of illness.
D. Prevention
1. CAUTI is considered a preventable complication. The NHSN, using CDC definitions, provides
population-specific event rates for institution surveillance and performance benchmarks.
2. The most effective way to reduce the incidence of catheter-associated asymptomatic bacteruria and
catheter-associated UTI is to reduce the use of urinary catheterization by restricting its use to patients
who have clear indications and by removing the catheter as soon as it is no longer needed.
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3. The foundation for preventing CAUTIs includes training and education, proper aseptic insertion
techniques, and active surveillance and performance improvement systems.
4. Recommended best practices for preventing CAUTIs have been proposed and endorsed by IDSA, SHEA,
and the Joint Commission. These evidence-based recommendations are categorized as basic practices
for all acute care hospitals or special practices wherein basic practices are less than effective at reducing
CAUTI rates. The entire document is available (Infect Control Hosp Epidemiol 2014;35:464-79). Major
recommendations include:
a. Basic practices
i. Minimize use and duration of indwelling catheters.
ii. Provide comprehensive education to and ensure competency for all involved with insertion,
care, and maintenance of urinary catheters.
iii. Use of a systematic process or checklist at the time of insertion to ensure adherence to proper
insertion technique
iv. Handwashing during insertion, care, and maintenance of the catheter
v. Proper care and maintenance of indwelling catheter and collection system
b. Special practices
i. Daily systematic assessment of continued need for indwelling catheter
ii. Development and implementation of a protocol to manage postoperative urinary retention
E. Diagnosis
1. Although clinical signs and symptoms are the mainstay for differentiating CAUTIs from catheter-
associated asymptomatic bacteruria, they are not specific for CAUTI. These include fever, rigors, altered
mental status, malaise, or lethargy with no other identified cause. Presence of flank pain, costovertebral
angle tenderness, acute hematuria, and pelvic discomfort may be more specific, but these are difficult to
assess in many critically ill patients.
2. Urine culture should be obtained in all critically ill patients with signs and symptoms of CAUTI.
Sampling should be done through the catheter port using aseptic technique. Catheters in place for
longer than 2 weeks should be replaced and a urine sample obtained from the port of the newly placed
catheter. Samples from the catheter collection system (e.g., catheter bag) should be avoided because of
the potential for colonization.
3. Urinalysis should be obtained in patients with a suspected CAUTI. Pyuria without signs and symptoms
does not indicate CAUTI; however, the absence of pyuria in a symptomatic patient suggests a diagnosis
other than CAUTI.
F. Treatment
1. A urinary culture should be obtained before initiation of antimicrobial therapy.
2. If an indwelling catheter has been in place for longer than 2 weeks, the catheter should be removed or, if
still indicated, replaced to hasten resolution of symptoms.
3. Similar to other health care–acquired infections, empiric antimicrobial therapy should be based on
local pathogen prevalence, pathogen-specific risk factors (e.g., MDRO risk factors), previously identified
pathogens, previous antimicrobial exposure, and local antibiotic susceptibility.
4. Empiric antimicrobial therapy should be de-escalated according to the identified pathogen(s) and
respective antimicrobial susceptibility on final urine culture results. Empiric antimicrobial therapy
should be discontinued in patients without CAUTI or other sources of infection.
5. Definitive antimicrobial therapy should be based on final antimicrobial susceptibility results and
presence of concomitant infection(s). Catheter irrigation (i.e., bladder washings) is not recommended.
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6. Shorter duration of antimicrobial therapy should be considered depending on clinical response.

Regardless of catheter removal, duration of antimicrobial therapy should be 7 days for patients with
resolution of signs and symptoms within 72 hours of appropriate antimicrobial therapy and up to 14 days
in patients with resolution after 72 hours.
7. Patients with persistent signs and symptoms of CAUTI should receive a urologic workup to assess for
abscess or other causes of relapse.
Patient Case

P.H. is a 67-year-old woman admitted from a long-term care facility to the MICU for respiratory failure secondary
to severe pneumonia. P.H. is initiated on vancomycin and levofloxacin and has a urethral catheter placed in the
emergency department. On ICU day 6, P.H. has a new fever with a temperature of 101.9°F (38.9°C) and an
elevated WBC to 18 x 103 cells/mm3, despite an initial clinical response to pneumonia therapy. Blood and urine
cultures are sent. Urinalysis reveals many bacteria and greater than 10 white blood cells/mm3.
9. Which intervention is most appropriate in P.H.?

A. Await final culture results before changing the current antibiotic regimen.
B. Continue health care–associated pneumonia (HCAP) therapy for an extended treatment duration.
C. Initiate empiric antibiotic therapy for a suspected catheter-associated urinary tract infection (CAUTI).
D. Insert a new urinary catheter and resend a urinalysis to confirm CAUTI.
10. Given P.H.’s risk factors for multidrug-resistant pathogens, which listing of pathogen would most likely be
associated with a CAUTI?
A. E. coli, P. aeruginosa, C. albicans.
B. Enterococcus spp., C. albicans, S. maltophilia.
C. MRSA, Enterococcus spp., C. albicans.
D. P. aeruginosa, Enterococcus spp., MRSA.
V. COMPLICATED INTRA-ABDOMINAL INFECTION
A. Epidemiology
1. Complicated intra-abdominal infection spans prehospital and in-hospital dispositions and a variety of
pathogenic processes involving several organ systems.
2. The incidence of complicated intra-abdominal infection is difficult to estimate, given the breadth of
illness. Appendicitis is the most prevalent cause of complicated intra-abdominal infection. Recent
controlled trials and large international observational sepsis studies report abdominal infection as the
second or third most common source of sepsis, accounting for 21% of sepsis and 30% of septic shock
cases.
3. Complicated intra-abdominal infection is the second most common cause of mortality in critically ill
patients. Crude mortality for primary intra-abdominal infection is almost 30%, whereas rates exceed
50% in patients with secondary intra-abdominal infection. Those presenting with sepsis caused by intra-
abdominal infection have crude mortality above 40%.
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B. Definitions
1. In 2010, the IDSA and Surgical Infection Society jointly published guidelines for the management of
intra-abdominal infection. In 2017, the Surgical Infection Society updated these guidelines, including
management for complicated intra-abdominal infection, which are reflected throughout this section.
2. A complicated intra-abdominal infection is defined by the IDSA and Surgical Infection Society as
infection that extends beyond the hollow viscus of origin into the peritoneal space and is associated with
either abscess formation or peritonitis. These infections usually arise from spillage of viscus-related
fluid and flora into the peritoneal cavity, causing inflammation and injury to the peritoneal membrane.
Retroperitoneal infections also are possible, but these are related to the individual retroperitoneal organ
rather than the peritoneum.
3. Peritonitis is described as primary, secondary, and tertiary.
a. Primary peritonitis, or spontaneous bacterial peritonitis, is peritonitis related to bacterial translocation
of proximal small bowel overgrowth and not peritoneal disruption or organ perforation. Primary
peritonitis is generally diffuse in nature.
b. Secondary peritonitis is caused by leakage of intraluminal fluid and microorganisms secondary to
macro- or microperforation of the GI tract. Secondary peritonitis can be diffuse or localized to an
organ, depending on the extent of peritoneal involvement. Causes of secondary peritonitis include
direct trauma, ischemia, thrombosis, ulceration, malignancy, and anastomotic leak.
c. Tertiary peritonitis is peritonitis that persists or recurs at least 48 hours after the management of
primary or secondary peritonitis. Tertiary peritonitis can represent a new intra-abdominal process
or host, anatomic, or therapeutic failure of treatment of primary or secondary peritonitis.
C. Etiology
1. Pathogens associated with complicated intra-abdominal infections and peritonitis are influenced by type/
cause of peritonitis, MDRO risk factors, previous antibiotic exposure, and patient-specific colonization.
Patients having health care–associated intra-abdominal infections more often tend to have antibiotic-
resistant, nosocomial pathogens compared with patients having community-acquired infection.
2. Primary peritonitis is usually monomicrobial and associated with translocation of organisms across the
diaphragm or proximal small bowel. The most prevalent organisms include S. pneumoniae, E. coli, and
Klebsiella spp.
3. Secondary peritonitis is typically polymicrobial related to the origin of GI tract leakage.
a. Gastric and duodenal secretions are usually sterile or with limited inocula of gram-positive bacteria
and Candida spp.
b. Proximal small bowel is densely populated with aerobic gram-negative bacilli including E. coli,
Klebsiella spp., Proteus spp., and Enterobacter spp., as well as populations of aerobic gram-positive
bacteria such as S. aureus, streptococci, and enterococci.
c. The distal small bowel and the large bowel are populated with proximal small bowel flora in
addition to anaerobic gram-negative and gram-positive organisms, including Bacteroides fragilis
and Clostridium spp. (usually non–C. difficile).
4. Tertiary peritonitis includes core organisms of primary and secondary peritonitis further compounded by
the influence of management strategies, including malnutrition, anatomic disruption, and antimicrobial
therapy.
D. Diagnosis
1. The diagnosis of complicated intra-abdominal infection relies on assessment of clinical signs and
symptoms, differentiation from other causes of infection, and radiographic evaluation.
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2. Rapid-onset abdominal pain and tenderness with signs of peritoneal irritation on physical examination
are the most common presenting signs and symptoms. Additional symptoms of anorexia, abdominal
distention, nausea, or vomiting, with or without fever, tachycardia, or tachypnea. These are often difficult
to assess in critically ill patients; therefore, intra-abdominal infection should be considered in patients
with unexplained new-onset organ dysfunction and sepsis.
3. Radiographic evaluation is commonly performed using abdominal radiographs, ultrasonography, and
CT, including contrast CT to assess for vascular thrombosis. Contrast studies of postoperative drains or
fistulae may also help assess anastomotic integrity.
4. Culture of intra-abdominal fluid associated with the primary source should be obtained in moderately
to severely ill patients. Gram stain results should be used to help guide empiric antimicrobial therapy.
Pathogens identified on final culture should guide definitive antimicrobial therapy.

1. Resuscitation for hemodynamic instability should be initiated and managed according to the Surviving
Sepsis Campaign guidelines.
2. Achieving primary source control of ongoing peritoneal contamination by operative diversion or
resection is recommended for patients with diffuse peritonitis. Patients with focal peritonitis should
undergo percutaneous abscess and fluid drainage.
3. Empiric antimicrobial therapy should be initiated in patients thought to have complicated intra-
abdominal infections.
a. Empiric antimicrobial regimens should be based on the source/location of intra-abdominal infection,
community-acquired or health care–associated disposition of infection, severity of infection, local
pathogen trends and susceptibilities, MDRO risk factors (e.g., hospitalization for greater than 48
hours during current admission or in the previous 90 days; recent broad-spectrum antimicrobial
therapy; infection developing greater than 48 hours after initial source control; home wound care or
dialysis within preceding 90 days), and patient-specific colonization patterns.
b. Individual antimicrobial agents should be dosed according to available pharmacokinetic and
pharmacodynamic principles to optimize efficacy and limit toxicity.
c. Community-acquired, mild to moderate severity
i. Routine culture is not recommended.
ii. Empiric antibiotic therapy should include agents active against aerobic and facultative enteric
gram-negative bacilli and enteric streptococci. Obligate anaerobic therapy should be initiated
in patients with distal small bowel, appendiceal, or colonic sources. Concerns with emergence
of antibiotic resistance may limit the utility of narrower-spectrum agents (e.g., cefazolin;
cefoxitin). Anti-enterococcal and antipseudomonal therapies are not recommended.
(a) Ceftriaxone or cefotaxime plus metronidazole
(b) Cefuroxime plus metronidazole
(c) Ertapenem
(d) Moxifloxacin alone; levofloxacin or ciprofloxacin plus metronidazole
(e) Tigecycline
(1) Pooled results from approval trials across all infections suggests increased mortality
in patients treated with tigecycline versus active comparator regimens. The cause of
this increase has not been established.
(2) FDA-approved label warns that the increase in all-cause mortality should be considered
when selecting among treatment options.
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d. Community acquired, high severity defined as severe physiologic disturbance (e.g., septic shock);
advanced age; immunocompromised state; delay in, or high likelihood of failure to achieve, primary
source control
i. Routine culture of intra-abdominal fluid is recommended as available.
ii. Empiric antimicrobial therapy should be broadened to include MDROs, enterococci, and
obligate anaerobes. Agents active against MRSA are not recommended empirically. Although
fluoroquinolones are recommended, emergence of resistant E. coli and P. aeruginosa is a
concern.
(a) Broad-spectrum carbapenem (e.g., doripenem, imipenem, meropenem)
(b) Cefepime or ceftazidime plus metronidazole (may need additional anti-enterococcal agent)
(c) Ciprofloxacin or levofloxacin plus metronidazole (may need additional anti-enterococcal
agent)
(d) Piperacillin/tazobactam
e. Health care associated
i. Routine culture of intra-abdominal fluid is recommended as available.
ii. Broad-spectrum empiric antimicrobial therapy should include coverage for MDR Gram
negative bacilli (e.g., P. aeruginosa) and obligate anaerobes. Depending on empiric antibiotic
susceptibility rates (i.e., local antibiogram), combination therapy against aerobic gram-negative
bacilli with aminoglycoside, or, if MDROs are prevalent, ceftolozane-tazobactam and/or
polymyxin.
(a) Broad-spectrum carbapenem (e.g., doripenem with or without anti-enterococcal therapy,
imipenem, meropenem with or without anti-enterococcal therapy)
(b) Cefepime or ceftazidime plus metronidazole
(c) Piperacillin/tazobactam
iii. Anti-enterococcal therapy should be considered in patients with recent exposure to broad-
spectrum antimicrobial therapy, septic shock, and those documented colonization with
enterococci.
iv. Anti-MRSA therapy should be considered in patients known to becolonized with MRSA or
with MDRO risk factors, including advanced age, co-morbid medical conditions, previous
hospitalization or surgery, and significant recent exposure to antibiotic agents.
v. Antifungal therapy should be added to the regimen of patients with yeast on Gram stain, recent
evidence of heavy colonization, surgically treated pancreatitis, prolonged broad-spectrum
antibiotic therapy, or critically ill patients with an upper gastrointestinal source. Fluconazole is
the drug of choice for fluconazole-susceptible strains. Echinocandins should be used first line
in critically ill patients until final culture results are available.
vi. Empiric antimicrobial therapy should be de-escalated to final culture results and related
antimicrobial susceptibilities.
4. Definitive antimicrobial therapy for complicated intra-abdominal infection should be continued for no
more than 4 days in patients who have adequate source control. Duration of antimicrobial therapy
in patients without definitive source control should be no more than 5-7 days, depending on clinical
response. Patients with delayed or incomplete clinical response to antimicrobial therapy should be
reassessed for additional source control intervention.
5. Considerations for short-term prophylactic courses no longer than 24 hours include:
a. Acute gastric or jejunal perforation in absence of malignancy or acid-reducing pharmacotherapy
with adequate source control within 24 hours
b. Traumatic or iatrogenic bowel injuries repaired within 12 hours of injury
c. Acute appendicitis without perforation or abscess
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Patient Cases
11. D.L. is a 69-year-old woman admitted from home to the SICU with severe acute abdominal pain in the left
lower quadrant. An abdominal CT reveals free air in the peritoneal cavity and evidence of distal ischemic
colitis. D.L. is taken urgently to the operating room, where she is noted to have gross contamination from
distal colonic perforation with marked peritonitis. After a partial collectomy and abdominal washout, she is
admitted to the SICU for continued resuscitation for septic shock. Which empiric antibiotic regimen would
be most appropriate for D.L.?
A. Ceftriaxone and vancomycin.
B. Ciprofloxacin and metronidazole.
C. Ertapenem.
D. Piperacillin/tazobactam.
12. K.D. is a 58-year-old man with severe peripheral vascular disease admitted from home to the SICU with
severe acute abdominal pain in the left lower quadrant. An emergency abdominal CT reveals free air in the
peritoneal cavity and evidence of distal small bowel ischemia. K.D. is taken emergently to the operating
room for an exploratory laparotomy, where she is noted to have gross peritoneal contamination with marked
peritonitis from a small bowel perforation. Intraoperative cultures were sent and are pending. After primary
repair of the distal small bowel and abdominal washout, K.D. returns to the SICU for continued resuscitation
for septic shock. Which empiric antibiotic regimen would be most appropriate for K.D.?
A. Piperacillin/tazobactam.
B. Ertapenem.
C. Ciprofloxacin and vancomycin.
D. Cefazolin, metronidazole, and fluconazole.
VI. ACUTE PANCREATITIS
A. Epidemiology
1. Acute pancreatitis is responsible for more than 200,000 acute care admissions annually in the United
States.
2. About 20% of acute pancreatitis episodes are severe, have evidence of pancreatic necrosis, and are
associated with local and systemic complications. An Acute Physiology and Chronic Health Evaluation
II (APACHE II) score of 8 or higher and a Ranson’s criteria score of 3 or greater, together with clinical
presentation, have been used to categorize patients as severe acute pancreatitis.
3. Between 30% and 78% of patients with necrotizing pancreatitis will have concomitant organ failure,
with the highest incidence in patients having infected necrosis. Pancreatitis-associated systemic sequelae
and organ failure includes:
a. Systemic inflammatory response syndrome (SIRS)
b. Hypovolemic shock
c. Hypoxemia secondary to ARDS
d. Acute kidney injury
e. Gastrointestinal (GI) bleeding
f. Disseminated intravascular coagulation and severe metabolic disturbances can also occur.
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4. Although most pancreatic necrosis is sterile, about one-third of patients with necrotizing pancreatitis
will have infected necrosis.
5. Overall, crude mortality for acute pancreatitis is 2%–9%; however, mortality rates for necrotizing and
infected necrotic pancreatitis are as high as 44% and 62%, respectively.
B. Pathophysiology
1. Pancreatitis is a result of glandular autodigestion from excessive ductal and tissue exposure to amylase,
lipase, and protease caused by trypsin-related hyperstimulation, macro-ductal blockade, or micro-ductal
blockade.
2. The pathophysiology of acute pancreatitis can be organized into three phases:
a. Excessive activation or decreased inactivation of trypsin leading to activation of pancreatic exocrine
enzymes
b. Local inflammatory and immune response to pancreatic injury
c. Systemic inflammatory and immune response, including SIRS, hypovolemia, and ARDS
3. Common causes of acute pancreatitis include biliary obstruction (e.g., gallstones), direct toxicity (e.g.,
alcohol), trauma, surgery/biliary procedures, and drugs.
C. Definitions
1. Severe pancreatitis is defined as pancreatitis associated with hypovolemia, organ failure, or local
complications including necrosis, abscess, or pseudocyst. Hypovolemia may increase the risk of
pancreatic necrosis and intestinal ischemia because of tissue hypoperfusion.
2. Pancreatic necrosis is evidenced on CT scan as diffuse or focal areas of nonviable pancreatic tissue
often associated with peripancreatic fat necrosis. In general, greater than 30% of the pancreas should
be affected. Infected necrosis is defined as the presence of pathogenic microorganisms in the necrotic
tissue.
3. Pancreatic pseudocyst is a non-epithelialized wall containing pancreatic excretions caused by acute or
chronic pancreatitis or pancreatic trauma. Pseudocysts are usually sterile.
4. Pancreatic abscess is an infected pseudocyst or liquefaction of pancreatic necrosis that becomes infected.
D. Diagnosis
1. The diagnosis of acute pancreatitis requires two of the following three features:
a. Acute and constant epigastric or right upper quadrant abdominal pain with or without nausea and
vomiting;
b. Serum amylase and/or lipase greater than 3 times the upper limit of normal; and
c. Characteristic findings of acute pancreatitis on CT scan.
2. Patients with severe pancreatitis may present with SIRS, hypovolemia, and new-onset organ failure,
including hypotension.

1. Management of severe acute pancreatitis includes acute pain management, fluid resuscitation, supportive
care of systemic complications and organ failure, and nutrition support. Surgical debridement of infected
necrosis or drainage of pancreatic abscess should be considered.
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2. Antibiotic therapy for acute pancreatitis is considered empiric, definitive, or prophylactic.

a. Empiric antibiotic therapy is indicated in patients with suspected or confirmed infected necrosis or
pancreatic abscess.
i. Patients with suspected infected necrosis or pancreatic abscess should undergo radiographically
(e.g., ultrasonography, CT) guided drainage with culture of recovered material/fluid. Common
organisms associated with infected necrosis or pancreatic abscess include:
(a) E. coli
(b) Klebsiella spp.
(c) Enterobacter spp.
(d) Proteus spp.
(e) Streptococci
ii. The antibiotics of choice include:
(a) Broad-spectrum carbapenems (e.g., imipenem; meropenem)
(b) Fluoroquinolone plus metronidazole
(c) Third-generation cephalosporin plus metronidazole
iii. Antifungal therapy should be added to antibiotic therapy if yeast is identified on culture Gram
stain. Fluconazole is recommended unless there is a high suspicion for fluconazole-resistant
fungi.
iv. Empiric antibiotics should be discontinued if pancreatic culture is negative. Patients with
persistent SIRS should undergo repeat imaging and drainage of identified abscess or fluid.
v. If infection is confirmed, antibiotic therapy should be de-escalated toward the identified
pathogen(s) according to antibiotic susceptibility.
vi. Definitive antibiotic therapy for confirmed infection should be continued for up to 14 days.
b. Prophylactic antimicrobial therapy in patients with sterile necrotizing pancreatitis is controversial.
Although small pilot investigations suggest benefit, a large, noninferiority, placebo-controlled trial
suggested no benefit with prophylactic meropenem. Current recommendations do not support routine
use of prophylactic antibiotic or antifungal therapy in patients with sterile necrotizing pancreatitis.
3. Ongoing assessment of resolution of SIRS and pancreatitis-associated organ failure is imperative.
Serial assessment of serum amylase or lipase has limited value over clinical assessment and physical
examination. Elevation of serum amylase or lipase for several weeks, however, should heighten concern
for persistent pancreatic/peripancreatic inflammation, blockage of the pancreatic duct, or development
of a pseudocyst.
Patient Cases
13. R.P. is a 43-year-old man with a history of chronic alcohol abuse who presents to the emergency department
from home with acute, severe epigastric abdominal pain; heart rate 142 beats/minute; MAP 62 mm Hg; WBC
24 x 103 cells/mm3; and serum lipase 1527 U/L. R.P. receives 3 L of normal saline intravenously over 60
minutes. An immediate abdominal CT scan is remarkable for significant pancreatic edema and greater than
30% necrosis of the pancreas. There is no evidence of an acute fluid collection. Which antimicrobial regimen
would be most appropriate for R.P.?
A. Ceftriaxone and vancomycin.
C. Meropenem.
D. None; prophylactic antibiotic therapy is not indicated in acute pancreatitis.
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Patient Cases (continued)
14. T.J. is a 27-year-old man who is admitted to the MICU from an outside hospital with alcohol-induced
acute pancreatitis and associated respiratory failure, SIRS, and blood pressure 100/55 mm Hg. Admission
abdominal CT shows severe pancreatitis with about 30% necrosis and a large focal fluid collection requiring
guided drainage. A fluid sample is sent for a Gram stain, which reveals many gram-negative rods and yeast.
Which antimicrobial regimen would best be initiated in T.J.?
A. None – low suspicion for infected pancreatitis.
C. Imipenem.
D. Meropenem and fluconazole.
VII. CLOSTRIDIUM DIFFICILE INFECTION
A. Epidemiology
1. C. difficile is a spore-forming, anaerobic, gram-positive bacillus. Stool carriage of C. difficile has been
found in up to 26% of acute care patients.
2. C. difficile is transmitted person to person through the fecal-oral route. The capability to become
dormant in spores increases the potential for environmental spread.
3. C. difficile is pathogenic through the production and expression of two primary toxins, C. difficile toxin
A (TcdA) and C. difficile toxin B (TcdB). North America has seen a recent emergence of strains with
increased virulence (e.g., BI/NAP1 strain) through increased production of toxins A and B, production
of additional toxins, and enhanced sporification.
4. CDI is responsible for almost 30% of antibiotic-associated diarrhea and is the most common cause of
infectious diarrhea in health care settings. The estimated incidence of CDI is 3–10 cases per 10,000
patient-days. Community-acquired CDI has increased in prevalence.
5. The clinical manifestations of CDI range from symptomless carriage to CDI spanning mild or moderate
diarrhea to fulminant and sometimes fatal pseudomembranous colitis, toxic megacolon, or colonic
perforation. Post-colectomy small bowel enteritis and rectal pouchitis related to CDI have been reported.
Additional complications of severe CDI include:
a. SIRS
b. Hypovolemia
c. Electrolyte disturbances
d. Sepsis and septic shock
e. Multiple organ failure
6. CDI is associated with medical costs greater than $3 billion per year.
7. Attributable mortality from CDI is estimated to be below 10%. However, crude mortality is as high as
75% in patients presenting with septic shock, colonic perforation, or toxic megacolon. Subtotal colectomy
in patients with a severe CDI is associated with an in-hospital mortality rate of up to 42%.
B. Definitions
1. CDI is defined as the presence of symptoms (e.g., diarrhea) and a stool test result positive for C. difficile
toxin, toxigenic C. difficile (e.g., DNA amplification detecting toxin-coding genes), or pseudomembranous
colitis on colonoscopic examination.
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2. Severe CDI, according to expert-based guidelines, is defined as above plus one of the following:
a. WBC 15 x 103 cells/mm3 or greater
b. Serum creatinine (SCr) of 1.5 times or greater the premorbid level
3. A severe, complicated CDI is defined as a severe CDI plus one of the following:
a. Hypotension or evidence of shock
b. Colonic ileus
c. Toxic megacolon
4. Recurrence is defined as the relapse of a recent infection or a reinfection after definitive therapy.
5. Additional categorizations of CDI are used for infection control surveillance and institutional/ICU
quality review. These are related to the locations of C. difficile acquisition (e.g., community acquired or
health care associated) and onset of symptoms (e.g., community onset vs. health care onset).
C. Risk Factors
1. Antibiotic therapy is the most important risk factor.
a. All antibiotic classes have been associated with CDI.
b. Highest-risk antibiotic classes include fluoroquinolones, cephalosporins, penicillins, and clindamycin.
2. Gastric acid–suppressing pharmacotherapy, including proton pump inhibitors and histamine-2 receptor
antagonists
3. Age older than 65 years
4. Duration of hospitalization
5. Cancer chemotherapy
6. GI surgery
7. Previous CDI
D. Prevention – There are two global strategies to prevent CDI:

1. Decrease the risk of acquiring C. difficile.
a. Staff, patient, family, caregiver education
b. Hand hygiene to remove C. difficile spores through non–alcohol-based handwashing using soap or
chlorhexidine gluconate and water
c. Contact isolation, including full-barrier precautions (gown and gloves), single-occupancy room, and
the cohorting of patients with a CDI
d. Limit reuse or between-patient sharing, and terminal clean patient care–related equipment (e.g.,
digital thermometers, point-of-care blood glucose machines, dietary trays, intravenous infusion
pumps).
e. Environmental decontamination using bleach-containing cleaning solution
2. Avoid or address reversible risk factors.
a. Limit overuse of, and discontinue unnecessary, antibiotic therapy.
b. Decrease duration of hospital stay.
c. Discontinue unnecessary gastric acid–reducing pharmacotherapy.
E. Diagnosis
1. Diagnosis of CDI is based on clinical and laboratory findings.
2. Clinical findings include presence of diarrhea, defined as passage of three or more unformed stools
within 24 consecutive hours.
a. Rarely, a symptomatic patient will present with ileus and colonic distension with minimal or no
diarrhea.
b. Patients with cecal CDI or right-sided CDI colitis may have formed stools.
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3. Laboratory findings include stool sample positive for toxigenic C. difficile, C. difficile toxin, or
colonoscopic or histopathologic findings showing pseudomembranous colitis. Available strategies for
detecting toxin-producing C. difficile include:
a. Testing for C. difficile should only be performed on unformed stool unless patients have ileus.
Identifying the ideal testing strategy remains difficult. Institution-specific decisions for which test(s)
to use should be evidence based and collaborative across interested parties.
b. Stool culture with detection of a toxigenic isolate through identification of neutralizable toxin
activity is considered the gold standard test. However, this process could take up to 9 days, limiting
its clinical utility.
c. Enzyme immunoassay (EIA) tests for C. difficile toxins A and B are rapid and widely available;
however, poor sensitivity may limit their utility. Obtaining serial samples has been used to increase
sensitivity. Sensitivity may also be increased using a two-step process with initial EIA to detect
the C. difficile antigen glutamate dehydrogenase and a follow-up stool culture with detection of the
toxigenic isolate.
d. PCR testing is rapid, sensitive, and specific. Widespread availability may be limited.
e. Emerging evidence supports an illumigene C. difficile assay, which uses loop-mediated isothermal
DNA amplification to detect a specific genetic region responsible for coding toxins A and B.
4. The same diagnostic criteria are used for recurrent CDI.
F. Management and Treatment

1. Removal of potential cause(s), as appropriate (e.g., discontinuation of associated antibiotic therapy)
2. Assessment of disease severity (mild or moderate vs. severe) and whether episode is initial or recurrent
3. Evaluation of need for surgical intervention
a. Subtotal colectomy with rectal preservation should be considered for severely ill patients.
b. Alternative colon-sparing operative surgical strategies have been described.
4. Antibiotic therapy targeted against C. difficile (Table 4)
a. Samples for diagnostic testing for C. difficile should be obtained before empiric antibiotic therapy is
initiated. Initiation of empiric antibiotic therapy before final test results should be based on clinical
assessment.
b. Antibiotic choices and respective routes of administration should be based on severity of CDI
and ability to achieve relevant intraluminal antibiotic concentrations relative to CDI. Special
considerations include:
i. For enema volumes in patients requiring rectal instillation of vancomycin, location of CDI-
affected area(s) and risk of colonic perforation should be considered. Patients receiving
vancomycin enemas may need a cuffed rectal delivery device/tube to facilitate retention.
ii. Patients with CDI-related colitis and proximal colonic diversion (i.e., no continuity with oral or
gastric route) may require rectal instillation of vancomycin enema.
iii. Fidaxomicin, an oral, limited bioavailability macrolide antibiotic, is indicated for treatment
of CDI. Evidence supports its noninferiority to oral vancomycin for clinical response with
decreased recurrence post-therapy in non-BI/NAP1 strains. Data are limited supporting its use
in critically ill patients.
iv. Fecal transplantation has improved outcomes compared with oral vancomycin in noncritically
ill patients with recurrent CDI.
v. There are no definitive recommendations for duration of CDI antibiotic therapy or prevention
of recurrence when non-CDI antibiotic therapy is continued concurrently.
c. Response to therapy should be assessed by evaluating clinical signs and symptoms, including
resolution of diarrhea, laboratory abnormalities, sepsis, and related organ failure. Results of stool
testing for C. difficile in patients with resolution of disease do not predict recurrence.
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Table 4. Treatment Options for CDI

Episode and Illness Category Therapy
Initial episode, mild to Metronidazole 500 mg orally or by OG/NG/feeding tube three times daily for
moderate CDI 10–14 days
Vancomycin 125–250 mg orally or by OG/NG/feeding tube four times daily for
Initial episode, severe CDI
10–14 days
Vancomycin 500 mg orally or by OG/NG tube four times daily and
metronidazole 500 mg intravenously three times daily
Initial episode, severe, If concerned for decreased distal delivery (e.g., ileus): Rectal instillation of
complicated CDI vancomycin 500 mg in 0.9% sodium chloride for irrigation by enema retained
for 1 hour administered every 6 hr; guidelines recommend 100 mL (IDSA) to
500 mL (American College of Gastroenterology) volumes; enema dose volumes
up to 1000 mL have been reported
First recurrence Same as initial episode, qualified by illness severity
Second recurrence Vancomycin orally, followed by a 28-day dosage taper
NG = nasogastric; OG = orogastric.
Patient Cases
15. K.L. is a 57-year-old man admitted to the MICU with diffuse abdominal pain, temperature 101.9°F (38.8°C),
WBC 27 x 103 cells/mm3, heart rate 125 beats/minute, and mean arterial pressure 57 mm Hg. An abdominal
CT scan reveals a large amount of intestinal air, suggestive of ileus and moderate transverse and sigmoid
colonic inflammation. On review of the patient’s history, it is learned that K.L. recently completed a 4-week
course of broad-spectrum antibiotic therapy for a postoperative osteomyelitis after repair of right comminuted
femur fracture, increasing the suggestion of CDI. Which regimen would be best for empiric management of
a suspected CDI in K.L.?
A. Metronidazole 500 mg intravenously every 8 hours.
B. Metronidazole 500 mg intravenously every 8 hours and intracolonic vancomycin 500 mg instilled every
8 hours.
C. Metronidazole 500 mg orally or by nasogastric tube every 8 hours and vancomycin 250 mg orally or by
nasogastric tube every 6 hours.
D. Vancomycin 250 mg orally or by nasogastric tube every 6 hours.
16. E.A. is a 79-year-old man admitted to the MICU for severe pneumonia. On day 5 of treatment with broad-
spectrum antibiotic therapy despite negative culture, E.A. is noted to have several liquid bowel movements
requiring a rectal pouch (around 1.6 L of stool in past 24 hours), a low-grade fever, elevation of WBC at 27
x 103 cells/mm3, heart rate 124 beats/minute, MAP 67 mm Hg, lactate 1.6 mmol/L, and SCr 1.5 mg/dL. A
stool sample is sent for a suspected C. difficile infection (CDI). Which regimen would be best for empiric
management of a suspected CDI in E.A.?
A. Metronidazole 500 mg intravenously every 8 hours and intracolonic vancomycin 500 mg instilled every
8 hours.
B. Metronidazole 500 mg intravenously every 8 hours.
C. Metronidazole 500 mg orally or by nasogastric tube every 8 hours and vancomycin 250 mg orally or by
nasogastric tube every 6 hours.
D. Vancomycin 250 mg orally or by nasogastric tube every 6 hours.
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VIII. WOUND INFECTION
A. Epidemiology
1. Postoperative wound infection is the most common health care–associated infection, affecting up to
5% of inpatient surgery patients. There are 150,000–300,000 cases of postoperative wound infections
annually in the United States.
2. Most postoperative wound infections are mild or moderate in severity. Major complications associated
with severe postoperative wound infections include wound dehiscence, reoperation, sepsis, and
necrotizing fasciitis.
3. Patients with postoperative wound infection have more than a 2-fold higher risk of death compared with
those without infection. Crude mortality in patients with streptococcal necrotizing fasciitis and shock
(e.g., streptococcal toxic shock) is high, ranging from 30% to 70%.
B. Definitions
1. Superficial incisional: Infection involving only the skin or subcutaneous tissue of the incision
2. Deep incisional: Infection involving fascia and/or muscular layers
a. Deep incision primary: Wound infection in the primary incision in a patient who has had an
operation with one or more incisions
b. Deep incision secondary: Wound infection in a secondary incision in a patient who has had an
operation with more than one incision
c. Necrotizing fasciitis is an aggressive, deep incisional infection tracking along the superficial fascia,
which consists of the tissues between the skin and the underlying muscles. Necrotizing fasciitis often
results in major tissue destruction. Fournier gangrene is a variant of necrotizing fasciitis involving
the scrotum and penis or vulva.
3. Organ or space: Infection involving any space or organ, opened or manipulated during the procedure,
excluding skin incision, fascia, or muscle layers.
C. Etiology
1. Pathogens causing postoperative wound infections are often related to local flora present on the skin at
the time of incision and flora associated with organs/tissues involved in the operative procedure.
2. Prevalence of drug-resistant strains (e.g., MRSA, multidrug-resistant gram-negative bacilli) depends on
local patterns of infection and patient colonization.
a. The most common bacterial pathogens causing postoperative wound infection are skin flora,
including staphylococci and streptococci.
b. Bacterial pathogens related to anatomic location of the operation:
i. Upper GI tract (gastric, biliary, proximal small intestine)
(a) Biliary: Aerobic and anaerobic gram-negative and gram-positive organisms
(b) Non-biliary: Enteric, aerobic gram-negative bacilli
ii. Lower GI tract (distal small bowel; colon): Mixed gram-positive and gram-negative flora,
facultative and anaerobic
iii. Female genitalia: Mixed gram-positive and gram-negative flora, facultative and anaerobic
iv. Axilla: Aerobic gram-negative organisms
v. Perineum: Aerobic gram-negative and mixed anaerobic organisms
vi. Respiratory: Aerobic gram-positive and gram-negative organisms
c. Necrotizing fasciitis
i. Most infections are monomicrobial, caused predominantly by group A streptococci
(Streptococcus pyogenes), S. aureus, and anaerobic streptococci (e.g., Peptostreptococcus).
Non–C. difficile clostridia (e.g., Clostridium septicum) and Aeromonas hydrophilia also are
associated with monomicrobial infection.
668
ii. Polymicrobial infections usually involve a broad range of pathogens, including aerobic and
anaerobic gram-positive and gram-negative organisms. Likelihood of polymicrobial infection
is increased if associated with:
(a) Decubitus ulcers
(b) Injection sites in illicit drug users
(c) Intestinal operation
(d) Penetrating abdominal trauma
(e) Perianal abscess
(f) Spread from genitalia (i.e., Fournier gangrene)
D. Prevention
1. Using evidence-based guidelines can prevent up to 60% of postoperative wound infections. Wound
infections after elective operation are considered preventable and are reportable health care–associated
infections.
2. Many organizations and agencies promote prevention and monitor the prevalence of postoperative wound
infection, including the CDC, the Surgical Care Improvement Project (SCIP), the Joint Commission, and
the Centers for Medicare & Medicaid Services.
3. Recommended strategies are basic or special approaches.
a. Basic approaches include:
i. Administer preoperative weight-based antibiotic therapy according to operative site and level
of expected operative field contamination. Timing of antibiotic therapy should maximize blood
and tissue concentrations at the time of incision. Antibiotics should be redosed every 2 half-
lives for prolonged procedures. Antibiotic duration should be limited to 24 hours unless there is
evidence of peritonitis or active infection during the operative procedure.
ii. Avoid use of hair removal. If necessary, use clippers or depilatory agent.
iii. Maintain glycemic control in immediate postoperative period; goal should be to avoid glucose
above 180 mg/dL.
iv. Avoid perioperative hypothermia.
v. Optimize tissue oxygenation by maintaining adequate perfusion and oxygen delivery.
vi. Interdisciplinary staff education, use of procedural checklists, and infection surveillance
b. Special approaches include:
i. Preoperative screening for S. aureus and consideration of decontamination in patients
undergoing orthopedic or cardiothoracic procedures
ii. Aseptic, intraoperative wound lavage
E. Diagnosis
1. Postoperative wound infections most commonly occur 48 hours after the procedure. Fever in the first 48
hours is usually idiopathic or from noninfectious causes.
2. Wounds should be physically examined serially until healed. Purulent material should be collected
aseptically and sent for Gram stain and culture. Cultures in patients with suspected deep tissue infections
should be obtained from deep tissues with concomitant blood cultures.
3. Signs and symptoms of superficial incisional postoperative wound infection include:
a. Purulent incisional drainage
b. Local pain or tenderness, swelling, and erythema after the incision is opened
c. Positive culture of purulent drainage
4. Necrotizing fasciitis should be suspected if the following are present:
a. Severe pain that seems disproportional to the appearance of the wound
b. Failure to respond to initial antibiotic therapy
669
c. Hard, wooden feel of the subcutaneous tissue, often extending beyond the area of affected skin
d. Crepitus on physical examination or radiographic (radiograph, CT scan) finding, indicating gas in
subcutaneous tissues
e. Skin necrosis or ecchymoses
f. Sepsis, severe sepsis, or septic shock
F. Management and Treatment

1. Opening of the incision, evacuation of the infected material, and continued dressing changes are the
foundation of treatment for confirmed postoperative wound infections.
2. Antibiotic therapy targeted against likely pathogens should be initiated in patients with systemic signs
and symptoms or suspected deep tissue infection.
3. Superficial incisional infection
a. Erythema and induration less than 5 cm and minimal systemic signs of infection (no fever, no
leukocytosis, and tachycardia):
i. Serial dressing changes
ii. No antibiotic therapy necessary
iii. Continue to assess wound for resolution or progression.
b. Erythema and induration greater than 5 cm, fever, leukocytosis, and tachycardia:
i. Open suture line.
ii. Initiate empiric antibiotic therapy targeted against operative site–related suspected pathogens.
Examples include:
(a) Extremity, head, neck, or trunk site: Cefazolin or vancomycin if MRSA suspected
(b) GI, genitalia, or perineum site: Cephalosporin or levofloxacin plus metronidazole;
ertapenem
iii. Adjust antibiotics according to culture results. Continue for up to 48 hours or until infection is
resolved.
iv. Serial dressing changes
v. Continue to assess wound for resolution or progression.
4. Necrotizing fasciitis
a. Surgical debridement of necrotic tissue serially (i.e., every 24–48 hours) until no further need for
debridement
b. Antibiotic therapy is empiric or definitive.
i. Empiric antibiotic therapy should be initiated as early as possible.
ii. Polymicrobial infection should be suspected, with empiric therapy that is active against aerobic
and anaerobic gram-positive and gram-negative pathogens
(a) Vancomycin, plus:
(b) Piperacillin/tazobactam, broad-spectrum carbapenem, or cefepime plus metronidazole
(c) Consider clindamycin to decrease pathogenic toxin and cytokine production if S. pyogenes
is suspected.
iii. Empiric antibiotic therapy should be de-escalated according to final culture results.
iv. Definitive antibiotic therapy should be based on final culture results and antibiotic susceptibility.
Infection caused by S. pyogenes should be treated with an active β-lactam or vancomycin (in
severe penicillin allergy) plus clindamycin. Use of intravenous immunoglobulin (IVIG) is
controversial. Limited evidence suggests a shorter time to no further need for debridement but
no effect on mortality.
v. Antibiotic therapy should be continued until surgical debridement is no longer necessary and
until resolution of infection-related signs and symptoms.
670
5. Organ or space infection: See individual chapters, sections, or guidelines for managing organ/space-
specific infection (e.g., pancreatitis, intra-abdominal infection; genitourinary tract).
Patient Case

R.J. is a 57-year-old man admitted to the SICU after a bowel resection following an acute bowel obstruction.
On postoperative day 3, R.J. has worsening tachycardia and decreased urinary output together with a maximum
temperature of 102.9°F (39.4°C) and a WBC of 18.2 x 103 cells/mm3. R.J. reports worsening pain around
his surgical wound despite minimal erythema. On opening a few sutures of the wound, pus is expressed on
examination, and crepitus is noted in the area surrounding the wound. R.J. is emergently taken to the operating
room for exploration and is noted to require significant debridement of necrotic subcutaneous tissue, including
the involved fascia. R.J.’s wound is left open with a temporary gauze dressing.
17. Which empiric antimicrobial regimen is most appropriate for R.J.?

A. Ceftaroline and vancomycin.
B. Clindamycin, penicillin G, and vancomycin.
C. Piperacillin/tazobactam, clindamycin, and vancomycin.
D. Vancomycin.
18. Intraoperative tissue culture from the first debridement of R.J.’s wound shows many gram-positive cocci in
chains and moderate non–lactose-fermenting gram-negative bacilli. R.J. is to undergo serial intraoperative
debridements of necrotic tissue. Given the concern for S. pyogenes, which pharmacotherapeutic intervention
would be most appropriate for definitive treatment of R.J.’s necrotizing fasciitis?
A. Add synergistic gentamicin.
B. Give adjunctive clindamycin for toxin production.
C. Ensure vancomycin is part of the regimen for concerns of S. pyogenes resistance.
D. Give intravenous immunoglobulin (IVIG).
IX. STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS
A. Epidemiology
1. Severe cutaneous reactions and related syndromes are unpredictable and rare. The primary causes of these
injuries include drugs, dysregulated immune response, and acute infection. Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN also referred to as Lyell’s Syndrome), and drug hypersensitivity
syndrome, or drug rash with eosinophilia and systemic symptoms (DRESS) are the most common
presentations. There is a suggestion of genetic influence on the occurrence of SJS and TEN.
2. SJS and TEN are the most severe of reactions, representing different points on a similar spectrum of
cutaneous injury involving epidermolysis or separation of the epidermis from the dermis.
3. Similar to thermal injury, the TBSA affected is used to describe the extent of cutaneous injury. According
to contemporary reports from U.S. burn centers, the mean TBSA involvement for patients with TEN is
greater than 60%.
671
4. The incidence of severe cutaneous reactions is difficult to estimate. The highest rates reported approach
20%; however, definitions include mild to moderate reactions. The estimated incidence of SJS and TEN
is 1 in 500,000–1,000,000 population. Patients infected with HIV may have a higher incidence.
5. The severity of clinical presentation is associated with the extent of tissue and mucosal injury and
necrosis. Most patients have a prodromal fever and malaise preceding cutaneous symptoms. Clinical
presentation usually includes fever, SIRS, hypotension from cytokine-mediated vasodilation, and mild
to moderate hypovolemia from volume depletion and third spacing. Bleeding may also be present,
depending on the extent of mucosal injury.
6. Health care–associated or nosocomial complications, including pneumonia, CAUTIs, CLABSIs, and
malnutrition, are common in severely injured patients.
7. SJS and TEN are life-threatening reactions. Average crude mortality associated with SJS/TEN is 25%–
55% and can be as high as 90%.
B. Definitions
1. SJS and TEN are part of the same disease process, differing in severity. Common features of SJS and
TEN include cutaneous erythema, progressive blistering, epidermolysis, and mucosal erosions.
2. The most widely accepted classification system for SJS and TEN was proposed by Bastuji-Garin et al.
This system includes five categories:
a. Bullous erythema multiforme: Epidermal detachment involving less than 10% TBSA and localized
typical targets or raised atypical targets
b. SJS: Epidermal detachment involving less than 10% TBSA and widespread erythematous or
purpuric macules or flat atypical targets
c. SJS/TEN overlap: Epidermal detachment involving 10%–30% TBSA and widespread purpuric
macules or flat atypical targets
d. TEN with spots: Epidermal detachment involving greater than 30% TBSA and widespread purpuric
macules or flat atypical targets
e. TEN without spots: Large sheets of epidermal detachment involving greater than 10% TBSA
without purpuric macules or target lesions
C. Etiology
1. Drugs are the most common cause of SJS and TEN and are implicated in more than 90%–95% of cases.
More than 200 medications have been reported as causing SJS and TEN. The most common agents
implicated are sulfonamide antibiotics and aromatic anticonvulsants (phenytoin, phenobarbital, and
carbamazepine). Other agents/classes include:
a. Abacavir
b. Allopurinol
c. β-Lactam antibiotics
d. Lamotrigine
e. Nevirapine
f. Nonsteroidal anti-inflammatory drugs, particularly the oxicams
g. Quinolones, particularly ciprofloxacin
h. Tetracyclines
2. Vaccinations also have been associated with SJS and TEN, including measles, mumps, and rubella
(MMR).
3. Exposure to industrial chemicals and fumigants
4. Infection with Mycoplasma pneumoniae
672
D. Diagnosis
1. Primary clinical signs/symptoms associated with SJS and TEN are fever and malaise, followed by
cutaneous blisters and erosive mucosal lesions of the mouth, lips, eyes, and genital area. The distribution
of cutaneous lesions is predominantly central, with mucosal involvement of usually at least two sites.
Lesions consist of widespread, flat atypical targets or purpuric macules. TBSA is used to differentiate
SJS from TEN and to categorize the severity of cutaneous and mucosal involvement. TBSA is calculated
by the following:
a. Arms – 9% each
b. Head and neck – 9%
c. Legs – 18% each
d. Perineum – 1%
e. Trunk – Anterior 18%; posterior 18%
2. The diagnosis of SJS and TEN is confirmed by histopathologic analysis of lesional tissue and is
corroborated with clinical presentation. Early lesions show scattered necrotic keratinocytes in the
epidermis, whereas late-stage lesions reveal confluent full-thickness epidermal necrosis, which leads to
formation of subepidermal bullae.
a. SCORTEN is a severity-of-illness system designed to predict mortality for TEN. It is computed
within the first 24 hours of presentation and on day 3 using the sum of seven objective clinical
variables (each item present is worth 1 point):
i. Age older than 40 years
ii. Heart rate greater than 120 beats/minute
iii. Presence of cancer or hematologic malignancy
iv. Epidermal detachment greater than 10% TBSA on day 1
v. Blood urea nitrogen greater than 28 mg/dL
vi. Glucose greater than 252 mg/dL
vii. Serum bicarbonate less than 20 mEq/L
b. Mortality prediction increases sharply with each additional point, starting at 3% for 0 or 1 point and
reaching 90% for 5 or more points. SCORTEN mortality estimates are often used as benchmark
rates to assess noncontrolled pharmacotherapy studies.

1. Identification, discontinuation, and avoidance of likely or suspected causes are imperative. Causative
agents with a long half-life should be identified and strategies to expedite removal considered.
2. Transfer to ICU, preferably at a certified burn center.
3. Overt assessment of mucus membranes to prevent extension of injury and related sequelae. This includes
the respiratory tract, eyes, and GI tract.
4. The cornerstones of management of SJS and TEN are:
a. Resuscitation and supportive care
i. Goal-directed fluid resuscitation should be initiated immediately to maintain:
(a) Mean arterial blood pressure above 65 mm Hg
(b) Central venous pressure 8–12 mm Hg
(c) Urine output 0.5–1 mL/kg/hour
(d) Central venous oxygen saturation above 70%
ii. Support respiratory function with respiratory therapy and continual assessment for intubation,
as appropriate
iii. Avoid using skin to anchor devices and catheters.
iv. Physical and occupational therapy when appropriate
b. Debridement of necrotic epidermis and coverage of affected areas with artificial or biologic dressing.
This may be done serially because progression of affected areas may occur.
673
c. Management of extracutaneous injuries

i. Ocular involvement
(a) Adequate ocular lubrication
(b) Consideration of topical, preservative-free ophthalmic corticosteroid drops
(c) Treatment of corneal fluorescein or ulceration
ii. Oral involvement
(a) Maintain lip barrier integrity (e.g., white paraffin)
(b) Consider antiseptic oral rinse (e.g., chlorhexidine)
(c) Consider topical corticosteroid rinse (e.g., betamethasone)
d. Nutrition support (see related chapter)
e. Avoidance and treatment of infectious complications
i. Implement infection prevention best practices, including minimizing unnecessary devices and
procedures related to health care–associated infection.
ii. Prophylactic antibiotic therapy is not recommended for SJS and TEN.
iii. Empiric antibiotic therapy should be carefully chosen and reserved for suspected infection, as
evidenced by signs and symptoms of sepsis or site-specific infection. Continuation of antibiotic
therapy should be reserved for confirmed infection, and duration should be limited according
to the specific infection.
5. Adjuvant therapies
a. Plasmapheresis – Support is derived from case series; thought to be generally safe and an effective
strategy to remove pathogenic, nondialyzable plasma factors, including some drugs, toxins,
metabolites, antibodies, immune complexes, and disease-inducing cytokines
b. Immunomodulating therapy
i. Corticosteroids – Despite some evidence of benefit, use is controversial and not universally
recommended. More recent case reports suggest that high-dose pulse therapy during the
first 3 days of presentation decreases disease progression. Associated risks (e.g., infection;
hyperglycemia, poor wound healing) may outweigh benefits.
ii. Cyclosporine – Information from individual case series suggests benefit at a dose of 3 mg/kg/
day. There are no formal recommendations for routine use.
iii. Cyclophosphamide – Early case reports suggested benefit, but cyclophosphamide is not
recommended.
iv. Colony-stimulating factor – May be used in conjunction with cyclosporine in patients with
neutropenia and TEN
v. IVIG
(a) IVIG for SJS and TEN is controversial.
(b) In vitro data support that immunoglobulin G (IgG) antibodies against Fas-FasL proteins
may decrease keratinocyte apoptosis.
(c) Many retrospective single-group and cohort studies suggest benefit (usual dosage 1 g/
kg/day for 3 days) over SCORTEN estimated mortality rates and similar control groups,
respectively.
(d) Given the rare incidence and logistical difficulty of designing a multicenter prospective
study, available prospective studies have been small and single center. Results from these
studies, however, have shown no benefit to trends of worse outcome.
(e) A systematic review and meta-analysis of use in TEN patients found no benefit over
standard of care.
(f) The decision to administer IVIG remains clinically supported by pathophysiology-
pharmacology interactions and observational data. Centers with expertise to care for
patients with TEN should assess the utility of IVIG and develop interdisciplinary guidance
for local use.
674
vi. Consensus guidelines from the United Kingdom recommend immunomodulating therapies be
used under the supervision of skin failure specialists in the context of a clinical study or registry.
Patient Case

L.H. is a 23-year-old woman with a recently diagnosed uncomplicated urinary tract infection. Two days after
starting sulfamethoxazole/trimethoprim, L.H. presents to the burn ICU from an outside hospital with severe
systemic inflammatory response and 30% total body surface area (TBSA) epidermolysis of her upper arms and
back. L.H. reportedly presented to the outside hospital 6 hours earlier with only 10% TBSA involvement. New
lesions since admission to the burn ICU include erythema of her thighs and oral cavity with TBSA now at 40%,
suggestive of toxic epidermal necrolysis (TEN). L.H.’s SCORTEN score is 3.
19. Which would be the best initial pharmacotherapeutic intervention?

A. Crystalloid resuscitation.
B. Cyclophosphamide.
C. Empiric vancomycin for wound prophylaxis.
D. High-dose systemic corticosteroids.
20. L.H. continues to worsen, with a TBSA involvement now at 50%, with worsening oral cavity involvement
and progressing acute kidney injury. You and your team consider IVIG as the next pharmacotherapeutic
intervention. Which best describes the evidence-based role of IVIG in managing TEN?
A. IVIG should be administered before the patient’s condition progresses to TEN.
B. IVIG should be reserved for specialty centers with interdisciplinary consensus protocols to guide use.
C. Multicenter pivotal trials show that IVIG is most efficacious for patients with ocular involvement.
D. Meta-analyses of the available evidence support that IVIG is standard of care in managing TEN.
675
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Syst Rev 2012;5:CD002941. Practice guidelines for the diagnosis and manage-
7. Whitcomb DC. Acute pancreatitis. N Engl J Med ment of skin and soft tissue infections: 2014 update
2006;354:2142-50. by the Infectious Diseases Society of America.
Clin Infect Dis 2014;59:e10-e52.
Clostridium difficile Infection
1. Apisarnthanarak A, Razavi B, Mundy LM. Severe Nonthermal Cutaneous Injury
Adjunctive intracolonic vancomycin for severe 1. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical
Clostridium difficile colitis: case series and review classification of cases of toxic epidermal necroly-
of the literature. Clin Infect Dis 2002;35:690-6. sis, Stevens-Johnson syndrome, and erythema
2. Cohen SH, Gerding DN, Johnson S, et al. Clinical multiforme. Arch Dermatol 1993;129:92-6.
practice guidelines for Clostridium difficile infec- 2. Creamer D, Walsh S, Smith C, et al. U.K. guidelines
tion in adults: 2010 update by the Society for for the management of Stevens-Johnson syndrome/
Healthcare Epidemiology of America (SHEA) and toxic epidermal necrolysis in adults 2016. British
the Infectious Diseases Society of America (IDSA). Journal Dermatology 2016;174:1194-1227.
Infect Control Hosp Epidemiol 2010;31:431-55. 3. Huang, YC, Li, YC, Chen, TJ. The efficacy of
3. Dubberke ER, Carling P, Carrico R, et al. Strategies intravenous immunoglobulin for the treatment of
to prevent Clostridium difficile infections in acute toxic epidermal necrolysis: a systematic review
care hospitals: 2014 update. Infect Control Hosp and meta-analysis. British Journal Dermatology
Epidemiol 2014;35:628-45. 2012;167:424-32.
4. Kelly CP, LaMont JT. Clostridium difficile—more 4. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A
difficult than ever. N Engl J Med 2008;359:1932-40. multicenter review of toxic epidermal necrolysis
5. Owens RC. Clostridium difficile–associated treated in U.S. burn centers at the end of the twen-
disease: an emerging threat to patient safety. tieth century. J Burn Care Rehabil 2002;23:87-96.
Pharmacotherapy 2006;26:299-311. 5. Pereira FA, Mudgil AV, Rosmarin DM. Toxic
6. Surawicz CM, Brandt LJ, Binion DG, et al. epidermal necrolysis. J Am Acad Dermatol
Guidelines for Diagnosis, Treatment, and 2007;56:181-200.
Prevention of Clostridium difficile Infections. Am 6. Struck MF, Hilbert P, Mockenhaupt M, et al. Severe
J Gastroenterol 2013;108:478–98. cutaneous adverse reactions: emergency approach
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comparison of vancomycin and metronidazole for Care Med 2010;36:22-32.
the treatment of Clostridium difficile–associated
678
ANSWERS AND EXPLANATIONS TO PATIENT CASES
1. Answer: A the cause of new-onset fever and leukocytosis, given

The patient has suspicion for MDR VAP, as evidenced by the emergency placement and related duration of
the presence of clinical signs of infection, the patient’s the CVC (Answer B is incorrect). Although catheter
increased sputum production, and the patient’s having removal should strongly be considered, cultures should
been in the ICU for 5 days or longer. Empiric antibiotic be obtained before catheter removal for documenta-
therapy should be initiated after obtaining a respiratory tion if the patient has a bloodstream infection (Answer
culture and be based on patient-specific risk factors for C is incorrect). Initiation of antibiotic therapy should
MDROs, together with local pathogen prevalence and be considered, if appropriate, but only after cultures of
antibiotic susceptibility, to increase the likelihood of the suspected source are obtained (Answer D is correct;
providing timely appropriate antibiotic therapy (Answer Answer A is incorrect).
A is correct). Gram stain results are often nonsensitive
for causative pathogens, and waiting for preliminary or 5. Answer: D
final respiratory culture results, as well as blood or urine This patient, who is thought to have a CLABSI, has risk
cultures, may cause an unacceptable delay in appropriate factors for MDROs, given that the patient was hospi-
antibiotic therapy (Answers B–D are incorrect). talized for 5 or more days. Empiric antibiotic therapy
choices should include agents active against MRSE
2. Answer: B and MRSA as well as P. aeruginosa (Answer D is cor-
Although this patient is suspected of having early-onset rect; Answer A is incorrect). Linezolid is active against
VAP for the current admission, a history of recent intra- MRSA; however, it should be considered only for defini-
venous antibiotic therapy is a risk factor for MDROs. tive therapy because its empiric use in patients with a
Empiric antibiotic therapy for VAP in patients with CLABSI is associated with worse outcomes (Answer C
MRDO risk factors should include agents active against is incorrect). Fluconazole may be considered in addition
P. aeruginosa and MRSA. Empiric combination therapy to antibiotic therapy, but monotherapy is not recom-
against P. aeruginosa is recommended to increase the mended empirically (Answer B is incorrect).
likelihood of appropriate antibiotic therapy (Answer B is
correct; Answers A and C are incorrect) with a β-lactam 6. Answer: B
antibiotic as one of the preferred agents (Answer D is The guideline recommendation for definitive antibiotic
incorrect). Atypical bacteria coverage is not necessary therapy duration is 7–14 days from the first negative
because their prevalence is low, although consideration blood culture in patients with uncomplicated gram-
should be given if there is a poor response to initial negative CLABSI. Longer durations of therapy should
therapy. be considered in patients with persistent bacteremia or
if the patient has a poor clinical response. (Answer B is
3. Answer: B correct; Answers A and C are incorrect). Patients with
Based on the PneumA trial and related meta-analyses, complicated bacteremia (e.g., endocarditis, septic throm-
the most recent IDSA VAP guidelines recommend bus, chronic intravascular hardware) should receive 4-6
definitive antibiotic therapy duration of 7 full treatment weeks of therapy (Answer D is incorrect).
days for all patients. This is further emphasized in this
patient, who has VAP caused by Klebsiella spp., which 7. Answer: D
are lactose-fermenting gram-negative bacilli, and who This patient likely has severe influenza amid a local
received appropriate empiric antibiotic therapy and had seasonal outbreak. Local infection patterns suggest a
an appropriate clinical response during therapy (Answer prevalence of influenza A and B strains. Empiric influ-
B is correct; Answers A, C, and D are incorrect). enza-specific therapy against these strains should be
initiated in patients with severe influenza before confirma-
4. Answer: D tory test results are known to avoid a delay in appropriate
In the absence of other suspected sources (i.e., no change therapy (Answer B is incorrect). Neuraminidase-based
in chest radiograph), CLABSI should be suspected as therapy is recommended for modern influenza A and
679
B stains (Answer D is correct; Answer C is incorrect). 11. Answer: D

Even if they are outside 48 hours from symptom onset, This patient has complicated intra-abdominal infection
patients with severe influenza have benefited from ther- from secondary peritonitis caused by colonic perfora-
apy initiated beyond this period (Answer A is incorrect). tion. Although it is community acquired, the presence of
septic shock suggests severe classification increasing the
8. Answer: B risk of gram-negative MDROs (Answer C is incorrect).
Neuraminidase inhibitors are the mainstay of treat- The involvement of the colon also obligates antibi-
ment because resistance to adamantanes has developed otic therapy active against anaerobes and enterococci
in contemporary influenza A strains, and these agents (Answer B is incorrect); MRSA is an unlikely pathogen
have no antiviral activity against influenza B (Answer (Answer A is incorrect). According to this, piperacillin/
A is incorrect). Inhaled zanamivir is not appropriate tazobactam is the most appropriate agent listed (Answer
for administration to mechanically ventilated patients D is correct).
(Answer C is incorrect). Intravenous peramivir also is
available; however, data are limited for its use in criti- 12. Answer: A
cally ill patients with severe, complicated influenza The approach to managing a complicated intra-
infection (Answer D is incorrect). Enteral oseltamivir abdominal infection includes timely source control
is the preferred therapy for current influenza B strains and initiation of empiric antimicrobial therapy active
in critically ill patients with severe, complicated influ- against likely pathogens. This involves assessment of
enza infection (Answer B is correct). Clinicians should the anatomic location of the source, risk factors for mul-
be mindful of the need for renal dosage adjustment, if tidrug-resistant organisms (i.e., community- or health
necessary. care–associated disposition), and severity of illness. This
patient has community-acquired secondary peritonitis
9. Answer: C from a distal small bowel perforation with concomi-
The presence of new fever and an elevated WBC in con- tant septic shock. Although her disease is community
junction with an indwelling urinary catheter and pyuria acquired, the presence of septic shock suggests a severe
on urinalysis is highly suggestive of a CAUTI rather than classification, increasing the risk of gram-negative mul-
worsening HCAP (Answer B is incorrect). Similar to tidrug-resistant organisms and involvement of the distal
other ICU-related infections, empiric antibiotic therapy small bowel obligates empiric coverage for anaerobic
should be considered if there is strong clinical suspicion pathogens and enterococci, for all of which piperacillin/
for infection (Answer C is correct). Waiting for final tazobactam should provide appropriate empiric cover-
culture results before initiating antimicrobial therapy in age (Answer A is correct). Ertapenem would likely have
patients thought to have a CAUTI may delay appropriate adequate empiric coverage for enteric, gram-negative
treatment (Answer A is incorrect). Although it is recom- pathogens, both aerobic and anaerobic; however, lack
mended to discontinue the urinary catheter and replace or enterococcal coverage makes it less optimal (Answer
as necessary, a confirmatory urinalysis is not needed if B is incorrect). Ciprofloxacin lacks sufficient activity
the catheter has been indwelling for less than 2 weeks against enterococci or anaerobic pathogens, and MRSA
(Answer D is incorrect). coverage with vancomycin is unnecessary (Answer C is
incorrect). Cefazolin is too narrow as empiric therapy
10. Answer: A for a severe community-acquired complicated intra-
The causative pathogens associated with a CAUTI, with abdominal infection, and fluconazole should be reserved
or without multidrug-resistant risk factors, are more for definitive therapy for fluconazole-susceptible yeast
heterogeneous than an uncomplicated or community- identified on final culture (Answer D is incorrect).
acquired urinary tract infection. Nonetheless, E. coli
remains the most common bacterial pathogen together 13. Answer: D
with other gram-negative bacilli and Candida spp. Acute necrotizing pancreatitis often presents with signs
(Answer A is correct). Except for S. maltophilia (Answer and symptoms consistent with systemic inflammatory
B is incorrect), other associated pathogens include those response syndrome. However, most cases of severe necro-
listed in Answers B–D; however, the absence of E. coli tizing pancreatitis are sterile and do not require antibiotic
makes these answers incorrect. therapy. The presence of a pancreatic pseudocyst or
680
abscess increases the likelihood of infected necrotizing recommended (Answer B is incorrect). The combination
pancreatitis, which thus warrants empiric antimicrobial of metronidazole and intracolonic is recommended for
therapy. However, this patient has no evidence of these on patients with a complicated CDI and concern for ileus or
CT scan; thus, empiric antibiotic therapy is not indicated inability to deliver oral/enteral vancomycin to the colon
(Answers A–C are incorrect). Moreover, prophylactic (Answer A is incorrect).
antimicrobial therapy is not recommended in the recent
guidelines, despite the presentation of systemic inflam- 17. Answer: C
mation and pancreatic necrosis (Answer D is correct). Necrotizing fasciitis is a severe, life-threatening infection
A prospective, randomized, noninferiority study most that is often polymicrobial. Prompt surgical debridement
strongly supports these recommendations. of necrotic tissue and broad-spectrum antibiotic therapy
are the mainstays of initial therapy. Agents active against
14. Answer: D S. pyogenes, MRSA, and aerobic and anaerobic gram-
This patient has acute, severe pancreatitis with CT evi- negative bacilli should be initiated empirically, together
dence of pancreatic abscess. Gram stain of fluid obtained with adjunctive clindamycin added, which may decrease
from CT-guided drainage suggests the presence of bacterial toxin production. The empiric regimen of
gram-negative bacilli and yeast (Answer A is incorrect). piperacillin/tazobactam, vancomycin, and clindamycin is
Empiric antimicrobial therapy is indicated for suspected most appropriate, given the severity of infection despite
infected pancreatitis. Extended-spectrum carbapenems, the absence of traditional multidrug-resistant organism
which achieve relevant pancreatic fluid concentrations, risk factors (Answer C is correct). Penicillin G is not broad
are effective in the management of infected pancreatitis. enough (Answer B is incorrect), and the combination of
Addition of anti-candidal therapy is indicated, given the ceftaroline and vancomycin does not contain clindamycin
presence of yeast on the Gram stain (Answer D is cor- (Answer A is incorrect). Vancomycin monotherapy
rect; Answers B and C are incorrect). does not include gram-negative activity or adjunctive
clindamycin (Answer D is incorrect).
15. Answer: B
This patient is thought to have severe, complicated CDI, 18. Answer: B
given his recent exposure to broad-spectrum antibiotic The intraoperative cultures of this patient’s necrotizing
therapy, signs of infection, CT findings, and the presence infection are of concern for S. pyogenes. S. pyogenes
of hypotension. Combination therapy with metronida- produces exotoxin, which is associated with tissue necrosis.
zole and vancomycin is indicated (Answers A and D are Although bactericidal antibiotic therapy is necessary for
incorrect). The presence of ileus requires consideration eradicating S. pyogenes, adjunctive clindamycin may
of intravenous metronidazole and intracolonic vancomy- decrease toxin production, which could limit the extent of
cin because of possible impaired delivery to the colon tissue necrosis (Answer B is correct). Vancomycin should
through enteral routes (Answer B is correct; Answer C be reserved for patients with an S. pyogenes infection
is incorrect). who have a β-lactam allergy because β-lactam resistance
is rare (Answer C is incorrect). Moreover, synergistic
16. Answer: D antibiotic therapy with gentamicin is not needed, given
The patient in this case presents with what is likely an the effectiveness of gram-positive β-lactams against
initial-episode, severe CDI, as supported by new-onset S. pyogenes (Answer A is incorrect). The role of IVIG
diarrhea and clinical signs and symptoms of infection. in streptococcal necrotizing fasciitis is controversial. A
Of note, the patient is not hypotensive and has a lactate small randomized, placebo-controlled trial – stratified on
below 2–4 mmol/L, suggesting the absence of shock the basis of need for surgery and clindamycin treatment
or other defining features of a complicated CDI; thus, – showed no improvement in survival or reduction in the
monotherapy with enteral vancomycin should be initi- time to no further progression of necrotizing fasciitis or
ated (Answer D is correct). Combination therapy with cellulitis in 21 patients with streptococcal toxic shock
oral/enteral vancomycin and intravenous metronida- syndrome. As such, the guidelines do not recommend
zole should be reserved for a complicated CDI (Answer IVIG until additional studies are available (Answer D is
C is incorrect), and intravenous metronidazole is not incorrect).
681
19. Answer: A
One of the cornerstones of managing severe cutane-
ous injury includes volume resuscitation, preferentially
with crystalloids (Answer A is correct). The usefulness
of immunomodulating therapies such as corticosteroids
and cyclophosphamide is limited by observational and
poorly controlled evidence or case reports; thus, use of
immunomodulating therapies should be reserved for spe-
cialty centers using formal protocols with consideration
for treatment under clinical study or registry (Answers B
and D are incorrect). Wound care is imperative in these
patients; however, adding unnecessary drugs that could
confound response or worsen the injury (e.g., antibiotics)
should be avoided (Answer C is incorrect) unless there is
an objectively suspected or confirmed infection.
20. Answer: B
Use of IVIG for Stevens-Johnson syndrome (SJS)/TEN
is controversial. Available evidence is from case reports/
series, observational cohort studies, or small, single-
center randomized trials (Answer C is incorrect). Because
of bias, limited external validity, and mixed results/
observations between publications, meta-analyses and
consensus guidelines do not broadly endorse the use of
IVIG (Answer D is incorrect). The available data analyses
that suggest that IVIG decreases the SCORTEN-related
mortality in patients with TEN and a middle to higher
SCORTEN score; there are even fewer data for the role
of IVIG in SJS (Answer A is incorrect). Given the limited
evidence supporting pharmacotherapeutic interventions
and the life-threatening severity of TEN, burn referral
centers should base the decision to use IVIG on local
protocols/guidelines developed by interdisciplinary
practitioners who have objectively evaluated the available
evidence regarding safety, efficacy, and pharmacogenomic
implications (Answer B is correct).
682
ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS
1. Answer: D contemporary influenza A and B subtypes (Answer D is

The patient described has early onset VAP without appar- correct). Zanamivir also has high-level activity against
ent updated risk factors for MDROs (Answers A, B, and these strains; however, inhaled therapy through the
C, are incorrect). Pathogens associated with early onset mechanical ventilator is not indicated because of insuf-
hospital-acquired pneumonia and VAP are usually com- ficient systemic delivery, and intravenous zanamivir is
munity-acquired organisms, including S. pneumoniae, available through compassionate use and indicated only
MSSA, H. influenzae, and enteric gram-negative bacilli if oseltamivir cannot be administered (e.g., patient is
(Answer D is correct). Although guideline updates rec- unable to receive enteral medications, has poor absorp-
ommend that P. aeruginosa coverage be considered as tion) (Answers B and C are incorrect). Amantadine has
empiric therapy for all patients suspected of VAP, lack insufficient activity against most contemporary influ-
of MDRO risk factors decreases the likelihood of MDR enza A and B strains (Answer A is incorrect).
strains. Atypical bacteria are rarely associated with early
onset VAP. If MDRO risk factors were present, MRSA 5. Answer: B
and P. aeruginosa would also be considered. Although a health care–associated CAUTI is caused by
a more diverse spectrum of pathogens, E. coli is still the
2. Answer: C most common pathogen and is responsible for around
Empiric antibiotic choices for VAP should be based on 30% of cases (Answer B is correct). The other pathogens
the likely causative pathogens, the presence of MDRO listed are also possible and should be considered when
risk factors, and local antibiotic susceptibility patterns. choosing empiric antibiotic therapy in patients with a
Ceftriaxone is a reasonable agent for empiric manage- suspected CAUTI (Answers A, C, and D are incorrect).
ment of early onset VAP with activity against common
pathogens (Answer C is correct). Broad-spectrum 6. Answer: D
regimens would provide adequate coverage but would This patient has community-acquired complicated
result in an unnecessary breadth of antibiotic expo- intra-abdominal infection involving the middle small
sure (Answer B is incorrect). Empiric monotherapy for intestine. Although enteric gram-negative bacilli (e.g.,
gram-positive organisms is insufficient (Answer D is E. coli, Klebsiella spp.) are the most common pathogens
incorrect). Atypical bacteria are rarely associated with related to this type of infection, patients with severe dis-
early-onset VAP (Answer A is incorrect). ease, as evidenced by concomitant septic shock, are at
a higher risk of MDROs, including P. aeruginosa and
3. Answer: D enterococci. Piperacillin/tazobactam has empiric activ-
Gram-positive organisms are the most common cause of ity against these organisms, whereas the other regimens/
CLABSI, including MRSE and MRSA. Vancomycin is agents listed have relevant gaps in the bacterial spec-
the best option listed for empiric management (Answer D trum relative to these pathogens (Answer D is correct;
is correct). Although linezolid has a sufficient spectrum Answers A–C are incorrect).
of activity against these organisms, it is not recom-
mended for empiric management of CLABSI because 7. Answer: A
of concerns for worse patient outcomes (Answer B is This patient presents with severe acute pancreatitis with
incorrect). The other options are inactive against MRSE radiographic evidence of pancreatic necrosis. Although
and MRSA and could be considered in addition to van- the patient presents with SIRS, the absence of significant
comycin if there were a high suspicion for additional fluid collection or abscess suggests there is no con-
pathogens (Answers A and C are incorrect). comitant infection. As such, there is no indication for
empiric antibiotic therapy at this time (Answer A is cor-
4. Answer: D rect; Answer B is incorrect). Most recent evidence and
Given the high prevalence of the 2009 H1N1 subtype of guideline recommendations do not support prophylactic
influenza A, oseltamivir is the empiric drug of choice. In antibiotic therapy for preventing infection of the necrotic
addition, oseltamivir has high-level activity against other tissue (Answer D is incorrect). The mainstay of therapy
683
for this patient is volume resuscitation and consideration

of surgical debridement of pancreatic necrosis if persis-
tent SIRS is evident (Answer C is incorrect).
8. Answer: B
Metronidazole orally or through a feeding tube is rec-
ommended for management of an initial-episode,
mild-moderate CDI. The absence of a WBC above 15
x 103 cells/mm3 and no apparent new increase in SCr
suggests this is not a severe CDI (Answer B is cor-
rect). Intravenous metronidazole and vancomycin are
indicated for more severe or recurrent cases of CDI
(Answers C and D are incorrect); data for fidaxomicin
use in critically ill patients are limited and should only
be considered for persistent recurrent CDI (Answer A is
incorrect).
9. Answer: A
This patient has a superficial incisional wound infec-
tion requiring opening and the local debridement of
infected material. Lack of systemic signs of infection
and no involvement of the fascia suggest that no anti-
biotic therapy is necessary at this time (Answer A is
correct; Answers B–D are incorrect). If the infection
extends to include these features or worsened erythema
consistent with cellulitis, empiric antibiotic therapy may
be warranted.
10. Answer: B
Similar to severe thermal cutaneous injury, the foun-
dation for managing TEN is volume resuscitation and
supportive care as well as removal of all suspected causes
(Answer B is correct). The utility of corticosteroids is
limited and may be harmful to wound healing (Answer
A is incorrect). Addition of unnecessary drugs that could
confound response or worsen the injury (e.g., antibiotics)
should be avoided (Answers C and D are incorrect).
684

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Infectious Diseases I

Eric W. Mueller, Pharm.D., FCCP, FCCM

Learning Objectives SIRS Systemic inflammatory response syndrome

Abbreviations in This Chapter 1. Which is the most likely causative pathogen of

C. Metronidazole 500 mg intravenously every 8

9. J.S. is a 42-year-old man admitted to the SICU after

10. A.C. is a 27-year-old man with human immunode-

I. VENTILATOR-ASSOCIATED PNEUMONIA

B. Classification and Etiology

Box 1. Risk Factors for MDROs Causing VAP

c. Maintain and improve physical conditioning while mechanically ventilated.

Table 2. Summary of Key Changes in 2016 IDS VAP Guidelines

Table 2. Summary of Key Changes in 2016 IDS VAP Guidelines (continued)

II. CENTRAL LINE–ASSOCIATED BLOODSTREAM INFECTIONS

Patient Cases (continued)

Questions 5 and 6 pertain to the following case.

E. Management and Treatment

Table 3. Influenza-Specific Pharmacotherapy

IV. CATHETER-ASSOCIATED URINARY TRACT INFECTIONS

3. CAUTIs account for 15%–21% of hospital-acquired bacteremias.

6. Shorter duration of antimicrobial therapy should be considered depending on clinical response.

Questions 9 and 10 pertain to the following case.

9. Which intervention is most appropriate in P.H.?

V. COMPLICATED INTRA-ABDOMINAL INFECTION

E. Management and Treatment

VI. ACUTE PANCREATITIS

E. Management and Treatment

2. Antibiotic therapy for acute pancreatitis is considered empiric, definitive, or prophylactic.

Patient Cases (continued)

VII. CLOSTRIDIUM DIFFICILE INFECTION

D. Prevention – There are two global strategies to prevent CDI:

F. Management and Treatment

Table 4. Treatment Options for CDI

VIII. WOUND INFECTION

F. Management and Treatment

Questions 17 and 18 pertain to the following case.

17. Which empiric antimicrobial regimen is most appropriate for R.J.?

IX. STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

E. Management and Treatment

c. Management of extracutaneous injuries

Questions 19 and 20 pertain to the following case.

19. Which would be the best initial pharmacotherapeutic intervention?

Ventilator-Associated Pneumonia for preventing VAP. Endorsed by many infection

Influenza module. Am J Infect Control 2013;41:1148-66.

ANSWERS AND EXPLANATIONS TO PATIENT CASES

1. Answer: A the cause of new-onset fever and leukocytosis, given

B stains (Answer D is correct; Answer C is incorrect). 11. Answer: D

ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS

1. Answer: D contemporary influenza A and B subtypes (Answer D is

for this patient is volume resuscitation and consideration

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